COMPOSITION COMPRISING A RETINOID AND BENZOYL PEROXIDE

Field of the Invention

The present invention relates to a stable topical aqueous composition of adapalene in combination with benzoyl peroxide comprising one or more gelling agents, wherein at least one of the gelling agents is a carbomer. It also relates to processes for preparing such composition.

Background of the Invention

Acne is a disease of the skin in which the pilosebaceous structures of the skin become inflamed, leading to the formation of comedones, pustules, and nodules. It is generally believed that acne arises when hyperkeratosis of the pilosebaceous structure wholly or partially blocks the opening of the structure, resulting in comedones filled with sebum, keratin, and Propionibacterium acnes ("P. acnes"). These lesions are commonly identified as acne. P. acnes naturally occurs in normal skin, but is especially and characteristically present in acne lesions. It is believed that metabolic by-products and waste from P. acnes within the pilosebaceous structures cause or contribute to the inflammation of acne lesions.

Conventional acne treatments have been available as oral and topical dosage forms. Oral drugs include antibiotics like tetracycline, minocycline, doxycycline, and erythromycin. Topical agents for the treatment of acne include retinoids such as tretinoin and adapalene; sulfur; resorcinol; salicylic acid; benzoyl peroxide; and antibiotics such as erythromycin, clindamycin, or tetracycline.

Antimicrobial resistance to topical therapy is becoming an important factor in the treatment of acne, and clinically an association between the presence of antimicrobial resistant organisms and therapeutic failure has been observed. The concomitant administration of two or more anti-acne agents prevents the development of resistant microorganisms, and proves to be more effective in the treatment of acne.

One currently available combination product is Epiduo ^® topical gel, which contains 0.1% of adapalene and 2.5% of benzoyl peroxide. Other combination products are Benzamycin ^® topical gel, which contains 3% of erythromycin and 5% of benzoyl peroxide, and Benzaclin ^® topical gel, which contains 1% of clindamycin phosphate and 5% of benzoyl peroxide. It has been noted that the combination of benzoyl peroxide and retinoids shows synergism in the treatment of acne. Benzoyl peroxide acts by destroying P. acnes, the bacteria that causes the condition acne. It acts as an antiseptic and as an oxidizing agent, reducing the number of comedones, or blocked pores. Retinoids allow the keratin plugs of microcomedones to be expelled, thus, fewer lesions are able to rupture and cause papules, pustules, and nodules of inflammatory acne. A combination drug of benzoyl peroxide and a retinoid should have both comedogenesis and bacteriostatic effect in acne treatment. Compositions and methods for the treatment of acne comprising benzoyl peroxide and/or a retinoid have been described in U.S. Patent Nos. 4,350,681 ; 4,361,584; 4,387, 107;

4,497,794; 4,671,956; 4,960,772; 5,086,075; 5, 145,675; 5,466,446; 5,632,996; 5,767,098; 5,851,538; 5,955,109; 5,879,716; 5,955,109; 5,998,392; 6,013,637; and 6,1 17,843; and U.S. Publication Nos. 2003/0170196; 2002/0064541; and 2005/0037087.

There have been many difficulties in formulating products containing a combination of a retinoid and benzoyl peroxide. The stability of benzoyl peroxide is greatly influenced by the chemical composition of the formulation and by storage temperature. Benzoyl peroxide is extremely reactive, and degrades in solution at low temperature on account of the instability of its peroxide bond. Hence, it is difficult to formulate a benzoyl peroxide composition in a solution form. In order to limit the problem of rapid instability of benzoyl peroxide in solution, it has been found to be advantageous to formulate benzoyl peroxide in dispersed form. However, this type of formulation is not entirely satisfactory since degradation of the benzoyl peroxide in the finished product is still observed.

A further obstacle in formulating the combination is instability of retinoids in the presence of benzoyl peroxide. Most retinoids are prone to oxidation, and since benzoyl peroxide is a strong oxidizing agent, the compatibility of these compounds in the same formulation poses numerous problems in terms of physical and chemical stability.

