Title of Invention	" A SYNERGISTIC ANTILEUKOTRIENE ANTIHISTAMINIC ANTI-ALLERGY ANTI-INFLAMMATORY COMPOSITION COMPRISING NIMESULIDE AND CETIRIZINE"
Abstract	A synergistic antileukotriene, antihistamine, anti-allergy and anti-inflammatory composition comprising Nimesuiide or salts thereof and Cetirizine or salts thereof wherein Nimesuiide is present in the composition from 1-53 parts, Cetirizine present in the composition is from 0.3 - 3.3 parts and pharmaceutical base and excipients present in the composition are from 44 - 98.5 parts is provided. Further the said composition is useful in allergic disorders such as rhinitis, bronchitis, asthma, urticaria and the like.

Title of Invention

" A SYNERGISTIC ANTILEUKOTRIENE ANTIHISTAMINIC ANTI-ALLERGY ANTI-INFLAMMATORY COMPOSITION COMPRISING NIMESULIDE AND CETIRIZINE"

Abstract

A synergistic antileukotriene, antihistamine, anti-allergy and anti-inflammatory composition comprising Nimesuiide or salts thereof and Cetirizine or salts thereof wherein Nimesuiide is present in the composition from 1-53 parts, Cetirizine present in the composition is from 0.3 - 3.3 parts and pharmaceutical base and excipients present in the composition are from 44 - 98.5 parts is provided. Further the said composition is useful in allergic disorders such as rhinitis, bronchitis, asthma, urticaria and the like.

