Polyanhydrides matrices

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. 

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... 

The property that makes polyanhydrides unique is their surface hydrophobic-ity. Due to this high hydrophobicity, polyanhydride matrices do not facilitate water absorption. Consequently, hydrolytic degradation is restricted to the surface—a property that is termed as surface erosion. This type of degradation allows for zero-order release of drugs, i.e., the drug release profile is independent of the residual concentration of the drug in the matrix. 

The release of a number of drugs from polyanhydride matrices has been studied including ciprofloxacin, p-nitroaniline, cortisone acetate, insulin, and a variety of proteins. ° In many instances, drug release was reported to coincide with polymer degradation. The biocompatibility of polyanhydrides has... 

The erosion in polyanhydride matrices has been reported to be purely surface of the heterogeneous type, and the results of this study support the past observation [82]. No lag time for drug release was found, as observed also for poly-lactic acid and poly-lactic acid-glycolic acid, which have been known to undergo bulk erosion [79]. In addition, fit of the data to Eqs. (1) and (2) (which have been derived for a surface eroding polymer), confirm the surface eroding nature of the polyanhydrides. 

Figure 9.22 Release of chemotherapy drugs from polyanhydride matrices. Release of anticancer drugs from a pCPP/SA polyanhydride matrix, (a) BCNU, (b) 4-hydroxy-cyclophosphamide, and (c) paclitaxel. The insets in panels (a) and (b) show diffusion-controlled release (i.e., the percentage released is proportional with respect to the square root of time) is 7 x 10 and 3 x 10 ° cm /s, respectively. Data from [77].

In the rabbit cornea bioassay, no evidence of inflammatory response was observed with any of the implants at any time. On an average, the bulk of the polymers disappeared completely between 7 and 14 days after the implantation [66]. In similar animal experiments in which polyanhydride matrices containing tumor angiogenic factor (TAF) were implanted in rabbit cornea, a significant vascularization response was observed without edema or white cells. Moreover, and most importantly from the biocompatibiUty standpoint, polymer matrices without incorporated TAF showed no adverse vascular response [67,68]. 

Domb et al. quantified the effect of monomer water solubility on the in vivo hydrolysis kinetics of polyanhydrides. They subcutaneously implanted polyanhydride matrices (2mmx2 mm x 4 mm) composed of aliphatic diacids, with differing carbon chain lengths, in rats and analyzed the... 

Akbari, H., D Emanuele, A., Attwood, D., 1998. Effect of geometry on the erosion characteristics of polyanhydride matrices. International Journal of Pharmaceutics 160, 83—89. 

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. 

Gopferich, A., Karydas, D., Langer, R., 1995. Predicting drug release from cyhndric polyanhydride matrix discs. European Journal of Pharmaceutics and Biopharmaceutics 41,... 

Figure 5 Erosion time series for a cylindrical polyanhydride matrix disc, complete cross-section (black pixels = non-eroded polymer, white pixels = eroded polymer). (Reproduced with permission of the American Institute of Chemical Engineers from (Gopferich Langer, 1995b). Cop)Tight 1995 AIChE. All rights reserved).

Dang, W. and Saltzman, W.M., Controlled release of macromolecules from a biodegradable polyanhydride matrix. J. Biomater. Sci., Polym. Ed., 1994,6 291-311. 

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... 

Chemically-Controlled Systems. In these systems, the polymer matrix contains chemically-labile bonds. On exposure to water or enzymes the bonds hydrolyze, erode the three dimensional structure of the polymer and release the incorporated reagent into the surrounding medium. Depending on the polymer used, the erosion products may act as interferences, such as by altering the pH of the solution. Examples of these systems are polyglycolic acid (PGA) and a polyglycolic acid - polylactic acid (PGA/PLA) copolymer. PGA hydrolyzes to hydroxyacetic acid, and PGA/PLA hydrolyzes to lactic acid and hydroxyacetic acid. Other chemically-controlled systems are based on polyorthoesters, polycaprolactones, polyaminoacids, and polyanhydrides. 

While many different polymer chemistries have been developed for drug delivery applications, only one class of polymer beside the polyesters has received regulatory approval. Gliadel is a thin wafer containing the chemotherapeutic agent carmustine (BCNU) in a polyanhydride polymer matrix. Gliadel received... 

Figure 8.36 Theoretical representation of a polymer matrix changes during erosion (dark pixels = nondegraded areas, white pixels = degraded areas), where (a rate constant) = 2.7 x 1 0 s for a sample containing 50% polyanhydride CPP.

A much more desirable erosion mechanism is surface erosion, where hydrolysis is confined to a narrow zone at the periphery of the device. Then, if the drug is weU-immobihzed in the matrix so that drug release due to diffusion is minimal, the release rate is completely controlled by polymer erosion, and an ability to control erosion rate would translate into an ability to control dmg delivery rate. For a polymer matrix that is very hydrophobic so that water penetration is limited to the surface (thus Hmiting bulk erosion), and at the same time, allowing polymer hydrolysis to proceed rapidly, it should be possible to achieve a drug release rate that is controlled by the rate of surface erosion. Two classes of biodegradable polymers successfully developed based on this rationale are the polyanhydrides [31] and poly (ortho esters) [32], the latter of which is the subject of this chapter. 

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