TWI903311B - 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 compounds, their preparation methods and their pharmaceutical uses

This case asserts the priority right of the applicant over the prior application filed on December 14, 2022, with the China National Intellectual Property Administration, application number 202211611803.1, entitled "A Topical Drug Composition and Its Application in Medicine." The full text of that prior application is incorporated herein by reference.

This case pertains to the pharmaceutical field and relates to a topical pharmaceutical composition and/or a cream and its pharmaceutical application, particularly in the manufacture of a medicine for the treatment and/or prevention of skin diseases or disorders, including but not limited to psoriasis, atopic dermatitis, acne, and pruritus; the active ingredient (API) of the topical composition and/or cream includes benvitimod or a pharmaceutically acceptable salt thereof, and one or more corticosteroids.

Autoimmune diseases are a class of diseases characterized by a decreased tolerance of the immune system to the body's own antigens, the production of large amounts of autoantibodies and immune complexes, and ultimately, damage to the function of multiple tissues and organs (Guan SY et al., Inflammation, 2017, 40(1): 303-310). As early as 1999, the World Health Organization listed autoimmune diseases as the third leading cause of death among humans after cardiovascular diseases 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 Plan (Pan Haifeng et al., Chinese Journal of Disease Control, 2018, 22(11): 1093-1095, 1105). Autoimmune diseases have a wide spectrum and diverse clinical manifestations, mainly including more than 70 diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and ankylosing spondylitis (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 epithelial cell proliferation and renewal, thickening of the epidermis, and the formation of inflamed, swollen skin lesions and raised areas covered with silvery-white scales. These inflamed, thickened, and scaly lesions are prone to itching, burning, stinging, and bleeding. As one of the most serious non-communicable diseases, psoriasis affects approximately 125 million people worldwide, significantly reducing their quality of life. Atopic dermatitis is a common, chronic, relapsing, inflammatory skin disease typically characterized by the overgrowth of Staphylococcus aureus, leading to the breakdown of the epidermal barrier through proteolytic activity and immune dysregulation. This disease is reportedly the non-fatal skin disease with the highest burden of 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, such as psoriasis and atopic dermatitis, conventional topical medication remains the primary clinical treatment. Corticosteroids, as first-line drugs, have high side effects with long-term use, and intermittent use provides short-term relief and is prone to relapse. Non-hormonal topical medications, such as vitamin D3 derivatives, retinoic acid, and calcineurin inhibitors, have drawbacks including slow onset of action, limited efficacy, widespread local side effects, and poor patient compliance. Existing topical formulations only provide temporary relief, are prone to relapse, and have unsatisfactory efficacy; more effective treatments are still needed for clinical use.

Benvitimod cream is a globally pioneering Class 1 new drug in China with complete independent intellectual property rights. It is a major achievement of China's "Major New Drug Development" science and technology project and was approved for marketing in China in May 2019 for the topical treatment of mild to moderate psoriasis in adults.

Benvimod's chemical structure is as follows:

Benvitimod was initially disclosed as an antibiotic by Paul et al. (Journal of Chemical Ecology, 1981, 7(3): 589-597). WO1995003695A1 (Agro-Biotech Corporation) disclosed the antifungal activity of the compound. The compound was further described in WO2001042231A2 (Welichem Biotech Inc.) as being suitable for the treatment of a variety of important skin conditions, including psoriasis and inflammation. Example 3 of US Patent US7868047B2 (Dermavant Sciences GmbH) describes an ointment formulation in which the active ingredient is prepared in a Galax matrix. WO 2016/185428 (GlaxoSmithKline Inc.) provides a method for preparing a topical pharmaceutical emulsion composition involving the compound. The immunosuppressive effects of corticosteroids are known to be crucial in inhibiting pro-inflammatory environments and T cell activation; benvitimod can suppress potential inflammation and normalize skin homeostasis, regulate keratinocyte proliferation and differentiation, and provide immunomodulation, exerting immunomodulatory effects on Th2, Th17, and T-reg cells.

To address the problems of low efficacy, high relapse rate, and poor patient compliance associated with existing topical medications, this case presents a novel topical drug combination that can be applied topically to treat immune, inflammatory, and autoimmune diseases, effectively improving clinical efficacy, reducing relapse rates, and enhancing patient compliance.

In view of this, the purpose of this case is to provide a topical drug combination whose active ingredient is benvimod or a pharmaceutically acceptable salt thereof and one or more corticosteroids, for combination use. This combination has been proven to overcome some of the insurmountable drawbacks of current monotherapy, such as the fact that corticosteroids, being hormonal drugs, easily cause skin atrophy and drug resistance, and are not suitable for long-term use.

Furthermore, this application provides a topical pharmaceutical composition characterized in that, by weight percentage of the total topical pharmaceutical composition, the topical pharmaceutical composition comprises: benvomod or a pharmaceutically acceptable salt thereof, in an amount of 0.5% to 2% by weight; one or more corticosteroids, each in an amount of 0.01% to 2% by weight; and pharmaceutically acceptable excipients suitable for topical application, wherein the excipients do not contain petrolatum and glyceryl monostearate and glyceryl distearate.