Full Text	A SYNERGISTIC ANTILEUKOTRIENE ANTIHISTAMINIC ANTI-ALLERGY ANTIINFLAMMATORY COMPOSITION COMPRISING NIMESULIDE AND CETIRI2INE Technical Field The present invention relates to a novel antileukotnene, antihistaminic, antiallergic and antiinflammatory composition of non-steroidal antiinflammatory sulfonanilide and salts thereof With second generation antihistamines (H1. blockers) More particularly the invention relates to a novel composition of Nimesulide and Cetinzine in a pharmaceutically acceptable combination in a suitable pharmaceutical base acceptable and excipients More particularly the invention relates to a composition for use in allergic disorders namely rhinitis, bronchitis, asthma, urticaria etc 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 (lgE) 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 bronchoconstnction 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 leukotnene receptor antagonists or 5-iipoxygenase 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 All asthma are 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 mechantsms 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, 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 H-,-blockers) are the most widely used agents for the treatment of allergic conditions (Gong, H, Tashkin, D P, Dauphinee, B et al, J.AIIergy. 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 lgE-mediated histamine release from mast cells and basophils resulting in vasomotor rhinitis, urticaria and bronchial asthma in these patients (Bianco, S, Robuschi, M, Petngni, Getai, 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 antihistamine, 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, Passah, 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 bronchoconstnctors (Casolaro.V, et al 1993, Berti.F, et al 1990). All 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 leukotnene inhibiting activities of Nimesulide has not been reported so far, and by careful experimentation and application of scientific logic, the inventors combined Nimesulide with Cetirizme 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 observed by the inventors and described in the present invention that a combination of Nimesulide with Cetirizme is synergistic composition and of immense utility in asthma Other anti-inflammatory drugs used in chronic rhinitis, chronic bronchitis and bronchial asthma are cromolyn sodium, nedocromil and glucocorticoids. The glucocorticoid therapy is not without an accompanied risk of myriad side effects (Serafin, WE, 1996) Cromolyn sodium and nedocromil can only be given by inhalation, only about 1% of an oral dose of cromolyn is absorbed Even when inhaled, cromolyn sodium has to be taken 4 times daily due to its short half-life of 45-100 minutes Nedocromil is reported to leave a bad taste in mouth Several other anti-inflammatory agents have been assessed, mainly as steroid-sparing agents These include methotrexate, gold, troleandomycin, hydroxychloroquine, dapsone and cyclosporin But their efficacy has not been firmly established (Szefler, S., Antiinflammatory drugs in the treatment of allergic diseases., Medical Clinics of North America, 76, 1992, 953 - 975) US Patent 5658948 granted to ALLERGAN INC., discloses a formulation and method includes an acceptable drug, such as Prostaglandins, Flurbiprofen, Keterolac, Tromethamine, Cetinzine HCI, 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 Histidme is also useful in reducing the cytotoxicity of the formulation US Patent no 5627183 granted to SEPRACOR INC , discloses methods for utilizing optically pure (+) Cetinzine for the treatment of urticaria in humans while avoiding the concomitant liability of adverse effects associated with the racemic mixture of Cetinzine US Patent no. 5419898 granted to SENJU PHARMACEUTICAL Co., LTD., discloses an anti-allergic composition for opthalmic or nasal use, comprising cetinzine 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. WO 9406429 granted to SEPRACOR INC., discloses methods and compositions utilizing optically pure (-) cetinzine 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 cetinzine The optically pure {-) isomer is also useful for the treatment of allergic asthma and chronic and physical urticaria (-) Cetinzine is an inhibitor of eosinophil chemotaxis and is therefore useful in the treatment of other conditions related to eosinophils such as allergic asthma, seasonal allergic rhinitis, atopic dermatitis, some parasitic diseases, some chronic obstructive lung diseases and certain gastrointestinal and genitourinary disorders No pharmacological composition has been reported in literature as well as no product is available where Nimesulide and salts thereof is employed in combination with second generation antihistamine Fixed dose drug combinations are rapidly being re-introduced in clinical practice after several years of ostracism as these have the potential of acting synergistically and predictably It is the objective of the present invention to provide a novel antileukotnene, antihistaminic, anti-allergic and antiinflammatory composition containing Nimesulide and salts thereof and Cetirizine It is the further objective of the present invention to provide a novel process for the manufacture of an antileukotnene, antihistaminic, anti-aiiergic and antiinflammatory composition containing Nimesulide and salts thereof and Cetirizine it is a further objective of the invention to provide a novel metered dose inhaler nasal delivery system for the above composition It is a further objective of the invention to provide a novel injectable delivery system of the above composition It is a further objective of the invention to provide a novel topical delivery system of the above composition It is a further objective of the invention to provide the above composition to be taken orally by way of a pediatric suspension/capsule/tablet SUMMARY OF THE INVENTION The present invention relates to a novel composition of Nimesulide and salts thereof and Cetirizme possessing antileukotriene, antihistaminic, antiallergic and antiinflammatory action The composition is useful in the cure of allergic disorders