Crush resistant delayed-release dosage forms

• US 10,675,278 B2
• Filed: 03/04/2016
• Issued: 06/09/2020
• Est. Priority Date: 02/04/2005
• Status: Active Grant

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: Arkenau-Maric, Elisabeth, Bartholomaus, Johannes, Kugelmann, Heinrich
• Primary Examiner(s): Tran, Susan T
• Application Number:
  US15/061,252
• Publication Number:
  US 20160184297A1
• Time in Patent Office: 1,558 Days
• Field of Search: None
• 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 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) is the only physiologically active substance within the dosage form, wherein the physiologically active substance (A) consists of oxycodone, a physiologically acceptable salt of oxycodone, or a physiologically acceptable derivative of oxycodone, and wherein the polymer (C) is polyethylene oxide (PEO) having a molecular weight of 500,000 g/mol to 7 million g/mol determined according to rheological measurements.

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

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

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

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

6. The dosage form according to claim 1, wherein the dosage form comprises a tubular domain and a core disposed therein, wherein the tubular domain is connected with the core in a seamless manner, and wherein the material forming the tubular domain and the material forming the core have substantially the same chemical composition but have different morphologies.

7. The dosage form according to claim 6, wherein the material forming the tubular domain and the material forming the core have different optical properties.

8. The dosage form according to claim 6, wherein the thickness of the tubular domain is within the range of 0.1 to 4 mm.

9. The dosage form according to claim 1, wherein the physiologically active substance (A), the polymer (C), the optional one or more physiologically acceptable auxiliary substances (B), and the optional synthetic, semi-synthetic, or natural wax (D) form a mixture and the volume of the dosage form increases by not more than 20% upon storage of the dosage form for at least 12 hours at a temperature of 20°

C. below the melting range of the mixture.

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

C.

11. The dosage form according to claim 10, wherein the synthetic, semi-synthetic, or natural wax (D) is carnauba wax or beeswax.

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

13. The dosage form according to claim 12, wherein the delayed-release matrix comprises at least one of the polymer (C) and the optional synthetic, semi-synthetic, or natural wax (D).

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

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

(a) mixing of the physiologically active substance (A), the polymer (C), the optional one or more physiologically acceptable auxiliary substances (B) and the optional synthetic, semi-synthetic, or natural wax (D);

(b) optionally preforming the mixture obtained from step (a);

(c) hardening the mixture or the optionally preformed mixture by applying heat and force, wherein the heat is supplied during and/or before the application of force and wherein the quantity of heat supplied is sufficient to heat the polymer (C) to at least up the softening point of the polymer (C) to form the dosage form;

(d) optionally singulating the hardened mixture before forming the dosage form;

(e) optionally shaping the dosage form; and

optionally providing a film coating to the dosage form.

16. The process according to claim 15, wherein step (c) is performed with a twin-screw-extruder or a planetary-gear extruder.

17. The process according to claim 15, wherein step (c) is performed with ultrasound and force.

18. The process according to claim 17, wherein step (e) is performed when the hardened mixture is in a plasticized state.

19. The product of the process of claim 15.

20. The product of the process of claim 16.

21. The product of the process of claim 18.

22. The product of the process of claim 17.

23. The dosage form according to claim 1, wherein the dosage form comprises the one or more physiologically acceptable auxiliary substances (B).

24. The dosage form according to claim 23, wherein the one or more physiologically acceptable auxiliary substances (B) comprises an at least one cellulose ether.

25. The dosage form according to claim 24, wherein said at least one cellulose ether is selected from the group consisting of ethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxymethylcellulose.

26. The dosage form according to claim 25, wherein said at least one cellulose ether is hydroxypropylmethylcellulose.

27. The dosage form according to claim 1, wherein the polyethylene oxide (PEO) has a molecular weight of 1 million g/mol to 7 million g/mol.

28. The dosage form according to claim 2, wherein the dosage form is in the form of a tablet.

29. The dosage form according to claim 28, wherein the physiologically active substance (A) consists of a physiologically acceptable salt of oxycodone, and wherein the physiologically acceptable salt of oxycodone is oxycodone hydrochloride.

30. The dosage form according to claim 28, wherein the physiologically active substance (A) consists of a physiologically acceptable derivative of oxycodone, and wherein the physiologically acceptable derivative of oxycodone is selected from the group consisting of an ester of oxycodone, an ether of oxycodone, and an amides of oxycodone.

31. The dosage form according to claim 29, wherein the dosage form comprises the one or more physiologically acceptable auxiliary substances (B), and the one or more physiologically acceptable auxiliary substances (B) comprises at least one cellulose ether.

32. The dosage form according to claim 31, wherein said at least one cellulose ether is selected from the group consisting of ethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxymethylcellulose.

33. The dosage form according to claim 32, wherein said at least one cellulose ether is hydroxypropylmethylcellulose.

34. The dosage form according to claim 3, wherein the physiologically active substance (A) consists of a physiologically acceptable salt of oxycodone, and wherein the physiologically acceptable salt of oxycodone is oxycodone hydrochloride.

35. The dosage form according to claim 3, wherein the physiologically active substance (A) consists of a physiologically acceptable derivative of oxycodone, and the physiologically acceptable derivative of oxycodone is selected from the group consisting of an ester of oxycodone, an ether of oxycodone, and an amide of oxycodone.

36. The dosage form according to claim 34, wherein the dosage form comprises the one or more physiologically acceptable auxiliary substances (B), wherein the one or more physiologically acceptable auxiliary substances (B) comprises an at least one cellulose ether.

37. The dosage form according to claim 36, wherein said at least one cellulose ether is selected from the group consisting of ethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxymethylcellulose.

38. The dosage form according to claim 37, wherein said at least one cellulose ether is hydroxypropylmethylcellulose.

39. The process according to claim 15, further comprising forming the hardened mixture into a tablet.

40. The process according to claim 16, wherein the process produces an extruded strand, and the process further comprises singulating the extruded strand into an at least one singulated extrudates, and packaging the at least one singulated extrudate into a capsule.