WO2015092602A1 - Topical pharmaceutical composition of a retinoid - Google Patents

Topical pharmaceutical composition of a retinoid

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Publication number
WO2015092602A1
WO2015092602A1 PCT/IB2014/066652 IB2014066652W WO2015092602A1 WO 2015092602 A1 WO2015092602 A1 WO 2015092602A1 IB 2014066652 W IB2014066652 W IB 2014066652W WO 2015092602 A1 WO2015092602 A1 WO 2015092602A1
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WO
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Application
Patent type
Prior art keywords
step
forming
microspheres
polymers
retinoid
Prior art date
Application number
PCT/IB2014/066652
Other languages
French (fr)
Inventor
Vaibhav Dubey
Simon Santosh JENA
Sumit Madan
Vinod Kumar Arora
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/20Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203Retinoic acids Salts thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/327Peroxy compounds, e.g. hydroperoxides, peroxides, peroxyacids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Abstract

The present invention relates to topical pharmaceutical compositions comprising microspheres or microcapsules of a retinoid, wherein said microspheres or microcapsules are further coated with a polymeric layer. The present invention also relates to topical pharmaceutical compositions comprising said coated microspheres or microcapsules of a retinoid in combination with benzoyl peroxide. It also relates to processes for the preparation of said topical pharmaceutical compositions and a method of treating acne by administering said topical pharmaceutical compositions.

Description

TOPICAL PHARMACEUTICAL COMPOSITION OF A RETINOID

Field of the Invention

The present invention relates to topical pharmaceutical compositions comprising microspheres or microcapsules of a retinoid, wherein said microspheres or microcapsules are further coated with a polymeric layer. The present invention also relates to topical pharmaceutical compositions comprising said coated microspheres or microcapsules of a retinoid in combination with benzoyl peroxide. It also relates to processes for the preparation of the topical pharmaceutical compositions and a method of treating acne by administering the topical pharmaceutical compositions.

Background of the Invention

Acne vulgaris is a common inflammatory skin disorder which affects the majority of the teenage population, as well as some adults. There are several causes for the development of acne. These include excessive sebum production, hyperkeratosis of the follicular epithelium, and proliferation of Propionibacterium acnes (P. acnes). These factors are primarily responsible for hyperkeratosis of the follicle lining, including retention of keratin and sebum, as well as the free fatty acid by-products of P. acnes metabolization which can lead to inflamed acne papules and pustules.

Retinoids are biologically active chemical compounds related to vitamin A and have been traditionally used for decades for the treatment of acne. These include tretinoin, retinol, retinal, isotretinoin, alitretinoin, tazarotene, adapalene, retinaldehyde, and etretinate. Among these, tretinoin, also known as dll-trans retinoic acid or vitamin A acid, treats acne by stimulating the turnover of skin cells and clearing the skin of plugged follicles. Tretinoin is commercially available in the form of creams, gels, and solutions. All of these compositions quickly release tretinoin, thereby necessitating frequent administration. Further, the quick release of tretinoin from these compositions causes irritation leading to patient noncompliance.

Retin-A Micro®, a controlled-release formulation of tretinoin, is based on a system of porous microspheres prepared by using methyl methacrylate and glycol dimethacrylate cross- polymer. The polymeric beads have a network of pores that retain tretinoin within the pores, permitting controlled-release of tretinoin depending upon the pore size.

U.S. Patent No. 5,955,109 discloses a topical pharmaceutical composition for the delivery of tretinoin comprising: (a) solid particles composed of a cross-linked copolymer of monoethylenically unsaturated monomers and polyethylenically unsaturated monomers, wherein said particles contain a continuous non-collapsible network of pores open to the exterior of said particles, and (b) an impregnant comprising tretinoin retained inside said pores in an amount effective to promote skin repair, wherein retention of said tretinoin inside said pores reduces irritancy of the composition. U.S. Patent Nos. 4,690,825, 5, 145,675, 5,135,740, 5,316,774, and 5,879,716 also disclose such polymeric beads based upon the use of synthetic polymers for making microspheres.

The use of synthetic polymers for making microspheres is not always preferred. Polymers of natural origin or chemically modified natural polymers such as cellulose derivatives e.g., ethyl cellulose, provide a useful and environmentally -friendly alternative to the formulators.

U.S. Patent No. 8,053,000 discloses substantially non-porous polymeric microspheres of tretinoin comprising a hydrophobic polymer, i.e., ethyl cellulose, and a plasticizer. The microparticles have surface pores, internal pores, or both, but have substantially no internal porosity connecting with the surface.

U.S. Publication No. 2011/0166101 discloses substantially porous microspheres of tretinoin comprising ethyl cellulose without the inclusion of a plasticizer.

The formulations disclosed in the prior art run the risk of the retinoid leaching out of the microspheres during storage. The free retinoid, upon contact with the skin surface, could cause irritation leading to patient non-compliance. Thus, there remains a need for an improved topical pharmaceutical composition of a retinoid which does not leach out of the microspheres and results in improved patient compliance. The present invention teaches topical pharmaceutical compositions of a retinoid comprising microspheres or microcapsules of a retinoid, wherein said microspheres or microcapsules are further coated with a polymeric layer. Also, the topical pharmaceutical compositions of the present invention can be combined with benzoyl peroxide in order to further enhance the efficacy of the compositions. The additional coating on said microspheres or microcapsules minimizes the problem of incompatibility between a retinoid and benzoyl peroxide and results in stable compositions.

Summary of the Invention

The present invention provides topical pharmaceutical compositions of a retinoid comprising microspheres or microcapsules of a retinoid, wherein said microspheres or microcapsules are coated with a polymeric layer. The compositions of the present invention comprise non-porous microspheres or microcapsules which are free of any leaching problems and which provide end users with a more compliant formulation. It further provides topical pharmaceutical compositions comprising said microspheres or microcapsules of a retinoid in combination with benzoyl peroxide. The additional coating on said microspheres or microcapsules overcomes the problem of incompatibility between a retinoid and benzoyl peroxide and results in stable compositions. It also provides processes of preparation of said topical pharmaceutical compositions and a method of treating acne by administering said topical pharmaceutical compositions.

Numerous other aspects are provided in accordance with these and other aspects of the invention. Other features and aspects of the present invention will become more fully apparent from the following detailed description and the appended claims.

Detailed Description of the Invention

A first aspect of the present invention provides a topical pharmaceutical composition of a retinoid comprising:

(a) microspheres comprising a retinoid and one or more microsphere-forming polymers; and

(b) a coating layer over said microspheres comprising one or more coat-forming polymers.

