ORIGINAL
FIELD OF THE INVENTION
The present invention relates to an antileukotriene, antihistaminic, antiallergic and antiinflammatory pharmaceutical composition. More particularly the invention relates to a composition for use in allergic disorders namely rhinitis such as allergic rhinitis, acute and chronic rhinitis, seasonal allergic rhinitis; bronchitis, 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, 65,1991,190-196).
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 pseudoallergic 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, is well tolerated by patients with all allergic disorders and aspirin idiosyncrasy (Casolaro,V, Meliota,S, Marino,0 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 anti-inflammatory action of Nimesulide for control of inflammation of upper respiratory tract. However, the use of nimesulide as an antiallergic agent 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 levocetirizine in different proportions and carried out several experiments to see the utility of such a combination for use as an antiallergic agent. It has been surprisingly found by the inventors of the present invention and described hereinbelow in the present invention that nimesulide and levocetirizine can be given in combination which provides a synergistic composition and is of immense utility in various allergic disorders.
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. Levocetirizine (as levocetirizine dihydrochloride) is a third generation non-sedative antihistamine, developed from the second generation antihistamine cetirizine. Chemically, levocetirizine is the active enantiomer of cetirizine. Levocetirizine is also known as (-) cetirizine. Levocetirizine works by blocking histamine receptors. It does not prevent the actual release of histamine from mast cells, but prevents it binding to its receptors. This in turn prevents the release of other allergy chemicals and increased blood supply to the area, and provides relief from the typical symptoms of hayfever.
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. JP publication no. 2001-247481 describes a medicinal composition which is effective for chronic rhinitis syndrome caused by influenza and rhinitis such as chronic allergic rhinitis, can especially be used for a long period, and is effective for removing or reducing nasal obstruction. The medicinal composition comprises a selective cyclooxygenase-2 inhibiting non-steroidal antiinflammatory medicine and an antiallergic or antihistaminic medicine.
The optically pure (-) Cetirizine isomer is also useful for the treatment of 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 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 third generation antihistamine, more preferably Levocetirizine. There is still an unmet medical need for the preparation of a pharmaceutical composition comprising a fixed dose combination, which has the potential of acting synergistically, predictably and effectively in the treatment of allergic disorders namely rhinitis, such as allergic rhinitis, acute and chronic rhinitis, seasonal allergic rhinitis, bronchitis, urticaria and the like.
SUMMARY OF THE INVENTION
An aspect of the present invention relates to an antileukotriene, antihistaminic, anti-allergic and anti-inflammatory pharmaceutical composition. The composition comprises a combination of a
non-steroidal antiinflammatory sulfonanilide or its pharmaceutically acceptable salts, esters, polymorphs, isomers, enantiomers, prodrugs, solvates, hydrates, or derivatives thereof as an active agent alongwith a third generation anti-histamine (Hi blockers) or its pharmaceutically acceptable salts, esters, polymorphs, isomers, enantiomers, prodrugs, solvates, hydrates, or derivatives as an active agent; optionally alongwith pharmaceutically acceptable excipients.
An aspect of the present invention relates to an antileukotriene, antihistaminic, anti-allergic and anti-inflammatory pharmaceutical composition comprising a non-steroidal anti-inflammatory sulfonanilide preferably nimesulide as an active agent and a third generation anti-histamine preferably levocetirizine as an active agent, optionally alongwith pharmaceutically acceptable excipients.
Another aspect of the present invention provides a composition comprising nimesulide and levocetirizine, wherein nimesulide and levocetirizine are present in ratio from about 2:1 to about 80:1.
A further aspect of the present invention relates to a process for the manufacture of the
composition of the invention comprising the following steps:
i) processing Nimesulide alongwith pharmaceutically acceptable excipients,
ii) processing Levocetirizine( alongwith pharmaceutically acceptable excipients,
iii) formulating the material of step i) and ii) into a suitable dosage form.
An aspect of the present invention also relates to a method of treatment of use in allergic disorders namely rhinitis such as allergic rhinitis, acute and chronic rhinitis, seasonal allergic rhinitis, bronchitis, urticaria and the like, by administering to a patient in need thereof, a pharmaceutical composition of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
It might be appreciated that the phrases "nimesulide" and "levocetirizine" wherever they appear in the patent specification also include their pharmaceutically acceptable salts, esters, polymorphs, isomers, enantiomers, prodrugs, solvates, hydrates, or derivatives unless otherwise mentioned.
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-g, 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 antiasthmatic 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.
Levocetirizine is the R-enantiomer of cetirizine. Levocetirizine, like cetirizine, has a potential anti-inflammatory effect in the treatment of allergic rhinitis. Levocetirizine is believed to have a two fold higher affinity for human H.i receptors than cetirizine. Levocetirizine is also believed to be rapidly and extensively absorbed. Levocetirizine has been shown to be free from side effects on the central nervous system. Journal of Allergy and Clinical Immunology, 111:3, pp. 623-627 (2003). Like cetirizine, levocetirizine inhibits eotaxin-induced eosinophil TEM through both dermal and a lung microvascular endothelial cell, suggesting that it has potential antiinflammatory effects. This anti-inflammatory effect is underlined by the ability of levocetirizine's ability to inhibit eosinophil chemotaxis. It has a very high affinity for the H1 receptor. The carboxylic function of cetirizine and levocetirizine is important in this regard (Journal of Drugs in Dermatology (2002).
The inventors of the present invention by way of expenditure of intellectual effort and careful experimentation have prepared compositions comprising an antileukotriene, antihistaminic, anti-
allergic and anti-inflammatory agent comprising a non-steroidal antiinflammatory sulfonanilide or pharmaceutically acceptable salts, esters, polymorphs, isomers, enantiomers, prodrugs, solvates, hydrates or derivatives thereof and a third generation anti-histamine (Hi blockers) or pharmaceutically acceptable salts, esters, polymorphs, isomers, enantiomers, prodrugs, solvates, hydrates, or derivatives thereof alongwith pharmaceutically acceptable excipients.
In an embodiment, the present invention relates to preparation of a composition comprising a non-steroidal anti-inflammatory sulfonanilide preferably nimesulide as an active agent and a third generation anti-histamine levocetirizine 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 another embodiment, the present invention relates to preparation of a composition comprising nimesulide from about 0.1% w/w to about 99.8% w/w, levocetirizine from about 0.1% w/w to about 99% w/w and pharmaceutical acceptable excipients from about 0.1% w/w to about 99.8%
w/w.
In an embodiment, the present invention relates to preparation of a composition comprising nimesulide and levocetirizine, wherein nimesulide and levocetirizine are present in ratio from about 2:1 to about 80:1. Further an embodiment also relates to a composition comprising nimesulide and levocetirizine, wherein nimesulide and levocetirizine are present in ratio from about 2:1 to about 40:1.
