Pharmaceutical combination and use thereof in treatment of acne

Abstract

Provided are a pharmaceutical combination and the use thereof in the treatment of acne. The pharmaceutical combination contains an antiandrogen, a retinoic acid drug and an antibacterial drug. The pharmaceutical combination has a synergistic effect in the treatment of acne.

Description

A drug combination and its application in the treatment of acne Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a drug combination containing colatel, which can be used to prevent or treat skin diseases. Background Technology

[0002] Acne vulgaris is a chronic inflammatory skin disease affecting the pilosebaceous unit, manifesting as comedones, papules, pustules, cysts, or nodules. Its pathogenesis is mainly related to androgen-induced sebaceous gland hypertrophy and excessive sebum secretion, abnormal keratinization of the pilosebaceous duct opening, abnormal proliferation of microorganisms such as Propionibacterium acnes, and immune inflammatory responses.

[0003] Currently, medications for treating acne include retinoids, antibiotics, and anti-androgens. Retinoids, such as retinoic acid, adapalene, tazarotene, and trafarotine, can inhibit keratinocyte proliferation, suppress sebum secretion, reduce inflammation, promote normal differentiation of hair follicle epithelial cells, and reduce comedone formation. Antibacterial drugs include antibiotics and oxidizing agents. Antibiotics, such as clindamycin, erythromycin, and metronidazole, primarily have antibacterial and bactericidal effects. Oxidizing agents, such as benzoyl peroxide (BPO), promote keratinocyte exfoliation and have antibacterial and anti-inflammatory effects.

[0004] clascoterone is an androgen receptor inhibitor, marketed as [brand name missing]. Approved by the FDA in 2020 for the topical treatment of acne vulgaris, clocatelon competitively binds to arsenic trioxide (AR) with dihydrotestosterone (DHT), limiting DHT's gene transcription and reducing sebum and inflammatory factor production.

[0005] In the prior art, acne treatment involves various combination regimens using different types of drugs. Reference 1 discloses an adapalene-clindamycin hydrochloride compound gel formulation for treating acne, containing 0.1% adapalene and 1% clindamycin hydrochloride by weight percentage, which shows better therapeutic efficacy compared to using adapalene or clindamycin hydrochloride alone. Reference 2 discloses a topical gel formulation containing clindamycin phosphate, benzoyl peroxide, and adapalene; clinical trial results showed that the three-component gel did not show an advantage in adverse event outcomes compared to the two-component gel. Although the prior art has explored various combination regimens of different types of acne treatment drugs, treatment outcomes are difficult to predict. Therefore, seeking combination regimens with better therapeutic effects and fewer side effects is of great significance for the treatment of acne.

[0006] Reference 1: CN 101485675 B.

[0007] Reference 2: CN 114126582 A. Summary of the Invention

[0008] In a first aspect, the present invention provides a pharmaceutical combination comprising:

[0009] (1) Antiandrogen drugs;

[0010] (2) Retinoic acid drugs;

[0011] And / or (3) antibacterial drugs.

[0012] The anti-androgen drugs include cloterone, furaten, or their salts or esters; preferred anti-androgen drugs are cloterone or their salts or esters, and more preferably cloterone.

[0013] The retinoids include retinoic acid, isotretinoin, isotretinoin, adapalene, tazarotene, trafarotine, etc., or their salts or esters. Preferred retinoids are adapalene, tazarotene, or trafarotine, or their salts or esters, with adapalene being a more preferred retinoid.

[0014] The antibacterial drugs include antibiotics, oxidizing agents, etc., including erythromycin, lincomycin, clindamycin, chloramphenicol, clindamycin, minocycline, sarrencycline, doxycycline, fusidic acid, polymyxin B, metronidazole, tinidazole, mupirocin, naflufloxacin, benzoyl peroxide, salicylic acid, azelaic acid, nicotinamide, etc. Preferred antibacterial drugs are clindamycin or its salts, esters, or benzoyl peroxide.

[0015] As one embodiment of the present invention, the drug combination comprises:

[0016] (1) Antiandrogen drugs;

[0017] (2) Retinoic acid drugs;

[0018] (3) Antibacterial drugs.

[0019] As one embodiment of the present invention, the drug combination comprises:

[0020] (1) Coratelon;

[0021] (2) Adapalene or trefarotin;

[0022] (3) Clindamycin or its salts, esters or benzoyl peroxide.

