US2012141583A1PendingUtilityA1

Alcohol resistant dosage forms

Individually held — no corporate assignee on recordPriority: Feb 12, 2004Filed: Jun 9, 2011Published: Jun 7, 2012

Est. expiryFeb 12, 2024(expired)· nominal 20-yr term from priority

Inventors:Richard O. Mannion William H. Mckenna Edward P. O'Donnell Helen Kathleen Danagher Geoffrey Gerard Hayes Hassan Mohammad Derek Allan Prater Harjit Tamber Malcom Walden Steve Whitelock Wolfgang Fleischer Udo Hahn Christof Spitzley Christian Leuner

A61P 25/04A61P 25/24A61P 29/00A61P 25/26A61P 25/36A61P 23/00B29B 9/06A61K 9/2095A61K 9/2054A61K 31/485A61K 9/20A61K 9/2086A61K 9/2027A61K 9/2077A61K 9/1652A61K 9/1694A61K 9/2013A61K 9/1635A61K 9/16A61K 9/0053B29K 2033/12B29K 2105/0085

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References

Claims

Abstract

Opioid controlled release formulation resistant to alcohol extraction of the opioid.

Claims

exact text as granted — not AI-modified

1 . Use of a sparingly water permeable thermoplastic polymer or a hydrophobic polymer as controlled release matrix material in the manufacture of an opioid controlled release matrix formulation to impart resistance to alcohol extraction of the opioid, wherein said formulation having the sparingly water permeable thermoplastic polymer or hydrophobic polymer as controlled release matrix material releases less opioid in an alcohol extraction test compared to the same formulation but with the sparingly water permeable thermoplastic polymer or hydrophobic polymer substituted entirely or partly by other matrix materials.

2 . Use of a sparingly water permeable thermoplastic polymer as controlled release matrix material in the manufacture of an opioid salt controlled release matrix formulation to impart resistance to alcohol extraction of the opioid salt, wherein said formulation after 15 minutes shaking in 40% ethanol at room temperature releases less than 35% of opioid salt.

3 . Use according to claim 2 , wherein said formulation releases less than 30%, more preferred less than 25% of opioid salt, or from 15 to 25% opioid salt.

4 . Use of a hydrophobic material as controlled release matrix material in the manufacture of an opioid salt controlled release matrix formulation to impart resistance to alcohol extraction of the opioid salt, wherein less than 25% of the opioid salt is released after 1 hour of in-vitro dissolution of a dosage form comprising said formulation in 900 ml of Simulated Gastric Fluid with 20% ethanol using USP Apparatus I (basket) operating at 100 rpm at 37° C.

5 . Use of a hydrophobic material as controlled release matrix material in the manufacture of an opioid salt controlled release matrix formulation to impart resistance to alcohol extraction of the opioid salt, wherein less than 25% of the opioid salt is released after 1 hour of in-vitro dissolution of a dosage form comprising said formulation in 500 ml of Simulated Gastric Fluid with 20% ethanol using USP Apparatus I (basket) operating at 100 rpm at 37° C.

6 . Use according claim 4 or 5 , wherein less than 20% opioid salt, more preferred less than 10% opioid salt, even more preferred less than 5% opioid salt or between 10% and 25% opioid salt is released after 1 hour.

7 . Use of a hydrophobic material as controlled release matrix material in the manufacture of an opioid salt controlled release matrix formulation to impart resistance to alcohol extraction of the opioid salt, wherein the ratio of the amount of opioid salt released after 1 hour of in-vitro dissolution of the dosage form comprising said formulation in 900 ml of Simulated Gastric Fluid with 20% ethanol using a USP Apparatus I (basket) apparatus at 100 rpm at 37° C., to the amount of opioid salt released after 1 hour of in-vitro dissolution of the dosage form comprising said formulation in 900 ml of Simulated Gastric Fluid with 0% ethanol using an USP Apparatus I (basket) apparatus at 100 rpm at 37° C., is less than about 2:1.

