Claims
- 1. A controlled release formulation comprising a substrate containing an active agent in an amount sufficient to provide a desired effect in an environment of use, said substrate coated with an aqueous dispersion of a plasticized water-insoluble acrylic polymer 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 said plasticized water-insoluble acrylic polymer 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° C. and at a relative humidity of 80%.
- 2. The formulation of claim 1, wherein said water-insoluble acrylic polymer is comprised of monomers selected from the group consisting of an ester of acrylic acid, an ester of methacrylic acid, an alkyl ester of acrylic acid, an alkyl ester of methacrylic acid, and mixtures of any of the foregoing.
- 3. The formulation of claim 2, wherein said water-insoluble acrylic polymer further comprises a permeability-enhancing compound.
- 4. The formulation of claim 3, wherein said permeability-enhancing compound is a monoethylenically unsaturated quaternary ammonium compound capable of free-radical polymerization.
- 5. The formulation of claim 1, wherein said substrate is coated to a weight gain from about 2% to about 50%.
- 6. 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.
- 7. The formulation of claim 3, 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.
- 8. The formulation of claim 6, wherein said locally active therapeutic agent is selected from the group consisting of an antifungal agent, an antibiotic, an antiviral agent, a breath freshener, an antitussive agent, an anti-cariogenic agent, an analgesic agent, a local anesthetic, an antiseptic, an antiflammatory agent, a hormonal agent, an antiplaque agent, an acidity reducing agent, and a tooth desensitizer.
- 9. The formulation of claim 6, 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.
- 10. The formulation of claim 6, wherein said active agent is an opioid analgesic selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, hydrocodone, tramadol, dihydromorphine, buprenorphine, mixed opiate receptor agonist-antagonists, salts, hydrates and solvents of any of the foregoing, and mixtures of any of the foregoing.
- 11. The formulation of claim 9, 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.
- 12. The formulation of claim 1, wherein said substrate is a tablet core.
- 13. The formulation of claim 9, wherein said formulation provides effective blood levels of said systemically active therapeutic agent for about 24 hours.
- 14. The formulation of claim 10, wherein said formulation provides effective blood levels of said systemically active therapeutic agent for about 24 hours.
- 15. The formulation of claim 11, wherein said beads are coated with said aqueous dispersion of water-insoluble acrylic polymer to a weight gain from about 2 to about 25 percent.
- 16. The formulation of claim 1, wherein said coating is cured for a time period from about 24 to about 48 hours, until said endpoint is reached.
- 17. The formulation of claim 1, wherein said aqueous dispersion further comprises a pore-former which is dissolved, extracted, or leached from the coating when exposed to aqueous solutions.
- 18. The formulation of claim 2, wherein said water-insoluble acrylic polymer comprises a mixture of copolymers of acrylic and methacrylic esters having a molar ratio of ammonium groups to (meth)acrylic esters from about 1:20 to about 1:40.
- 19. The formulation of claim 2, wherein said water-insoluble acrylic polymer comprises a mixture of a first copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to (meth)acrylic esters of about 1:20 and a second copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to (meth)acrylic esters of about 1:40, the ratio of said first copolymer to said second copolymer being from about 0:100 to about 100:0.
- 20. The formulation of claim 1, which provides a stable dissolution of said active agent which is unchanged after exposure to accelerated storage conditions of a temperature of 40° C. and a relative humidity of 75% for 3 months.
- 21. The formulation of claim 1, which provides a stable 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.
- 22. The formulation of claim 1, 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 15% of the total amount of active agent released when compared to in-vitro dissolution conducted prior to storage.
- 23. The formulation of claim 1, 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 10% of the total amount of active agent released when compared to in-vitro dissolution conducted prior to storage.
- 24. The formulation of claim 1, 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 7% of the total amount of active agent released when compared to in-vitro dissolution conducted prior to storage.
- 25. 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.
