Melt-extrusion multiparticulates
First Claim
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1. A unit dose sustained-release oral dosage form comprising a plurality of melt extruded particles, each of said particles comprising:
- (a) an opioid analgesic selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacyl morphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metophon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, salts thereof and mixtures thereof;
(b) one or more retardants; and
(c) an optional water insoluble binder, said particles having a (length) size from about 0.1 mm to about 12 mm, said unit dose providing a release of said opioid analgesic over at least about 6 hours.
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Abstract
A unit dose sustained-release oral dosage form containing a plurality of melt-extruded particles, each consisting essentially of a therapeutically active agent, one or more retardants, and an optional water-insoluble binder is disclosed. The particles have a length of from about 0.1 to about 12 mm and can be of varying diameters and each unit dose provides a release of therapeutically active agents over at least about 8 hours. Methods of preparing the unit doses as well as extrusion processes and methods of treatment are also disclosed.
306 Citations
39 Claims
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1. A unit dose sustained-release oral dosage form comprising a plurality of melt extruded particles, each of said particles comprising:
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(a) an opioid analgesic selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacyl morphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metophon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, salts thereof and mixtures thereof;
(b) one or more retardants; and
(c) an optional water insoluble binder, said particles having a (length) size from about 0.1 mm to about 12 mm, said unit dose providing a release of said opioid analgesic over at least about 6 hours. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)
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14. A unit dose sustained-release oral dosage form comprising a plurality of melt extruded particles, each of said particles comprising:
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(a) an opioid analgesic;
(b) one or more retardants; and
(c) an optional water insoluble binder;
said particles having a (length) size from about 0.1 mm to about 12 mm, said unit dose providing a release of said opioid analgesic over at least about 6 hours.
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15. A method of preparing a multiparticulate sustained release oral dosage form, comprising:
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(a) mixing together a therapeutically active agent, a water-insoluble retardant, and an optional binder to obtain a homogeneous mixture, the ratio of said water insoluble retardant to said therapeutically active agent in said mixture being sufficient to impart a release of said therapeutically active agent from said particles over a time period of at least about 4 hours when said particle is exposed to an aqueous fluid;
(b) heating said homogenous mixture;
(c) extruding said homogenous mixture to thereby form strands;
(d) cooling said strands containing said homogeneous mixture; and
(e) cutting said strands into particles having a size from about 0.1 mm to about 12 mm; and
(f) dividing said particles into unit doses. - View Dependent Claims (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 32, 33, 34, 39)
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30. A method of treating a patient with a sustained release multiparticulate formulation of a therapeutically active agent, comprising:
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(a) mixing together a therapeutically active agent, a water-insoluble retardant, and an optional binder to obtain a homogeneous mixture, the ratio of said water insoluble retardant to said therapeutically active agent in said mixture being sufficient to impart a release of said therapeutically active agent from said particles over a time period of at least about 4 hours when said particle is exposed to an aqueous fluid;
(b) heating said homogenous mixture;
(c) extruding said homogenous mixture to thereby form strands;
(d) cooling said strands containing said homogeneous mixture; and
(e) cutting said strands into particles having a size from about 0.1 mm to about 12 mm;
(f) dividing said particles into unit doses; and
(g) administering said unit dose to a patient.
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31. A method of preparing a multiparticulate sustained release oral dosage form, comprising:
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(a) directly metering into an extruder a water-insoluble retardant, a therapeutically active agent, and an optional binder;
(b) heating said homogenous mixture;
(c) extruding said homogenous mixture to thereby form strands;
(d) cooling said strands containing said homogeneous mixture; and
(e) cutting said strands into particles having a size from about 0.1 mm to about 12 mm; and
(f) dividing said particles into unit doses.
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35. An opioid unit dose sustained-release oral dosage form having substantially no feeding-fasting effect, comprising a plurality of melt extruded particles, each of said particles comprising:
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(a) an opioid analgesic;
(b) one or more retardants; and
(c) an optional water insoluble binder;
said particles having a (length) size from about 0.1 mm to about 12 mm, said unit dose providing a release of said therapeutically active agent over at least about 12-24 hours. - View Dependent Claims (37)
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36. An opioid unit dose sustained-release oral dosage form having substantially no feeding-fasting effect, comprising a plurality of melt extruded particles, each of said particles comprising:
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(a) an opioid analgesic;
(b) one or more retardants; and
(c) an optional water insoluble binder;
said particles having a (length) size from about 0.1 mm to about 12 mm, said unit dose providing a release of said therapeutically active agent over at least about 6 hours. - View Dependent Claims (38)
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Specification