Pharmaceutical compositions containing indistinguishable drug components

• US 20040110781A1
• Filed: 12/05/2002
• Published: 06/10/2004
• Est. Priority Date: 12/05/2002
• Status: Abandoned Application

• Current Assignee: Aptalis Pharmatech Incorporated
• Original Assignee: Aptalis Pharmatech Incorporated
• Inventors: Venkatesh, Gopi M., Harmon, Troy M.
• Application Number:
  US10/310,357
• Publication Number:
  US 20040110781A1
• Time in Patent Office: Days
• US Class Current: 514/282
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077

Abstract

An oral pharmaceutical multi-particulate dosage form comprising at least two populations of particles, a first population of opioid agonist particles and a second population of opioid antagonist particles and a method for producing the dosage form are described. The opioid agonist particles provide an analgesically effective amount of opioid agonist and the opioid antagonist particles provide an amount of opioid antagonist effective to attenuate side effects associated with chronic dosing of the opioid agonist. The first population of opioid agonist particles and the second population of opioid antagonist particles are visually indistinguishable, thereby reducing the potential for drug abuse of the opioid agonist by separation of the two particle populations. In accordance with particular aspects of the invention, the opioid agonist particles and opioid antagonist particles are each provided with sustained release membrane coatings capable of releasing the opioid agonist and opioid antagonist at proportionate rates over a dosing interval. The dosing interval may be at least about 8 hours and preferably from about 12-24 hours. The dosage form in accordance with particular embodiments of the present invention may further comprise a non-opioid analgesic, preferably in the form of immediate release or sustained release particles.

Claims

1. An oral pharmaceutical multi-particulate dosage form comprising at least two populations of particles, a first population of opioid agonist particles and a second population of opioid antagonist particles wherein said opioid agonist particles provide an analgesically effective amount of opioid agonist and said opioid antagonist particles provide an amount of opioid antagonist effective to attenuate side effects associated with chronic dosing of said opioid agonist, said first population of opioid agonist particles and said second population of opioid antagonist particles being visually indistinguishable, thereby reducing the potential for drug abuse of said opioid agonist by separation of said opioid agonist from said opioid antagonist.

2. A dosage form as defined in claim 1 wherein said opioid agonist particles comprise a core comprising an opioid agonist and a sustained release membrane coating substantially surrounding said core;

said opioid antagonist particles comprise a core comprising an opioid antagonist and a sustained release membrane coating substantially surrounding said core;

said sustained release membrane providing for sustained drug release;

wherein the dosage form provides for release of the opioid agonist and opioid antagonist at proportionate rates over a dosing interval.

3. A dosage form as defined in claim 2, wherein said sustained release membrane coating comprises a water insoluble polymer, a combination of a water insoluble polymer and a water soluble polymer at a ratio of about 9:

1 to about 1;

1 or a combination of a water insoluble polymer and an enteric polymer wherein said membrane has a thickness of from about 1% to about 20% based on weight of the coated beads.

4. A dosage form as defined in claim 3 wherein said water insoluble polymer is selected from the group consisting of ethylcellulose, cellulose acetate, polymethylmethacrylate copolymers and mixtures thereof.

5. A dosage form as defined in claim 3 wherein said water soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinyl pyrrolidone.

6. A dosage form as defined in claim 3 wherein the enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate and mixtures thereof.

7. A dosage form as defined in claim 1 wherein said opioid agonist is selected from the group consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, salts thereof, and mixtures thereof.

8. A dosage form as defined in claim 1 wherein said opioid antagonist is selected from the group consisting of naloxone, naltrexone, etorphine, pharmaceutically acceptable salts thereof and mixtures thereof.

9. A dosage form as defined in claim 1 further comprising a non-opioid analgesic.

10. A dosage form as defined in claim 9 further comprising a third population of particles comprising said non-opioid analgesic.

11. A dosage form as defined in claim 10 wherein said non-opioid analgesic is selected from the group consisting of aspirin, acetaminophen, non-steroidal anti-inflammatory drugs (SAIDS), dextromethorphan, COX-II inhibitors and combinations thereof.

12. A dosage form as defined in claim 1 wherein said opioid agonist comprises morphine sulfate and said opioid antagonist comprises naltrexone hydrochloride.

13. A dosage form as defined in claim 1 wherein said opioid agonist comprises oxycodone hydrochloride and said opioid antagonist comprises naltrexone hydrochloride.

14. A dosage form as defined in claim 2 wherein said dosing interval is at least 12 hours.

15. A dosage form as defined in claim 2 wherein said agonist core comprises a non-pareil seed coated with said opioid agonist in a polymeric binder and said antagonist core comprises a non-pareil seed coated with said opioid antagonist in a polymeric binder.

16. A method of preparing a pharmaceutical multi-particulate dosage form comprising a first population of particles comprising an opioid agonist and a second population of particles comprising an opioid antagonist, wherein said method comprises the steps of:

(a) preparing opioid agonist cores by layering an aqueous solution comprising said opioid agonist and a binder on non-pareil seeds;

(b) applying a sustained release coating on said opioid agonist cores, said sustained release coating comprising a water insoluble polymer or a combination of a water insoluble polymer and a water soluble polymer to produce a first population of particles comprising said opioid agonist;

(c) preparing opioid antagonist cores by layering an aqueous solution comprising said opioid antagonist and a binder on non-pareil seeds;

(d) applying a sustained release coating on said opioid antagonist cores, said sustained release coating comprising a water insoluble polymer or a combination of a water insoluble polymer and a water soluble polymer to produce a second population of particles comprising said opioid antagonist; and

(e) filling capsules with said first population of particles and said second population of particles wherein said opioid agonist particles provide an analgesically effective amount of opioid agonist and said opioid antagonist particles provide an amount of opioid antagonist effective to attenuate side effects associated with chronic dosing of said opioid agonists, said first population of particles and said second population of particles being visually indistinguishable, thereby reducing the potential for drug abuse of said opioid agonist by separation of said opioid agonist from said opioid antagonist.

17. The method of claim 16 wherein said sustained release coating comprises ethylcellulose.

18. The method of claim 16 wherein said water soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone.

19. The method of claim 16 wherein said opioid agonist is selected from the group consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, salts thereof, and mixtures thereof.

20. The method of claim 16 wherein said opioid antagonist is selected from the group consisting of naloxone, naltrexone, etorphine, pharmaceutically acceptable salts thereof and mixtures thereof.

21. The method of claim 16 wherein said pharmaceutical multi-particulate dosage form further comprises a third population of particles comprising a non-opioid analgesic, said method further comprising the steps of:

(f) preparing non-opioid analgesic cores by layering an aqueous solution comprising said non-opioid analgesic and a binder on non-pareil seeds;

(g) applying a sustained release coating on said non-opioid analgesic cores, said sustained released coating comprising a water insoluble polymer or a combination of a water insoluble polymer and a water soluble polymer; and

(h) incorporating said non-opioid analgesic particles into said pharmaceutical multi-particulate dosage form.

22. The method of claim 21 wherein said non-opioid analgesic is selected from the group consisting of aspirin, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS), dextromethorphan, COX-II inhibitors and combinations thereof.

23. The method of claim 16 wherein said opioid agonist comprises morphine sulfate and said opioid antagonist comprises naltrexone hydrochloride.

24. The method of claim 16 wherein said opioid agonist comprises oxycodone hydrochloride and said opioid antagonist comprises naltrexone hydrochloride.