WO2019186440A1

WO2019186440A1 - Topical pharmaceutical compositions of nimesulide

Info

Publication number: WO2019186440A1
Application number: PCT/IB2019/052520
Authority: WO
Inventors: Amit Kumar; Lakshmi Varahala Setti MOGALLAPALLI; Anup Avijit Choudhury; Pradip Kumar Sasmal; Rajeev Soni
Original assignee: Dr. Reddy's Laboratories Limited
Priority date: 2018-03-30
Filing date: 2019-03-28
Publication date: 2019-10-03

Abstract

This application relates to a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof. The composition comprises about 2% to about 5% w/w of nimesulide. It also provides method of alleviating joint pain and/or inflammation in a patient by applying such topical pharmaceutical compositions of nimesulide for at least about 2 times in a day.

Description

TOPICAL PHARMACEUTICAL COMPOSITIONS OF NIMESULIDE

FIELD OF THE APPLICATION

[001] This application relates to a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof. It also provides method of treating diseases associated with joint pain and/or inflammation in a patient by applying such topical pharmaceutical compositions of nimesulide.

BACKGROUND

[002] Nimesulide has a chemical name N-(4-Nitro-2 phenoxyphenyl) methanesulphonamide and is represented by the following structure.

[003] Nimesulide is a selective COX-2 inhibitor and belongs to non-steroidal anti inflammatory drug (NSAID) that has been well-known for some time, with analgesic, antipyretic and anti-inflammatory activities. It is practically insoluble in water, freely soluble in acetone, and slightly soluble in ethanol. It is used for the treatment of osteoarthritis and extraarticular rheumatic diseases, post- traumatic and post-operative inflammations and painful symptoms, high fever and in primary dysmenorrhoea.

[004] Nimesulide is mostly administrated orally. One disadvantage of the oral administration of nimesulide compositions is that the patient may experience unpleasant side effects, including gastrointestinal irritation. While such irritation may also result in chronic stomach upset, in some cases this can quickly manifest itself in spontaneous gastric bleeding, which can be life threatening. The use of oral nimesulide compositions for treating local pain and inflammation may often cause problems especially for patients having gastrointestinal system disorders. Various locally- administrable topical forms of nimesulide are developed, in order to avoid the systemic side-effects.

[005] Nimesulide has been formulated in various topical formulations like gel, cream or ointment. Usually such topical formulations are recommended to apply three times daily (TID) or four times daily (QID). Such topical formulations are largely available in market, but the drug has drawbacks of having unfavourable physicochemical characteristics. The main obstacle to develop nimesulide topical formulation is its insoluble nature in water and, on the other hand, its poor solubility in the solvents/raw materials usually employed in such formulations. Solubilized nimesulide may offer the advantage of immediate availability of free drug at the desired site of action, and the topical formulations comprising solubilized nimesulide have been prepared using different pharmaceutical solvents. However, when such products are applied topically, can cause irritation and can produce an unpleasant yellowish stain on the skin and/or clothing.

[006] For topical compositions of nimesulide, another key challenge is percutaneous penetration. Nimesulide has low penetration and requires relatively longer time period following the administration. Particularly in acute disorders, there arises the need of enhancing the absorption rate at the site of administration. Whilst it is known that surface-active agents and excipients providing percutaneous penetration are used for eliminating the aforesaid problem, but these agents have their own limitations. Particularly, the surfactants bring irritation at the primary site of administration.

[007] There are several arts describing topical formulations of nimesulide. EP 0880965 relates to a cream based micronized nimesulide composition; WO 2016/116909, RU 2593777, IN 204642, IN 183577, US 5716609, RU 2181285 relate to topical gel compositions of nimesulide.

[008] For the topical compositions meant for local effect, the consistency is an important feature that helps the application of composition topically over the skin. It must aid in the administration process by offering a uniform desired consistency in a stable level throughout its shelf life, which also helps in enhancing penetration of the drug.

[009] There is an unmet need exists in the area of topical delivery of nimesulide addressing the requirements of topical administration of nimesulide as discussed herein above.

[0010] It is therefore an object of the present application to provide a topical pharmaceutical composition of nimesulide with effective local delivery for treatment of joint pain and/or inflammation, and preventing possible staining or colour problems, reducing the dosing frequency, with desired stability and uniform viscoelastic consistency while administration.

BRIEF DESCRIPTION OF THE DRAWING

[0011] Figure 1 shows storage modulus (G’) and loss modulus (G”) profiles for example 6, example 11 and example 14 when measured using amplitude sweep at shear strain range of 0.01 to 100 %.

[0012] Figure 2 shows storage modulus (G’) and loss modulus (G”) profiles for example 6, example 11 and example 14 when measured using frequency sweep at range of 100 to 0.1 radiant /second.

[0013] Figure 3 shows loss factor (tan 5) profiles for example 6, example 11 and example 14 calculated as a ratio of the loss modulus (G'’) to storage modulus (G'), when said modulus measured using frequency sweep at range of 100 to 0.1 radiant /second.

DESCRIPTION OF THE EMBODIMENTS

[0014] The details of one or more embodiments of the present invention are set forth in this document. Modifications to embodiments described in this document, and other embodiments, will be evident to those of ordinary skill in the art after a study of the information provided in this document. The information provided in this document, and particularly the specific details of the described exemplary embodiments, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood therefrom.

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0016] Definitions: The terms as used herein have the following meanings:

[0017] As used herein, "comprising" is "open ended" and means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. All the ranges recited herein include the endpoints, including those that recite a range "between" two values.

[0018] The terms "a" and "the" as used herein are understood to encompass the plural as well as the singular or otherwise clearly mentioned wherever needed. For example, reference to“an excipient” includes reference to one or more of such excipients, and reference to“the carrier” includes reference to one or more of such carriers.

