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Details for Patent: 5,472,712

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Details for Patent: 5,472,712

Title: Controlled-release formulations coated with aqueous dispersions of ethylcellulose
Abstract:A stabilized solid controlled release formulation having a coating derived from an aqueous dispersion of a hydrophobic polymer is obtained by overcoating a substrate including an active agent selected from the group consisting of a systemically active therapeutic agent, a locally active therapeutic agent, a disinfecting and sanitizing agent, a cleansing agent, a fragrance agent and a fertilizing agent, with an aqueous dispersion of the plasticized hydrophobic polymer and then curing the coated substrate at a temperature above the glass transition temperature of the plasticized hydrophobic polymer, until a curing endpoint is reached at which the coated substrate provides a stabilized dissolution of the active agent which is unchanged after exposure to accelerated storage conditions, the endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of at least one month at a temperature of 37.degree. C. and at a relative humidity of 80%.
Inventor(s): Oshlack; Benjamin (New York, NY), Chasin; Mark (Manalpan, NJ), Pedi, Jr.; Frank (Yorktown Heights, NY)
Assignee: Euroceltique, S.A. (LU)
Filing Date:Jun 23, 1993
Application Number:08/081,618
Claims:1. A controlled release formulation comprising a substrate containing an active agent in an amount sufficient to provide an effect in an environment of use, said substrate coated with an aqueous dispersion of plasticized ethylcellulose in an amount sufficient to obtain a controlled release of said active agent when said formulation is exposed to an environmental fluid, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100% for a sufficient period of time until a curing endpoint is reached at which said coated substrate provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of at least one month at a temperature of 37.degree. C. and at a relative humidity of 80%.

2. The formulation of claim 1, wherein said substrate is coated to a weight gain from about 2 to about 30%.

3. The formulation of claim 1, wherein said active agent is selected from the group consisting of a systemically active therapeutic agent, a locally active therapeutic agent, a disinfecting agent, a cleansing agent, a fragrance, a fertilizing agent, a deodorant, a dye, an animal repellant, an insect repellant, a pesticide, a herbicide, a fungicide, and a plant growth stimulant.

4. The formulation of claim 3, wherein said locally active therapeutic agent is selected from the group consisting of an antibiotic, a breath freshener, an antitussive agent, an analgesic, a local anesthetic, an antiseptic, an anti-inflammatory agent, a hormonal agent, and an acidity reducing agent.

5. The formulation of claim 3, wherein said systemically active therapeutic agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, hormones, diuretics, anti-hypotensives, anti-hypertensives, bronchodilators, antibiotics, antivirals, antihemorrhoidals, steroids, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.

6. The formulation of claim 5, wherein said active agent is an opioid analgesic selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, dihydromorphine, buprenorphine, salts of any of the foregoing, and mixtures of any of the foregoing.

7. The formulation of claim 1, wherein said substrate is a pharmaceutically acceptable bead, and a plurality of said coated, cured beads are placed in a capsule in an amount sufficient to provide an effective controlled release dose when contacted by an aqueous solution.

8. The formulation of claim 1, wherein said substrate is a tablet core.

9. The formulation of claim 7, wherein said beads are coated with said aqueous dispersion of ethylcellulose to a weight gain from about 2 to about 25 percent.

10. The formulation of claim 9, wherein said coating is cured for a time period from about 48 to about 72 hours, until said endpoint is reached.

11. The formulation of claim 10, wherein said coating is cured at a relative humidity of about 85%.

12. The formulation of claim 1, wherein said coating further comprises a release-modifying agent in an amount effective to modify the rate of release of said active agent from said cured, coated substrate.

13. The formulation of claim 12, wherein said release-modifying agent is selected from the group consisting of a hydrophilic polymer, a semi-permeable polymer, an erosion-promoting polymer, an agent capable of making microporous lamina, a pore-former and mixtures of any of the foregoing.

14. The formulation of claim 12, wherein said coating comprises from about 0.1% to about 70% of said release-modifying agent.

15. The formulation of claim 12, wherein said coating comprises from about 0.1% to about 50% of said release-modifying agent.

