Robust sustained release formulations

• US 20080085304A1
• Filed: 10/10/2006
• Published: 04/10/2008
• Est. Priority Date: 10/10/2006
• Status: Abandoned Application

• Current Assignee: Endo Pharmaceuticals Incorporated (Endo International PLC)
• Original Assignee: Penwest Pharmaceuticals Company (Endo International PLC)
• Inventors: Baichwal, Anand R., Labudzinski, Steve, Fitzmaurice, Kevin
• Application Number:
  US11/545,954
• Publication Number:
  US 20080085304A1
• Time in Patent Office: Days
• US Class Current: 424/457
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• 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 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• 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

Abstract

Robust sustained release formulations, solid dosage forms comprising robust sustained release formulations, and methods for making and using these formulations and solid dosage forms are provided. Robustness of the sustained release formulation is related to the particle size of the hydrophilic gum. Sustained release formulations resist dose-dumping when ingested with alcohol. The formulations are useful for treating a patient suffering from a condition, e.g., pain. The formulations comprise at least one drug. In one embodiment, the drug is an opioid, e.g., oxymorphone.

Claims

1. A sustained release formulation comprising:

a drug; and

a sustained release delivery system comprising a hydrophilic gum, a homopolysaccharide gum, and a pharmaceutical diluent,

wherein at least about 30% of the hydrophilic gum used to make the sustained release formulation can pass through a #270 mesh sieve, and the sustained release formulation releases less than about 70% of the drug within 2 hours after ingestion with either an ethanol-free or an ethanol-containing beverage.

2. The sustained release formulation of claim 1, wherein the hydrophilic compound is xanthan gum.

3. The sustained release formulation of claim 1, wherein the sustained release delivery system further comprises a hydrophobic polymer.

4. The sustained release formulation of claim 1, wherein the sustained release delivery system further comprises a cationic cross-linking compound selected from monovalent cations, multivalent cations, and salts.

5. The sustained release formulation of claim 1, further comprising an outer coating, wherein the outer coating comprises a hydrophobic polymer.

6. The sustained release formulation of claim 1, further comprising an outer coating, wherein the outer coating comprises a plasticizer.

7. The sustained release formulation of claim 1 or 2, wherein the drug is selected from the group consisting of alprazolam, lithium carbonate, divalproex sodium, neutral sulfate salts of dextroamphetamine and amphetamine with the dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate monohydrate, tramadol hydrochloride, and other pharmaceutically acceptable salt of the active pharmaceutical ingredient thereof.

8. The sustained release formulation of claim 1 or 2, wherein the drug is an opioid.

9. The sustained release formulation of claim 8, wherein the opioid is a mu-agonist or a mixed mu-agonist/antagonist.

10. The sustained release formulation of claim 9, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normophine, norpipanone, opium, oxycodone, oxymorphone, 6-hydroxyoxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, a stereoisomer thereof, a metabolite thereof, an ether thereof, an ester thereof, and a derivative thereof.

11. The sustained release formulation of claim 10, wherein the opioid is oxymorphone.

102. A method for treating a patient having a condition comprising administering to the patient a therapeutically effective amount of the sustained release formulation of any one of claims 1, 2, 12, 13, 22, 23, 33 and 34.

103. A method for relieving pain comprising administering to a patient a therapeutically effective amount of the sustained release formulation of any one of claims 10, 11, 20, 21, 31, 32, 41, and 42.

104. A method for reducing dose dumping of a sustained release drug formulation comprising providing a patient a sustained release formulation according to any one of claims 1, 12, 22 and 33.

105. A solid dosage form comprising the sustained release formulation according to any one of claims 10, 11, 20, 21, 31, 32, 41, and 42.

106. The solid dosage form of claim 105 comprising a powder.

107. The solid dosage form of claim 105 comprising a tablet.

108. The solid dosage form of claim 105 comprising a capsule.

12. A sustained release formulation comprising:

a drug; and

a sustained release delivery system comprising a hydrophilic gum, a cationic cross-linking compound selected from monovalent cations, multivalent cations and salts, and a pharmaceutical diluent,

wherein at least about 30% of the hydrophilic gum used to make the sustained release formulation can pass through a #270 mesh sieve, and the sustained release formulation releases less than about 70% of the drug within 2 hours after ingestion with either an ethanol-free or an ethanol-containing beverage.

