Delivery of multiple doses of medications

• US 5,837,284 A
• Filed: 07/14/1997
• Issued: 11/17/1998
• Est. Priority Date: 12/04/1995
• Status: Expired due to Term

• Current Assignee: Celgene Corporation (Bristol-Myers Squibb Company)
• Original Assignee: Celgene Corporation (Bristol-Myers Squibb Company)
• Inventors: Zeitlin, Andrew L., Dariani, Maghsoud M., Mehta, Atul M.
• Primary Examiner(s): HENLEY III, RAYMOND J
• Application Number:
  US08/892,190
• Time in Patent Office: 491 Days
• Field of Search: 424/458, 424/459, 424/462, 424/468, 514/317
• US Class Current: 424/459
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• 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 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5078 with drug-free core
• 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 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07D 211/34 with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C12P 17/12 containing a six-membered hetero ring
• CPC Class Codes: C12P 41/006 by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures

Abstract

Dosage forms for oral administration of a methylphenidate drug are provided. The dosage forms provide a substantially immediate dose of methylphenidate upon ingestion, followed by one or more additional doses at predetermined times. By providing such a drug release profile, the dosage forms eliminate the need for a patient to carry an additional dose for ingestion during the day. The dosage forms and methods provided are useful in administering methylphenidate and pharmaceutically acceptable salts thereof, which generally require one or more doses throughout the day.

Claims

1. A dosage form for the oral administration of a methylphenidate drug, comprising two groups of particles, each containing said drug, wherein:

a) said first group of particles provides a substantially immediate dose of said drug upon ingestion by a mammal, and

b) said second group of particles comprises coated particles, said coated particles comprising from about 2% to about 75% by weight of said drug in admixture with one or more binders, said coating comprising a pharmaceutically acceptable ammonio methacrylate in a quantity sufficient to provide a dose of said medication delayed by from about 2 hours to about 7 hours following said ingestion.

2. The dosage form of claim 1 wherein said first group of particles comprises a pharmaceutically acceptable salt of methylphenidate in powder form.

3. The dosage form of claim 1 wherein said second group of particles comprises coated particles comprising a pharmaceutically acceptable salt of methylphenidate.

4. The dosage form of claim 2 wherein the amount of said pharmaceutically acceptable salt of methylphenidate in said first group of particles is from about 2% to about 99% by weight, based on the weight of said particles.

5. The dosage form of claim 4 wherein said pharmaceutically acceptable salt of methylphenidate comprises dl-threo methylphenidate hydrochloride.

6. The dosage form of claim 3 wherein said pharmaceutically acceptable salt of methylphenidate comprises dl-threo methylphenidate hydrochloride.

7. The dosage form of claim 1 wherein said second group of particles comprises from about 20% by weight to about 50% by weight of filler, based on the total weight of the copolymer.

8. The dosage form of claim 7 wherein said filler is selected from the group consisting of talc, colloidal silica, fumed silica, gypsum, and glycerine monostearate.

9. The dosage form of claim 8 wherein said filler is talc.

10. The dosage form of claim 9 wherein the amount of talc is from about 35% to about 45% by weight, based on the total weight of the copolymer.

11. The dosage form of claim 10 wherein the amount of talc is from about 38% to about 42% by weight, based on the total weight of the copolymer.

12. The dosage form of claim 11 wherein the amount of talc is about 40% by weight, based on the total weight of the copolymer.

13. The dosage form of claim 1 wherein the ammonio methacrylate copolymer comprises acrylic groups and quaternary ammonium groups in a ratio of from about 10:

1 to about 50;

1.

14. The dosage form of claim 13 wherein said ratio is from about 15:

1 to about 45;

1.

15. The dosage form of claim 14 wherein said ratio is from about 15:

1 to about 20;

1.

16. The dosage form of claim 15 wherein said ratio is from about 30:

1 to about 40;

1.

17. The dosage form of claim 1 comprising a first ammonio methacrylate copolymer comprising, as polymerized units, acrylic groups and trimethylammonioethyl methacrylate in a ratio of from about 30:

1 to about 40;

1, and a second ammonio methacrylate copolymer comprising, as polymerized units, acrylic groups and trimethylammonioethyl methacrylate in a ratio of from about 15;

1 to about 20;

1.

18. The dosage form of claim 17 wherein the ratio of said first copolymer to said second copolymer is from about 90:

10 to about 99;

1.

19. The dosage form of claim 18 wherein the ratio of said first copolymer to said second copolymer is from about 93:

7 to about 97;

3.

20. The dosage form of claim 19 wherein the ratio of said first copolymer to said second copolymer is about 95:

5.

21. The dosage form of claim 1 wherein said delay is from about 3 hours to about 6 hours.

22. The dosage form of claim 1 wherein said delay is from about 4 hours to about 5 hours.

23. A dosage form for once-daily oral administration of a methylphenidate drug comprising:

a) particles comprising from about 2% by weight to about 99% by weight of said methylphenidate drug, in admixture with one or more binders,

b) a coating exterior to said methylphenidate drug, comprising an ammonio methacrylate copolymer in a quantity sufficient to provide a dose of said methylphenidate delayed by from about 2 hours to about 7 hours following administration, and

c) on the exterior surface of said coating, a layer comprising said methylphenidate drug, to provide a substantially immediate dose of said methylphenidate upon administration.

24. The dosage form of claim 23 wherein said methylphenidate is dl-threo-methylphenidate hydrochloride.

25. The dosage form of claim 23 wherein said methylphenidate is d-threo-methylphenidate hydrochloride.

26. The dosage form of claim 23 wherein said coating comprises a first ammonio methacrylate copolymer comprising, as polymerized units, acrylic groups and trimethylammonioethyl methacrylate in a ratio of from about 30:

1 to about 40;

1, and a second ammonio methacrylate copolymer comprising, as polymerized units, acrylic groups and trimethylammonioethyl methacrylate in a ratio of from about 15;

1 to about 20;

1.

30. A dosage form according to claim 23 wherein said ammonio methacrylate copolymer comprises a first copolymer of methyl methacrylate, ethyl acrylate and TAMCl in a ratio of 2:

1;

0.1 and a second copolymer of methyl methacrylate, ethyl acrylate, and TAMCl in a ratio of 2;

1;

0.2.

27. A dosage form for the oral administration of d-threo-methylphenidate hydrochloride comprising two groups of particles, each containing d-threo-methylphenidate, wherein:

a) said first group of particles comprises d-threo-methylphenidate hydrochloride and provides a substantially immediate dose of said d-threo methylphenidate upon ingestion by a mammal, and

b) said second group of particles comprises coated particles, said coated particles comprising from about 2% to about 75% by weight of d-threo-methylphenidate hydrochloride in admixture with one or more binders, said coating comprising a pharmaceutically acceptable ammonio methacrylate copolymer in an amount sufficient to provide a dose of said d-threo-methylphenidate delayed by from about 2 hours to about 7 hours following said ingestion.

28. A dosage form of a pharmaceutically acceptable salt of d-threo-methylphenidate providing an in vitro release profile comprising two pulses of drug release, wherein said pulses are temporally separated by from about 2 hours to about 7 hours.

29. A dosage form of a pharmaceutically acceptable salt of d-threo-methylphenidate providing an in vivo plasma concentration of said d-threo-methylphenidate comprising two maxima, wherein said maxima are temporally separated by from about 2 hours to about 7 hours, and wherein the magnitude of said maxima differ by no more than about 30 percent.