DESC:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:

“TOPICAL PHARMACEUTICAL COMPOSITION”

2. APPLICANT:

(a) NAME: CIPLA LIMITED

(b)NATIONALITY: Indian Company incorporated under the
Companies Act, 1956

(c) ADDRESS: Cipla House, Peninsula Business Park, Ganpatrao Kadam
Marg, Lower Parel, Mumbai – 400013, Maharashtra. India.

3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

FIELD OF INVENTION:
The present invention relates to topical pharmaceutical compositions comprising an anti-inflammatory agent in combination with an antibacterial agent, particularly for the treatment of acne. This invention also discloses a process of preparation of the said topical pharmaceutical composition.

BACKGROUND AND PRIOR ART:
Acne vulgaris and acne rosacea are the most common skin disorders that affects virtually all individuals at least once. Incidence peaks in 18-year-olds, but substantial numbers of 20 to 40 year olds also develop the disease. The effects of acne should not be underestimated. It can persist for years; produce disfigurement and permanent scarring; and have significant psychosocial consequences, including diminished self-esteem, embarrassment, social withdrawal, depression, and unemployment.

Acne is a disorder of the sebaceous follicles, which are special pilosebaceous units located on the face, neck, chest, upper back, and upper arms. These units consist of relatively large sebaceous glands associated with small hair follicles and clogging of such hair follicles cause acne.

The pathophysiology of acne involves four key mechanism of action which are abnormal proliferation and differentiation of keratinocytes, increased sebum production, hyper proliferation of Propionibacterium acnes, and an inflammatory response initiated by bacterial antigens and cytokines.

Currently the treatment of acne is designed to target precursor lesions and active inflammatory lesions. Generally the milder cases are best managed with topical regimens whereas the systemic drugs are indicated in more severe cases.

Historically, the existing armamentarium of anti-acne agents has included topically applied or systemically administered antimicrobials or retinoids. The ideal agent would target each of the pathogenic factors without producing adverse effects. However, the anti-acne agents currently available target only one or two out of the four pathogenic factors.
Acne is commonly caused by a class of bacteria called Propionibacterium (P-bacteria). Several antibiotics are recommended for the treatment of acne which are administered either orally or topically or both and include tetrcyclines, macrolides, combination of trimethoprim andsulfamethoxazole, fluoroquinolones. Benzoyl peroxide, salicylic acid, retinoids, azelaic acid are also used for the management of acne.

Several studies have suggested that early stages of acne lesions may involve inflammation. . Effectiveness of anti-inflammatory agents have been shown through several clinical studies, Do et al (J Am Acad Dermatol. 2008 Apr; 58(4):603-8). This article concludes that inflammation is critical to all type of acne lesions and is multifactorial.

Further, depending upon the severity of the acne the treatment may be categorized as oral, topical or procedural which include hormonal, laser and light therapies.

Because of the multifactorial nature of the pathogenesis of acne, combinations of different classes of drugs that affect different areas of pathophysiology is preferred. Also there is no single therapy available which is able to counter the growth of P acnes and its pathogenesis.
Nadifloxacin is a topical fluoroquinolone antibiotic that has been used for the therapy of mild to moderate acne. This antimicrobial agent is effective against aerobic and anaerobic bacteria isolated from patients with infective skin disorders. It is effective against Gram-positive, Gram-negative and anaerobic bacteria, including P acnes.

Nadifloxacin is chemically known as (RS)-9-Fluoro-8-(4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid. Nadifloxacin is chemically represented as

Azelaic acid is a naturally occurring aliphatic dicarboxylic acid. Azelaic acid is effective in the treatment of mild-to-moderate acne vulgaris. Azelaic acid has a predominant antibacterial activity. Azelaic acid is bactericidal against a range of gram-negative and gram-positive microorganisms. Azelaic acid is chemically represented as

Dapsone, a sulfone exhibits both anti-inflammatory and antimicrobial activity, and is used for the treatment of acne. Dapsone is chemically known as 4-[(4-aminobenzene)sulfonyl] aniline and is chemically represented as

Dapsone 5% Gel: A New Option in Topical Therapy for Acne, Jerry Tan, Skin Therapy Letter, Volume 17 • Number 8 • September 2012.

Efficacy and Safety of Dapsone Gel 5% for the Treatment of Acne Vulgaris in Adolescents, Sharon Raimer, MD et al, Therapeutics for The clinician, volume 81, February 2008 171.
EP09818B discloses the use of nadifloxacin in the treatment of acne rosacea.’

Effectiveness and Tolerance of Topical Nadifloxacin in the Therapy of Acne Vulgaris (grade I-III): Results of a Non- Interventional Trial in 555 patients.