It is desirable to provide products combining the activity of a retinoid with the activity of benzoyl peroxide, with few or none of the disadvantages described above. Such compositions should provide improved compositions which are less irritating, easy to formulate, have a smooth consistency after formulation, are adequately stable, and have a sufficiently long storage life with or without refrigeration. A number of documents disclose formulations comprising combinations of benzoyl peroxide and adapalene with particular gelling agents. For example, U.S. Patent Nos. 7,820, 186 and 7,964,202; and U.S. Publication Nos. 2008/0176954 and 201 1/0070274 disclose combination formulations formulated with Simulgel ^® 600 gelling agent. U.S. Publication Nos. 201 1/0003894 and 2010/0143285 disclose combinations comprising carrageenan gelling agent and polyurethane polymer, respectively. U.S. Publication No. 2010/0022642 discloses a gelling system comprising of two categories of compounds selected from silicates, cellulose gelling agents, and polysaccharide gums.

U.S. Publication Nos. 2009/0318550 and 2010/0166852 disclose many gelling agents including polyacrylamides and polysaccharides, and in particular teach away from the use of carbomers for a combination composition of adapalene and benzoyl peroxide. It is being stated that the use of carbomers in an aqueous composition does not give good results in terms of chemical stability of the benzoyl peroxide or in terms of rheological stability. However, the present inventors have developed a stable topical composition comprising a combination of a retinoid with benzoyl peroxide and a carbomer gelling agent.

Summary of the Invention

The present invention relates to a stable topical aqueous composition of adapalene in combination with benzoyl peroxide comprising one or more gelling agents, wherein at least one of the gelling agents is a carbomer.

In one aspect, the present invention relates to a stable topical aqueous composition having a pH of about 4 to about 6.5 comprising:

(a) a therapeutically effective amount of retinoid;

(b) a therapeutically effective amount of benzoyl peroxide;

(c) one or more pharmaceutically acceptable excipients; and

(d) one or more gelling agents, wherein at least one of the gelling agents is a carbomer.

Embodiments of the composition may include one or more of the following features. For example, the topical aqueous composition of the present invention is in the form of a gel, solution, foam, lotion, or spray. More particularly, the topical aqueous composition of the present invention is in the form of a gel. In another embodiment, adapalene is present in a concentration from about 0.001% to about 20% by weight of the composition, and benzoyl peroxide is present in a concentration from about 0.001% to about 20% by weight of the composition. More particularly, adapalene is present in a concentration from about 0.01% to about 10% by weight of the composition, and benzoyl peroxide is present in a concentration from about 0.01% to about 20% by weight of the composition.

In an alternate embodiment, the composition comprises a retinoid other than adapalene. The retinoid is selected from natural or synthetic retinoids comprising tazarotene, retinoic acid, tretinoin, isotretinoin, bexarotene, alitretinoin, Vitamin A, retinol, retinal, retinyl palmitate, retinyl acetate, (6-((4,4-dimethyl thiochroman-6yl)ethynyl)pydin -3-yl)methanol, 2-(2-(4,4-dimethyl thiochroman-6-yl)-ethynyl)-5-pyridinecarboxaldehyde, ethyl 5-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)thiophene-2-carbo xylate, or salts or derivatives thereof.

According to another embodiment, the carbomer gelling agent alone or in combination with other gelling agents is present in a concentration of about 0.001% to about 30%, particularly in a concentration of about 0.01% to about 10%, more particularly in a concentration of about 0.1% to about 5% by weight of the composition.

According to another embodiment, the composition further comprises a film- forming agent.

According to another embodiment, the composition comprises one or more pharmaceutically acceptable excipients selected from the group comprising water-miscible solvents, pro-penetrating agents, preservatives, antioxidants, chelating agents, surfactants - particularly liquid wetting surfactants, sunscreens, humectants, moisturizers, pH-adjusting agents, colorants, fragrances, perfumes, or mixtures thereof.

