Sustained delivery of leuprolide using an implantable system

• US 5,728,396 A
• Filed: 01/30/1997
• Issued: 03/17/1998
• Est. Priority Date: 02/02/1996
• Status: Expired due to Term

• Current Assignee: Intarcia Therapeutics, Inc.
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Lautenbach, Scott D., Landrau, Felix A., Magruder, Judy A., Eckenhoff, James B., Wright, Jeremy C., Peery, John R., Dionne, Keith E.
• Primary Examiner(s): BROUILLETTE, D GABRIELLE
• Application Number:
  US08/791,699
• Time in Patent Office: 411 Days
• Field of Search: 424/473, 424/422, 424/423, 424/424, 604/891.1
• US Class Current: 424/422
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61M 2005/14513 with secondary fluid driving or regulating the infusion
• CPC Class Codes: A61M 2206/10 Flow characteristics
• CPC Class Codes: A61M 5/14526 the piston being actuated by fluid pressure

Abstract

The invention is directed to a device for delivering an active agent formulation for a predetermined administration period. An impermeable reservoir is divided into a water-swellable agent chamber and an active agent formulation chamber. Fluid from the environment is imbibed through a semipermeable plug into the water-swellable agent chamber and the active agent formulation is released through a back-diffusion regulating outlet. Delivery periods of up to 2 years are achieved.

Claims

1. An implantable leuprolide delivery system comprising:

(a) an impermeable reservoir;

(b) a piston that divides the reservoir into a first and a second chamber, the first and second chambers each having an open end;

(c) a water-swellable agent formulation in the first chamber;

(d) a leuprolide formulation in the second chamber;

(e) a semipermeable plug in the open end of the first chamber; and

(f) a back-diffusion regulating outlet in the open end of the second chamber;

wherein the system effectively seals the second chamber and isolates the leuprolide formulation from the environment of use.

2. The system of claim 1 wherein the reservoir is titanium or a titanium alloy.

3. The system of claim 1 wherein the piston is formed of styrene-ethylene-butylene-styrene copolymer.

4. The system of claim 1 wherein the water-swellable agent formulation contains at least about 64 mg NaCl.

5. The system of claim 1 wherein the water-swellable agent formulation contains NaCl, a gelling osmopolymer and granulation and processing aids.

6. The system of claim 1 further comprising an additive in the first chamber.

7. The system of claim 6 wherein the additive is PEG 400.

8. The system of claim 1 wherein the leuprolide formulation is leuprolide acetate dissolved in DMSO at an assayed content of 37% leuprolide.

9. The system of claim 1 which contains 65 mg leuprolide.

10. The system of claim 1 wherein the semipermeable plug is formed of polyurethane material with 20% water uptake.

11. The system of claim 1 wherein the back-diffusion regulating outlet is made of polyethylene and has a flow path helical in shape with a diameter between 0.003 and 0.020 inches and a length of 2 to 7 cm.

12. The system of claim 1 which delivers about 0.35 μ

L leuprolide formulation per day.

13. The system of claim 12 which provides continuous delivery of leuprolide formulation for about one year.

14. The system of claim 1 which reaches at least about 70% steady-state delivery by day 14.

15. The system of claim 1 which delivers about 150 μ

g leuprolide per day.

16. A method of treating a subject suffering from prostatic cancer comprising administering at least one system of claim 1.

17. An implantable leuprolide delivery system comprising:

(a) a titanium alloy reservoir;

(b) a styrene-ethylene-butylene-styrene copolymer piston that divides the reservoirs into a first and a second chamber, the first and second chambers each having an open end;

(c) a compressed NaCl-based osmotic engine and a PEG additive in the first chamber;

(d) 65 mg leuprolide as a leuprolide acetate solution in DMSO in the second chamber;

(e) a semipermeable polyurethane plug with 20% water uptake in the open end of the first chamber; and

(f) a polyethylene back diffusion regulating outlet with a helical flow path in the open end of the second chamber;

wherein the system continuously delivers about 150 μ

g leuprolide per day for about one year after subcutaneous implantation.