Abuse-proofed dosage form

• US 9,629,807 B2
• Filed: 04/19/2016
• Issued: 04/25/2017
• Est. Priority Date: 08/06/2003
• Status: Expired due to Term

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: Arkenau-Maric, Elisabeth, Bartholomaeus, Johannes, Kugelmann, Heinrich
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): PERREIRA, MELISSA JEAN
• Application Number:
  US15/132,325
• Publication Number:
  US 20160263037A1
• Time in Patent Office: 371 Days
• CPC Class Codes: A61J 3/07 into the form of capsules or similar small containers for oral use
• 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 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61K 9/2004 Excipients; Inactive ingredients
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• 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 9/2068 Compounds of unknown constitution, e.g. material from plants or animals oils, fats, waxes, shellac A61K9/2013
• 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 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• 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

Abstract

The invention relates to a dosage form that is thermoformed without discoloration and is safeguarded from abuse, comprising at least one synthetic or natural polymer having a breaking strength of at least 500 N in addition to one or more active substances that could be subject to abuse. The invention also relates to a corresponding method for producing said dosage form.

Claims

1. An abuse-proofed dosage form thermoformed by extrusion without discoloration comprising one or more active ingredients with abuse potential (A), optionally physiologically acceptable auxiliary substances (B), at least one synthetic or natural polymer (C) and optionally at least one wax (D), wherein the dosage form exhibits a breaking strength of at least 500 N, the one or more active ingredients with abuse potential (A) are selected from the group consisting of hydromorphone and physiologically acceptable compounds and derivatives thereof, the polymer (C) comprises polyethylene oxide having a molecular weight of at least 0.5 million g/mol, and the content of polymer (C) is at least 30 wt. % relative to the total weight of the dosage form.

2. The dosage form according to claim 1, which is in the form of a tablet.

3. The dosage form according to claim 1, wherein the molecular weight of the polyethylene oxide (C) is at least 1 million.

4. The dosage form according to claim 3, wherein the molecular weight of the polyethylene oxide is in the range of from about 1 to about 15 million.

5. The dosage form according to claim 1, which contains the wax (D), and the wax (D) is at least one natural, semi-synthetic or synthetic wax with a softening point of at least 60°

C.

6. The dosage form according to claim 5, wherein the wax (D) is carnauba wax or beeswax.

7. The dosage form according to claim 1, which additionally comprises

(a) at least one substance which irritates the nasal passages and/or pharynx;

and/or

(b) at least one viscosity-increasing agent, which in the presence of an active ingredient extracted from the dosage form using a liquid medium, forms a gel with the extract obtained from the dosage form, which gel optionally remains visually distinguishable when introduced into a further quantity of an aqueous liquid; and

/or

(c) at least one antagonist for the active ingredient or active ingredients with abuse potential; and

/or

(d) at least one emetic; and

/or

(e) at least one dye; and

/or

(f) at least one bitter substance.

8. The dosage form according to claim 7, which comprises component (b), wherein component (b) is at least one viscosity-increasing agent selected from the group consisting of microcystalline cellulose combined with carboxymethylcellulose sodium, polyacrylic acid, locust bean flour, pectins, waxy maize starch, sodium alginate, guar flour, iota carrageen, karaya gum, gellan gum, galactomannan, tara bean flour, propylene glycol alginate, apple pectin, sodium hyaluronate, tragacanth, tara gum, fermeted polysaccharide welan gum, and xanthan gum.

9. The dosage form according to claim 7, which comprises component (c), wherein component (c) is at least one opioid antagonist selected from the group consisting of naloxone, naltrexone, nalmefene, nalid, nalmexone, nalorphine, naluphine and a corresponding physiologically acceptable compound, a base, and a salt thereof.

10. The dosage form according to claim 1, which contains at least one active ingredient with abuse potential (A) at least partially in controlled release form.

11. The dosage form according to claim 10, wherein each of the active ingredients with abuse potential (A) is present in a controlled release matrix.

12. The dosage form according to claim 11, wherein the controlled release matrix material comprises component (C) and/or the optionally present component (D).

13. The dosage form according to claim 1, which comprises a core and a tubular domain surrounding the core, wherein said tubular domain has a morphology different from that of the core.

14. The dosage form according to claim 13, wherein the core and the tubular domain have substantially the same chemical composition.

15. The dosage form according to claim 13, wherein the tubular domain does not completely cover the core.

16. The dosage form according to claim 1, which comprises a physiologically acceptable auxiliary substance (B), wherein the physiologically acceptable auxiliary substance (B) is an antioxidant.

17. The dosage form according to claim 16, wherein the antioxidant is selected from the group consisting of ascorbic acid, salts of ascorbic acid, butylhydroxyanisole, butylhydroxytoluene, monothioglycerol, phosphorous acid, vitamin C, vitamin E and the derivatives thereof, sodium bisulfate and α

-tocopherol.

18. A process for the production of a dosage form according to claim 1, comprising

I) mixing components (A), the optionally present component (B), (C) and the optionally present component (D) and co-mixing or separately mixing the optionally present components (a) to (f) with the addition of component (C) and optionally (D) to form a resultant mixture or plurality of resultant mixtures;

II) heating the resultant mixture or the resultant mixtures in an extruder at least up to the softening point of component (C) and extruding the mixture as a plastic extrudate through an outlet orifice of the extruder by application of force; and

III) singulating and forming the still plastic extrudate into the dosage form;

or

IV) cooling and forming the optionally reheated singulated extrudate into the dosage form.

19. The process according to claim 18, wherein process step II) is performed by means of a twin-screw-extruder.

20. The process according to claim 18, wherein process steps II) and III) and optionally process steps I) and IV) are performed under an inert gas atmosphere.

21. The process according to claim 20, wherein the inert gas atmosphere is nitrogen.

22. The process according to claim 18, wherein mixing of the components according to process step I) proceeds in the extruder under an inert gas atmosphere.

23. The process according to claim 18, wherein the mixtures according to process step I) are co-extruded or separately extruded.

24. The process according to claim 18, wherein the mixture or the mixtures according to process step I) are extruded through a die with at least one bore.

25. The process according to claim 18, wherein the extrudate is singulated by cutting.

26. The process according to claim 18, wherein the extrudate is in the form of a strand and is shaped and singulated with the assistance of counter rotating calender rolls comprising opposing recesses in their outer sleeve.

27. The process according to claim 18, wherein the singulated extrudate is pelletized or pressed into tablets.

28. The process according to claim 18, wherein swelling and expansion of the dosage form upon storage is suppressed by press forming the singulated extrudate at a pressure of at least 1 kN and a temperature of between 25°

C. and 40°

C. below the melting range of the mixture of the components.

29. The dosage form according to claim 1, wherein the physiologically acceptable compounds and derivatives are salts, solvates, esters, ethers, and amides.