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1. (WO2017136460) EXTENDED RELEASE DRUG FORMULATION WITH OVERDOSE PROTECTION AND ABUSE DETERRENCE
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CLAIMS:

1. A solid oral extended release multi -particulate dosage form with abuse deterrent and overdose protection characteristics comprising:

(a.) a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix, a primary functional coat layer (FC 1) over the polymer matrix, a secondary functional coat layer (FC 2) over FC 1, and an over coat over FC 2,

wherein FC 1 comprises a nonionic water-insoluble polymer and, optionally, at least one of a cationic polymer, a nonionic water-soluble polymer, and a water-soluble plasticizer;

wherein FC 2 comprises at least one of a cationic polymer, a nonionic water-soluble polymer, and a water-soluble plasticizer and, optionally, a nonionic water-insoluble polymer; and

wherein the over coat comprises a nonionic water-soluble polymer; and

(b.) a second population of particulates comprising an alkaline agent and, optionally, a pH-stabilizing agent,

wherein the dosage form is suitable for twice-daily administration and provides an

extended release of the opioid for a period of at least about 4 hours, and releases less than about 40% by weight of the opioid or a pharmaceutically acceptable salt thereof from the dosage form at about 1 hour; and

wherein, when two or more dosage units are consumed, the alkaline agent raises the gastric pH and the pH-stabilizing agent, when present, maintains the elevated pH to further extend the release of the opioid from the dosage form.

2. A solid oral extended release multi -particulate dosage form with abuse deterrent and overdose protection characteristics comprising:

(a.) a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix, a primary functional coat layer (FC 1) over the polymer matrix, a secondary functional coat layer (FC 2) over FC 1, and an over coat over FC 2,

wherein FC 1 comprises a nonionic water-insoluble polymer and, optionally, at least one of a cationic polymer, a nonionic water-soluble polymer, and a water-soluble plasticizer;

wherein FC 2 comprises at least one of a cationic polymer, a nonionic water-soluble polymer, and a water-soluble plasticizer and, optionally, a nonionic water-insoluble polymer; and

wherein the over coat comprises a nonionic water-soluble polymer; and

(b.) a second population of particulates comprising an alkaline agent and a pH- stabilizing agent,

wherein the dosage form is suitable for once-daily administration and provides an

extended release of the opioid for a period of at least about 8 hours, and releases less than about 40% by weight of the opioid or a pharmaceutically acceptable salt thereof from the dosage form at about 1 hour; and

wherein, when two or more dosage units are consumed, the alkaline agent raises the gastric pH and the pH-stabilizing agent maintains the elevated pH to further extend the release of the opioid from the dosage form.

3. The dosage form of claim 1, wherein the at least one cationic polymer, water-soluble plasticizer, and/or nonionic water-soluble polymer acts as a pore former in FC 1 at a nonionic water-insoluble polymer to cationic polymer, water-soluble plasticizer, and/or nonionic water-soluble polymer ratio of from about 80:20 to about 99.9:0.1 wt% ratio.

4. The dosage form of claim 3, wherein the wt% ratio of the nonionic water-insoluble polymer to the cationic polymer in FC 1 is about 95:5.

5. The dosage form of claim 3, wherein the wt% ratio of the nonionic water-insoluble polymer to the cationic polymer in FC 1 is about 98:2.

6. The dosage form of claim 3, wherein the wt% ratio of the nonionic water-insoluble polymer to the nonionic water-soluble polymer in FC 1 is about 95:5.

7. The dosage form of claim 1, wherein FC 2 comprises a cationic polymer and a water- soluble plasticizer.

8. The dosage form of claim 1, wherein the nonionic water-insoluble polymer is

selected from the group consisting of cellulose acetate, cellulose acetate-based polymers, ethylcellulose, and polyvinyl acetate polymers.

9. The dosage form of claim 8, wherein the nonionic water-insoluble polymer is cellulose acetate.

10. The dosage form of claim 1, wherein the nonionic water-soluble polymer is

hydroxypropyl methylcellulose (HPMC).

11. The dosage form of claim 1, wherein the water-soluble plasticizer is tri ethyl citrate and/or a polyethylene glycol (MW 400-8000).

12. The dosage form of claim 1, wherein the cationic polymer present in FC 2 and, optionally, in FC 1, is a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

13. The dosage form of claim 1, wherein the polymer matrix comprises a nonionic pH- independent polymer.

14. The dosage form of claim 13, wherein the polymer matrix comprises a nonionic pH- independent polymer and an anionic pH-dependent polymer.

15. The dosage form of claim 14, wherein the anionic pH-dependent polymer is a

carbomer.

16. The dosage form of claim 15, wherein the carbomer provides resistance to extraction of the opioid from the dosage form into a dissolution medium or gastrointestinal (GI) fluid, and provides resistance to extraction of the opioid into a syringe when two or more dosage units are taken together or dissolved in the dissolution medium.

