ABUSE DETERRENT PHARMACEUTICAL COMPOSITIONS FOR CONTROLLED RELEASE

• US 20140010873A1
• Filed: 07/01/2013
• Published: 01/09/2014
• Est. Priority Date: 07/06/2012
• Status: Active Grant

• Current Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Original Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Inventors: Lindhardt, Karsten, Olsen, Martin Rex, Skak, Nikolaj, Tygesen, Peter Holm, Fischer, Gina Engslev, Overgard, Jan Martin, Boye, Georg, Elhauge, Torben
• Granted Patent: US 9,549,899 B2
• Time in Patent Office: Days
• US Class Current: 424/465
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• 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 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine

Abstract

The present disclosure relates to pharmaceutical compositions that are abuse resistant and may also provide controlled release. The present disclosure also relates to the use of pharmaceutical compositions in the treatment of pain.

Claims

1. An abuse-deterrent pharmaceutical composition, comprising:

(a) at least one active drug substance;

(b) at least one polyethylene oxide; and

(c) at least one plasticizer;

wherein the pharmaceutical composition does not provide immediate release of the at least one active drug substance after physical tampering;

wherein the at least one polyethylene oxide has an average molecular weight of at least 1,000,000 daltons, and

wherein the pharmaceutical composition comprises at least 5% w/w of the at least one plasticizer.

2. The pharmaceutical composition according to claim 1, wherein the composition comprises:

(a) about 1-50% w/w of the at least one active drug substance;

(b) about 10-98% w/w of the at least one polyethylene oxide; and

(c) about 5-40% w/w of the at least one plasticizer.

3. The pharmaceutical composition according to claims 1 or 2, wherein the at least one active drug substance comprises an opioid or a pharmaceutically acceptable salt or solvate thereof.

4. The pharmaceutical composition according to claim 3, wherein the at least one active drug substance is selected from the group consisting of buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, morphine, pentazocine, oxycodeine, oxycodone, oxymorphone, norhydrocodone, noroxycodone, morphine-6-glucuronode, tramadol, tapentadol, and dihydromorphine, or a pharmaceutically acceptable salt or solvate thereof.

5. The pharmaceutical composition according to claim 1, wherein the at least one polyethylene oxide has an average molecular weight in a range selected from at least one of about 1,000,000 daltons to about 3,500,000 daltons, about 1,000,000 daltons to about 3,000,000 daltons, about 1,000,000 daltons to about 2,500,000 daltons, about 1,000,000 daltons to about 2,000,000 daltons, about 1,000,000 daltons to about 1,500,000 daltons, about 1,500,000 daltons to about 3,500,000 daltons, about 1,500,000 daltons to about 3,000,000 daltons, about 1,500,000 daltons to about 2,500,000 daltons, and about 2,000,000 daltons.

6. The pharmaceutical composition according to claim 5, wherein the molecular weight of the at least one polyethylene oxide is selected from the group consisting of about 1,000,000 daltons, about 1,100,000 daltons, about 1,200,000 daltons, about 1,300,000 daltons, about 1,400,000 daltons, about 1,500,000 daltons, about 1,600,000 daltons, about 1,700,000 daltons, about 1,800,000 daltons, about 1,900,000 daltons, about 2,000,000 daltons, about 2,100,000 daltons, about 2,200,000 daltons, about 2,300,000 daltons, about 2,400,000 daltons, about 2,500,000 daltons, about 2,600,000 daltons, about 2,700,000 daltons, about 2,800,000 daltons, about 2,900,000 daltons, about 3,000,000 daltons, about 3,100,000 daltons, about 3,200,000 daltons, about 3,300,000 daltons, about 3,400,000 daltons, about 3,500,000 daltons, and mixtures thereof.

7. The pharmaceutical composition according to claim 1, wherein the plasticizer is selected from the group consisting of poloxamer, polyethylene oxides having a molecular weight of about 35,000 to about 600,000 daltons, and mixtures thereof.

8. The pharmaceutical composition according to claim 7, wherein the at least one plasticizer is a poloxamer having a molecular weight in the range of about 4,000 to about 15,000 daltons.

9. The pharmaceutical composition according to claims 7 or 8, wherein the at least one plasticizer is a poloxamer selected from the group consisting of poloxamer 188, poloxamer 407, and mixtures thereof.

10. The pharmaceutical composition according to claim 1, wherein the composition comprises two or more active drug substances.

