PARENT CASE TEXT
This application is a patent of addition application of 3184/DEL/97 filed on 06/11/1997; the contents of which are hereby incorporated by reference into the present application.
FIELD OF THE INVENTION
The present invention relates to an antileukotriene, antihistaminic, antiallergic and anti¬inflammatory composition of non-steroidal anti-inflammatory sulfonanilide (NSAID) or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agent with second generation anti-histamine (H1 blockers) or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agent alongwith pharmaceutically acceptable base and excipients. More particularly the invention relates to a composition of nimesulide and cetirizine as active agents alongwith pharmaceutically acceptable base and excipients. More particularly the invention relates to a composition for use in allergic disorders namely rhinitis, bronchitis, asthma, urticaria and the like.
BACKGROUND OF THE INVENTION
The clinical symptoms produced in the course of allergic reaction are the result of an early specific immune response and a late inflammatory reaction. The inhaled allergens (e.g. pollens, mite dust) mediate the early phase by stimulating high affinity immunoglobulin (IgE) receptors e.g. mast cells and basophils which in turn release histamine and cytokines. This early phase lasts for about 30 minutes. The cytokines released from mast cells and basophils then mediate the late phase by recruiting inflammatory cells into the nasal and upper respiratory tract passages (Serafin, WE, In Goodman and Gillmans "The Pharmacological Basis of Therapeutics ", Hardmen, Ja; Limbird, L, E eds, Mc Graw -Hill, New York, 1996, 659 - 682). The influx of eosinophils, macrophages, lymphocytes, neutrophils and platelets starts the vicious inflammatory cycle. This late phase lasting for 8-48 hours amplifies the initial immune response which in turn triggers the release of more inflammatory cells (Townley RG and Okada, C, Annals of Allergy, 68, 1991, 190 -196).
Seasonal allergic rhinitis (hay fever) is caused by deposition of allergens on the nasal mucosa resulting in an immediate hypersensitivity reaction. If the allergens (e.g. dust mite) are carried to the lower airways (i.e. bronchioles), in susceptible subjects, the result is bronchoconstriction of the airways (i.e. asthma). The allergen-induced release of leukotrienes, the 5-lipoxygenase products of arachidonic acid metabolism in activated airway cells, is critical in the pathophysiology of asthma. Leukotrienes are produced by mast cells, eosinophils, neutrophils and alveolar macrophages. The use of specific leukotriene receptor antagonists or 5-lipoxygenase pathway inhibitors results in increased airflow and reduction of symptoms in asthmatic patients (Henderson WR, Jr., Annals of Allergy, 72, 1994, 272-277). Immunologic concepts of asthma and related allergic disorders are undergoing revolutionary changes. Asthma is now proposed to have an allergic basis and all chronic allergic disorders have a basal ongoing inflammation which is never fully resolved. In the annual meeting of the European Academy of Allergy and Clinical Immunology which took place in Greece, June 1 - 5, 1997, the clinical implications of minimal persistent inflammation (MPI) have been emphasized. A mild presence of inflammatory cells and ICAM - 1 receptors on epithelial cells has been demonstrated even during asymptomatic periods in allergic subjects. So the correct treatment of allergic disorders should address allergic inflammation and not just the symptoms. In this annual meeting a redefinition of allergic disorders was also emphasized. Rhinitis and asthma were pooled together as the inflammatory mechanisms that represent a common unifying concept for the pathogenesis of allergic disorders. Allergic rhinitis and bronchial asthma frequently co-exist. Upto 40% of rhinitics have concomitant asthma and upto 80% of asthmatics also have rhinitis. Rhinitics have upto three fold greater risk of developing asthma as the inflammatory mediators, constantly being released in the airways, and may produce alterations in the airway epithelium such that an allergic person becomes prone to asthmatic attacks (Wenzel, S.E, Annals of Allergy, 72, 1994, 261 - 271). It was thus proposed that treating nasal and airway inflammation may be a key to asthma control. It was concluded that development of therapeutic strategies for the prevention and prophylaxis of respiratory allergy should be approached rather than the treatment except for asthmatic emergencies. Thus it is self-
evident that although antihistamines (second generation H1-blockers) are the most widely used agents for the treatment of allergic conditions (Gong, H, Tashkin, D.P, Dauphinee, B et al., J.Allergy. Clin. Immunol., 85, 1990, 632 - 641), NSAIDS can also prove to be very useful as anti-inflammatory drugs. Till date, NSAIDS like aspirin, its analogues and even unrelated chemical moieties could not be used in allergic disorders because of the precipitation of a pseudoallele reaction in aspirin intolerant patients. Despite their anti¬inflammatory effects, almost all NSAIDS potentiate IgE-mediated histamine release from mast cells and basophils resulting in vasomotor rhinitis, urticaria and bronchial asthma in these patients (Bianco, S, Robuschi, M, Petrigni, G et al., Drugs, 46, 1993, 115 -120). However, one unique NSAID stands out from the rest. Nimesulide, a sulfonanilide NSAID, is well tolerated by patients with all allergic disorders and aspirin idiosyncrasy (Casolaro,V, Meliota,S, Marino,O et al., J. Pharmacol. Exp. Ther., 267, 1993, 1375 -1385). It has a profound antihistaminic, antianaphylactic activity (Berti,F, Rossoni,G, Buschi, A et al., Arznemittel Forschung, 40, 1990, 1011- 1016) in addition to its potent anti inflammatory action (Serafin, WE, 1996; Bellusi, L, Passali, D, Drugs (46) Suppl. 1, 1993, 107 - 110). Nimesulide inhibits the allergen induced immunologic release of histamine and also improves bronchial responsiveness in asthmatic patients exposed to bronchoconstrictors (Casolaro,V, et al. 1993; Berti,F, et al. 1990).
