TW202432180A - Local pharmaceutical composition, preparation method and use in medicine thereof - Google Patents

Abstract

The present disclosure relates a local pharmaceutical composition and/or a cream and use as a therapeutic agent thereof, particularly an use in the preparation of a medicine for the treatment and/or prevention of a skin disease or disorder, including but not limited to psoriasis, atopic dermatitis, acne, and skin itching; wherein the local pharmaceutical and/or cream comprises Benvimod or a pharmaceutically acceptable salt thereof as an active ingredients (API), as well as one or more corticosteroids.

Description

Topical drug composition, method for its preparation and use in medicine

This case claims the priority of the applicant's prior application No. 202211611803.1, entitled "A topical drug composition and its use in medicine", filed with the National Intellectual Property Administration of China on December 14, 2022. The full text of the prior application is incorporated herein by reference.

This case belongs to the field of medicine and involves a topical drug composition and/or a cream and its application in medicine, especially its use in the preparation of drugs for the treatment and/or prevention of skin diseases or disorders, including but not limited to psoriasis, atopic dermatitis, acne and skin itching; the active ingredients (API) of the topical composition and/or cream include benvimod or a pharmaceutically acceptable salt thereof and one or more corticosteroids.

Autoimmune diseases are a type of disease characterized by decreased tolerance of the immune system to the body's own antigens, the production of large amounts of autoantibodies and immune complexes, and ultimately the impairment of multiple tissue and organ functions (Guan SY et al., Inflammation, 2017, 40(1): 303-310). As early as 1999, the World Health Organization listed autoimmune diseases as the third largest threat to human health after cardiovascular disease and cancer. At the same time, autoimmune diseases were also listed as one of the ten major diseases in China's medium- and long-term science and technology development guidelines (Pan Haifeng et al., Chinese Journal of Disease Control, 2018, 22(11): 1093-1095, 1105). The spectrum of autoimmune diseases is broad and has different clinical manifestations, mainly including more than 70 diseases, such as systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, etc. (Fang Xinyu et al., Chinese Journal of Disease Control, 2021, 25(8): 869-873).

Psoriasis is a common chronic, inflammatory, immune-mediated skin disease characterized by rapid proliferation and renewal of epithelial cells, thickening of the epidermis, and the production of inflamed, swollen skin lesions and bulges covered with silvery white scales. The inflamed, thickened and scaly lesions are prone to itching, burning, stinging and bleeding. As one of the most serious non-communicable diseases, about 125 million people worldwide have psoriasis, which greatly reduces the quality of life of patients. Atopic dermatitis is a common chronic, recurrent, inflammatory skin disease, usually characterized by excessive growth of Staphylococcus aureus, which then triggers proteolytic destruction of the epidermal barrier and immune disorders. It is reported that the disease is the non-fatal skin disease with the highest disease burden (Psoriasis Committee of the Dermatology and Venereology Branch of the Chinese Medical Association, Chinese Journal of Dermatology, 2019, 52(10), 667-710).

Although there are many treatment options for patients with immune, inflammatory and autoimmune diseases, conventional topical medications are still the main clinical basis for chronic inflammatory skin diseases such as psoriasis and atopic dermatitis. Corticosteroids are used as first-line medications, but long-term use has high side effects, intermittent use has a short relief period, and is prone to relapse. Non-hormonal topical medications such as vitamin D3 derivatives, retinoic acid, and calcineurin inhibitors have the disadvantages of slow onset, limited efficacy, widespread local side effects, and poor patient compliance. Existing topical preparations can only provide temporary relief, are prone to relapse, and have unsatisfactory efficacy. More effective treatment preparations are still needed for clinical use.

Benvimod Cream is a world-first Class 1 new drug in China with complete independent intellectual property rights. It is a major scientific and technological achievement of China's "Major New Drug Creation". It was approved for marketing in China in May 2019 for the topical treatment of mild to moderate common psoriasis in adults.

The chemical structure of Benvimod is as follows:

Benvimod was originally disclosed by Paul et al. as an antibiotic (Journal of Chemical Ecology, 1981, 7(3): 589-597). WO1995003695A1 (Agro-Biotech Corporation) discloses the fungicidal activity of the compound. The compound is further described in WO2001042231A2 (Welichem Biotech Inc.) as being suitable for treating various important skin conditions including psoriasis and inflammation. Example 3 of U.S. Patent US7868047B2 (Dermavant Sciences GmbH) describes a cream formulation in which the active ingredient is prepared in a Galax base. WO 2016/185428 (GlaxoSmithKline Inc.) provides a method for preparing a topical drug emulsion composition involving the compound. The immunosuppressive effects of corticosteroids are known to be critical for suppressing the pro-inflammatory environment and T-cell activation; Benvimod can inhibit underlying inflammation and normalize skin homeostasis, regulate keratinocyte proliferation and differentiation, and provide immunomodulation, and can exert immunomodulatory effects on Th2, Th17 and T-reg cells.

In response to the problems of low efficacy, easy recurrence and low compliance of existing topical preparations, this case provides a new type of topical drug composition that can be topically applied to treat immune, inflammatory and autoimmune diseases, effectively improve clinical efficacy, reduce disease recurrence rate, and improve patient compliance.

In view of this, the purpose of this case is to provide a topical drug composition, the active ingredients of which are benvimod or its pharmaceutically acceptable salt and one or more corticosteroids. It is a drug combination, which has been proven to solve some difficult-to-overcome defects of current single-drug medications, such as corticosteroids are hormonal drugs, which can easily cause skin atrophy and easily develop drug resistance, and are not suitable for long-term use.

Furthermore, the present invention provides a topical drug composition, characterized in that, based on the total weight percentage of the topical drug composition, the topical drug composition comprises: Benvimod or a pharmaceutically acceptable salt thereof, the content of which is 0.5% to 2% by weight; One or more corticosteroids, the content of which is 0.01% to 2% by weight respectively; and Pharmaceutically acceptable excipients suitable for topical use, wherein the excipients do not contain petrolatum and glyceryl mono- and di-stearate.

In some embodiments of the present case, the content of benvimod or its pharmaceutically acceptable salt in the topical drug composition described in the present case is 0.5% to 1.75% by weight, preferably 0.5% to 1.5%, and more preferably 0.75% to 1.25% by weight, based on the total weight percentage of the topical drug composition; specifically, the content of benvimod or its pharmaceutically acceptable salt may be 0.5%, 0.75%, 1%, 1.25% and 1.5%.

In some embodiments of the present case, the topical pharmaceutical composition described in the present case, based on the total weight percentage of the topical pharmaceutical composition, the content of the corticosteroid is 0.01% to 1.5%, preferably 0.01% to 1.25%, more preferably 0.01% to 1%, more preferably 0.01% to 0.75%, more preferably 0.01% to 0.5%, and most preferably 0.01% to 0.25%; specifically, the content of the corticosteroid can be 0.01%, 0.05%, 0.075%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.25%, 0.3%, 0.5%, 1% and 1.5%.

In some embodiments of the present invention, the topical drug composition described in the present invention, the corticosteroid is selected from one or more of alclomethasone or its derivatives, amcinonide or its derivatives, betamethasone or its derivatives, clobetasol or its derivatives, clocortolone or its derivatives, desonide or its derivatives, desoxymethasone or its derivatives, diflorasone or its derivatives, fluocinolone or its derivatives, fluticasone or its derivatives, halcinonide or its derivatives, ulbetasol or its derivatives, hydrocortisone or its derivatives, mometasone or its derivatives, prednicarbate or its derivatives, triamcinolone acetonide or its derivatives, fluocinolone or its derivatives, dexamethasone or its derivatives and methylprednisolone or its derivatives; Preferably, the corticosteroid is selected from one or more of betamethasone or its derivatives, clocortolone or its derivatives, desoxymethasone or its derivatives, fluocinolone or its derivatives, fluticasone or its derivatives, hydrocortisone or its derivatives, mometasone or its derivatives, prednicarbate or its derivatives, triamcinolone acetonide or its derivatives, fluanolone or its derivatives; More preferably, the corticosteroid is selected from one or more of betamethasone or its derivatives, clocortolone or its derivatives, desoxymethasone or its derivatives, fluocinolone or its derivatives, fluticasone or its derivatives, hydrocortisone or its derivatives, mometasone or its derivatives, prednicarbate or its derivatives and triamcinolone acetonide or its derivatives; More preferably, the corticosteroid is selected from one or more of betamethasone or its derivatives; More preferably, the corticosteroid is selected from one or more of betamethasone, betamethasone propionate, betamethasone dipropionate, betamethasone acetate and betamethasone valerate; Most preferably, the corticosteroid is betamethasone or betamethasone propionate.

