Crush resistant delayed-release dosage forms

• US 20140112984A1
• Filed: 12/27/2013
• Published: 04/24/2014
• Est. Priority Date: 02/04/2005
• Status: Abandoned Application

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: ARKENAU-MARIC, Elisabeth, BARTHOLOMUS, Johannes, KUGELMANN, Heinrich
• Application Number:
  US14/141,793
• Publication Number:
  US 20140112984A1
• Time in Patent Office: Days
• US Class Current: 424/457
• 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 comprising a physiologically effective amount of a physiologically active substance (A), a synthetic, semi-synthetic or natural polymer (C), optionally one or more physiologically acceptable auxiliary substances (B) and optionally a synthetic, semi-synthetic or natural wax (D), wherein the dosage form exhibits a resistance to crushing of at least 400 N and wherein under physiological conditions the release of the physiologically active substance (A) from the dosage form is at least partially delayed.

Claims

1. A dosage form comprising a physiologically effective amount of a physiologically active substance (A), a synthetic, semi-synthetic or natural polymer (C), optionally one or more physiologically acceptable auxiliary substances (B) and optionally a synthetic, semi-synthetic or natural wax (D), wherein the dosage form exhibits a resistance to crushing of at least 400 N, wherein under physiological conditions the release of the physiologically active substance (A) from the dosage form is at least partially delayed, wherein the physiologically active substance (A) consists of oxycodone, a physiologically acceptable derivative thereof, and wherein the polymer (C) is polyethylene oxide (PEO).

2. The dosage form according to claim 1, which exhibits a resistance to crushing of at least 500 N.

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

4. The dosage form according to claim 1 which is in multiparticulate form, the individual particles exhibiting a resistance to crushing of at least 400 N.

5. The dosage form according to claim 4, wherein the particles are pressed into tablets or packaged in capsules.

7. The dosage form according to claim 1, which comprises a tubular domain (82) and a core (83) located therein, wherein the tubular domain (82) is connected with the core (83) in a seamless manner and the material forming the tubular domain (82) and the material forming the core (83) have substantially the same chemical composition but different morphology.

8. The dosage form according to claim 7, wherein the material forming the tubular domain (82) and the material forming the core (83) have different optical properties.

9. The dosage form according to claim 7, wherein the thickness of the tubular domain (82) is within the range of 0.1 to 4 mm.

10. The dosage form according to claim 1, wherein upon storage for at least 12 hour at a temperature of 20°

C. below the melting range of the mixture of components (A), (C), optionally (B) and optionally (D) the volume of the dosage form increases by not more than 20%.

11. The dosage form according to claim 1, wherein wax (D) is at least one synthetic, semi-synthetic or natural wax with a softening point of at least 50°

C.

12. The dosage form according to claim 11, wherein wax (D) is carnauba wax or beeswax.

13. The dosage form according to claim 1, wherein substance (A) is present in a delayed-release matrix.

14. The dosage form according to claim 13, wherein the delayed-release matrix comprises polymer (C) and/or the optionally present wax (D).

15. The dosage form according to claim 1, wherein after 5 hours under physiological conditions it has released not more than 99% of substance (A).

16. A process for the production of a dosage form according to claim 1 comprising the following steps:

(a) mixing of component (A), (C), optionally (B) and optionally (D);

(b) optionally preforming the mixture obtained from step (a), preferably by applying heat and/or force to the mixture obtained from step (a), the quantity of heat supplied preferably not being sufficient to heat component (C) up to its softening point;

(c) hardening the mixture by applying heat and force, where the heat is supplied during and/or before the application of force and the quantity of heat supplied is sufficient to heat component (C) at least up to its softening point;

(d) optionally singulating the hardened mixture;

(e) optionally shaping the dosage form; and

(f) optionally providing a film coating.

17. The process according to claim 16, wherein step (c) is performed by means of a twin-screw-extruder or a planetary-gear extruder.

18. The process according to claim 19, wherein step (e) is performed in the plasticized state of the mixture of components (A), (C), optionally (B) and optionally (D).

19. The process according to claim 16, wherein step (c) is performed by the effect of ultrasound and force.

20. The product of the process of claim 16.

21. The product of the process of claim 17.

22. The product of the process of claim 18.

23. The product of the process of claim 19.

24. A method of preventing the misuse or abuse of a dosage form containing a physiologically active substance (A), due to comminution of the dosage form by mechanical action comprising administering the active substance to a patient in need thereof in a dosage form in accordance with claim 1.25. The method according to claim 24, wherein the mechanical action is selected from the group consisting of chewing, grinding in a mortar, pounding, and using apparatuses for pulverising conventional dosage forms.

25. A method for the prophylaxis and/or the treatment of a disorder treatable by the administration of a therapeutically effective amount of an agent capable of treating such disorder comprising administering a dosage form according to claim 1 to prevent the unintentional disruption of the controlled release mechanism of the physiologically active substance (A) which can result from crushing or chewing the dosage form.

26. A method of preventing an accidental overdose of a physiologically active substance comprising administering the active substance to a patient in need thereof in a dosage form in accordance with claim 1.

27. A method of preventing the misuse or abuse of a physiologically active substance comprising administering the active substance to a patient in need thereof in a dosage form in accordance with claim 1.

28. A method of preventing the disruption of a controlled release mechanism in a dosage form comprising a physiologically active substance intended for controlled release of such active substance comprising administering the active substance in a dosage form according to claim 1.

6. The dosage form according to claim 6, wherein polymer (C) has a molecular weight of at least 0.5 million according to rheological measurements.