Topical composition

Abstract

To provide a topical composition useful for the treatment of inflammatory skin diseases, including acne.SOLUTION: Provided is a topical gel formulation comprising 1-1.5 wt.% clindamycin phosphate, 2.5-3.5 wt.% benzoyl peroxide, and 0.1-0.2 wt.% adapalene, in combination with a gelling agent, a polyhydric alcohol, and water.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to topical compositions for the treatment of skin diseases including acne. In particular, the present disclosure provides topical compositions containing three different active ingredients, and methods for their manufacture and use.

Background Art

[0002] Acne (acne vulgaris) is a very common disorder of the sebaceous follicles, most commonly seen in adolescents in their teens, and is usually caused by an increase in androgen production occurring during puberty. Acne generally resolves by the age of 25, but about 3% - 8% of adults aged 25 - 44 suffer from acne. The etiology is complex and involves four main features: stimulation of sebaceous gland activity, bacterial proliferation (in particular Cutibacterium acnes, previously known as Propionibacterium acnes), abnormal follicular keratinization and resultant sebaceous follicle occlusion, and release of inflammatory mediators. These changes in acne patients result in the formation of clinical inflammatory lesions, including superficial pustules such as pimples (commonly known as "blackheads" or "whiteheads"), and deeper located papules, nodules and cysts. The areas most affected by this disease include the follicles of the sebaceous glands on the head and the upper half of the trunk, where the sebaceous glands are particularly active.

[0003] Increased production of sebum and keratin, which cause acne, is affected by an individual's genetics, a variety of drugs (such as corticosteroids, androgens, or halogens such as lithium, azathioprine, haloperidol, vitamin D, vitamin B12, iodide or bromide, phenytoin, or phenobarbital), and other possible factors such as diet and stress. Increased production of sebum and keratin is correlated with elevated levels of various hormones, including androgens (such as testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA)), growth hormone (GH), and insulin-like growth factor 1 (IGF-1). Infection of hair follicles by anaerobic bacteria (such as C. acnes) and / or the parasitic mite Demodex folliculorum may exacerbate the disease, although it is unclear whether the infection is involved in the onset of the disease.

[0004] Current treatment options for acne include (i) retinoids, and retinoid-like drugs such as tretinoin (Avita, Retin-A, etc.), adapalene (Differin), and tazarotene (Tazorac, Avage); antibiotics including clindamycin in combination with benzoyl peroxide (Benzaclin, Duac, Acanya), and erythromycin in combination with benzoyl peroxide (Benzamycin); salicylic acid and azelaic acid; and dapsone (Aczone).

[0005] Benzoyl peroxide is commonly found in over-the-counter products for treating acne and in prescription drugs combined with antibiotics. Although the exact mechanism of action is unknown, it is bactericidal, may break down keratin, remove pore blockages, and inhibit sebum production. However, benzoyl peroxide is a strong oxidizing agent and is often formulated in strong organic solvents because it is poorly soluble in water, so benzoyl peroxide formulations can cause local irritation. Also, due to its high chemical reactivity, it is incompatible with many other compounds.

[0006] Topical clindamycin can be administered in the form of clindamycin phosphate ester, which is a phosphate ester prodrug of clindamycin. Clindamycin has an anti-inflammatory effect in addition to the effect of antibiotics. One of the drawbacks of clindamycin (and other antibiotics) is the risk of the emergence of antibiotic-resistant bacteria on the skin.

[0007] Adapalene is a retinoid compound that is an agonist of specific retinoic acid nuclear receptors. It regulates cell differentiation, keratinization, and the inflammatory process, and topical formulations are approved for the treatment of acne. The exact mechanism of action of adapalene is unknown, but it may normalize the differentiation of follicular epithelial cells and reduce microcomedone formation.

[0008] Combination products have been tried, but the results are completely unpredictable. For example, Bowman, S et al. in “Comparison of clindamycin / benzoyl peroxide, tretinoin plus clindamycin, and the combination of clindamycin / benzoyl peroxide and tretinoin plus clindamycin in the treatment of acne vulgaris: a randomized, blinded study.” J Drugs Dermatol. 2005 Sep - Oct;4(5):611 - 8 reported that a regimen containing clindamycin / benzoyl peroxide was more effective than the combination of retinoid (tretinoin) and clindamycin in the treatment of acne, but there was no clinical advantage in adding the combination of retinoid and clindamycin to once - daily clindamycin / benzoyl peroxide treatment. Similar results were also seen in a large - scale trial studying the treatment with a combination of 5% benzoyl peroxide / 1% clindamycin gel and tazarotene, a different retinoid. Clinical trial NCT00713609 (available at clinicaltrials.gov) had its results posted in March 2017. After 12 weeks, there was said to be no statistically significant difference among the active combination treatment groups in the reduction of lesion counts. The three combinations were no better, and in fact the reduction in lesion counts was numerically lower, compared to the two single - agent treatments. Often, such combination therapies involve taking one or two drugs in the morning and one or more other drugs in the evening, which is not more convenient for patients than once - daily treatment, but may reduce unpredictable harmful interactions between the drugs.

[0009] Although various treatments for acne are known, more effective treatments are still needed. The lack of understanding and consensus regarding both the complex etiology of the disease and the exact mechanisms of action of common therapeutic agents makes it difficult to design effective treatments, and costly clinical trials are required to demonstrate efficacy and the lack of side effects. Simply increasing the concentration of existing active agents can lead to irritation and other side effects. Combinations of active agents can be limited due to unpredictable chemical interactions between drugs, unpredictable effects on the delivery of one drug by another, unpredictable efficacy, and the potential for unpredictable side effects. There is a need for improved formulations for treating acne that are more effective and without unacceptable side effects.

Summary of the Invention

[0010] Surprisingly, it has been found that a topical gel containing a specific combination of benzoyl peroxide, clindamycin phosphate, and adapalene significantly enhances efficacy compared to gels containing any two combinations of these agents.

[0011] Each of these agents has some anti-inflammatory activity; both benzoyl peroxide and clindamycin phosphate reduce the growth of C. acnes; benzoyl peroxide is also keratolytic; and adapalene further regulates keratinization (Zaenglein 2008). The combination therapeutic agent at a given dose improves patient adherence with a simplified application regimen (e.g., once daily as opposed to a morning / evening series of administrations of each active agent) and is optimal for eliminating incompatibilities of substances due to application errors (e.g., oxidation due to the use of an incompatible single-agent drug). However, whether such a formulation at a given dose could be designed to be stable, safe, and effective required empirical testing.

