Polymer glycolide

Poly(lactide-coglycolide). Mixtures of lactide and glycolide monomers have been copolymerised in an effort to extend the range of polymer properties and rates of in vivo absorption. Poly(lactide- (9-glycolide) polymers undergo a simple hydrolysis degradation mechanism, which is sensitive to both pH and the presence of ensymes (32). 

Controlled Release of Bioactive Agents from Lactide/Glycolide Polymers... 

The racemic poly(DL-lactide) DL-PLA is less crystalline and lower uelting than the two stereoregular polymers, D-PLA and L-PLA. Further, the copolymers of lactide and glycolide are less crystalline than the two homopolymers of the two monomers. In addition, the lactic acid polymer, because of the methyl group, is more hydrophobic than the glycolide polymer. 

Table 1 provides a summary of the glass transition temperatures of several lactide/glycolide polymers. Tg values range from about 40 to 65°C. Poly(L-lactide) has the highest Tg at about 65°C. 

Many investigators have studied the in vivo degradation kinetics of lactide/glycolide materials (5,35-39). There has been some confusion in the interpretation of results primarily because of lack of consistency in nomenclature and careful attention in describing the specific stereoisomers evaluated. Nevertheless, the overall degradation kinetics are fairly well established for the entire family of homopolymers and copolymers. At the present, this common knowledge of the in vivo lifetimes of various lactide/glycolide polymers is a primary reason for their popularity. 

Recently, Brich and coworkers (40) reported the synthesis of lactide/glycolide polymers branched with different polyols. Polyvinyl-alcohol and dextran acetate were used to afford polymers exhibiting degradation profiles significantly different from that of linear poly-lactides. The biphasic release profile often observed with the linear polyesters was smoothened somewhat to a monophasic profile. Further, the overall degradation rate is accelerated. It was speculated that these polymers can potentially afford more uniform drug release kinetics. This potential has not yet been fully demonstrated. 

Microspheres and microcapsules of lactide/glycolide polymers have received the most attention in recent years. Generally, three microencapsulation methods have been employed to afford controlled release formulations suitable for parenteral injection (1) solvent evaporation, (2) phase separation, and (3) fluidized bed coating. Each of these processes requires lactide/glycolide polymer soluble in an organic solvent. 

Fabrication of drug-containing fibers is a natural progression when one considers the extensive history of lactide/glycolides in suture applications. The lactide/glycolide polymers are easily melt-spun into mono- or multifilament products at relatively low temperatures. 

Sterilization of the finished drug delivery formulation is an important consideration often overlooked in the early design of lactide/glycolide delivery systems. Aseptic processing and terminal sterilization are the two major routes of affording an acceptably sterile product. Both of these methods are suitable for products based on lactide/glycolide polymers if proper care is exercised in processing or selection of the treatment procedures. 

Various studies have been made on the effects of radiation on lactide/glycolide polymers (24,38,58). Gilding and Reed (24) reported the effect of y rays on Dexon sutures. Those results confirmed that deterioration of the sutures occurs but that random chain scission is not the primary mechanism. Number average-molecular weight Mn showed a dramatic decrease at doses above 1.0 Mrad. Thus, unzipping of the polymer chain appeared to be the more dominant process, at least in the case of polyglycolide. 

FIGURE 4 Controlled release systems based on lactide/glycolide polymers with duration of action of a few days to 1 year. 

Classical or conventional pharmaceutical agents in combination with lactide/glycolide polymers have been widely studied since about 1973. In general, these compounds are bioactive agents usually produced by synthetic chemistry, with molecular weights of less than a few hundred and relatively stable structures. Examples include steroid hormones, antibiotics, narcotic antagonists, anticancer agents, and anesthetics. 

The steroid microsphere systems are probably the most successful drug delivery formulations thus far ba.sed on lactide/glycolide polymers. Several of these products appear to be on track for human and animal applications in the 1990s. The success of these formulations is due to the known safety of the polymer, the reproducibility of the microencapsulation process, reliability in the treatment procedure, and in vivo drug release performance (80). 

Recently, Tsakala et al. (90) formulated pyrimethamine systems based on several lactide/glycolide polymers. These studies were conducted with both microspheres (solvent evaporation process) and implants (melt extrusion process). In vitro studies indicated that pyrimethamine-loaded implants exhibited apparent zero-order release kinetics in aqueous buffer whereas the microspheres showed an initial high burst and considerably more rapid drug release. In vivo studies in berghi infected mice confirmed that the microspheres did not have adequate duration of release for practical application. However, the implants offer promise for future clinical work as more than 3 months protection was observed in animals. 

Strobel et al. (101) reported a unique approach to delivery of anticancer agents from lactide/glycolide polymers. The concept is based on the combination of misonidazole or adriamycin-releasing devices with radiation therapy or hyperthermia. Prototype devices consisted of orthodontic wire or sutures dip-coated with drug and polymeric excipient. The device was designed to be inserted through a catheter directly into a brain tumor. In vitro release studies showed the expected first-order release kinetics on the monolithic devices. 

Several antiinflammatory compounds have been formulated in lactide/ glycolide polymers (107-111). Methylprednisolone microspheres based on an 85 15 DL-lactide/glycolide copolymer were developed for intra-articulate administration (111). The microspheres, prepared by a solvent evaporation procedure, are 5—20 jam in diameter and are designed to release low levels of the steroid over a extended period in the joint. Controlled experiments in rabbits with induced arthritis showed that the microspheres afforded an antiinflammatory response for up to 5 months following a single injection. 

Lactide/glycolide polymers have been investigated for delivery of agents in applications outside the pharmaceutical field. For example, the microbiocidal properties of chlorine dioxide disinfectants have been improved by formulating a long-acting chlorine dioxide system based on lactide/glycolide copolymers. Blends of microspheres based on 50 50 and 87 13 copolymers were developed to afford the release of chlorine dioxide over several months (114). 

FIGURE 12 Scanning electron micrograph of contraceptive vaccine microspheres based on lactide/glycolide polymer. 

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