KR101760512B1 - Compositions comprising mixed herbal extracts for preventing, treating or improving chronic inflammatory diseases - Google Patents
Compositions comprising mixed herbal extracts for preventing, treating or improving chronic inflammatory diseases Download PDFInfo
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- KR101760512B1 KR101760512B1 KR1020150108612A KR20150108612A KR101760512B1 KR 101760512 B1 KR101760512 B1 KR 101760512B1 KR 1020150108612 A KR1020150108612 A KR 1020150108612A KR 20150108612 A KR20150108612 A KR 20150108612A KR 101760512 B1 KR101760512 B1 KR 101760512B1
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- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A61K36/185—Magnoliopsida (dicotyledons)
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Abstract
The present invention relates to a composition comprising, as an active ingredient, at least two herbal extracts of Inulae Flos and Schizonepetae Spica Magnolia Cortex, as a pharmaceutical composition, a pharmaceutical composition for the treatment or prevention of chronic inflammatory diseases, ≪ / RTI > The mixed herbal medicine extract composition of the present invention can be effectively used for prevention and treatment of chronic inflammatory diseases by inhibiting the secretion of cytokines affecting immune diseases.
Description
The present invention relates to a composition for the prevention, treatment or amelioration of chronic inflammatory diseases including mixed herbal extracts, and more particularly to a composition for preventing, treating or ameliorating chronic inflammatory diseases comprising the group consisting of Inulae Flos, Schizonepetae Spica and Magnolia Cortex The present invention relates to a pharmaceutical composition for the treatment or prevention of chronic inflammatory diseases and a composition for improving foods, which comprises an extract of two or more selected herbal medicines as an active ingredient.
Chronic inflammation is a state of persistent inflammation, which means that the immune system is constantly inadequate for certain exposures, especially autoimmune diseases arise from attacking organs due to immune system confusion. Chronic inflammation can be caused by single or complex genetic factors or by environmental factors such as food or smoke. Inflammation has occurred. It has been calmed down, but it has been continuing and sometimes the treatment has become less effective. Chronic inflammatory diseases cause considerable damage to the body tissues and various problems occur depending on the location. For example, chronic inflammation in the liver or digestive organs can cause changes in the brain, resulting in fatigue, personality changes, organ dysfunction, and systemic spread of the inflammation.
As a chronic inflammatory disease, psoriasis is a chronic recurrent skin disorder characterized by rapid proliferation of keratinocytes and accompanying inflammation of the skin. It is a chronic, recurrent skin disease characterized by lesions such as erythema, This skin can appear anywhere. Clinically, it can be classified as phlychis psoriasis, psoriasis psoriasis, pustular psoriasis, inverse psoriasis, and hyperpyritic psoriasis. Psoriasis is caused by a combination of genetic and environmental factors. The cause of psoriasis has not yet been clarified. However, the cause of psoriasis is not clear yet, but it can be affected by hormonal changes, psychological aspects such as stress, trauma, infections such as tonsillitis, Ability, climate, dry skin, drugs, heredity, etc. IL-23, IL-17, and IL-6, which are secreted by T-immunoreactive cells differentiated by immune system hypersensitivity or autoimmune abnormalities in patients with chronic inflammatory diseases. Excessive expression of cytokines such as TNF-α causes inflammation of the skin, promotes hyperproliferation and division of keratinocytes, and inhibits differentiation. These factors are caused by the fact that the cells of the stratum corneum are proliferating 6 to 7 times faster than the normal cells, and the excessively incompletely proliferated keratinocytes are layered with the scales of white scales. Psoriasis is often accompanied by other diseases and is called concomitant disease, and psoriatic arthritis, cardiovascular disease, depression, Crohn's disease, etc. are frequently found in patients with psoriasis. Psoriatic arthritis is a chronic inflammatory disease with pain. Up to 30% of psoriasis patients have arthritis symptoms, of which psoriasis leads to arthritis in 85%. Recent studies also concluded that arthritis The cause of the relationship is not clear yet. Severe psoriasis is also associated with increased metabolic syndrome and mortality, such as obesity, hypertension, hyperlipidemia, and
In order to treat inflammatory diseases, especially psoriasis, the immune system in the body is very diverse and complex, so that the overall immune system including T cells is normally operated, so that the immune system of the patient is weakened It is important to maintain the homeostasis of the body by adjusting the immune balance so that the immune balance is maintained. However, conventionally used medicines simply cause immune suppression, leading to various complications such as cancer and tuberculosis, and it is impossible to take them for a long time due to toxicity, and when the medication is stopped, the rebound phenomenon, Or the treatment efficiency is low. Currently, many patients with chronic inflammatory disease are not able to obtain sufficient clinical improvement with current standard drug therapy. Most of the drugs are expensive, and the treatment process is long and complicated, accompanied by various side effects, and it is difficult to avoid recurrence even if it is treated to some extent.
Therefore, it is necessary to prescribe new drugs with less side effects and better treatment efficiency than existing drugs. In the case of treating a disease using a composition using a natural product extract, there is no side effect or an excellent therapeutic effect can be obtained while reducing side effects, and development of a medicine using a natural extract has been suggested as an alternative.
