ORTHOESTER POLYMER

Choi, N.S. and Heller, J. (1979a). Novel orthoester polymers and orthocarbonate polymers. Alza Corporation, Mountain View, CA. 

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 ... 

Details are given of the successful construction of a novel reversible system of network polymers between bifunctional monomers by utilising the equilibrium polymerisation system of a spiro orthoester. Molecular structures were determined by NMR and IR spectroscopy. 9 refs. 

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

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. 

Chain transfer reactions in THF polymerizations have not been considered until rather recently. Compounds known to be effective chain transfer agents include dialkyl ethers, orthoesters, and water. In addition, chain transfer to polymer and with gegenion is possible. 

Finally, it may be noted that 4,6-orthoesters obtained for example by reaction of sucrose with ethyl orthoacrylate can be opened to form either the 6- or 4-esters,146 providing convenient starting materials for the preparation of biodegradable polymers (see Scheme 7). 

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. POEs have several merits as matrices for drug delivery. The orthoester linkage is pH sensitive, rendering the polymer rather stable at neutral pH with the degradation rate slowly increasing as the pH of the surrounding medium decreases. As a result, the degradation rate can be manipulated to range from hours to months by the incorporation of excipients of acidic or basic nature [122]. By careful formulation, it is possible to design systems in which erosion is confined to the surface of the device.

This reaction is thermodynamically controlled, because the polymer containing 1,3-dioxolane rings converts itself to a polyether when allowed to stand at room temperature for several days or heated at 80 °C for a few hours in the presence of an acid catalyst. Similar double ring-opening polymerizations were observed for 2,6,7-trioxabicyclo[2.2.2]octane and its derivatives [86, 87] and for spiro orthoesters and spiro orthocarbonates as well (see Sects. 6 and 7). 

Spiro orthoesters (92, R = Me, Ph, and H) show typical equilibrium polymerization behavior at or below ambient temperature. [92] The poly(cyclic orthoester)s derived from 92 depolymerize to the monomers, although they have sufficient strains to be able to undergo ring-opening polymerization. The polymerization enthalpies and entropies for these three monomers were evaluated from the temperature dependence of equilibrium monomer concentrations (Table 5). The enthalpy became less negative as the size of the substituent at the 2-position in 92 was increased H < Me < Ph. This behavior can be explained in terms of the polymer state being made less stable by steric repulsion between the bulky substituents and/or between the substituent and the polymer main chain. The entropy also changed in a similar manner with the size of the substituents. 

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). 

C.D. Dudgeon, Bis-Orthoesters as Polymer Intermediates, Thesis, University of Massachusetts, 1976. 

Endo, Suzuki, Sanda, and Takata [57] showed (Fig. 14b) that dithiol-linked bifunctional spiro orthoesters 48 can generate cross-linked polymers 49 in the bulk under acidic conditions (2 mol% CF3COOH). The increase of the temperature shifts the equilibrium in favor of the monomer. Conversely, the cross-linked polymers can be depolymerized from CH2C12 suspensions to form the initial monomers, also under acidic conditions (5 mol% CF3COOH). The yield of these processes is not quantitative. 

This is similar to polymerization of bicyclic orthoesters reported earlier where, depending on reaction conditions, polymers resulting from the opening of one or both rings could be prepared [210]. 

Many kinds of bicyclic ethers, acetals, and orthoesters have been cationically polymerized. Almost all bicyclic compounds have shown polymerizability. A few monomers give dimer or higher oligomers instead of polymers. The results are listed in Table 1. The polymerizability for unsubstituted bicyclic compounds is summarized in Table 2. 

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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