Abuse resistant forms of extended release hydrocodone, method of use and method of making

1. An oral, extended release pharmaceutical composition in tablet form configured to deter abuse, comprising:

an expansion layer comprising an 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 substantially covering the expansion layer, wherein the barrier layer comprises a first polymer selected from the group consisting of: acrylic or methacrylic polymers or copolymers 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 covering the barrier layer, the diffusion layer comprising a drug comprising hydrocodone or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount and a second polymer selected from the group consisting of: acrylic or methacrylic polymers or copolymers thereof,

wherein the diffusion layer is bonded to the barrier layer by curing the layers together,

wherein the diffusion layer is the only drug-containing layer in the pharmaceutical composition,

wherein the pharmaceutical composition does not comprise a drug that is not an opioid agonist or a central nervous system stimulant,

wherein the drug is substantially homogeneously distributed within the second polymer and diffuses from the diffusion layer within the GI tract;

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, and

wherein the first polymer and second polymer each comprise the same polymer.

2. The pharmaceutical composition of claim 1 , 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 dosage form.

3. The pharmaceutical composition of claim 1 , wherein when the pharmaceutical composition is crushed and particles of the pharmaceutical composition containing the expansion layer are formed and exposed to a liquid, the expandable polymer of the expandable layer absorbs at least a portion of the liquid.

4. The pharmaceutical composition of claim 1 , wherein the diffusion layer is physically bonded to the barrier layer.

5. The pharmaceutical composition of claim 1 , wherein the second polymer of the diffusion layer provides a timed release of drug over a period of about 6 to about 24 hours.

6. The pharmaceutical composition of claim 1 , wherein when the pharmaceutical composition is crushed and particles of the pharmaceutical composition containing the diffusion layer and the barrier layer are formed, the bond between the diffusion layer and barrier layer within the particles is substantially preserved.

7. An oral, extended release pharmaceutical composition in tablet form configured to deter abuse, comprising:

an expansion layer comprising an 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 substantially covering the expansion layer, wherein the barrier layer comprises a first polymer selected from the group consisting of: acrylic or methacrylic polymers or copolymers 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 covering the barrier layer, the diffusion layer comprising a drug comprising hydrocodone or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount and a second polymer selected from the group consisting of: acrylic or methacrylic polymers or copolymers thereof,

wherein the drug is substantially homogenously distributed within the second polymer and diffuses from the diffusion layer within the GI tract,

wherein the pharmaceutical composition does not comprise a drug that is not an opioid agonist or a central nervous system stimulant, wherein the diffusion layer is the only drug-containing layer in the pharmaceutical composition,

wherein the diffusion layer is bonded to the barrier layer by curing the layers together,

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, and

wherein when the pharmaceutical composition is orally or intranasally administered in crushed form to a subject, the Cmax/AUC achieved 8 hours after administration is lower than the Cmax/AUC achieved 8 hours after administration of a crushed bioequivalent composition not configured to deter abuse.

8. An oral, extended release pharmaceutical composition in tablet form configured to deter abuse, comprising:

an expansion layer comprising an 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 substantially covering the expansion layer, wherein the barrier layer comprises a first polymer selected from the group consisting of: acrylic or methacrylic polymers or copolymers 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 covering the barrier layer, the diffusion layer comprising a drug comprising hydrocodone or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount and a second polymer selected from the group consisting of: acrylic or methacrylic polymers or copolymers thereof,

wherein the drug is substantially homogeneously distributed within the second polymer and diffuses from the diffusion layer within the GI tract,

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 pharmaceutical composition does not comprise a drug that is not an opioid agonist or a central nervous system stimulant, and

wherein the diffusion layer is the only drug-containing layer in the pharmaceutical composition, wherein the diffusion layer is bonded to the barrier layer by curing the layers together, and

wherein when the pharmaceutical composition is orally administered in intact form at least 50% of the amount of drug is released within 8 hours after administration and when the pharmaceutical composition is administered in crushed form no more than 40% of the amount of drug is released within 1 hour after administration.

9. The pharmaceutical composition of claim 8 , wherein when the pharmaceutical composition is administered in crushed form no more than 35% of the amount of drug is released after 15 minutes.