17. The dosage form of claim 16, wherein the dissolution medium comprises aqueous and/or hydro-organic solvents.

18. The dosage form of claim 13, wherein the nonionic pH-independent polymer is selected from the group consisting of a copolymer of ethyl acrylate, methyl methacrylate, and a low content of methacrylic acid ester with quaternary ammonium groups (ammonium methacrylate copolymer), hydroxypropylcellulose, FIPMC, hydroxyethylcellulose, ethylcellulose, cellulose acetate butyrate, cellulose acetate, polyvinyl acetate polymers, and polyethylene oxide polymers.

19. The dosage form of claim 18, wherein the nonionic pH-independent polymer is a polyethylene oxide polymer and/or HPMC, or a polyvinyl acetate-polyvinyl pyrrolidone polymer.

20. The dosage form of claim 19, wherein the polyethylene oxide polymer provides resistance to extraction of the opioid from the dosage form into a dissolution medium or GI fluid, and provides resistance to extraction of the opioid into a syringe when two or more dosage units are dissolved in the dissolution medium or taken together.

21. The dosage form of claim 19, wherein the nonionic pH-independent polymer is a mixture of a polyethylene oxide polymer and HPMC.

22. The dosage form of claim 1, wherein the nonionic pH-independent polymer in the over coat comprises a cellulose ether polymer.

23. The dosage form of claim 22, wherein the cellulose ether polymer is HPMC.

24. The dosage form of claim 1, wherein the alkaline agent present in the second

population of particulates is selected from the group consisting of aluminum hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, calcium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine, N-methylglucamine, L-lysine, and combinations thereof.

25. The dosage form of claim 24, wherein the alkaline agent is magnesium hydroxide.

26. The dosage form of claim 25, wherein the alkaline agent elevates the gastric pH to a value of greater than about 5 when two or more dosage units are taken together.

27. The dosage form of claim 1, wherein the pH-stabilizing agent present in the second population of particulates is dibasic calcium phosphate and/or tricalcium phosphate.

28. The dosage form of claim 1, wherein the polymer matrix further comprises an

antioxidant, a plasticizer, and/or a surfactant.

29. The dosage form of claim 1, wherein the first population of particulates further comprises a seal coat disposed between the polymer matrix and FC 1.

30. The dosage form of claim 29, wherein the seal coat comprises a nonionic water- soluble polymer.

31. The dosage form of claim 30, wherein the nonionic water-soluble polymer comprises a cellulose ether polymer.

32. The dosage form of claim 31, wherein the cellulose ether polymer is HPMC.

33. The dosage form of claim 1, wherein the over coat is the outermost coat of the first population of particulates.

34. The dosage form of claim 1, wherein the first population of particulates further

comprises at least one additional coating layer between the seal coat and FC1, or between FC 1 and FC 2, or between FC 2 and the over coat.

35. The dosage form of claim 1, wherein the opioid is selected from the group consisting of oxycodone, oxymorphone, hydromorphone, hydrocodone, buprenorphine, codeine, phenazocine, tilidine, tramadol, meperidine, sufentanil, prodine, methadone, pentazoxine, tapentadol, morphine, fentanyl, pharmaceutically acceptable salts thereof, and a mixture thereof.

36. The dosage form of claim 35, wherein the opioid is selected from the group

consisting of oxycodone, hydrocodone, hydromorphone, oxymorphone,

pharmaceutically acceptable salts thereof, and a mixture thereof.

37. The dosage form of claim 1, further comprising a third population of particulates comprising a viscosity enhancing agent.

38. The dosage form of claim 37, wherein the viscosity enhancing agent is a viscosity- building polymer.

39. The dosage form of claim 38, wherein the viscosity -building polymer(s) is a nonionic polymer and/or an anionic polymer.

40. The dosage form of claim 39, wherein the nonionic polymer is a polyethylene oxide polymer and the anionic polymer is a carbomer.

41. The dosage form of claim 1, wherein the first population of particulates is present in an amount from about 10% to about 80% w/w of the total dosage form.

42. The dosage form of claim 1, wherein the second population of particulates is present in an amount from about 20% to about 42% w/w of the total dosage form.

43. The dosage form of claim 37, wherein the third population of particulates is present in an amount from about 2% to about 50% w/w of the total dosage form.

44. The dosage form of claim 1, wherein the abuse deterrent characteristics comprise syringeability resistance, extractability resistance in aqueous and/or hydro-organic solvents, resistance to alcohol dose dumping, and heat stability of the dosage form, wherein the heat stability comprises maintaining the abuse deterrent characteristics of the dosage form after the exposure to heat.

45. The dosage form of claim 44, wherein the heat stability is determined by subjecting the dosage form to heating at about 100°C for at least 2 hours in an oven, or heating in a microwave at 1200W for at least 13-15 minutes.

46. The dosage form of claim 1, wherein the abuse deterrent characteristics comprise resistance to crushing and grinding of the first population of particulates.

