TWI280884B - New pharmaceutical compositions containing epinastine and pseudoephedrine - Google Patents

Abstract

The present invention relates to novel oral pharmaceutical compositions comprising as pharmaceutically active compounds a combination of an antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof and of a decongestant-effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof and further comprising suitable pharmaceutically 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

1280884 A7 B7

The present invention relates to a novel oral pharmaceutical composition comprising an antihistamine effective amount of eptidatin or a pharmaceutically acceptable salt thereof and a decongested effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof Combinations as pharmaceutically active compounds also contain suitable pharmaceutically acceptable carriers or excipients. The present invention is also directed to methods of preparing such compounds and methods of using such compounds for treating allergic diseases and/or pathologies. BRIEF DESCRIPTION OF THE INVENTION The present invention provides a novel oral pharmaceutical composition comprising an anti-histamine effective acetophene acetophenine or a pharmaceutically acceptable salt thereof and a decongested effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof The combination, as a pharmaceutical active, is also a suitable pharmaceutically acceptable carrier or excipient, provided that the composition does not contain a leukotriene antagonist. Another active compound according to the invention may optionally comprise one or more compounds selected from the group consisting of dissolved mucus and analgesic-decalcifying compounds and vitamins. The preferred solution of the mucus is selected from the group consisting of bismuth (10) and ambroxol. Preferably, the analgesic antipyretic compound is selected from the group consisting of: acetamide (10) curry^ and oubufen (〇buprofen). Preferred vitamins are selected from the group consisting of vitamins ^, shame and ^. The pharmaceutical composition according to the present invention is suitable for the treatment of allergic rhinitis, allergic hyperemia of the eustachian tube and/or other allergic diseases suitable for administration of antihistamine and decongestant. Further, the composition according to the present invention is suitable for use in the treatment of, for example, cold and soothing symptoms associated with cough, cold and influenza. The pharmaceutical composition according to the present invention is preferably used for the treatment of allergic rhinitis, allergic hyperemia of the eustachian tube and/or other suitable anti-histamine and decongestant drugs.

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1280884 A7 B7 V. Inventions (2) Allergic diseases. Preferred embodiments of the pharmaceutical compositions according to the present invention comprise only an antihistamine effective amount of eptidatin or a pharmaceutically acceptable salt thereof and an anti-congestive effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof. As an active ingredient. A preferred embodiment of the present invention relates to an oral pharmaceutical composition, which is preferably a double-layered tablet, which can release an effective amount of pseudoephedrine and release an anti-histamine effective amount of an effective amount; . Particularly preferred according to the present invention is a two-layer tablet wherein the first layer A is capable of sustaining a pseudo-ephedrine test comprising a decongestant effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof, wherein the second layer B The epidistatin can be immediately released, and the anti-histamine effective amount of the eplestatin or the bilayer tablet thereof according to the present invention may further comprise a tablet coating C, which is a medicine for masking the bitterness of the active compound. An acceptable excipient composition. In a preferred embodiment of the present invention, 'the layer A of the double-layer tablet according to the present invention contains an effective amount for decongesting in the expandable hydrophilic polymer matrix: ephedrine or a pharmaceutically acceptable salt thereof' A sustained release profile is provided within 3 to 24 hours (preferably 6 hours, preferably about 12 hours). According to the present invention, "pharmaceutically acceptable words represent the acid addition salts of the active compounds pseudoephedrine and eplestatin. These acid addition salts may be formed with inorganic acids: hydrochloric acid, hydrogen acid, or sulfuric acid' or with organic acids such as: oxalic acid: fumaric acid or sulfonic acid. Preferably, it is used as an acid addition salt. The pseudo-aesthetic test is preferably used as a hydrochloride or a sulfate. In the present invention, pseudoephedrine sulfate is preferred.

