Methylphenidate extended release chewable tablet

• US 9,545,399 B2
• Filed: 07/01/2016
• Issued: 01/17/2017
• 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): YOUNG, MICAH PAUL
• Application Number:
  US15/200,625
• Publication Number:
  US 20160310479A1
• Time in Patent Office: 200 Days
• Field of Search: 424/465, 424/489
• 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 racemic methylphenidate chewable tablet, wherein said chewable tablet is a uniform solid dispersion comprising:

a sustained release racemic methylphenidate component comprising a water-insoluble, water-permeable, pH-independent barrier coated, racemic methylphenidate-cation exchange resin complex in an optional polymeric matrix, wherein said barrier coating is present in an amount of about 20% w/w to about 50% w/w % which provides a sustained release profile to the racemic methylphenidate and is over the racemic methylphenidate-cation exchange resin complex-optional matrix, and wherein when present the polymeric matrix comprises the methylphenidate-cation exchange resin complex and a water-insoluble polymer or copolymer or a water-soluble polymer or copolymer; and

at least one immediate release racemic methylphenidate component which provides a release in less than about 30 minutes as determined in an in vitro dissolution assay;

wherein about 50% w/w to about 90% w/w of the racemic methylphenidate active component is provided by the sustained release component based on the total amount of racemic methylphenidate in the tablet;

wherein said 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 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 and fed conditions in adults following a single oral administration of a chewable tablet which comprises the equivalent of 40 mg racemic methylphenidate HCl.

2. The extended release racemic methylphenidate chewable tablet according to claim 1, wherein the at least one immediate release component releases in about 10 minutes.

3. The extended release racemic methylphenidate chewable tablet according to claim 1, 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 tablet.

4. The extended release racemic methylphenidate chewable tablet according to claim 1, wherein the at least one immediate release component is a methylphenidate-cation exchange resin complex.

5. The extended release racemic methylphenidate chewable tablet according to claim 4, wherein the immediate release methylphenidate-cation exchange resin complex comprises about 20% w/w to about 40% w/w of the total racemic methylphenidate in the chewable tablet.

6. The extended release racemic methylphenidate chewable tablet according to claim 1, wherein the at least one immediate release component comprises uncomplexed methylphenidate or a pharmaceutically acceptable salt thereof.

7. The extended release racemic methylphenidate chewable tablet according claim 6, wherein the methylphenidate salt is racemic methylphenidate HCl.

8. The extended release racemic methylphenidate chewable tablet according to claim 6, wherein the composition comprises immediate release racemic uncomplexed methylphenidate or pharmaceutically acceptable salt in an amount of about 5% w/w to about 35% w/w of the total racemic methylphenidate in the chewable tablet.

9. 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.

10. The extended release racemic methylphenidate 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.

11. The extended release racemic methylphenidate chewable tablet according to claim 1, wherein the barrier coating over the methylphenidate-cation exchange resin complex-optional matrix of (a) 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.

12. The extended release racemic methylphenidate chewable tablet according to claim 11, wherein the barrier coating layer is about 25% to about 35%, by weight, of the coated racemic methylphenidate-cation exchange resin complex-optional matrix.

13. The extended release racemic methylphenidate chewable tablet according to claim 1, wherein the polymeric matrix is present and comprises polyvinylpyrolidone.

14. The extended release chewable racemic methylphenidate tablet according to claim 1, wherein the polymeric matrix is present and comprises a water-insoluble polymer.

15. The extended release racemic methylphenidate chewable tablet according to claim 14, wherein the barrier coating over the methylphenidate-cation exchange resin complex-optional matrix of (a) has a 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.

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

17. The extended release racemic methylphenidate chewable tablet according to claim 1 which further comprises one or more excipients.

18. The extended release racemic methylphenidate chewable tablet according to claim 1, wherein said tablet is scored.

19. A method for treating a subject having Attention Deficit Hyperactivity Disorder and/or Attention Deficit Disorder with a therapeutically effective amount of racemic methylphenidate, said method comprising orally administering to said subject a single methylphenidate extended release chewable tablet according to claim 1.

20. The extended release racemic methylphenidate chewable tablet according to claim 1, wherein no more than about 55% of the methylphenidate in the composition is released within one hour as determined in an in vitro dissolution assay.

21. The extended release racemic methylphenidate chewable tablet according to claim 1, wherein the tablet comprises more than one immediate release methylphenidate component.

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

23. The extended release racemic methylphenidate chewable according to claim 1, wherein pharmacokinetic profile further comprises the 90% confidence intervals of the geometric test/reference ratios of one or more of AUC0-3 or AUC0-4 of FIG. 1.

24. The extended release racemic methylphenidate chewable tablet according to claim 1, wherein the methylphenidate plasma concentration, as determined under fasted and fed conditions following a single oral administration of said chewable 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.

25. The extended release racemic methylphenidate chewable tablet according to claim 1, wherein said tablet comprises the equivalent of 40 mg racemic methylphenidate HCl.

26. The extended release racemic methylphenidate chewable tablet according to claim 1, wherein said tablet comprises the equivalent of 20 mg racemic methylphenidate HCl.

27. The extended release racemic methylphenidate chewable tablet according to claim 1, wherein said tablet comprises the equivalent of 30 mg racemic methylphenidate HCl.