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WO2024125500A1 - Composition pharmaceutique topique et son utilisation en médecine - Google Patents

Composition pharmaceutique topique et son utilisation en médecine Download PDF

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Publication number
WO2024125500A1
WO2024125500A1 PCT/CN2023/138109 CN2023138109W WO2024125500A1 WO 2024125500 A1 WO2024125500 A1 WO 2024125500A1 CN 2023138109 W CN2023138109 W CN 2023138109W WO 2024125500 A1 WO2024125500 A1 WO 2024125500A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
topical pharmaceutical
weight
cream
present disclosure
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/138109
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English (en)
Chinese (zh)
Inventor
马志龙
于林芳
唐梦洁
缪鹏飞
孙焕亮
秦金洁
陈明
贾剑敏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Thederma Shanghai Co Ltd
Original Assignee
Thederma Shanghai Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Publication of WO2024125500A1 publication Critical patent/WO2024125500A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present disclosure belongs to the field of medicine and relates to a topical pharmaceutical composition and/or a cream and its application in medicine, in particular, its use in the preparation of a medicament for treating and/or preventing skin diseases or disorders, wherein the skin diseases or disorders include but are not limited to psoriasis, atopic dermatitis, acne and pruritus; the active ingredient (API) of the topical composition and/or cream includes benvimod or a pharmaceutically acceptable salt thereof and one or more corticosteroids.
  • the skin diseases or disorders include but are not limited to psoriasis, atopic dermatitis, acne and pruritus
  • the active ingredient (API) of the topical composition and/or cream includes 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 a large number 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).
  • the World Health Organization listed autoimmune diseases as the third largest killer threatening human health after cardiovascular disease and cancer.
  • autoimmune diseases were also listed as one of the ten major diseases in my country's medium- and long-term science and technology development program (Pan Haifeng et al., Chinese Journal of Disease Control and Prevention, 2018, 22(11): 1093-1095, 1105).
  • autoimmune diseases The spectrum of autoimmune diseases is widely distributed, with 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 and Prevention, 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 and swollen skin lesions and bumps covered with silvery-white scales.
  • the inflamed, thickened and scaly lesions are prone to itching, burning, stinging and bleeding.
  • psoriasis affects approximately 125 million people worldwide, greatly reducing the quality of life of patients.
  • Atopic dermatitis is a common chronic, recurrent, inflammatory skin disease that is usually characterized by overgrowth of Staphylococcus aureus, which then triggers proteolytic destruction of the epidermal barrier and immune dysregulation.
  • the disease is reported to be the skin disease with the highest non-fatal disease burden (Chinese Society of Dermatology and Venereology, Psoriasis Committee, Chinese Journal of Dermatology, 2019, 52(10), 667-710).
  • Benvimod Cream is the world's first national Class 1 new drug with complete independent intellectual property rights. It is a major scientific and technological project achievement of my country's "Major New Drug Creation”. It was approved for marketing in my country in May 2019 for the topical treatment of mild to moderate psoriasis vulgaris in adults.
  • WO1995003695A1 (Agro-Biotech Corporation) discloses the antifungal 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 matrix.
  • WO2016/185428 (GlaxoSmithKline Inc.) provides a method for preparing a topical pharmaceutical emulsion composition involving the compound.
  • the immunosuppressive effects of corticosteroids are known to be critical for suppressing the proinflammatory environment and T cell activation; Benvimod can inhibit potential 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.
  • the present invention provides a new type of local pharmaceutical 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.
  • the purpose of the present disclosure is to provide a topical pharmaceutical composition, the active ingredients of which are benvimod or a pharmaceutically acceptable salt thereof and one or more corticosteroids. It is a combination medication, and it has been proven that it solves certain 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.
  • topical pharmaceutical composition characterized in that, based on the total weight percentage of the topical pharmaceutical composition, the topical pharmaceutical composition comprises:
  • Benvimod or a pharmaceutically acceptable salt thereof in an amount of 0.5% to 2% by weight;
  • one or more corticosteroids present in an amount of 0.01% to 2% by weight each;
  • a pharmaceutically acceptable excipient suitable for topical use wherein the excipient does not contain petrolatum and glyceryl mono- and distearate.
