Topical compositions

Abstract

The present invention provides topical gel formulations 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, together with a gelling agent, a polyol, and water, for the treatment of inflammatory skin diseases, including acne, and methods of making and using the same.

Description

[0001] This application is a divisional application of Chinese patent application 202080052185.4. The filing date of the original application is July 31, 2020, and the name is “Topical Composition”. Technical Field

[0002] The present invention relates to topical compositions for treating skin conditions including acne. In particular, the present invention provides topical compositions comprising three different active ingredients, and methods of making and using the same. background

[0004] Acne is a very common sebaceous follicular disorder that most commonly affects adolescents and is usually triggered by increased androgen secretion during puberty. Although acne typically resolves by age 25, it affects approximately 3% to 8% of adults aged 25 to 44 years. The pathogenesis of acne is complex and appears to involve 4 main features: stimulation of sebaceous gland activity, bacterial proliferation (particularly Keratosis acnes, formerly known as Propionibacterium acnes), abnormal follicular keratinization and obstruction of sebaceous follicles, and the release of inflammatory mediators. These changes in patients with acne lead to the formation of clinical inflammatory lesions, including superficial pustules such as comedones (commonly known as "blackheads" or "whiteheads"), as well as deeper papules, nodules, and cysts. The areas most affected by the disease include the sebaceous follicles of the head and upper trunk, where sebaceous glands are particularly active.

[0005] The increased production of oily sebum and keratin that causes acne is influenced by individual genetics, various medications (such as corticosteroids, androgens or lithium, azathioprine, haloperidol, vitamin D, vitamin B12, halogens (such as iodide or bromide), phenytoin or phenobarbital), and possibly other factors, such as diet and stress. The increased production of sebum and keratin is associated with increased levels of various hormones, including androgens (such as testosterone, dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA)), growth hormone (GH), and insulin-like growth factor 1 (IGF-1). Infection of hair follicles with anaerobic bacteria (such as Propionibacterium acnes) and / or parasitic mite Demodex folliculorum may exacerbate the condition, although it is unclear whether infection is responsible for initiating the condition.

[0006] Current treatment options for acne include (i) retinoids and retinoid-like drugs, such as tretinoin (Avita, Retin-A, others), adapalene (Differin), and tazarotene (Tazorac, Avage); antibiotics, including clindamycin with benzoyl peroxide (Benzaclin, Duac, Acanya) and erythromycin with benzoyl peroxide (Benzamycin); salicylic acid and azelaic acid; and dapsone (Aczone).

[0007] Benzoyl peroxide is commonly found in over-the-counter acne treatments and in prescription medications used in combination with antibiotics. While the exact mechanism of action is unclear, it has antiseptic properties, breaks down keratin to help unclog pores, and may inhibit sebum production. However, benzoyl peroxide preparations may cause local irritation, both because benzoyl peroxide is a strong oxidizing agent and because it is virtually insoluble in water and is often formulated using harsh organic solvents. It is also incompatible with many other compounds due to its high chemical reactivity.

[0008] Topical clindamycin can be administered in the form of clindamycin phosphate (the phosphate prodrug of clindamycin). Clindamycin has anti-inflammatory properties in addition to its antibacterial properties. One disadvantage of clindamycin (and other antibiotics) is the risk of developing resistant bacterial populations on the skin.

[0009] Adapalene is a retinoid compound that is an agonist of specific retinoic acid nuclear receptors. It regulates cell differentiation, keratinization, and inflammatory processes, and topical preparations have been approved for the treatment of acne. Although the exact mode of action of adapalene is unknown, it normalizes the differentiation of follicular epithelial cells, thereby reducing the formation of microcomedos.

[0010] Combination products have been tried, but the results have been unpredictable. For example, Bowman, S. et al., "Comparison of clindamycin / benzoylperoxide, tretinoin plus clindamycin, and the combination of clindamycin / benzoyl peroxide and tretinoin plus clindamycin in the treatment of acnevulgaris: a randomized, blinded study." J Drugs Dermatol 2005 Sep-Oct;4(5):611-8 reported that although a regimen containing clindamycin / benzoyl peroxide was more effective than tretinoin (retinoin) plus clindamycin in treating acne, there was no clinical advantage to adding tretinoin plus clindamycin to once-daily clindamycin / benzoyl peroxide therapy. Similar results were seen in a large trial investigating combination therapy with benzoyl peroxide 5% / clindamycin 1% gel and different retinoids, tazarotene. Clinical trial NCT00713609, results were published in March 2017 and are available at clinicaltrials.gov. After 12 weeks, there was no statistically significant difference in the reduction in the number of lesions between the active combination therapy groups. Triple therapy was no better than dual therapy and, in fact, resulted in less reduction in the number of lesions. Typically, this combination therapy uses one or two drugs in the morning and another or more drugs in the evening, which is less convenient for patients than taking one drug every day but may reduce unpredictable harmful interactions between drugs.

[0011] Although various treatments for acne are known, there is still a need for more effective treatments. Due to the lack of understanding and consensus on the complex pathogenesis of the disease and the exact mechanism of action of commonly used therapeutic drugs, it is difficult to design effective treatments, and expensive clinical trials are required to prove efficacy and fewer side effects. Simply increasing the concentration of existing active drugs may lead to irritation and other side effects. Due to unpredictable chemical interactions between active agents, unpredictable effects of one drug ingredient on the delivery of another drug ingredient, unpredictable efficacy and potential unpredictable side effects, the combination of active ingredients may be limited. It is necessary to improve the formulations for treating acne, providing better efficacy without unacceptable side effects.

[0012] Overview

[0013] We surprisingly found that a topical gel containing a fixed combination of benzoyl peroxide, clindamycin phosphate and adapalene (applied once daily) had significantly enhanced efficacy compared to gels containing any combination of the two drugs.

[0014] Each agent has some degree of anti-inflammatory activity; benzoyl peroxide and clindamycin phosphate both reduce the proliferation of Chlamydia acnes; benzoyl peroxide is also a keratolytic; and adapalene also modulates keratinization (Zaenglein 2008). Fixed-dose combination therapy is optimal and may improve patient compliance due to simplified dosing schedules (e.g., once daily versus sequential administration of each active agent in the morning / evening) and may also prevent substance incompatibilities due to medication errors (e.g., administration of an incompatible single agent leading to oxidation). However, whether such fixed-dose formulations can be designed to be stable, safe, and effective requires empirical testing.

[0015] In one embodiment, the present invention provides a topical gel formulation comprising 1-1.5% by weight (e.g., about 1.2% by weight) of clindamycin phosphate, 2.5-3.5% by weight (e.g., about 3.1% by weight) of benzoyl peroxide and 0.1-0.2% by weight (e.g., about 0.15% by weight) of adapalene, as well as a gelling agent (e.g., a carbomer homopolymer), a polyol (e.g., propylene glycol) and water.

[0016] In another embodiment, the present invention provides a method of treating acne vulgaris, comprising applying to the affected area a topical gel formulation, e.g., once a day, e.g., for at least 12 weeks, comprising 1-1.5% by weight (e.g., about 1.2% by weight) clindamycin phosphate, 2.5-3.5% by weight (e.g., about 3.1% by weight) benzoyl peroxide, and 0.1-0.2% by weight (e.g., about 0.15% by weight) adapalene, in combination with a gelling agent (e.g., a carbomer homopolymer), a polyol (e.g., propylene glycol), and water.

