Polyanhydrides erosion

Fatty acids have also been converted to difunctional monomers for polyanhydride synthesis by dimerizing the unsaturated erucic or oleic acid to form branched monomers. These monomers are collectively referred to as fatty acid dimers and the polymers are referred to as poly(fatty acid dimer) (PFAD). PFAD (erucic acid dimer) was synthesized by Domb and Maniar (1993) via melt polycondensation and was a liquid at room temperature. Desiring to increase the hydrophobicity of aliphatic polyanhydrides such as PSA without adding aromaticity to the monomers (and thereby increasing the melting point), Teomim and Domb (1999) and Krasko et al. (2002) have synthesized fatty acid terminated PSA. Octanoic, lauric, myristic, stearic, ricinoleic, oleic, linoleic, and lithocholic acid acetate anhydrides were added to the melt polycondensation reactions to obtain the desired terminations. As desired, a dramatic reduction in the erosion rate was obtained (Krasko et al., 2002 Teomim and Domb, 1999). 

Erosion Rate Constants for many Common Polyanhydrides... 

Polyanhydrides with Erosion rate constant Number-average Reference... 

Whether in copolymers or blends, inhomogeneous erosion has a nontrivial effect on drug release kinetics as will be shown later. Leong et al. (1985) demonstrated that the pH of the degradation media also has a dramatic effect on the erosion rate, which increases with increasing pH. The acceleration of degradation of polyanhydrides with increase in pH is widely reported and has been used to speed up experiments (Shakesheff et al., 1994). 

Modeling the behavior of bioerodible polyanhydrides is complicated by the many phenomena contributing to release profiles described in the previous section. The degradation kinetics may be coupled to other processes, such as diffusion and dissolution, and the overall erosion kinetics represent the sum of all of these multiple processes (Goepferich, 1996a). 

The past two decades have produced a revival of interest in the synthesis of polyanhydrides for biomedical applications. These materials offer a unique combination of properties that includes hydrolytically labile backbone, hydrophobic bulk, and very flexible chemistry that can be combined with other functional groups to develop polymers with novel physical and chemical properties. This combination of properties leads to erosion kinetics that is primarily surface eroding and offers the potential to stabilize macromolecular drugs and extend release profiles from days to years. The microstructural characteristics and inhomogeneities of multi-component systems offer an additional dimension of drug release kinetics that can be exploited to tailor drug release profiles. 

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. 

Shieh L, Tamada J, Chen I, Pang J, Domb A, Langer R. Erosion of a new family of biodegradable polyanhydrides. J Biomed Mater Res 1994 28 1465-1475. 

Keywords. Controlled drug delivery, Drug release, Microspheres, Degradation, Erosion, Polylactide, Poly(glycolide-co-lactide), Poly(e-caprolactone), Poly(hydroxyalkanoates) Polyanhydrides, Polycarbonates, Poly(orthoesters), Poly( l,5-dioxepan-2-one)... 

Pharmaceutical research has to date been focused on polyanhydrides derived from sebacic acid (SA) and its copolymers with bis(p-carboxyphenoxy)propane (CPP) [75,113,115,119]. More recently, a new class of polyanhydrides was presented, containing fatty acid dimers (FAD) [ 116,118,258]. Erosion characteristics, microsphere preparation, pH-dependence, release rates, morphology, and in vivo performance of polyanhydrides from SA, CPP, and FAD have been intensely studied [75, 111-115,117, 119, 258-260]. Other unsaturated polyanhydrides have been derived from ricinoleic acid [261] and ricinoleic acid half-es-... 

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. 

As pointed out by Heller (2), polymer erosion can be controlled by the following three types of mechanisms (1) water-soluble polymers insolubilized by hydrolytically unstable cross-links (2) water-insoluble polymers solubilized by hydrolysis, ionization, or protonation of pendant groups (3) hydrophobic polymers solubilized by backbone cleavage to small water soluble molecules. These mechanisms represent extreme cases the actual erosion may occur by a combination of mechanisms. In addition to poly (lactic acid), poly (glycolic acid), and lactic/glycolic acid copolymers, other commonly used bioerodible/biodegradable polymers include polyorthoesters, polycaprolactone, polyaminoacids, polyanhydrides, and half esters of methyl vinyl ether-maleic anhydride copolymers (3). 

Recently, a new polyanhydride, poly(fatty acid-sebacic acid), has been synthesized. This polyanhydride uses hydrophobic dimers of erucic acid. Some of its physical properties relevant to the fabrication of drug delivery devices are also improved over those of the other anhydrides based on CPP lower melting temperature, higher solubility in solvents, and higher mechanical strength. The erosion of the polymers is dependent on... 

Polyanhydrides have been modified by incorporating amino acids into im-ide bonds. The imide with the terminal carboxylic acids is activated with acetic anhydride and copolymerized with sebacic acid or CCP. Poly(anhydride-imides) increase the mechanical properties of the polyanhydrides. Degradation of poly(anhydride-imide)s is similar to that of polyanhydrides (i.e., surface erosion). Two different cleavable bonds (anhydride and ester) in the polymer chains have been included in polyanhydrides. Carboxylic acid-terminated e-caprolactone oligomers or carboxylic acid-terminated monomers (e.g., salicylic acid) have been polymerized with activated monomers (e.g., SA). 

In contrast to bulk-eroding PLA/PLGA polymers, the polyanhydride undergoes surface erosion. The thin-disk type morphology of the wafer confers a high surface-to-volume ratio on the implant, so that the total surface area of the implant is kept almost constant over the time of polymer degradation, which facilitates a constant release of carmustine with time. 

Polyanhydrides degrade primarily by surface erosion and possess excellent in vivo compatibility. In 1996 the FDA approved a polyanhydride-based drug delivery system to the brain of chemotherapeutic agent BCNU, which is currently being manufactured by Guilford Pharmaceutical, Inc. 

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