Role of polyanhydrides as localized drug carriers

Abstract

Many drugs that are administered in an unmodified form by conventional systemic routes fail to reach target organs in an effective concentration, or are not effective over a length of time due to a facile metabolism. Various types of targeting delivery systems and devices have been tried over a long period of time to overcome these problems. Targeted delivery or localized drug delivery offers an advantage of reduced body burden and systemic toxicity of the drugs, especially useful for highly toxic drugs like anticancer agents. Local drug delivery via polymer is a simple approach and hypothesized to avoid the above stated problems. Polyanhydrides are a unique class of polymer for drug delivery because some of them demonstrate a near zero order drug release and relatively rapid biodegradation in vivo. Further, the release rate of polyanhydride fabricated device can be altered over a thousand fold by simple changes in the polymer backbone. Hence, these are one of the best-suited polymers for drug delivery, with biodegradability and biocompatibility. The review focuses on the advantages of polyanhydride carriers in localized drug delivery along with their degradability behavior, toxicological profile and role in various disease conditions.

Introduction

The constant efforts of drug delivery scientists have been to maximize the therapeutic effect of the drug and minimize the adverse effects. Drugs given by conventional routes like oral, IV, IM injections are distributed to all body parts which include both, target and non-target sites. This creates a burden on the whole body system, while the requirement is only at a particular site in the body. There are many drugs, both old and new pharmaceuticals and new molecular entities, that can be administered in a way that it not only improves safety and efficacy but also in some cases, results in new therapies [1]. Many disease conditions like cancer (especially solid tumors) [2], thrombosis, restenosis [3], osteomyelitis [4], local infection [5], glaucoma and retinal disorders [6] are difficult to treat by systemic therapy. The complexity of these diseases and the serious consequences limit the systemic therapy. For example, diseases of the retina are difficult to treat with systemically administered drugs because of the blood-retinal barrier and potential systemic toxicity; hemorrhagic complications arise when antithrombotic agents are administered systemically; and cancer treatments such as systemic therapy for a localized tumor often results in serious side effects [7]. The last decade witnessed a huge amount of research aimed at creating new drug delivery systems, because of the disadvantages associated with systemic drug delivery. Several strategies have been explored to deliver the drug to a specific site or body compartment but delivery via polymer is one of the simplest approaches. Polymers find a widespread application in therapeutics and localized use of polymers has its own importance. Polymers for localized application can play structural, functional or both structural and functional roles. Functionally active classes of the polymers are used to improve the biocompatibility and the operation of a medical device or to deliver the pharmacologically active agents [8]. Though there is an enormous amount of work done for localized drug delivery using polymers, the advantages of using polymers should be weighed against following concerns: (1) the toxicity of polymers and their degradation products in the body i.e. biocompatibility (2) the overall cost of polymeric drug delivery systems (3) problems associated with release, i.e. dose dumping or release failure, and (4) the discomfort caused by the system itself or the means of insertion of the delivery system [9]. The polymers used in drug delivery can be broadly divided into two types: non-biodegradable and biodegradable [10]. Biodegradable polymers enjoy the advantages of self-elimination, avoiding the need to remove the polymer system from the site of implantation after its use. The wide acceptability of the biodegradable system can be appreciated from the fact that biodegradability can be manipulated by incorporating a variety of labile groups. Biodegradation can be enzymatic, chemical or of microbial origin or simply by hydrolysis [11].

The most desirable polymeric matrix for drug delivery is one that is hydrophobic, stable, strong, flexible, soluble in organic solutions, has a low melting point and degrades linearly over time in an aqueous environment [12]. Polyanhydrides are best suited to this class of polymers and are useful for controlled drug delivery as they degrade uniformly into non-toxic metabolites that are non-mutagenic, non-cytotoxic and non-inflammatory [12]. In 1980, Langer was the first to exploit the hydrolytically unstable nature of polyanhydrides for sustained release of drug in controlled drug delivery applications [13]. Since then, few polyanhydride products have reached the market or are in different clinical stages. Gliadel®, a device to deliver carmustine (BCNU) to the malignant glioma tumor, is the most successful story of polyanhydrides [14]. Polyanhydrides are the class of biodegradable polymers that release the drug majorly by simple hydrolysis, hence, ethnic enzymatic variation does not play an effective role on the polymer erosion and drug release or its pharmacological effects [15]. These have been investigated as an important biomaterial, used for short-term release of drugs and have been thoroughly investigated for their chemical and physical properties, degradation and stability, toxicity and applications in delivery of bioactive agents [16]. The degradation profile of these polymers can be modulated from days to months by varying the type and ratio of the monomers [12], [17]. Looking at all the aspects of localized delivery and disease conditions, this review focuses on the use of polyanhydrides in localized delivery with special attention to their degradability behavior in vitro and in vivo; toxicological profile; their uses in different disease conditions and recent advances in this field.