16. The formulation of claim 12., wherein said coating comprises from about 0.1% to about 25% of said release-modifying agent.

17. The formulation of claim 12, wherein said release-modifying agent is selected from the group consisting of hydroxypropylmethylcellulose, lactose, metal stearates and mixtures of any of the foregoing.

18. The formulation of claim 1, which provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions of a temperature of 40.degree. C. and a relative humidity of 75% for 3 months.

19. The formulation of claim 1, which provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions which are deemed appropriate by the United States Food & Drug Administration for the purpose of according expiration dating for said formulation.

20. The formulation of claim 17, wherein said cured coated substrate, when subjected to in-vitro dissolution after exposure to said accelerated conditions, releases an amount of said active agent which does not vary at any given time point by more than about 20% of the total amount of active agent released when compared to in-vitro dissolution conducted prior to storage.

21. The formulation of claim 1, wherein a portion of the amount of said active agent included in said formulation is incorporated into a coating on said substrate.

22. A method for obtaining an controlled release formulation of an active agent, comprising:

preparing a solid substrate comprising an active agent;

coating said substrate with a sufficient amount an aqueous dispersion of plasticized ethylcellulose to obtain a predetermined controlled release of said active agent when said coated substrate is exposed to an environmental fluid, and

curing said coated substrate at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100% until a curing endpoint is reached at which said coated substrate provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of at least one month at a temperature of 37.degree. C. and at a relative humidity of 80%.

23. The method of claim 22, further comprising preparing said substrate for oral administration by coating said therapeutically active agent onto the surface of pharmaceutically acceptable beads, and preparing an oral dosage form by placing a sufficient quantity of cured coated beads into a capsule.

24. The method of claim 22, further comprising preparing said substrate for oral administration by incorporating said therapeutically active agent into a tablet.

25. The method of claim 22, further comprising coating said substrate comprising said therapeutically active agent with a barrier agent prior to overcoating with said aqueous dispersion of ethylcellulose.

26. The method of claim 25, wherein said barrier agent comprises hydroxypropylmethylcellulose.

27. The method of claim 22, wherein said coated particles are cured for about 48 to about 72 hours, until said endpoint is reached.

28. The method of claim 22, further comprising coating said substrate to a weight gain from about 2 to about 25%.

29. The method of claim 22, wherein said active agent is selected from the group consisting of a systemically active therapeutic agent, a locally active therapeutic agent, a disinfecting agent, a cleansing agent, a fragrance, a fertilizing agent, a deodorant, a dye, an animal repellant, an insect repellant, a pesticide, a herbicide, a fungicide, and a plant growth stimulant.

30. The method of claim 22, wherein said locally active therapeutic agent is selected from the group consisting of an antibiotic, a breath freshener, an antitussive agent, an analgesic agent, a local anesthetic, an antiseptic, an anti-inflammatory agent, a hormonal agent, and an acidity-reducing agent.

31. The method of claim 22, wherein said therapeutically active agent is selected from the group consisting of anti-histamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, hormones, diuretics, anti-hypotensives, anti-hypertensives, bronchodilators, antibiotics, antivirals, antihemorrhoidals, steroids, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.

32. The method of claim 22, wherein said active agent is an opioid analgesic selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, dihydromorphine, buprenorphine, salts of any of the foregoing, and mixtures of any of the foregoing.

33. The method of claim 27, wherein said coating is cured at a relative humidity of about 85%.

34. The method of claim 22, wherein said coating further comprises a release-modifying agent in an amount effective to modify the rate of release of said active agent from said cured, coated substrate.

35. The method of claim 22, wherein said release-modifying agent is selected from the group consisting of a hydrophilic polymer, a semi-permeable polymer, an erosion-promoting polymer, an agent capable of making microporous lamina, a pore-former, and mixtures of any of the foregoing.

36. The method of claim 22, wherein said coating comprises from about 0.1% to about 70% of said release-modifying agent.

37. The method of claim 22, wherein said coating comprises from about 0.1% to about 50% of said release-modifying agent.

38. The method of claim 22, wherein said coating comprises from about 0.1% to about 25% of said release-modifying agent.

39. The method of claim 22, wherein said release-modifying agent is selected from the group consisting of hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing.

