Methods and compositions for treating acne

Abstract

The present application relates to regimens, methods of treatment, and compositions for treating acne in a subject suffering from acne.

Description

TECHNICAL FIELD

[0001] The present application relates to regimens, methods of treatment, and compositions for treating acne in a subject suffering from acne. BACKGROUND

[0002] Acne vulgaris is a common condition of the pilosebaceous units of the skin (hair follicle and oil gland). Acne is the most common skin disease in the United States, affecting 40-50 million Americans. Acne typically begins in adolescence, but the disease is not limited to any age group. Approximately 85% of people between 12 and 24 years of age experience acne at some point in their youth, most commonly on the face, chest, and back [Bhate and Williams].

[0003] Acne is caused by four main factors: (1) increased production of oil by the oil glands in the skin; (2) clogging of the hair follicle that releases the oil; (3) growth of bacteria called P. acnes within the follicle; and (4) inflammatory / immune response to P. acnes.

[0004] The pathophysiology of acne suggests that a combination therapy should be used early to attack multiple causative factors of the condition simultaneously [Gollnick and Cunliffe]. Antibacterial agents have been the mainstay of acne treatment for many years, with multiple mechanisms of action. The most important is probably the ability of antibiotics to reduce the number of P. acnes within and around the follicle. They have a bacteriostatic effect on P. acnes, preventing the bacteria from producing proinflammatory molecules [Leyden et al.].

[0005] In clinical practice, physicians often prescribe multiple topical products for acne. Patients use the topical products once or twice daily. However, many of these compounds are irritating, developing facial erythema, and the products are discontinued or noncompliant with treatment. Benzoyl peroxide (BPO) and all trans-retinoic acid (ATRA) are two active ingredients with different pharmacological actions that are commonly used to treat acne.

[0006] Topical retinoids are keratinization inhibitors. They act by reducing the cohesion of follicular epithelial cells. This results in inhibition of microcomedone formation, preventing the formation of mature comedones and inflammatory lesions [Gollnick and Cunliffe]. The use of retinoids promotes normal desquamation of follicular epithelium. The action of retinoids can enhance the penetration of other topical compounds used to treat acne.

[0007] BPO is a commonly used topical antibacterial agent for acne and is available through combination prescription or over-the-counter (OTC). BPO has been found to be lethal to P. acnes and other bacteria that can be present on the skin. To date, there is no evidence of any bacteria developing resistance to BPO. BPO has also been shown to have keratolytic activity, contributing to its efficacy in treating comedonal acne [Tanghetti]. BPO reduces the cohesiveness of corneocytes, thereby improving the delivery of topical medications through the epidermal barrier.

[0008] Silica microcapsule systems have been developed to overcome many of the limitations (e.g., degradation and irritation) associated with standard pharmaceutical formulations of multiple active ingredients. Encapsulation of active ingredients in silica microcapsules serves to protect the components in the formulation from interacting with each other and, thus, improves the overall stability of the formulation. Silica is chemically inert, photochemically and physically stable, and safe for topical use.

[0009] The applicant's silica encapsulated product meets the category exclusion criteria defined in 21 CFR 25.31 (e) and, to the applicant's knowledge, there are no special cases defined in 21 CFR 25.21. Therefore, no environmental assessment is required under 21 CFR 25.20 (1). In the case of encapsulated BPO (E-BPO) / encapsulated ATRA (E-ATRA), microencapsulation of BPO and tretinoin protects tretinoin from oxidative decomposition by BPO, thereby enhancing the stability of this novel combination product and ensuring an appropriate clinical and commercial shelf life (US 8,617,580 and US2012 / 0202695).

[0010] Clinicians have been reluctant to prescribe topical retinoids and BPO simultaneously and have preferred to recommend BPO or antibiotic / BPO combination in the morning and tretinoin in the evening due to the belief that BPO can cause oxidation and degradation of tretinoin molecules, thereby reducing their effectiveness (Yan AC. Current concepts in acne management. Adolesc. Med. Clin. 2006; 17(3): 613-637).

[0011] Another publication (Emmy Graber, Treatment of Acne Vulgaris, UpToDate.com, Jul 2016) states, "Topical tretinoin should not be used concurrently with benzoyl peroxide," despite the fact that novel retinoid compositions like Retin A Micro (Derm System) have minimal or no short-term interaction with BPO. Clearly, this publication does not teach concurrent application of tretinoin and BPO.

[0012] Unlike adapalene, which is often combined with BPO, tretinoin is significantly more irritating to the skin, and since BPO is also irritating, there is concern that the two APIs together would produce unacceptable skin side effects. In addition, BPO is known to oxidize tretinoin, and thus there is concern that the interaction on the skin when they are both administered together would reduce the therapeutic effect of tretinoin. Thus, despite some reports in the literature that the two compounds are applied one in the morning and the other at night, the consensus to date is that the two products should not be applied at the same time.

[0013] This understanding in the medical community explains why all previous attempts to solve the tretinoin / BPO stability problem, such as microcapsule technology, have not yet resulted in a commercial product.

[0014] Combination topical therapy is the recommended medical standard for the management of acne patients [Gollnick and Cunliffe]. Combination therapy targets multiple pathogenic factors: abnormal follicular keratinization, proliferation of P. acnes, and inflammation. Combining separate products into a single delivery system would provide the convenience of a single product to the patient, thereby improving patient compliance and improving therapeutic efficacy. SUMMARY

[0015] In some embodiments, the present application provides a method of treating acne comprising: topically applying to an affected skin area of a subject in need thereof a topical medicament comprising active agents:

[0016] - tretinoin or a pharmaceutically acceptable salt thereof in an amount of about 0.05% to about 0.1% by weight;

[0017] and

[0018] - benzoyl peroxide in an amount of at least about 3% by weight.

[0019] In some embodiments, in the method of the present application, the score of at least one parameter evaluated by the Investigator Cutaneous Safety Assessment is synergistically lower than the score of said parameter evaluated for each active agent respectively under the same treatment regimen. In another embodiment, said at least one parameter evaluated by the Investigator Cutaneous Safety Assessment is selected from the group consisting of erythema, scaling, pigmentation, and any combination thereof.

[0020] In some embodiments, in the methods of the present application, the score of at least one parameter assessed by the Local Tolerability Score is synergistically lower than the score of said parameter assessed using the same treatment regimen for each active agent, respectively. In another embodiment, said at least one parameter assessed by the Local Tolerability Score is selected from the group consisting of pruritus, burning, stinging, and any combination thereof.

[0021] In some embodiments, the amount / concentration of tretinoin or a pharmaceutically acceptable salt thereof in the medicament for the treatment of acne is at least about 0.05% by weight. In another embodiment, the amount / concentration of tretinoin or a pharmaceutically acceptable salt thereof in the medicament for the treatment of acne is about 0.1% by weight. In another embodiment, the amount / concentration of tretinoin or a pharmaceutically acceptable salt thereof in the medicament for the treatment of acne is about 0.1% by weight, and the concentration / amount of benzoyl peroxide is at least about 3% by weight. In another embodiment, the concentration / amount of benzoyl peroxide is 3% to 6% by weight. In another embodiment, the concentration of benzoyl peroxide is 3% by weight. In another embodiment, the concentration of benzoyl peroxide is 6% by weight. In another embodiment, the topical medicament in a single dose comprises two active agents (benzoyl peroxide and tretinoin). In another embodiment, the topical medicament comprises two separate compositions, each comprising each active agent (benzoyl peroxide and tretinoin). In another embodiment, the two separate compositions are administered simultaneously. In another embodiment, the two separate compositions are administered sequentially.

