Composition with synergistic therapeutic effect on acne lesions and preparation method therefor and use thereof

Abstract

The present disclosure belongs to the field of pharmaceutical formulations and particularly relates to a composition with a synergistic therapeutic effect on acne lesions and a preparation method therefor and use thereof. The composition provided by the present disclosure comprises active ingredients adapalene and dapsone, which exhibit a synergistic therapeutic effect on inflammatory acne lesions when used in combination. Compared with corresponding single drugs, the composition can significantly reduce the number of inflammatory lesions; meanwhile, relative to the topical use of adapalene alone, the composition of the present disclosure can mitigate skin irritation reactions caused by adapalene and exhibits good safety.

Description

Composition with synergistic effect in treating acne lesions, preparation method and use thereof

[0001] Citation of related applications This application claims all rights and interests in the invention patent application with application number 202311832258.3 filed with the State Intellectual Property Office of the People's Republic of China on December 28, 2023, and incorporates its entire contents into this application by reference. Technical Field

[0002] The present disclosure belongs to the field of pharmaceutical preparations, and particularly relates to a composition for synergistically enhancing the effect of treating acne lesions, and a preparation method and use thereof. Technical Background

[0003] Adapalene and dapsone are commonly used drugs for treating acne. Currently, the marketed products of adapalene include 0.1% and 0.3% gels and 0.1% cream, and the marketed products of dapsone include 5% and 7.5% gels.

[0004] Patent applications WO2012015487A1 and WO2014081674A1 respectively disclose compositions of dapsone and adapalene, which can be used to treat skin diseases including acne vulgaris, but do not describe their therapeutic effects on acne inflammatory lesions.

[0005] In addition, the 0.1% and 0.3% adapalene gels on the market are often accompanied by adverse reactions such as skin irritation during use. The existing technology does not describe the effect of dapsone on the irritation of adapalene when studying the combined treatment of dapsone and adapalene. Summary of the Invention

[0006] In one aspect of the present disclosure, a composition for synergistically enhancing the effect of treating acne lesions is provided, wherein the composition comprises 0.05%-0.5% adapalene and 2%-12% dapsone, based on the total weight of the composition, wherein the acne lesions are inflammatory lesions.

[0007] In some embodiments, the composition comprises 0.05%-0.4%, 0.05%-0.3%, 0.05%-0.2%, 0.05%-0.1%, 0.1%-0.4%, 0.1%-0.3%, 0.1%-0.2%, 0.2%-0.4%, 0.2%-0.3%, or 0.3%-0.4% adapalene, based on the total weight of the composition.

[0008] In some embodiments, the composition comprises 0.05%, 0.075%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45% or 0.5% adapalene by total weight of the composition.

[0009] In some embodiments, the composition comprises, based on the total weight of the composition, 2%-11%, 2%-10%, 2%-9%, 2%-8%, 2%-7%, 2%-6%, 2%-5%, 2%-4%, 2%-3%, 3%-11%, 3%-10%, 3%-9%, 3%-8%, 3%-7%, 3%-6%, 3%-5%, 3%-4%, 4%-11%, 4%-10%, 4%-9.0%, 4%-8 %, 4%-7%, 4%-6%, 5%-11%, 5%-10%, 5%-9%, 5%-8%, 5%-7%, 5%-6%, 6%-11%, 6%-10%, 6%-9%, 6%-8%, 6%-7%, 7%-11%, 7%-10%, 7%-9%, 7%-8%, 8%-11%, 8%-10%, 8.0%-9%, 9%-11%, 9%-10%, or 10%-11% dapsone.

[0010] In some embodiments, the composition comprises 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5% or 12% dapsone by total weight of the composition.

[0011] In some embodiments, the amounts of dapsone and adapalene in the composition are 7.5% and 0.1%, 6.0% and 0.1%, 5.0% and 0.1%, 7.5% and 0.15%, 6.0% and 0.15%, 5.0% and 0.15%, 7.5% and 2.0%, 6.0% and 2.0%, 5.0% and 2.0%, 7.5% and 3.0%, 6.0% and 3.0%, 5.0% and 3.0%, 12% and 0.3%, or 3% and 0.075%, respectively, based on the total weight of the composition.