[0012] In one embodiment, the present disclosure provides a topical gel formulation comprising 1 to 1.5% by weight (e.g., about 1.2% by weight) of clindamycin phosphate, 2.5 to 3.5% by weight (e.g., about 3.1% by weight) of benzoyl peroxide, and 0.1 to 0.2% by weight (e.g., about 0.15% by weight) of adapalene, in combination with a gelling agent (e.g., carbomer homopolymer), a polyhydric alcohol (e.g., propylene glycol), and water.

[0013] In another embodiment, the present disclosure provides a method for treating acne vulgaris, which includes administering to an affected area, for example, once a day, for at least 12 weeks, a topical gel formulation comprising 1 to 1.5% by weight (e.g., about 1.2% by weight) of clindamycin phosphate, 2.5 to 3.5% by weight (e.g., about 3.1% by weight) of benzoyl peroxide, and 0.1 to 0.2% by weight (e.g., about 0.15% by weight) of adapalene, in combination with a gelling agent (e.g., carbomer homopolymer), a polyhydric alcohol (e.g., propylene glycol), and water.

[0014] In another embodiment, the present disclosure provides a method for manufacturing a topical gel formulation, such as the above, which includes mixing 1 to 1.5% by weight (e.g., about 1.2% by weight) of clindamycin phosphate, 2.5 to 3.5% by weight (e.g., about 3.1% by weight) of benzoyl peroxide, 0.1 to 0.2% (e.g., about 0.15% by weight) of adapalene, a gelling agent (e.g., carbomer homopolymer), a polyhydric alcohol (e.g., propylene glycol), and water to form a dispersion, and then adjusting the pH of the mixture to pH 5 to 6.

[0015] Further areas of applicability of the present disclosure will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating the preferred embodiments of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.

Mode for Carrying Out the Invention

[0016] The following description of the preferred embodiments is merely exemplary in nature and is in no way intended to limit the invention, its application, or its use.