[0019] The terms such as‘about’,‘up to’,‘generally’,‘substantially’ and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skilled in the art. This includes, at very least, the degree of expected experimental error, technical error and instrumental error for a given experiment, technique or an instrument used to measure a value. The term“about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be“a little above” or“a little below” the endpoint. As used herein, the term "about" means a slight variation of the value specified, preferably within 10 % of the value specified. Nevertheless, the term "about" can mean a higher tolerance of variation depending on for instance the experimental technique used. Said variations of a specified value are understood by the skilled person and are within the context of the present invention.

[0020] The term "subject" as used herein, refers to a human or non-human mammals. The term does not denote a particular age or sex. A patient refers to a human or non-human mammals afflicted with a disease or disorder. In some aspects of the present application, the subject has been diagnosed with a need for the treatment or prevention or alleviating joint pain and/or inflammation and related diseases.

[0021] As used herein, the terms“treatment” or“treating” relate to curing or substantially curing a condition, as well as ameliorating at least one symptom of the condition, and are inclusive of prophylactic treatment and therapeutic treatment. As would be recognized by one or ordinary skill in the art, treatment that is administered prior to clinical manifestation of a condition then the treatment is prophylactic (i.e., it protects the subject against developing the condition). If the treatment is administered after manifestation of the condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, control, or maintain the existing condition and/or side effects associated with the condition). The terms relate to medical management of a subject with the intent to substantially cure, ameliorate, stabilize, or substantially prevent a condition, including but not limited to prophylactic treatment to preclude, avert, obviate, forestall, stop, or hinder something from happening, or reduce the severity of something happening, especially by advance action. As such, the terms treatment or treating include, but are not limited to: inhibiting the progression of a condition of interest; arresting or preventing the development of a condition of interest; reducing the severity of a condition of interest; ameliorating or relieving symptoms associated with a condition of interest; causing a regression of the condition of interest or one or more of the symptoms associated with the condition of interest; and preventing a condition of interest or the development of a condition of interest. As used herein the term "treating" includes treatment and/or prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed conditions associated with joint pain and/or inflammation, once it has been established or alleviation of the characteristic symptoms of such condition.

[0022] The term“joint pain and/or inflammation” refers to discomfort, pain or inflammation arising from any part of a joint including cartilage, bone, ligaments, tendons or muscles. It also refers to arthritis or arthralgia, which is inflammation or pain from within the joint itself including, knees, hips, elbows, shoulders, ankles or neck joints. Joint pain and/or inflammation can be mild, causing soreness only after certain activities, or it can be severe, making even limited movement, particularly bearing weight, extremely painful.

[0023] The term“composition” refers to compositions in topical dosage forms, which are generally understood to mean, to be applied to body surfaces such as skin. Such topical dosage forms include, but are not limited to, gel, ointment, cream, emulgel, lotion, liniment, salve, balm and the like or combinations thereof those are applied to the skin as a treatment for alleviating joint pain and/or inflammation in a patient in need thereof.

[0024] The term“emulgel” as used herein, refers to combined dosage form of gels and emulsion in form of gellified emulsion, wherein the emulsion is either “oil in water” or“water in oil” type, which is gelled by mixing with suitable gelling agent. Such emulgel may substantially improve penetration of drug and provides more tolerable dosage form that alleviates considerable skin dryness and irritation caused by the drug upon multiple applications.

[0025] The term“commercially available topical composition of nimesulide” as used herein, refers to topically applied compositions containing 1% of nimesulide or its pharmaceutical equivalents or its therapeutic equivalents. For example, in some embodiments, such commercially available topical composition includes NISE Gel® marketed by Dr. Reddy’s Laboratories Limited, India, which is a topical composition containing 1% nimesulide along with excipients such as N-methyl pyrrolidone, propylene glycol, polyethylene glycol, isopropyl alcohol, carbomer, butylated hydro xyanisole, thiomersal and monobasic potassium phosphate. The 1% composition is recommended to apply three times daily (TID) or four times daily (QID) on the affected area.

[0026] The terms“storage modulus (G’)” and "loss modulus (G")” as used herein refer to elasticity that characterizes viscosity measured from oscillatory rheology tests, which defines the relationship between shear stress (force per unit area) and shear strain (proportional deformation) in a composition. Generally“storage modulus (G’)” refers to elasticity and "loss modulus (G")” refers to viscosity of the composition.

[0027] The term“tan d” as used herein refers to a ratio of the loss modulus (G”) to storage modulus (G'). A purely elastic material would have a tan d=0, while a purely viscous material would have tan d=¥. The present pharmaceutical composition being a viscoelastic in nature has tan d values of about 1.

[0028] The term "stable" as used herein refers to a physical and chemical stability of the present topical pharmaceutical composition of nimesulide, which remains as clear/transparent; and the drug is present in an amount of not less than about 85% of the originally specified amount, total impurity of not more than about 2.0%, and viscosity drop of no more than 2.0 % relative to initial viscosity, when stored for a period of at least about 90 days at 25 °C/60% relative humidity (RH) and/or at 40 °C/75% relative humidity (RH).

[0029] In an embodiment, the present application relates to a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof comprising a therapeutically effective amount of nimesulide, wherein said composition has a viscosity drop of no more than about 2.0 % relative to initial viscosity, when stored for a period of at least about 90 days at 40 °C / 75% Relative Humidity (RH).

[0030] In an embodiment, the present application relates to a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof comprising a therapeutically effective amount of nimesulide, wherein said composition exhibits storage modulus (G’) of about 811 Pascal to about 532 Pascal when measured using frequency range of 100 to 0.1 radiant/second at 25 °C.

[0031] In another embodiment, the present application relates to a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof comprising a therapeutically effective amount of nimesulide, wherein said composition exhibits loss modulus (G”) of about 243 Pascal to about 42 Pascal when measured using frequency range of 100 to 0.1 radiant/second at 25 °C.

[0032] In an aspect of the above embodiments, the present topical composition of nimesulide exhibits tan d, i.e. ratio of storage modulus to loss modulus of about 0.26 to about 0.09 when said modulus measured using frequency range of 100 to 0.1 radiant/second at 25 °C.