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

In some embodiments of this case, the topical drug composition described herein, based on the total weight percentage of the topical drug composition, contains corticosteroids at a weight percentage of 0.01% to 1.5%, preferably 0.01% to 1.25%, more preferably 0.01% to 1%, more preferably 0.01% to 0.75%, even more preferably 0.01% to 0.5%, and most preferably 0.01% to 0.25%; specifically, the corticosteroid content 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 this case, the topical drug composition described herein includes a corticosteroid selected from one or more of the following: aclomethasone or a derivative thereof, ansilonide or a derivative thereof, betamethasone or a derivative thereof, clobetasol or a derivative thereof, clotroponin or a derivative thereof, desonide or a derivative thereof, desoxymethasone or a derivative thereof, diflubenzuron or a derivative thereof, fluticasone or a derivative thereof, fluticasone or a derivative thereof, halcinonide or a derivative thereof, urbetasol or a derivative thereof, hydrocortisone or a derivative thereof, mometasone or a derivative thereof, nicotinic acid ester or a derivative thereof, triamcinolone or a derivative thereof, fluazinam or a derivative thereof, dexamethasone or a derivative thereof, and methylprednisolone or a derivative thereof; preferably, the corticosteroid is selected from betamethasone or a derivative thereof, clotroponin or a derivative thereof, desoxymethasone or a derivative thereof, and fluticasone or a derivative thereof. Fluticasone or its derivatives, cortisone hydrochloride or its derivatives, mometasone or its derivatives, nicotinic acid ester or its derivatives, triamcinolone or its derivatives, fluazinam or its derivatives; more preferably, the corticosteroid is selected from betamethasone or its derivatives, clocrotropin or its derivatives, dehydromethasone or its derivatives, fluoxetine or its derivatives, fluticasone or its derivatives, cortisone hydrochloride or its derivatives, mometasone hydrochloride, or other similar products. The corticosteroid is selected from one or more of betamethasone or its derivatives, nicotinic acid ester or its derivatives, and triamcinolone acetonide 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 this case, the topical drug combination described herein preferably contains a glucocorticoid, which is classified into three categories according to its duration of action: short-acting (e.g., cortisone, hydrocortisone, etc.), intermediate-acting (e.g., phenylephrine, methylphenidate, etc.), and long-acting (e.g., dexamethasone, betamethasone, etc.).

In some embodiments of this case, the topical drug composition described herein is a cream, preferably an oil-in-water cream.

According to an embodiment of this case, the topical drug composition comprises a solvent and/or an penetration enhancer, the total content of which is 5% to 30% by weight.

According to an embodiment of this case, the topical pharmaceutical composition comprises: a surfactant in a total content of 0.1% to 10% by weight; and the surfactant does not contain glyceryl monostearate or glyceryl distearate.

According to an embodiment of this case, the topical drug composition comprises: a pH adjuster, in an appropriate amount, wherein the pH of the topical drug composition is 3-7; and the remainder being an aqueous phase.

According to an embodiment of this case, the surfactant is selected from one or more of emulsified wax, stearyl alcohol polyethers, polysorbates, cetomacrogol 1000, dehydrated sorbitan fatty acid esters, and polyethylene glycol hexadecanoate, preferably at least two of emulsified wax, stearyl alcohol polyethers, polysorbates, cetomacrogol 1000, dehydrated sorbitan fatty acid esters, and polyethylene glycol hexadecanoate, more preferably at least two of stearyl alcohol polyether-2, stearyl alcohol polyether-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%; and the content of Span-60 is 0.25% to 1.5% by weight, preferably 0.75%.

According to an embodiment of this case, the topical drug composition comprises a solvent and/or a penetration promoter, wherein the solvent and/or penetration promoter is selected from one or more of propylene glycol, diethylene glycol monoethyl ether, glycerin, and PEG400, preferably propylene glycol and/or diethylene glycol monoethyl ether, more preferably diethylene glycol monoethyl ether; and/or the topical drug composition comprises a pH adjuster, wherein the pH adjuster is a buffer, and the buffer is preferably selected from citrate/citric acid, acetate/acetic acid, phosphate/phosphate, citrate/citric acid, propionate/propionic acid, lactate/lactic acid, and ammonium salt/ammonia. One or more of the following: and/or the topical drug composition further comprises a stabilizer, the total content of which is 0.005% to 2% by weight, said stabilizer 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, this case relates to a cream characterized in that, by a total weight percentage, the cream comprises: 0.5% to 2% by weight of benvitide or a pharmaceutically acceptable salt thereof; 0.01% to 2% by weight of one or more corticosteroids; 5% to 30% by weight of an oil phase matrix; and the oil phase matrix does not contain petrolatum; a surfactant (emulsifier) by weight of 0.1% to 10% by weight; and the surfactant (emulsifier) does not contain glyceryl monostearate or glyceryl distearate; a solvent and/or a penetration enhancer by weight of 5% to 30% by weight; a pH adjuster, in appropriate amounts, wherein the pH is 3-7; and the remainder is an aqueous phase.

In some embodiments of this case, the cream described herein contains, by weight percentage, 0.5% to 1.75% of benvitimod or its pharmaceutically acceptable salts, preferably 0.5% to 1.5%, and more preferably 0.75% to 1.25%; specifically, the content of benvitimod or its pharmaceutically acceptable salts may be 0.5%, 0.75%, 1%, 1.25%, and 1.5%.