In some embodiments of the present case, the topical drug composition described in the present case, the corticosteroid is preferably a glucocorticoid drug, and the glucocorticoid drugs are divided into three categories according to the duration of action: short-acting (such as cortisone, hydrocortisone, etc.), medium-acting (such as prednisone, methylprednisolone, etc.) and long-acting (such as dexamethasone, betamethasone, etc.).

In some embodiments of the present invention, the topical pharmaceutical composition described herein is a cream, preferably an oil-in-water cream.

According to an embodiment of the present invention, the topical pharmaceutical composition comprises: a solvent and/or a penetration enhancer, the total content of which is 5% to 30% by weight.

According to an embodiment of the present invention, the topical pharmaceutical composition comprises: a surfactant, the total content of which is 0.1% to 10% by weight; and the surfactant does not contain mono- and di-stearic acid glyceryl.

According to an embodiment of the present invention, the topical pharmaceutical composition comprises: a pH adjuster in an appropriate amount, and the pH of the topical pharmaceutical composition is 3-7; and the rest is an aqueous phase.

According to the embodiments of the present case, the surfactant is selected from one or more of emulsifying wax, stearyl alcohol polyethers, polysorbate, cetomacrogol 1000, dehydrated sorbitan fatty acid esters and polyethylene glycol cetearyl ether, preferably at least two of emulsifying wax, stearyl alcohol polyethers, polysorbate, cetomacrogol 1000, dehydrated sorbitan fatty acid esters and polyethylene glycol cetearyl ether, more preferably at least two of steareth-2, steareth-20, Tween-80, Tween-60, Span-60 and cetomacrogol 1000, and most preferably two of Tween-80, Tween-60, Span-60 and cetomacrogol 1000.

For example, the surfactant comprises Tween-60 and Span-60, wherein: The content of Tween-60 is 1.75% to 4% by weight, preferably 2%; The content of Span-60 is 0.25% to 1.5% by weight, preferably 0.75%.

According to the embodiments of the present invention, the topical drug composition comprises a solvent and/or a penetration enhancer, and the solvent and/or the penetration enhancer is selected from one or more of propylene glycol, diethylene glycol monoethyl ether, glycerol and PEG400, preferably propylene glycol and/or diethylene glycol monoethyl ether, and more preferably diethylene glycol monoethyl ether; and/or The topical drug composition comprises a pH adjuster, and the pH adjuster is a buffer, and the buffer is preferably selected from one or more of citrate/citric acid, acetate/acetic acid, phosphate/phosphoric acid, citrate/citric acid, propionate/propionic acid, lactate/lactic acid, and ammonium/ammonia; and/or The topical drug composition further comprises a stabilizer, the total content of which is 0.005% to 2% by weight, and the stabilizer is preferably selected from one or more of citric acid and its salts, glucuronic acid and its salts, sodium hexametaphosphate, zinc hexametaphosphate, ethylenediaminetetraacetic acid (EDTA) and its salts and phosphonates; and/or The topical drug composition further comprises a preservative, the total content of which is 0.005% to 2% by weight; and/or The topical drug composition further comprises an antioxidant, the total content of which is 0.005% to 2% by weight.

Furthermore, the present case relates to a cream, characterized in that, based on the total weight percentage of the cream, the cream contains: Benvimod or a pharmaceutically acceptable salt thereof, the content of which is 0.5% to 2% by weight; One or more corticosteroids, the content of which is 0.01% to 2% by weight respectively; An oil phase base, the total content of which is 5% to 30% by weight; and the oil phase base does not contain vaseline; A surfactant (emulsifier), the total content of which is 0.1% to 10% by weight; and the surfactant (emulsifier) does not contain mono- and di-stearate; A solvent and/or a penetration promoter, the total content of which is 5% to 30% by weight; A pH adjuster, in an appropriate amount, and the pH is 3-7; and The rest is an aqueous phase.

In some embodiments of the present case, the content of benvimod or its pharmaceutically acceptable salt in the cream described in the present case is 0.5% to 1.75% by weight, preferably 0.5% to 1.5%, and more preferably 0.75% to 1.25% by weight, based on the total weight percentage of the cream; specifically, the content of benvimod or its pharmaceutically acceptable salt may be 0.5%, 0.75%, 1%, 1.25% and 1.5%.

In some embodiments of the present case, the cream described in the present case, based on the total weight percentage of the cream, the content of the corticosteroid is 0.01% to 1.5% by weight, preferably 0.01% to 1.25%, more preferably 0.01% to 1%, preferably 0.01% to 0.75%, preferably 0.01% to 0.5%, preferably 0.01% to 0.25%, preferably 0.01% to 0.2%, and most preferably 0.01% to 0.1%; specifically, the content of the corticosteroid can be 0.01%, 0.05%, 0.075%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.25%, 0.3%, 0.5%, 1% and 1.5%.

In some embodiments of the present invention, the corticosteroid in the cream described in the present invention is selected from one or more of alclomethasone or its derivatives, amcinonide or its derivatives, betamethasone or its derivatives, clobetasol or its derivatives, clocortolone or its derivatives, desonide or its derivatives, desoxymethasone or its derivatives, diflorasone or its derivatives, fluocinolone or its derivatives, fluticasone or its derivatives, halcinonide or its derivatives, ulbetasol or its derivatives, hydrocortisone or its derivatives, mometasone or its derivatives, prednicarbate or its derivatives, triamcinolone acetonide or its derivatives, fluocinolone or its derivatives, dexamethasone or its derivatives, and methylprednisolone or its derivatives; Preferably, the corticosteroid is selected from one or more of betamethasone or its derivatives, clocortolone or its derivatives, desoxymethasone or its derivatives, fluocinolone or its derivatives, fluticasone or its derivatives, hydrocortisone or its derivatives, mometasone or its derivatives, prednicarbate or its derivatives, triamcinolone acetonide or its derivatives, fluanolone or its derivatives; More preferably, the corticosteroid is selected from one or more of betamethasone or its derivatives, clocortolone or its derivatives, desoxymethasone or its derivatives, fluocinolone or its derivatives, fluticasone or its derivatives, hydrocortisone or its derivatives, mometasone or its derivatives, prednicarbate or its derivatives and triamcinolone acetonide or its derivatives; More preferably, the corticosteroid is selected from one or more of betamethasone or its derivatives; More preferably, the corticosteroid is selected from one or more of betamethasone propionate, betamethasone dipropionate, betamethasone acetate and betamethasone valerate; Even more preferably, the corticosteroid is selected from one of betamethasone propionate, betamethasone dipropionate, betamethasone acetate and betamethasone valerate; Most preferably, the corticosteroid is betamethasone or betamethasone propionate.

In some embodiments of the present case, the corticosteroid in the cream described in the present case is preferably a glucocorticoid drug, and the glucocorticoid drugs are divided into three categories according to the duration of action: short-acting (such as cortisone, hydrocortisone, etc.), medium-acting (such as prednisone, methylprednisolone, etc.) and long-acting (such as dexamethasone, betamethasone, etc.).

In some embodiments of the present invention, the total content of the oil phase base in the cream described in the present invention is 5% to 30%, preferably 5% to 25%, more preferably 5% to 20%, and most preferably 10% to 20%, based on the total weight percentage of the cream.

