Title of Invention

A BILAYER TABLET CONSISTING OF PHARMACEUTICAL COMPOSITIONS CONTAINING EPINASTINE OR PSEUDOEPHEDRINE

Abstract

"NEW PHARMACEUTICAL COMPOSITIONS CONTAINING EPINASTINE OR PSEUDOEPHEDRINE" A bilayer tablet consisting of a combination of an antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof and a decongestant-effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof and additional pharmaceutically acceptable carriers or excipients and ma additionally contain a tablet coating C consisting of pharmaceutically acceptable excipients with the proviso that the composition does not contain a leukotriene antagonist, wherein a first layer A, providing for the sustained release of pseudoephedrine comprises a decongestant-effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof in a matrix of a swellable hydrophilic polymer and wherein a second layer B, providing for the immediate release of epinastine, comprises an antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof and wherein the epinastine layer is prepared by direct compression. 3 0 APR 2007

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See Section 10; rule 13] "A BILAYER TABLET CONSISTING OF PHARMACEUTICAL COMPOSITIONS CONTAINING EPINASTINE OR PSEUDOEPHEDRINE" BOEHRINGER INGELHEIM INTERNATIONAL GMBH, a German company, of Binger Strasse 173, D-55216 Ingelheim am Rhein, Germany The following specification particularly describes the invention and the manner in which it is to be performed: GRANTED ORGN 313/MUMNP/03 16-5-2007 16 MAY 2007 Background of the invention The present invention relates to novel oral pharmaceutical compositions comprising as pharmaceuticaliy active compounds a combination of an antihistaminic-effective amount of epinastine or a pharmaceuticaliy acceptable salt thereof and of a decongestant-effective amount of pseudoephedrine or a pharmaceuticaliy acceptable salt thereof and further comprising suitable pharmaceuticaliy acceptable carriers or excipients. The invention further relates to methods for the preparation these compositions and methods of using them in the treatment of allergic diseases and/or disorders. Description of the invention The present invention provides for novel oral pharmaceutical compositions comprising as pharmaceuticaliy active compounds a combination of an antihistaminic-effective amount of epinastine or a pharmaceuticaliy acceptable salt thereof and of a decongestant-effective amount of pseudoephedrine or a pharmaceuticaliy accptable salt thereof and further comprising pharmaceuticaliy acceptable carriers or excipients under the proviso that the composition does not contain a leukotriene antagonist As an additional active compound the compositions according to the invention may optionally contain one or several compounds selected from the group consiting of mucolitic and analgesic-antipyretic compounds and vitamines. Preferred mucolitic ingredients are selected from bromhexine and ambroxol. Preferred analgesic-antipyretic compounds are selected from paracetamol and obuprofen. Preferred vitamines are selected from vitamine B2, B6 and C. The pharmaceutical compositions according to the invention are useful for the treatment of allergic rhinitis, allergic congestion of the Eustachian tubes and I or other diseases from allergic origin deserving the administration of antihistamine and decongestant drugs. Furthermore the compositions according to the invention are useful in the treatment of for instance common cold and in the symptomatic relief associated with cough, cold and flu symptoms. The use of the pharmaceutical compositions according to the invention for the treatment of allergic rhinitis, allergic congestion of the Eustachian tubes and / or other diseases from allergic origin deserving the administration of antihistamine and decongestant drugs is preferred. In a preferred embodiment the pharmaceutical composition according to the invention contains as the active ingredients only an antihistaminic-effective amount of epinastine or a pharmaceuticalJy acceptable salt thereof and a decongestant-effective amount of pseudoephedrine or a pharmaceutically accptable salt thereof In a preferred embodiment the present invention relates to an oral pharmaceutical composition, preferably a bilayer tablet, providing for a sustained release of the decongestant effective amount of pseudoephedrine and an immediate release of an antihistaminic effective amount of epinastine. Particularity preferred according to the invention is a bilayer tablet wherein a first layer A, providing for the sustained release of pseudoephedrine, comprises a decongestant effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof and wherein a second layer B, providing for the.immediate release of epinastine, comprises an antihistaminic effective amount of epinastine or a pharmaceutically acceptable salt thereof. The bilayer tablet according to the invention may additionally contain a tablet coating C consisting of pharmaceutically acceptable excipients which mask the bitter taste of one of the active compounds. In a preferred embodiment of the invention layer A of the bilayer tablet according