13. The sustained release formulation of claim 12, wherein the hydrophilic compound is xanthan gum.

14. The sustained release formulation of claim 12, wherein the sustained release delivery system further comprises a hydrophobic polymer.

15. The sustained release formulation of claim 12, further comprising an outer coating, wherein the outer coating comprises a hydrophobic polymer.

16. The sustained release formulation of claim 12, further comprising an outer coating, wherein the outer coating comprises a plasticizer.

17. The sustained release formulation of claim 12 or 13, wherein the drug is selected from the group consisting of alprazolam, lithium carbonate, divalproex sodium, neutral sulfate salts of dextroamphetamine and amphetamine with the dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate monohydrate, tramadol hydrochloride, and other pharmaceutically acceptable salt of the active pharmaceutical ingredient thereof.

18. The sustained release formulation of claim 12 or 13, wherein the drug is an opioid.

19. The sustained release formulation of claim 18, wherein the opioid is a mu-agonist or a mixed mu-agonist/antagonist.

20. The sustained release formulation of claim 19, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normophine, norpipanone, opium, oxycodone, oxymorphone, 6-hydroxyoxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, a stereoisomer thereof, a metabolite thereof, an ether thereof, an ester thereof, and a derivative thereof.

21. The sustained release formulation of claim 20, wherein the opioid is oxymorphone.

22. A sustained release formulation comprising:

a drug; and

a sustained release delivery system comprising a hydrophilic gum, a homopolysaccharide gum, and a pharmaceutical diluent,

wherein at least about 30% of the hydrophilic gum particles used to make the sustained release formulation are smaller than about 53 microns in diameter, and the sustained release formulation releases less than 70% of the drug within 2 hours after ingestion with either an ethanol-free or an ethanol-containing beverage.

23. The sustained release formulation of claim 22, wherein the hydrophilic gum is xanthan gum.

24. The sustained release formulation of claim 22, wherein the sustained release delivery system further comprises a hydrophobic polymer.

25. The sustained release formulation of claim 22, wherein the sustained release delivery system further comprises a cationic cross-linking compound selected from monovalent cations, multivalent cations, and salts.

26. The sustained release formulation of claim 22, further comprising an outer coating, wherein the outer coating comprises a hydrophobic polymer.

27. The sustained release formulation of claim 22, further comprising an outer coating, wherein the outer coating comprises a plasticizer.

28. The sustained release formulation of claim 22 or 23, wherein the drug is selected from the group consisting of alprazolam, lithium carbonate, divalproex sodium, neutral sulfate salts of dextroamphetamine and amphetamine with the dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate monohydrate, tramadol hydrochloride, and other pharmaceutically acceptable salts thereof.

29. The sustained release formulation of claim 22 or 23, wherein the drug is an opioid.

30. The sustained release formulation of claim 29, wherein the opioid is a mu-agonist or a mixed mu-agonist/antagonist.

31. The sustained release formulation of claim 30, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normophine, norpipanone, opium, oxycodone, oxymorphone, 6-hydroxyoxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, a stereoisomer thereof, a metabolite thereof, an ether thereof, an ester thereof, and a derivative thereof.

32. The sustained release formulation of claim 31, wherein the opioid is oxymorphone.

33. A sustained release formulation comprising:

a drug; and

a sustained release delivery system comprising a hydrophilic gum, a cationic cross-linking compound selected from monovalent cations, multivalent cations and salts, and a pharmaceutical diluent,

wherein at least about 30% of the hydrophilic gum particles used to make the sustained release formulation are smaller than about 53 microns in diameter, and the sustained release formulation releases less than 70% of the drug within 2 hours after ingestion with either an ethanol-free or an ethanol-containing beverage.

34. The sustained release formulation of claim 33, wherein the hydrophilic gum is xanthan gum.

35. The sustained release formulation of claim 33, wherein the sustained release delivery system further comprises a hydrophobic polymer.

36. The sustained release formulation of claim 33, further comprising an outer coating, wherein the outer coating comprises a hydrophobic polymer.

37. The sustained release formulation of claim 33, further comprising an outer coating, wherein the outer coating comprises a plasticizer.