Efficacy of topical azelaic acid gel in the treatment of mild to moderate acne vulgaris, Fariba Iraji et al, Indian J Dermatol Venerol Leprol, March-April 2007, Vol 73, Issue 2.

Versatility of azelaic acid 15% gel in treatment of inflammatory acne vulgaris, Thiboutot D.J Drugs Dermatol. 2008 Jan; 7(1):13-6.

The prior art discloses that dapsone, nadifloxacin and azelaic acid, each of them separately, can be employed for the treatment of acne. However, none of the prior art disclose these agents in a combination specifically for the treatment of acne.
As per the current practice for the treatment of acne, a combination therapy is always preferred wherein the topical therapy is followed by oral therapy.

However, the conditions that are associated with acne formation, such as bacterial attacks and inflammatory conditions have not been addressed by a single or combination topical therapy or.

OBJECT OF THE INVENTION:
The object of the present invention is to provide a topical pharmaceutical composition comprising an anti-inflammatory agent in combination with an antibacterial agent.

Another object of the present invention is to provide a topical pharmaceutical composition comprising an anti-inflammatory agent in combination with an antibacterial agent optionally with one or more pharmaceutically acceptable excipients.

Yet another object of the present invention is to provide a topical pharmaceutical composition comprising anti-inflammatory agent in combination with an antibacterial agent which ensures high efficacy.

Another object of the present invention is to provide a stable topical pharmaceutical composition comprising anti-inflammatory agent in combination with an antibacterial agent.

Another object of the present invention is to provide a topical pharmaceutical composition comprising anti-inflammatory agent in combination with an antibacterial agent which ensures patient compliance.

Another object of the present invention is to provide a process for preparing the topical pharmaceutical composition anti-inflammatory agent in combination with an antibacterial agent.

Another object of the present invention is to provide a method of treating acne by applying the topical pharmaceutical composition anti-inflammatory agent in combination with an antibacterial agent.

Another object of the present invention is to provide use of the topical pharmaceutical composition comprising anti-inflammatory agent in combination with an antibacterial agent for the treatment of acne.

SUMMARY OF THE INVENTION:
According to one aspect of the present invention, there is provided a topical pharmaceutical composition comprising anti-inflammatory agent in combination with an antibacterial agent.

According to another aspect of the invention, there is provided a process for the preparation of a topical pharmaceutical composition comprising anti-inflammatory agent in combination with an antibacterial agent optionally with one or more pharmaceutically acceptable excipients.

According to yet another aspect of the present invention there is provided a method of treating acne by applying a topical pharmaceutical composition comprising anti-inflammatory agent in combination with an antibacterial agent.

According to yet another aspect of the invention there is provided use of the topical pharmaceutical composition comprising anti-inflammatory agent in combination with an antibacterial agent for the treatment of acne.

DETAILED DESCRIPTION OF THE INVENTION:
Acne is polygenic and multifactorial condition wherein the contributory pathogenic factors are sebaceous gland hyperplasia and excess sebum production, abnormal follicular differentiation, propionic bacterium acne colonization as well as inflammatory and immune responses.

Successful management of acne requires careful patient evaluation followed by consideration of several “patient factors” and “pathophysiologic factors” in choosing a particular therapeutic regimen. Most patients have a mixture of non-inflammatory and inflammatory lesions. The predominance of one type, along with the number of lesions, plays a role in determining acne severity. In addition, other factors to be considered include age, skin type (dry, oily or combination), patient motivation, lifestyle, menstrual regularity and premenstrual flareups, evidence of hirsutism, effect of acne, and potential therapies on the patient’s quality of life.

However, the objective in choosing a specific agent or agents for the management of acne should be to achieve maximum efficacy and tolerability with minimum risk of adverse effects.

Hence, the inventors of the present invention have found a combination of anti-inflammatory agent and an antibacterial agent which exhibit promising anti acne effect when applied topically.

The topical route of administration would also minimize the systemic side effects of the otherwise orally administered medications and also would be less invasive compared to the other procedural therapy regimens. Secondly administration of the drug at the targeted site of action with a higher efficacy potential and ease of use would be the other contributory factors in the selection of the topical route of administration.

According to the present invention, antibacterial agents, may include but are not limited to one or more of nadifloxacin and azelaic acid and anti-inflammatory agent is but are not limited to dapsone.

The terms “nadifloxacin”, “azelaic acid” and “dapsone”, are used in a broad sense to include not only “nadifloxacin”, “azelaic acid” and “daposne” etc. per se but also their pharmaceutically acceptable derivatives. Suitable pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable isomers, pharmaceutically acceptable esters, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers and/or pharmaceutically acceptable complexes thereof.