[0017] In another embodiment, the present invention provides a method for preparing a topical gel formulation, e.g., as described above, comprising mixing 1-1.5% (e.g., about 1.2% by weight) clindamycin phosphate, 2.5-3.5% by weight (e.g., about 3.1% by weight) benzoyl peroxide, 0.1-0.2% (e.g., about 0.15% by weight) adapalene, a gelling agent (e.g., carbomer homopolymer), a polyol (e.g., propylene glycol), and water to form a dispersant, and then adjusting the pH of the combination to pH 5-6.

[0018] Other areas of applicability of the present invention will become apparent from the detailed description of the invention provided below.It should be understood that the detailed description and specific examples, while indicating preferred embodiments of the present invention, are for illustrative purposes only and are not intended to limit the scope of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0020] The following description of the preferred embodiment is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.

[0021] In a first embodiment, the present invention provides a topical gel formulation (Formulation 1) comprising 1-1.5% by weight of clindamycin phosphate, 2.5-3.5% by weight of benzoyl peroxide and 0.1-0.2% by weight of adapalene, a gelling agent, a polyol and water; e.g.

[0022] 1.1. Formulation 1, wherein the concentration of clindamycin phosphate is about 1.2% by weight.

[0023] 1.2. Formulation 1 or 1.1, wherein the concentration of benzoyl peroxide is about 3.1% by weight.

[0024] 1.3. Any of the preceding formulations, wherein the concentration of adapalene is about 0.15% by weight.

[0025] 1.4. Any of the preceding formulations, wherein the gelling agent is selected from hydroxypropyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymers (optionally cross-linked with allyl ethers of polyols, e.g., carbomers), carboxyvinyl copolymers, polyacrylates, acrylate copolymers, acrylamide / sodium acryloyldimethyl taurate copolymers, polyvinyl alcohol, polyethylene oxide, propylene glycol alginate, methylcellulose, hydroxypropyl methylcellulose, xanthan gum, carrageenan, and combinations thereof.

[0026] 1.5. Any of the preceding formulations, wherein the gelling agent is selected from carboxyvinyl polymers (optionally cross-linked with allyl ethers of polyols, e.g., carbomers), carboxyvinyl copolymers, polyacrylates, acrylate copolymers, acrylamide / sodium acryloyldimethyltaurate copolymers, propylene glycol alginate, hydroxypropyl methylcellulose, and xanthan gum.

[0027] 1.6. Any of the preceding formulations, wherein the gelling agent comprises acrylamide / sodium acryloyldimethyltaurate copolymer.

[0028] 1.7. Any of the preceding formulations, wherein the gelling agent comprises sodium acrylamide-acryloyldimethyltaurate / isohexadecane / polysorbate 80 gelling agent.

[0029] 1.8. Any of the preceding formulations, wherein the gelling agent comprises a carbomer homopolymer cross-linked with an allyl ether of a polyol (eg, allyl sucrose or allyl pentaerythritol).

[0030] 1.9. Any of the foregoing formulations, wherein the gelling agent is an acrylic polymer cross-linked with a polyol allyl ether; for example, containing 56%-68% carboxylic acid (-COOH) groups; for example, having a viscosity of 40,000-60,000 cPs (measured at 0.5% by weight at pH 7.5).

[0031] 1.10. Any of the foregoing formulations, wherein the gelling agent is a Type C carbomer homopolymer, such as a carbomer as defined in the United States Pharmacopeia / National Formulary (USP / NF) monograph, such as Carbomer 980.

[0032] 1.11. Any of the preceding formulations wherein the gelling agent is present in an amount of 1.5-2% by weight.

[0033] 1.12. Any of the preceding formulations wherein the gelling agent is present in an amount of about 1.75% by weight.

[0034] 1.13. Any of the preceding formulations wherein the amount of gelling agent is carbomer homopolymer Type C in an amount of about 1.75% by weight.

[0035] 1.14. Any of the preceding formulations, wherein the pH of the formulation is pH 5-6.

[0036] 1.15. Any of the preceding formulations, wherein the gelling agent is a crosslinked polymer comprising carboxyl moieties, and wherein the formulation further comprises a base selected from the group consisting of potassium hydroxide, sodium hydroxide, and combinations thereof, in an amount sufficient to deprotonate the carboxyl moieties sufficient to thicken the gelling agent.

[0037] 1.16. Any of the foregoing formulations, comprising a base selected from potassium hydroxide, sodium hydroxide, and combinations thereof, in an amount to provide a pH of 5-6.

[0038] 1.17. Any of the foregoing formulations containing potassium hydroxide in an amount to provide a pH of 5-6.

[0039] 1.18. Any of the preceding formulations, wherein a portion of the benzoyl peroxide is undissolved, and the undissolved portion of the benzoyl peroxide is uniformly dispersed in the formulation.

[0040] 1.19. Any of the preceding formulations wherein a portion of the benzoyl peroxide is undissolved and the undissolved portion of the benzoyl peroxide has an average particle size between 1-50 microns, eg, between 2.5 and 30 microns.

[0041] 1.20. Any of the preceding formulations wherein the benzoyl peroxide is not encapsulated or entrapped in a microsponge.

[0042] 1.21. Any of the preceding formulations wherein the benzoyl peroxide is free and not bound by any complex or polymer.

[0043] 1.22. Any of the preceding formulations, wherein a portion of the adapalene is undissolved, and wherein the undissolved portion of adapalene is uniformly dispersed in the formulation.

[0044] 1.23. Any of the preceding formulations, wherein a portion of the adapalene is not dissolved and is uniformly dispersed in the formulation, and a portion of the benzoyl peroxide is also not dissolved and is uniformly dispersed in the formulation.

[0045] 1.24. Any of the preceding formulations, wherein the adapalene and benzoyl peroxide do not undergo any substantial chemical reaction with each other.

[0046] 1.25. Any of the preceding formulations wherein the polyol is selected from propylene glycol, ethoxydiglycol, polyethylene glycol (eg, PEG 400), glycerol, and combinations thereof.

[0047] 1.26. Any of the preceding formulations wherein the polyol is selected from 1,2-propylene glycol and 1,3-propylene glycol.

[0048] 1.27. Any of the preceding formulations wherein the polyol is 1,2-propylene glycol.

[0049] 1.28. Any of the preceding formulations, wherein the weight content of the polyol in the formulation is 1-4 times (eg, 1-2 times) the weight content of benzoyl peroxide.

[0050] 1.29. Any of the preceding formulations wherein the weight ratio of water to polyol in the formulation is from 10:1 to 20:1.

[0051] 1.30. Any of the preceding formulations wherein the polyol is present in an amount of 3-7% by weight.

[0052] 1.31. Any of the preceding formulations wherein the polyol is present in an amount of about 5% by weight.

[0053] 1.32. Any of the preceding formulations wherein the polyol is about 5% by weight propylene glycol.

[0054] 1.33. Any of the preceding formulations wherein water is present in an amount of 80% to 90% by weight, such as 85% to 90% by weight.

