Claims for Patent: 11,590,081

Summary for Patent: 11,590,081

Title:	Extended release amphetamine tablets
Abstract:	An oral amphetamine extended release solid dose is described. The compositions contain a combination of an uncoated amphetamine-cation exchange resin complex, a barrier coated amphetamine—cation exchange resin complex—matrix, and an uncomplexed amphetamine, wherein one or more of these components contains blends of different forms of amphetamines. Either the modified release coated and/or the uncoated amphetamine—cation exchange resin complex may have two forms of amphetamine in a complex with a single cation exchange resin. Following administration of a single dose of the composition, a therapeutically effective amount of amphetamine is reached by about one hour and the composition provides at least a thirteen hour effect post-dose.
Inventor(s):	Ketan Mehta, Kalyan Kathala
Assignee:	Tris Pharma Inc
Application Number:	US16/139,251
Patent Claims:	1. An extended release amphetamine tablet, wherein the tablet provides a single plasma concentration peak for d-amphetamine and for l-amphetamine, wherein the tablet lacks a pH-dependent coating which provides delayed release to an amphetamine component, and wherein the tablet further comprises: (A) a modified release amphetamine component which comprises at least one modified release barrier coated amphetamine—cation exchange resin complex—optional matrix which comprises (i) two or more amphetamines bound to the same cation exchange resin, wherein when the optional matrix is present, the amphetamine—cation exchange resin complex—matrix further comprises a hydrophilic polymer or copolymer or a hydrophobic polymer and (ii) a pH-independent barrier coating which provides a modified release to the two or more amphetamines, wherein the two or more amphetamines are at least a d-amphetamine and an l-amphetamine, wherein the d-amphetamine and the l-amphetamine are provided by d-amphetamine and at least one of (d,l)-amphetamine and l-amphetamine, wherein the modified release amphetamine component (A) comprises at least 5% w/w of the total amphetamines in the tablet based on the weight of free amphetamine base; and (B) immediate release amphetamine components which comprise greater than 70% w/w of the total amphetamines in the tablet based on the total weight of free amphetamine base in the tablet, and wherein the immediate release amphetamine components further comprise: (i) a first immediate release amphetamine component which comprises d-amphetamine or a pharmaceutically acceptable salt thereof, and l-amphetamine or a pharmaceutically acceptable salt thereof, or mixtures thereof, wherein the d- and l-amphetamine are provided by d-amphetamine and at least one of (d,l)-amphetamine and l-amphetamine, wherein the immediate release amphetamine component B(i) comprises at least 5% w/w of the total amphetamines in the tablet based on the weight of free amphetamine base; and (ii) a second immediate release amphetamine component which comprises an amphetamine—cation exchange resin complex in an optional matrix, wherein the amphetamine—cation exchange resin complex—optional matrix comprises at least a d-amphetamine (d, l)-amphetamine and an l-amphetamine both bound to the same cation exchange resin, wherein the d-amphetamine and the l-amphetamine are provided by d-amphetamine and at least one of (d, l)-amphetamine or l-amphetamine, wherein the immediate release component B(ii) comprises at least 5% w/w of the total amphetamines in the tablet based on the weight of the free amphetamine base. 2. The tablet according to claim 1, wherein the amphetamines in first and second immediate release amphetamine component of (B) are about 80% w/w of the amphetamines in the total tablet. 3. The tablet according to claim 2, wherein the amphetamines in the first immediate release amphetamine component of (B)(i) are about 20% w/w of the total amphetamines in the tablet. 