8 . Use of a hydrophobic material as controlled release matrix material in the manufacture of an opioid salt controlled release matrix formulation to impart resistance to alcohol extraction of the opioid salt, wherein the ratio of the amount of opioid salt released after 1 hour of in-vitro dissolution of the dosage form comprising said formulation in 500 ml of Simulated Gastric Fluid with 20% ethanol using a USP Apparatus I (basket) apparatus at 100 rpm at 37° C., to the amount of opioid salt released after 1 hour of in-vitro dissolution of the dosage form comprising said formulation in 500 ml of Simulated Gastric Fluid with 0% ethanol using an USP Apparatus I (basket) apparatus at 100 rpm at 37° C., is less than about 2:1.

9 . Use according to claim 7 or 8 , wherein the ratio is less than 1.5:1, preferably less than 1:1.

10 . Use according to any one of the preceding claims, wherein the hydrophobic material or the sparingly permeable thermoplastic polymer is an alkyl cellulose.

11 . Use according to claim 10 , wherein the alkyl cellulose is ethyl cellulose.

12 . Use according to any one of the preceding claims, wherein the opioid salt is selected from opioid agonists, opioid antagonists in combination with opioid agonists the combination providing an analgesic effect, and mixed opioid agonist/antagonists partial opioid agonists or mixtures thereof in the form of the pharmaceutically acceptable salts thereof.

13 . Use according to any one of the preceding claims, wherein the opioid salt is selected from alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diarnorphone, dihydro codeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, hydroco done, 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, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, in the form of pharmaceutically acceptable salts thereof; 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.

14 . Use according to any one of the preceding claims, wherein the opioid salt is a combination of an opioid agonist salt and an opioid antagonist salt, the combination providing an analgesic effect, wherein the opioid antagonist is selected form the group of naloxone, naltrexone and nalorphine in the form of pharmaceutically acceptable salts thereof.

15 . Use according to claims 10 to 14 , wherein the alkyl cellulose, preferably ethyl cellulose, is used in an amount from 5 to 60% (by wt) of the matrix formulation, preferably from 10 to 50% (by wt), most preferably from 20 to 45% (by wt) of the matrix formulation, or in an amount of at least 40% (by wt), at least 45% (by wt), at least 50% (by wt), at least 55% (by wt) or at least 60% (by wt) of the matrix formulation.

16 . Use according to any one of the preceding claims, wherein the ethyl cellulose is combined with at least a second controlled release matrix material selected from a polymethacrylate polymer, preferably a neutral water-insoluble poly (ethyl acrylate, methyl methacrylate) copolymer.

17 . Use according to claim 16 , wherein the polymethacrylate polymer, preferably the neutral water-insoluble poly(ethyl acrylate, methyl acrylate) copolymer is used in an amount of 5% to 66% (by wt), preferably 15% to 50% (by wt), more preferred 20% to 45% (by wt) and most preferred 25% to 45% (by wt) or in a weight amount of at least 5% (by wt), at least 10% (by wt), at least 15% (by wt), at least 20% (by wt) or at least 25% (by wt) of the matrix formulation.

18 . Use according to claims 10 to 17 , wherein the opioid salt is oxycodone hydrochloride or hydromorphone hydrochloride.

19 . Use according to any one of the previous claims, wherein at least one binder, preferably hydroxy alkyl cellulose, is included in the matrix formulation.

20 . Use according to claims 10 to 14 , wherein the amount of the alkyl cellulose, preferably ethyl cellulose, is less than 20% (by wt), preferably less than 15% (by wt), most preferred less than 10% (by wt) of the matrix formulation.

21 . Use according to claim 20 , wherein the alkylcellulose, preferable ethylcellulose is combined with at least one plasticizer or second controlled release matrix material selected from C 12 to C 36 aliphatic alcohols or corresponding aliphatic acids, preferably stearyl alcohol, cetyl alcohol, cetostearyl alcohol, stearic acid or palmitic acid or mixtures thereof.

22 . Use according to claim 21 , wherein the alkyl cellulose, preferably the amount of C 12 to C 36 aliphatic alcohol is at least 5%, more preferred at least 10% (by wt), more preferred at least 15% (by wt) and most preferred 20% to 25% (by wt) of the matrix formulation.

23 . Use according to claims 20 to 22 , wherein the opioid salt is a mixture of oxycodone hydrochloride and naloxone hydrochloride in an amount ratio of 2:1.

24 . Use according to claims 19 to 23 , wherein the matrix formulation does not comprise a neutral water-insoluble poly (ethyl acrylate methyl acrylate) copolymer.