[0055] 1.34. Any of the preceding formulations wherein the formulation comprises about 1.2% by weight clindamycin phosphate, about 3.1% by weight benzoyl peroxide, and about 0.15% by weight adapalene.

[0056] 1.35. Any of the preceding formulations, wherein the formulation comprises:

[0057] about 1.2% by weight of clindamycin phosphate,

[0058] About 3.1% by weight of benzoyl peroxide,

[0059] About 0.15% by weight of adapalene,

[0060] about 5% by weight of propylene glycol,

[0061] About 1.75% by weight of carbomer homopolymer type C,

[0062] Potassium hydroxide is provided at a pH of 5-6, and

[0063] water.

[0064] 1.36. A formulation 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, wherein the formulation is clinically bioequivalent to the aforementioned formulation, for example, as demonstrated 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).

[0065] 1.37. Any of the preceding formulations wherein the formulation is free of an ionic surfactant.

[0066] 1.38. Any of the preceding formulations, wherein the formulation is free of organic solvents other than polyols.

[0067] 1.39. Any of the preceding formulations wherein the formulation contains less than 2% ethanol or isopropanol, eg, is free of ethanol and isopropanol.

[0068] 1.40. Any of the preceding formulations wherein the formulation is substantially free of monohydric alcohol.

[0069] 1.41. Any of the preceding formulations wherein the formulation is aqueous.

[0070] 1.42. Any of the preceding formulations wherein the formulation is a single-phase formulation.

[0071] 1.43. Any of the preceding formulations wherein the formulation is not an emulsion.

[0072] 1.44. Any of the preceding formulations wherein said formulation is free of mineral oil.

[0073] 1.45. Any of the preceding formulations wherein the formulation does not contain a polymer other than a gelling agent.

[0074] 1.46. Any of the preceding formulations wherein the formulation does not contain a polymer other than a carbomer homopolymer.

[0075] 1.47. Any of the foregoing formulations, wherein the formulation does not contain a preservative or antimicrobial agent, except for benzoyl peroxide and adapalene.

[0076] 1.48. Any of the foregoing formulations wherein the active ingredients are only clindamycin phosphate, benzoyl peroxide, and adapalene.

[0077] 1.49. Any of the foregoing formulations further comprising one or more additional inactive ingredients selected from moisturizers, emollients, pH stabilizers, preservatives, chelating agents, and antioxidants.

[0078] 1.50. Any of the foregoing formulations, further comprising an effective amount of a preservative, for example selected from paraben preservatives (parabens), for example selected from methylparaben, propylparaben, and combinations thereof.

[0079] 1.51. Any of the foregoing formulations prepared by mixing 1-1.5% by weight of clindamycin phosphate, 2.5-3.5% by weight of benzoyl peroxide, 0.1-0.2% by weight of adapalene, a gelling agent, a polyol and water to form a uniform dispersion and then adding a base selected from potassium hydroxide, sodium hydroxide and combinations thereof in an amount to provide a pH of 5-6.

[0080] 1.52. Any of the preceding formulations wherein the concentrations of clindamycin phosphate, benzoyl peroxide, and adapalene are effective for treating acne when the formulation is applied to the affected area once daily for at least 4 weeks, 6 weeks, or 8 weeks, such as for at least 12 weeks.

[0081] 1.53. Any of the preceding formulations wherein the formulation has fewer side effects than a formulation comprising 2.5-3.5% by weight benzoyl peroxide and 0.1-0.2% by weight adapalene.

[0082] 1.54. Any of the preceding formulations wherein the formulation has no significantly more side effects than a formulation comprising 2.5-3.5% by weight benzoyl peroxide and 0.1-0.2% by weight adapalene.

[0083] 1.55. Any of the foregoing formulations, wherein the formulation is more effective in treating acne than a formulation comprising the following active ingredients: (i) 1-1.5% by weight clindamycin phosphate and 2.5-3.5% by weight benzoyl peroxide, (ii) 2.5-3.5% by weight benzoyl peroxide and 0.1-0.2% by weight adapalene, and (iii) 1-1.5% by weight clindamycin phosphate and 0.1-0.2% by weight adapalene.

[0084] 1.56. Any of the preceding formulations wherein the formulation is stable at room temperature for at least six weeks, such as at least 10 weeks.

[0085] 1.57. Any of the preceding formulations wherein the formulation is stable when refrigerated at 2°C-8°C (36°F-46°F) prior to distribution to a patient and is stable at room temperature for at least six weeks, such as at least 10 weeks.

[0086] 1.58. Any of the foregoing formulations for use in treating acne, eg, according to any of Methods 1 et seq. by daily topical application to the affected area.

[0087] 1.59. Any of the foregoing preparations, obtained or obtainable by any of the methods of method 2 et seq.

[0088] In another embodiment, the present invention provides a drug product which is a container containing any of formulations 1-1.59, e.g., a pump container or a deformable tube containing any of formulations 1-1.59, e.g., a container containing a pump and any of formulations 1-1.59, wherein the pump is calibrated to release a specific amount (e.g., 0.5-1 cubic centimeter, e.g., a pea-sized portion) of the formulation each time the pump is pressed.

[0089] In another embodiment, the present invention provides a method of treating a patient with acne vulgaris in need thereof (method 1), comprising applying to the affected area at least daily a topical gel formulation containing 1-1.5% by weight (e.g., about 1.2% by weight) of clindamycin phosphate, 2.5-3.5% by weight (e.g., about 3.1% by weight) of benzoyl peroxide, and 0.1-0.2% by weight (e.g., about 0.15% by weight) of adapalene, a gelling agent (e.g., carbomer homopolymer), a polyol (e.g., propylene glycol) and water. For example, the present invention provides:

[0090] 1.1. Method 1, wherein the administration is once daily.

[0091] 1.2. Method 1 or 1.1, wherein the affected area is the face, neck, back and / or chest.

[0092] 1.3. Any of the preceding methods, wherein the affected area is the face.

[0093] 1.4. Any of the preceding methods, wherein administration is to the entire affected area, such as the entire face.

[0094] 1.5. Any of the foregoing methods, wherein a thin layer of the topical gel formulation is applied to the entire face each evening, at least 30 minutes before bedtime, at approximately the same time each day, for 12 weeks.

[0095] 1.6. Any of the preceding methods, wherein the amount of the topical gel formulation applied each time is about 0.5-1 cubic centimeter (a pea-sized amount).

[0096] 1.7. Any of the preceding methods, wherein the patient is at least 9 years old.

[0097] 1.8. Any of the preceding methods, wherein the patient has a clinical diagnosis of moderate to severe acne.

[0098] 1.9. Any of the above methods where the patient scores acne as 3 or 4 on the Evaluator Global Severity Scale (EGSS) as follows:

[0099]

[0100]

[0101] 1.10. Any of the preceding methods wherein the treatment continues for at least 4 weeks, such as at least 8 weeks, such as at least 12 weeks.

[0102] 1.11. Any of the above methods, wherein the treatment continues for at least 12 weeks.

[0103] 1.12. Any of the preceding methods wherein the treatment is for a period of time sufficient to improve the symptoms of the inflammatory skin disorder.

