Morphine controlled release system

• US 8,877,241 B2
• Filed: 03/26/2004
• Issued: 11/04/2014
• Est. Priority Date: 03/26/2003
• Status: Expired due to Fees

• Current Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Original Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Inventors: Fischer, Gina, Slot, Lillian, Andersen, Christine, Bar-Shalom, Daneil
• Primary Examiner(s): Sasan, Aradhana
• Application Number:
  US10/550,453
• Publication Number:
  US 20070003617A1
• Time in Patent Office: 3,875 Days
• Field of Search: 424/470, 424/468, 514/282
• US Class Current: 424/470
• 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 peak 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. A method for treating a patient suffering from pain that is sensitive to an opioid comprising orally administering such opioid in a controlled release pharmaceutical composition, comprising

an erodible matrix composition comprising a mixture of:

a) a polymer or a mixture of polymers,

b) an opioid, and optionally,

c) one or more pharmaceutically acceptable excipients,

wherein the erodible matrix composition comprises a polyethylene glycol, a polyethylene oxide and/or a block copolymer of ethylene oxide and propylene oxide, and does not comprise polyethylene glycol 2000 monostearate or polyethylene glycol 400 monostearate,

the matrix composition being provided with a single coating that is substantially insoluble in and impermeable to aqueous media, the coating comprising 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),

the coating having two openings and exposing at least one surface of the matrix, thereby allowing controlled release of said opioid by erosion of said matrix surface,

wherein the composition exhibits a zero order release profile and 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.

2. A method according to claim 1, wherein the amount of opioid on a daily basis sufficient to treat the pain in the patient is less than the amount of opioid sufficient to treat the pain to a similar degree by use of an immediate release composition.

3. A method according to claim 2, wherein the degree of pain treatment is measured by use of a 4 point verbal rating scale (VRSpi) where 0=none pain, 1=slight pain, 2=moderate pain, and 3=severe pain.

4. A method according to claim 1, wherein the mean plasma concentration 8 hours after oral administration is at least 40% of the mean maximal concentration obtained by the dose.

5. A method according to claim 1, wherein the mean plasma concentration 10 hours after oral administration is at least 35% of the mean maximal concentration obtained by the dose.

6. A method according to claim 1, wherein the mean plasma concentration 12 hours after oral administration is at least 25% of the mean maximal concentration obtained by the dose.

7. A method according to claim 1, wherein the mean plasma concentration after oral administration of a single dose is at least 33% of the mean maximal concentration over at least 15 hours.

8. A method according to claim 1, wherein the mean plasma concentration after oral administration of a single dose is at least 50% of the mean maximal concentration over at least 6 hours.

9. A method according to claim 1, wherein the mean plasma concentration after oral administration of a single dose is at least 75% of the mean maximal concentration over at least 3 hours.

10. A method according to claim 1, wherein the mean plasma concentration 12 hours after oral administration of a single dose is at least 20% of the mean maximal concentration, the mean plasma concentration 18 hours after oral administration is at least 20% of the mean maximal concentration, and the mean plasma concentration 24 hours after oral administration is at least 20% of the mean maximal concentration.

11. A method according to claim 1, wherein the method comprises administering the controlled release pharmaceutical composition once or twice daily.

12. A method according to claim 11, wherein the method comprises administering the controlled release pharmaceutical composition once daily.

13. A method according to claim 1, wherein the controlled release composition comprises 15 to 300 mg of morphine sulphate.

14. A method according to claim 1, wherein said pain is chronic pain.

15. The method according to claim 1, wherein the polyethylene glycol, polyethylene oxide or block copolymer has a molecular weight selected from the group consisting of about 20,000 daltons to about 700,000 daltons, about 20,000 to about 600,000 daltons, about 35,000 to about 500,000 daltons, about 35,000 to about 400,000 daltons, about 35,000 to about 300,000 daltons and about 50,000 to about 300,000 daltons.

16. The method according to claim 15, wherein the polyethylene glycol, polyethylene oxide or block copolymer has a molecular weight selected from the group consisting of about 35,000 daltons, about 50,000 daltons, about 75,000 daltons, 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.

17. A method according to claim 16, wherein the polyethylene oxide in the matrix composition has a molecular weight of at least 100,000 daltons.

18. A method according to claim 16, wherein the polyethylene oxide in the matrix composition has a molecular weight at most of 300,000 daltons.

19. A method according to claim 16, wherein the matrix composition comprises at least one of polyethylene oxide 200,000 NF and/or polyethylene oxide 200,000 LF.

20. The method according to claim 1, wherein the opioid is 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.