A gel-type pharmaceutical composition, a method for preparing the same, and a medical use thereof

Abstract

The present application discloses a gel type pharmaceutical composition, which comprises chloramphenicol or a pharmaceutically acceptable salt thereof 0.5-5 parts, salicylic acid or a pharmaceutically acceptable salt thereof 0.5-5 parts; a base 0.5-5 parts, the base comprising one or more of carbomer, polycarbophil, poloxamer, xanthan gum, hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose and povidone, a humectant 5-50 parts, the humectant comprising one or more of propylene glycol, glycerol and PEG, a penetration enhancer 5-25 parts, the penetration enhancer comprising one or more of diethylene glycol monoethyl ether, ethanol, menthol, N-methyl pyrrolidone, propylene carbonate and isosorbide dimethyl ether, water 20-100 parts, and the content of ethanol in the composition is less than 20% v / w. The gel type pharmaceutical composition has high stability and excellent effect on skin diseases, especially various types of acne.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a gel-type pharmaceutical composition, its preparation method, and its application in medicine, particularly its use in the preparation of medicaments for the treatment and / or prevention of skin diseases, including but not limited to acne, dermatitis, eczema, and pruritus. Background Technology

[0002] Skin diseases have complex pathogenesis, encompassing thousands of types and numerous causes, many of which remain unknown. Skin diseases are common and prevalent, seriously impacting public health. Currently, there are very few effective and highly specific drugs available, such as for acne and eczema.

[0003] Taking acne as an example, acne is a common chronic inflammatory disease of the pilosebaceous unit, clinically characterized by polymorphic skin lesions such as comedones, papules, pustules, and nodules, primarily on the face. Studies have shown that the occurrence of acne is closely related to factors such as excessive sebum secretion, blockage of the pilosebaceous duct, bacterial infection, and inflammatory response. For instance, excessive sebum production leads to abnormal keratinization of the pilosebaceous duct, causing blockage and hindering sebum excretion. Furthermore, the proliferation of various microorganisms, especially Propionibacterium acnes, in the hair follicle, along with the lipases produced by Propionibacterium acnes which decompose sebum into free fatty acids, simultaneously attracting inflammatory cells and mediators, inducing and exacerbating the inflammatory response, contributes to acne's persistent course, slow healing, and tendency to recur. Severe cases can lead to abscesses and scarring after healing.

[0004] Topical medications for acne treatment include retinoids and antibiotics such as lincomycin, clindamycin, and benzoyl peroxide. However, these treatments can irritate the skin and cause excessive dryness, redness, allergies, and peeling. Furthermore, the widespread use of systemic or topical broad-spectrum antibiotics in acne treatment has led to a significant increase in antibiotic resistance in related bacteria, and cross-resistance exists, reducing the effectiveness of the medications.

[0005] Salicylic acid, also known as o-hydroxybenzoic acid, is a simple phenolic compound mainly found in nature, such as willow bark, white beech leaves, and sweet birch. Due to its various pharmacological activities, including antibacterial, antiseptic, anti-inflammatory, and antirheumatic effects, it is widely used in medicine and other fields. When used on the skin, salicylic acid has whitening and acne-reducing effects. Its mechanism of action is that, without affecting the active epidermal structure, salicylic acid can dissolve the structural components between keratinocytes, causing the stratum corneum to shed and produce a scaly effect, removing excessively thick keratinocytes and promoting skin metabolism. Studies have reported the efficacy of salicylic acid in treating acne. For example, in 2006, the Dermatology Department of Nanjing General Hospital of Nanjing Military Region studied the therapeutic effect of 2% salicylic acid gel on acne. However, salicylic acid is an acid and can irritate the skin. Small amounts of salicylic acid have limited effect, while large amounts cause significant irritation and poor patient compliance. This is why salicylic acid is generally encapsulated in cosmetics to improve its water solubility, enhance its controlled-release properties, and reduce irritation. Another example is the 2009 study by the 260th Hospital affiliated with Bethune Military Medical College, which investigated the therapeutic effect of compound salicylic acid topical solution on acne. The main components of this solution are salicylic acid, chloramphenicol, diphenhydramine, nitrofurantoin, and ethanol. This compound utilizes the different mechanisms of action of salicylic acid, chloramphenicol, and diphenhydramine. However, this method is inconvenient to use and still has several side effects, such as skin peeling and itching.

[0006] In addition, CN114504581A discloses a compound triamcinolone acetonide and salicylic acid topical solution for the treatment of psoriasis. Its main components include salicylic acid, chloramphenicol, and triamcinolone acetonide. Chloramphenicol is a broad-spectrum antibiotic that binds to the 50S subunit protein of bacterial ribosomes, inhibiting protein synthesis and thus exhibiting antibacterial and bactericidal effects. Currently, the NMPA has approved a 5% topical solution for the treatment of acne (pimples, rosacea) caused by chloramphenicol-sensitive bacteria. Triamcinolone acetonide is a moderately potent glucocorticoid with anti-inflammatory, anti-allergic, and vasoconstrictive effects. Triamcinolone acetonide can regulate the synthesis of inflammatory mediators, such as prostaglandins and leukotrienes, by inhibiting phospholipase A2. Currently, the NMPA has approved 0.025%~0.1% triamcinolone acetonide for the treatment of allergic dermatitis, eczema, neurodermatitis, seborrheic dermatitis, and pruritus; the FDA has approved multiple strengths and dosage forms for the treatment of inflammatory skin diseases. Salicylic acid has an exfoliating effect and also has antibacterial and bactericidal effects against fungi and Gram bacteria, and is widely used in the local treatment of various skin diseases.

[0007] However, the CN114504581A solution has the following problems: The liniment is inconvenient to carry and use, leading to poor patient compliance. Furthermore, the Chinese Pharmacopoeia, Part IV, Section 0117, "Liniments," clearly defines liniments as "liquid preparations made from raw materials using ethanol, oil, or suitable solvents, for rubbing on unbroken skin." This indicates that the main solvent in liniments is ethanol, limiting their application to unbroken skin. Since skin diseases such as acne often involve scratching due to itching, patients cannot use liniments for treatment. On the other hand, many excipients disclosed in this patent (CN14504581A) are unsafe, such as azone and dimethyl sulfoxide, making their clinical application difficult.

[0008] A literature review (Hu Jianmei et al., Orthogonal Experiment to Optimize Compound Salicylate-Chloramphenicol Gel Matrix [J]. China Pharmacy, 2008) discloses a compound salicylate-chloramphenicol gel matrix for acne, with the following formula: chloramphenicol 20g, salicylic acid 20g, menthol 10g, glycerin 100g, sodium carboxymethyl cellulose 30g, ethanol 350ml, EDTA 0.1g, and purified water added to 1000g. However, the ethanol content in this gel is as high as 35%. Given that ethanol has a strong irritant effect on the skin, and acne often causes patients to scratch their skin due to itching, a gel with a high ethanol content will cause severe pain to patients, affect medication adherence, and is not conducive to long-term medication use.