[0104] 1.13. Any of the preceding methods, wherein the inflammatory skin disorder is acne vulgaris and the treatment outcome is an improvement in score on an Evaluator Global Severity Scale (EGSS).

[0105] 1.14. Any of the preceding methods wherein the administration is once daily in the evening.

[0106] 1.15. Any of the preceding methods wherein the side effects of the treatment are fewer than those of treatment with a formulation containing 2.5-3.5% by weight benzoyl peroxide and 0.1-0.2% by weight adapalene, for example, a lower incidence of pain and / or dryness at the site of application.

[0107] 1.16. Any of the preceding methods, wherein the treatment is more effective in treating acne than treatment with a formulation comprising an active ingredient selected from the group consisting of (i) 1-1.5% by weight clindamycin phosphate and 2.5-3.5% by weight benzoyl peroxide, (ii) 2.5-3.5% by weight benzoyl peroxide and 0.1-0.2% by weight adapalene, and (iii) 1-1.5% by weight clindamycin phosphate and 0.1-0.2% by weight adapalene.

[0108] 1.17. Any of the preceding methods, wherein the patient has 20 or more (e.g., 20-40) inflammatory lesions and / or 25 or more (e.g., 25-100) non-inflammatory lesions on the face at the start of treatment.

[0109] 1.18. Any of the preceding methods wherein the patient has been diagnosed with moderate to severe acne.

[0110] 1.19. Any of the preceding methods, wherein the patient has an EGSS of 3 (moderate) or 4 (severe) at the start of treatment.

[0111] 1.20. Any of the preceding methods wherein the patient is 9 years of age and older.

[0112] 1.21. Any of the preceding methods wherein the patient is 12 years of age and older.

[0113] 1.22. Any of the preceding methods, wherein at the start of treatment, the patient has a facial acne inflammatory lesion (papule, pustules, and nodules) count of not less than 30 but not more than 100.

[0114] 1.23. Any of the preceding methods, wherein the patient has a facial acne non-inflammatory lesion (open and closed comedones) count of not less than 35 but not more than 150 at the start of treatment.

[0115] 1.24. Any of the preceding methods wherein the patient is female, is not pregnant, and is using birth control throughout the treatment period.

[0116] 1.25. Any of the preceding methods wherein the topical gel formulation is a formulation selected from any one of Formulations 1-1.59.

[0117] 1.26. Any of the preceding methods wherein the topical gel formulation comprises about 1.2% by weight clindamycin phosphate, about 3.1% by weight benzoyl peroxide, and about 0.15% by weight adapalene.

[0118] 1.27. Any of the preceding methods, wherein the topical gel formulation comprises

[0119] about 1.2% by weight of clindamycin phosphate,

[0120] about 3.1% by weight of benzoyl peroxide, about 0.15% by weight of adapalene,

[0121] about 5% by weight of propylene glycol,

[0122] About 1.75% by weight of carbomer homopolymer type C,

[0123] Potassium hydroxide is provided at a pH of 5-6, and

[0124] water.

[0125] 1.28. Any of the foregoing methods, wherein the topical gel formulation is a formulation comprising about 1.2% by weight clindamycin phosphate, about 3.1% by weight benzoyl peroxide, and about 0.15% by weight adapalene, wherein the formulation is clinically bioequivalent to the foregoing formulations, for example, as demonstrated 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).

[0126] In another embodiment, the invention provides the use of clindamycin phosphate, benzoyl peroxide and adapalene in the preparation of a medicament (eg, a formulation according to any of Formulations 1-1.59) for treating a skin inflammatory disorder (eg, according to any of Methods 1-1.19).

[0127] In another embodiment, the present invention provides a method for preparing a topical gel formulation (Method 2), such as any one of Formulations 1-1.59, comprising

[0128] i. Provide the following premixes:

[0129] a. a premix A comprising a dispersion of a gelling agent in water,

[0130] b. a premix B comprising a dispersion of benzoyl peroxide in a polyol and water,

[0131] c. a premix C comprising clindamycin phosphate in an aqueous solution,

[0132] d. a premix D containing a dispersion of micronized adapalene in a polyol and water,

[0133] ii. Mixing premix A and premix D,

[0134] iii. mixing the premix B with the mixture of step ii,

[0135] iv. mixing the premix C with the mixture of step iii,

[0136] v. The pH of the mixture in step iv is adjusted to pH 5-6 to form a gel.

[0137] For example, the present invention provides:

[0138] 2.1. Method 2, wherein the gelling agent is selected from hydroxypropyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymers (optionally cross-linked with allyl ethers of polyols, e.g., carbomer), carboxyvinyl copolymers, polyacrylates, acrylate copolymers, acrylamide / sodium acryloyldimethyl taurate copolymers, polyvinyl alcohol, polyethylene oxide, propylene glycol alginate, methylcellulose, hydroxypropyl methylcellulose, xanthan gum, carrageenan, and combinations thereof.

[0139] 2.2. Any of the preceding methods, wherein the gelling agent is selected from carboxyvinyl polymers (optionally cross-linked with allyl ethers of polyols, e.g., carbomers), carboxyvinyl copolymers, polyacrylates, acrylate copolymers, acrylamide / sodium acryloyldimethyl taurate copolymers, propylene glycol sodium alginate, hydroxypropyl methylcellulose, and xanthan gum.

[0140] 2.3. Any of the preceding methods, wherein the gelling agent comprises acrylamide / sodium acryloyldimethyltaurate copolymer.

[0141] 2.4. Any of the preceding methods, wherein the gelling agent comprises acrylamide-acrylamide-sodium dimethyltaurate / isohexadecane / polysorbate 80 gelling agent.

[0142] 2.5. Any of the preceding methods, wherein the gelling agent comprises a carbomer homopolymer cross-linked with an allyl ether of a polyol (eg, allyl sucrose or allyl pentaerythritol).

[0143] 2.6. Any of the foregoing methods, wherein the gelling agent is an acrylic polymer cross-linked with a polyol allyl ether; for example, containing 56%-68% carboxylic acid (-COOH) groups; for example, having a viscosity of 40,000-60,000 cP (measured at 0.5% by weight at pH 7.5).

[0144] 2.7. Any of the preceding methods, wherein the gelling agent is a Type C carbomer homopolymer, such as a carbomer as defined in the United States Pharmacopeia / National Formulary (USP / NF) monograph, such as Carbomer 980.

[0145] 2.8. Any of the preceding methods, wherein the polyol is selected from the group consisting of propylene glycol, ethoxydiglycol, polyethylene glycol (eg, PEG 400), glycerol, and combinations thereof.

[0146] 2.9. Any preceding method wherein the polyol is selected from 1,2-propylene glycol and 1,3-propylene glycol.

[0147] 2.10. Any preceding method wherein the polyol is 1,2-propylene glycol.

[0148] 2.11. Any of the preceding methods wherein the amount of active ingredients in the final product is about 1.2% by weight clindamycin phosphate, about 3.1% by weight benzoyl peroxide, and about 0.15% by weight adapalene.