Binding

Pseudoephedrine can be released for up to 3 to 24 hours, preferably 6 to 18 hours, about

1280884 A7 ____-_B7 V. Description of invention (3) The best 12-hour, double-layer tablets are designed to be administered twice a day. The concentration of pseudoephedrine in the composition according to the invention ranges from 5 to 240 mg/tablet, preferably from 10 to 2 mg/tablet, from 6 to 18 g/piece, more preferably from 140 to 140. More mg/tablet, 120 mg/tablet. The concentration of the bismuth salt in the composition according to the present invention ranges from 2 to 20 mg/tablet, preferably from 5 to 1 g/piece, more preferably from 10 mg/tablet. Each layer of the tablet is in contact with a part of its surface, but the two active substances are independently released according to the release form. The sustained release layer A consists of pseudoephedrine or a pharmaceutically acceptable salt thereof and a swellable hydrophilic polymer. Typical swellable hydrophilic polymers include cellulose ethers such as fluorenyl cellulose, hydroxypropyl cellulose, hydroxypropyl fluorenyl cellulose, hydroxymethyl cellulose, ethyl cellulose, methylidene For cellulose and slow ethyl cellulose or a mixture thereof, it is preferred to use hydroxypropyl fluorenyl cellulose? %. . Particularly suitable are HPMC polymer USP291 (musP22〇8, for example: Meth〇cei E5, e4m, E15M, K15M and K100M (supplied by Dow Chemical Company). In the above abbreviations, 'E' code refers to USP2910, wherein, K&quot Refers to usp22〇8. The numerical code refers to the viscosity of 2% aqueous solution (for example: 5 represents viscosity 5 cps; i5M refers to viscosity 15000 cps) 〇 Sustained release layer A can be selected as the insoluble polymer, Soluble or insoluble fillers, anti-adhesives' colorants, lubricants and other binders. Typical fillers are, for example, lactose, microcrystalline cellulose, dibasic calcium phosphate and corn starch. They can be used to prevent tablets from sticking to the tablet press. Examples of anti-adhesion agents are silica dioxide, colloid and talc. Typical lubricants are magnesium stearate, talc and stearic acid. Typical binders are polyvinylpyrrolidone, and jade-6 - the paper size applies to China Standard (CNS) A4 specification (2l〇x 297 public)

Line A7 B7 1280884 V. Description of the invention (4 m powder killing. Immediate release of the parent layer B is included in the J. / Ding in different excipient combinations, immediate release layer 可视 can be used as needed. ^ . & Excipients are insoluble polys' soluble or insoluble fillers, Shiyanshan anti-attachment agent' lubricants, colorants, pharyngolytic agents and other binding agents. Typical 埴祖炎 y丨,. . For example: lactose, microcrystalline cellulose, dibasic calcium phosphate and corn + ^ 卞 / S powder. An example of an anti-adhesive agent that can be used to prevent the tablet from sticking to the tablet machine is - mulberry emulsified colloid and talc The typical friend is polyvinylpyrrolidone

^Phosphate sodium glycolate and sodium carboxymethylcellulose. Typical colorants are selected from the group consisting of: F ru & c, red 4 ht ht aluminum lake, 2-base group. U·撼 naphthalene _3,6,4,. three materials three (four) 'erythro red, iron oxide, H4-Drytphthyl small naphthylazo)-2_naphthalene age_6,8_二钱三纳盐, 2,,4,,5,,7·-四漠·4,5,6,7- Tetrachlorodi- sulphate disodium salt, mi four pick from the two ketones ridiculous-9-spiro- oxime (4 (10), 7. tetrachloroisoisobenzofuran-3, ketone dipotassium salt, 3- Carboxy-5-hydroxy-1-p-sulfophenyl-! 4-p-nonylphenylazopyrazole disodium, 6-3⁄4yl-5-((4- sureylphenyl) octene;虱 么 奈 奈 奈 奈 及 及 及 及 及 及 及 及 及 及 及 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型 典型It can be used to process the volatile components and ethanol of the two layers to form granulated powder. These volatile components can be removed during processing, and this is not in the final product. 曰^ Pill coating can be used as needed. Because it exists or not, it does not change the release rate of the active substances contained in the core layer. One of the bitter taste of the active substance, and strengthen the dosage form of the twins. Because of the different polymers can be used and plasticizers and other excipients form the same quality. 7 - 7 into the δ paper size of the paper applies to the Chinese national standard ( CNS) Α4 size (210Χ 297 mm) • Binding 1280884 A7 B7 V. INSTRUCTIONS (5) Many different coatings, so the condition is that the release form of the active substance in the core tablet cannot be significantly changed. Typical coatings include polymers ( Such as: hydroxypropyl fluorenyl cellulose) and plasticizer (such as: polyethylene glycol), can be added to the coating if necessary, such as: defoamer and opacifier. Defoamer examples Examples of opacifiers are titanium dioxide, talc and aluminum lake dyes. The following examples further illustrate the invention, and these examples disclose certain preferred embodiments of the invention. The compositions according to the invention are manufactured, for example: The granulation method, the tableting method, the tablet coating method, and the like are known to those skilled in the art, and it is understood by those skilled in the art that various changes, modifications, and substitutions can be made without departing from the scope of the invention. It is not intended to be limited by the following clearly disclosed examples. Example N° 1-Composition core A. First layer pseudoephedrine layer mg/pseudoephedrine sulfate 120.00 MethocelK 15M PRCR* 198.00 Lactose monohydrate 105.10 micro Crystal cellulose 106.00 ruthenium dioxide colloid 1.65 Magnesium stearate 2.75 Polyvinylpyrrolidone 16.50 First layer total 550.00 -8- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280884 A7 B7 Five , Invention B. I 丨 Description (6) Each of the two layers of Etistatin layer mg / piece Epottin HC1 10.00 FD & C red 40 HT aluminum lake (Alura red dye (allura red AC) 0.38 micro Crystalline cellulose 70.00 Lactose monohydrate 154.62 Polyvinylpyrrolidone 12.50 Magnesium stearate 2.50 Second layer total 250.00 Core total 800.00 C. Coating film mg/tablet Methocel E5 15.00 Polyethylene glycol 6000 1.97 Anthrone defoaming Agent S184 0.03 Total amount of film coat 17.00 Total amount of coated film tablets 817.00 * PR refers to special grade, CR refers to controlled release grade. Manufacturing Method A. First layer: A1. Dissolve polyvinylpyrrolidone in aqueous alcohol mixture; A2. Mix and mix pseudoephedrine sulfate, partial microcrystalline cellulose, lactose and Methocel K15M5 to 30 in a suitable mixture. minute. A3. Use the alcohol solution or the aqueous alcohol solution prepared in advance in step A1 to mix the powder. -9 - Binding The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 x 297 mm).

