Title of Invention

A NOVEL PHARMACEUTICAL COMBINATION

Abstract

A pharmaceutical composition comprising at least on therapeutically selective isomer of a B-2-adrenergic agonist. or a salt, solvate, physiologically functional derivative or prodrug thereof, and at least one therapeutically selective isomer of an H1-receptor antagonist, or a salt, solvate, physiologically functional derivative or produrg thereof, together with a pharmaceutically accptable carrier or excipient.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] "A NOVEL PHARMACEUTICAL COMBINATION" (a) CIPLALTD. (b) 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of this invention and the manner in which it is to be performed: ORIGINAL 1120/MUM/2003 22/10/03 GRANTED 12-12-2007 Technical Field: The present invention is concerned with pharmaceutical combinations comprising agents such as P-2 adrenoreceptor agonists and antihistamines. In particular, the present invention is concerned with pharmaceutical compositions comprising B-2 adrenoreceptor agonists and antihistamines, useful in the prophylaxis and treatment of respiratory diseases, and a process of preparing the same. Background: Asthma and Chronic Obstructive Pulmonary disorders are the most common chronic diseases worldwide. These represent an enormous and growing therapeutic market and there is therefore an opportunity for development of new drugs. Asthma per se is well treated with existing therapies, but there is a need to find better treatment for patients where asthma occurs along with severe allergic side effects. Treatment of asthma and other related disorders has been known to employ B-2 agonists, also known as P-2 adrenoreceptor agonists. Such P-2 adrenoreceptor agonists are known to provide a bronchodilator effect to patients by acting on the P-2 adrenergic receptors in the airway smooth muscles and the bronchial smooth muscles, resulting in relief from the symptoms of breathlessness. More particularly, P-2 adrenoreceptor agonists have been shown to increase the conductance of potassium channels in airway muscle cells, leading to membrane hyperpolarization and relaxation. Various prior art documents suggest different dosage forms of such B-2 adrenoreceptor agonists to be employed in treatment of respiratory diseases. For example, US 6,585,958 claims a pressure-liquefied propellant mixture for aerosols, comprising dinitrogen monoxide and a hydrofluoroalkane, wherein the active ingredient is selected from the group consisting of salbutamol, formoterol, salmeterol, fluticasone, budesonide, ciclesonide, glycopyrronium, tiotropium, cromoglycic acid, nedocromil, 2 mometasone, sildenafil, beclomethasone, levalbuterol and pharmaceutically acceptable salts and derivatives thereof. US 6,451,289 claims a stable, preservative-free pharmaceutical formulation comprising levalbuterol or a pharmaceutically acceptable salt thereof; sodium chloride; and having a pH of about 4. The formulation contains less than 0.08% by weight of albuterol aldehyde and less than 1 ppm dissolved oxygen, and continues to contain less than 0.08% by weight of albuterol aldehyde after storage at 40°C for six months. The formulation does not contain a chelating agent, a sequestering agent, an antioxidant, a preservative agent or an antioxidant. Another article, as published by Handley, Sepracor Inc., USA, indicates that further to clinical studies it has been shown that the active bronchodilatory isomer, (R)-albuterol (levalbuterol) is more efficacious than the racemic albuterol. Histamine, acting through H|-receptors, produces smooth muscle contraction, an increase in vascular permeability, and stimulation of parasympathetic nerves, all of which are pathophysiological features of asthma. It is also known from the literature that antihistamines may be effective in the treatment of allergic symptoms, for example, they have been seen to possess potent activity in treating seasonal and perennial allergic rhinitis, the symptoms of allergic asthma, chronic idiopathic urticaria, certain types of physical uricaria, and other disorders benefiting from an inhibiting action on eosinophil function. Examples of antihistamines include H1-receptor antagonists such as cetirizine, levocetirizine and functional derivatives thereof. Racemic cetirizine is an oral potent, long-acting peripheral antihistamine H1-receptor antagonist and is an example of the second generation