- 26. A solid controlled release formulation, comprising a substrate containing an active agent in an amount sufficient to provide a desired effect in an environment of use, said substrate coated with an aqueous dispersion of a plasticized water-insoluble acrylic polymer 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 plasticized water-insoluble acrylic polymer until an endpoint is reached at which said cured coated substrate, when exposed to an environment of use, 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.
- 27. The formulation of claim 26, 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° C. and at a relative humidity of 80%.
- 28. The formulation of claim 26, 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° C. and at a relative humidity of 75%.
- 29. The formulation of claim 26, wherein said water-insoluble acrylic polymer is comprised of monomers selected from the group consisting of an ester of acrylic acid, an ester of methacrylic acid, an alkyl ester of acrylic acid, an alkyl ester of methacrylic acid, and mixtures of any of the foregoing.
- 30. The formulation of claim 26, wherein said water-insoluble acrylic polymer further comprises a permeability-enhancing compound.
- 31. The formulation of claim 30, wherein said permeability-enhancing compound is a monoethylenically unsaturated quaternary ammonium compound capable of free-radical polymerization.
- 32. The formulation of claim 26, wherein said substrate is coated to a weight gain from about 2% to about 50%.
- 33. The formulation of claim 26, 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.
- 34. The formulation of claim 33, wherein said locally active therapeutic agent is selected from the group consisting of an antifungal agent, an antibiotic, an antiviral agent, a breath freshener, an antitussive agent, an anti-cariogenic agent, an analgesic agent, a local anesthetic, an antiseptic, an antiflammatory agent, a hormonal agent, an antiplaque agent, an acidity reducing agent, and a tooth desensitizer.
- 35. The formulation of claim 33, 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.
- 36. The formulation of claim 33, 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.
- 37. The formulation of claim 26, wherein said substrate is a tablet core.
- 38. The formulation of claim 35, 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.
- 39. The formulation of claim 35, 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 12 hours.
- 40. The formulation of claim 38, wherein said active agent is an opioid analgesic selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, hydrocodone, tramadol, dihydromorphine, buprenorphine, mixed opiate receptor agonist-antagonists, salts, hydrates and solvents of any of the foregoing, and mixtures of any of the foregoing.
- 41. The formulation of claim 26, wherein said coating is cured for a time period from about 24 to about 48 hours, until said endpoint is reached.
- 42. A solid controlled release oral dosage formulation, comprising a substrate containing a systemically active therapeutic agent in an amount sufficient to provide a desired therapeutic effect when said formulation is orally administered, said substrate being coated with an aqueous dispersion of a plasticized copolymer of acrylic and methacrylic acid esters having a permeability which is unaffected by the pH conditions prevailing in the digestive tract, to a weight gain sufficient to obtain a controlled release of said active agent when measured by the USP Paddle or Baslcet Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C. from about 0% 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 greater than about 55% (by wt) active agent released after 6 hours, said coated substrate when subjected to accelerated storage conditions of at least one month at 40° 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 15% of the total amount of therapeutically active agent released when compared to in-vitro dissolution conducted prior to storage, and when administered orally providing effective blood levels of said systemically active therapeutic agent for at least about 12 hours.
- 43. The formulation of claim 42, wherein said water-insoluble acrylic polymer further comprises a permeability-enhancing compound.
- 44. The formulation of claim 43, wherein said permeability-enhancing compound is a monoethylenically unsaturated quaternary ammonium compound capable of free-radical polymerization.
- 45. The formulation of claim-42, 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.
- 46. The formulation of claim 42, wherein said water-insoluble acrylic polymer comprises a mixture of copolymers of acrylic and methacrylic esters having a molar ratio of ammonium groups to (meth)acrylic esters from about 1:20 to about 1:40.
- 47. The formulation of claim 42, which provides a stable dissolution of said active agent which is unchanged after exposure to accelerated storage conditions of a temperature of 40° C. and a relative humidity of 75% for 3 months.
