DOSAGE FORMS FOR ORAL ADMINISTRATION AND METHODS OF TREATMENT USING THE SAME

• US 20140072645A1
• Filed: 07/22/2013
• Published: 03/13/2014
• Est. Priority Date: 06/28/2011
• Status: Abandoned Application

• Current Assignee: NEOS Therapeutics Incorporated
• Original Assignee: NEOS Therapeutics Incorporated
• Inventors: TENGLER, Mark, MCMAHEN, Russell
• Application Number:
  US13/947,861
• Publication Number:
  US 20140072645A1
• Time in Patent Office: Days
• US Class Current: 424/495
• 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

The invention relates to dosage forms that provide prolonged therapy. In particular, the invention relates to dosage forms including various pluralities of drug-containing resin particles. The invention also relates to methods of making these dosage forms and methods of treating using these dosage forms.

Claims

1. A method for treating Attention-Deficit Disorder or Attention-Deficit Hyperactivity Disorder comprising administering to a subject in need thereof an effective amount of 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, and wherein said composition comprises a first plurality of drug-resin particles that provide for an immediate release of methylphenidate and a second plurality of drug-resin particles that provide for a delayed release of methylphenidate.

2. The method of claim 1, wherein the second plurality of drug-resin particles comprises a triggered-release coating triggered by a pH change.

3. The method of claim 2, 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.

4. The method of claim 2, wherein said drug-resin particles coated with a triggered-release coating further comprise a diffusion barrier coating.

5. The method of claim 4, wherein the diffusion barrier coating is a water insoluble, water permeable membrane.

6. The method of claim 5, wherein the diffusion barrier coating contains polyvinylpyrrolidone, polyvinylacetate, polyvinylalcohol or mixtures thereof.

7. The method of claim 5, wherein the water insoluble, water permeable membrane is ethylcellulose.

8. The method of claim 4, wherein the triggered-release coating covers the diffusion barrier coating.

9. The method of claim 7, wherein the diffusion barrier coating is ethylcellulose.

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

11. The method of claim 1, wherein the composition comprises 20%-30% of the first plurality of drug-resin particles and 70-80% of the second plurality of drug-resin particles.

12. The method of claim 10, wherein the composition comprises about 25% of the first plurality of drug-resin particles and about 75% of the second plurality of drug-resin particles.

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

14. The method of claim 1, wherein the amount of drug delivered to said subject is between about 2 mg/24 hours to about 60 mg/24 hours.

15. The method of claim 1, wherein the effective amount is 0.5 mg/kg/day to 1.5 mg/kg/day.

16. The method of claim 1, wherein said pharmaceutical composition is sufficient to maintain an effective level of ADHD effective agent in the patient over the course of at least 8 hours without further administration of ADHD effective agent.

17. The method of claim 1, wherein 30-33% of the ADHD effective agent is released within the first 30 minutes after the drug-resin particles are introduced into an in vitro dissolution assay, 34-42% of the agent is released within 2 hours, 40-80% of the agent is released within 4 hours, and 80-100% of the agent is released within 24 hours, 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.

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

19. The method of claim 1, wherein the in vivo serum profile of the composition is statistically similar to the in vivo serum profile of a composition with the profiles of FIG. 24.

21. The method of claim 1, wherein the amount of ADHD effective agent is equivalent to a 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg reference composition without resin particles, said reference composition having the profiles of FIG. 24.

22. The method of claim 1, wherein administration of the composition to a human produces a mean plasma concentration profile in human patients 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_Tmas-12, AUC_5-t, AUC_Tmax-t, AUC_0-24, and AUC_0-∞

of methylphenidate, which is substantially similar to those parameters of a composition with the profiles of FIG. 24.

23. The method of claim 1, wherein said composition is an orally disintegrating tablet and is effective to provide a mean plasma concentration profile in human 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_-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 60 mg total dose, or respective AUC and C_max values directly proportional thereto for a total dose other than 60 mg.

24. The method of claim 1, wherein said composition is an orally disintegrating product and is effective to provide a mean plasma concentration profile in human 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 60 mg total dose, or respective AUC and C_max values directly proportional thereto for a total dose other than 60 mg.

25. The method of claim 1, wherein said composition is an orally disintegrating product and is effective to provide a mean plasma concentration profile in human 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 60 mg total dose, or respective AUC and C_max values directly proportional thereto for a total dose other than 60 mg.

26. The method of claim 1, wherein said composition is an orally disintegrating product and is effective to provide a mean plasma concentration profile in human 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 60 mg total dose, or respective AUC and C_max values directly proportional thereto for a total dose other than 60 mg.

27. The method of claim 1, wherein said composition, when containing about a total dose of 60 mg, will produce in a human, a mean plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC_0-∞

) of about 160 to about 180 for total methylphenidate.

28. The method 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_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-∞

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.

29. A method according to claim 1 wherein said pharmaceutical composition is administered to a subject substantially contemporaneously with ethanol and wherein the subject is exposed to a reduced amount of methylphenidate compared to when a reference composition without resin particles, said reference composition having the profiles of FIG. 24, is administered to a subject substantially contemporaneously with ethanol.

20. (canceled)