of H1-histamine receptor antagonists, which generally offer some significant advantages beyond the first generation compounds. The main advantages associated with the second generation of H1-histamine receptor antagonists are less sedation, little anticholinergic activity and longer duration of therapeutic activity, which increases patient compliance. Cetirizine is the international non-proprietary name of 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piprazinyl] ethoxyacetic acid. Cetirizine as referred to herein denotes 2-[4-[(4- 3 chlorophenyl)phenylmethyl]-l-piprazinyl] ethoxyacetic acid. The active isomer of cetirizine, levocetirizine, is seen to have more therapeutic activity and lesser side effects of the racemic mixture. The chemical synthesis of the racemic mixture of cetirizine can be performed by the method described in U.S. Patent 4,525,358 cited above or by an improved procedure disclosed in British application 2,225,320. For example, British application 2,225,321 (Cossement et al.) discloses a method for resolving the 1- [(4-chlorophenyl) phenylmethyl] piperazine precursor using tartaric acid in ethanol. Additionally, the optically pure (-) isomer can be prepared from the racemic mixture by enzymatic biocatalytic resolution as reported in U.S.Patent Nos. 5,057,427 and 5,077,217. EP 0950412 describes various methods and compositions using optically pure (-) cetirizine for treatment of seasonal and perennial allergic rhinitis in humans. WO9406429 and WO9406430 describe the methods and compositions for treating allergic disorders using optically pure (-) cetirizine and optically pure (+) cetirizine respectively. Also US patent no. 6,521,254 describes pharmaceutical compositions for oral administration comprising antihistamine preferably cetirizine and derivatives with decongestant for the treatment of allergic rhinitis. Another prior art US 6319927 describes a method for inducing sleep in a human suffering from a sleeping disorder comprising administering to the human a therapeutically effective amount of levocetirizine or a pharmaceutically acceptable salt thereof once daily. LU90898 describes methods and compositions comprising levocetirizine for the treatment of seasonal and perennial allergic rhinitis in humans while avoiding adverse effects associated with the racemic mixture of cetirizine. LU90870 describes New 2-[4-(diphenylmethyl)-l-piperazinyl]-acetic acids, their amides and their salts, processes for the preparation thereof and therapeutic compositions. LU870 claims an antihistaminic composition comprising dihydrochloride of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-acetic acid (i.e. cetirizine) in unit dosage form of 0.5 to 250 mg. This high dosage range can cause side effects. To avoid this, there is need of a pharmaceutical composition with reduced dosage form and exhibiting high efficacy. 4 Despite the large number of known treatments of respiratory diseases, there continues to exist a clinical need for therapies of respiratory diseases which exhibit advantageous profiles of action. To this end, it has now surprisingly been found that a novel pharmaceutical composition comprising at least one therapeutically selective isomer of a p-2-adrenergic agonist, or a salt, solvate, physiologically functional derivative or prodrug thereof, and at least one therapeutically selective isomer of an H1-receptor antagonist, or a salt, solvate, physiologically functional derivative or prodrug thereof, together with a pharmaceutically acceptable carrier or excipient, provides an enhanced, synergistic therapeutic effect in terms of treatment of respiratory diseases, such as asthma, allergic respiratory disorders and related disorders. Objectives: Accordingly, it is an object of the present invention to provide methods of treating asthma, allergic respiratory disorders and related disorders. It is a further object of the present invention to provide a pharmaceutical composition comprising pharmaceutically active agents for the treatment of asthma, allergic respiratory disorders and related disorders. Summary of the invention: According to the present invention, therefore, there is provided a pharmaceutical composition comprising at least one therapeutically selective isomer of a B-2-adrenergic agonist, or a salt, solvate, physiologically functional derivative or prodrug thereof, and at least one therapeutically selective