A second aspect of the present invention provides a topical pharmaceutical composition of a retinoid comprising:

(a) microcapsules comprising a retinoid and one or more microcapsule-forming polymers; and

(b) a coating layer over said microcapsules comprising one or more coat-forming polymers.

A third aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:

(a) a composition of a retinoid comprising:

(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and

(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and

(b) benzoyl peroxide in free-form. A fourth aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:

(a) a composition of a retinoid comprising:

(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and

(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and

(b) benzoyl peroxide in free-form.

A fifth aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:

(a) a first composition of a retinoid comprising:

(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and

(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and

(b) a second composition of benzoyl peroxide comprising:

(i) microcapsules comprising benzoyl peroxide and one or more

microcapsule-forming polymers; and

(ii) an optional coating layer over said microcapsules comprising one or more coat-forming polymers.

A sixth aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:

(a) a first composition of a retinoid comprising:

(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and

(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and

(b) a second composition of benzoyl peroxide comprising:

(i) microspheres comprising benzoyl peroxide and one or more

microsphere-forming polymers; and

(ii) an optional coating layer over said microspheres comprising one or more coat-forming polymers. A seventh aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:

(a) a first composition of a retinoid comprising:

(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and

(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and

(b) a second composition of benzoyl peroxide comprising:

(i) microcapsules comprising benzoyl peroxide and one or more

microcapsule-forming polymers; and

(ii) an optional coating layer over said microcapsules comprising one or more coat-forming polymers.

An eighth aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:

(a) a first composition of a retinoid comprising:

(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and

(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and

(b) a second composition of benzoyl peroxide comprising:

(i) microspheres comprising benzoyl peroxide and one or more

microsphere-forming polymers; and

(ii) an optional coating layer over said microspheres comprising one or more coat-forming polymers.

According to one embodiment of the above aspects, the retinoid is selected from the group comprising tretinoin, retinol, retinal, isotretinoin, alitretinoin, tazarotene, adapalene, retinaldehyde, and etretinate. In a preferred embodiment, the retinoid is tretinoin.

According to another embodiment of the above aspects, the microsphere-forming polymers, microcapsule-forming polymers, or coat-forming polymers are selected from the group comprising cellulose derivatives e.g., ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose; acrylates e.g., methacrylates, polyacrylates, and methacrylic acid and methyl methacrylate copolymers such as Eudragit® L 100; polyoxyethylene-polyoxypropylene copolymers; gums e.g., alginic acid, sodium alginate, carrageenan, gellan gum, and guar gum; propylene glycol alginate; chitosan; starch; dextran; gelatin; polyvinyl pyrrolidone; polyethylene glycol; polyethylene oxide; polyvinyl alcohol; lipids; fatty acids; waxes;

proteins e.g., albumin and collagen; poly(acryl) dextran; poly(acryl) starch; and mixtures thereof. In a preferred embodiment, the microsphere-forming polymer is ethyl cellulose and microcapsule-forming polymer or coat-forming polymer is chitosan, sodium alginate, or an acrylate.

A ninth aspect of the present invention provides a kit for dispensing a topical pharmaceutical composition of a retinoid and benzoyl peroxide, wherein the kit comprises:

(a) a first compartment comprising a composition of a retinoid comprising:

(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and

(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and

(b) a second compartment comprising benzoyl peroxide.

A tenth aspect of the present invention provides a kit for dispensing a topical pharmaceutical composition of a retinoid and benzoyl peroxide, wherein the kit comprises:

(a) a first compartment comprising a composition of a retinoid comprising:

(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and

(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and

(b) a second compartment comprising benzoyl peroxide.

According to one embodiment of the above aspects, the second compartment comprises benzoyl peroxide in free-form, in the form of microcapsules, or in the form of microspheres.

According to another embodiment of the above aspects, the compositions of a retinoid and benzoyl peroxide are applied concomitantly or sequentially onto a surface of a subject's body.

An eleventh aspect of the present invention provides a method of treating acne by administering a topical pharmaceutical composition of a retinoid comprising:

(a) microspheres comprising a retinoid and one or more microsphere-forming polymers; and (b) a coating layer over said microspheres comprising one or more coat-forming polymers.

A twelfth aspect of the present invention provides a method of treating acne by administering a topical pharmaceutical composition of a retinoid comprising:

(a) microcapsules comprising a retinoid and one or more microcapsule-forming polymers; and

(b) a coating layer over said microcapsules comprising one or more coat-forming polymers.

A thirteenth aspect of the present invention provides a method of treating acne by administering a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:

(a) a composition of a retinoid comprising:

(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and

(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and

(b) benzoyl peroxide.

A fourteenth aspect of the present invention provides a method of treating acne by administering a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:

(a) a composition of a retinoid comprising:

(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and

(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and

(b) benzoyl peroxide.

According to one embodiment of the above aspects, the benzoyl peroxide is present in free-form, in the form of microcapsules, or in the form of microspheres.

According to another embodiment of the above aspects, the topical pharmaceutical composition is co-administered with one or more additional drugs used to treat acne.

A fifteenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid comprising: (i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and

(ii) applying a coating layer over said microspheres comprising one or more coat- forming polymers.

According to one embodiment of the above aspect, the process comprises:

(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;

(ii) dissolving a retinoid into the solution of step (i);

(iii) mixing a stabilizer in an aqueous phase;

(iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion;

(v) homogenizing the emulsion of step (iv) using a homogenizer to form

microspheres; and

(vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres.

A sixteenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid comprising:

(i) forming microcapsules of a retinoid by using one or more microcapsule- forming polymers; and

(ii) applying a coating layer over said microcapsules comprising one or more coat- forming polymers.

According to one embodiment of the above aspect, the process comprises:

(i) mixing a stabilizer in an aqueous phase;

(ii) dispersing a retinoid into the solution of step (i);

(iii) homogenizing the dispersion of step (ii) using a homogenizer;

(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and

(v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules.

A seventeenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of: (i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and

(ii) applying a coating layer over said microspheres comprising one or more coat- forming polymers; and

wherein the process for the preparation of the second composition comprises the steps of:

(i) forming microcapsules of benzoyl peroxide by using one or more

microcapsule-forming polymers; and

(ii) optionally applying a coating layer over said microcapsules comprising one or more coat-forming polymers.