In some embodiments of this case, the cream described herein, based on a total weight percentage of the cream, contains corticosteroids at a weight percentage of 0.01% to 1.5%, 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 corticosteroid content 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 this case, the cream described herein contains a corticosteroid selected from aclomethasone or a derivative thereof, ancinonide or a derivative thereof, betamethasone or a derivative thereof, clobetasol or a derivative thereof, clotropone or a derivative thereof, desonide or a derivative thereof, deshydroepiandrone or a derivative thereof, diflubenzuron or a derivative thereof, fluticasone or a derivative thereof, fluticasone or a derivative thereof, halcinonide or a derivative thereof, umebetasol or a derivative thereof, and hydrocortisone. The corticosteroid is selected from one or more of the following: betamethasone or its derivatives, mometasone or its derivatives, nicotinic acid ester or its derivatives, triamcinolone or its derivatives, fluoxetine or its derivatives, dexamethasone or its derivatives, and methylprednisolone or its derivatives; preferably, the corticosteroid is selected from betamethasone or its derivatives, clocrotropin or its derivatives, dehydrophenamine or its derivatives, fluticasone or its derivatives, hydrocortisone or its derivatives, mometasone... The corticosteroid is selected from one or more of the following: betamethasone or its derivatives, nicotinic acid ester or its derivatives, triamcinolone or its derivatives, and fluticasone or its derivatives; more preferably, the corticosteroid is selected from one or more of the following: betamethasone or its derivatives, cloxacillin or its derivatives, dehydrophenamine or its derivatives, fluticasone or its derivatives, hydrocortisone or its derivatives, mometasone or its derivatives, nicotinic acid ester or its derivatives, and triamcinolone or its derivatives. More preferably, the corticosteroid is selected from one or more of betamethasone or its derivatives; even more preferably, the corticosteroid is selected from one or more of betamethasone propionate, betamethasone dipropionate, betamethasone acetate, and betamethasone valerate; 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 this case, the cream described herein preferably contains a glucocorticoid, which is classified into three categories according to its duration of action: short-acting (e.g., cortisone, hydrocortisone, etc.), intermediate-acting (e.g., phenylephrine, methylphenidate, etc.), and long-acting (e.g., dexamethasone, betamethasone, etc.).

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

In some embodiments of this case, the oil phase matrix of the cream described herein is selected from one or more of stearic acid, paraffin, isopropyl myristate, beeswax, medium-chain triglycerides, higher alcohols, and lanolin, preferably from one or more of stearic acid, isopropyl myristate, medium-chain triglycerides, cetyl alcohol, octadecyl alcohol, and cetyloctadecyl alcohol.

In some embodiments of this case, the cream described herein contains an oil phase matrix selected from one or more of stearic acid, isopropyl myristate, medium-chain triglycerides, cetyl alcohol, octadecyl alcohol, and cetyloctadecyl alcohol, with each oil phase matrix comprising 5% to 25%, preferably 5% to 20%, more preferably 5% to 15%, and most preferably 5% to 10%.

In some embodiments of this case, the cream described herein has an oil phase base that does not contain petrolatum (preferably not white petrolatum).

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

In some embodiments of this case, the cream described herein does not contain glyceryl monostearate or glyceryl distearate as the surfactant.

In some embodiments of this case, the total content of the surfactant in the cream, based on the total weight percentage of the cream, is 0.1% to 10%, preferably 0.5% to 8%, more preferably 0.5% to 6%, and most preferably 0.75% to 6%; 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 this case, the cream described herein contains at least two of the following surfactants: stearyl alcohol polyether-2, stearyl alcohol polyether-20, Tween-80, Tween-60, Span-60, and West Marco 1000, with each surfactant comprising 0.1% to 4.25% by weight; preferably, the surfactant is selected from at least two of the following: stearyl alcohol polyether-20, Tween-80, Tween-60, Span-60, and West Marco 1000, with each surfactant comprising 0.1% to 4% by weight; more preferably, one of the surfactants is Tween-60, comprising 1.75% to 4% by weight; and 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, more preferably 0.75%.

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%; and the content of Span-60 is 0.25% to 1.5% by weight, preferably 0.75%.

In some embodiments of this case, the cream described herein contains Tween-60 as one of the surfactants, and its content is greater than 1.5% by weight.

In some embodiments of this invention, the solvent and/or penetration promoter of the cream described herein is selected from one or more of propylene glycol, diethylene glycol monoethyl ether, glycerin, 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 this case, the total content of the solvent and/or penetration promoter in the cream, by weight percentage, is 5% to 30%, preferably 5% to 25%, more preferably 5% to 20%, even more preferably 10% to 20%, and most preferably 10% to 15%; specifically, the content of the surfactant can be 5%, 10%, 15%, 20%, 25%, and 30%.

In some embodiments of this application, the cream described herein contains a solvent and/or penetration promoter selected from one or more of propylene glycol, diethylene glycol monoethyl ether, and PEG400, with each solvent and/or penetration promoter comprising 5% to 25% by weight; preferably, the solvent and/or penetration promoter is propylene glycol and/or diethylene glycol monoethyl ether, with each solvent and/or penetration promoter comprising 10% to 25% by weight; most preferably, the solvent and/or penetration promoter is diethylene glycol monoethyl ether, comprising 10% to 20% by weight.

In some embodiments of this case, the cream described herein uses a pH adjuster as a buffer, preferably selected from one or more of citrate/citric acid, acetate/acetic acid, phosphate/phosphate, citrate/citric acid, propionate/propionic acid, lactate/lactic acid, and ammonium salt/ammonia, with citrate/citric acid being the most preferred.

In some embodiments of this case, the content of the pH adjuster in the cream is appropriate, adjusting 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 this case, the content of the pH adjuster is 0.01% to 5% by weight, preferably 0.1% to 3%, more preferably 0.1% to 2%, even more preferably 0.1% to 1%, and most preferably 0.1% to 0.5%.

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

In some embodiments of this case, the cream described herein further comprises a stabilizer in a content of 0.005% to 2% by weight, preferably 0.01% to 2%, more preferably 0.05% to 2%, even more preferably 0.075% to 1.5%, and most preferably 0.1% to 1%.