25 . Use according to any one of the preceding claims, wherein the matrix formulation does not comprise a poly(meth)acrylate trimethylammoniummethylacrylate chloride copolymer.

26 . Use according to any one of the preceding claims, wherein the matrix formulations is prepared in a melt extrusion process.

27 . Use according to any of the preceding claims wherein the controlled release matrix formulations after 15 minutes shaking in water at room temperature releases less than 15%, less than 10% of opioid salt, preferably less than 7.5% opioid salt, more preferably less than 5% opioid salt.

28 . Use according to any of the preceding claims wherein the controlled release matrix formulation after 5 minutes standing in water at 50° C. followed by 15 minutes shaking at the same temperature releases less than 20% opioid salt, preferably less than 15% opioid salt, more preferably less than 12% opioid salt.

29 . Use according to any of the preceding claims wherein the controlled release matrix formulation after 5 minutes standing at 75° C. followed by 15 minutes shaking at the same temperature releases less than 25% of opioid salt, preferably less than 20% of opioid salt, more preferably less than 15% of opioid salt.

30 . Use according to any of the preceding claims wherein the controlled release matrix formulation after 5 minutes standing at 100° C. followed by 15 minutes shaking at the same temperature releases less than 30% opioid salt, preferably less than 25% opioid salt, more preferably less than 20% opioid salts.

31 . Use according to any one of the preceding claims wherein the ratio of the weight % amount of the opioid salt released at 50° C., 120 minutes shaking of the controlled release matrix formulation to the weight % amount of opioid salt released at RT 120 minutes shaking of the controlled release matrix formulation is 1.2 or less, preferably 1 or less or 0.9 or less.

32 . Use according to any one of the preceding claims wherein the ratio of the weight % amount of the opioid salt released at 75° C., 15 minutes shaking of the controlled release matrix formulation to the weight % amount of opioid analgesic released at RT 15 minutes shaking of the controlled release matrix formulation is 1.2 or less, preferably 1 or less or 0.9 or less.

33 . Use according to any one of the preceding claims wherein the ratio of the weight % amount of the opioid salt released at 100° C., 15 minutes shaking of the controlled release matrix formulation to the weight % amount of opioid salt released at RT 15 minutes shaking of the controlled release matrix formulation is 1.3 or less, preferably 1.2 or less or 0.9 or less.

34 . Use according to any one of the preceding claims wherein the ratio of the weight % amount of the opioid salt released at 100° C., 120 minutes shaking of the controlled release matrix formulation to the weight % amount of opioid salt released at RT 120 minutes shaking of the controlled release matrix formulation is less than 2, preferably 1.5 or less or 1 or less or 0.9 or less.

35 . Use according to any one of the preceding claims wherein the controlled release matrix formulation after grinding in a mortar and pestle with 24 rotations of the pestle and extracting in 900 ml water at 37° C. for 45 minutes less than 12.5% opioid salt, preferably less than 10% opioid salt, more preferably less than 7.5% opioid salt are released.

36 . Use according to any one of the preceding claims wherein the controlled release matrix formulation after crushing between two spoons or in a pill crusher and extracting in 2 ml water heated to boiling on a spoon less than 27.5% opioid salt, preferably less than 15% opioid salt, more preferably less than 5% opioid salt are released.

37 . A controlled release dosage form comprising:
a matrix comprising a pharmaceutically acceptable salt of an opioid analgesic in a controlled release material; wherein less than 25% of the opioid salt is released after 1 hour of in-vitro dissolution of the dosage form in 900 ml of Simulated Gastric Fluid with 20% ethanol using a USP Apparatus I (basket) apparatus at 100 rpm at 37 degrees C.°.

38 . A controlled release dosage form comprising:
a matrix comprising a pharmaceutically acceptable salt of an opioid analgesic in a controlled release material; wherein less than 25% of the opioid salt is released after 1 hour of in-vitro dissolution of the dosage form in 500 ml of Simulated Gastric Fluid with 20% ethanol using a USP Apparatus I (basket) apparatus at 100 rpm at 37 degrees C.°.

39 . The dosage form of claim 37 or 38 comprising
a plurality of matrices comprising a pharmaceutically acceptable salt of an opioid analgesic in a controlled release material.