According to another embodiment, the composition of the present invention comprises an additional anti-acne agent.

According to another embodiment, the present invention relates to a method of treating acne by administering a stable topical aqueous composition having a pH of about 4 to about 6.5, comprising:

(a) a therapeutically effective amount of adapalene;

(b) a therapeutically effective amount of benzoyl peroxide; (c) one or more pharmaceutically acceptable excipients; and

(d) one or more gelling agents, wherein at least one of the gelling agents is a carbomer.

According to yet another embodiment, the composition comprises the other gelling agents selected from the group comprising cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, and hydroxypropylmethyl cellulose; polyvinylalcohol; natural and synthetic gums such as guar gum, hydroxypropyl guar gum, xanthan gum, acacia, and tragacanth; modified starch; acrylic acid/ethyl aery late copolymers; maleic anhydride-alkyl methylvinylethers and copolymers; polymethacrylate copolymers; oleogels; trihydroxystearin; aluminum magnesium hydroxy stearate;

poloxamer; polyvinyl alcohol; methyl hydroxybenzoate; ethyl hydroxybenzoate; propyl hydroxybenzoate; butyl hydroxybenzoate; polyacrylamide; or mixtures thereof.

In another aspect, the present invention relates to a stable topical aqueous composition having a pH of about 4 to about 6.5 comprising:

(a) a therapeutically effective amount of a retinoid or pharmaceutically

acceptable salts thereof;

(b) a therapeutically effective amount of benzoyl peroxide;

(c) one or more pharmaceutically acceptable excipients; and

(d) one or more gelling agents, wherein at least one of the gelling agents is a carbomer.

In another aspect, the present invention relates to a process for preparing a topical aqueous composition of adapalene and benzoyl peroxide, wherein the process comprises:

(a) dissolving all the excipients except the gelling agent in purified water to form an aqueous phase;

(b) dispersing adapalene and benzoyl peroxide in separate portions of the

aqueous phase of step (a) and mixing them to form the drug dispersion;

(c) dispersing the gelling agent in purified water;

(d) mixing the drug dispersion of step (b) with the gelling agent dispersion of step (c); and

(e) adjusting the pH to about 4 to about 6.5. In another aspect, the present invention relates to a process for preparing a topical aqueous composition of adapalene and benzoyl peroxide, wherein the process comprises:

(a) dispersing a gelling agent and one or more pharmaceutically acceptable excipients in a part of purified water under stirring to form a gelling phase;

(b) dispersing benzoyl peroxide and one or more pharmaceutically acceptable excipients in a part of purified water under stirring to get a uniform dispersion of benzoyl peroxide;

(c) dispersing adapalene and one or more pharmaceutically acceptable

excipients in another part of purified water under stirring to get a uniform dispersion of adapalene;

(d) adding the benzoyl peroxide dispersion obtained in step (b) to the gelling phase obtained in step (a) under stirring;

(e) adding the adapalene dispersion obtained in step (c) to the final material obtained in step (d);

(f) adjusting the pH to about 4 to about 6.5; and

(g) adjusting the weight of the composition to 100% with the remaining quantity of water.

Detailed Description of the Invention

The present invention provides a stable topical aqueous composition for the treatment of a skin disorder, particularly acne. The stable topical composition having a pH of about 4 to about 6.5 comprises a therapeutically effective amount of adapalene, a therapeutically effective amount of benzoyl peroxide, one or more pharmaceutically acceptable excipients, and one or more gelling agents, wherein at least one of the gelling agents is a carbomer.

The phrase "therapeutically effective amount", as used herein, means that amount of a compound which, when administered to a subject for treating a state, disorder, or condition, or causing an action, is sufficient to effect such treatment, or action. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, physical condition, and responsiveness of the mammal to be treated. The term "adapalene" includes the base as well as salts formed with a

pharmaceutically acceptable base, in particular, organic bases such as sodium hydroxide, potassium hydroxide, and aqueous ammonia, or organic bases such as lysine, arginine, or N-methylglucamine. The term "adapalene salts" also includes the salts formed with fatty amines such as dioctylamine and stearylamine.

