Oral pulsed dose drug delivery system

• US 6,605,300 B1
• Filed: 07/19/2001
• Issued: 08/12/2003
• Est. Priority Date: 10/21/1998
• Status: Expired

• Current Assignee: Shire LLC (Shire plc)
• Original Assignee: Shire Laboratories, Inc. (Supernus Pharmaceuticals Incorporated)
• Inventors: Treacy, Donald J., Chang, Rong-Kun, Fiske, Kimberly, Couch, Richard A., Rudnic, Edward M., Burnside, Beth A., Guo, Xiaodi, McGuinness, Charlotte M.
• Primary Examiner(s): TRAVERS, RUSSELL S
• Application Number:
  US09/807,462
• Time in Patent Office: 754 Days
• Field of Search: 424/457, 424/458, 424/468, 424/469, 424/470, 424/471, 424/472, 514/649
• US Class Current: 424/452
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• 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: A61P 25/00 Drugs for disorders of the nervous system
• 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

Abstract

A multiple pulsed dose drug delivery system for pharmaceutically active amphetamine salts, comprising an immediate-release component and an enteric delayed-release component wherein (1) the enteric release coating has a defined minimum thickness and/or (2) there is a protective layer between the pharmaceutically active amphetamine salt and the enteric release coating and/or (3) there is a protective layer over the enteric release coating. 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 formulation for delivery of a mixture of amphetamine base salts effective to treat ADHD in a human patient comprising:

an immediate release dosage form that provides immediate release upon oral administration to said patient;

a delayed enteric release dosage form that provides delayed release upon oral administration to said patient; and

a pharmaceutically acceptable carrier;

wherein said amphetamine base salts comprise dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine sulfate;

wherein said pharmaceutical formulation is sufficient to maintain an effective level of amphetamine base salts in the patient over the course of at least 8 hours without further administration of amphetamine base salt, and the peak plasma concentration of amphetamine base salts reached after release of said delayed enteric release dosage form exceeds the peak plasma concentration previously reached after release of said immediate release dosage form; and

wherein said pharmaceutical formulation, when containing about a total dose of 20 mg, will produce in a human individual a plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC) of about 467 to about 714 ng hr/ml.

2. A formulation of claim 1 wherein said plasma concentration curve has a maximum concentration (C_max) of about 22.5 to about 40 ng/ml for about a total dose of 20 mg.

3. A formulation of claim 2 wherein the time after said oral administration to reach said C_max value is about 7 to about 10 hours.

4. A formulation of claim 1 wherein the time after said oral administration to reach maximum concentration of said plasma concentration curve is about 7 to about 10 hours.

5. A formulation of claim 2, 3 or 4 wherein said AUC is about 714 ng hr/ml.

6. A formulation of claim 3 wherein said AUC is about 714 ng hr/ml, the time after said oral administration to reach said C_max value is about 7 hours and C_max is about 40 ng/ml.

7. A formulation of claim 2 wherein C_max is about 40 ng/ml.

8. A formulation of claim 3 or 4 wherein said time is about 7 hours.

9. A formulation of one of claims 1-4, 6 or 7 wherein said salts are contained in about equal amounts within each of said dosage forms.

10. A formulation of one of claims 1-4, 6 or 7 wherein said delayed enteric release dosage form comprises a coating of a thickness of at least 20 μ

m which comprises dried about 30% (dry substance) aqueous dispersion of an anionic copolymer based on methacrylic acid and acrylic acid ethyl ester, said coating being soluble at a pH of about 5.5 upwards.

11. A formulation of claim 10 wherein said thickness is at least 25 μ

m.

15. A formulation of claim 1 formulated for a total dose of 20 mg.

16. A formulation of claim 2 formulated for a total dose of 20 mg.

17. A formulation of claim 1 formulated for a total dose different from about 20 mg and having an AUC proportional to said 20 mg AUC.

18. A formulation of claim 2 formulated for a total dose different from about 20 mg and having a C_max proportional to said 20 mg C_max.

12. A pharmaceutical formulation for delivery of a mixture of amphetamine base salts effective to treat ADHD in a human patient comprising:

an immediate release dosage form that provides immediate release upon oral administration to said patient;

a delayed enteric release dosage form that provides delayed release upon oral administration to said patient, wherein said enteric release dosage form comprises a coating of a thickness of at least 20 μ

m which comprises dried aqueous dispersion of an anionic copolymer based on methacrylic acid and acrylic acid ethyl ester, said coating being soluble at a pH of about 5.5 upwards; and

a pharmaceutically acceptable carrier;

wherein said amphetamine base salts comprise dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine sulfate;

wherein said pharmaceutical formulation is sufficient to maintain an effective level of amphetamine base salts in the patient over the course of at least 8 hours without further administration of amphetamine base salt, and the peak plasma concentration of amphetamine base salts reached after release of said delayed enteric release dosage form exceeds the peak plasma concentration of said salts previously reached after release of said immediate release dosage form.

13. A formulation of claim 12 wherein said thickness is at least 25 μ

m.

14. A formulation of claim 12, wherein said dried aqueous dispersion of an anionic copolymer is a dried about 30% (dry substance) aqueous dispersion of an anionic copolymer.