[0022] In some embodiments, in the methods of the present application, the method reduces at least one of:

[0023] (i) the number of inflammatory acne lesions by at least 50%; or

[0024] (ii) the number of non-inflammatory acne lesions by at least 40%.

[0025] In other embodiments, the method reduces the number of inflammatory acne lesions by at least 50%; preferably, the number of non-inflammatory acne lesions by at least 40%.

[0026] In other embodiments, the method increases the IGA success rate by at least 20% compared to the baseline score.

[0027] In other embodiments, in the methods of the present application, the score of at least one efficacy parameter is synergistically higher than the parameter assessed using the same treatment regimen with each active agent separately. In another embodiment, the efficacy parameter is selected from at least one of IGA success rate, mean inflammatory lesion count reduction, mean non-inflammatory lesion count reduction, mean reduction in the acne symptom domain, mean reduction in the acne impact domain, and mean reduction in the verbal assessment scale.

[0028] In other embodiments, in the methods of the present application, the concentration of all-trans 5,6-epoxyretinoic acid is lower than 1% after storing the topical medicament at 40°C for two weeks. In other embodiments, in the methods of the present application, the degradation of the tretinoin is less than 2.5% after storing the topical medicament at 40°C for two weeks.

[0029] In other embodiments, in the methods of the present application, the method enhances the effect of tretinoin in the treatment of acne.

[0030] In other embodiments, in the methods of the present application, the release rate of the tretinoin from the topical medicament is less than 60% per hour. In other embodiments, the release rate of the tretinoin from the topical medicament is less than 60% per hour in a medium of 70% IPA (isopropyl alcohol) and 30% water at room temperature.

[0031] In one embodiment, the present application provides a method of treating acne comprising: topically applying a topical medicament comprising tretinoin or a pharmaceutically acceptable drug thereof as a single active agent in an amount of about 0.05% to about 0.1% by weight once a day on the affected skin area of a subject in need thereof for a period of time of up to 12 weeks; wherein the tretinoin is encapsulated in a shell; and wherein the score of at least one parameter assessed by a researcher skin safety assessment is lower than the score of the parameter assessed using non-encapsulated tretinoin under the same treatment regimen.

[0032] In other embodiments, in the methods of the present application, at least one active agent of the medicament is encapsulated in a shell. In another embodiment, both active agents of the medicament, BPO and tretinoin, are encapsulated in a shell. In another embodiment, the shell is a metal oxide or semi-metal oxide inorganic shell.

[0033] In other embodiments, the topical medicament in a single dose medicament comprises two of the active agents. BRIEF DESCRIPTION OF DRAWINGS

[0034] For a better understanding of the subject matter of the disclosure herein, and to show more clearly how it can be carried into practice, embodiments will now be described by way of non-limiting examples only, with reference to the accompanying drawings, in which:

[0035] Figure 1 HPLC chromatogram of an embodiment composition of the present application comprising 0.05% E-ATRA and 3% E-BPO on a Zorbax RX-C18 3.5 mμ, 4.6*75 mm column eluted with acetonitrile and 1% acetic acid in water showing a retention time of about 3.5 min for the RRT 0.44 product (all-trans 5,6-epoxy retinoic acid) (RRT product calculated relative to the ATRA peak at 7.8 min). DETAILED DESCRIPTION

[0036] In a first aspect, the present application provides a regimen for treating acne comprising: topically applying a topical medicament comprising active agents:

[0037] - tretinoin or a pharmaceutically acceptable salt thereof in an amount of about 0.05% to about 0.1% by weight;

[0038] and

[0039] - benzoyl peroxide in an amount of at least about 3% by weight.

[0040] In a further aspect, the present application provides a regimen for treating acne comprising: topically applying a topical medicament comprising active agents:

[0041] - tretinoin or a pharmaceutically acceptable salt thereof in an amount of about 0.05% to about 0.1% by weight;

[0042] and

[0043] - benzoyl peroxide in an amount of at least about 3% by weight;

[0044] wherein the score of at least one parameter assessed by the Investigator's Cutaneous Safety Assessment is synergistically lower than the score of said parameter assessed for the same treatment regimen for each active agent, respectively. In another embodiment, the topical medicament comprises about 0.1% tretinoin and about 3% benzoyl peroxide.

[0045] In some embodiments, the at least one parameter assessed by the Investigator's Cutaneous Safety Assessment is selected from the group consisting of erythema, scaling, pigmentation, and any combination thereof.

[0046] In yet another aspect, the present application provides a regimen for treating acne comprising: topically applying a topical medicament comprising active agents:

[0047] - Retinoic acid or a pharmaceutically acceptable salt thereof, in an amount of about 0.05% by weight to about 0.1% by weight;

[0048] and

[0049] - The amount is at least about 3% by weight of benzoyl peroxide;

[0050] The score of at least one parameter assessed by a local tolerability rating is conspiratorially lower than the score of the parameter assessed separately for each active agent using the same treatment regimen. In another embodiment, the topical medication comprises about 0.1% retinoic acid and about 3% benzoyl peroxide.

[0051] In some implementations, the at least one parameter assessed by a local tolerance score is selected from itching, burning, stinging, and any combination thereof.

[0052] In a further aspect, the present invention provides a treatment for acne comprising: applying a topical medication once daily to the affected skin area of ​​a subject in need for a period of up to 12 weeks, said topical medication comprising an active agent:

[0053] - Retinoic acid or a pharmaceutically acceptable salt thereof, in an amount of about 0.05% by weight to about 0.1% by weight;

[0054] and

[0055] - The amount is at least about 3% by weight of benzoyl peroxide;

[0056] Compared to the baseline score, the proposed protocol improves the IGA success rate by at least 20%. In another embodiment, the topical medication comprises approximately 0.1% retinoic acid and approximately 3% benzoyl peroxide.

[0057] In some implementations, the protocol improves IGA success rates by reducing the number of acne lesions and improving clinical condition in patients in need, compared to their baseline symptom / score.

[0058] On the other hand, the present invention provides a treatment for acne comprising applying a topical medication once daily to the affected skin area of ​​a subject in need for up to 12 weeks, said topical medication comprising retinoic acid or a pharmaceutically acceptable salt thereof as a single active agent in an amount of about 0.05% by weight to about 0.1% by weight; wherein said active agent is encapsulated in a shell; and

[0059] The score of at least one parameter assessed by the investigator's skin safety assessment is lower than the score of the parameter assessed using the same treatment regimen with a non-encapsulated active agent. In another embodiment, the topical medication comprises about 0.1% retinoic acid and about 3% benzoyl peroxide.