[0033] In an embodiment, the present application relates to a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof comprising a therapeutically effective amount of nimesulide, wherein said composition exhibits storage modulus (G’) of about 444 Pascal to about 53 Pascal when measured using amplitude sweep at shear strain range of 0.01 to 100 % at 25 °C.

[0034] In another embodiment, the present application relates to a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof comprising a therapeutically effective amount of nimesulide, wherein said composition exhibits loss modulus (G”) of about 63 Pascal to about 103 Pascal when measured using amplitude sweep at shear strain range of 0.01 to 100 % at 25 °C.

[0035] In an aspect of the above embodiments, the present topical composition of nimesulide exhibits tan d, i.e. ratio of storage modulus to loss modulus of about 0.12 to about 2.2 when said modulus measured using amplitude sweep at shear strain range of 0.01 to 100 % at 25 °C.

[0036] In another aspect of the above embodiments, the present topical composition of nimesulide has a viscosity of not less than about 5500 poise for at least about 90 days at 40 °C / 75% Relative Humidity (RH). [0037] In another aspect of the above embodiments, the present topical composition of nimesulide has a viscosity of from about 5500 to about 8000 poise for at least about 90 days at 40 °C / 75% Relative Humidity (RH).

[0038] In yet another aspect of the above embodiments, the present topical composition of nimesulide has a cumulative viscosity drop of no more than about 5.0% relative to initial viscosity for at least about 4 hours at 25 °C when measured at shear rate of about 500 rpm.

[0039] In yet another aspect of the above embodiments, the present topical composition of nimesulide has a cumulative viscosity drop of from about 3% to about 5.0 % relative to initial viscosity for at least about 4 hours at 25 °C when measured at shear rate of about 500 rpm.

[0040] In an aspect of the above embodiments, the present topical composition of nimesulide comprises therapeutically effective amount of about 2% to about 5% w/w of nimesulide.

[0041] In another aspect of the above embodiments, the present topical composition of nimesulide comprises therapeutically effective amount of about 2% w/w of nimesulide.

[0042] In an embodiment, the present application relates to a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof comprising about 2% to about 5% w/w of nimesulide, wherein said composition has a viscosity drop of no more than about 2.0 % relative to initial viscosity, for at least about 90 days at 40 °C / 75% Relative Humidity (RH).

[0043] In an aspect of the above embodiments, the nimesulide or pharmaceutically acceptable salts thereof used in the present application include, but not limited to, pharmaceutically acceptable, pharmacologically active derivatives of nimesulide, including both individual enantiomers of nimesulide (dextrogyral and levogyral enantiomers) in their substantially pure form and their pharmaceutically acceptable salts, mixtures (in any ratio) of nimesulide enantiomers and their pharmaceutically acceptable salts, and active metabolites of nimesulide and their pharmaceutically acceptable salts. The solid state form of nimesulide used in the composition is not critical. For example, nimesulide can be amorphous or crystalline. Examples of pharmaceutically acceptable salts include, but not limited to, any of the salts or co-crystals of nimesulide selected from hydrochloride, hydrobromide, benzoate, sulphate, citrate, phosphate, maleate, formate, acetate, nitrate, mesylate, succinate and the like. The salts may be in the form of solvate, hydrate, hemihydrates or anhydrous forms. The amount of nimesulide used in the present composition comprises more than about 1.0 % w/w of nimesulide. For example, the amount of nimesulide used in the present composition comprises about 2.0 % to about 5.0 % w/w of nimesulide.

[0044] In an embodiment, the present application relates to a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof comprising a therapeutically effective amount of nimesulide, wherein said composition comprises at least one pH independent polymer, at least one solvent and one or more pharmaceutically acceptable excipients.

[0045] In another embodiment, the present application relates to a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof comprising about 2.0 % to about 5.0 % w/w of nimesulide, wherein said composition comprises at least one pH independent polymer, at least one solvent and one or more pharmaceutically acceptable excipients.

[0046] In an aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises at least one solvent selected from, but not limited to, aprotic polar solvent.

[0047] In an embodiment, the present application relates to a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof comprising a therapeutically effective amount of nimesulide, wherein said composition comprises at least one pH independent polymer, at least one aprotic polar solvent and one or more pharmaceutically acceptable excipients. [0048] In another embodiment, the present application relates to a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof comprising a therapeutically effective amount of nimesulide, wherein said composition comprises at least one pH independent polymer, at least two aprotic polar solvents and one or more pharmaceutically acceptable excipients.

[0049] In an aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises at least one pH independent polymer and at least one aprotic polar solvent present in a weight ratio of at least about 0.01: 1.0.

[0050] In another aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises at least one pH independent polymer and at least one aprotic polar solvent present in a weight ratio of about 0.01:1.0 to about 0.1: 1.0.

[0051] In another aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises at least one pH independent polymer and at least two aprotic polar solvents present in a weight ratio of about 0.01:1.0 to about 0.1: 1.0.

[0052] In yet another aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises at least one pH independent polymer and at least two aprotic polar solvents present in a weight ratio of about 0.01:1.0, 0.02: 1.0, 0.03: 1.0, 0.04: 1.0, 0.05: 1.0, 0.06: 1.0, 0.07: 1.0, 0.08: 1.0, 0.09: 1.0 or 0.1: 1.0.

[0053] In an aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises nimesulide and at least one pH independent polymer present in a weight ratio of not more than about 1.5: 1.0.

[0054] In another aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises nimesulide and at least one pH independent polymer present in a weight ratio of about 0.5: 1.0 to about 1.5: 1.0. [0055] In yet another aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises nimesulide and at least one pH independent polymer present in a weight ratio of about 0.5: 1.0, 0.6: 1.0, 0.7: 1.0, 0.8: 1.0, 0.9: 1.0, 1.0: 1.0, 1.1: 1.0, 1.2: 1.0, 1.3: 1.0, 1.4: 1.0 or 1.5: 1.0.