40. A solid controlled release formulation, comprising a substrate containing an active agent in an amount sufficient to provide an effect in an environment of use, said substrate coated with an aqueous dispersion of plasticized ethylcellulose in an amount sufficient to obtain a controlled release of said active agent when said formulation is exposed to an environmental fluid, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100% to cause individual ethylcellulose particles in said coating to coalesce and to gradually slow the release of said active agent when exposed to an environmental fluid, until an endpoint is reached at which said cured coated substrate, when subjected to in-vitro dissolution, releases said active agent in amounts which do not vary at any time point along the dissolution curve by more than about 20% of the total amount of active agent released, when compared to the in-vitro dissolution of said coated substrate prior to curing.

41. The formulation of claim 40, wherein said cured, coated substrate provides the same rate of release immediately after curing to said endpoint, and after subsequent exposure to accelerated storage conditions of one month at a temperature of 37.degree. C. and at a relative humidity of 80%.

42. The formulation of claim 40, wherein said cured, coated substrate provides the same rate of release immediately after curing to said endpoint, and after subsequent exposure to accelerated storage conditions of one month at a temperature of 40.degree. C. and at a relative humidity of 75%.

43. The formulation of claim 40, wherein said substrate is coated to a weight gain from about 2% to about 25%.

44. The formulation of claim 40, wherein said active agent is selected from the group consisting of a systemically active therapeutic agent, a locally active therapeutic agent, a disinfecting agent, a cleansing agent, a fragrance, a fertilizing agent, a deodorant, a dye, an animal repellant, an insect repellant, a pesticide, a herbicide, a fungicide, and a plant growth stimulant.

45. The formulation of claim 40, wherein said locally active therapeutic agent is selected from the group consisting of an antibiotic, a breath freshener, an antitussive agent, an analgesic agent, a local anesthetic, an antiseptic, an anti-inflammatory agent, a hormonal agent, and an acidity reducing agent.

46. The formulation of claim 44, wherein said systemically active therapeutic agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, hormones, diuretics, anti-hypotensives, anti-hypertensives, bronchodilators, antibiotics, antivirals, antihemorrhoidals, steroids, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.

47. The formulation of claim 40, wherein said substrate is a pharmaceutically acceptable bead, and a plurality of said coated, cured beads are placed in a capsule in an amount sufficient to provide an effective controlled release dose when contacted by an aqueous solution.

48. The formulation of claim 40, wherein said substrate is a tablet core.

49. The formulation of claim 46, wherein said substrate is selected from the group consisting of a tablet core and a plurality of pharmaceutically inert beads, and said cured, coated formulation when administered orally provides effective blood levels of said systemically active therapeutic agent for about 24 hours.

50. The formulation of claim 49, wherein said systemically active therapeutic agent is an opioid analgesic selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, dihydromorphine, buprenorphine, salts of any of the foregoing, and mixtures of any of the foregoing.

51. The formulation of claim 50, wherein said coating is cured for a time period from about 48 to about 72 hours, until said endpoint is reached.

52. The formulation of claim 51, wherein said coating is cured at a relative humidity of about 85%.

53. The formulation of claim 40, wherein said coating further comprises a release-modifying agent in an amount effective to modify the rate of release of said active agent from said cured, coated substrate.

54. The formulation of claim 53, wherein said release-modifying agent is selected from the group consisting of a hydrophilic polymer, a semi-permeable polymer, an erosion-promoting polymer, an agent capable of making microporous lamina, a pore-former, and mixtures of any of the foregoing.

55. The formulation of claim 54, wherein said coating comprises from about 0.1% to about 70% of said release-modifying agent.

56. The formulation of claim 54, wherein said coating comprises from about 0.1% to about 50% of said release-modifying agent.

57. The formulation of claim 54, wherein said coating comprises from about 0.1% to about 25% of said release-modifying agent.