[0023] As one embodiment of the present invention, the drug combination comprises:

[0024] (1) Coratelon;

[0025] (2) Adapalene;

[0026] (3) Clindamycin phosphate.

[0027] As one embodiment of the present invention, the drug combination comprises:

[0028] (1) 1.5-2% of croton;

[0029] (2) 0.1% adapalene;

[0030] (3) 1.0% of clindamycin or its salts or esters.

[0031] As one embodiment of the present invention, the drug combination comprises:

[0032] (1) 1.5% of croton;

[0033] (2) 0.1% adapalene;

[0034] (3) 1.0% clindamycin phosphate.

[0035] As one embodiment of the present invention, the drug combination comprises:

[0036] (1) 2% of cyclophosphamide;

[0037] (2) 0.1% adapalene;

[0038] (3) 1.0% clindamycin phosphate.

[0039] As one embodiment of the present invention, the drug combination comprises:

[0040] (1) Coratelon;

[0041] (2) Adapalene;

[0042] (3) Benzoyl peroxide.

[0043] The three drugs in the drug combination of the present invention can be administered simultaneously or at staggered times; the three drugs in the drug combination of the present invention can be combined into a drug box by combining the three drugs into independent formulations; or any two drugs can be prepared into a single formulation and then combined with a formulation of another drug to form a drug box; or the three drugs can be prepared into a single formulation composition.

[0044] In another aspect, the present invention provides a compound preparation comprising the aforementioned drug combination and pharmaceutical excipients.

[0045] As one embodiment of the present invention, the compound preparation contains:

[0046] (1) Antiandrogen drugs;

[0047] (2) Retinoic acid drugs;

[0048] (3) Antibacterial drugs;

[0049] And pharmaceutical excipients.

[0050] In the compound preparation, the anti-androgen drug is selected from claterone; the retinoic acid drug is selected from adapalene or trafarotine; and the antibacterial drug is selected from clindamycin or its salts, esters or benzoyl peroxide.

[0051] As one embodiment of the present invention, the compound preparation contains:

[0052] (1) 1.5-2% of croton;

[0053] (2) 0.1% adapalene;

[0054] (3) 1.0% clindamycin or its salts or esters;

[0055] And pharmaceutical excipients.

[0056] As one embodiment of the present invention, the compound preparation contains:

[0057] (1) 1.5% of croton;

[0058] (2) 0.1% adapalene;

[0059] (3) 1.0% clindamycin phosphate;

[0060] And pharmaceutical excipients.

[0061] As one embodiment of the present invention, the compound preparation contains:

[0062] (1) 2% of cyclophosphamide;

[0063] (2) 0.1% adapalene;

[0064] (3) 1.0% clindamycin phosphate;

[0065] And pharmaceutical excipients.

[0066] The pharmaceutical excipients described in this invention are selected from one or more of the following: gel matrix, penetration enhancer, stabilizer, pH adjuster, dispersant, thickener, emulsifier, preservative, surfactant, chelating agent, wetting agent, polymer, oil or solvent.

[0067] The compound preparations described in this invention can be gels, creams, lotions, solutions, sprays, suspensions, foams, or lotions, preferably gels, creams, or lotions.

[0068] In another aspect, the present invention provides the use of therapeutically effective amounts of (1) an anti-androgen drug, (2) a retinoic acid drug and (3) an antibacterial drug in the preparation of a medicament for the prevention or treatment of skin diseases.

[0069] As one embodiment of the present invention, the use of therapeutically effective amounts of (1) colatelone, (2) adapalene and (3) clindamycin or their salts or esters in the preparation of a medicament for the prevention or treatment of skin diseases is provided.

[0070] As one embodiment of the present invention, the use of therapeutically effective amounts of (1) 1.5-2% of kelatalon, (2) 0.1% of adapalene and (3) 1% of clindamycin or their salts or esters in the preparation of a medicament for the prevention or treatment of skin diseases is provided.

[0071] As one embodiment of the present invention, the use of therapeutically effective amounts of (1) 1.5% of kelatalon, (2) 0.1% of adapalene and (3) 1% of clindamycin phosphate in the preparation of a medicament for the prevention or treatment of skin diseases is provided.

