WO2024125322A1

WO2024125322A1 - Dipyridamole for preventing and treating allergic and/or inflammatory diseases and preparation thereof

Info

Publication number: WO2024125322A1
Application number: PCT/CN2023/135865
Authority: WO
Inventors: 卢秉泰; 刘明; 彭博; 韩杨
Original assignee: 智泽童康(广州)生物科技有限公司
Priority date: 2022-12-16
Filing date: 2023-12-01
Publication date: 2024-06-20

Abstract

Discloses is use of dipyridamole and a preparation thereof in preventing and treating allergic and/or inflammatory diseases. In the present application, the inventor finds for the first time that external use of dipyridamole can effectively prevent, assist in treating, or treating allergic and/or inflammatory diseases, such as allergic conjunctivitis, allergic rhinitis, allergic urticaria, acne rosacea, and acne, and external preparations such as a dipyridamole cream and a dipyridamole gel are developed and obtained accordingly, which take effects quickly, have a remarkable treatment effect, are superior to a common positive drug, have high safety in the human body, do not have side effects in both human and animal experiments, and can be widely applied to any skin of the human body, especially high-sensitivity skin such as the face. Moreover, by optimizing a formula, it is found that adding diethylene glycol monoethyl ether and polyethylene glycol-7-stearate can significantly improve the permeability of the dipyridamole and the treatment and prevention effects thereof on diseases.

Description

Dipyridamole and its preparation for preventing and treating allergic and/or inflammatory diseases

Technical Field

The present application belongs to the field of drug development technology, and specifically relates to the use of dipyridamole and its preparations in preventing and treating allergic and/or inflammatory diseases.

Background technique

Dipyridamole (DIP) is also known as dipyridamole, with a chemical formula of 2,2',2",2-[4,8-dipiperidinylpyrimido[5,4-d]pyrimidine-2,6-diyl]bis-nitro]-tetraethanol. Dipyridamole is a phosphodiesterase inhibitor that can inhibit platelet aggregation and has an anti-thrombotic effect. In the related art, it was once a commonly used drug for the treatment of coronary heart disease, and was rarely used to prevent myocardial ischemia or to prevent platelet aggregation in cardiac surgery.

Inflammatory diseases can generally be divided into acute inflammatory diseases and chronic inflammatory diseases. They are mainly caused by the overactivation of the human immune system, which triggers the infiltration of immune cells in tissues and the massive release of inflammatory cytokines, leading to inflammatory diseases. Common acute inflammatory diseases include inflammatory bowel disease, autoimmune diseases, gastritis, pneumonia, gout, etc. Acute inflammation is usually an immune response that occurs after the body is stimulated by external factors (such as pathogenic microorganisms), and is usually manifested as pain, redness, swelling, fever, etc. in the tissues. Compared with acute inflammatory diseases, inflammatory skin diseases are a type of chronic inflammatory disease, usually caused by allergens, sources of infection or endocrine. Common chronic inflammatory skin diseases include acne and rosacea (rosacea). Acne is a common inflammatory skin disease, and common causes include excessive sebum secretion, blockage of the sebaceous gland ducts of the hair follicles, bacterial infection, and inflammatory response.

Allergic disease is a series of diseases caused by the body's immune system's hypersensitivity to harmless substances in the environment, mainly including atopic dermatitis, allergic rhinitis, allergic asthma, food allergies, hay fever and other severe allergic reactions. At present, allergic diseases are one of the most common diseases in the human body, affecting about 25% of the world's population. The manifestations and severity of the disease vary greatly. Mild diseases will affect the quality of life, and in severe cases, they can be life-threatening. Chronic allergic patients require long-term maintenance treatment, which brings a heavy economic burden to society. Most allergic diseases are caused by the local release of IgE-mediated mediators (such as histamine) when the affected parts such as the nasal cavity or airway come into contact with allergens, causing a variety of immune cell and cytokine-mediated inflammatory diseases such as asthma. For example, allergic conjunctivitis and atopic dermatitis are local inflammations of the skin caused by allergens.

The common feature of inflammatory diseases and allergic diseases is inflammatory infiltration in tissues. Inflammatory infiltration can be caused by the aggregation of inflammatory cells or the release of inflammatory cytokines. For the treatment of inflammatory diseases, anti-inflammatory therapy is the most commonly used means. Currently, the most effective anti-inflammatory means in clinical practice is the use of glucocorticoids, but the side effects of glucocorticoids greatly limit their application in this regard.

Therefore, developing a drug that can effectively prevent and treat allergic and/or inflammatory diseases is of great significance for the prevention and treatment of related diseases.

Summary of the invention

The present application aims to solve at least one of the technical problems existing in the above-mentioned prior art. To this end, the present application proposes the application of dipyridamole in the preparation of medicines for preventing, adjuvant therapy or treating allergic and/or inflammatory diseases. In the present application, by using dipyridamole, allergic and/or inflammatory diseases can be effectively prevented, adjuvant therapy or treated, with substantially no side effects, providing new treatment means and treatment ideas for clinically treating related diseases, reducing the impact of related diseases on the quality of life of patients, and having extremely high clinical significance and practical value.

The first aspect of the present application provides the use of dipyridamole derivatives in the preparation of medicines for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases.

In the present application, all types of allergic diseases should be included. As an example, in some embodiments of the present application, the allergic diseases include skin, respiratory, digestive and eye diseases caused by allergies.

Among them, the allergies include food allergies, dust allergies, mite allergies, drug allergies, etc.

In some embodiments of the present application, the allergic diseases include: allergic rhinitis, allergic conjunctivitis, allergic asthma, allergic dermatitis, allergic urticaria, food allergy, dust allergy, mite allergy, hay fever, drug allergy, allergic bronchial asthma, allergic sinusitis, and allergic respiratory distress syndrome.

In some embodiments of the present application, the allergic diseases include: allergic conjunctivitis, allergic rhinitis, allergic urticaria, and asthma caused by allergies.

Allergic urticaria, also known as acute urticaria or chronic urticaria, commonly known as wheals, is a localized edema reaction caused by dilation of small blood vessels and increased permeability of the skin and mucous membranes. It usually subsides within 2 to 24 hours, but new rashes occur repeatedly, and the course of the disease can last from a few days to several years. The cause of urticaria is very complicated, and about 3/4 of patients cannot find the cause, especially chronic urticaria. Common causes include: food and food additives; inhalants; infection; drugs; physical factors such as mechanical stimulation, cold and heat, sunlight, etc.; insect bites; mental factors and endocrine changes; genetic factors, etc.; the basic damage is the appearance of wheals on the skin. Skin itching often occurs first, followed by the appearance of wheals, which are bright red or Pale, skin-colored, a few patients have edematous erythema. The size and shape of the wheals vary, and the onset time is uncertain. The wheals gradually spread and merge into pieces. Due to the edema of the dermal papillae, the epidermal hair follicle openings can be seen to be sunken downward. The wheals last for several minutes to several hours, and in a few cases, they can last for several days before disappearing without leaving any traces. Those who recover from the disease in a short period of time are called acute urticaria. If the disease recurs at least twice a week and for more than 6 consecutive weeks, it is called chronic urticaria. Urticaria can be diagnosed based on the clinical appearance of wheal-like rashes.

Allergic conjunctivitis is conjunctivitis caused by allergies. The conjunctiva is stimulated by allergens such as pollen, dust, dust mites, and animal dander, resulting in hypersensitivity reactions, and allergic symptoms such as itchy eyes, redness of the whites of the eyes, tearing, and increased secretions appear. Allergic conjunctivitis is more common in children and young people, and has a high incidence rate worldwide. Based on differences in clinical manifestations, course of disease, and prognosis, allergic conjunctivitis can be divided into five different subtypes: seasonal allergic conjunctivitis, perennial allergic conjunctivitis, giant papillary conjunctivitis, vernal keratoconjunctivitis, and atopic keratoconjunctivitis.

Similarly, in the present application, all types and varieties of inflammatory diseases should be included therein. As an example, inflammatory diseases can be divided into different types according to different classification methods, for example, according to infectious/non-infectious/post-infectious hyperplasia, or according to the site of inflammation, or according to self/non-self, but specific diseases should be included therein, and the same disease may have different classifications according to different classification methods, but it does not affect the manifestations/pathogenic factors/and treatment methods and effects of the disease.

In some embodiments of the present application, the inflammatory diseases include, for example, dermatitis, asthma, conjunctivitis, rosacea, urticaria, sty, gastritis, rhinitis, pharyngitis, adnexitis, urethritis, vaginitis, mastitis, inflammatory bowel disease, frostbite, acne, etc.

Conjunctivitis is an inflammation of the conjunctiva caused by microbial infection (virus, bacteria, chlamydia, etc.), external stimulation (physical stimulation, chemical loss) or allergic reaction, commonly known as "pink eye". According to different causes, conjunctivitis includes infectious conjunctivitis, immune conjunctivitis, secondary conjunctivitis, and other types of conjunctivitis.

Rhinitis is an inflammation of the nasal mucosa caused by viruses, bacteria, allergens (such as pollen), various physical and chemical factors (such as irritating gases) or certain systemic diseases, and is mainly manifested by symptoms such as nasal congestion, nasal itching, runny nose, sneezing, etc. According to different classification methods, for example, according to the cause classification, it can be divided into allergic rhinitis and non-allergic rhinitis; according to the speed of onset classification, it can be divided into acute rhinitis and chronic rhinitis.

In some embodiments of the present application, the inflammatory disease includes infectious diseases, non-infectious diseases, and post-infectious hyperplasia.

In some embodiments of the present application, the infectious diseases include infectious conjunctivitis, infectious rhinitis, infectious rosacea, infectious urticaria, infectious asthma, etc.

In other embodiments of the present application, the infectious disease includes a microbial infectious disease, such as a viral infectious disease, a fungal infectious disease, a bacterial infectious disease, a parasitic infectious disease, and a mycoplasma infectious disease.

In some embodiments of the present application, the viral infectious diseases include herpes, viral conjunctivitis, viral rhinitis, new coronavirus pneumonia, influenza, viral hepatitis, viral rhinitis, viral pharyngitis, and viral enteritis.

In some embodiments of the present application, the viral hepatitis includes hepatitis A, hepatitis B, and hepatitis C.

In some embodiments of the present application, the herpes includes EV71 viral herpes.

Herpes is a viral skin disease characterized by changes in the skin and mucous membranes. It is mainly caused by infection with the human herpes virus (HHV). According to the cause of the disease, it can be classified into: herpes simplex (caused by herpes simplex virus), varicella (caused by varicella-zoster virus), and herpes zoster (caused by reactivation of herpes zoster virus lurking in the ganglia).

In some embodiments of the present application, viral enteritis manifests as nausea, abdominal pain, diarrhea, and vomiting.

Viral enteritis is usually an acute intestinal inflammatory lesion caused by a variety of viruses, including rotavirus, norovirus, canine parvovirus, and adenovirus. For example, in some embodiments of the present application, the viral enteritis includes rotavirus enteritis, norovirus enteritis, and adenovirus enteritis.

In some embodiments of the present application, the fungal infectious diseases include tinea pedis and ringworm of cats.

Ringworm is a skin disease of cats, which is often found on the face, trunk, limbs and tail. It is characterized by round or oval ringworm spots covered with gray scales, and the fur becomes rough. The fur of the ringworm spots falls off in clumps, breaks off or falls off. Ringworm is mainly caused by fungal infections, such as Microsporum canis and Trichophyton mentagrophytes.

In some embodiments of the present application, the bacterial infectious diseases include bacterial conjunctivitis, bacterial rhinitis, purulent tonsillitis, acne, sty caused by bacterial infection, bacterial gastritis, bacterial pharyngitis, and bacterial mastitis.

In some embodiments of the present application, the gastritis caused by bacteria includes gastritis caused by Helicobacter pylori.

In some embodiments of the present application, the bacterial mastitis includes mastitis caused by Staphylococcus aureus.

In some embodiments of the present application, the parasitic infectious disease includes ascariasis infection and malaria infection.

In some embodiments of the present application, the mycoplasma infectious disease includes adnexitis caused by mycoplasma infection.

In some embodiments of the present application, the non-infectious diseases include non-infectious dermatitis, abdominal pain caused by lactose intolerance, conjunctivitis caused by external stimuli, rosacea caused by neurological disorders, urticaria caused by physical stimulation, pharyngitis caused by external stimulation, inflammatory bowel disease, and mastitis caused by external pressure.

Inflammatory bowel disease refers to a group of nonspecific chronic gastrointestinal inflammatory diseases of unknown cause, including ulcerative colitis (UC), Crohn’s disease (CD) and indeterminate colitis (IC). The etiology and pathogenesis of IBD are still not fully understood, but it is generally recognized that it is the result of the combined effects of multiple factors such as genetics, environment and immunity. It is currently believed that its pathogenesis is an excessive intestinal mucosal immune response induced by a large number of intestinal bacteria, which causes intestinal mucosal damage in people with genetic susceptibility.

Acne is a chronic inflammatory skin disease of the pilosebaceous gland unit, which mainly occurs in adolescents and has a great impact on their psychological and social life. The clinical manifestations are characterized by polymorphic skin lesions such as acne, papules, pustules, nodules, etc. on the face. The onset of acne is mainly related to increased androgen levels and sebum secretion, as well as bacterial infection, abnormal sebaceous gland keratinization, inflammation and other causes.

In some embodiments of the present application, the non-infectious dermatitis includes traumatic dermatitis (traumatic dermatitis), dermatitis caused by surgical wounds, solar dermatitis, frostbite, and insect bite dermatitis.

In some embodiments of the present application, the post-infectious hyperplasia includes thyroid nodules, hemorrhoids, scar hyperplasia, sty, thyroid nodules, breast nodules, and breast hyperplasia.

Hemorrhoids, or hemorrhoids, are the most common anal disease in clinical practice. They refer to the pathological hypertrophy of the anal cushions at the lower end of the rectum. The cause of the disease is not yet fully understood. Depending on the location of occurrence, hemorrhoids include internal hemorrhoids, external hemorrhoids, and mixed hemorrhoids. Internal hemorrhoids are pathological changes or displacements of the supporting structure, vascular plexus, and arteriovenous anastomosis of the anal cushions (anal canal vascular cushions). External hemorrhoids are pathological dilation or thrombosis of the subcutaneous vascular plexus distal to the dentate line. Mixed hemorrhoids are a mixture of internal and external hemorrhoids.

Scar hyperplasia, also known as keloid, is caused by excessive proliferation of fibrous connective tissue. After the skin is traumatized, an inflammatory response occurs first, and then myofibroblasts appear in the wound, divide and proliferate to synthesize collagen fibers, causing collagen deposition to form scars, accompanied by itching, tenderness, or local decreased sensation.

In other embodiments of the present application, inflammatory diseases are classified according to the site of infection, and inflammatory diseases in various sites can be included therein. For example, the inflammatory diseases include: inflammatory diseases of the brain, inflammatory diseases of the heart, inflammatory diseases of the skin, inflammatory diseases of the eyes and their surrounding areas, inflammatory diseases of the nose, inflammatory diseases of the mouth, inflammatory diseases of the ears, inflammatory diseases of the parotid gland, inflammatory diseases of the pharynx, inflammatory diseases of the thyroid gland, inflammatory diseases of the thymus gland, inflammatory diseases of the adnexa, inflammatory diseases of the respiratory system, inflammatory wrist diseases, tendonitis, arthritis, gastroenteritis, inflammatory diseases of vulvar itching, vaginitis, prostatitis, pancreatitis, inflammatory diseases of the bladder, urethritis, inflammatory diseases of the kidneys, inflammatory diseases of the pelvis, inflammatory diseases of the spine, anal inflammatory diseases, vascular inflammatory diseases and other inflammatory diseases.

In some embodiments of the present application, the other inflammatory diseases include systemic lupus erythematosus, inflammatory edema, graft-versus-host disease, multiple sclerosis, cystic fibrosis, ischemia-reperfusion injury, vascular restenosis, osteoblastic inflammation, sepsis, and neurodegenerative diseases.

In some embodiments of the present application, the skin inflammatory diseases (inflammatory skin diseases) include: herpes, solar dermatitis, psoriasis, eczematous dermatitis, contact dermatitis, seborrheic dermatitis, rosacea, lichen planus, vasculitis, pityriasis rubra pilaris, cellulitis, folliculitis, carbuncle, pemphigus, epidermal blisters, urticaria, angioedema, vasculitis, erythema and cutaneous eosinophilia, acne, ringworm, hand, foot and mouth virus, sty, etc.

In some embodiments of the present application, the pemphigus includes bullous pemphigus.

Stye is clinically known as hordeolum, commonly known as "stye". It is an acute suppurative inflammatory lesion of the eyelid gland, with typical symptoms of acute inflammatory bowel such as redness, swelling, heat, and pain. There are hard nodules at the lesion. It is a common eye disease that can occur in people of any age. People with excessive sebum secretion, blepharitis, seborrheic dermatitis, rosacea, hypertension, diabetes and other people with decreased immunity are more susceptible to the disease. Other inducing factors include touching the eyes with unclean hands, poor hygiene of the eyelid area, staphylococcal infection, and aseptic inflammation caused by blockage of the meibomian gland opening.

In some embodiments of the present application, the brain inflammatory disease includes meningitis, encephalitis caused by viral infection, and autoimmune encephalomyelitis.

In some embodiments of the present application, the meningitis includes purulent meningitis caused by bacterial infection, tuberculosis caused by Mycobacterium tuberculosis, Type meningitis.

In some embodiments of the present application, the cardiac inflammatory disease includes myocarditis.

In some embodiments of the present application, the ocular inflammatory disease includes conjunctivitis, retinitis-diabetic retinopathy.

In some embodiments of the present application, the ear inflammatory disease includes otitis media, otitis interna, and otitis externa. For example, the otitis media includes acute otitis media, chronic otitis media, and secretory otitis media.

In some embodiments of the present application, the adnexal inflammatory disease includes inflammatory reactions caused by metritis, oophoritis, and dysmenorrhea.

In some embodiments of the present application, the respiratory inflammatory disease includes pneumonia and asthma.

In some embodiments of the present application, the arthritis includes rheumatoid arthritis, osteoarthritis, and rheumatoid arthritis.

In some embodiments of the present application, the gastroenteritis includes inflammatory bowel inflammation, acute or chronic colitis, acute or chronic proctitis.

In some embodiments of the present application, the spondylitis includes ankylosing spondylitis.

In some embodiments of the present application, the anal inflammatory disease includes hemorrhoids.

In some embodiments of the present application, the vascular inflammatory disease includes immune vasculitis.

In other embodiments of the present application, the inflammatory disease includes autoinflammatory disease and non-autoinflammatory disease.

In some embodiments of the present application, the inflammatory diseases include: acute and chronic inflammatory gastrointestinal diseases, acne, rosacea, acute and chronic inflammation of the eyes and their glands, solar dermatitis, gynecological inflammation, and pharyngitis.

In this application, solar dermatitis, also known as acute sunburn and sunburn, is an acute skin injury reaction caused by strong light exposure. It is more common in late spring and early summer, and is more common in children, women, skiers and water workers. The severity of symptoms is related to light intensity, exposure time, skin color, physical constitution, etc.

In some embodiments of the present application, the acute and chronic inflammatory gastrointestinal diseases include: gastritis, ulcerative colitis and Crohn's disease.

In some embodiments of the present application, the acute and chronic inflammation of the eye and its glands include sty, conjunctivitis, and blepharitis.

In the present application, the inventors found that dipyridamole has a significant soothing effect on the symptoms of allergic and inflammatory skin disease modeling mice induced by calcipotriol, especially for the expression of IL-4 and TSLP in allergic and/or inflammatory diseases. IL-4 and thymic stromal lymphopoietin (TSLP) are two important cytokines that induce allergic and/or inflammatory diseases. Specifically, in skin-related allergic or inflammatory diseases, increased IL-4 levels can cause mouse models to produce symptoms similar to allergic and inflammatory related dermatitis. Overexpression of IL-4 can lead to Th2 differentiation of T cells, IgE class switching in B cells, and increased mast cells. Studies on transgenic mice that overexpress IL-4 in the epidermis show symptoms of xerosis, inflammatory skin lesions, scratching behavior, skin infections, and elevated IgE. TSLP is highly expressed in the skin epithelial cells of patients with inflammatory skin diseases, and overexpression of TSLP in keratinocytes (the most common cell type in the skin) can cause strong itching, induce scratching, the development of dermatitis phenotypes, and even worse, can cause asthma-like lung inflammation.

Moreover, the inventors have also found that dipyridamole reduces plasma and inflammatory site IgE in allergic and/or inflammatory diseases and inhibits mast cell infiltration. IgE is considered to be a hallmark antibody for allergic and/or inflammatory diseases such as dermatitis. When IgE binds to its corresponding antigen, it prompts mast cells to release particles such as heparin and histamine, triggering an immune response.

In this application, the term "allergic reaction" refers to the reaction of tissue damage or functional disorder that occurs when an immune body is stimulated by the same antigen again. After the allergen enters the body, it induces allergen-specific B cells to produce antibody responses. Such antibodies bind to the surface receptors of mast cells and basophils, making the body sensitized to the allergen. When the same allergen enters the body again, it specifically binds to the antibodies on the surface of sensitized mast cells and basophils, stimulating cell degranulation and releasing bioactive mediators, which act on effector tissues and organs, causing local or systemic allergic reactions.

In some embodiments of the present application, the drug is an internal preparation or an external preparation, preferably an external preparation.

In some embodiments of the present application, the drug is in the form of an external dosage form, including but not limited to ointments, creams, gels, lotions, tinctures, suspensions, liniments, spirits, powders, oils, pastes, plasters, coatings, aerosols, solutions, sprays, and patches.

In some embodiments of the present application, the topical preparation further comprises one or more of the following substances: solvents, emulsifiers, softeners, antioxidants, preservatives, chelating agents, pH regulators, thickeners, penetration enhancers, and sunscreens.

In some embodiments of the present application, the drug is applicable to animals, and the animals are selected from humans, cats, cows, sheep, pigs, dogs, chickens, ducks, geese, rabbits, and mice; preferably, the animals are humans, more preferably infants, children, teenagers, adults, or the elderly; most preferably, children, such as infants aged 0-2 years, children aged 2-12 years, teenagers aged 12-18 years, or adults aged 18 years or older.

In some embodiments of the present application, the drug is applied to the skin, nails, or hair.

In some embodiments of the present application, the effective content of dipyridamole and/or its derivatives in the pharmaceutical composition (in terms of mass percentage) is 0.01% to 60%, preferably 0.05% to 20%, more preferably 0.1% to 12% or 0.1% to 10%, for example 0.1%, 0.2%, 0.3%, 0.5%, 0.8%, 1%, 2%, 3%, 5%, 6%, 8%, 10%, 12%.

In some specific embodiments of the present application, the concentration of dipyridamole and/or its derivatives in the pharmaceutical composition is 0.1 mg/g to 120 mg/g, 0.1 to 100 mg/g, 1 mg/g to 120 mg/g, preferably 1 to 50 mg/g, more preferably 1-20 mg/g, for example 3 mg/g, 5 mg/g.

In some embodiments of the present application, the frequency of use of the drug is: once every 1 to 24 hours.

In some embodiments of the present application, the frequency of use of the drug is: 1-3 times a day, preferably 2-3 times a day.

In some embodiments of the present application, the frequency of use of the drug is: once every 1 hour, every 2 hours, every 4 hours, every 6 hours, every 8 hours, every 12 hours or every 24 hours.

In some embodiments of the present application, the dosage of the drug per time is: calculated as dipyridamole, 1-250 mg per time, preferably 5-100 mg per time, and more preferably 10-50 mg per time.

In some embodiments of the present application, the drug is administered in a cosmetically effective amount. The term "cosmetically effective amount" refers to a dose sufficient to achieve the desired cosmetic effect on the treated subject.

In some embodiments of the present application, the drug is administered in a therapeutically effective amount. The term "therapeutically effective amount" refers to a dose sufficient to achieve the desired therapeutic effect in a subject.

In some embodiments of the present application, the drug is used in the form of a topical drug preparation for skin application.

In some embodiments of the present application, the drug is administered by coating or spraying the drug on the skin surface corresponding to the affected area.

In some embodiments of the present application, the dosage of the drug each time is: 0.1-25 mg/cm ² in terms of dipyridamole. For example, 0.1-25 mg/cm ² in terms of dipyridamole is applied or sprayed on the skin surface corresponding to the affected area.

In some embodiments of the present application, the dosage of the drug each time is: 0.2-10 mg/cm ² in terms of dipyridamole. For example, 0.2-10 mg/cm ² in terms of dipyridamole is applied or sprayed on the skin surface corresponding to the affected area.

In some embodiments of the present application, the dosage of the drug each time is: 0.5-5 mg/cm ² in terms of dipyridamole. For example, 0.5-5 mg/cm ² in terms of dipyridamole is applied or sprayed on the skin surface corresponding to the affected area.

In some embodiments of the present application, the drug further contains other pharmaceutically acceptable excipients.

In some embodiments of the present application, the pharmaceutically acceptable excipients include, but are not limited to, diluents, absorbents, wetting agents, adhesives, disintegrants, lubricants, colorants, coating materials, solvents, pH regulators, antibacterial agents, isotonic regulators, and chelating agents. In some embodiments of the present application, the topical preparation may further include one or more of the following: moisturizers, gels (also referred to as "gel bases"), water, and ointment bases.

In some embodiments of the present application, the drug further includes a second active ingredient.

In some embodiments of the present application, the second active ingredient includes at least one of an active ingredient for anti-inflammatory diseases, an active ingredient for anti-allergic diseases, an anti-inflammatory active ingredient, and an anti-allergic active ingredient.

For example, in some allergic diseases, the second ingredient in the drug is preferably at least one of an active ingredient for anti-allergic diseases and an anti-allergic active ingredient.

For example, in some inflammatory diseases, the second ingredient in the drug is preferably at least one of an active ingredient for anti-inflammatory diseases and an anti-inflammatory active ingredient.

In some embodiments of the present application, the anti-inflammatory active ingredients include: steroidal anti-inflammatory drugs or non-steroidal anti-inflammatory drugs.

In some embodiments of the present application, the non-steroidal anti-inflammatory drugs include aspirin, benolate, salicylic acid, acetaminophen, indomethacin, diclofenac, sulindac, nemetbutalone, ibuprofen, naproxen, piroxicam, meloxicam, celecoxib, etoricoxib, and nimesulide.

In some embodiments of the present application, the steroidal anti-inflammatory drugs include adrenal cortical hormones, androgens, estrogens, such as hydrocortisone, prednisone, dexamethasone, and the like.

In some embodiments of the present application, the anti-inflammatory active ingredients include: antifungal drugs or active ingredients, antiviral drugs or active ingredients, antifungal drugs or active ingredients, antiparasitic drugs or active ingredients, and antimycoplasma drugs or active ingredients.

In some embodiments of the present application, the antifungal drugs or active ingredients include amphotericin B, nystatin, griseofulvin, Clotrimazole, econazole, miconazole, ketoconazole, bifonazole, terbinafine, ciclopirox olamine, amorolfine.

In some embodiments of the present application, the antiviral drugs or active ingredients include acyclovir, acetaminophen, amantadine, chlorpheniramine maleate, ribavirin, amantadine and its salts (eg, hydrochloride), human interferon, and the like.

In some embodiments of the present application, the antibacterial drug or active ingredient includes antibiotics, sulfonamides, imidazoles, nitroimidazoles, quinolones, such as penicillin, cephalosporin, cephamycin antibiotics, sulfamethoxazole (SMZ), sulfadiazine (SD), ketoconazole, miconazole, econazole, clotrimazole, metronidazole (MNZ), dimetridazole (DMZ), isopronidazole (IPZ), seconidazole (SCZ), ornidazole (ONZ), tinidazole (TNZ) and ronidazole (RNZ), norfloxacin, pefloxacin (Pefloxacin, mefloxacin), enoxacin (Enoxacin, fluazinic acid), ofloxacin (Ofloxacin, fluazinic acid) and ciprofloxacin (Ciprofloxacin, ciprofloxacin).

In some embodiments of the present application, the active ingredient for anti-inflammatory diseases includes the active ingredient of the inflammatory disease drugs mentioned above in the present application, such as acne treatment drugs or active ingredients, rosacea treatment drugs or active ingredients, rhinitis treatment drugs or active ingredients, conjunctivitis treatment drugs or active ingredients, etc.

In some embodiments of the present application, the acne treatment drug or active ingredient includes sulfur, clindamycin, erythromycin, vitamin A ester, benzoyl peroxide, azelaic acid, tretinoin, isotretinoin, adapalene, hyaluronic acid or its salts (such as sodium, zinc, silver, calcium, potassium salt), ergothioneine.

In some embodiments of the present application, the rhinitis treatment drug or active ingredient includes at least one of a glucocorticoid, an antibacterial drug, and an α receptor agonist.

In some embodiments of the present application, the glucocorticoids include hydrocortisone acetate, hydrocortisone butyrate, dexamethasone, dexamethasone acetate, triamcinolone acetonide acetate, mometasone furoate, halometasone, beclomethasone dipropionate, fluocinolone acetonide, halcinonide, and betamethasone propionate.

In some embodiments of the present application, the alpha receptor agonist includes ephedrine, ephedrine hydrochloride, oxymetazoline, and xylometazoline.

In some embodiments of the present application, the conjunctivitis treatment drugs or active ingredients include aminoglycosides or active ingredients (such as gentamicin, neomycin, tobramycin, etc.), fluoroquinolones or active ingredients (such as gatifloxacin, norfloxacin, ofloxacin, etc.), amides or active ingredients (such as chloramphenicol), tetracyclines or active ingredients, macrolides or active ingredients (such as erythromycin, rifampicin), acyclovir eye drops and ganciclovir eye gel, sodium sulfacetamide (such as 15%) or rifampicin eye drops, and corticosteroid eye drops.

The active ingredient for allergic diseases/antiallergic active ingredient refers to the tissue damage or physiological dysfunction caused by the body being stimulated by antigenic substances. The drugs or ingredients that prevent and treat allergic diseases caused by various antigenic substances (such as bacteria, viruses, parasites, pollen, etc.) are antiallergic active ingredients or drugs.

In some embodiments of the present application, the anti-allergic active ingredients include: antihistamines, allergic reaction mediator release inhibitors, histamine desensitization drugs, leukotriene receptor antagonists, drugs that inhibit antigen-antibody reactions, drugs that improve or control allergic reaction symptoms, and active ingredients of the above drugs.

