Dosage form with impeded abuse

• US 8,722,086 B2
• Filed: 03/07/2008
• Issued: 05/13/2014
• Est. Priority Date: 03/07/2007
• Status: Expired due to Fees

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: Bartholomaeus, Johannes, Ziegler, Iris, Haupts, Marcel, Arkenau-Mari, Elisabeth
• Primary Examiner(s): GULLEDGE, BRIAN M
• Application Number:
  US12/044,586
• Publication Number:
  US 20090004267A1
• Time in Patent Office: 2,258 Days
• Field of Search: None
• US Class Current: 424/465
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds

Abstract

A multiparticulate dosage form formulated to make misuse more difficult containing least one active substance with potential for misuse (A), at least one synthetic or natural polymer (C), optionally at least one natural, semi-synthetic or synthetic wax (D), at least one disintegrant (E) and optionally one or more additional physiologically compatible excipients (B), wherein the individual particles of the dosage form display a breaking strength of at least 500 N and a release of active substance of at least 75% after 45 minutes measured according to Ph.Eur. in the paddle mixer with sinker in 600 ml of aqueous buffer solution with a pH value of 1.2 at 37° C. and 75 rpm.

Claims

1. A multiparticulate dosage form with impeded abuse, comprising

at least one active substance with abuse potential (A) having a psychotropic action and being selected from the group consisting of opioids,

at least one synthetic or natural polymer (C),

optionally at least one natural, semi-synthetic or synthetic wax (D),

at least one disintegrant (E), which is selected from the group consisting of crosspovidone and crosscarmellose, wherein at least part of the disintegrant (E) is mixed with the particles of the dosage form,

an auxiliary (B2), which is microcrystalline cellulose, and which is not a component of the particles,

optionally one or more additional, physiologically acceptable auxiliaries,

wherein the individual particles of the dosage form have a breaking strength of at least 500 N and a release of active substance of at least 75% after 45 minutes measured according to Ph.Eur. in a paddle mixer with sinker in 600 ml of aqueous buffer solution with a pH value of 1.2 at 37°

C. and 75 revolutions per minute.

2. A dosage form according to claim 1, wherein said dosage form is in the form of microtablets, micropellets, granules, spheroids, beads or pellets.

3. A dosage form as claimed in claim 1 wherein said at least one polymer is selected from the group consisting of polyalkylene oxides, polyethylenes, polypropylenes, polyvinyl chlorides, polycarbonates, polystyrenes, polyacrylates and copolymers thereof.

4. A dosage form as claimed in claim 1, wherein said at least one polymer comprises a polyalkylene oxide selected from the group consisting of polymethylene oxides, polyethylene oxides, polypropylene oxides, copolymers of polyethylene oxide, copolymers of polypropylene oxide, block copolymers of polyethylene oxide, block copolymers of polypropylene oxide, and mixtures thereof said polyalkylene oxide having a molecular weight of at least 0.5×

10⁶ based on rheological measurements.

5. A dosage form as claimed in claim 3, wherein said polymer has a molecular weight of from 1×

10⁶ to 15×

10⁶ based on rheological measurements.

6. A dosage form as claimed in claim 1, wherein the wax is carnauba wax, beeswax, or a mixture of carnauba wax and beeswax, and said wax has a softening point of at least 50°

C. and a breaking strength of at least 500 N.

7. A dosage form as claimed in claim 1, wherein said disintegrant is disposed in the particles, or on the particles, or loosely distributed among the particles, or two or more of the foregoing.

8. A dosage form as claimed in claim 7, wherein the disintegrant is at least partially present as a component in the particles.

9. A dosage form as claimed in claim 7, wherein the disintegrant is at least partially present in a coating enveloping the particles.

10. A dosage form as claimed in claim 7, wherein the disintegrant is admixed with particles of the dosage form.

11. A dosage form as claimed in claim 7, wherein the disintegrant is present both as a component in the particles and in a coating enveloping the particles.