such as rhinitis, bronchitis, asthma, urticaria and the like 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- 71, Prostaglandins, teukotnenes, 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 teukotnenes 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 (H-treceptor) 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 antihistamines 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 tn addition to its Hr antagonizing action Cetirizine inhibits inflammatory celt 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 10mg 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 antileukotnene, antihistaminic, anti-allergy and antiinflammatory composition By careful experimentation the inventors have found that although Nimesulide does not block an exogenousfy 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 leukotnene action which is synergistic when the drugs are combined as evident from the Table 3. In accordance with the present invention there is disclosed a novel composition of Nimesulide and salts thereof and Cetirizine possessing antileukotnene, antihistaminic, anti-allergy and antiinflammatory action In accordance with a preferred embodiment of the invention the composition comprises Nimesulide from 1 to 53 parts, Cetirizine from 0 3 to 3 3 parts and pharmaceutical base and excipients from 44 to 98.5 parts. The anti-inflammatory, antileukotnene, antihistaminic and antiallergic composition in accordance with the present invention can be in the form of a tablet, injection, once a day composition, metered dose inhaler, topical gel, capsules, sustained release tablets and the like The anti-inflammatory, antileukotriene, antihistaminic and antiallergic composition in accordance with the present invention is prepared by the process which comprises the following steps - Nimesulide and Cetinzine are blended uniformly and passed through a fine sieve to reduce the particle size in the form of a fine powder and any of the following steps affected to obtain the product in the desired form, 1 the said uniform powder is blended with excipients at 25 + 2°C temperature and 50± 5% Relative humidity and filled in empty gelatin capsules to yield capsule dosage form 2. the uniform blend is granulated with granutating fluid at ambient conditions and dried at temperature not exceeding 60°C for a period of time so as to yield moisture content around 1% After reduction in size and lubrication, the granules are compressed into tablets at 25 ± 2°C temperature and 50 + 5% Relative humidity 3. the uniform blend is dissolved in suitable diluents and a gelling agent is added to form a topical gel or a transdermal gel. 4 the uniform blend is dissolved in a solvent suitable for parenteral administration The solution is affected at temperature range of 25 ° C to 35 ° C under normal conditions of stirring The solution is then filtered, sterilized and asepticaily filled in ampoules Alternatively, the ampoules are autoclaved at around 121 ° C for a period of about 30 minutes Preferably the composition comprises Nimesuiide and Cetinzine in the ratio of 1:5 to 1 40 Preferably the granulating fluid for granulating the fine powdered blend of Nimesuiide and Cetirizine is Maize starch and/or Polyvinylpyrrolidone Preferably the diluents and gelling agent for dissolving the fine blend of Nimesuiide and Cetirizine for topical and transdermal ge! are Dimethylsulphoxide and/or dirnethylacetamide and Carbopol ® and/or Hydroxypropy) cellulose Preferably the solvent for dissolving the uniform blend of Nimesuiide and Cetirizine for parenteral administration is Water and/or dimethylacetamide. EXPERIMENT TO STUDY THE ANTIASTHMATIC ACTIVITY OF NIMESULIDE AND CETIRIZINE Antiasthmatic activity of Nimesulide and Cetinzine was studied on histamine-induced, egg albumin-induced and leukotnene-D4-induced brochospasm in guinea pig in vivo. Materials & Method : Animals Guinea pig 300 - 350 g either sex, housed in the Central Animal house of Panacea Biotec Ltd , Lalru and kept under standard laboratory conditions, were used Procedure Urethane - anaesthetised, 18-h fasted guinea pigs 300 - 350 g were used d-tubocurarme (3 mg/kg i v) was administered to prevent spontaneous respiratory movements Guinea pigs were artificially ventilated by a UGO Basile Rodent ventilator through a tracheal cannula at a rate of 60 strokes/min. and a stroke volume of 1 ml/100 g Insufflation pressure was measured by attaching a pressure transducer (UGO Basile) to a Gemini two channel recorder (UGO Basile) A polyethylene catheter was inserted in the left jugular vein for iv administration of drugs The animals were stabilized for 10 minutes % Insufflation pressure was calculated as the % increase in pressure due to constriction of the airways with respect to the basal pressure Less % insufflation pressure denotes less bronchoconstriction caused due to the effect of test compounds with respect to the basal tone of the airways Drugs Nimesulide and Cetinzine dihydrochlonde (Panacea Biotec Ltd., India), Histamine, Leukotnene D4 and Urethane (all from Sigma, USA), d-tubocuranne chloride (Diosynth, Netherlands), Egg albumin (Qualigens Fine Chemicals, Bombay). Cetirizine was dissolved in deionized water Nimesulide was suspended in 0 25% Xanthum gum. Histamine and d-tubocuranne chloride were dissolved in saline and Leukotnene D4 was diluted with Methanol and Ammonium Acetate buffer in a ratio of 70 30 at a pH of 5 4 Statistical Analysis Unpaired students t-test was applied and p Experimental Protocol Group I Histamine treated Histamine challenge (5 ng/kg and 10 _1g/kg iv) was given to the animal and increase in insufflation pressure was noted in the control group (Table 1) Test compounds (Nimesulide, Cetinzine, Ntmesulide + Cetirizine) were given 2 hours before histamine challenge in the test group Any decrease in the insufflation pressure was noted (Table. 