Abuse resistant forms of extended release morphine, method of use and method of making
An abuse resistant oral pharmaceutical composition, comprising: a barrier layer, comprising a first polymer; a diffusion layer, comprising a second polymer, substantially covering the barrier layer, wherein the diffusion layer is bonded to the barrier layer and comprises a drug that is substantially homogeneously distributed within the second polymer and diffuses from the diffusion layer within the gastrointestinal (GI) tract; and optionally an expansion layer comprising an expandable polymer, wherein the expansion layer is substantially covered by the barrier layer. Methods of making the same and methods of using the same are also provided.
1. A method of treating pain in a patient in need thereof, comprising
orally administering to the patient an abuse resistant extended release pharmaceutical composition in the form of a layered tablet, comprising
an inner expansion layer that does not contain any drug and comprises a hydrophilic expandable polymer that forms a gel when exposed to a liquid comprising water and/or alcohol, wherein the expandable polymer is selected from the group consisting of: methylcellulose, sodium carboxymethylcellulose, methylhydroxyethylcellulose, hydroxypropylmethylcellulose, alginic acid, tragacanth, and combinations thereof,
a barrier layer that substantially covers the expansion layer and comprises a first polymer selected from the group consisting of: acrylic or methacrylic polymers, acrylic or methacrylic copolymers, and mixtures thereof, wherein when the pharmaceutical composition is administered in intact form, the first polymer of the barrier layer is substantially undissolved in the gastrointestinal (GI) tract, and
a diffusion layer that substantially covers the barrier layer, the diffusion layer comprising morphine or a pharmaceutically acceptable salt thereof substantially homogeneously distributed within a second polymer selected from the group consisting of acrylic or methacrylic polymers, acrylic or methacrylic copolymers, and mixtures thereof, wherein the morphine or pharmaceutically acceptable salt thereof diffuses from the diffusion layer within the GI tract to provide extended release over a period of about 6 to about 24 hours to treat pain,
wherein the second polymer is present in an amount sufficient to release at least 50% of the amount of drug after 8 hours after administration in intact form,
wherein the first polymer and second polymer each comprise the same polymer,
wherein the diffusion layer is bonded to the barrier layer by curing the layers together,
wherein the pharmaceutical composition does not comprise a drug that is not morphine or a pharmaceutically acceptable salt thereof,
wherein the diffusion layer is the only drug-containing layer in the pharmaceutical composition, and
wherein when the pharmaceutical composition is crushed and administered to a subject, the Cmax/AUC of the morphine or pharmaceutically acceptable salt thereof achieved in the subject 8 hours after administration is lower than the Cmax/AUC achieved in the subject 8 hours after administration of a crushed bioequivalent composition not configured to deter abuse.
2. The method of claim 1 , wherein the morphine or pharmaceutically acceptable salt thereof is present in an amount of about 15 mg to about 800 mg.
3. The method of claim 1 , wherein the morphine or pharmaceutically acceptable salt thereof comprises morphine sulfate.
4. The method of claim 1 , wherein the hydrophilic expandable polymer is present in an amount of 5 to 90% by weight based on the total weight of the dosage form.
5. The method of claim 1 , wherein the expansion layer has a thickness of about 5 to 95% of the total thickness of the tablet.
6. The method of claim 1 , wherein the diffusion layer has a thickness of about 1 to 30% of the thickness of the tablet.
7. The method of claim 1 , wherein the barrier layer has a thickness of about 5 to 50% of the thickness of the tablet.
8. The method of claim 1 , wherein when the pharmaceutical composition is crushed and administered to a subject, the Cmax/AUC of the morphine or pharmaceutically acceptable salt thereof achieved in the subject 8 hours after administration is about 20-75% lower than the Cmax/AUC achieved in the subject 8 hours after administration of a crushed bioequivalent composition not configured to deter abuse.
9. The method of claim 1 , wherein the abuse resistant extended release pharmaceutical composition comprises morphine or a pharmaceutically acceptable salt thereof in an amount of about 15 mg to about 800 mg,
wherein the expansion layer comprises the expandable polymer present in the range of 5 to 90% by weight based on the total weight of the pharmaceutical composition,
and
wherein the expansion polymer comprises hydroxypropyl methylcellulose, the first polymer comprises a copolymer of ethyl acrylate and methyl methacrylate, and the second polymer comprises a copolymer of ethyl acrylate and methyl methacrylate.
