Oral sustained release acetaminophen formulation and process

• US 4,820,522 A
• Filed: 07/27/1987
• Issued: 04/11/1989
• Est. Priority Date: 07/27/1987
• Status: Expired due to Term

• Current Assignee: McNeil-PPC Incorporated (Johnson & Johnson)
• Original Assignee: McNeilab, Inc.
• Inventors: Glinecke, Robert, Radebaugh, Galen W., Murtha, John L.
• Primary Examiner(s): Dixon, Jr., William R.
• Assistant Examiner(s): Brunsman, David M.
• Application Number:
  US07/078,138
• Time in Patent Office: 624 Days
• Field of Search: 424/80, 424/465, 424/470, 424/473
• US Class Current: 424/468
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• 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: 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
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

An acetaminophen-sustained release tablet or tablet layer is formed by making a wet granulation, using Povidone (PVP) in water or alcohol-water as the granulating fluid which is mixed with acetaminophen, hydroxyethyl cellulose, a wicking agent e.g. microcrystalline cellulose, then drying and milling the granulation and blending with dry powdered erosion promoter, e.g. pregelatinized starch, wicking agent, lubricant e.g. magnesium stearate and glidant e.g. silicon dioxide, and compressing the resultant granulation, which upon administration results in a slow release of the acetaminophen.

Claims

1. The process of preparing an acetaminophen-sustained release shaped and compressed tablet characterized by a slow release of the acetaminophen upon administration comprising the following steps:

(A) forming a granulating agent by dissolving 5-25 parts by weight of the total composition of Povidone in water or in an alcohol-water mixture;

(B) blending together the following parts by weight of the total composition of ingredients with sufficient acetaminophen to comprise 68 to 94 percent by weight of the total composition in dry powder form;

space="preserve" listing-type="tabular">______________________________________ Ingredient Parts by Weight ______________________________________ Hydroxyethyl Cellulose 5-25 wicking agent 5-25 ______________________________________

(C) adding the granulating agent from Step A to the blended powders from Step B, and mixing in a high shear granulator to form a wet granulation;

(D) drying the wet granulation of Step C;

(E) milling the dried granulation from Step D;

(F) thoroughly blending the milled dried granulation from Step E with the following parts by weight of the total composition of ingredients in dry powder form;

space="preserve" listing-type="tabular">______________________________________ Ingredient Parts by Weight ______________________________________ erosion promoter 1-15 wicking agent 5-45 lubricant 0-10 glidant 0-5; and

______________________________________

(G) compressing the final granulation from Step F into a tablet or tablet layer.

2. The process of claim 1 wherein:

in Step A, when any alcohol is used, it is Alcohol USP or Dehydrated Alcohol USP or Methyl Alcohol USP or Isopropyl Alcohol USP, and is used in a quantity equal to or less than the water in the alcohol-water mixture;

in Step B the wicking agent used is Microcrystalline Cellulose or Powdered Cellulose;

in Step F the erosion promoter used is 2-15 parts by weight of either Pregelatinized Starch or Starch NF or rice starch, or is 1-10 Parts by Weight of Sodium Starch Glycolate or Croscarmellose Sodium or Crospovidone;

the lubricant used is Magnesium Stearate or Stearic Acid; and

, the Glidant used is Colloidal Silicon Dioxide or Fumed Silicon Dioxide.

3. The process of claim 2 wherein:

in Step A water is used;

in Step B the wicking agent used is Microcrystalline Cellulose;

in Step F the erosion promoter used is Pregelatinized Starch; and

the lubricant used is Magnesium Stearate.

4. The process of claim 3 wherein the specific ingredients and amounts used are:

space="preserve" listing-type="tabular">______________________________________ Step A Ingredient Parts by Weight ______________________________________ A water q.s Povidone 10.7 B Acetaminophen 325.0 Hydroxyethyl Cellulose 10.7 F Pregelatinized Starch 5.0 Microcrystalline Cellulose 15.0 Magnesium Stearate 5.0 ______________________________________

5. The process of claim 4 wherein the Parts by Weight shown refer to milligrams per tablet.

6. A shaped and compressed sustained release therapeutic composition comprising Acetaminophen, a granulating agent and excipients combined into a matrix, characterized by a slow release of the Acetaminophen upon administration, wherein the granulating agent and excipients include Hydroxyethyl Cellulose and Povidone, and wherein the total amount of granulating agent and excipients is effective to bind the Acetaminophen in a sustained release solid matrix but is less than about 35 percent of the weight of said shaped and compressed composition.

9. A composition according to claim 6 wherein the total amount of granulating agent and excipients is greater than about 6 but less than 15 percent of the total weight of said shaped and compressed composition.

7. A shaped and compressed Acetaminophen sustained release tablet made by wet granulating a sufficient amount of Acetaminophen to comprise from about 68 to 94 percent of the total composition with the Excipients of Part I and the Granulating Agent of Part II, drying and milling the resultant granulations, and then blending with the Excipients of Part III and compressing into a tablet, wherein the ingredients of Parts I, II and III comprise the following:

space="preserve" listing-type="tabular">______________________________________ Ingredient Parts by Weight ______________________________________ Part I Excipients Hydroxyethyl Cellulose 5-25 Microcrystalline Cellulose 5-25 Part II Granulating Agent Povidone 5-25 Water or Alcohol-Water q.s Part III Excipients Pregelatinized Starch 2-15 Microcrystalline Cellulose 5-45 Magnesium Stearate 0-10 Colloidal Silicon Dioxide 0-5 ______________________________________

8. The tablet of claim 7 wherein the Parts by Weight refer to milligrams per tablet, and wherein the ingredients are present either in the weights indicated or in such weights multiplied by an appropriate fraction.

