Erosion, and Drug Release Kinetics

In vitro Degradation, Erosion, and Drug Release Kinetics... 

When a water-insoluble drug such as hydrocortisone is physically dispersed in the polymer and the polymer fabricated into thin disks which are then placed in a buffer at pH 7.4, release kinetics shown in Fig. 1 are obtained. Clearly, this system exhibits excellent zero order drug release kinetics with concomitant linear rate of polymer weight loss. The simultaneous polymer erosion and drug release is a clear indication that erosion occurs at the surface of the device and that drug release is controlled by erosion of the polymer. 

The principal focus of our work is the development of a sub-dermally implantable, bioerodible monolithic device that would release contraceptive steroids by close to zero order kinetics for at least six months. Also, polymer erosion and drug release should be coupled so that no pol3iTner remains in the tissue after all the drug has been released. 

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). 

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. 

For water-soluble coatings that consist mainly of polymers, dissolution or erosion of the coat is the rate-limiting step toward the controlled release. After the coat is dissolved, the drug substance in the core is released, and the release kinetics depend on the core properties. Based on Eq. (5.2), solubility and dissolution/hydration behaviors of the pri-... 

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

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 ... 

The analysis of the release profiles and the kinetic data indicate two different behaviors and a sudden change between them. In the first behavior, which corresponds to the matrices that release the drug at slow rates, the release was controlled by the fully hydrated gel layer. For these matrices, erosion of the hydrophilic gel structure has shown an important influence on drug release. This is indicated by the better fit of the drug release kinetics to the zero-order equation, the n value of... 

Monolithic Devices—In these systems the drug is homogeneously dispersed within a bioerodible polymer matrix, and release of the drug can be controlled either by diffusion or by polymer erosion. If erosion of the matrix is very much slower than drug diffusion, then release kinetics follow the Higuchi model (37) and drug release rate decreases exponentially with time, following t dependence over a major portion of the release rate. 

Drug release rate for matrices undergoing bulk erosion is nonlinear and difficult to predict because it is determined by a combination of diffusion and erosion. However, drug release from devices undergoing surface erosion is predictable and can lead to zero order-kinetics provided diffusional release of the drug is minimal and the overall surface area of the device remains essentially constant. 

Dispersion of drug particles in a solid matrix, where there is diffusion and erosion control of release kinetics. 

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