Evac implants

The biocompatibility of EVAc matrices has been studied quite extensively. When implanted in the cornea of rabbits—which is sensitive to edema, white-cell infiltration, and neovascularization associated with inflammation— purified EVAc caused no inflammation, while unpurified EVAc caused mild inflammation [33]. After seven months of subcutaneous implantion, only a thin capsule of connective tissue surrounded EVAc implants no inflammation was present and the adjacent loose connective tissue was normal [34]. When implanted in the brains of rats, EVAc matrices produced only mild gliosis... 

Since EVAc is a non-biodegradable polymer, the implanted device has to be surgically removed from the host after completion of the immunization process. Hence, it would be advantageous to use biodegradable devices for the controlled release of antigen. 

Certain copolymers of ethylene and vinyl acetate, poly[ethylene-co-(vinyl acetate)] (EVAc, ELVAX , Dupont Corp.), have exceptionally good biocompatibility and are therefore widely used in implanted and topical devices. 

EVAc has been used in the fabrication of a variety of devices for drug delivery. For example, EVAc was used by Alza in devices to deliver pilocarpine to the surface of the eye for glaucoma treatment (Ocusert). Currently, EVAc is used in the Progestasert intra-uterine device for the delivery of contraceptive hormones to the female reproductive tract and as a rate-controlling membrane in a number of transdermal devices. Since EVAc is one of the most biocompatible of the polymers that have been tested as implant materials [30], it has been widely studied as a matrix for controlled drug delivery (see [31, 32] for reviews). 

EVAc has shown good biocompatibility in humans over the years and has been approved by the FDA for use in a variety of implanted and topically applied devices. 

Preclinical studies of BCNU-polymer preparations proceeded in four systematic stages. The first series of experiments examined in vivo release kinetics of BCNU loaded polymers. The initial study involved EVAc copolymer implantation in the rat brain (31). Subsequent to polymer placement, a Brat-ton-Marshall assay measured BCNU concentrations in both cerebral hemispheres, and serum samples were collected at prescribed time points. The hemisphere ipsilateral to polymer placement corresponded with peak BCNU levels at 4 h clinically significant concentrations persisted at day 7. In contrast, both contralateral hemisphere and serum BCNU levels were at least an order of magnitude lower throughout the experiment. Thus, the study served as proof of principle of the ability of polymer technology to simultaneously achieve sustained release and local delivery of chemotherapy within the CNS. 

Initially incorporated into EVAc polymers, sodium camp-tothecin demonstrated sustained release by in vitro kinetics experiments. Efficacy studies in the established rat intracranial 9L ghosarcoma model showed dramatically increased median survival from 19 days in control animals to > 120 days with 50% (w/w) polymer administration (p< 0.001). Additionally, 59% of treatment animals survived > 120 days no control rats lived beyond 32 days. Systemic camptothecin, in contrast, conferred no survival benefit. Animals undergoing polymer implantation suffered no associated local or systemic toxicity. 

Efficacy studies in the rat intracranial 9L gliosarcoma model compared systemic and EVAc polymer dexamethasone administration (28). Water weight percentage served as the edema endpoint both intracranial dexamethasone-loaded polymers (79.15% p<0.05) and intraperitoneal dexamethasone injections (79.16% p0.05) were superior to controls (79.45%) and intraperitoneal pol3nner implantation (79.39%). Thus, intracranial pol3nner implantation achieved equivalent edema reduction without the theoretical potential for systemic toxicity. 

In 1976, Langer and Folkman published a landmark paper in which several polymer systems were studied with respect to biocompatibility and sustained release of macromolecules. Ultimately, they determined that two of the polymer systems were most biocompatible. Pellets made from casting of ethylene-vinyl acetate copolymer (EVAC) showed no significant inflammation after implantation as did the pellets cast of Hydron, a polymer of hydrox-yethylmethacrylate. In terms of in vitro release kinetics, while both polymer systems exhibit a significant initial release (i.e., "burst kinetics"), the ethylene-vinyl acetate system had a slower overall release profile that persisted significantly longer, making it more ideally suited for the in vivo release of macromolecules. As a way to further retard the rapid release of the proteins. 

The second complicating factor is that multiple injections of GnRHa are often required to sustain sufficient levels of gonadotropins in the plasma, which further complicates this technique for tuna. An effective alternative to the use of multiple injections is to administer a slow-release implant that can maintain elevated plasma levels of gonadotropins for long periods (Mylonas, 2002 Mylonas et al, 2007). In 2004 and 2005, an agonist of GnRH prepared within a matrix of poly[Ethylene-Vinyl Acetate] (EVAc) was... 

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