Poly ortho esters

Poly(ortho esters) (POE) eontain ortho ester groups along the chain an ortho ester is a funetional group eontaining three alkoxy groups attached to one earbon atom. Degradation results from a hydrolysis mechanism. These polymers ean be formulated in order to obtain a surfaee erosion degradation. 

This means that with slab-like devices, if the drag is uniformly dispersed, its release is carried out at constant rate, whereas in PLA devices, for example, the drag release is a combination of erosion and diffusion because bulk degradation takes place. Polyfortho esters) are divided in four families (Heller et al., 2002)  

The following paragraphs review each of these families. 

POE 1 polymers are synthesized from 2,2 -dimethoxyfuran and a diol. Hydrolysis of POE 1 materials produces y-butyrolactone which becomes y-hydroxybutyric acid (Fig. 1.12). This compound enhances degradation since ortho ester linkages are acid sensitive it is necessary to stabilize the polymer with a basic compound such as Na2C03 in order to avoid autocatalytic and uncontrollable hydrolysis degradation. POE 1 polymers have been investigated for clinical devices, but the autocatalytic nature of the degradation and the low glass-transition temperature limited applications for these materials, that nowadays are not under development. 

POE II polymers are synthesized starting from3,9-diethylidene-2,4,8,10-tetraoxaspiro[5.5]undecane (a diketene acetal) and a diol another example is the addition of a diol with 1,1,4,4-tetramethoxy-13-butadiene. Their synthesis is simpler because it is only necessary to dissolve the monomers in a polar solvent and to add traces of an acidic catalyst (Fig. 1.13). Molecular weights 

The first poly(ortho ester) for biomedical applications was produced by Choi and Heller at Alza Corporation in the 1970s, and was given the trade name Alzamer . When placed in an aqueous environment, the polymer degrades to produce a diol and a lactone, which is rapidly converted into y-hydroxybutyric acid  

This degradation process is autocatalytic, since the g-hydroxybutyric acid that is produced catalyzes the hydrolysis reaction. To prevent abrupt degradation and erosion, a basic compound must be incorporated into the polymer. For example, sodium bicarbonate can be incorporated into a polymeric device composed of Alzamer to control the rate of polymer degradation and erosion. Although the polymer has been used for a number of drug delivery applications, it is difficult to produce and requires addition of significant amounts of a basic chemical to prevent uncontrolled degradation [21]. 

Several improvements in the design and synthesis of poly(ortho esters) have been reported over the last 20 years. One of the most useful of these polymers is shown in Equation A.2-8  

The poly(ortho ester), shown on the left-hand side of Equation A.2-8, can be synthesized under milder conditions those required for Alzamer. Since cross-linked polymeric drug delivery devices are usually fabricated by mixing a prepolymer and a diol with mild curing ( 40 °C), care must be taken when using drugs with reactive hydroxyl groups. Most recently, another group of poly-(ortho ester) materials was synthesized [22]  

This polymer is an ointment at room temperature, which may make it appropriate for a variety of topical and peridontal applications. Since the polymer is a viscous liquid at this temperature, proteins and other labile molecules can be mixed into the polymer without using solvents or high temperatures. 

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PEG/PBT copolymers are also very good matrix materials for the release of growth factors in tissue engineering. Proteins have been delivered from PEG/PBT microspheres with preservation of protein delivery of complete activity. In the case of protein delivery from PLGA and poly(ortho ester) microspheres, the protein activity was significantly reduced. " ... 

The required acid sensitivity can be achieved by preparing polymers with ortho ester linkages in their backbone. The first poly-(ortho ester) has been described in a series of patents by Choi and Heller (3-6), assigned to the ALZA corporation. These proprietary materials were first designated with the trade name Chronomer and later Alzamer. They are prepared by a transesterification as follows ... 

Hydrolysis of these polymers regenerates the diol and produces Y-butyrolactone, which rapidly hydrolyzes to w-hydroxybutyric acid. Because poly (ortho esters) are acid-sensitive, a base is used to neutralize the hydroxybutyric acid and to maintain the hydrolysis process under control. 

An entirely different class of poly(ortho esters) has also been described (11). These polymers are prepared by the addition of polyols to diketene acetals. Principally due to the relative ease of... 