In some embodiments of the present application, the antihistamine drugs or active ingredients include diphenhydramine, promethazine, chlorpheniramine, etc. Antihistamine drugs or active ingredients can compete with histamine for histamine H1 receptors on effector cells, so that histamine cannot bind to H1 receptors, thereby inhibiting its effect of causing allergic reactions.

In some embodiments of the present application, the allergic reaction mediator release-inhibiting drug or active ingredient includes sodium cromoglycate, ketotifen, etc. The allergic reaction mediator release-inhibiting drug or active ingredient can stabilize the mast cell membrane, prevent the release of histamine and other allergic reaction mediators, and produce an anti-allergic effect.

In some embodiments of the present application, the histamine desensitization drugs or active ingredients include betahistine, histamine diluent, dust mite injection, etc. These drugs are repeatedly injected into patients to improve tolerance to histamine.

In some embodiments of the present application, the leukotriene receptor antagonist drugs or active ingredients include montelukast, zafirlukast, etc., which are mainly used for respiratory allergies.

In some embodiments of the present application, the drug or active ingredient that inhibits antigen-antibody reaction includes glucocorticoids, immunosuppressants, etc., wherein the glucocorticoids are as described in the present application.

In some embodiments of the present application, the drugs for improving or controlling allergic symptoms include smooth muscle antispasmodics, such as salbutamol, etc.; and drugs for reducing edema caused by allergies, such as calcium gluconate, etc.

In some embodiments of the present application, the active ingredient for anti-allergic diseases includes the inflammatory disease drugs mentioned above in the present application. Active ingredients, such as drugs or active ingredients for treating allergic rhinitis, drugs or active ingredients for treating allergic conjunctivitis, etc.

In some embodiments of the present application, the drug is in the form of an external dosage form, including but not limited to ointments, lotions, tinctures, liniments, spirits, powders, oils, pastes, plasters, coatings, and aerosols.

For some common local inflammatory diseases, especially chronic inflammatory diseases, topical use of drugs can achieve the purpose of rapid suppression of inflammation, which is more direct and effective than oral drugs, and also effectively reduces systemic side effects. Therefore, local drugs or external preparations are also important means for treating inflammatory diseases. For this application, the oil-water partition coefficient (logP) of dipyridamole is -1.22, and it has poor water solubility, is soluble in oily solvents such as ethanol or DMSO, and has good transdermal absorption. Topical or external use of dipyridamole is suitable for controlling local inflammation of the skin, which can increase the drug concentration of the affected part and reduce systemic side effects. Moreover, it has been experimentally verified that dipyridamole has a good inhibitory effect on local allergies and inflammation when used externally.

In some embodiments of the present application, the medicine is a cream, a gel, or an ointment.

In the present application, a wipe (cream or gel) with dipyridamole as the main ingredient is provided for the first time, and it is found that it can effectively treat local inflammatory diseases and allergic diseases represented by allergic conjunctivitis, allergic rhinitis, inflammatory bowel disease, acne, rosacea, as well as other diseases such as scar hyperplasia and hemorrhoids.

The second aspect of the present application provides a pharmaceutical composition, which contains dipyridamole and/or its derivatives.

In some embodiments of the present application, the derivative includes a pharmaceutically acceptable salt, ester, hydrate, solvate, polymorph, isomer or prodrug of dipyridamole.

In some embodiments of the present application, the isomers include structural isomers (eg, tautomers), stereoisomers, optical isomers, regioisomers, and geometric isomers.

In some embodiments of the present application, the pharmaceutical composition further contains a pharmaceutically acceptable adjuvant.

In some embodiments of the present application, the excipients include but are not limited to solvents, emulsifiers, lubricants, humectants, preservatives, antioxidants, consistency regulators, pH regulators, diluents, absorbents, binders, disintegrants, colorants, coating materials, antibacterial agents, isotonic regulators, and chelating agents.

In some embodiments of the present application, the effective content of dipyridamole and/or its derivatives in the pharmaceutical composition is 0.01% to 60%, preferably 0.05% to 20%, more preferably 0.1% to 12% or 0.1% to 10%, for example 0.1%, 0.2%, 0.3%, 0.5%, 1%, 2%, 3%, 5%, 8%, 10%.

In some specific embodiments of the present application, the concentration of dipyridamole and/or its derivatives in the pharmaceutical composition is 0.1-100 mg/g, preferably 1-50 mg/g, more preferably 1-20 mg/g, for example 3 mg/g, 5 mg/g.

The third aspect of the present application provides a dipyridamole cream, which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, and 0.1% to 60% of diethylene glycol monoethyl ether.

In some embodiments of the present application, the mass percentage of dipyridamole and/or its derivatives is 0.01% to 10%, 0.1% to 12% or 0.1% to 10%.

In some embodiments of the present application, the mass percentage of diethylene glycol monoethyl ether is 0.3% to 50%, 1% to 45%, for example, 2%, 5%, 6%, 8%, 10%, 12%, 15%, 18%, 25%, 30%, 42%.

In some embodiments of the present application, the other ingredient of the cream is water.

In some embodiments of the present application, the cream contains, by mass percentage, 10% to 95% water, preferably 20% to 90% water, and more preferably 30% to 70% water, for example, about 30% water, about 35% water, about 40% water, about 45% water, about 50% water, about 55% water, about 60% water, about 62% water, about 65% water, about 68% water, and about 70% water.

In some embodiments of the present application, the dipyridamole cream contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether and water.

In some embodiments of the present application, the dipyridamole cream contains 0.01% to 10% of dipyridamole and/or its derivatives, and 0.3% to 50% of diethylene glycol monoethyl ether and water, by mass percentage. In some embodiments of the present application, the dipyridamole cream contains 0.1% to 15% of dipyridamole and/or its derivatives, 1% to 45% of diethylene glycol monoethyl ether and 10% to 95% of water, by mass percentage. In some embodiments of the present application, the dipyridamole cream contains 0.1% to 10% of dipyridamole and/or its derivatives, 1% to 45% of diethylene glycol monoethyl ether and 10% to 95% of water, by mass percentage.

In some embodiments of the present application, the dipyridamole cream contains, calculated by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether and 10% to 95% of water.

In the art, dipyridamole dissolves in water in a pH-dependent manner, and has a strong solubility when the pH is less than 3.5. However, when used as an external preparation, too low acidity may lead to the risk of irritation, resulting in no effective and available dipyridamole external preparations in the prior art. In the present application, it was found by a large number of screenings that by adding diethylene glycol monoethyl ether, the permeability of dipyridamole cream was successfully improved while maintaining the neutrality of the product, thereby improving the efficacy of dipyridamole cream.

In some embodiments of the present application, the cream further contains an emulsifier, preferably 0.3% to 40% of the emulsifier by mass, and more preferably 0.5% to 30% of the emulsifier by mass.

In some embodiments of the present application, the emulsifier includes one or more of polyethylene glycol stearate, phospholipids, sodium lauryl sulfate, Span surfactants, Tween surfactants, higher fatty alcohols, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, 15-hydroxystearate polyethylene glycol ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, triethanolamine, stearic acid glyceryl, caprylic acid capric acid polyethylene glycol glyceride, propylene glycol monocaprylate, propylene glycol monolaurate, polyglycerol oleate, and polyethylene glycol cetearyl alcohol ether.

Span (or "Span", "Siben", etc.), is the transliteration of Span, which is a polyol ester compound generated by the esterification reaction of sorbitan (anhydrous sorbitol) and fatty acids, namely, anhydrous sorbitan fatty acid ester, which is an important non-ionic, oil-in-water surfactant, including Span-20, Span-40, Span-60, Span-65, Span-80, Span-85, etc. Its melting point is 52-57℃, soluble in hot ethanol, ether, methanol and carbon tetrachloride, slightly soluble in ether, petroleum ether, and can be dispersed in hot water. It has strong emulsifying, dispersing and lubricating effects, and can be mixed with various surfactants, especially Tween-60, and the effect of compound use is better.

Tween (or polysorbate) is a non-ionic surfactant and is also widely used as an emulsifier and solubilizer for oily substances. It is a partial fatty acid ester of a series of polyoxyethylene sorbitan and is generally considered to be a non-toxic and non-irritating material. Its types include Tween 20 (TWEEN-20), Tween 21 (TWEEN-21), Tween 40 (TWEEN-40), Tween 60 (TWEEN-60), Tween 61 (TWEEN-61), Tween 80 (TWEEN-80), Tween 81 (TWEEN-81), Tween 85 (TWEEN-85), etc.

Higher alcohols, also known as higher fatty alcohols, refer to mixtures of monohydric alcohols containing more than three carbon atoms. Alcohols in the range of C6 to C10 are usually called plasticizer alcohols, while alcohols above C12 are called detergent alcohols. These alcohols include n-propanol, sec-butanol, amyl alcohol, isopentanol, isobutanol, etc.

Polyoxyethylene fatty acid esters are dispersed in water and soluble in hot ethanol, hot oil, benzene, xylene and other solvents. They are widely used as o/w emulsifiers. They are non-ionic surfactants with good surface activities such as emulsification, solubilization, wetting, dispersion, softening and antistatic properties. They are non-toxic and non-irritating. Types include polyoxyethylene-7 stearate; polyoxyethylene-10 stearate; polyoxyethylene-12 stearate; polyoxyethylene-20 stearate; polyoxyethylene-75 stearate; polyoxyethylene-150 stearate; PEG-2 stearate (CAS: 106-11-6); PEG-3 stearate (CAS: 10233-24-6); PEG-4 stearate (CAS: 106-07-0); PEG-5 stearate; PEG-6 stearate (CAS: 10108-28-8); PEG-8 stearate (CAS: 70802-40-3); PEG- 9 stearate (cas: 5349-52-0); PEG-14 stearate (cas: 10289-94-8); PEG-15 stearate; PEG-18 stearate; PEG-23 stearate; PEG-25 stearate; PEG-30 stearate; PEG-32 stearate; PEG-35 stearate; PEG-36 stearate; PEG-40 stearate; PEG-45 stearate; PEG-50 stearate; PEG-55 stearate; PEG-90 stearate; PEG-100 stearate; PEG-120 stearate, etc.

Fatty alcohol polyoxyethylene ether (AEO), also known as polyoxyethylene fatty alcohol ether, is a nonionic surfactant. This type of surfactant is an ether formed by the condensation of polyethylene glycol (PEG) and fatty alcohol, represented by the following general formula: RO(CH ₂ CH ₂ O)nH, where n is the degree of polymerization. There are different varieties due to the different degrees of polymerization of polyethylene glycol and the types of fatty alcohol. Such as AEO-3, AEO-7, AEO-9, AEO-10, AEO-15, AEO-20, etc.

Polyethylene glycol stearate, molecular formula: C ₁₈ H ₃₅ O ₂ ·(C ₂ H ₄ O) _n ·H, is used in cosmetics, pharmaceutical emulsifiers, soap thickeners, softeners, emulsion stabilizers, etc. Such as polyoxyethylene sorbitan monostearate, polyethylene glycol (400) monooctadecanoate, polyethylene glycol (400) monostearate, Travel Chemical T-60, polyoxyethylene stearate, polyoxyethylene sorbitan monostearate, PEG-5 stearate, PEG-7 stearate, PEG-25 stearate, PEG-23 stearate, PEG-30 stearate, PEG-18 stearate, PEG-20 stearate, PEG-10 stearate, etc.

In some embodiments of the present application, the emulsifier is polyethylene glycol-7-stearate.

Polyethylene glycol-7-stearate, non-ionic O/W emulsifier, white waxy solid, odorless, melting point 46.0-53.0℃.

In some embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and 0.3% to 40% of polyethylene glycol stearate.

In some embodiments of the present application, a dipyridamole cream is provided, wherein the dipyridamole cream contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and 0.3% to 40% of polyethylene glycol-7-stearate.

In some embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, 0.3% to 40% of polyethylene glycol-7-stearate, and the balance is water.

In some embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of polyethylene glycol-7-stearate, and the balance is water.

In some embodiments of the present application, in the dipyridamole cream, the mass ratio of diethylene glycol monoethyl ether and polyethylene glycol-7-stearate is 1-50:1-20, preferably 1-10:1-3, for example, 1:2, 3:2, etc.

In some embodiments of the present application, on the basis of containing dipyridamole and/or its derivatives and diethylene glycol monoethyl ether in the cream, or on the basis of containing dipyridamole and/or its derivatives, diethylene glycol monoethyl ether and an emulsifier (such as polyethylene glycol-7-stearate), the cream further comprises one or more of a lubricant, a moisturizer and a preservative.

In some embodiments of the present application, on the basis of containing dipyridamole and/or its derivatives and diethylene glycol monoethyl ether in the cream, or on the basis of containing dipyridamole and/or its derivatives, diethylene glycol monoethyl ether and an emulsifier (such as polyethylene glycol-7-stearate), the cream further comprises one or more of a lubricant, a moisturizer, a preservative and a consistency regulator.

In some embodiments of the present application, on the basis of containing dipyridamole and/or its derivatives and diethylene glycol monoethyl ether in the cream, or on the basis of also containing dipyridamole and/or its derivatives and diethylene glycol monoethyl ether, and an emulsifier (such as polyethylene glycol-7-stearate) in the cream, the cream further includes one or more of an antioxidant, a consistency regulator, a pH regulator, and a pigment.

In some embodiments of the present application, on the basis of the cream containing dipyridamole and/or its derivatives and diethylene glycol monoethyl ether, or on the basis of the cream also containing dipyridamole and/or its derivatives and diethylene glycol monoethyl ether, and an emulsifier (such as polyethylene glycol-7-stearate), the cream further contains one or both of a lubricant or a consistency regulator.

In some embodiments of the present application, on the basis of containing dipyridamole and/or its derivatives and diethylene glycol monoethyl ether in the cream, or on the basis of also containing dipyridamole and/or its derivatives and diethylene glycol monoethyl ether, and an emulsifier (such as polyethylene glycol-7-stearate) in the cream, the cream further comprises one or both of a lubricant or a consistency regulator, and also comprises one or more of a moisturizer, a preservative, an antioxidant, a pH regulator, and a pigment.

In some embodiments of the present application, on the basis of containing dipyridamole and/or its derivatives and diethylene glycol monoethyl ether in the cream, or on the basis of also containing dipyridamole and/or its derivatives and diethylene glycol monoethyl ether, and an emulsifier (such as polyethylene glycol-7-stearate) in the cream, the cream further comprises one or more of a lubricant, a moisturizer, a preservative, an antioxidant, a consistency regulator, a pH regulator, and a pigment.

Lubricants refer to substances that prevent skin moisture or irritation, make the skin soft, soften, smooth, supple, restore moisture, impermeable, lubricating, moisturizing, protecting and/or cleansing, including absorbent humectants or humidifying lubricants that can absorb moisture from the surrounding atmosphere and increase the moisture of the stratum corneum; including barrier protection lubricants that can form an occlusive layer when deposited on the skin surface to protect the skin from the influence of large molecules such as excreta, enzymes and other irritants.

Representative barrier protector lubricants for use in the present application include, but are not limited to, the following lubricants: petroleum-based lubricants; fatty acid esters; fatty alcohols; alkyl ethoxylates; fatty alcohol ethers; polyhydroxy polyesters; glycerides; free sterols; sterol esters and their derivatives; triglycerides and their derivatives; sphingolipids; vegetable or animal oils; hydrogenated vegetable oils; kaolin and its derivatives; vitamins such as B3 (niacinamide), VC (ascorbic acid), D3, VE (tocopherol), VE esters (nicotinate tocopheryl esters); or mixtures of these lubricants.

Suitable petroleum-based lubricants include paraffins, i.e., hydrocarbons or hydrocarbon mixtures; for example, those hydrocarbons having a chain length of 16-32 carbon atoms. Petroleum-based hydrocarbons with these chain lengths include mineral oil (also known as "liquid petrolatum") and petrolatum (also known as "ozokerite," "petroleum jelly," and "mineral jelly"). Mineral oil generally refers to a mixture of lower viscosity hydrocarbons with 16-20 carbon atoms. Petrolatum generally refers to a mixture of more viscous hydrocarbons with 16-32 carbon atoms. Petrolatum and mineral oil are preferred lubricants.

Suitable fatty acid ester lubricants include those derived from C12-C28 fatty acids, preferably C16-C22 saturated fatty acids, and short chain (C1-C8, preferably C1-C3) monohydric alcohols. Representative examples of the esters include methyl palmitate, methyl stearate, isopropyl laurate, isopropyl myristate, isopropyl palmitate, ethylhexyl palmitate, and mixtures thereof. Suitable fatty acid ester lubricants can also be derived from esters of longer chain fatty alcohols (C12-C28, preferably C12-C16) and shorter chain fatty acids (e.g., lactic acid), such as lauryl lactate and cetyl lactate.

Suitable alkyl ethoxylate type lubricants include C12-C22 fatty alcohol ethoxylates having an average degree of ethoxylation of about 2 to about 30, including lauryl, cetyl and stearyl ethoxylates having an average degree of ethoxylation of about 2 to about 23, laureth-3, laureth-23, ceteth-10, steareth-10, and the like.

Suitable fatty alcohol type lubricants include C12-C22 fatty alcohols, preferably C16-C18 fatty alcohols. Representative examples include cetyl alcohol and stearyl alcohol, and mixtures thereof.

Suitable fatty alcohol ether type lubricants include ethers derived from C12-C18 fatty alcohols or C12-C18 fatty alcohols and lower alcohols.

Suitable fatty ester lubricants also include polyol polyesters, especially "liquid" polyol polyesters whose complete melting temperature is body temperature or below (i.e., about 37°C). Examples of polyols include, but are not limited to, polyols such as pentaerythritol; sugars such as raffinose, maltose glucose, galactose, sucrose, glucose, xylose, fructose, maltose, lactose, mannose and erythritol; sugar alcohols such as erythritol, xylitol, maltitol, mannitol and sorbitol. These polyols are esterified with fatty acids and/or other organic groups having at least 2 carbon atoms and up to 30 carbon atoms. For example, sucrose polyol polyesters such as sucrose polycotton oil fatty acid esters, sucrose polysoybean oil fatty acid esters, and sucrose polybehenate and mixtures of these polyhydroxy polyesters.

Lubricants suitable for the present application include various C1-C30 monoesters and polyesters of glycerol and their derivatives, including glyceryl esters, acetylated glyceryl esters, ethoxylated glyceryl esters of C12-C28 fatty acids, triethylene glycol, and their derivatives, including glyceryl tri(behenic acid) ester, glyceryl stearate, glyceryl palmitate, glyceryl distearate, glyceryl dipalmitate, etc.

Lubricants suitable for the present application also include sphingolipids, such as ceramide, sphingosine, phytosphingosine, and the like.

An effective lubricant with super barrier properties can be a mixture of components that simulate the lipid complexes that form the skin's natural water barrier, such as fetal sebum or its mimics, such as a mixture of sterols, sterol esters and triglycerides as fetal sebum mimics; or other substances naturally produced in the stratum corneum, such as sodium pyrrolidone carboxylate, sodium lactate/lactic acid, free fatty acids, L-proline, guanidine, pyrrolidone, ceramide and urea. Other lubricants derived from natural sources are also suitable for this application, such as hydrolyzed proteins and other collagen-derived proteins; keratin and its derivatives; acetamide MEA, etc.

In some embodiments of the present application, the lubricant is selected from one or more of isopropyl palmitate, isopropyl myristate, dimethicone, diisopropyl adipate, caprylic glyceride, caprylic anhydride oil, caprylic capric macrogol glyceride, isohexadecane, hydrogenated castor oil, mineral oil, caprylic/capric triglyceride, lauric acid, and linoleic acid.

In some embodiments of the present application, the lubricant is one or both of isopropyl myristate and isopropyl palmitate.

In some embodiments of the present application, the mass proportion of the lubricant in the dipyridamole cream is 0.5% to 40%.

In some embodiments of the present application, the mass proportion of the lubricant in the dipyridamole cream is 1% to 30%.

In some embodiments of the present application, the mass proportion of the lubricant in the dipyridamole cream is 5% to 20%, for example, 5%, 8%, 10%, etc.

Moisturizers are a class of hydrophilic substances that replenish moisture to the skin, relieve dryness, maintain the moisture of the cosmetics themselves, and stabilize the main products. Common ones include polyols, polyols, hydroxyethyl urea, etc. According to different sources, they can be divided into natural moisturizers existing in humans, animals, and plants and non-natural synthetic moisturizers. Natural moisturizers include plant extracts, low molecular weight moisturizers, high molecular weight moisturizers, polyols, amino acids, polysaccharides, organic salts, sorbitol, hyaluronic acid, hydrolyzed hyaluronic acid, betaine, D-panthenol, trehalose, oligofructose and glycine. Synthetic moisturizers include polyols, polyols, hydroxyethyl urea, glycerol, urea, glycerol polyether-26, 1,2-pentanediol, 1,2-hexanediol, 1,3-propylene glycol, diglycerol, 1,3-butylene glycol, etc.

In some embodiments of the present application, the humectant is selected from one or more of glycerol, propylene glycol, 1,3-butylene glycol, and polyethylene glycol.

In some embodiments of the present application, the humectant is one or both of glycerol and 1,3-butylene glycol.

In some embodiments of the present application, the mass proportion of the moisturizer in the dipyridamole cream is 0.5% to 50%.

In some embodiments of the present application, the mass proportion of the moisturizer in the dipyridamole cream is 1% to 30%.

In some embodiments of the present application, the mass proportion of the moisturizer in the dipyridamole cream is 2% to 25%.

In some embodiments of the present application, the mass proportion of the moisturizer in the dipyridamole cream is 5% to 20%, for example, 5%, 10%, or 20%.

In some embodiments of the present application, the preservative is selected from at least one of a chemical preservative and a natural preservative.

The chemical preservative is selected from benzoic acid (sodium), sorbic acid (potassium), parabens (also known as parabens), propionates, sulfites and their salts, nitrates and nitrites. Further, the chemical preservatives of the present application include methyl paraben, sodium methyl paraben, ethyl paraben, sodium ethyl paraben, sorbic acid, potassium sorbate, dehydroacetic acid, sodium dehydroacetate, diacetic acid, sodium diacetate, propionic acid, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, At least one of sodium propionate, calcium propionate and benzyl alcohol.

Natural preservatives are food preservatives that use metabolites of plants, animals or microorganisms as raw materials and are produced through extraction, enzymatic conversion or fermentation. Natural preservatives include plant-based food preservatives, animal-based food preservatives and microbial-based food preservatives; plant-based food preservatives, such as spices, Chinese herbal medicine, pectin decomposition products, other plant extracts (gingko leaf extract, water chestnut peel extract, etc.); animal-based food preservatives, such as protamine, chitosan, propolis, etc.; microbial-based food preservatives, such as lysozyme, nisin, natamycin, ε-polylysine, etc. Further, natural preservatives include at least one of nisin, natamycin and chitosan.

In some embodiments of the present application, the preservative is selected from one or more of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sodium ethylparaben, benzyl alcohol, phenoxyethanol, sorbic acid, benzoic acid, and sodium benzoate.

In some embodiments of the present application, the preservative is sodium ethylparaben.

In some embodiments of the present application, the mass proportion of the preservative in the dipyridamole cream is 0% to 10%.

In some embodiments of the present application, the mass proportion of the preservative in the dipyridamole cream is 0% to 5%.

In some embodiments of the present application, the mass proportion of the preservative in the dipyridamole cream is 0% to 1%, for example, 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1%.

In some embodiments of the present application, the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), disodium edetate, ascorbic acid, sodium metabisulfite, propyl gallate, sodium ascorbate, isoascorbic acid, sodium pyrosulfite, sodium thiosulfate, propyl gallate, α, tocopherol, proanthocyanidins, glutathione, lipoic acid, astaxanthin, vitamin E, ββ-carotene, coenzyme Q, isoflavones, α-isohydroxy acids, flavonoids, phenylpropanoid phenolic compounds, fumaric acid, cysteine, methionine, thiodipropionic acid, sulfites (such as sodium sulfite), bisulfites (such as sodium bisulfite), dithioaminobenzoic acid compounds, citric acid, malic acid, sorbitol, glycerol, propylene glycol, hydroquinone, hydroxycoumarins, ethanolamine, phosphoric acid and phosphorous acid. One or more.

In some embodiments of the present application, the antioxidant is selected from one or more of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), disodium ethylenediaminetetraacetic acid, α, tocopherol (VE), ascorbic acid (AA), sodium metabisulfite, anhydrous sodium sulfite, propyl gallate, sodium ascorbate, isoascorbic acid, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, and thioglycerol.

In some embodiments of the present application, the antioxidant is one or both of butylated hydroxyanisole (BHA) and anhydrous sodium sulfite.

In some embodiments of the present application, the antioxidant accounts for 0% to 5% by mass in the dipyridamole cream.

In some embodiments of the present application, the mass proportion of the antioxidant in the dipyridamole cream is 0% to 1%, for example, 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1%.

In some embodiments of the present application, the consistency regulator is selected from one or more of a natural thickener, a synthetic thickener or an inorganic thickener.

Examples of natural thickeners include: plant-derived polymers such as gum arabic, carrageenan, galactan, agar, quince seed, guar gum, tragacanth gum, mannan, locust bean gum, wheat starch, rice starch, tara gum, corn starch and potato starch; microbial-derived polymers such as curdlan, xanthan gum, succinoglucan, dextran and pullulan, etc.; and protein polymers such as albumin, casein, collagen, gelatin and fibroin.

Examples of synthetic thickeners include: cellulose polymers such as ethyl cellulose, carboxymethyl cellulose and its salts, carboxymethyl ethyl cellulose and its salts, carboxymethyl starch and its salts, cross-linked carboxymethyl cellulose and its salts, crystalline cellulose, cellulose acetate, cellulose acetate phthalate, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, methyl cellulose and methyl hydroxypropyl cellulose; starch polymers such as pregelatinized starch, partially pregelatinized starch, hydroxymethyl starch, dextrin and methyl starch; alginate polymers such as sodium alginate, potassium alginate, ammonium sulfate and propylene glycol alginate; and other polysaccharide polymers, such as sodium chondroitin sulfate and sodium hyaluronate, cetearyl alcohol, cetyl alcohol, stearyl alcohol, glyceryl monostearate, glyceryl mono- and distearate, carbomer, liquid paraffin, petrolatum, glyceryl behenate, sodium polyacrylate, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, polyvinyl pyrrolidone, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-ethyl methacrylate copolymer, ethyl methacrylate-trimethylammoniumethyl chloromethylacrylate copolymer, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, etc.

Examples of the inorganic thickener include hydrated silica, colloidal alumina, bentonite, laponite, and the like.

In some embodiments of the present application, the consistency regulator is selected from one or more of an alcohol consistency regulator, an ester consistency regulator, kind.

In some embodiments of the present application, the consistency regulator is selected from one or more of cetearyl alcohol, cetyl alcohol, stearyl alcohol, glyceryl monostearate, glyceryl mono- and distearate, carbomer, liquid paraffin, vaseline, and glyceryl behenate.

In some embodiments of the present application, the consistency regulator is cetearyl alcohol, for example, 2% by mass of cetearyl alcohol or 3% by mass of cetearyl alcohol.

In some embodiments of the present application, the consistency regulator is hexadecanol, for example, 5% (wt%) hexadecanol, 8% (wt%) hexadecanol.

In some embodiments of the present application, the consistency regulator is liquid paraffin, for example, 8% (wt%) liquid paraffin.

In some embodiments of the present application, the consistency regulator is glyceryl monostearate, such as 5% (wt%) glyceryl monostearate, 10% glyceryl monostearate.

In some embodiments of the present application, the consistency regulator is glyceryl monostearate and cetearyl alcohol, for example, 5% (wt%) glyceryl monostearate and 8% cetearyl alcohol.

In some embodiments of the present application, the consistency regulator is cetyl alcohol and liquid paraffin, for example, 3% (wt%) cetyl alcohol and 8% (wt%) liquid paraffin.

In some embodiments of the present application, the mass proportion of the consistency regulator in the dipyridamole cream is 0% to 50%.

In some embodiments of the present application, the mass proportion of the consistency regulator in the dipyridamole cream is 0.1% to 30%.

In some embodiments of the present application, the mass proportion of the consistency regulator in the dipyridamole cream is 2% to 20%, for example, 2%, 3%, 5%, 8%, 12%, 13%, 15%, 18%, 20%, 30% of the consistency regulator.

In some embodiments of the present application, the pH adjuster includes an acidic pH adjuster or an alkaline pH adjuster, and the alkaline pH adjuster includes monosodium fumarate, sodium citrate, potassium citrate, monosodium citrate, sodium dihydrogen phosphate, phosphate, calcium sulfate, calcium lactate, sodium acetate, calcium hydroxide, potassium hydroxide, sodium hydroxide, triethanolamine, arginine, sodium hydroxide, potassium hydroxide, etc.; the acidic pH adjuster includes fumaric acid, metatartaric acid, citric acid, lactic acid, malic acid, L(+)-tartaric acid and tartaric acid, glacial acetic acid and acetic acid, adipic acid, phosphoric acid, hydrochloric acid, citric acid, lactic acid, etc.

In some embodiments of the present application, the pH adjuster includes an acidic pH adjuster or an alkaline pH adjuster, selected from one or more of sodium hydroxide, sodium bicarbonate, sodium citrate, triethanolamine, citric acid, hydrochloric acid, and sodium dihydrogen phosphate.

In some embodiments of the present application, the mass proportion of the pH regulator in the dipyridamole cream is 0% to 10%.

In some embodiments of the present application, the mass proportion of the pH regulator in the dipyridamole cream is 0% to 5%, for example, 0%, 1%, 2%, 3%, 4%, or 5%.

In some embodiments of the present application, the pH regulator is added in an amount such that the pH of the dipyridamole cream is between 5-8, preferably between 5-7, more preferably between 6-7, for example, 6-6.5.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, water, and one or more of an emulsifier, a lubricant, a moisturizer, and a preservative.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, an emulsifier, water, and one or more of a lubricant, a moisturizer, and a preservative.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, an emulsifier, a lubricant, water, and one or two of a moisturizer and a preservative.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, an emulsifier, a lubricant, a moisturizer, a preservative, and water.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, water, and one or more of an emulsifier, a lubricant, a moisturizer, and a preservative.