1) Group II Egg albumin treated Guinea pigs were sensitized by injections of 100 mg of Egg albumin ip and 100 mg Egg albumin sc in saline Guinea pigs were used after day 21st Animals were chaffenged with 1 mg/kg and 2 mg/kg of Egg albumin and increase in insufflation pressure was noted (Table 2) Group III Leukotriene D4 treated LTD4 challenge (1 pg/kg and 2 ug/kg) was given to the animal and increase in insufflation pressure was noted in the control group (Table 3). Test compounds (Nimesulide, Cetinzine, Nimesulide + Cetinzine) were given 2 hours before LTD4 challenge in the test group Any decrease in the insufflation pressure was noted (Table 3) with respect to the control group Results : Cetirizine (1 66 mg/kg) significantly reduced the histamine (5 and 10 Dg/kg) induced increase in insufflation pressure Nimesulide (single dose, S, 1166 mg/kg and double dose, D, 23 32 mg/kg) had no significant inhibitory effect on the insufflation pressure Combination of Nimesulide (single dose, S) and Cetinzine showed no significant effect whereas Nimesulide (double dose, D) and Cetirizine had potent antihistaminic effect Nimesulide (1166 mg/kg) significantly reduced the egg albumin induced (1 mg/kg, 2 mg/kg) insufflation pressure, the effect of Nimesulide was 92 0 to 94.0% Cetirizine (1.66 mg/kg) also reduced the insufflation pressure but it is slightly less than that of Nimesulide In combination Nimesulide and Cetinzine also showed a highly significant effect as compared to the control (Table. 2). Nimesulide (11 66 mg/kg) had no effect on the insufflation pressure whereas Cetirizine (1 16 mg/kg) significantly blocked LTD4-induced contractions Combination of Nimesulide (11 66 mg/kg) and Cetirizine (1.16 mg/kg) potently blocked the leukotriene induced contractions Double dose Nimesulide (23 32 mg/kg) itself had a potent inhibitory effect on LTD4-induced contractions. Combination of Nimesulide (23 32 mg/kg) and Cetirizine (1 16 mg/kg) had the maximum (H 90%) inhibitory action on LTD4-induced contractions (Table. 3). Discussion Cetirizine but not Nimesulide acts as a potent antihistaminic in guinea pig model of bronchoconstriction Nimesulide double dose in combination with Cetirizine shows a potent antihistaminic effect which may be due to Cetirizine alone. Hence Nimesulide itself has no antihistaminic action once histamine has been released to occupy the receptors Nevertheless, Nimesulide can have an inhibitory effect on the pre-formed allergic mediators thus having an indirect antihistaminic action Preliminary study reports suggest that Nimesulide has a highly potent anti-allergic action in antigen (egg albumin) induced bronchospastic studies. Combination of Nimesulide and Cetinzine offer a dual protection in cases of allergic asthma, as Cetirizine is a potent antihistaminic It is inferred that Nimesulide - Cetinzine combination can be used as a prophylactic for chronic allergic asthma Cetirizine and double-dose Nimesulide, both can block LTD4-induced bronchoconstnction in guinea pigs Combination of Cetirizine and Nimesulide is a very potent blocker of LTD4-mduced bronchoconstnction This effect may be due to selective inhibition of phosphodiesterase (PDE) isozyme III and IV. Such inhibition has been shown substantially anti-inflammatory effects in vivo PDE4 inhibitors act by inducing an increase in the intracellular levels of cAMP which in turn suppresses inflammatory cell activity and causes relaxation of airway smooth muscles Nimesulide is reported to be a potent PDE IV inhibitor in vitro with an IC50 H 40 µM. That the combination is effectively blocking exogenously administered LTD4 implies that either Nimesulide and Cetirizine have a combined PDE III and PDE IV isozyme inhibiting capacity or Nimesulide/Cetinzine are working as LTD4 receptor antagonists The inhibition, by this combination, of the antigen-induced (egg albumin) bronchoconstnction may also be through its capacity to act as a PDE lll/IV inhibitor These preclinical results indicate the potential therapeutic efficacy of the combination of Nimesulide and Cetirizine in the treatment of allergic inflammatory airway disorders such as asthma Inference As asthma is now viewed primanly as a chronic allergic disease with an underlying inflammatory activity the ideal antiasthmatic drug should possess the following three properties Antiallergic action Anti Leukotriene action Antihistamine action Nimesulide and Cetirizine when given together posses all the three properties as is evident from the following observations 1 Cetirizine (1 16 mg/kg p o) produces a decrease in % insufflation pressure by 42.86%, Nimesulide (23.32 mg/kg p o) by 61 0% whereas Nimesulide + Cetirizine synergistically decrease the pressure by 80 21% in case of LTD4-mduced bronchoconstriction in guinea pigs (Table. 3). 2. Cetinzine (1 16 mg/kg p o) produces a decrease in % insufflation pressure by 70 52%, Nimesulide (11 66 mg/kg p,o) by 90 24% whereas Nimesulide + Cetiriztne synergistically decrease the pressure by 96.57% in case of egg albumin induced bronchoconstriction in guinea pigs (Table. 2). 3. In case of histamine induced bronchoconstriction Cetinzine {1.16 mg/kg p o) decreases the % insufflation pressure by 62.71% whereas Nimesulide shows no antihistamine effect. Hence a combination of these two is required to produce a synergistic action in case of 1 and 2 as stated above In case of 3 any histamine which escapes the mast cell stabilizing action of Nimesulide and gets released would be blocked by Cetiriztne to reach the receptor sites and bronchoconstriction would be prevented. These preclinical results indicate a three pronged antiasthmatic action provided by the combination of Nimesulide and Cetinzine The inflammation associated with asthmatic decrease wilt be reduced by Nimesulide by selective COX-2 inhibition activity Therefore this invention teaches an art of treating asthma by a combination of NSAID Nimesulide alongwith an antihistamine drug Cetinzine and this combination due to a synergistically pharmacological action will have usefulness to elevate symptoms of asthmatic and related disorders in a much better fashion than the known agents for the drugs alone The invention will now be described with reference to the accompanying examples which are illustrative and by means should be construed to limit the scope of the invention- Example I Tablets 1. Nimesulide 200 mg 2 Cetirizine dihydrochlonde 10 mg 3 Microcrystallme Cellulose 100 mg 4. Maize Starch 40 mg 5 