[0009] In the existing technology, cream formulations are also a commonly used dosage form. However, they contain a large amount of oily base, which makes them greasy and makes oily skin such as acne more difficult to tolerate, which is not conducive to skin repair and may even aggravate the condition.

[0010] Therefore, improving product effectiveness and compliance, and reducing skin irritation and side effects are urgent technical problems that need to be solved. Summary of the Invention

[0011] In view of this, the purpose of this disclosure is to provide a gel-type pharmaceutical composition that is the first discovery of the applicant. It has been verified to solve a series of problems existing in the current treatment of skin diseases, such as poor effectiveness, frequent recurrence, and poor compliance. It has excellent effects in treating stubborn skin diseases such as acne, dermatitis, eczema, and pruritus, and thus has extremely high clinical significance.

[0012] Furthermore, this disclosure provides a gel-type pharmaceutical composition, characterized in that, by weight parts, the gel-type pharmaceutical composition comprises:

[0013] 0.5-10 parts of chloramphenicol or a pharmaceutically acceptable salt thereof;

[0014] 0.5-10 parts of salicylic acid or its pharmaceutically acceptable salt;

[0015] The matrix consists of 0.1-10 parts, and the matrix includes one or more of the following: carbomer, polycarbofil, poloxamer, xanthan gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and povidone.

[0016] 5-50 parts of a moisturizer, wherein the moisturizer comprises one or more of propylene glycol, glycerin, and PEG;

[0017] 5-25 parts of a penetration enhancer, wherein the penetration enhancer comprises one or more of diethylene glycol monoethyl ether, ethanol, menthol, N-methylpyrrolidone, propylene carbonate, and isosorbide dimethyl ether;

[0018] Add an appropriate amount of water.

[0019] In some embodiments of this disclosure, the gel-type pharmaceutical composition further comprises 0.005-0.5 parts of triamcinolone acetonide or a pharmaceutically acceptable salt thereof;

[0020] In some embodiments of this disclosure, the amount of water used is 5-200 parts or 20-100 parts; specifically, it can be 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts, 100 parts, 105 parts, 110 parts, 115 parts, 120 parts, 125 parts, 130 parts, 135 parts, 140 parts, 145 parts, 150 parts, 155 parts, 160 parts, 165 parts, 170 parts, 175 parts, 180 parts, 185 parts, 190 parts, and 195 parts.

[0021] In some embodiments of this disclosure, the content of chloramphenicol or its pharmaceutically acceptable salt is 0.5-8 parts, preferably 1-5 parts; specifically, the content of chloramphenicol can be 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts and 5 parts.

[0022] In some embodiments of this disclosure, the content of salicylic acid or its pharmaceutically acceptable salt is 0.5-8 parts, preferably 1-5 parts, more preferably 1.5-5 parts, and even more preferably 1.5-4.5 parts; specifically, the content of chloramphenicol can be 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, and 4.5 parts.

[0023] In some embodiments of this disclosure, the content of triamcinolone acetonide or its pharmaceutically acceptable salt is 0.005-0.45 parts, preferably 0.005-0.4 parts, more preferably 0.005-0.3 parts, and even more preferably 0.005-0.2 parts; the pharmaceutically acceptable salt of triamcinolone acetonide is preferably triamcinolone acetate. Specifically, the content of triamcinolone acetate or triamcinolone acetonide can be 0.005 parts, 0.008 parts, 0.01 parts, 0.015 parts, 0.02 parts, 0.05 parts, 0.1 parts, 0.15 parts, and 0.2 parts.

[0024] In some embodiments of this disclosure, the content of the matrix is ​​0.1-8 parts, preferably 0.5-7 parts, more preferably 0.5-6 parts, and even more preferably 1-5 parts; specifically, the content of the matrix can be 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, and 5 parts.

[0025] The gel-type pharmaceutical composition disclosed herein includes, as a matrix, one or more of carbomer, polycarboferrite, poloxamer, xanthan gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and povidone, preferably one or more of carbomer, polycarboferrite, and poloxamer, and more preferably carbomer.

[0026] Preferably, the carbomer described in this disclosure is one or more of carbomer 980, carbomer 974, carbomer 941, carbomer 934 and carbomer 940. Carbomer 980, carbomer 974, carbomer 941, carbomer 934 and carbomer 940 can be used alone or in combination as a gel matrix, and this disclosure is not limited thereto.

[0027] In some embodiments of this disclosure, the content of the moisturizer is 10-50 parts, preferably 10-40 parts, more preferably 10-35 parts, and even more preferably 15-35 parts; specifically, the content of the moisturizer can be 15 parts, 20 parts, 25 parts, and 30 parts; preferably, the moisturizer is propylene glycol.

[0028] In some embodiments of this disclosure, the content of the penetration enhancer is 5-40 parts, preferably 5-35 parts, more preferably 5-30 parts, further preferably 5-25 parts, and even more preferably 5-20 parts; specifically, the content of the penetration enhancer can be 5 parts, 10 parts, 15 parts, 20 parts, and 25 parts; preferably, the penetration enhancer is selected from diethylene glycol monoethyl ether and ethanol.

[0029] In some embodiments of this disclosure, the content of the pH adjuster is 0.1-4 parts, preferably 0.1-3.5 parts, more preferably 0.1-3 parts; specifically, the content of the penetration enhancer can be 0.1 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, and 3 parts; preferably, the pH adjuster is triethanolamine or tromethamine.

[0030] In some embodiments of this disclosure, the water content is 10-90 parts, preferably 20-85 parts, more preferably 25-80 parts; specifically, the penetration enhancer content can be 30 parts, 40 parts, 50 parts, 60 parts, 70 parts and 80 parts; preferably, the water is purified water.

[0031] In some embodiments of this disclosure, the pH value of the gel-type pharmaceutical composition is 2-7, preferably 2-6.5, more preferably 2-6, and even more preferably 2.5-5.5; specifically, the pH value of the gel-type pharmaceutical composition can be 2.5, 3, 3.5, 4, 4.5, 5, and 5.5.

[0032] In some embodiments of this disclosure, the gel-type pharmaceutical compositions described herein further include chelating agents, preservatives, and / or antioxidants.

[0033] In some embodiments of this disclosure, the gel-type pharmaceutical compositions described herein do not include chelating agents, preservatives, and / or antioxidants.

[0034] In some embodiments of this disclosure, the gel-type pharmaceutical composition may or may not contain a chelating agent. However, the formulation can be adjusted to enable the gel-type pharmaceutical composition to chelate metal ions without the addition of a chelating agent. If a chelating agent is required, as known in the art, an effective amount of one or more of the following chelating agents can be used: EDTA, EDTA-2Na, citric acid, gluconic acid, sodium gluconate, sodium polyacrylate, polyaspartic acid, GLDA, and EDDS.

[0035] In some embodiments of this disclosure, the content of the preservative is 0.005-1 parts, preferably 0.01-0.5 parts, and more preferably 0.01-0.25 parts; specifically, the content of the preservative can be 0.01 parts, 0.05 parts, 0.1 parts, 0.2 parts, and 0.25 parts.

