Hot-melt extruded pharmaceutical dosage form

• US 10,080,721 B2
• Filed: 07/21/2010
• Issued: 09/25/2018
• 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
• Primary Examiner(s): Thakor, Devang K
• Application Number:
  US12/840,439
• Publication Number:
  US 20110038930A1
• Time in Patent Office: 2,988 Days
• Field of Search: 424468
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• 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 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• 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 invention relates to a hot-melt extruded pharmaceutical dosage form with controlled release of a pharmacologically active ingredient (A) embedded in a matrix comprising a polymer (C), the dosage form exhibiting a breaking strength of at least 300 N and having an oblong shape comprising a longitudinal direction of extension, a transversal direction of extension orthogonal to the longitudinal direction of extension, a front side, an opposite back side and a circumferential rim between said front and back side;

wherein

• • the core of the pharmaceutical dosage form has a morphological orientation caused by hot-melt extrusion that is substantially orthogonal to the longitudinal direction of extension of the dosage form; and/or
  • the release per area of the pharmacologically active ingredient (A) through the front side and the opposite back side is faster than the release through the circumferential rim.

Claims

1. A hot-melt extruded tablet having a front side and an opposite back side, the tablet comprising:

(i) a pharmacologically active ingredient (A) embedded in a matrix comprising a polymer (C);

(ii) an oblong shape imparted by post-hot-melt-extrusion pressing of a hot-melt extrudate on a tablet-press; and

(iii) a circumferential rim between the front and back sides;

wherein the tablet exhibits a breaking strength of at least 300 N;

wherein the tablet exhibits controlled release of the pharmacologically active ingredient (A);

wherein the tablet comprises a direction of extrusion that runs parallel to a direction of extrusion of the hot-melt extrudate through an extrusion die;

wherein the tablet comprises a longitudinal direction of extension, which longitudinal direction of extension is the longest dimension of the tablet and runs orthogonal to the direction of extrusion;

wherein the tablet comprises a transversal direction of extension orthogonal to the longitudinal direction of extension and orthogonal to the direction of extrusion;

wherein the oblong shape is imparted by post-extrusion pressing of the extrudate on the tablet-press in a pressing direction parallel to said direction of extrusion and orthogonal to both said longitudinal direction of extension and said transversal direction of extension; and

wherein the tablet has a core having a morphological orientation caused by the hot-melt extrusion that is substantially orthogonal to the longitudinal direction of extension of the tablet.

2. The tablet according to claim 1, wherein the pharmacologically active ingredient (A) is an opioid.

3. The tablet according to claim 1, wherein polymer (C) is a polyalkylene oxide having a weight average molecular weight of at least 200,000 g/mol.

4. The tablet according to claim 1, wherein the content of polymer (C) is at least 30 wt.-%, based on the total weight of the tablet.

5. The tablet according to claim 1, wherein the relative length ratio of the longitudinal direction of extension to the transversal direction of extension is at least 1.1:

1.

6. The tablet according to claim 1, further comprising a film coating.

7. The tablet according to claim 1, which releases the pharmacologically active ingredient (A) under in vitro conditions in artificial gastric juice according to the following release profile:

after 0.5 h at least 5 wt.-%,

after 1 h at least 10 wt.-%,

after 3 h at least 20 wt.-%,

after 6 h at least 35 wt.-%, and

after 12 h at least 55 wt.-%,

based on the total weight of the pharmacologically active ingredient (A) initially contained in the tablet.

8. A process for the manufacture of a hot-melt extruded pharmaceutical tablet according to claim 1, said process comprising the steps of:

(a) hot-melt extruding a mass comprising;

the pharmacologically active ingredient (A), and

the polymer (C),

through an oblong die thereby obtaining an extrudate with an oblong cross-section;

(b) cutting said extrudate into slices having two opposing cut surfaces of oblong shape;

(c) placing said slices into a tabletting tool comprising an upper punch and a lower punch in a manner so that the two opposing cut surfaces of oblong shape face said upper and lower punch, respectively;

(d) press-forming tablets from the slices; and

(e) optionally, applying a film coating.

9. The process according to claim 8, wherein step (a) is performed by means of a twin-screw-extruder.

10. The process of claim 8, wherein at least 50% of the total surface of the slices obtained in step (b) is formed by the two opposing cut surfaces.

11. The process of claim 9, wherein at least 50% of the total surface of the slices obtained in step (b) is formed by the two opposing cut surfaces.

12. The tablet according to claim 1 comprising a monolithic core.

13. The tablet according to claim 1, which exhibits a release per unit area of the pharmacologically active ingredient (A) through the front side and the opposite back side that is faster than the release through the circumferential rim.

14. A hot-melt extruded tablet having a front side and an opposite back side, the tablet comprising:

(i) a pharmacologically active ingredient (A) in a matrix comprising a polymer (C);

(ii) an oblong shape imparted by post-hot-melt-extrusion pressing of a hot-melt extrudate on a tablet-press; and

(iii) a circumferential rim between the front and back sides;

wherein the tablet exhibits a breaking strength of at least 300 N;

wherein the tablet exhibits controlled release of the pharmacologically active ingredient (A);

wherein the tablet has a direction of extrusion that runs parallel to a direction of extrusion of said hot-melt extrudate through an extrusion die;

wherein the tablet has a longitudinal direction of extension, which is the longest dimension in the tablet and runs orthogonal to the direction of extrusion;

wherein the tablet has a transversal direction of extension that runs orthogonal to both the direction of extrusion and the longitudinal direction of extension; and

wherein the oblong shape is imparted by compressing the hot-melt extrudate parallel to the direction of extrusion and orthogonal to the longitudinal direction of extension.