* Corresponding author. Tel: #732-445-0361; fax: #732-445-5312.E-mail address: [email protected] (K.E. Uhrich).Biomaterials 21 (2000) 1941}1946Synthesis and degradation characteristics of salicylic acid-derivedpoly(anhydride-esters)L. Erdmann, K.E. Uhrich*Department of Chemistry, Rutgers University, 610 Taylor Road, Piscataway, NJ 08854-8087, USAReceived 21 April 1999; accepted 2 March 2000AbstractA biodegradable poly(anhydride-ester) was synthesized by melt condensation polymerization of the acetylated monomer to yielda novel polymeric prodrug. The polymer we have synthesized is composed of alkyl chains linked by ester bonds to aromatic moieties,speci"cally salicylic acid*the active component of aspirin. With the medicinal properties attributed to salicylic acid and the ease ofmetabolism, the incorporation of this compound into a polymer backbone yields a polymeric prodrug that may have potential ina variety of applications (i.e., in#ammatory bowel disease). For these reasons, we have designed a synthetic scheme that yields thedesired poly(anhydride-ester). The in vitro hydrolytic degradation of these polymers has been performed and results indicate that thepolymer degradation rate is pH-dependent.  2000 Elsevier Science Ltd. All rights reserved.Keywords: Biodegradable; Poly(anhydride-ester); pH-dependent; In vitro degradation1. IntroductionIn recent years, many polymeric and conjugated pro-drugs have been developed which prolong the bloodconcentrations of the drug upon administration as com-pared to the free drug given alone [1}4]. This phenom-enon is indicative of the prodrugs' ability to release thedrug in a controlled manner ultimately allowing for site-speci"c drug targeting [5}7] and reduced side e!ectswhich may be incurred if the drug is released immediate-ly. In two examples, salicylic acid-L-alanine conjugateand Naproxen coupled via lactic acid to a low molecularweight protein, signi"cantly extend the drug lifetime inthe blood relative to free drug [2}5].One factor that has considerable impact when devel-oping polymeric prodrugs is the amount of drug attachedto the polymer. In most cases, drug is attached to a poly-mer via a linker molecule that limits the drug attachment,or drug loading. For example, when ibuprofen iscovalently attached via side chains to a methacrylic poly-mer backbone, this polymeric prodrug has a maximum of55 wt% of attached drug [1]. Other polymericprodrugs include 5-aminosalicylic acid coupled to anacrylic polymer backbone and iodoxuridine coupled topoly(D,L-lactic acid) in which the maximum drug contentis 1 and 20 wt%, respectively [8,9]. With most polymerprodrug systems, the polymer backbone is water-solublebut does not degrade, which may be a drawback for someapplications.We designed a polymeric prodrug that allows fora higher percentage of deliverable drug (62 wt%) that isavailable as the polymer degrades. Unlike other poly-meric prodrug systems, our polymers are unique in thatthe drug is chemically incorporated into the polymerbackbone*not attached as a side group. This designallows for a maximum amount of drug to be incorpor-ated within the polymer structure*up to 100 wt% ispossible. An additional feature is that the polymer com-pletely degrades because of the anhydride and ester link-ages within the polymer backbone.In this paper, we describe the synthesis ofa poly(anhydride-ester) (I) composed of alkyl chains link-ed by ester bonds to aromatic moieties of salicylic acid(II). The polymer, by design, undergoes hydrolytic degra-dation to release salicylic acid (Scheme 1).Salicylic acid (II) is an antipyretic, anti-in#ammatoryanalgesic with a half-life of 2}3 h in low doses and 20 h inhigher doses [10]. With the medicinal properties at-tributed to salicylic acid (II) and the ease of metabolism,the incorporation of this compound into a polymer0142-9612/00/$ - see front matter  2000 Elsevier Science Ltd. All rights reserved.PII: S 0 1 4 2 - 9 6 1 2 ( 0 0 ) 0 0 0 7 3 - 9Scheme 1. Hydrolytic degradation of polymer I.backbone may yield a polymeric prodrug with potentialfor a variety of medical treatments. The alkyl component,sebacic acid (III) (Scheme 1), of these poly(anhydride-esters) is biocompatible and biodegradable in vivo [11].Polymer I is a unique example where the polymer back-bone degrades directly into the drug.2. Experimental2.1. MaterialsAll chemicals were purchased from Aldrich or Fisher,except for 10% Pd}C (Acros). Benzyl salicylate (IV) andthionyl chloride were puri"ed by distillation under re-duced pressure. Tetrahydrofuran was distilled over cal-cium hydride. All other chemicals were used withoutfurther puri"cation.2.2. MethodsChemical composition was determined using elemen-tal analysis, infrared (IR) spectroscopy, and proton nu-clear magnetic resonance (HNMR) spectroscopy.Elemental analysis was performed by Quantitative Tech-nologies (Whitehouse, NJ). IR data was obtained on anATI Mattson Genesis (M100) FTIR spectrophotometer.Samples were prepared by solvent casting "lms on NaClplates.HNMR spectra were obtained on a Varian200 MHz spectrometer using CDClor DMSO as thesolvent and internal reference.Thermal analysis was performed on a Perkin}Elmersystem consisting of a TGA7 thermal gravimetric ana-lyzer (TGA) and Pyris 1 di!erential scanning calorimeter(DSC). Pyris software was used to carry out data analysison a DEC Venturis 5100 computer. For DSC, an averagesample weight of 5}10 mg was heated at 203C/min undera #ow of N(30 psi). For TGA, an average sample weightof 10 mg is heated at 203C/min under a #ow of N(8 psi).Gel permeation chromatography (GPC) was per-formed on a Perkin}Elmer Advanced LC Sample Proces-sor (ISS 200) with a PE Series 200 LC Pump and PESeries LC refractive index detector. Turbochrom 4 soft-ware on a DEC Celebris 466 computer was used toanalyze the data. Samples were dissolved in tetrahyd-rofuran, "ltered (PTFE 0.45 lm pore size) and elutedthrough a mixed bed column (PE PL gel, 5 lm). Molecu-lar weights were determined relative to narrow molecularweight polystyrene standards (Polysciences).High-pressure liquid chromatography (HPLC) wasperformed on a Perkin}Elmer advanced LC sample pro-cessor (ISS 200) with a PE Series 200 LC pump andapplied biosystems 785A programmable absorbance de-tector. Turbochrom 4 software on a DEC Celebris 466computer was used to analyze the data. Samples were"ltered (PTFE 0.45 lm pore size) and resolved onaCreverse phase column (PE 5;15 CR C18)