The present invention provides a composition comprising nimesulide and levocetirizine, wherein the said composition is formulated in the form of powder, inert core, seeds selected from but not limited to water-soluble systems such as sugar spheres, lactose and the like or mixtures thereof and water-insoluble systems selected from but not limited to microcrystalline cellulose, silicon dioxide, calcium carbonate, dicalcium phosphate anhydrous, dicalcium phosphate monohydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like or alone or in combination thereof, compacts, granules, pellets, beads, shear form particles, floss, or the like, alone or in combination thereof. The said composition of the present invention may be filled into capsule or made into a capsule, wherein the said capsule is in the form of a hard gelatin capsule or a soft gelatin capsule. The pharmaceutical composition of the present invention can be
administered parenterally or topically, in the form of drops, injection, patch, ointment and the other formulations for oral administration, injection or topical application. The composition of the present invention can be administered by any conventional means available for use in conjunction with pharmaceuticals. It might be appreciated that the composition comprising nimesulide and levocetirizine can be given in any dosage form which is known in the art and which is also an important aspect of the invention.
In an embodiment, the present invention relates to a composition comprising nimesulide and levocetirizine, wherein the said composition is in the form of a multiparticulate composition comprising a blend of one or more types of particles, inert core, seeds, granules, pellets, beads, compacts, minitablets, inlay tablets, tablet in tablet, shear form particles, floss, or the like, or combinations thereof, having different release characteristics or a multiparticulate composition made into a capsule or filled into a capsule.
In yet another embodiment, the present invention relates to a composition comprising nimesulide and levocetirizine, wherein the composition is in a controlled release form, sustained release form, timed release form, pulsatile release form, prolonged release form, extended release form or delayed release form, or a combination thereof. The composition can also additionally comprise an immediate release form. In an embodiment, compositions for immediate delivery of active agent(s) include but are not limited to solutions, suspensions, emulsions, fast-dissolving tablets or capsules, disintegrating tablets, Self Microemulsifying Drug Delivery Systems (SMEDDS) or the like. Prolonged or sustained delivery formulations include but are not limited to pH independent drug release systems or pH sensitive drug release system based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the composition achieved by floatation or bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. Compressed tablets according to the present invention can be prepared by compressing, in a suitable machine, the material in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made, for example, by molding the powdered compound in a suitable machine. In an embodiment, the compositions of the present invention are formulated as solid oral dosage form compositions possessing good bioavailability comprising one or more alkaline substance and/or surfactants. Liquid dosage forms for oral administration can include
pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise excipients such as wetting agents, emulsifying and suspending agents, or sweetening, flavoring, or perfuming agents. Pharmaceutical compositions suitable for buccal or sublingual administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the drugs in an inert base such as gelatin and glycerin or sucrose and acacia.
In one of the embodiments, the present invention provides a controlled release composition of nimesulide and levocetirizine formulated as multilayered compositions like a bilayered composition, wherein one fraction is provided as an immediate release or fast release fraction providing an immediate release of the active agent and the other fraction as an extended release fraction that releases the active agent over an extended period of time.
In an embodiment, the present invention relates to preparation of a composition of nimesulide and levocetirizine formulated as multilayered compositions like a bilayered composition, wherein one fraction is provided as an immediate release or fast release fraction providing an immediate release of the active agent wherein the said fraction comprises nimesulide or levocetirizine or both and the other fraction as an extended release fraction that releases the active agent over an extended period of time wherein the said fraction comprises nimesulide optionally alongwith levocetirizine.
In an embodiment of the present invention, the dose of nimesulide present in the form of immediate release or fast release fraction or extended release fraction is about 200 mg.
In an embodiment of the present invention, the dose of nimesulide present in the form of immediate release or fast release fraction is about 100 mg and extended release fraction is about 100 mg.
In an embodiment of the present invention, the dose of nimesulide present in the form of immediate release or fast release fraction is about 50 mg and extended release fraction is about 150 mg or the dose of nimesulide present in the form of immediate release or fast release fraction is about 150 mg and extended release fraction is about 50 mg.
In another embodiment of the present invention, the dose of nimesulide present in the form of immediate release or fast release fraction or extended release fraction is about 100 mg.
In an embodiment of the present invention, the dose of nimesulide present in the form of immediate release or fast release fraction is about 50 mg and extended release fraction is about 50 mg.
In an embodiment of the present invention, the dose of nimesulide present in the form of immediate release or fast release fraction is about 25 mg and extended release fraction is about 75 mg or wherein the dose of nimesulide present in the form of immediate release or fast release fraction is about 75 mg and extended release fraction is about 25 mg.
The composition can be prepared by either direct compression, dry compression (slugging) or by granulation. The composition prepared by granulation technique is either by aqueous or nonaqueous technique or melt granulation technique. The non-aqueous solvent used is selected from a group comprising dehydrated alcohol, isopropyl alcohol, methylene chloride or acetone. In an embodiment, the compositions of the present invention are in the form of granules, beads or pellets that may be further compacted, compressed, or moulded, or made into capsules. The compositions may be coated with a functional coating. By the term 'functional coating' it is herein implied that the coating composition comprises a part of the active agent(s) and/or the composition comprises excipients which aid in controlling the rate of release of the active agent(s) and/or the composition comprises additionally another active agent which is different from the active agent present in the core composition.
In a further embodiment, the composition is in the form of a multilayer tablet, more preferably bilayer tablets or may be in the form of minitablets. In a further embodiment, the bilayer tablets or minitablets may be coated or uncoated. The tablet or minitablet is preferably coated with one or more coating layers by a coating material comprising at least a film forming agent, a channel forming agent, a plasticizer, and an aqueous/non-aqueous solvent. The coating may also be in the form of a semi-permeable type membrane. Further, the semi-permeable coat may have an orifice drilled through it on the drug layer side to provide passage for constant release of drug. In another aspect of the invention, the coating may be of microporous type through which the release of the
active agent takes place preferably at constant rate. The first layer providing fast release of the active agent comprises one or more materials such as binders, disintegrants, fillers, rapidly soluble/dispersible excipients, wetting agents, and the like or mixtures thereof. The second layer providing extended release of the active agent comprises one or more materials such as release controlling polymers, binders, wetting agents, disintegrants, fillers, and the like or mixtures thereof. In another embodiment the said tablet or minitablet composition is filled into capsule comprising at least two fractions, one fraction being in the fast release or immediate release form and the other fraction being in the extended release form.
