Polymer erosion

An example is poly(bis(p-carboxyphenoxy)propane) (PCPP) which has been prepared as a copolymer with various levels of sebacic anhydride (SA). Injection molded samples of poly (anhydride) / dmg mixtures display 2ero-order kinetics in both polymer erosion and dmg release. Degradation of these polymers simply releases the dicarboxyhc acid monomers (54). Preliminary toxicological evaluations showed that the polymers and degradation products had acceptable biocompatibiUty and did not exhibit cytotoxicity or mutagenicity (55). 

When a hydrophobic polymer with a physically dispersed acidic excipient is placed into an aqueous environment, water will diffuse into the polymer, dissolving the acidic excipient, and consequently the lowered pH will accelerate hydrolysis of the ortho ester bonds. The process is shown schematically in Fig. 6 (18). It is clear that the erosional behavior of the device will be determined by the relative movements of the hydration front Vj and that of the erosion front V2- If Vj > V2, the thickness of the reaction zone will gradually increase and at some point the matrix will be completely permeated with water, thus leading to an eventual bulk erosion process. On the other hand, if V2 = Vj, a surface erosion process wiU take place, and the rate of polymer erosion will be completely determined by the rate at which water intrudes into the matrix. 

The rate of polymer erosion in the presence of incorporated anhydride and release of an incorporated drug depends on the pK of the diacid formed by hydrolysis of the anhydride and its concentration in the matrix (20). This dependence is shown in Fig. 7 for 2,3-pyridine dicarboxylic anhydride and for phthaUc anhydride. In this study, methylene blue was used as a marker. The methylene blue release rate depends both on the pK and on the concentration of diacid hydrolysis product in the matrix. However, at anhydride concentrations greater than 2 wt%, the erosion rate reaches a limiting value and further increases in anhydride concentration have no effect on the rate of polymer hydrolysis. Presumably at that point Vj, the rate of water intrusion into the matrix, becomes rate limiting. 

A plausible mechanism for the erosion of devices that contain Mg(OH)2 is shown in Fig. 14 (2). According to this mechanism, the base stabilizes the interior of the device and erosion can only occur in the surface layers where the base has been eluted or neutralized. This is believed to occur by water intrusion into the matrix and diffusion of the slightly water-soluble basic excipient out of the device where it is neutralized by the external buffer. Polymer erosion then occurs in the base-depleted layer. 

Because swelling and consequent bulk erosion induced by the water-soluble salt is not desirable, use of the low-water-solubility, sUghtly acidic salt calcium lactate was investigated (30). By using this excipient it was hoped that a lowering of the pH within the surface layers of the device would take place and release of the drug would be controlled by polymer erosion confined to the surface layers of the device. In these experiments norethindrone was replaced by the currently favored steroid levonorgestrel. 

Because acid excipients can be used to achieve rapid polymer erosion, the possibility of preparing devices useful for oral delivery was investigated (31). In one such system, 2 wt% phthalic anhydride was incorporated into a polymer prepared from the diketene acetal, trans-cyclohexanedimethanol and C-labeled 1,6-hexanediol and polymer erosion followed in a pH 7 buffer and in pH 1.5 canine... 

Polymer Erosion rate constant (mol cm-2 day-1) Weight-average molecular weight Reference... 

More recently, a spaghetti model for a swollen matrix was developed to provide mechanistic understanding of the complex release process (Fig. 4.4). This model treats polymer erosion as diffusion of polymer across a diffusion layer adjacent to the gel layer.19,20 Thus two competitive diffusional processes contribute to overall drug release diffusion of polymer across the diffusion layer and diffusion of drug across the gel layer. Two parameters have been identified to characterize their relative contributions. Polymer disentanglement concentration Cp>dis gauges the... 

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). 

In developing such systems, we have investigated two enzyme-substrate reactions as a means of modulating polymer erosion rates ... 

FIGURE 6.28 Schematic diagram of a drug diffusion/polymer erosion controlled system containing a dispersed drug. 

FIGURE 6.29 Effects of drug diffusion, pofymer erosion, and drug loading on the drug release kinetics of drug dissolution/polymer erosion controlled systems. 

When the rate of drug diffusion is much slower than the rate of polymer erosion (i.e., B2 A), Equation (6.134) becomes ... 

Zero-order release kinetics expressed by Equation (6.139) agree with Equation (6.126) for heterogeneous erosion-controlled systems. However, when the rate of polymer erosion is very slow, the rate of drug diffusion through the swollen gel layer controls drug release kinetics (i.e., B2 A), and Equation (6.134) becomes ... 

Bittner, B., Witt, C., Mader, K., and Kissel, T. (1999), Degradation and protein release properties of microspheres prepared from biodegradable poly(lactide-co-glycolide) and ABA triblock copolymers Influence of buffer media on polymer erosion and bovine serum albumin release, J. Controlled Release, 60, 297-309. 

A refined picture of the interaction dynamics can be incorporated into models whose aim is to predict the extent of polymer erosion in LEO. For example, the empirical models mentioned in Sec. 3.1 have the possibility to make quantitative predictions of erosion yields, but they have suffered from a lack of information about the initiation steps and the reaction products. Both models have assumed that CO and CO2 carry carbon away from the surface, but quantitative predictions depend on the branching between these two products. The models can be extended to include contributions from all oxidation products that may carry mass away from the surface, as long as their identity and relative yields are known. In addition, the accuracy of the model predictions would be improved by knowledge of the initial trapping probability of incident oxygen atoms. Dynamical data, such as those described in Secs. 3.3 and 3.4, can bolster erosion models and thus expand their acceptance by the community. 

Reaction of a triol such as 1,2,6-hexanetriol with a DETOU prepolymer permits the formation of a cross-linked network. Rod-shape polymer systems (2.4 mm in diameter) were fabricated containing 30wt% levonor-gestrel and 7 wt%o micronized Mg(OH)2 as a stabilizer. These devices contained 1 wt% 9,10-dihydroxystearic acid to modify polymer erosion rate. SEM photomicrographs of the rods show evidence of surface... 

Figure 8.35 Characteristics of in vivo polymer erosion and metronidazole (MTZ) release from 50/50 CAP/Pluronic LI 01 films (with 10% metronidazole loading) in a dorsal rat model.

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