Synthesis And Application To Pharmaceutics Of Malic Acid Copolymers

Polyα-hydroxy acids are attracting attention as biodegradable polymers for use in biomedicine.Poly(malic acid)(PMLA),a well-known biodegradable,bioabsorbable water-soluble polymer,combines the advantages of being readily metabolized in the tricarboxylic acid(TCA) cycle and having pendant carboxylic groups that make it easy to introduce other functional groups and molecules,including drugs,into the polymer.These benefits make it important to develop an easy,high-yield route to synthesize this polymer.PMLA was synthesized by two ways,i.e.,ring-opening polymerization and direct polycondensation.Ring-opening polymerisation has the advantages of low reaction temperature,short reaction time,and high molecular weight.It has,however,some disadvantages.The procedure involves several steps and intermediate products must be repeatedly purified,yet yields only 3%.In contrast,direct polycondensation involves only one step.Besides being low molecular weight,it is more environmentally-friendly than ring-opening polymerisation because it requires less organic solvent.This work is to explore a new route to synthesize functional polyesters containing malic acid units.Several novel diblock copolymers containing malic acid units,synthesized with malic acid and lactic acid(or stearic acid,and PEG) by direct polycondensation for the first time.We studied reaction conditions for synthesizing these copolymers,i.e.,solvents,catalysts, temperature,and time,and produced diblock copolymers with a higher molecular weight and yield compared to PMLA.Meanwhile,the structure of these copolymers were characterized by IR and ~1H-NMR.By using Novozym 435 as the biocatalyst,L-malic acid was copolymerized with L-lactide acid(or s-caprolactone) for the first time.IR and ~1H-NMR studies on the structure of the products indicated that Novozym 435 was strictly selective for esterification of L-malic acid carboxyl groups while leaving the hydroxyl groups unchanged.Biotin-modified PMLA-co-PLA(B-PMALA) was synthesized with Biotin and PMALA by DCC/DMAP esterification.Biotin-modified PMLA-co -PCL(B-PMACL) was synthesized with Biotin and PMACL by via biocatalyzed direct polycondensation for the first time.The structure of B-PMAE and B-PMAE were characterized by IR and ~1H-NMR.Malic acid-modified chitosan(MLAC) was synthesized with malic acid and chitosan by DCC/DMAP esterification.In order to improve the reaction yield,process parameters such as molar ratio of chitosan to malic acid,amount of catalyst,reaction time,amount of solvent and reaction temperature were investigated,synthesis process of MLAC was optimized by means of orthogonal design,and the average yield of 25.6%was achieved.Structure of MLAC was identified through analysis of UV,IR and ~1H-NMR.Malic acid-chitosan complex was synthesized by ionic interaction and characterized with FT-IR,DSC and ~1 H-NMR.The introduction of malic acid into chitosan increases the solubility in water.Then,physico-chemical properties of co-PMLA-PLA and MLAC,such as solubility, degradation,swell,were studied.The MLAC was used as a carrier to felodipine sustained-release tablets and miconazole nitrate microspheres.The microsphere was prepared by emulsion-chemical cross-link method. The sustained-release tablets and microspheres had a good sustained-release function.The PMLA- co-PLA was used as a carrier to thiamphenicol in-situ-gel,metronidazole gel,and lomefloxacin hydrochloride microspheres.These in-situ-gel,gel and microspheres had a good sustained-release function.The methotrexate-loaded biotin- PMLA- co-PLA nanoparticles were prepared by emulsion solvent evaporation technique.The factors that will influence the drug-loading and recovery yield of the nanoparticles had been studied.Finally,the in vivo pharmacokinetics behavior of thiamphenicol in-situ-gel, metronidazole gel and lomefloxacin hydrochloride microspheres in rabbits was investigated and the results were fulfill these drug forms.