[0017] In a first embodiment, the present disclosure provides a topical gel formulation (Formulation 1) comprising 1 to 1.5 wt% clindamycin phosphate, 2.5 to 3.5 wt% benzoyl peroxide, and 0.1 to 0.2 wt% adapalene, and a gelling agent, a polyhydric alcohol, and water, and for example, the following may be mentioned: 1.1. Formulation 1 in which the concentration of clindamycin phosphate is about 1.2 wt%. 1.2. Formulation 1 or 1.1 in which the concentration of benzoyl peroxide is about 3.1 wt%. 1.3. Any of the above formulations in which the concentration of adapalene is about 0.15 wt%. 1.4. Any of the above formulations in which the gelling agent is selected from hydroxypropyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer (which may optionally be cross-linked with allyl ether of polyalcohol, for example, carbomer), carboxyvinyl copolymer, polyacrylate, acrylate copolymer, acrylamide / sodium acryloyldimethyltaurate copolymer, polyvinyl alcohol, polyethylene oxide, propylene glycol alginate, methyl cellulose, hydroxypropyl methyl cellulose, xanthan gum, carrageenan gum, and combinations thereof. 1.5. Any of the above formulations in which the gelling agent is selected from carboxyvinyl polymer (which may optionally be cross-linked with allyl ether of polyalcohol, for example, carbomer), carboxyvinyl copolymer, polyacrylate, acrylate copolymer, acrylamide / sodium acryloyldimethyltaurate copolymer, propylene glycol alginate, hydroxypropyl methyl cellulose, and xanthan gum. 1.6. Any of the above formulations in which the gelling agent comprises acrylamide / sodium acryloyldimethyltaurate copolymer. 1.7. The gelling agent contains an acrylamide acryloyldimethyltaurine sodium / isostearane / polysorbate 80 gelling agent, and any of the above-mentioned formulations. 1.8. The gelling agent contains a carbomer homopolymer crosslinked with an allyl ether of a polyalcohol (for example, allyl sucrose or allyl pentaerythritol), and any of the above-mentioned formulations. 1.9. The gelling agent is a polymer of acrylic acid crosslinked with an allyl ether of a polyalcohol, which contains, for example, 56% to 68% of carboxylic acid groups (-COOH); for example, the viscosity (measured at 0.5 wt%, pH 7.5) is 40,000 to 60,000 cPs, and any of the above-mentioned formulations. 1.10. The gelling agent is of the carbomer homopolymer type C, for example, as defined by the monograph of the United States Pharmacopeia / National Formulary (USP / NF), for example, Carbopol 980, and any of the above-mentioned formulations. 1.11. The amount of the gelling agent is 1.5 to 2 wt%, and any of the above-mentioned formulations. 1.12. The amount of the gelling agent is about 1.75 wt%, and any of the above-mentioned formulations. 1.13. The gelling agent is a carbomer homopolymer type C in an amount of about 1.75 wt%, and any of the above-mentioned formulations. 1.14. The pH of the formulation is pH 5 to 6, and any of the above-mentioned formulations. 1.15. The gelling agent is a crosslinked polymer containing a carboxy moiety, and the formulation further contains a base selected from potassium hydroxide, sodium hydroxide, and combinations thereof in an amount sufficient to deprotonate the carboxy moiety in an amount sufficient to thicken the gelling agent, and any of the above-mentioned formulations. 1.16. The formulation contains a base selected from potassium hydroxide, sodium hydroxide, and combinations thereof in an amount that results in a pH of 5 to 6, and any of the above-mentioned formulations. 1.17. The formulation contains potassium hydroxide in an amount that results in a pH of 5 to 6, and any of the above-mentioned formulations. 1.18. Any of the above formulations, wherein a part of benzoyl peroxide is undissolved and the undissolved part of benzoyl peroxide is uniformly dispersed in the formulation. 1.19. Any of the above formulations, wherein a part of benzoyl peroxide is undissolved and the undissolved part of benzoyl peroxide has an average particle size of 1 to 50 microns, for example, 2.5 to 30 microns. 1.20. Any of the above formulations, wherein benzoyl peroxide is neither encapsulated nor entrained in the microsponge. 1.21. Any of the above formulations, wherein benzoyl peroxide is free and not restricted by a complex or polymer. 1.22. Any of the above formulations, wherein a part of adapalene is undissolved and the undissolved part of adapalene is uniformly dispersed in the formulation. 1.23. Any of the above formulations, wherein a part of adapalene is uniformly dispersed in the formulation without dissolution, and a part of benzoyl peroxide is also uniformly dispersed in the formulation without dissolution. 1.24. Any of the above formulations, wherein adapalene and benzoyl peroxide do not undergo a substantial chemical reaction with each other. 1.25. Any of the above formulations, wherein the polyhydric alcohol is selected from propylene glycol, ethoxydiglycol, polyethylene glycol (for example, PEG400), glycerol, and combinations thereof. 1.26. Any of the above formulations, wherein the polyhydric alcohol is selected from 1,2 - propylene glycol and 1,3 - propylene glycol. 1.27. Any of the above formulations, wherein the polyhydric alcohol is 1,2 - propylene glycol. 1.28. Any of the above formulations, wherein the weight of the polyhydric alcohol in the formulation is 1 to 4 times (for example, 1 to 2 times) the amount of benzoyl peroxide. 1.29. Any of the above formulations, wherein the weight ratio of water to polyhydric alcohol in the formulation is 10:1 to 20:1. 1.30. Any of the above formulations, wherein the amount of the polyhydric alcohol is 3 to 7% by weight. 1.31. Any of the above formulations wherein the amount of polyhydric alcohol is about 5% by weight. 1.32. Any of the above formulations wherein the polyhydric alcohol is propylene glycol in an amount of about 5% by weight. 1.33. Any of the above formulations wherein the amount of water is 80% to 90% by weight, for example, 85% to 90% by weight. 1.34. Any of the above formulations wherein the formulation contains about 1.2% by weight of clindamycin phosphate, about 3.1% by weight of benzoyl peroxide, and about 0.15% by weight of adapalene. 1.35. The formulation is about 1.2% by weight of clindamycin phosphate, about 3.1% by weight of benzoyl peroxide, about 0.15% by weight of adapalene, about 5% by weight of propylene glycol, about 1.75% by weight of carbomer homopolymer type C, potassium hydroxide in an amount to provide a pH of 5 to 6, and water, and any of the above formulations containing 1.36. A formulation containing about 1.2% by weight of clindamycin phosphate, about 3.1% by weight of benzoyl peroxide, and about 0.15% by weight of adapalene, wherein the formulation is clinically biologically equivalent to the previously described formulations, for example, it is shown by one or more of (a) a clinical endpoint bioequivalence study, (b) an in vitro permeation test (IVPT), and / or (c) an in vitro release test (IVRT). 1.37. Any of the above formulations wherein the formulation does not contain an ionic surfactant. 1.38. Any of the above formulations wherein the formulation does not contain an organic solvent other than polyhydric alcohol. 1.39. Any of the above formulations wherein the content of ethanol or isopropanol is less than 2%, for example, does not contain ethanol and isopropanol. 1.40. Any of the above formulations, wherein the formulation is substantially free of monohydric alcohol. 1.41. Any of the above formulations, wherein the formulation is aqueous. 1.42. Any of the above formulations, wherein the formulation is single-phase. 1.43. Any of the above formulations, wherein the formulation is not an emulsion. 1.44. Any of the above formulations, wherein the formulation is free of mineral oil. 1.45. Any of the above formulations, wherein the formulation is free of polymers other than gelling agents. 1.46. Any of the above formulations, wherein the formulation is free of polymers other than carbomer homopolymers. 1.47. Any of the above formulations, wherein the formulation is free of preservatives or antibacterial agents other than benzoyl peroxide and adapalene. 1.48. Any of the above formulations, wherein the active ingredient is only clindamycin phosphate, benzoyl peroxide, and adapalene. 1.49. Any of the above formulations, further comprising one or more additional inert components selected from humectants, emollients, pH stabilizers, preservatives, chelating agents, and antioxidants. 1.50. Any of the above formulations, further comprising an effective amount of a preservative selected from, for example, para-hydroxybenzoic acid preservatives (parabens), for example, those selected from methylparaben, propylparaben, and combinations thereof. 1.51. Any of the above formulations, produced by mixing 1 to 1.5% by weight of clindamycin phosphate, 2.5 to 3.5% by weight of benzoyl peroxide, 0.1 to 0.2% by weight of adapalene, a gelling agent, polyhydric alcohol, and water to form a homogeneous dispersion, and then adding a base selected from potassium hydroxide, sodium hydroxide, and combinations thereof in an amount that provides a pH of 5 to 6. 1.52. Any of the above formulations, wherein clindamycin phosphate, benzoyl peroxide, and adapalene are present at effective concentrations for treating acne when the formulation is administered once daily to the affected area for at least 4, 6, or 8 weeks, for example, at least 12 weeks. 1.53. Any of the above preparations, wherein the preparation has fewer side effects than a preparation containing 2.5 to 3.5% by weight of benzoyl peroxide and 0.1 to 0.2% by weight of adapalene. 1.54. Any of the above preparations, wherein the preparation does not have significantly more side effects than a preparation containing 2.5 to 3.5% by weight of benzoyl peroxide and 0.1 to 0.2% by weight of adapalene. 1.55. Any of the above preparations, which is more effective in the treatment of acne than a preparation containing an active ingredient selected from (i) 1 to 1.5% by weight of clindamycin phosphate and 2.5 to 3.5% by weight of benzoyl peroxide, (ii) 2.5 to 3.5% by weight of benzoyl peroxide and 0.1 to 0.2% by weight of adapalene, and (iii) 1 to 1.5% by weight of clindamycin phosphate and 0.1 to 0.2% by weight of adapalene. 1.56. Any of the above preparations, wherein the preparation is stable at room temperature for at least 6 weeks, for example, at least 10 weeks. 1.57. Any of the above preparations, which is stable when refrigerated, for example, at 2°C to 8°C (36°F to 46°F), before being dispensed to a patient, and then stable at room temperature, for example, at 25°C (77°F) or lower, for at least 6 weeks, for example, at least 10 weeks. 1.58. Any of the above preparations for use in the treatment of acne, for example, by daily topical application to the affected area, for example, according to any of Method 1 below. 1.59. Any of the above preparations obtained or obtainable by any of the methods below Method 2.

[0018] In another embodiment, the present disclosure provides a pharmaceutical product which is a container containing any of Preparations 1 to 1.59, for example, a pump container or a deformable tube containing any of Preparations 1 to 1.59, for example, a container equipped with a pump and containing any of Preparations 1 to 1.59, wherein the pump is adjusted to discharge a specific amount of the preparation (for example, 0.5 to 1 cubic centimeter, for example, an amount the size of a pea) each time the pump is pressed.