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

In some embodiments of this case, the cream described in this case further includes preservatives.

As is known in the art, effective amounts of one or more of the following preservatives may be used: benzoxamethylene chloride, poly(ethylene methyl hydrochloride) (PHMB), sorbic acid, ethyl hydroxyphenyl ester, methyl hydroxyphenyl ester, propyl hydroxyphenyl ester, methyl salicylate, benzyl alcohol, and phenoxyethanol.

In some embodiments of this case, the total content of the preservative in the cream, based on the total weight percentage 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 may be 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, and 0.25%.

In some embodiments of this case, the cream described in this case further includes antioxidants.

As is known in the art, effective amounts of one or more antioxidants such as butylated hydroxytoluene (BHT), disodium ethylenediaminetetraacetate (EDTA-2Na), butylated hydroxyanisole (BHA), vitamin E, vitamin E acetate, and vitamin E niacinate can be used.

In some embodiments of this case, the total content of the antioxidant in the cream, based on the total weight percentage 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 this case, the particle size of the cream described herein is less than 10 μm, preferably 1-5 μm, and more preferably 1-3 μm.

In some embodiments of this application, the cream described herein, by weight percentage, contains 0.5% to 1.5% of benvitide or its pharmaceutically acceptable salts; 0.01% to 0.25% of the corticosteroid (preferably betamethasone or a derivative thereof); the oil phase matrix does not contain petrolatum (preferably not white petrolatum); the surfactant does not contain glyceryl mono- and distearate and is selected from at least two of stearyl alcohol polyether-2, stearyl alcohol polyether-20, Tween-80, Tween-60, Span-60, and West MacGregor 1000, and the total content of the surfactant is... The content is 0.5% to 6%; the solvent and/or penetration promoter is selected from one or more of propylene glycol, diethylene glycol monoethyl ether, and PEG400, and their total content is 5% to 25% by weight; the pH adjuster is citrate/citric acid or citric acid salt/citric acid, and its content is 0.01% to 5%; the stabilizer is ethylenediaminetetraacetic acid (EDTA) and its salt, and its content is 0.01% to 2% by weight; the total content of the preservative (preferably methylparaben or ethylparaben) is 0.01% to 0.5%; and the total content of the antioxidant (preferably BHT) is 0.01% to 0.5%.

Another aspect of this case relates to a method for preparing the cream as described above, the method comprising the following steps: 1) preparing the oil phase: adding an 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 above components; then adding the active ingredient, stirring and dissolving, and keeping warm for later use; 2) preparing... Preparation of the aqueous phase: Add the pH adjuster, stabilizer, and optionally preservatives and antioxidants to purified water. Heat and stir at 65-80℃ to dissolve all substances, and keep warm for later use; 3) Emulsification: Add the oil phase to the aqueous phase or vice versa. Maintain the temperature at 65-80℃, start stirring, and after stirring until homogenized, start homogenization. After homogenization is complete, transfer all substances to a storage container and cool to obtain the cream.

This case 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 skin diseases or disorders selected from psoriasis, atopic dermatitis, acne, and pruritus.

This case further relates to the use of a topical pharmaceutical composition or cream as described above in the preparation of a medicine for the treatment and/or prevention of psoriasis.

This case also relates to a method of treating and/or preventing skin diseases or disorders, comprising administering to a patient a therapeutically effective amount of the topical drug combination or cream described above, wherein the skin disease or disorder is selected from psoriasis, atopic dermatitis, acne, and pruritus.

This case also relates to a method of treating and/or preventing psoriasis, comprising administering to a patient in need a therapeutically effective amount of the topical drug combination or cream as described above.

This case also relates to a topical pharmaceutical composition or cream as described above, used as a medicine, such as a topical medication.

This case also relates to a topical pharmaceutical composition or cream as described above, used as a medicine for the treatment and/or prevention of skin diseases or disorders selected from psoriasis, atopic dermatitis, acne, and pruritus.

This case also relates to a topical pharmaceutical composition or cream as described above, used as a medicine for the treatment and/or prevention of psoriasis.

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

Definitions and explanations of terms

Unless otherwise stated, the definitions of terms used in this specification and the scope of the invention application, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific components in embodiments, may be freely combined and integrated with each other. Such combinations and integrations shall fall within the scope of this specification.

For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to a sufficient dose of a non-toxic drug or agent that achieves the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the receptor, as well as the specific active substance. In a given case, the appropriate effective amount can be determined by a person skilled in the art based on routine experiments.

The term "patient" refers to someone who needs prevention or treatment for a skin disease or disorder. Patients are mammals, such as rodents, cattle, pigs, dogs, cats, and primates, but humans are preferred.

To avoid ambiguity, the content of a particular type of excipient, such as an oily matrix, mentioned in this article refers to the total content. If the excipient contains more than one component, the content refers to the sum of all components, not the content of each individual component. Content explicitly stated as "each" refers to the content of each individual component.

As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

When the term "approximately" is applied to parameters such as pH, concentration, and temperature, it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by one of ordinary skill in the art to which this invention pertains, when a parameter is not critical, figures are typically given for illustrative purposes only, not as limitations.