[0036] In some embodiments of this disclosure, the gel-type pharmaceutical composition may or may not contain preservatives. However, the formulation can be adjusted to achieve a preservative effect without the addition of preservatives. If preservatives are required, as known in the art, effective amounts of one or more of the following preservatives can be used: benzalkonium chloride, poly(ethylene glycol monomethyl) hydrochloride (PHMB), sorbic acid, ethylparaben, methylparaben, propylparaben, methyl salicylate, benzyl alcohol, and phenoxyethanol.

[0037] In some embodiments of this disclosure, the content of the preservative is 0.005-1 parts, preferably 0.01-0.5 parts, and more preferably 0.01-0.25 parts; specifically, the content of the preservative can be 0.01 parts, 0.05 parts, 0.1 parts, 0.2 parts, and 0.25 parts.

[0038] In some embodiments of this disclosure, the gel-type pharmaceutical composition may or may not contain antioxidants. However, the formulation can be adjusted to enable the gel-type pharmaceutical composition to have an antioxidant effect without the addition of antioxidants. If antioxidants are required, as 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 nicotinate can be used.

[0039] In some embodiments of this disclosure, the content of the antioxidant is 0.001-1 parts, preferably 0.01-0.5 parts, and more preferably 0.01-0.1 parts; specifically, the content of the antioxidant can be 0.01 parts, 0.05 parts, and 0.1 parts.

[0040] In some embodiments of this disclosure, the content of chloramphenicol is 0.5-8 parts, the content of salicylic acid is 0.5-8 parts, the content of carbomer is 0.1-4.5 parts, the content of propylene glycol is 10-50 parts, the content of diethylene glycol monoethyl ether is 5-40 parts, and the pH adjuster is triethanolamine, and the pH value of the gel-type pharmaceutical composition is 2-6.

[0041] In some embodiments of this disclosure, the content of chloramphenicol is 0.5-8 parts, the content of salicylic acid is 0.5-8 parts, the content of triamcinolone acetonide or triamcinolone acetonide is 0.005-0.45 parts, the content of carbomer is 0.1-4.5 parts, the content of propylene glycol is 10-50 parts, the content of diethylene glycol monoethyl ether is 5-40 parts, and the pH adjuster is triethanolamine, and the pH value of the gel-type pharmaceutical composition is 2-6.

[0042] In some embodiments of this disclosure, the content of chloramphenicol is 0.5-8 parts, the content of salicylic acid is 0.5-8 parts, the content of the matrix carbomer is 0.1-4.5 parts, the content of propylene glycol is 10-50 parts, the content of diethylene glycol monoethyl ether is 5-40 parts, and the pH adjuster is tromethamine, and the pH value of the gel-type pharmaceutical composition is 2-6.

[0043] In some embodiments of this disclosure, the content of chloramphenicol is 0.5-8 parts, the content of salicylic acid is 0.5-8 parts, the content of triamcinolone acetonide or triamcinolone acetonide is 0.005-0.45 parts, the content of the matrix carbomer is 0.1-4.5 parts, the content of propylene glycol is 10-50 parts, the content of diethylene glycol monoethyl ether is 5-40 parts, and the pH adjuster is tromethamine, and the pH value of the gel-type pharmaceutical composition is 2-6.

[0044] In some embodiments of this disclosure, the content of chloramphenicol is 1-5 parts, the content of salicylic acid is 1-5 parts, the content of carbomer is 0.5-4 parts, the content of propylene glycol is 10-40 parts, the content of diethylene glycol monoethyl ether is 5-30 parts, the pH adjuster is triethanolamine, and the pH value of the gel-type pharmaceutical composition is 2-6.

[0045] In some embodiments of this disclosure, the content of chloramphenicol is 1-5 parts, the content of salicylic acid is 1-5 parts, the content of triamcinolone acetonide or triamcinolone acetonide is 0.005-0.4 parts, the content of carbomer is 0.5-4 parts, the content of propylene glycol is 10-40 parts, the content of diethylene glycol monoethyl ether is 5-30 parts, the pH adjuster is triethanolamine, and the pH value of the gel-type pharmaceutical composition is 2-6.

[0046] In some embodiments of this disclosure, the content of chloramphenicol is 1-5 parts, the content of salicylic acid is 1-5 parts, the content of carbomer is 0.5-4 parts, the content of propylene glycol is 10-40 parts, the content of diethylene glycol monoethyl ether is 5-30 parts, the pH adjuster is tromethamine, and the pH value of the gel-type pharmaceutical composition is 2-6.

[0047] In some embodiments of this disclosure, the content of chloramphenicol is 1-5 parts, the content of salicylic acid is 1-5 parts, the content of triamcinolone acetonide or triamcinolone acetonide is 0.005-0.4 parts, the content of carbomer is 0.5-4 parts, the content of propylene glycol is 10-40 parts, the content of diethylene glycol monoethyl ether is 5-30 parts, the pH adjuster is tromethamine, and the pH value of the gel-type pharmaceutical composition is 2-6.

[0048] In some embodiments of this disclosure, the gel-type pharmaceutical composition comprises the following components: 1-5 parts chloramphenicol, 1-5 parts salicylic acid, 20-50 parts propylene glycol, 5-15 parts diethylene glycol monoethyl ether, 0-15 parts ethanol, 1-5 parts carbomer, and 30-60 parts purified water.

[0049] In some embodiments of this disclosure, the gel-type pharmaceutical composition comprises the following components: 1-5 parts chloramphenicol, 1-5 parts salicylic acid, 20-50 parts glycerin, 5-15 parts diethylene glycol monoethyl ether, 0-15 parts ethanol, 1-5 parts carbomer, and 30-60 parts purified water.

[0050] In some embodiments of this disclosure, the gel-type pharmaceutical composition comprises the following components: 1-5 parts chloramphenicol, 1-5 parts salicylic acid, 20-50 parts glycerin, 5-15 parts menthol, 0-15 parts ethanol, 1-5 parts carbomer, and 30-60 parts purified water.

[0051] In some embodiments of this disclosure, the gel-type pharmaceutical composition comprises the following components: 1-5 parts chloramphenicol, 1-5 parts salicylic acid, 20-50 parts propylene glycol, 5-15 parts propylene carbonate, 0-15 parts ethanol, 1-5 parts poloxamer, and 30-60 parts purified water.

[0052] In some embodiments of this disclosure, the gel-type pharmaceutical composition comprises the following components: 1-5 parts chloramphenicol, 1-5 parts salicylic acid, 20-50 parts PEG, 5-15 parts diethylene glycol monoethyl ether, 0-15 parts ethanol, 1-5 parts povidone, and 30-60 parts purified water.

[0053] In some embodiments of this disclosure, the ethanol content in the composition is less than 20%, less than 15%, less than 12%, or less than 11% by volume mass ratio, the ethanol content can be 0, and the upper limit of the ethanol content can be 10%.

