In Vitro Release Model Investigation Of Food Effects On The Oral Drug Bioavailability

Interactions between food and drug may alter the drug therapeutic effects, and result in treatment failures and increased toxicities. Investigation the effects of food to orally administered drugs bioavailability will be of great significance to clinical medication and optimizing pharmaceutical dosage forms, which should also be considered during the development of a new drug.In order to simplify the complicated in vivo assessment, the correlation between in vivo absorption and in vitro dissolution of a drug was studied. The in vitro release condition which is relative to the in vivo absorption can be used to assess the in vivo performance of a drug.In order to use in vitro data in place of in vivo data, gastrointestinal dissolution environment had been simulated, and in vitro dissolution module had also been established recently. However, this kind of study still need develop.In addition, eating habit of eastern and western nations is different; the in vitro dissolution module according to western eating habit may be not suitable in our country where there is still no any dissolution module study about the effect of meal to drugs bioavailability. The aim of this study is to establish dissolution module suitable to our country, and explore the impact of food on the pharmacokinetics of a drug using in vitro-in vivo correlations (IVIVC), these should be of great significance to clinical medication, formulation development and minimizing the number of human studies5required during product development.This study includes the experiments both in vivo and in vitro. In in vivo experiment, Fleroxacin(FXC), gatifloxacin(GTFX) and tosufloxacin(TLFX) were used to get the blood drug level and urine drug level data under fasting and fed conditions. The aim of the experiment in vitro is to establish dissolution modules in vitro, and then the dissolution parameters of the three drugs were obtained after dissolution tests under these modules. All analyses were done statistically on computer. Least square method was used in the statistical disposal to get the IVIVC equations, and then dissolution modules that provide significant relationships between in vitro and in vivo data were selected. Result:1. The experiment in vivo shows that food is unlikely to have a clinically significant effect on the AUC of FXC, GFLX and TFLX tablets, and the extent of bioavailability doesn't alter either, but the absorption of these drugs may be delayed.2. The dissolution module under fasting condition was obtained through the experiment in vitro: tablets were dissolved in 900ml dissolution mediums(3mmol/L NaTC, 0.75 mmol/L PC, 3.9 g /L KH2PO4, 7.7 g /L KC1, pH 6.5 ) at 37 ?0.5 ; Rotation speed of dissolution test system is 50 pm. IVIVC equations of GFLX: /=0.83x - 20.94 r = 0.9895IVIVC equations of TFLX: /=0.79x - 18.21 r = 0.98123. The dissolution module under fed condition was obtained through the experiment in vitro: tablets were dissolved in 900ml dissolution mediums(12mmol/L NaTC, 3.75 mmol/L PC, 8.65 g /L HAc, 15.2 g /L KC1, l00g/L soluble starch, pH 5.0 ) at 37 ?0.5 癈; Rotation speed of dissolution test system is 40 rpm.IVIVC equations of GFLX: /=0.71x - 8.83 r = 0.9975 IVIVC equations of TFLX: /=0.68;c - 3.94 r = 0.99894. There was significant correlation between J/and zlx under fasting and fed conditions. The differences of dissolution rates under the two dissolution modules can reflect in vivo absorption differences of the two drugs under fasting and fed conditions.5. In this study, in vitro modeling of in vivo conditions might help provide a base for predicting in vivo drug behavior, which will be helpful to develop the study of IVIVC.The effects of gastrointestinal digestive and chyme to drug dissolution were simulated in new approaches. Through adjusting rotation speed of dissolution apparatus to simulate gastrointestinal motility, optimal rotation speed was confirmed and new in vitro dissolution modules were established.After comprehensively cons...