PVP K-30 4 mg 6 Sodium Lauryl Sulphate 1 mg 7. Magnesium Stearate 4 mg 8. Colloidal Silicon Dioxide 6 mg 9 Sodium Starch Glycollate 10 mg 10 Purified Water Mix 1, 2, 3 & 4 Dissolve 5 & 6 in 10 and granulate the above and mix Dry, soft and blend wrth 7, 8 & 9 Compress the tablets Example II Tablets 1 Nimesulide 200 mg 2. Cetirizine dihydrochlonde 5 mg 3 Microcrystallme Cellulose 81 mg 4 Maize Starch 30 mg 5 Polyoxyl 40 Hydrogenated Castor Oil 1 mg 6 PVP K-30 2 mg 7 Magnesium Stearate 2 mg 8 Colloidal Silicon Dioxide 4 mg 9 Sodtum Starch Glycollate 5 mg 10 Purified Water Mix 1, 2, 3 & 4. Dissolve 5 & 6 in 10 and granulate the above and mix. Dry, soft and blend with 7, 8 & 9 Compress the tablets Example III: Topical Gel 1 Nimesulide 1% 2 Cetirizine (Suitable Pharmaceutical form) 0.5% 3. Carbopol 1% 4 Hydroxypropyi Cellulose 1 5% 5. PEG 400 25% 6. Dimethyl Sulphoxide 15% 7 Isopropyl Alcohol 40% 8. Hydrochloric Acid q s to adjust pH 9 Propylene Glycol 5% 10 Purified Water 10% Disperse 1 in 5, 6 and 9 separately Dissolve 2 in 80% of 10. Disperse 3 & 4 in 7 with vigorous stirring. Add the two solutions to the dispersion. Allow to smell. Dilute 8 in remainder of 10 and adjust pH in the range of 2 to 6 Example IV : Capsules 1. Nimesulide 200 mg 2 Cetinzine dihydrochlonde 10mg 3 Maize Starch 80 mg 4 Sodium Lauryl Sulphate 1 5 mg 5 Colloidal Sfficon Dioxide 3 5 mg Empty hard gelatin capsules Sift 1, 3 & 5 through 30 mesh and 2 & 4 through 60 mesh. Mix uniformily and fill empty hard gelatin capsules at 295 mg Example V : Sustained Release Bilayered Tablets A. 1 Nimesulide 200 mg 2 Lactose 100 mg 3 Hydroxypropylmethyl Cellulose 35 mg 4 Polyoxyl 40 Hydrogenated Castor Oil 2 mg 5 PVP K-30 4 mg 6. Magnesium Stearate 2 mg 7. Colloidal Silicon Dioxide 2 mg 8. Isopropyl Alcohol 2 mg Mix 1, 2 & 3 Dissolve 4 & 5 in 8 and granulate the above and mix Dry, soft and blend with 6 & 7 B. 1. Cetinzine dihydrochloride 10 mg 2. Lactose 225 mg 3 Maize Starch 55 mg 4. PVP K-30 3 mg 5. Magnesium Stearate 3 mg 6 Sodium Starch Glycollate 4 mg 7. Purified Water Mix 1, 2 & 3 Dissolve 4 in 7 and granulate the above and mix Dry, soft and blend with 5 & 6. Compress the granules of A and B into bilayer tablets Example VI : Nimesulide (in osmotic pump) + Cetirizine Tablets I Drug layer Nimesulide 200 mg Sodium Chloride 15 mg Carbopol934P 100 mg Magnesium Stearate 1 mg Osmotic Layer Polyethylene Oil 100 mg Carbopol974 P 150mg Sodium Chloride 10 mg Magnesium Stearate 1 mg Iron Oxide Red 0 5 mg The two layers are mixed separately and compressed into a bilayer tablet II Casing Layer Cellulose Acetate 4% PEG 600 4% Purified Water 10% Acetone 82% 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 Cetirizine Coating Cetinzine hydrochloride 10 mg Hydroxypropylmethyl Cellulose 7 mg PEG 400 0.5 mg Isopropyl Alcohol q.s Purified Water q s Iron oxide red 0 05 mg Prepared a coating solution and coated the tablets of step II for 10 mg/ tablet Cetirizine dihydrochloride. Example VII: Metered dose inhaler 1 Nimesulide (within 1 to 5 microns) 33% 2. Cetirizine dihydrochloride (within 1 to 5 microns) 3 3% 3 Lactose 2% 4 Sorbitan Trioleate 0 5% 5. Propeflant114 30 60% 6 Propellant12 30 60% 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 VIII : Injection 1 Nimesulide Potassium Salt 2 % 2. Cetirizine dihydrochloride 0 33% 3 Benzyl Alcohol 2% 4 Ethylene diamine tetracetate disodium salt 0 002% 5 Water for injection q s to 100% 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 22u nylon membrane filter and fill aseptically into vials/ ampoules We claim: 1. A synergistic antileukotriene, antihistaminic, anti-allergy and anti-inflammatory composition comprising Nimesulide or salts thereof and Cetirizine or salts thereof wherein Nimesulide is present in the composition from 1-53 parts, Cetirizine present in the composition is from 0.3 - 3.3 parts and pharmaceutical base and excipients present in the composition are from 44 -98.5 parts. 2. A process for making a synergistic anti-inflammatory, antileukotriene, antihistaminic and antiallergic composition of Nimesulide or salts thereof with Cetirizine or salts thereof as claimed in claim 1 which comprises blending Nimesulide and Cetirizine uniformly and passing the mixture through a fine sieve to reduce the particle size in the form of a fine powder, subjecting the said powder to any one or all the undermentioned steps to produce the desired product: a) blending the said powder with excipients at 25 ± 2°C temperature and 50 ± 5% relative humidity and filled in empty gelatin capsules to yield capsule dosage form. b) granulating the said powder at ambient conditions and drying at temperature not exceeding 60°C for a period of time so as to yield moisture content around 1%, subjecting the resultant blend to reduction in size and lubrication, compressing into tablets at 25 ± 2°C temperature and 50 ± 5% Relative humidity. c) dissolving the said powder in diluents and a gelling agent to form a topical gel or a transdermal gel. d) dissolving the said powder in solvent suitable for parenteral administration at a temperature range of 25°C to 35°C under conditions of stirring, filtering and sterilizing the resultant solution. 3. A process as claimed in claim 2 wherein the composition comprises Nimesulide and Cetirizine in the ratio of 2:1 to 40:1, 4. A process as claimed in claim 2 wherein the granulating fluid for granulating the fine powdered blend of Nimesulide and Cetirizine is Maize starch and/or Polyvinylpyrrolidone. 5. A process as claimed in claim 2 (c) wherein the diluent is Dimethylsuiphoxide and/or dimethylacetamide 6. A process as claimed in claim 2 (c) wherein the gelling agent is Carbopol and/or Hydroxypropyl cellulose. 7. A process as claimed in claim 2 (d) wherein the solvent is water and/or dimethylacetamide. 8. A synergistic antileukotriene, antihistaminic, anti-allergy and anti-inflammatory composition substantially as herein described with reference to the accompanying examples. 9. A process for the preparation of a synergistic antileukotriene, antihistaminic, anti-allergy and anti-inflammatory composition substantially as herein described with reference to the accompanying examples.