[0019] In another embodiment, the present disclosure provides a method (Method 1) for treating acne vulgaris in a patient in need thereof, comprising administering a topical gel formulation containing at least once a day to the affected area, 1 to 1.5 wt% (e.g., about 1.2 wt%) of clindamycin phosphate, 2.5 to 3.5 wt% (e.g., about 3.1 wt%) of benzoyl peroxide, and 0.1 to 0.2 wt% (e.g., about 0.15 wt%) of adapalene, a gelling agent (e.g., carbomer homopolymer), a polyhydric alcohol (e.g., propylene glycol), and water. For example, the present disclosure provides the following method: 1.1. Method 1, wherein the administration is once a day. 1.2. Method 1 or 1.1, wherein the affected area is the face, neck, back, and / or chest. 1.3. Any of the above methods, wherein the affected area is the face. 1.4. Any of the above methods, wherein the administration is performed on the entire affected area, for example, the entire face. 1.5. Any of the above methods, wherein a thin layer of the topical gel formulation is applied once a day in the evening, at least 30 minutes before bedtime, at approximately the same time every day, for 12 weeks, to the entire face. 1.6. Any of the above methods, wherein the amount of the topical gel formulation used per application is about 0.5 to 1 cubic centimeter (an amount the size of a soybean). 1.7. Any of the above methods, wherein the patient is at least 9 years old. 1.8. Any of the above methods, wherein the patient has received a clinical diagnosis of moderate to severe acne. 1.9. Any of the above methods, wherein the patient has acne with a score of 3 or 4 based on the Evaluator Global Severity Score (EGSS) by the evaluator shown below:

Table 1

[0020] In another embodiment, the present disclosure provides the use of clindamycin phosphate, benzoyl peroxide, and adapalene in the manufacture of a medicament (e.g., a formulation as described in any one of Formulations 1 to 1.59) for the treatment of skin inflammatory diseases (e.g., by any one of Methods 1 to 1.19).

[0021] In another embodiment, the present disclosure is a method for manufacturing a topical gel formulation, e.g., any one of Formulations 1 to 1.59, comprising: i. The following premixes: a. Premix A, comprising a gelling agent dispersed in water; b. Premix B, comprising a polyhydric alcohol and benzoyl peroxide dispersed in water; c. Premix C, comprising an aqueous solution of clindamycin phosphate; d. Premix D, comprising a polyhydric alcohol and micronized adapalene dispersed in water. ii. Mixing Premix A and Premix D; iii. Mixing Premix B into the mixture of step ii; iv. Mixing Premix C into the mixture of step iii; v. Adjusting the pH of the mixture of step iv to pH 5 - 6 to form a gel. The present disclosure provides a method (Method 2) comprising the above steps. For example, the present disclosure provides the following: 2.1. Method 2, wherein the gelling agent is selected from hydroxypropyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer (optionally cross-linked with allyl ether of polyalcohol, e.g., carbomer), carboxyvinyl copolymer, polyacrylate, acrylate copolymer, acrylamide / sodium acryloyldimethyltaurate copolymer, polyvinyl alcohol, polyethylene oxide, propylene glycol alginate, methyl cellulose, hydroxypropyl methyl cellulose, xanthan gum, carrageenan gum, and combinations thereof. 2.2. The gelling agent is selected from carboxyvinyl polymer (which may be cross-linked with allyl ether of polyalcohol, for example, carbomer), carboxyvinyl copolymer, polyacrylate, acrylate copolymer, acrylamide / sodium acryloyldimethyltaurate copolymer, propylene glycol alginate, hydroxypropyl methylcellulose, and xanthan gum, and any of the above methods. 2.3. The gelling agent contains acrylamide / sodium acryloyldimethyltaurate copolymer, and any of the above methods. 2.4. The gelling agent contains acrylamide sodium acryloyldimethyltaurate / isostearane / polysorbate 80 gelling agent, and any of the above methods. 2.5. The gelling agent contains a carbomer homopolymer cross-linked with allyl ether of polyalcohol (for example, allyl sucrose or allyl pentaerythritol), and any of the above methods. 2.6. The gelling agent is a polymer of acrylic acid cross-linked with allyl ether of polyalcohol, which contains, for example, 56% to 68% of carboxylic acid (-COOH) groups; for example, the viscosity (measured at 0.5 wt%, pH 7.5) is 40,000 to 60,000 cPs, and any of the above methods. 2.7. The gelling agent is carbomer homopolymer type C, for example, as defined by the monograph of the United States Pharmacopeia (USP) / National Formulary (USP / NF), for example, Carbopol 980, and any of the above methods. 2.8. The polyhydric alcohol is selected from propylene glycol, ethoxydiglycol, polyethylene glycol (for example, PEG400), glycerol, and combinations thereof, and any of the above methods. 2.9. The polyhydric alcohol is selected from 1,2-propylene glycol and 1,3-propylene glycol, and any of the above methods. The polyhydric alcohol is 1,2-propylene glycol, and any of the above methods. 2.11. Any of the above methods, wherein the amount of the active ingredient in the final product is about 1.2% by weight of clindamycin phosphate, about 3.1% by weight of benzoyl peroxide, and about 0.15% by weight of adapalene. 2.12. The manufactured topical gel formulation is about 1.2% by weight of clindamycin phosphate, about 3.1% by weight of benzoyl peroxide, about 0.15% by weight of adapalene, about 5% by weight of propylene glycol, about 1.75% by weight of carbomer homopolymer type C, an amount of potassium hydroxide that provides a pH of 5 to 6, and water Any of the above methods, comprising. 2.13. Any of the above methods, wherein the pH of the premix C is adjusted to pH 6 to 7, for example, pH 6.2 to 6.8. 2.14. Any of the above methods, wherein in step v, the pH is adjusted to 5.4 to 5.8. 2.15. Any of the above methods, wherein the pH adjuster is selected from sodium hydroxide, potassium hydroxide, and mixtures thereof. 2.16. Any of the above methods, wherein the pH adjuster is potassium hydroxide. 2.17. Any of the above methods, further comprising the step of filling the product of step v into a dispensing container, such as a deformable tube or a pump container.

[0022] The present disclosure further provides any of the topical gel formulations of Formulations 1 to 1.59, which are, for example, the products of any of Methods 2 to 2.17.

[0023] Unless otherwise specified, all percentages of the components of the compositions shown herein are by weight, based on the total composition or formulation being 100% by weight.

[0024] The compositions and formulations provided herein are described and claimed with reference to their components, which are conventional in the art. As will be apparent to those skilled in the art, the components may in some cases react with each other, such that the true composition of the final formulation may not exactly correspond to the described components. Accordingly, the present invention is understood to extend to the product of the combination of the described components.

[0025] "About" with respect to an amount or concentration means 80% to 120%, or 90% to 110%, of the indicated value.

[0026] Throughout, numerical ranges are used as a shorthand for describing each and every value within the range. Any value within the range can be selected as the end point of the range. Further, all references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between the definitions of the present disclosure and those of the cited references, the present disclosure prevails.

[0027] Unless otherwise specified, all percentages and amounts expressed herein are to be understood as meaning weight percentages. The given amounts are based on the active weight of the materials.

[0028] The present invention is further illustrated by the following examples, which are meant to be illustrative and not limiting.

Example

[0029] Example 1: A clinical trial comparing three combinations and two combinations This study intends to evaluate the safety and efficacy of a novel fixed-dose combination of clindamycin phosphate (CP), benzoyl peroxide (BPO), and adapalene (1.2% / 3.1% / 0.15%) for the treatment of moderate to severe acne vulgaris in subjects 9 years of age and older, compared to its vehicle, and two-component combinations (BPO / adapalene, clindamycin / BPO, and clindamycin / adapalene).

