Dosage Form with Impeded Abuse

• US 20090004267A1
• Filed: 03/07/2008
• Published: 01/01/2009
• Est. Priority Date: 03/07/2007
• Status: Active Grant

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: Ziegler, Iris, Haupts, Marcel, Bartholomaeus, Johannes, Arkenau-Maric, Elisabeth
• Granted Patent: US 8,722,086 B2
• Time in Patent Office: Days
• 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 which impedes abuse, comprising:

at least one active substance with abuse potential (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 acceptable auxiliaries (B), wherein 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 as claimed in 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 the disintegrant is present in such an amount that the dosage form has 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, and 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, and wherein said disintegrant is selected from the group consisting of crosslinked sodium carboxymethylcellulose, modified maize starch, sodium carboxymethyl starch, and crosslinked polyvinyl pyrrolidone.

14. A dosage form as claimed in claim 1, comprising at least one auxiliary which is not part of the particles and which is a temperature stable formulation auxiliary selected from the group consisting of plasticizers, antioxidants, redox stabilisers and fillers or an additive excipient selected from the group consisting of fillers, lubricants and taste improving agents.

15. A dosage form as claimed in claim 14, wherein said at least one auxiliary comprises a filler selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, calcium dihydrogen phosphate, and tricalcium phosphate;

a plasticizer selected from the group consisting of polyalkylene glycols, fatty acids, fatty acid esters, waxes, and microcrystalline waxes;

an antioxidant or redox stabilizer selected from the group consisting of salts of ascorbinic acid, vitamin E, α

-tocopherol, vitamin E-succinate, vitamin E-palmitate, monothioglycerine, ascorbinic acid, Na-bisulfite, vitamin C, ascorbylic palmitate, butyl hydroxytoluene, butyl hydroxyanisole, and vitamin E TGPS;

or a chelating agent selected from the group consisting of EDTA, maleic acid, and fumaric acid.

16. A dosage form as claimed in claim 14, wherein said at least one auxiliary comprises a filler selected from the group consisting of microcrystalline cellulose, calcium dihydrogen phosphate, sugars, sugar alcohols, pulverized cellulose, polyvinyl pyrrolidone, and collidon;

a lubricant selected from the group consisting of sugar esters, fatty acid esters, talc, silica, stearic acid, and magnesium stearate;

or a taste improving agent selected from the group consisting of aromatic additives, effervescent additives, sugar, sugar alcohols, and sugar substitutes.

17. A dosage form as claimed in claim 1, wherein said at least one active substance with abuse potential is a compound which has a psychotropic effect selected from the group consisting of opioids, tranquillizers, stimulants, barbiturates and narcotics.

18. 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.

19. A dosage form as claimed in claim 18, 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.

20. 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.

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

22. A dosage form as claimed in claim 21, wherein the particles have a diameter in the range from 0.2 to 3 mm.

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

mixing components (A), (C), optionally (B1), optionally (D) and optionally at least a portion of the disintegrant (E);

optionally performing 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);

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;

dividing of the hardened mixture into partial masses;

dividing of the hardened partial masses and optionally forming;

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

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

24. A method as claimed in claim 23, 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.

25. A dosage form obtained by the method as claimed in claim 23.

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

mixing of components (A), (C), optionally (B1), 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) from a) and optionally additional auxiliaries (B2), and

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

27. A dosage form obtainable by a method according to claim 26.