All the above studies only indicated the possible extension of antiinflammatory action of Nimesulide for control of inflammation of upper respiratory tract. However, the use of nimesulide as an antiasthmatic due to antiallergic and leukotriene inhibiting activities of Nimesulide has not been reported so far, and by careful experimentation and application of scientific logic and intellectual expertise, the inventors of the present invention combined nimesulide with cetirizine in different proportions and carried out several experiments to see the utility of such a combination for use as an antiasthmatic agent. It has been surprisingly found by the inventors of the present invention and described hereinbelow in the present invention that nimesulide and cetirizine or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof can be given in combination which provides a synergistic composition and is of immense utility in asthma.
Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID) that also has antipyretic and analgesic properties. The compound is weakly acidic (pKa = 6.5) and differs from other NSAIDs in that its chemical structure contains a sulfonanilide moeity as the acidic group. The therapeutic effects of NSAIDs are largely the result of their ability to inhibit prostaglandin synthesis via inhibition of cyclooxygenase. Cetirizine hydrochloride, the second generation antihistamine and the active component of ZYRTEC® tablets and syrup, is an orally active and selective HI-receptor antagonist. The chemical name is (±) -[2- [4- [ (4-chlorophenyl)phenylmethyl] -1- piperazinyl] ethoxy] acetic acid, dihydrochloride. Cetirizine hydrochloride is a racemic compound with an empirical formula of C21H25ClN2O32HCl. Cetirizine crosses the blood-brain barrier only slightly, eliminating the sedative side-effect common with older antihistamines.
US Patent no. 5658948 Allergan Inc. discloses a formulation and method includes an acceptable drug, such as Prostaglandins, Flurbiprofen, Keterolac, Tromethamine, Cetirizine HC1, Indomethacin and Bufrolin, which are interactive with benzalkonium chloride to form a precipitate along with benzalkonium chloride acting as a preservative and an amino acid having enough positive charge at the pH of the formulation and/or Tromethamine present in an amount sufficient to interfere with the interaction between the drug and benzalkonium chloride in order to maintain the preservative activity of the benzalkonium chloride. Further, the use of Lysine, L-arginine, or Histidine is also useful in reducing the cytotoxicity of the formulation. US Patent no. 5627183 granted to Sepracor Inc., discloses methods for utilizing optically pure (+) Cetirizine for the treatment of urticaria in humans while avoiding the concomitant liability of adverse effects associated with the racemic mixture of Cetirizine. US Patent no. 5419898 granted to SENJU PHARMACEUTICAL Co., LTD., discloses an anti-allergic composition for opthalmic or nasal use, comprising cetirizine or a salt thereof as an active ingredient. The antiallergic composition may further contain a cyclodextrin compound, as well as surfactant and/or a water soluble polymer. US publication 20060247258 describes a pharmaceutical use of levocetirizine for the treatment of persistent allergic rhinitis. US publication 20060083786 describes a solid oral dosage composition is provided comprising a prophylactically or therapeutically effective amount of an active
pharmaceutical ingredient comprising levocetirizine or a pharmaceutically acceptable salt thereof, the solid oral dosage composition having a coating thereon capable of providing taste masking of the levocetirizine or pharmaceutically acceptable salt thereof. PCT publication WO94/06429 discloses methods and compositions utilizing optically pure (-) cetirizine for the treatment of seasonal and perennial allergic rhinitis in humans while avoiding the concomitant liability of adverse effects associated with the racemic mixture of cetirizine. The optically pure (-) isomer is also useful for the treatment of allergic asthma and chronic and physical urticaria. (-) Cetirizine is an inhibitor of eosinophil chemotaxis and is therefore useful in the treatment of other conditions related to eosinophilia such as allergic asthma, seasonal allergic rhinitis, atopic dermatitis, some parasitic diseases, some chronic obstructive lung diseases and certain gastrointestinal and genitourinary disorders. Till present, nowhere in the prior art is disclosed a composition comprising a combination of Nimesulide in combination with a second generation antihistamine, more preferably cetirizine. Hence, there is still an unmet medical need to prepare oral compositions comprising a fixed dose drug combination of Nimesulide and cetirizine which have the potential of acting synergistically, predictably and effectively useful in the treatment of allergic disorders namely rhinitis, bronchitis, asthma, urticaria and the like.