58. The formulation of claim 40, wherein said coated substrate includes at least one passageway through said coating which modifies the release of said systemically active therapeutic agent.

59. The formulation of claim 55, wherein said release-modifying agent comprises hydroxypropylmethylcellulose.

60. A solid controlled release oral dosage formulation, comprising a substrate containing a systemically active therapeutic agent in an amount sufficient to provide a therapeutic effect when said formulation is orally administered, said substrate being coated with a cured aqueous dispersion of plasticized ethylcellulose to a weight gain from about 2% to about 25%, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100% for a sufficient period of time until a curing endpoint is reached at which said coated substrate provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of at least one month at a temperature of 37.degree. C. and at a relative humidity of 80% and said coating being sufficient to obtain a controlled release of said active agent when measured by the USP Paddle Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. from about 12.5% to about 42.5% (by wt) active agent released after 1 hour, from about 25% to about 55% (by wt) active agent released after 2 hours, from about 45% to about 75% (by wt) active agent released after 4 hours and from about 55% to about 85% (by wt) active agent released after 8 hours, said coated substrate, when subjected to accelerated storage conditions of at least one month at 40.degree. C./75% RH, releasing an amount of said therapeutically active agent upon in-vitro dissolution which does not vary at any given time point by more than about 20% of the total amount of therapeutically active agent released when compared to in-vitro dissolution conducted prior to storage.

61. The formulation of claim 60, wherein said therapeutically active agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, hormones, diuretics, anti-hypotensives, anti-hypertensives, bronchodilators, antibiotics, antivirals, antihemorrhoidals, steroids, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.

62. The formulation of claim 61, wherein said active agent is an opioid analgesic selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, dihydromorphine, buprenorphine, salts thereof, and mixtures thereof.

63. The formulation of claim 61, wherein said substrate is selected from the group consisting of a tablet core and a pharmaceutically acceptable bead, and a plurality of said coated, cured beads are placed in a capsule in an amount sufficient to provide an effective controlled release dose when said capsule is orally administered.

64. The formulation of claim 62, which is a once-a-day formulation.

65. The formulation of claim 61, wherein said coating further comprises a release-modifying agent in an amount effective to modify the rate of release of said active agent from said cured, coated substrate.

66. The formulation of claim 61, wherein said release-modifying agent is selected from the group consisting of a hydrophilic polymer, a semi-permeable polymer, an erosion-promoting polymer, an agent capable of making microporous lamina, a pore-former and mixtures of any of the foregoing.

67. The formulation of claim 60, wherein said coating comprises from about 0.1% to about 70% of said release-modifying agent.

68. The formulation of claim 60, wherein said coating comprises from about 0.1% to about 50% of said release-modifying agent.

69. The formulation of claim 60, wherein said coating comprises from about 0.1% to about 25% of said release-modifying agent.

70. The formulation of claim 61, wherein said release-modifying agent comprises up to about 10% of said coating, by weight.

71. The formulation of claim 60, wherein said coated substrate includes at least one passageway through said coating which modifies the release of said systemically active therapeutic agent.

72. The formulation of claim 60, wherein said release-modifying agent is selected from the group consisting of hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing.

73. The formulation of claim 60, which provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions of a temperature of 40.degree. C. and a relative humidity of 75% for 3 months.

74. The formulation of claim 60, which provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions which are deemed appropriate by the United States Food & Drug Administration for the purpose of according expiration dating for said formulation.

75. The formulation of claim 60, wherein a portion of the amount of said active agent included in said formulation is incorporated into a coating on said substrate.

76. The formulation of claim 60, which provides therapeutically effective blood levels of said systemically active therapeutic agent when administered orally for about 12 hours.

77. The formulation of claim 60, which provides therapeutically effective blood levels of said systemically active therapeutic agent when administered orally for about 24 hours.

78. The formulation of claim 62, which provides therapeutically effective blood levels of said opioid analgesic when administered orally for about 24 hours.

