Enteric coating of oral solid dosage forms as a tool to improve drug bioavailability.

Enteric coating is a common procedure in the development of oral pharmaceutical dosage forms. The main advantage of enteric coating is that it protects the drug from acidic pH and enzymatic degradation in the stomach while protecting it from the undesirable effects of some drugs. There is certain controversy regarding the real influence of enteric coating on the bioavailability of many drugs. Various scientific articles have demonstrated an improvement in the extent of bioavailability of some drugs when enteric coating is used. In recent years, there have been many studies examining different formulation strategies for monolithic and multiparticulate systems, including different pharmaceutical oral dosage forms and delivery systems based on the combined use of enteric coating and other methods that improve the bioavailability of drugs administered orally. However, the real bioavailability, serum levels and therapeutic effect of these drugs may be influenced by gastrointestinal pH values, gastrointestinal environment, inter-individual or intra-individual variability in gastric emptying and gastrointestinal transit time, interpatient variability associated with the type of polymer used for enteric coating or other formulation variables. It deserves special attention to know the real influence of enteric coating on the bioavailability of new oral dosage forms.

Influence of the infusion rate on disposition of netilmicin in the isolated rat perfused kidney.

A study of the disposition of netilmicin in the isolated rat kidney was carried out in order to establish the influence of the infusion rate on the drug profile in this tissue. A dose of 800 microg administered as a bolus injection or at infusion times of 5, 7.5 and 10 min, respectively, was injected through the afferent cannula into the isolated kidney. Analysis of outflow curves was carried out using different kinetic approaches. Comparison of statistical moments and derived parameters pointed to changes in the distribution process with the infusion rate. In contrast, elimination remained constant, since the extraction coefficient and relative area under the curve values did not change with the infusion rate, although the MTT (mean transit time) and distribution volume decreased for the longest infusion times. The UDF (unit disposition function) profiles were not superimposed for the different infusion rates and combined with the results of the kinetic analysis revealed that the behaviour of netilmicin in the isolated kidney depends on infusion rate. The apparent partition coefficients in renal cortex and medulla showed higher values for the slower perfusion rates. Yet, a progressive decrease in the absolute amount of netilmicin was predicted in the tubular epithelium compartment whereas the residence time tended to increase. The latter phenomenon could account for the higher aminoglycoside nephrotoxicity reported when these drugs are administered over longer infusion times.

Influence of dose on the disposition kinetics of netilmicin in the isolated kidney of the rat.

The disposition of Netilmicin in the isolated rat kidney was studied in order to determine the influence of dose on the drug profile in this tissue. Doses of 50, 200, 800 or 10000 mg were injected through an afferent cannula into the isolated kidney as a bolus injection and outflow perfusate samples were collected. Statistical moments (AUC, MTT, VTT) were estimated from raw outflow curve data. Unit disposition function (UDF) was obtained by mass balance for each studied dose. The results of control assays addressing the viability of the isolated kidney preparations point to a high reproducibility for this preparation under the experimental conditions used, together with an acceptable viability. Comparison of statistical moments and derived parameters such as the extraction coefficient, distribution volume and drug renal clearance (E, Vd, ClE) suggest the existence of modifications in the distribution process with the dose, while elimination seems to remain unvariable; accordingly, the unit disposition function profiles were not superimposed for the different doses but differences during the early and final phases were observed.

Critical factors in the release of drugs from sustained release hydrophilic matrices.

Hydrophilic matrix systems are one of the most interesting drug delivery systems, and they are currently some of the most widely used to control the release rate of drugs. There are too much factors involved in drug release from hydrophilic matrix systems. The most important factors to be taken into account when developing a formulation based on hydrophilic matrices are the percentage, solubility and drug particle size; the type of polymer, the percentage incorporated, its degree of viscosity and the polymer particle size. Also important are the drug/polymer ratio and the amount of water entering the matrix. Other factors have been shown to be involved in the release of drugs, such as the percentage and mixtures of polymers and the dimensions of the matrix. The compression force is important among the formulation factors to the extent that it determines the amount of air trapped in the matrix. Knowledge of these factors involved in the release of the drugs is crucial for the optimal development of formulations based on hydrophilic systems.

Optimization of release kinetics from sustained-release formulations using model-independent pharmacokinetic simulation.

In the present work, a single model-independent approach was developed to optimize the release kinetics of drugs from sustained-release formulations, using stavudine (d4T) as a model drug. This approach is based on the pharmacokinetic simulation of drug plasma levels through a semiparametric approach of the input function and on convolution with an empirical polyexponential unit impulse response function. Input functions were evaluated using different zero-order and first-order release constants. Optimum drug release to obtain a specific pharmacokinetic profile was approached using target model-independent pharmacokinetic parameters such as C(max)(SS), C(min)(SS), t(max)(SS), and peak-trough fluctuations. A Monte Carlo simulation was performed to estimate the fractional attainment of d4T plasma concentrations over therapeutic d4T levels. Zero-order (K(0) = 4 mg/h) and first-order (K(1) = 0.05 h(-1)) release constants were optimal for the formulation of sustained-release d4T tablets, plasma concentrations within the therapeutic range being achieved.

Pharmacokinetic study of the digoxin-acenocoumarol interaction in rabbits.

A study was carried out to evaluate the potential pharmacokinetic interaction between digoxin and acenocoumarol. The binding of digoxin to rabbit cardiac tissue homogenates was assessed in vitro, using the equilibrium dialysis technique. An increase in the first-order constant (p<0.05) and a reduction in the partition coefficient in the equilibrium situation (p<0.001) of digoxin were observed when the cardiac homogenates were previously treated with acenocoumarol. In the in vivo study, the kinetics of digoxin administered in single and multiple dosage regimens were compared in control rabbits and in rabbits treated simultaneously with acenocoumarol. Kinetic analysis of the results was performed using Non-linear Mixed Effects Modeling (NONMEM). In the presence of acenocoumarol, the population distribution volume (Vd) of digoxin was increased by 40-60%, no differences being found as regards the elimination clearance. Also, joint administration of both drugs led to a reduction in digoxin concentrations in the heart (p<0.01) at the end of the dosage regimen. Both sets of results point to the hypothesis of a hitherto unreported possible pharmacokinetic interaction between the two drugs affecting the distribution process. This interaction could lead to lower plasma digoxin levels, in view of the increased Vd, and a possible reduction in the therapeutic effect, owing to the decrease in affinity and in concentration in heart tissue.