蘭索拉唑微粒及奈米粒緩釋劑型之設計及評估

Abstract

Lansoprazole (LPZ) is acid-labile and water insoluble drug used in the treatment of acid related disorders such as gastro-esophageal reflux disease (GERD). However, due to its short plasma half life, lansoprazole can not control a night-time (nocturnal) acidity especially in the case of GERD where the secretory activity of proton pump returns. My dissertation was aimed to develop sustained-release microparticles and nanoparticles to ameliorate the nocturnal acid breakthrough event while being administered on a once daily basis. In the first part of the study, LPZ loaded Eudragit RS100 microparticles were prepared using a solvent emulsion-evaporation method, and further enteric coated with HPMCP and Eudragit S100 by the spray drying method. The investigated enteric microparticles showed an excellent acid resistance. The rate of drug release was significantly delayed by an enteric-coated microparticles than a commercial extended release capsule (RICHR). The developed enteric-coated microparticles were capable of maintaining a constant plasma level of LPZ up to 24 h with a linear in vitro-in vivo correlation and promoted an ulcer healing activity in Wistar rats. In the second part of the study, LPZ loaded Eudragit RS100 nanoparticles (ERSNPs-LPZ) and PLGA nanoparticles (PLGANPs-LPZ) were formulated by solvent evaporation technique using probe sonication. The prepared nanoparticles showed sustained drug release up to 24 h. The LPZ transported across Caco-2 cell monolayers was significantly improved by positively charged nanoparticles (ERSNPs-LPZ) than negatively charged nanoparticles (PLGANPs-LPZ) while PLGANPs-LPZ improved LPZ transport in the presence of permeation enhancer. Similar results were observed with the fluorescent nanoparticles in the cellular uptake study. Confocal microscopic images of Caco-2 cell monolayers demonstrated nanoparticles localization in cytoplasm. The correlation between in vitro LPZ release and LPZ transported across Caco-2 cell monolayers suggested that drug absorption via nanoparticles was mainly controlled by drug release rate and extent of nanoparticles absorbed by Caco-2 cells. In vivo biodistribution study demonstrated that the total amount of positively charged fluorescent nanoparticles adhered to the ulcerated and non-ulcerated regions were higher than negatively charged fluorescent nanoparticles. Oral administration of non-enteric and enteric-coated capsule containing LPZ-loaded nanoparticles showed extended LPZ release up to 24 h which was linearly correlated to LPZ transported across a Caco-2 cell monolayer and promoted an ulcer healing activity in Wistar rats. There was no significant difference in the bioavailability of non-enteric and enteric coated nanoparticles formulations and nanoparticles showed higher bioavailability compared to enteric microparticles. Finally, non-enteric and enteric-coated capsules containing ERSNPs-LPZ were found to be the most efficacious formulations in the treatment of GERD especially to control nocturnal acid breakthrough.