Study On The Rebamipide Nanopreparations And The Mucosa Protective Effects

Rebamipide (REB) is a gastric mucosa protectant with the effect of improving mucoprotective and mucosa healing quality. It is classified as a Biopharmaceutics Classification System (BCS) Class-IV compound with poor aqueous solubility and poor permeability, but the local concentration in the mucosa makes REB exhibiting the therapeutic activities. So the strategy of increasing the dissolution rate has the possibility to improve the oral gastrointestinal (GI) distribution. The purpose of this work was to prepare two different nano preparations. The nanosuspensions can directly improve its solubility in the gastrointestinal tract and increase the local drug level, and the microemulsions can be used to protect the mucosa damage caused by microemulsions containing large amount of emulsifying agents after long term administration.Two kind of in vitro analysis methods, HPLC and UV methods were developed to determine the concentration of REB. Both of the methods were proved accurate and reliable; The solubility and the oil-water distribution coefficient of REB in different media were determined, and the results showed that the solubility and the distribution coefficient were pH dependent in aqueous media while in organic media, the solubility of REB were poor; The compatibility between REB and excipients (Kollidon 90F and Lutrol F127) in alkaline solution was investigeted, and the result showed that good compatibility between the drug and the adjuvants could meet the requirement of preparation at room temperature.The feasibility of using acid-base neutralization and microfiuidization to prepare REB-NSs was studied, and the preparation was optimized by central composite design (CCD), while the physical states were characterized by using some technical methods. The experimental results identified a formulation with 10 mg/mL REB,0.9%(w/v) Lutrol F127, and 0.6%(w/v) Kollidon 90F. Further, the nanoparticles were observed sphere like by TEM, and the mean particle size and zeta potential were determined to be 80.4±3.9 nm and-12±1.75 mV respectively while 82.5±3.2 nm and-10±1.25 mV after lyophilized; DSC and X-ray diffraction revealed that REB was crystallized with a little amorphous state in the preparations and the dissolution rate of the REB-NSs were faster than that of Mucosta(?) tablets in different media which proved that nanosuspensions could increase the dissolution rate.We established HPLC method to determine the biological specimens, and the oral pharmacokinetic and gastric distribution were studied. A slight increase (1.24 fold and 1.01 fold) in the AUCo-12h compared with REB-CSs and solutions were reported. Also, the GI distribution of REB-NSs was improved compared with REB-CSs. This would be preferable to assist in protecting GI mucosa.A gastrelcoma animal model induced by ethanol was established and the effects on preventing and treating stomach ulcer were systemicall researched. Pathology results confirmed that the high levels of alcohol could cause acute gastric mucosa damage, and showed that REB had superior mucosa repair effect, but the prevention effect was not apparent. Also, the treating effects of REB-NSs were better than REB-CSs on comprehensive considering of the level of UI, NO and PGE2. This indicated that REB-NSs could improve NO, and PGE2 level so as to achieve the purpose of the treatment of gastric mucosa damage induced by alcohol.A preparing method applicating saponification was developed to prepare REB microemulsion. Through preparing pseudo-ternary phase diagram, Cremophor RH40 was regarded as the nonionic emulsifier. Aethylis oleas, glycerin monostearate, Gelucire 44/14, Gelucire 50/13, and Plurol oleique CC497 were considered as ester phase or auxiliary emulsifier. The test investigated drug loadings, alkali liquor consumption, shear strength, stirring speed and the order that REB joined to determine the final preparation process and the folmulation. After continuously intragastric administrating blank microemulsion and REB microemulsion for 10 days, different mucosa damage occurred. For blank preparation, the damage presented lymphocyte infiltration while for REB preparation the mucosa cells was only a little edematous, this result indicated that REB could alleviate gastric mucosa damage, but colud not eliminate the damage effect induced by surfactants.