isomer of an H|-receptor antagonist, or a salt, solvate, physiologically functional derivative or prodrug thereof, together with a pharmaceutically acceptable carrier or excipient. Detailed Description: Beta-2 adrenoreceptors are known to provide a bronchodilator effect to patients by acting on the [3-2 adrenergic receptors in the airway smooth muscles and the bronchial smooth muscles, 5 resulting in relief from the symptoms of breathlessness. .They are thus preferred in the case of asthma treatment which requires the dilation of the bronchial smooth muscles and they relieve the patient of breathlessness associated with asthma. Inclusion of an antihistamine provides for the symptomatic relief of cough including but not limited to that associated with bronchoconstriction and excessive mucous production. The antihistamines suppress the cough reflex, dry excess secretions and in some cases may produce sedation which will assist in the patient"s rest and sleep patterns. Thus the two drugs provide an additive bronchodilatory effect that provides faster relief in an asthmatic attack. Preferably, the therapeutically selective isomer of the p-2-adrenergic agonist is levalbuterol or its salts, solvates or physiologically functional derivatives thereof. Preferably, the therapeutically selective isomer of an Hi-receptor antagonist is levocetirizine, or its salts, solvates or physiologically functional derivatives thereof. Albuterol is available as a racemic mixture comprising R and S forms. However, only the R-enantiomer (levalbuterol) is a potent B2 - adrenoreceptor stimulant, whereas the S-enantiomer (dextroalbuterol) shows little or no adrenoreceptor activity. The bronchodilatory property of racemic albuterol is attributable entirely to (R)-albuterol, which has an approximately 100. fold greater binding affinity for beta2 receptors as compared to (S)-albuterol. In the absence of (R)-albuterol, (S)-albuterol has the potential to induce bronchoconstriction in asthmatic patients. This divergent pharmacology accentuates the need of levalbuterol over racemic albuterol in the treatment of asthma and other airway diseases. Levocetirizine is the active R-enantiomcr of cetirizine and represents a new second-generation H|-receptor antagonist. It has a high affinity and selectivity for H1-receptors. Comparative studies have shown evidence of superior H1-receptor binding affinity over its racemate, cetirizine. Levocetirizine exhibits many favourable characteristics of an ideal antihistamine, both pharmacodynamically and pharmacokinetically, including high bioavailability, rapid onset of action, limited distribution and low degree of metabolism. Furthermore, clinical trials indicate that it is safe and effective with a minimal amount of untoward effects. 6 1 The salts of levocetirizine refers not only to addition salts with pharmaceutically acceptable non-toxic organic and inorganic acids, such as acetic, citric, maleic, succinic, ascorbic, hydrochloric, hydrobromic, sulfuric, and phosphoric acids and the like, but also its metal salts (for example sodium or potassium salts) or ammonium salts, amine salts and amino acid salts. A preferred salt is levocetirizine hydrochloride. The term levocetirizine hydrochloride is employed in a broad sense in the description and claims so as to include levocetirizine hydrochloride as the monohydrochloride and also as the dihydrochloride. The salts of levalbuterol include levalbuterol sulphate, levalbuterol tartrate and levalbuterol hydrochloride. Preferred salts are levalbuterol sulphate and levalbuterol hydrochloride. The phrase "therapeutically selective isomer" as described herein includes an isomer of an H1-receptor antagonist or a B-2-adrenergic agonist, which is more potent and shows lesser side effect than the racemic mixture of that compound. The phrase "respiratory diseases" as described herein can include in particular asthma, allergic respiratory disorders and other such related disorders. The term "physiologically functional derivative" as used herein denotes a chemical derivative of any of the specific therapeutic agents described herein having the same or similar physiological function as the free base therapeutic agent and, for example, being convertible in the body thereto. The pharmaceutical compositions according to the present invention may be solid dosage forms such as tablets, capsules, tablets and tablets