4. The tablet according to claim 2, wherein the amphetamines in the second immediate release amphetamine component (B)(ii) are about 60% w/w of the total amphetamines in the tablet. 5. The tablet according to claim 1, wherein the tablet comprises one or more of the pharmacokinetic parameters for d-amphetamine following dosing subjects under fasted conditions with the tablet comprising the equivalent of 20 mg total amphetamines: (a) as determined following a chewed dose: an arithmetic mean AUC0-∞ of about 965 to about 1508 ng-h/mL, a geometric mean AUC0-∞ of about 931 ng-h/mL to about 1455 ng-h/mL h/mL, an arithmetic mean AUC0-2 of about 24.8 ng-h/mL to about 38.79 ng-h/mL or a geometric mean AUC0-2 of about 22.85 ng-hr/mL to about 35.72 ng-hr/mL, an arithmetic mean AUC0-5 of about 138 ng-h/mL to about 216 ng-h/mL or a geometric mean AUC0-5 of about 134 ng-hr/mL to about 209 ng-hr/mL, an arithmetic mean AUC5-t 767 ng-hr/mL to about 1199 ng-hr/mL or a geometric mean AUC5-t of about of about 740 ng-h/mL to about 1156 ng-h/mL, an arithmetic mean Cmax of about 44 ng/mL to about 69 ng/mL, a geometric mean Cmax of about 43 ng/mL to about 68 ng/mL, or a Tmax of about 3 hours to about 7 hours, or (b) for a whole swallowed tablet dose: an arithmetic AUC0-∞ of about 972 to about 1519 ng-h/mL, a geometric mean AUC0-∞ of about 948 ng-h/mL to about 1481 ng-h/mL h/mL, an arithmetic mean AUC0-2 of about 26.30 ng-h/mL to about 41.10 ng-h/mL or a geometric mean AUC0-2 of about 24.48 ng-hr/mL to about 38.25 ng-hr/mL, an arithmetic mean AUC0-5 of about 141 ng-h/mL to about 220 ng-h/mL or a geometric mean AUC0-5 of about 138 ng-hr/mL to about 215 ng-hr/mL, an arithmetic mean AUC5-t of about 768 ng-h/mL to about 1200 ng-h/mL, or a geometric mean AUC5-t of about 749 ng-hr/mL to about 1170 ng-hr/mL, an arithmetic mean Cmax of about 42 ng/mL to 66 ng/mL, a geometric mean Cmax of about 42 ng/mL to 66 ng/mL, an arithmetic mean or a Tmax of about 2 hours to about 9 hours. 6. The tablet according to claim 5, wherein the tablet comprises one or more of the pharmacokinetic parameters for d-amphetamine following dosing subjects under fasted conditions with the tablet comprising the equivalent of 20 mg total amphetamines: for a chewed dose: an arithmetic mean AUC0-∞ of about 1206 ng-h/mL, a geometric mean AUC0-∞ of about 1164 ng-hr/mL, an arithmetic mean AUC0-2 of about 31 ng-h/mL, a geometric mean AUC0-2 of about 29 ng-hr/mL, an arithmetic mean AUC0-5 of about 173 ng-h/mL, a geometric mean AUC0-5 of about 167 ng-hr/mL, an arithmetic mean AUC5-t of about 959 ng-h/mL, a geometric mean AUC5-t of about 925 ng-hr/mL, an arithmetic mean Cmax of about 55 ng/mL, a geometric mean cmax of about 54 ng/mL, or a Tmax of about 5 hours; or for a whole swallowed dose: an arithmetic mean AUC0-∞ of about 1215 ng-h/mL, a geometric mean AUC0-∞ of about 1185 ng-hr/mL, an arithmetic mean AUC0-2 of about 33 ng-h/mL, a geometric mean AUC0-2 of about 31 ng-hr/mL, an arithmetic mean AUC0-5 of about 176 ng-h/mL, a geometric mean AUC0-5 of about 172 ng-hr/mL, an arithmetic mean AUC5-t of about 960 ng-h/mL, a geometric mean AUC5-t of about 936 ng-hr/mL, an arithmetic mean Cmax of about 53 ng/mL, a geometric mean Cmax of about 53 ng/mL, or a Tmax of about 5 hours. 7. The tablet according to claim 1, wherein the tablet comprises one or more of the pharmacokinetic parameters for l-amphetamine following dosing subjects under fasted conditions with the tablet comprising the equivalent of 20 mg total amphetamines: (a) as determined following a chewed dose: an arithmetic mean AUC0-∞ of about 378 to about 591 ng-h/mL, a geometric mean AUC0-∞ of about 362 ng-h/mL to about 566 ng-h/mL, an arithmetic mean AUC0-2 of about 7.57 ng-h/mL to about 11.85 ng-h/mL or a geometric mean AUC0-2 of about 6.97 ng-hr/mL to about 10.89 ng-hr/mL, an arithmetic mean AUC0-5 of about 43 ng-h/mL to about 68 ng-h/mL, a geometric mean AUC0-5 of about 42 ng-hr/mL to about 65 ng-hr/mL, an arithmetic mean AUC5-t 292 ng-hr/mL to about 456 ng-hr/mL, a geometric mean AUC5-t of about 280 ng-h/mL to