Full Text

A SYNERGISTIC ANTILEUKOTRIENE ANTIHISTAMINIC ANTI-ALLERGY ANTIINFLAMMATORY COMPOSITION COMPRISING NIMESULIDE AND CETIRI2INE
Technical Field
The present invention relates to a novel antileukotnene, antihistaminic, antiallergic and antiinflammatory composition of non-steroidal antiinflammatory sulfonanilide and salts thereof With second generation antihistamines (H1. blockers)
More particularly the invention relates to a novel composition of Nimesulide and Cetinzine in a pharmaceutically acceptable combination in a suitable pharmaceutical base acceptable and excipients
More particularly the invention relates to a composition for use in allergic disorders namely rhinitis, bronchitis, asthma, urticaria etc
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 (lgE) 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 bronchoconstnction 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 leukotnene receptor antagonists or 5-iipoxygenase 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 All asthma are 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 mechantsms 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, 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 H-,-blockers) are the most widely used agents for the treatment of allergic conditions (Gong, H, Tashkin, D P, Dauphinee, B et al, J.AIIergy. 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 lgE-mediated histamine release from mast cells and basophils resulting in vasomotor rhinitis, urticaria and bronchial asthma in these patients (Bianco, S, Robuschi, M, Petngni, Getai, 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 antihistamine, 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, Passah, 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 bronchoconstnctors (Casolaro.V, et al 1993, Berti.F, et al 1990).
All 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 leukotnene inhibiting activities of Nimesulide has not been reported so far, and by careful experimentation and application of scientific logic, the inventors combined Nimesulide with Cetirizme 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 observed by the inventors and described in the present invention that a combination of Nimesulide with Cetirizme is synergistic composition and of immense utility in asthma
Other anti-inflammatory drugs used in chronic rhinitis, chronic bronchitis and bronchial asthma are cromolyn sodium, nedocromil and glucocorticoids. The glucocorticoid therapy is not without an accompanied risk of myriad side effects (Serafin, WE, 1996) Cromolyn sodium and nedocromil can only be given by inhalation, only about 1% of an oral dose of cromolyn is absorbed Even when inhaled, cromolyn sodium has to be taken 4 times daily due to its short half-life of
45-100 minutes Nedocromil is reported to leave a bad taste in mouth Several other anti-inflammatory agents have been assessed, mainly as steroid-sparing agents These include methotrexate, gold, troleandomycin, hydroxychloroquine, dapsone and cyclosporin But their efficacy has not been firmly established (Szefler, S., Antiinflammatory drugs in the treatment of allergic diseases., Medical Clinics of North America, 76, 1992, 953 - 975)
US Patent 5658948 granted to ALLERGAN INC., discloses a formulation and method includes an acceptable drug, such as Prostaglandins, Flurbiprofen, Keterolac, Tromethamine, Cetinzine HCI, 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 Histidme is also useful in reducing the cytotoxicity of the formulation
US Patent no 5627183 granted to SEPRACOR INC , discloses methods for utilizing optically pure (+) Cetinzine for the treatment of urticaria in humans while avoiding the concomitant liability of adverse effects associated with the racemic mixture of Cetinzine
US Patent no. 5419898 granted to SENJU PHARMACEUTICAL Co., LTD., discloses an anti-allergic composition for opthalmic or nasal use, comprising cetinzine 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.
WO 9406429 granted to SEPRACOR INC., discloses methods and compositions utilizing optically pure (-) cetinzine 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 cetinzine The optically pure {-) isomer is also useful for the treatment of allergic asthma and chronic and physical urticaria (-) Cetinzine is an inhibitor of eosinophil chemotaxis and is therefore useful in the treatment of other conditions related to eosinophils such as allergic asthma,
seasonal allergic rhinitis, atopic dermatitis, some parasitic diseases, some chronic obstructive lung diseases and certain gastrointestinal and genitourinary disorders
No pharmacological composition has been reported in literature as well as no product is available where Nimesulide and salts thereof is employed in combination with second generation antihistamine Fixed dose drug combinations are rapidly being re-introduced in clinical practice after several years of ostracism as these have the potential of acting synergistically and predictably
It is the objective of the present invention to provide a novel antileukotnene, antihistaminic, anti-allergic and antiinflammatory composition containing Nimesulide and salts thereof and Cetirizine
It is the further objective of the present invention to provide a novel process for the manufacture of an antileukotnene, antihistaminic, anti-aiiergic and antiinflammatory composition containing Nimesulide and salts thereof and Cetirizine
it is a further objective of the invention to provide a novel metered dose inhaler nasal delivery system for the above composition
It is a further objective of the invention to provide a novel injectable delivery system of the above composition
It is a further objective of the invention to provide a novel topical delivery system of the above composition
It is a further objective of the invention to provide the above composition to be taken orally by way of a pediatric suspension/capsule/tablet
SUMMARY OF THE INVENTION
The present invention relates to a novel composition of Nimesulide and salts thereof and Cetirizme possessing antileukotriene, antihistaminic, antiallergic and antiinflammatory action
The composition is useful in the cure of allergic disorders such as rhinitis, bronchitis,
asthma, urticaria and the like
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- 71, Prostaglandins, teukotnenes, 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 teukotnenes 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 (H-treceptor) 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 antihistamines 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 tn addition to its Hr antagonizing action Cetirizine inhibits inflammatory celt 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 10mg 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 antileukotnene, antihistaminic, anti-allergy and antiinflammatory composition
By careful experimentation the inventors have found that although Nimesulide does not block an exogenousfy 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 leukotnene action which is synergistic when the drugs are combined as evident from the Table 3.
In accordance with the present invention there is disclosed a novel composition of Nimesulide and salts thereof and Cetirizine possessing antileukotnene, antihistaminic, anti-allergy and antiinflammatory action
In accordance with a preferred embodiment of the invention the composition comprises Nimesulide from 1 to 53 parts, Cetirizine from 0 3 to 3 3 parts and pharmaceutical base and excipients from 44 to 98.5 parts.
The anti-inflammatory, antileukotnene, antihistaminic and antiallergic composition in accordance with the present invention can be in the form of a tablet, injection, once a day composition, metered dose inhaler, topical gel, capsules, sustained release tablets and the like
The anti-inflammatory, antileukotriene, antihistaminic and antiallergic composition in accordance with the present invention is prepared by the process which comprises the following steps -
Nimesulide and Cetinzine are blended uniformly and passed through a fine sieve to reduce the particle size in the form of a fine powder and any of the following steps affected to obtain the product in the desired form,
1 the said uniform powder is blended with excipients at 25 + 2°C
temperature and 50± 5% Relative humidity and filled in empty gelatin capsules to yield capsule dosage form
2. the uniform blend is granulated with granutating fluid at ambient conditions and dried at temperature not exceeding 60°C for a period of time so as to yield moisture content around 1% After reduction in size and lubrication, the granules are compressed into tablets at 25 ± 2°C temperature and 50 + 5% Relative humidity
3. the uniform blend is dissolved in suitable diluents and a gelling agent is added to form a topical gel or a transdermal gel.
4 the uniform blend is dissolved in a solvent suitable for parenteral administration The solution is affected at temperature range of 25 ° C to 35 ° C under normal conditions of stirring The solution is then filtered, sterilized and asepticaily filled in ampoules Alternatively, the ampoules are autoclaved at around 121 ° C for a period of about 30 minutes
Preferably the composition comprises Nimesuiide and Cetinzine in the ratio of 1:5 to 1 40
