The effect of the aqueous solubility of xanthine derivatives on the release mechanism from ethylcellulose matrix tablets.

Release data from ethylcellulose (EC) matrix tablets was analyzed to determine which release equation provides the best fit to the data and to observe the effect of drug solubility on the release mechanism(s). Tablets were prepared by direct compression of drug, EC, and lubricant in an appropriate mass ratio to achieve a high and a low drug loading. Theophylline, caffeine, and dyphylline were selected as non-electrolyte xanthine derivatives with solubilities from 8.3 to 330 mg/ml at 25 degrees C. Drug release studies were conducted in 37 degrees C water with UV detection at 272 nm. Several equations to characterize release mechanisms were tested with respect to the release data. Drug diffusion, polymer relaxation, and tablet erosion were the mechanisms considered. Parameters were generated and ANOVA data presented by WinNonlin Pro(R) software. The Akaike Information Criterion was also considered to ascertain the best fit equation. At high drug loading, drug was released by a diffusion mechanism with a rate constant that increased with an increase in aqueous solubility. At low drug loading, polymer relaxation also became a component of the release mechanism. However, its contribution to drug release was less pronounced as solubility decreases, becoming negligible in the case of theophylline.

The antimicrobial activity of vancomycin in the presence and absence of sodium carboxymethyl starch.

The purpose of this work was to determine any effects the presence of sodium carboxymethyl starch may have on the antimicrobial activity of vancomycin given a previously described interaction between vancomycin and sodium carboxymethyl starch. In particular, the in-vitro activity of vancomycin against two clinically relevant bacteria, Staphylococcus aureus and Enterococcus faecalis, was studied in the presence of varying concentrations of sodium carboxymethyl starch. From two independent studies conducted using an agar dilution method, it appeared that the binding of vancomycin to sodium carboxymethyl starch had no effect on the in-vitro antimicrobial activity of vancomycin. The minimum inhibitory concentration of vancomycin against S. aureus in the presence of as much as 1 mg mL(-1) sodium carboxymethyl starch was similar to that of the control where no sodium carboxymethyl starch was added (1-4 microg mL(-1) vs 1-2 microg mL(-1), respectively). Likewise, the minimum inhibitory concentration of vancomycin against E. faecalis in the presence of 1 mg mL(-1) sodium carboxymethyl starch was also similar to that of the control where no sodium carboxymethyl starch was added (1-4 microg mL(-1) vs 1-4 microg mL(-1), respectively). However, there may be factors in the in-vitro method, such as high ionic strength, that could disrupt the interaction between vancomycin and sodium carboxymethyl starch. Therefore, the possibility of diminished vancomycin activity in-vivo cannot be ruled out. A small percentage (8-10%) of vancomycin was determined to be bound to sodium carboxymethyl starch in broth media. Given these results, the impact of sodium carboxymethyl starch on the in-vitro antimicrobial activity of vancomycin is expected to be minimal. Binding studies could not be conducted with gelled agar due to its semi-solid state.

Effect of intravenous drug administration mode on drug distribution in a tumor slab: a finite Fourier transform analysis.

Cancer therapy using chemotherapeutic drugs frequently involves injection of the drug into the body through some intravenous mode of administration, viz, continuous (drip) infusion or single/multiple bolus injection(s). An understanding of the effect of the various modes of administration upon tumor penetration of drug is essential to rational design of drug therapy. This paper investigates drug penetration into a model tumor of slab geometry (between two capillaries) in which the overall transport rate of drug is limited by intra-tumor transport characterized by an effective diffusion coefficient. Employing the method of Finite Fourier Transforms (FFT), analytical solutions have been obtained for transient drug distribution in both the plasma and the tumor following three modes of administration, viz, continuous infusion, single bolus injection and equally-spaced equal-dose multiple bolus injections, of a given amount of drug. The qualitative trends exhibited by the plasma drug distribution profiles are consistent with reported experimental studies. Two concepts, viz, the dimensionless decay constant and the plasma/tumor drug concentration trajectories, are found to be particularly useful in the rational design of drug therapy. The dimensionless decay constant provides a measure of the rate of drug decay in the plasma relative to the rate of drug diffusion into the tumor and is thus characteristic of the tumor/drug system. The magnitude of this parameter dictates the choice of drug administration mode for minimizing drug decay in the plasma while simultaneously maximizing drug transport into the tumor. The concentration trajectories provide a measure of the plasma drug concentration relative to the tumor drug concentration at various times following injection. When the tumor drug concentration exceeds the plasma drug concentration, the drug will begin to diffuse out of the tumor. Knowledge of the time at which this diffusion reversal occurs is especially useful for optimum scheduling of subsequent bolus injections in a multiple bolus dosing regimen. There are no reported applications of the FFT method to solve repeated input functions in either the chemical engineering or pharmaceutical science literature. Thus, the application of FFT method to solve multiple bolus injections is a unique one. Use of this FFT based analysis as a predictor tool can limit the number of costly experiments which are being done now to achieve this purpose. Even though the model in its present form is simplified, the analysis thereof has nevertheless led to a better understanding of the various factors that must be taken into account for rational design of drug therapy.