According to one embodiment of the above aspect, the process for the preparation of the first composition comprises the steps of:

(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;

(ii) dissolving a retinoid into the solution of step (i);

(iii) mixing a stabilizer in an aqueous phase;

(iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion;

(v) homogenizing the emulsion of step (iv) using a homogenizer to form

microspheres; and

(vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres; and

wherein the process for the preparation of the second composition comprises the steps of:

(i) mixing a stabilizer in an aqueous phase;

(ii) dispersing benzoyl peroxide into the solution of step (i);

(iii) homogenizing the dispersion of step (ii) using a homogenizer;

(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and

(v) optionally coating the microcapsules of step (iv) with one or more coat- forming polymers to obtain coated microcapsules.

An eighteenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of: (i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and

(ii) applying a coating layer over said microspheres comprising one or more coat- forming polymers; and

wherein the process for the preparation of the second composition comprises the steps of:

(i) forming microspheres of benzoyl peroxide by using one or more microsphere- forming polymers; and

(ii) optionally applying a coating layer over said microspheres comprising one or more coat-forming polymers.

According to one embodiment of the above aspect, the process for the preparation of a first composition comprises the steps of:

(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;

(ii) dissolving a retinoid into the solution of step (i);

(iii) mixing a stabilizer in an aqueous phase;

(iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion;

(v) homogenizing the emulsion of step (iv) using a homogenizer to form

microspheres; and

(vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres; and

wherein the process for the preparation of a second composition comprises the steps of:

(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;

(ii) dissolving benzoyl peroxide into the solution of step (i);

(iii) mixing a stabilizer in an aqueous phase;

(iv) admixing the solution of step (ii) with the solution of step (iii) using a

homogenizer to form microspheres; and

(v) optionally coating the microspheres of step (iv) with one or more coat-forming polymers to obtain coated microspheres.

A nineteenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of:

(i) forming microcapsules of a retinoid by using one or more microcapsule- forming polymers; and

(ii) applying a coating layer over said microcapsules comprising one or more coat- forming polymers; and

wherein the process for the preparation of the second composition comprises the steps of:

(i) forming microcapsules of benzoyl peroxide by using one or more

microcapsule-forming polymers; and

(ii) optionally applying a coating layer over said microcapsules comprising one or more coat-forming polymers.

According to one embodiment of the above aspect, the process for the preparation of the first composition comprises the steps of:

(i) adding a stabilizer in an aqueous phase;

(ii) dispersing a retinoid into the solution of step (i);

(iii) homogenizing the dispersion of step (ii) using a homogenizer;

(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and

(v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules; and

wherein the process for the preparation of a second composition comprises the steps of:

(i) adding a stabilizer in an aqueous phase;

(ii) dispersing benzoyl peroxide into the solution of step (i);

(iii) homogenizing the dispersion of step (ii) using a homogenizer;

(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and

(v) optionally coating the microcapsules of step (iv) with one or more coat- forming polymers to obtain coated microcapsules.

A twentieth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of: (i) forming microcapsules of a retinoid by using one or more microcapsule- forming polymers; and

(ii) applying a coating layer over said microcapsules comprising one or more coat- forming polymers; and

wherein the process for the preparation of the second composition comprises the steps of:

(i) forming microspheres of benzoyl peroxide by using one or more microsphere- forming polymers; and

(ii) optionally applying a coating layer over said microspheres comprising one or more coat-forming polymers.

According to one embodiment of the above aspect, the process for the preparation of the first composition comprises the steps of:

(i) mixing a stabilizer in an aqueous phase;

(ii) dispersing a retinoid into the solution of step (i);

(iii) homogenizing the dispersion of step (ii) using a homogenizer;

(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and

(v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules; and

wherein the process for the preparation of a second composition comprises the steps of:

(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;

(ii) dissolving benzoyl peroxide into the solution of step (i);

(iii) dissolving a stabilizer in an aqueous phase;

(iv) admixing the solution of step (ii) with the solution of step (iii) using a

homogenizer to form microspheres; and

(v) optionally coating the microspheres of step (iv) with one or more coat-forming polymers to obtain coated microspheres.

The term "topical," as used herein, refers to a composition meant for application to the skin, nail, or mucosal tissue.

The term "retinoid," as used herein, refers to chemical compounds related to vitamin

A. Specific examples of retinoids include tretinoin, retinol, retinal, isotretinoin, alitretinoin, tazarotene, adapalene, retinaldehyde, and etretinate. In particular, the retinoid used in the present invention is tretinoin. The term "tretinoin," as used herein, refers to all-trans retinoic acid or vitamin A acid. Chemically, tretinoin is 3,7-dimethyl-9-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2,4,6,8- nonatetraenoic acid. It further includes its salts, polymorphs, enantiomers, hydrates, solvates, prodrugs, chelates, and complexes.

The term "benzoyl peroxide," as used herein, refers to a peroxide consisting of two benzoyl groups joined by a peroxide group. Hydrous benzoyl peroxide may also be used. Benzoyl peroxide used in the present invention is present in free-form, in the form of microcapsules, or in the form of microspheres.

The term "free-form," as used herein, refers to the benzoyl peroxide present in the composition not intimately embedded, encapsulated, entrapped, or encased in a polymeric carrier, and is present in the composition in direct contact with the composition carrier.

Suitable additional drugs used to treat acne are selected from the group comprising antibiotics e.g., tetracycline, erythromycin, and clindamycin; salicylic acid; sulfur; resorcinol; and combinations thereof.

The microspheres or microcapsules of the present invention can be of any shape e.g., spherical, oblong, or ellipsoidal.

The term "microsphere," as used herein, refers to a matrix system in which a retinoid or benzoyl peroxide is dissolved or dispersed throughout the polymer matrix. The microspheres of the present invention have a D90 value in a range of from about 0.01 μιη to about 1000 μιη, particularly in a range of from about 0.1 μιη to about 500 μιη, and more particularly in a range of from about 1 μιη to about 200 μιη.

The term "microcapsule," as used herein, refers to a system comprising a retinoid or benzoyl peroxide surrounded by a polymeric shell. The microcapsules of the present invention have a D90 value in a range of from about 0.01 μιη to about 1000 μιη, particularly in a range of from about 0.1 μιη to about 500 μιη, and more particularly in a range of from about 1 μιη to about 200 μιη.

The term "D90," as used herein, refers to a diameter for which 90% of the

microspheres or microcapsules have diameters equal to or smaller than that diameter. The diameter of the microspheres or microcapsules can be determined using laser diffraction particle size analyzers such as a Malvern® instrument; electrical conductance instruments such as a Coulter counter; sieve analyzers; optical microscopes; sedimentation analyzers; and other known methods in the art. Particularly, the D90 value is determined by using a Malvern® instrument. The term "about," as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.