[0149] 2.12. Any of the preceding methods, wherein the resulting topical gel formulation comprises:

[0150] about 1.2% by weight of clindamycin phosphate,

[0151] About 3.1% by weight of benzoyl peroxide,

[0152] About 0.15% by weight of adapalene,

[0153] about 5% by weight of propylene glycol,

[0154] about 1.75% by weight of carbomer homopolymer of type C,

[0155] Potassium hydroxide is provided at a pH of 5-6, and

[0156] water.

[0157] 2.13. Any of the preceding methods, wherein the pH of premix C is adjusted to a pH of 6-7, eg, a pH of 6.2-6.8.

[0158] 2.14. Any of the preceding methods, wherein in step v, the pH is adjusted to 5.4-5.8.

[0159] 2.15. Any of the preceding methods wherein the pH adjuster is selected from the group consisting of sodium hydroxide, potassium hydroxide, and mixtures thereof.

[0160] 2.16. Any preceding method wherein the pH adjuster is potassium hydroxide.

[0161] 2.17. Any of the preceding methods, further comprising the step of filling a dispensing container (eg, a deformable tube or a pump container) with the product of step v.

[0162] The invention also provides a topical gel formulation, for example, according to any one of formulations 1-1.59, which is the product of any one of methods 2-2.17.

[0163] Unless otherwise indicated, all ingredient percentages given in this specification are based on 100% of the total weight of the composition or formulation.

[0164] The compositions and preparations provided herein are described and claimed with reference to their ingredients, as is common in the art. As will be apparent to those skilled in the art, the ingredients may react with each other in certain circumstances, so that the actual composition of the final preparation may not correspond exactly to the listed ingredients. Therefore, it should be understood that the present invention extends to products of the listed ingredient combinations.

[0165] "About" with respect to quantity or concentration means 80%-120%, 90%-110% of the stated value.

[0166] As used throughout, ranges are used as shorthand for describing each value within a range. Any value within a range can be selected as the endpoint of the range. In addition, all references cited herein are incorporated herein by reference in their entirety. If a definition in the present disclosure conflicts with a definition in the cited reference, the present disclosure shall prevail.

[0167] Unless otherwise specified, all percentages and amounts expressed herein and elsewhere in the specification are to be understood as percentages by weight. The amounts given are based on the active ingredient weight of the material being described.

[0168] The present invention is further illustrated by the following examples, which are intended to be illustrative rather than limiting. Example

[0169] Example 1: Clinical trial comparing a three-component combination with a two-component combination

[0170] The aim of this study was 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%) relative to its base and two-component combinations (BPO / adapalene, clindamycin / BPO, and clindamycin / adapalene) for the treatment of moderate-to-severe acne vulgaris in subjects 9 years of age and older.

[0171] This is a multicenter, randomized, double-blind, matrix-controlled, 12-week study designed to evaluate the safety, tolerability, and efficacy of a three-component gel containing clindamycin phosphate (CP), benzoyl peroxide (BPO), and adapalene (1.2% / 3.1% / 0.15%) relative to its matrix and two-component combinations (BPO / adapalene, clindamycin / BPO, and clindamycin / adapalene) at weeks 2, 4, 8, and 12. The study formulations are as follows:

[0172] Table 1

[0173]

[0174] Subjects were eligible to participate in the study if they were at least 9 years of age and had a clinical diagnosis of moderate to severe acne (defined as an Evaluator Global Severity Score [EGSS, as described above] of 3 or 4), 30–100 inflammatory facial lesions (papules, pustules, and nodules), 35–150 noninflammatory facial lesions (open and closed comedones), and ≤2 facial nodules. All subjects received the facial topical treatment once daily for 12 weeks. Subject visits included screening, baseline, Week 2, Week 4, Week 8, and Week 12, during which safety and efficacy assessments were performed (screening and baseline visits may be performed on the same day if washout was not required). Subjects were dispensed one pump of study medication at baseline, Week 4, and Week 8 study visits. Subjects were assessed for medication adherence at each post-baseline study visit (Weeks 2, 4, 8, and 12). Subjects applied the treatment once daily (in the evening) at home as directed by the study coordinator or designee at each study center.

[0175] The investigator assessed the subject's face at each study visit. Information on reported and observed adverse events (AEs) was obtained at each visit. A brief physical examination and vital sign measurements were performed on all subjects at baseline and Week 12 (end of study). Blood samples were collected from subjects at baseline and Week 12 for CBC / Diff and serum chemistry. For all female subjects of childbearing potential (FOCBP), a urine pregnancy test was performed at screening, baseline (prior to randomization), and Weeks 2, 4, 8, and 12. In addition, a serum pregnancy test was performed at baseline and Week 12.

[0176] In addition, standardized facial photography was performed at baseline and at weeks 4, 8, and 12 at selected study centers.

[0177] Approximately 750 subjects were randomly assigned in a 1:1:1:1:1 ratio to the following treatment groups:

[0178] 150 subjects to test gel (clindamycin phosphate 1.2% / BPO 3.1% / adapalene 0.15%),

[0179] 150 subjects to component A (BPO 3.1% / adapalene 0.15%),

[0180] 150 subjects to component B (clindamycin phosphate 1.2% / BPO 3.1%),

[0181] 150 subjects to component C (clindamycin phosphate 1.2% / adapalene 0.15%),

[0182] · 150 subjects to matrix gel.

[0183] At home, assigned study medication was applied topically to the face once daily in the evening for 12 weeks (ending the evening before the Week 12 visit), except on study visit days (baseline exam, Weeks 2, 4, and 8), when study medication was applied (also by the subject) at the study center after the study visit.

[0184] Subjects who met all of the following criteria were eligible for entry into the study:

[0185] 1. Male or female, at least 9 years old and above.

[0186] 2. Written and verbal informed consent must be obtained. Subjects younger than the age of consent must sign a research consent form, and parents or legal guardians must sign an informed consent form (if the subject reaches the age of consent during the study, they should consent again at the next study visit).

[0187] 3. The subject's EGSS at baseline must be 3 (moderate) or 4 (severe).

[0188] 4. The number of acne inflammatory lesions (papules, pustules and nodules) on the subject's face is not less than 30 but not more than 100.

[0189] 5. The number of non-inflammatory acne lesions (open and closed comedones) on the subject's face is not less than 35 but not more than 150.

[0190] 6. Subjects with 2 or fewer facial nodules.

[0191] 7. Women with FOCBP1 and premenopausal women must be willing to implement effective contraception during the study. (Effective contraception is defined as oral contraceptives for at least 3 months, intrauterine devices, condoms with spermicide, diaphragms with spermicide, implants, injections, transdermal patches, or abstinence. ) Women who are taking birth control pills must have been taking the same type of birth control pill for at least 3 months before entering the study and may not change types during the study. Those who have used birth control pills in the past must have stopped using them at least 3 months before the start of the study. Women who use birth control only for acne control should be excluded.

[0192] 8. Premenopausal women and FOCBP must have a negative urine pregnancy test at the screening visit and a negative urine pregnancy test at the baseline visit.

[0193] 9. Subjects must be willing to follow the study instructions and return to the clinic for necessary visits. Subjects under the age of consent must be accompanied by a parent or legal guardian when signing the consent / assent form.