38. The sustained release formulation of claim 33 or 34, wherein the drug is selected from the group consisting of alprazolam, lithium carbonate, divalproex sodium, neutral sulfate salts of dextroamphetamine and amphetamine with the dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate monohydrate, tramadol hydrochloride, and other pharmaceutically acceptable salt of the active pharmaceutical ingredient thereof.

39. The sustained release formulation of claim 33 or 34, wherein the drug is an opioid.

40. The sustained release formulation of claim 39, wherein the opioid is a mu-agonist or a mixed mu-agonist/antagonist.

41. The sustained release formulation of claim 40, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normophine, norpipanone, opium, oxycodone, oxymorphone, 6-hydroxyoxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, a stereoisomer thereof, a metabolite thereof, an ether thereof, an ester thereof, and a derivative thereof.

42. The sustained release formulation of claim 41, wherein the opioid is oxymorphone.

43. A method for making a sustained release formulation comprising:

a drug; and

a sustained release delivery system,

wherein the sustained release delivery system comprises a hydrophilic gum, a homopolysaccharide gum, and a pharmaceutical diluent, the method comprising;

providing the hydrophilic gum with at least 30% of particles less than about 53 microns in diameter;

granulating the hydrophilic gum, the homopolysaccharide gum and the pharmaceutical diluent to form granules;

mixing the granules with the drug to form a granulated composition; and

applying pressure to the granulated composition to make the formulation.

44. The method of claim 43, wherein the hydrophilic gum is xanthan gum.

45. The method of claim 43, wherein providing comprises receiving the hydrophilic gum.

46. The method of claim 43, wherein providing comprises manufacturing the hydrophilic gum.

47. The method of claim 43, wherein providing comprises processing the hydrophilic gum.

48. The method of claim 47, wherein processing comprises measuring the size of at least a fraction of the polysaccharide gum particles.

49. The method of claim 47, wherein processing comprises passing at least a fraction of the hydrophilic gum through a sieve.

50. The method of claim 49, wherein the sieve is a #270 mesh sieve.

51. The method of claim 43, further comprising applying an outer coating onto at least part of the sustained release formulation.

52. The method of claim 51, wherein the outer coating comprises a hydrophobic polymer.

53. The method of claim 51, wherein the outer coating comprises a plasticizer.

54. The method of claim 43, wherein granulating comprises mixing ingredients with a solution comprising water.

55. The method of claim 43, wherein granulating comprises mixing ingredients with an alcohol solution.

56. The method of claim 55, wherein the alcohol solution comprises ethanol.

57. The method of claim 43, wherein the sustained release delivery system further comprises a cationic cross-linking compound selected from monovalent cations, multivalent cations, and salts.

58. The method of claim 43 or 44, wherein the drug is selected from the group consisting of alprazolam, lithium carbonate, divalproex sodium, neutral sulfate salts of dextroamphetamine and amphetamine with the dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate monohydrate, tramadol hydrochloride, and other pharmaceutically acceptable salt of the active pharmaceutical ingredient thereof.

59. The method of claim 43 or 44, wherein the drug is an opioid.

60. The method of claim 59, wherein the opioid is a mu-agonist or a mixed mu-agonist/antagonist.

61. The method of claim 60, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normophine, norpipanone, opium, oxycodone, oxymorphone, 6-hydroxyoxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, a stereoisomer thereof, a metabolite thereof, an ether thereof, an ester thereof, and a derivative thereof.

62. The method of claim 43, further comprising recording a dissolution profile of the formulation in an ethanol-containing solution.

63. The method of claim 62, wherein the opioid is oxymorphone.

64. A method for making a sustained release formulation comprising:

a drug; and

a sustained release delivery system,

wherein the sustained release delivery system comprises a hydrophilic gum, a cationic cross-linking compound selected from monovalent cations, multivalent cations and salts, and a pharmaceutical diluent, the method comprising;

providing the hydrophilic gum with at least 30% of particles less than about 53 microns in diameter;

granulating the hydrophilic gum, the homopolysaccharide gum and the pharmaceutical diluent to form granules;

mixing the granules with the drug to form a granulated composition; and

applying pressure to the granulated composition to make the formulation.

