Pharmaceutical sustained release matrix and process

• US 5,200,193 A
• Filed: 10/22/1990
• Issued: 04/06/1993
• Est. Priority Date: 04/22/1987
• Status: Expired due to Term

• Current Assignee: McNeil Consumer Products Co. (Johnson & Johnson)
• Original Assignee: McNeilab, Inc.
• Inventors: Glinecke, Robert, Julian, Thomas N., Radebaugh, Galen W.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): HORNE, LEON
• Application Number:
  US07/600,279
• Time in Patent Office: 897 Days
• Field of Search: 424/468, 424/472, 424/469, 424/470
• US Class Current: 424/468
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• 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: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00

Abstract

A pharmaceutical sustained release homogeneous tablet or homogeneous tablet layer is formed by making a wet granulation using povidone (PVP) in alcohol as the granulating fluid which is mixed with a pharmaceutical active, ethylcellulose, a wicking agent, e.g. microcrystalline cellulose, an erosion promoter, e.g. pregelatinized starch, then drying and milling the granulation and blending with a dry powdered erosion promotor, wicking agent, lubricant, e.g. magnesium stearate and glidant, e.g. silicon dioxide, and compressing the resultant granulation, which upon administration results in a long-lasting slow and relatively regular incremental release of the pharmaceutical active, and multi-layered pharmaceutical active tablets comprising immediate release and/or sustained release layers.

Claims

1. A shaped and compressed sustained release therapeutic composition comprising an effective amount of an analgesic and a granulating agent and excipients combined into a matrix, characterized by a long-lasting slow and relatively regular incremental release of the analgesic upon administration, wherein the granulating agent and excipients includes a combination of two polymers, ethylcellulose and povidone, wherein the total amount of granulating agent and excipients is an amount effective to form a solid matrix of active and binder materials and is less than 20 percent of the weight of said shaped and compressed composition wherein the total amount of granulating agent, and granulating agent and excipients is in the range of 5 to less than 20 percent of the weight of pair shaped and compressed composition.

2. The composition of claim 1 wherein the total amount of granulating agent and excipients is in the range of 10 to 20 percent of the weight of said shaped and compressed composition.

12. The composition of claim 1 wherein the excipients comprise a wicking agent and an erosion promoter.

13. The composition of claim 12 wherein the wicking agent is microcrystalline cellulose and the erosion promoter is pregelatinized starch.

14. The composition of claim 1 wherein the granulating agent comprises a mixture of:

alcohol selected from the group consisting of alcohol USP, dehydrated alcohol USP, methyl alcohol USP and isopropyl alcohol USP; and

povidone.

3. A shaped and compressed pharmaceutical active sustained release tablet made by wet granulating an analgesic and the Excipients of Part I with the Granulating Agent of Part II to form a granulation, drying and milling the granulation to form a resultant granulation, and then blending with the Excipients of Part III and compressing into a tablet, wherein the analgesic is added in Part I and comprises at least 66% of the total weight of the tablet and the ingredients of parts I, II and II consists essentially of the following:

space="preserve" listing-type="tabular">______________________________________ Parts by Weight Range Total Ingredient Inactive Ingredients ______________________________________ Part I Excipients Ethyl Cellulose 3-12 Microcrystalline Cellulose 10-35 Pregelatinized Starch 5-25 Part II Granulating Agent Povidone 5-10 Alcohol or Alcohol-Water Part III Excipients Pregelatinized Starch 3-20 Microcrystalline Cellulose 2-10 Magnesium Stearate 2-10 Colloidal Silicon Dioxide 2-10 ______________________________________

wherein Alcohol is selected from the group consisting of alcohol USP, dehydrated alcohol USP, methyl alcohol USP and isopropyl alcohol USP.

4. A shaped and compressed bi-layer immediate release and sustained release therapeutic composition comprising a pharmaceutical active in both layers wherein the immediate release layer comprises a pharmaceutical active and pharmaceutically acceptable excipients and the sustained release layer comprises a granulating agent and excipients combined into a matrix, characterized by a long-lasting slow and relatively regular incremental release of the pharmaceutical active upon administration and at least one pharmaceutical active in the sustained release layer is an analgesic wherein the granulating agent and excipients includes a combination of two polymers, ethylcellulose and povidone, and wherein the total amount of granulating agent and excipients is less than 20 percent of the weight of the sustained release layer of said shaped and compressed bi-layer composition.

5. The therapeutic composition of claim 4 wherein the immediate release layer comprises a pharmaceutical active;

microcrystalline cellulose;

starch;

sodium starch glycolate; and

a granulating agent.

6. The bi-layered therapeutic composition of claim 5 wherein the pharmaceutical active in both layers is the same or different and is selected from the group consisting of analgesics, antiarthritics, antiasthmatics, antidepressants, appetite suppressants, antihistamines, antibiotics, antipsychotics, anti-ulcers, anti-inflammatories, antitussives, antiaginals, decongestants and combinations thereof.

7. A shaped and compressed bi-layer composition according to claim 4 wherein the pharmaceutical active in both layers is the same.

8. A shaped and compressed multilayered therapeutic composition comprising at least two layers of a sustained release composition according to claim 4 wherein the pharmaceutical actives of each layer are different.

10. A multilayered composition according to claim 8 comprising at least one additional of an immediate release composition comprising a pharmaceutical active wherein the pharmaceutical active is the same or different as the pharmaceutical active comprising the sustained release layers.

15. The composition of claim 4 wherein the excipients comprise a wicking agent and an erosion promoter.

16. The composition of claim 15 wherein the wicking agent is microcrystalline cellulose and the erosion promoter is pregelatinized starch.

17. The composition of claim 4 wherein the granulating agent comprises a mixture of povidone and alcohol selected from the group consisting of alcohol USP, dehydrated alcohol USP, methyl alcohol USP and isopropyl alcohol USP.

9. A shaped and compressed bi-layered immediate release and sustained release pharmaceutical active tablet made by combining an immediate release layer comprising a pharmaceutical active and pharmaceutically acceptable excipients with a sustained release layer made by wet granulating an analgesic and Excipients ingradients of Part II, to form a granulation drying and milling the granulation to form a resultant granulation then blending the resultant granulation with the Excipients of Part III and compressing the two layers into a tablet, wherein the ingredients of Parts I, II and III consist essentially of the following:

space="preserve" listing-type="tabular">______________________________________ Range of Ingredient Parts by Weight ______________________________________ Part I Pharmaceutical Active 170-2000 Ethyl Cellulose 3-12 Microcrystalline Cellulose 10-35 Pregelatinized Starch 5-25 Part II Granulating Agent Povidone 5-30 Alcohol or Alcohol-Water q.t. Part III Excipients Pregelatinized Starch 3-20 Microcrystalline Cellulose 2-10 Magnesium Stearate 2-10 Colloidal Silicon Dioxide 2-10 ______________________________________

wherein Alcohol is selected from the group consisting of alcohol USP, dehydrated alcohol USP, methyl alcohol USP, and isopropyl alcohol USP.

11. A bi-layered tablet according to claim 9 wherein at least one layer comprises caffeine.