79. A method of treating a patient with a controlled release oral solid dosage form which provides an effective blood level of a therapeutically active agent for a predetermined amount of time, comprising:

preparing a solid substrate comprising a sufficient amount of a therapeutically active agent to provide therapeutically effective blood levels in the patient for about 12 to about 24 hours,

coating said substrate with a sufficient amount an aqueous dispersion of plasticized ethylcellulose to obtain a predetermined controlled release of said active agent when said coated substrate is exposed to an environmental fluid, and

curing said coated substrate at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100% until a curing endpoint is reached at which said coated substrate provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of at least one month at a temperature of 37.degree. C. and at a relative humidity of 80%,

and administering an oral solid dosage form comprising said cured, coated substrate to the patient to thereby obtain the desired therapeutic effect for about 12 to about 24 hours.

80. The method of claim 79, wherein said coated substrate is cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100%.

81. The method of claim 80, wherein said substrate comprises pharmaceutically acceptable inert beads, further comprising coating said therapeutically active agent onto the surface of said inert beads, and preparing said oral dosage form by placing a sufficient quantity of cured coated beads into a capsule.

82. The method of claim 79, further comprising preparing said substrate for oral administration by incorporating said therapeutically active agent into a tablet.

83. The method of claim 81, wherein said coated substrate is cured for about 48 to about 72 hours, until said endpoint is reached.

84. The method of claim 79, further comprising coating said substrate to a weight gain from about 2% to about 25%.

85. The method of claim 79, wherein said therapeutically active agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, hormones, diuretics, anti-hypotensives, anti-hypertensives, bronchodilators, antibiotics, antivirals, antihemorrhoidals, steroids, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.

86. The method of claim 79, wherein said active agent is an opioid analgesic selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, dihydromorphine, buprenorphine, salts thereof, and mixtures thereof.

87. The method of claim 85, wherein said oral solid dosage form provides a desired therapeutic effect for about 24 hours.

88. The method of claim 86, wherein said oral solid dosage form provides a desired therapeutic effect for about 24 hours.

89. The method of claim 79, further comprising incorporating a release-modifying agent in said aqueous dispersion of ethylcellulose in an amount effective to modify the rate of release of said active agent from said cured, coated substrate.

90. The method of claim 89, wherein said release-modifying agent is selected from the group consisting of a hydrophilic polymer, a semi-permeable polymer, an erosion-promoting polymer, an agent capable of making microporous lamina, a pore-former, and mixtures of any of the foregoing.

91. The method of claim 89, wherein said release-modifying agent is selected from the group consisting of hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing.

92. An oral solid dosage form comprising:

a solid substrate comprising an effective amount of a therapeutically active agent,

a coating covering said substrate, said coating comprising a cured aqueous dispersion of ethylcellulose in an amount required to provide effective blood levels of said therapeutically active agent for at least about 12 hours, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100% for a sufficient period of time until a curing endpoint is reached at which said coated substrate provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of at least one month at a temperature of 37.degree. C. and at a relative humidity of 80% and said coated substrate upon in-vitro dissolution testing providing a band range, when comparing the dissolution profile after exposure to accelerated storage conditions of at least one month at a temperature of 40.degree. C. and a relative humidity of 75% to the dissolution profile prior to exposure to said accelerated conditions, which is not wider than about 20% of total active agent released at any point of time.

93. The oral solid dosage form of claim 92, wherein said coating further comprises from about 0.1% to about 70% by weight of a release-modifying agent.

94. The oral solid dosage form of claim 92, wherein said coating includes at least one passageway running from an exterior surface of said coating to said solid substrate, said passageway causing a desired modification of the release rate of said therapeutically active agent when said oral solid dosage form is exposed to aqueous fluids or gastrointestinal fluid.

95. The oral solid dosage form of claim 92, wherein the band range, when comparing the dissolution profile after exposure to accelerated storage conditions of at least one month at a temperature of 40.degree. C. and a relative humidity of 75% to the dissolution profile prior to exposure to said accelerated conditions, does not differ by more than about 15%.

96. The oral solid dosage form of claim 92, wherein the band range, when comparing the dissolution profile after exposure to accelerated storage conditions of at least one month at a temperature of 40.degree. C. and a relative humidity of 75% to the dissolution profile prior to exposure to said accelerated conditions, does not differ by more than about 10%.