65. The method of claim 64, wherein the hydrophilic gum is xanthan gum.

66. The method of claim 64, wherein providing comprises receiving the hydrophilic gum.

67. The method of claim 64, wherein providing comprises manufacturing the hydrophilic gum.

68. The method of claim 64, wherein providing comprises processing the least one hydrophilic gum.

69. The method of claim 68, wherein processing comprises measuring the size of at least a fraction of the hydrophilic gum particles.

70. The method of claim 68, wherein processing comprises passing at least a fraction of the hydrophilic gum through a sieve.

71. The method of claim 70, wherein the sieve is a #270 mesh sieve.

72. The method of claim 64, further comprising applying an outer coating onto at least part of the sustained release formulation.

73. The method of claim 72, wherein the outer coating comprises a hydrophobic polymer.

74. The method of claim 72, wherein the outer coating comprises a plasticizer.

75. The method of claim 64, wherein granulating comprises mixing ingredients with a solution comprising water.

76. The method of claim 64, wherein granulating comprises mixing ingredients with an alcohol solution.

77. The method of claim 76, wherein the alcohol solution comprises ethanol.

78. The method of claim 64 or 65, wherein the drug is selected from the group consisting of alprazolam, lithium carbonate, divalproex sodium, neutral sulfate salts of dextroamphetamine and amphetamine with the dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate monohydrate, tramadol hydrochloride, and other pharmaceutically acceptable salt of the active pharmaceutical ingredient thereof.

79. The method of claim 64 or 65, wherein the drug is an opioid.

80. The method of claim 79, wherein the opioid is a mu-agonist or a mixed mu-agonist/antagonist.

81. The method of claim 80, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normophine, norpipanone, opium, oxycodone, oxymorphone, 6-hydroxyoxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, a stereoisomer thereof, a metabolite thereof, an ether thereof, an ester thereof, and a derivative thereof.

82. The method of claim 81, wherein the opioid is oxymorphone.

83. The method of claim 64, further comprising recording a dissolution profile of the sustained release formulation or a solid dosage form comprising the sustained release formulation in an ethanol-containing solution.

84. A method for making a sustained release formulation comprising:

a drug; and

a sustained release delivery system,

wherein the sustained release delivery system comprises a hydrophilic gum, a homopolysaccharide gum, and a pharmaceutical diluent, the method comprising;

mixing the hydrophilic gum of average and/or mean particle size larger than about 53 microns in diameter, the homopolysaccharide gum and the pharmaceutical diluent with a solution comprising water to form granules;

mixing the granules with drug to form a granulated composition; and

applying pressure to the granulated composition to make the formulation.

85. The method of claim 84, wherein the hydrophilic gum is xanthan gum.

86. The sustained release formulation of claim 84, wherein the sustained release delivery system further comprises a cationic cross-linking compound selected from monovalent cations, multivalent cations, and salts.

87. The method of claim 84, further comprising applying an outer coating onto at least part of the sustained release formulation.

88. The method of claim 84, wherein the drug is selected from the group consisting of alprazolam, lithium carbonate, divalproex sodium, neutral sulfate salts of dextroamphetamine and amphetamine with the dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate monohydrate, tramadol hydrochloride, and other pharmaceutically acceptable salt of the active pharmaceutical ingredient thereof.

89. The method of claim 84 or 85, wherein the drug is an opioid.

90. The method of claim 89, wherein the opioid is a mu-agonist or a mixed mu-agonist/antagonist.

91. The method of claim 90, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normophine, norpipanone, opium, oxycodone, oxymorphone, 6-hydroxyoxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, a stereoisomer thereof, a metabolite thereof, an ether thereof, an ester thereof, and a derivative thereof.

92. The method of claim 91, wherein the opioid is oxymorphone.

93. The method of claim 84, further comprising recording a dissolution profile of the sustained release formulation or a solid dosage form comprising the sustained release formulation in an ethanol-containing solution.

94. A method for making a sustained release formulation comprising:

a drug; and

a sustained release delivery system,

wherein the sustained release delivery system comprises a hydrophilic gum, a cationic cross-linking compound selected from monovalent cations, multivalent cations and salts, and pharmaceutical diluent, the method comprising;

mixing the hydrophilic gum of average and/or mean particle size larger than about 53 microns in diameter, the cationic cross-linking compound and the pharmaceutical diluent with a solution comprising water to form granules;

mixing the granules with the drug to form a granulated composition; and

applying pressure to the granulated composition to make the formulation.

