Hypertension is a condition that requires long-term treatment and patients can greatly benefit from prolonged release antihypertensive dosage forms. Biodegradable polymer drug delivery systems have generally been composed of drug homogeneously dispersed throughout a polymer matrix. A novel approach in the design of drug delivery systems is the use of covalently bound polymer-drug release predictable. The polymer backbone is biodegradable at a much slower rate so that the system does not require removal after implantation. The goal of this work is to develop prolonged release (1-3 months) dosage forms for treatment of hypertension. Previously, we have shown the validity of biodegradable polymer-drug conjugates for controlled release using contraceptive steroids and the narcotic antagonist naltrexone. To extend this concept to the treatment of hypertension, minoxidil (a vasodilator), prazosin (an alpha-blocker) and libenzapril (CGGS 16617, an angiotensin-converting enzyme [ACE] inhibitor) were attached to biodegradable polymer backbones of glutamic acid, glutamine and leucine derivatives. Both the minoxidil-polymer and the prazosin-polymer conjugates showed zero order release of drug in vitro over a period of months. Upon subcutaneous injection of a particle system of prazosin conjugate into rabbits, a near constant release of drug was obtained for a period of weeks at a therapeutic level. Future work will characterize existing systems to optimize design to provide release of drug in vivo at therapeutic levels for periods of 1 to 3 months. We also plan to develop a similar delivery system for the ACE inhibitor enalapril. The therapeutic efficacy, biocompatibility, immunogenicity and histopathology of present and future systems will be examined in the effort to produce devices suitable for the long-term treatment of chronic hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
9R01HL044539-04A1
Application #
3363356
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1991-02-01
Project End
1995-01-31
Budget Start
1991-02-01
Budget End
1992-01-31
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Pharmacy
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Li, X L; Adams, N W; Bennett, D B et al. (1991) Synthesis of poly(hydroxypropylglutamine-prazosin carbamate) and release studies. Pharm Res 8:527-30