[0056] The pH independent polymers are used in the present application to provide desired thixotropic properties and viscoelastic nature to the present composition. Examples of such pH independent polymers include, but are not limited to, a single polymer or a combination of polymers, selected from, but not limited to polyacrylamide/polyacrylates, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, gelatin, hydrophilic fumed silica (AEROSIL® 200) or combinations thereof. Non-limiting examples of the polyacrylamide/polyacrylates include, but are not limited to, hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer sold under the name SEPINEO DERM; mixture of sodium acryloyldimethyltaurate copolymer/isohexadecane/polysorbate 80 sold under the name SEPINEO P600; mixture of polyacrylamide/isoparaffin Cl3-l4/laureth-7 such as, for example, the product sold under the name SEPIGEL 305; the family of acrylic polymers coupled to hydrophobic chains, such as the PEG- l50/decyl/SMDI copolymer sold under the name ACETLYN 44 (polycondensate comprising at least, as components, a polyethylene glycol containing 150 or 180 mol of ethylene oxide, decyl alcohol and methylenebis (4-cyclohexyl isocyanate) (SMDI), at 35% by weight in a mixture of propylene glycol (39%) and water (26%)); the family of modified starches, such as the modified potato starch sold under the name STRUCTURE SOLANACE, or combinations thereof.

[0057] In an aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises pH independent polymers selected from group of hydrophilic fumed silica sold under the name AEROSIL® 200, solid polyacrylamide/polyacrylates like hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer sold under the name SEPINEO DERM®, mixture of sodium acryloyldimethyltaurate copolymer/isohexadecane/polysorbate 80 sold under the name SEPINEO P600® or combinations thereof.

[0058] In another aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises at least two pH independent polymers selected from group of hydrophilic fumed silica sold under the name AEROSIL® 200 and solid polyacrylamide like hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer sold under the name SEPINEO DERM®.

[0059] In another aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises at least two pH independent polymers selected from group of hydrophilic fumed silica sold under the name AEROSIL® 200 and mixture of sodium acryloyldimethyltaurate copolymer/isohexadecane/polysorbate 80 sold under the name SEPINEO P600.

[0060] The amount of pH independent polymers that may be used in the present application comprises from about 1.5% to about 5.0% w/w of the composition.

[0061] The amount of pH independent polymers that may be used in the present application comprises about 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5% or 5.0% w/w of the composition.

[0062] Suitable solvents that may be used in the present application are selected from aprotic polar solvents, which are polar solvents that do not contain acidic hydrogen and do not act as a hydrogen bond donor. Such solvents provide solubilisation of nimesulide that result in optimal stability, maximum solubility and minimal degradation of drug in the composition. Examples of such aprotic polar solvents include, but are not limited to, dimethylsulfoxide, dimethylisosorbide, dimethylformamide, ethyl acetate, n-methylpyrrolidone, dimethyl acetamide, propylene carbonate, or combinations thereof. [0063] In an aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises aprotic polar solvents selected from dimethyl sulfoxide, dimethyl isosorbide or combinations thereof.

[0064] In another aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises combination of two aprotic polar solvents selected from dimethyl sulfoxide and dimethyl isosorbide.

[0065] In another aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises combination of two aprotic polar solvents selected from dimethyl sulfoxide and dimethyl isosorbide present in a weight ratio of at least about 1.0: 1.0.

[0066] In yet another aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application comprises combination of two aprotic polar solvents selected from dimethyl sulfoxide and dimethyl isosorbide present in a weight ratio of from about 1.0: 1.0 to about 3.0: 1.0.

[0067] The amount of aprotic polar solvents that may be used in the present application ranges from about 25% to about 55% w/w of the composition.

[0068] In another aspect, the present application relates to a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof comprising a therapeutically effective amount of nimesulide; wherein said composition is in a form of emulgel.

[0069] In an embodiment, the present application relates to a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof in a form of emulgel, wherein said composition comprises a therapeutically effective amount of nimesulide; at least two emulsifiers, at least one gelling agent/polymer; and one or more pharmaceutically acceptable excipients.

[0070] In another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises at least two emulsifiers and nimesulide are present in a weight ratio of from about 3.7: 1.0 to about 5.7: 1.0. [0071] Examples of such emulsifiers include, but are not limited to, polyoxylethylene stearates, mixture of PEG-6 stearate and ethylene glycol palmito stearate and PEG-32 stearate sold under the name Tefose® 63, mono and diglycerides and polyoxyl stearate sold under the name GelotTM 64, propylene glycol dicaprolate/dicaprate sold under the name LabrafacTM PG, polyoxyl 20 cetostearyl ether, polyoxyethylene sorbitan monolaurate sold under the name Tween 20, polyoxyethylene sorbitan monopalmitate sold under the name Tween 40, polyoxyethylene sorbitan monostearate sold under the name Tween 60, polyoxyethylene sorbitan monooleate sold under the name Tween 80, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oils, polyoxyl 40 hydrogenated castor oil sold under the name Cremophor® RH 40, fatty acid esters such as glyceryl monostearate, glyceryl distearate, glycerol monooleate, acetylated monoglycerides; and combinations comprising one or more of the foregoing materials known to one of ordinary skill in the art. The amount of at least two emulsifiers that may be used in the present application ranges from about 5.0% to about 15.0% w/w of the composition.

[0072] Examples of such gelling agents/polymers include, but are not limited to, carbomer and carbomer derivatives, polyvinyl pyrrolidone, locust gum, polyvinyl alcohol, cross-linked polyacrylate polymer, guar gum, locust bean gum, poloxamers, polysaccharides, and cellulose polymers such as carboxymethyl cellulose, hydrxypropyl methyl cellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose; and combinations comprising one or more of the foregoing materials known to one of ordinary skill in the art. The amount of gelling agents that may be used in the present application ranges from about 0.5% to about 3.0% w/w of the composition.