[0054] In some embodiments of this disclosure, the gel-type pharmaceutical composition comprises 0.005-0.5 parts of triamcinolone acetonide or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments of this disclosure, the gel-type pharmaceutical composition is free of dimethyl sulfoxide and azone.

[0056] Another aspect of this disclosure relates to a method for preparing a gel-type pharmaceutical composition as described above, the method comprising the following steps:

[0057] 1) Mix water and humectant, add the matrix, and stir to obtain a gel matrix;

[0058] 2) Mix chloramphenicol or a pharmaceutically acceptable salt thereof, salicylic acid or a pharmaceutically acceptable salt thereof, and a penetration enhancer, and stir to obtain solution I;

[0059] 3) Add solution I containing the active ingredient to the gel matrix and stir to obtain a gel-type composition.

[0060] In some embodiments of this disclosure, the preparation method described above further includes the step of adjusting the pH with a pH adjuster.

[0061] In some embodiments of this disclosure, the preparation method described above also includes the step of adding water to make up the weight.

[0062] This disclosure further relates to the use of a gel-type pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing skin diseases selected from acne, dermatitis, eczema, and pruritus.

[0063] This disclosure further relates to the use of a gel-type pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing acne.

[0064] This disclosure also relates to a method of treating a skin disease comprising administering to a patient a therapeutically effective amount of the gel-type pharmaceutical composition as described above, wherein the skin disease is selected from acne, dermatitis, eczema, and pruritus.

[0065] This disclosure also relates to a method of treating acne, comprising administering to a patient a therapeutically effective amount of the gel-type pharmaceutical composition as described above.

[0066] This disclosure also relates to a gel-type pharmaceutical composition as described above for use as a medicine.

[0067] This disclosure also relates to a gel-type pharmaceutical composition as described above for use as a medicament for treating and / or preventing skin diseases selected from acne, dermatitis, eczema, and pruritus.

[0068] This disclosure also relates to a gel-type pharmaceutical composition as described above for use as a medicament for treating and / or preventing acne.

[0069] Preferably, the dermatitis described in this disclosure is selected from allergic dermatitis, atopic dermatitis, neurodermatitis, seborrheic dermatitis, and folliculitis.

[0070] Preferably, the skin disease described in this disclosure is acne.

[0071] Preferably, the acne described in this disclosure includes mild acne (Grade I), moderate acne (Grade II), moderate to severe acne (Grade III), and severe acne (Grade IV). This disclosure demonstrates excellent therapeutic effects on all of the above-mentioned types of acne.

[0072] Terminology Definitions and Explanations

[0073] Unless otherwise stated, the definitions of terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific components in embodiments, can be arbitrarily combined and combined with each other. Such combinations and combinations shall fall within the scope of this application specification.

[0074] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0075] The term "gel-type pharmaceutical composition" can be understood as a gel formulation.

[0076] The term "mild acne (Grade I)" clinically manifests as comedones;

[0077] The term "moderate acne (grade II)" is clinically characterized by inflammatory papules;

[0078] The term "moderate to severe acne (grade III)" is clinically characterized by papules and pustules;

[0079] The term "severe acne (grade IV)" clinically manifests as nodules and cysts.

[0080] The term "patient" refers to a person who requires preventive or treatment for a disease associated with anaerobic bacteria, where the patient is a mammal, such as a rodent, cow, pig, dog, cat, or primate, and especially a human.

[0081] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0082] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are generally given for illustrative purposes only and not as limitations.

[0083] Beneficial effects

[0084] The beneficial effects of this disclosure are as follows:

[0085] 1) The formulation disclosed in this application, through the interaction of multiple active ingredients and with appropriate excipients and proportions, forms a gel-type pharmaceutical composition that has excellent effects on skin diseases, especially on various types of acne.

[0086] 2) The gel-type pharmaceutical composition prepared using the formulation disclosed in this application has good stability, is not prone to crystal precipitation, and has a good, transparent appearance. Due to the low content of the lipophilic phase in the product, it does not feel greasy after application to the skin, is easy to spread, and is easy to wash off;

[0087] 3) The gel-type pharmaceutical composition product disclosed herein contains a hydrophilic gel matrix, which can form a transparent film after being applied to the skin. The film has a uniform and delicate texture, is easy to apply, is non-irritating, has no side effects, and can increase patient compliance.

[0088] 4) The gel-type pharmaceutical composition disclosed herein contains almost no ethanol or contains only a small amount of ethanol, and does not contain dimethyl sulfoxide or azone. It reduces the irritation of the above solvents to the skin and wounds without reducing the solubility of the active ingredient, and can be used on skin lesions, thereby improving medication safety and increasing patient compliance.

[0089] 5) The gel-type pharmaceutical compositions prepared in this disclosure have unique advantages over liniments and creams in the preparation of applications for the treatment and / or prevention of oily skin diseases such as acne.

[0090] 6) The gel-type drug composition prepared in this disclosure has high stability and excellent transdermal effect of active ingredients; the formulation is simple and the process is simple, making it suitable for large-scale production. Attached Figure Description

[0091] Figure 1 In vitro release curve of gel-type drug composition - chloramphenicol.

[0092] Figure 2 In vitro release profile of a gel-type pharmaceutical composition - salicylic acid.

[0093] Figure 3 The total number of skin lesions changes with treatment time.

[0094] Figure 4 Weight of rabbit ears. Detailed Implementation

[0095] The following examples are used to further describe this disclosure, but these examples are not intended to limit the scope of this disclosure. Experimental methods in preferred examples, where specific conditions are not specified, are generally performed under conventional conditions.

[0096] Preparation Examples 1-4: Process Investigation of Gel Matrix Dispersion

[0097] In the early stages of formulation development, the percentage of carbomer in the gel-type drug composition was approximately 2%, purified water approximately 33%, and propylene glycol approximately 35%. The dispersion of carbomer in solvents was investigated using purified water, propylene glycol, and a mixture of the two.

[0098] Table 1. Dispersion of Carbomer in different solvents

[0099]

[0100] As shown above, using only purified water or propylene glycol is insufficient to completely disperse the prescribed amount of carbomer. Furthermore, using only propylene glycol to disperse carbomer results in a viscous gel matrix. A mixture of purified water and propylene glycol can disperse higher amounts of carbomer without forming lumps; the dispersed matrix is ​​uniform and easy to transfer.

[0101] Therefore, the gel matrix was subsequently prepared by dispersing the matrix in a mixed solution of water and propylene glycol.

[0102] Preparation Examples 5-7: Antibacterial Efficacy Investigation

[0103] This product is a multi-dose topical gel. To prevent microbial contamination and spoilage that may occur during normal storage or use, thus posing a risk to users, its antibacterial efficacy needs to be investigated. Methylparaben, a relatively safe preservative, was selected as the preservative. Based on the formulation in Example 7, the effect of adding different amounts of methylparaben on the antibacterial efficacy of the formulation was investigated. The experimental results are shown in Table 2.