40 . The dosage form of claim 37 or 38 comprising
a matrix comprising a pharmaceutically acceptable salt of an opioid analgesic in a pharmaceutically acceptable excipient; and

a layer comprising a controlled release material disposed about the matrix.

41 . The dosage form of claim 37 or 38 comprising
a plurality of matrices comprising a pharmaceutically acceptable salt of an opioid analgesic in a pharmaceutically acceptable excipient; and
a layer comprising a controlled release material disposed about each of the matrices.

42 . The dosage form of any of claims 37 to 41 , wherein the controlled release material is a hydrophobic material.

43 . The dosage form of claim 42 , wherein the hydrophobic material is ethylcellulose.

44 . The dosage form of claim 43 , wherein ethylcellulose in a weight amount of at least 40%, at least 45%, at least 50%, at least 55% or at least 60% of the matrix or matrices.

45 . The dosage form of claim 44 , wherein the ethylcellulose is in a weight amount of at most 70%, at most 80% or at most 90% of the matrix or matrices.

46 . The dosage form of claim 44 , wherein the controlled release material further comprises a polymethacrylate polymer in a weight amount of at least 5%, at least 10%, at least 15%, at least 20% or at least 25% of the matrix or matrices.

47 . The dosage form of claim 46 , wherein the polymethacrylate polymer is in a weight amount of at most 25% or at most 30%, or at most 35% of the matrix or matrices.

48 . The dosage form according to claims 37 to 47 , wherein the matrix or matrices do not contain a water-insoluble neutral poly (ethylacrylate methyl methacrylate) copolymer.

49 . The dosage form of any of claims 37 to 38 , wherein the dosage form further comprises a binder in a weight amount of at least 1%, at least 3%, or at least 5% of the matrix or matrices.

50 . The dosage form of claim 49 , wherein the binder is in a weight amount of at most 7%, or at most 10% of the matrix or matrices.

51 . The dosage form of claim 49 or 50 , wherein the binder is a hydroxyalkylcellulose.

52 . The dosage form of any of claims 37 to 51 , wherein the dosage form further comprises a plasticizer in a weight amount of at least 5%, at least 15%, or at least 25% of the matrix or matrices.

53 . The dosage form of claim 52 , wherein the plasticizer is in a weight amount of at most 30%, or at most 40% of the matrix or matrices.

54 . The dosage form of claim 52 or 53 , wherein the plasticizer has a melting point of at least 80° C.

55 . The dosage form of claim 54 , wherein the plasticizer is hydrogenated castor oil.

56 . The dosage form of claim 42 , wherein the hydrophobic material is an enteric polymer.

57 . The dosage form of any of claims 37 - 41 , wherein the matrix or matrices are extruded.

58 . The dosage form of claim 37 or 39 , wherein the matrix is a compressed granulation.

59 . The dosage form of any of claims 37 to 41 , wherein the dosage form releases less than 20% opioid salt after 1 hour of in-vitro dissolution of the dosage form in 900 ml of Simulated Gastric Fluid with 20% ethanol using a USP Apparatus I (basket) apparatus at 100 rpm at 37 degrees C.°.

60 . The dosage form of any of claims 37 to 41 , wherein the dosage form releases more than 5% or more than 10% opioid salt after 1 hour of in-vitro dissolution of the dosage form in 900 ml of Simulated Gastric Fluid with 20% ethanol using a USP Apparatus I (basket) apparatus at 100 rpm at 37 degrees C.°.

61 . The dosage form of any of claims 37 to 60 , wherein the opioid salt is hydromorphone hydrochloride, and the dosage form comprises:
2 mg hydromorphone hydrochloride,
4 mg hydromorphone hydrochloride,
8 mg hydromorphone hydrochloride,
12 mg hydromorphone hydrochloride,
16 mg hydromorphone hydrochloride,
24 mg hydromorphone hydrochloride,
32 mg hydromorphone hydrochloride,
48 mg hydromorphone hydrochloride or
64 mg hydromorphone hydrochloride.

