Title of Invention	PHARMACEUTICAL COMPOSITION OF A PDE4 OR A PDE3/4 INHIBITOR AND A HISTAMINE RECEPTOR ANTAGONIST
Abstract	The pharmaceutical composition comprising, in admixture, a first active ingredient which is selected from a PDE4 inhibitor, a PDE3/4 inhibitor and their pharmaceutically acceptable derivatives, and a second active ingredient which is selected from a histamine receptor antagonist and its pharmaceutically acceptable derivatives.

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FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See Section 10, rule 13) PHARMACEUTICAL COMPOSITION OF A PDE4 OR A PDE3/4 INHIBITOR AND A HISTAMINE RECEPTOR ANTAGONIST ALTANA PHARMA AG of BYK-GULDEN-STRASSE 2, D-78467 KONSTANZ, DEUTSCHLAND, GERMANY, GERMAN Company The following specification particularly describes the nature of the invention and the manner in which it is to be performed : - PHARMACEUTICAL COMPOSITION OF A PDE4 OR A PDE3/4 INHIBITOR AND A HISTAMINE RECEPTOR ANTAGONIST Field of application of the invention The present invention relates to combinations of pharmaceuticaly active substances for use in the treatment of respiratory diseases. The substances used in the combinations according to the invention are known active compounds from the PDE4 and PDE3/4 inhibitors class and active compounds from the class of the histamine receptor antagonists. Known technical background In the international application WO03/000289 compositions are described which comprise a PDE4 inhibitor and a H1-receptor antagonist and the use of these compositions for the manufacture of a medicament for the treatment of respiratory diseases. Description of the invention Asthma is a common inflammatory disease of the respiratory tract, accounting for 1 - 3% of all office visits, 500,000 hospital admissions per year and more pediatric hospital admissions than any other single illness in the US. Annually, more than 5000 children and adults die of asthma attacks in the United States (William E. S.; Goodmann Gilmann A.:The pharmacological Basis of Therapeutics, 9th • Edition, pp. 152 & 659-682, Mc Graw Hill, New York 1996). Asthma can no longer be viewed simply as a reversible airway obstruction. It should instead be considered primarily as an inflammatory illness that has bronchial hyperactivity and bronchospasm as its results. Allergen specific immunoglobulin E (IgE) is bound to the mast cells via Fc receptors. It is a fragment obtained by papain digestion of immunoglobulin molecules and contains most of the antigenic determinants. When an allergen comes into contact with IgE, the mast cells are activated and release a number of inflammatory mediators, which include granule contents like histamine, proteases, heparin, and tumor necrosis factor (TNF), a variety of lipid membrane derived molecules like prostaglandins, leukotrienes and platelet activating factor (PAF), and a number of cytokines like interleukin (IL)-1, 3, 4, 5, 6 and 8 and chemokines. An enormous variety of mediators are released which have more than one potent effect on airway inflammation. As a result of vasodilation, increased vasopermeability and increased endothelial adhesiveness towards leukocytes further leads to an influx of inflammatory cells like lymphocytes, eosinophils and macrophages from blood circulation into the tissues. This in turn leads to the release of mediators which have further inflammatory effects (Rao A. R. et al. Recent Perspectives in the design of antiasthmatic agents, Pharmazie, 55, 7,475-482, 2000). Thus, it can be understood that it is unlikely that drugs affecting a single mediator can satisfactorily treat the disease alone. As asthma is one of the major diseases affecting mankind, there is a need to develop drugs which can affect a wide variety of mediators. Therefore, it is the object of the present invention to make available respiratory tract therapeutics which fulfill the following conditions: Favorable simultaneous influence on several of the inflammatory mediators Marked bronchorelaxation and -dilatation Good oral availability Minor side effects Good suitability for long-term therapy Favorable influence on bronchial hyperreactivity It has now been found that the combined use of a PDE4 or a PDE3/4 inhibitor and a histamine receptor antagonist outstandingly fulfills the above-mentioned conditions. The invention thus relates to the combined use of a PDE4 or a PDE3/4 inhibitor and a histamine receptor antagonist in the treatment of respiratory diseases. By the expression "PDE4 inhibitor" is meant a selective phosphodiesterase inhibitor, which inhibits preferentially the type 4 phosphodiesterase when compared to other known types of phosphodiester¬ase, e.g. type 1, 2, 3, 5 etc., whereby the compound has a lower IC50 (more potent) for the type 4 phosphodiesterase, such as where the IC50 for PDE4 inhibition is about factor 10 lower compared to IC50 for inhibition of other known type of phosphodiesterase, e.g. type 1,2, 3,5 etc. Analogously, the expression "PDE3/4 inhibitor" is defined. Methods to determine the activity and selectivity of a phosphodiesterase inhibitor are known to the person skilled in the art. In this connec¬tion it may be mentioned, for example, the methods described by Thompson et al. (Adv Cycl Nucl Res 10: 69-92, 1979), Giembycz et al. (Br J Pharmacol 118:1945-1958, 1996) and the phosphodiesterase scintillation proximity assay of Amersham Pharmacia Biotech. By the expression "histamine receptor antagonist" are meant Hi-receptor