The substances that inhibit the functions of IL-17, IL-6 and TNF-a include psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, systemic erythema lupus, inflammatory bowel disease, Crohn's disease, IL-6, and TNF-α, which are known to have therapeutic effects on inflammatory bowel disease, colitis, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, periodontitis, and idiopathic inflammatory myopathy It does not exist until now.
Accordingly, the present inventors have studied natural substances that inhibit the activity of the inflammatory cytokines IL-17, IL-6 and TNF-α in order to develop a composition for the prophylaxis and treatment of chronic inflammatory diseases. As a result, ), Schizonepetae Spica, and Magnolia Cortex were found to be effective for the treatment of chronic inflammatory diseases, thereby completing the present invention.
Accordingly, an object of the present invention is to provide a method for the treatment or prevention of a chronic inflammatory disease, which comprises, as an active ingredient, two or more herbal medicine extracts selected from the group consisting of Inulae Flos, Schizonepetae Spica and Magnolia Cortex. And to provide a pharmaceutical composition.
Another object of the present invention is to provide a method for improving chronic inflammatory diseases, which comprises extracting two or more herbal medicines selected from the group consisting of Inulae Flos, Schizonepetae Spica and Magnolia Cortex as an active ingredient And to provide a food composition.
In order to achieve the above object, the present invention provides a pharmaceutical composition for treating a chronic inflammatory disease (inflammatory disease) comprising two or more herbal medicine extracts selected from the group consisting of Inulae Flos, Schizonepetae Spica and Magnolia Cortex, Or a pharmaceutically acceptable salt thereof.
In order to achieve another object of the present invention, the present invention is characterized by comprising an extract of two or more herbal medicines selected from the group consisting of Inulae Flos, Schizonepetae Spica and Magnolia Cortex as an active ingredient And a composition for food for improving chronic inflammatory diseases.
Hereinafter, the present invention will be described in detail.
The present invention relates to a pharmaceutical composition for the treatment or prophylaxis of chronic inflammatory diseases, which comprises as an active ingredient an extract of two or more herbal medicines selected from the group consisting of Inulae Flos, Schizonepetae Spica and Magnolia Cortex. Gt;
In the present invention, the extracts of L., L. and L. have the effect of inhibiting the secretion of IL-17, IL-6 and TNF-α cytokines. In particular, the mixture of these compounds has an increased cytokine secretion inhibition . In addition, it has been confirmed that the extracts containing two or more of the herbal medicines have excellent therapeutic effects in an animal model of psoriasis. The therapeutic effect of a chronic inflammatory disease, particularly psoriasis, of a composition containing an extract of two or more herbal medicines selected from the group consisting of L., L. and L. is disclosed for the first time in the present invention.
Fleet Chemistry (旋覆花, Inulae Flos) is a plant that has been used in traditional Chinese medicine, geumbulcho of the Asteraceae (Compositae) (Inula japonica Thunberg, or Inula britannica Linne, and has a diameter of 10 to 15 mm and a spherical shape. In terms of oriental medicine, the embryo has the action of gonghwa (鎭 痰) and gumdha (痰 痰), bronchial spasm is solved, diuretic action, sputum emerging symptoms, gastrointestinal dystrophy, Poor quality, and so on.
Spruce (Schizonepetae Spica) is a plant of the family Lamiaceae ( Schizonepeta tenuifolia Briquet) (Korean Pharmacopoeia), shaped in the shape of elongated barley, 5 ~ 10cm long and greenish brown with purple color. There is a calyx tube with a small purity and sometimes fruit, and a milky white hair can be seen in the forehead, and there is the efficacy of sea table, giant wind, and blood. (1998)).
Magnoliae Cortex is a deciduous tree belonging to the Magnoliaceae, which consists of Magnolia ovobata Thunberg, Magnolia officinalis Rehder et Wilson) or Magnolia officinalis Rehder et Wilson var. biloba Rehder et Wilson) (Korea Pharmacopoeia). It has been used since ancient times for headache, toothache, sinusitis, and blood pressure lowering (Korean Medicinal Plants Book, 1993, 179-180, Academy Book). The starch in the present invention means derived from Magnolia Cortex.
The composition of the present invention is a composition comprising as an active ingredient an extract of two or more herbal medicines selected from the group consisting of Inulae Flos, Schizonepetae Spica and Magnolia Cortex. That is, the composition of the present invention may be an extract containing two herbal medicine extracts, such as an embryo, an embryo, a embryo, a horn, or a mold and a horn, It may be one containing as a component.
The composition containing the extract of two or more herbal medicines may be a mixture of two or more herbal extracts alone or a combination of two or more herbal medicines. In the present specification, a mixture or a complex extract of the single extract may be collectively referred to as a mixed extract. The composition of the present invention is not limited to a mode of mixing two or more herbal medicine extracts as an active ingredient. There are no limitations on the form or properties of the extract, and it may be a solution, a concentrate, or a solid or powder from which the solvent used for the preparation of the extract is removed.
