Methylphenidate Extended Release Chewable Tablet

• US 20210093623A1
• Filed: 12/07/2020
• Published: 04/01/2021
• 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
• Granted Patent: US 11,103,494 B2
• Time in Patent Office: Days
• 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. (canceled)

2. 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)_0-∞

of about 110 ng-hr/mL to about 140 ng-hr/mL and further providing a geometric mean C_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_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.

3. The extended release racemic methylphenidate tablet according to claim 2, 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_max and the C_max following oral ingestion of the tablet.

4. The extended release racemic methylphenidate tablet according to claim 2, wherein the barrier coat has an elongation factor of at least about 150% to about 400% as measured by a texture analyzer.

5. The extended release racemic methylphenidate tablet according to claim 4, 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.

6. The extended release racemic methylphenidate tablet according to claim 2, wherein the plasticizer comprises triethyl citrate.

7. The extended release racemic methylphenidate tablet according to claim 2, wherein the plasticizer comprises polyethylene glycol.

8. The extended release racemic methylphenidate tablet according to claim 2, wherein the plasticizer is present in an amount of about 2.5% w/w to about 20% w/w of the barrier coating.

9. The extended release racemic methylphenidate tablet according to claim 2, wherein the plasticizer is present in an amount of 2.5% w/w to about 15% w/w of the barrier coating.

10. The extended release racemic methylphenidate tablet according to claim 2, wherein the barrier coating is applied as a solvent based suspension.

11. The extended release racemic methylphenidate tablet according to claim 2, wherein the barrier coating is cured.

12. The extended release racemic methylphenidate tablet according to claim 2, wherein the water-insoluble, water-permeable, pH-independent polymer is present in an amount of about 70% to about 90% w/w of the barrier coating.

13. The extended release racemic methylphenidate tablet according to claim 2, wherein the barrier coating is about 15% by weight to about 65% by weight of the methylphenidate-cation ion exchange resin complex according to (ii).

14. The extended release racemic methylphenidate tablet according to claim 2, wherein the barrier coating 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 of (ii).

15. The extended release racemic methylphenidate tablet according to claim 2, 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 of (ii).

16. The extended release racemic methylphenidate tablet according to claim 2, wherein the immediate release component comprises about 20% w/w to about 40% w/w of the total racemic methylphenidate in the tablet.

17. The extended release racemic methylphenidate tablet according to claim 2, 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.

18. The extended release racemic methylphenidate tablet according to claim 17, 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.

19. The extended release racemic methylphenidate tablet according to claim 2, wherein the methylphenidate component provides about 60% w/w to about 80% w/w of the methylphenidate in the tablet, based on the total amount of methylphenidate in the tablet.

20. The extended release racemic methylphenidate tablet according to claim 2, wherein the tablet has a hardness in the range of about 8 kp to about 23 kp.

21. The extended release racemic methylphenidate tablet according to claim 2, 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.

22. The extended release racemic methylphenidate tablet according to claim 2, wherein the immediate release component further comprises an immediate release methylphenidate-cation exchange resin complex comprising racemic methylphenidate bound to a pharmaceutically acceptable cation exchange resin.

23. The extended release racemic methylphenidate tablet according to claim 2, wherein the tablet comprises the equivalent of 40 mg racemic methylphenidate HCl.

24. The extended release racemic methylphenidate tablet according to claim 2, wherein the tablet comprises the equivalent of 20 mg racemic methylphenidate HCl.

25. The extended release racemic methylphenidate tablet according to claim 2, wherein the tablet is scored.

26. The extended release racemic methylphenidate tablet according to claim 2, 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.

27. The extended release racemic methylphenidate tablet according to claim 2, wherein the water-insoluble polymer in the barrier coating comprises cellulose acetate.

28. An extended release racemic methylphenidate tablet, wherein the tablet is a solid dispersion comprising:

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)_0-∞

of about 110 ng-hr/mL to about 140 ng-hr/mL and further providing a geometric mean C_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_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

29. The extended release racemic methylphenidate chewable tablet according to claim 28, 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.

30. The extended release racemic methylphenidate chewable tablet according to claim 28, wherein the plasticizer is present in an amount of about 2.5% w/w to about 20% w/w of the barrier coating.

31. The extended release racemic methylphenidate tablet according to claim 28, 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_max and the C_max following oral ingestion of the tablet.