to the invention comprises a decongestant effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof in a matrix of a swellable hydrophilic polymer which provides a sustained release profile in a period of 3 to 24, preferably 6 to 18, most preferably about 12 hours. According to the invention the term pharmaceutically acceptable salts stands for acid addition salts of the active compounds pseudoephedrine and epinastine. These acid addition salts can be formed with anorganic acids like hydrochloric acid, hydrobromic acid or sulfuric acid or with organic acids as for instance oxalic acid, fumaric acid or methansulfonic acid. Epinastine is preferably used as its hydrochloric acid addition salt. Pseudoephedrine is preferebly used as the hydrochloride or the sulfate. Within the present invention pseudoephedrine sulfate is most preferred. The release of pseudoephedrine takes place over 3 to 24, preferably 6 to 18, most preferably about 12 hours. This bilayer tablet is designed to be preferably administered twice daily.; The concentration range of pseudoephedrine salt in the compositions according to the invention is between 5 and 240 mg/tablet, preferably 10 to 200 mg/tablet, more preferably 60 to 180 mg/tablet, preferably 80 to 140 mg/tablet, most preferably 120 mg/tablet. The concentration range of epinastine salt in the compositions according to the invention is between 2 and 20 mg/tablet, preferably 5 to 10 mg/tablet, more preferably 10 mg/tablet. Each layer of the tablet is in contact with each other in a portion of their surface, but provides independent release profiles for both active substances mentioned before. The sustained release layer A consists of pseudoephedrine or a pharmaceutically acceptable salt thereof and a swellable hydrophilic polymer. Typical swellable hydrophilic polymers include cellulosic ethers such ,as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethyJcelJuIose, hydroxyethylcellulose, carboxymethylcellulose and carboxyethylcellulose or mixtures thereof. The use of hydroxypropylmethylcellulose (HPMC) is preferred. Particularly useful are the HPMC polymers HPMC USP2910 and USP2208 like for instance Methocel E5.E4M, E15M, K15M, and K100M supplied by the Dow Chemical Company. In the aformentioned abbreviations the designation nE" refers to USP2910 whereas "K" refers to USP2208. The number designation refers to the viscosity in a 2% aqueous solution (e.g. 5 designates a viscosity of 5 cps; 15M designates a viscosity of 15000 cps). The excipients that could be optionally used in the sustained release layer A. are insoluble polymers, soluble or insoluble fillers, antiadherents, coloring agents, lubricants and additional binders. Typical fillers are for example lactose, microcrystalline cellulose, dibasic calcium phosphate and cornstarch. Examples of antiadherents, which are used to prevent tablets from sticking to the tablet press, are colloidal silicon dioxide and talc. Magnesium stearate, talc and stearic acid are typical lubricants. Typical binders are povidone, and cornstarch. The immediate release matrix layer B comprises epinastine within different combinations of excipients. The excipients that could be optionally used in the immediate release layer B"are insoluble polymers, soluble or insoluble fillers, antiadherents, lubricants, coloring agents.disintegrants and additional binders. Typical fillers are for example lactose, microcrystalline cellulose, dibasic calcium phosphate and cornstarch. Examples of antiadherents, which are used to prevent tablets from sticking to the tablet press, are colloidal silicon dioxide and talc. Typical disintegrants are crospovidone, sodium starch glycoJate and crosscarmellose sodium. Typical coloring agents are selected from FD&C red 40 HT Aluminum lake, 2-hydroxy-1,1'-azonaphthaiene-3,6,4'-trisulfonic acid trisodium salt, erythrosine, iron oxides, 1-(4-sulpho-1-naphthylazo)-2-naphthol-6,8-disulphonic acid trisodium salt, 2,,4,,5'I7,-tetrabromo-4,5,6,7-tetrachloro-fIuorescein disodium salt, 2,4,5,7-Tetraiodo-3,6-dihydroxyxanthene-9-spiro-1,-(4',5,,6,,7'-tetrachloro-3'H-isobenzofuran-3'one dipotassium salt, trisodium 3-carboxy-5-hydroxy-1-p~sulphophenyl-4-p-sulfophenylazopyrazole, 6-hydroxy-5-((4-sulphonphenyl)azo-2-naphthalenesulphonic acid disodium salt and optionally aluminium lakes thereof. Magnesium stearate, talc and stearic acid are typical lubricants. Typical binders are povidone, and cornstarch. Water and ethanol are examples, of volatile components which can be used in the manufacture process of both layers to granulate powders. These volatile components are removed during processing and therefore do not appear in the finished product. The tablet coating is optional since the presence of it does not modifies significantly the release rates of the active substances present in the core layers. The presence of the coating is preferred because it masks the bitter taste of one of the active substances and enhances the properties of dosage form. Because of that a lot different coatings with different polymers, and plasticizers and other excipients could be used with the condition of not modifying significantly the