[0073] In an aspect of the above embodiments, the emulgel composition of the present application further comprises one or more solvents, preferably aprotic solvents to provide solubilization of nimesulide that results in optimal stability, maximum solubility and minimal degradation of drug in the composition. Examples of such solvents include, but are not limited to, dimethylsulfoxide, dimethylisosorbide, dimethylformamide, ethyl acetate, n-methylpyrrolidone, dimethyl acetamide, diethyl sebacate, diisopropyl adipate, propylene carbonate, or combinations thereof.

[0074] In an aspect of the above embodiments, the emulgel composition of the present application further comprises water in an amount of from about 25.0% to about 45.0% w/w of the composition. The use of water imparts a non-warming characteristic to the emulgel composition by releasing the heat during hydration.

[0075] In an aspect of the above embodiments, the emulgel composition of the present application is applied over a joint for at least about 2 times in a day and does not cause significant skin irritation.

[0076] In an aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application further comprises one or more penetration enhancers that assist in improved rate of percutaneous transport of drug across the skin. Examples of such penetration enhancers that may be used in the present application include, but are not limited to, polyols, glycols, ethers, glycol ethers, esters, sulfoxides, fatty acids, fatty acid esters, fatty alcohols, essential oils, terpenes, terpenoids, PEGylated fatty acids, PEGylated fatty acid esters, PEGylated fatty alcohols and combinations thereof, including polyethylene glycol, polyethylene glycol monolaurate, and butanediol; sulfoxides, including dimethylsulfoxide and decylmethylsulfoxide; ethers, including diethylene glycol monoethyl ether and diethylene glycol monomethyl ether; fatty acids, including lauric acid, oleic acid, and valeric acid; fatty acid esters, including isopropyl myristate, isopropyl palmitate, methyl propionate, and ethyl oleate; nitrogenous compounds including urea, dimethyl acetamide, dimethyl isosorbide, dimethylformamide 2-pyrrolidone, ethanolamine, methyl-2-pyrrolidone, diethanolamine, and triethanolamine; terpenes; terpenoids; alkanones; organic acids, including salicylic acid, citric acid, and succinic acid; ethanol, isopropyl alcohol, acetone, cyclomethicone, dimethicone or combinations thereof. The amount of such penetration enhancers that may be used in the present application ranges from about 1 % to about 30% w/w of the composition.

[0077] In another aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application further comprises one or more pharmaceutically acceptable excipients selected from pH modifying agent; a vehicle; and optionally one or more pharmaceutically acceptable excipients used in the cosmetics or pharmaceutical field such as sequestering agents, antioxidants, sunscreens, preservative agents, fillers, electrolytes, humectants, colorants, common mineral or organic acids or bases, fragrances, essential oils, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds such as dihydroxyacetone, and calmants and protective agents for the skin such as allantoin; or combinations thereof.

[0078] The "pH modifying agent", as used herein, refers to a substance that provides acidic pH to the formulation. Nimesulide is a weakly acidic molecule which tends to remain in unionized form at acidic pH. Thus maintaining the microenvironment of nimesulide at any pH below its pKa imparts the non-staining effect. The composition of the present application has a pH of less than about 6.5; or in a range of from about 2 to about 5. The composition of the present application may have a pH of about 3. The pH modifying agent employed in the present application is selected from, but not limited to, citric acid, hydrochloric acid, oleic acid, malic acid, tartaric acid, fumaric acid, phosphoric acid or combinations thereof. Skin and clothes generally have some buffer capacity due to the presence of basic molecules. Thus excess of acidifying agent is required in the composition in order to adjust the pH shift. The amount of acidifying agent that may be used in the present application ranges from about 1% to about 5% w/w of the composition.

[0079] The "vehicle", as used herein, refers to a substance, which imparts clarity, non- greasy, non- sticky and smooth appearance to the present composition. The vehicle employed in the present application is selected from, but not limited to, glycerol, propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol, polyethylene glycol, oleic acid, isostearic acid, glyceryl monooleate, ethoxydiglycol or combinations thereof.

[0080] In an aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application further comprises water in an amount of less than 50% w/w of the composition. Use of water imparts a non- warming characteristic to the gel composition by releasing the heat during hydration.

[0081] In an aspect of the above embodiments, the topical pharmaceutical composition of the present application further comprises one or more viscosifiers that assist in improved rate of percutaneous transport of drug across the skin.

[0082] Examples of such viscosifiers that may be used in the present application include, but are not limited to, cetyl alcohol, cetearyl alcohol, cetostearyl alcohol, stearyl alcohol; waxes including beeswax, cocoa butter, shea butter, wool wax; gums including gum acacia, gum tragacanth, locust bean gum, guar gum, xanthan gum, cellulose gum, sclerotium gum, carrageenan gum, karaya gum, resin or combinations thereof. The amount of such viscosifiers that may be present in the present application ranges from about 1.0% to about 10.0% w/w of the composition.

[0083] Suitable examples of fragrances that may be used in the present application include, but not limited to, plant extracts and essential oils like eucalyptus, lemon, orange, cinnamon, mint, tangerine, grapefruit, spearmint, peppermint, clove, or rosemary oil, or synthetic fragrances such as vanilline and calm valley. The amount of fragrance that may be used in the present application ranges from about 0.07% to about 0.3% w/w of the composition.

[0084] Suitable examples of sequestering agents that may be used in the present application include, but not limited to, ethylene diaminetetraacetic acid, and also derivatives or salts thereof, dihydroxy ethylglycine, or combinations thereof. [0085] Suitable examples of preserving agents that may be used in the present application include, but not limited to, benzalkonium chloride, phenoxy- ethanol, benzyl alcohol, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), sodium benzoate, diazolidinylurea and parabens, or combinations thereof.

[0086] Suitable examples of humectants that may be used in the present application include, but not limited to, glycerol and sorbitol.

[0087] Other suitable pharmaceutically acceptable excipients that may be used to formulate the present composition are any excipients known to a person skilled in the art and are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986), incorporated herein by reference.

