MORPHINE CONTROLLED RELEASE SYSTEM

• US 20160361269A1
• Filed: 05/09/2016
• Published: 12/15/2016
• Est. Priority Date: 03/26/2003
• Status: Active Grant

• Current Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Original Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Inventors: Fischer, Gina, Bar-Shalom, Daniel, Slot, Lillian, Andersen, Christine
• Granted Patent: US 9,884,029 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61K 9/70 Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug hollow drug-filled fibres A61K9/0092
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids

Abstract

A composition for controlled release of an opioid from a pharmaceutical composition, the method comprises controlling the release of at least one opioid into an aqueous medium by erosion of at least one surface of a pharmaceutical composition comprising I) a matrix composition comprising a) polymer or a mixture of polymers, b) an opioid and, optionally, c) one or more pharmaceutically acceptable excipients, and (i) a coating. The matrix composition has a conus-like shape so the surface area exposed to the aqueous medium increases at least during initial erosion of the matrix composition, and the dissolution of the opioid—when tested in a Dissolution Test as described herein with or without application of sinkers—results in a zero order release of at least 80% of the opioid contained in the composition. Such compositions are especially suitable for controlled release of an opioid to obtain a delayed pead concentration and a prolonged therapeutically effective plasma concentration upon oral administration. Once or twice daily administration is possible. The matrix typically comprises PEO and the active substance is typically an opioid such as morphine or a glucuronide thereof.

Claims

1-69. -69. (canceled)

70. An oral pharmaceutical composition for controlled release of at least one opioid, comprising:

an erodible matrix composition comprising a mixture of (a) a polymer or a mixture of polymers comprising a polyethylene glycol, a polyethylene oxide and/or a block copolymer of ethylene oxide and propylene oxide, (b) an opioid, and optionally, (c) one or more pharmaceutically acceptable excipients, wherein the erodible matrix composition does not comprise polyethylene glycol 2000 monostearate or polyethylene glycol 400 monostearate; and

a single coating on the erodible matrix having two openings exposing at least one surface of the matrix, wherein the coating is substantially insoluble in and impermeable to aqueous media and comprises one or more polymers selected from the group consisting of ethylcellulose, cellulose acetate, polyamide, polyethylene, polyethylene terephthalate, polypropylene, polyurethane, polyvinyl acetate, polyvinyl chloride, silicone rubber, latex, polyhydroxybutyrate, polyhydroxyvalerate, teflon, polylactic acid or polyglycolic acid and copolymers thereof, ethylene vinyl acetate (EVA), styrene-butadienestyrene (SBS) and styrene-isoprene-styrene (SIS),

wherein the composition exhibits controlled release of the opioid by erosion of the matrix and exhibits a zero order release profile wherein about 75% w/w of the opioid is released from the composition within 4-10 hours when tested in a Dissolution Test in accordance with USP 24, NF 19, (711), Dissolution, apparatus 2, equipped with a paddle, with or without sinkers.

71. The composition of claim 70, wherein the molecular weight of the polyethylene glycol, polyethylene oxide and/or block copolymer in the matrix composition is from about 20,000 daltons to about 700,000 daltons.

72. The composition of claim 70, wherein the average molecular weight of the polyethylene glycol, polyethylene oxide and/or block copolymer in the matrix composition is selected from the group consisting of about 100,000 daltons, about 150,000 daltons, about 200,000 daltons, about 250,000 daltons, about 300,000 daltons and about 400,000 daltons.

73. The composition of claim 70, wherein the matrix composition comprises at least two polyethylene oxide polymer(s) having different molecular weights, wherein the average molecular weight of the polyethylene oxide polymers in the matrix composition is from about 100,000 daltons to about 400,000 daltons.

74. The composition of claim 70, wherein the matrix composition comprises at least one of polyethylene oxide 200,000 NF and/or polyethylene oxide 200,000 LF.

75. The composition of claim 70, wherein the matrix composition further comprises a block copolymer of ethylene oxide and propylene oxide having a molecular weight of from about 3,000 to about 30,000 daltons.

76. The composition of claim 70, wherein the matrix composition further comprises a poloxamer.

77. The composition of claim 70, wherein the matrix composition further comprises an antioxidant selected from the group consisting of TPG, TPGS, BHA, BHT, t-butyl hydroquinone, calcium ascorbate, gallic acid, hydroquinone, maltol, octyl gallate, sodium bisulfate, sodium metabisulfite, tocopherol, citric acid, tartaric acid, and ascorbic acid.