In an embodiment, the compositions of the present invention can be administered in the form of a dry powder inhaler or metered dose inhaler and is preferably intended to be administered by pulmonary, nasal or oral route, most preferably by inhalation, and is useful preferably in the treatment of various allergic disorders. The composition may preferably be in the form of solution, suspension or aerosol and may be formulated as dry powder inhaler (DPI), metered dose inhaler (MDI), nebulizer, spray or drops such as nasal spray or nasal drops. Particularly the patients are often treated by the administration of appropriate topically active medicines to the nose either by means of pressurized aerosol, liquid (usually aqueous) or dry powder formulations of the active agent(s). Inhalation formulations contain the active agent(s) in the form of very fine particles intended to reach deep into the lung. In an embodiment of the present invention for the exact volumetric dosage of the active agent(s), the active agent(s) is diluted with a pharmaceutically acceptable vehicle in order to obtain a dosable unit amount meeting the demands on dosage accuracy. For this purpose, the preferably microfine, inhalable active agent(s) particles are mixed with pharmacologically acceptable vehicle. The dilution is chosen such that the amount applied from the powder inhaler exactly contains the desired dose. The vehicle used in the present invention also serves for the adjustment of a flowability of the powder mixture and maintain homogeneity of the mixture. The vehicle used in the present invention is selected from but not limited to a group comprising monosaccharides such as glucose, arabinose; disaccharides such as trehalose, sucrose, lactose; polysaccharides such as starch, raffinose, melezitose; sugar alcohols such as lactitol, maltitol, mannitol, xylitol; polylactic acid, cyclodextrin, and dextran. The dry powder inhalation compositions of the present invention can be in the form of unit dose powder inhalers which release the medicament from pre-dosed units, e.g. capsules or blister packs or multi-dose powder inhalers which contains a powder reservoir from which the individual doses are withdrawn by means of a dosage mechanism.
In yet another embodiment, the compositions of the present invention can be administered transdermally in the form of a gel. The gel is formed by the process known to a person skilled in art and comprises of a percutaneous enhancer, surfactants such as lipophilic as well as hydrophilic surfactants, gelling agents and one or more vehicle or bases. In another embodiment, the composition of the present invention can be administered parenterally, preferably in the form of i.v. injection wherein the composition comprises of a solvent, buffering agent, alkalizing agent alongwith pharmaceutically acceptable excipients. It might be emphasized that one skilled in the art can make various modifications in the pharmaceutical excipients and prepare the finished dosage form accordingly.
In another embodiment, the release controlling materials used in the present invention comprise
materials that are non-toxic and pharmaceutically acceptable. These may be natural, semi
synthetic, synthetic or man-modified. Suitable materials include but not limited to group
comprising cellulose and cellulose derivatives like microcrystalline cellulose, methylcellulose,
ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose acetate
phthalate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose
acetate trimellitate, cellulose carboxymethyl ethers and their salts, hydroxypropyl methylcellulose
phthalate, hydroxypropyl methylcellulose acetate succinate, polyethylene; polyquaternium-1;
polyvinyl acetate (homopolymer); polyvinyl acetate phthalate; propylene glycol alginate;
polyvinyl methacrylate(pvm)/methacrylic acid(ma) copolymer; polyvinyl pyrrolidone (pvp);
pvp/dimethiconylacrylate/polycarbamyl/polyglycol ester; pvp/dimethylaminoethyl methacrylate
copolymer; pvp/dimethylaminoethylmethacrylate/ polycarbamyl/polyglycol ester;
pvp/polycarbamyl polyglycol ester; pvp/vinyl acetate (va) copolymer; lanolin and lanolin derivatives; glyceryl monostearate; stearic acid; paraffins; beeswax; carnauba wax; tribehenin; polyalkylene polyols like polyethylene glycols; gelatin and gelatin derivatives; alginates; carbomers; polycarbophils; mefhacrylic acid polymers and copolymers; carrageenans; pectins; chitosans; cyclodextrins; lecithins; natural and synthetic gums containing galactomannans like xanthan gum, tragacanth, acacia, agar, guar gum, karaya gum, locust bean gum, gum arabic, and the like, used either alone or in combination thereof.
Pharmaceutical excipients used in the composition are selected from the group comprising 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 levocetirizine 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 levocetirizine 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; 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 200mg in combination with levocetirizine in the range from about 2 to about 25 mg.
Pharmacological study:
A randomized, open labeled, comparative evaluation of efficacy of a fixed dose combination of Nimesulide ER and Levocetirizine with Levocetirizine in symptomatic treatment of Acute Rhinosinusitis was carried out. The study design involved open labeled, comparative, Prospective, multicentric, Phase III trial with a total of 370 patients including dropouts which were enrolled for this study.
The overall efficacy was assessed on the basis of mean reduction in rhinosinusitis symptom score as assessed by Visual Analogue Scale (VAS). It was assumed that to detect a difference of 0.2 of Mean Visual Analogue Score with SD as 0.89, assuming an overall alpha error (a=0.05), the total sample size of 312 patients (excluding drop outs) was required for the study at 80% power. Considering an expected drop out rate of 13%, a total of approximately 360 patients were envisaged for enrollment.
Patients meeting the selection criteria were randomized to oral medication of fixed dose combination of Nimesulide ER (Nimesulide Extended Release) 100 mg and Levocetirizine 5 mg or Levocetirizine 5 mg per day. The drug was administered once daily till the symptoms subside for a maximum period of 10 days. The study required clinical attendance on day 0 (screening day), day 3, 5, 7 and day 9. Patient was advised to take the study treatment in morning and to conduct his symptom score evaluation in the evening to maintain uniformity in the study.
The efficacy was done by means of the Mean change in the rhinosinusitis symptom score (as assessed on patient self rated VAS) compared between the two arms and Responder rate in the two arms was compared at each assessment of the total symptom score by the patient. (A reduction by > 50%, in total rhinosinusitis symptom score from baseline defined as a responder).
Superiority of fixed dose combination of Nimesulide ER 100 mg and Levocetirizine 5 mg to Levocetirizine 5 mg alone was to be established if the lower bound of 95% confidence intervals of the difference between the test and the reference product (FDC of Nimesulide ER + Levocetirizine - Levocetirizine) for the primary efficacy endpoint (Mean reduction in
rhinosinusitis symptom score) is greater than zero (positive). This is equivalent to rejecting the null hypothesis of non-superiority of FDC of Nimesulide ER and Levocetirizine to Levocetirizine alone, in favor of the alternative hypothesis that FDC of Nimesulide ER and Levocetirizine is superior to Levocetirizine alone at the significance level (alpha) of 0.05.
