FORMULATIONS AND METHODS FOR THE CONTROLLED RELEASE OF ACTIVE DRUG SUBSTANCES

• US 20110159100A1
• Filed: 06/24/2010
• Published: 06/30/2011
• Est. Priority Date: 06/24/2009
• Status: Active Grant

• Current Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Original Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Inventors: Haahr, Anne-Mette, Lindhardt, Karsten, Lyhne-Iversen, Louise Inoka, Oevergaard, Martin, Andersen, Christine, Hoeyrup Hemmingsen, Pernille Kristine, Olsen, Martin Rex
• Granted Patent: US 8,563,038 B2
• Time in Patent Office: Days
• US Class Current: 424/486
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

Controlled release formulations and methods for preparing controlled release formulations for delivery of active drug substances are described herein. The formulations described herein may be employed to produce pharmaceutical compositions, such as controlled release dosage forms, adjusted to a specific administration scheme.

Claims

1-58. -58. (canceled)

59. A pharmaceutical composition comprising:

a) a matrix composition having a cylindrical shape with two ends, wherein each of the two ends is optionally tapered, the length of said matrix is in the range of 7.5 to 15 mm, and the matrix composition comprises (i) an active drug substance and (ii) at least one polyglycol; and

b) a coating substantially surrounding the matrix composition and having one or two openings exposing at least one surface of said matrix composition, said coating being substantially impermeable to an aqueous medium, wherein pharmaceutical said composition is formulated for continued administration of said active drug substance over an interval of about 20 to 28 hours.

60. The pharmaceutical composition according to claim 59, wherein the area of the cross section of said matrix is in the range of 1 to 75 mm².

61. The pharmaceutical composition according to claim 59, wherein the area of the cross section of said matrix is at least 20 mm²

62. The pharmaceutical composition according to claim 59, wherein the length of said matrix is in the range of 8 to 15 mm, preferably in the range of 8 to 10 mm, more preferably in the range of 9 to 9.5 mm.

63. The pharmaceutical composition according to claim 59, wherein the length of said matrix is in the range of 7.5 to 12 mm, preferably in the range of 7.5 to 10 mm, more preferably in the range of 7.5 to 8 mm.

64. The pharmaceutical composition according to claim 59, wherein the coating comprises two openings each exposing one end of the matrix.

65. The pharmaceutical composition according to claim 59, wherein a therapeutically effective response is achieved over the entire interval between administrations.

66. The composition according to claim 59, wherein steady state trough is at least 20%, such as at least 30%, such as at least 40%, for example at least 50% of steady state C_max.

67. The composition according to claim 59, wherein steady state trough is in the range of 30 to 80%, preferably in the range of 40 to 80% of steady state C_max.

68. The composition according to claim 59, wherein C_min is reached no earlier than 12 hours, preferably no earlier than 18 hours after last administration.

69. The composition according to claim 59, wherein the 2^nd point where a concentration of 50% of steady state C_max is reached is at least 4 hours, preferably at least hours after last administration.

70. The composition according to claim 59, wherein the 1^st point where a concentration of 50% of steady state C_max is reached is in the range of 0.5 to 2.5 hours after last administration.

71. The composition according to claim 59, wherein MRT is at least 11 hours, preferably at least 15 hours.

72. The composition according to claim 59, wherein T_max is in the range of 3 to 6 hours, preferably in the range of 4 to 6 hours after last administration to a steady state individual.

73. The composition according to claim 59, wherein the protraction index is at least 0.20, preferably at least 0.30.

74. The composition according to claim 59, wherein the active drug substance is an analgesic.

75. The composition according to claim 74, wherein the composition is for treatment of pain in an individual in need thereof.

78. The composition according to claim 74, wherein the composition is formulated for continued administration within the range of 20 to 28 hours interval between individual administrations and wherein pain relief is achieved over the entire interval between administrations.

79. The composition according to claim 74, wherein the analgesic is an opioid, which may be a naturally occurring, a synthetic or a semisynthetic opioid.

80. The composition according to claim 74, wherein the analgesic is selected from the group consisting of morphine, oxycodone, hydrocodone, hydromorphone, norhydrocodone oxymorphone, noroxycodone, morphine-6-glucuronode and pharmaceutically acceptable salts of any of the aforementioned.

81. The composition according to claim 75, wherein said pain is chronic pain.

82. The composition according to claim 75, wherein said pain is moderate to severe.

83. The composition according to claim 75, wherein said individual is an individual suffering from cancer.

84. The composition according to claim 75, wherein said individual is an individual suffering from a severe injury.

85. The composition according to claim 75, wherein said individual is a post-surgical individual.

87. The composition according to claim 59, wherein the polyglycol is a water soluble crystalline or semi-crystalline polymer.

88. The composition according to claim 59, wherein at least one polyglycol is a homopolymer.

89. The composition according to claim 59, wherein at least one polyglycol is a copolymer.

90. The composition according to claim 59, wherein the total concentration of the at least one polyglycol included in the matrix composition is from 5 to 99% w/w such as from 15 to 95% w/w, for example from 30 to 90% w/w, such as from 30 to 85% w/w, for example from 30 to 80% w/w, such as from 40 to 80% w/w, for example from 45 to 75% w/w, such as from 40 to 50% w/w, for example from 45 to 50% w/w, such as from 60 to 85% w/w, for example from 60 to 80% w/w, for example from 70 to 75% w/w.