about 438 ng-h/mL, an arithmetic mean Cmax of about 13.6 ng/mL to about 21.25 ng/mL, a geometric mean Cmax of about 3.6 ng/mL to about 21.25 ng/mL, or a Tmax of about 3 hours to about 7 hours, or (b) as determined following a whole swallowed dose: an arithmetic mean AUC0-∞ of about 385 ng-h/mL to about 601 ng-h/mL, a geometric mean AUC0-∞ of about 373 ng-h/mL to about 583 ng-h/mL h/mL, an arithmetic mean AUC0-2 of about 8.09 ng-h/mL to about 12.64 ng-h/mL or a geometric mean AUC0-2 of about 7.49 ng-hr/mL to about 11.71 ng-hr/mL an arithmetic mean AUC0-5 of about 44 ng-h/mL to about 69 ng-h/mL, a geometric mean AUC0-5 of about 43 ng-hr/mL to about 68 ng-hr/mL, an arithmetic mean AUC5-t of about 294 ng-hr/mL to about 459 ng-hr/mL, a geometric mean AUC5-t of about 286 ng-h/mL to about 446 ng-h/mL, an arithmetic mean Cmax of about 13.6 ng/mL to about 21.25 ng/mL, a geometric mean Cmax of about 3.6 ng/mL to about 21.25 ng/mL, or a Tmax of about 2 hours to about 9 hours. 8. The tablet according to claim 7, wherein the tablet comprises one or more of the pharmacokinetic parameters for l-amphetamine following dosing subjects under fasted conditions with the tablet comprising 20 mg total amphetamines: (a) for a chewed dose: an arithmetic mean AUC0-∞ of about 473 ng-h/mL, a geometric mean AUC0-∞ of about 453 ng-hr/mL, an arithmetic mean AUC0-2 of about 8.43 ng-h/mL, a geometric mean AUC0-2 of about 7.65 ng-hr/mL an arithmetic mean AUC0-5 of about 54 ng-h/mL, a geometric mean AUC0-5 of about 52 ng-hr/mL, an arithmetic mean AUC5-t of about 365 ng-h/mL, a geometric mean AUC5-t of about 350 ng-hr/mL, an arithmetic mean Cmax of about 17 ng/mL, a geometric mean Cmax of about 17 ng/mL, or a median Tmax of about 5 hours; or (b) for a whole swallowed dose: an arithmetic mean AUC0-∞ of about 481 ng-h/mL, a geometric mean AUC0-∞ of about 466 ng-hr/mL, an arithmetic mean AUC0-5 of about 55 ng-h/mL, an arithmetic mean AUC0-2 of about 10.11 ng-h/mL, a geometric mean AUC0-2 of about 9.64 ng-hr/mL a geometric mean AUC0-5 of about 54 ng-hr/mL, an arithmetic mean AUC5-t of about 367 ng-h/mL, a geometric mean AUC5-t of about 357 ng-hr/mL, an arithmetic mean cmax of about 17 ng/mL, a geometric mean cmax of about 17 ng/mL, or a median Tmax of about 5 hours. 9. The tablet according to claim 1, wherein the tablet has a plasma pharmacokinetic profile for d-amphetamine which is about 80% to about 125% of one or more of: a geometric mean AUCt of about 821 ng-h/mL, a geometric mean AUCinf of about 1013 ng-h/mL, a geometric mean Cmax of about 53 ng/mL, a geometric mean Tmax of about 3.85, an arithmetic mean AUCt of about 857 ng-h/mL, an arithmetic mean about AUCinf of about 1061 ng-h/mL, an arithmetic mean Cmax of about 55 ng/mL, or an arithmetic mean Tmax of about 4, as measured in children 6-12 years old under fasting conditions following dosing with the tablet having the equivalent of 20 mg of amphetamine base; or an arithmetic mean AUC0-4 of about 144 ng-h/mL, an arithmetic mean AUC4-t of about 1000 ng-h/mL, an arithmetic mean AUC0-5 of about 196 ng-h/mL, an arithmetic mean AUC5-t of about 948 ng-h/mL, a geometric mean AUC0-4 of about 139 ng-h/mL, a geometric mean AUC4-t of about 977 ng-h/mL, a geometric mean AUC0-5 of about 191 ng-h/mL, or a geometric mean AUC5-t of about 926 ng-h/mL, as measured in children 6-12 years old under fasting conditions following dosing with the tablet having the equivalent of 20 mg of amphetamine base. 10. The tablet according to claim 9, wherein the pharmacokinetic profile for d-amphetamine is about 90% to about 110% of one or more of the arithmetic mean, a geometric mean AUCt, geometric mean AUCinf, a geometric mean Cmax, a geometric mean Tmax, arithmetic mean AUCt, an arithmetic mean about AUCinf, arithmetic mean Cmax, or an arithmetic mean Tmax, or arithmetic mean AUC0-4, arithmetic mean AUC4-t, arithmetic mean AUC0-5, arithmetic mean AUC5-t, geometric mean AUC0-4, geometric mean AUC4-t, a geometric mean AUC0-5, or a geometric mean AUC5-t, as determined using a 90% confidence interval. 11. The tablet according to claim 1, wherein the tablet has a plasma pharmacokinetic profile for l-amphetamine which is about 80% to about 125% of one or more of one or more: a geometric mean AUCt of about 274 ng-h/mL, a geometric mean about AUCinf of about 362 ng-h/mL, a geometric mean cmax of about 16 ng/mL, a geometric mean Tmax of about 4.5, an arithmetic mean AUCt of about 286 ng-h/mL, an arithmetic mean about AUCinf of about 380 ng-h/mL, an arithmetic mean Cmax of about 17 ng/mL, or an arithmetic mean Tmax of about 4.5, as measured in children 6-12 years old under fasting conditions following dosing with the tablet having the equivalent of 20 mg of amphetamine base; or an arithmetic mean AUC0-4 of about 45 ng-h/mL, an arithmetic mean AUC4-t of about 380 ng-h/mL, an arithmetic mean AUC0-5 of about 62 ng-h/mL, an arithmetic mean AUC5-t of about 363 ng-h/mL, a geometric mean AUC0-4 of about 44 ng-h/mL, a geometric mean AUC4-t of about 370 ng-h/mL, a geometric mean AUC0-5 of about 60 ng-h/mL, or a geometric mean AUC5-t of about 354 ng-h/mL, as measured in adults under fasting conditions following dosing with the tablet having the equivalent of 20 mg of amphetamine base. 12. The tablet according to claim 11, wherein the pharmacokinetic profile for l-amphetamine is about 90% to about 110% of one or more of the arithmetic mean, geometric mean AUCt, geometric mean AUCinf, a geometric mean Cmax, a geometric mean Tmax, arithmetic mean AUCt, an arithmetic mean about AUCinf, arithmetic mean Cmax, or an arithmetic mean Tmax, or arithmetic mean AUC0-4, arithmetic mean AUC4-t, arithmetic mean AUC0-5, arithmetic mean AUC5-t, geometric mean AUC0-4, geometric mean AUC4-t, a geometric mean AUC0-5, or a geometric mean AUC5-t, as determined using a 90% confidence interval. 13. The tablet according to claim 1, wherein the modified release component (A) further comprises a water insoluble polymer or copolymer or a hydrophilic polymer which forms a matrix with the amphetamine—cation exchange resin complex of (i). 14. The tablet according to claim 1, wherein the modified release component (A) comprises (d,l)-amphetamine and d-amphetamine. 15. The tablet according to claim 1, wherein the immediate release component (C) comprises (d,l)-amphetamine and d-amphetamine. 16. The tablet according to claim 1, wherein the immediate release amphetamine—cation exchange resin complex of (C) has an optional matrix and a coating that permits release of the amphetamine in less than 45 minutes following administration of the tablet to a patient. 17. The tablet according to claim 1, wherein the immediate release component (B) comprises: (a) (d, l)-amphetamine or a pharmaceutically acceptable salt thereof, and d-amphetamine or pharmaceutically acceptable salt thereof, or a mixture thereof; or (l)-amphetamine or a pharmaceutically acceptable salt thereof, (d)-amphetamine or a pharmaceutically acceptable salt thereof, or mixtures thereof, optionally further comprising (d,l)-amphetamine or a salt thereof. 18. The tablet according to claim 1, wherein the tablet comprises at least two different amphetamine salts counterions. 19. The tablet according to claim 1, wherein the tablet is a chewable tablet. 20. The tablet according to claim 19, wherein the chewable tablet is also an orally dissolving or orally disintegrating or dispersible tablet. 21. The tablet according to claim 15, wherein the barrier coating is pH-independent and comprises (a) a cured, water-permeable, non-ionic, pH-independent barrier coating comprising polyvinylacetate, a stabilizer, and a plasticizer; (b) an ionic, pH-independent, acrylic based coating comprising a polymer or copolymer comprising ethyl acrylate and methyl methacrylate applied as an aqueous dispersion; (c) a solvent-based ethylcellulose, optionally with a plasticize, or (d) cellulose acetate and a plasticizer. 22. The tablet according to claim 15, wherein said tablet does not exceed 500 mg in total weight. 