Polyanhydrides

Polyanhydrides are produced by the self-condensation of certain aromatic dicarboxylic acids  

Furukawa and T. Saegusa, Polymerization of Aldehydes and Oxides. Wiley, New York, 1963. M. Sittig, Poly acetal Resins, Gulf Publishing Company, Houston, 1963. 

Weissermel, E. Fischer, K. Gutweiler, H. D. Hermann, and H. Cherdron, Polymerization of trioxane, Angew. Chem. Int. Ed. (Engl.) 6, 526 (1967). 

Barker and M. B. Price, Polyacetals, Butterworths, London, 1970 American Elsevier, New York, 1971. 

Stereospecific polymerization of aldehydes and epoxides, Adv. Polym. Sci. 11, 57 (1973). 

Polyanhydrides are characterized by anhydride bonds connecting monomers along the chain, or by anhydride groups located on the side of the chain and not along the backbone. Indeed, poly (malic anhydride) is a polyethylene chain with anhydride groups as side chains (Fig. 1.10). 

Polyanhydrides have been classified into several categories (Kumar et al., 2002, Kumar et al., 2005)  

The properties of polyanhydrides ean be modified by ehanging polymer composition and structure. This is obtained by realizing copolymers, polymer blends, erosslinking between ehains, partial hydrogenation and reaction with epoxides. Low moleeular weight PLA, PHB and PCL are miscible with polyanhydrides whereas high moleeular weight polyesters are not. 

Indeed, PCPP-SA systems were clinieally tested in order to deliver an anticancer agent into the brain for the treatment of brain neoplasm in rats, rabbits and monkeys, showing a satisfactory biocompatibility without adverse effects (Domb et al., 1997). Nowadays, this material is FDA approved and is currently in clinical use for the treatment of brain eancer (Lanza et al., 2007). 

Polyanhydrides degrade by hydrolytic cleavage of the anhydride bonds at a well predicted rate and are completely removed from the body within the period of a few weeks. Polyanhydrides are reported to ultimately xmdergo heterogeneous surface erosion, which is favored by the water lability of its anhydride bonds and the hydrophobic-ity of its surface. The extent of hydrophobicity of the polymer is based on the ratio of the monomer units used and makes it water impermeable, thus more stable. 

Some important groups of polyanhydrides already in medical use are based on para-(carboxyohenoxy)propane, para-(carboxyphenoxy)hexane, para-(carboxyphenoxy) methane and their copolymers with sebacic acid. Also reported has been the use of fatty-acid-based polyanhydrides synthesized from hydrophobic dimers of erucic acid and sebacic acid in drug release applications [456]. They also follow surface erosion degradation [457]. As the polymer degrades, the fatty acid monomers deposit on the surface of the polymer matrices and act as an obstacle to the diffusion of low molecular weight compounds (e.g., active small molecules), contributing to slow release [458]. 

Polyanhydride structures can be modified by the addition of aminoacids, linked via imide bonds at the amino terminus, so that the carboxylic acid terminus remains available for the interaction with acetic anhydride [459]. These poly(anhydride-imides) degrade in a similar way as the simple polyanhydride polymers. Other modifications that can take place are copolymers linked with esters. In that way, the polymer contains two types of hydrolytically cleavable bonds. In the presence of water, both types of bonds are hydrolyzed, releasing the dicarboxylic acid and the ester [460]. An example of a poly(anhydride-ester) with application in the medicinal field includes sebacic acid and salicylic acid, a therapeutically useful compound. The release of sebacic acid in the body opens up a variety of potential applications. 