in capsules, pellets and modified release solid dosage forms, wherein advantageously the antihistamine, preferably levocetirizine is available for immediate release, and theB-2-adrenergic agonist, preferably levalbuterol, is available for extended release. Optionally a part of the P-2-adrenergic agonist can also be made available in the immediate release portion along with the antihistamine. The P-2-adrenergic agonist may preferably be present in a range of about 0.5-5mg, while the anti-histaminic compound may be present in a range of about 5-30mg. 7 Fillers suitable for use in tablets as provided by the present invention may be selected from sugars, sugar alcohols, starches, and inert materials, such as kaolin and the like, that add up to the bulk of the tablets and make it suitable for compression. Disintegrating agents may be selected from celluloses and their derivatives, alginates, agar-agar, certain complex silicilates, starches, modified starches and their derivatives, polyvinylpyrolidones and the like. Binders may be selected from natural and synthetic gums, celluloses, starches, gelatins and povidones and the like. Lubricants may be selected from talc, magnesium stearate, microcrystalline cellulose, hydrogenated vegetable oils, polyethylene glycols and their derivatives, sodium lauryl sulphate and the like. The tablets may be coated for the purpose of providing protection. The coating material can be selected from celluloses and their derivatives, polyethylene glycols and their derivatives, fatty acids such as stearic acid and their derivatives, and waxes, among other suitanle coating materials well known in the art. The tablets of the present invention can he prepared by direct compression, wet granulation or dry granulation, so as to achieve substantially homogenous distribution of the drugs within the formulation. The tablets of the invention are orally administered in the amounts necessary to achieve a particular blood level and an optimum dosage size, which may be determined by observing the therapeutic results achieved, the side effects encountered and / or by blood serum analysis. For capsule preparation, excipienls such as tillers, binders, disintegrating agents and lubricants may be selected from those known in the art. The capsules may be hard or soft gelatin capsules. The capsules can be prepared by any method known in the art. The excipients for a fast releasing dosage !"orm may be required to be simply combined with the active or may provide a coating to the active and may include sugars and polyols that act as sweeteners and as disintegrating agents. The polyols may also be selected to act as cooling agents. The dosage form may contain several other agents that may act as binders and lubricants. Manufacture of such dosage forms may be carried out at conditions well known in the art for such fast dissolving dosage forms. The polyols may also render the advantage of providing the negative heat of solution and thus providing a cooling effect when chewed thus masking the bitter taste of the dosage form. 8 Liquid and semisolid preparations according to the present invention comprising an antihistamine, preferably levocetirizine or a salt, solvate, physiologically functional derivative or prodrug thereof, and a P-2-adrenergic agonist, preferably levalbuterol or a salt, solvate, physiologically functional derivative or prodrug thereof, can contain stabilizers, anti¬microbial agents, preservatives, colours, flavours, surfactants and other excipients used in the art. The anti-microbial preservative may be selected from benzoic acid, and its salts and esters, parabens, alcohols and the like. Surfactants can be selected from anionic, cationic and non-ionic surfactants. The present invention also provides a method for the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or moreB-2 adrenoreceptor agonists, and / or one or more antihistamines is indicated, which method comprises administration of a therapeutically effective amount of a pharmaceutical composition substantially as hereinbefore described. There is also provided by the present invention for use in the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more B—2 adrenoreceptor agonists, and / or one or more antihistamines is indicated, a pharmaceutical composition substantially as hereinbefore described. There is also provided by the present invention for use in the