release profile of the active substances present in the core tablet. A typical coating comprises a polymer such as hydroxypropylmethylcellulose and a plasticizer such as polyethylene glycol. Optional excipients could be added to the coating like antifoaming agents and opacifying. Example of an antifoaming agent is silicone. Examples of opacifying agents are Titanium dioxide, talc and aluminum lake dyes. The invention will be further described by the following examples. These examples disclose certain preferred embodiments of the invention. The methods of manufacturing the compositions according to the invention like for instance granulation, tablet compression, tablet coating etc. are well known to the person skilled in the art. Those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit of the invention. Accordingly, it is intended that the invention be not limited to the following explicitly disclosed examples. Example N°1 - Composition Core A. First layer Laver pseudoephedrine mg/tablet Pseudoephedrine sulfate 120.00 MethocelK15MPRCR* 198.00 Lactose Monohydrate 105.10 Microcrystalline cellulose 106.00 Colloidal silicon dioxide 1.65 Magnesium Stearate 2.75 Povidone 16.50 Total first layer 550.00 . Second layer Laver Epinastine mg / tablet Epinastine HCI 10.00 FD&C red 40 HT Aluminum lake (allura red AC) 0.38 Microcrystalline cellulose 70.00 Lactose Monohydrate 154.62 Povidone 12.50 Magnesium Stearate 2.50 Total second layer 250.00 Total core 800.00 C. Coating Film Coatinq mg/ tablet Methocel E5 15.00 Polyethylene Glycol 6000 1.97 Silicone antifoam S184 0.03 Total film coating 17.00 Total Film coated tablet 817.00 * PR means Premium grade and CR means Controlled Released grade. Method of Manufacture A. First layer: A1. Dissolve povidone in a hydroalcoholic mixture; A2. Blend pseudoephedrine sulfate, a portion of the microcrystalline cellulose, •'. lactose and Methocel K15M for 5-30 minutes in a suitable mixer. . granulate the powder mix. A4. Dry and mill the pseudoephedrine sulfate granulation from step A3, using . suitable size screen. A5. Blend the screened pseudoephedrine sulfate granulation with a portion of the microcrystalline cellulose and colloidal silicon dioxide for 3-15 minutes. A6. Add magnesium stearate and blend for 3-15 minutes. B Second layer: B1. Pass through a suitable screen Epinastine HCL, Allura red AC (FD & C red 40 HT) aluminum lake and microcrystalline cellulose. Blend for 5-30 minutes in a suitable mixer. B2. Add lactose and povidone. Blend for 60 minutes 15-120 minutes in a suitable mixer. B3. Add magnesium stearate. Blend for 3-20 minutes in a suitable mixer. C. Compression: Compress A and B into a suitable bilayer tableting machine in suitable size tablets. D, Coating D1. Dissolve Methocel E5 and Polyethylene Glycol in suitable amount of water. D2. Dissolve silicone antifoam in suitable amount of isopropilic alcohol. D3. Add 2. to and mix.. D4. Coat tablets with the Methocel E5 /Polyethylene glycol solution from step D3. in a suitable coater. Example NQ 2 - Composition Core A. First layer Layer pseudoephedrine Mg/tablet Pseudoephedrine sulfate 120.00 Methocei K15M PRCR 198.00 Lactose Monohydrate 126\50 Microcrystalline cellulose 100.00 Colloidal silicon dioxide 2.75 Magnesium Stearate 2.75 Total first layer 550.00 B. Second layer Layer Epinastine Mg/tablet Epinastine HCI 10.00 Lactose Monohydrate 168.40 MlcrocrystalYme cellulose 70.00 Punceau 4R red aluminum lake 0.38 Magnesium Stearate 1.25 Total second layer 250.00 Total core 800.00 C. Coating Film Coatinq mg/ tablet Methocel E5 4.42 Polyethylene Glycol 6000 2.72 Talc 8.76 Titanium dioxide 1.10 Total film coating 17.00 Total Film coated tablet 817.00 * PR means Premium grade and CR means Controlled Released grade. Method of Manufacture A _First layer; A1. Blend pseudoephedrine sulfate, microcrystalline cellulose, lactose,, colloidal silicon dioxide and HPMC K15M for 5-30 minutes in a suitable mixer. A2. Add magnesium stearate and blend for 3-15 minutes. B. Second layer: B1. Pass through a suitable screen Epinastine HCI, and microcrystalline cellulose. Blend for 5-30 minutes in a suitable mixer. B2. Add lactose. Blend for 60 minutes 15-120 minutes in a suitable mixer. B3. Add magnesium stearate. Blend for 3-20 minutes in a suitable mixer. C. Compression: Compress A and B into a suitable bilayer tableting machine in suitable size tablets. D Coating D1. Dissolve Methocel E5 and Polyethylene Glycol in suitable amount of water. D2. Add Titanium Dioxide and Talc in suitable amount of water and mix D3. Add 2. to 1. And mix. D4. Coat tablets with the Methocel E5 /Polyethylene glycol solution from step D3. in a suitable coater. Example N° 3 Core A. First layer Laver pseudoeohedrine Mg/tablet Pseudoephedrine sulfate 120.00 Methocel K4M PRCR 247.50 Lactose Monohydrate 166.00 Talc 11.00 Magnesium Stearate 5.50 Total first layer 550.00 * PR means Premium grade and CR means Controlled Released grade Second layer and coating are identical to example 2; the manufacture method was conducted analogously to the method outlined in example 2; Example N° 4 Core A. First layer Laver pseudoephedrine Mg/tablet Pseudoephedrine sulfate 120.00 Methocel K15MPRCR 198.00 Lactose Monohydrate 99.50 Microcrystalline cellulose 99.50 Colloidal silicon dioxide 2.75 Povidone 27.50 Magnesium stearate 2,75 Total 550.00 * PR means Premium grade and CR means Controlled Released grade Second layer and coating are identical to example 1; the manufacture method was conducted analogously to the method outlined in example 1; Example N° 5 Core A. First layer Second layer and coating are identical to example 1; the manufacture method was conducted analogously to the method outlined in example 1; Example N° 6 Core A. First layer Second layer and coating are identical to example 1; the manufacture method was conducted analogously to the method outlined in example 1; Example No 7 Core A, First layer Laver pseudoephedrine Mg/tablet Pseudoephedrine sulfate 120.00 Methocel K15M CR 215.00" Dibasic Calcium phosphate 108.50 Ethyfcelullose 40.00 Talc 11.00 Magnesium Stearate 5.50 Ethanol s.q. Total 500.00 * CR means Controlled Released arade. Second layer and coating are identical to example 1; the manufacture method was conducted analogously to the method outlined in example 1; Example N° 8 Core A. First layer Laver pseudoephedrine Mg/tablet Pseudoephedrine sulfate 120.00 Methocel K15M CR 137.50 Methocel K100M CR 137.50 Lactose 138.50 Talc 11.00 Magnesium Stearate 5.50 Ethanol s.q. Total 550.00 * CR means Controlled Released grade, Second layer and coating are identical to example 1; the manufacture method was conducted analogously to the method outlined in example 1; Example N° 9 Core A. First layer Layer pseudoephedrine Pseudoephedrine sulfate Mg/tablet 120.00 MethocelKIOOMCR 275.00 Lactose Talc 138.50 11.00 Magnesium Stearate 5.50 Ethanol s.q. Total 550.00 CR means Controlled Released grade. Second layer and coating are identical to example 1; the manufacture method was conducted analogously to the method outlined in example 1; Example N° 10 Core A. First layer Layer pseudoephedrine Mg/tablet Pseudoephedrine sulfate 120.00 MethocelK15MCR 206.20 MethocelKIOOMCR 68.80 Lactose 138.50 Talc 11.00 Magnesium Stearate 5.50 Ethanol s.q. Total 550.00 * CR means Controlled Released grade. Second layer and coating are identical to example 1; the manufacture method was conducted analogously to the method outlined in example 1; Example N° 11 Core A. First layer Laver pseudoephedrine Mg/tablet Pseudoephedrine sulfate 120.00 MethocelK15MCR 235.00 Dibasic Calcium phosphate 108.50 Ethylcellulose 20.00 Talc 11.00 Magnesium Stearate 5.50 Ethanol s.q. Total 500.00 * CR means Controlled Released grade. Second layer and coating are identical to example 1; the manufacture method was conducted analogously to the method outlined in example 1; Example N° 12 Core A. First layer Laver pseudoephedrine Mg/tablet Pseudoephedrine sulfate 120.00 Methocel K15MCR 255.00 Lactose 40.00 Microcrystalline Cellulose 68.50 Talc 11.00 Magnesium Stearate 5.50 Ethanol s.q. Total 500.00 ' CR means Controlled Released grade. Second layer and coating are identical to example 1; the manufacture method was conducted analogously to the method outlined in example 1; Example N° 13 Core A. First layer Laver Dseudoeohedrine Mg/tablet Pseudoephedrine sulfate 120.00 MethocelK15MCR 255.00 Dibasic calcium phosphate 108.50 Talc 11.00 Magnesium Stearate 5.50 Ethanol s.q. Total 500.00 * CR means Controlled Released grade. Second layer and coating are identical to example 1; the manufacture method was conducted analogously to the method outlined in example 1; We Claim: 1. A bilayer tablet consisting of a combination of an antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof and a decongestant-effective amount of pseudoephednne or a pharmaceutically acceptable salt thereof and additional pharmaceutically acceptable carriers or excipients and may additionally contain a tablet coating C consisting of pharmaceutically acceptable excipients, with the proviso that the composition does not contain a leukotriene antagonist, wherein a first layer A, providing for the sustained release of pseudoephednne comprises a decongestant-effective amount of pseudoephednne or a pharmaceutically acceptable salt thereof in a matrix of a swellable hydrophilic polymer and wherein a second layer B, providing for the immediate release of epinastine, comprises an antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof and wherein the epinastine layer is prepared by direct compression. 2 A bilayer tablet as claimed in claim 1, wherein the concentration range of the pharmaceutically acceptable salt of pseudoephedrine is 5 to 240 mg/tablet and the concentration range of the pharmaceutically acceptable salt of epinastine salt is 2 to 20 mg/tablet. 3. A bilayer tablet as claimed in claim 2, wherein layer A comprises 120 mg pseudoephedrine sulfate and layer B comprises 10 mg epinastine-HC1. 4 A bilayer tablet as claimed in claim 1, which contains as active ingredients only the antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof and the decongestant-effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof. Dated this 17th day of March, 2003. [DEEPA KACHROO TIKU] OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