[0194] 10. If cleansers, moisturizers, or sunscreens are required during the study, the subject must be willing to use only permitted cleansers, moisturizers, sunscreens, or moisturizer / sunscreen combination products (see Appendix 17.2). The subject must agree to use non-comedogenic products (including makeup and shaving products).

[0195] Subjects who met any of the following criteria were excluded from this study:

[0196] 1. Use of study drugs or devices within 30 days of enrollment or participation in a study conducted concurrently with this study.

[0197] 2. Any facial skin condition that may interfere with clinical evaluation, such as agglomerates, acne fulminans, secondary acne, perioral dermatitis, clinically significant rosacea, Gram-negative folliculitis, dermatitis, eczema.

[0198] 3. Any underlying disease or other dermatological condition of the face that requires the use of interfering topical or systemic treatment or makes the assessment and lesion count uncertain.

[0199] 4. Subjects with facial hair or beards that may interfere with study assessments.

[0200] 5. Subjects with more than two (2) facial nodules.

[0201] 6. Evidence or history of cosmetic-related acne.

[0202] 7. The subject has a history of significant burning or stinging when applying any facial care products (such as cosmetics, soap, mask, detergent, sunscreen, etc.) on the face.

[0203] 8. Female subjects who are pregnant, breastfeeding, planning to become pregnant during the study, or become pregnant during the study.

[0204] 9. Subjects who have used estrogen (such as Depogen, Depo-Testadiol, Gynogen, Valergen, etc.) for less than 12 weeks before entering the study; subjects who have taken estrogen for 12 weeks or more before the start of the study do not need to be excluded unless the subject wishes to change the dose, switch medications, or stop using estrogen during the study.

[0205] 10. If female, the subject has a history of hirsutism, polycystic ovary disease, or clinically significant menstrual irregularities.

[0206] 11. Patients with a history of local enteritis, ulcerative colitis, inflammatory bowel disease, pseudomembranous colitis, chronic or recurrent diarrhea, or antibiotic-associated colitis.

[0207] 12. Treatment for any type of cancer within the past 6 months, except complete surgical excision of skin cancer outside the treatment area.

[0208] 13. Subjects were using medications and / or vitamins reported to aggravate acne during the study period (azathioprine, haloperidol, vitamin D, vitamin B12, halogens (such as iodide or bromide), lithium, medium to very high potency corticosteroids applied systemically or topically to the treatment area, phenytoin, and phenobarbital). Multivitamins, including the recommended daily dose of vitamin A and a stable dose of vitamin D are acceptable.

[0209] 14. History of allergy or hypersensitivity reaction to any study agent as described in the Investigator's Brochure, including known sensitivity to any dosage form of clindamycin phosphate, BPO, or adapalene.

[0210] 15. Concurrent use of potentially irritating over-the-counter products containing ingredients such as BPO, alpha hydroxy acids, salicylic acid, retinol, or glycolic acid.

[0211] 16. Subjects who have used the following topical preparations or physical treatments on the face without undergoing the specified washout period, or subjects who need to use any of the following medications simultaneously on the treated area:

[0212] -Topical use of astringents and abrasives on the face (including comedone removal strips): 1 week;

[0213] - No moisturizer or sunscreen allowed on the face: 1 week;

[0214] - Antibiotics on face: 2 weeks;

[0215] - Other topical anti-acne medications for the face: 2 weeks;

[0216] - Antimicrobial soap for face: 2 weeks;

[0217] - Anti-inflammatory agents and corticosteroids for facial use: 4 weeks;

[0218] - Retinoids for the face, including tretinoin: 4 weeks;

[0219] - Facial procedures, including chemical peels, microdermabrasion, light (PDT, LED) and laser treatments, and acne surgery: 4 weeks.

[0220] If a subject requires topical treatment for acne on areas other than the face (e.g., chest and / or back), the investigator may prescribe a product that does not contain clindamycin phosphate, BPO, or adapalene and this must be noted in the source document and electronic case report form (eCRF).

[0221] 17. Subjects who have not undergone a designated washout period for the following systemic medications or subjects who need to use any of the following systemic medications simultaneously:

[0222] -Corticosteroids (including intramuscular injection) (inhaled corticosteroids are allowed): 4 weeks;

[0223] - Antibiotics: 4 weeks;

[0224] - Other systemic acne treatments: 4 weeks;

[0225] -Systemic retinoids: 6 months.

[0226] 18. The subject intends to use a tanning booth or solarium during the study.

[0227] 19. Subjects who are unable to communicate or cooperate with researchers due to the following reasons: language problems, intellectual disabilities, or impaired brain function.

[0228] 20. The subject has an underlying disease that the researcher believes is uncontrollable and the researcher expresses concerns about the subject's safety when participating in the study.

[0229] Subject withdrawal criteria: The reasons for withdrawal may include but are not limited to the following:

[0230] An acne flare determined by the investigator that requires treatment with an unapproved treatment.

[0231] At the request of the investigator, for tolerability reasons (e.g., serious adverse reactions), or at the request of the subject.

[0232] ·When the requirements of the stated program are not followed.

[0233] When a subject reports or requests concomitant treatment that may interfere with the study results (the investigator reports all such information in the source document / eCRF and the sponsor decides whether to withdraw the subject).

[0234] When a subject is lost to follow-up. The investigator makes two attempts to contact the subject by phone, email, and / or text message and sends a follow-up letter by registered mail when a subject is considered lost to follow-up. These actions are reported in the study end source file and the final eCRF, and a copy of the follow-up letter is kept in the investigator's file.

[0235] All premature discontinuations and the associated reasons must be carefully documented by the investigator on the source documents and final eCRF and, if necessary, on the Adverse Event Form. In any case, if a subject prematurely discontinues the study for any reason, the subject who was enrolled in the study and has an assigned study number cannot be replaced by another subject. All subject data collected prior to discontinuation are provided to the sponsor.

[0236] The reasons for study completion / discontinuation listed in the Final Report Form are defined as follows:

[0237] Normal Study Completion - The subject completed the study as planned in the protocol.

[0238] Adverse Events - Complete the Adverse Event Form.

[0239] Death - Complete the Serious Adverse Event (SAE) form.

[0240] Subject Requests - Withdrawal of consent, subject relocation, scheduling conflicts.

[0241] Protocol Violation - Contact the sponsor or designee before making a decision.

[0242] Lost to follow-up - documentation included 2 phone calls, emails and / or text messages, and one registered letter.

[0243] Pregnancy - Subjects will stop taking study medication immediately, but follow-up will continue until due.

[0244] Fill out the pregnancy form.

[0245] Worsening of disease - Subjects were required to replace treatment for acne before the end of the study, not due to lack of efficacy as determined by the investigator.

[0246] Lack of Efficacy - The subject requires an alternative treatment for acne after at least 2 weeks of study medication and the investigator determines that the risks to the subject's continued participation in the study outweigh the benefits.

[0247] Parent / Guardian Withdrawal - Indications that a research participant has been removed from the study by a parent or legal guardian; includes withdrawal of consent, subject moving, scheduling conflicts, etc.

[0248] Sponsor-Terminated Study - An indication that a clinical study was stopped by its sponsor.

[0249] Other - Please specify in the comments section of the eCRF.