[0088] It is well known in the art that the use of surfactants in the topical formulations is common. However, it may cause skin irritation. The use of surfactants selected from nonionic surfactants or surfactants with HLB (Hydrophilic-Lipophilic Balance) value from 7 to 9 are generally used, however as mentioned it may cause unwanted effects to the skin.

[0089] In some aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application is substantially devoid of surfactants, wherein said surfactants are fatty acids, alkyl sulfonates, benzalkonium chloride, dioctyl sodium sulfo succinate (docusate sodium) and sodium lauryl sulfate (sodium dodecyl sulfate), sorbitan fatty acid esters, Vitamin E TPGS, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oils, hydrogenated castor oils, sodium taurocholic acid, l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, other phospholipids and mono- and diglycerides, polyoxyethylene fatty acid glycerides, stearyl alcohol, cetostearyl alcohol, cholesterol, polyoxyethylene ricin oil, polyethylene glycol glycerides, poloxamers; and combinations thereof. [0090] In an aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application upon topical application does not cause significant skin irritation.

[0091] In another aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application upon topical application for at least about 2 times in a day does not cause significant skin irritation.

[0092] In yet another aspect of the above embodiments, the topical pharmaceutical composition of nimesulide of the present application upon topical application for at least about 2 to about 4 times in a day does not cause significant skin irritation.

[0093] In an embodiment, the present application relates to a method of alleviating joint pain and/or inflammation in a subject in need thereof, comprising applying a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof, wherein said composition comprises about 2% to about 5% w/w of nimesulide.

[0094] In an embodiment, the present application relates to a method of alleviating joint pain and/or inflammation in a subject in need thereof, comprising applying a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof over a joint, wherein said composition comprises about 2% to about 5% w/w of nimesulide; and said composition when applied over said joint exhibits synovial fluid concentration of at least about 3 fold higher compared to commercially available topical composition comprising 1% of nimesulide gel after about 4 hours of application.

[0095] In an aspect of the above embodiments, the present application relates to a method comprising applying a topical pharmaceutical composition of nimesulide, wherein said composition exhibits from about 3 to about 4 fold higher synovial fluid concentration compared to commercially available topical composition comprising 1% of nimesulide gel. [0096] In an embodiment, the present application relates to a method of alleviating joint pain and/or inflammation in a subject in need thereof, comprising applying a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof over a joint, wherein said composition comprises about 2% to about 5% w/w of nimesulide; and said composition when applied over said joint exhibits plasma concentration of at least about 2 fold higher compared to commercially available topical composition comprising 1% of nimesulide gel after about 4 hours of application.

[0097] In an aspect of the above embodiments, the present application relates to a method comprising applying a topical pharmaceutical composition of nimesulide, wherein said composition exhibits from about 2 to about 3 fold higher plasma concentration compared to commercially available topical composition comprising 1% of nimesulide gel.

[0098] In an aspect of the above embodiments, the present application relates to a method comprising applying a topical pharmaceutical composition of nimesulide, wherein said composition comprises not less than about 2% w/w of nimesulide.

[0099] In an embodiment, the present application relates to a method of alleviating joint pain and/or inflammation in a patient in need thereof, comprising topically applying a pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof, wherein said composition is applied over said joint for at least about 2 times in a day.

[00100] In an aspect of the above embodiments, the present method of alleviating joint pain and/or inflammation in a patient in need thereof, comprising topically applying a pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof, wherein said composition is applied over said joint for about 2 to about 4 times in a day.

[00101] In an embodiment, the present application relates to a method of alleviating joint pain and/or inflammation in a subject in need thereof, comprising applying a topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof over a joint, wherein said composition comprises about 2% to 5% w/w of nimesulide; and said composition when applied for about 2 times in a day exhibits plasma concentration of at least about 3 fold higher compared to commercially available topical composition comprising 1% of nimesulide gel applied for about 3 or 4 times in a day.

[00102] In an embodiment, the present application relates to a method of alleviating joint pain and/or inflammation in a patient in need thereof, comprising topically applying a pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof, wherein said composition upon topical application does not cause significant skin irritation.

[00103] In an aspect of the above embodiments, the present application relates to a method of alleviating joint pain and/or inflammation in a patient in need thereof, comprising topically applying a pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof, wherein said composition upon topical application for at least about 2 times in a day does not cause significant skin irritation.

[00104] In another aspect of the above embodiments, the present application relates to a method of alleviating joint pain and/or inflammation in a patient in need thereof, comprising topically applying a pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof, wherein said composition upon topical application for about 2 to about 4 times in a day does not cause significant skin irritation.

[00105] In an aspect of the above embodiments, the topical pharmaceutical composition of present application is prepared by any conventional known processes.

[00106] In an embodiment, the present application relates to processes to prepare the topical pharmaceutical composition of nimesulide, wherein said process comprises steps of, (a) preparing a mixture of solvents and excipients; (b) solubilizing suitable pH modifier to (a); (c) addition of nimesulide and suitable pH independent polymer to (b); and (d) addition of suitable vehicle to form desired dosage form.

[00107] In another embodiment, the present application relates to processes to prepare the topical pharmaceutical composition in a form of emulgel of nimesulide, wherein said process comprises steps of, (a) preparing oil phase by mixing oil soluble solvents and excipients; (b) preparing aqueous phase by mixing water, suitable vehicle and gelling agents; (c) addition of prepared oil phase of (a) to aqueous phase of (b) at suitable temperature followed by stirring to form desired dosage form.

[00108] In an aspect of the above embodiments, the present topical pharmaceutical composition of nimesulide is stable for at least about 90 days when stored at 40 °C / 75% Relative Humidity (RH).

[00109] In an aspect of the above embodiments, the present topical pharmaceutical composition of nimesulide is formulated into suitable topical dosage forms that include, but not limited to, gel, ointment, cream, emulgel, lotion, liniment, salve, balm and the like or combinations thereof.

[00110] The term“gel” as used herein refers to the present topical pharmaceutical composition of nimesulide comprising about 2% to about 5% w/w of nimesulide, which is non-staining in nature.