In some embodiments of the present invention, the oil phase base of the cream described in the present invention is selected from one or more of stearic acid, wax, isopropyl myristate, beeswax, medium-chain triglycerides, higher alcohols and lanolin, preferably selected from one or more of stearic acid, isopropyl myristate, medium-chain triglycerides, cetyl alcohol, stearyl alcohol and cetostearyl alcohol.

In some embodiments of the present case, the oil phase base of the cream described in the present case is selected from one or more of stearic acid, isopropyl myristate, medium chain triglycerides, hexadecanol, stearyl alcohol and cetostearyl alcohol, and the content of each oil phase base is 5% to 25%, preferably 5% to 20%, more preferably 5% to 15%, and most preferably 5% to 10%.

In some embodiments of the present invention, in the cream described in the present invention, the oil phase base does not contain petrolatum (preferably does not contain white petrolatum).

In some embodiments of the present case, the surfactant in the cream described in the present case is selected from one or more of emulsifying wax, stearyl alcohol polyethers, polysorbates, cetumago 1000, dehydrated sorbitan fatty acid esters and polyethylene glycol cetearyl ether, preferably selected from at least two of emulsifying wax, stearyl alcohol polyethers, polysorbates, cetumago 1000, dehydrated sorbitan fatty acid esters and polyethylene glycol cetearyl ether, more preferably selected from at least two of steareth-2, steareth-20, Tween-80, Tween-60, Span-60 and cetumago 1000, and most preferably selected from two of Tween-80, Tween-60, Span-60 and cetumago 1000.

In some embodiments of the present invention, the surfactant in the cream described in the present invention does not contain mono- and di-stearic glyceryl.

In some embodiments of the present case, the total content of the surfactant in the cream described in the present case is 0.1% to 10% by weight, preferably 0.5% to 8%, more preferably 0.5% to 6%, and most preferably 0.75% to 6%, based on the total weight percentage of the cream; specifically, the total content of the surfactant can be 0.1%, 0.25%, 0.5%, 0.75%, 1%, 1.5%, 2%, 3%, 4%, 5% and 6%.

In some embodiments of the present case, the surfactant in the cream described in the present case is selected from at least two of steareth-2, steareth-20, Tween-80, Tween-60, Span-60 and Citumago 1000, and the content of each of the surfactants is 0.1% to 4.25% by weight; preferably, the surfactant is selected from at least two of steareth-20, Tween-80, Tween-60, Span-60 and Citumago 1000, and the content of each of the surfactants is 0.1% to 4% by weight; more preferably, one of the surfactants is Tween-60, and its content is 1.75% to 4% by weight; preferably, the content of Tween-60 is 2%. More preferably, one of the surfactants is Span-60, and its content is 0.25% to 1.5% by weight, preferably 0.75% by weight.

More preferably, the surfactant comprises Tween-60 and Span-60, wherein: the content of Tween-60 is 1.75% to 4% by weight, preferably 2%; the content of Span-60 is 0.25% to 1.5% by weight, preferably 0.75%.

In some embodiments of the present invention, in the cream described in the present invention, one of the surfactants is Tween-60, and its content by weight is greater than 1.5%.

In some embodiments of the present invention, the solvent and/or penetration enhancer in the cream described in the present invention is selected from one or more of propylene glycol, diethylene glycol monoethyl ether, glycerol and PEG400, preferably one or more of propylene glycol, diethylene glycol monoethyl ether and PEG400, more preferably propylene glycol and/or diethylene glycol monoethyl ether, and most preferably diethylene glycol monoethyl ether.

In some embodiments of the present case, the total content of the solvent and/or penetration promoter in the cream described in the present case is 5% to 30% by weight, preferably 5% to 25%, more preferably 5% to 20%, more preferably 10% to 20%, and most preferably 10% to 15%, based on the total weight percentage of the cream; specifically, the content of the surfactant can be 5%, 10%, 15%, 20%, 25% and 30%.

In some embodiments of the present invention, in the cream described in the present invention, the solvent and/or penetration promoter is selected from one or more of propylene glycol, diethylene glycol monoethyl ether and PEG400, and the content of each of the solvent and/or penetration promoter is 5% to 25% by weight; preferably, the solvent and/or penetration promoter is propylene glycol and/or diethylene glycol monoethyl ether, and the content of each of the solvent and/or penetration promoter is 10% to 25% by weight; most preferably, the solvent and/or penetration promoter is diethylene glycol monoethyl ether, and its content is 10% to 20% by weight.

In some embodiments of the present case, the pH adjuster in the cream described in the present case is a buffer, and the buffer is preferably selected from one or more of citrate/citric acid, acetate/acetic acid, phosphate/phosphoric acid, citrate/citric acid, propionate/propionic acid, lactate/lactic acid, and ammonium/ammonia, preferably citrate/citric acid.

In some embodiments of the present case, the content of the pH adjuster in the cream described in the present case is appropriate to adjust the pH value of the cream to 3-7; preferably, the pH value of the cream is 3-6; more preferably, the pH value of the cream is 4-6; most preferably, the pH value of the cream is 4.5-5.5; specifically, the pH value of the cream can be 4, 4.5, 5, 5.5 and 6.

In some embodiments of the present invention, the content of the pH adjuster is 0.01% to 5% by weight, preferably 0.1% to 3%, more preferably 0.1% to 2%, more preferably 0.1% to 1%, and most preferably 0.1% to 0.5%.

In some embodiments of the present case, in the cream described in the present case, the pH adjuster is citrate/citric acid or citrate/citric acid, and its content is 0.01% to 5%; preferably, the pH adjuster is citrate/citric acid, and its content is 0.1% to 1%; most preferably, the pH adjuster is citrate/citric acid, and its content is 0.1% to 0.5%.

In some embodiments of the present invention, the cream described in the present invention further comprises a stabilizer, the content of which is 0.005% to 2% by weight, preferably 0.01% to 2%, more preferably 0.05% to 2%, more preferably 0.075% to 1.5%, and most preferably 0.1% to 1%.

In some embodiments of the present case, in the cream described in the present case, the stabilizer is selected from one or more of citric acid and its salts, glucuronic acid and its salts, sodium hexametaphosphate, zinc hexametaphosphate, ethylenediaminetetraacetic acid (EDTA) and its salts, and phosphonates; preferably, the stabilizer is ethylenediaminetetraacetic acid (EDTA) and its salts; more preferably, the stabilizer is EDTA-2Na.

In some embodiments of the present case, in the cream described in the present case, the stabilizer is ethylenediaminetetraacetic acid (EDTA) and its salts, and the content thereof is 0.01% to 2% by weight; preferably, the stabilizer is ethylenediaminetetraacetic acid (EDTA) and its salts, and the content thereof is 0.05% to 2% by weight; more preferably, the stabilizer is ethylenediaminetetraacetic acid (EDTA) and its salts, and the content thereof is 0.1% to 1% by weight.

In some embodiments of the present invention, the cream described in the present invention further comprises a preservative.

As is known in the art, an effective amount of preservatives such as ammonium benzoate, polyhexamethylene hydrochloride (PHMB), sorbic acid, ethyl hydroxyphenate, methyl hydroxyphenate, propyl hydroxyphenate, methyl salicylate, benzyl alcohol, phenoxyethanol, and the like may be used.

In some embodiments of the present case, the total content of the preservative in the cream described in the present case, calculated as a percentage of the total weight of the cream, is 0.005% to 1%, preferably 0.01% to 0.5%, and more preferably 0.01% to 0.25%; specifically, the content of the preservative can be 0.01%, 0.05%, 0.1%, 0.15%, 0.2% and 0.25%.

In some embodiments of the present invention, the cream described in the present invention further comprises an antioxidant.

As is known in the art, an effective amount of an antioxidant such as one or more of butylated hydroxytoluene (BHT), disodium ethylenediaminetetraacetate (EDTA-2Na), butylated hydroxyanisole (BHA), vitamin E, vitamin E acetate, and vitamin E nicotinate may be used.

