Europaisches Patentamt European Patent Office Office europeen des brevets (11) EP B1 EUROPEAN PATENT SPECIFICATION

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Europaisches Patentamt (19)

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European Patent Office Office europeen des brevets

(11)

EP

0 505

180

B1

E U R O P E A N PATENT S P E C I F I C A T I O N

(12)

(45) Date of publication and mention of the grant of the patent: 09.10.1996 Bulletin 1996/41

(51) mt ci6: A61K 31/19, A61 K 9 / 2 0

A61K9/16,

(21) Application number: 92302372.5 (22) Date of filing : 19.03.1 992 (54) High-content ibuprofen lysinate pharmaceutical formulation Arzneizubereitung mit hohem Gehalt an Ibuprofenlysinat Composition pharmaceutique a teneur elevee en lysinate d'ibuprofene (84) Designated Contracting States: AT BE CH DE DK ES FR GB GR IT LI LU NL PT SE (30) Priority: 22.03.1991 US 673613 (43) Date of publication of application: 23.09.1992 Bulletin 1992/39 (73) Proprietor: Merck & Co., Inc. Rahway New Jersey 07065-0900 (US) (72) Inventors: • Katdare, Ashok V. Norristown, PA 19401 (US)

• LUI, ChungY. West Point, PA 19486 (US) • KLEINHART, Scott N. West Point.PA 19486 (US) (74) Representative: Thompson, John Dr. et al Merck & Co., Inc. European Patent Department Terlings Park Eastwick Road Harlow, Essex CM20 2QR (GB) (56) References cited: EP-A- 0172 014

US-A- 4 279 926

CO o CO LO o LO o Q_ LU

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). Printed by Rank Xerox (UK)Business Services 2.13.7/3.4

EP 0 505 180 B1 Description BACKGROUND OF THE INVENTION Ibuprofen Is available in both prescription and OTC dosages for use as an analgesic, anti-inflammatory and antipyretic agent. Certain salts of ibuprofen, such as the basic amino acid salt, particularly the lysine salt may have beneficial properties over the free acid itself. One problem with such salts is that they add to an already high dosage size for ibuprofen. To reduce this problem it is desirable to minimize the inclusion of pharmaceutical excipients with the active agent. U.S. Patent 4,609,675 ("675") provides a dry granulation pharmaceutical ibuprofen formulation and a process for preparing this formulation. However the "675" formulation requires the use of a disintegrant (croscarmellose sodium) and preferably a flow agent silicon dioxide. There is no teaching or suggestion in the art for preparing a dry granulation pharmaceutical formulation of ibuprofen lysinate. DETAILED DESCRIPTION OF THE INVENTION This invention relates to a pharmaceutical ibuprofen lysinate dry granulation formulation comprising 90% w/w ibuprofen lysinate. Included within this invention are formulations containing each of the stereoisomers of ibuprofen lysinate including the racemic mixtures and specifically including the stereoisomer formed from (S)-ibuprofen and (S)-lysine. Furthermore, the hydrates of ibuprofen lysinate, specifically including the monohydrate are included within this invention. The formulations within the present invention also include one or more excipients selected from agents such as microcrystalline cellulose such as Avicel 102, binding agents such as povidone, and lubricants such as magnesium stearate. In general, a tablet will contain 90% weight/weight ibuprofen lysinate. The ibuprofen lysinate granulation formulations are prepared by (1) roller compacting the ibuprofen lysinate to manufacture a dry granulation; (1) mixing the ibuprofen lysinate granulation with at least one excipient. This formulation may then be compressed to form tablets or may be used to fill capsules. This invention provides a pharmaceutical dry granulation useful for the production of tablets containing 100 mg to 400 mg ibuprofen lysinate measured in mg ibuprofen. For example, the dry granulation may be adopted for preparing tablets of 200 mg ibuprofen lysine monohydrate. Each tablet is prepared by mixing a dry granulation containing ibuprofen lysine monohydrate

359.2 mg

avicel PH 102

18.0 mg

povidone

17.0 mg

magnesium stearate

4.0 mg

This invention also provides a process for preparing pharmaceutical ibuprofen lysine granulate compositions which useful in preparing compressed tablet or filled capsules containing from about 100 mg to 400 mg ibuprofen lysinate, are measured in weight ibuprofen which comprises: (1) roller compacting the ibuprofen lysinate to manufacture a dry granulation; (2) mixing the ibuprofen lysinate granulation with at least one excipient. This formulation may then be compressed to form tablets or may be used to fill capsules. The present invention exhibits the following advantages over current technology for preparing an ibuprofen pharmaceutical composition: (1) The current formulation does not contain a disintegrant such as that required in U.S. Patent 4,609,675 (2) The current formulation does not contain a "flow-aid" reagent such as silicon dioxide which is stated to be a preferred ingredient in the ibuprofen formulation of U.S Patent 4,609,675

EP 0 505 180 B1 (3) The dry granulation process disclosed herein allows the use of ibuprofen lysinate monohydrate as the active ingredient. Wet granulations requiring a drying step could result in the conversion of the monohydrate to anhydrous drug. The following examples illustrate the present invention and are not intended to be limiting. EXAMPLE I

150 mg (S)-ibuprofen-(S)-lysine Caplet Table Components Dry granulated (S)-ibuprofen-** (S)-lysine monohydrate

mg/caplet

500 gm (1674 caplets)

269.4

450.97 g

Cellulose microcystalline NF avicel PH 102

13.5

22.59 gm

Povidone USP K29/32 (Plasdone)

12.75

21 .34 gm

3.0

5.0 gm

Magnesium stearate impallable powder NF

Procedure: (S)-ibuprofen-(S)-lysine, avicel pH 102 and povidone were mixed in a suitable mixer for 10 minutes. The magnesium stearate was passed through a 60 mesh screen and then added to the mixture and mixed for 5 minutes. The dry granulation was compressed on a suitable tablet press using 7/32" x 17/32" caplet shaped tooling. ** equivalent to 150 mg of dexibuprofen acid

EXAMPLE II

150 mg Dexibuprofen Lysine Caplet Table Components

mg/caplet

500 gm batch size (1 748 caplets)

269.4

470.91 gm

Cellulose microcystalline NF avicel PH 102

13.5

23.59 gm

Magnesium stearate impallable powder NF

3.0

5.24 gm

Dry granulated (S)-ibuprofen-** (S)-lysine monohydrate

Procedure: (S)-ibuprofen-(S)-lysine and avicel pH 102 were mixed in a suitable mixer for 10 minutes. The magnesium stearate was passed through a 60 mesh screen and introduced into the powder mixture and mixed for 5 minutes. The dry granulation was compressed using a suitable tablet press using 7/32" x 17/32" caplet shaped tooling. ** equivalent to 150 mg of dexibuprofen acid

EP 0 505 180 B1 EXAMPLE III

200 mg Dexibuprofen Lysine Caplet Table Components

mg/caplet

14,304 gm batch size (36,000 caplets)

359.2

12,900.0 gm

Cellulose microcystalline NF avicel PH 102

18.0

648.0 gm

Magnesium stearate impallable powder NF

4.0

144.0 gm

17.0

612.0 gm

Dry granulated (S)-ibuprofen-** (S)-lysine monohydrate

Povidone USP K29/32 (Plasdone)

Procedure: (S)-ibuprofen-(S)-lysine, avicel pH 102 and povidone were mixed in a suitable mixer for 10 minutes. The magnesium stearate was passed through a 60 mesh screen and added to the dry powder and mixed for 5 minutes. The dry granulation was compressed on a suitable tablet press with 8/32" x 19/32" caplet shaped tooling. ** equivalent to 200 mg of dexibuprofen acid

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30

Claims Claims for the following Contracting States : AT, BE, CH, LI, DE, DK, FR, GB, IT, LU, NL, PT, SE 1. A tablet formed from a dry granulation formulation which is disintegrant free and comprises 90% w/w of ibuprofen lysinate. 2.

A composition according to Claim 1 wherein the ibuprofen lysinate is present as ibuprofen lysinate monohydrate.

3.

An ibuprofen lysinate dry granulation formulation according to Claim 1 prepared by (1) roller compacting the ibuprofen lysinate to manufacture a dry granulation; (2) mixing the ibuprofen lysinate granulation with at least one excipient.

35

40

4.

A tablet formed from the formulation of Claim 3.

5.

A formulation according to Claim 3 wherein the ibuprofen lysinate is present as (S)-ibuprofen-(S)-lysine monohydrate.

6.

A process for preparing a pharmaceutical ibuprofen lysinate dry granulate formulation useful for preparing compressed tablets or filled capsules containing from 100 to 400 mg of ibuprofen per dosage unit which comprises:

45

so

(1) roller compacting the ibuprofen lysinate to manufacture a dry granulation; (2) mixing the ibuprofen lysinate with at least one excipient so that the composition contains 90% w/w ibuprofen lysinate. 7.

A tablet according to Claim 4 prepared by: (1) roller compacting the ibuprofen lysinate to manufacture a dry granulation; (2) mixing the ibuprofen lysinate with at least one excipient so that the composition contains 90% w/w ibuprofen lysinate; and (3) compressing the mixture to form a tablet.

55 8.

A process for preparing compressed tablets containing from 100 to 400 mg of ibuprofen per dosage unit which comprises:

4

EP 0 505 180 B1

5

(1) roller compacting the ibuprofen lysinate to form a dry granulation; (2) mixing said dry granulation with at least one excipient to produce a formulation containing 90% w/w ibuprofen lysinate; and (3) compressing the formulation to form tablets containing 100 mg to 400 mg of ibuprofen. 9.

(1) roller compacting the ibuprofen lysinate to form a dry granulation; (2) mixing said dry granulation with at least one excipient to produce a formulation containing 90% w/w ibuprofen lysinate; and (3) filling capsules with said formulation with a fill per capsule effective to provide from 100 mg to 400 mg of ibuprofen per dosage unit.

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15

Claims for the following Contracting States : ES, GR 1.

2.

A process for preparing compressed tablets containing from 100 to 400 mg of ibuprofen per dosage unit which comprises: (1) roller compacting the ibuprofen lysinate to form a dry granulation; (2) mixing said dry granulation with at least one excipient to produce a formulation containing 90% w/w ibuprofen lysinate; and (3) compressing the formulation to form tablets containing 100 mg to 400 mg of ibuprofen.

30 3.

A process for preparing filled capsules containing from 100 to 400 mg of ibuprofen per dosage unit which comprises: (1) roller compacting the ibuprofen lysinate to form a dry granulation; (2) mixing said granulation with at least one excipient to produce a formulation containing 90% w/w ibuprofen lysinate; and (3) filling capsules with said formulation with a fill per capsule effect to provide from 100 mg to 400 mg of ibuprofen per dosage unit.

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40

A process for preparing a pharmaceutical ibuprofen lysinate dry granulate formulation useful for preparing compressed tablets or filled capsules containing from 100 to 400 mg of ibuprofen per dosage unit which comprises: (1) roller compacting the ibuprofen lysinate to manufacture a dry granulation; (2) mixing the ibuprofen lysinate with at least one excipient so that the composition contains 90% w/w ibuprofen lysinate.

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A process for preparing filled capsules containing from 100 to 400 mg of ibuprofen per dosage unit which comprises:

Patentanspruche Patentanspruche fur folgende Vertragsstaaten : AT, BE, CH, LI, DE, DK, FR, GB, IT, LU, NL, PT, SE

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so

1.

Tablette, hergestellt aus einer Trockengranulationszubereitung, die Sprengmittel-frei ist und 90 % Gew/Gew Ibuprofenlysinat enthalt.

2.

Zusammensetzung nach Anspruch 1, worin das Ibuprofenlysinat als Ibuprofenlysinat-Monohydrat vorliegt.

3.

Ibuprofenlysinat-Trockengranulationszubereitung nach Anspruch 1, hergestellt durch (1) Walzenpressen des Ibuprofenlysinats zur Herstellung einer Trockengranulation; (2) Mischen der Ibuprofenlysinat-Granulation mit mindestens einem Arzneimitteltrager.

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4.

Tablette, hergestellt aus der Zubereitung gemaB Anspruch 3.

5.

Zubereitung nach Anspruch 3, worin das Ibuprofenlysinat als (S)-lbuprofen-(S)-lysin-Monohydrat vorliegt.

5

EP 0 505 180 B1 6.

(1) Walzenpressen des Ibuprofenlysinats zur Herstellung einer Trockengranulation; (2) Mischen des Ibuprofenlysinats mit mindestens einem Arzneimitteltrager, so daB die Zusammensetzung 90 % Gew/Gew Ibuprofenlysinat enthalt.

5

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15

7.

Tablette nach Anspruch 4, hergestellt durch (1) Walzenpressen des Ibuprofenlysinats zur Herstellung einer Trockengranulation; (2) Mischen des Ibuprofenlysinats mit mindestens einem Arzneimitteltrager, so daB die Zubereitung 90 % Gew/Gew Ibuprofenlysinat enthalt; und (3) Verpressen der Mischung zur Bildung einer Tablette.

8.

Verfahren zur Herstellung gepreBter Tabletten, die 100 mg bis 400 mg Ibuprofen pro Dosierungseinheit enthalten, das umfaBt: (1) Walzenpressen des Ibuprofenlysinats zur Bildung einer Trockengranulation; (2) Mischen der Trockengranulation mit mindestens einem Arzneimitteltrager zur Herstellung einer Zubereitung, die 90 % Gew/Gew Ibuprofenlysinat enthalt; und (3) Verpressen der Zubereitung zur Bildung von Tabletten, die 100 mg bis 400 mg Ibuprofen enthalten.

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Verfahren zur Herstellung einer pharmazeutischen Ibuprofenlysinat-Trockengranulatzubereitung, die zur Herstellung gepreBter Tabletten oder gefullter Kapseln, die 100 mg bis 400 mg Ibuprofen pro Dosierungseinheit enthalten, geeignet ist, das umfaBt:

9.

Verfahren zur Herstellung gefullter Kapseln, die 100 mg bis 400 mg Ibuprofen pro Dosierungseinheit enthalten, das umfaBt: (1) Walzenpressen des Ibuprofenlysinats zur Bildung einer Trockengranulation; (2) Mischen der Trockengranulation mit mindestens einem Arzneimitteltrager zur Herstellung einer Zubereitung, die 90 % Gew/Gew Ibuprofenlysinat enthalt; und (3) Befullen von Kapseln mit dieser Zubereitung in einer Menge pro Kapsel, mit der 100 mg bis 400 mg Ibuprofen pro Dosierungseinheit bereitgestellt werden.

30

Patentanspruche fur folgende Vertragsstaaten : ES, GR 35

1.

(1) Walzenpressen des Ibuprofenlysinats zur Herstellung einer Trockengranulation; (2) Mischen des Ibuprofenlysinats mit mindestens einem Arzneimitteltrager, so daB die Zusammensetzung 90 % Gew/Gew Ibuprofenlysinat enthalt.

40 2. 45

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55

Verfahren zur Herstellung einer pharmazeutischen Ibuprofenlysinat-Trockengranulatzubereitung, die zur Herstellung gepreBter Tabletten oder gefullter Kapseln, die 100 mg bis 400 mg Ibuprofen pro Dosierungseinheit enthalten, geeignet ist, dat umfaBt:

Verfahren zur Herstellung gepreBter Tabletten, die 100 mg bis 400 mg Ibuprofen pro Dosierungseinheit enthalten, das umfaBt: (1) Walzenpressen des Ibuprofenlysinats zur Bildung einer Trockengranulation; (2) Mischen der Trockengranulation mit mindestens einem Arzneimitteltrager zur Herstellung einer Zubereitung, die 90 % Gew/Gew Ibuprofenlysinat enthalt; und (3) Verpressen der Zubereitung zur Bildung von Tabletten, die 100 mg bis 400 mg Ibuprofen enthalten.

3.

Verfahren zur Herstellung gefullter Kapseln, die 100 mg bis 400 mg Ibuprofen pro Dosierungseinheit enthalten, das umfaBt: (1) Walzenpressen des Ibuprofenlysinats zur Bildung einer Trockengranulation; (2) Mischen der Trockengranulation mit mindestens einem Arzneimitteltrager zur Herstellung einer Zubereitung, die 90 % Gew/Gew Ibuprofenlysinat enthalt; und (3) Befullen von Kapseln mir dieser Zubereitung in einer Menge pro Kapsel, mit der 100 mg bis 400 mg Ibuprofen pro Dosierungseinheit bereitgestellt werden.

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EP 0 505 180 B1 Revendications Revendications pour les Etats contractants suivants : AT, BE, CH, LI, DE, DK, FR, GB, IT, LU, NL, PT, SE 5

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1. Comprime forme a partir d'une formulation de granulation a sec qui est exempt de desintegrant et comprend environ 90% poids/poids de lysinate d'ibuprofene. 2.

Composition selon la revendication 1, ou le lysinate d'ibuprofene est present sous forme de lysinate d'ibuprofene monohydrate.

3.

Formulation de granulation a sec de lysinate d'ibuprofene selon la revendication 1, preparee par (1) compactage sur cylindre de lysinate d'ibuprofene pour realiser une granulation a sec ; (2) melange de la granulation de lysinate d'ibuprofene avec au moins un excipient.

4.

Comprime forme a partir de la formulation de la revendication 3.

5.

Formulation selon la revendication 3, ou le lysinate d'ibuprofene est present sous forme de (S)-ibuprofene-(S)lysine monohydrate.

6.

Procede de preparation d'une formulation de granule a sec de lysinate d'ibuprofene pharmaceutique utile pour preparer des pilules comprimees ou des capsules remplies contenant de 100 a 400 mg d'ibuprofene par unite de dosage qui comprend : (1) compactage sur cylindre du lysinate d'ibuprofene pour realiser une granulation a sec ; (2) melange du lysinate d'ibuprofene avec au moins un excipient, de sorte que la composition contient 90% poids/poids de lysinate d'ibuprofene.

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35

7.

(1) compactage sur cylindre du lysinate d'ibuprofene pour realiser une granulation a sec ; (2) melange de lysinate d'ibuprofene avec au moins un excipient, de sorte que la composition contient 90% poids/poids de lysinate d'ibuprofene ; et (3) compression du melange pour former un comprime. 8.

so

Procede pour preparer des pilules comprimees contenant de 100 a 400 mg d'ibuprofene par unite de dosage et qui comprend : (1) compactage sur cylindre du lysinate d'ibuprofene pour former une granulation a sec ; (2) melange de ladite granulation a sec avec au moins un excipient pour produire une formulation contenant 90% poids/poids de lysinate d'ibuprofene ; et (3) compression de la formulation pour former des comprimes contenant 100 a 400 mg d'ibuprofene.

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Comprime selon la revendication 4, prepare par

9.

Procede de preparation de capsules remplies contenant de 100 a 400 mg d'ibuprofene par unite de dosage, qui comprend : (1) compactage sur cylindre de lysinate d'ibuprofene pour realiser une granulation a sec ; (2) melange de ladite granulation a sec avec au moins un excipient pour produire une formulation contenant 90% poids/poids de lysinate d'ibuprofene ; et (3) remplissage de capsules avec ladite formulation avec un remplissage efficace par capsule pour fournir de 100 a 400 mg d'ibuprofene par unite de dosage.

Revendications pour les Etats contractants suivants : ES, GR 55

1. Procede de preparation d'une formulation de granule a sec de lysinate d'ibuprofene pharmaceutique utile pour preparer des pilules comprimees ou des capsules remplies contenant de 100 a 400 mg d'ibuprofene par unite de dosage qui comprend: (1) compactage sur cylindre du lysinate d'ibuprofene pour realiser une granulation a sec;

7

EP 0 505 180 B1 (2) melange du lysinate d'ibuprofene avec an moins un excipient, de sorte que la composition contient 90% poids/poids de lysinate d'ibuprofene. Procede pour preparer des pilules comprimees contenant du 100 a 400 mg d'ibuprofene par unite de dosage et qui comprend: (1) compactage sur cylindre du lysinate d'ibuprofene pour former une granulation a sec; (2) melange de ladite granulation a sec avec au moins un excipient pour produire une formulation contenant 90% poids/poids de lysinate d'ibuprofene; et (3) compression de la formulation pour former des comprimes contenant 100 a 400 mg d'ibuprofene. Procede de preparation de capsules remplies contenant de 100 a 400 mg d'ibuprofene par unite de dosage, qui comprend: (1) compactage sur cylindre de lysinate d'ibuprofene pour realiser une granulation a sec; (2) melange de ladite granulation a sec avec au moins un excipient pour produire une formulation contenant 90% poids/poids de lysinate d'ibuprofene; et (3) remplissage de capsules avec ladite formulation avec un remplissage efficace par capsule pour fournir de 100 a 400 mg d'ibuprofene par unite de dosage.

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