[0072] As one embodiment of the present invention, the use of therapeutically effective amounts of (1) 2% kelatalon, (2) 0.1% adapalene and (3) 1% clindamycin phosphate in the preparation of a medicament for the prevention or treatment of skin diseases is provided.

[0073] As one embodiment of the present invention, the use of a compound preparation containing (1) 1.5-2% kelatalon, (2) 0.1% adapalene and (3) 1% clindamycin or their salts or esters in the preparation of a medicament for the prevention or treatment of skin diseases is provided.

[0074] As one embodiment of the present invention, the use of a compound preparation containing (1) 1.5% kelatalon, (2) 0.1% adapalene and (3) 1% clindamycin phosphate in the preparation of a medicament for the prevention or treatment of skin diseases is provided.

[0075] As one embodiment of the present invention, the use of a compound preparation containing (1) 2% kelatalon, (2) 0.1% adapalene and (3) 1% clindamycin phosphate in the preparation of a medicament for the prevention or treatment of skin diseases is provided.

[0076] As one embodiment of the present invention, the use of therapeutically effective amounts of (1) kelatalon, (2) adapalene and (3) benzoyl peroxide in the preparation of a medicament for the prevention or treatment of skin diseases is provided.

[0077] The skin diseases described in this invention include proliferative, inflammatory, or keratotic skin diseases. These skin diseases include acne, pimples, papules, pustules, cysts, nodules, seborrheic dermatitis, eczema, psoriasis, ichthyosis, keratosis, or post-inflammatory hyperpigmentation. Preferably, the skin disease is acne.

[0078] In the drug combination, compound preparation or therapeutic use described in this invention, there are no particular restrictions on the dosage of the three drugs; specifically, the content of the anti-androgen drug is 0.1-15%; the content of the retinoid drug is 0.01-10%; and the content of the antibacterial drug is 0.1-15%.

[0079] As one embodiment of the present invention, the drug combination, compound preparation or therapeutic use contains 1.5-2% of cloterone.

[0080] In one embodiment of the present invention, the pharmaceutical combination, compound preparation, or therapeutic use contains 1%, 1.5%, 2%, 5%, or 10% of colatalon. Preferably, it contains 1.5% or 2% colatalon.

[0081] In one embodiment of the present invention, the drug combination, compound preparation, or therapeutic use contains 0.1%, 0.15%, or 0.3% adapalene. Preferably, it contains 0.1% adapalene.

[0082] In one embodiment of the present invention, the drug combination, compound preparation, or therapeutic use contains 1%, 1.5%, or 2% clindamycin or its salts or esters. Preferably, it contains 1% clindamycin or its salts or esters.

[0083] In one embodiment of the present invention, the pharmaceutical combination, compound preparation, or therapeutic use contains 1% or 2% clindamycin phosphate. Preferably, it contains 1% clindamycin phosphate.

[0084] As one embodiment of the present invention, the drug combination, compound preparation or therapeutic use contains 2.5%, 3%, 3.1%, 3.75% or 5% benzoyl peroxide.

[0085] The drug combination described in this invention contains anti-androgen drugs, retinoids, and / or antibacterial drugs, achieving a synergistic effect in the treatment of acne.

[0086] Specifically, the drug combination of the present invention contains kelatadine, adapalene, and clindamycin or its salts, esters, or benzoyl peroxide, and the drug combination has a significant therapeutic effect on acne. Furthermore, the therapeutic effect of the drug combination is superior to that of a compound preparation containing any two of the ingredients; the drug combination of the present invention achieves a synergistic effect. Attached Figure Description

[0087] Figure 1: Ear thickness of rats in each group in Example 4.

[0088] Figure 2: Swelling rate of rats in each group in Example 4.

[0089] Figure 3: IL-6 content of inflammatory factor in rats in each group in Example 4.