In some embodiments of the present case, the total content of the antioxidant in the cream described in the present case, calculated as a percentage of the total weight of the cream, is 0.001% to 1%, preferably 0.01% to 0.5%, and more preferably 0.01% to 0.1%; specifically, the content of the antioxidant can be 0.01%, 0.05%, 0.1%, 0.15, 0.2, 0.3%, 0.5% and 1%.

In some embodiments of the present invention, the particle size of the cream described in the present invention is less than 10 μm, preferably 1-5 μm, and more preferably 1-3 μm.

In some embodiments of the present invention, the cream described in the present invention has a content of benvimod or a pharmaceutically acceptable salt thereof of 0.5% to 1.5% based on the total weight percentage of the cream; the content of the corticosteroid (preferably betamethasone or a derivative thereof) is 0.01% to 0.25%; the oil phase base does not contain vaseline (preferably does not contain white vaseline); the surfactant does not contain mono- and di-stearate glyceryl and is selected from steareth-2, steareth-20, At least two of Tween-80, Tween-60, Span-60 and Citumago 1000, the total content of the surfactant is 0.5% to 6%; the solvent and/or penetration promoter is one or more selected from propylene glycol, diethylene glycol monoethyl ether and PEG400, and the total content is 5% to 25% by weight; the pH adjuster is citrate/citric acid or citrate/citric acid, and the content is 0.01% to 5%; the stabilizer is ethylenediaminetetraacetic acid (EDTA) and its salt, the content of which is 0.01% to 2% by weight; the total content of the preservative (preferably methyl hydroxybenzoate or ethyl hydroxybenzoate) is 0.01% to 0.5%; and the total content of the antioxidant (preferably BHT) is 0.01% to 0.5%.

Another aspect of the present case relates to a method for preparing the cream as described above, the method comprising the following steps: 1) Preparation of the oil phase: Add the oil phase base, solvent and/or penetration promoter, surfactant and optional preservative and antioxidant to a container of suitable size, start mixing and heat to 65-80°C to stir and dissolve the above ingredients; then add the active ingredient, stir to dissolve, and keep warm for later use; 2) Preparation of the water phase: Add the pH adjuster, stabilizer and optional preservative and antioxidant to purified water, heat and stir at 65-80°C to dissolve all substances, and keep warm for later use; 3) Emulsification: Add the oil phase to the water phase or add the water phase to the oil phase, maintain the temperature at 65-80°C, and stir to dissolve all substances; ℃, start stirring, start homogenization after stirring evenly, transfer all substances to a storage container and cool after homogenization to obtain the cream.

The present invention further relates to the use of a topical pharmaceutical composition or cream as described above for the preparation of a medicament for the treatment and/or prevention of a skin disease or disorder selected from psoriasis, atopic dermatitis, acne and pruritus.

The present invention further relates to the use of a topical pharmaceutical composition or cream as described above in the preparation of a medicament for the treatment and/or prevention of psoriasis.

The present invention also relates to a method for treating and/or preventing a skin disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of the topical pharmaceutical composition or cream as described above, wherein the skin disease or disorder is selected from psoriasis, atopic dermatitis, acne and skin itching.

The present invention also relates to a method for treating and/or preventing psoriasis, which comprises administering a therapeutically effective amount of the topical pharmaceutical composition or cream as described above to a patient in need thereof.

The present invention also relates to a topical pharmaceutical composition or cream as described above for use as a medicament, such as a topical medicament.

The present invention also relates to a topical pharmaceutical composition or cream as described above for use as a medicament for the treatment and/or prevention of skin diseases or disorders selected from psoriasis, atopic dermatitis, acne and skin itching.

The present invention also relates to a topical pharmaceutical composition or cream as described above for use as a medicament for the treatment and/or prevention of psoriasis.

Preferably, the skin disease or disorder described in this case is psoriasis.

Definitions and Explanations

Unless otherwise stated, the definitions of terms recorded in the description of this case and the scope of the invention application, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific components in embodiments, etc., may be arbitrarily combined and coupled with each other. Such combinations and couplings shall fall within the scope of the description of this case.

For drugs or pharmacologically active agents, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person of ordinary knowledge in the technical field to which the invention belongs based on routine experiments.

The term "patient" refers to a patient in need of prevention or treatment of a skin disease or disorder, wherein the patient is a mammal, such as selected from rodents, cattle, pigs, dogs, cats and primates, preferably a human.

To avoid ambiguity, the content of a certain type of auxiliary material, such as oily base, mentioned in this article refers to the total content. If the type of auxiliary material contains more than one ingredient, it refers to the sum of the contents of all ingredients, not the content of each ingredient separately. If the content is clearly stated as "each", it means the content of each ingredient separately.

As used herein, the singular form of "a", "an", and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art to which the invention belongs, when a parameter is not critical, the numbers are usually given only for the purpose of illustration and not limitation.

Beneficial Effects

The topical drug composition or cream provided in this case has a synergistic effect on the treatment of psoriasis, atopic dermatitis or other immune, inflammatory and autoimmune diseases during its application to individuals, which is higher than the efficacy of each single active ingredient drug, and is beneficial for reducing the side effects of corticosteroids and improving the individual's compliance with use. The details are as follows:

1. Improved efficacy compared to single drug - synergistic effect

The treatment of psoriasis focuses on achieving complete clearance of psoriasis plaques, and its intervention pathways include inhibiting the inflammatory process, restoring and maintaining normal proliferation and differentiation of keratinocytes, regulating the body's immunity, and maintaining skin homeostasis. Targeting the key pathogenic factors of psoriasis, the topical drug composition or cream disclosed herein (preferably a benvimod-betamethasone dipropionate compound preparation) is expected to produce synergistic and complementary effects, covering multiple links of the pathological process of psoriasis, achieving a multi-pronged approach, taking advantage of each other's strengths and making up for each other's weaknesses, and achieving the purpose of being superior to a single drug.

a) Corticosteroids (preferably betamethasone dipropionate) have strong anti-inflammatory, anti-allergic and immunosuppressive effects. They can inhibit local inflammation of psoriasis skin damage and restore the normal structure and function of skin tissue, thereby achieving the purpose of treating psoriasis.

b) Benvimod can activate AhR, promote normal differentiation of skin cells, inhibit abnormal keratinocytes; it has a regulatory effect on Th1, Th2, Th17 and T-reg cells; it can upregulate the expression of skin barrier proteins such as filamentous proteins, promote the repair of damaged skin and the integrity of skin barrier function, and regulate the expression of skin cell antioxidant proteins through Nrf2, thereby alleviating oxidative stress and restoring skin homeostasis.

c) The topical drug composition or cream disclosed herein (preferably a benvimod-betamethasone dipropionate combination preparation) is expected to be able to inhibit inflammatory cells and their cytokines in a synergistic manner, such as inhibiting the release of Th1 and Th17 and their cytokines, inhibiting the activation of keratinocytes and their abnormal proliferation and differentiation, thereby helping to subside inflammation and maintain the sustained homeostasis of keratinocytes.

d) Corticosteroids (preferably betamethasone dipropionate) can inhibit Th1, Th2 and Th17 when used alone, while benvimod can inhibit the proliferation of CD4 ⁺ T cells, increase the level of the immune regulatory factor IL-10, and improve the body's immune tolerance.

Therefore, the topical pharmaceutical composition or cream disclosed herein (preferably a bevimod-betamethasone dipropionate combination preparation) is expected to have a synergistic effect and enhance the anti-inflammatory effect.