62 . The dosage form of any of claims 37 to 60 , wherein the opioid salt is oxycodone hydrochloride and the dosage form comprises:
5 mg oxycodone hydrochloride,
10 mg oxycodone hydrochloride,
15 mg oxycodone hydrochloride
20 mg oxycodone hydrochloride,
30 mg oxycodone hydrochloride,
40 mg oxycodone hydrochloride,
45 mg oxycodone hydrochloride
60 mg oxycodone hydrochloride,
80 mg oxycodone hydrochloride,
90 mg oxycodone hydrochloride
120 mg oxycodone hydrochloride or
160 mg oxycodone hydrochloride

63 . A method of treating pain comprising administering to a patient in need thereof a
dosage form of any of claims 37 to 62 .

64 . A method of deterring abuse of an opioid agonist comprising preparing a
dosage form according to any of claims 37 to 62 .

65 . A method of manufacturing a controlled release dosage form of any of claims 37 to 62 comprising extruding the pharmaceutically acceptable salt of the opioid analgesic and the controlled release material.

66 . The method of claim 65 , comprising cutting the extrudate into a plurality of particles, optionally compressing the particles into a tablet, or filling the particles into a pharmaceutically acceptable capsule.

67 . A controlled release dosage form comprising an opioid analgesic salt and a controlled release material:
wherein the ratio of the amount of opioid analgesic salt released after 1 hour of in-vitro dissolution of the dosage form in 500 ml of Simulated Gastric Fluid with 20% ethanol using a USP Apparatus I (basket) apparatus at 100 rpm at 37 degrees C.° to the amount of opioid analgesic salt released after 1 hour of in-vitro dissolution of the dosage form in 500 ml of Simulated Gastric Fluid with 0% ethanol using a USP Apparatus I (basket) apparatus at 100 rpm at 37 degrees C.° is less than about 2:1.

68 . A controlled release dosage form comprising an opioid analgesic salt and a controlled release material:
wherein the ratio of the amount of opioid analgesic salt released after 1 hour of in-vitro dissolution of the dosage form in 900 ml of Simulated Gastric Fluid with 20% ethanol using a USP Apparatus I (basket) apparatus at 100 rpm at 37 degrees C.° to the amount of opioid analgesic salt released after 1 hour of in-vitro dissolution of the dosage form in 900 ml of Simulated Gastric Fluid with 0% ethanol using a USP Apparatus I (basket) apparatus at 100 rpm at 37 degrees C.° is less than about 2:1.

69 . The dosage form of claim 67 or 68 , comprising a matrix comprising the opioid analgesic salt and the controlled release material.

70 . The dosage form of claim 67 or 68 , comprising a plurality of matrices comprising the opioid analgesic salt and the controlled release material.

71 . A controlled release dosage form of claim 69 or 70 , wherein the opioid analgesic salt is not a combination of oxycodone salt and naloxone salt wherein the matrix comprises ethyl cellulose and stearyl alcohol.

72 . The dosage form of claim 67 or 68 , comprising a matrix comprising the opioid analgesic salt and a pharmaceutically acceptable excipient; and a layer comprising a controlled release material disposed about the matrix.

73 . The dosage form of claim 67 or 68 , comprising a plurality of matrices comprising the opioid analgesic and a pharmaceutically acceptable excipient; and a layer comprising a controlled release material disposed about each of the matrices.

74 . The dosage form of any of claims 67 to 73 , wherein the controlled release material is a hydrophobic material.

75 . The dosage form of claim 74 , wherein the hydrophobic material is ethylcellulose.

76 . The dosage form of claim 75 , wherein ethylcellulose in a weight amount of at least 40%, at least 45%, at least 50%, at least 55% or at least 60% of the matrix or matrices.

77 . The dosage form of claim 76 , wherein the ethylcellulose is in a weight amount of at most 70%, at most 80% or at most 90% of the matrix or matrices.

78 . The dosage form of claim 77 , wherein the controlled release material further comprises a polymethacrylate polymer in a weight amount of at least 5%, at least 10%, at least 15%, at least 20% or at least 25% of the matrix or matrices.

79 . The dosage form of claim 78 , wherein the polymethacrylate polymer is in a weight amount of at most 30%, or at most 35% of the matrix or matrices.

80 . The dosage form of any of claims 37 to 79 , wherein the dosage form further comprises a binder in a weight amount of at least 1%, at least 3%, or at least 5% of the matrix or matrices.

81 . The dosage form of claim 80 , wherein the binder is in a weight amount of at most 7%, or at most 10% of the matrix or matrices.

