ABUSE RESISTANT FORMS OF EXTENDED RELEASE HYDROMORPHONE, METHOD OF USE AND METHOD OF MAKING

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 comprising

an inner expansion layer that does not contain any drug and comprises a hydrophilic expandable polymer,

a barrier layer that substantially covers the expansion layer and comprises a first polymer that does not substantially dissolve in the gastrointestinal (GI) tract, and

a diffusion layer that substantially covers and is bonded to the barrier layer and comprises hydromorphone or pharmaceutically acceptable salt thereof substantially homogeneously distributed within a second polymer selected from the group consisting of ethyl cellulose, quarternary ammonium acrylic or methacrylic polymers, acrylic or methacrylic polymers, acrylic or methacrylic copolymers, synthetic waxes, natural waxes, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose acetate succinate, shellac, cellulose acetate trimellitate, and mixtures thereof, wherein the hydromorphone 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 pharmaceutical composition is configured such that when the pharmaceutical composition is physically compromised to produce particles having a particle size between 8 mesh and 500 mesh and exposed to a liquid comprising water and/or alcohol, the bond between the diffusion layer and the barrier layer is substantially preserved and the expandable polymer of the expansion layer absorbs at least a portion of the liquid and expands and/or forms a gel, wherein the amount of hydromorphone or pharmaceutically acceptable salt thereof released from the particles within a time period selected from the group consisting of 2 hours, 4 hours, 8 hours and 16 hours, is substantially the same or lower than the amount of hydromorphone or pharmaceutically acceptable salt thereof released from the pharmaceutical composition in intact form, wherein the release is determined under the following conditions: USP Apparatus I (basket) at 100 rpm in 900 mL aqueous buffer at pH 1.6 or 7.2 and 37° C.

2 . The method of claim 1 , wherein the hydromorphone or pharmaceutically acceptable salt thereof is present in an amount of about 1 mg to about 64 mg.

3 . The method of claim 1 , wherein the hydromorphone or pharmaceutically acceptable salt thereof comprises hydromorphone hydrochloride.

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 pharmaceutical composition is in a form selected from the group consisting of a tablet, a capsule, a micro tablet, granules, pellets, a lozenge, a lollipop, and a coated capsule.

6 . The method of claim 1 , wherein the pharmaceutical composition is in a form of a tablet.

7 . The method of claim 6 , wherein the expansion layer has a thickness of about 5 to 95% of the total thickness of the tablet.

8 . The method of claim 6 , wherein the barrier layer has a thickness of about 5 to 50% of the total thickness of the tablet.

9 . The method of claim 6 , wherein the diffusion layer has a thickness of about 1 to 30% of the total thickness of the tablet.

10 . The method of claim 1 , wherein the first polymer and the second polymer are each independently selected from the group consisting of acrylic polymers, methacrylic polymers, acrylic copolymers and methacrylic copolymers.

11 . The method of claim 1 , wherein the first polymer and the second polymer are independently selected from the group consisting of ethyl acrylate, methyl methacrylate, and copolymers thereof.

12 . A method of treating pain in a patient in need thereof, comprising

orally administering to the patient an abuse resistant extended release pharmaceutical composition comprising

an inner expansion layer that does not contain any drug and comprises a hydrophilic expandable polymer,

a barrier layer that substantially covers the expansion layer and comprises a first polymer that does not substantially dissolve in the gastrointestinal (GI) tract, and

a diffusion layer that substantially covers and is bonded to the barrier layer and comprises hydromorphone or pharmaceutically acceptable salt thereof substantially homogeneously distributed within a second polymer selected from the group consisting of ethyl cellulose, quarternary ammonium acrylic or methacrylic polymers, acrylic or methacrylic polymers, acrylic or methacrylic copolymers, synthetic waxes, natural waxes, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose acetate succinate, shellac, cellulose acetate trimellitate, and mixtures thereof, wherein the hydromorphone 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 pharmaceutical composition is configured such that when the pharmaceutical composition is physically compromised to produce particles having a particle size between 8 mesh and 500 mesh and administered to a subject, the maximum blood concentration (Cmax) and/or area under the serum concentration curve (AUC) of the hydromorphone or pharmaceutically acceptable salt thereof achieved in the subject after a time period selected from the group consisting of 2 hours, 4 hours, 8 hours and 12 hours is substantially the same or lower than the Cmax and/or AUC achieved in the subject when the pharmaceutical composition is administered in intact form.

