Details for Patent: 9,393,206

Title:	Encased tamper resistant controlled release dosage forms
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.
Inventor(s):	Huang; Haiyong Hugh (Princeton, NJ)
Assignee:	Purdue Pharma L.P. (Stamford, CT) The P.F. Laboratories, Inc. (Totowa, NJ) Purdue Pharmaceuticals L.P. (Wilson, NC)
Filing Date:	Sep 11, 2013
Application Number:	14/024,367
Claims:	1. A method of preparing a solid controlled release dosage form comprising: granulating hydrocodone or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients to form a granulate; incorporating a therapeutically effective amount of the granulate and a controlled release material in a dosage form comprising a core and a shell; wherein the core and the shell each comprise an amount of the granulate; wherein the amount of hydrocodone or salt thereof released from the dosage form is proportional within 20% to elapsed time, at any two time points 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.degree. C.; and 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 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.degree. C. 2. A method of preparing a solid controlled release dosage form comprising: granulating hydrocodone or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients to form a granulate; incorporating a therapeutically effective amount of the granulate and a controlled release material in a dosage form comprising a core and a shell; wherein the core and the shell each comprise an amount of the granulate; wherein the amount of hydrocodone or salt thereof released from the dosage form at 2 hours is less than about 25%; the amount of hydrocodone or salt thereof released from the dosage form at 4 hours is from about 10% to about 30%; the amount of hydrocodone or salt thereof released from the dosage form at 8 hours is from about 20% to about 60%; the amount of hydrocodone or salt thereof released from the dosage form at 12 hours is from about 40% to about 90%; and the amount of hydrocodone or salt thereof released from the dosage form at 18 hours is greater than about 70%, 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.degree. C.; and 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 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.degree. C.; and wherein the amount of hydrocodone or salt thereof released from the dosage form is proportional within 20% to elapsed time, at any two time points 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.degree. C. 3. A method of preparing a solid controlled release dosage form comprising: dispersing hydrocodone or a pharmaceutically acceptable salt thereof in a controlled release excipient to form a blend; compressing a therapeutically effective amount of the blend to form a dosage form wherein the inner 60% of the dosage form contains 80% to less than 100% of the hydrocodone or salt thereof; wherein the amount of hydrocodone or salt thereof 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.degree. C. 4. The method of preparing a solid controlled release dosage form of claim 2, wherein the hydrocodone or pharmaceutically acceptable salt thereof is hydrocodone bitartrate. 5. The method of preparing a solid controlled release dosage form of claim 4, wherein total amount of hydrocodone bitartrate in the dosage form is from about 0.5 mg to about 1250 mg. 6. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form provides a C.sub.24/C.sub.max ratio of hydrocodone of about 0.55 to about 1.0 after administration of the dosage form. 7. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form provides a T.sub.max (h) of hydrocodone from about 4 to about 20 hours after administration. 8. The method of preparing a solid controlled release dosage form in claim 2, wherein the dosage form provides a C.sub.24/C.sub.max ratio of hydrocodone of about 0.55 to about 1.0 after a first administration to a population of healthy subjects. 9. The method of preparing a solid controlled release dosage form in claim 2, wherein the dosage form provides a C.sub.24/C.sub.max ratio of hydrocodone of about 0.55 to about 1.0 after a steady state administration to a healthy subject. 10. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form contains about 20 mg hydrocodone or a pharmaceutically acceptable salt thereof. 11. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form contains about 120 mg hydrocodone or a pharmaceutically acceptable salt thereof. 12. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form provides a mean AUC (ng*h/mL) after administration of about 250 to 400 per each 20 mg hydrocodone included in the dosage form. 13. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form provides a mean C.sub.max (ng/mL) after administration of about 10 to about 30 per each 20 mg hydrocodone included in the dosage form. 14. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form provides a mean T.sub.max (h) after administration of about 10 to about 20. 15. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form provides a mean T.sub.1/2 (h) after administration of about 5 to about 10. 16. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form provides a mean T.sub.lag (h) after administration of about 0.01 to about 0.2. 17. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form provides a mean hydrocodone C.sub.24/C.sub.max ratio is about 0.2 to about 0.8 after administration. 18. The method of preparing a solid controlled release dosage form in claim 2, wherein the dosage form provides a mean AUC (ng*h/mL) after administration in a fasted state of about 250 to 400 per each 20 mg hydrocodone included in the dosage form. 19. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form provides a mean AUC (ng*h/mL) after administration in the fed state that is less than 20% higher than the AUC (ng*h/mL) after administration in the fasted state. 20. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form provides a mean C.sub.max (ng/mL) after administration in the fed state that is less than 80% higher than the C.sub.max after administration in the fasted state. 21. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form provides a mean T.sub.max (h) after administration in the fed state that is within 25% of the T.sub.max (h) after administration in the fasted state. 22. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form provides a mean T.sub.1/2 (h) after administration in the fed state that is within 8% of the T.sub.1/2 after administration in the fasted state. 23. The method of preparing a solid controlled release dosage form of claim 2, wherein the dosage form provides a mean T.sub.lag (h) after administration in the fed state that is less than 150% higher than the T.sub.1/2 after administration in the fasted state.