23. The tablet according to claim 15, wherein the therapeutic effect lasts up to about 18 hours following post dose administration to a patient. 24. The tablet according to claim 15, wherein each of the (d,l)-amphetamine and the d-amphetamine of modified release component (A) is bound to a separate cation exchange resin and/or each of the (d,l)-amphetamine and the d-amphetamine of the immediate release component (C) is bound to a separate cation exchange resin. 25. The tablet according to claim 15, wherein the barrier coating is a cured, water-insoluble, water-permeable, non-ionic, pH-independent barrier coating comprises about 70 to about 90% w/w polyvinylacetate, a stabilizer, and about 2 to about 10% w/w of a plasticizer. 26. The tablet according to claim 25, wherein the plasticizer comprises triacetin. 27. An extended release amphetamine solid composition, wherein the composition provides an immediate release and about a 13-hour therapeutic effect for d-amphetamine and for l-amphetamine, a single plasma concentration peak for d-amphetamine and for l-amphetamine, wherein the tablet lacks a pH-dependent coating which provides delayed release to an amphetamine component, and wherein the composition further comprises: (A) about 10% w/w to 30% w/w of a modified release amphetamine component which comprises at least one modified release barrier coated amphetamine—cation exchange resin complex—optional matrix which comprises (i) (d,l)- and (d)-amphetamines bound to the same cation exchange resin, wherein when the optional matrix is present, the amphetamine—cation exchange resin complex—matrix further comprises a hydrophilic polymer or copolymer or a hydrophobic polymer and (ii) a water-insoluble, water-permeable, pH-independent, barrier coating comprising a pH-independent, water-insoluble polymer and a plasticizer, which barrier coating provides a modified release to the amphetamines; (B) a first immediate release amphetamine component which comprises d-amphetamine or a pharmaceutically acceptable salt thereof, and l-amphetamine or a pharmaceutically acceptable salt thereof, or mixtures thereof, wherein the d- and l-amphetamine are provided by d-amphetamine and at least one of (d,l)-amphetamine and l-amphetamine, wherein the total amount of the first immediate release amphetamine component provides at least 15% w/w of the amphetamine components in the composition; and (C) a second immediate release amphetamine component which comprises an amphetamine—cation exchange resin complex in an optional matrix, wherein the amphetamine—cation exchange resin complex—optional matrix comprises at least a d-amphetamine and an l-amphetamine both bound to the same cation exchange resin, wherein the d-amphetamine and the l-amphetamine are provided by d-amphetamine and at least one of (d, l)-amphetamine or l-amphetamine, wherein the total amount of the second immediate release amphetamine component provides at least 15% w/w of the amphetamine components in the composition; and wherein the immediate release component comprises at least 70% w/w immediate release amphetamines based on the total weight of free amphetamine base in the composition. 28. The composition according to claim 27, wherein the composition is an orally dissolving or dispersible tablet. 29. The composition according to claim 27, wherein the composition is a chewable tablet. 30. The composition according to claim 27, wherein the composition is a scored tablet. 