The composition of the present invention may be obtained by mixing the sole extract of L., L., and L. at a weight ratio of 1: 0.1 ~ 10: 0.1 ~ 10. When the composition of the present invention contains a single extract of two herbal medicines (i.e., when the medicinal herb contains extracts of the embryo and the embryo, the embryo and the embryo, or the extract of the embryo) To < / RTI > 10 by weight. In addition, the composition of the present invention may be obtained by mixing the composition of the present invention on a dry weight basis at a weight ratio of 1: 0.1 ~ 10: 0.1 ~ 10. When the composition of the present invention includes a complex extract of two herbal medicines, the two herbal medicines may be mixed at a weight ratio of 1: 0.1 to 10 and then extracted.
The herbal medicine extract in the present invention may be extracted with any one solvent selected from the group consisting of water, an alcohol having 1 to 6 carbon atoms, hexane, ethyl acetate and a mixed solvent thereof. The extract of the present invention is preferably extracted with a solvent selected from water, an alcohol having 1 to 6 carbon atoms and a mixed solvent thereof, or a lower alcohol aqueous solution having 1 to 6 carbon atoms. The concentration of the aqueous alcohol solution may be 10 to 100% (v / v), preferably 70 to 100% (v / v). The extraction solvent of the present invention is most preferably an ethanol aqueous solution of 95% (v / v).
The extraction solvent used in the present invention may be used in an amount of about 3 times to 30 times, preferably about 5 times to 20 times, the weight of the dried herbal medicine.
Extraction of the herbal medicine of the present invention can be carried out at a temperature of 20 to 110 캜, preferably 60 to 90 캜.
Extraction of the herbal medicine of the present invention can proceed for about 1 to 48 hours, preferably about 4 to 24 hours. Extraction can be repeated one or more times. In one embodiment of the present invention, extraction was performed twice for four hours.
The extraction method in the present invention can be used without limitation as long as it is known in the art, and examples thereof include, but are not limited to, cold-pressing, hot water extraction, ultrasonic extraction, Preferably by reflux cooling and extraction.
The extract of the herbal medicine prepared by the above method is collected by filtration and re-extracted for 4 hours under reflux and cooling conditions by adding an extraction solvent such as an alcohol aqueous solution of 4 to 7 times the weight of the herbal medicine raw material to the residue, The extraction efficiency can be increased by mixing with the filtrate. In the present invention, a method of re-extraction after the first extraction is adopted. The extraction efficiency can be increased by mixing the extraction solution obtained after the second extraction and the filtrate obtained after each extraction, but the extract of the present invention is not limited to the number of extraction times.
The filtrate after the secondary extraction as described above is concentrated under reduced pressure at 40 to 60 ° C to remove the solvent remaining in the extract and is azeotropically concentrated 2 to 3 times with 25 to 50 times the weight of the concentrate under reduced pressure, And the resulting extract may be further purified. Alternatively, the extract may be dried by freeze-drying or the like to remove the solvent to solidify it, or may be prepared in powder form.
The inventors of the present invention have confirmed that the extracts of L. monocytogenes, L. and L. japonica have an effect of inhibiting the secretion of inflammatory cytokines IL-17, IL-6 and TNF-α in immune cells such as splenocytes and macrophages. Therefore, it can be seen that the sole extract of the herbal medicine has the effect of alleviating or treating the symptoms of an immunological disease or a chronic inflammatory disease caused or mediated by the cytokines through such immunomodulation. In particular, since IL-17 exacerbates abnormal cell proliferation and activity of keratinocyte that induces psoriasis, each of the extracts of L., L. and L. can be expected to treat psoriasis and psoriasis-associated diseases .
In addition, inhibition of IL-17, IL-6 and TNF-α secretion by herbal extracts was more pronounced when two herbal extracts were mixed than when each herbal extract was administered alone. It can be seen that a synergistic effect of inflammatory cytokine inhibition of each herbal medicine extract alone can be obtained through the composition comprising two or more herbal medicine extracts according to the present invention. That is, it can be seen that the administration of the herbal medicine mixed extract according to the present invention can achieve a more remarkable synergistic therapeutic effect on chronic inflammatory diseases such as psoriasis.
In the present invention, the therapeutic effect on psoriasis, a chronic inflammatory disease of the herbal composition extract, was confirmed in a mouse model of psoriasis. The combined extracts of L. and L. or L. and L. effectively reduced the thickness of the ear and the skin of the rats in the mouse model of IL-23-induced psoriasis, inhibited the infiltration of inflammatory cells, and the
Therefore, it can be expected that the composition of the present invention is effective for preventing, alleviating or treating a chronic inflammatory disease mediated or intensified by IL-17, IL-6, IL-23, TNF- In particular, inflammatory cytokines such as IL-17, IL-6, and TNF-a have an effect on the abnormal proliferation and activity of keratinocytes important for psoriasis induction, so that the composition of the present invention can prevent, It can be seen that there is an excellent effect in the treatment.
Accordingly, the composition of the present invention is a pharmaceutical composition for the treatment or prevention of chronic inflammatory diseases, wherein said chronic inflammatory disease is preferably psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, systemic erythema lupus, inflammatory bowel disease, , Ulcerative colitis, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, periodontitis, and idiopathic inflammatory myopathy.
