Methylphenidate extended release chewable tablet
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.
1. An extended release racemic methylphenidate chewable tablet, wherein the chewable tablet is a solid dispersion comprising:
(a) a sustained release, 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; wherein the barrier coating provides a sustained release profile to the racemic methylphenidate as defined in (a); and
wherein about 50% w/w to about 90% w/w of total racemic methylphenidate in the chewable tablet is provided by the sustained release component; and
(b) an immediate racemic methylphenidate component comprising racemic methylphenidate-cation exchange resin complex which provides a release of the racemic methylphenidate in less than about 30 minutes as determined in an in vitro dissolution assay, wherein the methylphenidate-cation exchange resin complex comprises racemic methylphenidate bound to a pharmaceutically acceptable cation exchange resin;
wherein the chewable tablet is capable of being divided and providing tablet portions which retain a therapeutically effective extended release profile, and a pharmacokinetic profile in which the racemic methylphenidate has at least one of: a geometric mean for area under the curve (AUC) 0-∞ of about 110 ng-hr/mL to about 140 ng-hr/mL or a geometric mean C max of about 10 ng/mL to about 15 ng/mL, under fasted conditions in adults following a single oral administration of the chewable 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 chewable tablet according to claim 1 , 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.
3. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein the plasticizer comprises triethyl citrate.
4. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein the plasticizer comprises polyethylene glycol.
5. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein the barrier coating is applied as a solvent based suspension.
6. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein the barrier coating is cured.
7. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein the water-insoluble, water-permeable, pH-independent polymer is present in the barrier coat an amount of about 70% to about 90% w/w, based on the weight of the final barrier coating layer.
8. The extended release racemic methylphenidate chewable 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 defined in (i) as determined prior to the racemic methylphenidate-cation exchange resin complex being coated with the barrier coating of (ii), wherein the racemic methylphenidate-cation exchange resin is optionally in a matrix which further comprises at least one polymer or copolymer.
9. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein the barrier coat is present in an amount of about 20% w/w to about 50% w/w % based on the weight of the racemic methylphenidate-cation exchange resin complex defined in (i) as determined prior to the racemic methylphenidate-cation exchange resin complex being coated with the barrier coating of (ii), wherein the racemic methylphenidate-cation exchange resin is optionally in a matrix which further comprises at least one polymer or copolymer.
10. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein the barrier coat is present in an amount of about 20% w/w to about 35% w/w % based on the weight of the racemic methylphenidate-cation exchange resin complex defined in (i) as determined prior to the racemic methylphenidate-cation exchange resin complex being coated with the barrier coating of (ii), wherein the racemic methylphenidate-cation exchange resin is optionally in a matrix which further comprises at least one polymer or copolymer.
11. The extended release racemic methylphenidate chewable tablet according to claim 10 , wherein the immediate release component comprises about 20% w/w to about 40% w/w of the total racemic methylphenidate in the chewable tablet.
12. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein the barrier coated 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.
13. The extended release racemic methylphenidate chewable tablet according to claim 12 , wherein the barrier coated 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.
14. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein the sustained release methylphenidate component provides about 60% w/w to about 80% w/w of the methylphenidate in the chewable tablet, based on the total amount of methylphenidate in the chewable tablet.
15. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein the tablet has a hardness in the range of about 8 kp to about 23 kp.
16. The extended release racemic methylphenidate chewable 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° C.±5° C. with a USP paddle speed of 75 rpm.
17. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein the tablet has a pharmacokinetic profile for racemic methylphenidate comprising a single mean plasma concentration peak which is about 4 hours to about 5.25 hours under fasted conditions.
18. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein said tablet comprises the equivalent of 40 mg racemic methylphenidate HCl.
19. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein said tablet comprises the equivalent of 20 mg racemic methylphenidate HCl.
20. A method for treating a patient who has been diagnosed with attention deficit hyperactivity disorder, postural orthostatic tachycardia syndrome, or narcolepsy, said method comprising dosing said patient with an effective amount of a methylphenidate extended release chewable tablet according to claim 1 .
21. The method according to claim 20 , wherein said patient has attention deficit hyperactivity disorder.
22. The method according to claim 20 , wherein the patient swallows the tablet intact.
23. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein the methylphenidate plasma concentration, as determined under fasting conditions following a single oral administration of said chewable tablet at a dose equivalent to 40 mg racemic methylphenidate HCl in adults under fasting conditions, has the fasting plasma concentration curve of FIG. 1 from about 0 to about 8 hours.
24. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein the pharmacokinetic profile for the methylphenidate further comprises an AUC0-3 which is bioequivalent to about 18 ng-hr/mL.
25. The extended release racemic methylphenidate chewable 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.
26. The extended release racemic methylphenidate chewable 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.
27. The extended release racemic methylphenidate chewable 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.
28. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein pharmacokinetic profile for methylphenidate further comprises one or more of an AUC0-3 of the fasting or fed plasma concentration curve of FIG. 1 or an AUC0-4 of the fasting or fed plasma concentration curve of FIG. 1 .
29. The extended release racemic methylphenidate chewable tablet according to claim 1 , wherein the barrier coating is about 10% by weight to about 40% by weight of the methylphenidate-cation ion exchange resin complex defined in (i) as determined prior to the racemic methylphenidate-cation exchange resin complex being coated with the barrier coating of (ii), wherein the racemic methylphenidate-cation exchange resin is optionally in a matrix which further comprises at least one polymer or copolymer.
30. The extended release racemic methylphenidate chewable tablet according to claim 29 , wherein the racemic methylphenidate-cation ion exchange resin complex defined in (i) is in a matrix, wherein at least one polymer or copolymer is hydrophilic.