Combination of Nimesulide ER + Levocetirizine showed a statistically significant decrease in Mean Symptoms Score at first assessment (6 hrs post dose) compared with Levocetirizine alone. Mean reduction in symptom scores in Nimesulide ER + Levocetirizine group was statistically significant till Day 7 when compared to Levocetirizine group (as mentioned hereinbelow table-
1).
Table 1: Mean Rhinosinusitis Symptom severity scores
(Table Removed)
The data as generated for mean reduction in Rhinosinusitis Symptom severity scores as mentioned hereinabove in Nimesulide ER + Levocetirizine group is represented in figl. It was observed that the lower bound of 95% confidence intervals of the difference between the test and the reference product (FDC of Nimesulide ER + Levocetirizine - Levocetirizine) for the primary efficacy endpoint (Mean reduction in rhinosinusitis symptom score) was greater than zero (positive) till day 5 of the treatment period. This indicated that the FDC of Nimesulide ER + Levocetirizine were superior to Levocetirizine alone in resolving the symptoms of acute rhinosinusitis up to day 5 of therapy (as mentioned hereinbelow table-2).
Table 2: Mean reduction (with 95% CI) in VAS from Baseline to each assessment.
(Table Removed)
The treatment responders were calculated. Treatment responder is defined as reduction by > 50%, in total symptom score from baseline. There were a significantly higher proportion of responders in the FDC of Nimesulide ER + Levocetirizine group as compared to Levocetirizine alone group from day 3 to day 8 (as mentioned hereinbelow tabIe-3 and represented herein in fig. 2).
Table 3: Number of Responder at each assessment points in Each Group
(Table Removed)
Conclusion:
The present study demonstrated that FDC of Nimesulide ER and Levocetirizine were more effective than Levocetirizine alone in treating the symptoms of acute rhinosinusitis.
In an embodiment the present invention provides a process for the manufacture of the
composition of the invention comprising the following steps:
i) processing Nimesulide alongwith pharmaceutically acceptable excipients,
ii) processing Levocetirizine alongwith pharmaceutically acceptable 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 composition comprising nimesulide and levocetirizine for the preparation of a medicament for treating allergic disorders namely rhinitis such as allergic rhinitis, acute and chronic rhinitis, seasonal allergic rhinitis, bronchitis, urticaria and the like.
In a further embodiment of the present invention, is provided a use of the composition of the invention for the management of one or more disease(s)/disorder(s) which includes prophylaxis, amelioration and/or treatment of allergic disorders namely rhinitis such as allergic rhinitis, acute and chronic rhinitis, seasonal allergic rhinitis, bronchitis, urticaria and the like.
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 200
2. Levocetirizine dihydrochloride 5
3. Microcrystalline Cellulose 95
4. Maize Starch 40
5. PVP K-30 4
6. Sodium Lauryl Sulphate 1
7. Magnesium Stearate 4
8. Colloidal Silicon Dioxide 6
9. Sodium Starch Glycollate 10
10. Purified Water q.s. Lost in processing Procedure:
Mix 1, 2, 3 & 4. Dissolve 5 & 6 in 10 and granulate the above and mix. Dry, sift and blend with 7, 8 & 9. Compress the tablets.
Example 2: Tablets
S. No. Ingredients Qty/ tab (mg)
1. Nimesulide 20
2. Levocetirizine dihydrochloride 10
3. Microcrystalline Cellulose 100
4. Maize Starch 40
5. PVP K-30 4
6. Sodium Lauryl Sulphate 1
7. Magnesium Stearate 4
8. Colloidal Silicon Dioxide 6
9. Sodium Starch Glycollate 10
10. Purified Water q.s. Lost in processing Procedure:
Mix 1, 2, 3 & 4. Dissolve 5 & 6 in 10 and granulate the above and mix. Dry, sift and blend with 7, 8 & 9. Compress the tablets.
Example 3: Tablets
S. No. Ingredients Qty/ tab (mg)
1. Nimesulide 100
2. Levocetirizine dihydrochloride 7.5
3. Caffeine citrate (equivalent 10 mg caffeine base) 20
4. Microcrystalline Cellulose 82.5
5. Maize Starch 40
6. PVP K-30 4
7. Sodium Lauryl Sulphate 1
8. Magnesium Stearate 4
9. Colloidal Silicon Dioxide 6
10. Sodium Starch Glycollate 10
11. Purified Water q.s. Lost in processing Procedure:
Mix 1, 2, 3, 4 & 5. Dissolve 6 & 7 in 11 and granulate the above and mix. Dry, sift and blend with 8, 9 & 10. Compress the tablets.
Example 4: Tablets
S. No. Ingredients Qty/ tab (mg)
1. Nimesulide 200
2. Levocetirizine dihydrochloride 5
3. Microcrystalline Cellulose 81
4. Maize Starch 30
5. Polyoxyl 40 Hydrogenated Castor Oil 1
6. PVP K - 30 2
7. Magnesium Stearate 2
8. Colloidal Silicon Dioxide 4
9. Sodium Starch Glycollate 5
10. Purified Water q.s. Lost in processing Procedure:
Mix 1, 2, 3 & 4. Dissolve 5 & 6 in 10 and granulate the above and mix. Dry, sift and blend with 7, 8 & 9. Compress the tablets.
Example 5: Tablets
S. No. Ingredients Qty/ tab (mg)
1. Nimesulide 50
2. Levocetirizine dihydrochloride 2.5
3. Microcrystalline Cellulose 210
4. Maize Starch 40
5. PVP K-30 4
6. Sodium Lauryl Sulphate 1
7. Magnesium Stearate 4
8. Colloidal Silicon Dioxide 6
9. Sodium Starch Glycollate 10
10. Purified Water q.s. Lost in processing Procedure:
Mix 1, 2, 3 & 4. Dissolve 5 & 6 in 10 and granulate the above and mix. Dry, sift and blend with 7, 8 & 9. Compress the tablets.
Example 6: Capsules
S. No. Ingredients Qty/ capsule (mg)
1. Nimesulide 200
2. Levocetirizine dihydrochloride 5
3. Maize Starch 75
4. Sodium Lauryl Sulphate 1.5
5. Colloidal Silicon Dioxide 3.5 Procedure:
Empty hard gelatin capsules. Sift 1, 3 & 5 through 30 mesh and 2 & 4 through 60 mesh. Mix uniformly and fill empty hard gelatin capsules at 285 mg.
Example 7: Capsules
S. No. Ingredients Qty/capsule (mg)
1. Nimesulide 200
2. Levocetirizine dihydrochloride 10
3. Maize Starch 80
4. Sodium Lauryl Sulphate 1.5
5. Colloidal Silicon Dioxide 3.5 Procedure:
Empty hard gelatin capsules. Sift 1, 3 & 5 through 30 mesh and 2 & 4 through 60 mesh. Mix uniformly and fill empty hard gelatin capsules at 295 mg.
