Polyanhydride

Acids react with acetic anhydride to furnish higher anhydrides (20). An acid which has a higher boiling point than acetic acid is refluxed with acetic anhydride until an equiUbrium is estabflshed. The low boiling acetic acid is distilled off and the anhydride of the higher acid is left. Adipic polyanhydride is obtained in this manner (21). 

A considerable number of non-cross-linked aromatic and heterocyclic polymers has been produced. These include polyaromatic ketones, aromatic and heterocyclic polyanhydrides, polythiazoles, polypyrazoles, polytriazoles, poly-quinoxalines, polyketoquinolines, polybenzimidazoles, polyhydantoins, and polyimides. Of these the last two have achieved some technical significance, and have already been considered in Chapters 21 and 18 respectively. The most important polyimides are obtained by reacting pyromellitic dianhydride with an aromatic diamine to give a product of general structure (Figure 29.17). 

This plastic, known as polyanhydride, was designed shapewise so that water would... 

We examined several approaches for synthesizing polyanhydrides, including melt polycondensation, dehydrochlorination, and dehydrative coupling. Extensive details of these new polymer synthesis techniques and numerous polymerization conditions for a wide variety of polyanhydrides were previously described (1). 

For many drug delivery applications, the preferred method of delivery of the dosage form is by injection. For controlled release applications, the most frequently used approach to allow this method of administration is to prepare microspheres of the polymer containing the drug to be delivered. Several different techniques have been developed for the preparation of microspheres from polyanhydrides. 

Within a series of closely related polyanhydride copolymers, the relative ratios of the two monomers have a marked effect on the rate of degradation of the resulting polymer. An example is shown in Fig. 

The polyanhydrides in general degrade more rapidly in basic media than in acidic media (4). This effect is shown in Fig. 2. 

Pure PCPP was used for this experiment to magnify the effect. At pH 7.4, pure PCPP degrades in about 3 years, as discussed above. However, this rate increases markedly as the pH rises, and at pH 10.0, this material degrades in just over 100 days. At very acidic pH values, many of the polyanhydrides virtually do not erode at all. 

Several new series of polyanhydrides with advantageous properties for a variety of applications were also synthesized (8). The first ai e aliphatic-aromatic homopolyanhydrides of the structure... 

FIGURE 1 Rate of polyanhydride degradation versus time. PCPP and SA copolymers were formulated into 1.4-cm-diameter disks 1 mm thick by compression molding, and placed into a 0.1 M pH 7.4 phosphate buffer solution at 37°C. The cumulative percentage of the polymer which degraded was measured by absorbance at 250 nm. 

The second type of polymer, unsaturated polyanhydrides of the structure [-(OOC-CH=CH-CO)x-(OOC-R-CO)y-]n, have the advantage of being able to undergo a secondary polymerization of the double bonds to create a crosslinked matrix. This is important for polymers requiring great strength, for instance. These polymers were prepared from the corresponding diacids polymerized either by... 

The incorporation and release kinetics from polyanhydride matrices of a number of drugs have been studied. Representative examples of several of these are described below. 

Cortisone acetate has been incorporated into several polyanhydrides (15). The rates of release of cortisone acetate from microcapsules of poly(terephthaUc acid), poly(terephthaUc acid-sebacic acid) 50 50, and poly(carboxyphenoxypropane-sebacic acid) 50 50 are shown in Fig. 8. These microcapsules were produced by an interfacial condensation of a diacyl chloride in methylene chloride with the appropriate dicarboxylic acid in water, with or without the crosslinking agent trimesoyl chloride. This process produces irregular microcapsules with a rough surface. The release rates of cortisone acetate from these microcapsules varied correspondingly with the rate of degradation of the respective polyanhydrides. It can be expected that the duration of release of cortisone acetate from solid microspheres, such as those produced by the hot-melt process, would be considerably longer. 

The controlled release from PTA-SA 50 50 of several drugs known to inhibit the formation of new blood vessels in vivo, cortisone and heparin, is shown in Fig. 9 (15). The inhibitors of angiogenesis delivered in vivo using this polyanhydride were shown to prevent new blood vessel growth for over 3 weeks, following the implantation of the VX2 carcinoma into rabbit cornea (15). 

FIGURE 8 Release of cortisone acetate from 10% loaded microspheres of various polyanhydrides. The microspheres were prepared by an interfacial condensation. Details of the experimental procedure are described in the text. 

A number of complex molecules such as proteins have been incorporated into the polyanhydrides, including insuhn, enzymes, chon-drogenic stimulating proteins, and a protein synthesized by genetic engineering techniques. 

Once the blood glucose values in the treated animals had returned to the high, diabetic levels, a second injection of insuUn-containing microspheres again reduced these levels to normal for about 5 more days. It is therefore possible to incorporate labile biological products into the polyanhydrides and to release them in a biologically active form. At the same time, this release can be sustained over a period of time in a controlled fashion. 

Alkaline phosphatase, an enzyme with a molecular weight of approximately 86,000, has been incorporated into a polyanhydride matrix using compression molded PCPP-SA 9 91. Five percent loaded wafers, 50 mg each, were perpared, and measured 1.4 cm in diameter, with a thickness of 0.5 mm. Release experiments were then conducted using techniques similar to those described for carmustine above. As can be seen in Pig. 13, the alkaline phosphatase was released in a well-controlled manner over a prolonged period of time, just over a month, from this polyanhydride. 

As in the alkaline phosphatase example above, p-galactosidase, an enzyme with a molecular weight of approximately 360,000, has also been incorporated into a polyanhydride and released in a well-controlled fashion. As is shown in Fig. 14, the release of 3-galactosidase was quite linear over most of the time examined, and was complete, reaching 100% release in about 800 hr. This experiment utilized 5% loaded, compression-molded wafers of PCPP-SA 9 91, 1.4 cm in diameter and 0.5 mm thick, weighing 50 mg. 

Bovine growth hormone, a difficult protein for which to develop controlled release systems due to its propensity toward self-aggregation and inactivation, has successfully been incorporated into polyanhydride matrices (18). The growth hormone was colyophilized with sucrose, dry-mixed with finely powdered polyanhydride, and then compression molded into 1.4-cm-diaraeter wafers, 1 mm thick. As is shown in Fig. 15, release of bovine growth hormone was well controlled over a prolonged period of time. The assay for bovine... 

These examples of incorporation of a variety of drugs and proteins is meant to be representative, not inclusive, and suggests that the polyanhydrides are capable of delivering a wide range of drugs and proteins for prolonged periods of time from a variety of different dosage forms. 

The stability of polyanhydrides composed of the diacids sebacic acid (SA), bis( -carboxyphenoxy)methane (CPM), l,3-bis(g-carboxyphe-noxy)propane (CPP), l,6-bis( -carboxyphenoxy)hexane (CPH), and phenylenedipropionic acid (PDP), in solid state and in organic solutions, was studied over a 1-year period. Aromatic polyanhydrides such as poly(CPM) and poly(CPH) maintained their original molecular weight for at least a year in both solid state and solution (20). 

In contrast, aliphatic polyanhydrides such as poly(SA) and poly-(PDP) decreased in molecular weight over time. The decrease in molecular weight shows first-order kinetics, with activation energies... 

TABLE 1 StaWlity of Various Polyanhydrides Versus Time in Solution... 

FIGURE 16 Stability of various polyanhydrides versus time. The molecular weight of various polyanhydrides stored in vacuo in glass ampules at room temperature was measured by GPC at various times. Details as described in the text. 

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