[0030] This is a multi-center, randomized, double-blind, vehicle-controlled, 12-week study designed to evaluate the safety, tolerability, and efficacy of a combination gel of three components (1.2% / 3.1% / 0.15%) containing clindamycin phosphate (CP), benzoyl peroxide (BPO), and adapalene, compared to its vehicle, and two-component combinations (BPO / adapalene, clindamycin / BPO, and clindamycin / adapalene) at weeks 2, 4, 8, and 12. The formulations tested are as follows: [Table 2]

[0031] For a study to be eligible, subjects must be at least 9 years old, have a clinical diagnosis of moderate to severe acne (defined by a total severity score [EGSS, supra] of 3 or 4 by an evaluator), and not exhibit 30 to 100 inflammatory facial lesions (papules, pustules, and nodules), 35 to 150 non-inflammatory facial lesions (open and closed comedones), and no more than two facial nodules. All subjects receive a topical treatment on the face once daily for 12 weeks. Subject visits include screening, baseline, week 2, week 4, week 8, and week 12, at which time safety and efficacy assessments are conducted (screening and baseline may be conducted on the same day if washout is not required). One pump of investigational product is dispensed to the subject at baseline, week 4, and week 8 study visits. Subjects are evaluated for medication compliance at each study visit after baseline (weeks 2, 4, 8, and 12). Subjects apply the treatment product once daily (in the evening) at home according to the instructions of the study coordinator or designee at each study center.

[0032] The investigator evaluates the subject's face at each study visit. Information on reported and observed adverse events (AEs) is obtained at each visit. A simplified physical examination and vital sign measurements are performed on all subjects at baseline and week 12 (end of study). Blood samples are collected from subjects at baseline and week 12 for CBC / Diff and serum chemistry tests. A urine pregnancy test is performed on all female subjects of childbearing potential (FOCBP) at screening, baseline (prior to randomization), and weeks 2, 4, 8, and 12. Additionally, a serum pregnancy test is performed at baseline and week 12.

[0033] Furthermore, at selected study centers, standardized facial photography is performed at baseline, and weeks 4, 8, and 12.

[0034] Approximately 750 subjects will be randomized in a 1:1:1:1:1 ratio to the following treatment groups: · 150 subjects applying test gel (clindamycin phosphate 1.2% / BPO 3.1% / adapalene 0.15%) · 150 subjects applying formulation A (BPO 3.1% / adapalene 0.15%) · 150 subjects applying formulation B (clindamycin phosphate 1.2% / BPO 3.1%) · 150 subjects applying formulation C (clindamycin phosphate 1.2% / adapalene 0.15%) · 150 subjects applying vehicle gel

[0035] Except for the test visit days (baseline, 2, 4, and 8 weeks) when the investigational drug is applied (by the subject) at the investigative center after the test visit is completed, the assigned investigational drug is applied topically to the face once daily in the evening for 12 weeks (until the evening before the 12th week visit) at home.

[0036] Subjects who meet all of the following criteria are eligible for study entry: 1. Males or females at least 9 years of age or older. 2. Written and oral informed consent must be obtained. Subjects under the age of consent for assent are required to sign the study consent form, and the parent or legal guardian is required to sign the informed consent (if the subject reaches the age of consent during the study, re-consent should be obtained at the next test visit). 3. The subject must have an EGSS of 3 (moderate) or 4 (severe) at baseline visit. 4. Subjects having 30 or more and 100 or fewer inflammatory lesions (papules, pustules, nodules) of facial acne. 5. Subjects having 35 or more and 150 or fewer non-inflammatory lesions (open comedones and closed comedones) of facial acne. 6. Subjects having two or fewer facial nodules. 7. Women with FOCBP1 and premenstrual women must practice effective contraception during the study period. (Effective contraception is defined as at least three months of oral contraceptive stabilization, intrauterine devices, condoms with spermicides, diaphragms with spermicides, implants, NuvaRing™, injections, transdermal patches, or self-control (abstinence).) Women taking oral contraceptives must have been taking the same type of medication for at least three months prior to entering the study and must not change the type during the study. Those who have previously used oral contraceptives must have discontinued use at least three months before the start of the study. Women who use oral contraceptives only for acne control should be excluded. 8. Premenstrual women and those with FOCBP must have a negative urine pregnancy test at screening visit and a negative urine pregnancy test at baseline visit. 9. Subjects must comply with the study instructions and come to the clinic for required visits. Subjects under the age of consent must be accompanied by a parent or legal guardian at the time of consent / assent signature. 10. If a cleanser, moisturizer, or sunscreen is needed during the study, subjects must only use the permitted cleanser, moisturizer, sunscreen, or a combination product of moisturizer / sunscreen (see Appendix 17.2). Subjects must consent to the use of non-comedogenic products (including makeup and shaving products).