The composition of the present invention may comprise a retinoid other than adapalene. The retinoid is selected from natural or synthetic retinoids comprising tazarotene, retinoic acid, tretinoin, isotretinoin, bexarotene, alitretinoin, Vitamin A, retinol, retinal, retinyl palmitate, retinyl acetate, (6-((4,4-dimethyl thiochroman-6yl)ethynyl)pydin -3-yl)methanol, 2-(2-(4,4-dimethyl thiochroman-6-yl)-ethynyl)-5-pyridinecarboxaldehyde, ethyl 5-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)thiophene-2-carbo xylate, or salts or derivatives thereof.

The topical aqueous composition of the present invention is present in the form of a gel, solution, foam, lotion, or spray. More particularly, it is in the form of a gel.

The term "about", as used herein, when used along with values assigned to certain measurements and parameters, means a variation of up to 10% from such values, or in case of a range of values, means up to a 10% variation from both the lower and upper limit of such ranges.

Adapalene is present in a concentration from about 0.001% to about 20% by weight of the composition, and benzoyl peroxide is present in a concentration from about 0.001% to about 20% by weight of the composition. More particularly, adapalene is present in a concentration from about 0.01% to about 10% by weight of the composition, and benzoyl peroxide is present in a concentration from about 0.01% to about 20% by weight of the composition.

The term "gelling agent", as used herein, is synonymous with viscosifying agent, solidifier, or thickening agent, and refers to an agent that increases the viscosity of the formulation by forming a crosslinking structure.

The gelling agent used in the present invention is a carbomer or a mixture of a carbomer with other gelling agents.

Generally, carbomers are high molecular weight water-soluble polymers of acrylic acid cross-linked with allyl ethers of sucrose and/or pentaerythritol. Carbomers have different viscosities depending on their polymeric composition. Examples of carbomers for use herein include various grades of Carbopol ^® such as, for example, Carbopol ^® 910, 934, 940, 941, 974, 980, 981, 1342, 5984, ETD 2020, ETD 2050, and Ultrez 10. The preferred grade is Carbopol ^® 980 because it is a highly efficient thickener and it is ideal for formulating clear aqueous and hydroalcoholic gels. Its benefits include short flow properties, high viscosity, high suspending ability, and high clarity.

Other gelling agents which may be used in combination with carbomers include cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, and hydroxypropylmethyl cellulose; polyvinylalcohol; natural and synthetic gums such as guar gum, hydroxypropyl guar gum, xanthan gum, acacia, and tragacanth; modified starch; acrylic acid/ethyl acrylate copolymers; maleic anhydride-alkyl methylvinylethers and copolymers; polymethacrylate copolymers; oleogels;

trihydroxystearin; aluminum magnesium hydroxy stearate; poloxamer; polyvinyl alcohol; methyl hydroxybenzoate; ethyl hydroxybenzoate; propyl hydroxybenzoate; butyl hydroxybenzoate; polyacrylamide; or mixtures thereof.

The gelling agent is present in the composition at a concentration that provides sufficient viscosity to the composition to allow the composition to adhere to the skin for a sufficient period of time to allow the active ingredients to act on the affected areas. In some embodiments, two or more gelling agents are used in combination. The gelling agent is present in a concentration of about 0.001% to about 30%, particularly in a concentration of about 0.01% to about 10%, more particularly in a concentration of about 0.1% to about 5% by weight of the composition.