13 . The method of claim 12 , wherein the hydromorphone or pharmaceutically acceptable salt thereof is present in an amount of about 1 mg to about 64 mg.

14 . The method of claim 12 , wherein the hydromorphone or pharmaceutically acceptable salt thereof comprises hydromorphone hydrochloride.

15 . The method of claim 12 , 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.

16 . The method of claim 12 , wherein the pharmaceutical composition is in a form selected from the group consisting of a tablet, a capsule, a micro tablet, granules, pellets, a lozenge, a lollipop, and a coated capsule.

17 . The method of claim 12 , wherein the pharmaceutical composition is in a form of a tablet.

18 . The method of claim 17 , wherein the expansion layer has a thickness of about 5 to 95% of the total thickness of the tablet.

19 . The method of claim 17 , wherein the barrier layer has a thickness of about 5 to 50% of the total thickness of the tablet.

20 . The method of claim 17 , wherein the diffusion layer has a thickness of about 1 to 30% of the total thickness of the tablet.

21 . The method of claim 12 , wherein the first polymer and the second polymer are each independently selected from the group consisting of acrylic polymers, methacrylic polymers, acrylic copolymers and methacrylic copolymers.

22 . The method of claim 12 , wherein the first polymer and the second polymer are independently selected from the group consisting of ethyl acrylate, methyl methacrylate, and copolymers thereof.

23 . A method of treating pain in a patient in need thereof, comprising

orally administering to the patient an abuse resistant extended release pharmaceutical composition comprising

an inner expansion layer that does not contain any drug and comprises a hydrophilic expandable polymer,

a barrier layer that substantially covers the expansion layer and comprises a first polymer that does not substantially dissolve in the gastrointestinal (GI) tract, and

a diffusion layer that substantially covers and is bonded to the barrier layer and comprises hydromorphone or pharmaceutically acceptable salt thereof substantially homogeneously distributed within a second polymer selected from the group consisting of ethyl cellulose, quarternary ammonium acrylic or methacrylic polymers, acrylic or methacrylic polymers, acrylic or methacrylic copolymers, synthetic waxes, natural waxes, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose acetate succinate, shellac, cellulose acetate trimellitate, and mixtures thereof, wherein the hydromorphone 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 pharmaceutical composition is configured such that when the pharmaceutical composition is contacted with an alcohol or consumed with an alcohol, the rate of release of the hydromorphone or pharmaceutically acceptable salt thereof from the pharmaceutical composition within a time period selected from the group consisting of 2 hours, 4 hours, 8 hours and 16 hours, is substantially the same or lower than the rate of release of the hydromorphone or pharmaceutically acceptable salt thereof from the pharmaceutical composition without alcohol, wherein when the release is determined in vitro, it is determined under the following conditions: USP Apparatus I (basket) at 100 rpm in 900 mL aqueous buffer at pH 1.6 or 7.2 and 37° C., and wherein when the release is determined in vivo, it is determined by comparing the maximum blood concentration (Cmax) and/or area under the serum concentration curve (AUC) of the hydromorphone or pharmaceutically acceptable salt thereof achieved in a subject after administration of the pharmaceutical composition with alcohol versus administration of the pharmaceutical composition without alcohol.

24 . The method of claim 23 , wherein the hydromorphone or pharmaceutically acceptable salt thereof is present in an amount of about 1 mg to about 64 mg.

25 . The method of claim 23 , wherein the hydromorphone or pharmaceutically acceptable salt thereof comprises hydromorphone hydrochloride.

26 . The method of claim 23 , wherein the pharmaceutical composition is in a form selected from the group consisting of a tablet, a capsule, a micro tablet, granules, pellets, a lozenge, a lollipop, and a coated capsule.

27 . The method of claim 23 , wherein the pharmaceutical composition is in a form of a tablet.

28 . The method of claim 23 , wherein the first polymer and the second polymer are each independently selected from the group consisting of acrylic polymers, methacrylic polymers, acrylic copolymers and methacrylic copolymers.

29 . The method of claim 23 , wherein the first polymer and the second polymer are independently selected from the group consisting of ethyl acrylate, methyl methacrylate, and copolymers thereof.

30 . The method of claim 23 , wherein the rate of release is determined by comparing the maximum blood concentration (Cmax) and/or area under the serum concentration curve (AUC) of the hydromorphone or pharmaceutically acceptable salt thereof achieved in a subject after administration of the pharmaceutical composition with alcohol versus administration of the pharmaceutical composition without alcohol.