10. The pharmaceutical composition of claim 1 , wherein the composition comprises hydrocodone or a pharmaceutically acceptable salt thereof in an amount of about 5 mg to about 400 mg.

11. A method of making an abuse resistant oral, extended release pharmaceutical composition, comprising:

forming an expansion layer comprising an 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;

applying a barrier layer over the expansion layer to cover the expansion layer, wherein the barrier layer comprises a first polymer selected from the group consisting of: acrylic or methacrylic polymers or copolymers thereof;

applying a diffusion layer over the barrier layer to substantially cover the barrier layer, wherein the diffusion layer comprises a second polymer selected from the group consisting of: acrylic or methacrylic polymers or copolymers thereof, and a drug that is homogeneously distributed within the second polymer; and

bonding the diffusion layer to the barrier layer by curing the layers together,

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 drug comprises hydrocodone or a pharmaceutically acceptable salt thereof, and wherein the pharmaceutical composition does not comprise a drug that is not an opioid agonist or a central nervous system stimulant, 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, wherein the diffusion layer is the only drug-containing layer in the pharmaceutical composition, and wherein the pharmaceutical composition is a tablet dosage form configured to deter abuse.

12. The method of claim 11 , wherein the bonding of the diffusion layer to the barrier layer is a physical bonding.

13. The pharmaceutical composition of claim 1 , wherein when the pharmaceutical composition is administered in crushed form to a subject, the intensity of euphoria is lower than the intensity of euphoria achieved after administration of a crushed bioequivalent composition not configured to deter abuse.

14. The pharmaceutical composition of claim 1 , wherein the composition comprises hydrocodone or a pharmaceutically acceptable salt thereof in an amount of about 5 mg to about 400 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.

15. The pharmaceutical composition of claim 7 , wherein the composition comprises hydrocodone or a pharmaceutically acceptable salt thereof in an amount of about 5 mg to about 400 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.

16. The pharmaceutical composition of claim 8 , wherein the composition comprises hydrocodone or a pharmaceutically acceptable salt thereof in an amount of about 5 mg to about 400 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.

17. The pharmaceutical composition of claim 1 , wherein the expandable polymer is selected from the group consisting of: methylcellulose, sodium carboxymethylcellulose, methylhydroxyethylcellulose, and hydroxypropylmethylcellulose.

18. The pharmaceutical composition of claim 1 , wherein the expandable polymer comprises hydroxypropylmethylcellulose.

19. The pharmaceutical composition of claim 7 , wherein the expandable polymer is selected from the group consisting of: methylcellulose, sodium carboxymethylcellulose, methylhydroxyethylcellulose, and hydroxypropylmethylcellulose.

20. The pharmaceutical composition of claim 7 , wherein the expandable polymer comprises hydroxypropylmethylcellulose.

21. The pharmaceutical composition of claim 8 , wherein the expandable polymer is selected from the group consisting of: methylcellulose, sodium carboxymethylcellulose, methylhydroxyethylcellulose, and hydroxypropylmethylcellulose.

22. The pharmaceutical composition of claim 8 , wherein the expandable polymer comprises hydroxypropylmethylcellulose.

23. An oral, extended release pharmaceutical composition in tablet form configured to deter abuse, comprising:

an expansion layer comprising an 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 substantially covering the expansion layer, wherein the barrier layer comprises a first polymer comprising 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 covering the barrier layer, the diffusion layer comprising a drug comprising hydrocodone or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount and a second polymer comprising a copolymer of ethyl acrylate and methyl methacrylate,

wherein the drug is substantially homogeneously distributed within the second polymer and diffuses from the diffusion layer within the GI tract,

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,

the pharmaceutical composition does not comprise a drug that is not an opioid agonist or a central nervous system stimulant, wherein the diffusion layer is the only drug-containing layer in the pharmaceutical composition, and wherein the diffusion layer is bonded to the barrier layer by curing the layers together.

24. The pharmaceutical composition of claim 23 , 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 dosage form.

25. The pharmaceutical composition of claim 23 , wherein when the pharmaceutical composition is crushed and particles of the pharmaceutical composition containing the expansion layer are formed and exposed to a liquid, the expandable polymer of the expandable layer absorbs at least a portion of the liquid.

