TAMPER RESISTANT DOSAGE FORMS

• US 20090169626A1
• Filed: 01/25/2007
• Published: 07/02/2009
• Est. Priority Date: 01/27/2006
• Status: Abandoned Application

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Euroceltique SA
• Inventors: Scherer, Sabine, Fleischer, Wolfgang, Leuner, Christian
• Application Number:
  US12/162,390
• Publication Number:
  US 20090169626A1
• Time in Patent Office: Days
• US Class Current: 424/484
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• 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: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/36 Opioid-abuse

Abstract

Tamper resistant controlled release formulations.

Claims

1-20. -20. (canceled)

21. :

A method to prevent extraction of an opioid agonist from a dosage form by a one step extraction procedure comprising steps of;

(i) crushing the dosage form using a pill crusher, a tablet mortar or two spoons, wherein the crushing is performed at least four times using the two spoons;

(ii) extracting the crushed dosage form on a spoon using 2 ml boiling tap water as an extracting agent and a cigarette lighter as a heating means for a time period sufficient to boil the tap water to obtain a solution; and

(iii) filtering the solution using cotton to obtain an extract,

wherein said method comprises forming a controlled release dosage form comprising;

(a) a therapeutic amount of the opioid agonist;

(b) an opioid antagonist in at least an amount sufficient to substantially antagonize the therapeutic amount of the opioid agonist when both the opioid agonist and the opioid antagonist are administered intravenously at the same time; and

(c) a hydrophobic material which comprises at least one hydrophobic polymer and at least one of a fatty alcohol or a fatty acid,

and wherein an extract obtained from said controlled release dosage form by the one step extraction procedure comprises the opioid antagonist in a weight percent amount, based on total amount of opioid antagonist in the controlled release dosage form, that is more than 20%-points less than the weight percent amount of the opioid agonist present in the extract, based on total amount of opioid agonist in the controlled release dosage form.

22. :

The method according to claim 21, wherein the extract obtained from said controlled release dosage form by the one step extraction procedure comprises the opioid antagonist in a weight percent amount, based on total amount of opioid antagonist in the dosage form, that is more than 15%-points less than the weight percent amount of the opioid agonist present in the extract, based on total amount of opioid agonist in the dosage form.

23. :

The method according to claim 21, wherein the extract obtained from said controlled release dosage form by the one step extraction procedure comprises the opioid antagonist in a weight percent amount, based on total amount of opioid antagonist in the dosage form, that is more than 12%-points less than the weight percent amount of the opioid agonist present in the extract, based on total amount of opioid agonist in the dosage form.

37. :

The method according to any of claims 21, 24, 27 and 35, wherein the controlled release dosage form is prepared by a melt extrusion step to form a homogeneous matrix.

38. :

The method according to any of claims 21, 24, 27 and 35, wherein the opioid agonist is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts of any of the forgoing and mixtures of any of the foregoing, and the like, preferably from pharmaceutically acceptable salts of any of codeine, morphine, oxycodone, hydrocodone, hydromorphone, or oxymorphone.

39. :

The method according to any of claims 21, 24, 27 and 35, wherein the opioid antagonist is selected from the group consisting of naloxone, naltrexone and nalorphine.

40. :

The method according to any of claims 21, 24, 27 and 35, wherein the opioid agonist is oxycodone hydrochloride, and the opioid antagonist is naloxone hydrochloride.

41. :

The method according to claim 40, wherein the oxycodone hydrochloride and the naloxone are present in the dosage form in an amount ratio of 2;

1.

42. :

The method according to any of claims 21, 24, 27 and 35, wherein the hydrophobic polymer is an alkyl cellulose.

43. :

The method according to claim 42, wherein the hydrophobic polymer is ethylcellulose.

44. :

The method according to claim 42, wherein the hydrophobic polymer is present in the dosage form in an amount less than 20% by weight.

45. :

The method according to claim 42, wherein the hydrophobic polymer is present in the dosage form in an amount less than 15% by weight.

46. :

The method according to claim 42, wherein the hydrophobic polymer is present in the dosage form in an amount less than 10% by weight.

47. :

The method according to claim 42, wherein the hydrophobic polymer is present in the dosage form in an amount less than 5% by weight.

48. :

The method according to any of claims 21, 24, 27 and 35, wherein the at least one of a fatty alcohol or fatty acid is a C₁₂ to C₃₆ aliphatic alcohol or acid.

49. :

The method according to claim 48, wherein the C₁₂ to C₃₆ aliphatic alcohol or acid is selected from the group consisting of stearyl alcohol, cetyl alcohol, cetostearyl alcohol, stearic acid, palmitic acid and mixtures thereof.

50. :

The method according to claim 48, wherein the C₁₂ to C₃₆ aliphatic alcohol or acid is present in the dosage form in an amount of at least 5% by weight.

51. :

The method according to claim 50, wherein the C₁₂ to C₃₆ aliphatic alcohol or acid is present in the dosage form in an amount of at least 10% by weight.

52. :

The method according to claim 51, wherein the C₁₂ to C₃₆ aliphatic alcohol or acid is present in the dosage form in an amount of at least 15% by weight.

53. :

The method according to claim 52, wherein the C₁₂ to C₃₆ aliphatic alcohol or acid is present in the dosage form in an amount from 20 to 25% by weight.

54. :

The method according to any of claims 21, 24, 27 and 35, wherein the dosage form comprises less than 10% ethyl cellulose by weight, stearyl alcohol in an amount between 20 and 25% by weight, and oxycodone hydrochloride and naloxone hydrochloride in an amount ratio of 2;

1.

24. :

A method to prevent extraction of an opioid agonist from a dosage form by a one step extraction procedure comprising steps of;

(i) crushing the dosage form using a pill crusher, a tablet mortar or two spoons, wherein the crushing is performed at least four times using the two spoons;

(ii) extracting the crushed dosage form on a spoon using 2 ml boiling deionized water as an extracting agent and a cigarette lighter as a heating means for a time period sufficient to boil the tap water to obtain a solution; and

(iii) filtering the solution using cotton to obtain an extract,

wherein said method comprises forming a controlled release dosage form comprising;

(a) a therapeutic amount of the opioid agonist;

(b) an opioid antagonist in at least an amount sufficient to substantially antagonize the therapeutic amount of the opioid agonist when both the opioid agonist and the opioid antagonist are administered intravenously at the same time; and

(c) a hydrophobic material which comprises at least one hydrophobic polymer and at least one of a fatty alcohol or a fatty acid,

and wherein an extract obtained from said controlled release dosage form by the one step extraction procedure comprises the opioid antagonist in a weight percent amount, based on total amount of opioid antagonist in the controlled release dosage form, that is more than 15%-points less than the weight percent amount of the opioid agonist present in the extract, based on total amount of opioid agonist in the controlled release dosage form.

25. :

The method according to claim 24, wherein the extract obtained from said controlled release dosage form by the one step extraction procedure comprises the opioid antagonist in a weight percent amount, based on total amount of opioid antagonist in the dosage form, that is more than 10%-points less than the weight percent amount of the opioid agonist present in the extract, based on total amount of opioid agonist in the dosage form.

26. :

The method according to claim 24, wherein the extract obtained from said controlled release dosage form by the one step extraction procedure comprises the opioid antagonist in a weight percent amount, based on total amount of opioid antagonist in the dosage form, that is more than 7%-points less than the weight percent amount of the opioid agonist present in the extract, based on total amount of opioid agonist in the dosage form.

27. :

A method to prevent extraction of an opioid agonist from a dosage form by a one step extraction procedure comprising steps of;

(i) crushing 10 of the dosage forms using a pill crusher; and

(ii) extracting the crushed dosage forms in a glass vial using 100 ml of an extraction solvent and shaking for at least 15 minutes at a temperature that is at least room temperature to obtain an extract, the extraction solvent being selected from the group consisting of deionized water, 2N hydrochloric acid, 2N acetic acid, 0.1 N sodium hydroxide solution, 0.5N sodium hydroxide solution, 1N sodium hydroxide solution, 2N sodium hydroxide solution at 40% ethanol

wherein said method comprises forming a controlled release dosage form comprising;

(a) a therapeutic amount of the opioid agonist;

(b) an opioid antagonist in at least an amount sufficient to substantially antagonize the therapeutic amount of the opioid agonist when both the opioid agonist and the opioid antagonist are administered intravenously at the same time; and

(c) a hydrophobic material which comprises at least one hydrophobic polymer and at least one of a fatty alcohol or a fatty acid,

and wherein an extract obtained from said controlled release dosage form by the one step extraction procedure comprises the opioid antagonist in a weight percent amount, based on total amount of opioid antagonist in the controlled release dosage form, that is more than 10%-points less than the weight percent amount of the opioid agonist present in the extract, based on total amount of opioid agonist in the controlled release dosage form.

28. :

The method according to claim 27, wherein the extract obtained from said controlled release dosage form by the one step extraction procedure comprises the opioid antagonist in a weight percent amount, based on total amount of opioid antagonist in the dosage form, that is more than 5%-points less than the weight percent amount of the opioid agonist present in the extract, based on total amount of opioid agonist in the dosage form.

29. :

The method according to claim 27, wherein the extract obtained from said controlled release dosage form by the one step extraction procedure comprises the opioid antagonist in a weight percent amount, based on total amount of opioid antagonist in the dosage form, that is more than 3%-points less than the weight percent amount of the opioid agonist present in the extract, based on total amount of opioid agonist in the dosage form.

30. :

The method according to claim 27, wherein the shaking is performed for 120 minutes.

31. :

The method according to claim 27, wherein the extraction solvent is deionized water.

32. :

The method according to claim 31, wherein the deionized water is heated to a temperature of at least 50°

C. for 5 minutes.

33. :

The method according to claim 32, wherein the deionized water is heated to a temperature of at least 75°

C. for 5 minutes.

34. :

The method according to claim 33, wherein the deionized water is heated to a temperature of at least 100°

C. for 5 minutes.

35. :

A method to prevent extraction of an opioid agonist from a dosage form by a one step extraction procedure comprising steps of;

(i) heating deionized water to 70°

C.;

(ii) adding the dosage form to the deionized water to form a mixture;

(iii) stirring the mixture for at least 15 minutes to obtain an extract; and

(iv) separating the extract from the mixture,

wherein said method comprises forming a controlled release dosage form comprising;

(a) a therapeutic amount of the opioid agonist;

(b) an opioid antagonist in at least an amount sufficient to substantially antagonize the therapeutic amount of the opioid agonist when both the opioid agonist and the opioid antagonist are administered intravenously at the same time; and

(c) a hydrophobic material which comprises at least one hydrophobic polymer and at least one of a fatty alcohol or a fatty acid,

and wherein an extract obtained from said controlled release dosage form by the one step extraction procedure comprises the opioid antagonist in a weight percent amount, based on total amount of opioid antagonist in the controlled release dosage form, that is more than 15%-points less than the weight percent amount of the opioid agonist present in the extract, based on total amount of opioid agonist in the controlled release dosage form.

36. :

The method according to claim 35, wherein the extract obtained from said controlled release dosage form by the one step extraction procedure comprises the opioid antagonist in a weight percent amount, based on total amount of opioid antagonist in the dosage form, that is more than 10%-points less than the weight percent amount of the opioid agonist present in the extract, based on total amount of opioid agonist in the dosage form.