antagonists, particularly the so called Hi-receptor antagonists of the second generation (Mutschler, Arzneimittelwirkungen, 8. Edition, 2001, pages 456-461). Exemplary PDE inhibitors are shown on the following pages with the aid of their formulae: We Claim: 1. A pharmaceutical composition comprising, in admixture, a first active ingredient which is selected from the group consisting of 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN:ROFLUMILAST], (-)-cis-9-ethoxy-8-methoxy-2-methyl-l,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c] [ 1,6]naphthyridine [INN: PUMAFENTRINE] and their pharmaceutically acceptable derivatives, and a second active ingredient, which is selected from the group consisting of (plus/minus)- [2 [4-(p-chloro-alpha-phenylbenzyl)-l-piperazinyl]ethoxy)-acetic acid [INN: CETIRIZINE] and its pharmaceutically acceptable derivatives. 2. A pharmaceutical composition according to claim 1, wherein the first and/or second active ingredient is in the form of a pharmaceutically acceptable salt, solvate, N-oxide, or solvate of a salt or N-oxide. 3. A pharmaceutical composition according to claim 1, wherein the first active ingredient is selected from the group consisting of 3-Cyclopropylmethoxy-4difluoromethoxy-N-(3,5-dichloropyrid-4-yl)- benzamide [INN:ROFLUMILAST], a pharmaceutically acceptable salt, solvate or N-oxide thereof, or solvate of an salt or N-oxide thereof. 4. A pharmaceutical composition according to claim 1, wherein the first active ingredient is selected from the group consisting of 3-Cyclopropymethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)- benzamide [INN:ROFLUMILAST] or a pharmaceutically acceptable salt, solvate or N-oxide thereof, or solvate of an salt or N-oxide thereof, and the second active ingredient is selected from the group consisting of (plus/minus)[-2-[4-(p-chloro-alpha-phenylbenzyl)-l-piperazinyl]ethoxy]-acetic acid [INN: CETIRIZINE] and its pharmaceutically acceptable derivatives. 5. A pharmaceutical composition according to any of claims 1 to 4, which is a fixed oral combination. 6. A process for the preparation of a pharmaceutical composition as defined in any of claims 1 to 5, which comprises mixing the first active ingredient with the second active ingredient. 7. A pharmaceutical product comprising in combination, a preparation of a first active ingredient which is selected from the group consisting of 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN:ROFLUMILAST], (-)-cis-9-emoxy-8-methoxy-2-methyl-l,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl-)-benzo-[c],[l,6]naphthyridine [INN:PUMAFENTRINE] and their pharmaceutically acceptable derivatives, and a preparation of a second active ingredient, which is selected from the group consisting of (plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-l-piperazinyl]ethoxy]-acetic acid [INN:CETIRIZINE] and its pharmaceutically acceptable derivatives for simultaneous, sequential or separate use in therapy. 8. A pharmaceutical product according to claim 7, wherein the first and/or second active ingredient is in the from of a pharmaceutically acceptable salt, solvate, N-oxide, or solvate of a salt or N-oxide. 9. A pharmaceutical product according to claim 7, wherein the first active ingredient is selected from the group consisting of 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN:ROFLUMILAST], a pharmaceutically acceptable salt, solvate or N-oxide thereof, or solvate of an salt or N-oxide thereof. 10. A kit comprising a preparation of a first active ingredient, which is selected from the group consisting of 3-Cyclopropylmethoxy-4-difluoromethozy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN:ROFLUMI-LAST],(-)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a, 10b-hexahydro-6-(4-diisopropylaminocarbonyl-Phenyl)-benzo-[c][l,6]naphtyridine [INNPUMAFENTRINE] and their pharmaceutically acceptable derivatives, a preparation of a second active ingredient which is selected from the group consisting of (plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-l-piperazinyl]ethoxy]-acetic acid[INN:CETIRIZINE] and its pharmaceutically acceptable derivatives, and instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof. 11. A kit according to claim 10, wherein the first and/or second active ingredient is in the form of a pharmaceutically acceptable salt, solvate, N-oxide, or solvate of a salt or N-oxide. 12. A kit according to claim 10, wherein the first active ingredient is selected from the group consisting of 3-Cyclopropymethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl) -benzamide [INN:ROFLUMILAST], a pharmaceutically acceptable salt, solvate or N-oxide thereof, or solvate of an salt or N-oxide thereof. 13. A kit comprising a preparation of a first active ingredient, which is selected from the group consisting of 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide (INN: ROFLUMILAST), (-)-cis-9-ethoxy-8-methoxy-2-methyl-l, 2, 3, 4, 4a, 10b-hexahydro-6-(4-diisopropylaminocarbonyl-phenyl)-benzo-[c][l, 6] naphthyridine [INN: PUMAFENTRINE] and their pharmaceutically acceptable derivatives, a preparation of a second active ingredient which is selected from the group consisting of (plus/minus)-[2-[4-p-chloro-alpha-phenylbenzyl)-l-piperazinyl]ethoxy]-acetic acid [INN: CETIRIZINE] and its pharmaceutically acceptable derivatives, and instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof Dated this 21st day of July, 2004. HIRAL CHANDRAKANT JOSHI AGENT FOR ALT ANA PHARMA AG

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00404-mumnp-2004-claims(granted)-(12-07-2007).doc

00404-mumnp-2004-claims(granted)-(12-07-2007).pdf

00404-mumnp-2004-correspondence(12-07-2007).pdf

00404-mumnp-2004-correspondence(ipo)-(04-07-2007).pdf

00404-mumnp-2004-form 18(03-02-2006).pdf

00404-mumnp-2004-form 1a(23-07-2004).pdf

00404-mumnp-2004-form 2(granted)-(12-07-2007).doc

00404-mumnp-2004-form 2(granted)-(12-07-2007).pdf

00404-mumnp-2004-form 3(21-07-2004).pdf

00404-mumnp-2004-form 5(21-07-2004).pdf

00404-mumnp-2004-pct-ipea-409(23-07-2004).pdf

00404-mumnp-2004-pct-isa-210(23-07-2004).pdf

00404-mumnp-2004-power of attorney(12-01-2007).pdf

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404-mumnp-2004-claims(granted)-(12-7-2007).pdf

404-mumnp-2004-correspondence(20-9-2007).pdf

404-mumnp-2004-correspondence(ipo)-(4-7-2007).pdf

404-mumnp-2004-form 18(3-2-2006).pdf

404-mumnp-2004-form 1a(23-7-2004).pdf

404-mumnp-2004-form 2(granted)-(12-7-2007).pdf

404-mumnp-2004-form 3(21-7-2004).pdf

404-mumnp-2004-form 5(21-7-2004).pdf

404-mumnp-2004-form-pct-ipea-409(12-1-2007).pdf

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