91. The composition according to claim 88, wherein at least one polyglycol is a polyethylene glycol and/or a polyethylene oxide.

92. The composition according to claim 89, wherein the polyethylene glycol and/or polyethylene oxide has a molecular weight of in the range of 20,000 to 700,000 daltons, such as in the range of 20,000 to 600,000 daltons, for example in the range of 35,000 to 500,000 daltons, such as in the range of 35,000 to 400,000 daltons, for example in the range off 35,000 to 300,000 daltons, such as in the range of 50,000 to 300,000 daltons, for example about 200,000 daltons, such as about 300,000 daltons.

93. The composition according to claim 89, wherein the matrix comprises at least two different polyglycols, wherein said different polyglycols are selected from the group consisting of polyethylene oxides.

94. The composition according to claim 91, wherein one PEO has an average molecular weight in the range of 150,000 to 250,000 daltons, preferably approximately 200,000 daltons and the other PEO has an average molecular weight in the range of 250,000 to 350,000 daltons, preferably approximately 300,000 daltons.

95. The composition according to claim 88, wherein the concentration of homopolymer in the matrix composition is in the range of 5 to 90% w/w, such as in the range of 20 to 85% w/w, for example in the range of 20 to 75% w/w, such as in the range of 20 to 70% w/w for example in the range of 20 to 40% w/w, such as in the range of 30 to 85% w/w, for example in the range of about 30 to 75% w/w, such as in the range of 30 to 50% w/w, for example in the range of 30 to 40% w/w, such as in the range of 30 to 35% w/w, such as in the range of 31 to about 33% w/w, such as in the range of 50 to 85% w/w, from 60 to 80% w/w, for example in the range of 70 to 80% w/w, for example in the range of 70 to 75% w/w, such as in the range of 71 to about 73% w/w.

96. The composition according to claim 84, wherein the copolymer is a poloxamer that has an average molecular weight in the range of 2,000 to 30,000 daltons, such as in the range of 2,000 daltons to 20,000 daltons, for example in the range of 4,000 daltons to 18,000 daltons, such as in the range of 6,000 daltons to 10,000 daltons.

97. The composition according to claim 89, wherein the matrix comprises one or more copolymers selected from the group consisting of poloxamers.

98. The composition according to claim 97, wherein the matrix comprises only one poloxamer and has a length of in a range selected from a range of 7.5 to 15 mm and a range of 7.5 to 10 mm.

99. The composition according to claim 89, wherein the concentration of co-polymer in the matrix composition is in the range of 0 to 30% w/w, such as in the range of 1 to 20% w/w, for example in the range of 2 to 10% w/w, such as in the range of 2 to 5%, w/w, such as in the range of 5 to 30% w/w, for example in the range of 5 to 20% w/w, such as in the range of 5 to 15.

100. The composition according to claim 59, wherein the coating is insoluble in an aqueous medium.

101. The compositions according to claim 59, wherein the coating comprises one or more polymers selected from the group consisting of starch based polymers, cellulose based polymers, synthetic polymers and biodegradable polymers.

102. The composition according to claim 59, wherein the coating comprises one or more polymers selected from the group consisting of ethyl cellulose grade 20, ethyl cellulose grade 100, polylactic acid (PLA), Cornpack 200, polycaprolactone, PEO 7000000 and polyhydroxybuturate.

103. The composition according to claim 59, wherein the coating comprises an ethyl cellulose selected from an ethyl cellulose of grade 20 and an ethyl cellulose of grade 100.

104. The composition according to claim 59, wherein the coating comprises one or more biodegradable polymers, selected from the group consisting of polylactic acid and polycaprolactone.

105. The composition according to claim 59, wherein the coating comprises at least 85% polymers, wherein the polymer are selected from the group consisting of biodegradable polymers and cellulose based polymers.

106. The composition according to claim 59, wherein the coating in addition comprises one or more plasticizers.

107. The composition according to claim 59, wherein the composition is designed for oral administration.

108. The composition according to claim 59, wherein the composition is in the form of tablets.

109. The composition according to claim 59, wherein the pharmaceutical composition is an injection moulded or extruded composition.

110. The composition according to claim 59, wherein the composition is compressed.

111. The composition according to claim 59, wherein the matrix composition has a solubility and/or release rate in ethanol that is equal to or lower than that in water.

112. The composition according to claim 59, wherein the composition is resistant to isolation of the active drug substance by crushing, melting and ethanol extraction.

113. The pharmaceutical composition claim 59, wherein the active drug substance is essentially not subject to entero-hepatic recirculation and the length of said matrix is in the range of 8 to 15 mm, preferably in the range of 8 to 10 mm, more preferably in the range of 9 to 9.5 mm.

114. The pharmaceutical composition according to claim 59, wherein the active drug substance is subject to entero-hepatic recirculation and the length of said matrix is in the range of 7.5 to 12 mm, preferably in the range of 7.5 to 10 mm, more preferably in the range of 7.5 to 8 mm.

115. A method of treating a clinical condition in an individual in need thereof, said method comprising administering the pharmaceutical composition according to claim 59 to an individual in need thereof.

116. The method according to claim 115, wherein said clinical condition is pain.

117. Use of the composition according to claim 59 for the preparation of a medicament for treatment of a clinical condition in an individual in need thereof.

118. Use according to claim 117, wherein said clinical condition is pain.

86. The composition according to claim 77, wherein each dosage of the active drug substance is in the range of 10 to 500 mg of said active drug substance.