82 . The dosage form of claim 80 or 81 , wherein the binder is a hydroxyalkylcellulose.

83 . The dosage form of any of claims 37 to 82 , wherein the dosage form further comprises a plasticizer in a weight amount of at least 5%, at least 15%, or at least 25% of the matrix or matrices.

84 . The dosage form of claim 83 , wherein the plasticizer is in a weight amount of at most 30%, or at most 40% of the matrix or matrices.

85 . The dosage form of claim 83 or 84 , wherein the plasticizer which has a melting point of at least 80° C.

86 . The dosage form of claim 85 , wherein the plasticizer is hydrogenated castor oil.

87 . The dosage form of claim 74 wherein the hydrophobic material is an enteric polymer.

88 . The dosage form of any of claims 67 to 73 wherein the matrix or matrices are extruded.

89 . The dosage form of claims 67 to 73 , wherein the matrix is a compressed granulation.

90 . The dosage form of any of claims 67 to 73 , wherein the ratio of the amount of opioid analgesic released after 1 hour of in-vitro dissolution of the dosage form in 500 ml of Simulated Gastric Fluid with 20% ethanol using a USP Apparatus I (basket) apparatus at 100 rpm at 37 degrees C.° to the amount of opioid analgesic released after 1 hour of in-vitro dissolution of the dosage form in 500 ml of Simulated Gastric Fluid with 0% ethanol using a USP Apparatus I (basket) apparatus at 100 rpm at 37 degrees C.° is less than about 1.5:1 or less than about 1:1.

91 . The dosage form of any of claims 37 to 90 , wherein the opioid salt is hydromorphone hydrochloride, and comprises:
2 mg hydromorphone hydrochloride,
4 mg hydromorphone hydrochloride,
8 mg hydromorphone hydrochloride,
12 mg hydromorphone hydrochloride,
16 mg hydromorphone hydrochloride,
24 mg hydromorphone hydrochloride,
32 mg hydromorphone hydrochloride,
48 mg hydromorphone hydrochloride, or
64 mg hydromorphone hydrochloride.

92 . The dosage form of any of claims 37 to 90 , wherein the opioid salt is oxycodone hydrochloride, and comprises:
5 mg oxycodone hydrochloride,
10 mg oxycodone hydrochloride,
15 mg oxycodone hydrochloride,
20 mg oxycodone hydrochloride,
30 mg oxycodone hydrochloride,
40 mg oxycodone hydrochloride,
45 mg oxycodone hydrochloride,
60 mg oxycodone hydrochloride,
80 mg oxycodone hydrochloride,
90 mg oxycodone hydrochloride,
120 mg oxycodone hydrochloride, or
160 mg oxycodone hydrochloride.

93 . A controlled release dosage form comprising a plurality of matrices comprising a therapeutically effective amount of a pharmaceutically acceptable salt of hydromorphone dispersed in a controlled release material;
wherein the ratio of the amount of the pharmaceutically acceptable salt of hydromorphone released after 1 hour of in-vitro dissolution of the dosage form in 500 ml of Simulated Gastric Fluid with 20% ethanol using a USP Apparatus I (basket) apparatus at 100 rpm at 37 degrees C.° to the amount of a pharmaceutically acceptable salt of hydromorphone released after 1 hour of in-vitro dissolution of the dosage form in 500 ml of Simulated Gastric Fluid with 0% ethanol using a USP Apparatus I (basket) apparatus at 100 rpm at 37 degrees C.° is less than about 2:1.

94 . The dosage form of claim 93 comprising a plurality of extruded matrices comprising a therapeutically effective amount of a pharmaceutically acceptable salt of hydromorphone dispersed in an alkylcellulose.

95 . The dosage form of claim 93 comprising a plurality of extruded matrices comprising a therapeutically effective amount of a pharmaceutically acceptable salt of hydromorphone dispersed in an ethylcellulose.

96 . The dosage form of claim 93 comprising a plurality of extruded matrices comprising a therapeutically effective amount of a pharmaceutically acceptable salt of hydromorphone dispersed in an alkylcellulose, the alkylcellulose being at least 50%, w/w of the matrices.

97 . The dosage form of claim 93 comprising a plurality of extruded matrices consisting essentially of a pharmaceutically acceptable salt of hydromorphone dispersed in an alkylcellulose.