2. Reduce the side effects associated with monotherapy - safety

Long-term use of corticosteroids alone may lead to a decrease in skin thickness and increased transepidermal water loss, which in turn causes skin atrophy, capillary dilation, and damage to the skin barrier function. The dermal atrophy caused by corticosteroids often occurs at the site of medication, mainly due to the reduction of collagen synthesis after binding to specific receptors. For skin atrophy, there is currently no better treatment method except minimally invasive surgery to inject relevant skin tissues. Benvimod can regulate the differentiation of keratinocytes by activating AhR, increase the expression of barrier-related protein genes, improve the integrity of the skin barrier, prevent transepidermal water loss, reduce the occurrence of skin atrophy caused by corticosteroids, reduce the risks associated with corticosteroid treatment, and provide better safety.

On the other hand, the two active ingredients have different pharmacological mechanisms and targets. Benvimod is locally effective and enters the body's circulatory system at extremely low concentrations. It does not interact with corticosteroids in the absorption, distribution, metabolism, and excretion of the drug, nor does it have the same or similar target organ toxicity or adverse reactions. The combination of the two will not lead to an accumulation of toxicities and cause significant toxicological concerns.

3. Compliance

This case takes advantage of the rapid response of corticosteroids to treat lesions and the long relief period of benvimod, which greatly improves patients' acceptance of treatment, provides good convenience for patients, and helps promote patients' adaptation to treatment during long-term management, which will help improve patients' acceptance of treatment and confidence in treatment. Itching is an important symptom of psoriasis patients. The topical drug composition or cream disclosed in this article (preferably benvimod-betamethasone dipropionate compound preparation) is expected to achieve rapid anti-itching effect, thereby improving patients' quality of life faster and better, and has positive significance for patients' treatment compliance.

4. Unique formula

The formula disclosed in this case is very different from the formula of the listed single-ingredient products benvimod cream and betamethasone dipropionate cream, including the uniqueness of the ratio of each excipient, which breaks the conventional technical thinking. After the applicant's creative work, the topical drug composition and/or cream made from the formula ingredients and formula ratio disclosed in this case has a very excellent transdermal effect.

The following examples are used to further describe the present invention, but these examples are not intended to limit the scope of the present invention. The creams prepared in the following examples are all prepared according to the preparation methods described above. If the experimental method does not specify specific conditions, it is usually carried out according to conventional conditions.

Example 1 Determination of initial formulation

By comparing the formulas disclosed in the instructions of the commercially available single-ingredient products Benvimod Cream and Betamethasone Dipropionate Cream (Table 1), both are common creams, composed of water phase, oil phase, emulsifier, solvent, and preservative. The excipients of the two are similar in function, both choose propylene glycol as the solvent, the oil phase base is similar, both contain white vaseline, liquid wax, etc., the water phase is purified water, and only the type of emulsifier is slightly different.

According to Table 1, the preliminary formulation compositions are shown in Table 2 and Table 3, and Preparation 1, Preparation 2, Preparation 3, Preparation 4, Preparation 5 and Preparation 6 were prepared.

From the preparation of Formulation 1 to Formulation 3, it was found that 5% propylene glycol could dissolve the two active ingredients well, so the amount of propylene glycol was adjusted to 5%, and the content of the two active ingredients was adjusted, and the emulsifier was appropriately adjusted to prepare Formulation 4, Formulation 5 and Formulation 6.

Table 1: Benvimod Cream Betamethasone Propionate Cream Accessories Solvent Propylene glycol Propylene glycol, isopropyl myristate, polyethylene glycol Emulsifier Glyceryl monostearate, polysorbate 80 Glyceryl fatty acid ester, dimethicone, polyethylene glycol stearate Oil phase Cetyl Alcohol, White Vaseline, Light Liquid Paraffin Vaseline, white wax, carboxyvinyl polymer, cetyl alcohol Water Phase Purified water Purified water other Ethyl Hydroxyphenate Glacial Acetic Acid, Sodium Acetate Potassium dihydrogen phosphate, D-sorbitol, methyl hydroxybenzate, butyl hydroxybenzate

Table 2: Preparation number 1 2 3 Formula Effect Recipe composition Ratio % (weight ratio) Proportion% Proportion% Benvimod 1.00 1.00 1.00 API Betamethasone propionate 0.064 0.064 0.064 API Propylene glycol 15.00 5.00 5.00 Solvent Cetyl Alcohol 8.50 8.50 8.50 Oil base White Vaseline 9.00 9.00 7.00 Light Liquid Paraffin 6.00 6.00 6.00 Glyceryl Mono- and Distearate 5.00 5.00 5.00 Emulsifier Polysorbate 80 1.00 1.00 2.00 Hydroxybenzoate 0.10 0.10 0.10 Preservatives Sodium citrate 0.19 0.19 0.19 pH Regulator Citric Acid 0.08 0.08 0.08 Purified water 54.066 64.066 65.066 Water Phase Total 100.00 100.00 100.00 N/A

Table 3: Preparation number 4 5 6 Formula Effect Recipe composition Proportion% Proportion% Proportion% Benvimod 0.5 1.00 2.00 API Betamethasone propionate 0.032 0.064 0.128 API Propylene glycol 5.00 5.00 5.00 Solvent Cetyl Alcohol 8.50 8.50 8.50 Oily base White Vaseline 12.00 9.00 15.00 Light Liquid Paraffin 6.00 6.00 6.00 Glyceryl mono- and distearate 5.00 5.00 5.00 Emulsifier Dimethicone 1.00 1.00 2.00 Glyceryl fatty acid esters 1.00 1.00 1.00 Hydroxybenzoate 0.10 0.10 0.10 Preservatives Sodium citrate 0.19 0.19 0.19 pH Regulator Citric Acid 0.08 0.08 0.08 Purified water 60.598 63.066 55.002 Water Phase Total 100.00 100.00 100.00 N/A

Example 2 Study on the physicochemical properties of preparations 1 to 7

The particle sizes of the six creams prepared in Example 1 were observed under a microscope, and it was found that the droplet particle sizes of the six batches of creams prepared in Example 1 were all large and uneven. The finished creams were frosty in appearance and grayish in color. In addition, the above six batches of creams all showed the phenomenon of oil-water separation during the preparation process. The relevant micrographs (400 times) are shown in Figures 1 to 6.

Example 3: Formula Optimization

Based on the particle size results of Formulations 1 to 6, consider further optimizing the formulation by adjusting the oil phase matrix and the appropriate emulsifier simultaneously. See Table 4 for the specific adjustments.

Table 4: Preparation 7 Preparation 8 Preparation 9 Preparation 10 effect Recipe composition Proportion % Recipe composition Proportion % Recipe composition Proportion % Recipe composition Proportion % Benvimod 1.00 Benvimod 1.00 Benvimod 1.00 Benvimod 1.00 API Betamethasone propionate 0.064 Betamethasone propionate 0.064 Betamethasone propionate 0.064 Betamethasone propionate 0.064 API Propylene glycol 5.00 Propylene glycol 5.00 Propylene glycol 5.00 Propylene glycol 5.00 Solvent Cetyl Alcohol 8.50 Glyceryl mono- and distearate 3.00 Cetyl Alcohol 7.00 Cetostearyl alcohol 6.00 Oily base White Vaseline 7.00 Medium Chain Triglycerides 5.00 White Vaseline 7.00 Isopropyl myristate 5.00 Light Liquid Paraffin 6.00 / / Light Liquid Paraffin 6.00 Medium Chain Triglycerides 8.00 Glyceryl mono- and distearate 5.00 PEG-7 Stearate 12 Polyethylene glycol stearate 8.00 Twain 60 3 Emulsifier Xitumago 1000 2.00 Oleyl Polyoxyethylene Glycerides 4 Twain 80 1.50 Pan 60 0.75 Hydroxybenzoate 0.10 Hydroxybenzoate 0.10 Hydroxybenzoate 0.10 Hydroxybenzoate 0.14 Preservatives Sodium citrate 0.19 Sodium citrate 0.19 Sodium citrate 0.19 Sodium citrate 0.19 pH Regulator Citric Acid 0.08 Citric Acid 0.08 Citric Acid 0.08 Citric acid 0.08 Purified water 65.066 Purified water 69.566 Purified water 64.066 Purified water 70.776 Water Phase Total 100.00 Total 100.00 Total 100.00 Total 100.00 N/A

After numerous analyses and combinations of various formulations, we found that when the cream formulation did not contain white petrolatum and glyceryl monostearate and distearate (Formulation 10), the droplet size after homogenization was uniform and all below 10 microns (Figure 7); while the droplet sizes of Formulations 7, 8, and 9 were uneven and larger after homogenization, and showed the phenomenon of oil-water separation (Figures 8 to 10). Therefore, the formulation of Formulation 10 was taken as the optimal formulation for further research.

Example 4 Emulsifier Research

Based on the formulation of preparation 10, the effects of different emulsifiers on the droplet size of the cream were investigated. The emulsifiers investigated included Tween 60 and Span 60, polyoxyethylene (54) hydrogenated castor oil, polyethylene glycol-7 stearate and oleyl polyoxyethylene glyceride, and cetumagogue 1000. The optimal emulsifier was further selected through this study. The formulations of different emulsifiers investigated are shown in Table 5.

Table 5: Preparation 10 Preparation 11 Preparation 12 Preparation 13 effect Recipe composition Proportion % Recipe composition Proportion % Recipe composition Proportion % Recipe composition Proportion % Benvimod 1.00 Benvimod 1.00 Benvimod 1.00 Benvimod 1.00 API Betamethasone propionate 0.064 Betamethasone propionate 0.064 Betamethasone propionate 0.064 Betamethasone propionate 0.064 API Propylene glycol 5.00 Propylene glycol 5.00 Propylene glycol 5.00 Propylene glycol 5.00 Solvent Cetostearyl alcohol 6.00 Cetostearyl alcohol 6.00 Cetostearyl alcohol 6.00 Cetostearyl alcohol 6.00 Oil base Isopropyl myristate 5.00 Isopropyl myristate 5.00 Isopropyl myristate 5.00 Isopropyl myristate 5.00 Medium Chain Triglycerides 8.00 Medium Chain Triglycerides 8.00 Medium Chain Triglycerides 8.00 Medium Chain Triglycerides 8.00 Twain 60 2.00 Polyoxyethylene (54) hydrogenated castor oil 2.00 PEG-7 Stearate 3.00 Xitumago 1000 2.00 Emulsifier Pan 60 0.75 / / Oleyl Polyoxyethylene Glycerides 1.00 / / Hydroxybenzoate 0.14 Hydroxybenzoate 0.14 Hydroxybenzoate 0.14 Hydroxybenzoate 0.14 Preservatives Sodium citrate 0.19 Sodium citrate 0.19 Sodium citrate 0.19 Sodium citrate 0.19 pH Regulator Citric Acid 0.08 Citric Acid 0.08 Citric Acid 0.08 Citric Acid 0.08 Purified water 71.776 Purified water 72.526 Purified water 70.526 Purified water 72.526 Water Phase Total 100.00 Total 100.00 Total 100.00 Total 100.00 N/A

It has been verified that the particle size distribution of most of the emulsion droplets of preparations 11 to 13 prepared according to the above formula is uneven, some are larger than 10 microns, and most are distributed around 6 microns, as can be seen from Figures 11 to 13. Preparation 10 is still the formula with the best emulsification effect, as shown in Figure 14.

Example 5 Study on the ratio of emulsifier

After determining that the formulation 10 is the optimal formulation, the applicant intends to adjust the ratio of Tween 60 to Span 60 to study the effect of this factor on the physical and chemical properties of the formulation. The formulation and ratio of the prepared formulation are shown in Table 6 below.

Table 6: Preparation number 10 10-1 10-2 10-3 10-4 effect Recipe composition Proportion% Proportion% Proportion% Proportion% Proportion% Benvimod 1.00 1.00 1.00 1.00 1.00 API Betamethasone propionate 0.064 0.064 0.064 0.064 0.064 API Propylene glycol 5.00 5.00 5.00 5.00 5.00 Solvent Cetostearyl alcohol 6.00 6.00 6.00 6.00 6.00 Oily base Isopropyl myristate 5.00 5.00 5.00 5.00 5.00 Medium Chain Triglycerides 8.00 8.00 8.00 8.00 8.00 Twain 60 2.00 1.5.00 1.5.00 1.5.00 1.5.00 Emulsifier Pan 60 0.75 0.75 1.00 1.50 2.00 EDTA-2Na / / 0.10 0.10 0.10 Chelating agents Hydroxybenzoate 0.14 0.14 0.14 0.14 0.14 Preservatives Sodium citrate 0.19 Moderate 0.19 0.19 0.19 pH Regulator Citric Acid 0.08 Moderate 0.08 0.08 0.08 Purified water 71.776 Add to 100 71.926 71.426 70.926 Water Phase Total 100.00 100.00 100.00 100.00 100.00 N/A

It has been verified that the droplet size of preparations 10-1, 10-2, 10-3 and 10-4 after homogenization is uneven and increases, and the emulsion quickly separates oil and water after homogenization, and there are large droplets larger than 10 microns. With the extension of homogenization time or the increase of homogenization speed, the droplet size and uniformity have no obvious improvement, as shown in Figures 15-18. The droplet size of preparation 10 is uniform, less than 5 microns, as shown in Figure 19. Therefore, the formula and proportion of the emulsifier are: Tween 60, dosage 2%; and Span 60, dosage 0.75%.

Example 6 Stability Study

The cream obtained from Preparation 10 was subjected to a stability study. By comparing the conditions after 0 day, 1 month at 30°C, and 3 months at 40°C, it was found that no API was precipitated from the cream, the pH value and droplet size were stable (see Figures 20 to 22 for particle size comparison), and there was no obvious difference in impurity content during the stability process.

Example 7 Skin penetration test

Based on the formulation of Preparation 10, multiple strength samples were prepared, namely Preparation 14, Preparation 15 and Preparation 16. The only difference between the three preparations was the content of betamethasone dipropionate and betamethasone dipropionate.

The steps of the skin penetration test are as follows:

Preparation 14, Preparation 15 and Preparation 16 were used for in vitro skin penetration test to evaluate the intradermal retention and permeability. Pig skin (thickness 0.8~1.0 mm) was mounted on the LOGAN System 918 vertical diffusion cell, exposing a surface area of 1.77 ^cm2 . The diffusion cell was connected to a multichannel pump with a speed of 600 rpm. The medium at the drug receiving end was PBS (phosphate buffer) with a pH of 7.4. Each cell was placed in a heating manifold to equilibrate the temperature to ensure that the skin surface temperature was 32 °C (at least 30 min before drug administration). The test sample was added at a dose of 10 mg per square centimeter. The medium at the drug receiving end was collected at 4, 8, 12, 16, 20, and 24 hours to measure the active ingredient that penetrated the skin. After the 24-hour sampling period, wipe the skin with a cotton swab to remove any residual sample that is believed not to have penetrated the skin. Cut the skin layer into pieces and add methanol to ultrasonically extract the drug. The concentrations of betamethasone dipropionate and betamethasone dipropionate were detected by high-performance liquid chromatography. The recovered drug concentrations were used to calculate the skin retention of betamethasone dipropionate and betamethasone dipropionate. The transdermal detection results of the betamethasone dipropionate component are shown in Table 7, and the retention comparison is shown in Figure 23; the transdermal detection results of the betamethasone dipropionate component are shown in Table 8, and the retention comparison is shown in Figure 24.

Table 7:

In vitro transdermal testing results — Benvimod Preparation number Specifications (Benvimod/Betamethasone Propionate) Retention amount μg/g Penetration rate% 14 0.5% / 0.032% 6.121 0.00274 15 1% / 0.064% 9.579 0.00250 16 2% / 0.128% 10.83 0.00392 Benvimod cream 1% Benvimod 4.893 0.00760

Table 8:

In vitro transdermal test results — Betamethasone propionate Preparation number Specifications (Benvimod/Betamethasone Propionate) Retention amount μg/g Penetration rate% 14 0.5% / 0.032% 0.3062 0.00963 15 1% / 0.064% 0.4615 0.00589 16 2% / 0.128% 0.6392 0.00774 Betamethasone propionate cream 0.064% Betamethasone propionate 1.284 0.0241

As shown in Table 7, the retention amount of betamethasone propionate in Preparation 14, Preparation 15 and Preparation 16 is higher than that of single betamethasone propionate cream; and as shown in Table 8, the retention amount of betamethasone propionate in the above three preparations is lower than that of single betamethasone propionate. Therefore, in order to increase the retention amount of betamethasone propionate, it is necessary to further optimize the formula.