Beneficial effects

The topical drug combination or cream provided in this case has a synergistic effect on the therapeutic efficacy of psoriasis, atopic dermatitis, or other immune, inflammatory, and autoimmune diseases during application to individuals. This effect is superior to the efficacy of individual single-active-ingredient drugs and helps to reduce the side effects of corticosteroids, thereby improving individual adherence. Specifically:

1. Enhanced efficacy compared to single-drug therapy - synergistic effect

The key to psoriasis treatment lies in achieving complete clearance of psoriatic plaques. The intervention pathways include inhibiting the inflammatory process, restoring and maintaining the 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 combinations or creams disclosed in this article (preferably benvitimod-betamethasone propionate combination preparations) are expected to produce synergistic and complementary effects, covering multiple stages of the psoriasis pathological process, achieving a multi-pronged approach, leveraging the strengths of each drug, and thus surpassing the advantages of single-drug therapy.

a) Corticosteroids (preferably betamethasone propionate) have potent anti-inflammatory, anti-allergic, and immunosuppressive effects. They can suppress local inflammation in psoriatic skin lesions and restore the normal structure and function of skin tissue, thereby achieving the goal of treating psoriasis.

b) Benvitimod can activate AhR, promote normal skin cell differentiation, and inhibit abnormal keratinization of keratinocytes; it has regulatory effects on Th1, Th2, Th17, and T-reg cells; and it can upregulate the expression of skin barrier proteins such as filaggrin, promoting the repair of damaged skin and the integrity of the skin barrier function. Furthermore, it alleviates oxidative stress and restores skin homeostasis by regulating the expression of antioxidant proteins in skin cells through Nrf2.

c) The topical drug combination or cream disclosed herein (preferably betamethasone dipropionate combination preparation) is expected to synergistically inhibit inflammatory cells and their cytokines, such as inhibiting the release of Th1 and Th17 cells and their cytokines, inhibiting keratinocyte initiation and its abnormal proliferation and differentiation, thus contributing to inflammation resolution and maintaining sustained keratinocyte homeostasis.

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

Therefore, the topical drug combination or cream disclosed in this article (preferably betamethasone dipropionate compound preparation) is expected to have a synergistic effect, enhancing anti-inflammatory efficacy.

2. Reduced side effects associated with monotherapy - safety

Long-term, monotherapy use of corticosteroids may lead to decreased skin thickness and increased transepidermal water loss, resulting in skin atrophy, capillary dilation, and impaired skin barrier function. Dermal atrophy caused by corticosteroids often occurs at the application site, primarily due to their binding to specific receptors and reducing collagen synthesis. Currently, there are no effective treatments for skin atrophy other than minimally invasive surgical injection of relevant skin tissue. Benvitimod can regulate keratinocyte differentiation by activating AhR, increasing the expression of barrier-related protein genes, improving skin barrier integrity, preventing transepidermal water loss, mitigating corticosteroid-induced skin atrophy, reducing the risks associated with corticosteroid treatment, and providing better safety.

On the other hand, the two active ingredients have different pharmacological mechanisms and target sites. Benvitimod is locally effective, with extremely low concentrations entering the circulatory system. It does not interact with corticosteroids during absorption, distribution, metabolism, and excretion, nor does it exhibit the same or similar target organ toxicity or adverse reactions. Therefore, the combination of the two will not lead to an additive toxicity and thus no significant toxicological concerns.

3. Compliance

This case utilizes the rapid response of corticosteroids to treat lesions and the long-lasting relief provided by benvitimod, significantly improving patient acceptance of treatment. It offers excellent convenience and helps patients adapt to treatment during long-term management, thus enhancing patient acceptance and confidence. Itching is a significant symptom of psoriasis. The topical drug combination or cream disclosed in this article (preferably benvitimod-betamethasone propionate combination preparation) promises to achieve rapid itch relief, thereby improving patients' quality of life more quickly and effectively, and positively impacting treatment adherence.

4. Unique Formula

The formula disclosed in this case differs significantly from the formulas of marketed single-agent products, Benvitimod Cream and Betamethasone Dipropionate Cream, including the unique proportions of each excipient, breaking through conventional technical thinking. Through the applicant's creative efforts, the topical drug combination and/or cream formulated with the ingredients and proportions disclosed in this case exhibit excellent transdermal penetration.

Figure 1 is a particle size micrograph of preparation 1 (400x magnification).

Figure 2 is a particle size micrograph of preparation 2 (400x magnification).

Figure 3 is a particle size micrograph of preparation 3 (400x magnification).

Figure 4 is a particle size micrograph of preparation 4 (400x magnification).

Figure 5 is a particle size micrograph of preparation 5 (400x magnification).

Figure 6 is a particle size micrograph of preparation 6 (400x magnification).

Figure 7 shows a particle size micrograph of preparation 10 (400x magnification).

Figure 8 is a particle size micrograph of preparation 7 (400x magnification).

Figure 9 is a particle size micrograph of preparation 8 (400x magnification).

Figure 10 is a particle size micrograph of preparation 9 (400x magnification).

Figure 11 is a particle size micrograph (400x) of preparation 11.

Figure 12 is a particle size micrograph of preparation 12 (400x magnification).

Figure 13 is a particle size micrograph of preparation 13 (400x magnification).

Figure 14 is a particle size micrograph of preparation 10 (400x magnification).

Figure 15 shows a particle size micrograph (400x) of formulation 10-1.

Figure 16 is a particle size micrograph (400x) of formulation 10⁻².

Figure 17 is a particle size micrograph (400x) of formulation 10⁻³.

Figure 18 shows a particle size micrograph (400x) of formulation 10⁻⁴.

Figure 19 is a particle size micrograph of preparation 10 (400x magnification).

Figure 20 shows the particle size micrograph (400x) of formulation 10 after 0 days of storage.

Figure 21 shows a particle size micrograph (400x) of Formulation 10 after being stored at 30°C for one month.