Documents:

313-mumnp-2003- form 2 (granted)-(16-05-2007).doc

313-mumnp-2003-abstract (16-05-2007).doc

313-mumnp-2003-abstract (16-05-2007).pdf

313-mumnp-2003-cancelled pages(16-05-2007).pdf

313-mumnp-2003-claims(granted)-(16-05-2007).doc

313-mumnp-2003-claims(granted)-(16-05-2007).pdf

313-mumnp-2003-correspondence(30-04-2007).pdf

313-mumnp-2003-correspondence(ipo)-(06-06-2006).pdf

313-mumnp-2003-form 18(30-11-2005).pdf

313-mumnp-2003-form 1a(16-05-2007).pdf

313-mumnp-2003-form 2(granted)-(16-05-2007).pdf

313-mumnp-2003-form 3(14-05-2007).pdf

313-mumnp-2003-form 3(17-03-2003).pdf

313-mumnp-2003-form 3(30-04-2007).pdf

313-mumnp-2003-form 5(17-03-2003).pdf

313-mumnp-2003-form-pct-isa-210(17-03-2003).pdf

313-mumnp-2003-petition uder rule 138(03-08-2006).pdf

313-mumnp-2003-petition under rule 137(14-05-2007).pdf

313-mumnp-2003-petition under rule 137(30-04-2007).pdf

313-mumnp-2003-petition under rule 138(14-05-2007).pdf

313-mumnp-2003-petition under rule 138(30-04-2007).pdf

313-mumnp-2003-power of authority(28-03-2003).pdf

313-mumnp-2003-power of authority(30-04-2007).pdf