98 . The dosage form of claim 93 comprising a plurality of extruded matrices consisting essentially of a pharmaceutically acceptable salt of hydromorphone dispersed in an alkylcellulose, an optional binder, and an optional plasticizer.

99 . The dosage form of claim 93 comprising a plurality of extruded matrices comprising a pharmaceutically acceptable salt of hydromorphone dispersed in an alkylcellulose, wherein the matrices do not comprise an acrylic polymer.

100 . The dosage form of any of claims 27 to 89 comprising a controlled release matrix formulation which does not contain more than 15% (by wt) preferably more than 20% (by wt) C 12 to C 36 aliphatic alcohol selected from the group consisting of stearyl alcohol, cetyl alcohol and cetostearyl alcohol.

101 . The dosage form according to any of the preceding claims wherein the dosage form after 15 minutes shaking in water at room temperature releases less than 15%, less than 10% of opioid salt, preferably less than 7.5% opioid salt, more preferably less than 5% opioid salt.

102 . The dosage form according to any of the preceding claims wherein the dosage form after 5 minutes standing in water at 50° C. followed by 15 minutes shaking at the same temperature releases less than 20% opioid salt, preferably less than 15% opioid salt, more preferably less than 12% opioid salt.

103 . The dosage form according to any of the preceding claims wherein the dosage form after 5 minutes standing at 75° C. followed by 15 minutes shaking at the same temperature releases less than 25% of opioid salt, preferably less than 20% of opioid salt, more preferably less than 15% of opioid salt.

104 . The dosage form according to any of the preceding claims wherein the dosage form after 5 minutes standing at 100° C. followed by 15 minutes shaking at the same temperature releases less than 30% opioid salt, preferably less than 25% opioid salt, more preferably less than 20% opioid sal.

105 . The dosage form according to any one of the preceding claims wherein the ratio of the weight % amount of the opioid salt released at 50° C., 120 minutes shaking of the dosage form to the weight % amount of opioid salt released at RT 120 minutes shaking of the dosage form is 1.2 or less, preferably 1 or less or 0.9 or less.

106 . The dosage form according to any one of the preceding claims wherein the ratio of the weight % amount of the opioid salt released at 75° C., 15 minutes shaking of the dosage form to the weight % amount of opioid analgesic released at RT 15 minutes shaking of the dosage form is 1.2 or less, preferably 1 or less or 0.9 or less.

107 . The dosage form according to any one of the preceding claims wherein the ratio of the weight % amount of the opioid salt released at 100° C., 15 minutes shaking of the dosage form to the weight % amount of opioid salt released at RT 15 minutes shaking of the dosage form is 1.3 or less, preferably 1.2 or less or 0.9 or less.

108 . The dosage form according to any one of the preceding claims wherein the ratio of the weight % amount of the opioid salt released at 100° C., 120 minutes shaking of the dosage form to the weight % amount of opioid salt released at RT 120 minutes shaking of the dosage form is less than 2, preferably 1.5 or less, 1 or less or 0.9 or less.

109 . The dosage form according to any one of the preceding claims wherein after grinding in a mortar and pestle with 24 rotations of the pestle and extracting in 900 ml water at 37° C. for 45 minutes less than 12.5% opioid salt, preferably less than 10% opioid salt, more preferably less than 7.5% opioid salt are released.

110 . Use according to any one of the preceding claims wherein after crushing between two spoons or in a pill crusher and extracting in 2 ml water heated to boiling on a spoon less than 27.5% opioid salt, preferably less than 15% opioid salt, more preferably less than 5% opioid salt are released.

111 . A method of treating pain comprising administering to a patient in need thereof a dosage form of any of claims 37 to 109 .

112 . Use of a dosage form according to claims 37 to 109 in the manufacture of a medicament for the treatment of pain.

113 . A method of deterring abuse of an opioid agonist comprising preparing a dosage form according to any of claims 37 to 109 .

114 . A method of manufacturing a controlled release dosage form of any of claims 69 to 109 comprising extruding the pharmaceutically acceptable salt of the opioid analgesic and the controlled release material.

115 . The method of claim 114 , comprising cutting the extrudate into a plurality of particles, optionally comprising compressing the particles into a tablet or filling the particles into a pharmaceutically acceptable capsule.

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