Sustained release drug delivery system suitable for oral administration

• US 5,885,616 A
• Filed: 08/18/1997
• Issued: 03/23/1999
• Est. Priority Date: 08/18/1997
• Status: Expired due to Term

• Current Assignee: Impax Laboratories Incorporated (Amneal Pharmaceuticals, LLC)
• Original Assignee: Impax Pharmaceuticals, Inc.
• Inventors: Hsiao, John, Sue, I-Lan
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Seidleck, Brian K.
• Application Number:
  US08/912,722
• Time in Patent Office: 582 Days
• Field of Search: 424/472, 424/490, 424/495, 424/494, 424/497, 424/461
• US Class Current: 424/472
• CPC Class Codes: A61K 9/5078 with drug-free core

Abstract

A single bead drug delivery system suitable for oral administration with multiply layered drug and polymer compartments can provide a two-step release of active agent to facilitate an immediate yet sustained drug delivery over a 24 hour period following oral administration with minimized variance between peak and trough levels of therapeutic drug amounts.

Claims

1. A single bead drug delivery system suitable for oral administration comprising:

a) a first drug compartment containing an effective amount of an active agent, or a pharmaceutically acceptable salt thereof, optionally in association with a pharmaceutically acceptable binder or excipient;

b) a first polymer compartment which substantially envelops said first drug compartment to form a first drug/polymer interface;

c) a second drug compartment containing an effective amount of an active agent, or a pharmaceutically acceptable salt thereof, optionally in association with a pharmaceutically acceptable binder or excipient, wherein said second drug compartment substantially envelops said first polymer compartment to form a second drug/polymer interface;

d) a second polymer compartment which substantially envelops said second drug compartment to form a third drug/polymer interface; and

wherein said single bead drug delivery system can release said active agent in multiple phases.

2. The drug delivery system of claim 1, which further comprises:

e) a cosmetic coat compartment which substantially envelops said second polymer compartment to form a polymer/cosmetic coat interface.

3. The drug delivery system of claim 1, which further comprises a seal coat compartment at said first drug/polymer interface.

4. The drug delivery system of claim 1, which further comprises a seal coat compartment at said second drug/polymer interface.

5. The drug delivery system of claim 1, which further comprises a seal coat compartment at said third drug/polymer interface.

6. The drug delivery system of claim 1, which further comprises a seal coat compartment that substantially envelops said second polymer compartment.

7. The drug delivery system of claim 2, which further comprises a seal coat compartment at said polymer/cosmetic coat interface.

8. The drug delivery system of claim 1, which further comprises a first seal coat compartment at said first drug/polymer interface and a second seal coat compartment at said third drug/polymer interface.

9. The drug delivery system of claim 1, which further comprises a first seal coat compartment at said second drug/polymer interface and a second seal coat compartment that substantially envelops said second polymer compartment.

10. The drug delivery system of claim 2, which further comprises a first seal coat compartment at said second drug/polymer interface and a second seal coat compartment at said polymer/cosmetic coat interface.

11. The drug delivery system of claim 1, wherein said first drug compartment substantially envelops an inert core.

12. The drug delivery system of claim 1, wherein said active agent is diltiazem, or a pharmaceutically acceptable salt thereof.

13. The drug delivery system of claim 12, wherein said diltiazem exhibits the following in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXIII at 37°

C. in simulated gastric fluid at 100 rpm;

a) from about 0% to about 40% of total diltiazem is released after 3 hours of measurement in said apparatus;

b) from about 10% to about 50% of total diltiazem is released after 6 hours of measurement in said apparatus; and

c) no more than about 60% of total diltiazem is released after 12 hours of measurement in said apparatus.

14. The drug delivery system of claim 12, wherein said diltiazem exhibits the following in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXIII at 37°

C. in simulated intestinal fluid at 100 rpm;

a) from about 20% to about 50% of total diltiazem is released after 3 hours of measurement in said apparatus;

b) from about 20% to about 60% of total diltiazem is released after 6 hours of measurement in said apparatus;

c) from about 35% to about 100% of total diltiazem is released after 12 hours of measurement in said apparatus; and

d) no less than about 70% of total diltiazem is released after 24 hours of measurement in said apparatus.

15. The drug delivery system of claim 12, wherein said diltiazem exhibits the following in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXIII at 37°

C. in simulated gastric fluid at 100 rpm;

a) from about 0% to about 40% of total diltiazem is released after 3 hours of measurement in said apparatus;

b) from about 10% to about 50% of total diltiazem is released after 6 hours of measurement in said apparatus; and

c) no more than about 60% of total diltiazem is released after 12 hours of measurement in said apparatus; and

wherein said diltiazem exhibits the following in vitro dissolution profile when measured in a type 2 dissolution apparatus (paddle) according to U.S. Pharmacopeia XXIII at 37°

C. in simulated intestinal fluid at 100 rpm;

a) from about 20% to about 50% of total diltiazem is released after 3 hours of measurement in said apparatus;

b) from about 20% to about 60% of total diltiazem is released after 6 hours of measurement in said apparatus;

c) from about 35% to about 100% of total diltiazem is released after 12 hours of measurement in said apparatus; and

d) no less than about 70% of total diltiazem is released after 24 hours of measurement in said apparatus.

16. The drug delivery system of claim 12, wherein the amount of diltiazem contained in said first drug compartment and the amount of diltiazem contained in said second drug compartment is present in a weight/weight ratio from 4:

1 to 1;

4.

17. The drug delivery system of claim 12, wherein the amount of diltiazem contained in said first drug compartment and the amount of diltiazem contained in said second drug compartment is present in a weight/weight ratio of 3:

2.

18. The drug delivery system of claim 1, wherein said first polymer compartment, or second polymer compartment, or both first and second polymer compartments, contains one or more water insoluble polymer(s) selected from the group consisting of cellulose esters, cellulose ethers, and acrylic resins.

19. The drug delivery system of claim 1, wherein said first polymer compartment, or second polymer compartment, or both first and second polymer compartments, contains one or more pH sensitive polymer(s) selected from the group consisting of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, other cellulose ethers or esters, and acrylic resins.

20. The drug delivery system of claim 1, wherein said first polymer compartment, or second polymer compartment, or both first and second polymer compartments, contains one or more water soluble polymer(s) selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, other cellulose ethers, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, starch, and hydroxyethyl cellulose.