[0104] Table 2. Results of antibacterial efficacy tests of gel-type pharmaceutical compositions.

[0105]

[0106] Conclusion: The study showed that this product had an inhibitory effect on microorganisms under three different conditions: no methylparaben, 0.05% methylparaben, and 0.1% methylparaben. The product met the antimicrobial efficacy requirements with and without the addition of antimicrobial agents. Therefore, the study concluded that no antimicrobial agents are needed for this product.

[0107] Preparation Examples 8-11 Antioxidant Investigation

[0108] Antioxidants may reduce compound degradation and promote formulation stability. The effects of different types of antioxidants, including butylated hydroxytoluene, propyl gallate, and sodium bisulfite, on product quality were investigated. The results are shown in the table below.

[0109] Table 3. Formulation analysis of different antioxidants in gel-type pharmaceutical compositions

[0110]

[0111] Table 4 Results of the investigation of different antioxidants in gel-type pharmaceutical compositions

[0112]

[0113] Experimental results showed that the related substance chloramphenicol diol (CAP-ImpA) increased in both the formulation with three different types of antioxidants and the formulation without antioxidants, while SA-ImpA, SA-ImpB, CAP-ImpB and unknown impurities did not increase significantly. The formulation with three different types of antioxidants failed to slow down the growth of chloramphenicol diol, and no new unknown impurities appeared in the formulation without antioxidants. Therefore, antioxidants should not be added to subsequent formulations.

[0114] Example 1

[0115] A gel-type pharmaceutical composition, formulation: 3 parts chloramphenicol, 2 parts salicylic acid, 0.01 parts triamcinolone acetonide, 35 parts propylene glycol, 10 parts diethylene glycol monoethyl ether, 10 parts ethanol, 2 parts carbomer, 0.5 parts tromethorphan, and 38 parts purified water.

[0116] The specific steps for preparing the gel-type pharmaceutical composition are as follows:

[0117] 1) Mix purified water and propylene glycol evenly, add carbomer under stirring, stir evenly, and let stand to obtain a gel matrix;

[0118] 2) Mix chloramphenicol, salicylic acid, triamcinolone acetonide, ethanol, and diethylene glycol monoethyl ether, and stir to obtain solution I;

[0119] 3) Dissolve tromethorphan in purified water and set aside.

[0120] 4) Add solution I containing the active ingredient to the gel matrix, stir, and adjust the pH value to 2-6 using tromethamine solution to obtain a gel-type composition.

[0121] Example 2

[0122] A gel-type pharmaceutical composition, formulation: chloramphenicol 3.5 parts, salicylic acid 2.5 parts, propylene glycol 40 parts, diethylene glycol monoethyl ether 10 parts, carbomer 2 parts, triethanolamine 0.5 parts, purified water 40 parts.

[0123] The specific steps for preparing the gel-type pharmaceutical composition are as follows:

[0124] 1) Mix purified water and propylene glycol evenly, add carbomer under stirring, stir evenly, and let stand to obtain a gel matrix;

[0125] 2) Mix chloramphenicol, salicylic acid, and diethylene glycol monoethyl ether, and stir to obtain solution I;

[0126] 3) Dissolve triethanolamine in purified water by stirring and set aside;

[0127] 4) Add solution I containing the active ingredient to the gel matrix, stir, and adjust the pH value to 2-6 using triethanolamine solution to obtain a gel-type composition.

[0128] Example 3

[0129] A gel-type pharmaceutical composition, formulation: 1 part chloramphenicol, 1 part salicylic acid, 10 parts propylene glycol, 5 parts ethanol, 3 parts carbomer, 0.2 parts tromethorphan, and 50 parts purified water.

[0130] The specific steps for preparing the gel-type pharmaceutical composition are as follows:

[0131] 1) Mix purified water and propylene glycol evenly, add carbomer under stirring, stir evenly, and let stand to obtain a gel matrix;

[0132] 2) Mix chloramphenicol, salicylic acid, and ethanol, and stir to obtain solution I;

[0133] 3) Dissolve tromethorphan in purified water and set aside.

[0134] 4) Add solution I containing the active ingredient to the gel matrix, stir, and adjust the pH value to 2-6 using tromethamine solution to obtain a gel-type composition.

[0135] Example 4

[0136] A gel-type pharmaceutical composition, formulation: chloramphenicol 3.5 parts, salicylic acid 2.5 parts, triamcinolone acetonide 0.02 parts, propylene glycol 35 parts, diethylene glycol monoethyl ether 5 parts, ethanol 3 parts, carbomer 2 parts, triethanolamine 2.5 parts, purified water 46 parts.

[0137] The specific steps for preparing the gel-type pharmaceutical composition are as follows:

[0138] 1) Mix purified water and propylene glycol evenly, add carbomer under stirring, stir evenly, and let stand to obtain a gel matrix;

[0139] 2) Mix chloramphenicol, salicylic acid, triamcinolone acetonide, diethylene glycol monoethyl ether, and ethanol, and stir to obtain solution I;

[0140] 3) Dissolve triethanolamine in purified water by stirring and set aside;

[0141] 4) Add solution I containing the active ingredient to the gel matrix, stir, and adjust the pH value to 2-6 using triethanolamine solution to obtain a gel-type composition.

[0142] Example 5

[0143] A gel-type pharmaceutical composition, formulation: 2 parts chloramphenicol, 3 parts salicylic acid, 40 parts glycerin, 15 parts menthol, 5 parts ethanol, 2 parts poloxamer, 0.5 parts triethanolamine, and 40 parts purified water.

[0144] The specific steps for preparing the gel-type pharmaceutical composition are as follows:

[0145] 1) Mix purified water and glycerol evenly, add poloxamer under stirring, stir evenly, and let stand to obtain a gel matrix;

[0146] 2) Mix chloramphenicol, salicylic acid, ethanol, and menthol, and stir to obtain solution I;

[0147] 3) Dissolve triethanolamine in purified water by stirring and set aside;

[0148] 4) Add solution I containing the active ingredient to the gel matrix, stir, and adjust the pH value to 2-6 using triethanolamine solution to obtain a gel-type composition.

[0149] Example 6

[0150] A gel-type pharmaceutical composition, formulation: 1 part chloramphenicol, 1 part salicylic acid, 5 parts PEG200, 10 parts propylene carbonate, 1 part hydroxypropyl methylcellulose, 0.2 parts triethanolamine, and 35 parts purified water.

[0151] The specific steps for preparing the gel-type pharmaceutical composition are as follows:

[0152] 1) Mix purified water and PEG evenly, add hydroxypropyl methylcellulose under stirring, stir evenly, and let stand to obtain a gel matrix;

[0153] 2) Mix chloramphenicol, salicylic acid, and propylene carbonate, and stir to obtain solution I;

[0154] 3) Dissolve triethanolamine in purified water by stirring and set aside;

[0155] 4) Add solution I containing the active ingredient to the gel matrix, stir, and adjust the pH value to 2-6 using triethanolamine solution to obtain a gel-type composition.

