Abuse-proofed dosage form

• US 8,075,872 B2
• Filed: 02/06/2006
• Issued: 12/13/2011
• 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: Bartholomäus, Johannes, Kugelmann, Heinrich, Arkenau-Maric, Elisabeth
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): PERREIRA, MELISSA JEAN
• Application Number:
  US11/349,544
• Publication Number:
  US 20070183979A1
• Time in Patent Office: 2,136 Days
• Field of Search: 424/10.1
• US Class Current: 424/10.1
• 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
• CPC Class Codes: A61P 25/36 Opioid-abuse

Abstract

The invention relates to a dosage form that is thermoshaped without being extruded and that 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 and optionally physiologically acceptable adjuvants. 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 and having a breaking strength of at least 500 N, which contains a mixture of:

i) one or more active ingredients with abuse potential (A) selected from the group consisting of opioids,

ii) optionally physiologically acceptable auxiliary substances (B),

iii) from 30% by weight to 99.9% by weight of at least one polyalkylene oxide (C), having a molecular weight of from about 4,000,000 g/mol up to 15,000,000 g/mol,

iv) optionally at least one wax (D), and

v) a further material selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose and hydroxymethylcellulose,

wherein said extrusion takes place in an extruder at a temperature of from at least the

softening point of the polyalkylene oxide up to a temperature of below 180°

C., and

wherein component (C) and/or the optionally present component (D) serve as a

controlled release matrix material in which the active ingredient with abuse potential

(A) is embedded and said dosage form not being in multiparticulate 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 said polyalkylene oxide is polyethylene oxide, polymethylene oxide, polypropylene oxide, a copolymer thereof or a mixture thereof.

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

C.

5. The dosage form according to claim 4, wherein the wax (D) is carnauba wax or beeswax.

6. The dosage form according to claim 1, which additionally comprises at least one of the following components a)-f):

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

(b) at least one viscosity-increasing agent, which, with the assistance of a necessary minimum quantity of an aqueous liquid, forms a gel with the extract obtained from the dosage form,

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

(d) at least one emetic,

(e) at least one dye as an aversive agent, and

(f) at least one bitter substance.

7. The dosage form according to claim 6, wherein the component (a) irritant substance causes burning, itching, an urge to sneeze, increased formation of secretions or a combination of at least two of these stimuli.

8. The dosage form according to claim 6, wherein the component (a) irritant substance is based on one or more constituents of at least one hot substance drug.

9. The dosage form according to claim 8, wherein the hot substance drug is at least one drug selected from the group consisting of Allii sativi bulbus (garlic), Asari rhizoma cum herba (Asarum root and leaves), Calami rhizoma (calamus root), Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper), Curcumae longae rhizoma (turmeric root), Curcumae xanthorrhizae rhizoma (Javanese turmeric root), Galangae rhizoma (galangal root), Myristicae semen (nutmeg), Piperis nigri fructus (pepper), Sinapis albae semen (white mustard seed), Sinapis nigri semen (black mustard seed), Zedoariae rhizoma (zedoary root) and Zingiberis rhizoma (ginger root).

10. The dosage form according to claim 8, wherein the constituent of the hot substance drug is an o-methoxy(methyl)phenol compound, an acid amide compound, a mustard oil or a sulfide compound or is derived from such a compound.

11. The dosage form according to claim 8, wherein the constituent of the hot substance drug is at least one constituent selected from the group consisting of myristicin, elemicin, isoeugenol, β

-asarone, safrole, gingerols, xanthorrhizol, capsaicinoids, piperine, glucosinolates, and a compound derived from these constituents.

12. The dosage form according to claim 6, wherein component (b) is at least one viscosity-increasing agent selected from the group consisting of microcrystalline cellulose with 11 wt. % carboxymethylcellulose sodium, carboxymethylcellulose sodium, polyacrylic acid, locust bean flour, pectins from citrus fruit or apples, 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, fermented polysaccharide welan gum, xanthan gum.

13. The dosage form according to claim 6, 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.

14. The dosage form according to claim 6, wherein the component (c) used is at least one neuroleptic as a stimulant antagonist.

15. The dosage form according to claim 6, wherein the component (d) emetic is based on one or more constituents of ipecacuanha (ipecac) root, and/or is apomorphine.

16. The dosage form according to claim 6, wherein component (e) is at least one physiologically acceptable dye.

17. The dosage form according to claim 6, wherein component (f) is at least one bitter substance selected from the group consisting of aromatic oils, fruit aroma substances, and mixtures thereof comprising at least 2 components, denatonium benzoate and mixtures thereof comprising at least 2 components.

18. The dosage form according to claim 6, wherein the active ingredient or active ingredients (A) is/are spatially separated from component (c) and/or (d) and/or (f), wherein the active ingredient or active ingredients (A) is/are present in at least one subunit (X) and components (c) and/or (d) and/or (f) is/are present in at least one subunit (Y), and, when the dosage form is correctly administered, components (c) and/or (d) and/or (f) from subunit (Y) do not exert their effect in the body and/or on taking

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

i) mixing one or more active ingredients with abuse potential selected from the group consisting of opioids with 30% to 99.9% by weight of a polyalkylene oxide having a molecular weight of from about 4,000,000 g/ mol up to 15,000,000 g/mol and a further material selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose and hydroxymethylcellulose to form one or more resultant mixtures,

ii) heating the resultant mixture or the resultant mixtures in the extruder to a temperature of from at least the softening point of the polyalkylene oxide up to a temperature below 180°

C. and extruding an extrudate through the outlet orifice of the extruder by application of sufficient force to apply a pressure of at least 10 bar to the mixture or mixtures immediately before emerging from the outlet orifice,

iii) singulating and forming the still plastic extrudate into the dosage form, or

iv) forming cooled and optionally reheated singulated extrudate into the dosage form,

wherein process steps ii) and iii) and optionally process steps i) and iv) are performed under an inert gas atmosphere.

20. The process according to claim 19, wherein mixing of the components i) also proceeds in the extruder under an inert gas atmosphere.

21. The process according to claim 19, wherein the mixtures according to i) are coextruded or separately extruded.

22. The process according to claim 19, wherein the mixture or the mixtures according to i) are extruded through a die with at least one bore.

23. The process according to claim 19, wherein the extrudate is singulated by chopping.

24. The process according to claim 19, wherein the extrudate is in the form of a strand and is shaped and singulated with the assistance of contrarotating calender rolls comprising opposing recesses in their outer sleeve.

25. The process according to claim 19, wherein the singulatable extrudate is pelletised or pressed into tablets.

26. The process according to claim 19, wherein nitrogen is used as the inert gas atmosphere.

27. The dosage form according to claim 1, which is obtainable by a process according to claim 19.

28. The dosage form of claim 1, wherein said extrusion is conducted at a temperature ranging from the softening point of said polyalkylene oxide up to a temperature below 180°

C. and under conditions which exert a pressure of at least 10 bar on the dosage form composition immediately before emerging from the outlet of the extruder.

29. The process of claim 19, wherein the extrudate is cooled and singulated into singulated extrudates.

30. The process of claim 29, wherein said singulated extrudates are press-molded into tablets.

31. The dosage form of claim 1, wherein said opioid (A) is selected from the group consisting of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, oxycodone, oxymorphone, hydromorphone and morphine, the physiologically acceptable esters thereof and the physiologically acceptable salts thereof.