Multiparticulate modified release composition

• US 6,793,936 B2
• Filed: 01/30/2003
• Issued: 09/21/2004
• Est. Priority Date: 11/02/1998
• Status: Expired due to Term

• Current Assignee: Recro Gainesville LLC (Societal CDMO, Inc.)
• Original Assignee: Elan Corporation PLC (Perrigo Company PLC)
• Inventors: Stark, Paul, Devane, John G., Fanning, Niall M. M.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Bennett, Rachel M.
• Application Number:
  US10/354,483
• Publication Number:
  US 20030170304A1
• Time in Patent Office: 600 Days
• Field of Search: 424/484, 424/464, 424/465, 424/468, 424/469, 424/456, 424/451, 424/472
• US Class Current: 424/484
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention relates to a multiparticulate modified release composition that in operation delivers an active ingredient in a pulsed or bimodal manner. The multiparticulate modified release composition comprises an immediate release component and a modified release component; the immediate release component comprising a first population of active ingredient containing particles and the modified release component comprising a second population of active ingredient containing particles coated with a controlled release coating; wherein the combination of the immediate release and modified release components in operation deliver the active ingredient in a pulsed or a bimodal manner. The invention also relates to a solid oral dosage form containing such a multiparticulate modified release composition. The plasma profile achieved by the multiparticulate modified release composition is advantageous in reducing patient tolerance to the active ingredient and in increasing patient compliance by reducing dosage frequency.

Claims

1. A multiparticulate modified-release composition comprising a first population of active ingredient-containing particles and at least one subsequent population of active ingredient-containing particles, the active ingredient contained in the first population being a sedative and the active ingredient in the subsequent population being a sedative or a non-sedative, wherein the subsequent population of active ingredient-containing particles further comprises a modified release coating or, alternatively or additionally, a modified release matrix material, such that the composition following oral delivery to a subject delivers the active ingredients of the first and subsequent populations in a pulsatile manner.

2. The composition according to claim 1, comprising a first population and one subsequent population.

3. The composition according to claim 2, wherein the first population comprises immediate-release particles and the subsequent population comprises modified-release particles.

4. The composition according to claim 3, wherein the modified release particles have a modified-release coating.

5. The composition according to claim 3, wherein the modified release particles comprise a modified-release matrix material.

6. The composition according to claim 1, wherein the subsequent population comprises sedative-containing particles.

7. The composition according to claim 1, wherein the first population contains at least one additional active ingredient.

8. The composition according to claim 1, wherein the subsequent population contains at least one additional active ingredient.

9. The composition according to claim 1, wherein at least one of the active ingredients of the first and subsequent populations comprises substantially one optically pure enantiomer or a mixture, racemic or otherwise, of enantiomers.

10. The composition according to claim 1, wherein at least one of the first and subsequent populations further comprises an enhancer.

11. The composition according to claim 1, wherein the amount of active ingredient contained in the first and subsequent populations is the same or different.

12. The composition according to claim 11, wherein the amount of active ingredient contained in each of the first and subsequent populations is from about 0.1 mg to about 1 g.

13. The composition according to claim 6, wherein the active ingredient of at least one of the first and subsequent populations is selected from the group consisting of benzodiazepines, phenothiozines, a pharmaceutically acceptable salt thereof, an enantiomer or mixtures thereof, and mixtures thereof.

14. The composition according to claim 1, wherein the first and subsequent populations have different in vitro dissolution profiles.

15. The composition according to claim 1, wherein the particles of the first population comprise immediate-release particles and the particles of the subsequent population comprise modified-release particles.

16. The composition according to claim 15, which in operation releases substantially all of the active ingredient from the first population prior to release of the active ingredient from the subsequent population.

17. The composition according to claim 1, wherein the in vivo release in the subject of the active ingredients from the first and subsequent populations mimics the in vivo release of the same active ingredients administered in the form of two or more doses of immediate-release forms of the active ingredients.

18. The composition according to claim 13, wherein the in vivo release in the subject of the active ingredients from the first and subsequent populations mimics the in vivo release of the same active ingredients administered in the form of two or more doses of immediate release forms of the active ingredients.

19. The composition according to claim 16, wherein the mean in vitro dissolution profile in an aqueous medium is such that substantially all of the active ingredient of the first population is released within about two hours.

20. A solid oral dosage form comprising a multiparticulate modified release composition according to claim 1.

21. The dosage form according to claim 20 comprising a blend of the particles of each of the first and subsequent populations contained in a hard gelatin or soft gelatin capsule.

22. The dosage form according to claim 21, wherein the particles of each of the populations are in the form of mini-tablets and the capsule contains a mixture of the mini-tablets.

23. The dosage form according to claim 21 in the form of a multilayer tablet comprising a first layer of compressed active ingredient-containing particles of the first population and another layer of compressed active ingredient-containing particles of the subsequent population.

24. The dosage form according to claim 20, wherein the first and subsequent populations of active ingredient-containing particles are provided in a rapidly dissolving dosage form.

25. The dosage form according to claim 24, comprising a fast-melt tablet.

26. A method for the treatment of insomnia comprising administering a therapeutically effective amount of a multiparticulate modified release composition according to claim 1.

27. A method for the treatment of insomnia comprising administering a therapeutically effective amount of a multiparticulate modified release composition according to claim 13.

28. The composition according to claim 3, wherein the modified-release particles comprise a pH-dependent polymer coating which is effective in releasing a pulse of the active ingredient following a time delay.

29. The composition according to claim 28, wherein the polymer coating comprises methacrylate copolymers.

30. The composition according to claim 28, wherein the polymer coating comprises a mixture of methacrylate and ammonio methacrylate copolymers in a ratio sufficient to achieve a pulse of the active ingredient following a time delay.

31. The composition according to claim 30, where the ratio of methacrylate to ammonio methacrylate copolymers is 1:

1.