Preferably the granulating fluid for granulating the fine powdered blend of Nimesuiide and Cetirizine is Maize starch and/or Polyvinylpyrrolidone
Preferably the diluents and gelling agent for dissolving the fine blend of Nimesuiide and Cetirizine for topical and transdermal ge! are Dimethylsulphoxide and/or dirnethylacetamide and Carbopol ® and/or Hydroxypropy) cellulose
Preferably the solvent for dissolving the uniform blend of Nimesuiide and Cetirizine for parenteral administration is Water and/or dimethylacetamide.
EXPERIMENT TO STUDY THE ANTIASTHMATIC ACTIVITY OF NIMESULIDE AND CETIRIZINE
Antiasthmatic activity of Nimesulide and Cetinzine was studied on histamine-induced, egg albumin-induced and leukotnene-D4-induced brochospasm in guinea pig in vivo.
Materials & Method : Animals
Guinea pig 300 - 350 g either sex, housed in the Central Animal house of Panacea Biotec Ltd , Lalru and kept under standard laboratory conditions, were used
Procedure
Urethane - anaesthetised, 18-h fasted guinea pigs 300 - 350 g were used d-tubocurarme (3 mg/kg i v) was administered to prevent spontaneous respiratory movements Guinea pigs were artificially ventilated by a UGO Basile Rodent ventilator through a tracheal cannula at a rate of 60 strokes/min. and a stroke volume of 1 ml/100 g Insufflation pressure was measured by attaching a pressure transducer (UGO Basile) to a Gemini two channel recorder (UGO Basile) A polyethylene catheter was inserted in the left jugular vein for iv administration of drugs The animals were stabilized for 10 minutes
% Insufflation pressure was calculated as the % increase in pressure due to constriction of the airways with respect to the basal pressure Less % insufflation pressure denotes less bronchoconstriction caused due to the effect of test compounds with respect to the basal tone of the airways
Drugs
Nimesulide and Cetinzine dihydrochlonde (Panacea Biotec Ltd., India), Histamine, Leukotnene D4 and Urethane (all from Sigma, USA), d-tubocuranne chloride (Diosynth, Netherlands), Egg albumin (Qualigens Fine Chemicals, Bombay). Cetirizine was dissolved in deionized water Nimesulide was suspended in 0 25% Xanthum gum. Histamine and d-tubocuranne chloride were dissolved in saline and Leukotnene D4 was diluted with Methanol and Ammonium Acetate buffer in a ratio of 70 30 at a pH of 5 4
Statistical Analysis
Unpaired students t-test was applied and p Experimental Protocol Group I Histamine treated
Histamine challenge (5 ng/kg and 10 _1g/kg iv) was given to the animal and increase in insufflation pressure was noted in the control group (Table 1)
Test compounds (Nimesulide, Cetinzine, Ntmesulide + Cetirizine) were given 2 hours before histamine challenge in the test group Any decrease in the insufflation pressure was noted (Table. 1)
Group II Egg albumin treated
Guinea pigs were sensitized by injections of 100 mg of Egg albumin ip and 100 mg Egg albumin sc in saline Guinea pigs were used after day 21st Animals were chaffenged with 1 mg/kg and 2 mg/kg of Egg albumin and increase in insufflation pressure was noted (Table 2)
Group III Leukotriene D4 treated
LTD4 challenge (1 pg/kg and 2 ug/kg) was given to the animal and increase in
insufflation pressure was noted in the control group (Table 3).
Test compounds (Nimesulide, Cetinzine, Nimesulide + Cetinzine) were given 2 hours before LTD4 challenge in the test group Any decrease in the insufflation pressure was noted (Table 3) with respect to the control group
Results :
Cetirizine (1 66 mg/kg) significantly reduced the histamine (5 and 10 Dg/kg) induced increase in insufflation pressure Nimesulide (single dose, S, 1166 mg/kg and double dose, D, 23 32 mg/kg) had no significant inhibitory effect on the insufflation pressure
Combination of Nimesulide (single dose, S) and Cetinzine showed no significant effect whereas Nimesulide (double dose, D) and Cetirizine had potent antihistaminic effect
Nimesulide (1166 mg/kg) significantly reduced the egg albumin induced (1 mg/kg, 2 mg/kg) insufflation pressure, the effect of Nimesulide was 92 0 to 94.0% Cetirizine (1.66 mg/kg) also reduced the insufflation pressure but it is slightly less than that of Nimesulide In combination Nimesulide and Cetinzine also showed a highly significant effect as compared to the control (Table. 2).
Nimesulide (11 66 mg/kg) had no effect on the insufflation pressure whereas Cetirizine (1 16 mg/kg) significantly blocked LTD4-induced contractions Combination of Nimesulide (11 66 mg/kg) and Cetirizine (1.16 mg/kg) potently blocked the leukotriene induced contractions Double dose Nimesulide (23 32 mg/kg) itself had a potent inhibitory effect on LTD4-induced contractions.
Combination of Nimesulide (23 32 mg/kg) and Cetirizine (1 16 mg/kg) had the maximum (H 90%) inhibitory action on LTD4-induced contractions (Table. 3).
Discussion
Cetirizine but not Nimesulide acts as a potent antihistaminic in guinea pig model of bronchoconstriction Nimesulide double dose in combination with Cetirizine shows a potent antihistaminic effect which may be due to Cetirizine alone.
Hence Nimesulide itself has no antihistaminic action once histamine has been released to occupy the receptors Nevertheless, Nimesulide can have an inhibitory effect on the pre-formed allergic mediators thus having an indirect antihistaminic action
Preliminary study reports suggest that Nimesulide has a highly potent anti-allergic action in antigen (egg albumin) induced bronchospastic studies. Combination of Nimesulide and Cetinzine offer a dual protection in cases of allergic asthma, as Cetirizine is a potent antihistaminic It is inferred that Nimesulide - Cetinzine combination can be used as a prophylactic for chronic allergic asthma
Cetirizine and double-dose Nimesulide, both can block LTD4-induced bronchoconstnction in guinea pigs Combination of Cetirizine and Nimesulide is a very potent blocker of LTD4-mduced bronchoconstnction This effect may be due to selective inhibition of phosphodiesterase (PDE) isozyme III and IV. Such inhibition has been shown substantially anti-inflammatory effects in vivo PDE4 inhibitors act by inducing an increase in the intracellular levels of cAMP which in turn suppresses inflammatory cell activity and causes relaxation of airway smooth muscles Nimesulide is reported to be a potent PDE IV inhibitor in vitro with an IC50 H 40 µM. That the combination is effectively blocking exogenously administered LTD4 implies that either Nimesulide and Cetirizine have a combined PDE III and PDE IV isozyme inhibiting capacity or Nimesulide/Cetinzine are working as LTD4 receptor antagonists
The inhibition, by this combination, of the antigen-induced (egg albumin) bronchoconstnction may also be through its capacity to act as a PDE lll/IV inhibitor
These preclinical results indicate the potential therapeutic efficacy of the combination of Nimesulide and Cetirizine in the treatment of allergic inflammatory airway disorders such as asthma
Inference
As asthma is now viewed primanly as a chronic allergic disease with an underlying inflammatory activity the ideal antiasthmatic drug should possess the following three properties
Antiallergic action
Anti Leukotriene action
Antihistamine action
Nimesulide and Cetirizine when given together posses all the three properties as
is evident from the following observations
1 Cetirizine (1 16 mg/kg p o) produces a decrease in % insufflation pressure
by 42.86%, Nimesulide (23.32 mg/kg p o) by 61 0% whereas Nimesulide +
Cetirizine synergistically decrease the pressure by
80 21% in case of LTD4-mduced bronchoconstriction in guinea pigs (Table. 3).
2. Cetinzine (1 16 mg/kg p o) produces a decrease in % insufflation pressure by 70 52%, Nimesulide (11 66 mg/kg p,o) by 90 24% whereas Nimesulide + Cetiriztne synergistically decrease the pressure by 96.57% in case of egg albumin induced bronchoconstriction in guinea pigs (Table. 2).
3. In case of histamine induced bronchoconstriction Cetinzine {1.16 mg/kg p o) decreases the % insufflation pressure by 62.71% whereas Nimesulide shows no antihistamine effect.
Hence a combination of these two is required to produce a synergistic action in case of 1 and 2 as stated above In case of 3 any histamine which escapes the mast cell stabilizing action of Nimesulide and gets released would be blocked by Cetiriztne to reach the receptor sites and bronchoconstriction would be prevented.
These preclinical results indicate a three pronged antiasthmatic action provided by the combination of Nimesulide and Cetinzine
The inflammation associated with asthmatic decrease wilt be reduced by Nimesulide by selective COX-2 inhibition activity
Therefore this invention teaches an art of treating asthma by a combination of NSAID Nimesulide alongwith an antihistamine drug Cetinzine and this combination due to a synergistically pharmacological action will have usefulness to elevate symptoms of asthmatic and related disorders in a much better fashion than the known agents for the drugs alone
The invention will now be described with reference to the accompanying examples which are illustrative and by means should be construed to limit the scope of the invention-
Example I Tablets
1. Nimesulide 200 mg
2 Cetirizine dihydrochlonde 10 mg
3 Microcrystallme Cellulose 100 mg 4. Maize Starch 40 mg