26. The pharmaceutical composition of claim 23 , wherein the diffusion layer is physically bonded to the barrier layer.

27. The pharmaceutical composition of claim 23 , wherein the second polymer of the diffusion layer provides a timed release of drug over a period of about 6 to about 24 hours.

28. The pharmaceutical composition of claim 23 , wherein when the pharmaceutical composition is crushed and particles of the pharmaceutical composition containing the diffusion layer and the barrier layer are formed, the bond between the diffusion layer and barrier layer within the particles is substantially preserved.

29. The pharmaceutical composition of claim 23 , wherein the expandable polymer is selected from the group consisting of: methylcellulose, sodium carboxymethylcellulose, methylhydroxyethylcellulose, and hydroxypropylmethylcellulose.

30. The pharmaceutical composition of claim 23 , wherein the expandable polymer comprises hydroxypropylmethylcellulose.

31. The pharmaceutical composition of claim 23 , wherein the composition comprises hydrocodone or a pharmaceutically acceptable salt thereof in an amount of about 5 mg to about 400 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 hydroxypropylmethylcellulose.

32. An oral, extended release pharmaceutical composition in tablet form configured to deter abuse, comprising:

an expansion layer comprising an 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 substantially covering the expansion layer, wherein the barrier layer comprises a first polymer comprising 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 covering the barrier layer, the diffusion layer comprising a drug comprising hydrocodone or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount and a second polymer comprising a copolymer of ethyl acrylate and methyl methacrylate,

wherein the drug is substantially homogeneously distributed within the second polymer and diffuses from the diffusion layer within the GI tract,

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 an opioid agonist or a central nervous system stimulant,

wherein the diffusion layer is the only drug-containing layer in the pharmaceutical composition; and

wherein when the pharmaceutical composition is orally or intranasally administered in crushed form to a subject, the Cmax/AUC achieved 8 hours after administration is lower than the Cmax/AUC achieved 8 hours after administration of a physically compromised bioequivalent composition not configured to deter abuse.

33. The pharmaceutical composition of claim 32 , wherein the expandable polymer is selected from the group consisting of: methylcellulose, sodium carboxymethylcellulose, methylhydroxyethylcellulose, and hydroxypropylmethylcellulose.

34. The pharmaceutical composition of claim 32 , wherein the expandable polymer comprises hydroxypropylmethylcellulose.

35. The pharmaceutical composition of claim 32 , wherein the composition comprises hydrocodone or a pharmaceutically acceptable salt thereof in an amount of about 5 mg to about 400 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 hydroxypropylmethylcellulose.

36. An oral, extended release pharmaceutical composition in tablet form configured to deter abuse, comprising:

an expansion layer comprising an 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 substantially covering the expansion layer, wherein the barrier layer comprises a first polymer comprising 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 covering the barrier layer, the diffusion layer comprising a drug comprising hydrocodone or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount and a second polymer comprising a copolymer of ethyl acrylate and methyl methacrylate,

wherein the drug is substantially homogenously distributed within the second polymer and diffuses from the diffusion layer within the GI tract,

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 pharmaceutical composition does not comprise a drug that is not an opioid agonist or a central nervous system stimulant, wherein the diffusion layer is the only drug-containing layer in the pharmaceutical composition, and wherein the diffusion layer is bonded to the barrier layer by curing the layers together; and

wherein when the pharmaceutical composition is orally administered in intact form at least 50% of the amount of drug is released within 8 hours after administration and when the pharmaceutical composition is administered in crushed form no more than 40% of the amount of drug is released within 1 hour after administration.

37. The pharmaceutical composition of claim 36 , wherein the expandable polymer is selected from the group consisting of: methylcellulose, sodium carboxymethylcellulose, methylhydroxyethylcellulose, and hydroxypropylmethylcellulose.

38. The pharmaceutical composition of claim 36 , wherein the expandable polymer comprises hydroxypropylmethylcellulose.

39. The pharmaceutical composition of claim 36 , wherein the composition comprises hydrocodone or a pharmaceutically acceptable salt thereof in an amount of about 5 mg to about 400 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 hydroxypropylmethylcellulose.