Claims for Patent: 9,707,217

Summary for Patent: 9,707,217

Title:	Dose-dumping resistant controlled release dosage form
Abstract:	The present invention provides a simple and improved dose form that is capable of providing a controlled release of methylphenidate contained in the core thereof. The invention also provides methods of administering the dosage form and of treating conditions that are therapeutically responsive to methylphenidate. The dosage form exhibits improved resistance to alcohol-related dose dumping.
Inventor(s):	Hernan D. Benedetti, Cristian R. FRANCO, Guido S. BIGATTI, Joaquina Faour, Ana C. PASTINI
Assignee:	Acella Pharmaceuticals LLC
Application Number:	US15/424,134
Patent Claims:	1. An osmotic device comprising a core and a semipermeable membrane enclosing the core, wherein the osmotic device provides a release of methylphenidate hydrochloride (MPH-HCl) from the core according to the following release profile when the osmotic device is placed in 40% ethanol in 0.1 N hydrochloric acid at 37±1° C. in a USP Apparatus type 7 Time Released (min) (% wt) 15 <1 30 2-4 45 2.5-4.5 60 3.5-5.5 75 4.7-6.7 90 6.2-8.2 105 7.7-9.7 120 9-11 wherein the percentage released is based upon the weight of MPH-HCl in the core. 2. The osmotic device of claim 1, wherein the osmotic device provides a release of MPH-HCl from the core according to the following release profile when the osmotic device is placed in 0.1 N hydrochloric acid at 37±1° C. in a USP Apparatus type 7 Time Released (min) (% wt) 15 <1 30 1-3 45 1-3.5 60 2-4 75 3-5 90 5-7 105 6-8 120 7.5-9.5 wherein the percentage released is based upon the weight of MPH-HCl in the core. 3. The osmotic device of claim 1, wherein the osmotic device provides a release of MPH-HCl from the core according to the following release profile when the osmotic device is placed in water at 37±1° C. in a USP Apparatus type 7 Time Released (hr) (% wt) Median or mean range 1 <10 2 10-30 4 35-60 6 55-85 8 70-100 10 80-100 wherein the percentage released is based upon the weight of MPH-HCl in the core. 4. The osmotic device of claim 1, wherein the osmotic device comprises a) a bi-layered core comprising: a pull layer comprising MPH-HCl, first water swellable poly(alkylene oxide) polymer, first hydrophilic cellulose derivative and acidic agent; and a push layer comprising second water swellable poly(alkylene oxide) polymer, second hydrophilic cellulose derivative, and osmotic salt; and b) a semipermeable membrane enclosing the core and comprising at least one preformed passageway and at least one cellulose acetate polymer. 5. The osmotic device of claim 4, wherein the semipermeable membrane comprises at least one preformed passageway, at least one plasticizer and a single grade of cellulose acetate polymer, wherein the cellulose acetate polymer is characterized by an acetyl content of about 39-40% wt and a hydroxyl content of about 3-4% wt. 6. An osmotic device comprising a core, a semipermeable membrane enclosing the core, and a drug-containing coating exterior to the semipermeable membrane, wherein the osmotic device provides a release of methylphenidate hydrochloride (MPH-HCl) according to one of the following release profiles when the osmotic device is placed in 40% ethanol in 0.1 N hydrochloric acid at 37±1° C. in a USP Apparatus type 7 released (% wt) released (% wt) Time Median or mean Median or mean (min) range range 15 4-12 11-20 30 7-15 12-22 45 8-16 13-23 60 9-17 15-25 75 10-18 18-28 90 12-19 19-30 105 13-21 22-34 120 15-22 24-39 wherein the percentage released is based upon the total weight of MPH-HCl in the osmotic device. 7. The osmotic device of claim 6, wherein the osmotic device provides a release of methylphenidate hydrochloride (MPH-HCl) according to one of the following release profiles when the osmotic device is placed in aqueous 0.1 N hydrochloric acid at 37±1° C. in a USP Apparatus type 7 released (% wt) released (% wt) Time Median or mean Median or mean (min) range range 1 20-30 15-25 2 25-35 25-35 4 45-60 42-60 6 68-85 58-85 8 90-100 71-95 10 91-100 79-100 wherein the percentage released is based upon the total weight of MPH-HCl in the osmotic device. 8. The osmotic device of claim 6, wherein the osmotic device comprises a) a bi-layered core comprising: a pull layer comprising MPH-HCl, first water swellable poly(alkylene oxide) polymer, first hydrophilic cellulose derivative and acidic agent; and a push layer comprising second water swellable poly(alkylene oxide) polymer, second hydrophilic cellulose derivative, and osmotic salt; b) a semipermeable membrane enclosing the core and comprising at least one preformed passageway, at least one plasticizer and at least one cellulose acetate polymer; and c) a rapid release or immediate release drug-containing coating exterior to the semipermeable membrane and comprising MPH-HCl. 9. The osmotic device of claim 8, wherein the semipermeable membrane comprises at least one preformed passageway, at least one plasticizer and a single grade of cellulose acetate polymer. 10. The osmotic device of claim 9, wherein the cellulose acetate polymer is characterized by an acetyl content of about 39-40% wt and a hydroxyl content of about 3-4% wt. 11. An osmotic device comprising methylphenidate (MPH) or salt thereof, wherein the osmotic device exhibits a less than 1.5-fold ethanol-related increase in the total amount of MPH or salt thereof released from the device during the first 120 minutes when comparing the MPH or salt thereof release rates in aqueous 0.1 N HCl at 37±1° C. and in 40% ethanol in aqueous 0.1 N HCl at 37±1° C.; wherein about 25% to about 35% wt of MPH or salt thereof is released by about 2 hours, about 45% to about 60% wt of MPH or salt thereof is released by about 4 hours, about 65% to about 85% of MPH or salt thereof is released by about 6 hours, about 85% to about 100% wt of MPH or salt thereof is released by about 8 hours and no less than 85% of MPH or salt thereof is released b about 10 hours after placement in an environment of use or after oral administration. 12. The osmotic device of claim 11, wherein the osmotic device exhibits a less than 2-fold ethanol-related increase in the average rate of MPH or salt thereof released from the device during the time period of 15 minutes to 120 minutes when comparing the release rates in aqueous 0.1 N HCl at 37±1° C. and in 40% ethanol in aqueous 0.1 N HCl at 37±1° C. 13. The osmotic device of claim 11, wherein the osmotic device comprises a bi-layered core enclosed within a semipermeable membrane, and wherein: a) the bi-layered core comprises: a pull layer comprising MPH or salt thereof; and a push layer comprising at least one water swellable polymer; and b) the semipermeable membrane comprises at least one preformed passageway, at least one plasticizer and at least one cellulose ester. 14. The osmotic device of claim 13, wherein the semipermeable membrane comprises at least one preformed passageway, at least one plasticizer and a single grade of cellulose acetate polymer, and the cellulose acetate polymer is characterized by an acetyl content of about 39-40% wt and a hydroxyl content of about 3-4% wt. 15. The osmotic device of claim 13, wherein the bi-layered core comprises: a pull layer comprising MPH or salt thereof, and first water swellable polymer; and a push layer comprising second water swellable polymer. 16. The osmotic device of claim 13, wherein the pull layer comprises MPH or salt thereof, first water swellable polymer, and first hydrophilic polymer; and the push layer comprises second water swellable polymer, and second hydrophilic polymer. 17. The osmotic device of claim 13, wherein the pull layer comprises MPH or salt thereof, first water swellable polymer, first hydrophilic polymer and acidic agent; and the push layer comprises second water swellable polymer, second hydrophilic polymer, and osmotic salt. 18. The osmotic device of claim 17, wherein the first and second water-swellable polymers are poly(alkylene oxide) polymers and the first and second hydrophilic polymers are hydrophilic cellulose derivatives. 19. The osmotic device of claim 13, wherein the pull layer comprises MPH or salt thereof, first water swellable poly(alkylene oxide) polymer, first hydrophilic cellulose derivative and acidic agent; and the push layer comprises second water swellable poly(alkylene oxide) polymer, second hydrophilic cellulose derivative, and osmotic salt. 20. The osmotic device of claim 19, wherein the first hydrophilic cellulose derivative is a different type and/or grade than the second hydrophilic cellulose derivative. 21. The osmotic device of claim 19, wherein the first hydrophilic cellulose derivative is the same type and/or grade as the second hydrophilic cellulose derivative. 22. The osmotic device of claim 19, wherein the hydrophilic cellulose derivative is independently selected upon each occurrence from the group consisting of alkylcellulose, hydroxyalkylcellulose and hydroxyalkyl alkylcellulose. 23. The osmotic device of claim 19, wherein the first and second poly(alkylene oxide) polymers are poly(ethylene oxide) polymers. 24. The osmotic device of claim 23, wherein the first water swellable poly(alkylene oxide) polymer has a lower viscosity and molecular weight than the second water swellable poly(alkylene oxide) polymer. 25. The osmotic device of claim 13 further comprising a rapid release or immediate release MPH- or MPH salt-containing coating exterior to the semipermeable membrane. 26. The osmotic device of claim 13, wherein the MPH or salt thereof is divided between the drug-containing coating and the core according to the following proportions: 1-40% wt in the coating and 99-60% wt in the core, 10-40% wt in the coating and 90-60% wt in the core, 15-35% wt in the coating and 85-65% wt in the core, 15-25% wt in the coating and 85-75% wt in the core, 15-20% wt in the coating and 85-80% wt in the core, 20% wt or less in the coating and 80% wt or more in the core, about 18% wt in the coating and about 82% wt in the core, or about 22% wt in the coating and about 78% wt in the coated core. 27. The osmotic device of claim 13, wherein the dosage form exhibits an in vitro release profile selected from any one of the following for MPH or salt thereof released from the core and the exterior drug-containing coating: Deionized water Deionized water Deionized water Dissolution Dissolution Dissolution Time (% wt) Median (% wt) Median (% wt) Median (hr) or mean range or mean range or mean range 1 20-30 22-27 21-27 2 25-35 29-33 27-34 4 45-60 51-57 46-57 6 68-85 74-83 68-83 8 90-100 97-100 92-100 10 91-100 99-100 95-100. 28. The osmotic device of claim 13, wherein the core exhibits a weight ratio of pull layer to push layer of at least 1, at least 1.1, at least 1.2, at least 1.3 at least 1.4, at least 1.5, at least 1.6, 1.1 to 2, 1.2 to 1.7, 1.3 to 1.7, 1.4 to 1.7, or 1.4-1.6; and not less than 1, not less than 0.9, or not less than 0.8. 29. The osmotic device of claim 6, wherein oral administration in the fasted or fed state of the osmotic device comprising a 54 mg dose of MPH provides a pharmacokinetic profile defined approximately as follows: Fed Fasted OSM Standard OSM Standard Parameter (mean) deviation (mean) deviation Tmax (h) 5.7 2.3 6 1 Cmax (ng/mL) 16 4.8 15 6 AUCinf (h * ng/mL) 180 54 180 82.