11. The pharmaceutical composition according to claim 1, wherein the composition further comprises at least one excipient selected from the group consisting of fillers, diluents, disintegrants, glidants, pH-adjusting agents, viscosity adjusting agents, solubility increasing or decreasing agents, osmotically active agents, solvents, gelling agents, stabilizers, release modifier, carboxylic acids, amino acids, inorganic compounds, saccharides, cellulose, cellulose derivatives, sweetening agents, flavoring agents, and coloring agents.

12. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises a cosmetic coat that at least partially covers the composition,

wherein the cosmetic coat is selected from the group consisting of taste-masking coat, coat with aqueous moisture barrier agents, coat with oxidative barrier agents, coat with coloring agents, and coat with sweetening/flavoring agents, and

wherein the cosmetic coat dissolves within 30 minutes after contact with an aqueous media.

13. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is formulated for oral administration.

14. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is formulated as a tablet.

15. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition exhibits or is formulated to exhibit at least one of a solubility in ethanol that is equal to or lower than that in water, and a release rate in ethanol that is equal to or lower than that in water.

16. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is resistant to isolation of the active drug substance as determined by at least one of the dissolution test, the viscosity test, and the particle size reduction test, as described in the specification.

17. The pharmaceutical composition according to claim 1, wherein at least 90 wt % of the particles obtained after physical tampering of the pharmaceutical composition is larger than about 1,100 μ

m, and

wherein physical tampering comprises any kind of physical interference or manipulation that may result in particle size reduction of the pharmaceutical composition.

18. The pharmaceutical composition according to claim 1, wherein the viscosity of the pharmaceutical composition is higher than about 170 mPa·

s.

19. The pharmaceutical composition according to claim 1 for use in the treatment of pain.

20. A method of treating a clinical condition in an individual in need thereof, wherein the method comprises administering the pharmaceutical composition according to claim 1 to an individual in need thereof.

21. The method according to claim 20, wherein the individual is a human being.

22. An abuse-deterrent pharmaceutical composition, comprising:

(a) at least one active drug substance;

(b) at least one polyethylene oxide;

wherein the pharmaceutical composition does not provide immediate release of the at least one active drug substance after physical tampering; and

wherein the at least one polyethylene oxide has a molecular weight of less than about 1,000,000 daltons.

23. The pharmaceutical composition according to claim 22, wherein the composition comprises:

(a) about 1-50% w/w of the at least one active drug substance; and

(b) about 10-98% w/w of the at least one polyethylene oxide.

24. The pharmaceutical composition according to claims 22 or 23, wherein the at least one active drug substance comprises an opioid or a pharmaceutically acceptable salt or solvate thereof.

25. The pharmaceutical composition according to claim 24, wherein the at least one active drug substance is selected from the group consisting of buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, morphine, pentazocine, oxycodeine, oxycodone, oxymorphone, norhydrocodone, noroxycodone, morphine-6-glucuronode, tramadol, tapentadol, and dihydromorphine, or a pharmaceutically acceptable salt or solvate thereof.

26. The pharmaceutical composition according to claim 22, wherein the at least one polyethylene oxide has an average molecular weight in a range selected from at least one of about 200,000 to about 1,000,000 daltons, about 300,000 to about 1,000,000 daltons, about 400,000 to about 1,000,000 daltons, about 200,000 to 900,000 daltons, about 200,000 to about 800,000 daltons, about 200,000 to about 700,000 daltons, about 200,000 to about 600,000 daltons, about 200,000 to about 500,000 daltons, about 300,000 to about 500,000 daltons, about 350,000 to about 450,000 daltons, and about 400,000 daltons.

27. The pharmaceutical composition according to claim 26, wherein the molecular weight of the at least one polyethylene oxide is selected from the group consisting of about 200,000 daltons, about 250,000 daltons, about 300,000 daltons, about 350,000 daltons, about 400,000 daltons, about 450,000 daltons, about 500,000 daltons, about 550,000 daltons, about 600,000 daltons, about 650,000 daltons, about 700,000 daltons, about 750,000 daltons, about 800,00 daltons, about 850,000 daltons, about 900,000 daltons, about 950,000 daltons, about 1,000,000 daltons, and mixtures thereof.

