Process for the production of an abuse-proofed dosage form

• US 10,729,658 B2
• Filed: 09/02/2016
• Issued: 08/04/2020
• Est. Priority Date: 02/04/2005
• Status: Active Grant

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: Arkenau-Maric, Elisabeth, Bartholomaus, Johannes
• Primary Examiner(s): Hartley, Michael G.
• Assistant Examiner(s): Rider, Lance W
• Application Number:
  US15/255,312
• Publication Number:
  US 20160367486A1
• Time in Patent Office: 1,432 Days
• Field of Search: None
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• 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

Abstract

The present invention relates to a process for the production of an abuse-proofed dosage form containing, apart from one or more active ingredients with potential for abuse and optionally physiologically acceptable auxiliary substances, at least one synthetic or natural polymer (C) with a breaking strength of at least 500 N, wherein the formulation mixture is combined with a solvent for the polymer (C) at least in quantities such that the formulation mixture is at least uniformly moistened, the at least moistened composition is optionally divided into sub-portions, dried and shaped to yield the dosage form.

Claims

1. A process for the production of a solid dosage form, said process comprising:

a) producing a formulation mixture by homogeneously mixing (i) at least one active ingredient with potential for abuse selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, tramadol, (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, and physiologically acceptable salts thereof, and (ii) at least 40 wt. %, based on the weight of the solid dosage form, of at least one polyalkylene oxide (C) having a molecular weight of at least 1,000,000 g/mol and exhibiting a breaking strength of at least 500 N;

b) producing a uniformly moistened formulation mixture by combining the formulation mixture produced in a) with (iii) a solvent for the polyalkylene oxide (C), wherein said solvent is in the form of a foam, the form is stabilized by foam stabilizers, and the solvent is in a quantity sufficient to provide uniform moistening of the formulation mixture;

c) optionally dividing the uniformly moistened formulation mixture into sub-portions;

d) drying the uniformly moistened formulation mixture or the sub-portions to granules; and

e) shaping the granules to produce a solid dosage form that exhibits a breaking strength of at least 500 N and cannot be comminuted using a hammer or with the assistance of a mortar and pestle.

2. The process according to claim 1, where the dried sub-portions in each case correspond to the mass of a unit of the dosage form.

3. The process according to claim 1, which further comprises dispersing the formulation mixture in a liquid dispersant in which the polymer component (C) is not soluble before addition of the solvent.

4. The process according to claim 3, which further comprises dividing the formulation mixture into sub-portions in each case corresponding to the mass of a unit of the dosage form either before or after the formulation mixture is dispersed.

5. The process according to claim 3, where the solvent and the dispersant are miscible with one another.

6. The process according to claim 1, which further comprises drying the uniformly moistened formulation mixture to granules, and then dividing the granules into sub-portions, which sub-portions in each case correspond to the mass of a unit of the dosage form, and shaping to yield the dosage form.

7. The process according to claim 1, which further comprises adding solvent to the formulation mixture in an amount such that a shapeable paste is obtained.

8. The process according to claim 7, which further comprises drying the paste and, before or after it is dried, the paste is divided into sub-portions and shaping or converting into the dosage form the dried portions, optionally after further dividing each case into a portion corresponding to the mass of a unit of the dosage form.

9. The process according to claim 8, where the sub-portions have the form of strands.

10. The process according to claim 9, which further comprises producing the strands with the assistance of a screen or strand former.

11. The process according to claim 9, which further comprises singulating and shaping dried strands to yield the dosage form.

12. The process according to claim 11, where shaping proceeds with the assistance of a tablet press.

13. The process according to claim 9, which further comprises shaping dried strands with the assistance of shaping rollers or shaping belts equipped with rollers to yield the dosage form.

14. The process according to claim 8, which further comprises converting the paste into a planar structure, from which the dosage form is stamped.

15. The process according to claim 7, where the process is performed with the assistance of an extruder.

16. The process according to claim 1, which further comprises adding a quantity of solvent sufficient to dissolve at least the polymer component (C) to the formulation mixture.

17. The process according to claim 16, which further comprises converting the solution into a planar structure.

18. The process according to claim 17, which further comprises producing the planar structure with the assistance of an extruder with a flat die or by casting the solution onto a level planar support.

19. The process according to claim 16, which further comprises shaping the dosage form by stamping from the dried planar structure or by calendaring.

20. The process according to claim 16, where the mixture is divided into portions such that, after drying, the portions correspond in each case to the mass of a unit of the dosage form.

21. The process according to claim 20, which further comprises placing the portions in molds corresponding to the shape of a unit of the dosage form.

22. The process according to claim 16, which further comprises dividing the mixture into any desired portions, and, after drying, optionally recombining the portions, and shaping to yield the dosage form.