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide an antileukotriene, antihistaminic, anti-allergic and anti-inflammatory composition a non-steroidal antiinflammatory sulfonanilide (NSAID) or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as an active agent and a second generation anti-histamine (H1 blockers) or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as an active agent alongwith pharmaceutically acceptable base and excipients.
It is an objective of the present invention to provide an antileukotriene, antihistaminic, anti-allergic and anti-inflammatory composition comprising a non-steroidal anti¬inflammatory sulfonanilide (NSAID) preferably nimesulide as an active agent and a
second generation anti-histamine cetirizine as an active agent alongwith pharmaceutical^ acceptable base and excipients. It might be appreciated that the phrase "nimesulide" and "cetirizine" wherever appears in the patent specification also covers their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives unless otherwise mentioned. It might be further emphasized that the inventors of the present invention by expenditure of intellectual effort and experimentation have surprisingly found while preparing different compositions that better management of the pharmaceutical process parameters for manufacturing of the compositions is achieved by using minimal quantities of pharmaceutical excipients thus aiding to cost effectiveness of the composition and which is also an important aspect of the present invention.
It is the further objective of the present invention to provide a process for the manufacture
of an antileukotriene, antihistaminic, anti-allergic and anti-inflammatory composition
comprising nimesulide and cetirizine which comprises of the following steps:
i) processing the Nimesulide(s) alongwith pharmaceutically acceptable base and
excipients, ii) processing the Cetirizine(s) alongwith pharmaceutically acceptable base and
excipients, iii) formulating the material of step i) and ii) into a suitable dosage form.
It is yet another objective to provide a method of treatment of use in allergic disorders namely rhinitis, bronchitis, asthma, urticaria and the like by administering to a patient in need thereof a pharmaceutical composition of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The following unique features of nimesulide may prove to be quite beneficial in all
allergic disorders.
1. Nimesulide is a potent stabilizer of mast cells and basophils. Thus, it prevents the
release of histamine, proteases, TNF-α, Prostaglandins, leukotrienes, PAF and other
cytokines from activated mast cells.
2. Nimesulide indirectly blunts the eosinophil deluge in asthmatic attacks because of its mast cell and basophil stabilizing property. Mast cells and basophils release an eosinophil chemotactic factor that causes eosinophils to migrate towards inflamed allergic tissue. Nimesulide is also reported to inhibit chemotaxis and synthesis of platelet activating factor and leukotrienes by human eosinophils.
3. Nimesulide potently inhibits the phosphodiesterase type IV in human polymorphonuclear leukocytes. The resultant increase in cAMP accounts for a marked decrease in chemotaxis, degranulation and free radical generation. PDE-IV inhibitors are finding a place as anti-asthmatic drugs.
4. Nimesulide inhibits the neutrophil respiratory burst and hence the release of free radicals, cytokines, eicosanoids, prostaglandins etc.
5. Nimesulide is a potent anti-oxidant. Hence it prevents tissue injury at sites of inflammation by maintaining natural host protective systems.