The pharmaceutical composition of the present invention can be variously formulated according to the route of administration by a method known in the art together with a pharmaceutically acceptable carrier for achieving immunomodulation and inflammation inhibiting effect of the herbal medicine extract described above. &Quot; Pharmaceutically acceptable " refers to a nontoxic composition which is physiologically acceptable and which, when administered to humans, does not inhibit the action of the active ingredient and does not normally cause an allergic reaction such as a gastrointestinal disorder, dizziness, or the like . Such carriers include all kinds of solvents, dispersion media, oil-in-water or water-in-oil emulsions, aqueous compositions, liposomes, microbeads and microsomes.
The route of administration may be oral or parenteral. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration .
When the pharmaceutical composition of the present invention is orally administered, the pharmaceutical composition of the present invention may be formulated into a powder, a granule, a tablet, a pill, a sugar, a tablet, a capsule, a liquid, a gel , Syrups, suspensions, wafers, and the like. Examples of suitable carriers include saccharides including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches including corn starch, wheat starch, rice starch and potato starch, Cellulose such as methyl cellulose, sodium carboxymethyl cellulose and hydroxypropylmethyl cellulose, and fillers such as gelatin, polyvinyl pyrrolidone and the like. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may optionally be added as a disintegrant. Further, the pharmaceutical composition may further comprise an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent.
In addition, when administered parenterally, the pharmaceutical composition of the present invention can be formulated together with a suitable parenteral carrier according to methods known in the art in the form of injection, transdermal drug delivery, and nasal inhalation. In the case of such injections, they must be sterilized and protected against contamination of microorganisms such as bacteria and fungi. Examples of suitable carriers for injectables include, but are not limited to, solvents or dispersion media containing water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof and / or vegetable oils . More preferably, suitable carriers include isotonic solutions such as Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, or sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose Etc. may be used. In order to protect the injection from microbial contamination, various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like may be further included. In addition, the injections may in most cases additionally include isotonic agents, such as sugars or sodium chloride.
Examples of transdermal dosage forms include ointments, creams, lotions, gels, solutions for external use, pastes, liniments, and air lozenges. By " transdermal administration " as used herein, it is meant that the pharmaceutical composition is locally administered to the skin, whereby an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin. For example, the pharmaceutical composition of the present invention may be prepared into a spray-type formulation, which may be administered by pricking the skin lightly with a 30-gauge thin injection needle or by directly applying it to the skin. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975, Mack Publishing Company, Easton, Pennsylvania, which is a commonly known formulary in pharmaceutical chemistry.
In the case of inhalation dosage forms, the extracts used in accordance with the present invention may be formulated in a pressurized pack or a pressurized pack using a suitable propellant, for example, dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, It can be conveniently delivered in the form of an aerosol spray from a nebulizer. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve that delivers a metered amount. For example, gelatin capsules and cartridges used in inhalers or insufflators may be formulated to contain the compound and a powder mixture of a suitable powder base such as lactose or starch.
Other pharmaceutically acceptable carriers can be found in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995).
The pharmaceutical composition according to the present invention may also contain one or more buffers (e.g., saline or PBS), a carbohydrate (e.g., glucose, mannose, sucrose or dextran), an antioxidant, a bacteriostatic, (E.g., EDTA or glutathione), an adjuvant (e.g., aluminum hydroxide), a suspending agent, a thickening agent, and / or a preservative.
The pharmaceutical compositions of the present invention may be formulated using methods known in the art so as to provide rapid, sustained or delayed release of the active ingredient after administration to the mammal.
The pharmaceutical composition of the present invention may be administered in combination with a known compound having an effect of preventing or treating a chronic inflammatory disease.
The present invention also relates to a food for improving chronic inflammatory diseases, which comprises an extract of two or more herbal medicines selected from the group consisting of Inulae Flos, Schizonepetae Spica and Magnolia Cortex as an active ingredient Lt; / RTI >
It has been demonstrated in the examples of the present invention that the composition of the present invention has the effect of improving chronic inflammatory diseases. The chronic inflammatory disease of the food composition of the present invention is preferably selected from psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, systemic erythema lupus, inflammatory bowel disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis, asthma, , Periodontitis, and idiopathic inflammatory myopathies.
The food composition of the present invention includes all forms such as functional food, nutritional supplement, health food and food additives. Food compositions of this type may be prepared in a variety of forms according to conventional methods known in the art.
For example, as the health food, the composition itself may be prepared in the form of tea, juice, and drink and then taken for drinking, granulated, encapsulated and powdered. Functional foods also include beverages (including alcoholic beverages), fruits and their processed foods (such as canned fruits, bottled, jam, marmalade, etc.), fish, meats and their processed foods (eg, ham, sausage, Breads and noodles (eg udon, buckwheat noodles, ramen noodles, spaghetti, macaroni, etc.), juice, various drinks, cookies, sugar, dairy products such as butter, cheese, edible vegetable oil, margarine, vegetable protein, Frozen foods, various seasonings (eg soybean paste, soy sauce, sauces, etc.), and the like. In order to use the composition of the present invention in the form of a food additive, it may be prepared in the form of a powder or a concentrated liquid.