In the present invention, stabilizers are used as suspending agents that help to prevent the aggregation of the microspheres or microcapsules. Stabilizers used in the present invention can be selected from the group comprising cationic, anionic, or non-ionic compounds. Specific examples of stabilizers include cetyltrimethylammonium bromide; cetyltrimethylammonium chloride; polyvinyl alcohol; cellulose derivatives e.g.,

carboxymethyl cellulose; polyvinyl pyrrolidone; sorbitan derivatives e.g., polysorbate 80; sodium lauryl sulphate; docusate sodium; lecithin; polyoxyethylene-castor oil derivatives; and mixtures thereof.

The term "organic phase," as used herein, includes all organic solvents. Suitable examples of organic solvents are alcohols such as methanol, ethanol, and isopropyl alcohol; chlorinated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, methyl dichloroacetate, ethyl chloroacetate, ethyl dichloroacetate, and ethylene dichloride;

fluorinated hydrocarbons such as methyl fluoroacetate, methyl difluoroacetate, ethyl fluoroacetate, and ethyl difluoroacetate; acetates such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate; formates such as methyl formate, ethyl formate, isopropyl formate, propyl formate, and butyl formate; anhydrides such as maleic anhydride, acetic anhydride, propionic anhydride, and phosphoric anhydride; amides such as acetamide, propionamide, and butylamide; acetone; acetonitrile; tetrahydrofuran; and mixtures thereof.

The term "aqueous phase," as used herein, includes water and all water-miscible solvents. Examples of water-miscible solvents include glycerin; sorbitol; glycols e.g., polyethylene glycol and propylene glycol; and mixtures thereof. In certain embodiments, the aqueous phase is selected from the group comprising water, glycerin, sorbitol, polyethylene glycol, propylene glycol, and mixtures thereof.

The microspheres or microcapsules of the present invention can be prepared by any suitable technique known in the art. Most commonly used techniques include

homogenization, solvent evaporation, coacervation phase separation, spray drying, spray congealing, polymer precipitation, and supercritical fluid extraction.

The microspheres of the present invention are preferably prepared by a

homogenization process. To prepare the microspheres using a homogenization process, the retinoid or benzoyl peroxide and one or more microsphere-forming polymers are first dissolved into an organic phase. Further, a stabilizer is mixed in an aqueous phase. These two phases are admixed together to form an emulsion. This emulsion is then homogenized using a homogenizer to form the microspheres. Alternatively, the retinoid or benzoyl peroxide can be dissolved in an organic phase which is added into an aqueous phase to form the emulsion. This emulsion is then homogenized using a homogenizer to form the microspheres.

The microcapsules of the present invention are preferably prepared by a polymer precipitation process. To prepare the microcapsules using a polymer precipitation process, a stabilizer is first mixed in an aqueous phase. Further, the retinoid or benzoyl peroxide is dispersed in said aqueous phase and is homogenized using a homogenizer. One or more microcapsule-forming polymers are then mixed into the homogenized dispersion. The pH of the dispersion is then adjusted using a pH-adjusting agent such that the microcapsule-forming polymers are precipitated over retinoid or benzoyl peroxide particles to form the

microcapsules. Alternatively, the retinoid or benzoyl peroxide is dispersed in an aqueous phase and is homogenized using a homogenizer. One or more microcapsule-forming polymers are then mixed into the homogenized dispersion. The pH of the dispersion is then adjusted using a pH-adjusting agent such that the microcapsule-forming polymers are precipitated over retinoid or benzoyl peroxide particles to form the microcapsules.

The microspheres or microcapsules can be separated from the emulsion/dispersion by any suitable technique known in the art. Suitable techniques include filtration, centrifugation, decantation, dialysis, and evaporation. The preferred technique is filtration.

The separated microspheres or microcapsules can be dried by any suitable technique known in the art. Suitable techniques include distillation, spray drying, lyophilization, oven drying, fluidized bed drying, rota-evaporation using a rotavapor, and combinations thereof.

The microspheres or microcapsules of the present invention can be coated with a coating layer comprising one or more coat-forming polymers.

The coating can be performed by a technique such as polymer precipitation in which one or more coat-forming polymers are coated onto the microspheres or microcapsules. The coat-forming polymers are dissolved or dispersed in an organic or aqueous phase to form the solution or dispersion. The microspheres or microcapsules are then dispersed into the solution or dispersion of the coat-forming polymers. The pH of the dispersion is then adjusted using a pH adjusting agent such that the coat-forming polymers are precipitated over the microspheres or microcapsules to form the coated microspheres or microcapsules. Suitable pH-adjusting agents are selected from the group comprising organic or inorganic acids, e.g., citric acid, acetic acid, fumaric acid, tartaric acid, phosphoric acid, and hydrochloric acid; organic or inorganic bases, e.g. , sodium hydroxide, potassium hydroxide, and ammonium hydroxide; tertiary amines, e.g., triethanolamine and tetrahydroxypropyl ethylendiamine; and buffers, e.g., phosphate buffer and acetate buffer.

Alternatively, one or more coat-forming polymers are dissolved or dispersed in an organic or aqueous phase along with one or more coating additives to form the solution or dispersion. This solution/dispersion is then coated onto microspheres or microcapsules using any suitable methods such as spray drying and fluidized bed coating.

Coating additives may be selected from the group consisting of plasticizers, binders, lubricants, and coloring agents.

Suitable plasticizers are selected from the group consisting of triethyl citrate, dibutyl sebacate, acetylated triacetin, tributyl citrate, glycerol tributyrate, monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, and mixtures thereof.

Suitable binders are selected from the group consisting of methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and mixtures thereof.

Suitable lubricants are selected from the group consisting of colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof.

Coloring agents includes any FDA approved color for topical use.

The microspheres of the present invention may also comprise pre-formed microspheres, such as silica microspheres, in which the retinoid or benzoyl peroxide can be impregnated. These microspheres can be further coated with a coating layer comprising one or more coat-forming polymers.

The microspheres and/or microcapsules of the present invention can be dispersed in a suitable pharmaceutical composition to allow for ease of topical application. The pharmaceutical composition of the present invention possesses good spreadability. Further, the pharmaceutical composition can be aqueous-based or non-aqueous based. The pharmaceutical composition of the present invention can be in the form of an ointment, a cream, a lotion, an oil, a solution, an emulsion, a gel, a paste, an aerosol, a powder, or a foam.

The pharmaceutical composition may comprises one or more pharmaceutically acceptable excipients selected from the group comprising gelling agents, preservatives, surfactants, chelating agents, pH-adjusting agents, humectants, antioxidants, permeation- enhancers, emulsifiers, solvents, and mixtures thereof.