[0060] In a further aspect, the present application provides a regimen for treating acne comprising topically applying to an affected skin area of a subject in need thereof a topical medicament comprising tretinoin or a pharmaceutically acceptable salt thereof as the sole active agent in an amount of about 0.05% to about 0.1% by weight, once a day for a period of time of up to 12 weeks; wherein the active agent is encapsulated; and

[0061] wherein the score of at least one parameter assessed by a local tolerability score is lower than the score of said parameter assessed using the same treatment regimen with a non-encapsulated active agent. In another embodiment, the topical medicament comprises about 0.1% tretinoin and about 3% benzoyl peroxide.

[0062] In some embodiments, the amount of encapsulated tretinoin is about 0.1% by weight.

[0063] In another of its aspects, the present application provides a regimen for treating acne comprising: topically applying to an affected skin area of a subject in need thereof a topical medicament comprising an active agent:

[0064] - tretinoin or a pharmaceutically acceptable salt thereof in an amount of about 0.05% to about 0.1% by weight;

[0065] and

[0066] - benzoyl peroxide in an amount of at least about 3% by weight;

[0067] wherein the regimen reduces at least one of:

[0068] (i) the number of inflammatory acne lesions by at least 50%; or

[0069] (ii) the number of non-inflammatory acne lesions by at least 40%.

[0070] In another embodiment, the topical medicament comprises about 0.1% tretinoin and about 3% benzoyl peroxide. In another embodiment, the topical medicament used in the regimen treatment or method of treatment of the present application is described in U.S. Patent Publication 2013 / 0095185, which is incorporated herein by reference.

[0071] In some embodiments, the amount of tretinoin is about 0.1% by weight and the amount of benzoyl peroxide is at least about 3% by weight. It should be noted that compositions having these active agents at these concentrations show unexpected and surprising benefits in terms of tolerability of the product (less side effects such as burning and itching, stinging, etc.), safety of the treatment (less erythema, scaling, pigmentation, etc.) and effectiveness of the treatment of acne (treatment with the compositions according to the regimen of the present application significantly reduces the number of non-inflammatory and inflammatory acne lesions). Unexpectedly, when the concentration of tretinoin is increased from 0.05% to 0.1%, while efficacy is increased, side effects are not increased and in some cases even decreased. For example, 44.8% of subjects complained of burning side effects at 12 weeks with a composition comprising 0.05% tretinoin and 3% benzoyl peroxide (Table 21), while only 38.1% of subjects complained of burning side effects when the concentration of tretinoin was increased to 0.1% (Table 18).

[0072] In some embodiments, the regimen reduces the number of non-inflammatory acne lesions by at least 40%. In other embodiments, the regimen reduces the number of inflammatory acne lesions by at least 50%. In further embodiments, the regimen reduces the number of inflammatory acne lesions by at least 50%; preferably, it reduces the number of non-inflammatory acne lesions by at least 40%.

[0073] In some embodiments, the topical medicament of the present application has a concentration of less than 1% of the degradation product of tretinoin, RRT (relative retention time) 0.44 (all trans 5,6-epoxy retinoic acid) after storage at 40°C for two weeks. In other embodiments, the degradation of tretinoin is less than 2.5% after storage of the topical medicament of the present application at 40°C for two weeks.

[0074] When referring to RRT 0.44, it is understood to refer to the degradation product of tretinoin in the presence of BPO, as shown in the HPLC chromatogram of the composition of the present application after storage at 40°C for two weeks. An example of the RRT product is visible at a retention time of 3.507 min in Figure 1 In other embodiments, RRT 0.44 refers to all trans 5,6-epoxy-retinoic acid represented by the following structure:

[0075]

[0076] The present application further provides a method of treating acne comprising topically applying to an affected skin area of a subject in need thereof a topical medicament comprising active agents: tretinoin or a pharmaceutically acceptable salt thereof in an amount of about 0.05% to about 0.1% by weight; and benzoyl peroxide in an amount of at least about 3% by weight, once a day for a period of time of up to 12 weeks, wherein the method enhances the effect of tretinoin in the treatment of acne.

[0077] The present application further provides a regimen for treating acne comprising topically applying to an affected skin area of a subject in need thereof a topical medicament comprising active agents: tretinoin or a pharmaceutically acceptable salt thereof in an amount of about 0.05% to about 0.1% by weight; and benzoyl peroxide in an amount of at least about 3% by weight, once a day for a period of time of up to 12 weeks, wherein the release rate (dissolution rate) of the tretinoin from the topical medicament is less than 60% per hour. In some embodiments, the release rate (dissolution rate) of the tretinoin from the topical medicament is less than 50% per hour. In some embodiments, the release rate (dissolution rate) of the tretinoin from the topical medicament is less than 45%, 40%, 35%, 30% or 25% per hour.

[0078] It should be noted that the release rate (dissolution rate) defined herein relates to a measure of the rate of release of an active ingredient (e.g. tretinoin) from a topical medicament of the present application to an extraction medium or skin (in vitro or in vivo). The release rate is measured using known methods, for example: (1) 70% IPA (isopropyl alcohol) and 30% water at room temperature with optional antioxidant (e.g. BHT); (2) 60-80% ethanol, ACN (acetonitrile) at room temperature; or (3) 2% Tween 80, IPA, ratio 2:1 and optional antioxidant (e.g. BHT) at 32°C.

[0079] In some embodiments, the release rate of the tretinoin from the topical medicament is less than 60% per hour in a medium of 70% IPA (isopropyl alcohol) and 30% water at room temperature.

[0080] The present application further provides a regimen for treating acne comprising: topically applying to an affected skin area of a subject in need thereof a topical medicament comprising active agents:

[0081] - tretinoin or a pharmaceutically acceptable salt thereof in an amount of about 0.05% to about 0.1% by weight;

[0082] and

[0083] - benzoyl peroxide in an amount of at least about 3% by weight;

[0084] wherein the score of at least one efficacy parameter is synergistically higher than the parameter assessed using the same treatment regimen of each active agent separately. In another embodiment, the topical medicament comprises about 0.1% tretinoin and about 3% benzoyl peroxide.

[0085] In some embodiments of the regimen of the application, the amount of benzoyl peroxide is about 3% by weight. In other embodiments of the regimen of the application, the amount of benzoyl peroxide is about 6% by weight. In other embodiments of the regimen of the application, the amount of benzoyl peroxide is about 3% to about 6% by weight. In other embodiments of the regimen of the application, the amount of benzoyl peroxide is about 3%, 4%, 5% or 6% by weight.

[0086] In some embodiments, the efficacy parameter is selected from at least one of IGA success rate, mean reduction in inflammatory lesion count, mean reduction in non-inflammatory lesion count, mean reduction in acne symptom domain (measured using a patient reported outcome study, including symptoms such as number of papules, whiteheads, blackheads, redness), mean reduction in acne impact domain (measured using a patient reported outcome study, including symptoms such as sadness, embarrassment, self-consciousness), and mean reduction in verbal rating scale.

[0087] As used herein, the term "regimen for treating acne" is used herein interchangeably with the term "method for treating acne", with all the same meaning and quality. As used herein, the term "regimen" is understood to relate to a medical treatment regimen that modulates the treatment of acne in a subject suffering from acne, including modulating the medicament administered (fixed dose combination of active agents: tretinoin or a pharmaceutically acceptable salt thereof and BPO), the frequency of administration (i.e. once a day), the duration of treatment (i.e. up to 12 weeks), the method of administration (i.e. topical) and the site of administration (i.e. topical administration to the affected skin area).

