CN118141762B

CN118141762B - Foam-type pharmaceutical agent and foam composition for topical application

Info

Publication number: CN118141762B
Application number: CN202410575482.7A
Authority: CN
Inventors: 李勇; 魏世峰; 汪鹤龄; 张小兰; 王新国
Original assignee: Innovaco Pharmaceuticals Inc
Current assignee: Innovaco Pharmaceuticals Inc
Priority date: 2024-05-10
Filing date: 2024-05-10
Publication date: 2024-07-12
Anticipated expiration: 2044-05-10
Also published as: CN118141762A

Abstract

The present invention relates to foam-type pharmaceutical agents and foam compositions for topical application. In one aspect, the invention provides a foam composition sealed within a container comprising an active drug, a lipid material, a surfactant, diethylene glycol monoethyl ether, water, and an aerosol propellant. The foam-type medicament for topical application includes an aerosol canister equipped with a valve, the canister being hermetically filled with a composition comprising: active drug, lipid material, surfactant, diethylene glycol monoethyl ether, water, aerosol propellant. The invention also relates to a method for producing such foam-type medicaments for topical administration, and to the use thereof for producing products for the prophylaxis and/or treatment of diseases by topical administration. The foam-type pharmaceutical agents and foam compositions of the present invention exhibit superior properties such as one or more of a large amount of foaming, a small foam density, slow foam collapse, stable particle size of suspended particles in the composition, and the like.

Description

Foam-type pharmaceutical agent and foam composition for topical application

Technical Field

The invention belongs to the technical field of medicines, relates to a pharmaceutical preparation for topical application, in particular to a foam type medicament for topical application, and also relates to a corresponding foam composition. The invention also relates to a method for producing such foam-type medicaments for topical administration, and to the use thereof for producing products for the prophylaxis and/or treatment of diseases by topical administration.

Background

Topical administration, also commonly referred to as in vitro administration, is a common route of administration that may be used to administer drugs locally or transdermally and then into the systemic blood stream to produce systemic effects.

The skin is the largest organ of the human body, which isolates potentially harmful substances from the body and also keeps molecular components of the body in the body. With a greater understanding of the important skin organ, transdermal formulations have become a new mode of administration.

Transdermal drug delivery formulations/systems (TRANSDERMAL THERAPEUTIC SYSTEM, TTS) are delivery systems that deliver drugs to the skin or mucosal surface at a constant rate through the layers or mucosa of the skin and into the systemic circulation for systemic treatment, an improved drug delivery system. The skin of a normal human body mainly consists of three parts of epidermis, dermis and subcutaneous tissue, namely sweat glands, sebaceous glands, hair follicles and other appendages. The stratum corneum is a main obstacle for transdermal absorption, belongs to an epidermis structure, has high density and low water content, can prevent drug permeation, and limits drug bioavailability. The dermis and subcutaneous tissue have small resistance to drug penetration, and the drug is easy to be absorbed by blood vessels and lymphatic vessels after entering.

Transdermal formulations are available for absorption via the epidermal and cutaneous annex routes. The epidermal route is the main route, and drug transport is performed by passive diffusion mode taking the concentration difference of the drug inside and outside the skin as the motive force. The drug reaches the active epidermis through the interstices between the stratum corneum cells, known as the intercellular pathway; through the stratum corneum cells to the active epidermis, known as the transcellular pathway. Fat-soluble and non-ionic drugs (non-polar molecules) pass more easily through the stratum corneum, while ionic drugs (polar molecules) pass more poorly. The skin attachment route is also a class, where drugs are absorbed through hair follicles, sebaceous glands and sweat glands.

Based on the special absorption mode of transdermal administration, the preparation has the following advantages: the first pass effect of the medicine is avoided; prolonging the action time and reducing the administration times; the constant blood concentration is maintained when the medicine is absorbed by the whole body, so that toxic and side effects are reduced; improving patient compliance.

In 1979, the U.S. FDA approved the world's first transdermal patch product, scopolamine (TRANSDERM SCOP) transdermal patch, for the treatment of motion sickness. The transdermal drug delivery system is the third drug delivery system after oral administration and injection because of the unique advantages, and plays an increasingly important role in preventing and treating diseases. Currently, hundreds of transdermal patch products are marketed worldwide. From the point of indications, transdermal administration preparations are mainly focused on the fields of mental nerves, anti-inflammatory and analgesic, cardiovascular and the like, and some typical transdermal administration preparations which are marketed at home and abroad comprise: buprenorphine patch (Butrans for moderate to severe chronic pain in patients requiring prolonged continuous use of opioid analgesics), testosterone patch (Androderm for improving hypogonadism in men 18 years and older), estradiol patch (MINIVELLE for improving moderate to severe vasomotor symptoms caused by menopause), oxybutynin patch (Oxytrol for treating overactive bladder in women), 1.8% lidocaine patch (Ztlido, for use in alleviating shingles-related neuropathic pain); 1% luliconazole cream (LUZU for topical treatment of toe tinea pedis, tinea cruris and tinea corporis caused by red Mao Xuanyin and epidermophyton floccosum in 18 years and older), 1% ivermectin cream (Soolantra for treatment of rosacea inflammatory lesions), 4% fluorouracil cream (Tolak for topical treatment of facial, ear and scalp actinic keratosis), 1% oxymetazoline hydrochloride cream (Rhofade for treatment of facial erythema of adult rosacea), 0.025% clobetasol propionate cream (Lmpoyz for treatment of moderate and severe plaque psoriasis in 18 years and older), 1% of an ozenoxacin cream (Xepi) for the topical treatment of impetigo in adults and children suffering from more than 2 months due to staphylococcus aureus or streptococcus pyogenes; 2% naftifine hydrochloride gel (Naftin for treating intertoe tinea pedis caused by Trichophyton rubrum, trichophyton mentagrophytes and Epidermophyton floccosum in 18 years old and older), 0.33% brimonidine gel (Mirvaso for topical treatment of persistent facial erythema caused by rosacea in 18 years old or older), 0.016% nitrogen mustard gel (Valchlor for topical treatment of stage IA and stage IB mycosis type skin T cell lymphoma in patients who have received at least 1 skin-directed treatment), testosterone gel (Vogelxo for male testosterone replacement therapy, Systemic treatment for endogenous testosterone deficiency or deficiency-related conditions), 0.3%/2.5% adapalene and benzoyl peroxide gels (Epiduo Forte for treatment of acne vulgaris), 7.5% dapsone gels (Aczone for topical treatment of acne vulgaris in patients 12 years and older), 10% aminolevulinic acid hydrochloride gels (Ameluz for focal directed and non-directed treatment of mild-moderate Actinic Keratosis (AK) of the face and scalp); 0.05% halobetasol propionate lotion (Ultravate for topical treatment of plaque psoriasis in patients 18 years and older), 0.05% retinoic acid lotion (Altreno for treatment of acne vulgaris), 0.01% halobetasol propionate lotion (Bryhali for topical treatment of adult plaque psoriasis), 0.01%/0.045% halobetasol propionate and tazarotene lotion (Duobrii for topical treatment of adult plaque psoriasis).

In addition, a particular class of formulations for transdermal use in vitro are currently marketed, namely foam (also known as topical foam), for example 1% econazole nitrate foam (Ecoza for the treatment of toe tinea pedis caused by trichophyton rubrum, trichophyton mentagrophytes and epizoon floccosum in 12 years old and older), 15% azelaic acid foam (Finacea for the topical treatment of inflammatory papules and mild to moderate rosacea pustules), 0.005%/0.064% calcipotriene and betamethasone dipropionate foam (Enstilar for the topical treatment of psoriasis vulgaris), 0.05% halobetaxopropionate foam (Halobetasol propionate for the topical treatment of plaque psoriasis in patients 18 years old and older).