  • the content of benvimod or its pharmaceutically acceptable salt is calculated by weight based on the total weight percentage of the topical pharmaceutical composition. It is calculated to be 0.5% to 1.75%, preferably 0.5% to 1.5%, more preferably 0.75% to 1.25%; specifically, the content of benvimod or its pharmaceutically acceptable salt can be 0.5%, 0.75%, 1%, 1.25% and 1.5%.
  • the topical pharmaceutical composition of the present disclosure based on the total weight percentage of the topical pharmaceutical composition, 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%, further preferably 0.01% to 0.75%, further preferably 0.01% to 0.5%, 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%.
  • 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, desoximetasone or its derivatives, diflorasone or its derivatives, fluocinolone or its derivatives, fluticasone or its derivatives, halcinonide or its derivatives, ubetasol or its derivatives, hydrocortisone or its derivatives, mometasone or its derivatives, prednicarbate or its derivatives, triamcinolone acetonide or its derivatives, flurandrenolide or its derivatives, dexamethasone or its derivatives, and methylprednisolone or its derivatives;
  • the corticosteroid is selected from one or more of betamethasone or its derivatives, clocortolone or its derivatives, desoximetasone 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, flurandrenolide or its derivatives;
  • the corticosteroid is selected from one or more of betamethasone or its derivatives, clocortolone or its derivatives, desoximetasone 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;
  • the corticosteroid is selected from one or more of betamethasone or its derivatives
  • the corticosteroid is selected from one or more of betamethasone, betamethasone propionate, betamethasone dipropionate, betamethasone acetate and betamethasone valerate;
  • the corticosteroid is betamethasone or betamethasone propionate.
  • the corticosteroid is preferably a glucocorticoid drug
  • the glucocorticoid drugs are divided into three categories according to the duration of action: short-acting (such as cortisone, hydrocortisone, etc.), medium-acting (prednisone, methylprednisolone, etc.) and long-acting (dexamethasone, betamethasone, etc.).
  • the topical pharmaceutical composition described in the present disclosure is a cream, preferably an oil-in-water cream.
  • the topical pharmaceutical composition comprises; a solvent and/or a penetration enhancer, the total content of which is 5% to 30% by weight.
  • the topical pharmaceutical composition comprises; a surfactant, the total content of which is 0.1% to 10% by weight; and the surfactant does not comprise glyceryl mono- and distearate.
  • 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.
  • the surfactant is selected from one or more of emulsifying wax, stearyl alcohol polyethers, polysorbates, cetumago 1000, sorbitan fatty acid esters and polyethylene glycol cetearyl ether, preferably at least two of emulsifying wax, stearyl alcohol polyethers, polysorbates, cetumago 1000, 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 cetumago 1000, most preferably two of Tween-80, Tween-60, Span-60 and cetumago 1000.
  • the surfactant comprises Tween-60 and Span-60, wherein:
  • Tween-60 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% by weight.
  • the topical pharmaceutical composition comprises a solvent and/or a penetration enhancer, wherein 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, more preferably diethylene glycol monoethyl ether; and/or
  • the topical pharmaceutical composition comprises a pH adjuster, which is a buffer, 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
  • a pH adjuster which is a buffer, 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 pharmaceutical 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 pharmaceutical composition further comprises a preservative in a total amount of 0.005% to 2% by weight; and/or
  • the topical pharmaceutical composition further comprises an antioxidant in a total content of 0.005% to 2% by weight.
  • the present disclosure relates to a cream, characterized in that, in terms of the total weight percentage of the cream, the cream comprises:
  • Benvimod or a pharmaceutically acceptable salt thereof in an amount of 0.5% to 2% by weight;
  • one or more corticosteroids in an amount of 0.01% to 2% by weight
  • An oil phase base the total content of which is 5% to 30% by weight; and the oil phase base does not contain vaseline;
  • Surfactant emulsifier
  • Solvent and/or penetration enhancer the total content of which is 5% to 30% by weight;
  • pH adjuster in an appropriate amount, wherein the pH is 3-7;
  • the rest is water phase.