Figure 22 shows the particle size micrograph (400x) of Formulation 10 after being stored at 40°C for 3 months.

Figure 23 shows a comparison of the retention levels of benvitide in formulations 14, 15, and 16 during in vitro transdermal experiments.

Figure 24 compares the retention levels of betamethasone propionate in formulations 14, 15, and 16 during in vitro skin penetration experiments.

Figure 25 is a particle size micrograph of formulation 20 (400x magnification).

Figure 26 is a particle size micrograph (400x) of preparation 17.

Figure 27 is a particle size micrograph (400x) of preparation 18.

Figure 28 is a particle size micrograph (400x) of formulation 19.

Figure 29 shows a comparison of the retention levels of benvitide in formulations 17 and 18 during in vitro transdermal experiments.

Figure 30 shows a comparison of the retention levels of betamethasone propionate in formulations 17 and 18 during in vitro skin penetration experiments.

Figure 31 shows a comparison of the retention levels of benvitimide in formulations 19 and 20 during in vitro transdermal experiments.

Figure 32 shows a comparison of the retention levels of betamethasone propionate in formulations 19 and 20 during in vitro skin penetration experiments.

Figure 33 shows a comparative particle size micrograph (400x magnification).

The following embodiments are used to further describe this case, but these embodiments are not intended to limit the scope of this case. The creams prepared in the following embodiments are all prepared according to the preparation method described above. Unless specific experimental conditions are specified, they are generally carried out under conventional conditions.

Example 1: Determination of the Initial Formulation

By comparing the formulations (Table 1) disclosed in the instruction manuals of commercially available single-component products, Benvitamin Propionate Cream and Betamethasone Dipropionate Cream, both are common creams, each composed of an aqueous phase, an oil phase, an emulsifier, a solvent, and a preservative, respectively. The excipients are similar in function, both using propylene glycol as a solvent, and their oil phase bases are similar, both containing white petrolatum and liquid paraffin, etc. The aqueous phase in both is purified water; the only difference lies in the type of emulsifier.

Based on Table 1, the preliminary formulation composition is shown in Tables 2 and 3, and formulations 1, 2, 3, 4, 5, and 6 were prepared.

During the preparation of formulations 1 to 3, it was found that 5% propylene glycol could effectively dissolve the two active ingredients. Therefore, the amount of propylene glycol was adjusted to 5%, and the content of the two active ingredients was also adjusted. The emulsifier was appropriately adjusted to produce formulations 4, 5, and 6.

Example 2: Physicochemical Property Study of Formulations 1 to 7

Microscopic observation of the particle size of the six creams prepared in Example 1 revealed that the droplet size of all six batches of creams was relatively large and uneven. Furthermore, the finished creams had a creamy appearance and a grayish color. Additionally, all six batches of creams exhibited oil-water separation during the preparation process. See Figures 1 to 6 for relevant micrographs (400x magnification).

Example 3: Formulation Optimization

Based on the particle size results of formulations 1 through 6, further formulation optimization will be considered. This will be achieved by adjusting the oil phase matrix and simultaneously adjusting the appropriate emulsifier. Specific adjustments are shown in Table 4.

After numerous analyses and combinations of various formulations, it was found that when the cream formulation did not contain white petrolatum and glyceryl mono- and distearate (Formula 10), the homogenized droplet size was uniform, with all droplets smaller than 10 micrometers (Figure 7). However, after homogenization, Formulations 7, 8, and 9 exhibited uneven droplet size and larger droplet sizes, along with oil-water separation (Figures 8 to 10). Therefore, Formulation 10 was selected as the optimal formulation for further investigation.

Example 4: Emulsifier Study

Based on the formulation of Formulation 10, the effect of different emulsifiers on the droplet size of the cream was investigated. The emulsifiers examined included Tween 60 and Span 60, polyoxyethylene (54) hydrogenated castor oil, polyethylene glycol-7 stearate and oleoyl polyoxyethylene glycerol ester, and Westminster 1000. This study further selected the optimal emulsifier. Formulations examined with different emulsifiers are shown in Table 5.

Verification showed that formulations 11 to 13 prepared according to the above formulas exhibited mostly uneven droplet size distribution, with some exceeding 10 micrometers and the majority around 6 micrometers, as can be seen in Figures 11 to 13. Formulation 10 remained the formula with the best emulsifying effect, as shown in Figure 14.

Example 5: Study on the Proportion of Emulsifiers

After determining that Formulation 10 was the optimal formulation, the applicant planned to study the effect of adjusting the ratio of Tween 60 to Span 60 on the physicochemical properties of the formulation. The resulting formulation and ratio are shown in Table 6 below.

Experience showed that after homogenization, the droplet size of formulations 10-1, 10-2, 10-3, and 10-4 all increased, and the emulsions rapidly separated into oil and water after homogenization, producing large droplets larger than 10 micrometers. Increased homogenization time or speed did not significantly improve droplet size or uniformity (see Figures 15-18). In contrast, formulation 10 produced uniform droplet size, below 5 micrometers (see Figure 19). Therefore, the emulsifier formulation and ratio are: Tween 60, 2%; and Wheatstone 60, 0.75%.

Implementation Example 6: Stability Study

The stability of the cream obtained from Formulation 10 was studied. By comparing the results after 0 days of storage, 1 month at 30℃, and 3 months at 40℃, it was found that no active pharmaceutical ingredient (API) precipitated in the cream, and the pH value and droplet size remained stable (particle size comparison is shown in Figures 20 to 22). Furthermore, there was no significant difference in impurity content during the stabilization process.