[0250] Evaluation criteria:

[0251] Main Benefits:

[0252] The co-primary efficacy endpoints were designed to compare the numerical superiority of once-daily application of the test gel, matrix gel, and each reference gel (components A, B, and C). Specifically, the endpoints summarized using descriptive and inferential statistics were as follows:

[0253] (1) Absolute change in mean inflammatory lesion count from baseline to week 12.

[0254] (2) Absolute change in mean non-inflammatory lesion count from baseline to week 12.

[0255] (3) The percentage of subjects who achieved a reduction of at least 2 grades from baseline and were “clear” or “almost clear” based on the Evaluator Global Severity Score (EGSS) at Week 12.

[0256] Secondary effects:

[0257] Secondary efficacy endpoints were designed to compare the numerical superiority of once-daily application of the test gel, matrix gel, and each reference gel (components A, B, and C). Specifically, secondary endpoints summarized using descriptive statistics included:

[0258] (1) Absolute changes in inflammatory and noninflammatory lesion counts from baseline at weeks 2, 4, and 8.

[0259] (2) The percentage of subjects who achieved a reduction of at least 2 grades from baseline and were “clear” or “almost clear” according to the EGSS at Weeks 2, 4, and 8.

[0260] (3) Mean percentage change in inflammatory and noninflammatory lesion counts relative to baseline at weeks 2, 4, 8, and 12.

[0261] Efficacy Measurements:

[0262] Lesion Counts: At each visit, the assessor counted the total number of inflammatory lesions (papules, pustules, and nodules) on the subject's face. Nodules were counted separately but included in the total number of inflammatory lesions. Eligible subjects could have no more than 2 nodules at the baseline examination. Nodules were included in the statistical analysis of the inflammatory lesion counts. All inflammatory lesions were counted at the same time, and papules and pustules were not counted separately. The assessor also counted the total number of non-inflammatory lesions (open and closed comedones). Lesion counts and EGSS assessments were performed by the same blinded assessor on the same subject at all visits from the baseline examination to Week 12.

[0263] Inflammatory lesions are defined as follows:

[0264] Papules - small, solid bumps less than 5 mm in diameter. Most lesions are above the surface of the skin.

[0265] Pustules - small, outer-rimmed elevations less than 5 mm in diameter, containing a yellowish-white exudate.

[0266] Nodule - a subcutaneous lesion greater than or equal to 5 mm in diameter.

[0267] Non-inflammatory lesions are defined as follows:

[0268] Open comedones (blackheads) - lesions in which the opening of the hair follicle is widely enlarged and the contents protrude to the surface of the skin.

[0269] Closed comedones (whiteheads) - lesions where the opening of the hair follicle is closed, but the sebaceous glands proliferate due to pressure from sebum accumulation, causing the skin around the hair follicle to thin and rise, giving it a white appearance.

[0270] Evaluator's Global Severity Score (EGSS): Severity is determined at each visit based on a blinded evaluator's assessment of signs and symptoms of acne vulgaris. Every effort should be made to have the same evaluator evaluate the same subject at each visit. If this is not possible, the same evaluator should evaluate the subject at the baseline exam and the Week 12 visit. The evaluation score is 0-4, with 0 being clean and 4 being severe:

[0271] Table 2

[0272]

[0273]

[0274] EGSS should always be completed before damage counting.

[0275] Safety measures: Safety assessment includes the following:

[0276] - Percentage of subjects experiencing skin reactions (erythema, scaling, hypo / hyperpigmentation, pruritus, burning, or stinging) rated as Grade 3 at any time point in the study after the first application of study medication.

[0277] - The percentage of subjects experiencing cutaneous adverse events (AEs), regardless of severity, at any time during the study after the first application of study drug.

[0278] - Changes from baseline in all safety laboratory values ​​and vital sign measurements summarized by treatment group and study visit using descriptive statistics.

[0279] - Evaluate subjects for new and ongoing adverse events.

[0280] Skin safety and tolerability were assessed by a list of adverse events and skin safety and tolerability assessment scores (scaling, erythema, hypo / hyperpigmentation, pruritus, burning, and stinging) assessed at each study visit. At each study visit, subjects were reviewed for pruritus, burning, and stinging (skin tolerability) as the average since the last visit. At each visit, assessors assessed scaling, erythema, and hypo / hyperpigmentation (skin safety). Signs and symptoms of skin tolerability that led to the need for concurrent treatment, interruption of treatment, or discontinuation of the study were reported as adverse events.

[0281] Statistical methods: Unless otherwise stated, Version 9.3 or later performs all statistical processing.

[0282] Statistical significance is based on a two-tailed test of the null hypothesis with a p-value of 0.05 or less. P-values ​​for selected variables are given to help reviewers evaluate the study results. Failure to obtain statistically significant results at an alpha level of 0.05 does not mean that the study has failed.

[0283] The absolute changes in mean inflammatory and noninflammatory lesion counts from baseline to week 12 were analyzed using analysis of covariance (ANCOVA) including factors of treatment group and analysis center and the covariate of the respective baseline lesion counts. Nonparametric analyses were used. In addition, 4 pairwise comparison tests were performed comparing the test gel to the matrix gel and the test gel to each of the two-component gels.

[0284] The percentage of subjects with treatment success, defined as at least a 2-grade improvement from baseline on the EGSS and a score of "clear" or "almost clear" on the EGSS at week 12, was analyzed by logistic regression tests with factors including treatment group and analysis center and covariates for baseline severity. Four pairwise comparison tests were performed comparing the test gel to the matrix gel and the test gel to each of the two-component gels.

[0285] The primary approach to handling missing efficacy data was MCMC multiple imputation. Other approaches, as well as MCMC imputation, were specified in detail in the statistical analysis plan finalized before the database was locked.

[0286] Analysis Population and Treatment Group: Inflammatory and non-inflammatory lesion counts were recorded for each subject at baseline and at weeks 2, 4, 8, and 12. At weeks 2, 4, 8, and 12, the absolute and percentage changes in inflammatory and non-inflammatory lesions from baseline were obtained for each subject. The EGSS was recorded for each subject. The EGSS was divided into "success" and "failure", and it was considered successful if the EGSS at weeks 2, 4, 8, and 12 was at least 2 levels lower than baseline and reached "clean" or "almost clean". Intention-to-treat (ITT) analysis was performed on all study subjects. The ITT population consisted of all randomized subjects who received study drug. The safety population included all randomized subjects who were assumed to have used study drug at least once and provided at least one post-baseline assessment. A per-protocol (PP) analysis was also performed. Subjects were eligible if they completed the 12-week assessment and had no notable protocol violations (any subject or investigator activities that could interfere with the accurate assessment of treatment or efficacy). The PP population included subjects in the ITT population who did not meet any of the following criteria:

[0287] ·Does not meet any of the inclusion / exclusion criteria.

[0288] Taking any interfering concomitant medications.

[0289] Failure to attend the Week 12 visit, unless discontinued from the study due to adverse events related to study treatment or documented lack of treatment effect.

[0290] Missed 1 or more post-baseline study visits before Week 12.

[0291] • Non-adherence to dosing regimen (i.e., the subject did not miss more than 5 consecutive days of dosing and must have taken 80%-120% of the expected dose). The expected dose for each subject was determined based on the length of time the subject had participated in the study.