Second generation histamine (Hi_receptor) antagonist (e.g. cetirizine, fexofenadine, acrivastine, astemizole, loratidine etc.) are the drugs of choice in the treatment of allergic rhinitis as they are long acting and are free from sedative and anticholinergic effects. In addition, second generation anti-histamines have the following unusual and potentially beneficial properties.
1) These non-sedative anti-histamines have demonstrated dose-related protection against histamine induced bronchoconstriction.
2) These have been shown to protect against exercise, ultrasonic nebulized distilled water and cold air induced bronchoconstriction.
3) These produce modest but statistically significant acute bronchodilation in mild to moderate asthma.
4) Cetirizine is reported to have an anti inflammatory property in addition to its Hi-antagonizing action. Cetirizine inhibits inflammatory cell migration by potently inhibiting eosinophil influx and eosinophil degranulation.
5) ICAM-1 expression is a sensitive marker of mucosal allergic inflammation. ICAM-1 is also the receptor for most human rhinoviruses, which are the cause of more than 80% of asthmatic attacks in children. It has been reported that Cetirizine is able to modulate and down regulate ICAM -1 expression in epithelial cells.
6) Cetirizine is very effective in inhibiting the cutaneous early & late phase responses by inhibiting PAF and eosinophil recruitment in skin. In a recent report, almost 70% chronic hives patients reported excellent results on a daily regimen of lOmg of cetirizine. Compared to other antihistamines cetirizine treatment produced faster, more potent and more long-lasting relief of wheals and flares.
7) Cetirizine does not cause cardiac arrhythmias reported by some other antihistamines.
8) Continuous Cetirizine treatment is reported to be better than on-demand treatment in
rhinitis sensitive to pollens.
Our findings as disclosed in this patent application indicate that sulfonanilide NSAIDs e.g. Nimesulide and thereof when combined with cetirizine forms an excellent synergistic antileukotriene, antihistaminic, anti-allergy and anti-inflammatory composition.
By careful experimentation the inventors have found that although Nimesulide does not block exogenously administered histamine but very effectively blocks the release of histamine by stabilizing the mast cells and basophills as evident from egg albumin experiment as disclosed in the present invention. The histamine released if any will be blocked by Cetirizine. Surprisingly, we also found out that Nimesulide as well as Cetirizine have a leukotriene action which is synergistic when the drugs are combined as evident from the Table. 3 (the details of the Table. 3 are disclosed in the application of 3184/DEL/97 filed on 06/11/1997; the disclosures of which are each incorporated herein by reference thereto as such.)
The inventors of the present invention by way of expenditure of intellectual effort and careful experimentation have prepared compositions comprising a combination of an
antileukotriene, antihistamine, anti-allergic and anti-inflammatory composition comprising a non-steroidal antiinflammatory sulfonanilide (NSAID) or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as an active agent and a second generation anti-histamine (H1 blockers) or their pharmaceuticalLY acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as an active agent alongwith pharmaceutically acceptable base and excipients.
In an embodiment, the present invention relates to preparation of composition comprising a non-steroidal anti-inflammatory sulfonanilide (NSAID) preferably nimesulide as an active agent and a second generation anti-histamine cetirizine as an active agent. The combination of the said active agents has substantial and excellent synergistic antileukotriene, antihistaminic, anti-allergy and anti-inflammatory activity.
In an embodiment, the present invention provides a composition comprising nimesulide from about 1 to about 90.7 parts, cetirizine from about 0.2 to about 9.07 parts and pharmaceutical base and excipients from about 0.23 to about 98.8 parts.
In another embodiment, the present invention provides a composition comprising nimesulide from about 1 to about 85 parts, cetirizine from about 0.5 to about 3 parts and pharmaceutical base and excipients from about 12 to about 98.5 parts.
In yet another embodiment, the present invention provides a composition comprising nimesulide from about 1 to about 70 parts, cetirizine from about 2 to about 5 parts and pharmaceutical base and excipients from about 25 to about 97 parts.
In another embodiment, the present invention provides a composition comprising nimesulide and cetirizine in the ratio of 2:1 to 80:1. In a further embodiment, the present invention provides a composition comprising nimesulide and cetirizine in the ratio of 2:1 to 40:1.

In another embodiment, the composition of the present invention can be in the form of a tablet, injection, metered dose inhaler, topical gel, capsules and the like.