[0037] Subjects who meet any of the following criteria will be excluded from the study: 1. Use of investigational drugs or devices within 30 days of registration or participation in an investigational study conducted concurrently with this study. 2. Skin diseases of the face that may interfere with clinical evaluation, such as acne conglobata, acne fulminans, secondary acne, perioral dermatitis, clinically severe rosacea, Gram-negative folliculitis, dermatitis, eczema, etc. 3. Facial underlying diseases or other dermatological diseases that require the use of interfering topical or systemic therapeutic agents or do not allow the determination of evaluation and variables. 4. Subjects with facial or facial hair that may interfere with the test evaluation. 5. Subjects with more than two facial nodules. 6. Evidence or history of acne related to cosmetics. 7. The subject has a history of experiencing significant burning or stinging when applying facial treatments (such as cosmetics, soap, masks, face washing, sunscreen, etc.) to the face. 8. Female subjects who are pregnant, lactating mothers, planning to become pregnant during the test period, or who become pregnant during the test. 9. Use of estrogen (such as Depogen, Depo-Testadiol, Ginogen, Valrogen, etc.) less than 12 weeks before the start of the test; subjects who have been continuously treated with estrogen for 12 weeks or more before the start of the test do not need to be excluded; however, they will be excluded if the dose, drug is changed or the use of estrogen is not discontinued during the test. 10. In the case of female subjects, the subject has a history of hirsutism, polycystic ovary disease, or clinically severe menstrual disorders. 11. History of regional enteritis, ulcerative colitis, inflammatory bowel disease, pseudomembranous colitis, chronic or recurrent diarrhea, or antibiotic-associated colitis. 12. Treatment of any type of cancer within the last 6 months, except for complete surgical resection of skin cancer outside the treatment area. 13. The subject uses drugs and / or vitamins reported to exacerbate acne during the trial (azathioprine, haloperidol, vitamin D, vitamin B12, halogens such as iodide and bromide, lithium, very high-potency corticosteroids from systemic or topical in the treatment area, phenytoin, and phenobarbital). Multivitamins containing the recommended daily dose of vitamin A and a stable amount of vitamin D are acceptable. 14. History of hypersensitivity or allergic reactions to any test formulation described in the investigational drug protocol, including known sensitivity to any dosage form of clindamycin phosphate, BPO, or adapalene. 15. Concomitant use of over-the-counter drugs that may be irritating, including components such as BPO, alpha-hydroxy acids, salicylic acid, retinol, or glycolic acid. 16. Subjects who have not undergone the designated washout period for the following topical formulations or physical therapies used on the face; or subjects who need to use any of the following simultaneously in the treatment area: · Topical astringents and abrasives (including acne removal strip agents) on the face: 1 week · Unapproved moisturizers or sunscreens on the face: 1 week · Antibiotics on the face: 2 weeks · Other topical anti-acne drugs on the face: 2 weeks · Soap containing antibacterial agents on the face: 2 weeks · Anti-inflammatory agents and corticosteroids on the face: 4 weeks · Retinoids containing retinol on the face: 4 weeks · Facial procedures including chemical peeling, microdermabrasion, light (PDT, LED) and laser therapy, and acne surgery: 4 weeks If the subject needs topical treatment for acne in areas other than the face (such as the chest and / or back), the responsible investigator may prescribe a product that does not contain any of clindamycin phosphate, BPO, or adapalene, but it is necessary to document it in the source document and the electronic case report form (eCRF). 17. Subjects who have not undergone the specified washout period for the following systemic medications; or subjects who need to use any of the following systemic medications simultaneously: · Corticosteroids (including intramuscular injection) (inhaled corticosteroids are permitted): 4 weeks · Antibiotics: 4 weeks · Other systemic acne treatments: 4 weeks · Systemic retinoids: 6 months 18. The subject intends to use a sunburn booth or sunbathe during the trial. 19. Subjects who are unable to communicate or cooperate with the principal investigator of the clinical trial due to language problems, mental retardation, or brain dysfunction. 20. Subjects with underlying diseases that the principal investigator deems uncontrolled and that pose a concern for the safety of the subject during the trial.

[0038] Subject withdrawal criteria: The reasons for withdrawal can include, but are not limited to, the following: · Sudden acne inflammation determined by the principal investigator of the clinical trial that requires an unapproved treatment. · Any of the principal investigator's request, reasons of tolerance (such as severe side effects), or the subject's request. · When the protocol requirements are not met. · When a concomitant therapy that may interfere with the results of the trial is reported or requested by the subject (the principal investigator of the clinical trial shall report all such information in the source document / eCRF and decide whether to withdraw the subject according to the sponsor of the clinical trial). · When the subject fails to follow up. The principal investigator of the clinical trial shall attempt to contact the subject twice by phone, email, and / or text message, and send a follow-up letter by registered mail before considering the subject to have failed to follow up. These actions shall be reported in the source document at the end of the trial and the final eCRF, and a copy of the follow-up letter shall be retained in the principal investigator's file.

[0039] All interim stops and the reasons associated therewith shall be carefully documented by the principal investigator of the clinical trial in the source documents and the final eCRF, and, if necessary, in the AE form. In any case, if a subject discontinues for any reason, a participant who has become a subject and has been assigned a study number cannot be replaced by another subject. All data collected regarding the subject before termination shall be made available to the sponsor of the clinical trial.

[0040] The reasons for termination / suspension of the trial as described in the final report are defined as follows: Normal trial termination - The subject completes the trial as planned in the protocol. Adverse event - Enter on the AE form. Death - Enter on the Serious Adverse Event (SAE) form. Subject request - Withdrawal of consent, subject's move, schedule conflict. Protocol violation - Contact the sponsor or designee before making a decision. Follow-up failure - Documented by two phone calls, emails and / or text messages, and a certified mail letter. Pregnancy - The subject immediately discontinues the investigational product but is followed up until the end of the period. Enter on the Pregnancy form. Worsening of condition - The subject requires alternative treatment for acne before the end of the trial and the principal investigator determines that it is not due to lack of efficacy. Lack of efficacy - The subject requires alternative treatment for acne at least two weeks after initiation of investigational product treatment and the principal investigator determines that the risk to the subject of continuing the trial exceeds the benefit. Withdrawal by parent / guardian - Indicates that a trial participant has been excluded from the trial by a parent or legal guardian; includes withdrawal of consent, subject's change of address, schedule conflict, etc. Trial termination by sponsor - Indicates that the clinical trial has been terminated by the sponsor. Others - Specify in the comment section of the eCRF.

[0041] Evaluation criteria:

[0042] Primary efficacy: The main efficacy endpoint aims to compare the numerical superiority when the test gel, vehicle gel, and each comparison gel (Formulations A, B, and C) are applied once daily. Specifically, the endpoints that can be summarized using descriptive statistics and inferential statistics are as follows: (1) The absolute change in the mean inflammatory lesion variable from baseline to week 12. (2) The absolute change in the mean non-inflammatory lesion variable from baseline to week 12. (3) The percentage of subjects who achieve a decrease of at least 2 grades from baseline based on the overall severity score (EGSS) by the evaluator and are "clean" or "almost clean" at week 12.

[0043] Secondary efficacy:

[0044] The secondary efficacy endpoint aims to compare the numerical superiority when the test gel, vehicle gel, and each comparison gel (Formulations A, B, and C) are applied once daily. Specifically, the secondary endpoints that can be summarized using descriptive statistics are as follows: (1) The absolute change in the inflammatory and non-inflammatory lesion variables from baseline at weeks 2, 4, and 8. (2) The percentage of subjects who achieve a decrease of at least 2 grades from baseline based on the EGSS and are "clean" or "almost clean" at weeks 2, 4, and 8. (3) The mean percentage change in the inflammatory and non-inflammatory lesion variables from baseline at weeks 2, 4, 8, and 12.

[0045] Efficacy measurement:

[0046] Lesion variables: At each visit, the evaluator counts the total number of inflammatory lesions (papules, pustules, and nodules) on the subject's face. Nodules are counted separately but are included in the total number of inflammatory lesions. At baseline, eligible subjects may have two or fewer nodules. Nodules are included in the statistical analysis of the inflammatory lesion variable. Instead of counting papules and pustules separately, all inflammatory lesions are counted simultaneously. The evaluator also counts the total number of non-inflammatory lesions (open comedones and closed comedones). The same masked evaluator performs the lesion variable and EGSS evaluations at all visits from baseline to 12 weeks for the same subject.