[0012] Furthermore, the composition comprises 0.1% adapalene and 7.5% dapsone based on the total weight of the composition.

[0013] Furthermore, the composition comprises 0.1% adapalene and 6% dapsone based on the total weight of the composition.

[0014] Furthermore, the composition comprises 0.1% adapalene and 5% dapsone based on the total weight of the composition.

[0015] In a preferred technical solution of the present disclosure, the treatment of inflammatory injuries is to reduce the number of inflammatory injuries.

[0016] In some embodiments, the inflammatory lesions are caused by Propionibacterium acnes.

[0017] In some embodiments, the inflammatory lesions comprise papules and pustules.

[0018] In a preferred technical solution of the present disclosure, the composition is a pharmaceutical composition loaded on a pharmaceutical carrier.

[0019] In some embodiments, the composition of the present disclosure is loaded on a pharmaceutical carrier, and the active ingredients adapalene and dapsone are delivered to the skin tissue via the pharmaceutical carrier.

[0020] In some embodiments, the pharmaceutically acceptable carrier is selected from one or more of latex, hydrogel, emulsion, liposome, vesicle, porous material and nanoemulsion.

[0021] In some embodiments, one or more of a preservative, an antioxidant, a chelating agent, and a pH adjuster may be added to the composition.

[0022] In some embodiments, the composition is loaded on a latex carrier to prepare a latex.

[0023] In some embodiments, the composition is loaded on a hydrogel carrier to prepare a hydrogel.

[0024] Another aspect of the present disclosure is to provide a method for preparing the above-mentioned composition, which comprises loading adapalene and dapsone on a pharmaceutical carrier to prepare different dosage forms.

[0025] Another aspect of the present disclosure is to provide a use of the above-mentioned pharmaceutical composition in preparing a drug for treating acne lesions.

[0026] Another aspect of the present disclosure is to provide a use of the above-mentioned pharmaceutical composition in preparing a drug for reducing the skin irritation of adapalene.

[0027] Preferably, the medicament is for treating acne lesions.

[0028] Furthermore, the acne lesions are inflammatory lesions.

[0029] Another aspect of the present disclosure is to provide a method for treating acne lesions using the pharmaceutical composition.

[0030] In the present disclosure, acne lesions refer to non-inflammatory lesions (comedones) and inflammatory lesions (papules and pustules) caused by acne.

[0031] The disclosed composition has the following beneficial effects:

[0032] The composition provided by the present disclosure contains the active ingredients adapalene and dapsone. The combination of the two has a synergistic effect in the treatment of inflammatory lesions of acne. Compared with the corresponding single-ingredient drugs, the number of inflammatory lesions can be significantly reduced. At the same time, compared with the topical use of adapalene alone, the composition of the present disclosure can reduce the skin irritation reaction caused by adapalene and has good safety. DETAILED DESCRIPTION

[0033] Hereinafter, the present disclosure will be explained in detail through the following examples in order to better understand the various aspects of the present disclosure and its advantages. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present application.

[0034] Example 1 Comparative Study on the Therapeutic Effects of Rabbit Ear Acne Skin Lesions

[0035] 1.1 Latex

[0036] A comparative study was conducted on the therapeutic effects of adapalene / dapsone latex (0.1% / 6%), adapalene latex (0.1%), and dapsone latex (6%) on rabbit ear acne.

[0037] Test method:

[0038] The experimental drug formulations are shown in Table 1.