In some specific embodiments of the present application, a dipyridamole cream is provided, wherein, by mass percentage, the dipyridamole cream It contains 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, an emulsifier, water, and one or more of a lubricant, a moisturizer, and a preservative.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, an emulsifier, a lubricant, water, and one or two of a moisturizer and a preservative.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, an emulsifier, a lubricant, a moisturizer, a preservative, and water.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and 0.3% to 40% of emulsifier, 0.5% to 40% of lubricant, 0.5% to 50% of moisturizer, 0% to 10% of preservative, 0.1% to 50% of consistency regulator, and one or more of water.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, 0.3% to 40% of emulsifier, 0.5% to 40% of lubricant, 0.5% to 50% of moisturizer, 0% to 10% of preservative, 0.1% to 50% of consistency regulator, and the balance of water.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, 0.3% to 40% of polyethylene glycol-stearate, 0.5% to 40% of lubricant, 0.5% to 50% of moisturizer, 0% to 10% of preservative, and the balance of water.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.3% to 40% of polyethylene glycol-stearate, 0.5% to 40% of lubricant, 0.5% to 50% of moisturizer, 0% to 10% of preservative, 0.1% to 50% of consistency regulator, and the balance of water.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of an emulsifier, 1% to 30% of a lubricant, 1% to 30% of a moisturizer, 0% to 1% of a preservative, 1% to 30% of a consistency regulator, and one or more of water.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier, 1% to 30% of lubricant, 1% to 30% of moisturizer, 0% to 1% of preservative, 1% to 30% of consistency regulator, and the balance water.

In some specific embodiments of the present application, a dipyridamole cream is provided. The dipyridamole cream contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of polyethylene glycol-stearate, 1% to 30% of lubricant, 1% to 30% of moisturizer, 0% to 1% of preservative, and the balance of water.

In some specific embodiments of the present application, a dipyridamole cream is provided. The dipyridamole cream contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of polyethylene glycol-stearate, 1% to 30% of lubricant, 1% to 30% of moisturizer, 0% to 1% of preservative, 1% to 30% of consistency regulator, and the balance of water.

In the above cream, the lubricant is isopropyl myristate and/or isopropyl palmitate.

In the above cream, the moisturizer is glycerol and/or 1,3-butylene glycol.

In the above cream, the preservative is sodium ethylparaben.

In the above cream, if a consistency regulator is contained, the consistency regulator is cetearyl alcohol, and/or cetyl alcohol, and/or liquid paraffin, and more preferably cetearyl alcohol.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and 0.3% to 40% of polyethylene glycol-7-stearate, 0.5% to 40% of isopropyl myristate and/or isopropyl palmitate, 0.5% to 50% of glycerol and/or 1,3-butylene glycol, water, and 0% to 10% of one or more of sodium ethylparaben.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, 0.3% to 40% of polyethylene glycol-7-stearate, 0.5% to 40% of isopropyl myristate and/or isopropyl palmitate, 0.5% to 50% of glycerol and/or 1,3-butylene glycol, 0% to 10% of sodium ethylparaben, and the remainder is water.

In some specific embodiments of the present application, a dipyridamole cream is provided, wherein, by mass percentage, the dipyridamole cream It contains 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, 0.3% to 40% of polyethylene glycol-7-stearate, 1% to 30% of isopropyl myristate, 1% to 30% of isopropyl palmitate, 1% to 30% of glycerol, 1% to 30% of 1,3-butylene glycol, 0% to 10% of sodium ethylparaben, and the balance is water.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, 0.3% to 40% of polyethylene glycol-7-stearate, 0.5% to 40% of isopropyl myristate and/or isopropyl palmitate, 0.5% to 50% of glycerol and/or 1,3-butylene glycol, 0.1% to 50% of cetearyl alcohol, 0% to 10% of sodium ethylparaben, and the balance is water.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, 0.3% to 40% of polyethylene glycol-7-stearate, 1% to 30% of isopropyl myristate, 1% to 30% of isopropyl palmitate, 1% to 30% of glycerol, 1% to 30% of 1,3-butylene glycol, 0.1% to 50% of cetearyl alcohol, 0% to 10% of sodium ethylparaben, and the balance is water.

In some specific embodiments of the present application, a dipyridamole cream is provided. The dipyridamole cream contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of polyethylene glycol-7-stearate, 1% to 30% of isopropyl myristate and/or isopropyl palmitate, 1% to 30% of glycerol and/or 1,3-butylene glycol, 0% to 1% of sodium ethylparaben, and the balance is water.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of polyethylene glycol-7-stearate, 5% to 20% of isopropyl myristate, 5% to 20% of isopropyl palmitate, 5% to 20% of glycerol, 5% to 20% of 1,3-butylene glycol, 0% to 1% of sodium ethylparaben, and the balance is water.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of polyethylene glycol-7-stearate, 1% to 30% of isopropyl myristate and/or isopropyl palmitate, 1% to 30% of glycerol and/or 1,3-butylene glycol, 1% to 30% of cetearyl alcohol, 1,3-butylene glycol, 0% to 10% of sodium ethylparaben, and the balance is water.

In some specific embodiments of the present application, a dipyridamole cream is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of polyethylene glycol-7-stearate, 5% to 20% of isopropyl myristate, 5% to 20% of isopropyl palmitate, 5% to 20% of glycerol, 5% to 20% of 1,3-butylene glycol, 1% to 30% of cetearyl alcohol, 0% to 1% of sodium ethylparaben, and the balance is water.

In some embodiments of the present application, the pigment is selected from pigments of different colors depending on the required color, including synthetic pigments, natural pigments, including red pigments, purple pigments, such as carmine, erythrosine, allura red, red iron oxide, titanium dioxide, zinc oxide, talc, kaolin, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, amaranth, new red, lemon yellow, sunset yellow, indigo, brilliant blue, carotene, chlorophyll, turmeric, impatiens glycoside, rose glycoside, capsanthin, etc. One or more.

In some embodiments of the present application, when the desired cream is skin color, the pigments are carmine and titanium dioxide, preferably 0% to 5% carmine and 0% to 5% titanium dioxide in mass percentage, for example 0.01% carmine and 3% titanium dioxide.

In the present application, the dipyridamole cream using the pigment has a significant color difference compared to the dipyridamole cream that does not contain a pigment component. The color is obviously closer to human skin color, and the visual sensory effect is better than the dipyridamole cream that does not contain a pigment component. It is particularly suitable for use on parts of the human body that need to be exposed, such as the face, neck, arms, and calves, and is more easily accepted by patients.

In some embodiments of the present application, when the desired cream is purple, the pigment is manganese violet, cobalt violet, ultramarine violet, sweet potato root extract, methyl violet, benzyl violet, or the like.

In some embodiments of the present application, when the desired cream is white, the pigment is titanium white, zinc oxide, lithopone (lidocone), antimony white, and the like.

In some embodiments of the present application, when the desired cream is green, the pigment is zinc green, iron green, chromium oxide, chromium hydroxide, cobalt titanate, chlorophyll, phthalocyanine green, and the like.

In some embodiments of the present application, when the desired cream is yellow, the pigment is lead chrome yellow, zinc chrome yellow, cadmium yellow, antimony yellow, iron yellow, fast yellow, benzidine yellow, hansa yellow, β-carotene, etc.

In some embodiments of the present application, when the desired cream is black, the pigment is carbon black, pine smoke, graphite, aniline black, etc.

In some embodiments of the present application, when the desired cream is blue, the pigment is ultramarine, iron blue, phthalocyanine blue, peacock blue, Indanthrene blue, etc.

In some embodiments of the present application, when the desired cream is red, the pigment is iron titanate, iron red, cadmium red, molybdenum red, toluidine red, lithotripsy red, para red, scarlet, or the like.

In some embodiments of the present application, when the desired cream is metallic in color, the pigment is aluminum powder, copper powder, or the like.

The above colors can also be prepared by those skilled in the art using more than one pigment according to the color mixing principle, for example, blue and yellow can be prepared into green.

In some embodiments of the present application, the pigment accounts for 0% to 10% by mass in the dipyridamole cream.

In some embodiments of the present application, the pigment accounts for 0% to 5% by mass in the dipyridamole cream.

The fourth aspect of the present application provides a dipyridamole gel, which comprises, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, and 0.1% to 60% diethylene glycol monoethyl ether.

In some embodiments of the present application, the dipyridamole gel comprises 0.01% to 10% or 0.01% to 12% by mass of dipyridamole or its derivatives, for example, 0.1% to 12%, 0.1% to 10%, 0.5% to 12%, 0.2%, 0.3%, 0.5%, 1%, 3%, 5%, 8%, 10%.

In some embodiments of the present application, the dipyridamole gel comprises a gelling agent in an amount of 0.2%-10% by mass.

In some embodiments of the present application, the dipyridamole gel comprises a gelling agent with a mass percentage of 0.5%-5%, for example, 1%, 1.5%, 1.6%, 2%, 2.5%, 3%, 3.5%, etc.

In some embodiments of the present application, the dipyridamole gel comprises 0.3%-50% by mass of ethylene glycol monoethyl ether.

In some embodiments of the present application, the dipyridamole gel comprises ethylene glycol monoethyl ether in a mass percentage of 2%-30%, for example, 2%, 5%, 10%, 15%, 30%.

In some embodiments of the present application, a dipyridamole gel, the remaining component of which is water, preferably 10% to 98% by mass of water.

In some embodiments of the present application, a dipyridamole gel comprises 20%-95% water by mass.

In some embodiments of the present application, a dipyridamole gel comprises 30%-90% water by mass, for example, about 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 85%, or 90% water.

In some embodiments of the present application, the gelling agent comprises one or more of carbomer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, and sodium carboxymethyl cellulose.

In some embodiments of the present application, the gel is carbomer.

In some embodiments of the present application, the dipyridamole gel comprises 0.1% to 20% by mass of carbomer, preferably 0.2% to 10% by mass of carbomer, and more preferably 0.5% to 5% by mass of carbomer.

Further preferably, the carbomer includes carbomer 980NF, carbomer 974NF, carbomer 940 and the like.

In some embodiments of the present application, the dipyridamole gel further comprises one or more of a surfactant, a pH adjuster, a moisturizer, an antioxidant, and a preservative.

In some embodiments of the present application, the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of a moisturizer, a surfactant, and a preservative.

In some embodiments of the present application, the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of 0.1% to 50% moisturizer, 0.1% to 50% surfactant, and 0% to 5% preservative.

In some embodiments of the present application, the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of an antioxidant and a surfactant.

In some embodiments of the present application, the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of a moisturizer, a pH regulator, and a preservative.

In some embodiments of the present application, the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of 0.1% to 50% moisturizer, 0% to 10% pH adjuster, and 0% to 5% preservative.

In some embodiments of the present application, the gel comprises, by mass percentage, one or more of 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gel, 0.1% to 60% diethylene glycol monoethyl ether, and 0% to 5% antioxidant and 0.1% to 50% surfactant.

In some embodiments of the present application, the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of a surfactant, a pH regulator, a moisturizer, an antioxidant, and a preservative.

In some embodiments of the present application, the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of 0.1% to 50% surfactant, 0% to 10% pH regulator, 0.1% to 50% moisturizer, 0% to 5% antioxidant, and 0% to 5% preservative.

In some embodiments of the present application, the moisturizer is selected from one or more of vaseline, glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol.

In some embodiments of the present application, the humectant is 1,3-butanediol.

In some embodiments of the present application, the mass proportion of the moisturizer in the dipyridamole gel is 0.1% to 50%.

In some embodiments of the present application, the mass proportion of the moisturizer in the dipyridamole gel is 1% to 30%, for example, 2%, 5%, 10%, 15%, 20%, etc.

In some embodiments of the present application, the mass proportion of the preservative in the dipyridamole ointment is 0% to 5%.

In some embodiments of the present application, the mass proportion of the preservative in the dipyridamole ointment is 0% to 2%.

In some embodiments of the present application, the mass proportion of the preservative in the dipyridamole gel is 0% to 1%, for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1%.

In some embodiments of the present application, the surfactant is selected from one or more of sodium lauryl sulfate, Spans, Tweens, poloxamers, triethanolamine, caprylic/capric acid macrogol glycerides, 15-hydroxystearate macrogol esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyethylene glycol cetearyl alcohol ether.

In some embodiments of the present application, the surfactant is triethanolamine.

In some embodiments of the present application, the mass proportion of the surfactant in the dipyridamole gel is 0.1% to 50%.

In some embodiments of the present application, the mass proportion of the surfactant in the dipyridamole gel is 0.5% to 30%, for example, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%.

In some embodiments of the present application, the pH adjuster may be one or more of sodium hydroxide, sodium bicarbonate, sodium citrate, triethanolamine, citric acid, hydrochloric acid, and sodium dihydrogen phosphate.

In some embodiments of the present application, the pH adjuster is triethanolamine.

In some embodiments of the present application, the mass proportion of the pH regulator in the dipyridamole gel is 0% to 10%.

In some embodiments of the present application, the mass proportion of the pH regulator in the dipyridamole gel is 0% to 5%, for example, 0.5%, 1%, 2%, 3%, 4%, or 5%.

In some embodiments of the present application, the pH adjuster is added according to the pH value required by the gel.

In some embodiments of the present application, the pH regulator is added in an amount such that the pH of the dipyridamole gel is between 5-8, preferably between 5-7, more preferably between 6-7, for example, 6-6.5.

In some embodiments of the present application, the antioxidant is selected from one or more of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), disodium ethylenediaminetetraacetate, α-tocopherol (VE), ascorbic acid (AA), sodium metabisulfite, propyl gallate, sodium ascorbate, and isoascorbic acid.

In some embodiments of the present application, the antioxidant is butylated hydroxyanisole (BHA) or ascorbic acid (AA).

In some embodiments of the present application, the antioxidant accounts for 0% to 5% by mass in the dipyridamole ointment.

In some embodiments of the present application, the mass proportion of the antioxidant in the dipyridamole ointment is 0% to 1%, for example, 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%.

In some embodiments of the present application, a dipyridamole gel comprises, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of a moisturizer, a preservative, a pH adjuster, a surfactant, and water.

In some embodiments of the present application, a dipyridamole gel comprises, by mass percentage, 0.01% to 10% dipyridamole or its derivatives, 0.5% to 5% gelling agent, 0.3% to 50% diethylene glycol monoethyl ether, and one or more of a moisturizer, a preservative, a pH adjuster, a surfactant, and water.

A dipyridamole gel comprises, by mass percentage, one or more of 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, 0.1% to 50% moisturizing agent, 0% to 5% preservative, 0% to 10% pH adjusting agent, 0.1% to 50% surfactant, 0% to 5% antioxidant, and 10% to 98% water.

A dipyridamole gel comprises, by mass percentage, one or more of 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, 0.1% to 50% moisturizing agent, 0% to 5% preservative, 0% to 10% pH regulator, 0.1% to 50% surfactant, and 10% to 98% water.

A dipyridamole gel comprises, by mass percentage, one or more of 0.01% to 10% dipyridamole or its derivatives, 0.5% to 5% gelling agent, 0.3% to 50% diethylene glycol monoethyl ether, 1% to 30% moisturizing agent, 0% to 1% preservative, 0% to 5% pH adjusting agent, 0.5% to 30% surfactant, and 30% to 90% water.

Preferably, the gel is carbomer, such as carbomer 980NF, carbomer 974NF, carbomer 940, etc.

Preferably, the humectant is 1,3-butylene glycol.

Preferably, the preservative is sodium ethylparaben.

Preferably, the pH regulator or surfactant is triethanolamine.

A dipyridamole gel comprises, by mass percentage, 0.01% to 20% of dipyridamole or its derivatives, 0.1% to 20% of carbomer, 0.1% to 60% of diethylene glycol monoethyl ether, and one or more of 1,3-butylene glycol, sodium ethylparaben, triethanolamine, and water.

A dipyridamole gel comprises, by mass percentage, 0.01% to 20% of dipyridamole or its derivatives, 0.1% to 20% of carbomer, 0.1% to 60% of diethylene glycol monoethyl ether, 1,3-butylene glycol, sodium ethyl hydroxybenzoate, triethanolamine and water.

A dipyridamole gel comprises, by mass percentage, 0.01% to 10% of dipyridamole or its derivatives, 0.5% to 5% of carbomer, 0.3% to 50% of diethylene glycol monoethyl ether, and one or more of 1,3-butylene glycol, sodium ethylparaben, triethanolamine, and water.

A dipyridamole gel comprises, by mass percentage, 0.01% to 10% of dipyridamole or its derivatives, 0.5% to 5% of carbomer, 0.3% to 50% of diethylene glycol monoethyl ether, 1,3-butylene glycol, sodium ethyl hydroxybenzoate, triethanolamine and water.

A dipyridamole gel comprises, by mass percentage, one or more of 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% carbomer, 0.1% to 60% diethylene glycol monoethyl ether, 0.1% to 50% 1,3-butylene glycol, 0% to 5% sodium ethylparaben, 0% to 50% triethanolamine, and 10% to 98% water.

A dipyridamole gel comprises, by mass percentage, 0.01% to 20% of dipyridamole or its derivatives, 0.1% to 20% of carbomer, 0.1% to 60% of diethylene glycol monoethyl ether, 0.1% to 50% of 1,3-butylene glycol, 0% to 5% of sodium ethyl hydroxybenzoate, and 0% to 50% of triethanolamine.

A dipyridamole gel comprises, by mass percentage, 0.01% to 20% of dipyridamole or its derivatives, 0.1% to 20% of carbomer, 0.1% to 60% of diethylene glycol monoethyl ether, 0.1% to 50% of 1,3-butylene glycol, 0% to 5% of sodium ethylparaben, 0% to 50% of triethanolamine, and 10% to 98% of water.

A dipyridamole gel comprises, by mass percentage, one or more of 0.01% to 10% dipyridamole or its derivatives, 0.5% to 5% carbomer, 0.3% to 50% diethylene glycol monoethyl ether, 1% to 30% 1,3-butylene glycol, 0% to 1% sodium ethylparaben, 0.5% to 30% triethanolamine, and 30% to 90%.

A dipyridamole gel comprises, by mass percentage, 0.01% to 10% of dipyridamole or its derivatives, 0.5% to 5% of carbomer, 0.3% to 50% of diethylene glycol monoethyl ether, 1% to 30% of 1,3-butylene glycol, 0% to 1% of sodium ethylparaben, and 0.5% to 30% of triethanolamine.

A dipyridamole gel comprises, by mass percentage, 0.01% to 10% of dipyridamole or its derivatives, 0.5% to 5% of carbomer, 0.3% to 50% of diethylene glycol monoethyl ether, 1% to 30% of 1,3-butylene glycol, 0% to 1% of sodium ethylparaben, 0.5% to 30% of triethanolamine, and 30% to 90% of water.

The fifth aspect of the present application provides a dipyridamole ointment.

The ointment described in the present application is based on the cream provided in the second aspect, and the final product does not contain water.

In some embodiments of the present application, the ointment described in the present application is based on the cream provided in the second aspect, and the final product does not contain Contains water, and the mass percentage of the consistency regulator is 0.1%-98%.

In some embodiments of the present application, the ointment described in the present application is based on the cream provided in the second aspect, the final product does not contain water, and the mass percentage of the consistency regulator is 0.5%-95%.

In some embodiments of the present application, the ointment described in the present application is based on the cream provided in the second aspect, the final product does not contain water, and the mass percentage of the consistency regulator is 1%-90%, for example 50%, 60%, 70%, 80%, 90%.

For example, in some embodiments, a dipyridamole ointment is provided, which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and 0.3% to 40% of emulsifier, 0.5% to 40% of lubricant, 0.5% to 50% of moisturizer, 0% to 10% of preservative, 0.1% to 50% of consistency regulator, 0% to 10% of pH regulator, 0% to 5% of antioxidant, and 0% to 10% of pigment. One or more.

For example, in some embodiments, a dipyridamole ointment is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier, 1% to 30% of lubricant, 1% to 30% of moisturizer, 0% to 1% of preservative, 1% to 90% of consistency regulator, 0% to 5% of pH regulator, 0% to 1% of antioxidant, and 0% to 5% of pigment. One or more.

For example, in some embodiments, a dipyridamole ointment is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of an emulsifier.

For example, in some embodiments, a dipyridamole ointment is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of an emulsifier, 1% to 30% of a lubricant, 1% to 30% of a moisturizer, and 1% to 90% of one or more of a consistency regulator.

For example, in some embodiments, a dipyridamole ointment is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of emulsifier, and 1% to 90% of consistency regulator.

For example, in some embodiments, a dipyridamole ointment is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 1% to 90% of a consistency regulator.

For example, in some embodiments, a dipyridamole ointment is provided, which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier, 1% to 30% of lubricant, 1% to 30% of moisturizer, and 1% to 90% of consistency regulator.

In some embodiments of the present application, the ointment described in the present application contains 0.01% to 60%, preferably 0.1% to 10%, 0.2% to 5% or 0.2% to 2.5% of dipyridamole and/or its derivatives by mass.

In some embodiments of the present application, the ointment described in the present application also includes one or more selected from the following: solvent, ointment base, thickener, humectant, preservative. In some embodiments of the present application, the ointment described in the present application includes dipyridamole and/or its derivatives, solvent, ointment base, humectant, preservative. In some embodiments of the present application, the ointment described in the present application includes dipyridamole and/or its derivatives, solvent, ointment base, humectant, preservative. In some embodiments of the present application, the ointment described in the present application includes dipyridamole and/or its derivatives, solvent, ointment base, thickener, preservative. In some embodiments of the present application, the ointment described in the present application includes dipyridamole and/or its derivatives, solvent, ointment base, thickener, preservative.

In some embodiments of the present application, the ointment described in the present application comprises 0.5% to 60, preferably 1% to 50%, 5% to 50%, 2% to 40% or 8% to 40% (such as 8%, 10%, 20%, 30%, 35%, 40%) of a solvent by mass percentage. In some embodiments of the present application, the solvent is selected from diols, such as one or two of hexylene glycol and 1,3-butanediol, such as hexylene glycol and 1,3-butanediol.

In some embodiments of the present application, the solvent is selected from diethylene glycol monoethyl ether, glycols, such as one or more of diethylene glycol monoethyl ether, hexanediol and 1,3-butanediol.

In some preferred embodiments, in the solvent, the mass ratio of hexanediol to 1,3-butanediol is 1:5-5:1, preferably 1:2-2:1, more preferably 3:5-5:3, for example 1:2; 3:5; 1:1; 5:3; 2:1, etc.

In some embodiments of the present application, the ointment described in the present application comprises 40% to 99%, preferably 50% to 95%, 50% to 99%, 55% to 92% or 60% to 98% (e.g., 57%, 60%, 65%, 70%, 75%, 80%, 90%) of an ointment base by mass percentage. In some embodiments of the present application, the ointment base is selected from liquid paraffin, vaseline, polyethylene glycol (e.g., selected from any one or more of PEG50 to PEG8000, PEG100 to PEG6000, PEG200 to PEG5000, PEG300 to PEG4000, PEG400, PEG500, PEG1000, PEG2000, and PEG3000). In some preferred embodiments, the ointment base is A mixture of PEG400 and PEG4000. In some preferred embodiments, the ointment base is a mixture of liquid paraffin and vaseline. In some preferred embodiments, the ointment base is a mixture of liquid paraffin, PEG400 and PEG4000. In some preferred embodiments, the ointment base is a mixture of vaseline, PEG400 and PEG4000. In some preferred embodiments, the ointment base is a mixture of liquid paraffin, vaseline, PEG400 and PEG4000. In some preferred embodiments, the ointment base is a mixture of liquid paraffin, vaseline, PEG400 and PEG4000. In some preferred embodiments, in the ointment base, the mass ratio of PEG400 and PEG4000 is 3.5:1 to 1:1, preferably 3:1 to 1.25:1, more preferably 2.5:1 to 1.5:1, for example 2:1; 2.1:1; 2.2:1; 2.3:1; 2.4:1; 2.5:1, etc.

In some embodiments of the present application, the ointment described in the present application contains 0.01% to 1%, preferably 0.02% to 0.5%, 0.05% to 0.5% or 0.05% to 0.3% (for example, 0.08%, 0.09%, 0.1%, 0.12%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%) of a preservative by mass.

In some embodiments of the present application, the ointment described in the present application contains 0% to 30%, preferably 0% to 10%, 0% to 5% of a thickener by mass percentage.

In some embodiments of the present application, the thickener is polyethylene glycol stearate, such as polyethylene glycol-7-stearate, polyethylene glycol-5-stearate, PEG-25 stearate, PEG-23 stearate, PEG-30 stearate, PEG-18 stearate, PEG-20 stearate, PEG-10 stearate, etc.

In some embodiments of the present application, the ointment described in the present application contains 0% to 50%, preferably 0% to 40% (e.g., 5%, 10%, 20%, 25%, 32%, 35) of moisturizer by mass.

In some embodiments of the present application, the polyol is, for example, one or more of glycerol, propylene glycol, and 1,3-butylene glycol.

In some embodiments of the present application, the ointment described in the present application includes 0.01% to 60% dipyridamole and/or its derivatives, 0.5% to 60% solvent, 40% to 99% ointment base, 0.01% to 1% preservative, 0% to 30% thickener, and 0% to 50% moisturizer.

In some embodiments of the present application, the ointment described in the present application includes 0.01% to 60% dipyridamole and/or its derivatives, 0.5% to 60% glycols, 40% to 99% liquid paraffin, vaseline, one or more of polyethylene glycol, 0.01% to 1% sodium ethylparaben, 0% to 30% polyethylene glycol stearate, and 0% to 50% polyol.

In some embodiments of the present application, the ointment described in the present application includes 0.01% to 60% dipyridamole and/or its derivatives, 0.5% to 60% of diethylene glycol monoethyl ether, one or more of hexylene glycol and 1,3-butylene glycol, 40% to 99% of liquid paraffin, vaseline, one or more of polyethylene glycol, 0.01% to 1% sodium ethylparaben, 0% to 30% polyethylene glycol stearate, and 0% to 50% polyol.

In some embodiments of the present application, the ointment described in the present application includes 0.01% to 60% dipyridamole and/or its derivatives, 0.5% to 60% of diethylene glycol monoethyl ether, one or more of hexylene glycol and 1,3-butylene glycol, 40% to 99% of liquid paraffin, vaseline, one or more of polyethylene glycol, and 0.01% to 1% sodium ethylparaben.

In some embodiments of the present application, the ointment described in the present application includes 0.01% to 60% dipyridamole and/or its derivatives, 0.5% to 60% of one or two of hexylene glycol and 1,3-butylene glycol, 40% to 99% of liquid paraffin, vaseline, one or more of polyethylene glycol, and 0.01% to 1% sodium ethylparaben.

In some embodiments of the present application, the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of diethylene glycol monoethyl ether, one or more of hexylene glycol and 1,3-butylene glycol, 50% to 95% of liquid paraffin, vaseline, one or more of polyethylene glycol, 0.02% to 0.5% sodium ethylparaben, 0% to 10% polyethylene glycol stearate, and 0% to 40% polyol.

In some embodiments of the present application, the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of one or two of hexylene glycol and 1,3-butylene glycol, 50% to 95% of one or two of PEG400 and PEG4000, 0.02% to 0.5% sodium ethylparaben, 0% to 10% polyethylene glycol stearate, and 0% to 40% propylene glycol.

In some embodiments of the present application, the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of a mixture of hexylene glycol and 1,3-butylene glycol, 50% to 95% of a mixture of PEG400 and PEG4000, 0.02% to 0.5% sodium ethylparaben, 0% to 10% polyethylene glycol-7-stearate, and 0% to 40% propylene glycol.

In some embodiments of the present application, the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of a mixture of hexylene glycol and 1,3-butylene glycol, wherein 50% to 95% of a mixture of PEG400 and PEG4000, 0.02% to 0.5% sodium ethylparaben, 0% to 10% polyethylene glycol-7-stearate, 0% to 40% propylene glycol; wherein the mass ratio of hexylene glycol to 1,3-butanediol is 1:5-5:1, and the mass ratio of PEG400 to PEG4000 is 3.5:1 to 1:1.

In some embodiments of the present application, the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of a mixture of hexylene glycol and 1,3-butylene glycol, wherein, 50% to 95% of a mixture of PEG400 and PEG4000, 0.02% to 0.5% sodium ethylparaben, 0% to 10% polyethylene glycol-7-stearate, and 0% to 40% propylene glycol; wherein, the mass ratio of hexylene glycol and 1,3-butylene glycol is 3:5-5:3, and the mass ratio of PEG400 and PEG4000 is 2.5:1 to 1.5:1.

In some embodiments of the present application, the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of one or more of diethylene glycol monoethyl ether, hexylene glycol and 1,3-butylene glycol, 50% to 95% of liquid paraffin, vaseline, one or more of polyethylene glycol, and 0.02% to 0.5% sodium ethylparaben.

In some embodiments of the present application, the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of one or two of hexylene glycol and 1,3-butylene glycol, 50% to 95% of one or two of PEG400 and PEG4000, and 0.02% to 0.5% sodium ethylparaben.

In some embodiments of the present application, the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of a mixture of hexylene glycol and 1,3-butanediol, 50% to 95% of a mixture of PEG400 and PEG4000, and 0.02% to 0.5% sodium ethylparaben.

In some embodiments of the present application, the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of a mixture of hexylene glycol and 1,3-butanediol, 50% to 95% of a mixture of PEG400 and PEG4000, and 0.02% to 0.5% sodium ethylparaben; wherein the mass ratio of hexylene glycol and 1,3-butanediol is 1:5-5:1, and the mass ratio of PEG400 and PEG4000 is 3.5:1 to 1:1.

In some embodiments of the present application, the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of a mixture of hexylene glycol and 1,3-butanediol, 50% to 95% of a mixture of PEG400 and PEG4000, and 0.02% to 0.5% sodium ethyl hydroxybenzoate; wherein the mass ratio of hexylene glycol and 1,3-butanediol is 3:5-5:3, and the mass ratio of PEG400 and PEG4000 is 2.5:1 to 1.5:1.

In the pharmaceutical composition, cream and gel, ointment provided above, the dipyridamole derivative includes a pharmaceutically acceptable salt, ester, hydrate, solvate, polymorph, isomer or prodrug of dipyridamole. In some embodiments of the present application, the pharmaceutically acceptable salt of dipyridamole includes a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, a salt formed with a basic or acidic amino acid, and the like. Preferred examples of metal salts include: alkali metal salts, such as sodium salts, potassium salts, and the like; alkaline earth metal salts, such as calcium salts, magnesium salts, barium salts, and the like; and aluminum salts. Preferred examples of salts formed with organic bases include salts formed with the following organic bases: trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like. Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and the like. Preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.