The preferred content of the extract in the food composition of the present invention may be 0.001 to 50%, preferably 0.1 to 50%, based on the total weight of the food composition.
The present invention is well illustrated in the examples.
In an embodiment of the present invention, 200 g of the embryo, broiler, and julienne were repeatedly extracted with 4 L of 95% ethanol under reflux and cooling conditions for 4 hours each time, and the extract solution was filtered with a sieve, Ethanol was removed to obtain a single extract.
In another embodiment of the present invention, the effects of the single extract and the mixed extract prepared through the above process on the secretion of inflammatory cytokines were confirmed in spleen cells of ICR mice and RAW264.7 cells of mouse macrophages. The splenocytes were stimulated with IL-23 and the secretion of IL-17 was measured. Macrophages were stimulated with LPS (lipopolysaccharide) and the secretion of IL-6 and TNF-α was measured. The single extract of each herbal medicine also had the effect of suppressing the secretion of inflammatory cytokines, especially when two or more single extracts were mixed, the cytokine inhibitory effect was more remarkable.
In another embodiment of the present invention, the content ratio that can maximize the synergistic effect of inhibition of inflammation between herbal extracts was examined. The combined extracts were prepared by mixing two or more herbal medicines selected from the group consisting of Lambschia fructus, Lambschia crassa and Lambs sp. At various weight ratios. The inhibitory effect of IL-17, IL-6 and TNF-α on the secretion of inflammatory cytokines The comparison of splenocytes with macrophages and the optimal composition ratio of herbal medicine were derived.
In another embodiment of the present invention, the therapeutic effect of the composition according to the present invention on chronic inflammatory diseases is confirmed in an animal model of psoriasis. IL-23 in the ear of C57BL / 6 mice induces psoriasis symptoms, and the therapeutic effect of the combined extract of embryo, embryo, or embryo, The expression levels of
Accordingly, the present invention provides a composition for preventing, treating or ameliorating chronic inflammatory diseases including mixed herbal medicine extracts. The composition of the present invention is effective for the prevention and treatment of chronic inflammatory diseases by effectively suppressing the secretion of inflammatory cytokines such as IL-17, IL-6 and TNF-alpha in the immune cells. In addition, since the composition of the present invention contains herbal medicine extract as an active ingredient, side effects on the human body are extremely smaller than those chemically synthesized.
FIG. 1 is a graph showing the results of an animal model of psoriasis according to the present invention. FIG. 1 is a graph showing the results of an animal model of psoriasis according to Example 1, ), And tofacitinib (positive control group) on ear thickness.
FIG. 2 is a graph showing the results of a comparison between the extracts of the combination of the combination of the embryoid body and the mold extract (Example <3-1>, weight ratio 1: 6) ), And tofacitinib (positive control group) on the epidermal thickness in the ear tissue.
FIG. 3 is a graph showing the results of a comparison between the extracts of the combination of the depressed type and the depressed type (Example <3-1>, weight ratio 1: 6) ) And topical application of tofacitinib (positive control group). Inflammatory cell infiltration was assessed by H & E staining followed by optical microscopy. We assessed asymptomatic 0, mild 1, moderate 2, and severe 3.
FIG. 4A is a graph showing the results of an animal model of psoriasis according to the present invention. FIG. 4A and FIG. ) And tofacitinib (positive control group), the amount of mRNA expression of
FIG. 4B is a graph showing the results of an animal model of psoriasis in which the combined extracts of the complexes and the complexes (Example <3-1>, weight ratio 1: 6) ), And TNF-α and IL-6 genes in the ear tissues when treated with tofacitinib (positive control group).
Hereinafter, the present invention will be described in detail.
However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.
≪ Example 1 >
Preparation of herbal medicine alone extract
≪ 1-1 > Preparation of single-stranded extract
Inulae Flos was washed with water to remove contaminants and completely dried. 200 g of the preparation thus prepared was refluxed and cooled twice with 4 L of a 95% (v / v) aqueous ethanol solution for 4 hours, and then the extract was filtered and concentrated under reduced pressure. After the majority of the solvent was evaporated, 0.2 L of water was added to the mixture for azeotropic concentration, and the mixture was concentrated twice. The same amount of water was added again to homogeneously suspend the mixture, followed by lyophilization to obtain 26 g of the powdery lyophilized extract.
≪ 1-2 > Preparation of single extract of mold
The mold (Schizonepetae Spica) was washed with water to remove contaminants and dried completely. 200 g of the thus-prepared mold was refluxed and cooled twice with 4 L of a 95% (v / v) aqueous ethanol solution for 4 hours, and then the extract was filtered and concentrated under reduced pressure. 0.2 L of water was added to the mixture in the state where most of the solvent was evaporated, followed by azeotropic distillation. The mixture was again mixed twice, and the same amount of water was added thereto again to homogeneously suspend it and then lyophilized to obtain 10 g of powdery mold extract.