The pharmaceutical composition of the present invention can further include one or more film-forming agents. The term "film-forming agent" means an ionic or non-ionic hydrophilic polymer having a molecular mass at least greater than 10,000, which during application to the skin forms a continuous film. Examples of film- forming agents include, but are not limited to, hydroxypropylmethylcellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, cellulose acetate, hydroxypropylmethylcellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers such as Eudragit ^® , polyvinylpyrrolidone, polyvinylalcohol, polyethylene glycol, or mixtures thereof. The pharmaceutical composition of the present invention can further include one or more pharmaceutically acceptable excipients selected from the group comprising water- miscible solvents, pro-penetrating agents, preservatives, antioxidants, chelating agents, surfactants - particularly liquid wetting surfactants, sunscreens, humectants, moisturizers, pH-adjusting agents, colorants, fragrances, perfumes, or mixtures thereof.

Suitable examples of water-miscible solvents include, but are not limited to, water, ethanol, propylene glycol, glycerin, polyethylene glycol, or mixtures thereof.

The compositions of the invention may contain one or more pro-penetrating agents in preferential concentrations ranging from about 0% to about 20% by weight, and more preferably, ranging from about 2% to about 6% by weight, relative to the total weight of the composition. They should generally not dissolve the active agents at the percentage used, should not cause any exothermic reactions harmful to benzoyl peroxide, should aid in the satisfactory dispersion of the active agents, and should have antifoaming properties. Suitable pro-penetrating agents are selected from the group comprising of propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol, ethoxydiglycol, or mixtures thereof.

The composition of the present invention may comprise about 0% to about 2.0% by weight of preservatives by total weight of the composition. Examples of preservatives include, but are not limited to, methyl, ethyl, propyl, and butyl esters of hydroxy benzoic acid, benzoic acid, chlorhexedine, benzalkonium chloride, 2-phenoxyethanol, cetrimide, potassium sorbate, thiomersal, or mixtures thereof.

As the active ingredients are more susceptible to oxidation in an aqueous medium, an antioxidant is used in the composition to retard oxidation and deterioration of the active ingredients, thus providing the composition with long-term stability. Specific examples of antioxidants include, but are not limited to, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, ascorbic acid, ascorbyl palmitate, thiourea, acetylcysteine, dithiothreitol, cysteine hydrochloride, propyl gallate, tocopherol, or mixtures thereof. Particularly, the antioxidant is butylated hydroxytoluene (BHT).

Antioxidants may be present in an amount of about 0% to about 0.3% by weight of the composition.

Examples of chelating agents include, but are not limited to, edetate salts, for example, edetate disodium and citric acid. Chelating agents chelate metal ions present in the composition that may be detrimental to the shelf life of the formulation. Particularly, the chelating agent is present in an amount of about 0.01% to about 0.5% by weight of the composition.

A surfactant may also be included in the formulation of the present invention to allow good dispersion of the active ingredients. Examples of surfactants include, but are not limited to, polyethoxylated fatty acid esters, polyoxyethylene sorbitan esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan esters, sodium lauryl sulphate, docusate sodium, nonooxynol, glyceryl monostearate, or mixtures thereof. Particularly, the liquid wetting surfactants used in the present invention include compounds of the poloxamer family, and more particularly poloxamer 124, and poloxamer 182.

The pharmaceutical composition of the present invention may also include one or more pH-adjusting agents. Examples of pH-adjusting agents include, but are not limited to, pharmaceutically acceptable organic or inorganic acids or bases, for example, sodium hydroxide, tromethamine, hydrochloric acid, or mixtures thereof. Particularly, the compositions of the present invention have a pH of about 4 to about 6.5.

Examples of humectants include, but are not limited to, glycerol and sorbitol.

Examples of fragrances and perfumes include, but are not limited to, lavender oil, rose oil, lemon oil, and almond oil.