manufacture of a medicament for the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more B-2 adrenoreceptor agonists, and / or one or more antihistamines is indicated, at least one therapeutically selective isomer of a B-2-adrenergic agonist, or a salt, solvate, physiologically functional derivative or prodrug thereof, and at least one therapeutically selective isomer of an H1-receptor antagonist, or a salt, solvate, physiologically functional derivative or prodrug thereof, together with a pharmaceutically acceptable carrier or excipient therefor. The present invention also provides a process of preparing a pharmaceutical composition substantially as hereinbefore described, which process comprises admixing a 9 pharmaceutically acceptable carrier or excipient with at least one therapeutically selective isomer of a P-2-adrenergic agonist, or a salt, solvate, physiologically functional derivative, or prodrug thereof, and at least one therapeutically selective isomer of an H1-receptor antagonist, or a salt, solvate, physiologically functional derivative or prodrug thereof. Preferred therapeutic agents for the above method, use or"process as provided by the present invention are substantially as hereinbefore described with reference to a pharmaceutical composition according to the present invention. The term respiratory disease as used herein can include in particular asthma, allergic respiratory disorders and other related disorders. It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention. The following examples are thus for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention. Examples Example1 SR. NO. INGREDIENTS QTY/TAB (mg) 1. Levalbuterol sulfate equivalent to levalbuterol 1.0 2. Levocetirizine dihydrochhride 7.5 3. Lactose 43.50 4. Starch 25.0 5. Microcrystalline cellulose 20.0 6. Magnesium stearate 1.0 7. Colloidal Silicon Dioxide 2.00 TOTAL 100.00 10 Procedure Levalbuterol sulfate and a part of the starch were cosifted. A blend of cosifted levalbuterol sulphate, levocetirizine dihydrochloride, lactose, the remaining part of the starch, microcrystalline cellulose and colloidal silicon dioxide was made in a suitable blender. This blend was then lubricated with magnesium stearate and compressed to form tablets. Example 2 SR. NO. INGREDIENTS QTY/TAB (mg) 1. Levalbuterol sulfate equivalent to levalbuterol 2.0 2. Levocetirizine dihydrochloride 5.0 3. Lactose 60.5 4. Microcrystalline cellulose. 25.0 5. Crospovidone 4.00 6. Magnesium Stearate 0.5 TOTAL 100.00 FILM COATING. 7. Opadry WhiteIM 3.00 8. Purified Water q.s. Procedure Levalbuterol sulfate and a part of the lactose were cosifted. A blend of cosifted levalbuterol sulfate, levocetirizine dihydrochloride, microcrystalline cellulose, the remaining part of the lactose and crospovidone was made in a suitable blender. This blend was then lubricated with magnesium stearate and compressed to form tablets. The tablets so formed were coated with a film coating dispersion made by dispersing opadry white in water. 11 Example 3 Levocetirizine and Levalbuterol syrup. INGREDIENTS QTTY (% w/v) Levalbuterol sulfate equivalent to levalbuterol 0.05 Levocetirizine dihydrochioride 0.1 Propyl paraben 0.2 Methyl paraben 0.02 Sodium chloride 0.1 Sodium citrate 0.0725 Sorbitol solution (70 %) non-crystallising 10.00 Pharma grade sugar 45.00 Citric acid monohydrate 0.10 Orange flavour 0.28 Carmoisine supra 0.0011 Purified water 100 ml. Procedure Water was heated to boiling and to this methyl paraben and propyl paraben were added. To the above solution, sugar was added and dissolved, followed by the addition of sorbitol. The solution so formed was then cooled. Sodium citrate and citric acid buffer were added to this solution. This was followed by the addition of sodium chloride. Levocetirizine dihydrochioride and levalbuterol sulfate were then added to the above solution and mixed to dissolve. This was followed by the addition of the flavor and color. Finally the volume was made up. Example 4 SR. NO. INGREDIENTS QTY/TAB (Mg) 1. Levalbuterol hydrochloride, equivalent 1.0 12 to levalbuterol 2. Levocetirizine dihydrochloride 7.5 3. Lactose 43.50 4. Starch 25.0 5. Microcrystalline cellulose 20.0 6. Magnesium stearate 1.0 7. Colloidal Silicon Dioxide 2.00 8. Water Qs Procedure Levalbuterol hydrochloride and a part of the starch were cosifted. A blend of cosifted levalbuterol sulphate, levocetirizine