Line 1280884 A7 B7 V. Description of Invention (7) The composition forms particles. A4. The pseudoephedrine sulfate particles obtained in the step A3 are dried and milled using a sieve of a suitable size. A5· Mix the sieved pseudoephedrine sulfate particles with a portion of microcrystalline cellulose and cerium oxide colloid for 3 to 15 minutes. A6. Add magnesium stearate and mix for 3 to 15 minutes. B. Second layer: B1. Pass the Epotatin HCL, aluminum lake dye red AC (FD & C Red No. 40 HT) and microcrystalline cellulose through a suitable sieve. Mix for 5 to 30 minutes in a suitable mixer. B2·Add lactose and polyvinylpyrrolidone. Mix for 15 to 120 minutes in a suitable mixer. - λ Β 3. Add magnesium stearate. Mix in a suitable mixer for 3 to 20 minutes. C. Compression: In a suitable double laminator, the crucible and the crucible are compressed to form a tablet of a suitable size. D. Coating Coating D1 · Take Methocel E5 and polyethylene glycol dissolved in an appropriate amount of water. D2. The ketone antifoaming agent is dissolved in an appropriate amount of isopropyl alcohol. D3. Add 2 to 1 and mix. D4. The tablets are coated with a Methocel E5/polyethylene glycol solution from step D3 in a suitable coating machine. Example N° 2-Composition Core A. First layer -10- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm)