Pharmaceutical excipients used in the composition are selected from the group of excipients generally used by persons skilled in the art e.g. carrier, filler, binders, disintegrants, bulking agent, colorant, stabilizer, preservative, lubricant, glidant, chelating agent, antiadherants, plasticizers, coating agents, opacifiers, antioxidants, stabilizers, preservatives, surfactants, hydrophilic polymers, solubility enhancing agents, osmotic agents, and the like used either alone or in combination thereof. In another embodiment, the composition of the present invention further comprises one or more release modifiers selected from a group comprising but not limited to wetting agents, solubilizers, surfactants, plasticizers, pore formers, pH modifiers and tonicity adjusting agents, or combination thereof.
The pharmaceutically acceptable carrier of the present invention comprises a polymeric material selected from but not limited to the group comprising pH dependent polymers; pH independent polymers; swellable polymers; hydrophilic polymers; hydrophobic polymers and/or one or more other hydrophobic materials; ionic polymers such as sodium alginate, carbomer, calcium carboxymethylcellulose or sodium carboxymethylcellulose; non-ionic polymers such as hydroxypropyl methylcellulose; synthetic or natural polysaccharide selected from the group comprising alkylcelluloses, hydroxyalkylcelluloses, cellulose ethers, cellulose esters, nitrocelluloses, dextrin, agar, carrageenan, pectin, furcellaran, starch and starch derivative, and mixtures thereof. The polymeric material used in the present invention is selected from but not limited to a group comprising cellulosic polymer, methacrylate polymer, PVP, alginate, PVP-PVA copolymer, ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(alkyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(alkyl acrylate), poly(octadecyl acrylate), poly(alkylene), poly(alkylene oxide), poly(alkylene
terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) and polyurethane or a mixture thereof; used either alone or in combination thereof.
In a further embodiment, the compositions of the present invention comprising nimesulide and cetirizine may be combined with one or more suitable active agent(s). The other active agent may be present in an immediate release form or controlled release form or a combination of both forms. Suitable active agents that can be used along with nimesulide and cetirizine is selected from but not limited to a group comprising antihistaminics, decongestants such as phenylpropanolamine, tyramine, psychoactive stimulants such as caffeine, xanthine, and derivatives thereof, antispasmodics e.g. pitofenone, hyoscine hydrobromide; antiasthmatics e.g. ketotifen, salbutamol; antipyretics such as paracetamol, aspirin, and the like or mixture thereof. In an embodiment of the present invention, nimesulide can be used in the range from about 25 mg to about 500mg in combination with cetirizine in the range from about 2 to about 25 mg.
In an embodiment the present invention provides provides a process for the manufacture
of an antileukotriene, antihistaminic, anti-allergic and anti-inflammatory composition
comprising nimesulide and cetirizine which comprises of the following steps:
i) processing the Nimesulide(s) alongwith pharmaceutically acceptable base and
excipients, ii) processing the Cetirizine(s) alongwith pharmaceutically acceptable base and
excipients, iii) formulating the material of step i) and ii) into a suitable dosage form.
In yet another embodiment of the present invention is provided a method of using such composition according to the present invention which comprises administering to a subject in need thereof an effective amount of the composition.
In still another embodiment of the present invention is provided a use of the dosage form composition comprising nimesulide, and cetirizine for the preparation of a medicament for treating allergic disorders namely rhinitis, bronchitis, asthma, urticaria and the like.
In a further embodiment of the present invention, is provided a use of the dosage form for the management of one or more disease(s)/disorder(s) which includes prophylaxis, amelioration and/or treatment of allergic disorders namely rhinitis, bronchitis, asthma, urticaria and the like.
The experimental study of Nimesulide and Cetirizine is disclosed in the application of 3184/DEL/97 filed on 06/11/1997; the disclosures of which are each incorporated herein by reference thereto as such.
The foregoing examples are illustrative embodiments of the invention and are merely exemplary. A person skilled in the art may make variations and modifications without deviating from the spirit and scope of the invention. All such modifications and variations are intended to be included within the scope of the invention.
Example 1: Tablets
S. No. Ingredients Qty/ tab (mg)
1. Nimesulide : 100
2. Cetirizine : 10
3. PVP K-30 : 1
4. Docusate sodium : 0.5
5. Magnesium stearate : 0.5
6. Croscarmellose sodium 0.5
7. Purified water : q.s. (Lost in processing) Procedure:
i). Nimesulide and Cetirizine were mixed together.
ii). PVP K-30 and docusate sodium were dissolved in purified water to form the
binder solution, iii). The binder solution of step (ii) was mixed with the contents of step (i) to form the
granules followed by drying of the granules, iv). The dried granules of step (iii) were blended with magnesium stearate and
croscarmellose sodium.
v). The granules of step (iv) were compressed to obtain tablets.