Example 8 Study on Solvents and/or Penetration Accelerators

In order to increase the retention of betamethasone propionate, the types and dosages of different solvents and/or penetration enhancers were investigated. See the ingredients and proportions of Preparation 17, Preparation 18, Preparation 19 and Preparation 20 in the table below.

Table 9: Preparation number 17 18 19 20 effect Recipe composition Proportion% Proportion% Proportion% Proportion% Benvimod 1.00 1.00 1.00 1.00 API Betamethasone propionate 0.064 0.064 0.064 0.064 API Propylene glycol 15.00 5.00 N/A N/A Solvent Diethylene glycol monoethyl ether N/A 5.00 10.00 15.00 Solvents, penetration enhancers Cetostearyl alcohol 5.00 5.00 5.00 5.00 Oily base Isopropyl myristate 5.00 5.00 5.00 5.00 Medium Chain Triglycerides 5.00 5.00 5.00 5.00 Twain 60 2.00 2.00 2.00 2.00 Emulsifier Pan 60 0.75 0.75 0.75 0.75 EDTA-2Na 0.10 0.10 0.10 0.10 Stabilizer Butylated Hydroxytoluene 0.10 0.10 0.10 0.10 Antioxidants Hydroxybenzoate 0.14 0.14 0.14 0.14 Preservatives Sodium citrate 0.19 0.19 0.19 0.19 pH Regulator Citric Acid 0.08 0.08 0.08 0.08 Purified water 65.576 70.576 70.576 65.576 Water Phase Total 100.00 100.00 100.00 100.00 N/A

It was verified that most of the emulsion droplets in preparation 20 were larger in size (see Figure 25), non-uniform, and showed oil-water separation. The particle sizes of preparations 17 to 19 were smaller and more uniform, with most of them ranging from 1 to 5 µm, and some around 8 µm (see Figures 26 to 28).

The transdermal test results of the benavidin component of Preparation 17 and Preparation 18 are shown in Table 10, and the comparison of the retention amounts is shown in Figure 29; the transdermal test results of the betamethasone dipropionate component of Preparation 17 and Preparation 18 are shown in Table 11, and the comparison of their retention amounts is shown in Figure 30.

The transdermal test results of the benavidin component of Preparation 19 and Preparation 20 are shown in Table 12, and the comparison of the retention amounts is shown in Figure 31; the transdermal test results of the betamethasone dipropionate component of Preparation 19 and Preparation 20 are shown in Table 13, and the comparison of their retention amounts is shown in Figure 32.

Table 10:

Preparation 17 and preparations 18 In vitro transdermal testing results — Benvimod Preparation number Retention amount μg/g Penetration rate% Notes 17 32.36 0.00438 Increase the amount of propylene glycol to 15% 18 36.75 0.00683 Propylene glycol 5%, diethylene glycol monoethyl ether 5% 1% Benvimod cream 30.39 0.00639

Table 11:

Preparation 17 and preparations 18 In vitro transdermal testing results — Betamethasone propionate Preparation number Retention amount μg/g Penetration rate% Notes 17 1.160 0.007567 Increase the amount of propylene glycol to 15% 18 1.585 0.006902 Propylene glycol 5%, diethylene glycol monoethyl ether 5% 0.064% Betamethasone Dipropionate Cream 2.865 0.011114

Table 12:

Preparation 19 and preparations 20 In vitro transdermal testing results — Benvimod Preparation number Retention amount μg/g Penetration rate% Notes 19 52.38 0.00447 Diethylene glycol monoethyl ether 10% 20 55.27 0.00500 Diethylene glycol monoethyl ether 15% 1% Benvimod cream 68.33 0.00266

Table 13:

Preparation 19 and preparations 20 In vitro transdermal testing results — Betamethasone propionate Preparation number Retention amount μg/g Penetration rate% Notes 19 1.730 0.0285 Diethylene glycol monoethyl ether 10% 20 2.011 0.0349 Diethylene glycol monoethyl ether 15% 0.064% Betamethasone Dipropionate Cream 1.837 0.0209

According to the above analysis,

1) For the sample with propylene glycol dosage increased to 15% (Preparation 17), the retention amount of betamethasone dipropionate in the in vitro transdermal experiment was close to that of betamethasone dipropionate cream, but the retention amount of betamethasone dipropionate cream was lower than that of betamethasone dipropionate cream;

2) For the sample with 5% propylene glycol and 5% diethylene glycol monoethyl ether (Preparation 18), the retention amount of betamethasone component in the in vitro transdermal experiment was close to that of betamethasone cream; however, the retention amount of betamethasone propionate was lower than that of betamethasone propionate cream;

3) In the in vitro skin penetration test, the sample (preparation 19) with diethylene glycol monoethyl ether as a penetration enhancer and a diethylene glycol monoethyl ether dosage of 10% showed that the retention amount of bevimod component was close to that of bevimod cream; the retention amount of betamethasone propionate was close to that of betamethasone propionate cream;

4) In the sample with diethylene glycol monoethyl ether as a penetration enhancer and a diethylene glycol monoethyl ether dosage of 15% (Preparation 20), the retention amount of bevimod component in the in vitro transdermal experiment was close to that of bevimod cream; the retention amount of betamethasone dipropionate was close to that of betamethasone dipropionate cream.

However, the droplet size of Formulation 20 was not uniform, so diethylene glycol monoethyl ether at a dosage of 10% was a more ideal solvent and/or penetration enhancer.

Comparative Example 10: Prepare the preparation according to the prescription in Table 14

Table 14: Prescription composition Proportion% Prescription amount (g) Benvimod 1 1 Betamethasone dipropionate 0.064 0.064 Menthol 0.5 0.5 Butylated Hydroxyanisole (BHA) 0.1 0.1 Propylene glycol 15 15 Polysorbate 80 10 10 Glyceryl mono- and distearate 10 10 Cetostearyl alcohol 10 10 0.1M HCl Moderate Moderate 0.1M NaOH Moderate Moderate Purified water 53.336 53.336 Total 100.00 100.00

The preparation steps are as follows:

Oil phase: Weigh the prescribed amount of propylene glycol, place in a water bath and heat to 60°C, add bevimod, betamethasone dipropionate, BHA, and menthol and stir until dissolved, add glyceryl monostearate and cetostearyl alcohol and stir until melted, keep warm for 20 min and set aside.

Aqueous phase: Weigh the prescribed amount of polysorbate 80 and add it to the prescribed amount of purified water, stir to dissolve. After complete dissolution, adjust the pH to 6.0-7.0 with 0.1 mol HCl and 0.1 mol NaOH, and keep warm for later use.

Stirring: Maintaining the temperature at 60°C, add the water phase to the oil phase, stir for 1 min, then stir at room temperature for 1 min, and let the product stand at room temperature.

Results: The cream became viscous after being stirred for one minute at room temperature. After stopping stirring and letting it stand at room temperature, microscopic observation showed that the droplet size distribution was uneven, with the smallest being around 5 microns and the largest being over 10 microns. Polarized light under a microscope revealed that needle-like and cluster-like crystals were precipitated, as shown in Figure 33.