Among these, pharmaceutically acceptable salts are preferred. For example, when the active ingredient contains an acidic functional group, examples thereof include inorganic salts, for example, alkali metal salts (for example, sodium salts, potassium salts, etc.), alkaline earth metal salts (for example, calcium salts, magnesium salts, etc.), ammonium salts, etc., and when the compound contains a basic functional group, examples thereof include salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., and salts formed with organic acids, for example, acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

In some embodiments of the present application, the dipyridamole salt is dipyridamole sodium chloride or dipyridamole hydrochloride.

In some embodiments of the present application, the isomers include structural isomers, stereoisomers, optical isomers, regioisomers, and geometric isomers.

The sixth aspect of the present application provides a method for preparing the dipyridamole cream described in the third aspect of the present application, comprising the following steps: mixing the oil phase components in the cream matrix and heating them to 70-80°C to melt, adding dipyridamole and/or its derivatives to obtain an oil phase mixture; mixing the water phase components in the cream matrix and heating them to 70-80°C to obtain an water phase mixture; under stirring conditions, adding the water phase mixture to the oil phase mixture, homogenizing and continuously stirring, and obtaining the dipyridamole ointment after cooling.

In some embodiments of the present application, the dipyridamole ointment is a cream.

In some embodiments of the present application, the oil phase component in the cream base includes cetearyl alcohol, isopropyl myristate, isopropyl palmitate, diethylene glycol monoethyl ether and polyethylene glycol-7-stearate.

In some embodiments of the present application, the aqueous phase component in the cream base includes glycerin, 1,3-butylene glycol, sodium ethylparaben and water.

In some specific embodiments of the present application, the oil phase components in the cream base are mixed and heated to 80° C. to melt.

In some specific embodiments of the present application, the aqueous phase components in the cream base are mixed and heated to 80°C.

In some specific embodiments of the present application, the homogenizing rotation speed is 1000-10000 rpm.

In some specific embodiments of the present application, the homogenization time is 1-20 min.

In some specific embodiments of the present application, the homogenization is performed at 5000 rpm for 3 min.

The seventh aspect of the present application provides another preparation method of the dipyridamole cream described in the third aspect of the present application, comprising the following steps: dissolving or dispersing dipyridamole and/or its derivatives in diethylene glycol monoethyl ether, heating to 50°C to obtain a premixed solution; mixing the other oil phase components in the cream matrix except diethylene glycol monoethyl ether and heating to 70-80°C to melt to obtain an oil phase mixed solution; mixing the water phase components in the cream matrix and heating to 70-80°C to obtain an water phase mixed solution; under stirring, adding the water phase mixed solution to the oil phase mixed solution, cooling to 50°C, adding the premixed solution, homogenizing and continuously stirring, and obtaining the dipyridamole cream after cooling.

In some specific embodiments of the present application, the oil phase components in the cream base except diethylene glycol monoethyl ether are mixed and heated to 80° C. to melt.

The eighth aspect of the present application provides a method for preparing the dipyridamole gel described in the fourth aspect of the present application, comprising the following steps: dissolving dipyridamole and/or its derivatives in diethylene glycol monoethyl ether, adding a moisturizer to obtain a premixed solution; mixing the other components in the gel matrix except the pH adjuster, adding the gelling agent, stirring until swelling, and obtaining a gel solution; adding the premixed solution to the gel solution, adjusting the pH, and stirring evenly to obtain the dipyridamole gel.

The ninth aspect of the present application provides a use of the dipyridamole cream described in the third aspect of the present application, the gel described in the fourth aspect, or the dipyridamole ointment described in the fifth aspect in the preparation of medicines for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases.

In the tenth aspect of the present application, a method for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases is provided, the method comprising administering dipyridamole to a patient.

In some embodiments of the present application, the effective content of dipyridamole and/or its derivatives in the drug is 0.01% to 60%, preferably 0.05% to 20%, and more preferably 0.1% to 10%, for example 0.1%, 0.2%, 0.3%, 0.5%, 1%, 2%, 3%, 5%, 8%, 10%.

In some specific embodiments of the present application, the concentration of dipyridamole and/or its derivatives in the drug is 1-100 mg/g, preferably 1-50 mg/g, more preferably 1-20 mg/g, for example 3 gm/g, 5 mg/g.

In some embodiments of the present application, the dipyridamole drug includes a dipyridamole external preparation or an internal preparation.

Wherein, the dipyridamole topical preparation includes dipyridamole cream, gel and ointment.

In some embodiments of the present application, the drug is used once every 1 to 24 hours.

In some embodiments of the present application, the drug is administered in a cosmetically effective amount.

In some embodiments of the present application, the drug is administered in a therapeutically effective amount.

In some embodiments of the present application, the drug further comprises a second active ingredient.

Wherein, the second active ingredient is as described in the first aspect of the present application.

Wherein, the dipyridamole topical preparation includes the cream described in the third aspect of the present application, the gel described in the fourth aspect, or the ointment described in the fifth aspect.

The eleventh aspect of the present application provides the use of diethylene glycol monoethyl ether or a composition thereof with polyethylene glycol stearate in the preparation of a dipyridamole topical preparation.

In some embodiments of the present application, a dipyridamole topical preparation is prepared based on the diethylene glycol monoethyl ether as a raw material.

In some embodiments of the present application, a dipyridamole topical preparation is prepared based on the composition of diethylene glycol monoethyl ether and polyethylene glycol stearate as a raw material.

In some embodiments of the present application, diethylene glycol monoethyl ether is used as a solvent in the dipyridamole topical preparation.

In some embodiments of the present application, the topical preparation includes ointments, creams, gels, lotions, tinctures, suspensions, liniments, spirits, powders, oils, pastes, plasters, coatings, aerosols, solutions, sprays, patches, such as ointments, creams, and gels.

In some embodiments of the present application, the mass percentage of diethylene glycol monoethyl ether in the external preparation is 0.1% to 60%, preferably 0.3% to 50%.

In some embodiments of the present application, the mass percentage of the polyethylene glycol stearate in the external preparation is 0.3% to 40%, preferably 0.5% to 30%.

In some embodiments of the present application, the polyethylene glycol stearate includes polyethylene glycol-7-stearate, polyethylene glycol-5-stearate, PEG-25 stearate, PEG-23 stearate, PEG-30 stearate, PEG-18 stearate, PEG-20 stearate, PEG-10 stearate, etc., for example, polyethylene glycol-7-stearate.

In some embodiments of the present application, the use of diethylene glycol monoethyl ether or a combination of diethylene glycol monoethyl ether and polyethylene glycol stearate in a dipyridamole topical preparation can increase skin permeability by 10%, 20%, 30%, 40%, 50%, 60% or more; the efficacy of diethylene glycol monoethyl ether or its combination with polyethylene glycol stearate can be improved.

In some embodiments of the present application, the use of diethylene glycol monoethyl ether or a composition thereof with polyethylene glycol stearate in a dipyridamole topical preparation is used to prepare a topical preparation for treating allergic and/or inflammatory diseases.

Among them, the allergic and/or inflammatory diseases described in the ninth aspect, the tenth aspect or the eleventh aspect of the present application are as described in the allergic and/or inflammatory diseases described in the first aspect of the present application.

In the twelfth aspect of the present application, there is provided an external preparation comprising dipyridamole and/or its derivatives as an active ingredient for preventing, adjuvant therapy or treating allergic and/or inflammatory diseases.

In some embodiments of the present application, the topical preparation comprises 0.01% to 60%, 0.05% to 20%, 0.1% to 15%, 0.1% to 12%, or 0.1% to 10% of dipyridamole and/or its derivatives.

In some embodiments of the present application, the topical preparation is a cream, a gel or an ointment.

In some embodiments of the present application, the external preparation is a cream, and the composition of the cream is as described above.

In some embodiments of the present application, the external preparation is a gel, and the composition of the gel is as described above.

In some embodiments of the present application, the external preparation is an ointment, and the composition of the ointment is as described above.

In some embodiments of the present application, the topical preparation can be used in combination with a second active ingredient to prevent, assist in the treatment of, or treat allergies. In some embodiments of the present application, the second active ingredient is as described above.

In some embodiments of the present application, the allergic and/or inflammatory disease is as described above.

In the thirteenth aspect of the present application, provided is the use of dipyridamole and/or its derivatives, pharmaceutical compositions or topical preparations containing the same in the preparation of medicaments for reducing the levels of inflammatory cytokines, IgE levels and/or mast cell degranulation in the skin and/or plasma of patients with allergic and/or inflammatory diseases.

In some embodiments of the present application, the inflammatory cytokine can be selected from IL-4, TSLP, IL-1b, IL-6, TNF-α and the like.

In some embodiments of the present application, the pharmaceutical composition or topical preparation contains 0.01% to 60%, 0.05% to 20%, 0.1% to 15%, 0.1% to 12%, or 0.1% to 10% of dipyridamole and/or its derivatives.

In some embodiments of the present application, dipyridamole and/or its derivatives, pharmaceutical compositions or topical preparations containing the same are provided for reducing the levels of inflammatory cytokines, IgE levels and/or mast cell degranulation in the skin and/or plasma of patients with allergic and/or inflammatory diseases.

In some embodiments of the present application, the topical preparation can be used in combination with a second active ingredient for the prevention, adjuvant treatment or treatment of allergic and/or inflammatory diseases. In some embodiments of the present application, the second active ingredient is as described above.

The beneficial effects of this application are:

1. This application discovered for the first time that topical dipyridamole can effectively treat allergic diseases and inflammatory diseases, such as allergic conjunctivitis, allergic rhinitis, allergic urticaria, rosacea, acne, etc., and it has a rapid onset and significant therapeutic effect, which is superior to the positive drugs commonly used on the market and in clinical practice.

2. The dipyridamole topical preparation in this application is highly safe for human body, has no side effects in human and animal experiments, and can be widely used on any skin of human body, especially on highly sensitive skin such as face.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a physical photo of the dipyridamole natural skin color cream and the dipyridamole cream without pigment components in the examples of the present application, wherein the right picture is the dipyridamole natural skin color cream, and the left picture is the dipyridamole cream without pigment components.

FIG2 is a comparison of the cumulative retention results of creams with different solvents.

FIG3 is a comparison of the cumulative retention results of gels in different solvents.

Figures 4 and 5 are representative images of the back skin of mice with allergic and inflammatory skin diseases modeled by calcipotriol in the validation example of this application on the 5th day after application of different formulations of dipyridamole topical preparations.

Figure 6 shows the back skin scoring results of mice with allergic and inflammatory skin diseases modeled by calcipotriol in the verification example of the present application after applying different formulations of dipyridamole topical preparations on the 5th day; wherein, Ns: no statistical difference; *: P<0.05; **: P<0.01; ***: P<0.001; ****: P<0.001.

Figure 7 shows the levels of inflammatory factors IL-4 and TSLP in the back of mice with allergic and inflammatory skin diseases modeled by calcipotriol 14 days after modeling in the validation example of the present application; wherein, Ns: no statistical difference; *: P<0.05; **: P<0.01; ***: P<0.001; ****: P<0.001.

FIG8 is a comparison of the TSLP protein concentrations in the plasma of each group of model mice in the verification example of the present application; wherein, Ns: no statistical difference; *: P<0.05; **: P<0.01; ***: P<0.001; ****, P<0.001.

FIG9 is a comparison of TSLP protein concentrations in the skin tissues of the model mice in each group in the verification example of the present application; wherein, Ns: no statistical difference; *: P<0.05; **: P<0.01; ***: P<0.001; ****: P<0.001.

FIG10 is a comparison of the IgE protein concentrations in the plasma of each group of model mice in the verification example of the present application; wherein, Ns: no statistical difference; *: P<0.05; **: P<0.01; ***: P<0.001; ****: P<0.001.

FIG11 is a comparison of the IgE protein concentrations in the back skin tissues of the model mice in each group in the verification example of the present application; wherein, Ns: no statistical difference; *: P<0.05; **: P<0.01; ***: P<0.001; ****: P<0.001.

FIG. 12 is a representative case diagram of the actual therapeutic effect of dipyridamole cream and gel on human acne in the verification example of this application.

FIG. 13 is a representative case diagram of the actual therapeutic effect of using the dipyridamole cream and gel in the verification example of this application to treat human urticaria half an hour before and after.

FIG. 14 is a representative case diagram of the actual treatment effect of using the dipyridamole cream and gel in the verification example of this application to treat human urticaria before and after 2 months.

FIG. 15 is a representative case diagram of the actual therapeutic effect of using the dipyridamole cream and gel in the verification example of this application to treat ringworm in cats.

FIG. 16 shows the results of the antihistamine allergy to the dipyridamole cream and ointment of the present application as determined by skin prick test.

FIG. 17 shows a comparison of the results before and after application of the dipyridamole cream of the present application to allergy patients.

Detailed ways

Unless otherwise indicated, the following terms and phrases used herein are intended to have the following definitions. A particular term or phrase should not be considered ambiguous or unclear without a special definition, but should be understood according to the ordinary meaning commonly defined in the art.

Unless the context clearly indicates otherwise, singular terms include plural referents and vice versa. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

As used herein, unless otherwise specified, the terms "comprise, comprises and comprising" or their equivalents (contain, contains, containing, include, includes, including) are open-ended expressions, meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

Unless otherwise indicated, all numbers used herein to express the amount of ingredients, measured values or reaction conditions should be understood to be modified by the term "about" in all cases, and the meaning of the term "about" herein should be considered to be within the acceptable error range of the corresponding value. When connected with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, and more preferably ±0.1%.

The exemplary embodiments of the present application may be explained by the contents in the following numbered paragraphs, but the protection scope of the present application is not limited thereto.

1. Use of dipyridamole or its derivatives in the preparation of drugs for preventing, adjuvant therapy or treating allergic and/or inflammatory diseases.

2. The application according to item 1 is characterized in that the allergic diseases include skin diseases caused by allergies, respiratory diseases caused by allergies, digestive tract diseases caused by allergies, and eye diseases caused by allergies.

3. The application according to 1 is characterized in that the allergic diseases include: allergic rhinitis, allergic conjunctivitis, allergic asthma, allergic dermatitis, allergic urticaria, food allergy, dust allergy, mite allergy, hay fever, drug allergy, allergic bronchial asthma, allergic sinusitis, allergic respiratory distress, preferably allergic conjunctivitis, allergic rhinitis, allergic urticaria.

4. The use according to item 1 is characterized in that the inflammatory diseases include infectious diseases, non-infectious diseases, and post-infectious hyperplasia.

5. The use according to 4 is characterized in that the infectious diseases include infectious conjunctivitis, infectious rhinitis, infectious rosacea, infectious urticaria, infectious asthma, and infectious diarrhea.

6. The use according to 4 is characterized in that the infectious diseases include viral infectious diseases, fungal infectious diseases, bacterial infectious diseases, parasitic infectious diseases, and mycoplasma infectious diseases.

7. The use according to 6 is characterized in that the viral infectious diseases include herpes, viral conjunctivitis, viral rhinitis, new coronavirus pneumonia, influenza, viral hepatitis, viral rhinitis, viral pharyngitis, viral enteritis, viral diarrhea, chickenpox, and mumps.

8. The use according to item 7, characterized in that the viral hepatitis includes hepatitis A, hepatitis B, and hepatitis C.

9. The use according to item 7, characterized in that the herpes includes EV71 viral herpes.

10. The use according to item 6, characterized in that the fungal infectious diseases include tinea pedis and ringworm of cat.

11. The use according to item 6, characterized in that the bacterial infectious diseases include bacterial conjunctivitis, bacterial rhinitis, purulent tonsillitis, acne, sty caused by bacterial infection, bacterial gastritis, bacterial pharyngitis, and bacterial mastitis.

12. The use according to 11, characterized in that the gastritis caused by bacteria includes gastritis caused by Helicobacter pylori.

13. The use according to 11, characterized in that the bacterial mastitis includes mastitis caused by Staphylococcus aureus.

14. The use according to item 6, characterized in that the parasitic infectious diseases include ascariasis infection and malaria infection.

15. The use according to item 6, characterized in that the mycoplasma infectious disease includes adnexitis caused by mycoplasma infection.

16. The use according to 4 is characterized in that the non-infectious diseases include non-infectious dermatitis, abdominal pain caused by lactose intolerance, conjunctivitis caused by external stimulation, glaucoma, cataracts, dry eyes, non-specific keratitis, rosacea caused by neurological disorders, urticaria caused by physical stimulation, pharyngitis caused by external stimulation, inflammatory bowel disease, and mastitis caused by external pressure.

17. The use according to 16, characterized in that the non-infectious dermatitis includes traumatic dermatitis, dermatitis caused by surgical wounds, solar dermatitis, frostbite, and insect bite dermatitis.

18. The use according to 16, characterized in that inflammatory bowel disease includes ulcerative colitis, Crohn's disease, and indeterminate colitis.

19. The use according to paragraph 4, characterized in that the post-infectious hyperplasia includes thyroid nodules, hemorrhoids, scar hyperplasia, sty, thyroid nodules, breast nodules, and breast hyperplasia.

20. The use according to 1, characterized in that the inflammatory diseases include dermatitis, asthma, conjunctivitis, rosacea, urticaria, sty, gastritis, rhinitis, pharyngitis, adnexitis, urethritis, vaginitis, mastitis, inflammatory bowel disease, frostbite, acne, blackheads, enlarged pores, red blood streaks, seborrheic dermatitis, seborrheic alopecia, scleroderma, vitiligo, purpura, nevus, melanoma, preferably conjunctivitis, rosacea, rhinitis, acne.

21. The use according to any one of 1-20, characterized in that the drug is an internal preparation or an external preparation, preferably an external preparation.

22. The use according to 21, characterized in that the external preparation comprises ointments, creams, gels, lotions, tinctures, suspensions, liniments, spirits, powders, oils, pastes, plasters, coatings, aerosols, solutions, sprays, and patches.

23. The use according to 21, characterized in that the external preparation is an ointment.

24. The use according to 21, characterized in that the external preparation is a gel.

25. The use according to 21, characterized in that the external preparation is an ointment.

26. The use according to 21, characterized in that the external preparation further comprises one or more of the following substances: solvents, emulsifiers, softeners, antioxidants, preservatives, chelating agents, pH regulators, thickeners, penetration enhancers, and sunscreens.

27. The use according to any one of 1-26, characterized in that the frequency of use of the drug is: 1-3 times every 1 to 24 hours, or 1-3 times a day, preferably 2-3 times a day.

28. The use according to 27, characterized in that the dosage of the drug each time is: 1-250 mg each time, preferably 5-100 mg each time, more preferably 10-50 mg each time, calculated as dipyridamole; or; the drug is administered in a cosmetically effective amount; or the drug is administered in a therapeutically effective amount.

29. The use according to 28 is characterized in that the drug is administered by coating or spraying the drug on the skin surface corresponding to the affected area.

30. The use according to 29, characterized in that the dosage of the drug each time is: 0.1-25 mg per cm ² , preferably 0.2-10 mg/cm ² , and more preferably 0.5-5 mg/cm ² , calculated as dipyridamole.

31. The use according to any one of 1-30, wherein the derivative comprises a pharmaceutically acceptable salt, hydrate, solvate, polymorph, structural isomer or prodrug of dipyridamole.

32. According to the use described in 31, the pharmaceutically acceptable salt of dipyridamole includes dipyridamole sodium chloride or dipyridamole hydrochloride.

33. The use according to any one of 31-32 is characterized in that the mass percentage of dipyridamole and/or its derivatives in the drug is 0.01% to 60%, preferably 0.1% to 10%; or the concentration of dipyridamole or its salt is 0.1 to 100 mg/g, preferably 1 to 50 mg/g, and more preferably 1 to 20 mg/g.

34. The use according to any one of 1-33, characterized in that the drug further comprises a second active ingredient.

35. The use according to 34 is characterized in that the second active ingredient includes at least one of an active ingredient for anti-inflammatory diseases, an active ingredient for anti-allergic diseases, an anti-inflammatory active ingredient, and an anti-allergic active ingredient.

36. The use according to 35 is characterized in that the anti-inflammatory active ingredients include: steroidal anti-inflammatory drugs or non-steroidal anti-inflammatory drugs.

37. The use according to 36, characterized in that the non-steroidal anti-inflammatory drugs include aspirin, benolate, salicylic acid, acetaminophen, indomethacin, diclofenac, sulindac, nemetbutalone, ibuprofen, naproxen, piroxicam, meloxicam, celecoxib, etoricoxib, nimesulide; or, the steroidal anti-inflammatory drugs include adrenal cortical hormones, androgens, estrogens, such as hydrocortisone, prednisone, dexamethasone.

38. The use according to 35 is characterized in that the anti-inflammatory active ingredients include: antifungal drugs and/or their active ingredients, antiviral drugs and/or their active ingredients, antibacterial drugs and/or their active ingredients, antiparasitic drugs and/or their active ingredients, antimycoplasma drugs and/or their active ingredients.

39. The use according to 38, characterized in that the antifungal drugs or active ingredients include amphotericin B, nystatin, griseofulvin, clotrimazole, econazole, miconazole, ketoconazole, bifonazole, terbinafine, ciclopirox olamine, and amorolfine;

The antiviral drugs or active ingredients include acyclovir, acetaminophen, amantadine, chlorpheniramine maleate, ribavirin, amantadine and its salts, and human interferon;

The antibacterial drugs or active ingredients include antibiotics, sulfonamides, imidazoles, nitroimidazoles, quinolones, preferably penicillin, cephalosporin, cephamycin antibiotics, sulfamethoxazole, sulfadiazine, ketoconazole, miconazole, econazole, clotrimazole, Nidazole, dimetridazole, isopronidazole, seconidazole, ornidazole, tinidazole and ronidazole, norfloxacin, pefloxacin, enoxacin, ofloxacin and ciprofloxacin.

40. The use according to 35 is characterized in that the active ingredient for anti-inflammatory diseases includes the active ingredient of a drug for treating any inflammatory disease described in 4-20, preferably an acne treatment drug or active ingredient, a rosacea treatment drug or active ingredient, a rhinitis treatment drug or active ingredient, or a conjunctivitis treatment drug or active ingredient.

41. The use according to 40, characterized in that the acne treatment drugs or active ingredients include sulfur, clindamycin, erythromycin, vitamin A ester, benzoyl peroxide, azelaic acid, retinoic acid, isotretinoin, adapalene, hyaluronic acid or its salt, ergothioneine;

The rhinitis treatment drugs or active ingredients include glucocorticoids, antibacterial drugs, and alpha receptor agonists;

The conjunctivitis treatment drugs or active ingredients include aminoglycoside drugs or active ingredients, fluoroquinolone drugs or active ingredients, amide drugs or active ingredients, tetracycline drugs or active ingredients, macrolide drugs or active ingredients, acyclovir eye drops and ganciclovir eye gel, sulfacetamide sodium or rifampicin eye drops, and corticosteroid eye drops.

42. The use according to 41, characterized in that the glucocorticoids include hydrocortisone acetate, hydrocortisone butyrate, dexamethasone, dexamethasone acetate, triamcinolone acetonide acetate, mometasone furoate, halometasone, beclomethasone dipropionate, fluocinolone acetonide, halcinonide, and betamethasone propionate;

The alpha receptor agonists include ephedrine, ephedrine hydrochloride, oxymetazoline, and xylometazoline.

43. The use according to 41, characterized in that the aminoglycoside drugs or active ingredients include gentamicin, neomycin, and tobramycin;

The fluoroquinolone drugs or active ingredients include gatifloxacin, norfloxacin, and ofloxacin;

The amide alcohol drugs or active ingredients include chloramphenicol;

The macrolide drugs or active ingredients include erythromycin and rifampicin.

44. The use according to 35 is characterized in that the anti-allergic active ingredients include: antihistamines, allergic reaction mediator release inhibitors, histamine desensitization drugs, leukotriene receptor antagonists, antigen-antibody reaction inhibitors, drugs for improving or controlling allergic reaction symptoms, and active ingredients of the above drugs.

45. The use according to 44, characterized in that the antihistamine drugs or active ingredients include diphenhydramine, promethazine, and chlorpheniramine;

The allergic reaction mediator release-inhibiting drugs or active ingredients include sodium cromoglycate and ketotifen;

The histamine desensitization drugs or active ingredients include betahistine, histamine diluent, and dust mite injection;

The leukotriene receptor antagonist drugs or active ingredients include montelukast and zafirlukast;

The drugs or active ingredients that inhibit antigen-antibody reactions include glucocorticoids and immunosuppressants;

The drugs for improving or controlling allergic symptoms include smooth muscle spasmolytics and drugs for alleviating edema caused by allergies.

46. The use according to 45, characterized in that the glucocorticoids include hydrocortisone acetate, hydrocortisone butyrate, dexamethasone, dexamethasone acetate, triamcinolone acetonide acetate, mometasone furoate, halometasone, beclomethasone dipropionate, fluocinolone acetonide, halcinonide, and betamethasone propionate;

The smooth muscle antispasmodics include salbutamol;

The drug for reducing edema caused by allergies includes calcium gluconate.

47. The use according to 34, characterized in that the second active ingredient accounts for 0.01%-20% of the total mass of the drug, preferably 0.1-10%, and more preferably 0.5-5%.

48. The use according to any one of 1-47, characterized in that the drug is applicable to animals, and the animals are selected from humans, cats, cows, sheep, pigs, dogs, chickens, ducks, geese, rabbits, and mice; preferably, the animals are humans, more preferably infants, children, teenagers, adults or the elderly; most preferably, children.

49. The use according to any one of 1-48, characterized in that the drug is applied to skin, nails, or hair.

50. A dipyridamole cream, characterized in that, in terms of mass percentage, the dipyridamole cream contains 0.01%-20% of dipyridamole and/or its derivatives, and 0.1%-60% of diethylene glycol monoethyl ether.

51. The dipyridamole cream according to 50, characterized in that the mass percentage of the dipyridamole and/or its derivatives is 0.01%-10%.

52. The dipyridamole cream according to 50 or 51, characterized in that the mass percentage content of diethylene glycol monoethyl ether is 0.3% to 50%.

53. The dipyridamole cream according to 50 or 51, characterized in that the mass percentage of diethylene glycol monoethyl ether is 2%-30%.

54. The dipyridamole cream according to any one of 50-53, characterized in that the cream base further comprises an emulsifier, preferably 0.3% to 40% of the emulsifier, more preferably 0.5% to 30% of the emulsifier.

55. The dipyridamole cream according to any one of 50-53, characterized in that the cream further comprises one or more of an emulsifier, a lubricant, a moisturizer, a preservative, an antioxidant, a consistency regulator, a pH regulator, a pigment, and water.

56. The dipyridamole cream according to 55 is characterized in that the emulsifier includes one or more of polyethylene glycol stearate, phospholipids, sodium lauryl sulfate, Span surfactants, Tween surfactants, higher fatty alcohols, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, 15-hydroxystearate polyethylene glycol ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, triethanolamine, stearic acid glyceryl, caprylic acid capric acid polyethylene glycol glyceride, propylene glycol monocaprylate, propylene glycol monolaurate, polyglycerol oleate, and polyethylene glycol cetearyl alcohol ether.

57. The dipyridamole cream according to 56, characterized in that the polyethylene glycol stearate includes polyoxyethylene sorbitan monostearate, polyethylene glycol monooctadecanoate, polyethylene glycol monostearate, T-60, polyoxyethylene stearate, polyoxyethylene sorbitan monostearate, PEG-5 stearate, PEG-7 stearate, PEG-25 stearate, PEG-23 stearate, PEG-30 stearate, PEG-18 stearate, PEG-20 stearate, PEG-10 stearate, preferably PEG-7 stearate.

58. The dipyridamole cream according to 55, characterized in that the cream further comprises a lubricant and/or a consistency regulator.

59. The dipyridamole cream according to 58, characterized in that the cream further comprises one or more of a moisturizer, a preservative, an antioxidant, a pH adjuster, a pigment, and water.

60. The dipyridamole cream according to 58, characterized in that the lubricant is selected from one or more of isopropyl palmitate, isopropyl myristate, dimethicone, diisopropyl adipate, caprylic glyceride, caprylic anhydride oil, caprylic capric macrogol glyceride, isohexadecane, hydrogenated castor oil, mineral oil, caprylic/capric triglyceride, lauric acid, and linoleic acid, and is preferably one or both of isopropyl myristate and isopropyl palmitate.

61. The dipyridamole cream according to 58, characterized in that the mass proportion of the lubricant in the dipyridamole cream is 0.5% to 40%, preferably 1% to 30%, and more preferably 5% to 20%.

62. The dipyridamole cream according to 58, characterized in that the consistency regulator is selected from one or more of cetearyl alcohol, cetyl alcohol, stearyl alcohol, glyceryl monostearate, glyceryl mono- and distearate, carbomer, liquid paraffin, vaseline, and glyceryl behenate, preferably one or more of cetearyl alcohol, cetyl alcohol, liquid paraffin, and glyceryl monostearate.

63. The dipyridamole cream according to 58, characterized in that the mass proportion of the consistency regulator in the dipyridamole cream is 0% to 50%, preferably 0.1% to 30%, and more preferably 0.1% to 30%.

64. The dipyridamole cream according to 59, characterized in that the moisturizer is selected from one or more of glycerol, propylene glycol, 1,3-butylene glycol, and polyethylene glycol, preferably one or two of glycerol and 1,3-butylene glycol.

65. The dipyridamole cream according to 59 is characterized in that the mass proportion of the moisturizer in the dipyridamole cream is 0.5% to 50%, preferably 1% to 30%, more preferably 2% to 25%, and more preferably 5%-20%.

66. The dipyridamole cream according to 59, characterized in that the preservative is selected from at least one of a chemical preservative and a natural preservative; preferably, the preservative is selected from one or more of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sodium ethylparaben, benzyl alcohol, phenoxyethanol, sorbic acid, benzoic acid, and sodium benzoate.

67. The dipyridamole cream according to 59, characterized in that the mass proportion of the preservative in the dipyridamole cream is 0% to 10%, preferably 0% to 5%, and more preferably 0% to 1%.