[0156] Example 7

[0157] A gel-type pharmaceutical composition, formulation: 3 parts chloramphenicol, 2 parts salicylic acid, 35 parts propylene glycol, 10 parts diethylene glycol monoethyl ether, 10 parts ethanol, 2 parts carbomer, 0.5 parts tromethorphan, and 38 parts purified water.

[0158] The specific steps for preparing the gel-type pharmaceutical composition are as follows:

[0159] 1) Mix purified water and propylene glycol evenly, add carbomer under stirring, stir evenly, and let stand to obtain a gel matrix;

[0160] 2) Mix chloramphenicol, salicylic acid, ethanol, and diethylene glycol monoethyl ether, and stir to obtain solution I;

[0161] 3) Dissolve tromethorphan in purified water and set aside.

[0162] 4) Add solution I containing the active ingredient to the gel matrix, stir, and adjust the pH value to 2-6 using tromethamine solution to obtain a gel-type composition.

[0163] Example 8

[0164] A gel-type pharmaceutical composition, formulation: 1 part chloramphenicol, 1 part salicylic acid, 0.2 parts triamcinolone acetonide, 20 parts PEG200, 5 parts ethanol, 10 parts diethylene glycol monoethyl ether, 4 parts povidone, 0.2 parts triethanolamine, and 60 parts purified water.

[0165] The specific steps for preparing the gel-type pharmaceutical composition are as follows:

[0166] 1) Mix purified water and PEG evenly, add povidone under stirring, stir evenly, and let stand to obtain a gel matrix;

[0167] 2) Mix chloramphenicol, salicylic acid, triamcinolone acetonide, and ethanol, and stir to obtain solution I;

[0168] 3) Dissolve triethanolamine in purified water by stirring and set aside;

[0169] 5) Add solution I containing the active ingredient to the gel matrix, stir, and adjust the pH value to 2-6 using triethanolamine solution to obtain a gel-type composition.

[0170] Compare with Example 1

[0171] Compound triamcinolone acetonide salicylic acid liniment was prepared according to the formula disclosed in Example 1 of patent CN 114504581A.

[0172] Specific preparation method:

[0173] Dissolve 0.05g triamcinolone acetonide, 2g chloramphenicol, and 2g salicylic acid in an appropriate amount of 95% ethanol aqueous solution to obtain a drug solution; disperse 2ml azone, 3ml dimethyl sulfoxide, and 10ml propylene glycol in an appropriate amount of 95% ethanol aqueous solution to obtain an excipient solution; mix the above drug solution and excipient solution, and continue to add 95% ethanol aqueous solution to make up to 100ml, mix thoroughly, and the control example compound triamcinolone acetonide and salicylic acid liniment is obtained.

[0174] Compare with Example 2

[0175] The preparation process is the same as in Example 1, except that it does not contain chloramphenicol and triamcinolone.

[0176] Compare with Example 3

[0177] The preparation process is the same as in Example 1, except that it does not contain salicylic acid and triamcinolone.

[0178] Compare with Example 4

[0179] The preparation process is the same as in Example 1, except that it does not contain salicylic acid and chloramphenicol.

[0180] Compare with Example 5

[0181] The preparation process is the same as in Example 1, except that it does not contain salicylic acid and triamcinolone, and the amount of chloramphenicol used is 5 parts.

[0182] Test Example 1: Stability Experiment

[0183] The stability of the gel-type pharmaceutical composition obtained in Example 1 was tested, and the results are shown in the table below.

[0184] Table 5 Results of the stability study of gel-type pharmaceutical compositions

[0185]

[0186] Table 6 Results of accelerated and long-term stability studies of gel-type drug compositions

[0187]

[0188] The gel-type drug composition prepared in Example 1 showed no crystal precipitation and no significant changes in properties after being stored for 3 months under stability test conditions. The drug content was higher than 90%, which met the requirements. Therefore, the gel-type drug composition prepared in this application has high stability and is easy to promote and use in clinical practice.

[0189] Test Case 2: Patient User Experience Evaluation

[0190] The gel-type pharmaceutical composition prepared in Example 1 of this application and the control were used on 8 subjects, and the evaluation results were obtained based on a questionnaire survey conducted on the subjects after use.

[0191] 100% of the subjects found that the gel-type pharmaceutical composition prepared in Example 2 was non-greasy, formed a transparent film on the skin, was easy to wash off, felt comfortable, and was easy to carry and apply to the affected area. In contrast, 100% of the subjects found that the compound triamcinolone acetonide salicylic acid lotion prepared in the control example had a strong smell, a strong alcohol smell, and caused dryness, irritation, and stinging sensations on the skin after application. Furthermore, the control example product was in solution form, making it difficult to carry and inconvenient to use.

[0192] Therefore, it can be seen that the triamcinolone acetonide chloramphenicol salicylic acid liniment prepared in the comparative example is a solution with a strong alcohol smell and is highly irritating to some skin types; while the gel-type pharmaceutical composition prepared in this application is semi-transparent, non-greasy, and forms a transparent film after being applied to the skin, providing a comfortable feeling.

[0193] Test Example 3: In Vitro Release Test

[0194] Example 7 was used for an in vitro release test to evaluate the release of the formulation in vitro. A nylon membrane was installed on a LOGAN System 918 vertical diffusion cell, exposed at 1.77 cm. 2 The surface area of ​​the diffusion cell was determined. The diffusion cell was connected to a multichannel pump at 600 rpm, and the receiving solution was 50% ethanol. Each cell was placed in a heated manifold to equilibrate the temperature, ensuring the inner membrane surface temperature was 32℃ ± 1℃ for at least 30 minutes before administration. A dose of 300 mg of the test sample was added. The receiving solution was collected at 0.5, 1, 1.5, 2, 3, and 4 hours to detect the released active ingredient. Results are shown in the table below and appendix. Figure 1-2 .

[0195] Table 7 Results of in vitro release tests of gel-type pharmaceutical compositions

[0196]

[0197] In vitro release assay results showed that the cumulative release of chloramphenicol and salicylic acid from the gel-type drug composition obtained in Example 7 was directly proportional to the square root of time. The slope of the straight line represented the in vitro release rate of the drug, and the linear correlation coefficient r was [value missing]. 2 ≥0.99, the average release rate of chloramphenicol over 4 hours was 2123.42 μg / cm³. 2 / h 1 / 2 The average release rate of salicylic acid was 1515.34 μg / cm³. 2 / h 1 / 2This ensures that two drugs with different physicochemical properties can be released synchronously and in equal proportions, avoiding the imbalance caused by the delayed precipitation of a single component. The above-mentioned in vitro release curve has ideal controlled-release characteristics, which can effectively reduce drug concentration fluctuations and reduce the side effects caused by drug concentration fluctuations.

[0198] Test Example 4: Stimulation Test

[0199] The study observed the irritation of normal and damaged skin and the reversibility of irritation after repeated skin application to Japanese white rabbits with the gel-type drug composition obtained in Example 1.

