Abuse-proofed dosage form

• US 10,058,548 B2
• Filed: 03/15/2017
• Issued: 08/28/2018
• Est. Priority Date: 11/20/2003
• 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:
  US15/459,180
• Publication Number:
  US 20170209379A1
• Time in Patent Office: 531 Days
• Field of Search: 424 101
• CPC Class Codes: A61J 3/005 Coating of tablets or the like coating of sweetmeats or confectionery A23G3/20; coating of granules in general B01J2/006
• CPC Class Codes: A61J 3/06 into the form of pills, lozenges or dragees
• CPC Class Codes: A61J 3/10 into the form of compressed tablets tablet presses B30B11/00
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/4422 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/554 having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• 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
• CPC Class Codes: A61K 9/2893 : Tablet coating processes mechanical aspects A61J3/06
• 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: A61P 1/00 : Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 13/00 : Drugs for disorders of the urinary system
• CPC Class Codes: A61P 17/00 : Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 : Drugs for skeletal disorders
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 27/00 : Drugs for disorders of the senses
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: B29B 7/002 : Methods chemical aspects C08J3/00
• CPC Class Codes: B29B 9/02 : by dividing preformed material
• CPC Class Codes: B29B 9/12 : characterised by structure or composition
• CPC Class Codes: B29C 2793/009 : after shaping
• CPC Class Codes: B29C 35/0261 : using ultrasonic or sonic vibrations
• CPC Class Codes: B29C 43/02 : of articles of definite length, i.e. discrete articles B29C35/0227 takes precedence
• CPC Class Codes: B29C 43/24 : Calendering
• CPC Class Codes: B29C 45/0001 : characterised by the choice of material
• CPC Class Codes: B29C 48/0011 : combined with compression moulding
• CPC Class Codes: B29C 48/0022 : combined with cutting
• CPC Class Codes: B29C 48/022 : characterised by the choice of material
• CPC Class Codes: B29C 48/146 : in the die
• CPC Class Codes: B29C 48/21 : the layers being joined at their surfaces
• CPC Class Codes: B29C 48/40 : using two or more parallel screws or at least two parallel non-intermeshing screws, e.g. twin screw extruders
• CPC Class Codes: B29C 48/44 : Planetary screws
• CPC Class Codes: B29K 2105/0035 : Medical or pharmaceutical agents
• CPC Class Codes: B29K 2105/0044 : Stabilisers, e.g. against oxydation, light or heat
• CPC Class Codes: B29K 2105/251 : Particles, powder or granules expandable particles B29K2105/046
• CPC Class Codes: B29K 2995/0056 : Biocompatible, e.g. biopolymers or bioelastomers
• CPC Class Codes: B29L 2031/753 : Medical equipment; Accessories therefor bloodbags, medical bags B29L2031/7148; artificial eyes B29L2011/0008
• CPC Class Codes: B29L 2031/772 : Articles characterised by their shape and not otherwise provided for closed loop B29L2031/709; ring-like B29L2031/7096; corrugated B29L2016/00, flat B29L2007/00; hollow B29L2022/00; screw-threaded B29L2001/00; toothed B29L2031/775; corrugated tubes B29L2023/18

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, in the form of a tablet, which is not in multiparticulate form, thermoformed by extrusion without discoloration comprising:

i) one or more opioids (A),

ii) at least 30% by weight, based on the weight of the dosage form, of polyalkylene oxide (C) with a molecular weight of at least 0.5 million g/mol,

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

iv) a film coating,

wherein the extrusion is performed at a temperature from the softening point of the polyalkylene oxide up to about 185°

C. and the dosage form exhibits a breaking strength of at least 500 N.

2. The dosage form according to claim 1, wherein the polyalkylene oxide (C) is selected from the group consisting of polyalkylene oxide and copolymers and mixtures thereof with one or more of polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, and polyacrylate.

3. The dosage form according to claim 2, wherein the polyalkylene oxide (C) comprises a polyalkylene oxide selected from the group consisting of polymethylene oxide, polyethylene oxide, polypropylene oxide, copolymers thereof and mixtures thereof.

4. The dosage form according to claim 1, wherein the polyalkylene oxide (C) comprises polyethylene oxide having a molecular weight of at least 0.5 million g/mol.

5. The dosage form according to claim 4, wherein the molecular weight of the polyethylene oxide is at least 1 million g/mol.

6. The dosage form according to claim 5, wherein the molecular weight of the polyethylene oxide is in the range of from about 1 to about 15 million g/mol.

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

C.

8. The dosage form according to claim 7, wherein the wax (D) is carnauba wax or beeswax.

9. 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.

10. The dosage form according to claim 9, 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, fermented polysaccharide welan gum, and xanthan gum.

11. The dosage form according to claim 9, 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, a salt and a solvate thereof.

12. 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.

13. The dosage form according to claim 12, wherein each of the active ingredients with abuse potential (A) is present in a controlled release matrix.

14. The dosage form according to claim 13, wherein the controlled release matrix material comprises component (C) and/or the optionally present component (D).

15. 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.

16. The dosage form according to claim 15, wherein the core and the tubular domain have substantially the same chemical composition.

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

18. A process for the production of a dosage form according to claim 1, comprising I) mixing components (A), the polyalkylene oxide (C) and the optionally present component (D) to form a mixture;

II) heating the resultant mixture in an extruder at least up to the softening point of the polyalkylene oxide (C) and extruding the mixture through the outlet orifice of the extruder at a pressure of at least 10 bar 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, and applying a film coating to 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 nitrogen is used as the inert gas atmosphere.

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 mixture according to process step I) is extruded through a die with at least one bore.

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

25. 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.

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

27. 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.

28. A process for the production of a dosage form according to claim 9, comprising I) mixing components (A), a material selected from the group consisting of cellulose ethers, cellulose esters, nitrocelluloses and polymers of (meth)acrylic acid or the esters thereof, the polyalkylene oxide (C) and the optionally present component (D) and co-mixing or separately mixing the optionally present components (a) to (f) with the addition of the polyalkylene oxide (C) and optionally (D) to form a mixture or a plurality of mixtures;

II) heating the resultant mixture or the resultant mixtures in an extruder at least up to the softening point of the polyalkylene oxide (C) and extruding the mixture through the outlet orifice of the extruder at a pressure of at least 10 bar 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, and applying a film coating.

29. 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.