[0047] Inflammatory lesions are defined as follows: Papule - A small, firm elevation less than 5 mm in diameter. Most of the lesion is above the surface of the skin. Pustule - A small, circumscribed elevation less than 5 mm in diameter. It contains a yellow to white exudate. Nodule - A subcutaneous lesion greater than or equal to 5 mm in diameter.

[0048] Non-inflammatory lesions are defined as follows: Open comedone (blackhead) - A lesion in which the opening of the hair follicle is widely dilated and the contents protrude onto the surface of the skin. Closed comedone (whitehead) - A lesion in which the opening of the hair follicle is closed, but the sebaceous gland is enlarged by the pressure of sebum accumulation, causing the skin around the hair follicle to become thin and bulge with a white appearance.

[0049] Evaluator's Global Severity Score (EGSS): At each visit, severity is determined based on the evaluator's masked assessment of the signs and symptoms of acne vulgaris. Every effort should be made to have the same evaluator assess the same subject at each visit. If this is not possible, the same evaluator should assess the subject at both the baseline and 12-week visits. The assessment is scored on a scale of 0 - 4, where 0 is clear and 4 is severe.

Table 3

[0050] Safety measurements: The safety assessment includes the following: · The percentage of subjects who experienced skin reactions (erythema, scaling, hypo- or hyperpigmentation, pruritus, burning, or stinging) classified as level 3 at any point during the trial after the first application of the test drug. · The percentage of subjects who experienced skin adverse events (AEs), regardless of severity, at any point during the trial after the first application of the test drug. · Changes from baseline for all safety test values and vital sign measurements summarized using descriptive statistics by treatment group and trial visit. · Subjects are evaluated for the occurrence of new and ongoing AEs.

[0051] Skin safety and tolerability are evaluated by AE aggregation and skin safety and tolerability assessment scores (scaling, erythema, hypo- or hyperpigmentation, pruritus, burning, and stinging), which are evaluated at each trial visit. Pruritus, burning, and stinging (skin tolerability) are reviewed by subjects at each trial visit as the average over the period since the previous visit. Scaling, erythema, and hypo- or hyperpigmentation (skin safety) are evaluated by the assessor at each visit. Signs and symptoms of skin tolerability that result in the subject requiring concomitant therapy, treatment interruption, or trial discontinuation are reported as AEs.

[0052] Statistical methods: All statistical procedures are performed using SAS (trademark) version 9.3 or later, unless otherwise specified.

[0053] Statistical significance is based on a two-sided test of the null hypothesis that yields a p-value of 0.05 or less. The p-values for the selected variables are presented to assist the reviewer in evaluating the results of the trial. Failure to achieve statistically significant results at the α level of 0.05 does not necessarily mean that the trial has failed.

[0054] The absolute changes in the mean number of inflammatory and non-inflammatory lesions from baseline to week 12 are analyzed using analysis of covariance (ANCOVA) with factors for treatment group and analysis center, and covariates of their respective baseline lesion variables. Non-parametric analysis can be used. Additionally, four pairwise tests are performed comparing the test gel with the vehicle gel, and the test gel with each of the two-component gels.

[0055] The percentage of subjects who achieved treatment success, defined as at least a 2-grade improvement from baseline in the EGSS and an EGSS equal to "clean" or "almost clean", is analyzed using a logistic regression test with factors for treatment group and analysis center, and a covariate of baseline severity at week 12. Four pairwise tests are performed comparing the test gel with the vehicle gel, and the test gel with each of the two-component gels.

[0056] The main method for handling missing efficacy data is the MCMC multiple imputation method. Other methods, and the MCMC imputation method, are specified in the statistical analysis plan finalized before database lock.

[0057] Analyzed population and treatment groups: The number of inflammatory and non-inflammatory lesions is recorded for each subject at baseline and at 2, 4, 8, and 12 weeks. Absolute and percent changes from baseline in inflammatory and non-inflammatory lesions are obtained for each subject at 2, 4, 8, and 12 weeks. The EGSS is recorded for each subject. The EGSS is dichotomized into "success" and "failure", and if the EGSS at 2, 4, 8, or 12 weeks is at least 2 grades lower than baseline and "clean" or "almost clean" is achieved, the subject is considered a success. The intention-to-treat (ITT) analysis is performed on all study subjects. The ITT population consists of all randomized subjects who received the study drug. The safety population consists of all randomized subjects who are presumed to have used the study drug at least once and provided at least one post-baseline assessment. The per-protocol (PP) analysis is also performed. A subject becomes eligible for PP analysis if they complete the 12-week assessment without having a notable protocol violation (i.e., activities of the subject or the investigator that could interfere with the therapeutic administration of the treatment agent or the accurate assessment of the treatment effect). The PP population includes subjects in the ITT population who do not meet any of the following criteria. ·Failed according to the inclusion / exclusion criteria. ·Took interfering concomitant medications. ·Did not participate in the 12-week visit, except for discontinuation of the study due to an AE related to the study treatment or lack of documentation of the treatment effect. ·Did not participate in more than one post-baseline study visit before 12 weeks. ·Did not comply with the dosing schedule (i.e., the subject must not miss dosing for more than 5 consecutive days and must apply 80% - 120% of the scheduled dose). The number of scheduled doses is determined for each subject based on the length of participation in the study. ·Was out of scope for the 12-week visit.

[0058] Before breaking the blind, other additional criteria can be added to the list to address unexpected events that occur during the conduct of the trial and that lead to notable protocol violations.

[0059] The statistical and baseline characteristics of the subjects are summarized for the treatment groups using descriptive statistics for the ITT, PP, and safety analysis sets.

[0060] Efficacy evaluation - primary: The primary efficacy analysis of the absolute change from baseline in inflammatory and non-inflammatory lesions is conducted in the ITT population. The pre-specified time point is week 12. Descriptive statistics are presented by treatment group for inflammatory and non-inflammatory lesions and by absolute change in inflammatory and non-inflammatory lesions. All tests related to the analysis of inflammatory and non-inflammatory lesions use the methods described above. The primary analysis of the dichotomized EGSS (success is at least a 2-grade improvement and achieves "clean" or "almost clean") in the ITT population is based on a logistic regression test using treatment group and analysis center factors and a covariate of baseline severity..

[0061] Efficacy evaluation - secondary: The mean percent change from baseline for inflammatory and non-inflammatory variables and the percentage of subjects with at least a 2-grade improvement from baseline for EGSS are evaluated at weeks 2, 4, 8, and 12.