68. The dipyridamole cream according to 59, characterized in that the antioxidant is selected from one or more of butylated hydroxytoluene, butylated hydroxyanisole, disodium edetate, α-tocopherol, ascorbic acid, sodium metabisulfite, anhydrous sodium sulfite, propyl gallate, sodium ascorbate, isoascorbic acid, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, and thioglycerol.

69. The dipyridamole cream according to 59, characterized in that the mass proportion of the antioxidant in the dipyridamole cream is 0% to 5%, preferably 0% to 1%.

70. The dipyridamole cream according to 59, characterized in that the pH adjuster comprises an acidic pH adjuster or an alkaline pH adjuster, preferably, the pH adjuster is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium citrate, triethanolamine, citric acid, hydrochloric acid, and sodium dihydrogen phosphate.

71. The dipyridamole cream according to 59, characterized in that the mass proportion of the pH regulator in the dipyridamole cream is 0% to 10%, preferably 0% to 5%.

72. The dipyridamole cream according to 59, characterized in that the pigment comprises a synthetic pigment or a natural pigment; preferably, the pigment comprises one or more of carmine, erythrosine, allura red, red iron oxide, titanium dioxide, zinc oxide, talc, kaolin, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, amaranth, new red, lemon yellow, sunset yellow, indigo, brilliant blue, carotene, chlorophyll, turmeric, impatiens glycoside, rose glycoside, and capsanthin.

73. The dipyridamole cream according to 59, characterized in that the mass proportion of the pigment in the dipyridamole cream is 0% to 10%, preferably 0% to 5%.

74. The dipyridamole cream according to 59 is characterized in that the cream contains 10% to 95% water by mass, preferably 20% to 90% water, and more preferably 30% to 70% water.

75. The dipyridamole cream according to 59 is characterized in that, in terms of mass percentage, the dipyridamole cream contains 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and 0.3% to 40% of emulsifier, 0.5% to 40% of lubricant, 0.5% to 50% of moisturizer, 0% to 10% of preservative, 0.1% to 50% of consistency regulator, and one or more of water.

76. The dipyridamole cream according to 59 is characterized in that, in terms of mass percentage, the dipyridamole cream contains 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier, 1% to 30% of lubricant, 1% to 30% of moisturizer, 0% to 1% of preservative, 1% to 30% of consistency regulator, and one or more of water.

77. The dipyridamole cream according to any one of 75-76, characterized in that the emulsifier is polyethylene glycol-stearate; and/or the lubricant is isopropyl myristate and/or isopropyl palmitate; and/or the moisturizer is glycerol and/or 1,3-butylene glycol; and/or the preservative is sodium ethylparaben; and/or the consistency regulator is cetearyl alcohol.

78. The preparation method of the dipyridamole cream described in any one of 50 to 77 comprises the following steps: mixing the oil phase components in the cream matrix and heating them to 70 to 80°C to melt, adding dipyridamole and/or its derivatives to obtain an oil phase mixture; mixing the water phase components in the cream matrix and heating them to 70 to 80°C to obtain an water phase mixture; adding the water phase mixture to the oil phase mixture under stirring, homogenizing and continuously stirring, and obtaining the dipyridamole cream after cooling.

79. The preparation method of the dipyridamole cream described in any one of 50 to 77 comprises the following steps: dissolving or dispersing dipyridamole and/or its derivatives in diethylene glycol monoethyl ether, heating to 50 to 60°C to obtain a premixed solution; mixing the other oil phase components in the cream matrix except diethylene glycol monoethyl ether and heating to 70 to 80°C to melt to obtain an oil phase mixed solution; mixing the water phase components in the cream matrix and heating to 70 to 80°C to obtain an water phase mixed solution; adding the water phase mixed solution to the oil phase mixed solution under stirring, cooling to 50 to 60°C, adding the premixed solution, homogenizing and continuously stirring, and obtaining the dipyridamole cream after cooling.

80. A dipyridamole gel, characterized in that, in terms of mass percentage, it comprises 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, and 0.1% to 60% diethylene glycol monoethyl ether.

81. The dipyridamole gel according to 80, characterized in that the mass percentage of the dipyridamole and/or its derivatives is 0.01%-10%.

82. The dipyridamole gel according to 81 is characterized in that the mass percentage of diethylene glycol monoethyl ether is 0.3% to 50%, preferably 2% to 30%.

83. The dipyridamole gel according to 80 is characterized in that the mass percentage of the gel is 0.2% to 10%, preferably 0.5% to 5%.

84. The dipyridamole gel according to 80 is characterized in that the gelling agent comprises one or more of carbomer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, and sodium carboxymethyl cellulose, preferably carbomer.

85. The dipyridamole gel according to 84, characterized in that the carbomer includes carbomer 980NF, carbomer 974NF, and carbomer 940.

86. The dipyridamole gel according to any one of 80-86, characterized in that the dipyridamole gel further comprises one or more of a surfactant, a pH adjuster, a moisturizer, an antioxidant, a preservative, and water.

87. The dipyridamole gel according to 86 is characterized in that the mass percentage of water is 10% to 98%, preferably 20% to 95%, and more preferably 30% to 90%.

88. The dipyridamole gel according to 86 is characterized in that the moisturizer is selected from one or more of vaseline, glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol.

89. The dipyridamole gel according to 86 is characterized in that the mass proportion of the moisturizer in the dipyridamole gel is 0.1% to 50%, preferably 1% to 30%.

90. The dipyridamole gel according to 86 is characterized in that the preservative is selected from one or more of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sodium ethylparaben, benzyl alcohol, phenoxyethanol, sorbic acid, benzoic acid, and sodium benzoate.

91. The dipyridamole gel according to 86 is characterized in that the mass proportion of the preservative in the dipyridamole ointment is 0% to 5%, preferably 0% to 2%, and more preferably 0% to 1%.

92. The dipyridamole gel according to 86 is characterized in that the surfactant is selected from one or more of sodium lauryl sulfate, Spans, Tweens, poloxamers, triethanolamine, caprylic/capric acid macrogol glycerides, 15-hydroxystearate macrogol esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyethylene glycol cetearyl alcohol ether, and is preferably triethanolamine.

93. The dipyridamole gel according to 86 is characterized in that the mass proportion of the surfactant in the dipyridamole gel is 0.1% to 50%, preferably 0.5% to 30%.

94. The dipyridamole gel according to 86 is characterized in that the pH regulator is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium citrate, triethanolamine, citric acid, hydrochloric acid, and sodium dihydrogen phosphate.

95. The dipyridamole gel according to 86 is characterized in that the mass proportion of the pH regulator in the dipyridamole gel is 0% to 10%, preferably 0% to 5%.

96. The dipyridamole gel according to 86 is characterized in that the antioxidant is selected from one or more of butylated hydroxytoluene, butylated hydroxyanisole, disodium ethylenediaminetetraacetic acid, α-tocopherol, ascorbic acid, sodium metabisulfite, propyl gallate, sodium ascorbate, and isoascorbic acid.

97. The dipyridamole gel according to 86 is characterized in that the mass proportion of the antioxidant in the dipyridamole ointment is 0% to 5%, preferably 0% to 1%.

98. The dipyridamole gel according to 86 is characterized in that, in terms of mass percentage, it comprises one or more of 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and 0.1% to 50% moisturizer, 0% to 5% preservative, 0% to 10% pH adjuster, 0.1% to 50% surfactant, 0% to 5% antioxidant, and 10% to 98% water.

99. The dipyridamole gel according to 86 is characterized in that, in terms of mass percentage, it comprises one or more of 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% carbomer, 0.1% to 60% diethylene glycol monoethyl ether, 0.1% to 50% 1,3-butanediol, 0% to 5% sodium ethyl hydroxybenzoate, 0% to 50% triethanolamine, and 10% to 98% water.

The method for preparing the dipyridamole gel described in any one of 100.80 to 99 comprises the following steps: dissolving dipyridamole and/or its derivatives in diethylene glycol monoethyl ether, adding a moisturizer to obtain a premixed solution; mixing the other components in the gel matrix except the pH adjuster, adding the gelling agent, stirring until swelling, and obtaining a gel solution; adding the premixed solution to the gel solution, adjusting the pH, and stirring evenly to obtain the dipyridamole gel.

101. A dipyridamole ointment, characterized in that it comprises the cream component described in any one of 50-77 and does not contain water.

102. A dipyridamole ointment, characterized in that it comprises the cream component described in any one of 50-77 and does not contain water, and the mass percentage of the consistency regulator in the dipyridamole ointment is 0.1%-98%, preferably 0.5%-95%, and more preferably 1%-90%.

103. A dipyridamole ointment, characterized in that it contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and one or more of 0.3% to 40% of emulsifier, 0.5% to 40% of lubricant, 0.5% to 50% of moisturizer, 0% to 10% of preservative, 0.1% to 50% of consistency regulator, 0% to 10% of pH regulator, 0% to 5% of antioxidant, and 0% to 10% of pigment.

104. The dipyridamole ointment according to 103 is characterized in that, in terms of mass percentage, the ointment contains 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier, 1% to 30% of lubricant, 1% to 30% of moisturizer, 0% to 1% of preservative, 1% to 90% of consistency regulator, 0% to 5% of pH regulator, 0% to 1% of antioxidant, and 0% to 5% of pigment. One or more.

105. The dipyridamole ointment according to 104 is characterized in that it contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier, 1% to 30% of lubricant, 1% to 30% of moisturizer, and 1% to 90% of one or more of consistency regulator.

106. The dipyridamole ointment according to 104 is characterized in that it contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier.

107. The dipyridamole ointment according to 104 is characterized in that it contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 1% to 90% of a consistency regulator.

108. The dipyridamole ointment according to 104 is characterized in that it contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of emulsifier, and 1% to 90% of consistency regulator.

109. Use of the dipyridamole cream described in any one of 50 to 77 in the preparation of a medicament for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases.

110. Use of the dipyridamole gel described in any one of 80 to 99 in the preparation of a medicament for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases.

111. Use of the dipyridamole ointment described in any one of 101 to 108 in the preparation of a medicament for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases.

112. The use according to any one of 109-111, characterized in that the allergic disease is the disease described in 2 or 3; or the inflammatory disease is the disease described in any one of 4-20.

113. A method for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases, comprising the following steps: administering dipyridamole or a derivative thereof to a patient in need thereof.

114. The method according to 113 is characterized in that it includes the following steps: administering dipyridamole or its derivatives to the patient in need thereof in an external manner.

115. The method according to 114 is characterized in that it includes the following steps: topically administering the dipyridamole cream described in any one of items 50 to 77 and/or the dipyridamole gel described in any one of items 80 to 99 and/or the dipyridamole ointment described in any one of items 101 to 108 to the patient in need thereof.

116. The method according to any one of 114-115 is characterized in that the method of topical administration is: applying the dipyridamole cream described in any one of 50 to 77 and/or the dipyridamole gel described in any one of 80 to 99 and/or the dipyridamole ointment described in any one of 101 to 108 to the skin surface corresponding to the affected area.

117. The method according to any one of 112-116 is characterized in that the frequency of administration is: 1-3 times every 1 to 24 hours, or 1-3 times a day, preferably 2-3 times a day.

118. The method according to any one of 112-117 is characterized in that the dosage of the drug is: 1-250 mg each time, preferably 5-100 mg each time, and more preferably 10-50 mg, calculated as dipyridamole; or; the drug is administered in a cosmetically effective amount; or the drug is administered in a therapeutically effective amount.

119. The method according to any one of 112-118, characterized in that the dosage of the administration is: 0.1-25 mg/cm ² ; more preferably 0.2-10 mg/cm ² , calculated as dipyridamole.

120. The method according to 113 is characterized in that the allergic disease is the disease described in 2 or 3; or the inflammatory disease is any one of the diseases described in 4-20.

In order to make the invention purpose, technical solution and technical effect of this application clearer, the present application is further described in detail below in conjunction with specific implementation methods. It should be understood that the specific implementation methods described in this specification are only for explaining this application, not for limiting this application.

Unless otherwise specified, the experimental materials and reagents used were conventional consumables and reagents available from commercial channels.

Cream Example 1 A dipyridamole topical preparation (0.5% dipyridamole cream 1)

In this embodiment, a dipyridamole cream is provided, and its composition is shown in the following table:

Table 1 Dipyridamole cream formula composition and content

The preparation method of dipyridamole cream in this embodiment is as follows: weigh the A phase components according to the ratio shown in the above table, mix the other components except the main drug (API, i.e., dipyridamole) and heat to 80°C to melt, add API and stir to dissolve, and obtain the A phase solution. Weigh the B phase components according to the ratio shown in the above table, stir to uniformity after mixing, and heat to 80°C to obtain the B phase solution. Under stirring conditions, add the B phase solution to the A phase solution, homogenize at 5000rpm for 3min, continue stirring and cool to room temperature to obtain the dipyridamole cream.

In this embodiment, the effective content of the main drug dipyridamole in the dipyridamole cream is 5 mg/g.

Cream Example 2 A dipyridamole topical preparation (0.5% dipyridamole cream 2)

Table 2 Dipyridamole cream formula composition and content

The preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1. In this embodiment, the effective content of the main drug dipyridamole in the dipyridamole cream is 5 mg/g.

Cream Example 3 A dipyridamole topical preparation (0.5% dipyridamole cream 3)

Table 3 Dipyridamole cream formula composition and content

The preparation method of dipyridamole cream in the present embodiment is as follows: weigh the A phase components according to the ratio shown in the above table, disperse or dissolve the main drug (API, i.e., dipyridamole) in diethylene glycol monoethyl ether, and keep warm at 50°C to obtain a phase A solution. Weigh the B phase components according to the ratio shown in the above table, mix and heat to 80°C to melt, and obtain a phase B solution. Weigh the C phase components according to the ratio shown in the above table, stir until dissolved after mixing, and heat to 80°C to obtain a phase C solution. Under stirring, add the B phase solution to the C phase solution, and when the temperature of the BC phase mixed solution drops to 55°C, add the A phase solution, homogenize at 5000rpm for 3min, continue stirring and cool to room temperature to obtain a dipyridamole cream.

Cream Example 4 A dipyridamole topical preparation (0.5% dipyridamole cream 4)

Table 4 Dipyridamole cream formula composition and content

The preparation method of the dipyridamole cream in this embodiment is the same as that in embodiment 2. In this embodiment, the effective content of the main drug dipyridamole in the dipyridamole cream is 5 mg/g.

Cream Example 5 A dipyridamole topical preparation (0.1% dipyridamole cream)

Table 5: Dipyridamole cream formula composition and content

The preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1. In this embodiment, the effective content of the main drug dipyridamole in the dipyridamole cream is 1 mg/g.

Cream Example 6 A dipyridamole topical preparation (0.2% dipyridamole cream)

Table 6: Dipyridamole cream formula composition and content

The preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1. In this embodiment, the effective content of the main drug dipyridamole in the dipyridamole cream is 2 mg/g.

Cream Example 7 A dipyridamole topical preparation (1% dipyridamole cream)

Table 7: Dipyridamole cream formula composition and content

The preparation method of the emulsifiable paste of the present embodiment is as follows:

1) Weigh phase A according to the prescription amount, disperse or dissolve the API in diethylene glycol monoethyl ether, keep warm at 50°C and set aside;

2) Weigh phase B according to the prescription amount and heat to melt at 80°C;

3) Weigh phase C according to the prescription amount, stir to dissolve, and heat to 80°C;

4) Add phase B to phase C under stirring;

5) At 55°C, add phase A to the mixture, homogenize for 3 min (5000 rpm) and continue stirring. Cool the sample to room temperature to obtain dipyridamole cream.

In this embodiment, the effective content of the main drug dipyridamole in the dipyridamole cream is 10 mg/g.

Cream Example 8 A dipyridamole topical preparation (2% dipyridamole cream)

In this embodiment, a 2% dipyridamole cream 1 is provided, and its composition is shown in the following table:

Table 8 Dipyridamole cream formula composition and content

The preparation method of the dipyridamole cream in this embodiment is the same as that in embodiment 7. In this embodiment, the effective content of the main drug dipyridamole in the dipyridamole cream is 20 mg/g.

Cream Example 9 A dipyridamole external preparation (0.2% dipyridamole cream)

Table 9: Dipyridamole cream formula composition and content

Cream Example 10 A dipyridamole external preparation (5% dipyridamole cream)

Table 10: Dipyridamole cream formula composition and content

The preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1. In this embodiment, the content of the main drug dipyridamole in the cream is 50 mg/g.

Cream Example 11 A dipyridamole external preparation (12% dipyridamole cream)

Table 11: Dipyridamole cream formula composition and content

The preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1. In this embodiment, the content of the main drug dipyridamole in the cream is 120 mg/g.

Cream Example 12 A dipyridamole external preparation (0.8% dipyridamole cream)

Table 12: Dipyridamole cream formula composition and content

The preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1. In this embodiment, the content of the main drug dipyridamole in the cream is 8 mg/g.

Cream Example 13 A dipyridamole external preparation (6% dipyridamole cream)

Table 13: Composition and content of dipyridamole cream formula

The preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1. In this embodiment, the content of the main drug dipyridamole in the cream is 60 mg/g.

Cream Example 14 A dipyridamole external preparation (5% dipyridamole cream)

Table 14: Dipyridamole cream formula composition and content

Cream Example 15 A dipyridamole topical preparation (dipyridamole natural skin color cream)

In the present embodiment, a topical pharmaceutical preparation (dipyridamole natural skin color cream) based on the dipyridamole cream in the above embodiment is provided. The topical pharmaceutical preparation is the dipyridamole cream in the above embodiment with the addition of auxiliary materials such as pigments, so that the color of the dipyridamole topical pharmaceutical preparation is closer to human skin color, as shown in FIG1 , thereby improving the visual perception of the patient, reducing the patient's psychological resistance, giving the patient a more pleasant and comfortable use experience, and improving the patient's willingness to use.

The ingredients of the dipyridamole natural skin color cream are shown in the following table:

Table 15 Dipyridamole natural skin color cream formula composition and content

The preparation method of the dipyridamole natural skin color cream in this embodiment is the same as that in Example 1, except that: in this embodiment, after adding the phase B solution to the phase A solution, the pigment is added, and then homogenized at 5000 rpm for 3 minutes, continuously stirred and cooled to room temperature to obtain the dipyridamole natural skin color cream.

In this embodiment, the effective content of the main drug dipyridamole in the dipyridamole natural skin color cream is 5 mg/g.

At the same time, according to the same method, a dipyridamole cream without pigment components was prepared as a control. The actual photos of the dipyridamole natural skin color cream and the dipyridamole cream without pigment components are shown in Figure 1, where the right picture is the dipyridamole natural skin color cream and the left picture is the dipyridamole cream without pigment components. It can be found that the color difference between the two is significant. The color of the dipyridamole natural skin color cream is obviously closer to the human skin color, and the visual sensory effect is better than the dipyridamole cream without pigment components, and it is easier to be accepted by patients.

Cream Comparative Example 1 A dipyridamole topical preparation (dipyridamole cream)

Table 16 Dipyridamole cream formula composition and content

Compared with Example 1, in Comparative Example 1, Tween 80 is used as an emulsifier instead of polyethylene glycol-7-stearate, and diethylene glycol monoethyl ether is removed.

Cream comparative example 2 a dipyridamole cream

Table 17 Dipyridamole cream formula composition and content

On the basis of Cream Comparative Example 2, Cream Comparative Examples 3 to 5 were prepared, and the mass percentages of dipyridamole were adjusted to 0.4%, 0.3%, 0.2%, and 0.1%, respectively, and the water content was adaptively adjusted, while other components and contents remained unchanged.

Cream Comparative Example 6: A dipyridamole cream

Table 18 Dipyridamole cream formula composition and content

Compared with Example 2, in Comparative Example 6, Tween 80 is used as an emulsifier instead of polyethylene glycol-7-stearate, and diethylene glycol monoethyl ether is removed.

Cream Comparative Example 7: A dipyridamole cream

Table 19: Dipyridamole cream formula composition and content

Preparation method: Mix stearic acid, glyceryl monostearate, white vaseline and liquid paraffin as the oil phase; separately mix glycerol, sodium lauryl sulfate, triethanolamine, ethylparaben and water as the water phase. Place them in appropriate containers, heat until they are melted or dissolved, put dipyridamole into the oil phase, slowly add the water phase into the oil phase after heating, and stir in the same direction while adding, until solidified and then packaged.

Cream Comparative Example 8: a dipyridamole cream

This example prepares a cream product.

The preparation method of the product comprises: uniformly mixing 1-100g of dipyridamole with a vanishing cream base to prepare 1000g of the product, and preparing an ointment with a dipyridamole concentration of 0.1-10% (in which the dipyridamole is difficult to dissolve and presents a granular texture visible to the naked eye).

Conclusion: The inventors have found through a series of experimental explorations including subsequent verification examples that the cream of the present application and the cream of the comparative example have effective therapeutic and preventive effects on dermatitis model mice, but the cream of the present application, especially Example 1 and Example 2, has significantly improved therapeutic and preventive effects compared with the cream comparative example. Compared with the cream comparative example 8, the cream comparative example 1 of the present application has better cream properties, such as cream skin feel, viscosity, etc.

Gel Example 1 A dipyridamole gel

In this embodiment, a dipyridamole gel is provided, and its composition is shown in the following table:

Table 20 Dipyridamole gel formula composition and content

The preparation method of dipyridamole gel in the present embodiment is: weigh each component according to the ratio shown in the above table, stir and dissolve the main drug (API, i.e., dipyridamole) in a solvent (diethylene glycol monoethyl ether), add a moisturizing agent (1,3-butylene glycol) and stir until uniform to obtain a main drug mixture. The preservative (sodium ethyl hydroxybenzoate) is stirred and dissolved with water, and a gelling agent (carbomer 980NF) is slowly added under continuous stirring, and stirred until completely swollen to obtain a gel matrix. The main drug mixture is added to the gel matrix, and a pH adjusting agent (trolamine) is added to adjust the pH to 6.0-6.5, and dipyridamole gel is obtained after stirring evenly.

In this embodiment, the effective content of the main drug dipyridamole in the dipyridamole gel is 5 mg/g.

Gel Example 2 A dipyridamole gel

Table 21 Dipyridamole gel formula composition and content

The preparation method of dipyridamole gel in the present embodiment is similar to that of gel embodiment 1: each component is weighed according to the ratio shown in the above table, the main drug (API, i.e., dipyridamole) is stirred and dissolved in the solvent (diethylene glycol monoethyl ether), and a moisturizer (1,3-butylene glycol) is added and stirred until uniform to obtain a main drug mixture. The preservative (sodium ethyl hydroxybenzoate) is stirred and dissolved in water, and a gelling agent (carbomer 980NF) is slowly added under continuous stirring conditions, and stirred until completely swollen to obtain a gel matrix. The main drug mixture is added to the gel matrix, and a pH adjusting agent (triethanolamine) is added to adjust the pH to 6.0-6.5, and dipyridamole gel is obtained after stirring evenly.

Gel Example 3 A dipyridamole gel

Table 22 Dipyridamole gel formula composition and content

The preparation method of dipyridamole gel in this embodiment is the same as or similar to that of gel embodiment 1.

Gel Example 4 A dipyridamole gel

Table 23 Dipyridamole gel formula composition and content

Gel Example 5 A dipyridamole gel

Table 24 Dipyridamole gel formula composition and content

Gel Example 6 A dipyridamole gel

Table 25 Dipyridamole gel formula composition and content

Gel Example 7 A dipyridamole gel

Table 26 Dipyridamole gel formula composition and content

Gel Example 8 A dipyridamole gel

Table 27 Dipyridamole gel formula composition and content

Gel Example 9 A dipyridamole gel

Table 28 Dipyridamole gel formula composition and content

Gel Example 10 A dipyridamole gel

Table 29 Dipyridamole gel formula composition and content

Gel Example 11 A dipyridamole gel

Table 30 Dipyridamole gel formula composition and content

Gel Comparative Example 1: A dipyridamole gel

Table 31 Dipyridamole gel formula composition and content

Gel Comparative Example 2: A dipyridamole gel

Table 32 Dipyridamole gel formula composition and content

In this embodiment, the effective content of the main drug dipyridamole in the dipyridamole gel is 50 mg/g.

Gel Comparative Example 3: A dipyridamole gel

Table 33 Dipyridamole gel formula composition and content

Conclusion: The inventors found through a series of experimental explorations including subsequent verification examples that the gel of the present application and the gel of the comparative example both have effective therapeutic and preventive effects on dermatitis model mice. However, the gel of the present application, especially gel example 1, has significantly improved therapeutic and preventive effects, as well as safety, compared with gel comparative example 1.

Ointment Example 1

In this embodiment, a dipyridamole ointment is provided, and its composition is shown in the following table:

Table 34 Dipyridamole ointment formula composition and content

The preparation method of the dipyridamole ointment in this embodiment is as follows: weigh the components according to the ratio shown in the above table, mix the components except dipyridamole, heat to 70-80°C to melt, then add dipyridamole to dissolve, and cool to room temperature to obtain the ointment.

Ointment Example 2

Table 35 Dipyridamole ointment formula composition and content

The preparation method of dipyridamole ointment in this embodiment is the same as or similar to that of dipyridamole ointment embodiment 1.

Ointment Example 3

Table 36 Dipyridamole ointment formula composition and content

Ointment Example 4

Table 37 Dipyridamole ointment formula composition and content

Ointment Example 5

The dipyridamole ointment of this embodiment was prepared according to the following method:

1) After taking the solvent into a beaker, slowly add the API in a 60°C water bath and stir until completely dissolved to obtain the solvent phase;

2) Take the ointment base PEG400 and PEG4000 and heat them in a water bath at 70-80°C, then add the remaining excipients and stir until they are completely dissolved to obtain a matrix phase;

3) Cool the matrix phase to 60°C, slowly add the solvent phase into the matrix phase while stirring, mix evenly, cool to 30-40°C with stirring to form a paste, and fill.

Table 38 Dipyridamole ointment formula composition and content

Ointment Example 6

The dipyridamole ointment of this example was prepared according to the method of ointment example 5.

Table 39 Dipyridamole ointment formula composition and content

Ointment Example 7

Table 40 Dipyridamole ointment formula composition and content

Ointment Example 8

Table 41 Dipyridamole ointment formula composition and content

Ointment Example 9

Table 42 Dipyridamole ointment formula composition and content

Ointment Example 10

Table 43 Dipyridamole ointment formula composition and content

Ointment Example 11

Table 44 Dipyridamole ointment formula composition and content

In the above embodiments, the selection of each component is unique. The change of any one component will actually have a great impact on the effect of the external preparation. For this reason, the inventor provides the following specific experimental content to prove this situation.

Component screening experiment example 1 In vitro transdermal effect of cream

In the component screening process of dipyridamole cream preparation, the dissolution effect of the main drug, the skin feel of the cream, the viscosity of the cream, etc. are all indicators that need to be paid attention to. However, unexpectedly, in this process, the use of different solvents has a certain influence on the transdermal performance of the cream. In particular, the inventor unexpectedly found that the use of diethylene glycol monoethyl ether of the present application as a solvent has a very significant improvement effect compared with other commonly used oily solvents (for example, including but not limited to olive oil, liquid paraffin, vaseline, cetearyl alcohol, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, polyglycerol oleate), thereby achieving an unexpectedly significantly improved therapeutic effect in the treatment effect of the mouse dermatitis model.

The following is an illustrative comparison of the in vitro transdermal effects of diethylene glycol monoethyl ether, diethylene glycol monoethyl ether and polyethylene glycol-7-stearate, and glyceryl monostearate as solvents.

The Franz diffusion cell method was used to take the back skin of Bama miniature pigs, wash it with physiological saline, check the skin integrity, and install it in a diffusion device. The effective diffusion area of the diffusion cell was 1.77 cm ² , the volume of the receiving cell was 12 ml, the receiving solution was pH 7.4 phosphate buffer solution-anhydrous ethanol (70:30), the stirring speed was 600±60rpm, and the skin surface temperature was 32.0±1.0℃. 0.3g of the preparation was evenly applied to the stratum corneum of the skin. After 12 hours, the experimental skin was taken, the residual preparation on the skin was removed, cut into pieces, homogenized with ethanol, centrifuged, and the supernatant was taken to detect the concentration, and the cumulative retention amount was calculated (n=6). Using the components of cream Example 1, diethylene glycol monoethyl ether was replaced with a combination of diethylene glycol monoethyl ether and polyethylene glycol-7-stearate, monostearic acid glyceryl, and the difference in cumulative retention was compared. As shown in Figure 2.

As can be seen from Figure 2, compared with glyceryl monostearate, diethylene glycol monoethyl ether has a very significant improvement in transdermal effect, about On this basis, the combination of diethylene glycol monoethyl ether and polyethylene glycol-7-stearate can further improve its transdermal effect.

For topical preparations that need to be used on the skin surface, their skin feel (or tactile properties) is directly related to the patient's acceptance of them. Therefore, it is very important for a topical drug preparation to have a good skin feel to reduce the rebellious or resistant psychology generated by patients when using it. The inventors selected different emulsifiers and thickeners for comparison to analyze the actual skin feel experience of different emulsifiers-thickeners on the human body. The emulsifiers and thickeners provided in this application have the characteristics of delicate skin feel. In addition, the selection of moisturizers can increase the viscosity of the cream, increase the convenience of use and compliance.

Component screening experiment example 2 Transdermal absorption effect of gel

During the screening process of the components of the gel, the inventors also unexpectedly discovered that the use of diethylene glycol monoethyl ether of the present application as a solvent has a very significant improvement effect compared with other commonly used solvents (for example, including but not limited to ethanol, isopropanol, propylene glycol, 1,3-butanediol, glycerol, etc.), thereby achieving an unexpectedly significantly improved therapeutic effect in the treatment of mouse dermatitis models.

The inventors adopted the cumulative retention test method of the above-mentioned component screening experimental example 1, exemplarily adopted the components of gel example 1, replaced diethylene glycol monoethyl ether with ethanol, and compared the difference in cumulative retention, as shown in FIG3 .

As can be seen from Figure 3, compared with ethanol, diethylene glycol monoethyl ether has a very significant improvement in transdermal effect, which is about 40%, and thus has achieved unexpectedly significant improvement in the treatment effect of mouse dermatitis models. At the same time, compared with solvents such as ethanol, diethylene glycol monoethyl ether is non-irritating and highly safe in gel preparations.

