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In Vivo Studies on Drug—Polymer Sustained-Release Systems JAMES M . ANDERSON Case Western Reserve University, Departments of Pathology and Macromolecular Science, Cleveland, OH 44106
The pharmacodynamic performance was studied for three drug-polymer matrix systems and comparisons were made between the in vivo and the in vitro results. The systems studied were: (a) gentamicin in silicone rubber, (b) tetracycline in HEMA/MMA copolymers, and (c) niridazole in silicone rubber. In general, the in vitro models fall short of predicting the actual in vivo results accurately, even in those cases where the controlled release of the agent showed positive, desirable results in the test animals. Sustained release of biological agents i s a concept that has received increased attention over the past decade. The primary goal of sustained drug release i s the prolonged delivery of a drug to a particular body compartment or anatomical target site* This goal i s accomplished by the application of a therapeutic drug delivery system designed to control both temporal and spatial aspects of drug disposition. Numerous drug-polymer delivery systems have been proposed with the expressed purpose of releasing a biologically active agent into the surrounding medium at a constant (zero-order) release rate. Attempts to achieve zero-order release rates have included infusion pumps CI), erodable matrices (2), controlled geometries (3), and various membrane-enclosed reservoir devices (4^, , 6). Unfortunately, many of these systems f a l l far short of their goal, suffering from prolonged burst effects, device breakdown, and constraints in design, fabrication, or material properties. The result is usually an exponential release pattern with time and a relatively limited period of constant release* Previous investigations in the f i e l d of controlled drug delivery have centered on the design and in vitro testing of the device. Animal experimentation has been largely limited to reports on the temporal pharmacodynamic performance of the drugs released from the implanted, inserted, or surface-applied polymer vehicles. Few studies have attempted to provide details of the kinetic
0097-6156/82/0186-0085$5.00/0 © 1982 American Chemical Society In Biological Activities of Polymers; Carraher, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.
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behavior of these release systems throughout the period of in vivo evaluation. These data are essential to exploring the pharmacokinetic characteristics of such systems and providing for the development of predictive models. These models also increase experimental efficiency by allowing the use of preliminary measurements and analyses to optimize the further design of the controlled drug-release systems, conserving time and animal resources• We wish to review here our efforts which have been directed toward evaluating the in vivo release behavior of various drug-polymer devices. We have used dogs, rats and mice in these studies for reasons which w i l l be explained. Our studies, which are b r i e f l y summarized i n Table 1, have had two major themes: the investigation of drug release behavior i n a disease model i n an animal, and the investigation of the pharmacokinetics of a drug-polymer sustained release system i n an animal model. Both of these themes are pertinent to the evaluation of drug-polymer sustained release systems intended for use i n humans or animals. We intend only a brief review here and refer the reader to the references for experimental techniques, details and an in-depth discussion of each system. Table 1. Drug-Polymer Sustained Release Systems General Theme or Disease Model
Studies
Animal
Drug
Polymer Silicone Rubber
Prosthetic Valve Endocarditis
in vitro dog in vivo pharmacokinetics
Gentamicin
Antibiotic Delivery
in vitro rat in vivo pharmacokinetics
Tetra- HEMA/MMA cycline
Schistosomiasis
in vivo mouse
Niridazole
Silicone Rubber
References 7-11
12-15
16
Sustained Release of Gentamicin From Prosthetic Heart Valves Although prosthetic heart valves have been extensively and successfully employed c l i n i c a l l y , problems s t i l l exist during the postoperative period concerning thromboembolism, infection and valvular incompetence. Infectious prosthetic valve endocarditis (PVE) remains as a serious and potentially devastating consequence of valve replacement surgery with mechanically fabricated
In Biological Activities of Polymers; Carraher, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.
Downloaded by NORTH CAROLINA STATE UNIV on May 3, 2015 | http://pubs.acs.org Publication Date: May 12, 1982 | doi: 10.1021/bk-1982-0186.ch007
7.
ANDERSON
Drug-Polymer
Sustained-Release
Systems
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prosthetic valves. Prophylactic antibiotic usage has reduced the c l i n i c a l l y confirmed incidence of PVE but early mortality due to such infections remains high, 70% or greater as reported in several studies. An earlier study has indicated the a b i l i t y of parenteral prophylactic antibiotic therapy to reduce the incidence of prosthetic mitral valve failure in dogs associated with valve related infections. As an alternative to the above approach, we have investigated the therapeutic efficacy of a system providing for a sustained release of gentamicin, incorporating the antibiotic in silicone rubber which is in the sewing rim of a mitral valve prosthesis implanted in dogs. In vitro studies with the uncoated gentamicin loaded valve rim inserts revealed an i n i t i a l burst of drug released which peaked on the f i r s t day and slowly f e l l through day 10. At that time, a near constant pattern ensued during which 2.5-7.0 mg/day were released for a period of 2-3 wks followed by lower levels of drug release for up to 2 mos. Valve rim inserts with the additional drug-free silicone rubber layer (coated samples) exhibited a different release pattern with a reduced burst effect and greater persistence of long-term drug delivery. Peak release with the coated valve rim insert was delayed to the third or fourth day and after 4 days mean cumulative gentamicin release was only 59% of that of the uncoated inserts. Serum measurements in dogs receiving the uncoated antibiotic loaded valve rims containing the H-gentamicin exhibited a large early burst of gentamicin release, similar to that observed in the in vitro experiments. Peak serum gentamicin levels occurred during the cardiopulmonary bypass procedure. Serum drug concentrations rapidly f e l l over the f i r s t 3 to 4 days following valve implantation and remained at levels of approximately 0.2 yg/ml for the next 2 to 3 wks. Serum gentamicin concentrations were measurable for 1 to 2 mos before f a l l i n g below detectable levels (< 0.1 ug/ml). The i n i t i a l burst of gentamicin release was absent as measured in the serum of dogs implanted with prosthetic valves containing the coated rim inserts. The additional layer of drug-free silicone over the drug loaded valve insert effectively reduced peak serum gentamicin concentrations such that levels remained relatively constant over the observable drug delivery period* Survival data on dogs implanted with mitral valves containing drug-free silicone rubber rim inserts (controls) and rim inserts loaded with 40% gentamicin sulfate, by weight, both uncoated and coated samples, are presented in Table I I . A significant increase in survival i s readily apparent for dogs receiving gentamicin loaded valves (uncoated and coated) compared to the animals receiving the control valves with the drug-free silicone rubber inserts. Long-term survival (dogs l i v i n g 5 mos or greater) was 70% for the combined uncoated and coated gentamicin loaded valve implants, compared to only 31% in the control group. Three of the
In Biological Activities of Polymers; Carraher, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.
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BIOLOGICAL ACTIVITIES OF POLYMERS
dogs in the gentamicin loaded valve rim group were alive 22 mos or more post implantation. Table I I . Survival Data on Dogs Receiving Control and Gentamicin Loaded Prosthetic Mitral Valves
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Group (Total # Animals) Control Valves 9
Died Before 1 mo.
Alive After 1 mo.
Percent Survival After 1 mo.
6
3
33%
4
20
83% (p
