Extruded orally administrable opioid formulations
First Claim
Patent Images
1. A sustained-release pharmaceutical formulation comprising an extruded blend of a therapeutically active agent, one or more hydrophobic materials selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof;
- and one or more hydrophobic fusible carriers having a melting point from about 30°
to about 200°
C. and selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof, said extruded blend divided into a unit dose containing an effective amount of said therapeutically active agent to render a desired therapeutic effect and providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours, said extruded blend being formed by mixing the therapeutically active agent, the one or more hydrophobic materials, and the one or more hydrophobic fusible carriers in an extruder to form said blend and extending said blend through the extruder.
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Abstract
Bioavailable sustained release oral opioid analgesic dosage forms, comprising a plurality of multiparticulates produced via melt extrusion techniques are disclosed.
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Citations
69 Claims
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1. A sustained-release pharmaceutical formulation comprising an extruded blend of a therapeutically active agent, one or more hydrophobic materials selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof;
- and one or more hydrophobic fusible carriers having a melting point from about 30°
to about 200°
C. and selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof, said extruded blend divided into a unit dose containing an effective amount of said therapeutically active agent to render a desired therapeutic effect and providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours, said extruded blend being formed by mixing the therapeutically active agent, the one or more hydrophobic materials, and the one or more hydrophobic fusible carriers in an extruder to form said blend and extending said blend through the extruder. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 26, 28, 30, 31, 32, 62)
- and one or more hydrophobic fusible carriers having a melting point from about 30°
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17. A sustained-release pharmaceutical formulation comprising an extruded blend of oxycodone, one or more hydrophobic materials selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof;
- and one or more hydrophobic fusible carriers having a melting point from about 30°
to about 200°
C. and selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof, said extruded blend divided into a unit dose containing an effective amount of said therapeutically active agent to render a desired therapeutic effect and providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours, said extruded blend being formed by mixing the therapeutically active agent, the one or more hydrophobic materials, and the one or more hydrophobic fusible carriers in an extruder to form said blend and extruding said blend through the extruder, said formulation providing an in-vitro release when assessed 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 1 to about 42.5% oxycodone released after one hour, from about 5 to about 65% oxycodone released after 2 hours, from about 15 to about 85% oxycodone released after 4 hours, from about 20 to about 90% oxycodone released after 6 hours, from about 35 to about 95% oxycodone released after 12 hours, from about 45 to about 100% oxycodone released after 18 hours, and from about 55 to about 100% oxycodone released after 24 hours, by weight. - View Dependent Claims (25, 63, 64, 65, 66, 67, 68, 69)
- and one or more hydrophobic fusible carriers having a melting point from about 30°
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18. A method of preparing a sustained-release pharmaceutical extrudate suitable for oral administration, comprising:
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blending a therapeutically active agent together with (1) a hydrophobic material selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof and (2) a hydrophobic fusible carrier selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof, said retardant material having a melting point between 30-200°
C. and being included in an amount sufficient to further slow the release of the therapeutically active agent,heating said blend to a temperature sufficient to soften the mixture sufficiently to extrude the same; extruding said heated mixture as a strand having a diameter of from 0.1-3 mm; cooling said strand; and dividing said strand to form non-spheroidal multi-particulates of said extrudate having a length from 0.1-5 mm; and dividing said non-spheroidal multi-particulates into unit doses containing an effective amount of said therapeutically active agent, said unit dose providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours. - View Dependent Claims (19, 20, 21, 22)
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23. A sustained-release pharmaceutical formulation comprising an extruded blend of an opiod analgesic, one or more hydrophobic materials selected from the group consisting of alkylcellulose, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof;
- and one or more hydrophobic fusible carriers having a melting point from about 30°
to about 200°
C. and selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof, said extruded blend divided into a unit dose containing an effective amount of said therapeutically active agent to render a desired therapeutic effect and providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours, said extruded blend being formed by mixing the therapeutically active agent, the one or more hydrophobic materials, and the one or more hydrophobic fusible carriers in an extruder to form said blend and extruding said blend through the extruder. - View Dependent Claims (24, 27, 29)
- and one or more hydrophobic fusible carriers having a melting point from about 30°
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33. A sustained-release pharmaceutical formulation comprising an extruded blend of tramadol, one or more hydrophobic materials selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof;
- and one or more hydrophobic fusible carriers having a melting point from about 30°
to about 200°
C. and selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof, said extruded blend divided into a unit dose containing an effective amount of said therapeutically active agent to render a desired therapeutic effect and providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours, said extruded blend being formed by mixing the therapeutically active agent, the one or more hydrophobic materials, and the one or more hydrophobic fusible carriers in an extruder to form said blend and extruding said blend through the extruder, said formulation providing an in-vitro release when assessed 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 1 to about 42.5% tramadol released after one hour, from about 5 to about 65% tramadol released after 2 hours, from about 15 to about 85% tramadol released after 4 hours, from about 20 to about 90% tramadol released after 6 hours, from about 35 to about 95% tramadol released after 12 hours, from about 45 to about 100% tramadol released after 18 hours, and from about 55 to about 100% tramadol released after 24 hours, by weight. - View Dependent Claims (34, 35, 36, 37, 38, 39, 40)
- and one or more hydrophobic fusible carriers having a melting point from about 30°
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41. A sustained-release pharmaceutical formulation comprising an extruded blend of hydromorophone, one or more hydrophobic materials selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof;
- and one or more hydrophobic fusible carriers having a melting point from about 30°
to about 200°
C. and selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof, said extruded blend divided into a unit dose containing an effective amount of said therapeutically active agent to render a desired therapeutic effect and providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours, said extruded blend being formed by mixing the therapeutically active agent, the one or more hydrophobic materials, and the one or more hydrophobic fusible carriers in an extruder to form said blend and extruding said blend through the extruder, said formulation providing an in-vitro release when assessed 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 1 to about 42.5% hydromorphone released after one hour, from about 5 to about 65% hydromorphone released after 2 hours, from about 15 to about 85% hydromorphone released after 4 hours, from about 20 to about 90% hydromorphone released after 6 hours, from about 35 to about 95% hydromorphone released after 12 hours, from about 45 to about 100% hydromorphone released after 18 hours, and from about 55 to about 100% hydromorphone released after 24 hours, by weight. - View Dependent Claims (42, 43, 44, 45, 46, 47, 48, 49, 50)
- and one or more hydrophobic fusible carriers having a melting point from about 30°
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51. A sustained-release pharmaceutical formulation comprising an extruded blend of morphone, one or more hydrophobic materials selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof;
- and one or more hydrophobic fusible carriers having a melting point from about 30°
to about 200°
C. and selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof, said extruded blend divided into a unit dose containing an effective amount of said therapeutically active agent to render a desired therapeutic effect and providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours, said extruded blend being formed by mixing the therapeutically active agent, the one or more hydrophobic materials, and the one or more hydrophobic fusible carriers in an extruder to form said blend and extruding said blend through the extruder, said formulation providing an in-vitro release when assessed 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 1 to about 42.5% morphine released after one hour, from about 5 to about 65% morphine released after 2 hours, from about 15 to about 85% morphine released after 4 hours, from about 20 to about 90% morphine released after 6 hours, from about 35 to about 95% morphine released after 12 hours, from about 45 to about 100% morphine released after 18 hours, and from about 55 to about 100% morphine released after 24 hours, by weight. - View Dependent Claims (52, 53, 54, 55, 56, 57, 58, 59, 60, 61)
- and one or more hydrophobic fusible carriers having a melting point from about 30°
Specification