Example 8: Capsules
S. No. Ingredients Qty/ capsule (mg)
1. Nimesulide 200
2. Levocetirizine dihydrochloride 7.5
3. Maize Starch 82.5
4. Sodium Lauryl Sulphate 1.5
5. Colloidal Silicon Dioxide 3.5 Procedure:
Empty hard gelatin capsules. Sift 1, 3 & 5 through 30 mesh and 2 & 4 through 60 mesh. Mix uniformly and fill empty hard gelatin capsules at 295 mg.
Example 9: Capsules
S. No. Ingredients Qty/ capsule (mg)
1. Nimesulide 200
2. Levocetirizine dihydrochloride 5
3. Maize Starch 85
4. Sodium Lauryl Sulphate 1.5
5. Colloidal Silicon Dioxide 3.5 Procedure:
Empty hard gelatin capsules. Sift 1, 3 & 5 through 30 mesh and 2 & 4 through 60 mesh. Mix uniformly and fill empty hard gelatin capsules at 295 mg.
Example 10: Capsules
S. No. Ingredients Qty/ capsule (mg)
1. Nimesulide 200
2. Levocetirizine dihydrochloride 2.5
3. Sodium Lauryl Sulphate 0.5
4. Colloidal Silicon Dioxide 1.5 Procedure:
Empty hard gelatin capsules. Sift 1 & 2 through 30 mesh and 3 & 4 through 60 mesh. Mix uniformly and fill in empty hard gelatin capsules.
Example 11: Sustained Release Bilayered Tablets A.
5. No. Ingredients Qty/ tab (mg)
1. Nimesulide 200
2. Lactose 115
3. Hydroxypropyl methylcellulose 25
4. Magnesium Stearate 2
5. Colloidal Silicon Dioxide 2
6. Purified water q.s. Lost in processing Procedure:
Mix 1 & 2. Dissolve 3 in 6 and granulate the above and mix. Dry, sift and blend with 4 & 5.
B.
S. No. Ingredients Qty/ tab (mg)
1. Levocetirizine dihydrochloride 10
2. Caffeine citrate (equivalent base 10 mg) 20
3. Lactose 205
4. Maize Starch 55
5. PVP K-30 3
6. Magnesium Stearate 3
7. Sodium Starch Glycollate 4
8. Purified Water q.s. Lost in processing Procedure:
Mix 1, 2, 3 & 4. Dissolve 5 in 8 and granulate the above and mix. Dry, sift and blend with 6 & 7. Compress the granules of A and B into bilayer tablets.
Example 12: Sustained Release Bilayered Tablets
A.
S. No. Ingredients Qty/ tab (mg)
1. Nimesulide 200
2. Lactose 100
3. Hydroxypropyl methylcellulose 35
4. Polyoxyl 40 Hydrogenated Castor Oil 2
5. PVP K-30 4
6. Magnesium Stearate 2
7. Colloidal Silicon Dioxide 2
8. Isopropyl Alcohol 2
Procedure:
Mix 1, 2 & 3. Dissolve 4 & 5 in 8 and granulate the above and mix. Dry, sift and blend with 6 & 7.
B.
S. No. Ingredients Qty/ tab (mg)
1. Levocetirizine dihydrochloride 10
2. Caffeine citrate (equivalent base 10 mg) 20
3. Lactose 205
4. Maize Starch 55
5. PVP K-30 3
6. Magnesium Stearate 3
7. Sodium Starch Glycollate 4
8. Purified Water q.s. Lost in processing Procedure:
Mix 1, 2, 3 & 4. Dissolve 5 in 8 and granulate the above and mix. Dry, sift and blend with 6 & 7.
Compress the granules of A and B into bilayer tablets.
Example 13: Sustained Release Bilayered Tablets
A.
S. No. Ingredients Qty/ tab (mg)
1. Nimesulide 100
2. Lactose 100
3. Hydroxypropylmethyl Cellulose 35
4. Polyoxyl 40 Hydrogenated Castor Oil 2
5. PVP K-30 4
6. Magnesium Stearate 2
7. Colloidal Silicon Dioxide 2
8. Isopropyl Alcohol 2 Procedure:
Mix 1, 2 & 3. Dissolve 4 & 5 in 8 and granulate the above and mix. Dry, sift and blend with 6 &
7.
B.
S. No. Ingredients Qty/ tab (mg)
1. Nimesulide 100
2. Levocetirizine dihydrochloride 7.5
3. Lactose 127.5
4. Maize Starch 55
5. PVP K-30 3
6. Magnesium Stearate 3
7. Sodium Starch Glycollate 4
8. Purified Water q.s. Lost in processing Procedure:
Mix 1, 2, 3 & 4. Dissolve 5 in 8 and granulate the above and mix. Dry, sift and blend with 6 & 7. Compress the granules of A and B into bilayer tablets.
Example 14: Sustained Release Bilayered Tablets
A.
S. No. Ingredients Qty/ tab (mg)
1. Nimesulide 100
2. Lactose 195
3. Levocetirizine dihydrochloride 5
4. Hydroxypropyl methyl cellulose 35
5. Polyoxyl 40 Hydrogenated Castor Oil 2
6. PVP K-30 4
7. Magnesium Stearate 2
8. Colloidal Silicon Dioxide 2
9. Isopropyl Alcohol 2 Procedure:
Mix 1, 2, 3 & 4. Dissolve 5 & 6 in 9 and granulate the above and mix. Dry, sift and blend with 7
&8.
B.
S. No. Ingredients Qty/ tab (mg)
1. Levocetirizine dihydrochloride 5
2. Lactose 230
3. Maize Starch 55
4. PVP K-30 3
5. Magnesium Stearate 3
6. Sodium Starch Glycollate 4
7. Purified Water q.s. (lost in processing) Procedure:
Mix 1, 2 & 3. Dissolve 4 in 7 and granulate the above and mix. Dry, sift and blend with 5 & 6. Compress the granules of A and B into bilayer tablets.
Example 15: Sustained Release Bilayered Tablets
A.
S. No. Ingredients Qty/ tab (mg)
1. Nimesulide 200
2. Lactose 100
3. Hydroxypropyl methylcellulose 35
4. Polyoxyl 40 Hydrogenated Castor Oil 2
5. PVP K-30 4
6. Magnesium Stearate 2
7. Colloidal Silicon Dioxide 2
8. Isopropyl Alcohol 2 Procedure:
Mix 1, 2 & 3. Dissolve 4 & 5 in 8 and granulate the above and mix. Dry, sift and blend with 6 &
7.