- 48. The formulation of claim 45, wherein said active agent is an opioid analgesic selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, hydrocodone, tramadol, dihydromorphine, buprenorphine, mixed opiate receptor agonist-antagonists, salts, hydrates and solvents of any of the foregoing, and mixtures of any of the foregoing.
- 49. The formulation of claim 42, 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 said capsule is orally administered.
- 50. The formulation of claim 42, wherein said aqueous dispersion further comprises a pore-former which is dissolved, extracted, or leached from the coating when exposed to aqueous solutions.
- 51. The formulation of claim 48, wherein a portion of the amount of said active agent included in said formulation is incorporated into a coating on said substrate.
- 52. A solid controlled release oral dosage formulation, comprising a substrate containing a systemically active therapeutic agent in an amount sufficient to provide a desired therapeutic effect when said formulation is orally administered, said substrate being coated with an aqueous dispersion of a plasticized copolymer of acrylic and methacrylic acid esters having a permeability which is unaffected by the pH conditions prevailing in the digestive tract, to a weight gain sufficient to obtain a controlled release of said active agent when measured by the USP Paddle or Basket Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C. from about 0% to about 42.5% (by wt) active agent released after 1 hour, from about 5% to about 60% (by wt) active agent released after 2 hours, from about 15% to about 75% (by wt) active agent released after 4 hours and from about 20% to about 90% (by wt) active agent released after 8 hours, said coated substrate when subjected to accelerated storage conditions of at least one month at 40° 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 15% of the total amount of therapeutically active agent released when compared to in-vitro dissolution conducted prior to storage, and when administered orally providing effective blood levels of said systemically active therapeutic agent for about 24 hours.
- 53. The formulation of claim 52, wherein said water-insoluble acrylic polymer further comprises a permeability-enhancing compound.
- 54. The formulation of claim 53, wherein said permeability-enhancing compound is a monoethylenically unsaturated quaternary ammonium compound capable of free-radical polymerization.
- 55. The formulation of claim 52, 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.
- 56. The formulation of claim 52, wherein said water-insoluble acrylic polymer comprises a mixture of copolymers of acrylic and methacrylic esters having a molar ratio of ammonium groups to (meth)acrylic esters from about 1:20 to about 1:40.
- 57. The formulation of claim 52, which provides a stable dissolution of said active agent which is unchanged after exposure to accelerated storage conditions of a temperature of 40° C. and a relative humidity of 75% for 3 months.
- 58. The formulation of claim 55, wherein said agent is an opioid analgesic selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, hydrocodone, tramadol, dihydromorphine, buprenorphine, mixed opiate receptor agonist-antagonists, salts, hydrates and solvents of any of the foregoing, and mixtures of any of the foregoing.
- 59. The formulation of claim 52, 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 dose when said capsule is orally administered.
- 60. The formulation of claim 52, wherein said aqueous dispersion further comprises a pore-former which is dissolved, extracted, or leached from the coating when exposed to aqueous solutions.
- 61. The formulation of claim 52, wherein a portion of the amount of said active agent included in said formulation is incorporated into a coating on said substrate.
- 62. A controlled release dosage form, comprising a solid substrate comprising a therapeutically active agent, said solid substrate being coated with an aqueous dispersion of (i) a plasticized water-insoluble acrylic polymer comprised of monomers selected from the group consisting of an ester of acrylic acid, an ester of methacrylic acid, an alkyl ester of acrylic acid, an alkyl ester of methacrylic acid, and mixtures of any of the foregoing, and (ii) a further material selected from the group consisting of a polymerizable permeability-enhancing agent, a water-soluble acrylic polymer, a pore-former, and mixtures of any of the foregoing, said coating being applied to said substrate 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 in-vitro dissolution after exposure to accelerated storage conditions of at least one month at 40° 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 15% of the total amount of therapeutically active agent released when compared to in-vitro dissolution of said coated substrate prior to storage.
- 63. The controlled release dosage form of claim 62 which is administered once a day.
- 64. The controlled release dosage form of claim 62 which is administered twice a day.
- 65. The formulation of claim 62, 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 dose when said capsule is orally administered.
