Compositions comprising methylphenidate complexed with ion-exchange resin particles

• US 9,072,680 B2
• Filed: 03/15/2013
• Issued: 07/07/2015
• Est. Priority Date: 06/28/2011
• Status: Active Grant

• Current Assignee: NEOS Therapeutics Incorporated
• Original Assignee: NEOS Therapeutics LLP
• Inventors: Tengler, Mark, McMahen, Russell
• Primary Examiner(s): Pallay, Michael B
• Application Number:
  US13/844,584
• Publication Number:
  US 20140037728A1
• Time in Patent Office: 844 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• 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 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: C12N 9/2402 hydrolysing O- and S- glycosyl compounds (3.2.1)

Abstract

Pharmaceutical compositions of methylphenidate complexed with ion-exchange resin particles to form drug-resin particles are provided. The compositions have a first plurality of drug-resin particles that are uncoated and a second plurality of drug-resin particles that are coated with a delayed release coating. Preferably, the second plurality of drug-resin particles are coated with a triggered-release coating triggered by a pH change and a diffusion barrier coating.

Claims

1. A pharmaceutical composition comprising an ADHD effective agent complexed with ion-exchange resin particles to form drug-resin particles,

wherein said ADHD effective agent is methylphenidate,

wherein said composition comprises a first plurality of drug-resin particles that provide for immediate release of said ADHD effective agent and a second plurality of drug-resin particles that are coated with a triggered-release coating triggered by a pH change and a diffusion barrier coating, and

wherein administration of the composition to a human produces a mean plasma concentration profile for d-methylphenidate in human subjects which has one or more parameters selected from the group consisting of AUC_0-3, AUC_0-5, AUC_0-Tmax, AUC_5-12, AUC_5-24, AUC_Tmax-24, AUC_Tmax-12, AUC_5-t, AUC_Tmax-t, AUC_0-24, and AUC_0-∞

which is substantially similar to those parameters of at least one of the in vivo serum profiles of the compositions comprising methylphenidate-containing drug-resin particles shown in FIG. 20A.

2. The composition of claim 1, wherein the triggered-release coating is cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters, co-polymerized methacrylic acid/acrylic acid ethyl esters, or mixtures thereof.

3. The composition of claim 2, wherein the composition additionally contains polistirex, polacrilex, cholestyramine, polacrilin or mixtures thereof.

4. The composition of claim 1, wherein the diffusion barrier coating contains polyvinylpyrrolidone, polyvinylacetate, polyvinylalcohol or mixtures thereof.

5. The composition of claim 1, wherein the diffusion barrier coating is a water insoluble, water permeable membrane.

6. The composition of claim 5, wherein the water insoluble, water permeable membrane is ethylcellulose.

7. The composition of claim 1, wherein the triggered-release coating covers the diffusion barrier coating.

8. The composition of claim 7, wherein the diffusion barrier coating is ethylcellulose.

9. The composition of claim 1, wherein the resin particles are strong acidic cation exchange resins, selected from the group consisting of polistirex, polacrilex, cholestyramine, polacrilin and mixtures thereof.

10. The composition of claim 1, wherein said first plurality of particles comprise 20%-30% by number of the drug-resin particles present in said composition and said second plurality of particles comprise 70%-80% by number of the drug-resin particles present in said composition.

11. The composition of claim 8, wherein said first plurality of particles comprise about 25% by number of the drug-resin particles present in said composition and said second plurality of particles comprise about 75% by number of the drug-resin particles present in said composition.

12. The composition of claim 1, wherein the composition is a liquid suspension, chewable composition, or an orally disintegrating tablet composition.

13. The composition of claim 1, wherein the amount of methylphenidate is 10-60 mg.

14. The composition of claim 1, wherein the composition has an in vitro dissolution profile wherein 30-33% by weight of the ADHD effective agent is released from the drug-resin particles within the first 30 minutes, 34-42% by weight of the agent is released within 2 hours, 40-80% of the agent is released within 4 hours, and 80-100% by weight of the agent is released within 24 hours, wherein the dissolution profile is determined by an in vitro dissolution assay, wherein the conditions of the dissolution assay are an initial dissolution medium of 0.1 N HCl, and after 2 hours, the medium is adjusted to a pH of about 6.8;

and the dissolution assay is performed using a USP Apparatus 2.

15. The composition of claim 1, wherein the composition has an in vivo serum profile that is statistically similar to at least one profile selected from FIGS. 27A, 27B, 28A, and 28B.

16. The composition of claim 1, wherein a mammal receiving said composition, in the presence of ethanol, is exposed to a reduced amount of methylphenidate compared to an extended release composition without resin particles comprising methylphenidate hydrochloride.