[00111] The topical pharmaceutical composition of present application provides no stain or substantially causes no stain to skin or cloth after application as compared to commercially available 1% nimesulide gel compositions.

[00112] In some embodiments, the term “gel” refers to homogenous, clear/transparent, relatively viscoelastic and thixotropic dosage form at about 25° C and provides a viscosity drop of no more than about 2.0 % relative to initial viscosity, when stored for a period of at least about 90 days at 40 °C / 75% Relative Humidity (RH).

[00113] In an aspect of the above embodiments, the present topical pharmaceutical composition of nimesulide is a gel.

[00114] In an embodiment, the present topical pharmaceutical composition of nimesulide may be used for treatment of alleviating joint pain and/or inflammation associated with muscle-skeletal system, osteoarthritis or rheumatoid arthritis and related symptoms thereof.

[00115] In an embodiment, the present topical pharmaceutical composition of nimesulide can also be co- administered (simultaneously or sequentially) with one or more pharmaceutical agents of value in the form of commercially available dosage forms or which can be developed in a suitable pharmaceutically acceptable dosage forms for treating or alleviating joint pain and/or inflammation and associated conditions.

[00116] Suitable examples of the pharmaceutical agents that can be co-administered are selected from, but not limited to, systemic and topical; steriodal and non- steriodal anti-inflammatory agents generally well-known in the art; or any other commercially available anti-inflammatory dosage forms and/or devices and the like or mixtures thereof.

[00117] The topical compositions of the present application can be part of a kit or device and may be filled into laminated tubes, jars, bottles, pumps, aerosol containers, and any other forms of packaging that facilitate application topically. The compositions are meant to be applied topically, either manually or by using a convenient applicator, for patient compliance and ease of application. The dose, number, and frequency of applications can be determined by a person skilled in the art of treating conditions, such as a physician, a dermatologist, and the like.

[00118] Laminated tubes may be used for packaging. The features and advantages of laminated tubes include ability to retain smoothness, flexibility and softness, increase in product shelf life, excellent barrier properties, excellent seal ability, resistance to print bleeding, tamper evident closures with nozzle seals available, and hot foil stamping. HDPE tubes may also be used for packaging. Examples are pre-printed monolayer plastic tubes made of LDPE/LLDPE blends by extrusion processes and fitted with snap-on flip caps made up of polypropylene.

[00119] The present application is further illustrated by the examples which are provided merely to be exemplary of the pharmaceutical composition described above and do not limit the scope of the application. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

[00120] The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the present invention, and not to be construed as limiting the application. The following examples may include compilations of data that are representative of data gathered at various times during the course of development and experimentation related to the present invention.

EXAMPLES

[00121] Example 1-15:

[00122] The present topical pharmaceutical compositions of nimesulide were prepared as given in following table 1 and table 2.

Table 1

Table 2

[00123] Procedure:

1. Homogenous mixture was prepared by mixing dimethyl isosorbide, dimethyl sulfoxide and diethylene glycol monoethyl ether.

2. Citric acid was solubilised to the mixture of step 1 followed by addition of nimesulide.

3. Calm valley, hydrophilic fumed silica and hydro xyethyl acrylate/ sodium acryloyldimethyl taurate copolymer or acrylamide/sodium acryloyldimethyl taurate copolymer /isohexadecane & polysorbate 80 were mixed and added to the mixture of step 2.

4. Propylene glycol and water were added with stirring to the mixture of step 3 to form uniform transparent dosage form. [00124] Example 16:

[00125] The pharmaceutical compositions as prepared in Examples 5-7, 12 and 13 were subjected to storage at 40 °C/75% Relative Humidity (RH) for 90 days. The compositions were studied for viscosity drop relative to initial viscosity using Brookfield RVDV viscometer at 1 rpm with spindle no. 29 for 5 minutes at 25 °C. The results are given in following table 3.

Table 3

[00126] Example 17:

[00127] The effects of shear on viscosity drop for pharmaceutical compositions as prepared in examples 7 and 13 were studied by using Brookfield RVDV viscometer at 1 rpm with spindle no. 29 for 5 minutes at shear rate of 450- 500 rpm at 25 °C. The results are given in following table 4.

Table 4

[00128] Example 18:

[00129] The pharmacokinetic parameters for pharmaceutical compositions as prepared in examples 10-11 comprising 2% of nimesulide and example 14 comprising 1% of nimesulide were studied in comparison with NISE Gel® (1% nimesulide), marketed by Dr. Reddy’s Laboratories Limited, India. The study was conducted using rats and the composition was applied to right knee (l.5cm X 2cm) at 8 hours apart. The samples were collected from synovial fluid and plasma at 1, 4, 8, 9, 16 and 24 hours using 4 rats at each time point; the results are given in following table 5, table 6, table 7 and table 8.

Table 5 (Synovial fluid)

Table 6 (Synovial fluid levels)

Table 7 (Plasma levels)

Table 8 (Plasma)

[00130] Example 19:

[00131] The pharmaceutical compositions as prepared in examples 6 and 11 were subjected to stability studies for at least 3 months. The results are given in following table 9 and table 10 respectively.

Table 9

Example-6

Table 10

Example- 11

[00132] Example 20:

[00133] The pharmaceutical compositions as prepared in examples 6, example 11 and example 14 were subjected to studies of storage modulus (G’), loss modulus (G”) and loss factor (tan d) using Anton Paar Rheometer (MCR 102) with parallel plate no. 25 at 25 °C. The study and results are given in following table 11 and shown in figures 1-3.

