Biodegradable microspheres of novel segmented poly(ether-ester-amide)s based on poly(epsilon-caprolactone) for the delivery of bioactive compounds

A novel class of multiblock poly(epsilon -caprolactone)-based polymers cont aining hydrophilic trioxyethylene segments and potentially relevant to the delivery of drugs is described in this work. L-phenylalanine residues mag; also be inserted into the hydrophilic blocks to generate peptide bonds susc eptible to enzymatic attack. The investigated polymers mere poly(ether-este r-amide)s (PEEAs) obtained by a two-step polymerization procedure from OH- end capped low molecular weight poly(epsilon -caprolactone), sebacoyl chlor ide and either 4,7,10-trioxa - 1,13-tridecanediamine (PEEA1) or 1,13-di(L-p henylalaninamido)-3,7,10-trioxatridecane (PEEA2). PEEAs were characterized by H-1-NMR spectroscopy, differential scanning calorimetry, gel permeation chromatography and were tested for their suitability in producing microsphe res. Particles obtained by the single emulsion-solvent evaporation techniqu e were regular and smooth (SEM analysis) showing a monomodal distribution o f dimensions. To assess the potentiality of PEEAs in the oral delivery of d rugs, three model compounds with different pK(a) and solubilities - diclofe nac, nicardipine and dicumarol - were encapsulated within PEEA microspheres . For the sake of comparison, microspheres prepared from poly(epsilon -capr olactone) (PCL) with a molecular weight similar to PEEAs: were also prepare d and tested. The release of diclofenac from all the microspheres was very rapid (100% released within 1h) whereas nicardipine release was slower and biphasic. The initial phase approximated a near zero-order release, being t he fraction of nicardipine released after X h from PEEA microspheres higher with respect to PCL particles (about 70 vs. 30%). This result was ascribed to the lower crystallinity of PEEAs with respect to PCL which results in a facilitated access of water molecules through the polymer matrix. The lipo philic-unionizable dicumarol was released from PEEA microspheres at a very slow rate. Therefore, dicumarol-loaded PEEA microspheres allowed the study of the influence on the release rate of the insertion into the polymer chai n of enzymatically degradable bonds. PEEA2 microspheres released dicumarol at the same rate in a medium with or without the proteolitic enzyme alpha - chymotrypsin. Although the insertion of an isolated amino acid was not suff icient to confer enzyme susceptibility to the polymer, the distinctive prop erties of PEEAs make their use very attractive in the field of controlled r elease. (C) 2001 Elsevier Science Ltd. All rights reserved.