dihydrochloride, lactose, a part of starch and microcrystalline cellulose was prepared. The above blend was then granulated using starch paste. The granules so formed were lubricated with colloidal silicon dioxide and magnesium stearate and compressed to form tablets. Example 5 Sr, no Ingredients Mg/tab Immediate release part 1. Levocetirizine dihydrochloride 5.0 2. Levalbuterol sulfate equivalent to levalbuterol 0.6 3. Lactose 60.6 4. Gelatin 0.65 5. Microcrystalline cellulose 3.75 6. Starch 32.2 7. Starch 2.0 8. Color erythrosine 0.01 9. Magnesium stearate 0.65 10. Talc 1.35 13 11. Crospovidone 2.0 12. Colloidal silicon dioxide 0.6 13 Water Qs Slow release part 14. Levalbuterol sulfate equivalent to levalbuterol 4.20 15. HPMC 142.8 16. Lactose 7.0 17. Colloidal silicon dioxide 2.0 18. Talc 2.0 19. Magnesium stearate 2.0 Procedure Slow release granules Levalbuterol sulfate and lactose were cosifted to form premix I. A blend of HPMC, colloidal silicon dioxide, talc, magnesium stearate and premix I was made. This blend was then subjected to slugging. The tablets so formed were then milled and further passed through appropriate mesh. The granules so obtained were then lubricated with magnesium stearate. Immediate release granules Levalbuterol sulfate and a part of the starch were cosifted to form premix I. A blend of levocetirizine dihydrochloride, lactose, microcrystalline cellulose, the remaining part of the starch and premix I was made. A starch-gelatin paste was made using starch, gelatin, color erythrosine and water. The above blend was granulated using starch gelatin paste. The granules so formed were then lubricated with magnesium stearate, talc, crospovidone and colloidal silicon dioxide. 14 The final tablets were made by precompressing a layer of slow release granules followed by compressing a second layer of immediate release granules with the first layer of slow release granules. Example 6 Sr. no Ingredients Mg/tab Immediate release part 1. Levocetirizine dihydrochloride 5.0 2. Lactose monohydrate 16.5 3. Lactose anhydrous 49.0 4. Microcrystalline cellulose 25.0 5. Crospovidone 4.0 6. Magnesium stearate 0.5 Slow release portion 7. Levalbuterol sulfate equivalent to levalbuterol 4.8 8. HPMC 65.0 9. Lactose 121.7 10. Talc 3.0 11. Colloidal silicon dioxide 3.0 12. Magnesium stearate 2.5 Procedure Slow release granules Levalbuterol sulfate and lactose were cosifted to form premix I. A blend of HPMC, colloidal silicon dioxide, talc, magnesium stearate and premix I was made. This blend was then subjected to slugging. The tablets so formed were then milled and further passed through appropriate mesh. The granules so obtained were then lubricated with magnesium stearate. 15 Immediate release layer Levocetirizine dihydrochloride and lactose monohydrate were cosifted to form premix I. A blend of lactose anhydrous, crospovidone, microcrystalline cellulose and premix I was made. The blend was lubricated with magnesium stearate. The final tablets were made by precompressing a layer of slow release granules followed by compressing a second layer of immediate release blend with the first layer of slow release granules. 16 We claim: 1. A pharmaceutical composition comprising at least one therapeutically active isomer of P-2-adrenergic agonist, or a salt, solvate, physiologically functional derivative or prodrug thereof, and at least one therapeutically selective isomer of an H|-receptor antagonist, or a salt, solvate, physiologically functional derivative or prodrug thereof, together with pharmaceutically acceptable carrier or excipient wherein, at least one medicament exhibits immediate release pattern and/or extended release pattern.. 2. The composition as claimed in claim 1, wherein said B-2-adrenergic agonist is levalbuterol, or its salt such as sulphate, tartrate, hydrochloride; solvate; physiologically functional derivative or prodrug thereof. 3. The composition according to claim 1 wherein said H|-receptor antagonist is levocetirizine, or a salt, solvate, physiologically functional derivative or prodrug thereof. 4. The composition according to claim 3, wherein said levocetirizine salt is formed with a pharmaceutically acceptable non-toxic organic or inorganic acid selected from the group consisting of acetic acid, citric acid, maleic acid, succinic acid, ascorbic acid, hydrochloride acid, hydrobromic acid, sulfuric acid and phosphoric acid.; or is a salt selected from the group consisting of a metal salt, an ammonium salt, an amine salt and an amino salt. 5. The composition according to claim 4, wherein said levocetirizine salt is levocetirizine hydrochloride. 