The above description discloses the preferred embodiments of the present invention. The embodiments of the present invention are only illustrative and are not intended to limit the scope of the present invention in any way. Within the spirit of the present invention, modifications and improvements made by a person skilled in the art to which the present invention belongs to the present invention to the embodiments specifically disclosed in the present invention shall be covered by the scope of protection defined by the scope of the invention application of the present invention. A person skilled in the art to which the present invention belongs can use the above description to make the most of the present invention.

without

Figure 1 is a micrograph of the particle size of preparation 1 (400 times). Figure 2 is a micrograph of the particle size of preparation 2 (400 times). Figure 3 is a micrograph of the particle size of preparation 3 (400 times). Figure 4 is a micrograph of the particle size of preparation 4 (400 times). Figure 5 is a micrograph of the particle size of preparation 5 (400 times). Figure 6 is a micrograph of the particle size of preparation 6 (400 times). Figure 7 is a micrograph of the particle size of preparation 10 (400 times). Figure 8 is a micrograph of the particle size of preparation 7 (400 times). Figure 9 is a micrograph of the particle size of preparation 8 (400 times). Figure 10 is a micrograph of the particle size of preparation 9 (400 times). Figure 11 is a micrograph of the particle size of preparation 11 (400 times). Figure 12 is a micrograph of the particle size of preparation 12 (400 times). Figure 13 is a micrograph of the particle size of preparation 13 (400 times). Figure 14 is a micrograph of the particle size of preparation 10 (400 times). Figure 15 is a micrograph of the particle size of preparation 10-1 (400 times). Figure 16 is a micrograph of the particle size of preparation 10-2 (400 times). Figure 17 is a micrograph of the particle size of preparation 10-3 (400 times). Figure 18 is a micrograph of the particle size of preparation 10-4 (400 times). Figure 19 is a micrograph of the particle size of preparation 10 (400 times). Figure 20 is a micrograph of the particle size of preparation 10 after 0 days of storage (400 times). Figure 21 is a micrograph of the particle size of preparation 10 after 1 month of storage at 30°C (400 times). Figure 22 is a micrograph of the particle size of preparation 10 after 3 months of storage at 40°C (400 times). Figure 23 is a comparison of the retention amount of the benvimod component in preparations 14, 15 and 16 in the in vitro transdermal experiment. Figure 24 is a comparison of the retention amount of the betamethasone propionate component in preparations 14, 15 and 16 in the in vitro transdermal experiment. Figure 25 is a micrograph of the particle size of preparation 20 (400 times). Figure 26 is a micrograph of the particle size of preparation 17 (400 times). Figure 27 is a micrograph of the particle size of preparation 18 (400 times). Figure 28 is a micrograph of the particle size of preparation 19 (400 times). Figure 29 is a comparison of the retention amount of the betamethasone dipropionate component in preparations 17 and 18 in the in vitro transdermal experiment. Figure 30 is a comparison of the retention amount of the betamethasone dipropionate component in preparations 17 and 18 in the in vitro transdermal experiment. Figure 31 is a comparison of the retention amount of the betamethasone dipropionate component in preparations 19 and 20 in the in vitro transdermal experiment. Figure 32 is a comparison of the retention amount of the betamethasone dipropionate component in preparations 19 and 20 in the in vitro transdermal experiment. Figure 33 is a micrograph of the particle size of the comparative example (400 times).

Claims (10)

A topical drug composition, characterized in that, based on the total weight percentage of the topical drug composition, the topical drug composition comprises: Benvimod or a pharmaceutically acceptable salt thereof, the content of which is 0.5% to 2% by weight, preferably 0.5% to 1.5%, preferably 0.5% to 1.25%, and more preferably 0.75% to 1%; One or more corticosteroids, the content of which is 0.01% to 2% by weight, preferably 0.01% to 0.25%; and Pharmaceutically acceptable excipients suitable for topical use, wherein the excipients do not contain vaseline and mono- and di-stearic acid glyceryl; Preferably, the corticosteroid is one or more of betamethasone or its derivatives. The topical pharmaceutical composition of claim 1 is characterized in that the topical pharmaceutical composition is a cream, preferably an oil-in-water cream. The topical drug composition as described in claim 2 is characterized in that the topical drug composition further comprises: An oil phase base, the total content of which is 5% to 30% by weight; and the oil phase base does not contain vaseline. The topical drug composition as described in claim 2 or 3 is characterized in that the topical drug composition further comprises: Solvent and/or penetration enhancer, the total content of which is 5% to 30% by weight. The topical drug composition as described in claim 3 or 4 is characterized in that the topical drug composition further comprises: A surfactant, the total content of which is 0.1% to 10% by weight; and the surfactant does not contain mono- and di-stearic acid glyceryl. The topical drug composition as described in claim 5 is characterized in that the topical drug composition further comprises: a pH adjuster, in an appropriate amount, and the pH of the topical drug composition is 3-7; and the rest is an aqueous phase. The topical drug composition as described in claim 5 or 6 is characterized in that the surfactant is selected from one or more of emulsifying wax, stearyl alcohol polyethers, polysorbates, cetumago 1000, dehydrated sorbitan fatty acid esters and polyethylene glycol ceteareth, preferably at least two of emulsifying wax, stearyl alcohol polyethers, polysorbates, cetumago 1000, dehydrated sorbitan fatty acid esters and polyethylene glycol ceteareth, more preferably at least two of steareth-2, steareth-20, Tween-80, Tween-60, Span-60 and cetumago 1000, and most preferably two of Tween-80, Tween-60, Span-60 and cetumago 1000; For example, the surfactant comprises Tween-60 and Span-60, wherein: The content of Tween-60 is 1.75% to 4% by weight, preferably 2%; The content of Span-60 is 0.25% to 1.5% by weight, preferably 0.75%. A topical drug composition as described in any one of claims 2 to 7, characterized in that: The topical drug composition further comprises a solvent and/or a permeation enhancer, wherein the solvent and/or permeation enhancer is selected from one or more of propylene glycol, diethylene glycol monoethyl ether, glycerol and PEG400, preferably propylene glycol and/or diethylene glycol monoethyl ether, more preferably diethylene glycol monoethyl ether; and/or The topical drug composition further comprises a pH adjuster, which is a buffer, and the buffer is preferably selected from one or more of citrate/citric acid, acetate/acetic acid, phosphate/phosphoric acid, citrate/citric acid, propionate/propionic acid, lactate/lactic acid, and ammonium/ammonia; and/or The topical drug composition further comprises a stabilizer, the total content of which is 0.005% to 2% by weight, and the stabilizer is preferably one or more selected from citric acid and its salts, glucuronic acid and its salts, sodium hexametaphosphate, zinc hexametaphosphate, ethylenediaminetetraacetic acid (EDTA) and its salts, and phosphonates; and/or The topical drug composition further comprises a preservative, the total content of which is 0.005% to 2% by weight; and/or The topical drug composition further comprises an antioxidant, the total content of which is 0.005% to 2% by weight. A method for preparing a topical drug composition as described in any one of claims 3 to 8, characterized in that it comprises the following steps: 1) preparing the oil phase: adding the oil phase base, solvent and/or penetration promoter, surfactant and optionally preservative and antioxidant to a container of suitable size, starting mixing and heating to 65-80°C to stir and dissolve the oil phase base, the solvent and/or penetration promoter, the surfactant and optionally the preservative and antioxidant; then adding the active ingredient, stirring to dissolve, and keeping warm for use; 2) preparing the water phase: adding the pH adjuster, stabilizer and optionally preservative and antioxidant to purified water, 65-80°C ℃, heat and stir to dissolve the pH adjuster, the stabilizer, and optionally the preservative and the antioxidant, and keep warm for later use; 3) Emulsification: add the oil phase to the water phase or add the water phase to the oil phase, maintain the temperature at 65-80 ℃, start stirring, and start homogenization after stirring evenly. After homogenization is completed, transfer the obtained homogenate to a storage container and cool it to obtain the topical drug composition. A use of a topical pharmaceutical composition as claimed in any one of claims 1 to 8 for the preparation of a medicament for the treatment and/or prevention of a skin disease or disorder selected from psoriasis, atopic dermatitis, acne and skin pruritus, preferably psoriasis.