78. The composition of claim 70, wherein the matrix composition further comprises BHT.

79. The composition of claim 70, wherein the matrix composition further comprises a cellulose derivative selected from the group consisting of microcrystalline cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose.

80. The composition of claim 70, wherein the matrix composition further comprises hydroxypropylmethylcellulose.

81. The composition of claim 70, wherein the matrix composition further comprises a release modifier selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and methacrylic acid copolymers.

82. The composition of claim 70, wherein the matrix composition further comprises a release modifier selected from the group consisting of methacrylic acid copolymers.

83. The composition of claim 70, wherein the matrix composition further comprises a pharmaceutically acceptable excipient selected from the group consisting of mannitol, xylitol, sorbitol and inositol.

84. The composition of claim 70, wherein the opioid is one or more selected from the group consisting of alfentanil, allylprodine, alphaprodine, aniloridine, benzylmorphine, bezitramide, buprenorphine, butophanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diapromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimephetanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, dextropropoxyphene, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, morphine 6-glucuronide, morphine 3-glucuronide, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, and pharmaceutically acceptable salts, complexes, solvates or anhydrates thereof, and mixtures thereof.

85. The composition of claim 70, wherein the opioid is one or more selected from the group consisting of morphine, oxycodone, oxymorphone, hydrocodone, hydromorphone, dihydromorphine, and pharmaceutically acceptable salts, complexes, solvates or anhydrates thereof, and mixtures thereof.

86. The composition of claim 70, wherein the opioid is one or more selected from the group consisting of oxycodone, and pharmaceutically acceptable salts, complexes, solvates or anhydrates thereof and mixtures thereof.

87. The composition of claim 70, wherein the opioid is one or more selected from the group consisting of hydrocodone, and pharmaceutically acceptable salts, complexes, solvates or anhydrates thereof and mixtures thereof.

88. The composition of claim 70, wherein the opioid is one or more selected from the group consisting of morphine, morphine 6-glucuronide, morphine 3-glucuronide, and pharmaceutically acceptable salts, complexes, solvates or anhydrates thereof and mixtures thereof.

89. The composition of claim 70, wherein the matrix composition comprises from about 10 to about 60% w/w/of the opioid.

90. The composition of claim 70, wherein, in the aqueous medium in which the composition is to be used, the coating does not completely crumble or erode before the matrix has completely eroded.

91. The composition of claim 70, wherein, the coating comprises polylactic acid.

92. The composition of claim 70, wherein, the plasticizer of the coating comprises polyethylene oxide.

93. The composition of claim 70, formulated for once daily administration.

94. The composition of claim 70, formulated for twice daily administration.

95. The composition of claim 70, wherein the composition is prepared by injection molding the matrix inside the coating.

96. The composition of claim 70, wherein the coating and the matrix are each prepared by separate injection molding processes.

97. The composition of claim 70, wherein the composition achieves a mean plasma concentration 8 hours after oral administration that is at least 40% of the mean maximal concentration (C_max).

98. The composition of claim 70, wherein the composition achieves a mean plasma concentration 10 hours after oral administration that is at least 35% of the mean maximal concentration (C_max).

99. The composition of claim 70, wherein the composition achieves a mean plasma concentration 12 hours after oral administration that is at least 25% of the mean maximal concentration (C_max).

100. The composition of claim 70, wherein the composition achieves a mean plasma concentration after oral administration of a single dose that is at least 35% of the mean maximal concentration over at least 15 hours.

101. The composition of claim 70, wherein the composition achieves a mean plasma concentration after oral administration of a single dose that is at least 50% of the mean maximal concentration over at least 6 hours.

102. The composition of claim 70, wherein the composition achieves a mean plasma concentration after oral administration of a single dose that is at least 75% of the mean maximal concentration over at least 3 hours.

103. The composition of claim 70, wherein the composition achieves a mean plasma concentration 12 hours after oral administration of a single dose that is at least 20% of the mean maximal concentration (C_max), a mean plasma concentration 18 hours after oral administration that is at least 20% of the mean maximal concentration, and a mean plasma concentration 24 hours after oral administration that is at least 20% of the mean maximal concentration.