[0090] Figure 4: Symptom scores of rats in each group in Example 4. Detailed Implementation

[0091] Terminology Explanation

[0092] The "Kolactron" described in this invention has the following chemical structure:

[0093] In this invention, the content of "anti-androgen drugs," "retinoin drugs," "antibacterial drugs," "colatalon," "adapalene," "clindamycin or its salts or esters," or "benzoyl peroxide," etc., refers to the weight percentage of the free form of the active ingredient in its unit formulation. For example, a content of "1%" means that the weight percentage of the active ingredient in the unit formulation is 1% based on the free form of the drug. When prepared as a compound formulation, the content refers to the weight percentage of the active ingredient in the compound formulation based on the free form of the drug. For example, a 1% content of clindamycin phosphate means that the content of clindamycin in the unit formulation is 1%, or approximately 1.2% based on the content of clindamycin phosphate in the unit formulation.

[0094] The content of the anti-androgen drug described in this invention is 0.1-15%, preferably 0.1-10%; the specific content includes 1%, 2%, 3%, 4%, 5%, 6%, 8% or 10%.

[0095] The content of the retinoic acid drug described in this invention is 0.01-10%, preferably 0.01-5%; the specific content includes 0.1%, 0.15%, 0.3%, 0.5%, 1.0% or 2.0%.

[0096] The content of the antibacterial drug described in this invention is 0.1-15%, preferably 0.1-10%; the specific content includes 1%, 2%, 2.5%, 3%, 3.1%, 3.5%, 3.75% or 5%.

[0097] The clindamycin or its salts described in this invention include clindamycin, clindamycin hydrochloride, clindamycin phosphate, etc. The clindamycin or its esters described in this invention include clindamycin and clindamycin phosphate.

[0098] The "therapeutic effective dose" as described in this invention refers to the minimum dose that has a therapeutic effect on the disease.

[0099] The technical solution of the present invention will be further illustrated below through specific embodiments. These embodiments are merely illustrative of the invention and should not be construed as limiting its scope.

[0100] Example 1: Preparation of Compound Preparation

[0101] Table 1 Formulation Prescription

[0102] According to the formulations in Table 1, carbomer was dispersed in water and allowed to swell fully. Adapalene aqueous dispersion was added and stirred evenly. Corateron aqueous dispersion was added and stirred evenly. Clindamycin phosphate aqueous solution was added and stirred evenly. Water was added to 100% and stirred evenly to obtain formulations of the same specifications.

[0103] Example 2: Animal Acne Efficacy Test

[0104] Grouping: SD rats, weighing 180-220g. Healthy SD rats were randomly divided into 8 groups according to their weight, with 10 rats in each group: normal control group, model group, preparation group 1, control group 1-1, control group 1-2, control group 1-3, control group 1-4, solvent group, and positive control group.

[0105] Modeling: In the normal control group, 50 μL of sterile saline was injected intradermally into the right auricle of rats. In the other groups, 50 μL of Propionibacterium acnes solution was injected intradermally into the right auricle once a day for 7 consecutive days. The left ear of each group of rats served as the self-control.

[0106] Administration: After 7 consecutive days of modeling, administration began on the 8th day. The normal control group and the model group were given saline solution, the solvent group was given a blank gel without drugs, and the other groups were given drugs according to their grouping. The drugs were administered once a day for 14 consecutive days (topical administration).

[0107] Fourteen days after administration, the rats were euthanized, and both ears were cut off along the auricular baseline. A portion of the earlobe was harvested from the same location on both ears and weighed using an electronic balance. The weight of the right earlobe minus the weight of the left earlobe for each rat was the degree of swelling. The degree of swelling and the swelling inhibition rate for each group were calculated and statistically analyzed.

[0108] in:

[0109] Swelling degree = Weight of right earpiece after drug administration - Weight of left earpiece

[0110] Swelling rate = (Auricular thickness after treatment - Auricular thickness before treatment) / Auricular thickness before treatment * 100%

[0111] Swelling inhibition rate = (Average swelling degree of model group - Average swelling degree of treatment group) / Average swelling degree of model group * 100%

[0112] Indicator Testing:

[0113] Body weight: During and after the modeling process, the vital signs of the rats were observed, and their body weight was measured twice a week.

[0114] Symptom scoring: Changes in the skin lesions were recorded before and after administration. The skin of the ear was evaluated and scored according to its condition. Each clinical symptom was scored as 0 (none), 1 (mild), 2 (moderate), and 3 (severe). The symptom scores of each animal were totaled.

[0115] Auricular thickness, inflammatory factors, and pathological sections: The thickness of the left and right auricles of rats was measured using calipers (measured every 3 days). After the administration of the drug, the rats were euthanized, and the swelling degree and swelling inhibition rate of each group were calculated and statistically analyzed.

