Methylphenidate extended release chewable tablet

• US 9,180,100 B2
• Filed: 02/18/2015
• Issued: 11/10/2015
• Est. Priority Date: 08/15/2012
• Status: Active Grant

• Current Assignee: Tris Pharma Incorporated
• Original Assignee: Tris Pharma Incorporated
• Inventors: Tu, Yu-Hsing, Perumal, Ashok, Kathala, Kalyan
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): YOUNG, MICAH PAUL
• Application Number:
  US14/624,998
• Publication Number:
  US 20150157574A1
• Time in Patent Office: 265 Days
• Field of Search: 424465-489
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 47/585 Ion exchange resins, e.g. polystyrene sulfonic acid resin
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61K 9/284 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

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.

Claims

1. An extended release chewable tablet having a therapeutically effective immediate release and a 12-hour extended release profile, wherein said chewable tablet is a uniform solid dispersion comprising:

(a) a sustained release dexmethylphenidate component comprising a water-insoluble, water-permeable, pH-independent barrier coated, dexmethylphenidate-ion exchange resin complex in a polymeric matrix, wherein said barrier coating is over the dexmethylphenidate-ion exchange resin complex-matrix;

(b) a first immediate release component which comprises an immediate release uncoated dexmethylphenidate-ion exchange resin complex;

(c) a second immediate release dexmethylphenidate component which comprises an uncomplexed dexmethylphenidate;

wherein said first immediate release component (b) has a slower onset of release than (c);

wherein about 50% w/w to about 90% w/w of the dexmethylphenidate active component is provided by the sustained release component based on the total amount of dexmethylphenidate in the tablet, and wherein said chewable tablet is capable of being divided and providing tablet portions which retain a therapeutically effective immediate release and a 12-hour extended release profile, and a pharmacokinetic profile in which the dexmethylphenidate has an area under the curve (AUC)_0-∞

of about 110 ng-hr/mL to about 140 ng-hr/mL and a C_max of about 10 ng/mL to about 15 ng/mL following a single oral administration of the chewable tablet comprising the equivalent of 40 mg racemic methylphenidate HCl in adults under fasted and fed conditions.

2. The extended release chewable tablet according to claim 1, wherein the chewable tablet has a pharmacokinetic profile for dexmethylphenidate comprising a single mean plasma concentration peak.

3. The extended release chewable tablet according to claim 2, wherein the single mean plasma concentration peak is between about 4 hours to about 5.25 hours under fasted and fed conditions.

4. The extended release chewable tablet according to claim 1, wherein the sustained release dexmethylphenidate component provides about 60% w/w to about 80% w/w of the dexmethylphenidate in the chewable tablet, based on the total amount of dexmethylphenidate in the tablet.

5. The extended release chewable tablet according to claim 1, wherein the immediate release dexmethylphenidate components (b) and (c) together comprise about 20% w/w to about 40% w/w of the dexmethylphenidate in the chewable tablet.

6. The extended release chewable tablet according to claim 1, wherein the immediate release dexmethylphenidate-ion exchange resin complex (b) is about 5% w/w to about 35% w/w of the dexmethylphenidate in the chewable tablet.

7. The extended release chewable tablet according to claim 1, wherein the immediate release uncomplexed dexmethylphenidate is about 5% w/w to about 35% w/w of the dexmethylphenidate in the chewable tablet.

8. The extended release chewable tablet according to claim 1, wherein the immediate release dexmethylphenidate-ion exchange resin complex provides about 15% w/w of the dexmethylphenidate in the tablet and faster onset immediate release uncomplexed dexmethylphenidate provides about 15% w/w of the dexmethylphenidate in the tablet.

9. The extended release chewable tablet according to claim 1, wherein the ratio of the immediate release uncoated dexmethylphenidate-ion exchange resin complex (b) to immediate release component uncomplexed dexmethylphenidate (c) is in the range of about 3:

1 based on the total weight of immediate release components.

10. The extended release chewable tablet according to claim 1, wherein the tablet has a hardness in the range of about 8 kp to about 23 kp.

11. The extended release chewable tablet according to claim 1, wherein the water insoluble, water-permeable, pH-independent barrier coating has a tensile strength in a range of about 150% to about 400% and is selected from (a) a cured, water-permeable, non-ionic, pH-independent barrier coating comprising polyvinylacetate, a stabilizer, and a plasticizer, applied as an aqueous dispersion;

(b) an ionic, pH-independent, acrylic based coating comprising a polymer or copolymer comprising ethyl acrylate and methyl methacrylate applied as an aqueous dispersion; and

(c) a solvent-based ethylcellulose coating, optionally with a plasticizer.

12. The extended release chewable tablet according to claim 11, wherein the barrier coating over the dexmethylphenidate-ion exchange resin complex-matrix 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.