[0292] · Not within the visit window at the 12th week visit.

[0293] Other additional criteria may be added to the list before unblinding to accommodate unforeseen events during the trial that result in noteworthy protocol violations.

[0294] Demographic and baseline characteristics of the subjects were summarized by treatment group using descriptive statistics for the ITT, PP, and safety analysis data sets.

[0295] Efficacy Assessments - Primary Efficacy: A co-primary efficacy analysis of the absolute change from baseline in inflammatory and non-inflammatory lesions was performed in the ITT population. The pre-specified time point was Week 12. Descriptive statistics were performed by treatment group for inflammatory and non-inflammatory lesions and the absolute change in inflammatory and non-inflammatory lesions. All tests related to the analysis of inflammatory and non-inflammatory lesions were performed using the methods described above. The co-primary efficacy analysis of the dichotomous EGSS in the ITT population (successful improvement of at least 2 levels to "clean" or "almost clean") was based on a logistic regression test with factors including treatment group and analysis center and baseline severity as a covariate.

[0296] Efficacy Assessments - Secondary efficacy: Mean percent change from baseline in inflammatory and non-inflammatory lesion counts and the proportion of subjects with at least a 2-grade improvement in EGSS from baseline were assessed at Weeks 2, 4, 8, and 12.

[0297] Safety Assessments: All subjects who received medication and provided at least one post-baseline assessment comprised the safety population. Safety was assessed by adverse event listings, skin safety and tolerability assessments, vital signs / brief physical examinations, and safety laboratory results. Skin safety and tolerability assessment scores (erythema, scaling, hypo / hyperpigmentation, pruritus, burning, and stinging) were presented as descriptive statistics at baseline and at weeks 2, 4, 8, and 12. Frequencies and percentages for each outcome category were included in these statistics. Means were presented graphically by week and treatment group. Vital sign measurements, brief physical examinations, and safety laboratory results were performed at designated visits for all subjects. For premenopausal women and FOCBP, urine pregnancy and serum pregnancy tests were performed at designated visits. Changes from baseline in safety laboratory values ​​and vital sign measurements were summarized for each treatment group at all applicable study visits, and descriptive statistics were performed. A shift table of safety laboratory value changes is presented to summarize laboratory test results collected at baseline and week 12. Normal ranges established by the central laboratory were used to determine shifts. A list of all out-of-range laboratory test results for any evaluation time point should also be provided. The clinical significance of all out-of-range laboratory values ​​was determined by each investigator and included in the list. In addition, a list of all clinically significant laboratory test results was provided.

[0298] All previous concomitant medications were classified according to terms from the World Health Organization Drug Dictionary. Data on previous treatments and concomitant medications are listed in the data tabulation. All adverse events occurring during the study were recorded and classified using the Medical Dictionary for Regulatory Activities (MedDRA) terms. The description of the adverse event included the date of onset, the date the adverse event ended, the severity of the adverse event, the relationship to the study drug, the measures related to the use of the study drug, the measures taken to treat the adverse event, and the outcome. Adverse events were summarized by treatment group and severity. Each subject was counted only once in one system organ class or one preferred term.

[0299] The most severe AE in each category is used. Adverse events are summarized by treatment group and relationship to study drug. Each subject is counted only once in one system organ class or one preferred term by using the AE with the greatest relationship in each category. All information related to adverse events recorded during the study is listed by subject, detailing the verbatim description given by the investigator, preferred term, system organ class, start date, stop date, severity, actions taken, and drug relationship. The occurrence of the adverse event is related to the initial dose of randomized study drug (days). Serious adverse events (SAEs) are listed by subject within treatment group. In addition, a list of subjects who discontinued the study and a list of subjects who experienced serious adverse events are provided.

[0300] Subject Self-Assessment: During the study, subjects were asked to complete an acne-specific quality of life questionnaire. Investigator assessments (EGSS and lesion counts) were performed independently of subject self-assessment. No inferential statistical analysis was performed on the questionnaires; subjective responses were compared across treatment groups.

[0301] This study complies with Good Clinical Practice, including archiving of essential study documents. This protocol follows the guidelines outlined by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.

[0302] Clinical trials have shown that the test gel is significantly more effective than the matrix or any of the three two-component references:

[0303] Table 3: Primary efficacy analysis: absolute change in lesion count and dichotomous global severity at week 12 compared with baseline (intention-to-treat population)

[0304]

[0305]

[0306] (a) Least squares means, standard deviations, comparison p-values, and overall p-values ​​for analysis of covariance with treatment group and analysis center factors, and respective baseline lesion counts as covariates. Values ​​are adjusted for multiple imputation.

[0307] (b) The median, minimum, and maximum values ​​represent the mean values ​​and are obtained by averaging the summary statistics generated for each imputed dataset.

[0308] (c) Skewness test, evaluated for each imputed dataset. The average p-value is given.

[0309] (d) p-values ​​from the ordinal analysis of covariance and overall p-values ​​comparing treatment group and analysis center, with the respective baseline lesion counts as covariates. Values ​​are adjusted for multiple imputation.

[0310] (e) Comparison and overall p-values ​​from logistic regression of treatment group and analysis center. Values ​​are adjusted for multiple imputation.

[0311] Note: Multiple imputation (MCMC) was used to impute missing values. Changes were calculated as Week 12 - Baseline.

[0312] The three-component test gel was not only more effective than the two-component reference, but also had fewer side effects than the benzoyl peroxide / adapalene combination:

[0313] Table 4: Summary of characteristics of adverse events occurring during treatment (safety population)

[0314]

[0315]

[0316] Note: Treatment-emergent adverse events are those that occur on or after the first dose of study drug.

Claims

1. A topical gel preparation comprising 1-1.5% by weight of clindamycin phosphate, 2.5-3.5% by weight of benzoyl peroxide and 0.1-0.2% by weight of adapalene, as well as a gelling agent, a polyol and water.

2. The formulation of claim 1, wherein the formulation comprises 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 of claim 2, wherein the formulation comprises: 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. providing potassium hydroxide in an amount of 5-6 pH, and g. Water.

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

5. The method of claim 4, wherein the inflammatory skin disorder is acne.

6. The method of claim 4 or 5, wherein administration is once daily for a period of at least 4 weeks, such as at least 12 weeks.

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

8. A pharmaceutical product which is a container comprising a pump and comprising the topical gel formulation of any one of claims 1 to 3, wherein the pump is calibrated to release a specific amount of the formulation each time the pump is depressed.

9. A method for preparing a topical gel formulation according to any one of claims 1 to 3, comprising i. Provide the following premixes: a) a premix A comprising a dispersion of a gelling agent in water, b) a premix B comprising a dispersion of benzoyl peroxide in a polyol and water, c) a premix C comprising clindamycin phosphate in an aqueous solution, d) a premix D comprising a dispersion of micronized adapalene in a polyol and water, ii. Mixing premix A and premix D, iii. mixing the premix B with the mixture of step ii, iv. mixing the premix C with the mixture of step iii, v. Adjust the pH of the mixture in step iv to pH 5-6 to form a gel.

10. A topical gel formulation according to claim 1, 2 or 3 for use in any method of claim 4, 5, 6 or 7.

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