[0039] Table 1

[0040] Modeling, grouping and treatment:

[0041] In addition to the blank control group, 2% coal tar was applied daily to a 2cm x 2cm area at the outlet of the right ear canal of New Zealand white rabbits at a rate of 0.5-1ml per rabbit for 18 consecutive days. Starting on the eighth day, Propionibacterium acnes was injected intradermally into the right ear at 7-8 sites per rabbit, at a rate of 30μL per site, every other day for a total of 6 injections. Twenty-four hours after the last injection, all rabbit ears were photographed and observed, and the number of inflammatory lesions was counted.

[0042] After modeling, the animals were randomly divided into latex matrix group, adapalene latex group (0.1%), dapsone latex group (6%) and adapalene / dapsone latex group (0.1% / 6%).

[0043] After grouping, medication was started, and each group was smeared with the corresponding drug for 2 consecutive weeks. The blank control group did not receive any treatment.

[0044] Evaluation of therapeutic effect: 2 weeks after administration, the inflammatory damage and changes compared with the baseline in each group.

[0045] The results are shown in Table 2.

[0046] Table 2

[0047] The results show:

[0048] After two weeks of treatment, the latex matrix group showed a decrease of 5.4 inflammatory lesions compared to baseline (day 0), while the adapalene / dapsone latex group (0.1% / 6%) showed a decrease of 7.2 lesions, resulting in a net benefit (excluding matrix effects) of 7.2-5.4 = 1.8. The adapalene latex group (0.1%) and the dapsone latex group (6%) showed a decrease of 5.6 and 6.5 lesions, respectively, with a clinical net benefit of 5.6-5.4 = 0.2 and 6.5-5.4 = 1.1 lesions, respectively. Thus, the net benefit of the adapalene / dapsone latex group (1.8) was greater than the sum of the net benefits of the adapalene latex group and the dapsone latex group (0.2 + 1.1 = 1.3), indicating that the combined adapalene / dapsone composition exhibits a synergistic therapeutic effect on inflammatory lesions of acne vulgaris.

[0049] 1.2 Hydrogel

[0050] The inventors of the present disclosure also compared and studied the therapeutic effects of adapalene / dapsone (0.1% / 7.5%), adapalene (0.1%) and dapsone (7.5%) in the hydrogel on rabbit ear acne skin lesions.

[0051] The experimental drugs were adapalene / dapsone hydrogel (0.1% / 7.5%), adapalene hydrogel (0.1%), dapsone hydrogel (7.5%) and hydrogel matrix (without active pharmaceutical ingredients). Except for the drug ingredients and water content, the matrix components and contents of other drugs were the same.

[0052] The test method is the same as in 1.1.

[0053] The results showed that the net benefit of the adapalene / dapsone hydrogel group (0.1% / 7.5%) in treating acne inflammatory lesions was greater than the sum of the net benefits of the adapalene gel (0.1%) group and the dapsone gel (7.5%) group, indicating that the composition of the present disclosure exhibits a synergistic therapeutic effect on acne inflammatory lesions.

[0054] Example 2: Comparative study of skin irritation

[0055] A comparative study was conducted on the skin irritation of Bama miniature pigs after administration of adapalene / dapsone (0.15% / 6%), adapalene / dapsone (0.3% / 7.5%) and adapalene (0.3%).

[0056] Test drug: According to the formulation of Example 1 (except for the drug component and water content, the matrix components and contents of other drugs are the same), the above-mentioned drug was formulated into an emulsion.

[0057] Grouping: Bama miniature pigs were divided into blank control group, latex group (containing only latex carrier), adapalene / dapsone latex group (0.15% / 6%), adapalene / dapsone latex group (0.3% / 7.5%) and adapalene group (0.3%).

[0058] Dosage: Apply transdermally on the back, once a day for 28 consecutive days;

[0059] Preparation before administration: Before administration, remove the fur from the back of the miniature pigs and prepare the skin. The preparation area should be slightly larger than the application area of ​​each animal. The frequency of skin preparation should be at least once a week. Before administration, mark the application area with a marker pen. Pay attention to the skin condition to avoid skin damage. Clean the application area before administration.