[0088] When referring to "acne" treatment it should be understood to refer to the treatment of any form or its location of onset or severity of the skin condition or disease also known as acne vulgaris. Mild acne is generally defined as open (blackhead) and closed (whitehead) comedones (pimples) limited to the face with occasional inflammatory lesions. Acne can be considered moderate in severity when a large number of inflammatory papules and pustules appear on the skin. Severe acne is considered to occur when nodules are the typical facial lesions and there is extensive involvement of other parts of the body. Inflammatory acne lesions include papular lesions (small solid elevations less than 5 mm in diameter, most lesions on the surface of the skin), pustular lesions (small circumscribed elevations less than 5 mm in diameter containing yellow-white exudate), nodular lesions (inflammatory lesions greater than or equal to 5 mm in diameter) and cystic lesions (inflammatory lesions greater than or equal to 5 mm in diameter containing yellow-white exudate). Non-inflammatory lesions include open comedones (blackheads) (lesions with extensive dilation of the follicular orifice, contents project to the surface of the skin, melanin cells compacted giving the appearance of a black plug) and closed comedones (whiteheads) (lesions with the follicular orifice closed, but the sebaceous gland enlarged due to pressure of the accumulated sebum, in turn thinning the skin around the follicle and making it protrude with a white appearance).

[0089] As used herein, the term "synergistically lower" is to be understood to relate to the degree of reduction in side effects (as measured using Investigator's Cutaneous Safety Assessment and Local Tolerability Score) caused by the topical administration of the active agents in the regimen of the application compared to the sum of side effects produced by the separate administration of each agent.

[0090] As used herein, the term "synergistically higher" is to be understood to relate to the degree of therapeutic efficacy caused by the topical administration of the active agents in the regimen of the application (as measured using efficacy outcomes selected from at least one of IGA success rate, average reduction in inflammatory lesion count, average reduction in non-inflammatory lesion count; and / or PRO outcomes measures selected from at least one of average reduction in acne symptom domain, average reduction in acne impact domain and average reduction in verbal rating scale) compared to the sum of effects produced by the separate administration of each agent.

[0091] Synergistically lower side effects of the regimen of the application are calculated according to the following formula:

[0092] (TWIN-V) < (ATRA-V) + (BPO-V)

[0093] TWIN - Side effects measured for the drugs defined in the application (using the scoring measures indicated above and below).

[0094] V - Side effects measured for the vehicle alone (using the scoring measures indicated above and below).

[0095] ATRA - Side effects measured for ATRA alone (using the scoring measures indicated above and below).

[0096] BPO - Side effects measured for BPO alone (using the scoring measures indicated above and below).

[0097] When measuring the effect of the drug of the application, the net side effects of the drug of the application (TWIN-V) are numerically lower than the sum of the net clinical benefits of each active agent alone after subtracting the effect of the vehicle from the ATRA and BPO arms, respectively.

[0098] The synergistically higher effect of the regimen of the application is calculated according to the following formula:

[0099] (TWIN-V) > (ATRA-V) + (BPO-V)

[0100] TWIN - Therapeutic effect measured for the drug as defined in the application (using the scoring measures indicated above and below).

[0101] V - Therapeutic effect measured for the vehicle alone (using the scoring measures indicated above and below). ATRA - Therapeutic effect measured for ATRA alone (using the scoring measures indicated above and below).

[0102] BPO - Therapeutic effect measured for BPO alone (using the scoring measures indicated above and below).

[0103] When measuring the effect of the drug of the application, the net therapeutic effect of the drug of the application (TWIN-V) is numerically higher than the sum of the net clinical benefits of each active agent alone after subtracting the effect of the vehicle from the ATRA and BPO arms, respectively.

[0104] It should be noted that the effect of the regimen of the application, wherein two active agents are administered in combination, is at least additive, and preferably synergistic. In some embodiments, synergistic effect refers to synergistic reduction in side effects caused by administration of the active agents. In some other embodiments, the additive effect of the regimen of the application is attributed to the clinical therapeutic effect of the active agents. In other embodiments, the synergistic effect of the regimen of the application is attributed to the clinical therapeutic effect of the active agents.

[0105] It is also noted that any of the above synergies can be attributed to an effect at at least one of weeks 2, 4, 8, 12 of the regimen of the application. In some embodiments, the synergistic effect is provided at week 4 of the regimen of the application. In some embodiments, the synergistic effect is provided at week 8 of the regimen of the application. In some embodiments, the synergistic effect is provided at week 12 of the regimen of the application.

[0106] When referring to "improvement", "improvement" and any other linguistic derivatives of this term, it is understood to include an additive or synergistic effect of the regimen of the application. When referring to "at least 20% increase in IGA success rate", it is understood to relate to an additive or, in some embodiments, synergistic increase in the global research assessment (IGA) success rate, measured in terms of the degree of success in reducing the number of acne lesions and improving the clinical condition of the patient compared to the baseline condition / score.

[0107] The term "enhancing the effect of tretinoin in the treatment of acne" is understood to encompass any therapeutic enhancement of the treatment of acne achieved by administering tretinoin to a subject suffering from acne. The therapeutic effect of administering a topical medicament comprising tretinoin and benzoyl peroxide is additive or synergistic to the effect of tretinoin alone in the treatment of acne.

[0108] In some embodiments, the medicament is administered at least twice a day. In some other embodiments, the medicament is administered once a day. In some other embodiments, the medicament is administered twice a day. In other embodiments, the medicament is administered twice a day, with an interval of at least 8 hours between administrations. In some embodiments, the medicament is administered once every other day.

[0109] In some embodiments, the medicament is administered for a period of up to 12 weeks. In some embodiments, the medicament is administered for a period of 12 weeks. In other embodiments, the medicament is administered for a period of 1 week. In some embodiments, the period of administration of the medicament is selected from the group consisting of 1, 2, 4, 8 and 12 weeks.

[0110] In some embodiments, the amount of tretinoin or the pharmaceutically acceptable salt thereof is at least 0.05% by weight.

[0111] In other embodiments, the amount of tretinoin or the pharmaceutically acceptable salt thereof is about 0.1% by weight.

[0112] In some embodiments, the medicament is administered as a single composition comprising both active agents (BPO and ATRA), a single fixed dose medicament. In such embodiments, the weight % of active agents relates to their weight in the single composition. The term "fixed dose medicament" is understood as a combination in which the active agents are combined in a fixed dose in the same carrier (single formulation), delivering them together to the point of application.

[0113] In further embodiments, the medicament comprises two separate compositions, each comprising each of the active agents. In such embodiments, the weight % amount of each active agent relates to their respective weight in each composition, respectively. In some embodiments, the two separate compositions of the medicament are administered simultaneously. In further embodiments, the two separate compositions are administered sequentially.

[0114] In some embodiments, at least one of the active agents in the medicament disclosed above is encapsulated in a shell.

[0115] In some other embodiments, both active agents of the medicament, BPO and retinoic acid, are encapsulated in a shell. In some embodiments, the shell is an inorganic shell. In further embodiments, the encapsulating shell is a metal oxide or semi-metal oxide inorganic shell.

