CONTROLLED DOSE DRUG DELIVERY SYSTEM

• US 20070264323A1
• Filed: 05/12/2006
• Published: 11/15/2007
• Est. Priority Date: 05/12/2006
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Shire LLC (Shire plc)
• Inventors: Shojaei, Amir, Couch, Richard, Hodgkins, Paul, Read, Stephanie
• Granted Patent: US 8,846,100 B2
• Time in Patent Office: Days
• US Class Current: 424/451
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• 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 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• 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

Abstract

A multiple pulsed dose drug delivery system for pharmaceutically active amphetamine salts, comprising a pharmaceutically active amphetamine salt covered with an immediate-release coating and a pharmaceutically active amphetamine salt covered with an enteric coating wherein the immediate release coating and the enteric coating provide for multiple pulsed dose delivery of the pharmaceutically active amphetamine salt. The product can be composed of either one or a number of beads in a dosage form, including either capsule, tablet, or sachet method for administering the beads.

Claims

1. A pharmaceutical composition comprising:

(a) an immediate release bead comprising at least one amphetamine salt;

(b) a first delayed release bead comprising at least one amphetamine salt; and

(c) a second delayed release bead comprising at least one amphetamine salt;

wherein the first delayed release bead provides pulsed release of the at least one amphetamine salt and the second delayed release bead provides sustained release of the at least one amphetamine salt.

2. The pharmaceutical composition of claim 1, wherein the first delayed release bead and the second delayed release bead comprise an enteric coating.

3. The pharmaceutical composition of claim 2, wherein the enteric coating is pH dependent.

4. The pharmaceutical composition of claim 2, wherein the first delayed release bead and the second delayed release bead comprise different enteric coatings.

5. The pharmaceutical composition of claim 2, wherein the first delayed release bead and the second delayed release bead comprise the same enteric coating.

6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is bioequivalent to ADDERALL®

XR followed by an immediate release amphetamine formulation administered 8 hours after the ADDERALL®

XR;

wherein the combined dosage of the ADDERALL®

XR and the immediate release formulation is equal to the dosage of the pharmaceutical composition.

7. The pharmaceutical composition of claim 1, wherein administration of a 37.5 mg dose of the pharmaceutical composition to a human patient results in a d-amphetamine C_max of about 50 ng/ml.

8. The pharmaceutical composition of claim 1, wherein the d-amphetamine area under the curve from time 0 to the last measured time (AUC_0-last) after administration of a 37.5 mg dose of the pharmaceutical composition to a human patient is about 1058 ng·

hr/ml.

9. The pharmaceutical composition of claim 1, wherein the d-amphetamine area under the curve from time 0 to time infinity (AUC_0-inf) after administration of a 37.5 mg dose of the pharmaceutical composition to a human patient is about 1085 ng·

hr/ml.

10. The pharmaceutical composition of claim 1, wherein the d-amphetamine T_max is about 8.2 hours after administration of a 37.5 mg dose of the pharmaceutical composition to a human patient.

11. The pharmaceutical composition of claim 1, wherein the l-amphetamine C_max after administration of a 37.5 mg dose of the pharmaceutical composition to a human patient is about 15 ng/ml.

12. The pharmaceutical composition of claim 1, wherein the l-amphetamine area under the curve from time 0 to the last measured time (AUC_0-last) after administration of a 37.5 mg dose of the pharmaceutical composition to a human patient is about 354 ng·

hr/ml.

13. The pharmaceutical composition of claim 1, wherein the l-amphetamine area under the curve from time 0 to time infinity (AUC_0-inf) after administration of a 37.5 mg dose of the pharmaceutical composition to a human patient is about 373 ng·

hr/ml.

14. The pharmaceutical composition of claim 1, wherein the l-amphetamine T_max is about 8.4 hours after administration of a 37.5 mg dose of the pharmaceutical composition to a human patient.

15. The pharmaceutical composition of claim 1, wherein the immediate release bead and at least one delayed release bead are present on a single core.

16. The pharmaceutical composition of claim 1, wherein the immediate release bead and at least one delayed release bead are present on different cores.

17. The pharmaceutical composition of claim 1, wherein the at least one amphetamine salt is coated onto a core.

18. The pharmaceutical composition of claim 1, wherein the at least one amphetamine salt is incorporated into a core.

19. The pharmaceutical composition of claim 2, which further comprises a protective layer over at least one enteric coating.

20. The pharmaceutical composition of claim 2, which further comprises a protective layer between the amphetamine salt and at least one enteric coating.

21. The pharmaceutical composition of claim 1, wherein the at least one amphetamine salt is selected from the group consisting of dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate, amphetamine sulfate, and mixtures thereof.

22. The pharmaceutical composition of claim 21, wherein the at least one amphetamine salt is a mixture of dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate, and amphetamine sulfate.

23. The pharmaceutical composition of claim 1, wherein the composition does not exhibit a food effect.

24. The composition of claim 6, wherein the amount of at least one amphetamine salt is about 12.5 mg.

25. The composition of claim 6, wherein the amount of at least one amphetamine salt is about 18.75 mg.

26. The composition of claim 6, wherein the amount of at least one amphetamine salt is about 25 mg.

27. The composition of claim 6, wherein the amount of at least one amphetamine salt is about 31.25 mg.

28. The composition of claim 6, wherein the amount of at least one amphetamine salt is about 37.5 mg.

29. The composition of claim 6, wherein the amount of at least one amphetamine salt is about 43.75 mg.

30. The composition of claim 6, wherein the amount of at least one amphetamine salt is about 50 mg.

31. The composition of claim 6, wherein the amount of at least one amphetamine salt is about 62.5 mg.

32. The composition of claim 6, wherein the amount of at least one amphetamine salt is about 75 mg.

33-58. -58. (canceled)

59. A pharmaceutical composition comprising:

at least one amphetamine salt and a pharmaceutically acceptable carrier;

wherein the composition provides an about bioequivalent plasma level of amphetamine in a patient compared to an equivalent amount of at least one amphetamine salt contained in the combination of ADDERALL®

XR and an immediate release amphetamine salt composition when the immediate release composition is administered to the patient about 8 hours after the ADDERALL®

XR.

60. The composition of claim 59, wherein the composition provides an about bioequivalent plasma level of d-amphetamine in the patient compared to an equivalent amount of at least one amphetamine salt contained in the combination of ADDERALL®

XR and an immediate release amphetamine salt composition when the immediate release composition is administered to the patient about 8 hours after the ADDERALL®

XR.

61. The composition of claim 59, wherein the composition provides an about bioequivalent plasma level of l-amphetamine in the patient compared to an equivalent amount of at least one amphetamine salt contained in the combination of ADDERALL®

XR and an immediate release amphetamine salt composition when the immediate release composition is administered to the patient about 8 hours after the ADDERALL®

XR.