[0200] Twelve healthy Japanese white rabbits (6 females / 6 males) were selected and divided into two groups according to sex and weight using TOXSTAT2006 software: a group with normal skin and a group with damaged skin. Each group consisted of six rabbits (3 females / 3 males).

[0201] The method of self-comparison between left and right sides of the same organism was used. Hair was trimmed 2 cm to the left and right of the spine on the front back of the animal, with each trimmed area being approximately 3 × 3 cm. 2 During the drug administration period, the animals were groomed once a week. For animals with broken skin, the groomed area was locally disinfected with 75% alcohol, and a "#" mark was made with a sterile needle until bleeding occurred to prepare broken skin.

[0202] The test gel was applied to the hair-removed area on the right (R) side of the animal, and 0.9% sodium chloride injection was applied to the hair-removed area on the left (L) side. The administration method was as follows: filter paper was attached to the groove of a blank plaster on the control side, and 0.9% sodium chloride injection was placed in the filter paper and applied to the administration site. On the administration side, the gel was directly and evenly applied to the groove of a blank plaster and applied to the administration site. The drug and non-irritating medical tape were removed after 3-4 hours. The dosage was 0.5 g / animal / time (0.5 ml / animal / time on the control side), twice a day, each time for 3-4 hours, for 28 consecutive days.

[0203] On the first day of administration, local symptoms were observed 1 hour after drug removal, 30–60 minutes after drug removal on the last day of administration, and at 24h±2h, 48h±2h, and 72h±2h. On non-administration days, local symptoms were observed once a day and scored (if no erythema and / or edema are observed, the default value is 0 and no further scoring is performed).

[0204] Half of the animals in each group were euthanized under CO2 anesthesia 72 h ± 2 h after the last administration (2♀ / 1♂ after administration, 1♀ / 2♂ during the recovery period). Skin samples were cut from the administration site, fixed in 10% neutral buffered formalin, and routinely sectioned for histopathological examination.

[0205] The remaining animals were observed for another 14 days. After the observation period, the remaining animals were euthanized under CO2 anesthesia and subjected to another pathological examination to understand the status and reversibility of the irritant reaction.

[0206] result:

[0207] During the experiment, the animals were generally in good condition and no deaths occurred. Gross observation of the treatment site revealed no obvious abnormalities in any animal in the normal skin group or the damaged skin group during the experiment. Histopathological examination showed no significant drug-related histopathological changes in either the control or treatment sides of all animals in the normal skin group and the damaged skin group 72 hours after the last administration and after a 14-day recovery period.

[0208] As can be seen, under the conditions of this experiment, no obvious drug-related irritation was observed on normal skin or damaged skin after repeated skin application of the gel-type drug composition obtained in Example 1 to Japanese white rabbits.

[0209] Test Example 5: Pharmacokinetic Test

[0210] This study aimed to investigate the effects of topical administration of gel-type drug compositions of Example 1 (a combination of salicylic acid, chloramphenicol, and triamcinolone), Control Example 2 (a single-component salicylic acid), Control Example 3 (a single-component chloramphenicol), and Control Example 4 (a single-component triamcinolone) to Bama miniature pigs. Skin tissue was collected, and the epidermis, dermis, and subcutaneous tissue were separated. The concentrations of salicylic acid, chloramphenicol, and triamcinolone in the epidermis, dermis, and subcutaneous tissue of Bama miniature pigs were determined using a partially validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. Pharmacokinetic parameters were calculated to evaluate the distribution of the gel in the skin tissue of miniature pigs and the pharmacokinetic characteristics of the skin.

[0211] Four groups of Bama miniature pigs were formed, with six pigs in each group (half male and half female). The pigs were administered a topical medication at a dose of 5 mg / cm³. 2 In Examples 1, 2, 3, and 4, the skin application area was 6.25 cm². 2 / At the drug administration site, skin tissue was collected at 1 h, 4 h (drug removed), 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h and 192 h after drug administration, and then analyzed.

[0212] Bama miniature pigs at 5 mg / cm 2 After applying the gel-type pharmaceutical composition of Example 1, the T-cell concentration of salicylic acid in the epidermis, dermis, and subcutaneous tissue... max The average C values ​​were 24, 16, and 16 hours, respectively. max The values ​​were 187±110, 41.6±19.6, and 2.83±2.07 μg / g, respectively, with mean exposure AUCs of 187±110, 41.6±19.6, and 2.83±2.07 μg / g.0-t The concentrations of chloramphenicol in epidermis, dermis, and subcutaneous tissues were 12307±6005, 2655±1131, and 188±110 h*μg / g, respectively. max The average C values ​​were 60, 144, and 192 hours, respectively. max The mean exposure values ​​were 108±48.5, 29.8±9.65, and 2.37±2.08 μg / g, respectively, with AUC values ​​of 108±48.5, 29.8±9.65, and 2.37±2.08 μg / g. 0-t The concentrations of triamcinolone acetonide in the epidermis, dermis, and subcutaneous tissues were 7885±3734, 1869±927, and 139±110 h*μg / g, respectively. max The average C values ​​were 96, 144, and 108 h, respectively. max The mean exposure AUCs were 0.344±0.162, 0.0956±0.0397, and 0.0154 μg / g, respectively. 0-t The values ​​were 24.5±11.0, 5.97±3.05, and 1.14 h*μg / g, respectively.

[0213] Bama miniature pigs at 5 mg / cm 2 After applying the gel-type drug composition of Control Example 2, the T-cell concentration of salicylic acid in the epidermis, dermis, and subcutaneous tissue was... max The average C values ​​were 24, 16, and 16 hours, respectively. max The values ​​were 198±89.1, 39.4±18.2, and 4.24±4.07 μg / g, respectively, with mean exposure AUCs of 198±89.1, 39.4±18.2, and 4.24±4.07 μg / g. 0-t The values ​​were 12700±7168, 2970±1648, and 292±191 h*μg / g, respectively.

[0214] Bama miniature pigs at 5 mg / cm 2 After applying the gel-type drug composition of Control Example 3, the T-cell concentration of chloramphenicol in the epidermis, dermis, and subcutaneous tissue was... max The average C values ​​were 24, 40, and 96 hours, respectively. max The mean exposure AUCs were 82.7±46.0, 20.3±15.3, and 3.37±3.30 μg / g, respectively. 0-t The values ​​were 7017±3450, 1725±1071, and 235±215 h*μg / g, respectively.

[0215] Bama miniature pigs at 5 mg / cm 2 After applying the gel-type drug composition of Control Example 4, the T-cell concentration of triamcinolone acetonide in the epidermis, dermis, and subcutaneous tissue was significantly reduced. max The average C values ​​were 16, 144, and 144 hours, respectively. max The mean exposure values ​​were 0.330±0.233, 0.101±0.0755, and 0.0124±0.00672 μg / g, respectively, with AUC values ​​of 0.330±0.233, 0.101±0.0755, and 0.0124±0.00672 μg / g.0-t The values ​​were 26.0±13.4, 7.38±5.38, and 0.777±0.922 h*μg / g, respectively.

