Tamper resistant co-extruded dosage form containing an active agent and an adverse agent and process of making same

• US 8,883,204 B2
• Filed: 09/23/2008
• Issued: 11/11/2014
• Est. Priority Date: 12/09/2003
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Flath, Robert P., Masselink, John K.
• Primary Examiner(s): PURDY, KYLE A
• Application Number:
  US12/236,063
• Publication Number:
  US 20090022790A1
• Time in Patent Office: 2,240 Days
• US Class Current: 424/458
• 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 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• 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 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings

Abstract

The present invention relates to co-extruded pharmaceutical compositions and dosage forms including an active agent, such as an opioid agonist, and an adverse agent, such as an opioid antagonist. Such compositions and dosage forms are useful for preventing or discouraging tampering, abuse, misuse or diversion of a dosage form containing an active pharmaceutical agent, such as an opioid. The present invention also relates to methods of treating a patient with such a dosage form, as well as kits containing such a dosage form with instructions for using the dosage form to treat a patient.

Claims

1. A method of making a tamper-resistant dosage form comprising:

a) forming a multilayer extrudate by co-extruding a core comprising an adverse agent and a hydrophobic material;

a sheath comprising a hydrophobic material which at least partially surrounds the core wherein the sheath is free of an adverse agent and free of an active agent; and

a shell comprising an active agent and a hydrophobic material which at least partially surrounds the sheath;

b) using a rolling punch to form one more particles from the multilayer extrudate; and

c) incorporating one or more particles into a dosage form;

wherein there active agent is an opioid agonist and the adverse agent is an opioid antagonist.

2. The method of claim 1, wherein the dosage form provides a controlled release of the active agent upon administration to a patient.

3. The method of claim 1, wherein the opioid agonist is 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, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, pharmaceutically acceptable salts thereof, and mixtures of two or more of the foregoing.

4. The method of claim 1, wherein the opioid agonist is selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, pharmaceutically acceptable salts thereof, and mixtures of two or more of the foregoing.

5. The method of claim 1, wherein the opioid antagonist is selected from the group consisting of cyclazocine, naloxone, naltrexone, nalmefene, nalbuphine, nalorphine, cyclazacine, levallorphan, pharmaceutically acceptable salts thereof, and mixtures of two or more of the foregoing.

6. The method of claim 1, wherein the opioid antagonist is selected from the group consisting of nalmefene, naloxone, naltrexone, pharmaceutically acceptable salts thereof, and mixtures of two or more of the foregoing.

7. The method of claim 1, wherein the particles have a size of from about 0.1 mm to about 3 mm in all dimensions.

8. The method of claim 7, further comprising placing a plurality of particles into a capsule.

9. The method of claim 1, wherein the tamper-resistant dosage form is an oral dosage form.

10. The method of claim 1, wherein the hydrophobic material comprises at least one material selected from the group consisting of acrylic and methacrylic acid polymers and copolymers, alkylcelluloses, natural and synthetic waxes, water insoluble waxes, fatty alcohols, fatty acids, hydrogenated fats, fatty acid esters, fatty acid glycerides, hydrocarbons, hydrophobic and hydrophilic polymers having hydrocarbon backbones, and mixtures of two or more of the foregoing.

11. The method of claim 10, wherein the hydrophobic material comprises an ammonio-methacrylate copolymer.

12. The method of claim 1, wherein the tamper-resistant dosage form provides a controlled release of the active agent in vivo for at least about 12 hours.

13. The method of claim 1, wherein the tamper-resistant dosage form provides a controlled release of the active agent in vivo for at least about 24 hours.

14. The method of claim 13, wherein the active agent is an opioid agonist, the adverse agent is an opioid antagonist;

and the tamper-resistant dosage form releases about 0.5 mg or less of the opioid antagonist in vivo following administration.

15. The method of claim 14, wherein the tamper-resistant dosage form releases about 0.05 mg or less of the opioid antagonist in vivo following administration.