[0060] Dosing: Weigh the required amount of test article and apply it evenly to the depilated area on the back of miniature pigs. The dosage and application area of ​​each animal are calculated based on the most recent weight. Application area = dosage ÷ application volume.

[0061] Evaluation indicators:

[0062] Daily observation: 1 to 2 times a day; including but not limited to the pig's physical signs, administration site, coat, general behavior, mental state, glandular secretions, skin and mucous membrane color, respiratory status, fecal characteristics, genitals, death, and other toxic symptoms.

[0063] Irritation score at the administration site: On day 28 of the experiment, the skin irritation score of all pigs in each group was examined. The scoring criteria are shown in Table 3. The mean score of each minipig and each group was calculated, and the irritation intensity was evaluated according to Table 4. The results are shown in Table 5.

[0064] Table 3

[0065] Table 4

[0066] Table 5

[0067] The results showed that on day 28 of the experiment, the irritation score at the administration site of pigs in the adapalene latex group (0.3%) was 0.75 points, with no edema and mild irritation to the skin at the administration site. In addition, on day 28 of the experiment, the irritation score at the administration site of pigs in the other groups was 0 points, with no abnormal symptoms such as erythema and edema, and no irritation to the skin at the administration site.

[0068] In addition, during the administration period, some miniature pigs in the adapalene latex group (0.3%) occasionally developed dorsal erythema. Otherwise, the pigs in the other groups were generally in good condition, with normal autonomous activities, and no deaths or near-deaths were observed, nor were there other obvious signs of toxicity.

[0069] In summary, the pharmaceutical composition of adapalene and dapsone disclosed herein can reduce the skin irritation of adapalene, which was unexpected by the inventors of the present disclosure.

[0070] It will be appreciated from the foregoing that, although specific embodiments of the present disclosure have been described for illustrative purposes, various modifications or variations may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. Such modifications or variations are intended to fall within the scope of the appended claims of the present disclosure.

Claims

1. A composition for synergistically treating acne lesions, based on the total weight of the composition, the composition contains 0.05%-0.5% adapalene and 2%-12% dapsone, and is characterized in that, The acne lesion is an inflammatory lesion.

2. The composition according to claim 1, wherein Based on the total weight of the composition, the composition contains 0.05%-0.2% of adapalene.

3. The composition according to claim 1, wherein Based on the total weight of the composition, the composition contains 4%-8% of dapsone.

4. The composition according to claim 1, characterized in that, Based on the total weight of the composition, the composition contains 0.1% of adapalene and 7.5% of dapsone.

5. The composition according to claim 1, characterized in that, Based on the total weight of the composition, the composition contains 0.1% of adapalene and 6% of dapsone.

6. The composition according to claim 1, wherein Based on the total weight of the composition, the composition contains 0.1% of adapalene and 5% of dapsone.

7. The composition according to claim 1, wherein The treatment of the inflammatory lesion is to reduce the number of inflammatory lesions.

8. The composition according to claim 1, wherein The composition is a pharmaceutical composition loaded on a pharmaceutical carrier.

9. The composition according to claim 8, characterized in that, The pharmaceutical carrier is selected from one or more of latex, hydrogel, emulsion, liposome, vesicle, porous material and nanoemulsion.

10. The composition according to claim 9, wherein The composition is loaded on a latex carrier to prepare a latex agent.

11. The composition according to claim 9, characterized in that, The composition is loaded on a hydrogel carrier to prepare a hydrogel agent.

12. The preparation method of the composition according to any one of claims 1-11, the preparation method includes loading adapalene and dapsone on a pharmaceutical carrier to prepare different dosage forms.

13. Use of the composition according to any one of claims 1-11 in the preparation of a drug for treating acne lesions.

14. Use of the composition according to any one of claims 1-11 in the preparation of a drug for reducing the skin irritation of adapalene.

15. The use according to claim 14, characterized in that, The drug is used for treating acne lesions.

16. A method for treating acne lesions with the composition according to any one of claims 1-11.

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