47. The dosage form of claim 1, wherein the abuse deterrent characteristics comprise resistance to segregation of the opioid into the fines fraction of the dosage form upon grinding.

48. The dosage form of claim 47, wherein the fines fraction comprises a fraction of

particulates with a size that can be snorted or insufflated.

49. A method of preparing a solid oral extended release multi-particulate dosage form with abuse deterrent and overdose protection characteristics comprising:

(a.) preparing a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix, a primary functional coat layer (FC 1) over the polymer matrix, a secondary functional coat layer (FC 2) over FC 1, and an over coat over FC 2,

wherein FC 1 comprises a nonionic water-insoluble polymer and, optionally, at least one of a cationic polymer, a nonionic water-soluble polymer, and a water-soluble plasticizer;

wherein FC 2 comprises at least one of a cationic polymer, a nonionic water-soluble polymer, and a water-soluble plasticizer and, optionally, a nonionic water-insoluble polymer; and

wherein the over coat comprises a nonionic water-soluble polymer;

(b.) preparing a second population of particulates comprising an alkaline agent and a pH-stabilizing agent; and

(c.) combining the first and second populations of particulates;

wherein the dosage form provides an extended release of the opioid for a period of at least about 4 hours, and releases less than about 40% by weight of the opioid or a pharmaceutically acceptable salt thereof from the dosage form at about 1 hour; and wherein, when two or more dosage units are consumed, the alkaline agent raises the gastric pH and the pH-stabilizing agent maintains the elevated pH to further extend the release of the opioid from the dosage form.

50. The method of claim 49, wherein the at least one cationic polymer, water-soluble plasticizer, and/or nonionic water-soluble polymer acts as a pore former in FC 1 at a nonionic water-insoluble polymer to cationic polymer, water-soluble plasticizer, and/or nonionic water-soluble polymer ratio of from about 80:20 to about 99.9:0.1 wt% ratio.

51. The method of claim 50, further comprising coating the polymer matrix of the first population of particulates with a seal coat prior to coating with FC 1.

52. The method of claim 51, wherein the seal coat comprises a nonionic water-soluble polymer.

53. The method of claim 49, wherein FC 2 comprises a cationic polymer and a water- soluble plasticizer.

54. The method of claim 53, wherein the cationic polymer is a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

55. The method of claim 49, further comprising combining the particulate populations in a tablet, a tablet-in-tablet, a bilayer tablet, or a capsule dosage form.

56. A method for providing overdose protection from an opioid overdose, the method comprising orally administering to a subject a solid extended release multiparticulate dosage form with abuse deterrent and overdose protection characteristics comprising:

(a.) a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix, a primary functional coat layer (FC 1) over the polymer matrix, a secondary functional coat layer (FC 2) over FC 1, and an over coat over FC 2,

wherein FC 1 comprises a nonionic water-insoluble polymer and, optionally, at least one of a cationic polymer, a nonionic water-soluble polymer, and a water-soluble plasticizer;

wherein FC 2 comprises at least one of a cationic polymer, a nonionic water-soluble polymer, and a water-soluble plasticizer and, optionally, a nonionic water-insoluble polymer; and

wherein the over coat comprises a nonionic water-soluble polymer; and

(b.) a second population of particulates comprising an alkaline agent and a pH- stabilizing agent,

wherein the dosage form provides an extended release of the opioid for a period of at least about 4 hours, and releases less than about 40% by weight of the opioid or a pharmaceutically acceptable salt thereof from the dosage form at about 1 hour; and wherein, when two or more dosage units are consumed, the alkaline agent raises the gastric pH and the pH-stabilizing agent maintains the elevated pH to further extend the release of the opioid from the dosage form.

57. A method for providing analgesia by administering an extended release opioid

dosage form in an overdose protection formulation without impeding release of the opioid when taken as directed, the method comprising orally administering to a subject a solid extended release multi -particulate dosage form with abuse deterrent and overdose protection characteristics comprising:

(a.) a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix, a primary functional coat layer (FC 1) over the polymer matrix, a secondary functional coat layer (FC 2) over FC 1, and an over coat over FC 2,

wherein FC 1 comprises a nonionic water-insoluble polymer and, optionally, at least one of a cationic polymer, a nonionic water-soluble polymer, and a water-soluble plasticizer;

wherein FC 2 comprises at least one of a cationic polymer, a nonionic water-soluble polymer, and a water-soluble plasticizer and, optionally, a nonionic water-insoluble polymer; and

wherein the over coat comprises a nonionic water-soluble polymer; and

(b.) a second population of particulates comprising an alkaline agent and a pH- stabilizing agent,

wherein the dosage form provides an extended release of the opioid for a period of at least about 4 hours, and releases less than about 40% by weight of the opioid or a pharmaceutically acceptable salt thereof from the dosage form at about 1 hour; and wherein, when two or more dosage units are consumed, the alkaline agent raises the gastric pH and the pH-stabilizing agent maintains the elevated pH to further extend the release of the opioid from the dosage form.