B.
S. No. Ingredients Qty/ tab (mg)
1. Levocetirizine dihydrochloride 2.5
2. Lactose 232.5
3. Maize Starch 55
4. PVP K-30 3
5. Magnesium Stearate 3
6. Sodium Starch Glycollate 4
7. Purified Water q.s. Lost in processing
Procedure:
Mix 1, 2 & 3. Dissolve 4 in 7 and granulate the above and mix. Dry, sift and blend with 5 & 6. Compress the granules of A and B into bilayer tablets.
Example 16: Bilayer tablets comprising nimesulide and levocetirizine
A) Nimesulide and levocetirizine in immediate release layer:
S. No. Ingredients Qty/ tab (mg)
1. Nimesulide (micronized) 25
2. Sodium Lauryl Sulphate 0.75
3. Lactose 41.36
4. Croscarmellose sodium 1.88
5. Maize starch 9.78
6. Color lake of sunset yellow 0.53
7. Polyvinylpyrrolidone K-30 0.75
8. Purified water q.s. Lost in processing
9. Levocetirizine dihydrochloride 5
10. Magnesium stearate 0.4
11. Croscarmellose sodium 3.63
12. Colloidal silicon dioxide 0.63
13. Polyvinylpyrrolidone K-30 1.25
14. Colour lake of sunset yellow 0.04 Procedure:
i) Comill nimesulide and sodium lauryl sulphate together.
ii) Comill material of step (i), lactose, croscarmellose sodium together and then sift through
mesh size #30. iii) Sift the color of sunset yellow and starch through sieve of mesh size # 100. iv) Mix materials of step (ii) and (iii) together.
v) Prepare binder solution by mixing polyvinylpyrrolidone K-30 in purified water, vi) Mix the binder solution of step (v) with the material of step (iv) to prepare the granules, vii) Dry the granules of step (vi) followed by sifting, viii) Sift levocetirizine, croscarmellose sodium, colloidal silicon dioxide and
polyvinylpyrrolidone K-30 together and pass through sieve of mesh size #40.
ix) Sift magnesium stearate and colour lake of sunset yellow through sieve of mesh size
#100. x) Mix the material of step (viii) and (ix) together, xi) Mix the material of step (x) with the granules of step (vii) to finally obtain the immediate
release granules.
B) Nimesulide in extended release layer:
S. No. Ingredients Qty/ tab (mg)
1. Nimesulide (micronized) 75
2. Lactose 34.12
3. Docusate sodium 1.5
4. Polyvinylpyrrolidone K-30 1.5
5. Purified water q.s. Lost in processing
6. Hydroxypropyl methylcellulose K4MCR 26.25
7. Colloidal silicon dioxide 0.75
8. Magnesium stearate 0.75
9. Colour lake of quinoline yellow 0.375
10. Sodium lauryl sulphate 0.38
11. Polyvinylpyrrolidone K-30 1.5
12. Colloidal silicon dioxide 0.75
13. Magnesium stearate 0.75
14. Colour lake of quinoline yellow 0.375 Procedure:
i) Sift nimesulide and lactose together through sieve of mesh size #30.
ii) Prepare the binder solution by mixing docusate sodium in purified water.
iii) Prepare the granules by mixing material of step (i) with step (ii).
iv) Dry the granules of step (iii) followed by sifting the granules.
v) Sift hydroxypropyl methylcellulose, colloidal silicon dioxide, sodium lauryl sulphate
together through sieve of mesh size #40.
vi) Sift color lake of quinoline yellow and magnesium stearate through sieve of mesh size
#100.
vii) Mix the materials of step (iv), (v) and (vi) together.
viii) Compact the mixture of step (vii) to obtain granules and pass the granules through sieve
of mesh size 20. ix) Sift polyvinylpyrrolidone K-30 and silicon dioxide through sieve of mesh size #40. x) Sift color lake of quinoline yellow and magnesium stearate through sieve of mesh size
#100. xi) Mix the material of step (ix) and (x) together, xii) The material of step (xi) was mixed with the material of step (viii) to obtain granules.
Preparation of bilayer tablet:
The bilayered tablet compression machine consists of two tablet compression machines with a transfer arm in between. The first layer is compressed using first tablet compression machine and it gets transferred to second tablet compression machine through the transfer arm. The precompressed tablets are then placed on the granules of the second layer and then compressed as bilayer tablet. The extended release granules of (B) step (xii) were compressed using first tablet compression machine. The precompressed extended release layer was transferred to second compression machine through transfer arm where it get placed upon the second layer granules i.e. immediate release granules of (A) step (xi) and both get compressed to obtain a bilayer tablet.
Example 17: Nimesulide (in osmotic pump) + Levocetirizine Tablets
S. No. Ingredients Qty/ tab (mg)
I Drug layer
1. Nimesulide 200
2. Sodium Chloride 5
3. Carbopol934P 100
4. Magnesium Stearate 1 Osmotic Layer
5. Polyethylene Oil 100
6. Carbopol974P 150
7. Sodium Chloride 10
8. Magnesium Stearate 1
9. Iron Oxide Red 0.5
The two layers are mixed separately and compressed into a bilayer tablet.
II Casing Layer
10. Cellulose Acetate 4%
11. PEG 600 4%
12. Purified Water 10%
13. Acetone 82%
Procedure: Dissolved Cellulose acetate in the solvents. Added the plasticizer to the solution. Coated the bilayer tablet with casing layer of suitable thickness. An orifice was drilled into the drug layer.
III Levocetirizine Coating
1. Levocetirizine hydrochloride 5
2. Hydroxypropyl methylcellulose 2
3. PEG 400 0.5
4. Isopropyl Alcohol q.s. (lost in processing)
5. Purified Water q.s. (lost in processing)
6. Iron oxide red 0.05 mg
Procedure: Prepared a coating solution and coated the tablets of step II for 10 mg/ tablet Levocetirizine dihydrochloride.
Example 18: Nimesulide (in osmotic pump) + Levocetirizine Tablets
I Drug layer
1. Nimesulide 200
2. Sodium Chloride 15
3. Carbopol934P 100
4. Magnesium Stearate 1 Osmotic Layer
5. Polyethylene Oil 100
6. Carbopol974P 150
7. Sodium Chloride 10
8. Magnesium Stearate 1
9. Iron Oxide Red 0.5
10. The two layers are mixed separately and compressed into a bilayer tablet.
II Casing Layer
11. Cellulose Acetate 4%
12. PEG 600 4%
13. Purified Water 10%
14. Acetone 82%
Procedure: Dissolved Cellulose acetate in the solvents. Added the plasticizer to the solution. Coated the bilayer tablet with casing layer of suitable thickness. An orifice was drilled into the drug layer. Ill Levocetirizine Coating
1. Levocetirizine hydrochloride 10
2. Hydroxypropyl methylcellulose 7
3. PEG 400 0.5
4. Isopropyl Alcohol q.s. (lost in processing)
5. Purified Water q.s. (lost in processing)
6. Iron oxide red 0.05
Prepared a coating solution and coated the tablets of step II for 10 mg/ tablet Levocetirizine
dihydrochloride.