[0116] In addition, a portion of the infected ear was homogenized and inflammatory factors (such as TNF-α, IL-6, and IL-1β) were detected. The remaining ear portion was fixed in 10% formaldehyde, embedded, sectioned, stained with hematoxylin and eosin (HE), and observed under a light microscope.

[0117] Experimental results:

[0118] After modeling, the swelling of the right ear of the rats increased significantly, the skin was obviously red and swollen, and the inflammatory cell infiltration and epidermal thickness at the injection site increased, thus forming an acne model.

[0119] Formulation 1 significantly reduced swelling in the right ear of rats, increased the swelling inhibition rate, and improved skin condition scores, showing a significant difference compared to the model group.

[0120] The therapeutic effect of formulation 1 was significantly better than that of any two-component combination formulation (control formulations 1-2, 1-3, or 1-4), and also better than the sum of control formulations 1-1 and 1-2, indicating that the three-component combination formulation of the present invention achieved a synergistic effect.

[0121] Example 3: Preparation of Compound Preparation

[0122] Pharmaceutical formulation

[0123] Preparations 3-1, 3-2 and 3-3 were prepared according to the method described in Exercise 1.

[0124] Example 4: Animal Acne Efficacy Test

[0125] Animal acne efficacy tests were conducted on formulation 1 of Example 1 and formulations 3-1, 3-2 and 3-3 of Example 3 according to the method of Example 2.

[0126] Experimental results:

[0127] Compared with the model group, formulations 1, 3-1, 3-2, and 3-3 significantly reduced the auricle thickness and swelling rate, decreased the content of the inflammatory factor IL-6, and also reduced side effects (symptom scores) in rats after modeling. The therapeutic effect (auricle thickness and swelling rate) of formulation 1 was slightly better than that of formulation 3-3, and the therapeutic effects of formulations 1 and 3-3 were significantly better than those of formulations 3-1 and 3-2; the side effects (symptom scores) of formulations 1 and 3-3 were also significantly lower than those of formulations 3-1 and 3-2 (see Figures 1-4 in the instructions).

Claims

1. A pharmaceutical combination comprising: (1) 1.5-2% of croton; (2) 0.1% adapalene; (3) 1.0% of clindamycin or its salts or esters.

2. The drug combination according to claim 1, wherein the clindamycin or its salt or ester is clindamycin hydrochloride or clindamycin phosphate.

3. The pharmaceutical combination according to claim 1, wherein the pharmaceutical combination comprises: (1) 1.5% or 2% of croton; (2) 0.1% adapalene; (3) 1.0% clindamycin phosphate.

4. A compound preparation comprising the drug combination of claim 1 and pharmaceutical excipients.

5. The compound preparation according to claim 4, wherein the compound preparation comprises: (1) 1.5% or 2% of croton; (2) 0.1% adapalene; (3) 1.0% clindamycin phosphate.

6. The compound preparation according to claim 4, wherein the pharmaceutical excipient is selected from one or more of the following: gel matrix, penetration enhancer, stabilizer, pH adjuster, dispersant, thickener, emulsifier, preservative, surfactant, chelating agent, wetting agent, polymer, oil or solvent.

7. The compound preparation according to claim 4, wherein the compound preparation is selected from gels, creams, lotions, solutions, sprays, suspensions, foams, or lotions; preferably gels, creams, or lotions.

8. Use of a therapeutically effective amount of (1) 1.5-2% of kelatalon, (2) 0.1% of adapalene and (3) 1% of clindamycin or their salts or esters in the preparation of a medicament for the prevention or treatment of skin diseases.

9. The use according to claim 8, the use of a therapeutically effective amount of (1) 1.5% or 2% of kelatalon, (2) 0.1% of adapalene and (3) 1% of clindamycin phosphate in the preparation of a medicament for the prevention or treatment of skin diseases.

10. The use according to claim 8, wherein the skin disease includes proliferative, inflammatory, or keratotic skin diseases; preferably, the skin disease includes acne, pimples, papules, pustules, cysts, nodules, seborrheic dermatitis, eczema, psoriasis, ichthyosis, keratosis, or post-inflammatory hyperpigmentation; preferably, the skin disease is acne.

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