Component Screening Example 3 Investigation of Solubility Effect of Ointment

In the ointment component screening test, as shown in Table 45, the inventors found through screening of various solvents that dipyridamole was insoluble in a very large number of solvents, but was completely dissolved in hexylene glycol and 1,3-butanediol by heating at 60°C.

Table 45 Solvent screening table in ointment

Verification of the effect of dipyridamole (DIP)

Verification Example 1: The soothing effect of dipyridamole on the symptoms of allergic and inflammatory skin disease model mice

In order to confirm whether dipyridamole has a therapeutic effect on allergic and inflammatory skin diseases, in this verification case, calcipotriol solution will be applied to the right ear and back skin of mice to induce allergic and inflammatory dermatitis in mice, thereby testing the therapeutic effect of DIP on allergic and inflammatory skin diseases.

The specific test method is as follows:

Experimental animals selected female 8-week-old C57BL/6 mice, a total of 80, and were randomly divided into 8 groups, 10 mice/group. They were respectively a blank group (no treatment), a modeling group (no treatment), a cream comparative group (using cream comparative example 1 for treatment after modeling, referred to as cream group 1), a cream treatment group (using dipyridamole cream of cream example 2 for treatment after modeling, referred to as cream group 2), a gel comparative group (using gel comparative example 1 for treatment after modeling, named gel group 1), a gel treatment group 1 (using gel example 1 for treatment after modeling, referred to as gel group 2), a crisaborole group (using non-hormone positive drug crisaborole for treatment after modeling), a gel treatment group 2 (using gel example 2 for treatment after modeling, referred to as gel group 3), a dexamethasone group (using hormone positive drug dexamethasone for treatment after modeling), and a blank cream group (using a blank cream without adding dipyridamole for treatment after modeling)

Except for the blank group, all experimental animals in other groups were sensitized by applying 2nmol calcipotriol (10μL) on the inner side of the right ear and 4nmol (20μL) calcipotriol on the back skin, and waited for 1 hour to complete the modeling. Except for the blank and model groups, animals in other groups were smeared with the corresponding dosage form of DIP or positive drug crisaborole or positive drug dexamethasone or blank cream on the sensitized area, 0.075g each time (0.025g on the ear, 0.05g on the back, the dosage of positive drugs crisaborole and dexamethasone is the same as DIP), once a day, and continued to be administered for 14 days.

After the end of the administration on the 14th day, blood was drawn from the eyeballs of all mice to collect serum. After the mice were killed, the right ears and the central skin of the back of the mice were cut off. Among them, the ears were cut in half, one half was immersed in RNaselater for RNA extraction and fluorescence quantitative PCR detection; the other half was immersed in 4% paraformaldehyde solution for HE staining.

On the 5th day of administration, photos of the back of each mouse in each group were taken.

The results are shown in Figures 4 and 5.

From the representative pictures of the back skin of each group of mice, it can be seen that the redness, peeling and dryness of the back skin of the mice in the cream treatment group and the gel treatment group (fourth and sixth from left) were significantly improved compared with the modeling group (no treatment, second from left), and the effect was comparable to that of the dexamethasone group.

At the same time, the severity of the skin lesions on the back of each group of mice was evaluated and scored. The scoring system is as follows: erythema/hemorrhage, edema, exfoliation/erosion, and dryness. Each symptom is scored from 0 to 3 points, among which, the standard for none (0 point) is: cannot be confirmed after careful observation; the standard for mild (1 point) is: can be confirmed after careful observation; the standard for moderate (2 points) is: obvious signs and can be confirmed immediately; the standard for severe (3 points) is: the signs are particularly obvious and can be confirmed immediately.

The scoring results are shown in Figure 6. It can be found that on the 5th and 8th days of drug treatment, the symptom scores of erythema/hemorrhage, edema, exfoliation/erosion, and dryness of the mice in the modeling untreated group showed a significant increase compared with the blank group (blank group vs. modeling untreated group, erythema/hemorrhage p<0.0001, exfoliation/erosion p<0.0001, dryness p<0.0001, total score p<0.0001), which proves that the mouse allergy and inflammatory-related dermatitis model was successfully established. The exfoliation/erosion, dryness and total score of mice treated with the positive drug crisaborole were significantly lower than those of the modeling untreated group (modeling untreated group vs crisaborole group, exfoliation/erosion score p<0.0001, dryness score p<0.0001, total score p<0.0001), however, there was no difference in the erythema/hemorrhage score between the two groups (p>0.05), which proves that the use of crisaborole can significantly improve the exfoliation/erosion, dryness and other symptoms of allergic and inflammatory dermatitis, but the effect on improving erythema caused by allergic and inflammatory dermatitis is not obvious. The symptoms and total scores of erythema/hemorrhage, edema, exfoliation/erosion, and dryness in the cream-treated and gel-treated groups were significantly reduced compared with those in the model-untreated group (cream-treated group vs. model-untreated group, erythema/hemorrhage score p<0.0001, exfoliation/erosion score p<0.0001, dryness score p<0.0001, total score p<0.0001; gel-treated group vs. model-untreated group, erythema/hemorrhage score p<0.0001, exfoliation/erosion score p<0.0001, dryness score p<0.0001, total score p<0.0001), demonstrating that the use of dipyridamole-containing cream-treated and gel-treated groups can significantly improve symptoms such as erythema/hemorrhage, exfoliation/erosion, and dryness caused by dermatitis associated with allergies and inflammation. In addition, the erythema/hemorrhage and total score of mice in the cream treatment group were significantly lower than those in the crisaborole group (erythema/hemorrhage score p<0.0001, exfoliation/erosion score p>0.05, dryness score p>0.05, total score p<0.0001), and the erythema/hemorrhage, edema, exfoliation/erosion, dryness and total score of mice in the gel treatment group were significantly lower than those in the crisaborole group (erythema/hemorrhage score p<0.0001, exfoliation/erosion score p<0.0001, dryness score p<0.0001, total score p<0.0001), which proved that the use effect of the cream treatment group and the gel treatment group containing dipyridamole is better than that of the non-hormonal therapeutic drug crisaborole currently on the market. In addition, although not shown in Figure 6, the inventors found that the erythema/hemorrhage and total score of the mice in the cream treatment group were basically equivalent to those in the dexamethasone group, with no significant difference (erythema/hemorrhage score p>0.05, exfoliation/erosion score p>0.05, dryness score p>0.05, total score p>0.05), and the erythema/hemorrhage, edema, exfoliation/erosion, dryness symptoms and total score of the mice in the gel treatment group were equivalent to those of the dexamethasone group, with no significant difference (erythema/hemorrhage score p>0.05, exfoliation/erosion score p>0.05, dryness score p>0.05, total score p>0.05), which proves that the use effects of the cream treatment group and the gel treatment group containing dipyridamole are equivalent to those of the hormone therapy drug dexamethasone currently on the market.

In addition, after comparing the therapeutic effects of the cream treatment group, gel treatment group and other formulations, it was found that the mice in the cream treatment group The erythema/hemorrhage score and total score were significantly lower than those in the cream control group (p<0.0001). All skin symptom scores of the gel-treated group were significantly lower than those of the gel control group (erythema/hemorrhage p<0.05, exfoliation/erosion p<0.0001, dryness p<0.0001, total score p<0.0001).

Therefore, the formulation process of the present application, including the cream treatment group and the gel treatment group, is significantly superior to other formulations, including the comparative example, in improving the overall skin symptoms of allergic and inflammatory dermatitis in mice.

Verification Example 2: Dipyridamole reduces the expression of IL-4 and TSLP in allergic and/or inflammatory diseases

IL-4 and thymic stromal lymphopoietin (TSLP) are two important cytokines that induce allergic and/or inflammatory diseases. Specifically in skin-related allergic or inflammatory diseases, elevated IL-4 levels can cause atopic dermatitis symptoms similar to those associated with allergies and inflammation in mouse models. TSLP is highly expressed in the skin epithelial cells of patients with inflammatory skin diseases, and overexpression of TSLP in keratinocytes (the most common cell type in the skin) can cause intense itching, scratching, the development of dermatitis phenotypes, and even worse, asthma-like lung inflammation. In order to verify whether DIP has an inhibitory effect on the production of IL-4 and TSLP mRNA, in this example, the mRNA of the mouse skin obtained in Verification Example 1 was extracted for fluorescence quantitative PCR detection.

The specific steps are as follows: Add 1 mL TRIZOL to the mouse skin tissue in Verification Example 1 and grind thoroughly, incubate at room temperature for 5 minutes to allow the cells to be fully lysed. Add 200 μL chloroform, shake vigorously for 15 seconds, and incubate at room temperature for 2 to 15 minutes. Centrifuge at 12000×g for 15 minutes, take the aqueous phase and mix it evenly with 500 μL isopropanol, and incubate at room temperature for 5 to 10 minutes. Centrifuge at 12000×g for 10 minutes and discard the supernatant. Use 1 mL of ethanol to immerse the precipitated RNA and shake and wash. Centrifuge at 7500×g for 5 minutes and discard the excess ethanol. After natural air drying, add 20 μL DEPC water to dissolve the RNA. Use the reverse transcription kit (purchased from Novazon) and the qPCR kit (purchased from Novazon) to detect the obtained RNA according to the instructions.

The results are shown in Figure 7. The mRNA and protein concentrations of IL-4 and TSLP in the back skin of mice in the modeling untreated group were significantly increased compared with those in the blank group (blank group vs modeling untreated group, IL-4 mRNA p<0.0001, TSLP mRNA p<0.0001). Compared with the model group, mice using each group of preparations (including cream control group, cream treatment group, gel control group, gel treatment group, and crisaborole) were observed to have a significant decrease in IL-4 mRNA level (P<0.001), indicating that various DIP preparations and crisaborole can reduce the expression level of IL-4. The mRNA level of TSLP in the skin of mice in the cream treatment group was significantly lower than that of mice in the modeling untreated group and crisaborole group (P<0.05).

At the same time, some back skin tissue and plasma samples were taken and tested using mouse IL-4 and TSLP ELISA kits (mouse IL-4 ELISA kit and mouse TSLP ELISA kit were purchased from Sizhengbai) to verify the protein levels of IL-4 and TSLP in the back skin tissue and plasma samples. Among them, 10 μL of RIPA protein lysis buffer was added to the skin tissue per mg sample, and the tissue was fully ground on ice until it was completely dissolved. Then, it was shaken on ice for 30 minutes, and then centrifuged at 12000×g to remove the precipitate. The supernatant was taken and the protein concentration was detected using an ELISA kit. The detection method was carried out according to the instructions.

The results are shown in Figures 8 and 9.

It can be found that the protein concentration of TSLP in the plasma of mice in the modeling untreated group was significantly increased compared with that of mice in the blank group (blank group vs. modeling untreated group, TSLP protein concentration p<0.0001). Compared with the modeling untreated group, mice using each group of preparations (including cream control group, cream treatment group, gel control group, gel treatment group, and crisaborole) were observed to have a significant decrease in the protein level of TSLP (P<0.05), indicating that various DIP preparations and crisaborole can reduce the expression level of TSLP. In general, each group of DIP preparations and crisaborole can reduce the expression of TSLP in mouse plasma, and the DIP cream treatment group has the most significant reduction in the expression of TSLP in mouse skin and plasma, both at the protein level and at the mRNA level, which is significantly better than the cream control group and is equivalent to the hormone-positive drug dexamethasone group.

Verification Example 3: Dipyridamole reduces plasma and inflammatory site IgE in allergic and/or inflammatory diseases and inhibits mast cell infiltration

IgE is considered to be a hallmark antibody for allergic and/or inflammatory diseases such as dermatitis. According to statistics, up to 80% of dermatitis patients have elevated IgE levels. IgE can bind to the FcεRI molecule (IgE receptor) on the surface of mast cells. When IgE binds to its corresponding antigen, it prompts mast cells to release particles such as heparin and histamine, triggering an immune response.

In this example, a mouse IgE ELISA detection kit (commercially available) was used to further detect the protein level of IgE in the skin tissue and plasma of the mouse model of allergic and inflammatory dermatitis obtained in Verification Example 1. Among them, 10 μL of RIPA protein lysis buffer was added to the skin tissue per mg sample, and the tissue was fully ground on ice until it was completely dissolved, and then continued to shake and lyse on ice for 30 minutes, and then centrifuged at 12000×g to remove the precipitate, and the supernatant was taken to detect the protein concentration using an ELISA kit, and the detection method was carried out according to the instructions.

The results are shown in Figures 10 and 11.

It can be found that the IgE protein concentration in the plasma and skin of the mice in the modeling untreated group was significantly increased compared with that in the blank group (blank The IgE protein concentration in the skin and plasma of the mice in the cream treatment group was significantly lower than that in the modeling untreated group, the crisaborole group, and the cream control group (P<0.001). The IgE mRNA levels in the skin and plasma of the mice in the gel treatment group showed a decreasing trend compared with those in the crisaborole group and the gel control group.

Verification Example 4: Dipyridamole inhibits immediate hypersensitivity reaction in mice

In order to confirm whether dipyridamole has an inhibitory effect on allergic reactions, in this example, a mouse model of rapid hypersensitivity reaction induced by trichosanthin was used as a disease model, and its therapeutic effect was determined by observing whether intraperitoneal injection of dipyridamole could inhibit the hypersensitivity reaction induced by trichosanthin.

The specific experimental method is:

Thirty female 8-week-old C57BL/6 mice were randomly divided into three groups, 10 mice in each group, namely, the blank group (no treatment), the modeling group (no treatment, injection of control solution) and the dipyridamole group (injection of dipyridamole).

Except for the blank group, all experimental animals in other groups were intraperitoneally injected with dipyridamole (50 mg/kg mouse body weight) once a day for 7 consecutive days. One hour after the first administration, all experimental animals in other groups, except the blank group, were sensitized by intraperitoneal injection of 0.2 mL/mouse of trichosanthin injection (injection concentration 1.2 mg/mL). One hour after the last administration, all experimental animals in other groups, except the blank group, were injected with 0.2 mL/mouse of trichosanthin injection (injection concentration 1.2 mg/mL) through the tail vein for antigen attack. The reaction of mice in each group after antigen attack was observed, and the number of mice that died within 2 hours was recorded. All mice were killed after 2 hours, and peritoneal lavage fluid was taken.

Observations showed that the mortality rate in the dipyridamole intraperitoneal injection group was significantly lower than that in the modeling group, proving that dipyridamole can significantly inhibit the allergic reaction induced by trichosanthin.

Flow cytometry was used to quantitatively observe the number and proportion of mast cells in the peritoneal lavage fluid of mice.

It was observed that dipyridamole significantly reduced the number of mast cells in the peritoneal lavage fluid of mice.

Further, the peritoneal lavage fluid was taken for cell smear, and the mast cell degranulation ratio was observed and calculated using toluidine blue staining. After staining, the mast cells without degranulation were intact, with clear outlines, and intact granular substances could be seen inside the cells; while the mast cells with degranulation were ruptured, with unclear outlines, and granules were excreted outward.

It was observed that dipyridamole could significantly reduce the degranulation ratio of mast cells in the peritoneal lavage fluid of mice.

In summary, the use of dipyridamole can inhibit the number and degranulation ratio of peritoneal mast cells in mice, thereby effectively inhibiting the hypersensitivity reaction of mice induced by trichosanthin.

Verification Example 5: Dipyridamole inhibits allergic conjunctivitis in mice

Allergic conjunctivitis is an inflammation of the conjunctiva caused by an allergic reaction. The main symptoms include redness, itching, swelling, tearing, and thread-like secretions. The important feature of allergic conjunctivitis is the infiltration and degranulation of a large number of mast cells in the ocular tissue.

In this example, the inventors constructed an allergic conjunctivitis mouse model to observe whether dipyridamole eye drops can effectively treat allergic conjunctivitis.

The specific experimental method is:

Forty female 8-week-old C57BL/6 mice were randomly divided into four groups, 10 mice in each group, including a blank group (without any treatment), a modeling group (without any treatment), a dipyridamole eye drop group, and a 0.1% emedastine eye drop group.

Except for the blank group, all experimental animals in other groups were sensitized by intraperitoneal injection of sensitizer (100 mg OVA + 1 mg aluminum hydroxide adjuvant dissolved in 200 mL saline) on days 0, 7, and 14. From days 21 to 27, 20 mL of stimulator (500 μg/mL OVA dissolved in saline) was dripped into both eyes of mice every day. From days 15 to 28, 20 mL of saline (modeling group), 5 mg/mL dipyridamole solution (dipyridamole eye drops group) or 0.1% emedastine (0.1% emedastine eye drops group) was dripped into both eyes of mice according to the grouping of each group.

On day 28 of modeling, the eye swelling of each mouse was evaluated, and the evaluation content included four parameters: eyelid swelling, conjunctival edema, conjunctival redness and tearing. The score range for each item ranged from 0 (no obvious symptoms) to 3 (the most severe symptoms), and the sum of the scores of the four parameters was combined to obtain the total eye swelling score for each animal. After the evaluation, the mice were killed, serum was collected, and the IgE concentration in the serum was detected (the IgE detection method is the same as that of Verification Example 3).

The results showed that the scores of eyelid swelling, conjunctival edema, conjunctival redness and tearing in the modeling group mice were significantly higher than those in the blank group mice, while the average scores of various parameters in the 0.1% emedastine eye drops group were significantly lower than those in the modeling group. It proved that the experimental model was successfully constructed and the positive reference drug worked well. The scores of eyelid swelling, conjunctival edema, conjunctival redness and tearing in the dipyridamole eye drops group mice were significantly lower than those in the modeling group. The therapeutic effect of the dipyridamole eye drops group mice was significantly different from that in the modeling group (P<0.05). It was proved that dipyridamole eye drops can significantly relieve the symptoms of eyelid swelling, conjunctival edema, conjunctival redness and tearing caused by allergic conjunctivitis, and the effect is significantly better than the reference drug 0.1% emedastine eye drops.

IgE is the main mediator molecule in allergic reactions, which can induce mast cells to release heparin, histamine and other particles, triggering immune responses. In allergic conjunctivitis, the concentration of serum IgE can be used as an indicator to judge the course of the patient's disease. In this experimental case, it was found that the serum IgE content of mice in the modeling group was significantly higher than that in the blank group. The serum IgE concentrations of the dipyridamole eye drops group and the 0.1% emedastine eye drops group were significantly decreased to varying degrees.

In summary, the above results can prove that dipyridamole eye drops can reduce the serum IgE concentration of allergic conjunctivitis model mice and alleviate the eye swelling and inflammation in allergic conjunctivitis.

Verification Example 6: Dipyridamole inhibits allergic rhinitis in mice

Allergic rhinitis, also known as allergic rhinitis, is an allergic disease that can cause a variety of complications. Allergic rhinitis is the most common type of rhinitis. It is usually caused by the release of histamine mediated by IgE after the body comes into contact with allergens, triggering the infiltration of multiple immune cells and inflammatory factors downstream. The main symptoms of allergic rhinitis include nasal itching, sneezing, hypersecretion of the nose, and swelling of the nasal mucosa. The main treatment methods are antihistamines and nasal inhaled hormones. It is generally believed that allergic rhinitis cannot be cured, but can only be controlled.

In this example, the inventors constructed an allergic rhinitis mouse model to observe whether nasal drops of dipyridamole can effectively treat allergic rhinitis.

The specific experimental method is:

Forty female C57BL/6 mice aged 6 to 8 weeks were randomly divided into four groups, 10 mice in each group, including a blank group (without any treatment), a modeling group (without any treatment), a dipyridamole intranasal drop group, and a levocabastine (0.5 mg/mL) intranasal drop group.

Except for the blank group, all experimental animals in other groups were sensitized by intraperitoneal injection of sensitizer (50 mg OVA + 2 mg aluminum hydroxide adjuvant dissolved in 200 mL normal saline) on days 0, 7, and 14. From day 21 to 27, 20 mL of stimulator (10 mg/mL OVA dissolved in normal saline) was dripped into both nostrils of mice every day. From day 15 to 27, before using the stimulator, 20 mL of normal saline (modeling group), 5 mg/mL dipyridamole solution (dipyridamole nasal drops group) or 0.5 mg/mL levocabastine (levocabastine nasal drops group) was applied to both sides of the mouse nostrils once a day according to the grouping of each group. On day 28 of modeling, the mice were killed.

On the 27th day, after the nasal provocation, the number of scratching and sneezing of the mice within 1 hour after each injection of the provocation was recorded; on the 28th day, the mice were killed, serum was collected, and the IgE concentration in the serum was detected (the IgE detection method was the same as that of Verification Example 3).

The evaluation method for rhinitis-related behaviors (scratching, sneezing) in mice is as follows: after intranasal OVA stimulation for 1 hour, the number of nose rubbing and sneezing behaviors of the mice within 5 minutes is recorded.

The number of sneezing and scratching in the modeling group mice was significantly higher than that in the blank group mice, while the average scores of various parameters in the levocabastine nasal drops group were significantly lower than those in the modeling group. This proves that the experimental model was successfully constructed and the positive reference drug worked well. The number of sneezing and scratching in the dipyridamole nasal drops group mice was lower than that in the modeling group, and the therapeutic effect of dipyridamole nasal drops was significantly different from that in the modeling group mice (P<0.05). This proves that dipyridamole eye drops can significantly relieve symptoms such as sneezing and scratching caused by allergic rhinitis, and the effect is significantly better than that of the reference drug.

Allergic rhinitis is a non-infectious inflammatory disease of the nasal mucosa in which an individual produces IgE and mediates the release of mediators (mainly histamine) after contact with allergens, and involves a variety of immune-active cells and cytokines. Therefore, allergic rhinitis is often accompanied by elevated serum IgE. In this experimental case, the serum IgE content of mice in the modeling group was significantly higher than that in the non-modeling group. The serum IgE concentrations of the dipyridamole eye drops group and the levocabastine nasal drops group were significantly decreased to varying degrees.

In summary, dipyridamole nasal drops can reduce the serum IgE concentration of allergic rhinitis model mice and alleviate the symptoms of allergic rhinitis.

Verification Example 7: Dipyridamole inhibits inflammatory bowel disease (IBD) in mice

In this example, the inventors constructed an inflammatory bowel disease mouse model to observe whether dipyridamole can treat inflammatory bowel disease.

The specific experimental method is:

Forty female C57BL/6 mice aged 6 to 8 weeks were randomly divided into four groups, 10 mice in each group, including a blank group (without any treatment), a modeling group (without any treatment), a dipyridamole group (5 mg/mL), and a mesalazine group (5 mg/mL).

Except for the blank group, all experimental animals in other groups were fed with deionized water (DI water) containing 2% dextran sulfate sodium (DSS) for 7 days. After DSS modeling, the dipyridamole group and mesalazine group were gavaged with corresponding dipyridamole and mesalazine, and the diet and hair of mice in each group were observed every day, and the body weight, fecal characteristics, occult blood, etc. of mice were observed every day, and the severity of colitis symptoms of mice was evaluated according to the disease activity index (DAI).

Table 46: Disease Activity Index (DAI) Scoring Criteria

Note: Normal stool characteristics refer to formed stool; loose stool refers to pasty, semi-formed stool that does not adhere to the anus; loose stool refers to watery stool that can adhere to the anus.

On the 8th day, the experimental mice were killed, and the colon, small intestine and other tissues were collected. The colon length of each group of mice was measured, and the rectal side of the colon was cut off. After being rinsed with PBS, it was fixed in 4% polyformaldehyde solution, and HE staining was used to analyze the pathological damage of the colon in each group.

The steps of HE staining are as follows: fix the tissue sample in 4% paraformaldehyde for 24 hours. After paraffin embedding, cut the lung tissue into 4-5 mm slices with a freezing slicer, wash with distilled water for 1-2 seconds, stain with hematoxylin (60℃) for 30-60 seconds, wash away the hematoxylin with running water, 1% hydrochloric acid ethanol for 1-3 seconds, wash with water, turn blue with blueing solution for 5-10 seconds, rinse with running water for 15-30 seconds, stain with 0.5% eosin solution for 30-60 seconds, wash with distilled water for 1-2 seconds, and then dehydrate with 80%, 95% and 100% ethanol gradient alcohol in turn, dehydrate for 1-2 seconds each step, soak in xylene 3 times, 2-3 seconds each time, and finally seal with neutral resin. Observe under a microscope.

The detection method of intestinal inflammatory cytokines (IL-1b, IL-6, TNF-a) is as follows: the residual fat layer of the mouse colon mesentery is peeled off, weighed and dispersed into 1 mL PBS to obtain a single cell suspension. After centrifugation at 4°C and 1000g for 10 minutes, the supernatant is taken and the level of inflammatory cytokines in the supernatant is measured by ELISA kits (IL-1b, IL-6, TNF-a ELISA kits are all purchased from the market). The ELISA measurement process refers to the instruction manual of each detection kit.

The experimental results showed that the use of dipyridamole can significantly reduce the weight loss of mice (P<0.05), and the stool characteristics and occult blood of mice were significantly reduced compared with the DSS model group, while there was no significant difference in the DSS model group (i.e., modeling group); histopathological results showed that feeding DSS significantly shortened the colon length (P<0.05), and HE staining results showed structural changes such as crypt atrophy and twisting, infiltration of inflammatory cells such as lymphocytes and plasma cells in the intestinal wall, and chronic inflammatory changes such as thinning of the intestinal wall; in the group using dipyridamole cream and gel, the colon of mice was significantly longer than that of the DSS model group, and the pathological damage was significantly reduced, while there was no significant difference in the DSS model group.

Verification Example 8: Dipyridamole inhibits acne in mice

Acne is a chronic inflammatory disease that usually affects the hair follicles and sebaceous glands. It mainly manifests as comedones, papules, pustules, nodules, cysts, and scars. Acne can occur in people of all ages, with the highest incidence in adolescents. Acne that occurs in adolescents is generally acne vulgaris, also commonly known as acne. Acne can also manifest as papules, pustules, nodules, cysts, scars, etc.

In this example, the inventors constructed a mouse acne model to observe whether dipyridamole can effectively treat acne.

The specific experimental method is:

Fifty female C57BL/6 mice aged 6 to 8 weeks were selected as experimental animals and randomly divided into 5 groups, 10 mice in each group, including a blank group (without any treatment), a modeling group (without any treatment), a dipyridamole cream Example 4 group (5 mg/mL), a dipyridamole gel Example 2 group (5 mg/mL), and a metronidazole (5 mg/mL) group.

Except for the blank group, all experimental animals in other groups need to undergo acne modeling, and the method is as follows: after Propionibacterium (ATCC1182) is cultured on agar and harvested, it is heat-inactivated at 95°C for 5 minutes and freeze-dried. The acne modeling bacterial suspension is prepared at a concentration of ¹⁰⁸ colony-forming units (CFU)/mL. The acne modeling bacterial suspension is injected into the skin on both sides of the back of the mouse using a 30-gauge needle. After modeling, dipyridamole cream Example 4, dipyridamole gel Example 2 and metronidazole are applied to the skin on both sides of the back of the mouse, and the condition of the mice is observed 2 weeks before and after the injection of the acne modeling bacterial suspension, and the degree of acne is evaluated by taking pictures.

After the experiment, the acne on the back of each group of mice was removed to obtain skin tissue samples. The tissue was made into paraffin-embedded tissue sections and HE staining (HE operation method is the same as the above verification example 7) was used to evaluate the results using Image J software.

Evaluation method of inflammatory cell infiltration and inflammatory cell cytokines: Take the cut part of the mouse acne skin, use commercial digestion solution (purchased from Xingeyuan Company) to digest the lesions and control skin (blank group), centrifuge to remove the precipitate, and keep the supernatant. Use ELISA kit to determine the concentration of IL-1b inflammatory cytokines in the skin. The lower cell precipitate is analyzed by flow cytometry for the levels of CD45+ (immune cells), CD3+ (T cells), CD19+ (B cells), Gr-1+ (granulocytes), and F4/80+ (macrophages) cells and compared.

The experiment found that the use of dipyridamole cream and gel can significantly change the histopathological changes of the acne model, significantly improve the cure rate (P<0.05), and significantly reduce the concentration of inflammatory cytokines. The metronidazole group can also improve the histopathological characteristics and The concentration of inflammatory cytokines was reduced (P<0.05), but there was still a certain gap compared with dipyridamole cream and gel. This shows that dipyridamole cream and gel have significant acne treatment effects.

Verification Example 9: Dipyridamole inhibits rosacea in mice

Rosacea, also known as rosacea, is a skin disease that occurs in the central part of the face. It is also a chronic inflammatory disease caused by dysfunction of facial nerve vasoconstriction and capillary dilation. The main manifestations of rosacea are redness of the nose, papules, pustules, etc. It is common in people with more facial oil secretion. Emotional tension and excessive fatigue will aggravate the condition.

In this example, the inventors constructed a rosacea mouse model to observe whether dipyridamole can treat rosacea.

As experimental animals, 50 female C57BL/6 mice aged 6 to 8 weeks were selected and randomly divided into 4 groups, 10 mice in each group, namely, a blank group (without any treatment), a modeling group (without any treatment), a dipyridamole cream Example 6 group (2 mg/mL), and a dipyridamole gel Example 4 group (5 mg/mL).

Except for the blank group, all experimental animals in other groups need to undergo rosacea modeling by using LL-37 peptide (amino acid sequence: LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES (SEQ ID NO: 1)). The hair on the back skin of the experimental mice was shaved with an electric razor. After 24 hours, LL-37 (320 μM, InvivoGen) was dissolved in 40 μL of injection water, and then subcutaneously injected into the shaved area using a 0.5 mL insulin syringe (No. 31) to form dermal blebs. Mice in the blank group were subcutaneously injected with 40 μL of injection water. Repeat twice a day for 48 hours. In the dipyridamole group, dipyridamole cream and dipyridamole gel were wiped on the mouse skin every 6 hours. After the end, the dorsal skin condition was photographed, and the skin score was performed according to Table 49 to evaluate the back skin condition.

After the experiment was completed, the experimental mice were anesthetized and killed. The dorsal skin tissue specimens were taken and the tissues were fixed and sliced for evaluation.

The evaluation of inflammatory cell infiltration and inflammatory cell cytokines was the same as in Validation Example 8.

The results showed that the use of dipyridamole cream and gel could significantly improve rosacea-like dermatitis, including improving inflammatory infiltration and angiogenesis in rosacea mice.

Verification Example 10: The actual effect of dipyridamole on human body

1. Human skin safety:

In this example, the safety of different dosage forms of dipyridamole for human use was tested. The dosage forms used include:

Dipyridamole tincture 1: Stir 5 g of dipyridamole with 1000 mL of 75% ethanol until dissolved to obtain a 5 mg/mL dipyridamole tincture product.

