# US 10,441,547 B2 · Tamper resistant co-extruded dosage form containing an active agent and an adverse agent and process of making same

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- Number: US 10,441,547 B2
- Document ID: US10441547B2
- Status: Granted
- Kind: B2
- Application number: 14/513,585
- Filed: 2014-10-14
- Published: 2015-05-21
- Granted: 2019-10-15
- Earliest claimed: 2003-12-09
- Assignees: Purdue Pharma L.P.
- Applicants: Purdue Pharma L.P.
- Inventors: Robert P. Flath; John K. Masselink
- Web page: https://patentgrep.com/patent/US10441547B2

## CPC

- A61K 9/5073: {having two or more different coatings optionally including drug-containing subcoatings}
- 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)}
- A61K 9/1694: {resulting in granules or microspheres of the matrix type containing more than 5% of excipient}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/5047: {Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose}
- A61K 31/135: having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)}
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## 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

### Claim 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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.

### Claim 4 (depends on 3)

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

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 5)

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

### Claim 7 (depends on 5)

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

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

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.

### Claim 10 (depends on 1)

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.

### Claim 11 (depends on 8)

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.

### Claim 12 (depends on 8)

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.

### Claim 13 (depends on 8)

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

### Claim 14 (depends on 8)

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.

### Claim 15 (depends on 8)

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.

### Claim 16 (depends on 1)

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.

### Claim 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.