Preferably, the anti-inflammatory agent may be present in an amount ranging from about 0.1% to about 20% by weight of the total composition.

Preferably, the antibacterial agent may be present in an amount ranging from about 0.1% to about 10% by weight of the total composition.

A particularly preferred topical pharmaceutical composition according to the invention comprises dapsone and nadifloxacin along with one or more pharmaceutically acceptable excipients.

Another particularly preferred topical pharmaceutical composition according to the invention comprises dapsone and azelaic acid along with one or more pharmaceutically acceptable excipients.

The topical pharmaceutical composition of the present invention comprising anti-inflammatory agent and an antibacterial agent may be in the dosage form such as, but not limited to gels, creams, lotions, liniments, patches, pastes, jellies, foams, films, solutions, ointments or sprays and the like.

The topical pharmaceutical composition, of the present invention, may also be provided in a support base or matrix that may be directly applicable to a desired area of the skin. Examples of such support base include, but are not limited to gauze or bandages.

Preferably, the topical pharmaceutical composition according to the present invention may be in the form of a gel or cream.

According to one embodiment of the present invention, the topical pharmaceutical composition of the present invention, may be dispensed via airless dispensing pumps, such as dual bottle airless pumps.
The topical pharmaceutical composition of the present invention comprising anti-inflammatory agent and an antibacterial agent may be in the form of controlled release formulation, delayed release formulation, extended release formulation, pulsatile release formulation, and dual immediate release and controlled release formulation and the like. The composition is formulated such that it releases the active ingredient/s at a rate which will result in an effective concentration at the site of application.

General desirable aspects of topical pharmaceutical composition include, safety (e.g. isomolar aqueous gels), efficacy, stability, and patient acceptability. More specific formulation aspects include optimal retention time, appropriate drug diffusion, spreadability, targeted drug delivery as well as aesthetic appeal.

It will be understood that the pH of the composition can be varied by the skilled person as required. A topical pharmaceutical composition according to the invention preferably has a pH from about 4 to about 7.

The topical pharmaceutical composition comprising anti-inflammatory agent and an antibacterial agent may further comprise suitable excipients that may be used for formulating the composition according to the present invention.

The composition of the present invention is intended for topical application. In the context of the present invention, it is to be understood that the term “topical application” involves application to the skin.

The topical pharmaceutical composition, of the present invention, may further comprise pharmaceutically acceptable excipients as desired for any topical application.

Suitable excipients that may be used in the topical pharmaceutical composition include, but are not limited to gelling agents, chelating agents, preservatives, bioadhesives or polymers or film forming polymers, viscosity modifiers or regulators, humectants/emollients, organic or aqueous solvents, propellants, skin protectants, antioxidants, emulsifiers/surfactants, pH adjusting agents, solvents/co-solvents, tonicity modifiers or osmolar agents, oils, stabilizers, stiffening agent, skin conditioners, , moisturizers, soothing agents, thickeners, salts, fragrances, perfumes, colorants.

Suitable gelling agents, that may be employed, in the topical pharmaceutical composition include, but are not limited to, xanthan gum, sodium alginate (Manugel DMB), Carbopol® ETD 2020, polycarbophil, polysaccharides, natural gums, acacia, tragacanth, starch, cellulose derivatives such as carboxy methyl cellulose, hydroxyl propyl methyl cellulose, hydroxypropyl methylcellulose (Methocel K4 M), acrylate polymers, methacrylate polymers, acrylamide/sodium acryloyldimethyl taurate copolymer, polyvinyl pyrrolidone, bentonite, alginic acid, carbomer, ethyl cellulose, gelatin, guar gum, hydroxyl ethyl cellulose, hydroxyl propyl cellulose, hydroxyethyl methylcellulose, glyceryl behenate, algae extracts, gums, polysaccharides, polyethylene oxide, poloxamer, pectins, hydrolysed proteins, polymers comprising pendant carboxylic acid groups, or esters thereof, polymers comprising pendant anhydrides of dicarboxylic acid groups and block co-polymers based on ethylene oxide and/or propylene oxide and the like or combinations thereof.

Preferably, the one or more gelling agent may be present in an amount ranging from about 0.05% to about 10% by weight of the total composition.

Chelating agents that may be used in the topical pharmaceutical composition include, but are not limited to disodium edetate, condensed sodium phosphate, diethylenetriamine penta-acetic acid and the like or combinations thereof.

Preferably, the chelating agents may be present in an amount ranging from about 0.05% to about 0.5% by weight of the total composition.