13. The extended release chewable tablet according to claim 11, wherein the barrier coating over the dexmethylphenidate-ion exchange resin complex-matrix is (b) the ionic, pH-independent, acrylic based coating, which said coating comprises a blend of (i) a poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) in a ratio of 1:

2;

0.1 and (ii) poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) in a ratio of 1;

2;

0.2.

14. The extended release chewable tablet according to claim 1, wherein the tablet further comprises a non-functional outer top coating layer.

15. The extended release chewable tablet according to claim 1, wherein the dexmethylphenidate active drug is dexmethylphenidate HCl.

27. A method of providing a subject with a therapeutically effective amount of dexmethylphenidate over at least twelve hours, said method comprising delivering to said subject a single extended release chewable tablet according to claim 1.

28. The method according to claim 27, wherein the single extended release chewable tablet according to claim 1 further provides an onset as early as about 20 minutes.

29. The extended release chewable tablet according to claim 1, wherein the chewable tablet further comprises one or more of the pharmacokinetic parameters for dexmethylphenidate, in which the 90% confidence intervals of the geometric test/reference ratios of one or more of AUC0-3 or AUC0-4 is that of FIG. 1 following administration of the chewable tablet to adults at a dose equivalent to 40 mg racemic methylphenidate HCl.

30. The extended release chewable tablet according to claim 2, wherein the AUC0-3 is bioequivalent to about 18 ng-hr/mL.

16. An extended release chewable tablet having a 12-hour extended release profile and a rapid on-set, wherein said chewable tablet is a uniform solid dispersion comprising:

(a) a sustained release dexmethylphenidate component comprising about of a cured, water-insoluble, water-permeable, non-ionic, pH-independent barrier coated, dexmethylphenidate-barrier ion exchange resin complex in a polyvinylpyrrolidone matrix, wherein said barrier coating is about 25% to about 40%, by weight, over the dexmethylphenidate-ion exchange resin complex-matrix and the barrier coating comprises polyvinylacetate, a stabilizer, and a plasticizer;

(b) a first immediate release component which comprises an immediate release dexmethylphenidate-ion exchange resin complex and (c) a second immediate release dexmethylphenidate component which comprises a dexmethylphenidate active component, and pharmaceutically acceptable excipients;

wherein said first immediate release component (b) has a slower onset of release than (c);

wherein about 50% w/w to about 90% w/w of the dexmethylphenidate active component is provided by the sustained release component based on the total amount of dexmethylphenidate in the tablet, and wherein said chewable tablet is capable of being divided and providing tablet portions which retain a therapeutically effective immediate release and the extended release profile, and a pharmacokinetic profile in which the dexmethylphenidate has an area under the curve (AUC)_0-∞

of about 110 ng-hr/mL to about 140 ng-hr/mL and a C_max of about 10 ng/mL to about 15 ng/mL following a single oral administration of the chewable tablet comprising the equivalent of 40 mg racemic methylphenidate HCl in adults under fasted and fed conditions.

17. The extended release chewable tablet according to claim 16, wherein the sustained release dexmethylphenidate component provides about 60% w/w to about 80% w/w of the dexmethylphenidate in the chewable tablet, based on the total amount of dexmethylphenidate in the tablet.

18. The extended release chewable tablet according to claim 16, wherein the immediate release dexmethylphenidate components (b) and (c) together comprise about 20% w/w to about 40% w/w of the dexmethylphenidate in the chewable tablet.

19. The extended release chewable tablet according to claim 16, wherein the immediate release dexmethylphenidate-ion exchange resin complex (b) is about 5% w/w to about 35% w/w of the dexmethylphenidate in the chewable tablet.

20. The extended release chewable tablet according to claim 16, wherein the dexmethylphenidate active drug is about 5% w/w to about 35% w/w of the dexmethylphenidate in the chewable tablet.

21. The extended release chewable tablet according to claim 16, wherein the immediate release dexmethylphenidate-ion exchange resin complex provides about 15% w/w of the dexmethylphenidate in the tablet and the dexmethylphenidate active drug provides about 15% w/w of the dexmethylphenidate in the tablet.

22. The extended release chewable tablet according to claim 16, wherein the tablet has a hardness in the range of about 8 kp to about 23 kp.

23. The extended release chewable tablet according to claim 22, wherein the barrier coating over the dexmethylphenidate-ion exchange resin complex-matrix is a cured, 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.

24. The extended release chewable tablet according to claim 23, wherein the immediate release dexmethylphenidate-ion exchange resin complex further comprises a finishing and/or pigment coating layer.

25. The extended release chewable tablet according to claim 16, wherein the ratio of the immediate release component (b) to immediate release component (c) is in the range of about 3:

1 based on the total weight of immediate release components.

26. The extended release chewable tablet according to claim 16, wherein the dexmethylphenidate active drug is dexmethylphenidate HCl.