# US 9,750,703 B2 · Encased tamper resistant controlled release dosage forms

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- Number: US 9,750,703 B2
- Document ID: US9750703B2
- Status: Granted
- Kind: B2
- Application number: 15/045,975
- Filed: 2016-02-17
- Published: 2016-08-25
- Granted: 2017-09-05
- Earliest claimed: 2010-12-22
- Assignees: Purdue Pharma L.P.
- Applicants: Purdue Pharma L.P.
- Inventors: Haiyong Hugh Huang
- Web page: https://patentgrep.com/patent/US9750703B2

## CPC

- A61K 9/2077: {Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/2031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2086: {Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat (active cores with a complete drug-free outer coat A61K9/28)}
- A61K 9/209: {containing drug in at least two layers or in the core and in at least one outer layer}
- A61K 9/28: Dragees; Coated pills or tablets {, e.g. with film or compression coating (A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209)}
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

In certain embodiments, the present invention is directed to a solid controlled release dosage form comprising: a core comprising a first portion of an opioid analgesic dispersed in a first matrix material; and a shell encasing the core and comprising a second portion of the opioid analgesic dispersed in a second matrix material; wherein the amount of opioid analgesic released from the dosage form is proportional within 20% to elapsed time from 8 to 24 hours, as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 C.

## Claims

### Claim 1

A solid controlled release dosage form comprising:
a core comprising a first portion of hydrocodone or a pharmaceutically acceptable salt thereof dispersed in a first matrix material; and
a shell encasing the core and comprising a second portion of the hydrocodone or pharmaceutically acceptable salt thereof dispersed in a second matrix material;
wherein the first matrix material, the second matrix material, or both the first and second matrix material comprises polyethylene oxide having an average molecular weight from about 300,000 to about 10,000,000, wherein the dosage form is cured at a temperature of at least 60 ° C. for at least 1 minute;
wherein the amount of hydrocodone or pharmaceutically acceptable salt thereof released from the dosage form at 2 hours is less than about 25%, at 4 hours is from about 10% to about 30%, at 8 hours is from about 20% to about 60%, at 12 hours is from about 40% to about 90%, and at 18 hours is greater than about 70%;
wherein the dosage form can be flattened without breaking, wherein the thickness of the dosage form after flattening corresponds to no more than about 20% of the thickness of the dosage form before flattening; and
the amount of hydrocodone or pharmaceutically acceptable salt thereof released at 0.5 hour from a flattened dosage form deviates no more than about 20% points from a non-flattened dosage form as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

### Claim 2 (depends on 1)

The solid controlled release dosage form of claim 1, wherein the second matrix material comprises polyethylene oxide having an average molecular weight from about 1,000,000 to about 10,000,000 as measured by correlation to viscosity.

### Claim 3 (depends on 1)

The solid controlled release dosage form of claim 1, wherein the first matrix material, the second matrix material, or both the first and second matrix materials comprise a cellulose ether.

### Claim 4 (depends on 3)

The solid controlled release dosage form of claim 3, wherein the first matrix material, the second matrix material, or both the first and second matrix materials comprise a hydroxyalkylcellulose.

### Claim 5 (depends on 4)

The solid controlled release dosage form of claim 4, wherein the hydroxyalkylcellulose is hydroxypropylcellulose.

### Claim 6 (depends on 3)

The solid controlled release dosage form of claim 3, wherein the first matrix material, the second matrix material, or both the first and second matrix materials comprise microcrystalline cellulose.

### Claim 7 (depends on 6)

The solid controlled release dosage form of claim 6, comprising a compressed dispersion of the first portion of hydrocodone or pharmaceutically acceptable salt thereof and the second matrix material.

### Claim 8 (depends on 6)

The solid controlled release dosage form of claim 6, comprising granules comprising the first portion of hydrocodone or pharmaceutically acceptable salt thereof and the first matrix material.

### Claim 9 (depends on 8)

The solid controlled release dosage form of claim 8, wherein the granules are compressed into a tablet.

### Claim 10 (depends on 6)

The solid controlled release dosage form of claim 6, wherein the hydrocodone or pharmaceutically acceptable salt thereof is hydrocodone bitartrate.

### Claim 11 (depends on 10)

The solid controlled release dosage form of claim 10, wherein the amount of hydrocodone bitartrate in the dosage form is from about 0.5 mg to about 1250mg.

### Claim 12 (depends on 6)

The solid controlled release dosage form of claim 6, which provides a C24/Cmax ratio of hydrocodone of about 0.55 to about 1.0 after oral administration to a subject.

### Claim 13 (depends on 6)

The solid controlled release dosage form of claim 6, which provides a Tmax (h) of hydrocodone from about 4 to about 20 hours after oral administration to a subject.

### Claim 14 (depends on 12)

The solid controlled release dosage form of claim 12, wherein the administration is a first administration to a population of subjects.

### Claim 15 (depends on 12)

The solid controlled release dosage form of claim 12, wherein the administration is steady state administration to a subject.

### Claim 16 (depends on 6)

The solid controlled release dosage form of claim 6, which contains about 20 mg hydrocodone or pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 6)

The solid controlled release dosage form of claim 6, which contains about 120 mg hydrocodone or pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 6)

The solid controlled release dosage form of claim 6, which provides a mean AUC (ng*h/mL) after oral administration to a subject of about 250 to about 400 per each 20 mg hydrocodone or pharmaceutically acceptable salt thereof included in the dosage form.

### Claim 19 (depends on 6)

The solid controlled release dosage form of claim 6, which provides a mean Cmax (ng/mL) after oral administration to a subject of about 10 to about 30 per each 20 mg hydrocodone or pharmaceutically acceptable salt thereof included in the dosage form.

### Claim 20 (depends on 6)

The solid controlled release dosage form of claim 6, which provides a mean Tmax (h) after oral administration to a subject of about 10 to about 20.

### Claim 21 (depends on 6)

The solid controlled release dosage form of claim 6, which provides a mean T1/2 (h) after oral administration to a subject of about 5 to about 10.

### Claim 22 (depends on 6)

The solid controlled release dosage form of claim 6, which provides a mean Tlag (h) after oral administration to a subject of about 0.01 to about 0.2.

### Claim 23 (depends on 6)

The solid controlled release dosage form of claim 6, wherein the mean C24/Cmax ratio is about 0.2 to about 0.8 after oral administration to a subject.

### Claim 24 (depends on 23)

The solid controlled release dosage form of claim 23, wherein the administration is in the fasted state.

### Claim 25 (depends on 6)

The solid controlled release dosage form of claim 6, wherein the mean AUC (ng*h/mL) after oral administration to a subject in the fed state is less than 20% higher than the AUC (ng*h/mL) after oral administration to a subject in the fasted state.

### Claim 26 (depends on 6)

The solid controlled release dosage form of claim 6, wherein the mean Cmax (ng/mL) after oral administration to a subject in the fed state is less than 80% higher than the Cmax after oral administration to a subject in the fasted state.

### Claim 27 (depends on 6)

The solid controlled release dosage form of claim 6, wherein the mean Tmax (h) after oral administration to a subject in the fed state is within 25% of the Tmax (h) after oral administration to a subject in the fasted state.

### Claim 28 (depends on 6)

The solid controlled release dosage form of claim 6, wherein the mean T1/2 (h) after oral administration to a subject in the fed state is within 8% of the T1/2 after oral administration to a subject in the fasted state.

### Claim 29 (depends on 1)

The solid controlled release dosage form of claim 1, wherein the shell comprises a compression coating.

### Claim 30 (depends on 29)

The solid controlled release dosage form of claim 29, wherein the shell further comprises a hydrophilic coating over the compression coating.

### Claim 31 (depends on 30)

The solid controlled release dosage form of claim 30, wherein the hydrophilic coating is a cosmetic coat.

### Claim 32 (depends on 1)

The solid controlled release dosage form of claim 1, wherein the first matrix material comprises polyethylene oxide having an average molecular weight from about 300,000to about 3,000,000 and the second matrix material comprises polyethylene oxide having an average molecular weight from about 4,000,000 to about 10,000,000, all as measured by correlation to viscosity.

### Claim 33 (depends on 1)

The solid controlled release dosage form of claim 1, wherein the amount of hydrocodone or pharmaceutically acceptable salt thereof released from the dosage form is proportional within 20% at 8 and 24 hours, all as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

### Claim 34

A solid controlled release dosage form comprising:
a core comprising a first portion of hydrocodone bitartrate dispersed in a first matrix material; and
a layer encasing the core and comprising a second portion of hydrocodone bitartrate dispersed in a second matrix material;
wherein the first matrix material, the second matrix material, or both the first and second matrix materials comprise polyethylene oxide having an average molecular weight from about 300,000 to about 10,000,000, wherein the dosage form is cured at a temperature of at least 60° C. for at least 1 minute;
wherein the amount of hydrocodone bitartrate released from the dosage form at 2 hours is less than about 25%, at 4 hours is from about 10% to about 30%, at 8 hours is from about 20% to about 60%, at 12 hours is from about 40% to about 90%, and at 18 hours is greater than about 70%;
wherein the dosage form can be flattened without breaking, wherein the thickness of the dosage form after flattening corresponds to no more than about 20% of the thickness of the dosage form before flattening; and
the amount of hydrocodone bitartrate released at 0.5 hour from a flattened dosage form deviates no more than about 20% points from a non-flattened dosage form as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C.

### Claim 35 (depends on 33)

The solid controlled release dosage form of claim 33, wherein the layer is a compression coating.

### Claim 36 (depends on 35)

The solid controlled release dosage form of claim 35, further comprising a hydrophilic coating over the layer.

### Claim 37 (depends on 35)

The solid controlled release dosage form of claim 35, wherein the hydrophilic coating is a cosmetic coat.

### Claim 38 (depends on 33)

The solid controlled release dosage form of claim 33, wherein the first matrix material comprises polyethylene oxide having an average molecular weight from about 300,000to about 3,000,000 and the second matrix material comprises polyethylene oxide having an average molecular weight from about 4,000,000 to about 10,000,000, all as measured by correlation to viscosity.

### Claim 39 (depends on 34)

The solid controlled release dosage form of claim 34, wherein the amount of hydrocodone bitartrate released from the dosage form is proportional within 20% at 8 and 24hours, all as measured by an in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900ml simulated gastric fluid without enzymes (SGF) at 37° C.