  • the content of benvimod or a pharmaceutically acceptable salt thereof in the cream described in the present disclosure 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 benvimod or a pharmaceutically acceptable salt thereof may be 0.5%, 0.75%, 1%, 1.25% and 1.5%.
  • the cream of the present disclosure 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%, further preferably 0.01% to 0.75%, further preferably 0.01% to 0.5%, further preferably 0.01% to 0.25%, further preferably 0.01% to 0.2%, 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%.
  • 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, desoximetasone or its derivatives, diflorasone or its derivatives, fluocinolone or its derivatives, fluticasone or its derivatives, halcinonide or its derivatives, ubetasol or its derivatives, hydrocortisone or its derivatives, mometasone or its derivatives, prednicarbate or its derivatives, triamcinolone acetonide or its derivatives, flurandrenolide or its derivatives, dexamethasone or its derivatives and methylprednisolone or its derivatives;
  • the corticosteroid is selected from one or more of betamethasone or its derivatives, clocortolone or its derivatives, desoximetasone 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, flurandrenolide or its derivatives;
  • the corticosteroid is selected from one or more of betamethasone or its derivatives, clocortolone or its derivatives, desoximetasone 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;
  • the corticosteroid is selected from one or more of betamethasone or its derivatives
  • the corticosteroid is selected from one or more of betamethasone propionate, betamethasone dipropionate, betamethasone acetate and betamethasone valerate;
  • the corticosteroid is selected from one of betamethasone propionate, betamethasone dipropionate, betamethasone acetate and betamethasone valerate;
  • the corticosteroid is betamethasone or betamethasone propionate.
  • the corticosteroid in the cream of the present disclosure is preferably a glucocorticoid drug, and the glucocorticoid drug is divided into short-acting (such as cortisone, There are three types of drugs: hydrocortisone, intermediate-acting (prednisone, methylprednisolone, etc.) and long-acting (dexamethasone, betamethasone, etc.).
  • the total content of the oil phase matrix in the cream of the present disclosure is 5% to 30%, preferably 5% to 25%, more preferably 5% to 20%, and most preferably 10% to 20%.
  • the oil phase matrix of the cream described in the present disclosure is selected from one or more of stearic acid, paraffin, isopropyl myristate, beeswax, medium chain triglycerides, higher alcohols and lanolin, preferably selected from one or more of stearic acid, isopropyl myristate, medium chain triglycerides, hexadecanol, stearyl alcohol and cetostearyl alcohol.
  • the oil phase matrix of the cream described in the present disclosure 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 matrix is 5% to 25%, and the content is preferably 5% to 20%, more preferably 5% to 15%, and most preferably 5% to 10%.
  • the oil phase base does not contain petrolatum (preferably does not contain white petrolatum).
  • the surfactant in the cream of the present disclosure is selected from one or more of emulsifying wax, stearyl alcohol polyethers, polysorbates, cetumago 1000, sorbitan fatty acid esters and polyethylene glycol cetearyl ether, preferably selected from at least two of emulsifying wax, stearyl alcohol polyethers, polysorbates, cetumago 1000, 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, most preferably selected from two of Tween-80, Tween-60, Span-60 and cetumago 1000.
  • the surfactant does not contain glyceryl mono- and distearate.
  • the total content of the surfactant in the cream of the present disclosure 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%; specifically, the total content of the surfactant may be 0.1%, 0.25%, 0.5%, 0.75%, 1%, 1.5%, 2%, 3%, 4%, 5% and 6%.
  • the surfactant in the cream of the present disclosure, 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 the content thereof 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 the content thereof is 2.5% to 4.5% by weight. 0.25% to 1.5%, preferably 0.75%.
  • 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%.
  • one of the surfactants is Tween-60, and its content is greater than 1.5% by weight.
  • the solvent and/or penetration enhancer 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, most preferably diethylene glycol monoethyl ether.
  • the total content of the solvent and/or penetration enhancer in the cream of the present disclosure is 5% to 30% by weight, preferably 5% to 25%, more preferably 5% to 20%, further preferably 10% to 20%, and most preferably 10% to 15%; specifically, the content of the surfactant may be 5%, 10%, 15%, 20%, 25% and 30%.
  • the solvent and/or penetration enhancer 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 enhancer is 5% to 25% by weight; preferably, the solvent and/or penetration enhancer is propylene glycol and/or diethylene glycol monoethyl ether, and the content of each of the solvent and/or penetration enhancer is 10% to 25% by weight; most preferably, the solvent and/or penetration enhancer is diethylene glycol monoethyl ether, and its content is 10% to 20% by weight.
  • the pH adjuster in the cream of the present disclosure is a buffer
  • 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 salt/ammonia, preferably citrate/citric acid.
  • the content of the pH regulator in the cream of the present disclosure 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.
  • the content of the pH adjuster is 0.01% to 5% by weight, preferably 0.1% to 3%, more preferably 0.1% to 2%, further preferably 0.1% to 1%, and most preferably 0.1% to 0.5%.
  • 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%.
  • the cream of the present disclosure further comprises a stable
  • the content of the agent is 0.005% to 2% by weight, preferably 0.01% to 2%, more preferably 0.05% to 2%, further preferably 0.075% to 1.5%, and most preferably 0.1% to 1%.
  • the stabilizer in the cream of the present disclosure 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.
  • the stabilizer in the cream described in the present disclosure, 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.
  • EDTA ethylenediaminetetraacetic acid
  • EDTA ethylenediaminetetraacetic acid
  • the cream described in the present disclosure further comprises a preservative.
  • preservatives such as one or more of benzalkonium chloride, polyhexamethylene hydrochloride (PHMB), sorbic acid, ethylparaben, methylparaben, propylparaben, methyl salicylate, benzyl alcohol and phenoxyethanol may be used.
  • PHMB polyhexamethylene hydrochloride
  • sorbic acid ethylparaben, methylparaben, propylparaben, methyl salicylate, benzyl alcohol and phenoxyethanol
  • the total content of the preservative in the cream of the present disclosure 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%.
  • the cream described in the present disclosure further comprises an antioxidant.
  • antioxidants 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 can be used.
  • the total content of the antioxidant in the cream of the present disclosure 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%.
  • the particle size of the cream described in the present disclosure is less than 10 ⁇ m, preferably 1-5 ⁇ m, and more preferably 1-3 ⁇ m.
  • the cream of the present disclosure based on the total weight percentage of the cream, the content of benvimod or a pharmaceutically acceptable salt thereof is 0.5% to 1.5%; the content of the corticosteroid (preferably betamethasone or a derivative thereof) is 0.01% to 0.25%; the oil phase matrix does not contain vaseline (preferably does not contain white vaseline); the surfactant does not contain mono- and distearic acid glyceryl and is selected from at least two of steareth-2, steareth-20, Tween-80, Tween-60, Span-60 and Situmago 1000, and the total content of the surfactant is 0.5% to 6%; the solvent and/or penetration enhancer is selected from one or more of propylene glycol, diethylene glycol monoethyl ether and PEG400, and the total content thereof is 5% by weight.
  • the content of benvimod or a pharmaceutically acceptable salt thereof is 0.5% to 1.5%
  • the content of the corticosteroid preferably betamethasone or a
  • the pH adjuster is citrate/citric acid or citrate/citric acid, and its content is 0.01% to 5%
  • the stabilizer is ethylenediaminetetraacetic acid (EDTA) and its salts, and its content is 0.01% to 2% by weight
  • the total content of the preservative preferably methylparaben or ethylparaben
  • the total content of the antioxidant preferably BHT
  • Another aspect of the present disclosure relates to a method for preparing the cream as described above, the method comprising the following steps:
  • Oil phase Add the oil phase matrix, solvent and/or penetration enhancer, surfactant and optional preservative and antioxidant ingredients into 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 and dissolve, and keep warm for later use;
  • Emulsification adding the oil phase to the water phase or the water phase to the oil phase, maintaining the temperature at 65-80° C., starting stirring, stirring evenly and then starting homogenization, after homogenization, transferring all substances to a storage container for cooling to obtain the cream.
  • the present disclosure 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 the group consisting of psoriasis, atopic dermatitis, acne and pruritus.
  • the present disclosure 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 disclosure also relates to a method for treating and/or preventing a skin disease or disorder selected from psoriasis, atopic dermatitis, acne and pruritus, comprising administering to a patient in need thereof a therapeutically effective amount of a topical pharmaceutical composition or cream as described above.
  • the present disclosure also relates to a method for treating and/or preventing psoriasis, which comprises administering to a patient in need thereof a therapeutically effective amount of the topical pharmaceutical composition or cream as described above.
  • the present disclosure also relates to a topical pharmaceutical composition or cream as described above for use as a medicament, such as a topical medicament.
  • the present disclosure 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 the group consisting of psoriasis, atopic dermatitis, acne and pruritus.
  • the present disclosure 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.
  • the skin disease or disorder of the present disclosure is psoriasis.
  • 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 skilled in the art based on routine experiments.
  • patient refers to a patient in need of prevention or treatment of a skin disease or disorder, wherein the patient is a mammal, for example selected from rodents, cows, pigs, dogs, cats and primates, particularly humans.
  • the content of a certain type of excipients refers to the total content. If the excipient of this type 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.
  • the topical pharmaceutical composition or cream provided in the present application has a synergistic effect on the efficacy of the disease during the application to individuals with psoriasis, atopic dermatitis or other immune, inflammatory and autoimmune diseases, which is higher than the efficacy of each single active ingredient drug, and is conducive to reducing the side effects of corticosteroids and improving the individual's compliance with use.
  • the details are as follows:
  • 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.
  • the topical pharmaceutical composition or cream disclosed herein preferably a compound preparation of benvimod-betamethasone propionate
  • Corticosteroids preferably betamethasone dipropionate
  • Corticosteroids have powerful anti-inflammatory, anti-allergic and immunosuppressive effects, which can inhibit local inflammation of psoriasis lesions and restore the normal structure and function of skin tissue, thereby achieving the purpose of treating psoriasis;
  • Benvimod can activate AhR, promote normal differentiation of skin cells, and inhibit abnormal keratinocytes Keratinization; It has a regulatory effect on Th1, Th2, Th17 and T-reg cells; It can also upregulate the expression of skin barrier proteins such as filaggrin, promote the repair of damaged skin and the integrity of skin barrier function, and regulate the expression of antioxidant proteins in skin cells through Nrf2, thereby alleviating oxidative stress and restoring skin homeostasis;
  • the topical pharmaceutical composition or cream disclosed herein preferably a benavidin-betamethasone propionate combination preparation
  • the topical pharmaceutical composition or cream disclosed herein 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 keratinocyte activation and its abnormal proliferation and differentiation, helping to resolve inflammation and maintain a continuous homeostasis of keratinocytes.
  • Corticosteroids preferably betamethasone dipropionate
  • Benvimod can inhibit the proliferation of CD4+T cells, increase the level of the immunomodulatory factor IL-10, and improve the body's immune tolerance.
  • topical pharmaceutical composition or cream disclosed herein preferably the bevimod-betamethasone dipropionate combination preparation
  • the topical pharmaceutical composition or cream disclosed herein is expected to act synergistically and enhance the anti-inflammatory effect.
  • 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.
  • 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, and does not have the same or similar target organ toxicity or adverse reactions. The combination of the two will not lead to the superposition of toxicity and cause obvious toxicological concerns.
  • the present disclosure utilizes the rapid response of corticosteroids to treat lesions, as well as the long remission period of benvimod, which greatly improves patients' acceptance of treatment, can provide patients with good convenience, and help promote patients to adapt 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 pharmaceutical composition or cream disclosed herein preferably a benvimod-betamethasone propionate compound preparation
  • the formula disclosed in this disclosure is very different from the formula of the listed single-ingredient products benvimod cream and betamethasone propionate cream, including the uniqueness of the ratio of each auxiliary material, which breaks through the conventional technical thinking.
  • the composition and/or cream has a very excellent transdermal effect.
  • Figure 1 is a micrograph of the particle size of Formulation 1 (400 times);
  • Figure 2 is a micrograph of the particle size of Formulation 2 (400 times);
  • Figure 3 is a micrograph of the particle size of Formulation 3 (400 times);
  • FIG4 is a micrograph of the particle size of formulation 4 (400 times).
  • FIG5 is a micrograph of the particle size of Formulation 5 (400 times).
  • FIG6 is a micrograph of the particle size of Formulation 6 (400 times).
  • FIG7 is a micrograph of the particle size of formulation 10 (400 times).
  • FIG8 is a micrograph of the particle size of formulation 7 (400 times).
  • FIG9 is a micrograph of the particle size of Formulation 8 (400 times).
  • FIG10 is a micrograph of the particle size of formulation 9 (400 times).
  • FIG11 is a micrograph of the particle size of formulation 11 (400 times).
  • FIG12 is a micrograph of the particle size of formulation 12 (400 times).
  • FIG13 is a micrograph of the particle size of formulation 13 (400 times).
  • FIG14 is a micrograph of the particle size of formulation 10 (400 times).
  • FIG15 is a micrograph of the particle size of formulation 10-1 (400 times);
  • FIG16 is a micrograph of the particle size of formulation 10-2 (400 times).
  • FIG17 is a micrograph of the particle size of formulation 10-3 (400 times).
  • FIG18 is a micrograph of the particle size of formulation 10-4 (400 times).
  • FIG19 is a micrograph of the particle size of formulation 10 (400 times).
  • FIG20 is a micrograph of the particle size of formulation 10 after 0 days of storage (400 times);
  • FIG21 is a micrograph (400 times) of the particle size of formulation 10 after being placed at 30° C. for 1 month;
  • FIG22 is a micrograph (400 times) of the particle size of formulation 10 after being placed at 40° C. for 3 months;
  • FIG23 is a comparison of the retention amounts of the bevimod component in formulations 14, 15, and 16 in an in vitro transdermal experiment
  • FIG24 is a comparison of the retention amounts of betamethasone propionate components in Preparations 14, 15, and 16 in an in vitro transdermal experiment;
  • FIG25 is a micrograph of the particle size of formulation 20 (400 times).
  • FIG26 is a micrograph of the particle size of formulation 17 (400 times).
  • FIG27 is a micrograph of the particle size of formulation 18 (400 times).
  • FIG28 is a micrograph of the particle size of formulation 19 (400 times).
  • FIG29 is a comparison of the retention amounts of the bevimod component in formulations 17 and 18 in an in vitro transdermal experiment
  • FIG30 is a comparison of the retention amounts of betamethasone propionate components in Preparation 17 and Preparation 18 in an in vitro transdermal experiment;
  • FIG31 is a comparison of the retention amounts of the bevimod component in formulations 19 and 20 in an in vitro transdermal experiment
  • FIG32 is a comparison of the retention amounts of betamethasone propionate components in formulations 19 and 20 in an in vitro transdermal experiment;
  • Figure 33 is a micrograph of the particle size of the comparative example (400 times).
  • Benvimod Cream and Betamethasone Propionate Cream are common creams, composed of water phase, oil phase, emulsifier, solvent, and preservative.
  • the functions of the excipients of the two are similar, both choose propylene glycol as the solvent, the oil phase matrix is similar, both contain white vaseline, liquid paraffin, etc., the water phase is purified water, and only the type of emulsifier is slightly different.
  • the preliminary formulation composition is shown in Table 2, and Preparation 1, Preparation 2 and Preparation 3 were prepared.
  • Example 1 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 large and uneven. The finished creams had a frosty appearance and a grayish color. In addition, the above six batches of creams all showed oil-water separation during the preparation process. The relevant micrographs (400 times) are shown in Figures 1 to 6.
  • the emulsifiers investigated included Tween 60 and Span 60, polyoxyethylene (54) hydrogenated castor oil, polyethylene glycol-7 stearate and oleoyl polyoxyethylene glyceride, and cetumago 1000.
  • the optimal emulsifier was further selected through this study.
  • the formulas investigated with different emulsifiers are shown in Table 5.
  • 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.
  • the stability of the cream obtained from Preparation 10 was studied by comparing the stability of the cream after 0 days and after 1 month at 30°C. After being placed at 40°C for 3 months, it was found that the prepared cream had no precipitation of the raw material drug, the pH value and the droplet size were stable (see Figures 20 to 21 for particle size comparison), and there was no obvious difference in the impurity content during the stability process.
  • preparation 14 Based on the formula of preparation 10, multiple specifications of samples were prepared, namely preparation 14, preparation 15 and preparation 16. The only difference between the three preparations was the different contents of betamethasone propionate and betamethasone propionate.
  • Preparations 14, 15, and 16 were subjected to in vitro permeation tests to evaluate intradermal retention and permeability.
  • Porcine skin (thickness 0.8-1.0 mm) was mounted on a LOGAN System 918 vertical diffusion cell, exposing a surface area of 1.77 cm2 .
  • the diffusion cell was connected to a multichannel pump at 600 rpm, and the receptor solution was PBS (phosphate buffered saline) at pH 7.4.
  • PBS phosphate buffered saline
  • Each cell was placed in a heating manifold to equilibrate the temperature, ensuring that the skin surface temperature was 32°C (at least 30 min before administration).
  • the sample was added at a dose of 10 mg of the test sample per square centimeter.
  • the receptor solution was collected at 4, 8, 12, 16, 20, and 24 hours to measure the active ingredients that penetrated the skin. After the 24-hour sampling, the skin was wiped with a cotton swab to remove any residual sample that was considered not to penetrate the skin. The skin layer was cut into pieces and added to methanol for ultrasonic extraction of the drug, and the concentrations of betamethasone propionate and betamethasone propionate were detected by high-performance liquid chromatography. The recovered drug concentrations were used to calculate the skin retention of betamethasone propionate and betamethasone propionate.
  • transdermal test results of the bevimod component are shown in Table 7, and the comparison of the retention amounts is shown in Figure 23; the transdermal test results of the betamethasone propionate component are shown in Table 8, and the comparison of the retention amounts is shown in Figure 24.
  • the retention amounts of betamethasone dipropionate in Preparations 14, 15 and 16 were all higher than that in the single-prescription betamethasone dipropionate cream; and as shown in Table 8, the retention amounts of betamethasone dipropionate in the above three preparations were all lower than that in the single-prescription betamethasone dipropionate cream. Therefore, in order to increase the retention of betamethasone propionate, the formula needs to be further optimized.
  • transdermal test results of the betamethasone dipropionate components of Preparations 17 and 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 components of Preparations 17 and 18 are shown in Table 11, and the comparison of their retention amounts is shown in Figure 30.
  • transdermal test results of the betamethasone dipropionate components of Preparations 19 and 20 are shown in Table 12, and the comparison of retention amounts is shown in Figure 31; the transdermal test results of the betamethasone dipropionate components of Preparations 19 and 20 are shown in Table 13, and the comparison of retention amounts is shown in Figure 32.
  • Oil phase Weigh the prescribed amount of propylene glycol, place it in a water bath and heat it 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 minutes 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, use 0.1 mol HCl and 0.1 mol NaOH to adjust the pH to 6.0-7.0. Keep warm for later use.

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Abstract

L'invention concerne une composition pharmaceutique topique et/ou un onguent et leur utilisation en tant qu'agent thérapeutique, en particulier, leur utilisation dans la préparation d'un médicament pour le traitement et/ou la prévention d'une maladie ou d'un trouble cutané. La maladie ou le trouble cutané comprend, sans s'y limiter, le psoriasis, la dermatite atopique, l'acné et le prurit cutané. Les ingrédients pharmaceutiques actifs (IPA) de la composition topique et/ou de l'onguent comprennent le benvitimod ou un de ses sels pharmaceutiquement acceptables et un ou plusieurs corticostéroïdes.
PCT/CN2023/138109 2022-12-14 2023-12-12 Composition pharmaceutique topique et son utilisation en médecine Ceased WO2024125500A1 (fr)

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US20220054467A1 (en) * 2019-02-25 2022-02-24 Sol-Gel Technologies Ltd. Treatment of psoriasis with topical tapinarof-tazarotene combination compositions
WO2023109906A1 (fr) * 2021-12-16 2023-06-22 上海泽德曼医药科技有限公司 Composition pharmaceutique comprenant du tapinarof et un corticostéroïde
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WO2016198997A1 (fr) * 2015-06-10 2016-12-15 Subramaniam Vanangamudi Sulur Crème médicale préparée en utilisant du valérate de bêtaméthasone et en incorporant un biopolymère et procédé pour la préparer
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