This paper reviews the development of the polyanhydrides as bioerodible polymers for drug delivery applications. The topics include design and synthesis of the polymer, physical properties, techniques to fabricate the polymer into drug delivery devices, evaluation of biocompatibility, and example applications of the polyanhydrides. Discussion of the interrelationship between the physical-chemical properties of the polyanhydrides, fabrication methods, and drug release rates is included. One section is devoted to a case study to provide a historical perspective of the development a polyanhydride-based drug delivery treatment from the conception of the idea to the final stages of human clinical trials. This section includes an outline of the extensive in vitro and in vivo testing that is necessary for development of a new material for biomedical applications.
"A polyol is an alcohol containing multiple hydroxyl groups (e.g., glycerol, mannitol, sorbitol and xylitol). Sebacic acid, a dicarboxylic acid with the structure (HOOC)(CH 2 ) 8 (COOH), is a naturally occurring chemical derived from castor oil, which has been proven safe in vivo     . PGS is the most widely studied PPS member [4, 8, 21–24]. "
[Show abstract][Hide abstract] ABSTRACT: In order to develop degradable elastomers with a satisfactory combination of flexibility and enzyme-mediated degradation rate, the mechanical properties, enzymatic degradation kinetics and biocompatibility of poly(xylitol sebcate) (PXS) has been systematically investigated in comparison with poly(glycerol sebacate) (PGS). Under the same level of crosslinked density, the PXS elastomer networks have approximately twice the stretchability (elongation at break) of their PGS counterparts. This observation is attributable to the relatively longer and more orientable xylitol monomers, compared with glycerol molecules. Although xylitol monomers have two more hydroxyl groups, we, surprisingly, found that the hydrophilic side chains did not accelerate the water attack on the ester bonds of the PXS network, compared with their PGS counterpart. This observation was attributed to a steric hindrance effect, i.e. the large-sized hydroxyl groups can shield ester bonds from the attack of water molecules. In conclusion, the use of polyols of more than three -OH groups is an effective approach enhancing flexibility, whilst maintaining the degradation rate of polyester elastomers. Further development could be seen in the copolymerization of PPS with appropriate thermoplastic polyesters, such as poly(lactic acid) and polyhydroxyalkanoate.
"Surface eroding devices are particularly well suited for sustained release and drug stabilization. Additionally, polyanhydrides of varying hydrophobicity have erosion rates that span several orders of magnitude . The potential for not only sustaining the release of a drug, but also achieving desirable release profiles can be realized by combining polyanhydrides with differing erosion rates in an advantageous way. "
[Show abstract][Hide abstract] ABSTRACT: The fabrication, morphological characterization, and drug release kinetics from microspheres of three bioerodible polyanhydrides, poly[1,6-bis(p-carboxyphenoxy)hexane] (poly(CPH)), poly(sebacic anhydride) (poly(SA)), and the copolymer poly(CPH-co-SA) 50:50 (CPH:SA 50:50) is reported. The fabrication technique yields microspheres with different morphologies for each of the three polymers studied, ranging from very smooth exterior surfaces for poly(CPH) to coarse surface roughness with large pores for poly(SA). Release profiles for the model drug, p-nitroaniline are also different for each polymer. The release profile from poly(CPH) has a large initial burst and shows little additional release after 2 days. The release from poly(SA) is nearly zero-order and lasts for about 8 days. The release profile from CPH:SA 50:50 shows a relatively small burst and then exhibits zero-order release for about I month. The different release profiles are attributed to both polymer erosion rates and drug distribution characteristics of the microspheres. Tailored release profiles of a burst followed by zero-order release are obtained by appropriately combining the microspheres. This technique enables independent modulation of both the burst and the zero-order release rate by varying the number of poly(CPH) and poly(SA) microspheres respectively. Additionally, the zero-order release can be extended from about a week to a month by including CPH:SA 50:50 microspheres.
"Polyanhydride structure where R and R are dicarboxylic acid groups and x and y are the number of times each unit is repeated. Fig. 2. (a) Kinetics of polymer erosion from 20 : 80 CPP : SA , and (b) hydrophobic p-nitroanline  where ⅷ"drug release and *"polymer degradation from 20 : 80 CPP : SA (Reproduced with permission from  ). pro"le of both SA and CPP co-monomers from a 20 : 80 CPP : SA device. "
[Show abstract][Hide abstract] ABSTRACT: This research examines the microstructure of bioerodible polyanhydrides with an eye towards precise design of drug delivery devices. Our main hypothesis is that the bioerodible copolymer poly(1,6-bis-p-carboxyphenoxyhexane-co-sebacic anhydride) (CPH : SA) undergoes micro-phase separation at certain copolymer compositions due to differences in relative hydrophobicity of the co-monomers, resulting in thermodynamic partitioning of drugs incorporated into these copolymers. We investigate the thermal properties, degree of crystallinity, and surface microstructure of several compositions of CPH : SA using differential scanning calorimetry (DSC), wide-angle X-ray diffraction (WAXD), and atomic force microscopy (AFM). We observe that the degree of crystallinity decreases, while the crystal lamellar thickness increases with CPH content. Phase-imaging using AFM indicates the presence of micro-domains in 20 : 80 and 80 : 20 CPH : SA, while poly(SA) and 50 : 50 CPH : SA show no micro-phase separation. Finally, drug-polymer interactions are studied by loading the polymers with different amounts of brilliant blue (hydrophilic) and p-nitroaniline (hydrophobic). DSC and WAXD analysis shows that loading hydrophobic drugs into relatively hydrophobic polymers (poly(SA)) lowers melting point that becomes more pronounced with increased drug loading.
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