Poly orthoesters

Due to their lack of toxicity, POEs have been proposed as potential carriers of proteins [381], DNA vaccines [382] and other bioactive molecules [373]. Chemical modifications on the backbone of polyesters could yield in analogues, such as amides, enhanced release characteristics [383,384]. 

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Poly(orthoesters) represent the first class of bioerodible polymers designed specifically for dmg deUvery appHcations (52). In vivo degradation of the polyorthoester shown, known as the Al amer degradation, yields 1,4-cydohexanedimethanol and 4-hydroxybutyric acid as hydrolysis products (53). 

In order to become useful dmg delivery devices, biodegradable polymers must be formable into desired shapes of appropriate size, have adequate dimensional stability and appropriate strength-loss characteristics, be completely biodegradable, and be sterilizahle (70). The polymers most often studied for biodegradable dmg delivery applications are carboxylic acid derivatives such as polyamides poly(a-hydroxy acids) such as poly(lactic acid) [26100-51-6] and poly(glycolic acid) [26124-68-5], cross-linked polyesters poly(orthoesters) poly anhydrides and poly(alkyl 2-cyanoacrylates). The relative stabiUty of hydrolytically labile linkages ia these polymers (70) is as follows ... 

J. Heller, AU Daniels. Poly(orthoesters). In SW Shalaby, ed. Biomedical Polymers Designed-to-Degrade Systems. Cincinnati, OH Hanser/Gardner, 1994, pp 1-34. 

Choi, N.S. and Heller, J. (1978a). Dmg delivery devices manufactured from poly(orthoesters) and poly(orthocarbonates). Alza Corporation, Mountain View, CA. 

Heller J, Barr J, Ng SY, et al. Poly(orthoesters)—their development and some recent applications. Eur J Pharm Biopharm 2000 50(1) 121—128. 

Incorporation of the tetrahydrofuran ring into condensation polymers has been accomplished (79USP4180646) by transesterification of orthoester (43) with polyols to prepare poly (orthoesters) (44 Scheme 11). This polymerization reaction has been extended to a wide variety of other orthoester and orthocarbonate starting materials. The product polymers are reported to be excellent biodegradable matrices for drug delivery. 

Finally, poly(orthoesters) may be prepared (79USP4136252) from monomers such as 2-ethoxy-4-hydroxymethyl-1,3-dioxolane (91 Scheme 25), and find use in areas such as controlled release of drugs and other beneficial agents due to their slow and controlled degradation in aqueous biological environments. 

Keywords. Controlled drug delivery, Drug release, Microspheres, Degradation, Erosion, Polylactide, Poly(glycolide-co-lactide), Poly(e-caprolactone), Poly(hydroxyalkanoates) Polyanhydrides, Polycarbonates, Poly(orthoesters), Poly( l,5-dioxepan-2-one)... 

In the early 1970s, the ALZA Corporation began its search for polymers suitable for erodible drug delivery systems. The ideal polymer was identified as one undergoing surface erosion in vivo and degrading to non-toxic, low molecular weight products at a rate that could be manipulated over a broad time span. To meet these criteria, a novel family of hydrolyzable polymers was developed, the poly(orthoesters), POEs [285]. The general structure is schematically shown in... 

Fig. 12. The molecular structure of different classes of poly(orthoesters)...

FIGURE 6.25 The release of levonorgestrel from a poly(orthoester) slab containing 30% drug and 2% calcium lactate. [Graph reconstructed from data by Heller et al. in Controlled Release of Bioactive Materials, R. W. Baker (Ed.), Academic Press, New York, 1980, p. 1.]... 

Degradation of poly(orthoesters) based on 3,9-bis(ethylidene-2,4,8,10-tetraoxaspiro[5,5] undecane) (DETOSU)... 

FIGURE 7.25 Release of propionic acid and weight loss of poly(orthoester) containing lactoyl-lactic dimers (PE095LAC5). [Graph reconstructed from data by Schwach-Abdellaoui et al., Proceed. Int. Symp. Control. Rel. Bioact. Mater., 25, 713 (1998).]... 

Poly(amino acids) are insoluble in common solvents, are difficult to fabricate due to high melting point, and absorb a significant amount of water when their acid content reaches over 50 mol%. To solve these problems, polyesters derived from amino acids and lactic acids [e.g., poly (lactic acid-co-lysine) PLAL] are developed. The PLAL system is further modified by reaction with lysine A-carboxyanhydride derivatives. Another modification of poly(amino acids) includes poly(iminocarbon-ates), which are derived from the polymerization of desaminotyrosyl tyrosine alkyl esters. These polymers are easily processable and can be used as support materials for cell growth due to a high tissue compatibility. Mechanical properties of tyrosine-derived poly(carbonates) are in between those of poly(orthoesters) and poly(lactic acid) or poly(gly-colic acid). The rate of degradation of poly(iminocarbonates) is similar to that of poly (lactic acid). 

Schuerch2) reviewed the medical application of synthetic poly-saccharides. Capozza199 reported that the poly-orthoester prepared from 2-ethoxy-4-hydroxymethyl-l,3-diox-olane in the presence of add are useful as slow-release agents for drugs. Poly-2,6,7-trioxabicyclo[2.2.1]heptane VIII showed the same behavior200). 

These results suggest that poly-orthoesters are also useful for medical applications. If hydroxyl or amino groups are incorporated into the skeleton, the corresponding polymers will become more valuable by being more water-soluble. 

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