Aromatic and aliphatic polyanhydrides, especially sebacic acid-derived ones, are usually copolymerized with other classes of polyanhydrides or conjugated with fatty acids to be used in drug delivery [461-463], They are studied for their use in the treatment of various disease conditions such as cancer, osteomyehtis, local infections, restenosis [464], eye disorders and Alzheimer s disease [465], They are also used in local anaesthesia and in gene delivery [466,465], 

Polyanhydrides have been intensively investigated as important biomaterials in medical fields due to their excellent biodegradability and biocompatibility. Over the decades, numerous studies have been carried out in academia and industry which were mainly concerned with chemical and physical characterization of these polymers, degradation properties, toxicity studies and various 

Hydrolysis is the most common mechanism of polymer degradation in biomaterials. Of the linkages that commonly occur in polymers, the anhydride linkage is one of the least stable in the presence of water. In fact, polyanhydride polymers are so sensitive to water that they are unsuitable for many potential applications. However, the potential for rapid hydrolysis of the polymer backbone makes anhydride-based polymers attractive candidates as biodegradable materials. 

Because of the instability of the anhydride bond in the presence of water, special properties are required for stable polyanhydride devices. A critical element in the development of polyanhydride biomaterials is controlling hydrolysis within a polymeric device. To obtain implants where hydrolysis is confined to the surface of the polymer, hydrophobic monomers can be polymerized via anhydride linkages to produce a polymer that resists water penetration, yet degrades into low molecular weight oligomers at the poly-mer/water interface. By modulating the relative hydrophobicity of the matrix, which can be achieved by appropriate selection of monomers, the rate of degradation can then be adjusted. For example, copolymers of sebacic acid, a hydrophilic monomer, with carboxyphenoxypropane, a hydrophobic monomer, yield  

Polymers prepared with different copolymerization ratios can be used to produce implants that degrade in controlled fashion. For more information, recent 

These polymers are capable of undergoing a hydrolysis process primarily confined to the surface of devices. Domb and Langer (1987) have indicated that the hydrolysis of anhydride linkages is inhibited by the presence of acids bulk erosion of these materials is therefore suppressed by 

Recently, a new family of polyanhydrides has been explored (Domb et al, 1987 Tabata and Langer, 1993). These copolymers are based on fatty acid dimers derived from oleic and sebacic acids (6) and are termed 

The incorporation of a variety of proteins into polyanhydride microspheres has been examined, including insulin (Mathiowitz et al, 1985 Mathiowitz and Langer, 1987), bovine somatotropin (Ron et al, 1989), chondrogenic stimulating proteins (Lucas et al, 1990), and several enzymes (Chasin et al, 1990). These matrices have been extensively characterized in vitro and efforts for in vivo characterization continue (Chasin et al., 1990). 

The polymers represented by 6 have been used to incorporate proteins of different molecular sizes into microspheres by a double-emulsion technique (Tabata et al, 1993b). The proteins—lysozyme, trypsin, heparinase, ovalbumin, BSA, and immunoglobulin—were primarily incorporated into a 25 75 fatty acid/sebacic acid copolymer at a loading of 2 wt%. The microspheres produced by this method were spherical, irrespective of the 

FIGURE 16.7 (a) DSC thermograms in the second heating runs for solution/precipitation PDLLA/PMMA blends with compositions from 100 0 to 0 100, and (b) Tg versus composition in solution/ precipitation PDLLA/PMMA blends. ( ) Experimental results. Line A corresponds to the weight average, and line B is drawn according to Equation 16.1 with k — 0.5. Reprinted from Ref. 71. Copyright 2002, with permission from John Wiley Sons, Inc. 

More recently, a new synthetic route has been reported for producing linear poly(adipic anhydride]s by using ketene gas. This route has the advantage of avoiding the formation of acetic acid. 

Poly(amide enamine]s have been synthesized for this purpose and have been found to be susceptible to hydrolysis and biodegradation by both fungi and enz5mies. 

Pulapura and coworkers replaced bisphenol A with derivatives of tyrosine dipeptide resulting in a iminocarbonate-amide copolymer. The iminocarbonate bond was formed between the phenolic hydroxyl group at the tyrosine side chains. These iminocarbonate-amide copolymers can be regarded as pseudo-poly(amino acids) and are being evaluated in biomedical applications. 

Starch has been used as a filler in degradable materials, in blends such as starch-urethanes, and starch-polyethylene with ethylene-acrylic acid copolymer. 

---

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. 

---