Polyanhydrides: an overview

Abstract

Polyanhydrides have been considered to be useful biomaterials as carriers of drugs to various organs of the human body such as brain, bone, blood vessels, and eyes. They can be prepared easily from available, low cost resources and can be manipulated to meet desirable characteristics. Polyanhydrides are biocompatible and degrade in vivo into non-toxic diacid counterparts that are eliminated from the body as metabolites. Owing to their usefulness, this review focuses on the development, synthesis methods, structures and characterization of polyanhydrides, which will provide an overview for the researchers in the field. Their in vitro and in vivo degradability, toxicity, biocompatibility and applications are discussed in the subsequent chapters of this special issue on polyanhydrides and poly(ortho esters).

Introduction

Polyanhydrides have been investigated as an important biomaterial used for short-term release of drugs for more than two decades [1], [2], [3]. Over these years, intensive research has been conducted in academia and industry which yielded hundreds of publications and patents describing new polymer structures, studies on chemical and physical characterization of these polymers, degradation and stability properties, toxicity studies, and applications of these polymers for mainly controlled delivery of bioactive agents. It also yielded a device (Gliadel^®) in clinical use for treating brain cancer [4]. Due to rapid degradation and limited mechanical properties, the main application for this class of polymers is in short-term controlled delivery of bioactive agents.

Initially, synthesis of polyanhydrides was reported by Bucher and Slade [5]. Years latter, Hill and Carothers [6], [7] synthesized aliphatic polyanhydrides and studied the behavior of diacids towards anhydride formation. They prepared super-anhydrides from homologous aliphatic dicarboxylic acid and used them to spin fibers having good mechanical strength. Conix [8] reported the polyanhydrides derived from aromatic acids and found that these compounds were hydrolytically stable and have excellent film and fiber forming properties. He proposed a general method for the preparation of aromatic polyanhydrides as shown below:

Conix studied a large number of aromatic polyanhydrides and found that they had glass transition temperatures in the range of 50–100 °C, were transformed into opaque porcelain-like solids and were resistant to hydrolysis even on exposure to alkaline solutions. Yoda [9], [10] introduced a new class of heterocyclic crystalline compounds in the polyanhydrides’ family. He synthesized various types of five member heterocyclic dibasic acids and polymerized these compounds with acetic anhydride at 200–300 °C under vacuum and nitrogen atmosphere. The heterocyclic polymers thus obtained, had melting points in the range 70–190 °C and good fiber and film forming properties. Aliphatic polyanhydrides were considered as less important compounds due to their unstable nature against hydrolysis. In 1980, Langer was the first to exploit the hydrolytically unstable nature of the polyanhydrides for sustained release of drugs in controlled drug delivery applications [11] and used these compounds as biodegradable carriers in various medical devices.

For clarification, the class of polyanhydrides discussed in this special issue belongs to those polyanhydrides which have the anhydride bond in polymer backbone and degrade to shorter chains after breakdown of the anhydride bonds. There are other polyanhydrides where the anhydride is a side group and not part of the polymer backbone. For example, poly(malic anhydride) is a polyethylene chain having anhydride groups as side groups to the polymeric backbone. After the breakdown of anhydride bond in poly(malic anhydride) no change in the initial molecular weight is expected. The difference in degradation behavior of both types of polyanhydrides is shown below:

Polyanhydrides form a new class of biodegradable polymers in the biomaterials family and have hydrophobic backbone with hydrolytically labile anhydride linkages such that hydrolytic degradation can be controlled by manipulation of the polymer composition. They are of great interest because they show no evidence of inflammatory reaction. They degrade in vitro as well as in vivo to their acid counterparts as non-mutagenic and non-cytotoxic products [12], [13]. Polyanhydrides are biocompatible and have excellent controlled release characteristics [14], [15]. Pharmaceutical research has been focused on polyanhydrides derived from SA, 1,3-bis(p-carboxyphenoxy) propane (CPP) and fatty acid dimer (FAD). Recently, the Food and Drug Administration (FDA) has approved the use of the polyanhydride poly(sebacic acid-co-1,3-bis(p-carboxyphenoxy) propane) (P(CPP-SA)) to deliver the chemotherapeutic agent BCNU for the treatment of brain cancer [16]. Introduction of imide group into polyanhydrides enhances the mechanical properties of the polymers [17], [18], [19], [20], while the presence of polyethylene glycol (PEG) groups in polyanhydrides increases hydrophilicity and induces fast drug release [21]. The main limitation of polyanhydrides is their storage stability requiring storage under refrigeration. Several articles published on polyanhydrides have demonstrated different aspects with special emphasis on controlled drug delivery applications [22], [23], [24], [25]. This article focuses on the history, synthesis methods, structure, and characterization of polyanhydrides. Degradation, biocompatibility, drug release behavior and various applications of polyanhydrides are described in subsequent chapters of this special issue.