5 PVP K-30 4 mg
6 Sodium Lauryl Sulphate 1 mg

7. Magnesium Stearate 4 mg
8. Colloidal Silicon Dioxide 6 mg

9 Sodium Starch Glycollate 10 mg
10 Purified Water
Mix 1, 2, 3 & 4 Dissolve 5 & 6 in 10 and granulate the above and mix Dry, soft and blend wrth 7, 8 & 9 Compress the tablets
Example II Tablets
1 Nimesulide 200 mg
2. Cetirizine dihydrochlonde 5 mg
3 Microcrystallme Cellulose 81 mg
4 Maize Starch 30 mg
5 Polyoxyl 40 Hydrogenated
Castor Oil 1 mg
6 PVP K-30 2 mg
7 Magnesium Stearate 2 mg
8 Colloidal Silicon Dioxide 4 mg
9 Sodtum Starch Glycollate 5 mg
10 Purified Water
Mix 1, 2, 3 & 4. Dissolve 5 & 6 in 10 and granulate the above and mix. Dry, soft and blend with 7, 8 & 9 Compress the tablets
Example III: Topical Gel
1 Nimesulide 1%
2 Cetirizine (Suitable
Pharmaceutical form) 0.5%
3. Carbopol 1%
4 Hydroxypropyi Cellulose 1 5%
5. PEG 400 25%
6. Dimethyl Sulphoxide 15% 7 Isopropyl Alcohol 40%
8. Hydrochloric Acid q s to adjust pH
9 Propylene Glycol 5%
10 Purified Water 10%
Disperse 1 in 5, 6 and 9 separately Dissolve 2 in 80% of 10. Disperse 3 & 4 in 7 with vigorous stirring. Add the two solutions to the dispersion. Allow to smell. Dilute 8 in remainder of 10 and adjust pH in the range of 2 to 6
Example IV : Capsules
1. Nimesulide 200 mg
2 Cetinzine dihydrochlonde 10mg
3 Maize Starch 80 mg
4 Sodium Lauryl Sulphate 1 5 mg
5 Colloidal Sfficon Dioxide 3 5 mg
Empty hard gelatin capsules Sift 1, 3 & 5 through 30 mesh and 2 & 4 through 60
mesh. Mix uniformily and fill empty hard gelatin capsules at 295 mg
Example V : Sustained Release Bilayered Tablets A.
1 Nimesulide 200 mg
2 Lactose 100 mg
3 Hydroxypropylmethyl Cellulose 35 mg
4 Polyoxyl 40 Hydrogenated
Castor Oil 2 mg
5 PVP K-30 4 mg
6. Magnesium Stearate 2 mg
7. Colloidal Silicon Dioxide 2 mg
8. Isopropyl Alcohol 2 mg
Mix 1, 2 & 3 Dissolve 4 & 5 in 8 and granulate the above and mix Dry, soft and
blend with 6 & 7
B.
1. Cetinzine dihydrochloride 10 mg
2. Lactose 225 mg
3 Maize Starch 55 mg
4. PVP K-30 3 mg
5. Magnesium Stearate 3 mg
6 Sodium Starch Glycollate 4 mg
7. Purified Water
Mix 1, 2 & 3 Dissolve 4 in 7 and granulate the above and mix Dry, soft and blend with 5 & 6. Compress the granules of A and B into bilayer tablets
Example VI : Nimesulide (in osmotic pump) + Cetirizine Tablets
I Drug layer
Nimesulide 200 mg
Sodium Chloride 15 mg
Carbopol934P 100 mg
Magnesium Stearate 1 mg
Osmotic Layer
Polyethylene Oil 100 mg
Carbopol974 P 150mg
Sodium Chloride 10 mg
Magnesium Stearate 1 mg
Iron Oxide Red 0 5 mg
The two layers are mixed separately and compressed into a bilayer tablet
II Casing Layer
Cellulose Acetate 4%
PEG 600 4%
Purified Water 10%
Acetone 82%
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 Cetirizine Coating
Cetinzine hydrochloride 10 mg
Hydroxypropylmethyl Cellulose 7 mg
PEG 400 0.5 mg
Isopropyl Alcohol q.s
Purified Water q s
Iron oxide red 0 05 mg
Prepared a coating solution and coated the tablets of step II for 10 mg/ tablet
Cetirizine dihydrochloride.
Example VII: Metered dose inhaler
1 Nimesulide
(within 1 to 5 microns) 33%
2. Cetirizine dihydrochloride
(within 1 to 5 microns) 3 3%
3 Lactose 2%
4 Sorbitan Trioleate 0 5%
5. Propeflant114 30 60%
6 Propellant12 30 60%
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 VIII : Injection
1 Nimesulide Potassium Salt 2 %
2. Cetirizine dihydrochloride 0 33%
3 Benzyl Alcohol 2%
4 Ethylene diamine tetracetate
disodium salt 0 002%
5 Water for injection q s to 100%
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 22u nylon membrane filter and fill aseptically into vials/ ampoules

We claim:
1. A synergistic antileukotriene, antihistaminic, anti-allergy and anti-inflammatory composition comprising Nimesulide or salts thereof and Cetirizine or salts thereof wherein Nimesulide is present in the composition from 1-53 parts, Cetirizine present in the composition is from 0.3 - 3.3 parts and pharmaceutical base and excipients present in the composition are from 44 -98.5 parts.
2. A process for making a synergistic anti-inflammatory, antileukotriene, antihistaminic and antiallergic composition of Nimesulide or salts thereof with Cetirizine or salts thereof as claimed in claim 1 which comprises blending Nimesulide and Cetirizine uniformly and passing the mixture through a fine sieve to reduce the particle size in the form of a fine powder, subjecting the said powder to any one or all the undermentioned steps to produce the desired product:

a) blending the said powder with excipients at 25 ± 2°C temperature and 50 ± 5% relative humidity and filled in empty gelatin capsules to yield capsule dosage form.
b) granulating the said powder at ambient conditions and drying at temperature not exceeding 60°C for a period of time so as to yield moisture content around 1%, subjecting the resultant blend to reduction in size and lubrication, compressing into tablets at 25 ± 2°C temperature and 50 ± 5% Relative humidity.
c) dissolving the said powder in diluents and a gelling agent to form a topical gel or a transdermal gel.
d) dissolving the said powder in solvent suitable for parenteral administration at a temperature range of 25°C to 35°C under conditions of stirring, filtering and sterilizing the resultant solution.

3. A process as claimed in claim 2 wherein the composition comprises Nimesulide and Cetirizine in the ratio of 2:1 to 40:1,
4. A process as claimed in claim 2 wherein the granulating fluid for granulating the fine powdered blend of Nimesulide and Cetirizine is Maize starch and/or Polyvinylpyrrolidone.
5. A process as claimed in claim 2 (c) wherein the diluent is Dimethylsuiphoxide and/or dimethylacetamide
6. A process as claimed in claim 2 (c) wherein the gelling agent is Carbopol and/or Hydroxypropyl cellulose.
7. A process as claimed in claim 2 (d) wherein the solvent is water and/or dimethylacetamide.
8. A synergistic antileukotriene, antihistaminic, anti-allergy and anti-inflammatory composition substantially as herein described with reference to the accompanying examples.
9. A process for the preparation of a synergistic antileukotriene, antihistaminic, anti-allergy and anti-inflammatory composition substantially as herein described with reference to the accompanying examples.

Documents:

3184-del-1997-abstract.pdf

3184-del-1997-claims.pdf

3184-del-1997-correspondence-others.pdf

3184-del-1997-correspondence-po.pdf

3184-del-1997-description (complete).pdf

3184-del-1997-form-1.pdf

3184-del-1997-form-13.pdf

3184-del-1997-form-19.pdf

3184-del-1997-form-2.pdf

3184-del-1997-form-3.pdf

3184-del-1997-form-5.pdf

3184-del-1997-form-6.pdf

3184-del-1997-petition-137.pdf

« Previous Patent

Next Patent »

Patent Number

232425

Indian Patent Application Number

3184/DEL/1997

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

17-Mar-2009

Date of Filing

06-Nov-1997

Name of Patentee

PANACEA BIOTEC LIMITED

Applicant Address

B-1EXTN./A-27 MOHAN CO-OPERATIVE INDUSTRIAL ESTATE, MATHURA ROAD,NEW DELHI-110044

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. AMARJIT SINGH	PANACEA BIOTEC LTD., B-1EXTN./A-27 MOHAN CO-OPERATIVE INDUSTRIAL ESTATE, MATHURA ROAD,NEW DELHI-110044
2	JAIN RAJESH	DIRECTOR,PANACEA BIOTEC LTD., B-1EXTN./A-27 MOHAN CO-OPERATIVE INDUSTRIAL ESTATE, MATHURA ROAD,NEW DELHI-110044

PCT International Classification Number

A61K 31/63

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA