Oxidation-stabilized tamper-resistant dosage form

• US 9,925,146 B2
• Filed: 09/01/2015
• Issued: 03/27/2018
• Est. Priority Date: 07/22/2009
• Status: Active Grant

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: Barnscheid, Lutz, Galia, Eric, Schwier, Sebastian, Bertram, Ulrike, Geissler, Anja, Griessmann, Kornelia, Bartholomus, Johannes
• Primary Examiner(s): Thomas, Timothy P
• Assistant Examiner(s): Kosturko, George W
• Application Number:
  US14/841,829
• Publication Number:
  US 20150366809A1
• Time in Patent Office: 938 Days
• Field of Search: 514282
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• 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: A61K 9/284 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/30 for treating abuse or dependence

Abstract

A thermoformed pharmaceutical dosage form having a breaking strength of at least 300 N, said dosage form comprising

• • a pharmacologically active ingredient (A),
  • a free physiologically acceptable acid (B) in an amount of from 0.001 wt.-% to 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form, and
  • a polyalkylene oxide (C) having a weight average molecular weight M_w of at least 200,000 g/mol.

Claims

1. A tamper-resistant pharmaceutical dosage form in form of a tablet having a breaking strength of at least 300 N thermoformed by hot-melt extrusion of a mixture comprising the following components:

a pharmacologically active ingredient (A) selected from the group consisting of oxymorphone and physiologically acceptable salts thereof;

citric acid in an amount of from 0.5 wt.-% to 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form;

α

-tocopherol in an amount of from 0.001 wt.-% to 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form;

wherein the weight ratio of citric acid to α

-tocopherol being in a range of from 4.2;

1 to 1;

3; and

a polyalkylene oxide (C) having a weight average molecular weight M_w of at least 500,000 to 15,000,000 g/mol, the polyalkylene oxide (C) being present in the pharmaceutical dosage form in an amount of 56.8-77.8 wt.-% based on the total weight of the pharmaceutical dosage form and wherein the polyalkylene oxide (C) is polyethylene oxide.

2. The pharmaceutical dosage form according to claim 1, wherein after storage for 4 weeks at 40°

C. and 75% rel. humidity, the content of pharmacologically active ingredient (A) amounts to at least 98.0% of its original content before storage.

3. The pharmaceutical dosage form according to claim 1, wherein after storage for 4 weeks at 40°

C. and 75% rel. humidity, the content of the polyethylene oxide (C) amounts to at least 98.0% of its original content before storage.

4. The pharmaceutical dosage form according to claim 1, wherein the pharmacologically active ingredient (A) is embedded in a matrix comprising the polyalkylene oxide (C), said matrix controlling the release of the pharmacologically active ingredient (A) from the pharmaceutical dosage form.

5. The pharmaceutical dosage form according to claim 1, which is adapted for administration once daily or twice daily.

6. The pharmaceutical dosage form according to claim 1, which has a breaking strength of at least 500 N.

7. A packaging containing a pharmaceutical dosage form according to claim 1 and an oxygen scavenger.

8. A process for the production of the pharmaceutical dosage form according to claim 1 comprising the steps:

a) mixing the components of claim 1 to form a resultant mixture;

b) heating the resultant mixture in an extruder at least up to the softening point of the polyalkylene oxide (C) of claim 1 and extruding extrudate through the outlet orifice of the extruder by application of force,

c) singulating the extrudate to yield singulated extrudate and forming into the pharmaceutical dosage form, or

d) cooling and optionally reheating the singulated extrudate and forming it into the pharmaceutical dosage form.

9. A method of treating pain in a patient in need of such treatment, said method comprising administering to said patient a pharmaceutical dosage form according to claim 1.