17. The composition of claim 1, wherein the amount of said methylphenidate in said composition is equivalent to the amount present in a 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg dose of methylphenidate hydrochloride.

18. The composition of claim 1, wherein said composition is an orally disintegrating tablet and is effective to provide a mean plasma concentration profile in human adult ADHD patients which has an AUC_0-3 of 20.53 ng hr/mL −

20%/+25% and a C_max of 20.17 ng/mL −

20%/+25% for d-methylphenidate, an AUC_0-3 of 0.62 ng hr/mL −

20%/+25% and a C_max of 0.44 ng/mL −

20%/+25% for l-methylphenidate, and/or an AUC_0-3 of 21.29 ng hr/mL −

20%/+25% and a C_max of 20.60 ng/mL −

20%/+25% for total methylphenidate, for a total methylphenidate dose that is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride, or respective AUC and C_max values directly proportional thereto for a total methylphenidate dose other than that which is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride.

19. The composition of claim 1, wherein said composition is an orally disintegrating tablet and is effective to provide a mean plasma concentration profile in human adult ADHD patients which has an AUC_0-5 of 50.16 ng hr/mL −

20%/+25% and a C_max of 20.17 ng/mL −

20%/+25% for d-methylphenidate, an AUC_0-5 of 1.07 ng hr/mL −

20%/+25% and a C_max of 0.44 ng/mL −

20%/+25% for l-methylphenidate, and/or an AUC_0-5 of 51.43 ng hr/mL −

20%/+25% and a C_max of 20.60 ng/mL −

20%/+25% for total methylphenidate, for a total methylphenidate dose that is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride, or respective AUC and C_max values directly proportional thereto for a total methylphenidate dose other than that which is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride.

20. The composition of claim 1, wherein said composition is an orally disintegrating tablet and is effective to provide a mean plasma concentration profile in human adult ADHD patients which has an AUC_5-24 of 103.84 ng hr/mL −

20%/+25% and a C_max of 20.17 ng/mL −

20%/+25% for d-methylphenidate, an AUC_5-24 of 0.96 ng hr/mL −

20%/+25% and a C_max of 0.44 ng/mL −

20%/+25% for l-methylphenidate, and/or an AUC_5-24 of 105.07 ng hr/mL −

20%/+25% and a C_max of 20.60 ng/mL −

20%/+25% for total methylphenidate, for a total methylphenidate dose that is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride, or respective AUC and C_max values directly proportional thereto for a total methylphenidate dose other than that which is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride.

21. The composition of claim 1, wherein said composition is an orally disintegrating tablet and is effective to provide a mean plasma concentration profile in human adult ADHD patients which has an AUC_0-24 of 156.72 ng hr/mL −

20%/+25% and a C_max of 20.17 ng/mL −

20%/+25% for d-methylphenidate, an AUC_0-24 of 2.19 ng hr/mL −

20%/+25% and a C_max of 0.44 ng/mL −

20%/+25% for l-methylphenidate, and/or an AUC_0-24 of 159.25 ng hr/mL −

20%/+25% and a C_max of 20.60 ng/mL −

20%/+25% for total methylphenidate, for a total methylphenidate dose that is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride, or respective AUC and C_max values directly proportional thereto for a total methylphenidate dose other than that which is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride.

22. The composition of claim 1, wherein said composition, would produce, in a human adult, a mean plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC_0-∞

) of about 160 ng hr/ml to about 180 ng hr/ml for total methylphenidate when said composition contains a total methylphenidate dose that is equivalent to that present in about a 60 mg total dose of methylphenidate hydrochloride.

23. The composition of claim 1, wherein one or more in vivo pharmacokinetic parameters of the composition selected from the group consisting of C_max, AUC_0-3, AUC_O-5, AUC_0-Tmax, AUC_5-12, AUC_5-24, AUC_Tmax-24, ACU_Tmax-12, AUC_5-t, AUC_Tmax-t, AUC_0-24, and AUC_0-∞

have a 90% confidence interval with upper and lower bounds within a range from 90%-115% of the value of the same parameter(s) for a bioequivalent reference composition.

24. The composition of claim 1, wherein said composition has an in vivo serum profile with a T_max of approximately six hours.

25. The composition of claim 24, wherein said composition has a bimodal profile with two peaks, having a first peak at approximately 3 hours.

26. The composition of claim 1, wherein said composition has an in vivo serum profile with a first and second peak and said second peak is the C_max.

27. The composition of claim 1, wherein a dose of said composition comprising a total amount of said methylphenidate that is equivalent to that present in about a 60 mg total dose of methylphenidate hydrochloride produces a C_max greater than 16.55 ng/mL.

28. The composition of claim 1, wherein said first plurality of drug-resin particles is uncoated.