95. The method of claim 94, hydrophilic gum is xanthan gum.

96. The method of claim 94, further comprising applying an outer coating onto at least part of the sustained release formulation.

97. The method of claim 94 or 95, wherein the drug is selected from the group consisting of alprazolam, lithium carbonate, divalproex sodium, neutral sulfate salts of dextroamphetamine and amphetamine with the dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate monohydrate, tramadol hydrochloride, and other pharmaceutically acceptable salt of the active pharmaceutical ingredient thereof.

98. The method of claim 94 or 95, wherein the drug is an opioid.

99. The method of claim 98 wherein the opioid is a mu-agonist or a mixed mu-agonist/antagonist.

100. The method of claim 99, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normophine, norpipanone, opium, oxycodone, oxymorphone, 6-hydroxyoxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, a stereoisomer thereof, a metabolite thereof, an ether thereof, an ester thereof, and a derivative thereof.

101. The method of claim 100, wherein the opioid is oxymorphone.

109. A sustained release formulation comprising from about 5 to about 80 mg of oxymorphone hydrochloride and from about 80 mg to about 360 mg of a sustained release delivery system;

wherein the sustained release delivery system comprises from about 8.3% to about 41.7% by weight locust bean gum, from about 8.3% to about 41.7% by weight xanthan gum wherein at least about 30% of the xanthan gum particles can pass through a #270 mesh sieve, from about 20% to about 55% by weight dextrose, from about 5% to about 20% by weight calcium sulfate dihydrate, and from about 2% to about 10% ethyl cellulose, and the sustained release formulation releases less than 70% of the drug within 2 hours after ingestion with either an ethanol-free or an ethanol-containing beverage.

110. The sustained release formulation of claim 109, comprising about 20 mg of oxymorphone hydrochloride.

111. The sustained release formulation of claim 109, comprising about 160 mg of a sustained release delivery system.

112. The sustained release formulation of claim 109, wherein the sustained release delivery system comprises about 25% locust bean gum, about 25% xanthan gum, about 35% dextrose, about 10% calcium sulfate dihydrate, and about 5% ethyl cellulose.

113. The sustained release formulation of claim 109, further comprising an outer coating.

114. A method for treating a patient suffering from pain comprising administering a therapeutically effective amount of the sustained release formulation of claim 109.

121. A solid dosage form comprising the sustained release formulation according to any one of claims 109-113 and 115-119.

122. The solid dosage form of claim 121 comprising a powder.

123. The solid dosage form of claim 121 comprising a tablet.

124. The solid dosage form of claim 121 comprising a capsule.

115. A sustained release formulation comprising from about 5 to about 80 mg of oxymorphone hydrochloride and from about 300 mg to about 420 mg of a sustained release delivery system;

wherein the sustained release delivery system comprises from about 8.3% to about 41.7% by weight locust bean gum, from about 8.3% to about 41.7% by weight xanthan gum having at least about 30% of particles smaller than about 53 microns in diameter, from about 20% to about 55% by weight dextrose, from about 5% to about 20% by weight calcium sulfate dihydrate, and from about 2% to about 10% ethyl cellulose, and the sustained release formulation releases less than 70% of the drug within 2 hours after ingestion with either an ethanol-free or an ethanol-containing beverage.

116. The sustained release formulation of claim 115, comprising about 20 mg of oxymorphone hydrochloride.

117. The sustained release formulation of claim 115, comprising about 360 mg of a sustained release delivery system.

118. The sustained release formulation of claim 115, wherein the sustained release delivery system comprises about 25% locust bean gum, about 25% xanthan gum, about 35% dextrose, about 10% calcium sulfate dihydrate, and about 5% ethyl cellulose.

119. The sustained release formulation of claim 115, further comprising an outer coating.

120. A method for treating a patient suffering from pain comprising administering a therapeutically effective amount of the sustained release formulation of claim 115.

125. A method of preventing dose-dumping of a drug in the presence of ethanol comprising:

providing a patient who could consume ethanol while being treated with the drug an effective amount of the drug in the form of an ethanol-resistant sustained release formulation comprising;

the drug; and

a sustained release delivery system,

the delivery system comprising at least one hydrophilic gum, at least one homopolysaccharide gum and at least one pharmaceutical diluent, wherein at least about 30% of the hydrophilic gum used to make the sustained release formulation can pass through a #270 mesh sieve, and the sustained release formulation releases less than about 70% of the drug within 2 hours after ingestion with either an ethanol-free or an ethanol-containing beverage.

126. The method of claim 125, wherein the patient has a history of substance abuse.

127. The method of claim 126, wherein the substance abuse is alcohol abuse.

128. The method of claim 126, wherein the substance abuse is drug abuse.

129. The method of claim 125, wherein the ethanol-resistant sustained release formulation is a solid dosage form.

130. The method of claim 125, wherein the hydrophilic gum is xanthan gum.

131. The method of claim 129, wherein the solid dosage form forms a gel matrix with muco-adhesive properties when crushed or powdered upon contact with a fluid.

132. The method of claim 129, wherein the solid dosage form forms a viscous solution when crushed or powdered upon contact with a fluid.

133. The method of claim 129, wherein the solid dosage form is a tablet.

134. The method of claim 125, wherein the sustained release delivery system further comprises at least one hydrophobic polymer in an amount of less than about 5% by weight.

135. The method of claim 125, wherein the delivery system further comprises at least one cationic cross-linking compound selected from monovalent cations, multivalent cations, and salts.

136. The method of claim 125, wherein the drug is an anti-depressant.

137. The method of claim 125, wherein the drug is a drug used to treat bipolar disorder, panic disorder, epilepsy, migraine, and/or attention deficit hyperactivity disorder.

138. The method of claim 125, wherein the drug is an opioid.

139. The method of claim 138, wherein the opioid is a mu-agonist or a mixed mu-agonist/antagonist.

140. The method of claim 138, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normophine, norpipanone, opium, oxycodone, oxymorphone, 6-hydroxyoxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, a stereoisomer thereof, a metabolite thereof, a salt thereof, an ether thereof, an ester thereof and a derivative thereof.

141. A method of preventing dose-dumping of a drug in the presence of beverage-strength ethanol comprising:

providing a patient who could consume ethanol while being treated with the drug an effective amount of the drug in the form of an ethanol-resistant sustained release formulation comprising;

the drug; and

a sustained release delivery system,

the delivery system comprising at least one hydrophilic gum, at least one cationic cross-linking compound selected from monovalent metal cations, multivalent metal cations and salts, and at least one pharmaceutical diluent, wherein at least about 30% of the hydrophilic gum used to make the sustained release formulation can pass through a #270 mesh sieve, and the sustained release formulation releases less than about 70% of the drug within 2 hours after ingestion with either an ethanol-free or an ethanol-containing beverage.

142. The method of claim 141, wherein the patient has a history of substance abuse.

143. The method of claim 142, wherein substance abuse is alcohol abuse.

144. The method of claim 142, wherein the substance abuse is drug abuse.

145. The method of claim 141, wherein the ethanol-resistant sustained release formulation is a solid dosage form.

146. The method of claim 141, wherein the hydrophilic gum is xanthan gum.

147. The method of claim 145, wherein the solid dosage form forms a gel matrix with muco-adhesive properties when crushed or powdered upon contact with a fluid.

148. The method of claim 145, wherein the solid dosage form forms a viscous solution when crushed or powdered upon contact with a fluid.

149. The method of claim 145, wherein the solid dosage form is a tablet.

150. The method of claim 141, wherein the sustained release delivery system further comprises at least one hydrophobic polymer in an amount of less than about 5% by weight.

151. The method of claim 141, wherein the at least one cationic cross-linking compound is a sodium salt.

152. The method of claim 141, wherein the drug is an anti-depressant.

153. The method of claim 141, wherein the drug is a drug used to treat bipolar disorder, panic disorder, epilepsy, migraine, and/or attention deficit hyperactivity disorder.

154. The method of claim 141, wherein the drug is an opioid.

155. The method of claim 154, wherein the opioid is a mu-agonist or a mixed mu-agonist/antagonist.

156. The method of claim 155, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normophine, norpipanone, opium, oxycodone, oxymorphone, 6-hydroxyoxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, a stereoisomer thereof, a metabolite thereof, a salt thereof, an ether thereof, an ester thereof and a derivative thereof.

157. A method of improving safety of a drug formulation comprising:

providing a patient who could consume ethanol while being treated with the drug an effective amount of the drug in the form of an ethanol-resistant sustained release formulation comprising;

the drug; and

a sustained release delivery system,

the sustained release delivery system comprising at least one hydrophilic gum, at least one homopolysaccharide gum and at least one pharmaceutical diluent, wherein the improvement in safety is a result of controlled hydrophilic gum particle size and ethanol-resistant sustained release properties of the formulation.

158. The method of claim 157, wherein the patient has a history of substance abuse.

159. The method of claim 158, wherein the substance abuse is alcohol abuse.

160. The method of claim 158, wherein the substance abuse is drug abuse.

161. The method of claim 157, wherein the ethanol-resistant sustained release formulation is a solid dosage form.

162. The method of claim 157, wherein the hydrophilic gum is xanthan gum.

163. The method of claim 161, wherein the solid dosage form forms a gel matrix with muco-adhesive properties when crushed or powdered upon contact with a fluid.

164. The method of claim 161, wherein the solid dosage form forms a viscous solution when crushed or powdered upon contact with a fluid.

165. The method of claim 160, wherein the solid dosage form is a tablet.

166. The method of claim 157, wherein the sustained release delivery system further comprises at least one hydrophobic polymer in an amount of less than about 5% by weight.

167. The method of claim 157, wherein the delivery system further comprises at least one cationic cross-linking compound selected from monovalent cations, multivalent cations, and salts.

168. The method of claim 157, wherein the drug is an anti-depressant.

169. The method of claim 157, wherein the drug is a drug used to treat bipolar disorder, panic disorder, epilepsy, migraine, and/or attention deficit hyperactivity disorder.

170. The method of claim 157, wherein the drug is an opioid.

171. The method of claim 170, wherein the opioid is a mu-agonist or a mixed mu-agonist/antagonist.

172. The method of claim 171, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normophine, norpipanone, opium, oxycodone, oxymorphone, 6-hydroxyoxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, a stereoisomer thereof, a metabolite thereof, a salt thereof, an ether thereof, an ester thereof and a derivative thereof.

173. A method of improving safety of a drug formulation comprising:

providing a patient who could consume ethanol while being treated with the drug an effective amount of the drug in the form of an ethanol-resistant sustained release formulation comprising;

the drug; and

a sustained release delivery system,

the delivery system comprising at least one hydrophilic gum, at least one cationic cross-linking compound selected from monovalent metal cations, multivalent metal cations and salts, and at least one pharmaceutical diluent, wherein the improvement in safety is a result of controlled hydrophilic gum particle size and ethanol-resistant sustained release properties of the formulation.

174. The method of claim 173, wherein the patient has a history of substance abuse.

175. The method of claim 174, wherein substance abuse is alcohol abuse.

176. The method of claim 174, wherein the substance abuse is drug abuse.

177. The method of claim 173, wherein the ethanol-resistant sustained release formulation is a solid dosage form.

178. The method of claim 173, wherein the hydrophilic gum is xanthan gum.

179. The method of claim 177, wherein the solid dosage form forms a gel matrix with muco-adhesive properties when crushed or powdered upon contact with a fluid.

180. The method of claim 177, wherein the solid dosage form forms a viscous solution when crushed or powdered upon contact with a fluid.

181. The method of claim 177, wherein the solid dosage form is a tablet.

182. The method of claim 173, wherein the sustained release delivery system further comprises at least one hydrophobic polymer in an amount of less than about 5% by weight.

183. The method of claim 173, wherein the at least one cationic cross-linking compound is a sodium salt.

184. The method of claim 173, wherein the drug is an anti-depressant.

185. The method of claim 173, wherein the drug is a drug used to treat bipolar disorder, panic disorder, epilepsy, migraine, and/or attention deficit hyperactivity disorder.

186. The method of claim 173, wherein the drug is an opioid.

187. The method of claim 186, wherein the opioid is a mu-agonist or a mixed mu-agonist/antagonist.

188. The method of claim 187, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normophine, norpipanone, opium, oxycodone, oxymorphone, 6-hydroxyoxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, a stereoisomer thereof, a metabolite thereof, a salt thereof, an ether thereof, an ester thereof and a derivative thereof.