In these studies cleavage of the endocyclic alkoxy group produces ethylene glycol and since only about 5% was found, it was concluded that hydrolysis proceeds 95% via exocyclic cleavage, in excellent agreement with results found for poly(ortho esters). 

Convincing evidence for a surface erosion process is shown in Fig. 8, which shows the concomitant release of the incorporated marker, methylene blue, release of the anhydride excipient hydrolysis product, succinic acid, and total weight loss of the device. According to these data, the release of an incorporated drug from an anhydride-catalyzed erosion of poly (ortho esters) can be unambiguously described by a polymer surface erosion mechanism. 

The development of a bioerodible implant capable of releasing controlled amounts of a contraceptive steriod from a subcutaneous implant for periods of time ranging from three months to about a year has been in progress for many years. The three principal bioerodible polymers currently in use are copolymers of lactic and glycolic acid (25), poly(e-caprolactone) (26), and poly (ortho esters) (14). The desire to develop such a contraceptive system was the principal motivation for the initial development of the poly(ortho ester) polymer system. 

Initial work with poly (ortho esters) focused on norethindrone and the use of water-soluble excipients such as Na2C03, NaCl, and Na2S04 (27). As described by Fedors (28), the inclusion of such water-soluble salts leads to an osmotically driven water intake into the polymer. This water intake leads to polymer swelling with consequent release of the incorporated norethindrone. The effect of incorporated NaCl and Na2C03 on erosion rate as compared to the... 

Even though poly(ortho esters) contain hydrolytically labile Linkages, they are highly hydrophobic materiads and for this reason are very stable and can be stored without careful exclusion of moisture. However, the ortho ester linkage in the polymer is inherently thermally unstable and at elevated temperatures is believed to dissociate into an alcohol and a ketene acetal (33). A possible mechanism for the thermal degradation is shown below. This thermal degradation is similar to that observed with polyurethanes (34). 

Another important consideration in the thermal processing of linear poly (ortho esters) is the possibility of reactions between cata-lyst/polymer/drug. Because anhydrides are very good acylating... 

TABLE 1 Processing an Acid-Catalyzed Poly-(ortho ester) Under Different Relative Humidities (RH)... 

A. Processing Methods for Linear Poly (ortho esters)... 

TABLE Comparing the Compounding of Poly(ortho ester) with 5 wt% Stearic Acid Using Different Compounding Methods... 

TABLE 5 Comparing the Shaping of a Poly(ortho ester) Compound by Flux-Mixing with 5 wt% Stearic Acid... 

Choi, N. S., and Heller, J., Erodible agent releasing device comprising poly(ortho esters) and poly(ortho carbonates), U.S. Patent 4,138,344, February 6, 1979. 

World Health Organization 10th Annual Report, 1981, pp. 62-63. World Health Organization 11th Annual Report, 1982, p. 61. Heller, J., Penhale, D. W. H., and Helwing, R. F., Preparation of poly(ortho esters) by the reaction of ketene acetals and polyols, J. Polym. Sci., Polym. Lett. Ed., 18, 82-83, 1980. 

Heller, J., Penhale, D. W. H., Fritzinger, B. K., and Ng, S. Y., Controlled release of contraceptive agents from poly(ortho ester), in Long Acting Contraceptive Delivery Systems (G. I. Zatuchni, A. Goldsmith, J. D. Shelton, and J. Sciarra, eds.), Harper and Row, Philadelphia, 1984, pp. 113-128. 

H., In vitro and in vivo release of levonorgestrel from poly-(ortho esters). II. Crosslinked polymers, J. Control. Rel., 1, 233-238, 1985. 

Heller, J., Controlled drug release from poly(ortho esters) A surface eroding polymer, J. Control. Rel., 2, 167-177, 1985. 

Nguyen, T. H., Himmelstein, K. J., and Higuchi, T., Some equilibrium and kinetic aspects of water sorption in poly(ortho esters), Int. J. Pharm.. 25, 1-12, 1985. 

Zentner, G. M., Pogany, S. A., Sparer, R. V., Shih, C., and Kaul, F., The design, fabrication and performance of acid catalyzed poly(ortho ester) erodible devices. Abstracts of the Third Annual Meeting. American Association of Pharmaceutical Scientists. Orlando, FL, 1988. 

Heller, J., and Himmelstein, K. J., Biodegradable poly (ortho esters) as drug delivery forms, in Directed Drug Delivery (R. 

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