Order

1280884 A7 B7 V. INSTRUCTIONS (Pseudoephedrine layer mg/pseudoephedrine sulfate 120.00 MethocelK 15M PRCR* 198.00 Lactose monohydrate 126.50 Microcrystalline cellulose 100.00 Ceria colloid 2.75 Magnesium stearate 2.75 First The total amount of layers is 550.00 B. The second layer is based on the titer layer mg/tablet epoxide HC1 10.00 lactose monohydrate 168.40 microcrystalline cellulose 70.00 Punceau 4R red color chamber 0.38 magnesium stearate 1.25 second layer total 250.00 Total core _[800.00 C. Coated film coated mg/piece Methocel E5 4.42 Polyethylene glycol 6000 2.72 Talc 8.76 Titanium dioxide 1.10 Total amount of film coat 17.00 Total amount of coated clothes _1817.00 -11 - This paper size applies China National Standard (CNS) A4 Specification (210X297 mm) 1280884 A7 B7 V. Invention Description (9) * PR refers to special grade, CR refers to controlled release grade. Manufacturing Method A. First layer: A1· In a suitable mixer Mix pseudoephedrine sulfate, microcrystalline cellulose, lactose, cerium oxide colloid, and HPMC K 15 for 5 to 30 minutes. Α 2. Add magnesium stearate and mix for 3 to 15 minutes. Β. Β1. The phase HCl and the microcrystalline cellulose are passed through a suitable sieve and mixed in a suitable mixer for 5 to 30 minutes. Β 2 · Add lactose. Mix in a suitable mixer for 15 to 120 minutes. Β 3 · Add magnesium stearate. Mix in a suitable mixer for 3 to 20 minutes C. Compression: Compress the crucible and crucible into a suitable size in a suitable double laminator D. Coating: D1. Take Methocel E5 and Polyethylene The alcohol is dissolved in an appropriate amount of water D2·Add the dioxins and talc to an appropriate amount of water and mix. D3. Add 2 to 1 and mix. D4. In a suitable coating machine, take Methocel E5/polyethylene from step D3 Alcohol solution coated tablets. Example N. 3 Core A. First layer-12- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1280884 A7 B7 V. Invention description (10) Yellow test layer mg/pseudoephedrine sulfate 120.00 Methocel K 4M PRCR 247.50 Lactose monohydrate 166.00 talc 11.00 Magnesium stearate 5.50 First layer total 550.00 *PR refers to special grade, CR refers to controlled release grade. The second layer and the coating were the same as in Example 2; the preparation method was similar to that of Example 2; Example N°4 Core A · First layer of pseudoephedrine layer mg/pseudoephedrine sulfate 120.00 Methocel K 15M PRCR 198.00 Lactose Monohydrate 99.50 microcrystalline cellulose 99.50 cerium oxide colloid 2.75 polyvinylpyrrolidone 27.50 magnesium stearate 2.75 total 550.00 *PR refers to special grade, CR refers to controlled release grade. The second layer and the coating are the same as in Example 1; the method is similar to the method of Example 1; Example N° 5 -13 This paper scale is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1280884 A7 B7 V. Description of invention (11) 枋心 A · The first layer of pseudoephedrine test layer mg / piece of pseudoephedrine sulfate 120.00 Methocel K 15M CR 330.00 lactose 83.50 talc 11.00 magnesium stearate 5.50 total 550.00 *CR refers to the controlled release level. _ - The second layer and the coating were the same as in Example 1; the preparation method was similar to that of Example 1; Example N°6 Core A. The first layer of pseudoephedrine layer mg/piece of pseudoephedrine sulfate 10.00 Methocel K 15M CR 275.00 Microcrystalline cellulose 138.50 Talc 11.00 Magnesium stearate 5.50 Ethyl alcohol amount 550.00 *CR refers to the controlled release grade.

The second layer and the coating are the same as in Example 1; the preparation method is similar to the method of Example 1; -14- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1280884 A7 B7 V. Invention Description (12) Example N. 7 Core A · First layer of pseudoephedrine layer mg/pseudoephedrine sulfate 120.00 Methocel K 15M CR 215.00 Dibasic calcium phosphate 108.50 Ethyl cellulose 40.00 Talc 11.00 Magnesium stearate 5.50 Ethyl alcohol amount 500.00 *CR refers to the control release level. The second layer and the coating were the same as in Example 1; the preparation method was similar to that of Example 1; Example N° 8 Core A. First layer -15- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 PCT) 1280884 A7 B7 V. INSTRUCTIONS (13) Pseudoephedrine layer mg/pseudoephedrine sulfate 120.00 Methocel K 15M CR 137.50 Methocel K 100Μ CR 137.50 Lactose 138.50 talc 11.00 Magnesium stearate 5.50 Ethyl alcohol 550.00 Second Example N° Core A • The first *CR refers to the control release level. The layer and coating were the same as in Example 1; the preparation method was similar to that of Example 1; 9 layers of pseudoephedrine layer mg/pseudoephedrine sulfate 120.00 Methocel K 100M CR 275.00 lactose 138.50 talc 11.00 magnesium stearate 5.50 ethanol amount The total amount is 550.00 *CR refers to the control release level. -16- This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm)

1280884 A7 B7 V. INSTRUCTIONS (14) The second layer and coating are the same as in Example 1; the method of preparation is similar to that of Example 1; Example N. 10 core A · first layer of pseudoephedrine layer mg / piece of pseudoephedrine sulfate 120.00 Methocel K 15M CR 206.20 Methocel K 100Μ CR 68.80 lactose 138.50 talc 11.00 magnesium stearate 5.50 ethanol amount of total 550.00 *CR refers to control Release level. The second layer and the coating were the same as in Example 1; the preparation method was similar to that of Example 1; Example N° 11 Core A. First layer -17- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Second install