10. The method of claim 1 , wherein the hydrophilic expandable polymer is selected from the group consisting of: methylcellulose, sodium carboxymethylcellulose, methylhydroxyethylcellulose, and hydroxypropylmethylcellulose.
11. The method of claim 1 , wherein the hydrophilic expandable polymer comprises hydroxypropylmethylcellulose.
12. The method of claim 1 , wherein the first polymer comprises a copolymer of ethyl acrylate and methyl methacrylate, and the second polymer comprises a copolymer of ethyl acrylate and methyl methacrylate.
13. A method of treating pain in a patient in need thereof, comprising
orally administering to the patient an abuse resistant extended release pharmaceutical composition in the form of a layered tablet, comprising
an inner expansion layer that does not contain any drug and comprises a hydrophilic expandable polymer that forms a gel when exposed to a liquid comprising water and/or alcohol, wherein the expandable polymer is selected from the group consisting of: methylcellulose, sodium carboxymethylcellulose, methylhydroxyethylcellulose, hydroxypropylmethylcellulose, alginic acid, tragacanth, and combinations thereof,
a barrier layer that substantially covers the expansion layer and comprises a first polymer, wherein the first polymer is a copolymer of ethyl acrylate and methyl methacrylate, wherein when the pharmaceutical composition is administered in intact form, the first polymer of the barrier layer is substantially undissolved in the gastrointestinal (GI) tract, and
a diffusion layer that substantially covers the barrier layer, the diffusion layer comprising morphine or a pharmaceutically acceptable salt thereof substantially homogeneously distributed within a second polymer, wherein the second polymer is a copolymer of ethyl acrylate and methyl methacrylate, wherein the morphine or pharmaceutically acceptable salt thereof diffuses from the diffusion layer within the GI tract to provide extended release over a period of about 6 to about 24 hours to treat pain,
wherein the second polymer is present in an amount sufficient to release at least 50% of the amount of drug after 8 hours after administration in intact form,
wherein the diffusion layer is bonded to the barrier layer by curing the layers together,
wherein the pharmaceutical composition does not comprise a drug that is not morphine or a pharmaceutically acceptable salt thereof,
wherein the diffusion layer is the only drug-containing layer in the pharmaceutical composition, and
wherein when the pharmaceutical composition is crushed and administered to a subject, the Cmax/AUC of the morphine or pharmaceutically acceptable salt thereof achieved in the subject 8 hours after administration is lower than the Cmax/AUC achieved in the subject 8 hours after administration of a crushed bioequivalent composition not configured to deter abuse.
14. The method of claim 13 , wherein the morphine or pharmaceutically acceptable salt thereof is present in an amount of about 15 mg to about 800 mg.
15. The method of claim 13 , wherein the morphine or pharmaceutically acceptable salt thereof comprises morphine sulfate.
16. The method of claim 13 , wherein the hydrophilic expandable polymer is present in an amount of 5 to 90% by weight based on the total weight of the dosage form.
17. The method of claim 13 , wherein the expansion layer has a thickness of about 5 to 95% of the total thickness of the tablet.
18. The method of claim 13 , wherein the diffusion layer has a thickness of about 1 to 30% of the thickness of the tablet.
19. The method of claim 13 , wherein the barrier layer has a thickness of about 5 to 50% of the thickness of the tablet.
20. The method of claim 13 , wherein when the pharmaceutical composition is crushed and administered to a subject, the Cmax/AUC of the morphine or pharmaceutically acceptable salt thereof achieved in the subject 8 hours after administration is about 20-75% lower than the Cmax/AUC achieved in the subject 8 hours after administration of a crushed bioequivalent composition not configured to deter abuse.
21. The method of claim 13 , wherein the hydrophilic expandable polymer is selected from the group consisting of: methylcellulose, sodium carboxymethylcellulose, methylhydroxyethylcellulose, and hydroxypropylmethylcellulose.
22. The method of claim 13 , wherein the hydrophilic expandable polymer comprises hydroxypropylmethylcellulose.
23. The method of claim 13 , wherein the abuse resistant extended release pharmaceutical composition comprises morphine or a pharmaceutically acceptable salt thereof in an amount of about 15 mg to about 800 mg,
wherein the expansion layer comprises the expandable polymer present in the range of 5 to 90% by weight based on the total weight of the pharmaceutical composition,
and wherein the expansion polymer comprises hydroxypropyl methylcellulose.