Suitable gelling agents are selected from the group comprising carboxyvinyl polymers, e.g., Carbopol® 980, Carbopol® 974P, Carbopol® 97 IP, and Carbopol® 934P; natural gums, e.g., karaya gum, locust bean gum, guar gum, xanthan gum, arabic gum, tragacanth gum, carrageenan, pectin, agar, alginic acid, and sodium alginate; cellulose derivatives, e.g., hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose; acrylates, e.g., methacrylates and polyacrylates; alginic acid-propylene glycol ester; polyoxyethylene-polyoxypropylene copolymers; polyvinyl pyrrolidone; polyethylene glycol; polyethylene oxide; polyvinyl alcohol; silicon dioxide; polyacrylamide; and mixtures thereof.

Suitable preservatives are selected from the group comprising methyl-, ethyl-, propyl-, or butyl-esters of hydroxy benzoic acid or sodium salts thereof, benzoic acid, sodium benzoate, chlorhexedine, benzalkonium chloride, 2-phenoxyethanol, cetrimide, potassium sorbate, benzyl alcohol, imidurea, dichlorobenzyl alcohol, thiomersal, diazolidinylurea, and mixtures thereof.

Suitable surfactants are selected from the group comprising polyethoxylated fatty acid esters, polyoxyethylene sorbitan esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene-polyoxypropylene glycol, sorbitan esters, sodium lauryl sulphate, docusate sodium, nonooxynol, glyceryl monostearate, and mixtures thereof.

Suitable chelating agents are selected from the group comprising

ethylenediaminetetraacetic acid or derivatives or salts thereof, e.g. , disodium edetate;

dihydroxyethyl glycine; glucamine; acids, e.g., citric acid, tartaric acid, gluconic acid, and phosphoric acid; and mixtures thereof.

Suitable humectants or emollients are selected from the group comprising propylene glycol, glycerin, butylene glycol, sorbitol, triacetin, cyclomethicone, dimethicone copolyol, caprylic/capric triglyerides, castor oil, ceteareth-20, ceteareth-30, ceteth-20, cetostearyl alcohol, cetyl alcohol, cocoa butter, diisopropyl adipate, glycerin, glyceryl monooleate, glyceryl monostearate, glyceryl stearate, isopropyl myristate, isopropyl palmitate, lanolin, lanolin alcohol, hydrogenated lanolin, liquid paraffins, linoleic acid, mineral oil, oleic acid, white petrolatum, polyethylene glycol, polyoxyethylene glycol fatty alcohol ethers, polyoxypropylene 15 stearyl ether, propylene glycol stearate, squalane, steareth-2, steareth- 100, stearic acid, stearyl alcohol, urea, and mixtures thereof.

Suitable antioxidants include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite, ascorbic acid, propyl gallate, thiourea, tocopherols, beta-carotene, and mixtures thereof.

Suitable permeation-enhancers are selected from the group comprising sulfoxides, e.g., dimethyl sulfoxide (DMSO); ethers, e.g.,diethylene glycol monoethyl ether (e.g., Transcutol®); surfactants, e.g., sodium laurate, sodium lauryl sulfate, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80; alkyl glycosides; alcohols, e.g., ethanol, propanol, and benzyl alcohol; fatty acids, e.g., lauric acid, oleic acid, valeric acid, and isostearic acid; fatty acid esters, e.g., isopropyl myristate and isopropyl palmitate; polyols or esters thereof, e.g., propylene glycol, ethylene glycol, glycerol, butanediol, and polyethylene glycol; amides or other nitrogenous compounds, e.g., urea, dimethyl acetamide, dimethyl formamide, 2-pyrrolidone, l-methyl-2-pyrrolidone, ethanolamine, diethanolamine, and triethanolamine; terpenes; dimethyl isosorbide; alkanones; and mixtures thereof.

Suitable emulsifiers are selected from the group comprising tri-block copolymers, e.g., Poloxamer 407, Poloxamer 188; polyoxyl stearates, e.g., poly oxyethylene-20 stearate (Myrj® 49); polysorbates, e.g., Tween® 80, Tween® 60 and Tween® 20; sorbitan fatty acid esters, e.g., Span® 60 or Span® 80; polyoxyethylene alkyl ethers, e.g., Brij® 97;

polyoxyethylene alkylphenyl ethers; sucrose fatty acid esters; and mixtures thereof.

Suitable solvents are selected from the group comprising water; alcohols, e.g., methanol, ethanol, isopropyl alcohol, and higher alcohols; glycerin; sorbitol; glycols, e.g., polyethylene glycol and propylene glycol; tetrahydrofuran; liquid petrolatum; ether;

petroleum ether; aromatics, e.g., benzene and toluene; alkanes, e.g., pentane, hexane, and heptane; ketones, e.g., acetone and methyl ethyl ketone; chlorinated hydrocarbons e.g., chloroform, carbon tetrachloride, methylene chloride, and ethylene dichloride; acetates, e.g., ethyl acetate; lipids, e.g., isopropyl myristate, diisopropyl adipate, and mineral oil; and mixtures thereof.

Any suitable pH-adjusting agents well known in the art can be used, including, for example, NaOH, acetic acid, hydrochloric acid, etc. The following examples represent various embodiments according to the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

EXAMPLES

Example 1

Figure imgf000020_0001

Procedure:

1. Ethyl cellulose and tretinoin were dissolved in dichloromethane.

2. Cetyltrimethylammonium bromide was dissolved in purified water.

3. The solution of step 1 was added into the solution of step 2 to form an emulsion.

4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.

5. The dichloromethane from the emulsion of step 4 was evaporated to form the

microsphere dispersion.

6. Sodium alginate was dissolved in purified water.

7. The solution of step 6 was added into the microsphere dispersion of step 5.

8. The pH of the dispersion of step 7 was adjusted to 3.0 using a hydrochloric acid solution to obtain coated microspheres.

9. The coated microspheres of step 8 were filtered and dried. Example 2

Figure imgf000021_0001

Procedure:

1. Ethyl cellulose and tretinoin were dissolved in dichloromethane.

2. Polyvinyl alcohol was dissolved in purified water.

3. The solution of step 1 was added into the solution of step 2 to form an emulsion.

4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.

5. The dichloromethane from the emulsion of step 4 was evaporated to form a

microsphere dispersion.

6. Sodium alginate was dissolved in purified water.

7. The solution of step 6 was added to the microsphere dispersion of step 5.

8. The pH of the dispersion of step 7 was adjusted to 3.0 using a hydrochloric acid solution to obtain coated microspheres.

9. The coated microspheres of step 8 were filtered and dried.

Example 3

Figure imgf000021_0002
Procedure:

1. Ethyl cellulose and tretinoin were dissolved in dichloromethane.

2. Purified water was heated and docusate sodium was dissolved in the heated water while stirring.

3. The solution of step 1 was added into the solution of step 2 to form an emulsion.

4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.

5. The dichloromethane from the emulsion of step 4 was evaporated to form a

microsphere dispersion.

6. Chitosan was added to purified water acidified with a hydrochloric acid solution. 7. The solution of step 6 was added into the microsphere dispersion of step 5.

8. The pH of the dispersion of step 7 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microspheres.

9. The coated microspheres of step 8 were filtered and dried. Example 4

Figure imgf000022_0001

Procedure:

1. Ethyl cellulose and benzoyl peroxide were dissolved in dichloromethane.

2. Purified water was heated and docusate sodium was dissolved in the heated water while stirring.

3. The solution of step 1 was added into the solution of step 2 to form an emulsion.

4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.

5. The dichloromethane from the emulsion of step 4 was evaporated to form a

microsphere dispersion.

6. Chitosan was added to purified water acidified with a hydrochloric acid solution. 7. The solution of step 6 was added into the microsphere dispersion of step 5.

8. The pH of the dispersion of step 7 was adjusted to 7.0 using sodium hydroxide solution to obtain coated microspheres.

9. The coated microspheres of step 8 were filtered and dried.

Example 5

Figure imgf000023_0001

Procedure:

1. Purified water was heated and docusate sodium was dissolved in the heated water while stirring.

2. Glycerin was added into the solution of step 1.

3. Benzoyl peroxide was dispersed into the solution of step 2, and the mixture was homogenized using a homogenizer.

4. The dispersion of step 3 was filtered to obtain benzoyl peroxide particles.

5. Purified water was heated and docusate sodium was dissolved in the heated water while stirring.

6. The benzoyl peroxide particles of step 4 were redispersed into the solution of step 5 and stirred.

7. Chitosan was added to purified water acidified with hydrochloric acid solution (for coating).

8. The solution of step 7 was added into the dispersion of step 6.

9. The pH of the dispersion of step 8 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microcapsules.

10. The coated microcapsules of step 9 were filtered and dried. Example 6

Figure imgf000024_0001

Procedure:

1. Tazarotene was dissolved in dichloromethane.

2. Silica microspheres (preformed) were added into the solution of step 1 while stirring.

3. The dispersion of step 2 was dried in a rotavapor to obtain tazarotene loaded silica microspheres.

4. Eudragit® L 100 was dissolved in ethanol while stirring.

5. The tazarotene loaded silica microspheres of step 3 were dispersed into the solution of step 4.

6. The dispersion of step 5 was spray dried to obtain coated microspheres.

Example 7

Figure imgf000024_0002

Procedure:

1. Ethyl cellulose and tretinoin were dissolved in dichloromethane.

2. Purified water was heated and polyvinyl alcohol was dissolved in the heated water while stirring.

3. The solution of step 1 was added into the solution of step 2 to form an emulsion.

4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres. 5. The dichloromethane from the emulsion of step 4 was evaporated to form a microsphere dispersion.

6. Chitosan was added to purified water acidified with a hydrochloric acid solution.

7. The solution of step 6 was added into the microsphere dispersion of step 5.

8. The pH of the dispersion of step 7 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microspheres.

9. The coated microspheres of step 8 were filtered and dried.

Example 8

Figure imgf000025_0001

Procedure:

1. Ethyl cellulose and benzoyl peroxide were dissolved in dichloromethane.

2. Purified water was heated and polyvinyl alcohol was dissolved in the heated water while stirring.

3. The solution of step 1 was added into the solution of step 2 to form an emulsion. 4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.

5. The dichloromethane from the emulsion of step 4 was evaporated to form a

microsphere dispersion.

6. Chitosan was added to purified water acidified with a hydrochloric acid solution.

7. The solution of step 6 was added into the microsphere dispersion of step 5.

8. The pH of the dispersion of step 7 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microspheres.

9. The coated microspheres of step 8 were filtered and dried. Example 9

Figure imgf000026_0001

Procedure:

1. Ethyl cellulose and benzoyl peroxide were dissolved in dichloromethane.

2. Purified water was heated and polyvinyl alcohol was dissolved in the heated water while stirring.

3. The solution of step 1 was added into the solution of step 2 to form an emulsion.

4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.

5. The dichloromethane from the emulsion of step 4 was evaporated to form a

microsphere dispersion.

6. Sodium alginate was dissolved in purified water.

7. The solution of step 6 was added into the microsphere dispersion of step 5.

8. The pH of the dispersion of step 7 was adjusted to 3.0 using a hydrochloric acid solution to obtain coated microspheres.

9. The coated microspheres of step 8 were filtered and dried.

Example 10

Figure imgf000026_0002
Procedure:

1. Ethyl cellulose and benzoyl peroxide were dissolved in dichloromethane.

2. Cetyltrimethylammonium bromide was dissolved in purified water.

3. The solution of step 1 was added into the solution of step 2 to form an emulsion. 4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.

5. The dichloromethane from the emulsion of step 4 was evaporated to form a

microsphere dispersion.

6. Sodium alginate was dissolved in purified water.

7. The solution of step 6 was added into the microsphere dispersion of step 5.

8. The pH of the dispersion of step 7 was adjusted to 3.0 using a hydrochloric acid solution to obtain coated microspheres.

9. The coated microspheres of step 8 were filtered and dried.

Example 11

Figure imgf000027_0001

Procedure:

1. Purified water was heated and docusate sodium was dissolved in the heated water while stirring.

2. Glycerin was added into the solution of step 1.

3. Benzoyl peroxide was dispersed into the solution of step 2 and the mixture was

homogenized using a homogenizer.

4. The dispersion of step 3 was filtered to obtain benzoyl peroxide particles.

5. The benzoyl peroxide particles of step 4 were redispersed in purified water.

6. Chitosan was added to purified water acidified with a hydrochloric acid solution.

7. The solution of step 6 was added into the dispersion of step 5. 8. The pH of the dispersion of step 7 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microcapsules.

9. The coated microcapsules of step 8 were filtered and dried. Example 12

Figure imgf000028_0001

Procedure:

1. Ethyl cellulose and tazarotene were dissolved in dichloromethane.

2. Purified water was heated and polyvinyl alcohol was dissolved in the heated water while stirring.

3. The solution of step 1 was added into the solution of step 2 to form an emulsion.

4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.

5. The dichloromethane from the emulsion of step 4 was evaporated to form a

microsphere dispersion.

6. Eudragit®L 100 was dissolved in ethanol while stirring.

7. The dispersion of step 5 was added into the solution of step 6.

8. The dispersion of step 7 was spray dried to obtain coated microspheres.

Example 13

Figure imgf000028_0002
Procedure:

1. Ethyl cellulose and tazarotene were dissolved in dichloromethane.

2. Purified water was heated and polyvinyl alcohol was dissolved in the heated water while stirring.

3. The solution of step 1 was added into the solution of step 2 to form an emulsion.

4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.

5. The dichloromethane from the emulsion of step 4 was evaporated to form a

microsphere dispersion.

6. Sodium alginate was dissolved in purified water.

7. The solution of step 6 was added into the microsphere dispersion of step 5.

8. The pH of the dispersion of step 7 was adjusted to 3 using a hydrochloric acid

solution to obtain coated microspheres.

9. The coated microspheres of step 8 were filtered and dried.

Microspheres of tretinoin obtained from Examples 1-3, microspheres of benzoyl peroxide obtained from Example 4, and microcapsules of benzoyl peroxide obtained from Example 5 were incorporated either separately or in combination into a gel composition as described in Examples 14-16 provided below.

Example 14

Figure imgf000029_0001

Procedure:

1. Purified water was divided into three portions.

2. The first portion of purified water was heated and docusate sodium was dissolved ' the heated water while stirring. 3. Benzoyl peroxide microspheres were added into the solution of step 2.

4. Glycerin and ethylenediaminetetraacetic acid were added into the second portion of purified water.

5. Tretinoin microspheres were added into the solution of step 4.

6. Carbopol® 974P was dispersed into the third portion of purified water.

7. The dispersions of step 3 and step 5 were added into the dispersion of step 6 while stirring.

8. The pH of the dispersion of step 7 was adjusted to 5.5 with a sodium hydroxide solution.

Example 15

Figure imgf000030_0001

Procedure:

1. Purified water was divided into three portions.

2. The first portion of purified water was heated and docusate sodium was dissolved in the heated water while stirring.

3. Benzoyl peroxide microcapsules were added into the solution of step 2.

4. Glycerin and ethylenediaminetetraacetic acid were added into the second portion of purified water.

5. Tretinoin microspheres were added into the solution of step 4.

6. Hydroxyethyl cellulose was dispersed into the third portion of purified water.

7. The dispersions of step 3 and step 5 were added into the dispersion of step 6 while stirring. Example 16

Figure imgf000031_0001

Procedure:

1. Propylene glycol was divided into two portions.

2. Docusate sodium was dissolved in the first portion of propylene glycol.

3. Benzoyl peroxide microcapsules were added into the solution of step 2.

4. Carbopol® 974P was dispersed into the second portion of propylene glycol.

5. Tretinoin microspheres were dispersed in glycerin.

6. The dispersion of step 3 was added into the carbopol dispersion of step 4 while

stirring.

7. The dispersion of step 5 was added into the dispersion of step 6.

Other Embodiments

The foregoing description discloses only exemplary embodiments of the invention. It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. Thus, while only certain features of the invention have been illustrated and described, many modifications and changes will occur to those skilled 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 invention.

Claims

Claims What is claimed is:
1. A topical pharmaceutical composition of a retinoid comprising:
(a) microspheres comprising a retinoid and one or more microsphere-forming polymers; and
(b) a coating layer over said microspheres comprising one or more coat-forming polymers.
2. A topical pharmaceutical composition of a retinoid comprising:
(a) microcapsules comprising a retinoid and one or more microcapsule-forming polymers; and
(b) a coating layer over said microcapsules comprising one or more coat-forming polymers.
3. A topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a composition of a retinoid comprising:
(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and
(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and
(b) benzoyl peroxide in free-form.
4. A topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a composition of a retinoid comprising:
(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and
(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and
(b) benzoyl peroxide in free-form.
5. A topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a first composition of a retinoid comprising:
(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and (ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and
(b) a second composition of benzoyl peroxide comprising:
(i) microcapsules comprising benzoyl peroxide and one or more
microcapsule-forming polymers; and
(ii) an optional coating layer over said microcapsules comprising one or more coat-forming polymers.
6. A topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a first composition of a retinoid comprising:
(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and
(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and
(b) a second composition of benzoyl peroxide comprising:
(i) microspheres comprising benzoyl peroxide and one or more
microsphere-forming polymers; and
(ii) an optional coating layer over said microspheres with comprising one or more coat-forming polymers.
7. A topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a first composition of a retinoid comprising:
(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and
(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and
(b) a second composition of benzoyl peroxide comprising:
(i) microcapsules comprising benzoyl peroxide and one or more
microcapsule-forming polymers; and
(ii) an optional coating layer over said microcapsules comprising one or more coat-forming polymers.
8. A topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a first composition of a retinoid comprising: (i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and
(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and
(b) a second composition of benzoyl peroxide comprising:
(i) microspheres comprising benzoyl peroxide and one or more
microsphere-forming polymers; and
(ii) an optional coating layer over said microspheres comprising one or more coat-forming polymers.
9. The topical pharmaceutical composition of claims 1 to 8, wherein the retinoid is selected from the group consisting of tretinoin, retinol, retinal, isotretinoin, alitretinoin, tazarotene, adapalene, retinaldehyde, and etretinate.
10. The topical pharmaceutical composition of claim 9, wherein the retinoid is tretinoin.
1 1. The topical pharmaceutical composition of claims 1 to 8, wherein the microsphere- forming polymers, microcapsule-forming polymers, or coat-forming polymers are selected from the group consisting of cellulose derivatives; acrylates; polyoxyethylene- polyoxypropylene copolymers; gums; propylene glycol alginate; chitosan; starch; dextran; gelatin; polyvinyl pyrrolidone; polyethylene glycol; polyethylene oxide; polyvinyl alcohol; lipids; fatty acids; waxes; proteins; poly(acryl) dextran; poly(acryl) starch; and mixtures thereof.
12. A kit for dispensing a topical pharmaceutical composition of a retinoid and benzoyl peroxide, wherein the kit comprises:
(a) a first compartment comprising a composition of a retinoid comprising:
(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and
(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and
(b) a second compartment comprising benzoyl peroxide.
13. A kit for dispensing a topical pharmaceutical composition of a retinoid and benzoyl peroxide, wherein the kit comprises:
(a) a first compartment comprising a composition of a retinoid comprising: microcapsules comprising a retinoid and one or more microcapsule- forming polymers;and
a coating layer over said microcapsules comprising one or more coat- forming polymers; and
(b) a second compartment comprising benzoyl peroxide.
14. The kit for dispensing the topical pharmaceutical composition of claim 12 or 13, wherein the second compartment comprises benzoyl peroxide in free-form, in the form of microcapsules, or in the form of microspheres.
15. A method of treating acne by administering a topical pharmaceutical composition of any one of a composition of claims 1 to 8.
16. A process for the preparation of a topical pharmaceutical composition of a retinoid comprising:
(i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and
(ii) applying a coating layer over said microspheres comprising one or more coat- forming polymers.
17. The process for the preparation of the topical pharmaceutical composition of claim 16 comprising:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving a retinoid into the solution of step (i);
(iii) mixing a stabilizer in an aqueous phase;
(iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion;
(v) homogenizing the emulsion of step (iv) using a homogenizer to form
microspheres; and
(vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres.
18. A process for the preparation of a topical pharmaceutical composition of a retinoid comprising: (i) forming microcapsules of a retinoid by using one or more microcapsule- forming polymers; and
(ii) applying a coating layer over said microcapsules comprising one or more coat- forming polymers.
19. The process for the preparation of the topical pharmaceutical composition of claim 18 comprising:
(i) mixing a stabilizer in an aqueous phase;
(ii) dispersing a retinoid into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer;
(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules.
20. A process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of:
(i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and
(ii) applying a coating layer over said microspheres comprising one or more coat- forming polymers; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) forming microcapsules of benzoyl peroxide by using one or more
microcapsule-forming polymers; and
(ii) optionally applying a coating layer over said microcapsules comprising one or more coat-forming polymers.
21. The process for the preparation of the topical pharmaceutical composition of claim 20, wherein the process for the preparation of the first composition comprises the steps of:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving a retinoid into the solution of step (i);
(iii) mixing a stabilizer in an aqueous phase; (iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion;
(v) homogenizing the emulsion of step (iv) using a homogenizer to form
microspheres; and
(vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) mixing a stabilizer in an aqueous phase;
(ii) dispersing benzoyl peroxide into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer;
(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) optionally coating the microcapsules of step (iv) with one or more coat- forming polymers to obtain coated microcapsules.
22. A process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of:
(i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and
(ii) applying a coating layer over said microspheres comprising one or more coat- forming polymers; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) forming microspheres of benzoyl peroxide by using one or more microsphere- forming polymers; and
(ii) optionally applying a coating layer over said microspheres comprising one or more coat-forming polymers.
23. The process for the preparation of the topical pharmaceutical composition of claim 22, wherein the process for the preparation of the first composition comprises the steps of:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving a retinoid into the solution of step (i); (iii) mixing a stabilizer in an aqueous phase;
(iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion;
(v) homogenizing the emulsion of step (iv) using a homogenizer to form
microspheres; and
(vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving benzoyl peroxide into the solution of step (i);
(iii) mixing a stabilizer in an aqueous phase;
(iv) admixing the solution of step (ii) with the solution of step (iii) using a
homogenizer to form microspheres; and
(v) optionally coating the microspheres of step (iv) with one or more coat-forming polymers to obtain coated microspheres.
24. A process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of:
(i) forming microcapsules of a retinoid by using one or more microcapsule- forming polymers; and
(ii) applying a coating layer over said microcapsules comprising one or more coat- forming polymers; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) forming microcapsules of benzoyl peroxide by using one or more
microcapsule-forming polymers; and
(ii) optionally applying a coating layer over said microcapsules comprising one or more coat-forming polymers.
25. The process for the preparation of the topical pharmaceutical composition of claim 24, wherein the process for the preparation of the first composition comprises the steps of:
(i) adding a stabilizer in an aqueous phase; (ii) dispersing a retinoid into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer;
(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) adding a stabilizer in an aqueous phase;
(ii) dispersing benzoyl peroxide into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer;
(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) optionally coating the microcapsules of step (iv) with one or more coat- forming polymers to obtain coated microcapsules.
26. A process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of:
(i) forming microcapsules of a retinoid by using one or more microcapsule- forming polymers; and
(ii) applying a coating layer over said microcapsules comprising one or more coat- forming polymers; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) forming microspheres of benzoyl peroxide by using one or more microsphere- forming polymers; and
(ii) optionally applying a coating layer over said microspheres comprising one or more coat-forming polymers.
27. The process for the preparation of the topical pharmaceutical composition of claim 26, wherein the process for the preparation of the first composition comprises the steps of:
(i) mixing a stabilizer in an aqueous phase;
(ii) dispersing a retinoid into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer; (iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules; and
wherein the process for the preparation of a second composition comprises the steps of:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving benzoyl peroxide into the solution of step (i);
(iii) dissolving a stabilizer in an aqueous phase;
(iv) admixing the solution of step (ii) with the solution of step (iii) using a
homogenizer to form microspheres; and
(v) optionally coating the microspheres of step (iv) with one or more coat-forming polymers to obtain coated microspheres.
28. The process for the preparation of the topical pharmaceutical composition of claims 17, 19, 21, 23, 25, and 27, wherein the stabilizer is selected from the group consisting of cationic, anionic, or non-ionic compounds; cellulose derivatives; sorbitan derivatives;
polyoxyethylene-castor oil derivatives; polyvinyl alcohol; polyvinyl pyyrolidone; and mixtures thereof.
29. The process for the preparation of the topical pharmaceutical composition of claims 17, 19, 21, 23, 25, and 27, wherein the organic phase is selected from the group consisting of methanol, ethanol, isopropyl alcohol, dichloromethane, chloroform, carbon tetrachloride, methyl dichloroacetate, ethyl chloroacetate, ethyl dichloroacetate, ethylene dichloride, methyl fluoroacetate, methyl difluoroacetate, ethyl fluoroacetate, ethyl difluoroacetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl formate, ethyl formate, isopropyl formate, propyl formate, butyl formate, maleic anhydride, acetic anhydride, propionic anhydride, phosphoric anhydride, acetamide, propionamide, butylamide, acetone, acetonitrile, tetrahydrofuran, and mixtures thereof.
30. The process for the preparation of the topical pharmaceutical composition of claims 17, 19, 21, 23, 25, and 27, wherein the aqueous phase is selected from the group consisting of water, glycerin, sorbitol, polyethylene glycol, propylene glycol, and mixtures thereof.
PCT/IB2014/066652 2013-12-17 2014-12-05 Topical pharmaceutical composition of a retinoid WO2015092602A1 (en)

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