Preservatives that may be used in the topical pharmaceutical composition include, but are not limited to hydroxybenzoates (parabens such as methyl paraben, propyl paraben, butyl paraben), benzyl alcohol, benzoic acid, chlorphenesin, sorbic acid, phenoxyethanol and the like or combinations thereof.

Preferably, one or more preservatives may be present in an amount ranging from about 0.05% to about 0.5% by weight of the total composition.
Bioadhesives or polymers that may be used in the topical pharmaceutical composition, include, but are not limited to hydroxyethyl cellulose, gelatin, carbopol, polycarbophil, cross-linked polymethacrylic acid, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, polyethylene glycol, polysaccharide hyaluronic, polyvinylpyrrolidone, sodium alginate, sodium carboxymethylcellulose, methyl cellulose, starch and the like or combinations thereof.

Suitable humectants and/or emollients provide smoothness and lubricity which in turn facilitate the filling and dispensing of the topical pharmaceutical composition.

Emollients that may be used in the topical pharmaceutical composition, include, but are not limited to, polyhydric alcohols such as glycols, and polysaccharides, such as glycerin, ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, dipropylene glycol, diglycerin, sorbitol, malvitol, trehalose, raffinose, xylitol, mannitol, polyethylene glycol, propylene glycol, polyglycerin, cholesterol, squaline, fatty acids, octyldodecanol, myristyl alcohol, urea, lanolin, lactic acid, esters such as isopropyl stearate, isopropyl myristate, isopropyl palmitate and isopropyl laurate and the like or combinations thereof.

Preferably, the emollients may be present in an amount ranging from about 0.5% to about 20% by weight of the total composition.

Viscosity enhancing agents improve the formation of a gel. Suitable viscosity modifiers or regulators that may be used in the topical pharmaceutical composition, include, but are not limited to, polyolefins, polyethylenes, polypropylenes, polyalphaolefins, ethylene-propylene copolymers, maleneated derivatives of the materials herein, polyisobutylenes, maleic anhydride and their diene derivatives, polymethacrylates, maleic anhydride-styrene copolymers and esters and their diene derivatives, hydrogenated copolymers of styrene-butadiene, cetostearyl alcohol, ethylene-propylene copolymers, polyisobutenes, poloxamers, hydrogenated styrene-isoprene polymers, hydrogenated isoprene polymers, polymethacrylates, polyacrylates, polyethylene polypropylene copolymers, polyethylene propylene copolymers, polyalkyl styrenes, alkenyl aryl conjugated diene copolymers, polyolefins, esters of maleic anhydride-styrene copolymers, ethylene-propylene copolymers functionalized with the reaction product of maleic anhydride and an amine, polymethacrylate functionalized with an amine, styrene-maleic anhydride copolymers reacted with an amine, polymethacrylate polymers, esterified polymers, esterified polymers of a vinyl aromatic monomer and an unsaturated carboxylic acid or derivative thereof, olefin copolymers, ethylene-propylene copolymer, polyisobutylene and the like or combinations thereof.

Preferably, the viscosity enhancing agents may be present in an amount ranging from about 0.05% to about 5% by weight of the total composition.

Suitable tonicity modifiers or osmolar agents to match the osmolarity (mosm) of the physiological fluids include, but are not limited to, glycerine, sodium chloride, potassium chloride, mannitol, sucrose, lactose, fructose, maltose, dextrose, dextrose anhydrous, propylene glycol, glycerol and the like or combinations thereof.

Suitable stiffening agents, which, may be employed in the topical composition of the present invention, comprise fatty alcohol, having a hydrocarbon chain containing 16 to 18 carbon atoms and having a melting point in pure state of about 45ºC to 65ºC.

Examples of suitable stiffening agents include, but are not limited to, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, eicosanol, docosanol, sorbitane monopalmitate, sorbitane monostearate, glyceryl monopalmitate, glyceryl monostearate, or glyceryl monopalmitostearate and combinations thereof.

The term “skin conditioner" refers to a substance which improves the quality of skin by providing a soothing effect and giving the skin a shine without greasiness.

Suitable skin conditioners, which may be employed, in the topical composition of the present invention include, but are not limited to, medium chain triglycerides (MCT's) such as, caprylic/capric triglycerides and the like.

Suitable emollients or waterproofing agents or film formers may also be incorporated in the topical composition of the present invention.

Examples of suitable emollients, which may be employed in the topical foam composition of the present invention, include, but are not limited to, dimethicone, polyhydric alcohols such as glycols, and polysaccharides, such as ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, dipropylene glycol, glycerin, diglycerin, sorbitol, malvitol, trehalose, raffinose, xylitol, mannitol, polyethylene glycol, propylene glycol, polyglycerin, cholesterol, squaline, fatty acids, octyldodecanol, myristyl alcohol, urea, lanolin, lactic acid, esters such as isopropyl stearate, isopropyl myristate, isopropyl palmitate and isopropyl laurate and the like.

Suitable stabilizing agents, which may be employed, in the topical composition of the present invention include, but are not limited to, myristyl lactate, isopropyl palmitate, light liquid paraffin, cetearyl alcohol, lanolin, lanolin derivatives, mineral oil, petrolatum, cetyl esters wax, cholesterol, glycerol, glycerol monostearate, isopropyl myristate, lecithin and combinations thereof.

The term "moisturizer" refers to a substance designed to make the epidermis softer and more pliable, by increasing the extent of its hydration, allowing the addition of water to the epidermis, or the retention of water by the epidermis, or both.

Suitable moisturizers and/or occlusive moisturizers, which may be employed in the topical composition of the present invention, include, but are not limited to, white petroleum jelly, aloe extract, urea, sodium lactate, and some amino acids, such as glycine or histidine and combinations thereof.

The topical pharmaceutical composition of the present invention, may further comprise additional skin care active, which may include, but are not limited to, desquamatory actives, anti-acne actives, vitamin B3 compounds, peptides, hydroxy acids, synthetic anti-oxidants, radical scavengers, chelators, anti-inflammatory agents, topical anesthetics, tanning actives, skin lightening agents, anti-cellulite agents, flavonoids, antimicrobial actives, skin soothing agents, skin healing agents, antifungal actives, sunscreen actives, conditioning agents, structuring agents, thickening agents, and mixtures thereof.

Suitable antioxidants, which may be employed in the topical composition of the present invention, include, but are not limited to, a-tocopherol, all-rac-Alpha-Tocopherol, BHT (butylhydroxytoluene) and BHA (butylhydroxyanisole) and combinations thereof.

Skin soothing agents are compounds having the ability to reduce the irritation or stinging/burning/itching effect of some chemicals.

Suitable soothing agents, which may be employed in the topical composition of the present invention, include, but are not limited to, German Chamomile extract, aloe, avocado oil, green tea extract, hops extract, colloidal oatmeal, calamine, cucumber extract, and combinations thereof.

Suitable amphoteric, non-ionic, cationic or anionic surfactants may be included in the topical pharmaceutical composition of the present invention.

According to the present invention, surfactants may comprise, but are not limited to, one or more of coconut fatty acid diethanolamide, Polysorbates, Sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl amine oxide, Docusate sodium, Cetyl trimethyl ammonium bromide (CTAB) Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N, N–dimethyldodecylamine–N–oxide, Cetostearyl alcohol, Hexadecyltrimethylammonium bromide, Polyoxyl 10 lauryl ether, Brij, Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil, Nonylphenol ethoxylate, Cyclodextrins, Lecithin, Methylbenzethonium chloride. Carboxylates, Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates, Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated natural oils & fats, Sulphated esters, Sulphated alkanolamides, Alkylphenols, ethoxylated & sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters Polyethylene glycol esters, Anhydrosorbitol ester & it's ethoxylated derivatives, Glycol esters of fatty acids, Carboxylic amides, Monoalkanolamine condensates, Polyoxyethylene fatty acid amides, Quaternary ammonium salts, Amines with amide linkages, Polyoxyethylene alkyl & alicyclic amines, N,N,N,N tetrakis substituted ethylenediamines 2- alkyl 1- hydroxyethyl 2-imidazolines, N -coco 3-aminopropionic acid/ sodium salt, N-tallow 3 -iminodipropionate disodium salt, N-carboxymethyl n dimethyl n-9 octadecenyl ammonium hydroxide, n-cocoamidethyl n-hydroxyethylglycine sodium salt, Phosal 53 MCT, Polyoxyethylene (20) sorbitan trioleate (Tween 85), Tween 20, Tween 60, Tween 80, Span 20, Span 60, Span 80, Poloxamers, Oleoyl macrogolglycerides (Labrafil M1944CS), Linoleoyl macrogolglycerides (Labrafil M2125CS), PG monolaurate (Lauroglycol 90), D-alpha-tocopheryl PEG 1000 succinate (Vitamin E TPGS), Polyoxyl 35 castor oil (Cremophor EL, Cremophor ELP), Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40, Cremophor RH 60), Lauroyl macrogolglycerides (Gelucire 44/14, Gelucire 50/13), Lauroyl macrogol-32 glycerides, Lauroyl polyoxyl-32 glycerides, Lauroyl polyoxylglycerides, Macrogol Cetostearyl Ether ((Cetomacrogol 1000), Caprylocaproyl macrogol glycerides (Labrasol), Polyoxyethylene (20) sorbitan monooleate, (Polysorbate 80/ Tween 80), Polyoxyethylene (20) sorbitan monolaurate (Polysorbate 20/ Tween 20), polyglycerol (polyglyceryl oleate: Plural™ Oleique CC497) propylene glycol (propylene glycol monocaprylate: Capryol™ 90, propylene glycol monolaurate: Lauroglycol 90), polyoxyethylene glycols (PEG-8 stearate: Mirj 45, PEG- 40 stearate: Mirj® 52, PEG-15 hydroxystearate: Solutol® HS15), sorbitan or monoanhydrosorbitol (sorbitan monooleate: Span® 80, sucrose (sucrose monopalmitate: Surfhope® D-1616), Lutrol E 300, Transcutol HP, Transcutol P, Soyabean oil, Labrafac PG, Milyol 840, Pluronic L44, Pluronic L64, Polaxamer 188 and the like or combinations thereof.

Preferably, one or more surfactants may be present in an amount ranging from about 0.1% to about 10% by weight of the total composition.

Suitable pH adjusting agents or buffering agents that may be used in the topical pharmaceutical composition, include, but are not limited to acidulants such as hydrochloric acid, acetic acid, citric acid, tartaric acid, propionic acid, sodium hydroxide, sodium phosphate, ammonia solution, triethanolamine, sodium borate, triethylamine, 2-amino-2-methyl-1-propanol solution (AMP 95), sodium carbonate, potassium hydroxide and the like or combinations thereof.

Preferably, one or more buffering agent may be present in an amount ranging from about 0.05% to about 10% by weight of the total composition.

Suitable solvents/co-solvents, solubilizer or vehicles, that may be employed, in the topical pharmaceutical composition include, but are not limited to, water, glycerine, coconut fatty acid diethanolamide, medium and/or long chain fatty acids or glycerides, microcrystalline wax, liquid paraffin, monoglycerides, diglycerides, transcutol, transcutol P, diethyleneglycol monomethyl ether, triglycerides, structured triglycerides, soyabean oil, peanut oil, corn oil, corn oil mono glycerides, corn oil di glycerides, corn oil triglycerides, polyethylene glycol, caprylocaproyl macroglycerides, caproyl 90, propylene glycol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, castor oil, cottonseed oil, olive oil, sunflower oil, safflower oil, peppermint oil, coconut oil, palm seed oil, , beeswax, oleic acid, methanol, ethanol, isopropyl alcohol, butanol, acetone, methylisobutyl ketone, methylethyl ketone, cetostearyl alcohol or combinations thereof.
Preferably, the one or more solvent may be present in an amount ranging from about 1% to about 90% by weight of the total composition.

The topical pharmaceutical composition of the invention may further include fragrances and any such excipients which may improve the aesthetic appeal of the said composition.

In another aspect of the present invention the topical pharmaceutical composition may also be in the form of a nanoemulsion. Nanoemulsions are emulsions with mean droplet diameters ranging from 50 to 1000 nm and the droplet size between 100 and 500 nm. The particles can exist as water-in-oil and oil-in-water forms. Nanoemulsions can be obtained by any of the processes such as, but not limited, to high pressure homogenization, phase inversion temperature technique and microfluidization.

The nanoemulsions may comprise suitable excipients that may be used for formulating the nanoemulsions, such as, but not limited to oils, emulsifiers, antioxidants, tonicity modifiers, pH adjusting agents and preservatives.

In another aspect of the present invention the topical pharmaceutical composition may also be in the form of a nanosuspension. Nanosuspensions are very finely colloidal, biphasic dispersed solid drug particles in an aqueous vehicle, size below 1µm.

In another aspect of the present invention, the topical pharmaceutical composition may also be in the form of solid lipid nanoparticles.

In another aspect of the present invention, the topical pharmaceutical composition may also comprise micelles. A micelle is an aggregate of surfactant molecules dispersed in a liquid colloid. When surfactants are present above the CMC (Critical micelle concentration), they can act as emulsifiers that will allow a compound that is normally insoluble (in the solvent being used) to dissolve.

According to one embodiment of the present invention the topical pharmaceutical composition may comprise actives in a nanosize range.

Nanosizing leads to increase in the exposure of surface area of particles leading to an increase in the rate of dissolution. The nanoparticles of the present invention can be obtained by any process such as, but not limited to milling, precipitation, homogenization, spray-freeze drying, supercritical fluid technology, PRINT (Particle replication in non-wetting templates), capillary aerosol generator, ultrasonication and spray drying.

The present invention also provides a process for preparing a topical pharmaceutical composition in the form of a cream, which process comprises, preparing an aqueous phase by adding suitable excipients, preparing an oily phase by adding suitable excipients, preparing an emulsion under homogenization, adding nadifloxacin or azelaic acid and dapsone followed by remaining excipients.

The present invention also provides a process for preparing a topical pharmaceutical composition in the form of a gel, which process comprises, preparing a gel phase along with suitable excipients, adding nadifloxacin or azelaic acid and dapsone followed by remaining excipients.

The topical pharmaceutical composition of the present invention, may be dispensed through conventional dispensing modes, such as but not limited to tubes, bottles etc.

Alternatively, the topical pharmaceutical composition of the present invention, may be dispensed via airless dispensing pumps, such as dual bottle airless pumps.

The present invention also provides a method of treating acne, specifically acne vulgaris and acne rosacea, by applying a topical pharmaceutical composition comprising an anti-inflammatory agent and an antibacterial agent.
The present invention also provides a use of the topical pharmaceutical composition comprising an anti-inflammatory agent and an antibacterial agent for the treatment of acne, specifically acne vulgaris and acne rosacea.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.

Example 1
Nadifloxacin + Dapsone cream 1%/5%w/w
Sr. No. Ingredients Quantity (%w/w)
1. Nadifloxacin 1.00
2. Dapsone 5.00
4. Diethylene glycol monoethyl ether
(Transcutol P) 25.00
5. Disodium Edetate 0.10
6. Propylene Glycol 15.0
6. Methyl Paraben 0.18
7. Propyl Paraben 0.02
8. Cetostearyl Alcohol 7.20
9. Liquid Paraffin 5.00
10. Microcrystalline Wax 3.00
11. Macrogol Cetostearyl Ether (Cetomacrogol) 2.00
12. Dimethicone 0.10
13. all-rac-Alpha-Tocopherol 0.03
14. Triethanolamine q.s. to pH 5.5
15. Purified Water q.s to 100%
Process
Preparation of Aqueous Phase
1) Disodium edetate, methyl paraben and propyl paraben was added to purified water under stirring.
Preparation of Oil Phase
2) Cetostearyl alcohol, microcrystalline wax, cetomacrogol and dimethicone were added to liquid paraffin.
Preparation of Dapsone solution
3) Dapsone was added to Transcutol P to form a solution.
Preparation of Emulsion
4) The oil phase obtained in step (2) was added to the aqueous phase obtained in step (1) under stirring, homogenization and vacuum to form an emulsion.
5) Nadifloxacin was dispersed along with the dapsone solution obtained in step (3) in the emulsion that was obtained in step (4) and was homogenized to obtain a cream.
6) All-rac-alpha-tocopherol was added to the cream obtained in step (5)
7) pH was adjusted with triethanolamine solution and the weight was made up with purified water.

Example 2
Nadifloxacin + dapsone gel 1%/5%w/w
Sr. No. Ingredients Quantity (%w/w)
1. Nadifloxacin 1.0
2. Dapsone 5.0
3. Carbomer (Carbopol 980NF) 0.5
4. Diethylene glycol monoethyl ether
(Transcutol P) 25.0
5. Methyl Paraben 0.2
6. Sodium Hydroxide q.s to pH 5.50
7. Purified Water q.s to 100%

Process
Preparation of Gel Base
1) Carbopol was dispersed in purified water.

Preparation of Sodium Hydroxide Solution
2) Sodium hydroxide solution was prepared by dissolving sodium hydroxide in purified water.
3) Sodium hydroxide solution obtained in step (2) was added to the carbopol dispersion obtained in step (1) to obtain a gel.

Preparation of Dapsone Solution
4) Methyl paraben and dapsone was dissolved in Transcutol P to obtain a clear solution.

Addition of Drug to Gel Base:
5) The dapsone solution obtained in step (4) was added to the gel obtained in step (3) and was homogenized under vacuum.
6) Nadifloxacin was dispersed to the gel obtained in step (5) and was homogenized to obtain a gritty translucent gel.