Example 19: Nimesulide (in osmotic pump) + Levocetirizine Tablets
S. No. Ingredients Qty/ tab (mg)
I Drug layer
1. Nimesulide 200
2. Sodium Chloride 15
3. Carbopol934P 100
4. Magnesium Stearate 1 Osmotic Layer
5. Polyethylene Oil 100
6. Carbopol974P 150
7. Sodium Chloride 10
8. Magnesium Stearate 1
9. Iron Oxide Red 0.5
The two layers are mixed separately and compressed into a bilayer tablet.
II Casing Layer
10. Cellulose Acetate 4%
11. PEG 600 4%
12. Purified Water 10%
13. Acetone 82%
Procedure: Dissolved Cellulose acetate in the solvents. Added the plasticizer to the solution. Coated the bilayer tablet with casing layer of suitable thickness. An orifice was drilled into the drug layer. Ill Levocetirizine Coating
1. Levocetirizine hydrochloride 7.5
2. Hydroxypropyl methylcellulose 9.5
3. PEG 400 0.5
4. Isopropyl Alcohol q.s. (lost in processing)
5. Purified Water q.s. (lost in processing)
6. Iron oxide red 0.05
Procedure: Prepared a coating solution and coated the tablets of step II for 10 mg/ tablet Levocetirizine dihydrochloride.
Example 20: Nimesulide (in osmotic pump) + Levocetirizine Tablets
I Drug layer
1. Nimesulide 200
2. Sodium Chloride 15
3. Carbopol 934 P 100
4. Magnesium Stearate 1 Osmotic Layer
5. Polyethylene Oil 100
6. Carbopol 974 P 150
7. Sodium Chloride 10
8. Magnesium Stearate 1
9. Iron Oxide Red 0.5
The two layers are mixed separately and compressed into a bilayer tablet.
II Casing Layer
10. Cellulose Acetate 4%
11. PEG 600 4%
12. Purified Water 10%
13. Acetone 82%
Procedure: Dissolved Cellulose acetate in the solvents. Added the plasticizer to the solution. Coated the bilayer tablet with casing layer of suitable thickness. An orifice was drilled into the drug layer. Ill Levocetirizine Coating
1. Levocetirizine hydrochloride 5
2. Hydroxypropyl methylcellulose 12
3. PEG 400 0.5
4. Isopropyl Alcohol q.s. (lost in processing)
5. Purified Water q.s. (lost in processing)
6. Iron oxide red 0.05 mg
Prepared a coating solution and coated the tablets of step II for 10 mg/ tablet Levocetirizine dihydrochloride.
Example 21: Nimesulide (in osmotic pump) + Levocetirizine Tablets
S. No. Ingredients Qty/ tab (mg)
I Drug layer
1. Nimesulide 200
2. Sodium Chloride 15
3. Carbopol934P 100
4. Magnesium Stearate 1 Osmotic Layer
5. Polyethylene Oil 100
6. Carbopol974P 150
7. Sodium Chloride 10
8. Magnesium Stearate 1
9. Iron Oxide Red 0.5
The two layers are mixed separately and compressed into a bilayer tablet.
II Casing Layer
10. Cellulose Acetate 4%
11. PEG 600 4%
12. Purified Water 10%
13. Acetone 82%
Procedure: Dissolved Cellulose acetate in the solvents. Added the plasticizer to the solution. Coated the bilayer tablet with casing layer of suitable thickness. An orifice was drilled into the drug layer. III Levocetirizine Coating
1. Levocetirizine hydrochloride 2.5
2. Hydroxypropylmethyl Cellulose 14.5
3. PEG 400 0.5
4. Isopropyl Alcohol q.s. (lost in processing)
5. Purified Water q.s. (lost in processing)
6. Iron oxide red 0.05
Prepared a coating solution and coated the tablets of step II for 10 mg/ tablet Levocetirizine dihydrochloride.
Example 22: Metered dose inhaler
1. Nimesulide (within 1 to 5 microns) 33%
2. Levocetirizine dihydrochloride
3. (within 1 to 5 microns) 3.3%
4. Lactose 2%
5. Sorbitan Trioleate 0.5%
6. Propellant 114 30.60%
7. Propellant 12 30.60%
Procedure: Suspended 1, 2 & 3 in a mixture of 4, 5 and 6 and filled into metered dose inhalation assembling using cold filling apparatus as well known to people skilled in the art.
Example 23 : Injection
1. Nimesulide Potassium Salt 2 %
2. Levocetirizine dihydrochloride 0.33%
3. Benzyl Alcohol 2%
4. Ethylene diamine tetracetate disodium salt 0.002%
5. Water for injection q.s. to 100%
Procedure: Dissolve 4 in 90% of 5 by heating upto 80°C. Add 3 and mix. Then add 1 and 2 and stir till a clear solution is formed. Make up the volume to 100% with 5. Filter through 0.22µ nylon membrane filter and fill aseptically into vials/ ampoules.

We claim:
1. A composition comprising an antileukotriene, antihistaminic, anti-allergic and antiinflammatory agent comprising a non-steroidal antiinflammatory sulfonanilide preferably nimesulide as an active agent or pharmaceutically acceptable salts, esters, polymorphs, isomers, enantiomers, prodrugs, solvates, hydrates or derivatives thereof and a third generation anti-histamine (H1 blockers) preferably levocetirizine as an active agent or pharmaceutically acceptable salts, esters, polymorphs, isomers, enantiomers, prodrugs, solvates, hydrates, or derivatives thereof alongwith pharmaceutically acceptable excipients wherein nimesulide is from about 0.1% w/w to about 99.8% w/w, levocetirizine from about 0.1% w/w to about 99% w/w and pharmaceutical acceptable excipients from about 0.1% w/w to about 99.8% w/w and wherein the composition is used for the management of one or more disease(s)/disorder(s) which includes prophylaxis, amelioration and/or treatment of allergic disorders namely rhinitis such as allergic rhinitis, acute and chronic rhinitis, seasonal allergic rhinitis, bronchitis and the like.