Example 2: Tablets
S. No. Ingredients Qty/ tab (mg)
1. Nimesulide : 200
2. Cetirizine : 10
3. PVPK-30 3.0
4. Docusate sodium : 1.5
5. Magnesium stearate 1.5
6. Purified water : q.s. (Lost in processing) Procedure:
i). Nimesulide and Cetirizine were mixed together.
ii). PVP K-30 and docusate sodium were dissolved in purified water to form the
binder solution, iii). The binder solution of step (ii) was mixed with the contents of step (i) to form the
granules followed by drying of the granules, iv). The dried granules of step (iii) were blended with magnesium stearate. v). The granules of step (iv) were compressed to obtain tablets.
Example 3: Capsules
S. No. Ingredients Qty/ capsule (mg)
1. Nimesulide : 200
2. Cetirizine : 5
3. Maize Starch : 25
4. Sodium Lauryl Sulphate 0.5
5. Colloidal Silicon Dioxide : 1.5 Procedure:
i). Nimesulide, maize starch and colloidal silicon dioxide were, sifted through # 30
sieve, ii). Cetirizine and sodium lauryl sulphate were sifted through # 60 sieve.
iii). The contents of step (i) and (ii) were mixed uniformly and filled into empty hard gelatin capsules.
Example 4: Capsules
S. No. Ingredients Qty/capsule (mg)
1. Nimesulide : 100
2. Cetirizine : 10
3. Magnesium stearate : 0.25 Procedure:
i). Nimesulide was sifted through #30 sieve.
ii). Cetirizine and magnesium stearate were sifted through # 60 sieve, iii). The contents of step (i) and (ii) were mixed uniformly and filled into empty hard gelatin capsules.

claim:
1. An antileukotriene, antihistamine, anti-allergic and anti-inflammatory composition comprising nimesulide or its pharmaceutically acceptable salts, egfers, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as an active agent from about 1 to about 90.7 parts and cetirizine or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as an active agent from about 0.2 to about 9.07 parts alongwith pharmaceutically acceptable base and excipients from about 0.23 to about 98.8 parts.
2. A composition according to claim 1, wherein the composition comprises nimesulide and cetirizine in the ratio of 2:1 to 80:1.
3. A composition according to claim 2, wherein the composition comprises nimesulide and cetirizine in the ratio of 2:1 to 40:1.
4. A composition according to claims 1 to 3, wherein the composition is in the form of a tablet, minitablets, injection, metered dose inhaler, topical gel and capsules.
5. The composition according to any one of the claims 1 to 4, which further comprises one or more release modifiers selected from a group comprising wetting agents, solubilizers, surfactants, plasticizers, pore formers, pH modifiers or tonicity adjusting agents.
6. A composition as claimed in claim 1, wherein the other pharmaceutically acceptable excipients are carrier, filler, binders, disintegrants, bulking agent, colorant, stabilizer, preservative, lubricant, glidant, chelating agent, antiadherants, plasticizers, coating agents, opacifiers, antioxidants, stabilizers, preservatives, surfactants, hydrophilic polymers, solubility enhancing agents, osmotic agents, and the like used either alone or in combination thereof.

7. A composition according to anly one of the claims 1 to 6 which additionally comprises one or more other active agent(s).
8. A composition according to claim 7, wherein the additional active agent(s) is selected from a group comprising antihistaminics, decongestants such as phenylpropanolamine, tyramine, psychoactive stimulants such as caffeine, xanthine,
and derivatives thereof, antispasmodics e.g. pitofenone, hyoscine hydrobromide; antiasthmatics e.g. ketotifen, salbutamol; antipyretics such as paracetamol, aspirin, and the like or mixture thereof.
9. A composition according to claim 1, wherein nimesulide is present in the range of from about 25 mg to about 500mg and cetirizine in the range from about 2 to about 25 mg.
10. A process for the preparation of composition according to claim 1, which comprises of the following steps:
i). processing the Nimesulide(s) with pharmaceutically acceptable excipients, ii). processing the cetirizine(s) with pharmaceutically acceptable excipients, iii). formulating the material of step i) and ii) into a suitable dosage form.
11. The pharmaceutical compositions and process for the preparation of pharmaceutical
compositions substantially as herein described and illustrated by the examples.