31. The composition according to claim 27, wherein the composition comprises a dose of 5 mg to 20 mg amphetamine, as calculated based on the amount of free amphetamine base. 32. A method of treating a patient having attention deficit hyperactivity disorder (ADHD) comprising administering a composition according to claim 1 once a day. 33. A method of treating a patient having attention deficit hyperactivity disorder (ADHD) comprising administering a composition according to claim 27 once a day. 34. An extended release amphetamine tablet, wherein the tablet provides an immediate release and at least about a 13-hour therapeutic effect for d-amphetamine and for l-amphetamine, a single plasma concentration peak for d-amphetamine and for l-amphetamine, and wherein the tablet further comprises: (A) a modified release amphetamine component which comprises at least one modified release barrier coated amphetamine—cation exchange resin complex—optional matrix which comprises (i) two or more amphetamines bound to the same cation exchange resin or each bound to a different cation exchange resin, wherein when the optional matrix is present, the amphetamine—cation exchange resin complex—matrix further comprises a hydrophilic polymer or copolymer or a hydrophobic polymer and (ii) a water-insoluble, water-permeable, pH-independent, barrier coating which provides a modified release to the two or more amphetamines, wherein the two or more amphetamines are at least a d-amphetamine and an l-amphetamine, wherein the d-amphetamine and the l-amphetamine are provided by d-amphetamine and at least one of (d,l)-amphetamine and l-amphetamine, wherein the barrier coating comprises polyvinyl acetate and a plasticizer; and wherein the ratio of d-amphetamine to l-amphetamine is about 3.2 to about 1; (B) immediate release amphetamine components which comprise greater than 60% w/w of the total amphetamines in the tablet based on the total weight of free amphetamine base in the tablet, and wherein the immediate release amphetamine components further comprise: (i) an immediate release amphetamine—cation exchange resin complex in an optional matrix, wherein the amphetamine—cation exchange resin complex—optional matrix comprises at least a d-amphetamine and an l-amphetamine both bound to the same cation exchange resin, wherein the d-amphetamine and the l-amphetamine are provided by d-amphetamine and at least one of (d, l)-amphetamine or l-amphetamine; and (ii) amphetamine aspartate; and (iii) dextroamphetamine sulfate. 35. A method of treating attention deficit hyperactivity disorder once a day comprising providing a chewable extended release tablet to a subject in need thereof in the morning, wherein the tablet comprises: (A) a modified release amphetamine component which comprises at least one modified release barrier coated amphetamine—cation exchange resin complex—optional matrix which comprises (i) two or more amphetamines bound to the same cation exchange resin or each bound to a different cation exchange resin, wherein when the optional matrix is present, the amphetamine—cation exchange resin complex—matrix further comprises a hydrophilic polymer or copolymer or a hydrophobic polymer and (ii) a pH-independent barrier coating which provides a modified release to the two or more amphetamines, wherein the two or more amphetamines are at least a d-amphetamine and an l-amphetamine, wherein the d-amphetamine and the l-amphetamine are provided by d-amphetamine and at least one of (d,l)-amphetamine and l-amphetamine; and (B) immediate release amphetamine components which comprise greater than 60% w/w of the total amphetamines in the tablet based on the total weight of free amphetamine base in the tablet, and wherein the immediate release amphetamine components further comprise: (i) an amphetamine—cation exchange resin complex in an optional matrix, wherein the amphetamine—cation exchange resin complex—optional matrix comprises at least a d-amphetamine and an l-amphetamine both bound to the same cation exchange resin, wherein the d-amphetamine and the l-amphetamine are provided by d-amphetamine and at least one of (d, l)-amphetamine or l-amphetamine; and (ii) amphetamine aspartate; and (iii) dextroamphetamine sulfate. 36. The method according to claim 35, wherein the tablet provides therapeutic effect from 1 to 13 hours as determined in a SKAMP rating scale. 37. The method according to claim 35, wherein the Tmax is about 5.0 as determined by arithmetic or geometric mean post-dosing with a 20 mg extended-release tablet swallowed whole.