The foam technology has also been described in the literature, for example 200910069409.8 (CN 101926765 a) discloses a mometasone furoate foam composition containing mometasone furoate as an active ingredient and one or more pharmaceutically acceptable auxiliary materials suitable for the foam, wherein the mometasone furoate as an active ingredient has a content of 0.05% -0.2% (w/w) and a volume expansion ratio of 25-50. For another example, 201680023469.4 (CN 107530255 a) discloses a method of treating hair comprising providing a concentrated hair care composition in an aerosol foam dispenser. The concentrated hair care composition comprises one or more silicones, fragrances, stearyl alcohol, and cetyl alcohol. The method further comprises dispensing a concentrated hair care composition from the aerosol foam dispenser in the form of a foam dose; applying the foam to hair; and rinsing the foam from the hair. The foam has a density of about 0.025g/cm ³ to about 0.30g/cm ³ when dispensed from an aerosol foam dispenser. For another example, 202211408956.6 (CN 115554243B) discloses a minocycline foam for treating rosacea, comprising the following raw and auxiliary materials in parts by mass: 0.5 to 2.5 parts of minocycline and/or minocycline derivative micropowder, 70 to 85 parts of hydrophobic oil, 3 to 7 parts of silicone solvent, 3 to 6 parts of C12-C32 fatty alcohol, 2 to 3 parts of C12-C32 fatty acid, 0.3 to 0.5 part of C6-C10 dibasic acid, 3 to 5 parts of wax, 2 to 3 parts of disaccharide and/or monosaccharide, 1.2 to 2 parts of maltosyl-beta-cyclodextrin and 0.5 to 1.0 part of penetration enhancer, 0.5-1.0 part of alginic acid and 5-10 parts of propellant. The minocycline foam agent provided by the invention can obtain a foam agent product with excellent stability under the condition of not using water and a surfactant; by adding the penetration enhancer and the maltosyl-beta-cyclodextrin, the penetration capability of the minocycline foam agent to the skin is improved, and the curative effect is enhanced. In addition, there are many reports of a foaming agent for administration through a lumen such as vaginal mucosa, for example 200910019723.5 (CN 101502510B) which discloses a pharmaceutical composition for treating vaginal inflammation in the form of a foaming agent, specifically a foaming agent using metronidazole, clotrimazole and chlorhexidine acetate as main drugs. The medicine can be uniformly distributed in the cavity and the way, the coating surface is wide, the effect is better, the use feeling is more comfortable than other dosage forms, and the detention is stronger than other dosage forms. In the prescription of the foaming agent, mist particles with the particle size of only a few microns are dispersed in a foam shape through pressure, so that the medicine can quickly and effectively permeate into the mucous membrane wall of a cavity, the medicine can be absorbed more quickly with the aid of various fat-soluble auxiliary materials than a spray taking water as the only solvent, and the medicine pollution and cross pollution can not occur in the using process.

Foam dosage forms are typically formulations in which the drug is dissolved or suspended in a foam-producing liquid, and a prescribed amount of the drug is expelled by means of a propellant (sometimes also using a mechanical pump), which forms a foam on the body surface,

However, the solubility of the existing foamer drug solution systems is insufficient for many active agents, and suspension particle systems must be formed in which the active agent is not completely dissolved, but because of the addition of the nonpolar propellant to the liquid composition, they can have an adverse effect on the variation in particle size of the undissolved active agent.

In addition, it is known that the absorption of a drug is premised on the dissolution of the drug. The development of the poorly soluble drugs into foam preparations is difficult, because on one hand, the dissolution of the poorly soluble drugs usually requires an organic solvent and a nonpolar propellant, and the organic solvent has the function of defoaming, but when the poorly soluble drugs are used as a foam agent, the foam is expected to be maintained for a longer time, and the foam rupture process is slow; on the other hand, foam formation requires the presence of water, which in turn may lead to crystallization of the drug, which forms a pair of contradictors.

Thus, there is still an urgent need for those skilled in the art to prepare a pharmaceutical composition having one or more advantages of being able to effectively form foam, having a long foam-maintaining time, maintaining a stable dissolution or suspension state of an active drug in a liquid medicine, and the like.

Disclosure of Invention

The present invention aims to provide a foam-type drug which can be administered via the body surface, and is expected to have one or more advantages such as the ability to effectively form foam, the long foam-retaining time, and the stability of the dissolution or suspension state of an active drug in a drug solution. It is another object of the present invention to provide a method for preparing the above foam-type pharmaceutical agent. It has been unexpectedly discovered that the foamed medicament produced by the process of the present invention exhibits the benefits of one or more aspects as described herein, and the present invention has been completed based on such findings.

To this end, a first aspect of the present invention provides a foam composition sealed within a container comprising: 2-15 parts of active medicine, 10-30 parts of lipid substances, 2-15 parts of surfactant, 10-35 parts of diethylene glycol monoethyl ether, 0.2-1 part of disodium azelate, 1-5 parts of glycylglycine, 10-20 parts of water and 10-20 parts of aerosol propellant.

The foam composition according to the first aspect of the invention comprises: 5-15 parts of active medicine, 15-30 parts of lipid substances, 3-12 parts of surfactant, 15-30 parts of diethylene glycol monoethyl ether, 0.2-0.8 part of disodium azelate, 2-5 parts of glycylglycine, 10-18 parts of water and 10-20 parts of aerosol propellant.

The foam composition according to the first aspect of the invention, wherein the active drug is selected from the group consisting of: itraconazole, selenium sulphide, ketoconazole, terbinafine, bifonazole, posaconazole, econazole, butenafine, calcipotriol, tacalcitol, tretinoin, tacrolimus, minoxidil, finasteride, clindamycin, metronidazole, fusidic acid, lidocaine, and a corticosteroid active substance selected from the group consisting of: betamethasone, beclomethasone dipropionate, betamethasone acetate, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, fluodichloropine, fluocinolone acetonide, budesonide, clodrolone acetonide, fluocinolone acetonide, beclomethasone butyrate, valvular, desoxymethasone, difluosone diacetate, difluomethasone valerate, difluomethasone pivalate, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone acetate, mometasone furoate, triamcinolone, minocycline, clobetasol, halobetasol or esters thereof such as halobetasol propionate, calcipotriene or esters or pharmaceutically acceptable salts thereof, and combinations thereof. The foam composition according to the first aspect of the invention, wherein the active agent is suspended in the foam composition in the form of fine particles.

The foam composition according to the first aspect of the present invention, wherein the active drug is suspended in the foam composition in the form of fine particles, the particle size distribution of the fine particles is determined, and D50 is 10 to 50 μm.

The foam composition according to the first aspect of the present invention, wherein the active drug is suspended in the foam composition in the form of fine particles, the particle size distribution of the fine particles is measured, and S value is in the range of 0.8 to 1.2 calculated by the formula s= (D90-D10)/(D50), wherein D10, D50 and D90 are parameters obtained by particle size distribution measurement.

The foam composition according to the first aspect of the present invention forms a foam after release from the container, the foam having been completely lost for a period of 10 to 20 minutes, for example, 10 to 16 minutes.

The foam composition according to the first aspect of the invention forms a foam after release from the container, the foam density being in the range of 20 to 150mg/cm ³.

The foam composition according to the first aspect of the invention, wherein the lipid material is selected from the group consisting of: caprylic capric polyethylene glycol glyceride, isopropyl palmitate, cetostearyl phosphate, cetostearyl polyether-10 phosphate, and combinations thereof.

The foam composition according to the first aspect of the invention, wherein the surfactant is selected from: tween 40, tween 60, tween 65, tween 80, tween 85 and combinations thereof.

The foam composition according to the first aspect of the invention, wherein the aerosol propellant is selected from the group consisting of: r134a, R404a, propane, butane, isobutane, and combinations thereof.

The foam composition according to the first aspect of the invention is sealed in a container which is a valve-equipped aerosol canister, for example a valve-equipped aerosol aluminium canister.

The foam composition according to the first aspect of the invention is prepared by: mixing various raw materials and auxiliary materials except the aerosol propellant at an elevated temperature (60-80 ℃), grinding the obtained mixed liquid until all the materials can pass through a screen mesh with a pore diameter of 10-50 mu m, for example, 20-40 mu m, naturally cooling the liquid to room temperature after discharging, subpackaging the obtained materials into aerosol cans provided with valves, and pressurizing and filling a specified amount of aerosol propellant to obtain the foam composition. This method is a conventional method of preparing pharmaceutical agents in the art.

The foam composition according to the first aspect of the present invention further comprises an alcoholic solvent selected from the group consisting of: propylene glycol, 1, 2-hexanediol, polyethylene glycol 200, glycerin, and combinations thereof.

The foam composition according to the first aspect of the invention, wherein the surfactant may also be selected from: ammonium lauryl sulfate, ammonium laureth sulfate, triethylamine lauryl sulfate, triethylamine laureth sulfate, triethanolamine lauryl sulfate, triethanolamine laureth sulfate, monoethanolamine laureth sulfate, diethanolamine lauryl sulfate, diethanolamine laureth sulfate, sodium monolaurate sulfate, sodium lauryl sulfate, sodium laureth sulfate, potassium laureth sulfate, sodium laurylsarcosinate, cocoyl sarcosinate, ammonium cocoyl sulfate, ammonium lauroyl sulfate, sodium cocoyl sulfate, sodium lauroyl sulfate, sodium cocoyl sulfate, potassium cocoyl sulfate, monoethanolamine cocoyl sulfate, sodium trideceth-1 sulfate, sodium trideceth-2 sulfate, sodium trideceth-3 sulfate, sodium trideceth sulfate, sodium methyl lauroyl taurate, sodium undecyl sulfate, sodium decyl sulfate, sodium methyl cocoyl taurate, sodium lauroyl isethionate, sodium lauroyl taurate, sodium lauroyl sulfosuccinate, sodium dodecyl sulfosuccinate, sodium phenyl sulfonate, sodium dodecyl sulfonate, and mixtures thereof.

The foam composition according to the first aspect of the invention, wherein the surfactant may also be selected from: sodium cocoamidopropionate, sodium cocoamidodipropionate, sodium cocoamphoacetate, sodium cocoampholytic hydroxypropyl sulfonate, sodium cocoampholytic propionate, sodium corn oleoyl ampholytic propionate, sodium lauramidopropionate, sodium lauramidoampholytic propionate, sodium corn oleoyl ampholytic propionate, sodium lauramidodipropionate, ammonium cocoamidodipropionate, ammonium cocoamidoampholytic acetate, ammonium cocoamidoampholytic sulfonate, ammonium cocoamidoampholytic propionate, ammonium lauryl ampholytic propionate, ammonium lauramidoampholytic sulfonate, ammonium lauramidodipropionate, triethanolamine cocoamidodipropionate, ammonium lauramidoampholytic propionate, ammonium lauramidodipropionate cocoamidodipropionate triethanolamine, cocoamphoacetate triethanolamine, cocoampholytic hydroxypropylsulfonate triethanolamine, cocoampholytic propionate triethanolamine, corn oleoyl ampholytic propionate triethanolamine laurylaminopropionic acid triethanolamine, lauroyl amphoacetic acid triethanolamine, lauroyl ampholytic acid triethanolamine, lauroyl amphopropionic acid triethanolamine, corn oleoyl amphopropionic acid triethanolamine lauriminodipropionate triethanolamine, cocoyl amphodipropionic acid, decanoyl amphodiacetate disodium, decanoyl amphodipropionic acid disodium, octanoyl amphodiacetate disodium, octanoyl amphodipropionic acid disodium, cocoyl amphodisodium carboxyethyl hydroxypropyl sulfonate disodium, cocoyl amphodiacetate disodium, cocoyl amphodipropionic acid disodium, dicarboxyethyl cocoyl propyldiamine disodium, and cocoyl amphodipropionic acid disodium, lauryl polyoxyethylene ether-5 carboxyamphodiacetate, disodium lauriminodipropionate, disodium lauroyl amphodiacetate, disodium lauroyl amphodipropionate, disodium oleyl amphodipropionate, PPG-2-isodecyl polyether-7 carboxyamphodiacetate, disodium laurylaminopropionate, lauroyl amphodipropionic acid, laur Gui Jian propylglycine, lauroyl Gui Jier ethylenediaminoglycine, and mixtures thereof.

The foam composition according to the first aspect of the invention, wherein the surfactant may also be selected from: polyoxyethylene alkylphenols, polyoxyethylene alcohols, polyoxyethylene polypropylene glycols, glyceryl alkanoates, polyglyceryl alkanoates, propylene glycol alkanoates, sorbitol alkanoates, polyoxyethylene glycol alkanoates, polyoxyethylene alkanoic acids, alkanolamides, N-alkylpyrrolidones, alkyl glycosides, alkyl polyglucosides, alkyl amine oxides, and polyoxyethylene siloxanes.

The foam composition according to the first aspect of the invention, wherein the aerosol propellant may further be selected from: r134a, propane, n-butane, isobutane, n-pentane, isopentane, dichlorodifluoromethane, 1-dichloro-1, 2-tetrafluoroethane, 1-chloro-1, 1-difluoro-2, 2-trifluoroethane, 1-chloro-1, 1-difluoroethylene, chlorodifluoromethane 1, 1-difluoroethane, 1, 3-tetrafluoropropene, 2, 3-tetrafluoropropene, dimethyl ether, methylethyl ether, carbon dioxide, nitrous oxide, nitrogen, compressed air, trichlorofluoromethane, tetrafluoroethane, and combinations thereof.

Further, a second aspect of the present invention provides a topical foam formulation comprising an aerosol canister, such as an aluminium canister, fitted with a valve, the aerosol canister being hermetically filled with a composition comprising: 2-15 parts of active medicine, 10-30 parts of lipid substances, 2-15 parts of surfactant, 10-35 parts of diethylene glycol monoethyl ether, 0.2-1 part of disodium azelate, 1-5 parts of glycylglycine, 10-20 parts of water and 10-20 parts of aerosol propellant.

The foam-type medicament according to the second aspect of the present invention, wherein the aerosol canister is filled hermetically with a composition comprising: 5-15 parts of active medicine, 15-30 parts of lipid substances, 3-12 parts of surfactant, 15-30 parts of diethylene glycol monoethyl ether, 0.2-0.8 part of disodium azelate, 2-5 parts of glycylglycine, 10-18 parts of water and 10-20 parts of aerosol propellant.

The foam medicament according to the second aspect of the present invention, wherein the active drug is selected from the group consisting of: itraconazole, selenium sulphide, ketoconazole, terbinafine, bifonazole, posaconazole, econazole, butenafine, calcipotriol, tacalcitol, tretinoin, tacrolimus, minoxidil, finasteride, clindamycin, metronidazole, fusidic acid, lidocaine, and a corticosteroid active substance selected from the group consisting of: betamethasone, beclomethasone dipropionate, betamethasone acetate, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, fluodichloropine, fluocinolone acetonide, budesonide, clodrolone acetonide, fluocinolone acetonide, beclomethasone butyrate, valvular, desoxymethasone, difluosone diacetate, difluomethasone valerate, difluomethasone pivalate, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone acetate, mometasone furoate, triamcinolone, minocycline, clobetasol, halobetasol or esters thereof such as halobetasol propionate, calcipotriene or esters or pharmaceutically acceptable salts thereof, and combinations thereof.

The foam-type medicament according to the second aspect of the present invention, wherein the active drug is suspended in the composition in the form of fine particles.

According to the foam-type medicament of the second aspect of the present invention, the active drug is suspended in the composition in the form of fine particles, the particle size distribution of the fine particles is measured, and D50 is 10-50 μm.

The foam-type pharmaceutical agent according to the second aspect of the present invention, wherein the active drug is suspended in the composition in the form of fine particles, the particle size distribution of the fine particles is measured, and S value is in the range of 0.8 to 1.2 calculated by the formula s= (D90-D10)/(D50), wherein D10, D50 and D90 are parameters obtained by particle size distribution measurement.

According to the foam-type medicament of the second aspect of the present invention, the composition forms foam after being released from the container, and the foam is completely disappeared for 10 to 20 minutes, for example, 10 to 16 minutes.

According to the foam-type medicament of the second aspect of the invention, the composition forms foam after being released from the container, and the foam density is in the range of 20-150 mg/cm ³.

The foam medicament according to the second aspect of the present invention, wherein the lipid substance is selected from the group consisting of: caprylic capric polyethylene glycol glyceride, isopropyl palmitate, cetostearyl phosphate, cetostearyl polyether-10 phosphate, and combinations thereof.

The foam formulation according to the second aspect of the present invention, wherein the surfactant is selected from the group consisting of: tween 40, tween 60, tween 65, tween 80, tween 85 and combinations thereof.

The foamed medicament according to the second aspect of the present invention, wherein the aerosol propellant is selected from the group consisting of: r134a, R404a, propane, butane, isobutane, and combinations thereof.

The foam-type pharmaceutical agent according to the second aspect of the present invention is prepared by: mixing various raw materials and auxiliary materials except the aerosol propellant at an elevated temperature (60-80 ℃), grinding the obtained mixed liquid until all the materials can pass through a screen mesh with a pore diameter of 10-50 mu m, for example, 20-40 mu m, naturally cooling the liquid material to room temperature after discharging, sub-packaging the obtained materials into an aerosol tank provided with a valve, and pressurizing and filling a specified amount of aerosol propellant to obtain the foam medicament.

The foam-type pharmaceutical agent according to the second aspect of the present invention, wherein the composition further comprises an alcoholic solvent selected from the group consisting of: propylene glycol, 1, 2-hexanediol, polyethylene glycol 200, glycerin, and combinations thereof.

The foam formulation according to the second aspect of the present invention, wherein the surfactant may be further selected from: ammonium lauryl sulfate, ammonium laureth sulfate, triethylamine lauryl sulfate, triethylamine laureth sulfate, triethanolamine lauryl sulfate, triethanolamine laureth sulfate, monoethanolamine laureth sulfate, diethanolamine lauryl sulfate, diethanolamine laureth sulfate, sodium monolaurate sulfate, sodium lauryl sulfate, sodium laureth sulfate, potassium laureth sulfate, sodium laurylsarcosinate, cocoyl sarcosinate, ammonium cocoyl sulfate, ammonium lauroyl sulfate, sodium cocoyl sulfate, sodium lauroyl sulfate, sodium cocoyl sulfate, potassium cocoyl sulfate, monoethanolamine cocoyl sulfate, sodium trideceth-1 sulfate, sodium trideceth-2 sulfate, sodium trideceth-3 sulfate, sodium trideceth sulfate, sodium methyl lauroyl taurate, sodium undecyl sulfate, sodium decyl sulfate, sodium methyl cocoyl taurate, sodium lauroyl isethionate, sodium lauroyl taurate, sodium lauroyl sulfosuccinate, sodium dodecyl sulfosuccinate, sodium phenyl sulfonate, sodium dodecyl sulfonate, and mixtures thereof.

The foam formulation according to the second aspect of the present invention, wherein the surfactant may be further selected from: sodium cocoamidopropionate, sodium cocoamidodipropionate, sodium cocoamphoacetate, sodium cocoampholytic hydroxypropyl sulfonate, sodium cocoampholytic propionate, sodium corn oleoyl ampholytic propionate, sodium lauramidopropionate, sodium lauramidoampholytic propionate, sodium corn oleoyl ampholytic propionate, sodium lauramidodipropionate, ammonium cocoamidodipropionate, ammonium cocoamidoampholytic acetate, ammonium cocoamidoampholytic sulfonate, ammonium cocoamidoampholytic propionate, ammonium lauryl ampholytic propionate, ammonium lauramidoampholytic sulfonate, ammonium lauramidodipropionate, triethanolamine cocoamidodipropionate, ammonium lauramidoampholytic propionate, ammonium lauramidodipropionate cocoamidodipropionate triethanolamine, cocoamphoacetate triethanolamine, cocoampholytic hydroxypropylsulfonate triethanolamine, cocoampholytic propionate triethanolamine, corn oleoyl ampholytic propionate triethanolamine laurylaminopropionic acid triethanolamine, lauroyl amphoacetic acid triethanolamine, lauroyl ampholytic acid triethanolamine, lauroyl amphopropionic acid triethanolamine, corn oleoyl amphopropionic acid triethanolamine lauriminodipropionate triethanolamine, cocoyl amphodipropionic acid, decanoyl amphodiacetate disodium, decanoyl amphodipropionic acid disodium, octanoyl amphodiacetate disodium, octanoyl amphodipropionic acid disodium, cocoyl amphodisodium carboxyethyl hydroxypropyl sulfonate disodium, cocoyl amphodiacetate disodium, cocoyl amphodipropionic acid disodium, dicarboxyethyl cocoyl propyldiamine disodium, and cocoyl amphodipropionic acid disodium, lauryl polyoxyethylene ether-5 carboxyamphodiacetate, disodium lauriminodipropionate, disodium lauroyl amphodiacetate, disodium lauroyl amphodipropionate, disodium oleyl amphodipropionate, PPG-2-isodecyl polyether-7 carboxyamphodiacetate, disodium laurylaminopropionate, lauroyl amphodipropionic acid, laur Gui Jian propylglycine, lauroyl Gui Jier ethylenediaminoglycine, and mixtures thereof.

The foam formulation according to the second aspect of the present invention, wherein the surfactant may be further selected from: polyoxyethylene alkylphenols, polyoxyethylene alcohols, polyoxyethylene polypropylene glycols, glyceryl alkanoates, polyglyceryl alkanoates, propylene glycol alkanoates, sorbitol alkanoates, polyoxyethylene glycol alkanoates, polyoxyethylene alkanoic acids, alkanolamides, N-alkylpyrrolidones, alkyl glycosides, alkyl polyglucosides, alkyl amine oxides, and polyoxyethylene siloxanes.

The foam medicament according to the second aspect of the invention, the aerosol propellant in the composition may also be selected from: r134a, propane, n-butane, isobutane, n-pentane, isopentane, dichlorodifluoromethane, 1-dichloro-1, 2-tetrafluoroethane, 1-chloro-1, 1-difluoro-2, 2-trifluoroethane, 1-chloro-1, 1-difluoroethylene, chlorodifluoromethane 1, 1-difluoroethane, 1, 3-tetrafluoropropene, 2, 3-tetrafluoropropene, dimethyl ether, methylethyl ether, carbon dioxide, nitrous oxide, nitrogen, compressed air, trichlorofluoromethane, tetrafluoroethane, and combinations thereof.

Further, a third aspect of the present invention provides a method of preparing a foam composition according to the first aspect of the present invention or a foam medicament according to the second aspect of the present invention, comprising the steps of: mixing various raw materials and auxiliary materials except the aerosol propellant at an elevated temperature (60-80 ℃), grinding the obtained mixed liquid until all the materials can pass through a screen mesh with a pore diameter of 10-50 mu m, such as 20-40 mu m, naturally cooling the liquid to room temperature after discharging, sub-packaging the obtained materials into an aerosol tank provided with a valve, and pressurizing and filling a specified amount of aerosol propellant to obtain the foam composition or foam medicament sealed in the container.

Further, a fourth aspect of the invention provides the use of a foam composition or a foam formulation according to the invention for the manufacture of a product for administration by the topical route for the prevention and/or treatment of a disease.

To the foam composition of the present invention or the composition of the foam-type pharmaceutical agent, the following alcoholic solvents may be added: dipropylene glycol, tripropylene glycol, diethylene glycol, ethylene glycol, propylene glycol, glycerol, 1, 3-propanediol, 2-propanediol, 1, 2-butanediol, 1, 3-butanediol, 1, 4-butanediol, 2, 3-butanediol, 2-methyl-2, 4-pentanediol, triethyl citrate, 5-methyl-3-heptanone oxime, hydroxycitronellal, camphorgum, 2-isopropyl-5-methyl-2-hexenal, eucalyptol, 1-dimethoxyoctane, isobutyl hexanoate, dihydroisojasmonate, and combinations thereof.

Preservatives, fragrances or perfumes, moisturizers, emollients, sunscreens, acid and base conditioners, antimicrobial agents may also be added to the foam compositions of the present invention or to the compositions of the foam-type medicaments.

To the foam composition of the present invention or the composition of the foam-type pharmaceutical agent, an agent selected from the following may be further added: diethylene glycol monoethyl ether, ethanol, propylene glycol, cyclodextrin, hydroxypropyl-betacyclodextrin, sulfobutyl betacyclodextrin, glycerol, polyethylene glycol, isopropanol, benzyl alcohol, phenethyl alcohol, benzoic acid, liquid paraffin, medium chain triglycerides, propylene glycol dicaprylate, glycerol monolinoleate, glycerol monooleate, mineral oils, waxes, oleyl alcohol, isopropyl myristate, octyldodecanol, cetyl palmitate, caprylic caprate dodecanol, and the like

To the foam composition of the present invention or the composition of the foam-type pharmaceutical agent, a nonionic surfactant selected from the following may be further added: (1) fatty acid glycerides: such as glyceryl monostearate, glyceryl distearate, glyceryl monostearate, glyceryl behenate, glyceryl cocoate, etc.; (2) polyol type: sucrose fatty acid esters (e.g., sucrose laurate, sucrose palmitate, sucrose stearate, etc.); sorbitan fatty powder (trade name: span such as span 20, 40, 60, 65, 80, 85, etc.); polysorbates (trade name tween: such as tween 20, 40, 60, 65, 80, 85, etc.); (3) polyoxyethylene type: polyoxyethylene fatty acid esters (e.g., polyoxyethylene 7 stearate, polyoxyethylene 32 stearate, polyoxyethylene 40 stearate, polyoxyethylene 6 stearate, and polyoxyethylene 32 stearate mixtures, caprylic capric polyethylene glycol ester, shan Shuangxin capric glyceride, oleoyl polyoxyethylene glyceride, linoleoyl polyoxyethylene glyceride, lauroyl polyoxyethylene glyceride); polyoxyethylene fatty alcohol ether (such as polyoxyethylene lauryl alcohol ether, polyethylene glycol monodecanol ether, etc.); polyoxyethylene polyoxypropylene copolymers (also known as poloxamers, such as poloxamers 124, 188, 237, 338, 407, etc.) and other polyoxyethylene species, such as polyoxyethylene 35 castor oil, polyoxyethylene 35 hydrogenated castor oil, polyoxyethylene 40 hydrogenated castor oil, 15-hydroxystearic acid polyethylene glycol ester, polyethylene glycol cetostearyl ether 12, polyethylene glycol cetostearyl ether 20; (4) Other examples are polyglycerol oleate, propylene glycol monocaprylate, propylene glycol laurate (II), propylene glycol laurate (I), glyceryl monocaprylate, glyceryl monostearate and polyoxyethylene 75 stearate mixtures, polyoxyethylene 6 stearate and cetyl and stearyl polyether-20 mixtures, tricetyl stearyl polyether and ethylene glycol palmitate and diethylene glycol palmitate mixtures, polyglycerol-3 diisostearate, cetyl palmitate, propylene glycol monopalmitate stearate.

To the foam composition of the present invention or the composition of the foam-type pharmaceutical agent, an ionic surfactant selected from the following may be further added: (1) cationic surfactant: benzalkonium chloride, benzalkonium bromide, domiphen bromide, and the like; (2) anionic surfactant: higher fatty acid salts (sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, aluminum salt of fatty acid, and salts of fatty acid with organic amine such as triethanolamine stearate, etc.), sulfated oils and higher fatty alcohol sulfates (sodium dodecyl sulfate, sodium hexadecyl sulfate, etc.), sulfonates (aliphatic sulfonate, alkylaryl sulfonate, alkyl naphthalene sulfonate, such as sodium di Xinji succinate sulfonate, sodium dihexylsuccinate sulfonate, etc.).

To the foam composition of the present invention or the composition of the foam-type pharmaceutical agent, a zwitterionic surfactant selected from the group consisting of: lecithin, amino acid type and betaine type surfactants.

In the foam composition of the present invention or the composition of the foam-type pharmaceutical agent, a thickener selected from the following may be further added: hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polypyrrolidone, sodium carboxymethylcellulose, carbomer, xanthan gum, gelatin, cetyl palmitate, mixed fatty acid glycerides, propylene glycol palmitate, tetradecanol, hexadecanol, octadecanol, mixtures of hexadecanol and octadecanol in different proportions, hydrogenated castor oil, glycerol monostearate 40-55, stearic acid

To the foam composition of the present invention or the composition of the foam-type pharmaceutical agent, a preservative selected from the following may be further added: methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate, butyl hydroxybenzoate, and the like.

To the foam composition of the present invention or the composition of the foam-type pharmaceutical agent, an antioxidant selected from the following may be added: tea Polyphenols (TP), tocopherols, flavonoids, butyl Hydroxy Anisole (BHA), dibutyl hydroxy toluene (BHT), tert-butyl hydroquinone (TBHQ), etc.

In the foam composition of the present invention or in the composition of the foam-type pharmaceutical agent, a propellant selected from the group consisting of: hydrofluoroalkanes (e.g., trichloro-monofluoromethane, tetrafluoroethane, etc.), fluorochloroalkanes (e.g., F11), dimethyl ether, hydrocarbons (propane, n-butane, and isobutane), compressed gases (carbon dioxide, nitrogen, nitric oxide, etc.).

To the foam composition of the present invention or the composition of the foam-type pharmaceutical agent, an acid-base modifier selected from the following may be added: various acids such as sodium hydroxide, hydrochloric acid, and citric acid, and salts thereof.

The foam-type medicament or foam composition provided by the invention is essentially a pharmaceutical preparation which can be called aerosol in pharmacy. The foamed pharmaceutical agent or foam composition of the present invention exhibits superior properties as described in the context of this document, such as one or more of a large amount of foaming, a small foam density, slow foam collapse, particle size stabilization of suspended particles in the composition, and the like.

Drawings

Fig. 1: example 1 the foam composition was examined for a typical microscopic field of particle size distribution.

Fig. 2: typical foam compositions extrude the resulting foam pattern.

Detailed Description

The various aspects of the invention and the effects that they exhibit are illustrated by the following specific examples, which are not intended to limit the invention. In the following formulation of the composition, the total amount of each ingredient is not less than 1kg unless otherwise specifically indicated. In the following specific examples, the amounts of materials may be expressed as either specific amounts or ratios, for example, when a product obtained in a step is insufficient for the next step, the amounts of materials sufficient for the next step may be obtained by repeating or amplifying the steps.

In the present document, when referring to parts representing the amounts of materials, unless otherwise stated, they refer to parts by weight and are used to represent the weight ratio between the materials, and may be any unit by weight such as g, kg, etc.

Example 1: foam composition of itraconazole

Prescription:

itraconazole: 10 parts by weight,

Caprylic capric polyethylene glycol glyceride: 20 parts by weight,

Isopropyl palmitate: 8 parts by weight,

Diethylene glycol monoethyl ether: 25 parts by weight,

Tween 60:10 parts by weight,

Propylene glycol: 10 parts by weight,

1, 2-Hexanediol: 2 parts by weight,

Pure water: 15 parts by weight,

R134a (propellant): 15 parts by weight.

The preparation method comprises the following steps:

(1) Stirring diethylene glycol monoethyl ether, tween, propylene glycol, 1, 2-hexanediol and water at 70 ℃ to be miscible;

(2) Stirring caprylic/capric acid polyethylene glycol glyceride and isopropyl palmitate at 70 ℃ to be mixed, slowly adding (pre-crushing to 120 meshes) the API while stirring, and continuously adding the mixed solution obtained in the step (1) while stirring;

(3) Transferring the heat-preserving mixed material obtained in the step (2) into a high-speed colloid mill, grinding until all the material can pass through a screen mesh with the aperture of 30 mu m (about 1.3 hours), and naturally cooling the temperature of the liquid material to room temperature (20-25 ℃) after discharging;

the high-speed colloid mill is a Nantong Del specialty CMS2000/4 type high-speed colloid mill, and is configured with BS410-1 type mesh screen produced by Endecotts company in the United kingdom, and the model and the configuration of the high-speed colloid mill are not described otherwise;

(4) And (3) subpackaging the product obtained in the last step into an aerosol aluminum pot provided with a valve, and pressurizing and filling a specified amount of propellant to obtain the foam composition.

The aluminum cans used in the invention are manufactured by European Asia and are provided with 1' single universal valves manufactured by Zhongshan Mitsui, unless otherwise specified.

The foamer valve was opened to place the foam on a microscope slide, coverslip, and the values of its typical parameters D10, D50, D90 were detected in a digital microscope (DSX 1000 model, olympus) and calculated by its software, and the symmetry S value of the particle size distribution curve was calculated as follows: s= (D90-D10)/(D50). The S value is preferably in the range of 0.8 to 1.2 and preferably in the range of 0.9 to 1.1, which means that the S value is excellent in symmetry, i.e., the closer the S value is to 1.0, the more the distribution curve is a bell-shaped curve symmetrically distributed with a D50 boundary. Both the S value and the D50 value may essentially describe the particle size distribution of a material system. In the present invention, unless otherwise specified, the method for measuring the particle size and the data calculation method for the S value, D50 value, and the like are performed as described above.

The foam composition obtained in example 1 was measured for its S value and D50 value within 2 days after preparation as a result of time 0 (T0): s=1.063, d50=16.71 μm, typical microscopic fields of view of which are shown in fig. 1; the foam composition obtained in example 1 was left to stand at a temperature of 4 (±1) ° C for 3 weeks and then shaken well, and its S value and D50 value were measured by the above method using a digital microscope as a result of 3 weeks (T3 w): s=1.087, d50= 30.63 μm; in the present invention, unless otherwise specified, the S value and D50 value of T0 and T3w are measured in this way. From this result, it was found that the fine particles in the foam composition of the present example were excellent in distribution symmetry after undergoing low temperature treatment for 3 weeks, but the overall particle diameter became large, indicating a significant increase in suspended particle diameter in the foam composition.

Example 2: foam composition of itraconazole

Prescription:

itraconazole: 10 parts by weight,

Caprylic capric polyethylene glycol glyceride: 17 parts by weight,

Isopropyl palmitate: 6 parts by weight,

Diethylene glycol monoethyl ether: 27 parts by weight,

Tween 80:7 parts by weight,

Propylene glycol: 12 parts by weight,

1, 2-Hexanediol: 5 parts by weight,

Pure water: 16 parts by weight,

Propane/butane/isobutane (2:2:1) (propellant): 20 parts by weight.

The preparation method comprises the following steps:

(1) Stirring diethylene glycol monoethyl ether, tween, propylene glycol, 1, 2-hexanediol and water at 60 ℃ to make them miscible;

(2) Stirring caprylic/capric acid polyethylene glycol glyceride and isopropyl palmitate at 60 ℃ to be mixed, slowly adding (pre-crushing to pass through 100 meshes of API) while stirring, and continuously adding the mixed solution obtained in the step (1) while stirring;

(3) Transferring the heat-preserving mixed material obtained in the step (2) into a high-speed colloid mill, grinding until all the material can pass through a screen mesh with the aperture of 40 mu m (about 1.5 hours), and naturally cooling the temperature of the liquid material to room temperature (20-25 ℃) after discharging;

(4) And (3) subpackaging the product obtained in the last step into aerosol aluminum cans, and pressurizing and filling a specified amount of propellant to obtain the foam composition.

As measured, s=1.058 for T0, d50=20.38 μm, s=1.027 for T3w, d50= 38.47 μm, again indicating that the particles in the foam composition of this example, although distribution symmetry is still good after 3 weeks of cryogenic treatment, have a larger overall particle size, indicating a significant increase in suspended particle diameter in the foam composition.

Example 3: foam composition of itraconazole

Prescription:

itraconazole: 10 parts by weight,

Caprylic capric polyethylene glycol glyceride: 21 parts by weight,

Isopropyl palmitate: 7 parts by weight,

Diethylene glycol monoethyl ether: 25 parts by weight,

Tween 40:8 parts by weight,

Propylene glycol: 10 parts by weight,

1, 2-Hexanediol: 4 parts by weight,

Pure water: 15 parts by weight,

R404a (propellant): 10 parts by weight.

The preparation method comprises the following steps:

(1) Stirring diethylene glycol monoethyl ether, tween, propylene glycol, 1, 2-hexanediol and water at 80 ℃ to make them miscible;

(2) Stirring caprylic/capric acid polyethylene glycol glyceride and isopropyl palmitate at 80 ℃ to be mixed, slowly adding (pre-crushing to pass 150 meshes of API) while stirring, and continuously adding the mixed solution obtained in the step (1) while stirring;

(3) Transferring the heat-preserving mixed material obtained in the step (2) into a high-speed colloid mill, grinding until all the material can pass through a screen mesh with the aperture of 20 mu m (about 2 hours), and naturally cooling the temperature of the liquid material to room temperature (20-25 ℃) after discharging;

As measured, s=1.058 for T0, d50=12.43 μm, s=0.937 for T3w, d50=22.52 μm, which also indicates that the particles in the foam composition of the present example, although the distribution symmetry is still good after 3 weeks of low temperature treatment, have a larger overall particle size, indicating a significant increase in suspended particle diameter in the foam composition.

According to some of the examples described above, it is shown that there is a significant increase in API particle size in the foam composition system produced, which is particularly desirable to avoid. The inventors have found in additional experiments that the problem of increased API particle diameter can be significantly overcome when small amounts of glycylglycine (i.e., N-glycylglycine GLYCYLGLYCINE, also known as glycylglycine, a dipeptide formed by condensation of 2 glycine, molecular formula C4H8N2O3, CAS No. 556-50-3) are added to the foam compositions of these formulations, see in particular the examples below.

Example 4: foam composition of itraconazole

Prescription:

itraconazole: 10 parts by weight,

Caprylic capric polyethylene glycol glyceride: 20 parts by weight,

Isopropyl palmitate: 8 parts by weight,

Diethylene glycol monoethyl ether: 25 parts by weight,

Tween 60:10 parts by weight,

Propylene glycol: 10 parts by weight,

1, 2-Hexanediol: 2 parts by weight,

Glycylglycine: 4 parts by weight,

Pure water: 15 parts by weight,

R134a (propellant): 15 parts by weight.

The preparation method comprises the following steps:

(1) Stirring diethylene glycol monoethyl ether, tween, propylene glycol, 1, 2-hexanediol, glycylglycine and water at 70 ℃ to be mixed and dissolved;

As measured, s= 1.085, d50=15.54 μm, s=1.033, d50=17.36 μm for T3w, the results indicate that the fine particles in the foam composition of this example have substantially unchanged symmetry of the distribution curve after 3 weeks of low temperature treatment, and the suspended particles in the foam composition also have substantially no significant change.

Example 5: foam composition of itraconazole

Prescription:

itraconazole: 10 parts by weight,

Caprylic capric polyethylene glycol glyceride: 17 parts by weight,

Isopropyl palmitate: 6 parts by weight,

Diethylene glycol monoethyl ether: 27 parts by weight,

Tween 80:7 parts by weight,

Propylene glycol: 12 parts by weight,

1, 2-Hexanediol: 5 parts by weight,

Glycylglycine: 3 parts by weight,

Pure water: 16 parts by weight,

Propane/butane/isobutane (2:2:1) (propellant): 20 parts by weight.

The preparation method comprises the following steps:

(1) Stirring diethylene glycol monoethyl ether, tween, propylene glycol, 1, 2-hexanediol, glycylglycine and water at 60 ℃ to be mixed and dissolved;

As measured, s= 1.113, d50=19.74 μm, s=1.084, d50=21.56 μm for T3w, the results indicate that the fine particles in the foam composition of this example have substantially unchanged symmetry of the distribution curve after 3 weeks of low temperature treatment, and the suspended particles in the foam composition also have substantially no significant change.

Example 6: foam composition of itraconazole

Prescription:

itraconazole: 10 parts by weight,

Caprylic capric polyethylene glycol glyceride: 21 parts by weight,

Isopropyl palmitate: 7 parts by weight,

Diethylene glycol monoethyl ether: 25 parts by weight,

Tween 40:8 parts by weight,

Propylene glycol: 10 parts by weight,

1, 2-Hexanediol: 4 parts by weight,

Glycylglycine: 5 parts by weight,

Pure water: 15 parts by weight,

R404a (propellant): 10 parts by weight.

The preparation method comprises the following steps:

(1) Stirring diethylene glycol monoethyl ether, tween, propylene glycol, 1, 2-hexanediol, glycylglycine and water at 80 ℃ to make them miscible;

As measured, s=0.986 for T0, d50=11.67 μm, s=1.046 for T3w, d50=12.86 μm, and the results indicate that the fine particles in the foam composition of the present example have substantially unchanged symmetry of the distribution curve after 3 weeks of low temperature treatment, and that the suspended particles in the foam composition also have substantially no significant change.

Example 7: foam composition comprising active drug

Referring to examples 1 and 4, respectively, except that the active API therein was changed to an equivalent amount of selenium sulphide, 2 batches of foaming agents were obtained, designated example 7a foaming agent and example 7b foaming agent, respectively.

The S and D50 values of T0 and T3w were determined using the method of the invention, determined that the s=0.974, d50=18.93 μm for T0 of the example 7a foam, s=1.037, d50=31.27 μm for T3 w; s=1.042, d50=19.67 μm for T0 of the foam of example 7b, s=1.006, d50=21.53 μm for T3 w.

Example 8: foam composition comprising active drug

Referring to examples 1 and 4, respectively, except that the active API therein was changed to half the amount (5 parts) of ketoconazole, 2 batches of foam were obtained, which were designated as example 8a foam and example 8b foam, respectively.

The S and D50 values of T0 and T3w were determined using the method of the invention, determined that the s=1.042, d50=17.25 μm for T0 of the example 8a foam, s=0.975, d50=29.22 μm for T3 w; s= 1.085, d50=18.35 μm for T0, and s=1.057, d50=29.74 μm for T3w for the foam of example 8 b.

Example 9: foam composition comprising active drug

Referring to examples 1 and 4, respectively, except that the active API therein was changed to 1.2 times (12 parts) amount of terbinafine, 2 batches of foam were obtained, designated example 9a foam and example 9b foam, respectively.

The S and D50 values of T0 and T3w were determined using the method of the invention, determined that s=1.125, d50=19.56 μm for T0 of the foam of example 9a, s=1.167, d50=33.22 μm for T3 w; s= 1.034, d50=18.54 μm for T0, and s=1.086, d50=19.73 μm for T3w for the foam of example 9 b.

Example 10: foam composition comprising active drug

Referring to examples 1 and 4, respectively, except that the active API therein was changed to 0.8 times (8 parts) amount of bifonazole, 2 batches of foam were obtained, designated example 10a foam and example 10b foam, respectively.

The S and D50 values of T0 and T3w were determined using the method of the invention, and determined, for example 10a, T0, s=1.073, d50=17.65 μm, s=1.104, d50=28.86 m for the foam; s=1.036, d50= 18.36 μm for T0, s=0.975, d50=18.07 μm for T3w for the foam of example 10 b.

Example 11: foam composition comprising active drug

Referring to example 4, the only difference is that the active API therein was changed to the following chemicals in equal amounts: posaconazole, econazole, butenafine, calcipotriol, betamethasone, tacalcitol, tretinoin, tacrolimus, minoxidil, finasteride, clindamycin, metronidazole, fusidic acid, lidocaine, respectively, to prepare foam compositions containing different active drugs.

Using the method of the invention to determine the S and D50 values of T0 and T3w of these foam compositions, the S values of all compositions T0 are determined to be in the range of 0.85 to 1.15, e.g., s=1.037 for T0 of posaconazole foam composition, and the D50 values of all compositions T0 are determined to be in the range of 14 to 22 μm, e.g., d50=17.83 μm for T0 of posaconazole foam composition; the S value of all compositions T3w is in the range of 0.85 to 1.15, e.g. s=1.086 for T0 of posaconazole foam composition, and the D50 value of all compositions T3w is in the range of 16 to 23 μm, e.g. d50=19.16 μm for T0 of posaconazole foam composition. These results demonstrate that foam compositions obtained using some of the formulations and methods of the present invention exhibit excellent properties.

Example 12: foam composition comprising active drug

Prescription:

itraconazole: 10 parts by weight,

Caprylic capric polyethylene glycol glyceride: 20 parts by weight,

Diethylene glycol monoethyl ether: 25 parts by weight,

Tween 60:10 parts by weight,

1, 2-Hexanediol: 4 parts by weight,

Glycylglycine: 4 parts by weight,

Pure water: 15 parts by weight,

R134a (propellant): 15 parts by weight.