Example 7: Skin Penetration Experiment

Based on formulation 10, multiple samples were prepared, namely formulations 14, 15, and 16. The only difference between the three formulations is the content of benvitimide and betamethasone propionate.

The in vitro percutaneous transdermal assay procedure is as follows: Preparations 14, 15, and 16 are used for in vitro percutaneous transdermal assays to assess intradermal retention and permeability. Pigskin (0.8–1.0 mm thick) is mounted on a LOGAN System 918 vertical diffusion cell, exposing a surface area of 1.77 ^cm² . The diffusion cell is connected to a multichannel pump at 600 rpm, using PBS (phosphate buffer) at pH 7.4 as the receiving medium. Each cell is placed in a heating manifold to equilibrate the temperature, ensuring the skin surface temperature is 32°C (at least 30 minutes before administration). The sample is added at a dose of 10 mg per square centimeter. The transdermal mediator was collected at 4, 8, 12, 16, 20, and 24 hours to measure the active ingredient that penetrated the skin. After 24 hours of sampling, the skin was wiped with a cotton swab to remove any residue considered non-transdermal. The skin layer was minced and subjected to ultrasonic extraction with methanol. The concentrations of benvitimod and betamethasone propionate were determined by high-performance liquid chromatography (HPLC). The recovered drug concentrations were used to calculate the skin retention of benvitimod and betamethasone propionate. The transdermal test results for benvitimod are shown in Table 7, and the retention comparison is shown in Figure 23; the transdermal test results for betamethasone propionate are shown in Table 8, and the retention comparison is shown in Figure 24.

Table 7 shows that the retention of betamethasone propionate in formulations 14, 15, and 16 is higher than that of betamethasone propionate cream alone; while Table 8 shows that the retention of betamethasone propionate in the above three formulations is lower than that of betamethasone propionate alone. Therefore, further optimization of the formulation is needed to improve the retention of betamethasone propionate.

Example 8: Solvent and/or Penetrating Agent Study

To improve the retention of betamethasone propionate, the types and amounts of different solvents and/or penetration enhancers were investigated, as shown in the table below for the components and proportions of formulations 17, 18, 19, and 20.

Experience showed that Formulation 20 had a predominantly large (see Figure 25) and non-uniform droplet size, exhibiting oil-water separation. Formulations 17 to 19 had smaller and more uniform droplet sizes, mostly distributed between 1 and 5 μm, with some around 8 μm (see Figures 26 to 28).

The transdermal assay results of the benvitimide component in formulations 17 and 18 are shown in Table 10, and the comparison of retention amounts is shown in Figure 29; the transdermal assay results of the betamethasone propionate component in formulations 17 and 18 are shown in Table 11, and the comparison of their retention amounts is shown in Figure 30.

The results of transdermal testing of the benvitamin A component in formulations 19 and 20 are shown in Table 12, and the comparison of retention amounts is shown in Figure 31; the results of transdermal testing of the betamethasone propionate component in formulations 19 and 20 are shown in Table 13, and the comparison of their retention amounts is shown in Figure 32.

Table 13:

Based on the above analysis, it can be concluded that: 1) In the sample with propylene glycol content increased to 15% (Formulation 17), the retention of benvitimod in the in vitro transdermal test was close to that of benvitimod cream; however, the retention of betamethasone propionate was lower than that of betamethasone propionate cream; 2) In the sample with propylene glycol content of 5% and diethylene glycol monoethyl ether content of 5% (Formulation 18), the retention of benvitimod in the in vitro transdermal test was close to that of benvitimod cream; however, the retention of betamethasone propionate was lower than that of betamethasone propionate cream; 3) Diethylene glycol... In the in vitro transdermal test, the retention of benvitimod as a penetration promoter and the amount of diethylene glycol monoethyl ether used was 10% (Formulation 19) was similar to that of benvitimod cream; the retention of betamethasone propionate was similar to that of betamethasone propionate cream. In the in vitro transdermal test, the retention of benvitimod as a penetration promoter and the amount of diethylene glycol monoethyl ether used was 15% (Formulation 20) was similar to that of benvitimod cream; the retention of betamethasone propionate was similar to that of betamethasone propionate cream.

However, the droplet size of Formulation 20 is uneven; therefore, diethylene glycol monoethyl ether at a concentration of 10% is a more ideal solvent and/or penetration promoter.

Comparative Example 10: Preparation of the formulation according to the prescription in Table 14

The preparation steps are as follows: Oil phase: Weigh the prescribed amount of propylene glycol, place it in a water bath and heat to 60°C. Add betamethasone dipropionate, BHA, and menthol, stirring until dissolved. Add glyceryl monostearate and cetearyl alcohol, stirring until melted. Keep warm for 20 minutes.

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

Stirring: Maintain a temperature of 60°C, add the aqueous phase to the oil phase, stir for 1 minute, then stir for 1 minute at room temperature, and allow the product to stand until it reaches room temperature.

Results: The cream thickened after stirring for one minute at room temperature. After stopping stirring and allowing it to stand at room temperature, microscopic observation revealed uneven distribution of droplet size, with the smallest droplets around 5 micrometers and the largest exceeding 10 micrometers. Polarized light microscopy revealed needle-like and cluster-like crystal precipitates, as shown in Figure 33.

The foregoing description discloses preferred embodiments of this invention. These embodiments are merely illustrative and not intended to limit the scope of the invention in any way. Within the spirit of this invention, any modifications and improvements made to the specifically disclosed embodiments by those skilled in the art to which this invention pertains shall be covered by the scope of protection defined in this patent application. Those skilled in the art to which this invention pertains may utilize this invention to the fullest extent possible using the foregoing description.

Claims (13)

A topical pharmaceutical composition, characterized in that, by weight percentage of the total topical pharmaceutical composition, the topical pharmaceutical composition comprises: benvitimide or a pharmaceutically acceptable salt thereof, in a content of 0.5% to 1.25% by weight; a corticosteroid selected from one or more of betamethasone, betamethasone propionate, betamethasone dipropionate, betamethasone acetate, and betamethasone valerate, and the content of said corticosteroid is 0.01% to 0.25% by weight; and an oil phase matrix selected from one or more of stearic acid, paraffin, isopropyl myristate, beeswax, medium-chain triglycerides, higher alcohols, and lanolin, and the total content of said oil phase matrix is... The content of the topical drug composition is 10% to 25%; Tween-60 and Span-60, wherein the content of Tween-60 is 1.75% to 2% by weight and the content of Span-60 is 0.25% to 0.75% by weight; a solvent and a penetration promoter, which are propylene glycol and/or diethylene glycol monoethyl ether, wherein when propylene glycol is included, the content is 5% to 15% by weight and when diethylene glycol monoethyl ether is included, the content is 5% to 10% by weight, and the total content of the solvent and penetration promoter is 5% to 20% by weight; and a pH adjuster, in appropriate amounts, wherein the pH of the topical drug composition is 3-7; the topical drug composition does not contain petrolatum and glyceryl monostearate and glyceryl distearate. The topical pharmaceutical composition as described in claim 1 is characterized in that the topical pharmaceutical composition is a cream, and the topical pharmaceutical composition comprises: benvitimide, in a content of 0.75% to 1% by weight; betamethasone propionate, in a content of 0.05% to 0.075% by weight; an oil phase matrix, which is cetearyl alcohol, isopropyl myristate and medium-chain triglycerides, and the total content of the oil phase matrix is 10% to 20% by weight; and the pH value of the cream is 4-6. The topical drug composition as described in claim 2 is characterized in that the solvent and the penetration promoter are diethylene glycol monoethyl ether, and the content of diethylene glycol monoethyl ether is 5% to 10% by weight. The topical drug composition as described in claim 2 is characterized in that the solvent and the penetration enhancer are propylene glycol, and the content of propylene glycol is 5% to 15% by weight. The topical pharmaceutical composition as described in claim 2 is characterized in that it comprises: benvitimide in an amount of 1% by weight; betamethasone propionate in an amount of 0.064% by weight; an oil phase matrix consisting of cetearyl alcohol, isopropyl myristate and medium-chain triglycerides, wherein the total amount of the oil phase matrix is 15% by weight; and a pH adjuster, in an appropriate amount, wherein the pH of the cream is 4.5-5.5. The topical drug composition as described in claim 5 is characterized in that the solvent and the penetration enhancer are diethylene glycol monoethyl ether, and their total content is 10% by weight. The topical drug composition as described in claim 5 is characterized in that the solvent and the penetration enhancer are propylene glycol, and the content of propylene glycol is 5% to 15% by weight. The topical drug composition as described in any one of claims 1 to 7 is characterized in that the topical drug composition is an oil-in-water cream. The topical drug composition as described in any one of claims 1 to 7 is characterized in that the topical drug composition further comprises: a stabilizer 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, wherein the stabilizer is present in an amount of 0.01% to 2% by weight; and an antioxidant selected from dibutylhydroxytoluene (BHT) and disodium ethylenediaminetetraacetic acid (EDTA). The antioxidant is selected from one or more of the following: A-2Na, butyl hydroxyanisole (BHA), vitamin E, vitamin E acetate, and vitamin E niacinate, wherein the total content of the antioxidant is 0.01% to 1%; and a preservative selected from one or more of the following: benzoxamethylene chloride, polyhexamethylene hydrochloride (PHMB), sorbic acid, ethyl hydroxyphenyl ester, methyl hydroxyphenyl ester, propyl hydroxyphenyl ester, methyl salicylate, benzyl alcohol, and phenoxyethanol, wherein the total content of the preservative is 0.01% to 1%. The topical drug composition as described in any one of claims 1 to 7 is characterized in that the pH adjuster is a buffer selected from one or more of citrate/citric acid, acetate/acetic acid, phosphate/phosphate, citrate/citric acid, propionate/propionic acid, lactate/lactic acid, and ammonium salt/ammonia. The topical drug composition as described in claim 10 is characterized in that the pH adjuster is present in an amount of 0.01% to 5% by weight; and the remainder is an aqueous phase. A method for preparing a topical drug composition as described in any one of claims 1 to 11, characterized by comprising the following steps: 1) Preparing the oil phase: adding an oil phase matrix, 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 matrix, solvent and/or penetration promoter, surfactant, and optionally the preservative and antioxidant; then adding the active ingredient, stirring and dissolving, and keeping warm for later use; 2) Preparing the aqueous phase: adding a pH adjuster, stabilizer, and optionally preservative and antioxidant to purified water, heating to 65-80 °C. 3) Emulsification: Add the oil phase to the aqueous phase or the aqueous phase to the oil phase, maintain the temperature at 65-80 ℃, start stirring, and after stirring evenly, start homogenization. After homogenization is completed, transfer the resulting homogenate to a storage container for cooling to obtain the local drug composition. Use of a topical pharmaceutical composition as described in any one of claims 1 to 11 in the preparation of a medicament for treating and/or preventing a skin disease or disorder selected from psoriasis, atopic dermatitis, acne, and pruritus.