12. A dosage form as claimed in claim 1, comprising from 0.1 to 15 wt. % of said disintegrant relative to the total weight of the dosage form.

13. A dosage form as claimed in claim 12, comprising from 3 to 7 wt. % of said disintegrant relative to the total weight of the dosage form.

14. A dosage form as claimed in claim 1, wherein said active substance with abuse potential is distributed in a matrix having a breaking strength of at least 500 N and comprising at least one polymer.

15. A dosage form as claimed in claim 14, wherein said matrix further comprises at least one wax, or at least one formulation auxiliary, or at least part of the disintegrant, or two or more of the foregoing.

16. A dosage form as claimed in claim 1, wherein the particles are compressed to tablets or chewable tablets or are filled in capsules, sachets or stick-packs.

17. A dosage form as claimed in claim 1, wherein the particles have a particle size in the range from 0.1 to 5 mm.

18. A dosage form as claimed in claim 17, wherein the particles have a diameter in the range from 0.2 to 3 mm.

21. A method of preparing a dosage form as claimed in claim 1, said method comprising:

(a) mixing components (A), (C), optionally auxiliaries (B1) selected from the group consisting of fillers, plasticizers, lubricants and colorants, optionally (D) and optionally at least a portion of the disintegrant (E);

(b) optionally preforming of the mixture obtained from step a) under the action of heat or force or both on the mixture obtained from a) without softening of component (C);

(c) hardening of the mixture under the action of heat and force, wherein the heat is supplied during or before or both during and before the action of force and is sufficient to heat component (C) at least to its softening point;

(d) dividing of the hardened mixture into partial masses;

(e) dividing of the hardened partial masses and optionally forming;

(f) enveloping, coating or mixing with the portion of disintegrant (E) remaining from a) and optionally additional auxiliaries (B2); and

(g) optionally final forming or filling to a unit dose of the dosage form.

22. A method as claimed in claim 21, wherein a screw extruder or a planetary roller extruder is used at least in step c), and in step c), heat is supplied by exposure to ultrasound.

23. A dosage form obtained by the method of claim 21.

24. A method of preparing a dosage form as claimed in claim 1, said method comprising:

mixing of components (A), (C), optionally auxiliaries (B1) selected from the group consisting of fillers, plasticizers, lubricants and colorants, optionally (D) and optionally at least one portion of disintegrant (E) with addition of a solvent for polymer (C) at least in amounts such that the mixture is simultaneously moistened and is deformable, dividing the formable mass into partial masses before or after drying, dividing the partial masses obtained, optionally after further distribution, and optionally forming, enveloping, coating or mixing the divided partial masses with the remainder of disintegrant (E) and optionally additional auxiliaries (B2), and optionally final forming or filling to a unit dose of the dosage form.

25. A dosage form obtainable by the method of claim 24.

19. A multiparticulate dosage form with impeded abuse comprising a mixture of the following distinct components:

(a) particles comprising;

(i) at least one active substance with abuse potential (A) having a psychotropic action and being selected from the group consisting of opioids;

(ii) optionally one or more additional, physiologically acceptable auxiliaries (B);

(iii) at least one synthetic or natural polymer (C); and

(iv) optionally at least one natural, semi-synthetic or synthetic wax (D);

(b) at least one disintegrant (E), which is selected from the group consisting of crosspovidone and crosscarmellose, said at least one disintegrant (E) being separate from the particles; and

(c) a filler (B2), which is microcrystalline cellulose, said filler (B2) also being separate from the particles;

wherein the particles have a breaking strength of at least 500 N and a release of active substance of at least 75% after 45 minutes measured according to Ph.Eur. in a paddle mixer with sinker in 600 ml of aqueous buffer solution with a pH value of 1.2 at 37°

C. and 75 revolutions per minute.

20. The dosage form as claimed in claim 19, wherein the particles themselves comprise some content of disintegrant (E) and this content of disintegrant (E) is in addition to the disintegrant (E) kept separate from the particles.