Katsuyoshi Aikawa

Drug release from pH-response polyvinylacetal diethylaminoacetate hydrogel, and application to nasal delivery

Abstract Nasal formulations of polyvinylacetal diethylaminoacetate (AEA) were prepared and the effect of AEA concentration on drug release was evaluated in in vitro and in vivo experiments. The profiles of release of drug from dialysis tubes had both a rapid and a slow phase, and had an inflection point, at which AEA hydrogel formation appeared to occur. The higher the AEA concentration, the lower the rate of drug release observed. The apparent disappearance rate constant ( k app ) of drug was determined by the deposit method, which estimates changes in the amount of residual drug in the nasal cavity with the lavage technique following administration. Drug k app values decreased with increase in AEA concentration. Hydrogel formation on mucous membranes was also visually confirmed in rat nasal cavity. AEA preparations which facilitate instillation into the nose but which form hydrogel on the mucous membrane are potentially useful for controlled-release nasal delivery systems.

Hydrogel formation of the pH response polymer polyvinylacetal diethylaminoacetate (AEA)

The effects of pH and temperature on hydrogel formation of polyvinylacetal diethylaminoacetate (AEA) and drug release were examined. When a dialysis tube containing AEA dissolved in pH 4 solution was immersed in phosphate buffer pH 7.4 at 37°C, AEA hydrogel was formed inside the tube and drug release became slow. Various porous structures in the inner region of hydrogel were observed by Scanning Electron Microscopy. The effects of temperature change on lattice distance of hydrogel were determined by dynamic light scattering. The average pore size of AEA hydrogel was also determined by the release of FITC-dextrans of various molecular weights from AEA hydrogel. AEA solution with low viscosity at pH 4 but which form hydrogel at neutral pH condition has the potential for use in controlled release of drugs applied to physiological membranes.

The Effect of Hyperosmosis on Paracellular Permeability in Caco-2 Cell Monolayers

The intestinal epithelium is a significant barrier to oral absorption of hydrophilic compounds, and their passage through the intercellular space is restricted by the tight junctions. In this study we found that hyperosmosis is a significant factor altering paracellular transport in Caco-2 cell monolayers. Osmotic regulators, such as sodium chloride, mannitol, and raffinose, decreased transepithelial electrical resistance and enhanced lucifer yellow permeability. The effect of these osmotic regulators on Caco-2 cell monolayers was not likely to be caused by gross cytotoxicity. Although certain amino acids and oligosaccharides have been reported to have specific tight junction-modulating activity, we found that the increased paracellular permeability of Caco-2 monolayers induced by these compounds was at least partly due to the increased osmotic pressure of the test solutions. These findings provide a new potential precaution in the evaluation of paracellular permeability-modulating substances using the Caco-2 cell monolayer system.

Prolonged Release of Drug from O/W Emulsion and Residence in Rat Nasal Cavity

The present study evaluated the usefulness of an o/w emulsion for slowing the release of chlorpheniramine maleate (CM) and prolonging drug residence in the nasal cavity. O/w emulsion formulations of medium chain triglycerides (MCT) were prepared, and their physicochemical properties and drug release kinetics were evaluated using the in vitro dialysis tube method. Drug disappearance from the rat nasal cavity was determined in in situ nasal experiments. CM partitioned in oil droplets by pH, as predicted by pH partition theory. With higher MCT concentration and pH, slower release of CM was observed. CM disappearance (kapp) from the rat nasal cavity was influenced by the amount of drug partitioned in the oil droplets with both the perfusion and deposit methods, and the kapp of CM decreased with increase in MCT concentration and pH. Moreover, with the deposit method, CM remaining in the nasal cavity exhibited a biphasic profile of disappearance, which complied with a saturated process. Because a very small portion of MCT might be adsorbed and formed a pseudooily layer on the mucous membranes, prolongation of CM residence on the mucous membrane was attained. These findings suggest that emulsion containing 30% MCT at pH 8 may be useful for inclusion in controlled-release formulations of CM for intranasal drug delivery in the treatment of allergy.