6. The composition according to claim 4, wherein said levocetirizine salt is a sodium or potassium salt. 7. A pharmaceutical composition as claimed in claim 1, comprising at least one therapeutically selective isomer of a (3-2-adrenergic agonist present in salt form and 17 which is levaibuterol sulphate, and at least one therapeutically selective isomer of an H|-receptor antagonist present in salt form and which is levocetirizine hydrochloride, together with a pharmaceutically acceptable carrier or excipient. 8. A pharmaceutical composition as claimed in claim 1, comprising at least one therapeutically selective isomer of a B-2-adrenergic agonist present in salt form and which is levaibuterol hydrochloride, and at least one therapeutically selective isomer of an H|-receptor antagonist present in salt form and which is levocetirizine hydrochloride, together with a pharmaceutically acceptable carrier or excipient. 9. A pharmaceutical composition comprising at least one therapeutically active isomer of p-2-adrenergic agonist, or a salt, solvate, physiologically functional derivative or prodrug thereof, and at least one therapeutically selective isomer of an Hi-receptor antagonist, or a salt, solvate, physiologically functional derivative or prodrug thereof, together with pharmaceutically acceptable carrier or excipients, wherein a part of said p-2-adrenergic agonist along with said H1-receptor antagonist is in the immediate release portion. 10. The composition according to any preceding claim, wherein the p-2-adrenergic agonist is present in the range of about 0.5-5 mg. 11. The composition according to any preceding claim, wherein the H|-receptor antagonist is present in the range of about 5-30 mg. 12. The composition according to any preceding claims is in the form of a coated or uncoated tablet. 13. The composition as claimed in claim 12, further comprises one or more fillers, binders, disintegrants, lubricants and/or any other pharmaceutically acceptable carriers or excipients. 18 14. The composition according to any preceding claims is in the form of a hard gelatin or soft gelatin capsule. 15. The composition as claimed in claim 14, comprises fillers, binders, disintegrating agents, lubricants and/or any other pharmaceutically acceptable carriers or excipients. 16. The composition as claimed in claims 1 to 11, is in the form of pharmaceutically acceptable liquid dosage form. 17. The composition according to claim 16, further comprises one or more of stabilizers, anti-microbial agents, preservatives, colours, flavours, surfactants and/or any other pharmaceutically acceptable carriers or excipients. 18. The composition according to any preceding claim, which comprises levocetirizine hydrochloride exhibits immediate release pattern and levoalbuterol sulphate exhibits extended release pattern. 19. The composition according to any preceding claim which comprises levocetirizine hydrochloride exhibits immediate release pattern and levalbuterol hydrochloride exhibits extended release pattern. 20. A process of preparing a pharmaceutical composition according to any preceding claim, which process comprises admixing a pharmaceutically acceptable carrier or excipient with at least one therapeutically selective isomer of a P-2-adrenergic agonist, or a salt, solvate, physiologically functional derivative, or prodrug thereof, and at least one 19 therapeutically selective isomer of an H1-receptor antagonist, or a salt, solvate, physiologically functional derivative or prodrug thereof. Dated this the 21st day of Oct 2004 Dr. Gopakumar G. Nair Agent for the Applicant 20

Documents:

1120-mum-2003 cancelled pages(12-12-2007).pdf

1120-mum-2003 claims(12-12-2007).pdf

1120-mum-2003 claims(granted)-(12-12-2007).doc

1120-mum-2003 correspondence(12-12-2007).pdf

1120-mum-2003 correspondence(ipo)(24-6-2008).pdf

1120-mum-2003 form 1(22-10-2003).pdf

1120-mum-2003 form 1(24-11-2003).pdf

1120-mum-2003 form 18(8-3-2006).pdf

1120-mum-2003 form 2(granted)(12-12-2007).pdf

1120-mum-2003 form 2(granted)-(12-12-2007).doc

1120-mum-2003 form 26(21-10-2003).pdf

1120-mum-2003 form 3(12-12-2007).pdf

1120-mum-2003 form 3(21-12-2003).pdf

1120-mum-2003 form 5(21-10-2004).pdf