Example 3
Azelaic acid + dapsone cream 5%/5%w/w
Sr. No. Ingredients Quantity (%w/w)

1. Azelaic acid 5.00
2. Dapsone 5.00
4. Diethylene glycol monoethyl ether
(Transcutol P) 25.00
5. Disodium Edetate 0.10
6. Propylene Glycol 15.0
6. Methyl Paraben 0.18
7. Propyl Paraben 0.02
8. Cetostearyl Alcohol 7.20
9. Liquid Paraffin 5.00
10. Microcrystalline Wax 3.00
11. Macrogol Cetostearyl Ether (Cetomacrogol) 2.00
12. Dimethicone 0.10
13. all-rac-Alpha-Tocopherol 0.03
14. Triethanolamine q.s. to pH 5.5
15. Purified Water q.s to 100%

Process
Preparation of Aqueous Phase
1) Azelaic acid, Disodium Edetate, methyl paraben and propyl paraben was dissolved in purified water to obtain an aqueous phase.
Preparation of Oil Phase
2) Cetostearyl alcohol, microcrystalline wax, cetomacrogol were added and melted in liquid paraffin.
3) Dimethicone was added to the melt obtained in step (2) to produce the oil phase.
Preparation of Dapsone solution
4) Dapsone was dissolved in Transcutol P to obtain a clear solution
Preparation of Emulsion
5) The oil phase obtained in step (3) was transferred to the aqueous phase obtained in step (1) under stirring and homogenization.
6) Dapsone solution obtained in step (4) was added to the emulsion obtained in step (5) under homogenization and vacuum to obtain a cream.
7) All-rac-alpha-tocopherol was added to the cream obtained in step (6)
8) pH was adjusted with triethanolamine solution and the weight was made up with purified water.

Example 4
Azelaic acid + Dapsone gel 5%/5%w/w
Sr. No. Ingredients Quantity (%w/w)

1. Azelaic acid 5.0
2. Dapsone 5.0
3. Carbomer (Carbopol) 0.5
4. Diethylene glycol monoethyl ether
(Transcutol P) 25.0
5. Ethanol 10
5. Methyl Paraben 0.2
6. Sodium Hydroxide q.s to pH 5.50
7. Purified Water q.s to 100%

Process
Preparation of Gel Base
1) Carbopol was dispersed in purified water.
Preparation of Azelaic acid Solution:
2) Azelaic acid was dissolved in ethanol to obtain a clear solution.
3) The dispersion obtained in step (1) was added to the clear solution obtained in step (2).
Preparation of Sodium Hydroxide Solution
4) Sodium hydroxide solution was prepared by dissolving sodium hydroxide in purified water.
5) Sodium hydroxide solution otained in step (5) was added to the solution obtained in step (3) to obtain a gel.
Preparation of Dapsone Solution
6) Methyl paraben was dissolved in Transcutol P
7) Dapsone was dissolved to the solution obtained in step (6).
8) The dapsone solution obtained in step (7) was added to the gel obtained in step (5) with stirring and homogenization under vacuum to obtain a gritty translucent gel.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.

It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "cosolvent" refers to a single cosolvent or to combinations of two or more cosolvents, and the like. ,CLAIMS:1) A topical pharmaceutical composition comprising an anti-inflammatory agent in combination with an antibacterial agent along with one or more pharmaceutically acceptable excipients.

2) A topical pharmaceutical composition according to claim 1, wherein the anti-inflammatory agent is dapsone or its pharmaceutically acceptable derivatives thereof.

3) A topical pharmaceutical composition according to claim 1, wherein the antibacterial agent is nadifloxacin or azelaic acid or their pharmaceutically acceptable derivatives thereof.

4) A topical pharmaceutical composition according to any preceding claim wherein dapsone is present in an amount ranging from about 0.1% to about 20% by weight of the composition and nadifloxacin or azelaic acid is present in an amount ranging from about 0.1% to about 10% by weight of the composition.

5) A topical pharmaceutical composition according to any preceding claim, wherein the composition has a pH from about 4 to about 7.

6) A topical pharmaceutical composition according to any preceding claim, wherein the dosage form is provided as gels, creams, lotions, liniments, patches, pastes, jellies, foams, films, solutions, ointments or sprays.

7) A topical pharmaceutical composition according to claim 6, wherein the dosage form is provided through airless dispensing pumps.

8) A process for preparing a topical pharmaceutical composition in the form of a cream, which process comprises preparing an aqueous phase by adding suitable excipients, preparing an oily phase by adding suitable excipients, preparing an emulsion under homogenization, adding nadifloxacin or azelaic acid and dapsone followed by the remaining excipients.
9) A process for preparing a topical pharmaceutical composition in the form of a gel, which process comprises preparing a gel phase along with suitable excipients, adding nadifloxacin or azelaic acid and dapsone followed by the remaining excipients.

10) A topical pharmaceutical composition according to any preceding claims for the treatment of acne.