Tamper resistant and dose-dumping resistant pharmaceutical dosage form

• US 10,335,373 B2
• Filed: 04/17/2013
• Issued: 07/02/2019
• Est. Priority Date: 04/18/2012
• Status: Active Grant

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: Wening, Klaus, Barnscheid, Lutz, Schwier, Sebastian
• Primary Examiner(s): Palenik, Jeffrey T.
• Application Number:
  US13/864,450
• Publication Number:
  US 20130280338A1
• Time in Patent Office: 2,267 Days
• Field of Search: None
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 9/0002 Galenical forms characterised by the drug release technique; Application systems commanded by energy
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• 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 9/2031 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: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/36 Opioid-abuse

Abstract

A tamper-resistant pharmaceutical dosage form comprising a pharmacologically active ingredient embedded in a prolonged release matrix, which comprises a prolonged release matrix material selected from the group consisting of nonionic acrylic polymers and waxy materials and which provides prolonged release of the pharmacologically active ingredient, resistance against solvent extraction, resistance against grinding, and resistance against dose-dumping in aqueous ethanol.

Claims

1. A tamper-resistant pharmaceutical dosage form comprising a pharmacologically active ingredient embedded in a prolonged release matrix, which prolonged release matrix comprises a prolonged release matrix material selected from the group consisting of nonionic acrylic polymers and which prolonged release matrix provides prolonged release of the pharmacologically active ingredient, resistance against solvent extraction, resistance against grinding, and resistance against dose-dumping in aqueous ethanol, and the pharmaceutical dosage form not comprising either ethyl cellulose or an ionic acrylic polymer;

wherein;

(a) the pharmaceutical dosage form is monolithic, has a breaking strength of at least 300 N, and has an extension in any direction of at least 2.0 mm;

or

(b) the pharmaceutical dosage form is oligoparticulate or multiparticulate, comprising a plurality of individual particulates, wherein each of the individual particulates comprises a homogeneous mixture of said pharmacologically active ingredient and said prolonged release matrix, wherein at least a fraction of the individual particulates have a breaking strength of at least 300 N, and wherein said individual particulates have an extension in any direction of at least 2.0 mm.

2. The pharmaceutical dosage form according to claim 1, wherein the prolonged release matrix material comprises a nonionic acrylic polymer which is derived from a monomer mixture comprising a first C_1-4-alkyl (meth)acrylate and a second C_1-4-alkyl (meth)acrylate differing from said first C_1-4-alkyl (meth)acrylate.

3. The pharmaceutical dosage form according to claim 2, wherein the first C_1-4-alkyl (meth)acrylate is ethyl acrylate and the second C_1-4-alkyl (meth)acrylate is methyl methacrylate.

4. The pharmaceutical dosage form according to claim 3, wherein the relative molar content of the ethyl acrylate within the nonionic acrylic polymer is greater than the relative molar content of the methyl methacrylate within the nonionic acrylic polymer.

5. The pharmaceutical dosage form according to claim 1, wherein the nonionic acrylic polymer has a weight average molecular weight within the range of from 100,000 g/mol to 2,000,000 g/mol.

6. The pharmaceutical dosage form according to claim 1, wherein the prolonged release matrix material further comprises a waxy material selected from the group consisting of monoglycerides, diglycerides, triglycerides, esters of fatty acids with fatty alcohols, and paraffins.

7. The pharmaceutical dosage form according to claim 6, wherein the waxy material has a melting point of at least 45°

C.

8. The pharmaceutical dosage form according to claim 1, which is monolithic, has a breaking strength of at least 300 N and has an extension in any direction of at least 2.0 mm.

9. The pharmaceutical dosage form according to claim 1, which is oligoparticulate or multiparticulate, comprising a plurality of individual particulates, wherein at least a fraction of the individual particulates have a breaking strength of at least 300 N, and wherein individual particulates comprising the pharmacologically active ingredient have an extension in any direction of at least 2.0 mm.

10. The pharmaceutical dosage form according to claim 1, wherein the prolonged release matrix comprises an additional prolonged release matrix material.

11. The pharmaceutical dosage form according to claim 10, wherein the additional prolonged release matrix material is a hard fat according to Ph. Eur. or a polymer selected from the group consisting of polyalkylene glycols, and polyalkylene oxides.

12. The pharmaceutical dosage form according to claim 10, wherein the total content of the prolonged release matrix material and the optionally present additional prolonged release matrix material is within the range of from 5.0 to 95 wt.-%, relative to the total weight of the pharmaceutical dosage form.

13. The pharmaceutical dosage form according to claim 1, wherein the pharmacologically active ingredient has potential for abuse and potential for dose dumping in ethanol.

14. The pharmaceutical dosage form according to claim 1, wherein the pharmacologically active ingredient is an opioid or a physiologically acceptable salt thereof.

15. The pharmaceutical dosage form according to claim 1, wherein the prolonged release matrix comprises no polyalkylene oxide having a weight average molecular weight of at least 200,000 g/mol.

16. The pharmaceutical dosage form according to claim 1, which is melt-extruded.

17. The pharmaceutical dosage form according to claim 1, which at any given time point exhibits an in vitro release profile in ethanol/simulated gastric fluid (40 vol.-%) at 37°

C. that is not more than 25% greater than the in vitro release profile of the dosage form at the same time point at 37°

C. in simulated gastric fluid.

20. 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 14.

18. A process for the production of a tamper-resistant pharmaceutical dosage form comprising a pharmacologically active ingredient embedded in a prolonged release matrix, which comprises a prolonged release matrix material selected from the group consisting of nonionic acrylic polymers and which provides prolonged release of the pharmacologically active ingredient, wherein the prolonged release matrix material is employed in the form of an aqueous dispersion, and the pharmaceutical dosage form not comprising either ethyl cellulose or an ionic acrylic polymer, and

wherein:

(a) the pharmaceutical dosage form is monolithic, has a breaking strength of at least 300 N, and has an extension in any direction of at least 2.0 mm;

or

(b) the pharmaceutical dosage form is oligoparticulate or multiparticulate, comprising a plurality of individual particulates, wherein at least a fraction of the individual particulates have a breaking strength of at least 300 N, and wherein individual particulates comprising the pharmacologically active ingredient have an extension in any direction of at least 2.0 mm;

said process comprising extruding a homogeneous mixture comprising the pharmacologically active ingredient and the prolonged release matrix material in the presence of water, and evaporating the water in the course of extrusion.

19. A tamper-resistant pharmaceutical dosage form obtainable by the process according to claim 18.