≪ 1-3 >
Magnolia Cortex was washed with water to remove contaminants and dried completely. 200 g of the thus-prepared supernatant was refluxed and cooled twice with 4 L of a 95% (v / v) aqueous ethanol solution for 4 hours, and the extract was filtered and concentrated under reduced pressure. After most of the solvent was evaporated, 0.2 L of water was added to the mixture to azeotropically concentrate, and then the mixture was again mixed twice. The same amount of water was added again to homogeneously suspend the mixture, followed by lyophilization to obtain 34 g of powdery extract.
≪ Example 2 >
Preparation of mixture of herbal extracts alone
<2-1> Manufacture of Sambucongeae and Mixed Extracts
The lone single extract prepared in Example <1-1> and the single extract of the mold prepared in Example <1-2> were mixed at a weight ratio of 1: 1.
<2-2> Manufacture of mixed extracts of Sambukwa
The single-stranded extract prepared in Example <1-1> and the single-strand extract prepared in Example <1-3> were mixed at a weight ratio of 1: 1.
<2-3> Manufacture of mixed extracts of dogs and beans
The mold extract alone prepared in Example <1-2> and the extract prepared from Example <1-3> were mixed at a weight ratio of 1: 1.
≪ Example 3 >
Preparation of herbal medicine complex extract
≪ 3-1 > Preparation of a combination extract of L.
The lobsters and molds were mixed at a weight ratio of 1:15, 1: 9, 1: 6, 1: 3, 1: 1, and 1.6: 1. To the thus prepared mixture was added a 95% (v / v) aqueous ethanol solution, and the mixture was refluxed and cooled for 4 hours and then filtered. The filtrate was collected by filtration, The filtrate obtained by ash-on extraction was mixed with the filtrate previously collected and concentrated under reduced pressure.
≪ 3-2 &
The lyophilization and starch were mixed at a weight ratio of 3: 1, 2: 1, 1: 1, 1: 2, 1: 3. To the thus prepared mixture was added a 95% (v / v) aqueous ethanol solution, and the mixture was refluxed and cooled for 4 hours and then filtered. The filtrate was collected by filtration, The filtrate obtained by ash-on extraction was mixed with the filtrate previously collected and concentrated under reduced pressure.
≪ 3-3 > Production of complex extracts
Type dogs and scallops were mixed at a weight ratio of 3: 1, 1: 1, and 1: 1.6. To the thus prepared mixture was added a 95% (v / v) aqueous ethanol solution, and the mixture was refluxed and cooled for 4 hours and then filtered. The filtrate was collected by filtration, The filtrate obtained by ash-on extraction was mixed with the filtrate previously collected and concentrated under reduced pressure.
≪ 3-4 > Preparation of a combination extract of L., L., and L.
The embryo, mold, and starch were mixed in a weight ratio of 3: 1: 1. To the thus prepared mixture was added a 95% (v / v) aqueous ethanol solution, and the mixture was refluxed and cooled for 4 hours and then filtered. The filtrate was collected by filtration, The filtrate obtained by ash-on extraction was mixed with the filtrate previously collected and concentrated under reduced pressure.
< Example 4>
Pharmacological activity experiment of herbal medicine extract
<4-1> Herbal medicine extract IL -23-induced IL - 17
The effects of the herbal extracts prepared in Example 1 alone and the herbal medicine mixed extracts prepared in Example 2 and Example 3 on the secretory activity of IL-17 were confirmed in spleen cells of mice.
Experimental animals (ICR mice) were treated with CO 2 Anesthesia or cervical dislocation. The abdomen was wiped with 70% ethanol, and the spleen was removed using surgical scissors. The peripheral tissues were removed, and the cells were placed in a phosphate buffered saline (PBS) solution. The separated spleen was washed twice with PBS, and the spleen was transferred to a culture dish. The spleen was cut into a size of 1 to 2 mm with a scalpel blade, and cells were separated using a cell strainer and a syringe. The separated solution at the bottom of the strainer was transferred to a microtube and centrifuged at 800 g for 3 minutes. The supernatant was removed, 5 ml of Ammonium-Chloride-Potassium Lysis buffer was added, the pellet was re-dispersed and incubated at 4 ° C for 5 minutes. 40 ml of PBS was added, followed by centrifugation at 800 g for 3 minutes. Again, the supernatant was removed and 5 ml of RPMI-1640 complete media was added and resuspended gently. Then, the cells were filtered with a cell strainer to remove clumps. Cells were counted and seeded at a concentration of 6 × 10 5 / well in a 96-well plate. After the test substance was treated, it was cultured for 1 hour, and treated with 10 ng / ml of IL-23, followed by incubation for 72 hours. The supernatant was collected and stored at -70 ° C. ELISA assay was performed using the R & D IL-17 (Cat No. DY421) assay system and recommended by the manufacturer. The cytokine inhibition rate excluded the cytotoxic effect. The experimental results are shown in Table 1 and Table 2 as the efficiency (inhibition rate,%) of inhibiting the secretion of IL-17 in mouse spleen cells in the IL-17 column.