Dipyridamole comparative cream 1: that is, the dipyridamole cream in the above-mentioned cream comparative example 1.

The dipyridamole cream of the present application is the dipyridamole cream in the above-mentioned cream embodiment 2.

Dipyridamole comparative cream 2: that is, the dipyridamole cream in cream comparative example 8.

Dipyridamole comparative gel 1: the dipyridamole gel in the above-mentioned gel comparative example 1.

The dipyridamole gel of the present application is the dipyridamole gel in the above-mentioned gel embodiment 1.

Dipyridamole comparative gel 2: the dipyridamole gel in the above-mentioned gel comparative example 2.

70 healthy volunteers were selected and divided into 7 groups, 10 in each group. 0.20g of the above cream and 0.2mL of gel were taken into the spot tester respectively. The control well was used as a blank control and no substance was placed. The spot tester with cream or gel was applied to the skin of the forearm of the subject with medical tape for 24 hours. 30 minutes after removing the test spot tester, observe the skin reaction after the indentation disappears. For those with negative results, observe again 24 hours and 48 hours after the test. Record the skin reaction results according to the skin adverse reaction grading standard in Table 47.

Table 47 Classification criteria for adverse skin reactions

The skin reaction results of the subjects are shown in Table 48.

Table 48 Skin reaction results of subjects

The results show that no skin reaction was found in the subjects using the cream and gel of the present application, and no skin irritation reactions or phenomena such as erythema, edema, papules, and tingling were visible, indicating that the cream or gel formula in the above cream embodiment and gel embodiment has no irritation or adverse reaction to human skin and good safety. In contrast, one subject using tincture 1 had erythema of level 3 exceeding the test area, two had level 2 erythema, and one had weak level 1 erythema. Two subjects using contrast cream 2 had level 2 papules, one subject using contrast gel 1 and one subject using contrast gel 2 had suspicious reactions, and the safety was poor.

In order to further verify its safety, different from the non-facial skin in the above verification, the inventor uses facial skin that is more sensitive to external stimuli to verify the safety (irritation) of the above-mentioned effects and products (creams and gels) with better safety. The test method is: 20 healthy volunteers were selected and divided into 2 groups, with 10 volunteers in each group. After thorough face cleansing, the cream of cream embodiment 2 or the gel of gel embodiment 1 was gently massaged and applied to the same side of the face and the depression behind the ear, respectively, with an application area of about 2×2 cm ^2. After 2 hours, the skin condition was investigated (the erythema and edema after applying cream 2 or gel 2 were scored). Among them, the skin condition grading standard is shown in Table 49.

Table 49 Skin condition classification standards

The skin conditions of the subjects are shown in Tables 50 and 51.

Table 50 Skin irritation results of the face and the depression behind the ear of the cream example 1 of the present application

Table 51 Skin irritation results of the face and the depression behind the ear of the gel example 1 of the present application

From the above results, it can be seen that the cream and gel of the present application did not cause erythema or edema in the trial participants, have low skin irritation, high safety, and are suitable for a wide range of groups.

2. The actual therapeutic effect of the dipyridamole cream of this application on human allergic skin diseases:

2.1 Concentrated experimental effect

In this embodiment, 12 volunteers (requirement: no anti-allergic drugs were used within one week) were selected as test subjects to verify the actual therapeutic effect of the dipyridamole cream of the present application (selecting the 0.5% dipyridamole cream shown in Cream Example 1 - light yellow and uniform, recorded as "0.5% self-developed cream"; the 2% dipyridamole ointment shown in Ointment Example 5 - bright yellow and uniform, recorded as "2% self-developed ointment"), dipyridamole cream prepared by other methods (selecting the dipyridamole comparative cream prepared with vanishing cream as the matrix shown in Ointment Comparative Example 8, the dipyridamole concentration was selected as 2%, specifically, 0.25g of dipyridamole was mixed with 12.5g of Pechoin brand vanishing cream, and undissolved particles were visible to the naked eye, recorded as "2% vanishing cream") and the positive drug Pi Yan Ping on human allergic skin diseases.

Experimental method: The skin prick test, which is recognized by European countries and the United States as the most convenient, economical, safe and effective allergen diagnostic method, was used for verification. Histamine allergy generally refers to the skin stimulating the production of histamine, an inflammatory mediator, after the patient contacts the allergen and has an allergic reaction, which causes the surrounding capillaries to dilate and form edema/itching/erythema symptoms, thus causing skin allergic reactions. It is used to show the efficacy of the drug to be tested on allergic and inflammatory diseases. In order to ensure the smooth progress of the experiment, the histamine concentration (10mg/ml) that can cause an allergic skin bulge of about 1cm in diameter within 15min was selected as the drug efficacy screening model concentration after preliminary experiments. The specific experimental steps are as follows: the inside of the volunteer's arm was wiped and disinfected with 75% alcohol and evaporated to dry; PBS and histamine allergen (10 mg/ml, dissolved in PBS) were respectively transferred to the skin surface with a pipette of 20 μl and then pricked with a pricking needle with the same force (PBS and histamine allergen were grouped into two, and a total of 4 groups were used for drug administration testing). After waiting for 5 minutes, the rash was wiped off and the area of the rash was measured, and then the drug was administered (2% vanishing cream of dipyridamole, 0.5% dipyridamole cream, 2% dipyridamole ointment, positive control drug Pi Yan Ping), and then the rash area was recorded once at 5min, 15min, 30min and 60min, and the largest and smallest bulge areas were selected for data statistical analysis.

Experimental results (Note: In the following results, the effective rate is the reduction rate of the blister diameter compared with the blank PBS group; the most effective rate is the horizontal comparison of the administration of 4 drugs to the same person after histamine allergen stimulation; the range of blister reduction is the longitudinal comparison after collecting data from 12 people; please see Figure 16):

① 2% vanishing cream formula of dipyridamole (2% vanishing cream):

The effective rate is 83.3% (10/12), the most effective rate is 8.3% (1/12), and the bulge reduction range is 0-50%

②0.5% dipyridamole cream (0.5% self-developed cream):

The effective rate was 66.7% (8/12), the most effective rate was 16.7% (2/12), and the range of bulge reduction was 0-44.4%.

③2% dipyridamole ointment (2% self-developed ointment):

The effective rate was 100% (12/12), the most effective rate was 66.7% (8/12), and the range of bulge reduction was 14.3-83.3%

④ Positive drugs (piyanping, hormones):

The effective rate was 100% (12/12), the most effective rate was 33.3% (4/12), and the range of bulge reduction was 14.3-100%.

Experimental conclusions: ① 0.5% self-developed dipyridamole cream can achieve the effect of 2% vanishing cream of dipyridamole; 2% self-developed dipyridamole ointment achieves an effect far exceeding that of 2% vanishing cream of dipyridamole; it can be seen that dipyridamole can be used to prevent and treat allergic skin diseases, and the better the solubility state of dipyridamole in topical preparations and the higher the drug loading, the more obvious the drug effect, and the cream formula of the present application is superior to the similar cream formula of the prior art; ② 2% self-developed dipyridamole ointment is equivalent to or better than the positive drug dermatitis cream, but the side effects and drug resistance are lower in terms of mechanism and practical experience.

2.2 Individual application effects

Mr. Liu reported that he often suffered from allergies. When he had allergies, he tried the 2% self-developed dipyridamole cream of the present application and was able to quickly stop itching and reduce redness (see Figure 17, which is a comparison of the patient's before and after use of the cream of the present application, 3 times a day, and the photo was taken after 2 days of use).

3. The actual therapeutic effects of the dipyridamole cream and gel of the present application on human allergic conjunctivitis and allergic rhinitis:

In this embodiment, some actual cases were selected as test subjects to verify the actual therapeutic effects of dipyridamole cream 2 and gel 2 on human allergic conjunctivitis and allergic rhinitis.

For allergic conjunctivitis: 20 patients diagnosed with allergic conjunctivitis by Western medicine were selected, aged 7 to 45 years old, among which 10 patients were smeared with the above-mentioned dipyridamole cream (cream example 2) of the present application, and the other 10 patients were smeared with the above-mentioned dipyridamole gel (gel example 1) of the present application for treatment, and the cream was applied once on the affected area, around the eyes and the corners of the eyes after cleansing in the morning and evening every day (close the eyes for 1 minute after application), and used for a total of 7 days, and interviews and registrations on the use effect were conducted on the 0th day, the 7th day, and the 14th day. No other topical medications were used during the trial.

For allergic rhinitis: 20 patients diagnosed with allergic rhinitis by Western medicine, aged 21 to 50 years old, were selected, among which 10 patients were smeared with the above-mentioned cream of the present application (cream example 2), and the other 10 patients were smeared with the above-mentioned dipyridamole gel of the present application (gel example 1) for treatment, and the cream was applied once every morning and evening after cleansing the face around the nasal cavity and the Yingxiang acupoints on both sides and slightly massaged, and used for a total of 7 days, and interviews and registrations on the use effect were conducted and statistics were collected on the 0th day, the 14th day, and the 28th day. No other external medications were used during the trial.

The efficacy standards for the above-mentioned allergic conjunctivitis and allergic rhinitis are: cured, markedly effective, effective, and ineffective. Among them, the standard for cure is: the clinical symptoms basically disappear (for conjunctivitis, the symptoms such as apparent redness, swelling, itching, and pain basically return to normal; for rhinitis, the symptoms such as runny nose, nasal congestion, nasal itching, sneezing, and headache basically disappear), and the efficacy is ≥90%. The standard for marked efficacy is: the clinical symptoms are significantly improved (for conjunctivitis, the corneal and conjunctival lesions disappear and the itching of the eyes is eliminated; for rhinitis, the frequency of runny nose, nasal congestion, nasal itching, sneezing, etc. is significantly reduced), 50%≤efficacy＜89%. The standard for effective is: clinical symptoms are improved (for conjunctivitis, the corneal and conjunctival lesions are relieved and the itching of the eyes is relieved; for rhinitis, the symptoms such as runny nose, nasal congestion, nasal itching, sneezing, etc. are relieved), 20%≤efficacy＜50%. The criteria for ineffectiveness are: there is basically no improvement in clinical symptoms (for conjunctivitis, there is no improvement in corneal and conjunctival lesions and eye itching; for rhinitis, there is no improvement in the frequency or severity of runny nose, nasal congestion, nasal itching, and sneezing), and the efficacy index is less than 20%.

At the same time, patients self-scored according to the following VAS scoring scales for conjunctivitis and rhinitis (which represent the perceptual indicators of allergic diseases in terms of psychophysics and physiology to the human body and the pain of the disease) (confirming the corresponding symptom degree by filling out forms and interviews). Among them, for conjunctivitis: no symptoms are 0 points, and the most uncomfortable is 10 points (symptoms include the overall feeling of red eyes, swelling, itching, pain, congestion, tearing, photophobia, and foreign body sensation); for rhinitis: no symptoms are 0 points, and the most uncomfortable is 10 points (symptoms include the overall feeling of nasal discharge, sneezing, nasal itching, and nasal congestion).

The results are shown in Tables 52 to 53 and Tables 54 to 55.

Table 52 Results of efficacy evaluation of allergic conjunctivitis on day 14

Table 53 Comprehensive scoring results of the efficacy of allergic conjunctivitis

It can be seen from the above results that after two weeks of treatment, the patients' apparent efficacy results and self-conjunctivitis scores were significantly improved, and the patients responded that the rapid relief of eye itching symptoms was more obvious, followed by obvious pain relief, redness relief, swelling relief, and foreign body sensation relief functions, indicating that the above-mentioned dipyridamole cream and dipyridamole gel of the present application have the effect of treating allergic conjunctivitis. Moreover, improper use of clinically used glucocorticoid eye drops can cause ocular hypertension, which is more obvious in children. Therefore, it is more conducive to helping patients and children quickly relieve symptoms such as eye itching, avoiding the side effects of other drugs such as glucocorticoids, and more dosage forms suitable for eye use can be prepared or adjusted according to needs for subsequent application, such as eye drops.

Table 54 Results of efficacy evaluation of allergic rhinitis on day 28

Table 55 Comprehensive scoring results of allergic rhinitis efficacy

It can be seen from the above results that after four weeks of treatment, the patients' apparent efficacy results and self-rhinitis scores were significantly improved, and the patients responded that they tended to choose a more refreshing gel formulation (the dipyridamole gel of the present application) for facial skin, which could quickly relieve nasal itching and nasal congestion, and the number of sneezing was also significantly reduced, indicating that the dipyridamole cream and dipyridamole gel of the present application have It has the effect of effectively controlling rhinitis. In the future, more dosage forms suitable for the nasal cavity can be prepared according to demand, and more dosage forms suitable for use in the eyes and nose can be prepared according to demand for application, such as nasal drops.

4. Actual therapeutic effects of dipyridamole cream and gel on human acne:

In this example, some actual cases were selected as test subjects to verify the actual therapeutic effect of dipyridamole cream and gel on human acne.

20 patients aged 12 to 35 with obvious acne on the face, chin and/or forehead were selected, 10 of whom were treated with the dipyridamole cream (cream example 2) of the present application, and the other 10 were treated with the dipyridamole gel (gel example 1) of the present application. The treatment was applied once every morning and evening after cleansing the face for a total of 28 days, and the use effect interviews and statistics were conducted on the 0th, 7th, 14th and 28th days. No other topical medications or antibiotics were used during the trial. It should be noted that the selected patients had applied compound polymyxin B ointment, tretinoin cream, aloe vera gel, oral doxycycline hydrochloride enteric-coated capsules and other drugs to treat acne before this test, but the effects were repeated.

The efficacy criteria for the above-mentioned acne are: the main efficacy parameters are the reduction in the total number of inflammatory lesions (the sum of papules and pustules, the degree of reduction of redness, swelling and red marks) and the area of lesions (measured in centimeters "cm"). Among them, the standard for cure is: lesion reduction ≥90%; the standard for marked effect is: lesion reduction 50%~89%; the standard for onset of effectiveness is: lesion reduction 20%~49%; the standard for ineffectiveness is: no change in the condition, or the lesion reduction result is less than 20%.

The results are shown in Table 56 and Figure 12.

Table 56 Acne efficacy evaluation results on day 28

It can be seen from the above results that the cream and gel in the above embodiments can achieve a basic effective effect after 7 days of use, and have good acne removal and anti-inflammatory effects after 28 days, and have obvious skin lesion repair effects. It has the advantages of hidden blemish concealment, gentle and easy application, promoting wound healing, and preventing scar hyperplasia. Among them, a representative case can be seen in Figure 12.

5. Actual therapeutic effects of dipyridamole cream and gel on human rosacea:

In this example, some actual cases were selected as test subjects to verify the actual therapeutic effect of dipyridamole cream and gel on human rosacea.

21 patients diagnosed with rosacea (aged 11-51 years old) were selected, of which 11 were treated with the dipyridamole cream (cream example 2) of the present application, and the other 10 were treated with the dipyridamole gel (gel example 1) of the present application. The cream was applied once a day after cleansing in the morning and evening for a total of 28 days. Interviews and statistics on the effects of use were conducted on the 0th, 7th, 14th and 28th days. No other topical medications or antibiotics were used during the trial. Then, the severity of patients diagnosed with rosacea (or pityriasis rosea) on the 0th day (before treatment) and the 28th day (after treatment) were graded according to the Investigator Global Assessment (IGA). The grading standards are shown in Table 57.

Table 57 IGA-based grading criteria for severity of rosacea

The therapeutic effects are shown in Tables 58 and 59.

Table 58 The therapeutic effect of dipyridamole cream

Table 59 The therapeutic effect of dipyridamole gel

From the above results, it can be seen that after using the cream and gel in the above examples, the rosacea ratings of all patients were reduced. Patients reported that the cream and gel had good ductility, were easy to apply, were invisible, and were willing to use them. Moreover, after one cycle of use (28 days), it can be clearly felt that the number of facial redness and hotness, the number of papules or pustules, and facial scales were reduced. Some patients also showed a significant reduction in the number of capillaries after visia detection.

6. The actual therapeutic effect of dipyridamole cream and gel on human scar hyperplasia:

In this example, some actual cases were selected as test subjects to verify the actual therapeutic effect of dipyridamole cream and gel on human scar hyperplasia.

Ten patients with scar constitution (3 patients) or newly formed scars (7 patients) after trauma (among which, the gender distribution of the patients was 3 males and 7 females) were treated with the above-mentioned dipyridamole cream and dipyridamole gel (5 patients each). The dipyridamole cream (cream example 1) and dipyridamole gel (gel example 4) were applied to the affected area and massaged until absorbed, once in the morning and evening, for 2 consecutive months. At the end of the first and second months, interviews on the effects of use were registered and statistics were conducted.

After one month of use, all 10 patients felt that the pain and itching symptoms of the wound surface were significantly improved; after two months of use, among the three patients with scabs, two did not form scars, one patient's scars were significantly reduced after formation, and the scar surface of the remaining seven patients with newly formed scars became softer, the protrusions were reduced or became less obvious, and the pigmentation was significantly improved. All 10 patients had no itching on the wound surface/scar surface, and no patient said that there was no change in the wound surface or scar surface (i.e., 100% effective). The above results show that dipyridamole topical preparations can effectively prevent and treat scar hyperplasia.

7. Actual therapeutic effects of dipyridamole cream and gel on human hemorrhoids:

In this example, some actual cases were selected as test subjects to verify the actual therapeutic effect of dipyridamole cream and gel on human hemorrhoids.

Thirty patients with hemorrhoids (8 males and 12 females) were randomly divided into three groups, each with 10 patients. They were treated with dipyridamole cream (cream example 1 group), dipyridamole gel (gel example 4) and positive drug Mayinglong ointment (control group), respectively. Each group used it once in the morning and once in the evening (after defecation in the morning and before going to bed at night) for 14 consecutive days, and interviews and registrations of the effects of use and statistical records were conducted on the 0th day, the 7th day, the 14th day and the 3rd month.

The efficacy criteria for the above hemorrhoids are as follows: Cured: no bleeding, oozing, and basically no pain. Significantly effective: no bleeding, oozing, pain is significantly relieved, and wound healing time is significantly shortened. Effective: no bleeding, oozing, pain is relieved, and wound healing time is shortened. Ineffective: still There is no bleeding or oozing, no relief of pain, and no significant shortening of wound healing time.

The results are shown in Table 60.

Table 60 Hemorrhoids efficacy evaluation results on the 14th day and recurrence rate survey results after 3 months

It can be seen from the above results that the dipyridamole topical ointment (cream and gel) in the above embodiments has a significant therapeutic effect on hemorrhoids, and has the effect of quickly reducing swelling, relieving itching and relieving pain. Among them, about 80% of the patients who tried the cream and gel responded that they had achieved relatively obvious symptom improvement on the 7th day of the first follow-up visit, and after a 3-month follow-up visit, it was found that the recurrence rate of hemorrhoids in patients using the cream and gel was low (no recurrence in the cream group, only 1 recurrence in the gel group), while the number of recurrences in the control group reached 4. It can be seen that the dipyridamole topical ointment is superior to the currently available positive control drug in terms of effectiveness, recurrence prevention rate, etc.

8. Actual therapeutic effects of dipyridamole cream and gel on human sty:

In this embodiment, some actual cases were selected as test subjects to verify the actual therapeutic effect of dipyridamole cream and gel on human sty.

Among 12 patients (7 to 35 years old) with newly developed styes, 6 were treated by applying dipyridamole cream (cream example 2) to the affected area, and 6 were treated by applying dipyridamole gel (gel example 1) to the affected area. The medication was administered once in the morning, afternoon and evening for 3 consecutive days, and the effect of use was followed up and registered and counted at the end of the 3rd day and on the 14th day.

The efficacy criteria for the above-mentioned styes are as follows: Cured: The subjective symptoms disappear within 3 days, and the local redness, swelling and nodules subside and return to normal. Effective: The symptoms disappear within 3 days or only mild discomfort remains, and the local redness and swelling are significantly reduced, or there is only a subcutaneous nodule and the appearance is normal. Ineffective: The above criteria are not met after more than 3 days of treatment or the ulcer heals spontaneously.

The results are shown in Table 61.

Table 61 Efficacy evaluation results on day 3

From the above results, it can be seen that the cream group was effective for all patients, the gel group also achieved an effective rate of 83.33%, and more than 90% of the patients' eyelid edema and induration subsided significantly, and the symptoms were basically eliminated within 1 day at the fastest. No recurrence was found in the cured patients after a follow-up visit after 14 days. The above results show that dipyridamole topical preparations have significant efficacy in treating sty diseases. In order to facilitate popularization and application, they can also be prepared into other local eye preparations (such as eye drops) for application in the later stage.

9. The actual therapeutic effect of dipyridamole cream and gel on other allergic and inflammatory diseases in the human body:

Since the above examples have fully demonstrated that the dipyridamole topical preparation has good animal experimental effects and high safety, and its anti-allergic, anti-inflammatory, antipruritic, analgesic and other efficacy and mechanism have been preliminarily analyzed, the above dipyridamole cream and gel can be further distributed and expanded to various groups of people who need anti-allergic and anti-inflammatory treatments for application based on its therapeutic mechanism. The following are the actual verification results of some cases.

a. Urticaria:

Case 1: Patient Lin, male, 15 years old, had urticaria on his body for unknown reasons about 5 years ago. Among them, some acute urticaria would itch, and 5-8mm wheals would appear after scratching, which would be relieved after taking a bath or applying antipruritic ointment, but the urticaria at the elbows would not disperse for a long time after applying the ointment, forming a rash with pieces of aggregates. In severe cases, urticaria would appear all over the body, with wheals all over the body. He had been to the hospital for treatment and was prescribed the antiallergic drug cetirizine for three days, but the patient would still have an attack after stopping the drug. When acute urticaria and wheals appeared again on the upper left waist, after using the above-mentioned dipyridamole cream (cream embodiment 2) of the present application, it was found that the antipruritic effect was very obvious, and the wheals were basically disappeared after about half an hour (as shown in Figure 13). In addition, sometimes after sweating during exercise, urticaria would also appear in the armpits, sometimes around the elbows, waist, thighs, etc. During the period of frequent urticaria, the above-mentioned dipyridamole cream was used for treatment, with obvious effects and no adverse reactions. The chronic urticaria on the elbows was basically cured after two months of continuous use of dipyridamole cream 2 (twice a day, morning and evening) (as shown in Figure 14).

Case 2: Patient Deng, female, 45 years old, developed urticaria on her abdomen and waist. The rash was in the form of red wheals. After applying the dipyridamole gel of this application, itching was quickly relieved within 5 minutes, and the wheals disappeared after 1 hour.

Case 3: Patient Liu, male, 36 years old, had recurrent urticaria on the back of his hands about 2 years ago, with redness, swelling and multiple The patient had a wheal and applied the dipyridamole cream of the present application. The patient reported that the immediate antipruritic effect was very good. After using it twice a day for two weeks, the redness, swelling and wheal were significantly reduced, the itching basically disappeared, and no side effects were observed.

b. Solar dermatitis:

Case 1: Patient Li, female, 44 years old, and her 10-year-old daughter, both suffered sunburn due to improper protection when traveling on the beach. They had symptoms such as flushing of the skin on their limbs, burning and stinging, and partial skin desquamation. The mother and daughter tried the dipyridamole cream (cream example 3) and gel (gel example 2) of the present application, respectively, twice a day, thickly applied. After the trial, they reported that the burning and stinging sensation was significantly reduced on the same day, the skin no longer desquamated on the second day, and was basically cured on the third day.

c. Gastroenteritis (including inflammatory bowel disease):

Case 1: Patient Ms. Wu, 30 years old, suffers from chronic gastritis and suffers from irregular gastric colic attacks all year round. She needs to take omeprazole, domperidone tablets and the like to relieve the symptoms. When gastric pain attacks occur on different days, she tries the dipyridamole cream (cream example 3) and gel (gel example 2) of the present application respectively, and finds that both can quickly stop gastric colic and thus relieve the symptoms of gastritis.

Inflammatory bowel disease mainly includes ulcerative colitis and Crohn's disease. It is a chronic recurrent disease with intestinal inflammation and epithelial damage as pathological characteristics and is difficult to cure. Moreover, according to epidemiological data, the duration and severity of chronic colitis are important risk factors for colitis-related colorectal cancer. In this regard, two patients with Crohn's disease and ulcerative colitis were found and the above-mentioned dipyridamole topical preparation was tried respectively. The results are as follows:

Case 1: Ms. Zhang, 65 years old, was previously diagnosed with Crohn's disease, a type of inflammatory bowel disease, by the hospital and applied the dipyridamole cream of this application externally.

Case 2: Mr. Ye, 45 years old, was previously diagnosed with ulcerative colitis among inflammatory bowel diseases by the hospital and applied the dipyridamole gel of this application externally.

The two applied the corresponding topical preparations to the entire gastrointestinal tract twice a day and massaged until absorbed, and increased the frequency of application when the disease flared up. The results showed that after one month of trial use, both reported that the use of the corresponding topical preparations during an attack could effectively relieve abdominal pain, and that after regular application, the frequency of diarrhea and abdominal pain decreased, appetite increased, and there was no skin allergic reaction. The safety was good and they planned to continue using it.

The above cases show that the dipyridamole topical preparation of the present application can be absorbed transdermally, can be anti-inflammatory and analgesic, and can be used to prevent and treat inflammatory bowel disease and prevent its progression to colorectal cancer.

d. Gynecological inflammation (vulvar pruritus, dysmenorrhea, mastitis):

Case 1: Ms. Zhang, 33 years old, had vulvar itching for several days, which tended to become more and more itchy and accompanied by more and more small red rashes. She used dipyridamole gel (gel example 1) once each morning and evening after cleaning her vulva with clean water. After using it for 7 consecutive days, she reported that the antipruritic effect was good and lasted for a long time. She was cured after 7 days, indicating that the dipyridamole gel had certain anti-inflammatory and antibacterial effects, and also showed good compliance for patients with gynecological inflammation.

Case 2: Ms. Li, 29 years old, had obvious menstrual dysmenorrhea symptoms during work. After applying the dipyridamole cream of the present application (cream example 5) externally, the dysmenorrhea was well relieved.

Case 3: Ms. Jiang, 35 years old, was found to have blocked breasts, mastitis and breast nodules after giving birth. However, she could not take medication at will during the lactation period, so she endured the pain and did not take medication for more than 3 months. Later, she rubbed and massaged the dipyridamole gel (gel example 5) of the present application on the affected area twice a day for 1 month. During the follow-up visit, it was found that the swelling and pain in her breasts had basically disappeared, and there were no lumps or nodules that could be touched.

e. Pharyngitis:

Case 1: Patient Liang, 46 years old, a teacher, often suffered from pharyngitis, dry throat, hoarseness, itching and occasional throat swallowing pain. He then insisted on trying the dipyridamole gel of the present application (gel embodiment 5), evenly applied it on the external skin of the affected area, once in the morning and once in the evening, for 2 months. Feedback: the symptoms of itchy throat were significantly improved, hoarseness and pain were also significantly improved, and the number of attacks was greatly reduced after discontinuation of use.

f. Herpes virus infection:

Case 1: Patient Zhang, female, 5 years old, was infected with hand, foot and mouth disease. Small blisters appeared on her hands, neck and face. The dipyridamole cream of the present application (cream example 1) was applied externally to the affected area, once in the morning and evening, for 7 days. The rash and blisters disappeared, and the patient recovered without any adverse reactions.

g. Frostbite:

Case 1: Yu Moumou, female, 37 years old, gets frostbite on the back of her hands every winter, with multiple scattered red, swollen, hard masses, unbearable itching, and some ulcers, which are painful. Apply the dipyridamole cream (cream example 1) of the present application to the affected area, once in the morning and once in the evening, for a long time. Continue for 14 days. After the second day, the itching was significantly relieved, and the antipruritic and analgesic effects were obvious. After 5 days, the red and swollen hard lumps became relatively flat. Continue to use it until the frostbite is cured, the scar disappears, there is no recurrence that year, and there are no adverse reactions during use.

h. Fungal infection:

Case 1: Zhang Moumou, who had a pet cat with ringworm (fungal infection), had obvious hair loss on the cat's ears and neck. After using multiple medicines at the pet hospital, they were ineffective and the hair loss became more and more serious. Later, he insisted on using the dipyridamole cream of the present application (cream example 2). After using a 50g bottle, the cat has basically recovered (as shown in Figure 15, it can be seen that the hair has grown again).

Case 2: Qi, male, 13 years old, had an obvious round red patch with a diameter of about 3 cm on his face, slightly scaly at the border, and itchy. He was diagnosed with fungal infection by the hospital. He applied dipyridamole cream (cream example 7) on time once in the morning and evening. After a follow-up visit, he was informed that the condition was significantly relieved and the antipruritic effect was outstanding after the fourth day of application of the cream. After continuous medication for 1 month, the symptoms disappeared and the skin was completely healed.

The above embodiments are preferred implementation modes of the present application, but the implementation modes of the present application are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present application should be equivalent replacement methods and are included in the protection scope of the present application.

For the purpose of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements about the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents.