[0116] As used herein, unless otherwise indicated, the term "microcapsule" refers to a microparticle having a core-shell structure, wherein the core comprises an active agent (core material) as defined herein, and is coated by a shell forming the microcapsule that encloses the core. In some embodiments, the coating / shell is deposited directly on the core material. In some embodiments, the core material is solid. In other embodiments, the core material is semi-solid. In some embodiments, the core material consists of solid particles of the active agent. In other embodiments, the core material comprises solid particles of the active agent. In some other embodiments, the core material is a liquid / oil phase.

[0117] The size of a microcapsule (also denoted herein by the general terms "particle" or "microparticle") as referred to herein refers to the D 90 , which means that 90% of the particles have the size or less (measured by volume). Thus, for example, for a spherical particle of which the diameter is stated to be 10 micrometers ("microns"), this means that 90% of the particles have a D 90 of 10 micrometers. The D 90 (also denoted as d(0.9)) can be measured by laser diffraction. For particles having a non-spherical shape, the D 90 refers to the average of the diameters of the plurality of particles.

[0118] In some embodiments, the microcapsules are formed using the methods disclosed in the following documents (incorporated herein by reference): US Patent Nos. 6,303,149, 6,238,650, 6,468,509, 6,436,375, US2005037087, US2002064541 and International Publication Nos. WO 00 / 09652, WO 00 / 72806, WO 01 / 80823, WO 03 / 03497, WO 03 / 039510, WO 00 / 71084, WO 05 / 009604 and WO 04 / 81222, which disclose sol-gel microcapsules and methods for their preparation; EP 0934773 and US Patent 6,337,089 teach microcapsules comprising a core material and a capsule wall made of an organopolysiloxane and their production; EP 0941761 and US Patent US 6,251,313 also teach the preparation of microcapsules having a shell wall of organopolysiloxane; US Patent 4,931,362 describes a method of forming microcapsules or microsomes having an internal water-immiscible phase comprising an active water-immiscible ingredient. Microcapsules prepared by sol-gel methods are also disclosed in GB2416524, US6855335, WO03 / 066209.

[0119] According to some embodiments of the application, the coated form of the active ingredient (microcapsule) can be in the form of polymeric microsponges / silica microspheres, in which the active ingredient is adsorbed, embedded, impregnated or entrapped in the microsponges / silica microspheres, for example as described in US Patents 4,690,825; 5,145,675, 5,879,716, 5,955,109 and US 9,452,137, which are hereby incorporated by reference in their entirety.

[0120] In other embodiments, the microcapsules are formed by the encapsulation methods disclosed in the following publications (incorporated herein by reference): US 7,629,394, US 9,205,395, US 2015 / 0328615, US 2014 / 0186630. Controlled release capsules: IN01958CH2007, IN02080CH2007, US 4,235,872, US4670250, EP 0248531, US 4,970,031, US 5,238,714, WO9321764, US 5,575,987, WO9420075, US 2004 / 137031, US 2006 / 003014, US 2010 / 180464.

[0121] The core (where it is a solid particulate material) can have any shape, for example rod-like, plate-like, oval, cubic or spherical.

[0122] In case the core is spherical, the diameter (D 90 ) can be in the range of 0.3 to 90 microns, in some embodiments 0.3 to 50 microns, in some other embodiments 1 to 50, in some other embodiments 5 to 30 microns.

[0123] The term "diameter (D90) can be in the range of 0.3 to 90 microns" means that 90% by volume of the particles (in this case the core of the particles) can be less than or equal to a value in the range of 0.3 to 90 microns.

[0124] For a substantially cuboid core or a core having a shape similar to a cuboid, the average size of the side faces can be in the range of 0.3 to 80 microns, in some embodiments 0.3 to 40 microns, in some other embodiments 0.8 to 40 microns, in some other embodiments 4 to 15 microns.

[0125] For rod-like, oval and plate-like cores, the largest dimension (dimension of the longest axis) is typically in the range of 10 to 100 microns, in some embodiments 15 to 50 microns; and the smallest dimension is typically in the range of 0.5 to 20 microns, and in some other embodiments 2 to 10 microns.

[0126] According to embodiments of the present application, the microcapsules (coated particulate matter) have a diameter (d90) of 0.5 to 100 pm or in some embodiments the diameter of the microcapsules is in the range of 1 to 50 pm and in some other embodiments in the range of 5 to 30 pm. It is to be understood that the microcapsules of the present application consist of different regions of the metal oxide layer in the core material (i.e. the water-insoluble particulate matter).

[0127] Further according to embodiments of the present application, the resulting metal oxide coating has a width (thickness) of 0.1 pm or more, in some embodiments the metal oxide coating has a width (thickness) of 0.1 - 10 pm. Moreover, according to embodiments of the present application, the resulting metal oxide coating has a width (thickness) of 0.3 pm or more, in some embodiments the metal oxide coating has a width of 0.3 - 10 pm.

[0128] Moreover, according to embodiments of the present application, the thickness of the metal oxide layer is in the range of 0.1 - 10 pm. In some further embodiments, the thickness of the metal oxide layer is in the range of 0.1 - 3 pm and in some other embodiments in the range of 0.1 - 1 pm. The thickness of the metal oxide layer can also be in the range of 0.3 to 3 pm in some embodiments and in the range of 0.3 to 2 pm in some other embodiments.

[0129] Furthermore, according to embodiments of the present application, the metal oxide coating obtained has a width (thickness) of about 0.1, 0.2, 0.3, 0.5, 0.7, 1, 1.5, 2 or 5 μm or more, in some embodiments up to 10 μm.

[0130] The width of the metal oxide layer can be determined, for example, by transmission electron microscopy or confocal microscopy, such that the minimum width in the circular cross-sectional area of the particle is at least, for example, 0.1 μm (this width is determined as the minimum distance from the particle surface (i.e. metal oxide surface) to the core-metal oxide interface).

[0131] In some embodiments the microcapsules are characterized in that the core material is essentially free of metal oxide and further in that the metal oxide layer is essentially free of core material, for example as a particulate dispersion of particles in the nanometer range below 0.1 μm or as a molecular dispersion of particles.

[0132] Accordingly, according to one embodiment of the present application, the metal oxide layer is essentially free of core material (in molecular form or as nanoscale particles). In this context, the term "essentially free" means that the concentration of molecules of core material or the concentration of nanoscale particles of core material can be negligible compared to the metal oxide. Similarly, the term "core material essentially free of metal oxide" means that the concentration of metal oxide in the core can be negligible compared to the core material. In some embodiments, the microcapsules (i.e. the first microcapsules) are non-leaching when dispersed in a carrier, while in other embodiments they are non-leaching in a water-based carrier.

[0133] According to another embodiment, when the microcapsules are prepared by a process such as spray drying, the core material comprising the active agent can further comprise up to about 30% w / w, in some embodiments up to about 20% of the metal oxide, and the metal oxide coating can further comprise up to about 30% w / w, in some embodiments up to about 20% w / w of the active agent.

[0134] The term "non-leaching" means that less than 5% w / w of the particulate material (active agent) leaches from the granule into a water-based liquid at room temperature (20°C) with slow stirring for 1 hour or until steady state concentration is reached, in some embodiments less than 3% w / w, in some further embodiments less than 1% w / w, in some further embodiments less than 0.5% w / w, and in some other embodiments less than 0.1% w / w. Typically, the water-based liquid is water. The above values refer to the percentage of active agent leached into the aqueous medium relative to the initial amount of active agent in the granule. The above leaching values refer to dispersions in which the concentration of particulate in the aqueous medium is higher than 0.1% w / w, in some further embodiments higher than 1% w / w, in some further embodiments higher than 3% w / w and in some other embodiments higher than 10% w / w. For tretinoin, in some embodiments the above indicated leaching values refer to dispersions in which the concentration of particulate in the aqueous medium is higher than 0.01% w / w.

[0135] According to embodiments of the present application, the weight ratio of the metal oxide to the solid particulate material is in the range of 1 :99 to 50:50. The weight ratio of the metal oxide layer to the solid particulate material can also be in the range of 3:97 to 50:50, 5:95 to 50:50, 10:90 to 50:50, 5:95 to 30:70, 10:90 to 30:70. Further, according to embodiments of the present application, the ratio of the metal oxide to the solid particulate material is 10:90 to 20:80.

[0136] According to another embodiment of the present application, when using a spray drying process, the weight ratio of the metal oxide to the solid particulate material can be in the range of 5:95 to 95:5.

[0137] As used herein, the term "uncoated free form" means that the active ingredient (BPO or tretinoin) is present in the composition in its "naked" form, meaning that it is not intimately embedded, encapsulated, wrapped or inlaid in a polymeric carrier, and is present in the composition in direct contact with the composition carrier. As used herein, the term "coated form of the active ingredient" means that the active ingredient is embedded, dispersed, entrapped or inlaid in a polymeric carrier, which can be an organic or inorganic carrier, and which can serve as a matrix for dispersing the active ingredient or as an encapsulating material for coating said active ingredient (i.e., the active ingredient is present in a core, or is a core material encapsulated by a shell composed of a polymeric material, which can be an organic or inorganic polymer).

[0138] According to another embodiment of the present application, the coated form of the active ingredient is a second microcapsule comprising the solid particulate of the active ingredient coated by a layer of the metal oxide.

[0139] Furthermore, according to embodiments of the present application, the first microcapsules comprise solid particulate matter of BPO coated by a metal oxide layer.

[0140] According to embodiments of the present application, the BPO is in the form of first microcapsules comprising solid particulate matter of BPO coated by a metal oxide layer, while the tretinoin is in the form of second microcapsules comprising solid particulate matter of tretinoin coated by a metal oxide layer.

[0141] In these embodiments, the metal oxide coating is advantageous as it is able to isolate the particulate matter of the active agent from its surrounding medium, thus preventing cross-reactions of the active agents present in the same composition, and still being able to release the particulate matter after application on the surface to be treated.

[0142] The term "solid medicament insoluble in water" refers to a solid material having a solubility in water at room temperature (20°C) of less than 3% w / w, typically less than 1%, and sometimes less than 0.5% w / w. The "solid medicament insoluble in water" can have a solubility of less than 0.1% w / w.

[0143] The "solid medicament insoluble in water" can also be referred to herein as "solid particulate matter insoluble in water" or "solid particulate matter".

[0144] The term "topical medicament" (also referred to as "composition") as used herein is understood to include any pharmaceutical preparation capable of applying an active agent to the skin tissue of a patient to whom the medicament is applied. The composition or topical medicament of the present application comprises a carrier. According to embodiments of the present application, the carrier is in the form of an ointment, cream, lotion, oil, solution (in some embodiments, an aqueous solution), emulsion, gel, paste, milk, aerosol, powder or foam. In some embodiments, the carrier is a water-based carrier (e.g. a gel, an oil-in-water emulsion or an oil-in-water cream, an aqueous solution, a foam, a lotion, a spray).

[0145] Thus, the final form of the composition can be any of the above-mentioned forms in relation to the carrier, wherein the microcapsules are dispersed in the carrier. The final form of the composition can also be in the form of a lotion or a cleanser.

[0146] In some embodiments, the metal oxide is selected from the group consisting of silicon dioxide, titanium dioxide, aluminum oxide, zirconium oxide, ZnO and mixtures thereof. In some other embodiments, the metal oxide is silicon dioxide.

[0147] Furthermore, according to embodiments of the present application, the microcapsules (coated particulate matter) have a diameter of 0.5-100 pm. In some embodiments, the diameter of the particles is 0.8-100 pm, in some other embodiments 1-50 pm, in some other embodiments 2-30 pm.

[0148] According to certain embodiments of the application, the surface of the metal oxide layer of the coated particulate can be chemically modified by organic groups, in some embodiments hydrophobic groups, attached to its surface.

[0149] The hydrophobic groups can be, for example, alkyl groups (such alkyl groups can be further substituted by one or more fluorine atoms), aryl groups (such as benzyl or phenyl), and combinations thereof. These groups can be as described below with respect to the methods.

[0150] In some embodiments, the topical medicament comprises tretinoin or a pharmaceutically acceptable salt, hydrate or solvate thereof. Suitable pharmaceutically acceptable salts of the active ingredient of the present application (i.e. tretinoin) include inorganic salts such as: ammonium, alkali metals to include lithium, sodium, potassium, cesium; alkaline earth metals to include calcium, magnesium, aluminum; zinc, barium or quaternary ammonium salts; or organic salts such as arginine, organic amines to include aliphatic organic amines, aromatic amines, t-butylamine, (N-benzylphenethylamine), dicyclohexylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, imidazole, lysine, methylamine, N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, pyridine, picolinate, piperazine, tris(hydroxymethyl)methylamine, triethylamine, triethanolamine, trimethylamine or urea.

[0151] In one embodiment, the term "about" refers to a deviation of between 0.0001-5% from the indicated number or range of numbers. In one embodiment, the term "about" refers to a deviation of between 1-10% from the indicated number or range of numbers.

[0152] The following examples are given in order to more fully illustrate certain embodiments of the application. They should in no way, however, be construed as limiting the broad scope of the application.

[0153] Example

[0154] Example 1

[0155] Product 3149 is a combination formulation of 3% encapsulated benzoyl peroxide (E-BPO) prepared as described in U.S. Patent Publication 2010-0016443 and 0.1% encapsulated all-trans retinoic acid (E-ATRA) prepared as described in U.S. Patent Publication 2012 / 0202695.

[0156] Product 3156 is a similar combination formulation of E-BPO 3% and similar E-ATRA 0.05%.

[0157] A clinical trial was designed to evaluate if the combination of E-BPO and E-ATRA provides safe and synergistic efficacy compared to either product alone in the treatment of acne vulgaris. As described in U.S. Patent Publication 2013 / 0095185, products 3149 and 3156 provided improved results due to the stability of the products and resulted in increased patient compliance.

[0158] The objective of this study was to evaluate the efficacy, safety, and tolerability of products 3149 and 3156 compared to individual components E-BPO 3%, E-ATRA 0.1%, E-ATRA 0.05%, and placebo (vehicle).

[0159] This was a randomized, double-blind, multicenter, parallel-group, active ingredient and vehicle-controlled study of efficacy, tolerability, and safety of products 3149 and 3156 for the treatment of acne vulgaris.

[0160] Approximately 720 subjects, 9 years of age and older, with moderate to severe facial acne (3 or 4 on a 5-point Investigator's Global Assessment [IGA]) were enrolled at up to 37 sites. Participants were randomized 1 : 1 : 1 : 1 : 1 : 1 to receive E-BPO / E-ATRA (3% / 0.05%); E-BPO / E-ATRA (3% / 0.1%); E-BPO (3%); E-ATRA (0.05%); E-ATRA (0.1%); and vehicle cream once daily. After a screening period, eligible subjects were randomized and treated for 12 weeks at the baseline visit.

[0161] Efficacy assessments included facial lesion counts (inflammatory and noninflammatory) and IGA assessments, ranging from 0 (clear) to 4 (severe). Lesion count instructions were provided to the investigators to ensure consistency of procedures. Patient- reported outcomes (PROs) were assessed at baseline, weeks 4, 8, and 12, or early termination. Safety was assessed at all visits, including monitoring of local and systemic adverse experiences; investigator's global assessment of skin safety ratings for hyperpigmentation and hypopigmentation, erythema, and scaling on a scale of 0 (none) to 3 (severe); and subject assessment of local tolerability ratings pruritus, burning, and stinging on a scale of 0 (none) to 3 (severe).

[0162] Subjects returned to the skin safety and local tolerability assessment center at weeks 2, 4, 8, and 12; IGA and lesion counts were repeated at weeks 4, 8, and 12. Adverse events and concomitant medications were assessed throughout the treatment period.

[0163] All products were provided as 80-gram pumps (50 grams of which was cream). A pea-sized amount was applied to each area of the face (chin, left cheek, right cheek, nose, and forehead) once daily at bedtime once daily for 12 weeks.

[0164] Table 1. Investigator Global Assessment Scale of Acne Severity

[0165]

[0166] Inflammatory Lesion Definition

[0167] Papule: A small, solid elevation of skin less than 5 mm in diameter. Most lesions are on the surface of the skin.

[0168] Pimple: A small, solid elevation of skin less than 5 mm in diameter. Most lesions are on the surface of the skin.

[0169] Nodule: An inflammatory lesion greater than or equal to 5 mm in diameter.

[0170] Cyst: An inflammatory lesion containing yellow-white exudate greater than or equal to 5 mm in diameter.

[0171] Non-Inflammatory Lesion Definition

[0172] Open comedones (blackheads): Lesions with widely dilated openings of the hair follicle with the contents projecting to the skin surface, melanocytes compacted, giving the appearance of a black plug.

[0173] Closed comedones (whiteheads): Lesions with closed openings of the hair follicle, but the sebaceous gland enlarged due to pressure from the build-up of sebum, which in turn thins the skin around the follicle and makes it raised, with a white appearance.

[0174] Table 2. Cutaneous Safety Assessment (Investigator)

[0175]

[0176] Table 3. Local Tolerability Score (Subject)

[0177]

[0178]

[0179] Example 2

[0180] Efficacy:

[0181] This study evaluated the co-primary efficacy variables, including the following:

[0182] • Investigator's Global Assessment (IGA)

[0183] • Lesion counts (separately inflammatory and non-inflammatory)

[0184] The co-primary endpoints were:

[0185] • Proportion of subjects with clear or almost clear improvement of at least 2 grades on IGA at Week 12

[0186] • Absolute and percentage reduction in lesion count on the face from baseline at Week 12 (for inflammatory and non-inflammatory lesions, respectively)

[0187] Safety:

[0188] Safety variables include Investigator's Cutaneous Safety Assessment score, Subject's Tolerability Assessment score, treatment emergent adverse events (AEs), SAEs, treatment-related AEs, AEs leading to discontinuation from the study, concomitant medications, clinical chemistry, hematology, and urinalysis, and ECG assessments.

[0189] Success Criteria:

[0190] The following statistical comparisons (numerical and inferential) were performed:

[0191] • Product 3149 (E BPO / E ATRA 3% / 0.1%) versus E-BPO 3%, E-ATRA 0.1%, and vehicle

[0192] • Product 3156 (E BPO / E ATRA (3% / 0.05%) versus E-BPO 3%, E-ATRA 0.05%, and vehicle.

[0193] Patient-Reported Outcomes Questionnaire

[0194] Patient-Reported Facial Acne Evaluation (PRE-FACE) and Patient Facial Acne Severity Assessment were assessed at study visits 1-6 (including screening, baseline, and at Weeks 2, 4, 8, and 12 or early termination (ET)) to record patient-reported experiences with acne vulgaris. PRE-FACE comprises 7 items that constitute two domains. The Acne Symptom Domain (ASD) assessed the severity of acne symptoms (four items) on an 11-point numerical rating scale (NRS), with scores ranging from 0 = none to 10 = as bad as you can imagine. The Acne Impact Domain (AID) assessed the impact of acne on how the patient feels (three items) on an 11-point NRS, ranging from 0 = not at all to 10 = extremely high. Higher scores in the Patient-Reported Outcomes (PRO) questionnaire indicate higher severity of symptoms and impact associated with acne vulgaris. In addition, Patient Facial Acne Severity Assessment was assessed alongside PRE-FACE, which is a global item that assessed the overall severity of patient-reported acne vulgaris on a 5-point verbal rating scale (VRS), ranging from 0 (no acne) to 4 (very severe acne). Language descriptions were also provided to the respondents to facilitate their assessment.

[0195] Results:

[0196] Results:

[0196] Table 4. Results for Product 3149 at 12 Weeks

[0197]

[0198] Table 5. Results for Product 3149 at 4 Weeks

[0199]

[0200] Table 6. Results for Product 3149 at 8 Weeks

[0201]

[0202] Table 7. Results for Product 3156 at 12 Weeks

[0203]

[0204] Table 8. Results for Product 3156 at 4 Weeks

[0205]

[0206] Table 9. Results for Product 3156 at 8 Weeks

[0207]

[0208] Table 10. Results for Product 3149 at 2 Weeks

[0209]

[0210] Table 11. Results for Product 3149 at 4 Weeks

[0211]

[0212] Table 12. Results for Product 3149 at 8 Weeks

[0213]

[0214] Table 13. Results for Product 3149 at 12 Weeks

[0215]

[0216] Table 14. Results for Product 3156 at 2 Weeks

[0217]

[0218] Table 15. Results for Product 3156 at 4 Weeks

[0219]

[0220] Table 16. Results for Product 3156 at 8 Weeks

[0221]

[0222] Table 17. Results for Product 3156 at 12 Weeks

[0223]

[0224] Table 18. Results for Product 3149 at 12 Weeks

[0225]

[0226] Table 19. Results for Product 3149 at 12 Weeks

[0227]

[0228] Table 20. Results for Product 3149 at 2 Weeks

[0229]

[0230] Table 21. Results for Product 3156 at 12 Weeks

[0231]

[0232] Conclusions:

[0233] The above results clearly demonstrate the synergistic effect of the claimed regimen. For example:

[0234] - At week 12, synergistic lower side effects were observed for product 3149 in scaling, stinging, burning, pruritus (Table 18), and for product 3156 in pigmentation, pruritus (Table 21).