First, as shown in Table 1 below, the effects of the herbal extracts prepared in Example 1 alone and the herbal medicine mixed extracts prepared in Example 2 were compared. The extract of each herbal medicine also showed the effect of suppressing the secretion of IL-17, but it was confirmed that the effect of inhibiting the secretion of IL-17 was further improved when the mixed extract was treated with the herbal extract alone. In other words, the synergistic effect of suppressing the secretion of IL-17, an inflammatory cytokine, can be obtained by mixing the herbal extracts.
Next, as shown in Table 2 below, in order to examine the most preferable composition ratio of herbal medicine extracts, the inhibitory effect of IL-17 on secretion of crude herbal medicine extract prepared in Example 3 was compared. As a result, the combined extract of L. and L. showed excellent inhibitory effect of IL-17 when the two herbs were mixed at a weight ratio of 1: 6, and the complex extract of L. and L. showed 3: 1 2: 1 weight ratio. In addition, the combined extracts of the molds and horses showed the best inhibitory effect of IL-17 when the two herbs were mixed at a weight ratio of 3: 1.
≪ 4-2 > LPS Treatment-induced IL- 6 and TNF -α secretion
The effects of the herbal extracts prepared in Example 1 alone and the herbal medicine mixed extracts prepared in Examples 2 and 3 on the secretion activity of IL-6 and TNF-α were evaluated using mouse macrophage line RAW 264.7 cells.
RAW 264.7 cells were cultured in DMEM medium containing 10% FBS and 1% penicillin / streptomycin. On the day of the experiment, the cells were collected with a scraper, and the number of cells was measured using a hematocytometer and seeded in a 96-well plate at 5 × 10 4 cells / well. The cells were cultured for 24 hours. The serum free medium was completely dissolved in DMSO (dimethyl sulfoxide) using condition medium. One hour after the end of the sample treatment, LPS (lipopolysaccharide) was treated to 100 ng / ml and cultured for 24 hours. After incubation for 24 hours, the medium supernatants of mouse macrophages were collected and used for mouse IL-6 and TNF-α immunoassay kit. Dilute the supernatant of the culture medium with serum free medium and dilute the standard concentration to 15.625 ~ 1000 pg / ml. Diluted solution is added to 96 well plate and allowed to react at room temperature for 2 hours. After the reaction, the plate was washed 5 times with the washing solution, and each antibody conjugate was added thereto, followed by reaction at room temperature for 1 hour. After the reaction, the substrate is washed 7 times with the washing solution, and the substrate is added and reacted at room temperature for 30 minutes. Stop the reaction with stop solution and measure the absorbance at 450 nm. The above immunoassay kit (mouse IL-6 ELISA kit, BD science and mouse TNF-alpha ELISA kit, BD science) was used and the sample treatment concentration was not cytotoxic.
As shown in Table 1 , the secretion inhibitory effects of IL-6 and TNF-? Were compared between the herbal extracts prepared in Example 1 alone and the herbal medicine mixed extracts prepared in Example 2. Although the extract of each herbal medicine showed the effect of inhibiting the secretion of IL-6 and TNF-α, the inhibitory effect of IL-6 and TNF-α was further enhanced when the mixed extract was treated with herbal medicine alone Respectively. In other words, when the herbal extracts are mixed, the synergistic effect of IL-6, which is an inflammatory cytokine, and TNF-α secretion inhibition is exhibited.
As shown in Table 2, in order to examine the most preferable composition ratio of herbal medicine extracts, secretion inhibitory effects of IL-6 and TNF-α of the crude herbal medicine extract prepared in Example 3 were compared. As a result, the inhibitory effect of IL-6 on the secretion inhibition of TNF-α was remarkable at the ratio of 1: 1 and 1.6: 1, . On the other hand, the combined extracts of L. and L. showed high inhibitory effects on the secretion of IL-6 and TNF-α. On the other hand, the combined extracts of molds and horses showed less inhibitory effect on secretion of IL-6 and TNF-α than the combined extracts of the embryos.
<4-3> Therapeutic effect of herbal medicine extracts in an animal model of psoriasis
(Example <3-1>, weight ratio 1: 6), which showed a synergistic effect of suppressing the secretion of IL-17, IL-6 and TNF- (Example < 3-2 >: weight ratio 2: 1), the effect of treating psoriasis in the body was evaluated according to the method of Ma [J. Clin. Cell Immunol. 4: 6 (2013)].
Psoriasis was induced by intradermal administration of 500 ng of IL-23 every day to the ear of C57BL / 6 mice (6 weeks old, Orient Bio). As a positive control, tofacitinib, an oral agent, was used and 10 mg / kg bid and 30 mg / kg bid were administered with reference to the literature. The administration method of the combination of the lyophilization and the mold extract (Example <3-1>, weight ratio 1: 6) and the combination of the lyophilization and the lyophilized composite extract (Example <3-2>, weight ratio 2: 1) The doses were 100 mg / kg bid and 200 mg / kg bid, respectively. The vehicle without the drug or extract (Vehicle) was used as a negative control. PBS control was a PBS-treated control instead of IL-23. Total of 14 doses were administered for 16 days. After the end of the experiment, the ear thickness of the mouse was measured, and then the ear tissue was extracted to analyze the epidermal thickness, inflammatory cell infiltration and mRNA expression level. The results are shown in Figures 1-4.
