Polyanhydrides medical applications

Polyanhydrides are useful bioabsorbable materials for controlled drug delivery. They are hydrolytically unstable and hydrolyze to diacid monomers in contact with body fluids. Since their introduction to the field of controlled drug delivery, about 10 years ago, extensive research has been conducted to study their chemistry as well as their toxicity and medical applications. Several review articles have been published on polyanhydrides and the focus has been on controlled drug delivery applications [1, 2]. 

The present volume comprises five review articles written especially for this series by leading authorities in the field. The first three adresses major structural characteristics of biodegradable polymers. Robert Lenz provides athorough review of biodegradable polymers. Jorge Heller offers a critical analysis of the structure, properties and medical applications of polyorthoesters, whereas Abraham Domb and his associates offer the same critical analysis of polyanhydrides. Eric Doelker discusses the structure and properties of cellulose derivatives. Finally Michael Sefton presents the use of polyacrylates for the microencapsulation of live animal cells. 

ROP offers an alternate approach to the synthesis of polyanhydrides used for medical applications. Albertsson and coworkers prepared adipic acid polyanhydride from cyclic adipic anhydride (oxepane-2,7-dione) using cationic (e.g., AICI3 and BFjTCjHj) ), anionic (e.g., CHjCOO K and NaH), and coordination-type inhibitors snch as stannous-2-ethylhexanoate and dibutyltin oxide [24,25]. ROP takes place in two steps (1) preparation of the cyclic monomer and (2) polymerization of the cyclic monomers [26]. 

Abstract A review is presented of the main types of bioresorbable or bioabsorbable materials used in medical applications such as drug delivery. Groups discussed include aliphatic polyesters, polyanhydrides, poly(ortho esters) (POE), polyphosphazenes, poly(amino acids) and pseudo poly(amino acids), polyalkylcyanoacrylates, poly(propylene fumarate) (PPF), poloxamers, poly(p-dioxanone) (PPDO) and polyvinyl alcohol (PVA). 

The overall science around polyanhydrides is summarised in Figure 5.1. The main focus of this chapter is to introduce and provide an extensive review of the various promising aspects of one specific class of synthetic biodegradable medical polymer — poly anhydride. In the first part of the chapter the classification, chemical stmctures, and synthesis methods of various polyanhydrides are discussed. This is followed by a discussion of the in vitro and in vivo behaviour and degradation mechanism of these materials. Also, the various processing techniques that are employed are introduced and explained. Finally, medical applications of polyanhydride systems are presented, highlighting their role and their potential to be used as a family of medical polymers of the future generation . 

There are many polymers that are suitable for the production of nanoparticles employed for drug delivery, which can generally be divided into two groups natural polymers, e.g., polysaccharides (chitosan), proteins (albumin, gelatin), as well as synthetic polymers, e.g., polyesters (poly(lactic add), poly(glycolic add), poly(hydroxy butyrate), poly-e-caprolactone, poly-p-malic add, poly(dioxanones)) polyanhydrides (poly(adipic add)) polyamides (poly(amino acids)) phosphorous-based polymers (polyphosphate) poly(cyano acrylates) polyurethanes polyortho esters and polyacetals. Extreme attention has to be paid to the biodegradability and biocompatibility of the polymers. It is essential that polymers used for medical applications are not detrimental for the tissue or cells and that they can be easily decomposed into simple harmless molecules and eliminated by the human body [ 18-22]. 

Figure 2.1 Basic structures for some groups of synthetic polymers commonly employed as degradable materials in medical applications a) polylactide-co-polyglycolides (also commonly used as their homopolymers (i.e., n/m = 0), b) polycaprolactones, c) polydioxanones, d) polyorthoesters, e) polyanhydrides, f) polyalkylcyanoacrylates, g) poly(organo)phosphazenes and h) polyphosphoesters...

The ability to undergo biodegradation producing nontoxic by-products is a useful property for some medical applications. Biodegradable polymers [71] have been formulated for uses such as sutures, vascular grafts, drug delivery devices, and scaffolds for tissue regeneration, artihcial skin, orthopedic implants, and others. The polymers commonly known in the medical field for such applications include poly(a-hydroxy esters), poly(e-caprolactone), poly(ortho esters), polyanhydrides, poly(3— hydroxybutyrate), polyphosphazenes, polydioxanones, and polyoxalates (see Chapter 2 of Industrial Polymers, Specialty Polymers, and Their Applications). 

An abbreviated list of medical applications for commodity polymers (Table 13.6) is an indication of the wide scope of both materials and their uses. Since many of these uses require small volumes of premium materials, it is often feasible to supplement commodity plastics by developing specialty polymers that would not otherwise be justified on an economic basis. In the examples that follow, one encounters both commodity polymers such as ultrahigh-molecular-weight polyethylene (UHMWPE) and poly(tetrafluoroethylene) (PTFE), and specialty polymers such as the polyanhydrides and poly(glycolic acid). 

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]. 

In the 1930 s, Carothers prepared a series of aliphatic poly(anhydride)s for potential use as fibers in the textile industry (1). However, the hydrolytic stability of these materials was very poor. By the mid-1950 s, Conix was able to synthesize aromatic poly(anhydride)s with improved film and fiber forming properties (2). Despite these properties, the polyanhydrides poor thermal and hydrolytic stability resulted in their limited use, and no conunercial applications were found. By the late 1960 s, however, hydrolytic instability became an important factor for polymers utilized in the manufacture of medical devices such as absorbable sutures and drug delivery systems. 

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