The present invention relates to a process of preparing a stable topical aqueous composition of adapalene and benzoyl peroxide, wherein the process comprises:

(a) dissolving all of the excipients except the gelling agent in purified water to form an aqueous phase;

(b) dispersing adapalene and benzoyl peroxide in separate portions of the

aqueous phase of step (a), and mixing them to form the drug dispersion;

(c) dispersing the gelling agent in purified water;

(d) mixing the drug dispersion of step (b) with the gelling agent dispersion of step (c); and

(e) adjusting the pH to about 4 to about 6.5. The present invention also relates to a process of preparing a stable topical aqueous composition of adapalene and benzoyl peroxide, wherein the process comprises:

(a) dispersing a gelling agent and one or more pharmaceutically acceptable excipients in a part of purified water under stirring to form a gelling phase;

(b) dispersing benzoyl peroxide and one or more pharmaceutically acceptable excipients in a part of purified water under stirring to get a uniform dispersion of benzoyl peroxide;

(c) dispersing adapalene and one or more pharmaceutically acceptable excipients in another part of purified water under stirring to get a uniform dispersion of adapalene;

(d) adding the benzoyl peroxide dispersion obtained in step (b) to the gelling phase obtained in step (a) under stirring;

(e) adding the adapalene dispersion obtained in step (c) to the final material obtained in step (d);

(f) adjusting the pH to about 4 to about 6.5; and

(g) adjusting the weight of the composition to 100% with the remaining quantity of water.

The present invention also relates to a method for treating acne by administering the composition of the present invention to an affected area of the subject's skin having such a disorder in an amount and for a period of time sufficient to improve the skin disorder.

The composition of the present invention may further include an additional antiacne agent. Examples of additional anti-acne agents include, but are not limited to, an antibiotic, salicylic acid, azelaic acid, retinoids other than adapalene, metronidazole, or mixtures thereof.

The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and are not to be construed as limiting the invention. EXAMPLES

Example 1 :

Manufacturing Process:

(1) Preparation of Aqueous Phase

(a) A part of purified water was taken in the main manufacturing vessel and disodium edetate was added under stirring to dissolve.

(b) Propylene glycol was added to the step (a) solution, and mixed under stirring.

(c) Sodium docusate was dissolved in glycerin.

(d) Step (c) material was added to step (b) material, and mixed under stirring.

(e) Poloxamer 124 was added to step (d) material, and mixed under stirring.

(2) Preparation of Drug Dispersion

(a) Benzoyl peroxide was added to a portion of aqueous phase and homogenized to get a uniform dispersion.

(b) Adapalene was added to another portion of aqueous phase, and mixed under stirring.

(c) Step (a) material was added to step (b) material and mixed under stirring.

(3) Addition of Gelling Agents

Carbomer was added to a portion of purified water, and mixed under stirring.

(4) Preparation of Gel

The drug dispersion of step (2) was mixed with the gelling agent dispersion of step (3). (b) The pH was checked, and adjusted to 5 ± 0.5 with sodium hydroxide solution.

(c) The weight was adjusted to 100% with the remaining quantity of water.

Table 1 shows physical properties of the gel composition prepared according to Example 1 after storage under normal and accelerated conditions.

Table 1 :

* Not checked

Example 2:

Manufacturing Process:

(1) Preparation of the Gelling Phase

(a) Disodium edetate was dissolved in a part of purified water.

(b) Carbopol ^® 980 was added to the solution of step (a), and mixed under stirring. Preparation of Benzoyl Peroxide Dispersion

(a) A part of purified water was taken and hydroxypropyl cellulose was added and mixed under stirring.

(b) Benzoyl peroxide was added to step (a) material, mixed under stirring, and homogenized to get a uniform dispersion.

Preparation of Adapalene Dispersion

(a) A part of purified water was taken, and propylene glycol, glycerin,

poloxamer, and disodium docusate were added and mixed under stirring.

(b) Adapalene was added to the step (a) material, mixed under stirring, and

homogenized to get a uniform dispersion.

Preparation of Gel

(a) Step (2) material was added to step (1) material under stirring.

(b) Step (3) material was added to step (a) material under stirring.

(c) The pH was checked and adjusted to 5 ± 0.5 with sodium hydroxide solution.

(d) The weight was adjusted to 100% with the remaining quantity of water.

Table 2 shows physical properties of the gel composition prepared according to Example 2 after storage under accelerated conditions.

Table 2:

While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention.