Claims for Patent: 9,855,258

Summary for Patent: 9,855,258

Title:	Dose-dumping resistant controlled release dosage form
Abstract:	The present invention provides a simple and improved dosage 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:	US15/624,209
Patent Claims:	1. An osmotic device comprising a core comprising methylphenidate or salt thereof, a semipermeable membrane enclosing the core, and a rapid release or immediate release coating comprising methylphenidate or salt thereof surrounding the semipermeable membrane, wherein: a) the osmotic device exhibits a less than 1.5-fold ethanol-related increase in the total amount of methylphenidate (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.; b) 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.; and c) the osmotic device provides a controlled release of MPH from the core for a period of at least 8 h according to a first order, pseudo-first order, zero order or pseudo-zero order release profile, and does not provide a continuously ascending rate of release over a period of at least 8 hours. 2. An osmotic device comprising a bi-layered core comprising methylphenidate or salt thereof, a semipermeable membrane enclosing the core, and a rapid release or immediate release coating comprising methylphenidate or salt thereof surrounding the semipermeable membrane, wherein: a) the osmotic device exhibits a less than 1.5-fold ethanol-related increase in the total amount of methylphenidate (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.; b) 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.; c) the bi-layered core comprises: 1) a pull layer comprising of MPH or salt thereof, and at least one water swellable polymer; and 2) a push layer comprising at least one water swellable polymer and osmotic salt, wherein the weight ratio of pull layer to push layer is at least 1.1:1; d) the semipermeable membrane comprises at least one preformed passageway, 1-10% wt of at least one plasticizer, and 90-99% wt of a single grade of cellulose acetate polymer characterized by an acetyl content of about 39-40% wt and a hydroxyl content of about 3-4% wt; and e) the osmotic device provides a controlled release of MPH from the core for a period of at least 8 h according to a first order, pseudo-first order, zero order or pseudo-zero order release profile, and does not provide a continuously ascending rate of release over a period of at least 8 hours. 3. The osmotic device of claim 2, wherein: a) the osmotic device comprises a total dose of about 2.5 mg to about 90 mg of MPH or salt thereof; and b) the total dose of MPH or salt thereof is divided as follows: 1) 1-40% wt in the rapid release or immediate release coating and 99-60% wt in the pull layer; or 2) 20% wt or less in the rapid release or immediate release coating and about 80% wt or more in the pull layer. 4. The osmotic device of claim 3, wherein: a) the pull layer comprises MPH or salt thereof, first water swellable poly(alkylene oxide) polymer, first hydrophilic cellulose derivative, and acidic agent; and b) the push layer comprises second water swellable poly(alkylene oxide) polymer, second hydrophilic cellulose derivative, and osmotic salt. 5. The osmotic device of claim 4, wherein: a) the first water swellable poly(alkylene oxide) polymer is present in a greater amount than the first hydrophilic cellulose derivative; and b) the second water swellable poly(alkylene oxide) polymer is present in a greater amount than the second hydrophilic cellulose derivative. 6. The osmotic device of claim 4, wherein the total dose of MPH or salt thereof is divided as follows: 10-40% wt in the rapid release or immediate release coating and 90-60% wt in the pull layer. 7. The osmotic device of claim 2, wherein: a) the pull layer comprises MPH or salt thereof, first water swellable poly(alkylene oxide) polymer, first hydrophilic cellulose derivative and acidic agent; b) the push layer comprises second water swellable poly(alkylene oxide) polymer, second hydrophilic cellulose derivative, and osmotic salt. 8. The osmotic device of claim 7, wherein: a) the first water swellable poly(alkylene oxide) polymer is present in a greater amount than the first hydrophilic cellulose derivative; and b) the second water swellable poly(alkylene oxide) polymer is present in a greater amount than the second hydrophilic cellulose derivative. 9. The osmotic device of claim 8, wherein the weight ratio of pull layer to push layer is about 1.1:1 to about 2:1. 10. The osmotic device of claim 7, wherein the total dose of MPH or salt thereof is divided as follows: 10-40% wt in the rapid release or immediate release coating and 90-60% wt in the pull layer. 11. The osmotic device of claim 2, wherein the total dose of MPH or salt thereof is about 2.5 mg, about 5 mg, about 7.5 mg, about 9 mg, about 10 mg, about 12.5 mg, about 14 mg, about 15 mg, about 17.5 mg, about 18 mg, about 20 mg, about 25 mg, about 27 mg, about 30 mg, about 35 mg, about 36 mg, about 40 mg, about 45 mg, about 50 mg, about 54 mg, about 60 mg, about 63 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 81 mg, or about 90 mg. 12. The osmotic device of claim 7, wherein the hydrophilic cellulose derivative is independently selected upon each occurrence from the group consisting of alkylcellulose, hydroxyalkylcellulose and hydroxyalkyl alkylcellulose. 13. The osmotic device of claim 7, wherein the first and second water swellable poly(alkylene oxide) polymers are poly(ethylene oxide) polymers. 14. The osmotic device of claim 13, 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. 15. The osmotic device of claim 2, wherein the osmotic device 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: Time (% wt) mean (% wt) mean (% wt) mean (% wt) mean (hr) range range range range 1 20-30 15-25 15-25 2 25-35 25-35 25-35 25-35 4 45-60 45-60 45-60 42-60 6 68-85 62-85 65-85 58-80 8 90-100 80-95 85-100 71-95 10 91-100 85-100 ≧85 79-100 wherein the percentage released is based upon the total weight of MPH or salt thereof in the osmotic device when the osmotic device is placed in water or aqueous 0.1 N hydrochloric acid at 37±1° C. in a USP Apparatus type 7. 16. The osmotic device of claim 2, wherein MPH is present as a mineral acid salt. 17. The osmotic device of claim 16, wherein the MPH salt and the osmotic salt have an ion in common. 18. An osmotic device comprising a bi-layered core, a semipermeable membrane enclosing the core, and a rapid release or immediate release coating surrounding the semipermeable membrane, wherein: a) the osmotic device exhibits a less than 1.5-fold ethanol-related increase in the total amount of methylphenidate (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.; b) 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.; c) the bi-layered core comprises: 1) a pull layer comprising MPH or salt thereof, first water swellable poly(alkylene oxide) polymer, first hydrophilic cellulose derivative, and acidic agent; and 2) a push layer comprising second water swellable poly(alkylene oxide) polymer, second hydrophilic cellulose derivative, and osmotic salt, wherein: i) the weight ratio of pull layer to push layer is at least 1.1:1; ii) the first water swellable poly(alkylene oxide) polymer is present in a greater amount than the first hydrophilic cellulose derivative; and iii) the second water swellable poly(alkylene oxide) polymer is present in a greater amount than the second hydrophilic cellulose derivative; d) the semipermeable membrane comprises at least one preformed passageway, 1-10% wt of at least one plasticizer, and 90-99% wt of a single grade of cellulose acetate polymer characterized by an acetyl content of about 39-40% wt and a hydroxyl content of about 3-4% wt; e) the osmotic device provides a controlled release of MPH from the core for a period of at least 8 h according to a first order, pseudo-first order, zero order or pseudo-zero order release profile, and does not provide a continuously ascending rate of release over a period of at least 8 hours; and f) the total dose of MPH or salt thereof in the osmotic device is divided as follows: 10-40% wt in the rapid release or immediate release coating and 90-60% wt in the pull layer. 19. The osmotic device of claim 18, wherein the total dose of MPH or salt thereof is about 2.5 mg, about 5 mg, about 7.5 mg, about 9 mg, about 10 mg, about 12.5 mg, about 14 mg, about 15 mg, about 17.5 mg, about 18 mg, about 20 mg, about 25 mg, about 27 mg, about 30 mg, about 35 mg, about 36 mg, about 40 mg, about 45 mg, about 50 mg, about 54 mg, about 60 mg, about 63 mg, about 70 mg, about 72 mg, about 75 mg, about 80 mg, about 81 mg, or about 90 mg. 20. The osmotic device of claim 18, wherein: a) the pull layer comprises MPH or salt thereof, about 5% to about 85% wt of first water swellable poly(alkylene oxide) polymer, about 2% to about 20% wt of first hydrophilic cellulose derivative, and about 5% to about 20% wt of acidic agent; b) the push layer comprises about 5% to about 85% wt of second water swellable poly(alkylene oxide) polymer, about 2% to about 20% wt of second hydrophilic cellulose derivative, and about 10% to about 40% wt of osmotic salt. 21. The osmotic device of claim 20, wherein the hydrophilic cellulose derivative is independently selected upon each occurrence from the group consisting of alkylcellulose, hydroxyalkylcellulose and hydroxyalkyl alkylcellulose. 22. The osmotic device of claim 20, wherein the first and second water swellable poly(alkylene oxide) polymers are poly(ethylene oxide) polymers. 23. The osmotic device of claim 22, 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. 24. The osmotic device of claim 18, wherein the osmotic device 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: Time (% wt) mean (% wt) mean (% wt) mean (% wt) mean (hr) range range range range 1 20-30 15-25 15-25 2 25-35 25-35 25-35 25-35 4 45-60 45-60 45-60 42-60 6 68-85 62-85 65-85 58-80 8 90-100 80-95 85-100 71-95 10 91-100 85-100 ≧85 79-100 wherein the percentage released is based upon the total weight of MPH or salt thereof in the osmotic device when the osmotic device is placed in water or aqueous 0.1 N hydrochloric acid at 37±1° C. in a USP Apparatus type 7. 25. The osmotic device of claim 18, wherein MPH is present as MPH hydrochloride. 26. The osmotic device of claim 25, wherein the osmotic salt is sodium chloride or potassium chloride. 27. A method of treating a condition that is therapeutically responsive to MPH or salt thereof, the method comprising orally administering at least one osmotic device according to claim 1. 28. The method of claim 27, wherein the condition is selected from the group consisting of attention deficit hyperactivity disorder, narcolepsy, postural orthostatic tachycardia syndrome, lethargy, fatigue, bipolar disorder, lack of attention (lack of attentiveness), opioid induced somnolence, major depressive disorder and obesity. 29. The method of claim 27, wherein oral administration to a subject in the fasted state of a single osmotic device comprising about a 72 mg dose of MPH or salt thereof provides a pharmacokinetic profile defined approximately as follows: Fasted OSM Standard Parameter (mean) deviation Tmax (h) 5.68 0.96 Cmax (ng/mL) 20.6 6.24 AUCinf (h * ng/mL) 218.1 83.78. 30. The method of claim 27, wherein oral administration in the fasted or fed state of a single osmotic device comprising about a 54 mg dose of MPH or salt thereof 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.