[0235] - Synergistically higher effects were observed for the mean reduction of non-inflammatory lesion counts at week 4 for product 3149 (Table 5), for the IGA success rate, mean reduction of non-inflammatory lesion counts at week 8 for product 3149 (Table 6), for the reduction of inflammatory and non-inflammatory lesion counts at week 4 for product 3156 (Table 8), for the IGA success rate, mean reduction of inflammatory lesion counts, mean reduction of non-inflammatory lesion counts at week 8 for product 3156 (Table 9), for the mean reduction of inflammatory and non-inflammatory lesion counts at week 12 for product 3156 (Table 7).

[0236] Surprisingly, it was found that both combinations were significantly superior to the single active ingredient. Furthermore, the tolerability and safety of the combination therapy and regimen of the present application showed a synergistic effect compared to each composition applied alone.

[0237] While certain features of the application have been illustrated and described, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the application.

Claims

1. A topical medicament, which is a fixed dose medicament comprising active agents, which are a combination of benzoyl peroxide and tretinoin or a pharmaceutically acceptable salt thereof, and the amount of tretinoin or a pharmaceutically acceptable salt thereof is 0.1% by weight and the amount of benzoyl peroxide is 3% by weight, based on the total amount of the medicament, for the treatment of acne in a subject suffering from acne, wherein the medicament is administered once a day for a period of up to 12 weeks.

2. The medicament of claim 1, wherein the concentration of tretinoin degradation product all-trans 5,6-epoxyretinoic acid is less than 1% after the topical medicament is stored at 40°C for two weeks.

3. The medicament of claim 1, wherein the degradation of the tretinoin is less than 2.5% after the topical medicament is stored at 40°C for two weeks.

4. A topical medicament, which is a fixed dose medicament comprising active agents, which are a combination of benzoyl peroxide and tretinoin or a pharmaceutically acceptable salt thereof, and the amount of tretinoin or a pharmaceutically acceptable salt thereof is 0.1% by weight and the amount of benzoyl peroxide is 3% by weight, based on the total amount of the medicament, for the treatment of acne in a subject suffering from acne, wherein the medicament is administered once a day for a period of up to 12 weeks; and wherein the score of at least one parameter assessed by Investigator Cutaneous Safety Assessment is synergistically lower than the score of the parameter assessed using the same treatment regimen for each active agent, respectively.

5. The medicament of claim 4, wherein the at least one parameter assessed by Investigator Cutaneous Safety Assessment is selected from the group consisting of erythema, scaling, pigmentation, and any combination thereof.

6. A topical medicament, which is a fixed dose medicament comprising active agents, which are a combination of benzoyl peroxide and tretinoin or a pharmaceutically acceptable salt thereof, and the amount of tretinoin or a pharmaceutically acceptable salt thereof is 0.1% by weight and the amount of benzoyl peroxide is 3% by weight, based on the total amount of the medicament, for the treatment of acne in a subject suffering from acne, wherein the medicament is administered once a day for a period of up to 12 weeks; and wherein the score of at least one parameter assessed by Local Tolerability Score is synergistically lower than the score of the parameter assessed using the same treatment regimen for each active agent, respectively.

7. The medicament of claim 6, wherein the at least one parameter assessed by Local Tolerability Score is selected from the group consisting of pruritus, burning, stinging, and any combination thereof.

8. A topical medicament, which is a fixed dose medicament comprising active agents, which are a combination of benzoyl peroxide and tretinoin or a pharmaceutically acceptable salt thereof, and the amount of tretinoin or a pharmaceutically acceptable salt thereof is 0.1% by weight and the amount of benzoyl peroxide is 3% by weight, based on the total amount of the medicament, for the treatment of acne in a subject suffering from acne, wherein the medicament is administered once a day for a period of up to 12 weeks; and wherein the treatment reduces at least one of: (i) the number of inflammatory acne lesions by at least 50%; or (ii) the number of non-inflammatory acne lesions by at least 40%. ​ ​ ​ ​ ​ 9. The medicament of claim 8, wherein the treatment reduces the number of non-inflammatory acne lesions by at least 40%.

10. The medicament of claim 8, wherein the treatment reduces the number of inflammatory acne lesions by at least 50%.

11. The medicament of claim 8, wherein the treatment reduces the number of inflammatory acne lesions by at least 50% and the number of non-inflammatory acne lesions by at least 40%.

12. A topical medicament which is a fixed dose medicament comprising active agents which are a combination of benzoyl peroxide and tretinoin or a pharmaceutically acceptable salt thereof, and the amount of tretinoin or a pharmaceutically acceptable salt thereof is 0.1% by weight and the amount of benzoyl peroxide is 3% by weight, based on the total amount of the medicament; for use in treating acne in a subject suffering from acne, wherein the medicament is administered once a day for a period of up to 12 weeks; wherein the treatment increases the IGA success rate by at least 20% compared to the baseline score.

13. A topical medicament which is a fixed dose medicament comprising active agents which are a combination of benzoyl peroxide and tretinoin or a pharmaceutically acceptable salt thereof, and the amount of tretinoin or a pharmaceutically acceptable salt thereof is 0.1% by weight and the amount of benzoyl peroxide is 3% by weight, based on the total amount of the medicament; for use in treating acne in a subject suffering from acne, wherein the medicament is administered once a day for a period of up to 12 weeks; wherein the use enhances the effect of tretinoin in the treatment of acne.

14. A topical medicament which is a fixed dose medicament comprising active agents which are a combination of benzoyl peroxide and tretinoin or a pharmaceutically acceptable salt thereof, and the amount of tretinoin or a pharmaceutically acceptable salt thereof is 0.1% by weight and the amount of benzoyl peroxide is 3% by weight, based on the total amount of the medicament; for use in treating acne in a subject suffering from acne, wherein the medicament is administered once a day for a period of up to 12 weeks; wherein the release rate of the tretinoin from the topical medicament is less than 60% per hour.

15. The medicament of any one of claims 1-14, wherein the release rate of the tretinoin from the topical medicament is less than 60% per hour in a medium of 70% isopropyl alcohol and 30% water at room temperature.

16. The medicament of any one of claims 1-14, wherein at least one active agent of the medicament is encapsulated in a shell.

17. The medicament of any one of claims 1-14, wherein both active agents of the medicament, BPO and tretinoin, are encapsulated in a shell.

18. The medicament of claim 16, wherein the shell is an inorganic shell.

19. The medicament of claim 17, wherein the shell is an inorganic shell.

20. The medicament of claim 18 or 19, wherein the shell is a metal oxide or semi-metal oxide inorganic shell.

21. A topical medicament, which is a fixed-dose medicament comprising an active agent, which is a combination of benzoyl peroxide and tretinoin or a pharmaceutically acceptable salt thereof, and the amount of tretinoin or a pharmaceutically acceptable salt thereof is 0.1% by weight and the amount of benzoyl peroxide is 3% by weight, based on the total amount of the medicament; for use in the treatment of acne in a subject suffering from acne, wherein the medicament is administered once a day for a period of up to 12 weeks, wherein the score of at least one efficacy parameter is synergistically higher than the parameter assessed using the same treatment regimen of each active agent separately.

22. The medicament of claim 21, wherein the efficacy parameter is selected from at least one of IGA success rate, mean inflammatory lesion count reduction, mean non-inflammatory lesion count reduction, mean reduction in acne symptom domain, mean reduction in acne impact domain, and mean reduction in verbal assessment scale.

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