28. The pharmaceutical composition according to claim 22, wherein the composition further comprises at least one excipient selected from the group consisting of fillers, diluents, disintegrants, glidants, pH-adjusting agents, viscosity adjusting agents, solubility increasing or decreasing agents, osmotically active agents, solvents, gelling agents, stabilizers, release modifier, carboxylic acids, amino acids, inorganic compounds, saccharides, cellulose, cellulose derivatives, sweetening agents, flavoring agents, and coloring agents.

29. The pharmaceutical composition according to claim 22, wherein the pharmaceutical composition further comprises a cosmetic coat that at least partially covers the composition,

wherein the cosmetic coat is selected from the group consisting of taste-masking coat, coat with aqueous moisture barrier agents, coat with oxidative barrier agents, coat with coloring agents, and coat with sweetening/flavoring agents, and

wherein the cosmetic coat dissolves within 30 minutes after contact with an aqueous media.

30. The pharmaceutical composition according to claim 22, wherein the pharmaceutical composition is formulated for oral administration.

31. The pharmaceutical composition according to claim 30, wherein the pharmaceutical composition is formulated as a tablet.

32. The pharmaceutical composition according to claim 22, wherein the pharmaceutical composition exhibits or is formulated to exhibit at least one of a solubility in ethanol that is equal to or lower than that in water, and a release rate in ethanol that is equal to or lower than that in water.

33. The pharmaceutical composition according to claim 22, wherein the pharmaceutical composition is resistant to isolation of the active drug substance as determined by at least one of the dissolution test, the viscosity test, and the particle size reduction test, as described in the specification.

34. The pharmaceutical composition according to claim 22, wherein at least 90 wt % of the particles obtained after physical tampering of the pharmaceutical composition is larger than about 1,100 μ

m, and

wherein physical tampering comprises any kind of physical interference or manipulation that may result in particle size reduction of the pharmaceutical composition.

35. The pharmaceutical composition according to claim 22, wherein the viscosity of the pharmaceutical composition is higher than about 170 mPa·

s.

36. The pharmaceutical composition according to claim 22 for use in the treatment of pain.

37. A method of treating a clinical condition in an individual in need thereof, wherein the method comprises administering the pharmaceutical composition according to claim 22 to an individual in need thereof.

38. The method according to claim 37, wherein the individual is a human being.

39. The pharmaceutical composition according to claim 22, wherein the composition comprises two or more active drug substances.

40. An abuse-deterrent pharmaceutical composition, comprising:

(a) at least one active drug substance selected from opioids or pharmaceutically acceptable salts or solvates thereof;

(b) at least one polyethylene oxide having an average molecular weight of about 400,000 daltons;

wherein the pharmaceutical composition does not provide immediate release of the at least one active drug substance after physical tampering; and

wherein physical tampering comprises any kind of physical interference or manipulation that may result in particle size reduction of the pharmaceutical composition.

41. The pharmaceutical composition according to claim 40, wherein the composition further comprises at least one plasticizer, and

wherein the at least one plasticizer comprises a poloxamer selected from the group consisting of poloxamer 188, poloxamer 407, and mixtures thereof.

42. An abuse-deterrent pharmaceutical composition, comprising:

(a) at least one active drug substance selected from opioids or pharmaceutically acceptable salts or solvates thereof;

(b) at least one polyethylene oxide having an average molecular weight of about 600,000 daltons;

wherein the pharmaceutical composition does not provide immediate release of the at least one active drug substance after physical tampering; and

wherein physical tampering comprises any kind of physical interference or manipulation that may result in particle size reduction of the pharmaceutical composition.

43. The pharmaceutical composition according to claim 42, wherein the composition further comprises at least one plasticizer, and

wherein the at least one plasticizer comprises a poloxamer selected from the group consisting of poloxamer 188, poloxamer 407, and mixtures thereof.

44. An abuse-deterrent pharmaceutical composition, comprising:

(a) at least one active drug substance selected from opioids or pharmaceutically acceptable salts or solvates thereof;

(b) at least one polyethylene oxide having an average molecular weight of about 2,000,000 daltons; and

(c) at least one plasticizer selected from poloxamer 188, poloxamer 407, and mixtures thereof;

wherein the pharmaceutical composition comprises at least 5% w/w of the at least one plasticizer;

wherein the pharmaceutical composition does not provide immediate release of the at least one active drug substance after physical tampering; and

wherein physical tampering comprises any kind of physical interference or manipulation that may result in particle size reduction of the pharmaceutical composition.