Tablet for instant and prolonged release of one or more active substances

• US 6,372,255 B1
• Filed: 06/21/2000
• Issued: 04/16/2002
• Est. Priority Date: 12/23/1997
• Status: Expired due to Term

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Saslawski, Olivier, Orlando, Laurence
• Primary Examiner(s): Spear, James M.
• Application Number:
  US09/581,992
• Time in Patent Office: 664 Days
• Field of Search: 424/472, 424/473, 424/474, 424/475, 424/479, 424/480, 424/484, 424/471, 424/469, 424/470, 424/468
• US Class Current: 424/473
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61P 11/06 Antiasthmatics

Abstract

A multi-layer tablet for the instant and prolonged release of active substances comprises at least two layers where the first outer layer comprises a mixture of excipients and an active substance, allowing for the immediate release of the active substance within the first layer, and a second layer, arranged in contact with the first layer. The second layer comprises a nonbiodegradable inert porous polymeric matrix in which an active substance is dispersed, allowing for the prolonged release of the active substance within the second layer.

Claims

1. A multilayer tablet comprises at least two superposed layers, wherein:

a first outer layer comprises a mixture of excipients and a first active substance, wherein the first layer allows immediate release of the first active substance;

a second layer, which is in contact with the first layer, comprises at least one nonbiodegradable, inert porous polymeric matrix in which a second active substance is dispersed;

wherein the second active substance is identical to the first active substance.

2. A tablet according to claim 1, wherein the nonbiodegradable inert polymeric matrix comprises one or more nonbiodegradable inert polymeric materials selected from polyvinyl chlorides, vinyl acetate/vinyl chloride copolymers, copolymers derived from acrylic and/or methacrylic acids, acrylonitrile/vinylidene chloride copolymers and poydimethylsiloxanes.

3. A tablet according to claim 2, wherein the copolymers derived from methacrylic and/or acrylic acids are selected from copolymers of esters of ethyl acrylate and methyl methacrylate, ethylammonium methacrylate and ethyl acrylate copolymers, ethylammonium methacrylate and methyl methacrylate copolymers, ethylammonium methacrylate and ethyl methacrylate copolymers, methacrylic acid and ethyl acrylate copolymers, methacrylic acid and methyl methacrylate copolymers.

4. A tablet according to claim 2, wherein the second layer comprises 1 to 25% by weight of said nonbiodegradable inert polymeric materials.

5. A tablet according to claim 1, wherein the second layer comprises 1 to 98.5% by weight of the second active substance.

6. A tablet according to claim 1, wherein the first layer further comprises one or more disintegrating agents.

7. A tablet according to claim 1, wherein the first layer comprises 1 to 99.0% by weight of the first active substance.

8. A tablet according to claim 1, wherein the second layer has a top surface and a bottom surface, only one of those surfaces being in contact with the first layer.

9. A tablet according to claim 1, wherein the first layer and the second layer are concentric.

10. A method for preparing a tablet according to claim 1, comprising:

a) preparing a granule of a first active substance from a pulverulent mixture of the said first active substance, a disintegrating agent and optionally one or more additives suitable for the preparation of a layer for the immediate release of the first active substance;

b) preparing a granule of a second active substance from a pulverulent mixture of the said second active substance, one or more nonbiodegradable inert polymeric materials and optionally one or more additives suitable for the preparation of a layer for the prolonged release of the said second active substance; and

c) combining, by compressing, the granules obtained in steps a) and b) to obtain tablets in which the first layer, results from the compression of the granule obtained in step a), and the second layer results from the compression of the granule obtained in step b).

11. A tablet according to claim 1, wherein the active substance is 2-ethoxymethyl-4(3H)-pteridinone.

12. A tablet according to claim 6, wherein said disintegrating agents are selected from alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, anhydrous colloidal silica, croscarmellose sodium, crospovidone, guar gum, magnesium and aluminium silicate, methyl cellulose, microcrystalline cellulose, potassium polacrilin, cellulose, pregelatinized starch, sodium alginate, starch sodium glycolate, starch and effervescent mixtures having disintegrating action.

13. A tablet according to claim 1, further comprising a coating of gastro resistant or enterosoluble polymeric film.

14. A tablet according to claim 1, wherein the second layer is completely enveloped or partially covered by the first layer.

15. A tablet according to claim 1, comprising one or more of diluents, binders, lubricants, antioxidants, colorings, sweeteners, flavorings, acidulants, wetting agents, hydrophilizing agents, osmotic agents, pH correctors, stabilizing agents, gastroresistant film-coating excipients, absorbents, chelating and/or sequestering agents.

16. A method for treating asthma comprising administering a tablet of claim 1 to a patient.

17. A method for treating asthma comprising administering a tablet of claim 11 to a patient.

18. A tablet according to claim 1, wherein the second layer comprises 1 to 95% by weight of the second active substance.