97. The oral solid dosage form of claim 92 which provides effective blood levels of said therapeutically active agent for about 24 hours.

98. The dosage form of claim 92, wherein said substrate comprises a pharmaceutically acceptable inert bead upon which said therapeutically active agent is coated and a plurality of said coated beads are placed in a capsule to provide said effective amount of said therapeutically active agent.

99. The oral solid dosage form of claim 92 which is a coated tablet.

100. The controlled release dosage form of claim 93, wherein said release-modifying agent is selected from the group consisting of a hydrophilic polymer, a semi-permeable polymer, an erosion-promoting polymer, an agent capable of making microporous lamina, a pore-former, and mixtures of any of the foregoing.

101. A controlled release dosage form, comprising

a solid substrate comprising an effective amount of a therapeutically active agent, said solid substrate being coated with a cured aqueous dispersion of ethylcellulose in an amount effective to provide a controlled release of said therapeutically active agent when said coated substrate is exposed to gastrointestinal fluid, said coated substrate when subjected to invitro dissolution after exposure to accelerated storage conditions of at least one month at 40.degree. C./75% RH releasing an amount of said therapeutically active agent which does not vary at any given dissolution time point by more than about 20% of the total amount of therapeutically active agent released when compared to in-vitro dissolution conducted prior to storage, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100% for about 48 to about 72 hours.

102. The controlled release dosage form of claim 101 which is administered once a day.

103. The controlled release dosage form of claim 101 which is administered twice a day.

104. The controlled release dosage form of claim 101 wherein said substrate comprises a pharmaceutically acceptable inert bead upon which said therapeutically active agent is coated and a plurality of said coated beads are placed in a capsule to provide said effective amount of said therapeutically active agent.

105. The controlled release dosage form of claim 101 which is a coated tablet.

106. The controlled release dosage form of claim 101, wherein said coating further comprises a release-modifying agent in an amount effective to modify the rate of release of said therapeutically active agent from said coated substrate.

107. The controlled release dosage form of claim 101, wherein said substrate is coated with said aqueous dispersion of ethylcellulose to a weight gain from about 2 to about 25%.

108. The controlled release dosage form of claim 102, wherein said therapeutically active agent is an opioid analgesic selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, dihydromorphine, buprenorphine, salts thereof, and mixtures thereof.

109. The formulation of claim 40, wherein said cured coated substrate, when subjected to in-vitro dissolution, releases said active agent in amounts which do not vary at any time point along the dissolution curve by more than about 15% of the total amount of active agent released, when compared to the in-vitro dissolution of said coated substrate prior to curing.

110. The formulation of claim 40, wherein said cured coated substrate, when subjected to in-vitro dissolution, releases said active agent in amounts which do not vary at any time point along the dissolution curve by more than about 10% of the total amount of active agent released, when compared to the in-vitro dissolution of said coated substrate prior to curing.

111. A method of treating a human patient, comprising orally administering the oral solid dosage form of claim 92.

112. A method of treating a human patient, comprising orally administering the controlled release dosage form of claim 101.

113. A method of treating a human patient, comprising orally administering the solid controlled release oral dosage formulation of claim 60.

114. A method of treating a human patient, comprising orally administering the solid controlled release formulation of claim 40.

115. A method of treating a human patient, comprising orally administering the formulation of claim 5.

116. The formulation of claim 3, wherein said locally active therapeutic agent is selected from the group consisting of an antiviral agent, an antifungal agent, an antiplaque agent, an anti-cariogenic agent, and a tooth desensitizer.

117. The method of claim 22, wherein said locally active therapeutic agent is selected from the group consisting of an antiviral agent, an antifungal agent, an antiplaque agent, an anticariogenic agent, and a tooth desensitizer.

118. The formulation of claim 40, wherein said locally active therapeutic agent is selected from the group consisting of an antiviral agent, an antifungal agent, an antiplaque agent, an anti-cariogenic agent, and a tooth desensitizer.
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