Claims for Patent: 11,103,494

Summary for Patent: 11,103,494

Title:	Methylphenidate extended release chewable tablet
Abstract:	An oral methylphenidate extended release tablet is described, which can be scored and still retain its extended release profile. The tablet contains a combination of an uncoated methylphenidate-ion exchange resin complex, a barrier coated methylphenidate-ion exchange resin complex-matrix, and an uncomplexed methylphenidate active component. Following administration of a single dose of the extended release methylphenidate chewable tablet, a therapeutically effective amount of methylphenidate is reached in less than about 20 minutes and the composition provides a twelve-hour extended release profile.
Inventor(s):	Tu; Yu-Hsing (West Windsor, NJ), Perumal; Ashok (Monmouth Junction, NJ), Kathala; Kalyan (Monmouth Junction, NJ)
Assignee:	TRIS PHARMA, INC (Monmouth Junction, NJ)
Application Number:	17/113,856
Patent Claims:	1. An extended release racemic methylphenidate tablet, wherein the tablet is a solid dispersion comprising: (a) a racemic methylphenidate component comprising a water-insoluble, water-permeable, pH-independent barrier coated, racemic methylphenidate-cation exchange resin complex which comprises: (i) a racemic methylphenidate-cation exchange resin complex comprising racemic methylphenidate and a pharmaceutically acceptable cation ion exchange resin, wherein the racemic methylphenidate is bound to the pharmaceutically acceptable cation exchange resin; (ii) a water-insoluble, water-permeable, pH-independent, barrier coating comprising a water-insoluble polymer and a plasticizer over the racemic methylphenidate-cation exchange resin complex of (a)(i), wherein the barrier coating modifies the release of the racemic methylphenidate in the complex; and wherein about 50% w/w to about 90% w/w of total racemic methylphenidate in the tablet is provided by the racemic methylphenidate component of (a); and (b) at least one immediate release methylphenidate component which provides a release of the racemic methylphenidate in less than about 30 minutes as determined in an in vitro dissolution assay; wherein the tablet is capable of being swallowed intact or following being divided or chewed and the tablet provides a pharmacokinetic profile for racemic methylphenidate comprising a geometric mean area under the curve (AUC).sub.0-.infin. of about 110 ng-hr/mL to about 140 ng-hr/mL and further providing a geometric mean C.sub.max of about 10 ng/mL to about 15 ng/mL and/or a single mean plasma concentration peak for racemic methylphenidate, and optionally further comprising a T.sub.max of about 4 hours to about 5.25 hours for racemic methylphenidate, under fasted conditions in adults following a single oral administration of the tablet which has a total amount of racemic methylphenidate which is the equivalent of 40 mg racemic methylphenidate HCl. 2. The extended release racemic methylphenidate tablet according to claim 1, wherein the tablet provides a pharmacokinetic profile for racemic methylphenidate further comprising the single mean plasma concentration peak and optionally further comprising one or more of the T.sub.max and the C.sub.max following oral ingestion of the tablet. 3. The extended release racemic methylphenidate tablet according to claim 1, wherein the barrier coat has an elongation factor of at least about 150% to about 400% as measured by a texture analyzer. 4. The extended release racemic methylphenidate tablet according to claim 3, wherein the plasticizer is selected from propylene glycol, polyethylene glycol, dibutyl sebacate, propylene glycol, polyethylene glycol, polyvinyl alcohol, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, triacetin, 2-pyrrolidone, or mixtures thereof. 5. The extended release racemic methylphenidate tablet according to claim 1, wherein the plasticizer comprises triethyl citrate. 6. The extended release racemic methylphenidate tablet according to claim 1, wherein the plasticizer comprises polyethylene glycol. 7. The extended release racemic methylphenidate tablet according to claim 1, wherein the plasticizer is present in an amount of about 2.5 w/w to about 20% w/w of the barrier coating. 8. The extended release racemic methylphenidate tablet according to claim 1, wherein the plasticizer is present in an amount of 2.5% w/w to about 15% w/w of the barrier coating. 9. The extended release racemic methylphenidate tablet according to claim 1, wherein the immediate release component comprises about 20% w/w to about 40% w/w of the total racemic methylphenidate in the tablet. 10. The extended release racemic methylphenidate tablet according to claim 1, wherein the barrier coated racemic methylphenidate-cation exchange resin complex as defined in (ii) are particulates having a mean particle size in the range of about 100 microns to about 450 microns. 11. The extended release racemic methylphenidate tablet according to claim 10, wherein the barrier coated racemic methylphenidate-cation exchange resin complex as defined in (ii) are particulates having a mean particle size in the range of about 150 microns to about 300 microns. 12. The extended release methylphenidate tablet according to claim 1, wherein the racemic methylphenidate component of (a) provides about 60% w/w to about 80% w/w of the racemic methylphenidate in the tablet, based on the total amount of racemic methylphenidate in the tablet. 13. The extended release racemic methylphenidate tablet according to claim 1, wherein the tablet has a hardness in the range of about 8 kp to about 23 kp. 14. The extended release racemic methylphenidate tablet according to claim 1, wherein the pharmacokinetic profile further comprises one or more of the following: the 90% confidence intervals of the geometric mean test/reference ratios of one or more of AUC0-3 or AUC0-4 of FIG. 1; the pharmacokinetic profile for the methylphenidate further comprises an AUC0-3 which is bioequivalent to about 18 ng-hr/mL; and/or the methylphenidate plasma concentration, as determined under fasted and fed conditions following a single oral administration of said tablet at a dose equivalent to 40 mg racemic methylphenidate HCl in adults, is equivalent to the plasma concentration curve of FIG. 1 from about 0 to about 8 hours. 15. The extended release racemic methylphenidate tablet according to claim 1, wherein the immediate release component comprises an immediate release methylphenidate-cation exchange resin complex comprising racemic methylphenidate bound to a pharmaceutically acceptable cation exchange resin and/or a pharmaceutically acceptable racemic methylphenidate salt. 16. The extended release racemic methylphenidate tablet according to claim 1, wherein the tablet comprises the equivalent of 40 mg racemic methylphenidate HCl. 17. The extended release racemic methylphenidate tablet according to claim 1, wherein the tablet comprises the equivalent of 20 mg racemic methylphenidate HCl. 18. The extended release racemic methylphenidate tablet according to claim 1, wherein the tablet is scored. 19. The extended release racemic methylphenidate tablet according to claim 1, wherein the in vitro dissolution assay is performed placing the tablet in 900 mL 0.4 M potassium phosphate buffer with 37.degree. C..+-.5.degree. C. with a USP paddle speed of 75 rpm. 20. The extended release racemic methylphenidate tablet according to claim 1, wherein the water-insoluble polymer in the barrier coating comprises cellulose acetate. 21. An extended release racemic methylphenidate tablet, wherein the tablet is a solid dispersion comprising: (a) a racemic methylphenidate component comprising a water-insoluble, water-permeable, pH-independent barrier coated, racemic methylphenidate-cation exchange resin complex which comprises: (i) a racemic methylphenidate-cation exchange resin complex comprising racemic methylphenidate and a pharmaceutically acceptable cation ion exchange resin, wherein the racemic methylphenidate is bound to the pharmaceutically acceptable cation exchange resin; (ii) a water-insoluble, water-permeable, pH-independent, barrier coating comprising cellulose acetate and a plasticizer over the racemic methylphenidate-cation exchange resin complex of (a)(i), wherein the barrier coating modifies the release profile of the racemic methylphenidate; and wherein about 50% w/w to about 90% w/w of total racemic methylphenidate in the chewable tablet is provided by the racemic methylphenidate component of (a); and (b) at least one immediate release methylphenidate component which provides a release of the racemic methylphenidate in less than about 30 minutes as determined in an in vitro dissolution assay and which comprises an immediate release methylphenidate-cation exchange resin complex comprising racemic methylphenidate bound to a pharmaceutically acceptable cation exchange resin; wherein the tablet is capable of being swallowed intact or following being divided or chewed and the tablet provides a pharmacokinetic profile for racemic methylphenidate comprising a geometric mean area under the curve (AUC).sub.0-.infin. of about 110 ng-hr/mL to about 140 ng-hr/mL and further providing a geometric mean C.sub.max of about 10 ng/mL to about 15 ng/mL and/or a single mean plasma concentration peak for racemic methylphenidate, and optionally further comprising a T.sub.max of about 4 hours to about 5.25 hours for racemic methylphenidate, under fasted conditions in adults following a single oral administration of the tablet which has a total amount of racemic methylphenidate which is the equivalent of 40 mg racemic methylphenidate HCl. 22. The extended release racemic methylphenidate chewable tablet according to claim 21, wherein the plasticizer is selected from propylene glycol, polyethylene glycol, dibutyl sebacate, propylene glycol, polyethylene glycol, polyvinyl alcohol, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, triacetin, 2-pyrrolidone, or mixtures thereof. 23. The extended release racemic methylphenidate chewable tablet according to claim 21, wherein the plasticizer is present in an amount of about 2.5% w/w to about 20% w/w of the barrier coating. 24. The extended release racemic methylphenidate tablet according to claim 21, wherein the tablet provides a pharmacokinetic profile for racemic methylphenidate further comprising the single mean plasma concentration peak and optionally further comprising one or more of the T.sub.max and the C.sub.max following oral ingestion of the tablet. 25. The extended release racemic methylphenidate tablet according to claim 1, wherein the barrier coating is about 15% by weight to about 65% by weight of the methylphenidate-cation ion exchange resin complex according to (a) prior to coating. 26. A racemic methylphenidate tablet, wherein the tablet is a uniform solid dispersion comprising: (a) a water-insoluble, water-permeable, pH-independent barrier coated, racemic methylphenidate-cation exchange resin complex which comprises: (i) a racemic methylphenidate-cation exchange resin complex comprising racemic methylphenidate and a pharmaceutically acceptable cation ion exchange resin, wherein the racemic methylphenidate is bound to the pharmaceutically acceptable cation exchange resin; (ii) a water-insoluble, water-permeable, pH-independent, barrier coating comprising a water-insoluble polymer and a plasticizer over the racemic methylphenidate-cation exchange resin complex of (a)(i), wherein the barrier coating modifies the release of the racemic methylphenidate in the complex; (b) a first immediate release component which comprises an immediate release uncoated racemic methylphenidate-ion exchange resin complex, wherein about 5% to about 20% w/w of the total racemic methylphenidate in the tablet is provided by (b); and (c) a second immediate release racemic methylphenidate component which comprises an uncomplexed racemic methylphenidate, wherein about 5% w/w to about 20% w/w of the total racemic methylphenidate in the tablet is provided by (c); wherein the tablet is capable of being swallowed intact or following being divided or chewed, and wherein the tablet provides a pharmacokinetic profile for racemic methylphenidate comprising a geometric mean area under the curve (AUC).sub.0-.infin.of about 10 ng/mL to about 15 ng/mL and/or a single mean plasma concentration peak for racemic methylphenidate, and optionally further comprising a T.sub.max of about 4 hours to about 5.25 hours for racemic methylphenidate, under fasted conditions in adults following a single oral administration of the tablet which has a total amount of racemic methylphenidate which is the equivalent of 40 mg racemic methylphenidate HCl. 27. The racemic methylphenidate chewable tablet according to claim 26, wherein about 60% w/w to about 80% w/w of the racemic methylphenidate in the tablet is provided to (a). 28. The racemic methylphenidate chewable tablet according to claim 26, wherein the first immediate release component (b) is about 15% w/w of the total racemic methylphenidate in the tablet, the second immediate release component (c) is about 15% w/w of the total racemic methylphenidate in the tablet, or each (b) and (c) are about 15% w/w of the total racemic methylphenidate in the tablet. 29. The racemic methylphenidate tablet according to claim 26, wherein the barrier coating is present in an amount of about 10 % w/w to about 70% w/w % based on the weight of the racemic emthylphenidate-cation exchange resin complex of (a)(ii) prior to coating. 30. The racemic methylphenidate tablet according to claim 26, wherein the barrier coat is present in an amount of about 15 % w/w to about 60% w/w % based on the weight of the racemic methylphenidate-cation exchange resin complex of (a)(ii) prior to coating.