Biodegradable hollow fibres of poly-L-lactic acid (PLEA) filled with a suspension of the contraceptive hormone levonorgestrel in castor oil were implanted subcutaneously in rats to study the rate of drug release, rate of biodegradation and tissue reaction caused by the implant. The in viva drug release was compared with the release in vitro using different release media. Fibres, disinfected with alcohol showed a zero-order release, both in vitro and in viva, for over 6 months. Fibres, either y-sterilized or disinfected with alcohol were harvested at time intervals ranging from 1 d to 6 months after implantation. Molecular weights of PLLA, tensile strengths, and remaining amounts of drug were determined as a function of time.The tissue reaction can be described as a very moderate foreign body reaction with the initial presence of macrophages, which are gradually replaced by fibroblasts which form a collagen capsule. Molecular weight determinations of PLEA showed a decrease from an initial M, of 1.59 X lo5 to 5.5 X 19" in 4 months (after alcohol sterilization). A gradual decrease in fibre strength with time was observed which did not significantly impair the release rate of levonorgestrel. Keywords: Drugs, controlled release, hollow fibre, biodegradable, poly-L-lactic acidThe development of improved methods of drug delivery has received a lot of attention in the last two decades. In many cases a constant effective non-toxic level of the drug at a particular body location is needed. To reach this goal many variations of controlled release have been investigated. These include the useof bioerodible matrices',' (from which the drug is released by controlled degradation of the top layers of the matrix), microspheres or even nanoparticles, with a polymer body, (from which the drug is slowly released)3 or controlled delivery by (mini) devices4.The methods mentioned above may have one or more disadvantages e.g. (i) either no zero-order release can be achieved, (ii) the appliance cannot, or not easily, be removed in case of an emergency, (iii) an operation is needed to insert the device, (iv), the materials used are not optimally biocompatible.Therefore a release system was developed with none of these disadvantages 5-7 i.e. a hollow fibre of poly-L-lactic acid (PLLA) containing the drug suspended in oil from which it is released at a zero-order rate. Its dimensions (1 cm long, diam. 0.7 mm) allow a simple application, using a syringe.Correspondence to Dr J.M. Schakenraad.Removal of the fibre can easily be performed by a small incision, in case of an emergency.In this paper we present the results of studies on the in vivo and in vitro release of levonorgestrel from hollow fibres, the rate of biodegradation of the fibre material, and the cell-biological evaluation as a response to the subcutaneous implantation of the fibre in rats. MATERIALS AND METHODS Fibres.The hollow fibres were spun from poly-L-lactic acid (M, 159 000) using a 'dry-wet' coagulation spinning process5* 6 . Molecular weight.After harvesting, the fibrou...

In our earlier work [lOI on aminor~bosyl-bound prodrugs of adriamy~in (ADR) using poly(a-L-glutamic acid) (PGA) grafted in high yield (90-l 00 mol.%) with various peptide spacers as a plasma-soluble macromolecular carrier we observed rather low cytotoxie activities in L1210 leukemia and B16 melanoma in vitro assays. These results may be tentatively explained by a decreased susceptibility of the spacer-bound adriamycin moiety to hydrolysis by lysosomal enzymes due to the high spacer load. This hypothesis was tested by the study of two conjugates prepared by a different route. Peptide conjugates of adriamycin (Gly-GlyLeu-ADR and Gly-Gly-Gly-Leu-ADR) were synthesized using the trityl N-protecting group and were coupled to PGA in 4.5 mol.% load according to the method described earlier (I1 f. Howeuer, these conjugates were almost totally devoid of cell ~owth-inhibiting activity in L1210 and B16 in vitro tests. The data suggest that either the uptake of the polymeric prodrugs into the cell by pinocytosis is highly dependent on spacer load or molecular weight, or that lysosomal digestion is too slow for efficient release of ADR. Possibly, enzymatic de~adation of PGA which is known to occur only between pH 4 and 6 is rate-limiting for release of the drug. Current studies include the enzymatic degradation of PGA-peptide spacer-drug systems using ~-nitroaniline as a model drug and papain as the enzyme. By variation of the length and load of spacer it can be estimated under which conditions the release of drug (using UV spectrometry) is faster than de~adation of the polymer (as determined by viscometry). In addition, the uptake of PGA and derivatives with a fluorescent label into tumor cells is studied using laser flow cytometry and laser microscopy.

The hydrophilicity of polyetherimide-polyvinylpyrrolidone (PEI-PVP) microfiltration membranes can be adjusted by means of a suitable post-treatment.The influence of the nature of the membrane surface on fouling properties was studied using permeation experiments before and after exposure to a protein (BSA) solution and adsorption experiments with i*C labelled BSA. A correlation between the permeation experiments and the radiolabelled BSA adsorption experiments was found. The PVP in the membrane matrix prevents BSA adsorption taking place to a large extent and it appeared that heat-treated PEI-PVP membranes showed the same nonfouling behaviour as, for example, cellulose acetate membranes.

Poly(a-L-glutamic acid) (PGA) was grafted with amino acid and ofigopeptide spacers up to 5 amino acids with the use of ~,~I-~arbony~diimidazo~e and 2~3-dihydro-1,2-bentisoth~azole-3~n-l~l-dioxide (saecharin~ as an additive, and these polypeptides were characterized. The antitumor antibiotic adriamycin was covalently coupled via an amide bond onto PGA and onto the grafted polymers with the use of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ); these conjugates were characterized. The conjugates containing Gly-Gly--L-Leu spacer arms did yield free adriamycin upon digestion with papain. Adriamy~in gave fairly stable complexes with PGA-~driamy~in and branched po~ypeptide-adriamycin conjugates; these complexes were characterized.

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