Robert C. Schmeltzer

Synthesis and Cytotoxicity of Salicylate-Based Poly(anhydride esters)

This paper describes the synthesis and cytotoxicity of poly(anhydride esters) that are composed of several salicylate derivatives, including halogenated salicylates, aminosalicylates, salicylsalicylic acid, and thiolsalicylic acid. The incorporation of these nonsteroidal antiinflammatory drugs (NSAIDs) into a biodegradable polymer backbone yields drug-based polymers that have potential for a variety of applications. The poly(anhydride esters) were synthesized by melt condensation polymerization. The halogenated salicylate derivatives yielded the highest molecular polymers as well as the highest glass transition temperatures. All polymers displayed in vitro degradation lag times from 1 to 3 days, depending on the water solubility of the salicylate derivative. Cell viability and proliferation were determined with L929 fibroblast cells in serum-containing medium to assess the polymer cytotoxicities, which varied as a function of the saliyclate chemistry. Cell morphology was normal for most of the polymers evaluated.

Comparison of salicylate-based poly(anhydride-esters) formed via melt-condensation versus solution polymerization

Salicylate-based poly(anhydride-esters) were synthesized via two different methods, melt-condensation and solution polymerization, and the resulting polymers were compared. Acetylsalicylic acid was used as a model compound to mimic the active polymer chain-ends during melt-condensation, and formed a low-molecular-weight (<1500) polymer when subjected to melt-condensation polymerization conditions. The polymers and model compounds were analyzed by NMR (1H and 13C) and IR spectroscopies to elucidate the structures. Spectroscopic analysis revealed the formation of a thermodynamically stable salicylate ester via salicylate–anhydride rearrangement during melt-condensation polymerization, which did not occur during solution polymerization. The salicylate-based poly(anhydride-esters) undergo a thermodynamic rearrangement during melt-condensation polymerization that is not observed for solution polymerization.

Synthesis and Characterization of Salicylic Acid-Based Poly(Anhydride-Ester) Copolymers

A series of poly(anhydride-esters) based on poly(1,10-bis(o-carboxyphenoxy)decanoate) (CPD) and poly(1,6-bis(p-carboxyphenoxy)hexane) (p-CPH) were synthesized by melt-condensation polymerization. Poly-(anhydride-esters) that contain CPD hydrolytically degraded into salicylic acid, however, these homopolymers have mechanical and thermal characteristics that limit their use in clinical applications. The synthesis and characterization of copolymers of CPD with p-CPH, a monomer known to generate mechanically stable homopolymers, was investigated. By changing the CPD to p-CPH monomer ratios, the salicylic acid loading and thermal/mechanical properties of the copolymers was a controlling factor; increasing the CPD concentration increased the salicylate loading but decreased the polymer stability; whereas increasing the p-CPH concentration increased the thermal and mechanical stability of the copolymers. Specifically, decreasing the CPD:p-CPH ratio resulted in lower salicylate loading and increased thermal decomposition temperatures. The glass transition temperatures (°C) varied from 27 to 38°C, a desirable range for elastomeric biomedical implants.

Characterization and in vitro degradation of salicylate-derived poly(anhydride-ester microspheres).

The aim of this study was to investigate how glass transition temperature (Tg) influenced polymer microsphere formation and degradation of three chemically, similar novel salicylatebased poly(anhydride-esters): poly[1,6-bis(o-carboxyphenoxy)hexanoate] (CPH), Tg = 59°C; poly[1,8-bis(o-carboxyphenoxy)octanoate] (CPO), Tg = 30°C; and poly[1,10-bis(ocarboxyphenoxy) decanoate] (CPD), Tg = 27°C. Microspheres of these polymers were prepared using a modified oil-in-water solvent evaporation method and processed by either resuspension or washed by centrifugation. The morphology of the microspheres determined by scanning electron microscopy (SEM) revealed that an extra washing step appears to increase aggregation as the Tg decreases; whereas only limited aggregation occurred in the polymer with the lowest Tg, CPD, in those not washed by centrifugation. Residual polyvinyl alcohol apparently affected the drug release rates from the microspheres by a stabilization process that produced an 8 h lag time and a 5% decrease in the amount of drug released over a 7 day period compared to microspheres washed free of PVA. These results demonstrate that salicylate-based poly(anhydride-esters) with sufficiently high Tgs, can be processed into microspheres that release salicylate over a time period amenable for drug delivery applications.