Line 1280884 A7 B7 V. Description of invention (15) pseudoephedrine layer mg/pseudoephedrine sulfate 120.00 Methocel K 15M CR 235.00 dibasic calcium phosphate 108.50 ethyl cellulose 20.00 talc 11.00 magnesium stearate 5.50 ethanol A modest amount of 500.00 *CR refers to the controlled release level. The second layer and the coating were the same as in Example 1; the preparation method was similar to that of Example 1; Example N° 12 Core A. The first layer of pseudoephedrine layer mg/pseudoephedrine sulfate 120.00 Methocel K 15M CR 255.00 Lactose 40.00 Microcrystalline cellulose 68.50 Talc 11.00 Magnesium stearate 5.50 Ethyl alcohol amount 500.00 -18 - This paper scale applies to China National Standard (CNS) A4 size (210x 297 mm) 1280884 A7 B7 V. Invention description (16) *CR refers to the control release level. The second layer and the coating were the same as in Example 1; the preparation method was similar to that of Example 1; Example N° 13 Core A·The first layer of pseudoephedrine layer mg/pseudoephedrine sulfate 120.00 Methocel K 15M CR 255.00 II Alkali-valent calcium phosphate 108.50 Talc 11.00 Magnesium stearate 5.50 Ethyl alcohol amount 500.00 *CR refers to the controlled release level. The second layer and the coating were the same as in Example 1; the preparation method was similar to that of Example 1.

* binding

Line -19-This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm)

Claims (1)

I280RR4 Patent Application歆--Patent Range Replacement Tai (8) 6 Years U) C8 Yan 1 VI. Application for Patent Model j ' ""~ --~—^.. _ 幽• A treatment for allergic rhinitis, eustachian tube An allergic hyperemia and/or other oral pharmaceutical composition suitable for administration of an allergic disease of an antihistamine and an anti-waxing agent, which comprises an anti-histamine effective amount of epitastatin (-) or a pharmaceutically acceptable A combination of a salt acceptable and a decongested effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof as a pharmaceutically active compound' and a pharmaceutically acceptable carrier or excipient, provided that the composition is Does not contain leukoenol antagonists. 2. The oral pharmaceutical composition according to claim 1 of the invention, characterized in that it comprises an effective amount of guanidine, or a pharmaceutically acceptable salt thereof, and an anti-hypertensive effective amount of pseudoephedrine A base or a pharmaceutically acceptable salt thereof is used as an active ingredient. 3. According to the oral pharmaceutical composition of the lsiu item of the patent application, it is possible to continuously release an effective amount of pseudoephedrine and to release an effective amount of an antihistamine. 4. An oral pharmaceutical composition according to the scope of the patent application of the invention, which is characterized in that it represents a two-layer tablet. 5. The oral pharmaceutical composition according to item 4 of the scope of the patent application, wherein the first layer A can continuously release pseudoephedrine, which comprises an anti-hypertensive effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof, and wherein The second layer is an immediate release of eplestatin comprising an antihistamine effective amount of eptidatin or a pharmaceutically acceptable salt thereof. An oral pharmaceutical composition according to claim 5, characterized in that it further comprises a tablet coating C consisting of a pharmaceutically acceptable excipient. 73385-960208.doc 1280884 B8 C8 7. The oral pharmaceutical composition according to item 5 of the scope of the patent application, wherein the μ layer is contained in the swellable hydrophilic polymer matrix, and comprises an effective amount of pseudoephedrine or a pharmaceutically acceptable substance thereof. salt. 8. The oral pharmaceutical composition according to item 5 of the patent application, characterized in that the concentration of the pseudoephedrine salt in the composition according to the invention ranges from 5 to 240 g/piece, and the concentration range of the eperatin salt It is 2 to 2 mg/tablet. 9. The oral pharmaceutical composition according to item 5 of the patent application, characterized in that the layer A contains 120 mg of pseudoephedrine sulfate and the layer B contains 10 mg of eplestatin-HC1 〇10. Or 4 medical compositions for the treatment of general cold and soothing symptoms associated with cough, cold and flu. 11. A pharmaceutical composition according to claim 1 of the invention, which is for the treatment of allergic rhinitis. -2- 73385-960208.doc This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)