As shown in FIG. 1, Chemistry and fleet type of complex extract (Example <3-1>, a weight ratio of 1: 6) and compound extract of magnolia and a fleet Chemistry (Example <3-2>, a weight ratio of 2: 1) Can reduce the ear thickness in an animal model of psoriasis. In addition, when comparing the efficacy with the positive control group, tofacitinib in the ear thickness reduction part, it can be confirmed that it has non-inferiority.
2 (Example 3-1> weight ratio 1: 6), and the combination of the longevity and the loess compound (Example 3-2> weight ratio 2: 1) the effect of reducing the epidermal thickness in the ear tissue in the psoriasis animal model can be confirmed as compared with the positive control treated with tofacitinib.
(Example 3-1, weight ratio 1: 6), and the combined extracts of L. and L. (Example 3-2, weight ratio 2: 1) as shown in FIG. 3 , Can reduce the infiltration of inflammatory cells in an animal model of psoriasis. In addition, it was confirmed that the efficacy of the combination of L. and L. complex (Example <3-1>, weight ratio of 1: 6) was relatively better than that of L. and L. complex extract (Example <3-2>, weight ratio 2: 1) .
As shown in FIGS . 4A and 4B , the combined extract of L. and L. (Example 3-1, weight ratio 1: 6), the combined extract of L. and L. (Example 3-2, weight ratio 2 : 1) is effective in reducing the mRNA expression of
INDUSTRIAL APPLICABILITY As described above, the present invention provides a composition for preventing, treating or ameliorating a chronic inflammatory disease comprising two or more crude herbal extracts selected from the group consisting of L. The composition of the present invention can be effectively used for the prevention and treatment of chronic inflammatory diseases by effectively inhibiting the activity of inflammatory cytokines.
Claims (4)
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| PCT/KR2016/008130 WO2017023000A1 (en) | 2015-07-31 | 2016-07-26 | Composition containing mixed medicinal herb extract for preventing, treating, or alleviating chronic inflammatory diseases |
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| WO2019124666A3 (en) * | 2017-12-19 | 2019-08-15 | 포항공과대학교 산학협력단 | Pharmaceutical composition comprising interleukin-17 inhibitor and tumor necrosis factor-alpha inhibitor as effective ingredient for preventing or treating neutrophilic lung inflammation disease |
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| KR102210566B1 (en) | 2018-03-16 | 2021-02-03 | 주식회사 헬릭스미스 | Herbal Composition for Preventing or Treating Respiratory Disease |
| KR102379395B1 (en) * | 2019-04-29 | 2022-03-29 | 주식회사 헬릭스미스 | Pharmaceutical composition comprising a mixture extract of coptis rhizome and schizonepeta tenuifolia briquet as an active ingredient for preventing or treating inflammatory bowel disease |
| KR20210043067A (en) * | 2019-10-10 | 2021-04-21 | 주식회사 헬릭스미스 | Composition for preventing or treating inflammatory bowel diseases comprising mixed herbal extracts |
| KR20220053486A (en) * | 2020-10-21 | 2022-04-29 | 주식회사 헬릭스미스 | Composition for Preventing or Treating Inflammatory Bowel Diseases Comprising Mixed Herbal Extracts |
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| KR960007923B1 (en) * | 1992-09-09 | 1996-06-17 | 주식회사 대웅제약 | Antibacterial composition comprising magnolol and honokiol of machili cortex extracted components |
| JP3154285B2 (en) * | 1992-09-18 | 2001-04-09 | カネボウ株式会社 | Collagenase activity inhibitor |
| KR100307947B1 (en) * | 1999-10-06 | 2001-09-13 | 서경배 | A method for preparation of plant extract powder and oral compositions containing plant extract powder prepared by the same |
| KR100999598B1 (en) * | 2008-05-07 | 2010-12-10 | 영남대학교 산학협력단 | A Composition comprising the extract of Inula flos as an active ingredient for preventing and treating inflammatory, allergy and asthmatic diseases |
| KR101456044B1 (en) * | 2013-12-02 | 2014-11-04 | 주식회사 엘지생활건강 | Cosmetic composition for preventing of kin trouble |
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2015
- 2015-07-31 KR KR1020150108612A patent/KR101760512B1/en active IP Right Grant
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2016
- 2016-07-26 WO PCT/KR2016/008130 patent/WO2017023000A1/en active Application Filing
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| Fitoterapia. 2000. Vol.71, S13-S20.* |
| International Journal of Pharmaceutics. 2013. Vol.445, pp.153-162.* |
| 선복탕. 한국 전통지식포탈(DB 공개 2007.12.06.)* |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019124666A3 (en) * | 2017-12-19 | 2019-08-15 | 포항공과대학교 산학협력단 | Pharmaceutical composition comprising interleukin-17 inhibitor and tumor necrosis factor-alpha inhibitor as effective ingredient for preventing or treating neutrophilic lung inflammation disease |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20170014758A (en) | 2017-02-08 |
| WO2017023000A1 (en) | 2017-02-09 |
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