[0216] As can be seen, after applying the same dose of the gel from Example 1 and Control Example 2 to the skin of Bama miniature pigs, salicylic acid was detected in the epidermis, dermis, and subcutaneous tissue, and the exposure levels were basically the same. After applying the same dose of the gel from Example 1 and Control Example 3 to the skin, chloramphenicol was detected in the epidermis, dermis, and subcutaneous tissue, and the exposure levels were basically the same. After applying the same dose of the gel from Example 1 and Control Example 4 to the skin, triamcinolone was detected in the epidermis, dermis, and subcutaneous tissue, and the exposure levels were basically the same.

[0217] The single-agent formulations of Comparative Examples 2-4 require multiple administrations to the site of disease, which is cumbersome. In contrast, the gel-type drug composition of this application has better in vivo release properties, and the release behavior between the active ingredients is not interfered with. It only requires a single administration, making it more convenient to use and beneficial for patients to continue treatment.

[0218] Test Example 6: Pharmacodynamic Test

[0219] This study aims to evaluate the efficacy of the gel-type pharmaceutical composition of this application in treating a coal tar-induced rabbit ear acne model combined with Propionibacterium acnes.

[0220] Male New Zealand White rabbits of standard grade were acclimatized for 16 days. Six rabbits were randomly selected to enter the blank control group (G1, Sham group) without any treatment. The remaining rabbits underwent modeling treatment. 0.5-1 mL of 2% coal tar was applied daily to a 2 cm x 2 cm area at the outlet of the right ear canal for 18 consecutive days. Starting on day 8, Propionibacterium acnes was injected intradermally into the right ear at 7-8 sites per rabbit, 30 μL per site, every other day for a total of 6 injections. Twenty-four hours after the last injection, the number of skin lesions (including comedones, papules, and pustules) was counted, and the animals were randomly divided into four groups: G2 (blank gel group), G3 (control example 2), G4 (control example 5), and G5 (example 1), with six rabbits in each group. Each group received the corresponding drug treatment for 8 days, and the rabbit ears were scored on days 4, 6, and 8 of treatment. Twenty-four hours after the last treatment, a circular ear with a diameter of 2.8 cm was weighed.

[0221] The experimental animals were divided into 5 groups: the Sham group and 4 acne model groups. The drug was administered from the start of the grouping (Day 1), twice a day for 8 consecutive days (Day 8), with each dose being 0.4 g / ear / animal. The specific grouping and drug administration regimens are shown in Table 8.

[0222] Table 8 Animal grouping and dosing regimen

[0223]

[0224] The results are as follows Figure 3 As shown in Table 9, in the rabbit ear acne model induced by coal tar and Propionibacterium acnes, compared with the G2 group, the total number of skin lesions (comedones + papules + pustules) in the treatment groups showed a decreasing trend from Day 4 to Day 8, with a significant decrease in the G5 group. The skin lesion healing rates of the G2-G5 groups on Day 8 were 49.5%, 60.2%, 62.6%, and 73.1%, respectively. The skin lesion healing rate of the G5 group was significantly better than that of the G3 and G4 groups, demonstrating that the combined use of salicylic acid and chloramphenicol has a synergistic effect, and the drugs have low irritation to the animals during the experiment.

[0225] Table 9 Summary of data from the rabbit ear acne model

[0226]

[0227] like Figure 4 As shown in Table 9, after 8 days of treatment, compared with groups G2-G4, group G5 showed reduced ear redness and swelling, thinner ear thickness, and significantly lower weight, which was significantly better than groups G3 and G4. The ear weights of rabbits in groups G1-G5 were 0.77 g, 1.17 g, 1.13 g, 1.04 g, and 0.97 g, respectively.

[0228] The results showed that in the rabbit ear acne model induced by coal tar combined with Propionibacterium acnes, compared with the blank gel group, the total number of skin lesions (comedones + papules + pustules) in the treatment groups showed a decreasing trend from Day 4 to Day 8, with a significant decrease in Group G5. The skin lesion healing rates of Groups G2-G5 at Day 8 were 49.5%, 60.2%, 62.6%, and 73.1%, respectively. After treatment, compared with Groups G2-G4, the redness and swelling of rabbit ears in Group G5 were reduced, and the ear weight was significantly reduced, which was significantly better than Groups G3 and G4. The ear weights of rabbits in Groups G1-5 were 0.77 g, 1.17 g, 1.13 g, 1.04 g, and 0.97 g, respectively.

[0229] The specific embodiments of the present invention have been described above by way of example. However, the scope of protection of the present invention is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A gel-type pharmaceutical composition, characterized in that, The gel-type pharmaceutical composition comprises, by weight parts: 1-5 parts of chloramphenicol or a pharmaceutically acceptable salt thereof; 1-5 parts of salicylic acid or its pharmaceutically acceptable salt; Carbomer 1-5 servings; 5-50 parts of a moisturizer, wherein the moisturizer comprises one or more of propylene glycol, glycerin, and PEG; 5-25 parts of diethylene glycol monoethyl ether, 0-15 parts of ethanol; 30-60 parts water; and, The ethanol content in the composition is less than 20% v / w.

2. The gel-type pharmaceutical composition according to claim 1, characterized in that, The gel-type pharmaceutical composition also includes a pH adjuster.

3. The gel-type pharmaceutical composition according to claim 1, characterized in that, The gel-type pharmaceutical composition comprises: 1-5 parts chloramphenicol, 1-5 parts salicylic acid, 20-50 parts humectant, 5-15 parts diethylene glycol monoethyl ether, 5-15 parts ethanol, 1-5 parts carbomer, and 30-60 parts purified water, wherein the ethanol content in the composition is less than 15% v / w.

4. The gel-type pharmaceutical composition according to any one of claims 1-3, characterized in that, The gel-type pharmaceutical composition further comprises 0.005-0.5 parts of triamcinolone acetonide or a pharmaceutically acceptable salt thereof.

5. A method for preparing the gel-type pharmaceutical composition as described in claim 1, characterized in that, Includes the following steps: 1) Mix water, humectant, and carbomer, and stir to obtain a gel matrix; 2) Mix chloramphenicol or a pharmaceutically acceptable salt thereof, salicylic acid or a pharmaceutically acceptable salt thereof, diethylene glycol monoethyl ether, and ethanol, and stir to obtain solution I; 3) Add solution I containing the active ingredient to the gel matrix and stir to obtain a gel-type composition.

6. Use of a gel-type pharmaceutical composition as described in any one of claims 1 to 4 in the preparation of a medicament for treating and / or preventing skin diseases, said skin diseases being selected from acne, dermatitis, eczema, or pruritus.

7. The use according to claim 6, wherein the dermatitis is selected from allergic dermatitis, neurodermatitis, seborrheic dermatitis, atopic dermatitis or folliculitis, and the acne is acne with skin lesions.

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