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

• US 10,441,547 B2
• Filed: 10/14/2014
• Issued: 10/15/2019
• 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:
  US14/513,585
• Publication Number:
  US 20150140086A1
• Time in Patent Office: 1,827 Days
• 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 co-extruded dosage form comprising a plurality of co-extruded multilayer extrudates, each extrudate comprising:

an extruded core comprising a matrix of an adverse agent and a hydrophobic material, wherein the hydrophobic material is present in an amount of about 30 wt % to about 99 wt % of the extruded core;

an extruded sheath comprising a hydrophobic material which surrounds at least a portion of the core, wherein the sheath is free of an adverse agent and free of an active agent, wherein the hydrophobic material is present in an amount of about 10 wt % to about 99 wt % of the extruded sheath; and

an extruded shell comprising an active agent and a hydrophobic material which surrounds at least a portion of the sheath, wherein the hydrophobic material is present in an amount of about 1 wt % to about 80 wt % of the extruded shell, and wherein the shell has a thickness of about 0.05 mm to about 3 mm;

wherein each extrudate is a portion of a multilayer extrudate sheet; and

wherein the dosage form releases about 10% or less adverse agent over a 36 hour period when subjected to an in-vitro dissolution test using USP Basket Method at 100 rpm in 700 ml simulated gastric filled at pH 1.2 without enzyme at 37°

C. for 1 hour followed by 900 ml simulated intestinal fluid at pH 7.5 without enzyme for the duration of the test.

2. The co-extruded dosage form of claim 1, wherein the sheath surrounds a majority of the core;

and the shell surrounds a majority of the sheath.

3. The co-extruded dosage form of claim 1, wherein each hydrophobic material independently comprises a 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 any two or more of the foregoing.

4. The co-extruded dosage form of claim 3, wherein the hydrophobic material in the core comprises an ammonio methacrylate copolymer.

5. The co-extruded dosage form of claim 1, wherein the dosage from is an oral dosage form.

6. The co-extruded dosage form of claim 5, wherein the oral dosage form is a tablet or caplet.

7. The co-extruded dosage of claim 5, wherein the oral dosage form is a capsule containing a plurality of co-extruded particles.

8. The co-extruded dosage form of claim 1, wherein the active agent is an opioid agonist and the adverse agent is an opioid antagonist.

9. The co-extruded dosage form 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, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, pharmaceutically acceptable salts thereof, and mixtures of any two or more of the foregoing.

10. The co-extruded dosage form 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 any two or more of the foregoing.

11. The co-extruded dosage form of claim 8, 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 any two or more of the foregoing.

12. The co-extruded dosage form of claim 8, wherein the opioid antagonist is selected from the group consisting of naloxone, naltrexone, nalmefene, pharmaceutically acceptable salts thereof, and mixtures of any two or more of the foregoing.

13. The co-extruded dosage form of claim 8, wherein the dosage form provides controlled release of the opioid agonist following administration to a patient.

14. The co-extruded dosage form of claim 8, wherein the dosage form releases about 0.5 mg or less of the opioid antagonist in vivo following administration to a patient.

15. The co-extruded dosage form of claim 8, wherein the dosage form releases about 0.05 mg or less of the opioid antagonist in vivo following administration to a patient.

16. A method for treating pain in a patient, comprising administering a co-extruded dosage form according to claim 1 to a patient, wherein the active agent is an opioid agonist and the adverse agent is an opioid antagonist.

17. A co-extruded dosage form comprising:

a plurality of co-extruded multilayer extrudates, each extrudate comprising;

an extruded core comprising a matrix of an adverse agent and a hydrophobic material;

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

an extruded shell comprising an active agent and a hydrophobic material which surrounds at least a portion of the sheath, wherein the extruded shell has a thickness of about 0.05 mm to about 3 mm;

wherein each extrudate is a portion of a multilayer extrudate sheet,

wherein each of the plurality of particles is from about 0.05 mm to about 3.0 mm in all dimensions,

wherein the dosage form releases about 10% or less adverse agent over a 36 hour period when subjected to an in-vitro dissolution test using USP Basket Method at 100 rpm in 700 ml simulated gastric filled at pH 1.2 without enzyme at 37°

C. for 1 hour followed by 900 ml simulated intestinal fluid at pH 7.5 without enzyme for the duration of the test.