The preparation method comprises the following steps:

(1) Stirring diethylene glycol monoethyl ether, tween, 1, 2-hexanediol, glycylglycine and water at 70 ℃ to be mixed and dissolved;

(2) Stirring caprylic/capric acid polyethylene glycol glyceride at 70 ℃ to be mixed, slowly adding (pre-crushing to 120 meshes) the API under stirring, and continuously adding the mixed solution obtained in the step (1) under stirring;

As measured, s=0.958, d50=16.83 μm, s=0.974, d50=17.47 μm for T3w, the results indicate that the fine particles in the foam composition of the present example have substantially unchanged symmetry of the distribution curve after 3 weeks of low temperature treatment, and the suspended particles in the foam composition also have substantially no significant change.

Example 13: foam composition comprising active drug

Prescription:

itraconazole: 10 parts by weight,

Isopropyl palmitate: 24 parts by weight,

Diethylene glycol monoethyl ether: 25 parts by weight,

Tween 65:10 parts by weight,

Glycerol: 8 parts by weight,

1, 2-Hexanediol: 3 parts by weight,

Glycylglycine: 4 parts by weight,

Pure water: 15 parts by weight,

R134a (propellant): 15 parts by weight.

The preparation method comprises the following steps:

(1) Stirring diethylene glycol monoethyl ether, tween, glycerol, 1, 2-hexanediol, glycylglycine and water at 70 ℃ to be mixed and dissolved;

(2) Mixing isopropyl palmitate under stirring at 70 ℃ to be miscible, slowly adding (pre-crushing to 120 meshes) the API under stirring, and continuously adding the mixed solution obtained in the step (1) under stirring;

As measured, s=0.983, d50=18.67 μm, s=1.073, d50= 17.63 μm for T3w, the results indicate that the fine particles in the foam composition of this example have substantially unchanged symmetry of the distribution curve after 3 weeks of low temperature treatment, and that the suspended particles in the foam composition also have substantially no significant change.

Example 14: foam composition comprising active drug

Prescription:

Itraconazole: 5 parts by weight,

Cetyl stearyl phosphate: 20 parts by weight,

Cetyl stearyl polyether-10 phosphate: 8 parts by weight,

Diethylene glycol monoethyl ether: 35 parts by weight,

Tween 85:15 parts by weight,

Propylene glycol: 10 parts by weight,

1, 2-Hexanediol: 4 parts by weight,

Glycylglycine: 4 parts by weight,

Pure water: 15 parts by weight,

R134a (propellant): 15 parts by weight.

The preparation method comprises the following steps:

(2) Mixing cetyl stearyl phosphate and cetyl stearyl polyether-10 phosphate at 70deg.C under stirring, slowly adding (pulverizing to 120 mesh) API under stirring, and adding the mixed solution obtained in step (1) under stirring;

As measured, s=0.983 for T0, d50=18.85 μm, s=1.043 for T3w, and d50=20.04 μm, the results indicate that the fine particles in the foam composition of the present example have substantially unchanged symmetry of the distribution curve after 3 weeks of low temperature treatment, and the suspended particles in the foam composition also have substantially no significant change.

Example 15: foam composition comprising active drug

Prescription:

Itraconazole: 15 parts by weight,

Caprylic capric polyethylene glycol glyceride: 20 parts by weight,

Cetyl stearyl phosphate: 8 parts by weight,

Diethylene glycol monoethyl ether: 25 parts by weight,

Tween 60:10 parts by weight,

Propylene glycol: 10 parts by weight,

1, 2-Hexanediol: 3 parts by weight,

Glycylglycine: 4 parts by weight,

Pure water: 15 parts by weight,

R134a (propellant): 15 parts by weight.

The preparation method comprises the following steps:

(2) Stirring caprylic/capric acid polyethylene glycol glyceride and cetostearyl phosphate at 70 ℃ to be mixed, slowly adding (pre-crushing to 120 meshes) the API under stirring, and continuously adding the mixed solution obtained in the step (1) under stirring;

As measured, s=1.077 for T0, d50=17.88 μm, s=0.986 for T3w, d50=17.93 μm, and the results indicate that the fine particles in the foam composition of the present example have substantially unchanged symmetry of the distribution curve after 3 weeks of low temperature treatment, and that the suspended particles in the foam composition also have substantially no significant change.

Example 16: foam composition comprising active drug

Prescription:

Itraconazole: 2 parts by weight,

Caprylic capric polyethylene glycol glyceride: 20 parts by weight,

Cetyl stearyl phosphate: 8 parts by weight,

Diethylene glycol monoethyl ether: 25 parts by weight,

Tween 60:10 parts by weight,

Polyethylene glycol 200:10 parts by weight,

1, 2-Hexanediol: 4 parts by weight,

Glycylglycine: 4 parts by weight,

Pure water: 15 parts by weight,

R134a (propellant): 15 parts by weight.

The preparation method comprises the following steps:

(1) Stirring diethylene glycol monoethyl ether, tween, polyethylene glycol, 1, 2-hexanediol, glycylglycine and water at 70 ℃ to be mixed and dissolved;

As measured, s=0.978, d50=18.57 μm, s=1.024, d50=19.84 μm for T3w, the results indicate that the fine particles in the foam composition of this example have substantially unchanged symmetry of the distribution curve after 3 weeks of low temperature treatment, and the suspended particles in the foam composition also have substantially no significant change.

In addition, the defoaming time t of the foam composition obtained in the present invention was measured using the following method: the foam was extruded into a plastic cuvette at a constant temperature of 32 ℃, under which conditions the time for complete disappearance of the foam was recorded. As a result, the defoaming time of all the foams obtained in examples 1 to 16 was determined to be in the range of 2 to 4 minutes, for example, the defoaming time of the foam composition of example 4 was determined to be 2.73 minutes. It has been unexpectedly found that when small amounts of disodium azelate are added to the formulation, the defoaming time can be significantly prolonged.

Example 17: foam composition

Prescription:

itraconazole: 10 parts by weight,

Caprylic capric polyethylene glycol glyceride: 20 parts by weight,

Isopropyl palmitate: 8 parts by weight,

Diethylene glycol monoethyl ether: 25 parts by weight,

Tween 60:10 parts by weight,

Propylene glycol: 10 parts by weight,

1, 2-Hexanediol: 2 parts by weight,

Disodium azelate: 0.5 part by weight,

Glycylglycine: 4 parts by weight,

Pure water: 15 parts by weight,

R134a (propellant): 15 parts by weight.

The preparation method comprises the following steps:

(1) Stirring diethylene glycol monoethyl ether, tween, propylene glycol, 1, 2-hexanediol, glycylglycine, disodium azelate and water at 70 ℃ to be miscible;

As measured, s= 1.034, d50=18.47 μm for T0, s=1.006 for T3w, d50=17.94 μm, the results indicate that the fine particles in the foam composition of this example have substantially unchanged symmetry of the distribution curve after 3 weeks of low temperature treatment, and the suspended particles in the foam composition also have substantially no significant change.

Example 18: foam composition

Prescription:

itraconazole: 10 parts by weight,

Caprylic capric polyethylene glycol glyceride: 17 parts by weight,

Isopropyl palmitate: 6 parts by weight,

Diethylene glycol monoethyl ether: 27 parts by weight,

Tween 80:7 parts by weight,

Propylene glycol: 12 parts by weight,

1, 2-Hexanediol: 5 parts by weight,

Disodium azelate: 0.8 part by weight,

Glycylglycine: 3 parts by weight,

Pure water: 16 parts by weight,

Propane/butane/isobutane (2:2:1) (propellant): 20 parts by weight.

The preparation method comprises the following steps:

(1) Stirring diethylene glycol monoethyl ether, tween, propylene glycol, 1, 2-hexanediol, glycylglycine, disodium azelate and water at 60 ℃ to be miscible;

As measured, s=0.927 for T0, d50=20.13 μm, s=0.982 for T3w, and d50= 21.44 μm, the results indicate that the fine particles in the foam composition of this example have substantially unchanged symmetry of the distribution curve after 3 weeks of low temperature treatment, and that the suspended particles in the foam composition also have substantially no significant change.

Example 19: foam composition

Prescription:

itraconazole: 10 parts by weight,

Caprylic capric polyethylene glycol glyceride: 21 parts by weight,

Isopropyl palmitate: 7 parts by weight,

Diethylene glycol monoethyl ether: 25 parts by weight,

Tween 40:8 parts by weight,

Propylene glycol: 10 parts by weight,

1, 2-Hexanediol: 4 parts by weight,

Disodium azelate: 0.2 part by weight,

Glycylglycine: 5 parts by weight,

Pure water: 15 parts by weight,

R404a (propellant): 10 parts by weight.

The preparation method comprises the following steps:

(1) Stirring diethylene glycol monoethyl ether, tween, propylene glycol, 1, 2-hexanediol, glycylglycine, disodium azelate and water at 80 ℃ to be miscible;

As measured, s=0.994, d50=17.13 μm, s=1.103, d50=16.85 μm for T3w, the results indicate that the fine particles in the foam composition of this example have substantially unchanged symmetry of the distribution curve after 3 weeks of low temperature treatment, and the suspended particles in the foam composition also have substantially no significant change.

The foam compositions obtained in examples 17 to 19 were measured to have defoaming times of 13.73min, 14.12min, and 13.57min.

Example 20: foam composition

Referring to the various prescriptions and the preparation methods of examples 7-16 respectively, but adding 0.5 parts by weight of disodium azelate to prepare various foam compositions, determining that the S of T0, D50 and S of T3w are respectively in the range of 0.87-1.14, 17-23 mu m, 18-24 mu m and 12-15 min respectively; for example, with reference to example 16 and with the addition of 0.5 parts by weight of disodium azelate, the foam composition prepared has s=1.074, d50=18.73 μm for T0, s=1.026, d50=20.03 μm for T3w, and defoaming time=14.25 min.

Based on the above results, it has been unexpectedly found that adding an appropriate amount of glycylglycine and disodium azelate to the composition of the present invention provides a foam composition having stable particle size, uniform distribution, and slow defoaming of the suspension particles, which is advantageous for longer retention of the drug at the site of administration.

Example 21: foam composition

Prescription:

itraconazole: 10 parts by weight,

Caprylic capric polyethylene glycol glyceride: 25 parts by weight,

Diethylene glycol monoethyl ether: 30 parts by weight,

Tween 60:10 parts by weight,

Disodium azelate: 0.5 part by weight,

Glycylglycine: 4 parts by weight,

Pure water: 15 parts by weight,

R134a (propellant): 15 parts by weight.

The preparation method comprises the following steps:

(1) Stirring diethylene glycol monoethyl ether, tween, glycylglycine, disodium azelate and water at 70 ℃ to be mixed and dissolved;

As determined, s=1.074 for T0, d50=16.43 μm, s= 1.021 for T3w, d50=17.76 μm, defoaming time=13.83 min.

Example 22: foam composition

Prescription:

corticosteroid actives or other actives: 10 parts by weight,

Caprylic capric polyethylene glycol glyceride: 25 parts by weight,

Diethylene glycol monoethyl ether: 30 parts by weight,

Tween 60:10 parts by weight,

Disodium azelate: 0.5 part by weight,

Glycylglycine: 4 parts by weight,

Pure water: 15 parts by weight,

R134a (propellant): 15 parts by weight.

The preparation method comprises the following steps:

This example uses the following corticosteroid actives or other actives, respectively, for the preparation of the foam composition: beclomethasone dipropionate, cyclopentanone triamcinolone acetate, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, fluocinolone acetonide, clodrosone, fluocinolone acetonide, clodrolone acetonide, desoxymethasone, difluor-acetate, difluormesone valerate, difluormethyl pivalate, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone acetate, mometasone furoate, triamcinolone, minocycline, clobetasol, halobetasol propionate, calcipotriene.

The prepared foam compositions have the advantages that S of T0 is in the range of 0.91-1.12, D50 is in the range of 14-19 mu m, S of T3w is in the range of 0.90-1.09, D50 is in the range of 16-21 mu m, defoaming time is in the range of 12-15 min, for example, S=1.046, D50=17.41 mu m, S=1.074, D50=20.03 mu m and defoaming time=14.14 min of a foaming agent prepared from hydrocortisone are measured.

Test example 1: determination of foam Density

The foam composition sealed in the aluminum can was precisely weighed as an initial weight, then the foam was slowly extruded into a 200ml measuring tank, the foam volume in the measuring tank was read, then the weight of the foam composition was precisely weighed again as a final weight, the difference between the initial weight and the final weight was taken as the weight of the foam, and the density of the extruded foam was calculated as milligrams of foam per cubic millimeter of volume.

As a result of measurement, the foam densities of all the foam compositions obtained in examples 1 to 22 were in the range of 20 to 150mg/cm ³, and for example, the foam densities of the three foam compositions obtained in examples 17 to 19 were 43.2mg/cm ³、36.2mg/cm³、46.7mg/cm³, respectively, indicating that the foam compositions of the present invention were excellent in foaming performance.

Example 17 foam composition the foam obtained by extrusion is typically as shown in figure 2, showing that the foam is very uniform and fine.

Although embodiments of the invention have been described using specific terms and methods, such description is for illustrative purposes only. The words used are words of description rather than limitation. It should be understood that variations and changes may be made by those of ordinary skill in the art without departing from the spirit and scope of the present disclosure as set forth in the following claims. Additionally, it should be understood that aspects of the various embodiments may be interchanged both in whole or in part. The spirit and scope of the appended claims should not be limited to the description of the preferred versions contained therein.

Claims

1. A foam composition sealed within a container, comprising: 2-15 parts of active medicine, 10-30 parts of lipid substances, 2-15 parts of surfactant, 10-35 parts of diethylene glycol monoethyl ether, 0.2-1 part of disodium azelate, 1-5 parts of glycylglycine, 10-20 parts of water and 10-20 parts of aerosol propellant; the lipid material is selected from the group consisting of: caprylic capric polyethylene glycol glyceride, isopropyl palmitate, cetostearyl phosphate, cetostearyl polyether-10 phosphate, and combinations thereof, the surfactant being selected from the group consisting of: tween 40, tween 60, tween 65, tween 80, tween 85 and combinations thereof.

2. The foam composition according to claim 1, comprising: 5-15 parts of active medicine, 15-30 parts of lipid substances, 3-12 parts of surfactant, 15-30 parts of diethylene glycol monoethyl ether, 0.2-0.8 part of disodium azelate, 2-5 parts of glycylglycine, 10-18 parts of water and 10-20 parts of aerosol propellant.

3. The foam composition according to claim 1, wherein the active drug is selected from the group consisting of: itraconazole, selenium disulfide, ketoconazole, terbinafine, bifonazole, posaconazole, econazole, butenafine, calcipotriol, tacalcitol, tretinoin, tacrolimus, minoxidil, finasteride, clindamycin, metronidazole, fusidic acid, lidocaine, betamethasone, beclomethasone dipropionate, cyclopentanone triamcinolone acetate, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, fluocinolone acetonide, fluocinol, fluorometholone acetate, budesonide, clobetasone, fluocinolone acetonide, clodrone butyrate, valproine, desoxymethasone, difluosone diacetate, difluosone valerate, difluosone pivalate, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone acetate, furoic acid, propitis, clobetasol, halobetasol, and combinations thereof.

4. Foam composition according to claim 1, wherein the active drug is suspended in the foam composition in the form of fine particles, the particle size distribution of which is determined, D50 being in the range of 10-50 μm.

5. The foam composition according to claim 1, wherein the active agent is suspended in the foam composition in the form of fine particles, the particle size distribution of the fine particles is determined, S value is in the range of 0.8 to 1.2 calculated by the formula s= (D90-D10)/(D50), wherein D10, D50 and D90 are parameters obtained by particle size distribution determination.

6. The foam composition according to claim 1, which forms a foam after being released from the container, the foam having completely disappeared for 10 to 20 minutes.

7. The foam composition according to claim 1, which forms a foam after release from the container, the foam density being in the range of 20 to 150mg/cm ³.

8. The foam composition according to claim 1, said aerosol propellant being selected from the group consisting of: r134a, R404a, propane, butane, isobutane, and combinations thereof.

9. The foam composition according to claim 1, which is sealed in a container, said container being an aerosol canister fitted with a valve.

10. The foam composition according to claim 1, which is prepared by: mixing various raw materials and auxiliary materials except the aerosol propellant at 60-80 ℃, grinding the obtained mixed liquid until all the materials can pass through a screen mesh with the aperture of 10-50 mu m, naturally cooling the liquid to room temperature after discharging, subpackaging the obtained materials into an aerosol tank provided with a valve, and pressurizing and filling a specified amount of aerosol propellant to obtain the foam composition.

11. The foam composition according to claim 1, further comprising an alcoholic solvent selected from the group consisting of: propylene glycol, 1, 2-hexanediol, polyethylene glycol 200, glycerin, and combinations thereof.

12. A foam-type medicament for topical application comprising an aerosol canister fitted with a valve, the aerosol canister being hermetically filled with a composition comprising: 2-15 parts of active medicine, 10-30 parts of lipid substances, 2-15 parts of surfactant, 10-35 parts of diethylene glycol monoethyl ether, 0.2-1 part of disodium azelate, 1-5 parts of glycylglycine, 10-20 parts of water and 10-20 parts of aerosol propellant; the lipid material is selected from the group consisting of: caprylic capric polyethylene glycol glyceride, isopropyl palmitate, cetostearyl phosphate, cetostearyl polyether-10 phosphate, and combinations thereof, the surfactant being selected from the group consisting of: tween 40, tween 60, tween 65, tween 80, tween 85 and combinations thereof.

13. Use of a foam composition according to any one of claims 1 to 11 or a foam medicament according to claim 12 for the manufacture of a product for the prevention and/or treatment of a disease by administration via the body surface route.