Methylphenidate extended release chewable tablet

• US 8,999,386 B2
• Filed: 06/10/2014
• Issued: 04/07/2015
• 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:
  US14/300,580
• Publication Number:
  US 20140287041A1
• Time in Patent Office: 301 Days
• Field of Search: 424/464, 424/465, 424/468, 424/469, 424/472, 424474-480
• US Class Current: 424/464
• 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 racemic methylphenidate component comprising a water-insoluble, water-permeable, pH-independent barrier coated, racemic methylphenidate-ion exchange resin complex in a polymeric matrix, wherein said barrier coating which provides a sustained release profile to the racemic methylphenidate is over the racemic methylphenidate-ion exchange resin complex-matrix;

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

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

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 racemic methylphenidate active component is provided by the sustained release component based on the total amount of racemic methylphenidate 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 12 hour extended release profile, and a pharmacokinetic profile in which the methylphenidate has a geometric mean for area under the curve (AUC)_0-∞

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

2. The extended release chewable tablet according to claim 1, wherein the chewable tablet has a pharmacokinetic profile in which the single mean plasma concentration profile for racemic methylphenidate has a T_max of about 4 hours to about 5.25 hours, and an AUC_0-3 of about 18 ng-hr/mL, under fasted and fed conditions following a single oral administration of an extended release chewable tablet comprising 40 mg racemic methylphenidate HCl in adults.

3. The extended release chewable tablet according to claim 1, wherein the pharmacokinetic profile of racemic methylphenidate has a geometric mean for AUC_0-∞

of about 113 ng-hr/mL under fasted conditions and about 138 ng-hr/mL under fed conditions, a geometric mean C_max of about 12 ng/mL to about 13 ng/mL under fasted and fed conditions, an arithmetic mean T_max of about 4 to about 4.5 hours under fasted and fed conditions and an arithmetic mean T_1/2 of about 5 hours to about 7 hours under fasted and fed conditions following a single oral administration of an chewable tablet comprising 40 mg racemic methylphenidate HCl in adults.

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

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

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

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

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

9. The extended release chewable tablet according to claim 1, wherein the ratio of the immediate release uncoated racemic methylphenidate-ion exchange resin complex (b) to immediate release component uncomplexed racemic methylphenidate (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 racemic methylphenidate-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 racemic methylphenidate-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, comprising:

about 15% w/w to about 20% w/w coated racemic methylphenidate-ion exchange resin complex which is the sustained release component;

about 1.5% w/w to about 5% w/w uncoated racemic methylphenidate-ion exchange resin complex which is the slower onset immediate release component;

about 0.5% w/w to about 1% w/w of a racemic methylphenidate which is the faster onset immediate release component;

about 45% w/w to about 85% w/w of one or more fillers;

about 5% w/w to about 10% w/w of one or more disintegrant(s);

about 0.1% w/w to about 10% w/w of one or more buffering agent;

about 1% w/w to about 3% w/w of one or more sweeteners;

about 0.1% w/w to about 3% w/w flavoring agent;

about 0.2% to about 3% w/w of one or more lubricant(s);

about 0.01% to about 1% w/w of one or more glidants;

about 0.01% to about 0.5% w/w of one or more colorants, wherein the weight percentages are based on the total tablet weight prior to any optional non-functional tablet coating.

16. The extended release chewable tablet according to claim 1 comprising:

about 16% w/w to about 18% w/w coated racemic methylphenidate-ion exchange resin complex which is the sustained release component;

about 2% w/w to about 3% w/w uncoated racemic methylphenidate-ion exchange resin complex which is the slower onset immediate release component;

about 0.5% w/w to about 0.8% w/w of an uncomplexed racemic methylphenidate which is the faster onset immediate release component;

about 50% w/w to about 70% w/w of one or more fillers;

about 7% w/w to about 8% w/w of one or more disintegrant(s);

about 0.5% w/w to about 1.5% w/w of one or more buffering agent;

about 1% w/w to about 2% w/w of one or more sweeteners;

about 0.1% w/w to about 1% w/w flavoring agent;

about 1.5% w/w to about 3% w/w of one or more lubricant(s);

about 0.01% to about 1% w/w of one or more glidants;

about 0.02% to about 0.08% w/w of one or more colorants, wherein the weight percentages are based on the total tablet weight prior to any optional non-functional tablet coating.

17. The extended release chewable tablet according to claim 16, wherein the fillers are selected from the group consisting of mannitol, xanthan gum, microcrystalline cellulose, guar gum, and mixtures thereof;

the disintegrant is crospovidone;

the lubricants are selected from one or more of talc, magnesium stearate, and mixtures thereof; and

the buffering agent is selected from citric acid and salts thereof.

18. The extended release chewable tablet according to claim 1, wherein the racemic methylphenidate active drug is racemic methylphenidate HCl.

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

19. 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 racemic methylphenidate component comprising about 25% w/w to about 40% w/w of a cured, water-insoluble, water-permeable, non-ionic, pH-independent barrier coated, racemic methylphenidate-barrier ion exchange resin complex in a polyvinylpyrrolidone matrix, wherein said barrier coating is over the racemic methylphenidate-ion exchange resin complex-matrix and comprises polyvinylacetate, a stabilizer, and a plasticizer;

(b) a first immediate release component which comprises an immediate release racemic methylphenidate-ion exchange resin complex and

(c) a second immediate release racemic methylphenidate component which comprises a racemic methylphenidate 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 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 immediate release and 12 hour extended release profile, and

wherein the chewable tablet has a pharmacokinetic profile in which the single mean plasma concentration profile for racemic methylphenidate has a geometric mean for AUC_0-∞

of about 110 ng-hr/mL to about 140 ng-hr/mL and a geometric mean for C_max of about 10 ng/mL to about 15 ng/mL following a single oral administration of an extended release chewable tablet comprising 40 mg racemic methylphenidate HCl in adults under fasted and fed condition.

20. The extended release chewable tablet according to claim 19, wherein the sustained release racemic methylphenidate component provides about 60% w/w to about 80% w/w of the racemic methylphenidate in the chewable tablet, based on the total amount of racemic methylphenidate in the tablet.

21. The extended release chewable tablet according to claim 19, wherein the immediate release racemic methylphenidate components (b) and (c) together comprise about 20% w/w to about 40% w/w of the racemic methylphenidate in the chewable tablet.

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

23. The extended release chewable tablet according to claim 19, wherein the racemic methylphenidate active drug is about 5% w/w to about 35% w/w of the racemic methylphenidate in the chewable tablet.

24. The extended release chewable tablet according to claim 19, wherein the immediate release racemic methylphenidate-ion exchange resin complex provides about 15% w/w of the racemic methylphenidate in the tablet and the racemic methylphenidate active drug provides about 15% w/w of the racemic methylphenidate in the tablet.

25. The extended release chewable tablet according to claim 19, wherein the tablet has a hardness in the range of about 8 kp to about 23 kp.

26. The extended release chewable tablet according to claim 25, wherein the barrier coating over the racemic methylphenidate-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.

27. The extended release chewable tablet according to claim 26, wherein the immediate release racemic methylphenidate-ion exchange resin complex further comprises a finishing and/or pigment coating layer.

28. The extended release chewable tablet according to claim 19, 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.

29. The extended release chewable tablet according to claim 19, wherein the racemic methylphenidate active drug is racemic methylphenidate HCl.