Dose-Dependent Solubility–Permeability Interplay for Poorly Soluble Drugs under Non-Sink Conditions

We investigated the solubility–permeability interplay using a solubilizer additive under non-sink conditions. Sodium lauryl sulfate (SLS) was used as a solubilizer additive. The solubility and permeability of two poorly soluble drugs at various doses, with or without SLS, were evaluated by flux measurements. The total permeated amount of griseofulvin, which has high permeability, increased by the addition of SLS. On the other hand, triamcinolone, which has low permeability, showed an almost constant rate of permeation regardless of the SLS addition. The total permeated amount of griseofulvin increased by about 20–30% when the dose amount exceeded its solubility, whereas its concentration in the donor chamber remained almost constant. However, the total permeated amount of triamcinolone was almost constant regardless of dose amount. These results suggest that the permeability of the unstirred water layer (UWL) may be affected by SLS and solid drugs for high-permeable drugs. The effect of solid drugs could be explained by a reduction in the apparent UWL thickness. For the appropriate evaluation of absorption, it would be essential to consider these effects.

Morphofunctional characteristic of the unstirred water layer intestinal epithelium and its role in absorption/bioavailability of drugs (literature review)

The aim of the article – analysis of the main morphological and functional characteristics of intestine epithelium unstirred water layer (UWL) and its role in molecular mechanisms of absorption/bioavailability of orally administered drugs. The method of UWL thickness determination based on effective permeability (Peff) values under various speed of intestinal perfusion flow as well as this indicator importance for solutions absorption determination there was also discussed the process of drugs is discussed absorption in the gastrointestinal tract which is provided by such physical processes as passive diffusion, facilitated diffusion and active transport, involving the UWL, membranes and endothelial tight junctions. The diffusion of small molecules to the cytoplasm is a rather fast process, thus passive transcellular permeability is determined by only the intestinal apical membrane diffusion. The mechanisms of transcellular and paracellular drugs transport in the intestinal epithelium are described. The possible molecular mechanisms of drugs molecules permeability by facilitated diffusion without energy consumption with channel formers and transfer proteins are discussed. The attention was to the active transport process through the enterocyte membrane with the help of transporters against the concentration gradient which is fulfilled with energy consumption due to ATP or other energy supplies. The classification of such transporters is given based an the transport direction (inside the cell – influx, or out off the cell – efflux) and regarding the organic substance transferred. The role of enterocyte enzymatic system CYP3A4 in drugs metabolism processes regulation is mentioned, which can influence their bioavailability. Key words: drugs, absorption, intestine epithelium, unstirred water layer, entherocyte, transcellular transport, intercellular transport

Unstirred Water Layer Effects on Biodegradable Microspheres

This study explores the mechanistic aspects of in vitro release from biodegradable microspheres with the objective of understanding the effect of the unstirred water layer on polymer degradation and drug release. In vitro drug release experiments on Leuprolide PLGA microspheres were performed under “static” and “continuous” agitation conditions using the “sample and separate” method. At specified time intervals, polymer degradation, mass loss, and drug release were assessed. While molecular weight and molecular number profiles for “static” and “continuous” samples were indistinct, mass loss occurred at a faster rate in “continuous” samples than under “static” conditions. In vitro results describe a fourfold difference in drug release rates between the “continuous” and “static” samples, ascribed to the acceleration of various processes governing release, including elimination of the boundary layer. The findings were confirmed by the fourfold increase in drug release rate when “static” samples were subjected to “continuous” agitation after 11 days. A schema was proposed to describe the complex in vitro release process from biodegradable polymer-drug dosage forms. These experiments highlight the manner in which the unstirred water layer influences drug release from biodegradable microspheres and stress the importance of selecting appropriate conditions for agitation during an in vitro release study.