10. A process of preparing an acetaminophen sustained release bi-layer tablet comprising a first layer of immediate release and a second layer of sustained slow release of acetaminophen according to the steps of:

(A) preparing an immediate release layer comprising acetaminophen and pharmaceutically acceptable excipients; and

(B) preparing a sustained release layer comprising acetaminophen as the active ingredient according to the steps of;

(1) forming a granulating agent by dissolving about 5-25 parts by weight of the total sustained release layer of Povidone in alcohol or an alcohol-water mixture;

(2) blending together a sufficient amount of acetaminophen to comprise 68 to 94 percent of the total weight of the sustained release layer with the following ingredients in dry powder form in parts by weight of the total sustained release layer as indicated;

space="preserve" listing-type="tabular">______________________________________ Ingredient Parts by Weight ______________________________________ hydroxyethyl cellulose 5-25 wicking agent 5-25;

______________________________________

(3) adding the granulating agent from Step 1 to the blended powders from Step 2, and forming a wet granulation;

(4) drying the wet granulation of Step 3;

(5) milling the dried granulation Step 4;

(6) thoroughly blending the milled dried granulation from Step 5 with the following ingredients in dry powder form;

space="preserve" listing-type="tabular">______________________________________ Ingredient Parts bv Weight ______________________________________ erosion promoter 1-15 wicking agent 5-45 lubricant 0-10 glidant 0-5; and

______________________________________

(C) combining and compressing the immediate release layer of Step A with the sustained release layer of Step B into a bi-layered tablet.

11. The process of claim 10 wherein:

in Step 1 the alcohol is alcohol USP, dehydrated alcohol USP, methyl alcohol USP or isopropyl alcohol USP;

in Step 2 the wicking agent is microcrystalline cellulose or powdered cellulose; and

in Step 6 the erosion promoter is 2-15 parts by weight of the total sustained release layer and is either pregelatinized starch NF or rice starch, or is 1-10 parts by weight of the total sustained release layer and is sodium starch glycolate, croscarmellose sodium or crospovidone, the lubricant is magnesium stearate or stearic acid and the glidant is colloidal silicon dioxide or fumed silicon dioxide.

12. The process of claim 11 wherein:

in Step 1 the alcohol is alcohol USP;

in Step 2 the wicking agent is microcrystalline cellulose;

in Step 3 the wet granulation is formed by mixing in a high shear granulator; and

in Step 6 the erosion promoter is pregelatinized starch, the lubricant is magnesium stearate, and the glidant is colloidal silicon dioxide.

13. The process of claim 10 wherein the immediate release layer comprises a composition of the following ingredients:

acetaminophen;

powdered cellulose;

starch;

pregelatinized starch;

sodium laurel sulphate; and

a granulating agent.

14. A shaped and compressed bi-layer therapeutic composition comprising acetaminophen in a first immediate release layer and a second sustained release layer wherein the immediate release layer comprises acetaminophen and pharmaceutically acceptable excipients and the sustained release layer comprises acetaminophen, a granulating agent and excipients combined into a matrix, wherein the granulating agent and excipients of the sustained release layer include hydroxyethyl cellulose and povidone, and wherein the total amount of said granulating agent and excipients is effective to bind the acetaminophen in a sustained release solid matrix but is less than about 32 percent of the weight of the sustained release layer of said shaped and compressed bi-layer composition.

15. The therapeutic composition of claim 14 wherein the immediate release layer comprises acetaminophen;

powdered cellulose;

starch;

pre-gelatinized starch;

sodium laurel sulphate; and

a granulating agent.

16. The therapeutic composition of claim 14 wherein the amount of granulating agent and excipients is greater than about 6 percent but less than about 15 percent of the total weight of the sustained release layer of said shaped and compressed bi-layer composition.

17. A shaped and compressed bi-layered immediate release layer and sustained release layer acetaminophen tablet made by combining an immediate release layer comprising acetaminophen and pharmaceutically acceptable excipients with a sustained release layer made by wet granulating a sufficient amount of acetaminophen to comprise 68 to 94 percent of the total weight of the sustained relase layer with the Excipients of Part I and the Granulating Agent of Part II, drying and milling the resultant granulations, and then blending with the Excipients of Part III and compressing the two layers into a tablet, wherein the ingredients of Parts I, II and III comprise the following:

space="preserve" listing-type="tabular">______________________________________ Range of Parts by Weight of the Total Ingredient Sustained Release Layer ______________________________________ Part I Excipients Hydroxyethyl Cellulose 5-25 Microcrystalline Cellulose 5-25 Part II Granulating Agent Povidone 5-25 Alcohol or Alcohol-Water q.s. Part III Excipients Pregelatinized Starch 2-15 Microcrystalline Cellulose 5-45 Magnesium Stearate 0-10 Colloidal Silicon Dioxide 0-5 ______________________________________