Table 11

[00134] Example 21:

[00135] The pharmacokinetic parameter of the pharmaceutical composition as prepared in Example 6 comprising 2% nimesulide was studied in an open label, randomized, 3-treatment, 3-period, crossover, steady state, comparative bioavailability study in healthy, adult, male subjects under fasting conditions in comparison with NISE Gel® (1% nimesulide, reference product), marketed by Dr. Reddy’s Laboratories Limited, India. The composition was applied to topical knee (right or left)- lOxlOcm area and 3 cm length. The nimesulide gel 2 % w/w (test product) was applied BID (l2-hrs apart) and nimesulide 1% (reference product) gel was applied TID (8 hrs apart) and QID (6 hrs apart) under fasting conditions. The steady state plasma concentration was measured and shown in table 12. The nimesulide gel 2% composition according to present invention applied BID showed 3-folds higher exposure than the reference product, Nise Gel 1% applied TID or QID.

Table 12

[00136] Example 22-26:

[00137] The present topical pharmaceutical compositions of nimesulide in a form of emulgel were prepared as given in following table 13.

Table 13

[00138] Procedure:

1. Oil phase was prepared by dissolving suitable amount of N-methyl pyrrolidone, Dimethyl sulfoxide, Dimethyl isosorbide, Diethyl sebacate, Diisopropyl adipate, Cetyl alcohol, Oleic acid, Isostearic acid, Butylated hydroxyl toluene, Tefose® 63, Gelot™ 64, Labrafac™ PG, Polyoxyl 40 hydrogenated castor oil, Polyoxyl 20 cetostearyl ether and/or Glyceryl mono stearate at 65 °C to 75 °C.

2. Aqueous phase was prepared by dissolving suitable amount of Sodium benzoate, Narcissus 938, Purified water, Propylene glycol followed by dispersing Carbomer 980 at 65 °C to 75 °C.

3. Emulsification was done by adding prepared oil phase into aqueous phase followed by stirring to form homogenous emulgel at room temperature. [00139] Example 27:

[00140] The pharmaceutical composition as prepared in example 22 was subjected to stability studies for at least 6 months. The results are given in following table 14.

Table 14

[00141] Example 28:

[00142] The pharmacokinetic parameters for pharmaceutical compositions as prepared in examples 22-24 and example 26 were studied in comparison with NISE Gel® (1% Nimesulide), marketed by Dr. Reddy’s Laboratories Limited, India. The study was conducted using rats and the composition was applied to right knee (l.5cm X 2cm) at 8 hours apart. The samples were collected from synovial fluid and plasma at 1, 4, 8, 9, 16 and 24 hours using 4 rats at each time point; the results are given in following table 15, table 16 and table 17.

Table 15 (Synovial fluid)

Table 16 (Synovial fluid levels)

Table 17 (Plasma)

Claims

We Claim:

1. A topical pharmaceutical composition comprising: a therapeutically effective amount of nimesulide, at least one aprotic polar solvent, at least one pH independent polymer and one or more pharmaceutically acceptable excipients.

2. The composition of claim 1, wherein said therapeutically effective amount nimesulide comprises about 2% to about 5% w/w of nimesulide.

3. The composition of claim 2, wherein said therapeutically effective amount nimesulide comprises about 2% w/w of nimesulide.

4. The composition of claim 1, wherein said aprotic polar solvent is selected from one or more of dimethylsulfoxide, dimethylisosorbide, dimethylformamide, ethyl acetate, n-methylpyrrolidone, dimethyl acetamide, diethyl sebacate, diisopropyl adipate, propylene carbonate, or combinations thereof.

5. The composition of claim 4, wherein said aprotic polar solvent is dimethy lsulfo xide .

6. The composition of claim 1, wherein said pH independent polymer is selected from one or more of polyacrylamide/polyacrylates, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, gelatin, hydrophilic fumed silica or combinations thereof.

7. The composition of claim 1, wherein said at least one pH independent polymer and at least one aprotic polar are solvent present in a weight ratio of about 0.01: 1.0 to about 0.1: 1.0.

8. The composition of claim 1, wherein said one or more pharmaceutically acceptable excipients comprises one or more pH modifying agent and vehicle.

9. The composition of claim 8, wherein said pH modifying agent is selected from one or more of citric acid, hydrochloric acid, oleic acid, malic acid, tartaric acid, fumaric acid, phosphoric acid or combinations thereof.

10. The composition of claim 1, wherein said composition is having a pH of less than about 6.5.

11. The composition of claim 8, wherein said vehicle is selected from one or more of glycerol, propylene glycol, dipropylene glycol, propylene glycol dipelargonate, polyethylene glycol, lauroglycol, oleic acid, isostearic acid, glyceryl monooleate, ethoxydiglycol or combinations thereof.

12. The composition of claim 1, wherein said composition further comprises one or more penetration enhancer selected form polyethylene glycol, polyethylene glycol monolaurate, butanediol, dimethylsulfoxide, decylmethylsulfoxide, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, lauric acid, oleic acid, valeric acid, isopropyl myristate, isopropyl palmitate, methyl propionate, ethyl oleate, urea, dimethyl acetamide, dimethyl isosorbide, dimethylformamide 2- pyrrolidone, ethanolamine, methyl-2-pyrrolidone, diethanolamine, triethanolamine, terpenes, terpenoids, alkanones, salicylic acid, citric acid, succinic acid, ethanol, isopropyl alcohol, acetone, cyclomethicone, dimethicone or combinations thereof.

13. A method of alleviating joint pain and/or inflammation in a subject in need thereof, comprising: applying a topical pharmaceutical composition comprising about 2% to 5% w/w of nimesulide or pharmaceutically acceptable salts thereof over a joint, wherein the said composition when applied for about 2 times in a day exhibits steady state plasma concentration of at least about 3 fold higher compared to commercially available topical composition comprising 1% of nimesulide gel applied over for about 3 or 4 times in a day.

14. A topical pharmaceutical composition of nimesulide or pharmaceutically acceptable salts thereof in a form of emulgel, wherein said composition comprises a therapeutically effective amount of nimesulide, at least two emulsifiers, at least one gelling agent/polymer and one or more pharmaceutically acceptable excipients.

15. The composition of claim 14, wherein the at least two emulsifiers and nimesulide are present in a weight ratio of from about 3.7: 1.0 to about 5.7: 1.0.