- 66. The formulation of claim 62, wherein said substrate is a coated tablet.
- 67. The formulation of claim 62, wherein said therapeutically active agent is an opioid analgesic selected from the group consisting of hydromorphone, oxycodone, morphine, levorphanol, methadone, meperidine, heroin, dihydrocodeine, codeine, hydrocodone, tramadol, dihydromorphine, buprenorphine, mixed opiate receptor agonist-antagonists, salts, hydrates and solvents of any of the foregoing, and mixtures of any of the foregoing.
- 68. The formulation of claim 62, wherein said coated substrate, when subjected to in-vitro dissolution after exposure to accelerated storage conditions of at least one month at 40° 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 10% of the total amount of therapeutically active agent released when compared to in-vitro dissolution of said coated substrate prior to storage.
- 69. The formulation of claim 62, wherein said coated substrate, when subjected to in-vitro dissolution after exposure to accelerated storage conditions of at least one month at 40° 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 7% of the total amount of therapeutically active agent released when compared to in-vitro dissolution of said coated substrate prior to storage.
- 70. A controlled release dosage form, comprising
a solid substrate comprising a therapeutically active agent, a controlled release coating covering said solid substrate, said coating comprising an aqueous dispersion of (i) a plasticized water-insoluble acrylic polymer comprised of monomers selected from the group consisting of an ester of acrylic acid, an ester of methacrylic acid, an alkyl ester of acrylic acid, an alkyl ester of methacrylic acid, and mixtures of any of the foregoing, and (ii) a further material selected from the group consisting of a polymerizable permeability-enhancing agent, a water-soluble acrylic polymer, a pore-former, and mixtures of any of the foregoing, 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 40° C./75% RH to the dissolution profile prior to exposure of said coated substrate to said accelerated conditions, which is not wider than about 15% of total active agent released at any point of time during said dissolution.
- 71. The formulation of claim 70, which provides effective blood levels of said therapeutically active agent when administered orally for about 24 hours.
- 72. The formulation of claim 70, which provides effective blood levels of said therapeutically active therapeutic agent when administered orally for about 12 hours.
- 73. A solid controlled release formulation, comprising a substrate containing an active agent in an amount sufficient to provide a desired effect in an environment of use, said substrate coated with an aqueous dispersion of a plasticized water-insoluble acrylic polymer comprised of monomers selected from the group consisting of an ester of acrylic acid, an ester of methacrylic acid, an alkyl ester of acrylic acid, an alkyl ester of methacrylic acid, and mixtures of any of the foregoing, 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 including at least one passageway through said coating through which said active agent is released, said coated substrate being cured at a temperature greater than the glass transition temperature of the plasticized aqueous dispersion 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 15% of the total amount of active agent released, when compared to the in-vitro dissolution of said coated substrate prior to curing.
- 74. A method of treating a human patient, comprising orally administering the oral solid dosage form of claim 8.
- 75. A method of treating a human patient, comprising orally administering the oral solid dosage form of claim 35.
- 76. A method of treating a human patient, comprising orally administering the oral solid dosage form of claim 42.
- 77. A method of treating a human patient, comprising orally administering the oral solid dosage form of claim 52.
- 78. A method of treating a human patient, comprising orally administering the oral solid dosage form of claim 62.
- 79. A method of treating a human patient, comprising orally administering the oral solid dosage form of claim 70.
- 80. A method of treating a human patient, comprising orally administering the oral solid dosage form of claim 73.
- 81. 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 a plasticized water-insoluble copolymer of acrylic and methacrylic acid esters having a permeability which is unaffected by the pH conditions prevailing in the digestive tract, 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 plasticized aqueous dispersion 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° 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.
- 82. The method of claim 81, wherein said permeability enhancing material is a monoethylenically unsaturated quaternary ammonium compound capable of free-radical polymerization.
- 83. The method of claim 81, 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.
- 84. The method of claim 81, further comprising preparing said substrate for oral administration by incorporating said therapeutically active agent into a tablet.
- 85. The method of claim 81, 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.
- 86. The method of claim 81, 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 81, wherein said water-insoluble acrylic polymer further comprises a permeability-enhancing compound.
- 88. The method of claim 87, wherein said permeability-enhancing compound is a monoethylenically unsaturated quaternary ammonium compound capable of free-radical polymerization.
- 89. The method of claim 81, wherein said water-insoluble acrylic polymer comprises a mixture of copolymers of acrylic and methacrylic esters having a molar ratio of ammonium groups to (meth)acrylic esters from about 1:20 to about 1:40.
- 90. The method of claim 81, wherein said coated substrate upon in-vitro dissolution testing provides a band range, when comparing the dissolution profile after exposure to accelerated storage conditions of at least one month at 40° C./75% RH to the dissolution profile prior to exposure of said coated substrate to said accelerated conditions, which is not wider than about 15% of total active agent released at any point of time during said dissolution.
- 91. The method of claim 90, wherein the band range does not differ by more than about 10%.
- 92. The method of claim 81, 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.
- 93. The method of claim 81 which is a coated tablet.
- 94. A controlled release dosage form, comprising
a solid substrate comprising an effective amount of a therapeutically active agent, said solid substrate coated with an aqueous dispersion of a copolymer of acrylic and methacrylic acid esters having a low content of quaternary ammonium groups, 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 in-vitro dissolution after exposure to accelerated storage conditions of at least one month at 40° 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 15% of the total amount of therapeutically active agent released when compared to in-vitro dissolution conducted prior to storage.
- 95. The controlled release dosage form of claim 94 which is administered once a day.
- 96. The controlled release dosage form of claim 94 which is administered twice a day.
- 97. The controlled release dosage form of claim 94 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.
- 98. The controlled release dosage form of claim 94 which is a coated tablet.
- 99. The controlled release dosage form of claim 94, 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.
- 100. 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 (i) a plasticized water-insoluble acrylic polymer comprised of monomers selected from the group consisting of an ester of acrylic acid, an ester of methacrylic acid, an alkyl ester of acrylic acid, an alkyl ester of methacrylic acid, and mixtures of any of the foregoing, and (ii) a further material selected from the group consisting of a polymerizable permeability-enhancing agent, a water-soluble acrylic polymer, a pore-former, and mixtures of any of the foregoing, 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 water-insoluble acrylic polymer until a curing endpoint is reached at which said coated substrate upon exposure to an environmental fluid provides a band range, when comparing the dissolution profile after exposure to accelerated storage conditions of at least one month at 40° C./75% RH to the dissolution profile prior to exposure of said coated substrate to said accelerated conditions, which is not wider than about 15% of total active agent released at any point of time during said dissolution.
- 101. The method of claim 100, wherein said controlled release formulation is an oral solid dosage form, further comprising preparing said substrate for oral administration by coating said 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.
- 102. The method of claim 100 wherein said controlled release formulation is an oral solid dosage form, further comprising preparing said substrate for oral administration by incorporating said therapeutically active agent into a tablet.
Parent Case Info
[0001] This application is a continuation-in-part of U.S. application Ser. No. 07/826,084 filed Jan. 27, 1992.
Divisions (2)
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Number |
Date |
Country |
Parent |
08459110 |
Jun 1995 |
US |
Child |
08816023 |
Mar 1997 |
US |
Parent |
08097558 |
Jul 1993 |
US |
Child |
08459110 |
Jun 1995 |
US |
Continuations (2)
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Number |
Date |
Country |
Parent |
09707276 |
Nov 2000 |
US |
Child |
10273434 |
Oct 2002 |
US |
Parent |
08816023 |
Mar 1997 |
US |
Child |
09707276 |
Nov 2000 |
US |
Continuation in Parts (1)
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Number |
Date |
Country |
Parent |
07826084 |
Jan 1992 |
US |
Child |
08097558 |
Jul 1993 |
US |