POLYANHYDRIDE ESTER

An attempt is made to synthesise a polymer that will act as a controlled delivery device in targeting specific areas, such as the colon, over an extended period of time. The polymers being synthesised, polyanhydride esters, are composed of alkyl chains linked by ester bonds to aromatic moieties, specifically salicylic acid - the active component of aspirin. With the medicinal properties attributed to salicyclic acid and the ease of metabolism, the incorporation of this compound into a polymer backbone yields a polymeric prodrug that may have potential in a variety of applications, in particular, inflammatory bowel disease. For these reasons, a synthetic scheme that yields the desired polyanhydride esters is designed. Characterisation of the polymers is performed and presented along with preliminary in vitro and possible... 

So far, various dicarboxylic acid derivatives, dicarboxylic acids, their activated and non-activated esters, cyclic acid anhydrides, and polyanhydrides have been polymerized with glycols through lipase catalysis to give polyesters. 

Various combinations of dicarboxylic acid derivatives and glycols enzymatically afforded polyesters under mild reaction conditions. Dicarboxylic acids as well as derivatives, activated and non-activated esters, cyclic acid anhydride, and polyanhydrides, were found to be useful as monomer for the enzymatic synthesis of polyesters. 

Jiang and Zhu (2001) became interested in synthesizing additional polyanhydrides with fluorescence after their discovery of the fluorescent properties of PCPS. They synthesized the series of poly(anhydride-co-amide)s poly p-[carboxyphenoxy(ethyl/propyl/butyl)formamido]benzoic anhydride (PCEFB, PCPFB, and PCBFB) (Jiang et al., 2001c). Only the ethyl polymer emitted strong fluorescence, which was consistent with their previous study of the poly(anhydride-co-ester)s of similar chemistry... 

Biodegradable polymers, both synthetic and natural, have gained more attention as carriers because of their biocompatibility and biodegradability and therewith the low impact on the environment. Examples of biodegradable polymers are synthetic polymers, such as polyesters, poly(orfho-esters), polyanhydrides and polyphosphazenes, and natural polymers, like polysaccharides such as chitosan, hyaluronic acid and alginates. 

As pointed out by Heller (2), polymer erosion can be controlled by the following three types of mechanisms (1) water-soluble polymers insolubilized by hydrolytically unstable cross-links (2) water-insoluble polymers solubilized by hydrolysis, ionization, or protonation of pendant groups (3) hydrophobic polymers solubilized by backbone cleavage to small water soluble molecules. These mechanisms represent extreme cases the actual erosion may occur by a combination of mechanisms. In addition to poly (lactic acid), poly (glycolic acid), and lactic/glycolic acid copolymers, other commonly used bioerodible/biodegradable polymers include polyorthoesters, polycaprolactone, polyaminoacids, polyanhydrides, and half esters of methyl vinyl ether-maleic anhydride copolymers (3). 

Polyanhydrides have been modified by incorporating amino acids into im-ide bonds. The imide with the terminal carboxylic acids is activated with acetic anhydride and copolymerized with sebacic acid or CCP. Poly(anhydride-imides) increase the mechanical properties of the polyanhydrides. Degradation of poly(anhydride-imide)s is similar to that of polyanhydrides (i.e., surface erosion). Two different cleavable bonds (anhydride and ester) in the polymer chains have been included in polyanhydrides. Carboxylic acid-terminated e-caprolactone oligomers or carboxylic acid-terminated monomers (e.g., salicylic acid) have been polymerized with activated monomers (e.g., SA). 

A much more desirable erosion mechanism is surface erosion, where hydrolysis is confined to a narrow zone at the periphery of the device. Then, if the drug is weU-immobihzed in the matrix so that drug release due to diffusion is minimal, the release rate is completely controlled by polymer erosion, and an ability to control erosion rate would translate into an ability to control dmg delivery rate. For a polymer matrix that is very hydrophobic so that water penetration is limited to the surface (thus Hmiting bulk erosion), and at the same time, allowing polymer hydrolysis to proceed rapidly, it should be possible to achieve a drug release rate that is controlled by the rate of surface erosion. Two classes of biodegradable polymers successfully developed based on this rationale are the polyanhydrides [31] and poly (ortho esters) [32], the latter of which is the subject of this chapter. 

Thus, considerable effort has been devoted to the development of polymers that are able to erode by a well controlled surface hydrolysis process. Dominant among these are polyanhydrides [2] and poly (ortho esters) [3]. 

Polyanhydrides can be transformed into poly(anhydride-esters) without degradation of the polymer. The reaction between propylene oxide and a polyanhydride yielded a poly(anhydride-ester) [43]. The reaction was carried out at... 

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