[0062] Safety assessment: All subjects who receive treatment and provide at least one post-baseline assessment constitute the safety population. Safety is evaluated by AE aggregation, assessment of skin safety and tolerability, vital signs / simplified physical examination, and safety test results. The assessment scores for skin safety and tolerability (erythema, scaling, hypo- or hyperpigmentation, pruritus, burning sensation, and stinging) are presented descriptively for each treatment group at baseline and at weeks 2, 4, 8, and 12. The frequency and percentage of each result category are included in these statistics. The mean values are presented graphically by week and treatment group. Measurements of vital signs, simplified physical examination, and safety test results are performed on all subjects at the scheduled visits. For premenopausal women and FOCBP, urine and serum pregnancy tests are performed at the scheduled visits. Changes from baseline in safety test values and vital sign measurements are summarized descriptively for each treatment group at all applicable test visits. A shift table is presented for changes in safety test values to summarize the test results collected at baseline and week 12. The normal range established by the central laboratory is used to determine the shift. A list of out-of-range test results at any assessment time point is also provided. The determination of the clinical significance of out-of-range test values is made by each principal investigator and included in the list. In addition, a list of all clinically significant test results is provided.

[0063] All conventional combination drugs are classified based on the terms of the World Health Organization's Drug Dictionary. Data on conventional therapeutic agents and combination drugs are shown in the data list. All AEs occurring during the trial are recorded and classified using the terms of the Medical Dictionary for Regulatory Activities (MedDRA). Descriptions of AEs include the onset date, the end date of the AE, the severity of the AE, the relationship to the investigational drug, the measures taken regarding the use of the investigational drug, the measures taken for the treatment of the AE, and the outcome. Adverse events are summarized by treatment group and severity. Each subject is counted only once within the scope of the system organ class or preferred term using the most severe AE within each category.

[0064] Adverse events are summarized by treatment group and the relationship to the investigational drug. Each subject is counted only once within the scope of the system organ class or preferred term using the AE with the greatest relationship within each category. All information related to AEs recorded during the trial is listed for each subject, detailing the verbatim description by the principal investigator of the clinical trial, the preferred term, the system organ class, the start date, the stop date, the severity, the measures taken, and the drug relatedness. The onset of the AE is indicated (in days) relative to the first administration date of the randomized investigational drug. Serious adverse events (SAEs) are tabulated for each subject within the treatment group. Additionally, a list of subjects who discontinued the trial and a list of subjects who experienced SAEs are also provided.

[0065] Subject self - assessment: Subjects are required to fill out a questionnaire regarding the quality of life specific to acne during the trial. The principal investigator's assessment (EGSS and lesion count) is performed independently of this subject self - assessment. No inferential statistical analysis is performed on the questionnaire. Subject responses are compared between treatment groups for trends.

[0066] This trial is conducted in accordance with the implementation standards of clinical trials of pharmaceuticals, including the archiving of essential study documents. This protocol follows the guidelines outlined in the International Conference on Harmonization.

[0067] Clinical trials show that the test gel is significantly more effective than either the vehicle or the three two-component comparators. Table 3: Primary efficacy analysis: absolute change from baseline in lesion variables and dichotomized overall severity at week 12 (intention-to-treat (ITT) population) [Table 4] (a) Least squares mean, standard deviation, contrast p-value, and overall p-value from analysis of covariance with factors of treatment group and analysis center, and each baseline lesion variable as a covariate. Values adjusted for multiple imputation. (b) Median, minimum, and maximum values represent the mean of the summary statistics generated from each imputed data set. (c) Skewness test. This is evaluated for each imputed data set. Mean p-value is shown. (d) Contrast p-value and overall p-value from ranking of analysis of covariance using factors of treatment group and analysis center, and each baseline lesion variable as a covariate. Values adjusted for multiple imputation. (e) Contrast p-value and overall p-value by logistic regression using factors of treatment group and analysis center. Values adjusted for multiple imputation. Note: Multiple imputation (MCMC) method is used to impute missing values. Changes are calculated as week 12 - baseline.

[0068] The three-component test gel was not only more effective than the two-component comparators, but also had fewer side effects than the combination of benzoyl peroxide / adapalene. Table 4: Summary of characteristics of adverse events occurring during treatment (safety population) [Table 5] Note: Adverse events occurring during treatment are those that developed after the first administration of the test drug.

Claims

1. A topical gel formulation comprising 1 to 1.5% by weight of clindamycin phosphate, 2.5 to 3.5% by weight of benzoyl peroxide, and 0.1 to 0.2% by weight of adapalene, in combination with a gelling agent, a polyhydric alcohol, and water.

2. The formulation according to claim 1, comprising about 1.2% by weight of clindamycin phosphate, about 3.1% by weight of benzoyl peroxide, and about 0.15% by weight of adapalene.

3. The formulation, wherein a. about 1.2% by weight of clindamycin phosphate, b. about 3.1% by weight of benzoyl peroxide, c. about 0.15% by weight of adapalene, d. about 5% by weight of propylene glycol, e. about 1.75% by weight of carbomer homopolymer type C, f. an amount of potassium hydroxide that provides a pH of 5 to 6, and g. water, and is the formulation according to claim 2.

4. A method for treating acne vulgaris in a patient in need thereof, comprising administering the topical gel formulation according to any one of claims 1, 2, or 3 to the affected area at least once a day.

5. The method according to claim 4, wherein the inflammatory skin disease is acne.

6. The method according to claim 4 or 5, wherein the administration is once a day for at least 4 weeks, for example, at least 12 weeks.

7. The treatment is more effective in the treatment of acne than treatment with a formulation comprising an active ingredient selected from (i) 1 to 1.5% by weight of clindamycin phosphate and 2.5 to 3.5% by weight of benzoyl peroxide, (ii) 2.5 to 3.5% by weight of benzoyl peroxide and 0.1 to 0.2% by weight of adapalene, and (iii) 1 to 1.5% by weight of clindamycin phosphate and 0.1 to 0.2% by weight of adapalene, and is the method according to claim 4, 5, or 6.

8. A pharmaceutical product in the form of a container equipped with a pump and containing the topical gel formulation according to any one of claims 1 to 3, wherein the pump is adjusted to release a specific amount of the formulation each time it is pressed.

9. A method for manufacturing the topical gel formulation according to any one of claims 1 to 3, comprising i. the following premixes: a) Premix A containing a gelling agent dispersed in water, b) Premix B containing a polyhydric alcohol and benzoyl peroxide dispersed in water, c) Premix C containing an aqueous solution of clindamycin phosphate, d) providing a premix D comprising a polyhydric alcohol and micronized adapalene dispersed in water; ii. mixing premix A and premix D; iii. mixing premix B into the mixture of step ii; iv. mixing premix C into the mixture of step iii; v. adjusting the pH of the mixture of step iv to pH 5 - 6 to form a gel; A method comprising the above steps. **Claim 10** A topical gel formulation according to any one of claims 1, 2, or 3 for use in the method according to any one of claims 4, 5, 6, or 7.

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