Claims

Application of dipyridamole or its derivatives in the preparation of drugs for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases.
The use according to claim 1, wherein the allergic diseases include skin diseases caused by allergies, respiratory diseases caused by allergies, digestive tract diseases caused by allergies, and eye diseases caused by allergies.
According to the use according to claim 1, the allergic diseases include allergic rhinitis, allergic conjunctivitis, allergic asthma, allergic dermatitis, allergic urticaria, food allergy, dust allergy, mite allergy, hay fever, drug allergy, allergic bronchial asthma, allergic sinusitis, allergic respiratory distress syndrome, preferably allergic conjunctivitis, allergic rhinitis, allergic urticaria.
The use according to claim 1, wherein the inflammatory disease includes infectious diseases, non-infectious diseases, and post-infectious hyperplasia.
The use according to claim 4, wherein the infectious diseases include infectious conjunctivitis, infectious rhinitis, infectious rosacea, infectious urticaria, infectious asthma, and infectious diarrhea.
The use according to claim 4, wherein the infectious disease includes viral infectious diseases, fungal infectious diseases, bacterial infectious diseases, parasitic infectious diseases, and mycoplasma infectious diseases.
The use according to claim 6, wherein the viral infectious diseases include herpes, viral conjunctivitis, viral rhinitis, novel coronavirus pneumonia, influenza, viral hepatitis, viral rhinitis, viral pharyngitis, viral enteritis, viral diarrhea, chickenpox, and mumps.
The use according to claim 7, wherein the viral hepatitis includes hepatitis A, hepatitis B, and hepatitis C.
The use according to claim 7, wherein the herpes includes EV71 viral herpes.
The use according to claim 6, wherein the fungal infectious diseases include tinea pedis and ringworm of cats.
The use according to claim 6, wherein the bacterial infectious diseases include bacterial conjunctivitis, bacterial rhinitis, purulent tonsillitis, acne, sty caused by bacterial infection, bacterial gastritis, bacterial pharyngitis, and bacterial mastitis.
The use according to claim 11, wherein the gastritis caused by bacteria includes gastritis caused by Helicobacter pylori.
The use according to claim 11, wherein the bacterial mastitis includes mastitis caused by Staphylococcus aureus.
The use according to claim 6, wherein the parasitic infectious disease comprises ascariasis infection and malaria infection.
The use according to claim 6, wherein the mycoplasma infectious disease includes adnexitis caused by mycoplasma infection.
The use according to claim 4, wherein the non-infectious diseases include non-infectious dermatitis, abdominal pain caused by lactose intolerance, conjunctivitis caused by external stimulation, glaucoma, cataracts, dry eyes, non-specific keratitis, rosacea caused by neurological disorders, urticaria caused by physical stimulation, pharyngitis caused by external stimulation, inflammatory bowel disease, and mastitis caused by external pressure.
The use according to claim 16, wherein the non-infectious dermatitis includes traumatic dermatitis, dermatitis caused by surgical wounds, solar dermatitis, frostbite, and insect bite dermatitis.
The use according to claim 16, wherein the inflammatory bowel disease includes ulcerative colitis, Crohn's disease, and indeterminate colitis.
The use according to claim 4, wherein the post-infectious hyperplasia includes thyroid nodules, hemorrhoids, scar hyperplasia, sty, thyroid nodules, breast nodules, and breast hyperplasia.
The use according to claim 1, wherein the inflammatory disease includes dermatitis, asthma, conjunctivitis, rosacea, urticaria, sty, gastritis, rhinitis, pharyngitis, adnexitis, urethritis, vaginitis, mastitis, inflammatory bowel disease, frostbite, acne, blackheads, enlarged pores, red blood streaks, seborrheic dermatitis, seborrheic alopecia, scleroderma, vitiligo, purpura, nevus, melanoma, preferably conjunctivitis, rosacea, rhinitis, acne.
The use according to any one of claims 1 to 20, wherein the drug is an internal preparation or an external preparation, preferably an external preparation.
The use according to claim 21, wherein the external preparation includes ointments, creams, gels, lotions, tinctures, suspensions, liniments, spirits, powders, oils, pastes, plasters, coatings, aerosols, solutions, sprays, and patches.
The use according to claim 21, wherein the external preparation is a cream.
The use according to claim 21, wherein the external preparation is a gel.
The use according to claim 21, wherein the external preparation is an ointment.
The use according to claim 21, wherein the external preparation further comprises one or more of the following substances: a solvent, an emulsifier, a softener, an antioxidant, a preservative, a chelating agent, a pH adjuster, a thickener, a penetration enhancer, and a sunscreen.
According to the use of claim 26, the external preparation may further comprise one or more of the following: a moisturizer, a gel base, water, and an ointment base.
The use according to any one of claims 1 to 27, wherein the frequency of use of the drug is: 1 to 3 times every 1 to 24 hours, or 1 to 3 times a day, preferably 2 to 3 times a day.
The use according to claim 28, wherein the dosage of the drug per time is: calculated as dipyridamole, 1-250 mg per time, preferably 5-100 mg per time, more preferably 10-50 mg per time; or; the drug is administered in a cosmetically effective amount; or the drug is administered in a therapeutically effective amount.
The use according to claim 29, wherein the drug is administered by coating or spraying the drug on the skin surface corresponding to the affected area.
The use according to claim 30, wherein the dosage of the drug per time is: 0.1-25 mg per cm 2 of dipyridamole; preferably 0.2-10 mg/cm 2 ; more preferably 0.5-5 mg/cm 2 .
According to the use according to any one of claims 1-31, the derivative comprises a pharmaceutically acceptable salt, hydrate, solvate, polymorph, structural isomer or prodrug of dipyridamole.
According to the use of claim 32, the pharmaceutically acceptable salt of dipyridamole includes dipyridamole sodium chloride or dipyridamole hydrochloride.
The use according to any one of claims 32-33, wherein the mass percentage of dipyridamole and/or its derivatives in the drug is 0.01% to 60%, preferably 0.1% to 10%; or the concentration of dipyridamole or its salt is 0.1 to 100 mg/g, preferably 1 to 50 mg/g, and more preferably 1 to 20 mg/g.
The use according to any one of claims 1-34, wherein the medicine further comprises a second active ingredient.
The use according to claim 35, wherein the second active ingredient comprises at least one of an active ingredient for anti-inflammatory diseases, an active ingredient for anti-allergic diseases, an anti-inflammatory active ingredient, and an anti-allergic active ingredient.
The use according to claim 6, wherein the anti-inflammatory active ingredient comprises: a steroidal anti-inflammatory drug or a non-steroidal anti-inflammatory drug.
The use according to claim 37, wherein the non-steroidal anti-inflammatory drugs include aspirin, benolate, salicylic acid, acetaminophen, indomethacin, diclofenac, sulindac, nemetbutalone, ibuprofen, naproxen, piroxicam, meloxicam, celecoxib, etoricoxib, nimesulide; or, the steroidal anti-inflammatory drugs include adrenal cortical hormones, androgens, estrogens, such as hydrocortisone, prednisone, dexamethasone.
The use according to claim 36, wherein the anti-inflammatory active ingredients include: antifungal drugs and/or their active ingredients, antiviral drugs and/or their active ingredients, antibacterial drugs and/or their active ingredients, antiparasitic drugs and/or their active ingredients, antimycoplasma drugs and/or their active ingredients.
The use according to claim 39, wherein the antifungal drugs or active ingredients include amphotericin B, nystatin, griseofulvin, clotrimazole, econazole, miconazole, ketoconazole, bifonazole, terbinafine, ciclopirox olamine, and amorolfine;

The antiviral drugs or active ingredients include acyclovir, acetaminophen, amantadine, chlorpheniramine maleate, ribavirin, amantadine and its salts, and human interferon;

The antibacterial drugs or active ingredients include antibiotics, sulfonamides, imidazoles, nitroimidazoles, and quinolones, preferably penicillin, cephalosporin, cephamycin antibiotics, sulfamethoxazole, sulfadiazine, ketoconazole, miconazole, econazole, clotrimazole, metronidazole, dimetridazole, isopronidazole, seconidazole, ornidazole, tinidazole and ronidazole, norfloxacin, pefloxacin, enoxacin, ofloxacin and ciprofloxacin.
The use according to claim 36, wherein the active ingredient for anti-inflammatory diseases comprises an active ingredient of a drug for treating an inflammatory disease according to any one of claims 4 to 20, preferably an acne treatment drug or active ingredient, a rosacea treatment drug or active ingredient. Ingredients, rhinitis treatment drugs or active ingredients, conjunctivitis treatment drugs or active ingredients.
The use according to claim 41, wherein the acne treatment drug or active ingredient comprises sulfur, clindamycin, erythromycin, vinpoxetine, benzoyl peroxide, azelaic acid, retinoic acid, isotretinoin, adapalene, hyaluronic acid or its salt, ergothioneine;

The rhinitis treatment drugs or active ingredients include glucocorticoids, antibacterial drugs, and alpha receptor agonists;

The conjunctivitis treatment drugs or active ingredients include aminoglycoside drugs or active ingredients, fluoroquinolone drugs or active ingredients, amide drugs or active ingredients, tetracycline drugs or active ingredients, macrolide drugs or active ingredients, acyclovir eye drops and ganciclovir eye gel, sulfacetamide sodium or rifampicin eye drops, and corticosteroid eye drops.
The use according to claim 42, wherein the glucocorticoids include hydrocortisone acetate, hydrocortisone butyrate, dexamethasone, dexamethasone acetate, triamcinolone acetonide acetate, mometasone furoate, halometasone, beclomethasone dipropionate, fluocinolone acetonide, halcinonide, and betamethasone propionate;

The alpha receptor agonists include ephedrine, ephedrine hydrochloride, oxymetazoline, and xylometazoline.
The use according to claim 42, wherein the aminoglycoside drugs or active ingredients include gentamicin, neomycin, and tobramycin;

The fluoroquinolone drugs or active ingredients include gatifloxacin, norfloxacin, and ofloxacin;

The amide alcohol drugs or active ingredients include chloramphenicol;

The macrolide drugs or active ingredients include erythromycin and rifampicin.
The use according to claim 36, wherein the anti-allergic active ingredients include: antihistamines, allergic reaction mediator release inhibitors, histamine desensitization drugs, leukotriene receptor antagonists, drugs that inhibit antigen-antibody reactions, drugs that improve or control allergic reaction symptoms, and active ingredients of the above drugs.
The use according to claim 45, wherein the antihistamine drugs or active ingredients include diphenhydramine, promethazine, and chlorpheniramine;

The allergic reaction mediator release-inhibiting drugs or active ingredients include sodium cromoglycate and ketotifen;

The histamine desensitization drugs or active ingredients include betahistine, histamine diluent, and dust mite injection;

The leukotriene receptor antagonist drugs or active ingredients include montelukast and zafirlukast;

The drugs or active ingredients that inhibit antigen-antibody reactions include glucocorticoids and immunosuppressants;

The drugs for improving or controlling allergic symptoms include smooth muscle spasmolytics and drugs for alleviating edema caused by allergies.
The use according to claim 46, wherein the glucocorticoids include hydrocortisone acetate, hydrocortisone butyrate, dexamethasone, dexamethasone acetate, triamcinolone acetonide acetate, mometasone furoate, halometasone, beclomethasone dipropionate, fluocinolone acetonide, halcinonide, and betamethasone propionate;

The smooth muscle antispasmodics include salbutamol;

The drug for reducing edema caused by allergies includes calcium gluconate.
The use according to claim 35, wherein the second active ingredient accounts for 0.01%-20% of the total mass of the drug, preferably 0.1-10%, and more preferably 0.5-5%.
The use according to any one of claims 1-48, wherein the drug is applicable to animals, and the animals are selected from humans, cats, cows, sheep, pigs, dogs, chickens, ducks, geese, rabbits, and mice; preferably, the animals are humans, more preferably infants, children, teenagers, adults, or the elderly; most preferably, children.
The use according to any one of claims 1 to 49, wherein the drug is applied to skin, nails, or hair.
A dipyridamole cream, wherein, by mass percentage, the dipyridamole cream contains 0.01% to 20% of dipyridamole and/or its derivatives, and 0.1% to 60% of diethylene glycol monoethyl ether.
The dipyridamole cream according to claim 51, wherein the mass percentage of dipyridamole and/or its derivatives is 0.01% to 10%.
The dipyridamole cream according to claim 51 or 521, wherein the mass percentage content of diethylene glycol monoethyl ether is 0.3% to 50%.
The dipyridamole cream according to claim 51 or 52, wherein the mass percentage of diethylene glycol monoethyl ether is 2% to 30%.
The dipyridamole cream according to any one of claims 51-54, wherein the cream base further comprises an emulsifier, preferably 0.3% to 40% of the emulsifier, more preferably 0.5% to 30% of the emulsifier.
The dipyridamole cream according to any one of claims 51 to 54, wherein the cream further comprises one or more of an emulsifier, a lubricant, a moisturizer, a preservative, an antioxidant, a consistency regulator, a pH regulator, a pigment, and water.
The dipyridamole cream according to claim 56, wherein the emulsifier comprises one or more of polyethylene glycol stearate, phospholipids, sodium lauryl sulfate, Span surfactants, Tween surfactants, higher fatty alcohols, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, 15-hydroxystearate polyethylene glycol ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, triethanolamine, stearic acid glyceryl, caprylic acid capric acid polyethylene glycol glyceride, propylene glycol monocaprylate, propylene glycol monolaurate, polyglycerol oleate, and polyethylene glycol cetearyl alcohol ether.
The dipyridamole cream according to claim 57, wherein the polyethylene glycol stearate includes polyoxyethylene sorbitan monostearate, polyethylene glycol monooctadecanoate, polyethylene glycol monostearate, T-60, polyoxyethylene stearate, polyoxyethylene sorbitan monostearate, PEG-5 stearate, PEG-7 stearate, PEG-25 stearate, PEG-23 stearate, PEG-30 stearate, PEG-18 stearate, PEG-20 stearate, PEG-10 stearate, preferably PEG-7 stearate.
The dipyridamole cream according to claim 56, wherein the cream further comprises a lubricant and/or a consistency regulator.
The dipyridamole cream according to claim 59, wherein the cream further comprises one or more of a moisturizer, a preservative, an antioxidant, a pH adjuster, a pigment, and water.
The dipyridamole cream according to claim 59, wherein the lubricant is selected from one or more of isopropyl palmitate, isopropyl myristate, dimethicone, diisopropyl adipate, caprylic glyceride, caprylic anhydride oil, caprylic capric macrogol glyceride, isohexadecane, hydrogenated castor oil, mineral oil, caprylic/capric triglyceride, lauric acid, and linoleic acid, preferably one or two of isopropyl myristate and isopropyl palmitate.
The dipyridamole cream according to claim 59, wherein the mass proportion of the lubricant in the dipyridamole cream is 0.5% to 40%, preferably 1% to 30%, and more preferably 5% to 20%.
The dipyridamole cream according to claim 59, wherein the consistency regulator is selected from one or more of cetearyl alcohol, cetyl alcohol, stearyl alcohol, glyceryl monostearate, glyceryl mono- and distearate, carbomer, liquid paraffin, vaseline, and glyceryl behenate, preferably one or more of cetearyl alcohol, cetyl alcohol, liquid paraffin, and glyceryl monostearate.
The dipyridamole cream according to claim 59, wherein the mass proportion of the consistency regulator in the dipyridamole cream is 0% to 50%, preferably 0.1% to 30%, and more preferably 0.1% to 30%.
The dipyridamole cream according to claim 60, wherein the moisturizer is selected from one or more of glycerol, propylene glycol, 1,3-butylene glycol, and polyethylene glycol, preferably one or two of glycerol and 1,3-butylene glycol.
The dipyridamole cream according to claim 60, wherein the mass proportion of the moisturizer in the dipyridamole cream is 0.5% to 50%, preferably 1% to 30%, more preferably 2% to 25%, and more preferably 5% to 20%.
The dipyridamole cream according to claim 60, wherein the preservative is selected from at least one of a chemical preservative and a natural preservative; preferably, the preservative is selected from one or more of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sodium ethylparaben, benzyl alcohol, phenoxyethanol, sorbic acid, benzoic acid, and sodium benzoate.
The dipyridamole cream according to claim 60, wherein the mass proportion of the preservative in the dipyridamole cream is 0% to 10%, preferably 0% to 5%, and more preferably 0% to 1%.
The dipyridamole cream according to claim 60, wherein the antioxidant is selected from one or more of butylated hydroxytoluene, butylated hydroxyanisole, disodium edetate, alpha-tocopherol, ascorbic acid, sodium metabisulfite, anhydrous sodium sulfite, propyl gallate, sodium ascorbate, isoascorbic acid, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, and thioglycerol.
The dipyridamole cream according to claim 60, wherein the weight proportion of the antioxidant in the dipyridamole cream is 0% to 5%, preferably 0% to 1%.
The dipyridamole cream according to claim 60, wherein the pH adjuster comprises an acidic pH adjuster or an alkaline pH adjuster, and preferably, the pH adjuster is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium citrate, triethanolamine, citric acid, hydrochloric acid, and sodium dihydrogen phosphate.
The dipyridamole cream according to claim 60, wherein the mass proportion of the pH regulator in the dipyridamole cream is 0% to 10%, preferably 0% to 5%.
The dipyridamole cream according to claim 60, wherein the pigment comprises a synthetic pigment or a natural pigment; preferably, the pigment comprises one or more of carmine, erythrosine, allura red, red iron oxide, titanium dioxide, zinc oxide, talc, kaolin, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, amaranth, new red, tartrate, sunset yellow, indigo, brilliant blue, carotene, chlorophyll, turmeric, impatiens, rose glycosides, and capsanthin.
The dipyridamole cream according to claim 60, wherein the mass proportion of the pigment in the dipyridamole cream is 0% to 10%, preferably 0% to 5%.
The dipyridamole cream according to claim 60, wherein the cream contains 10% to 95% water by mass, preferably 20% to 90% water, and more preferably 30% to 70% water.
The dipyridamole cream according to claim 60, wherein the dipyridamole cream contains, by mass percentage: 0.01% to 20% of dipyridamole and/or its derivatives,

0.1%～60% diethylene glycol monoethyl ether, and

One or more of 0.3% to 40% emulsifier, 0.5% to 40% lubricant, 0.5% to 50% moisturizer, 0% to 10% preservative, 0.1% to 50% consistency regulator, and water.
The dipyridamole cream according to claim 60, wherein the dipyridamole cream contains, by mass percentage: 0.01%-10% of dipyridamole and/or its derivatives,

0.3% to 50% diethylene glycol monoethyl ether, and

One or more of 0.5% to 30% emulsifier, 1% to 30% lubricant, 1% to 30% moisturizer, 0% to 1% preservative, 1% to 30% consistency regulator, and water.
The dipyridamole cream according to any one of claims 76-77, wherein the emulsifier is polyethylene glycol-stearate; and/or the lubricant is isopropyl myristate and/or isopropyl palmitate; and/or the moisturizer is glycerol and/or 1,3-butylene glycol; and/or the preservative is sodium ethylparaben; and/or the consistency regulator is cetearyl alcohol.
The preparation method of the dipyridamole cream according to any one of claims 51 to 78 comprises the following steps: mixing the oil phase components in the cream base and heating them to 70 to 80°C to melt, adding dipyridamole and/or its derivatives to obtain an oil phase mixture; mixing the water phase components in the cream base and heating them to 70 to 80°C to obtain an water phase mixture; under stirring conditions, adding the water phase mixture to the oil phase mixture, homogenizing and continuously stirring, and obtaining the dipyridamole cream after cooling.
The preparation method of the dipyridamole cream according to any one of claims 51 to 78 comprises the following steps: dissolving or dispersing dipyridamole and/or its derivatives in diethylene glycol monoethyl ether, heating to 50 to 60° C. to obtain a premix; mixing the other oil phase components in the cream matrix except diethylene glycol monoethyl ether and heating to 70 to 80° C. to melt to obtain an oil phase mixture; mixing the water phase components in the cream matrix and heating to 70 to 80° C. to obtain an aqueous phase mixture; under stirring, adding the aqueous phase mixture to the oil phase mixture, cooling to 50 to 60° C., adding the premix, homogenizing and continuously stirring, and obtaining the dipyridamole cream after cooling.
A dipyridamole gel, which comprises, by mass percentage, 0.01% to 20% of dipyridamole or its derivatives, 0.1% to 20% of gelling agent, and 0.1% to 60% of diethylene glycol monoethyl ether.
The dipyridamole gel according to claim 81, wherein the mass percentage of dipyridamole and/or its derivatives is 0.01% to 10%.
The dipyridamole gel according to claim 82, wherein the mass percentage of diethylene glycol monoethyl ether is 0.3% to 50%, preferably 2% to 30%.
The dipyridamole gel according to claim 81, wherein the mass percentage of the gel is 0.2%-10%, preferably 0.5% to 5%.
The dipyridamole gel according to claim 81, wherein the gelling agent comprises one or more of carbomer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, and sodium carboxymethyl cellulose, preferably carbomer.
The dipyridamole gel according to claim 85, wherein the carbomer comprises carbomer 980NF, carbomer 974NF, and carbomer 940.
The dipyridamole gel according to any one of claims 81-86, wherein the dipyridamole gel further comprises one or more of a surfactant, a pH adjuster, a moisturizer, an antioxidant, a preservative, and water.
The dipyridamole gel according to claim 87, wherein the mass percentage of water is 10% to 98%, preferably 20% to 95%, and more preferably 30% to 90%.
The dipyridamole gel according to claim 87, wherein the moisturizer is selected from one or more of vaseline, glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol.
The dipyridamole gel according to claim 87, wherein the mass proportion of the moisturizer in the dipyridamole gel is 0.1% to 50%, preferably 1% to 30%.
The dipyridamole gel according to claim 87, wherein the preservative is selected from one or more of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sodium ethylparaben, benzyl alcohol, phenoxyethanol, sorbic acid, benzoic acid, and sodium benzoate.
The dipyridamole gel according to claim 87, wherein the mass proportion of the preservative in the dipyridamole ointment is 0% to 5%, preferably 0% to 2%, and more preferably 0% to 1%.
The dipyridamole gel according to claim 87, wherein the surfactant is selected from one or more of sodium lauryl sulfate, Spans, Tweens, poloxamers, triethanolamine, caprylic/capric acid macrogol glycerides, 15-hydroxystearate macrogol esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyethylene glycol cetearyl alcohol ether, and is preferably triethanolamine.
The dipyridamole gel according to claim 87, wherein the mass proportion of the surfactant in the dipyridamole gel is 0.1% to 50%, preferably 0.5% to 30%.
The dipyridamole gel according to claim 87, wherein the pH adjuster is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium citrate, triethanolamine, citric acid, hydrochloric acid, and sodium dihydrogen phosphate.
The dipyridamole gel according to claim 87, wherein the mass proportion of the pH regulator in the dipyridamole gel is 0% to 10%, preferably 0% to 5%.
The dipyridamole gel according to claim 87, wherein the antioxidant is selected from one or more of butylated hydroxytoluene, butylated hydroxyanisole, disodium edetate, α-tocopherol, ascorbic acid, sodium metabisulfite, propyl gallate, sodium ascorbate, and isoascorbic acid.
The dipyridamole gel according to claim 87, wherein the weight proportion of the antioxidant in the dipyridamole ointment is 0% to 5%, preferably 0% to 1%.
The dipyridamole gel according to claim 87, wherein the composition comprises, by mass percentage: 0.01%-20% dipyridamole or its derivatives, 0.1%-20% gelling agent, 0.1%-60% diethylene glycol monoethyl ether, and

One or more of 0.1% to 50% moisturizer, 0% to 5% preservative, 0% to 10% pH adjuster, 0.1% to 50% surfactant, 0% to 5% antioxidant, and 10% to 98% water.
The dipyridamole gel according to claim 87, wherein the gel comprises, by mass percentage: 0.01%-20% dipyridamole or its derivatives, 0.1%-20% carbomer, 0.1%-60% diethylene glycol monoethyl ether, and

One or more of 0.1% to 50% 1,3-butylene glycol, 0% to 5% sodium ethylparaben, 0% to 50% triethanolamine, and 10% to 98% water.
The method for preparing the dipyridamole gel according to any one of claims 81 to 100 comprises the following steps: dissolving dipyridamole and/or its derivatives in diethylene glycol monoethyl ether, adding a moisturizer to obtain a premixed solution; mixing the other components in the gel matrix except the pH adjuster, adding the gelling agent, stirring until swelling, and obtaining a gel solution; adding the premixed solution to the gel solution, adjusting the pH, and stirring evenly to obtain the dipyridamole. No gel.
A dipyridamole ointment, comprising the cream component according to any one of claims 51 to 78 and containing no water.
A dipyridamole ointment, comprising the cream component according to any one of claims 51 to 78 and containing no water, wherein the mass percentage of a consistency regulator in the dipyridamole ointment is 0.1% to 98%, preferably 0.5% to 95%, and more preferably 1% to 90%.
A dipyridamole ointment, which contains, by mass percentage: 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and

One or more of 0.3% to 40% emulsifier, 0.5% to 40% lubricant, 0.5% to 50% moisturizer, 0% to 10% preservative, 0.1% to 50% consistency regulator, 0% to 10% pH regulator, 0% to 5% antioxidant, and 0% to 10% pigment.
The dipyridamole ointment according to claim 104, wherein the ointment contains, by mass percentage: 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and

One or more of 0.5% to 30% emulsifier, 1% to 30% lubricant, 1% to 30% moisturizer, 0% to 1% preservative, 1% to 90% consistency regulator, 0% to 5% pH regulator, 0% to 1% antioxidant, and 0% to 5% pigment.
The dipyridamole ointment according to claim 105, wherein the ointment contains, by mass percentage: 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and

One or more of 0.5% to 30% emulsifier, 1% to 30% lubricant, 1% to 30% humectant, and 1% to 90% consistency regulator.
The dipyridamole ointment according to claim 105, wherein, by mass percentage, it contains 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier.
The dipyridamole ointment according to claim 105, wherein, by mass percentage, it contains 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 1% to 90% of a consistency regulator.
The dipyridamole ointment according to claim 105, wherein, by mass percentage, it contains 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of emulsifier, and 1% to 90% of consistency regulator.
A dipyridamole ointment comprises 0.01% to 60% by mass of dipyridamole and/or its derivatives.
The dipyridamole ointment according to claim 110, wherein the ointment further comprises one or more selected from the following: a solvent, an ointment base, a thickener, a humectant, and a preservative.
The dipyridamole ointment according to claim 110 or 111, wherein the ointment contains 0.5% to 60% of a solvent by mass.
The dipyridamole ointment according to any one of claims 110-112, wherein the ointment contains 40% to 99% of the ointment base by mass percentage.
The dipyridamole ointment according to any one of claims 110-113, wherein the ointment contains 0.01% to 1% of preservative by mass.
The dipyridamole ointment according to any one of claims 110-114, wherein the ointment contains 0% to 30% of a thickener by mass percentage.
The dipyridamole ointment according to any one of claims 110-115, wherein the ointment contains 0% to 50% of a moisturizer by mass percentage.
Use of the dipyridamole cream according to any one of claims 51 to 78 in the preparation of a medicament for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases.
Use of the dipyridamole gel according to any one of claims 81 to 100 in the preparation of a medicament for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases.
Use of the dipyridamole ointment according to any one of claims 102 to 116 in the preparation of a medicament for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases.
The use according to any one of claims 117 to 119, wherein the allergic disease is the disease according to claim 2 or 3 Disease; or, the inflammatory disease is a disease according to any one of claims 4-20.
A method for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases comprises the following steps: administering dipyridamole or a derivative thereof to a patient in need thereof.
The method according to claim 121, comprising the step of administering dipyridamole or a derivative thereof to a patient in need thereof in an external manner.
The method according to claim 122, comprising the step of externally administering the dipyridamole cream according to any one of claims 51 to 78 and/or the dipyridamole gel according to any one of claims 81 to 100 and/or the dipyridamole ointment according to any one of claims 102 to 116 to a patient in need thereof.
The method according to any one of claims 122-123, wherein the administration method for topical administration is: applying the dipyridamole cream according to any one of claims 51 to 78 and/or the dipyridamole gel according to any one of claims 81 to 100 and/or the dipyridamole ointment according to any one of claims 102 to 116 to the skin surface corresponding to the affected area.
The method according to any one of claims 121-124, wherein the frequency of administration is: 1-3 times every 1 to 24 hours, or 1-3 times a day, preferably 2-3 times a day.
The method according to any one of claims 121-125, wherein the dosage of the administration is: 1-250 mg each time, preferably 5-100 mg each time, more preferably 10-50 mg, calculated as dipyridamole; or; the drug is administered in a cosmetically effective amount; or the drug is administered in a therapeutically effective amount.
The method according to any one of claims 121 to 126, wherein the dosage of the administration is: 0.1-25 mg/cm 2 , more preferably 0.2-10 mg/cm 2 , calculated as dipyridamole.
The method according to claim 122, wherein the allergic disease is the disease according to claim 2 or 3; or the inflammatory disease is the disease according to any one of claims 4-20.
An external preparation containing dipyridamole and/or its derivatives as an active ingredient for preventing, assisting in the treatment or treating atopic dermatitis.
The topical preparation for the use according to claim 129, wherein the topical preparation comprises 0.01% to 60%, 0.05% to 20%, 0.1% to 15%, or 0.1% to 10% of dipyridamole and/or its derivatives.
The external preparation for use according to claim 129 or 109, wherein the external preparation is a cream, a gel or an ointment.
The topical preparation for the purpose according to any one of claims 129-130, wherein the topical preparation can be combined with other anti-allergic or anti-inflammatory drugs, or anti-atopic dermatitis drugs for the prevention, adjuvant treatment or treatment of atopic dermatitis.
The topical preparation for use according to claim 132, wherein the antiallergic drugs include antihistamines, glucocorticoids, allergic reaction mediator blockers, and calcium agents;

The anti-inflammatory drugs include non-steroidal anti-inflammatory drugs and steroidal anti-inflammatory drugs; or

The anti-atopic dermatitis drug is selected from glucocorticoids, calcineurin inhibitors, antibiotics, antihistamines, immunosuppressants, antibody biological preparations, phosphodiesterase 4 inhibitors, JAK inhibitors, tropomyosin receptor kinase, liver X receptor agonists, probiotics or other active ingredients for treating atopic dermatitis.
Use of dipyridamole and/or its derivatives, pharmaceutical compositions or external preparations containing the same in the preparation of medicaments for reducing the levels of inflammatory cytokines, IgE levels in the skin and/or plasma of patients with allergic and/or inflammatory diseases and/or reducing mast cell degranulation.
The use according to claim 134, wherein the inflammatory cytokine is selected from IL-4, TSLP, IL-1b, IL-6, and TNF-α.
The use according to claim 134 or 135, wherein the pharmaceutical composition or external preparation contains 0.01% to 60%, 0.05% to 20%, 0.1% to 15%, 0.1% to 12%, or 0.1% to 10% of dipyridamole and/or its derivatives.
Dipyridamole and/or its derivatives, and pharmaceutical compositions or external preparations containing the same, for reducing the level of inflammatory cytokines, IgE levels and/or mast cell degranulation in the skin and/or plasma of patients with allergic and/or inflammatory diseases.
The use according to claim 137, wherein the inflammatory cytokine is selected from IL-4, TSLP, IL-1b, IL-6, TNF- α.
The use according to claim 137 or 138, wherein the pharmaceutical composition or external preparation contains 0.01% to 60%, 0.05% to 20%, 0.1% to 15%, 0.1% to 12%, or 0.1% to 10% of dipyridamole and/or its derivatives.