2. A composition according to claim 1, wherein nimesulide and levocetirizine are present in ratio from about 2:1 to about 80:1, preferably nimesulide and levocetirizine are present in ratio from about 2:1 to about 40:1.
3. A composition according to claim 1 or 2, wherein the said composition is formulated in the form of powder, inert core, seeds selected from water-soluble systems or mixtures thereof and water-insoluble systems selected from microcrystalline cellulose, silicon dioxide, calcium carbonate, dicalcium phosphate anhydrous, dicalcium phosphate monohydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide or alone or in combination thereof, compacts, granules, pellets, beads, shear form particles, floss, alone or in combination thereof.
4. A composition according to any one of the preceding claims, wherein the said composition is in the form of a multiparticulate composition comprising a blend of one or more types of particles, inert core, seeds, granules, pellets, beads, compacts, minitablets, inlay tablets, tablet in tablet, shear form particles, floss, or the like, or combinations thereof, having different release characteristics or a multiparticulate composition made into a capsule or filled into a capsule.

5. A composition according to any one of the preceding claims, wherein the composition is in a controlled release form, sustained release form, timed release form, pulsatile release form, prolonged release form, extended release form or delayed release form, or a combination thereof.
6. A composition according to any one of the preceding claims, wherein the composition additionally comprises an immediate release composition.
7. A composition according to any one of the preceding claims, wherein the present invention provides a controlled release composition of nimesulide and levocetirizine formulated as multilayered compositions like a bilayered composition, wherein one fraction is provided as an immediate release or fast release fraction providing an immediate release of the active agent and the other fraction as an extended release fraction that releases the active agent over an extended period of time.
8. A composition according to any one of the preceding claims, wherein the present invention relates to preparation of a composition of nimesulide and levocetirizine formulated as multilayered compositions like a bilayered composition, wherein one fraction is provided as an immediate release or fast release fraction providing an immediate release of the active agent wherein the said fraction comprises nimesulide or levocetirizine or both and the other fraction as an extended release fraction that releases the active agent over an extended period of time wherein the said fraction comprises nimesulide optionally alongwith levocetirizine.
9. A composition according to claims 1 to 8, wherein the dose of nimesulide present in the form of immediate release or fast release fraction or extended release fraction is about 200 mg.
10. A composition according to claims 1 to 9, wherein the dose of nimesulide present in the form of immediate release or fast release fraction is about 100 mg and extended release fraction is about 100 mg.
11. A composition according to claims 1 to 10, wherein the dose of nimesulide present in the form of immediate release or fast release fraction is about 50 mg and extended release

fraction is about 150 mg or the dose of nimesulide present in the form of immediate release or fast release fraction is about 150 mg and extended release fraction is about 50 mg.
12. A composition according to claims 1 to 11, wherein the dose of nimesulide present in the form of immediate release or fast release fraction or extended release fraction is about 100 mg.
13. A composition according to claims 1 to 12, wherein the dose of nimesulide present in the form of immediate release or fast release fraction is about 50 mg and extended release fraction is about 50 mg.
14. A composition according to claims 1 to 13, wherein the dose of nimesulide present in the form of immediate release or fast release fraction is about 25 mg and extended release fraction is about 75 mg or wherein the dose of nimesulide present in the form of immediate release or fast release fraction is about 75 mg and extended, release fraction is about 25 mg.
15. A composition according to any one of the preceding claims, wherein the composition is in the form of a multilayer tablet, more preferably bilayer tablets or may be in the form of minitablets.
16. A composition according to any one of the preceding claims, wherein the first layer providing fast release of the active agent comprises one or more materials such as binders, disintegrants, fillers, rapidly soluble/dispersible excipients, wetting agents, and the like or mixtures thereof and the second layer providing extended release of the active agent comprises one or more materials such as release controlling polymers, binders, wetting agents, disintegrants, fillers, and the like or mixtures thereof.
17. A composition according to any one of the preceding claims, wherein the tablet or minitablet composition is filled into capsule comprising at least two fractions, one fraction being in the fast release or immediate release form and the other fraction being in the extended release form.

18. A composition according to claim 16, wherein the release controlling materials used in the present invention comprise materials selected from group comprising cellulose and cellulose derivatives; polyquaternium-1; polyvinyl acetate (homopolymer); polyvinyl acetate phthalate; propylene glycol alginate; polyvinyl methacrylate(pvm)/methacrylic acid(ma) copolymer; polyvinyl pyrrolidone (PVP); pvp/dimethiconylacrylate/polycarbamyl/polyglycol ester; pvp/dimethylaminoethyl methacrylate copolymer; pvp/dimethylaminoethylmethacrylate/ polycarbamyl/polyglycol ester; pvp/polycarbamyl polyglycol ester; pvp/vinyl acetate (va) copolymer; lanolin and lanolin derivatives; glyceryl monostearate; stearic acid; paraffins; beeswax; carnauba wax; tribehenin; polyalkylene polyols; gelatin and gelatin derivatives; alginates; carbomers; polycarbophils; methacrylic acid polymers and copolymers; carrageenans; pectins; chitosans; cyclodextrins; lecithins; natural and synthetic gums containing galactomannans.
19. A composition according to any of the preceding claims, wherein the pharmaceutical excipients used in the composition are selected from the group comprising 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, used either alone or in combination thereof.
20. A composition according to any of the preceding claims, wherein the composition further comprises one or more release modifiers selected from a group comprising wetting agents, solubilizers, surfactants, plasticizers, pore formers, pH modifiers and tonicity adjusting agents, or combination thereof.
21. A composition according to claim 19, wherein the pharmaceutically acceptable carrier of the present invention comprises a polymeric material selected from 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; non-ionic polymers; synthetic or natural polysaccharide and mixtures thereof.

22. A composition according to any one of the preceding claims, wherein nimesulide and levocetirizine may be combined with one or more suitable active agent(s) present in an immediate release form or controlled release form or a combination of both forms.
23. A composition according to claim 22, wherein the suitable active agents are selected from a group comprising antihistaminics; decongestants; psychoactive stimulants and derivatives thereof; antispasmodics; antipyretics or mixture thereof.
24. A composition according to any one of the preceding claims, wherein nimesulide can be used in the range from about 25 mg to about 200mg in combination with levocetirizine in the range from about 2 to about 25 mg.
25. A process for the manufacture of the composition of the invention, wherein the preparation of the composition comprises of the following steps:
i) processing Nimesulide alongwith pharmaceutically acceptable excipients, ii) processing Levocetirizine alongwith pharmaceutically acceptable excipients, iii) formulating the material of step i) and ii) into a suitable dosage form.
26. The pharmaceutical compositions and processes for the preparation of pharmaceutical
compositions substantially as herein described and illustrated by the examples.