Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level

• US 20030035837A1
• Filed: 06/04/2002
• Published: 02/20/2003
• Est. Priority Date: 11/23/1993
• Status: Abandoned Application

• Current Assignee: Paul Goldenheim, Richard S. Sackler, Robert F. Kaiko
• Original Assignee: Paul Goldenheim, Richard S. Sackler, Robert F. Kaiko
• Inventors: Kaiko, Robert F., Sackler, Richard S., Goldenheim, Paul
• Application Number:
  US10/162,132
• Publication Number:
  US 20030035837A1
• Time in Patent Office: Days
• US Class Current: 424/468
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61K 9/5078 with drug-free core
• 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

Patients are treated with 24-hour oral sustained release opioid formulations which, upon administration, provide an initially rapid opioid absorption such that the minimum effective analgesic concentration of the opioid is more quickly achieved. These sustained release opioid formulations include an effective amount of at least one retardant material to cause said opioid analgesic to be released at a such a rate as to provide an analgesic effect after oral administration to a human patient for at least about 24 hours, and are characterized by providing an absorption half-life from 1 to about 8 hours. A method of titrating a human patient utilizing these sustained release opioid formulations is also disclosed.

Claims

1. An oral sustained release opioid formulation comprising:

an opioid analgesic,

an effective amount of at least one retardant material to cause said opioid analgesic to be released at an effective rate to provide an analgesic effect after oral administration to a human patient for at least about 24 hours, said formulation when administered in humans providing an initially rapid rate of rise in the plasma concentration of said opioid characterized by providing an absorption half-life from 1 to about 8 hours in the fasted state.

2. The sustained release formulation of claim 1, wherein said oral sustained release provides an absorption half-life from 1 to about 6 hours.

3. The sustained release formulation of claim 1, wherein said oral sustained release provides an absorption half-life from 1 to about 3 hours.

4. The sustained release formulation of claims 1-3, wherein said opioid analgesic is selected from the group consisting of hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, salts of any of the foregoing, and mixtures of any of the foregoing.

5. The sustained release formulation of claims 1-3, wherein said opioid analgesic is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, 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, metopon, morphine, 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, tramadol, tilidine, salts thereof and mixtures thereof.

6. The sustained release formulation of claims 1-3, wherein said opioid is morphine and the maximum plasma concentration of said opioid is from about 2 ng/ml to about 14 ng/ml, based on a 30 mg dose of morphine sulfate.

7. The sustained release formulation of claims 1-3, wherein said opioid is morphine and the maximum plasma concentration of said opioid is from about 3 ng/ml to about 8;

ng/ml, based on a 30 mg dose of morphine sulfate.

8. The sustained release formulation of claims 1-3, wherein said opioid analgesic consists of from about 2 mg to about 649 mg hydromorphone.

9. The sustained release formulation of claims 1-3, wherein said opioid analgesic consists of from about 5 mg to about 800 mg morphine.

10. The sustained release formulation of claims 1-3, wherein said opioid analgesic consists of from about 5 mg to about 400 mg oxycodone.

11. The sustained release formulation of claims 1-10, which provides a peak plasma level of said opioid in-vivo from about 2 to about 10 hours after administration.

12. The sustained release formulation of claims 1-11, wherein said retardant material is selected from the group consisting of an acrylic polymer, an alkylcellulose, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, and mixtures of any of the foregoing.

13. The sustained release formulation claims 1-12, which comprise a plurality of substrates including said opioid, each of said substrates having a diameter from about 0.5 mm to about 2 mm.

14. The sustained release formulation of claim 13, wherein said retardant material is coated on the surface of said substrates.

15. The sustained release formulation of claim 13, wherein said substrates comprise inert beads coated with said opioid analgesic, said subtrates further comprising an outer coating imparting sustained release properties to said formulation and comprising said retardant material.

16. The sustained release formulation of claim 13, wherein said substrates comprise matrices of a substantially uniform mixture of said opioid analgesic and said retardant material.

17. The sustained release formulations of claims 1-16, wherein a portion of the dose of said opioid is included in said formulation in immediate release form.

18. The sustained release formulations of claims 1-17, which provide a peak plasma level of said opioid in-vivo from about 2 to about 10 hours after administration.

19. A method for titrating human patients with a sustained release oral opioid formulation, comprising:

(1) administering to a human patient on a once-a-day basis a unit dose of an oral sustained release formulation comprising a dose of an opioid analgesic and an effective amount of at least one retardant material to cause said opioid to be released at an effective rate to provide an analgesic effect after oral administration to a human patient for at least about 24 hours, said formulation when administered in humans providing an initially rapid rate of rise in the plasma concentration of said opioid characterized by providing an absorption half-life from 1 to about 8 hours in the fasted state;

(2) monitoring pharmacokinetic and pharmacodynamic parameters elicited by said formulation in said human patient and determining whether said pharmacokinetic and/or pharmacodynamic parameters are appropriate to treat said patient on a repeated basis;

(3) titrating the patient by adjusting the dose of said opioid analgesic administered to the patient by administering a unit dose of said sustained release opioid analgesic formulation containing a different amount of opioid analgesic if it is determined that said pharmacokinetic and/or said pharmacodynamic parameters are not satisfactory or maintaining the dose of said opioid analgesic in said unit dose at a previously administered amount if said pharmacokinetic and/or pharmacodynamic parameters are deemed appropriate;

(4) continuing the step (3) titration by adjusting the dose of said opioid analgesic until appropriate steady-state pharmacokinetic/pharmacodynamic parameters are achieved in said patient; and

(5) continuing the administration of the dose of said opioid analgesic in said oral sustained release formulation on a once-a-day basis until treatment is terminated.

21. The method of claims 19-20, wherein said oral sustained release formulation provides an absorption half-life from 1 to about 6 hours.

22. The method of claims 19-20, wherein said oral sustained release formulation provides an absorption half-life from 1 to about 3 hours.

20. A method for preparing a oral sustained release opioid formulation for once-a-day administration which includes a dose of an opioid analgesic and an effective amount of at least one retardant material to cause said opioid to be released at an effective rate to provide an analgesic effect after oral administration to a human patient for at least about 24 hours, characterized in that said formulation is prepared to provide an initially rapid rate of rise in the plasma concentration of said opioid characterized by providing an absorption half-life from 1 to about 8 hours when administered to a patient in the fasted state.

23. A method of treating a patient with a bioavailable sustained-release opioid analgesic dosage form for once-a-day oral administration, comprising preparing a plurality of substrates comprising a unit dose of an opioid analgesic, each of said substrates having a diameter from about 0.1 mm to about 3 mm, said substrates being manufactured in a sustained release form to provide therapeutically effective blood levels of said opioid analgesic for about 24 hours or more, and administering said unit dose to a patient to alleviate moderate to severe pain for about 24 hours or more.

24. The method of claim 23, further comprising preparing said substrates in a form selected from the group consisting of spheroids, beads, microspheres, seeds, pellets, ion-exchange resin beads, granules, and mixtures thereof.

25. The method of claim 23, further comprising preparing said substrates by coating inert beads with said opioid analgesic, and thereafter overcoating with a hydrophobic material is selected from the group consisting of an acrylic polymer, an alkylcellulose, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, and mixtures of any of the foregoing.

26. The method of claim 23, further comprising preparing said substrates as matrices of a substantially uniform mixture of said opioid analgesic and a hydrophobic material.