Intestinal Transit And Lipolysis Of Lipid Formulations - Absorption Model

Lipid formulations may include triglycerides,mono and diglycerides,lipophilic surfactants,hydrophilic surfactants and cosolvents.A classification system is introduced to help identify the critical performance characteristics of lipid systems,such as,TypeⅠ,TypeⅡ,TypeⅢA,TypeⅢB,TypeⅣlipid formulations which have been shown to enhance the oral bioavailability of various poorly water-soluble.The colloidal species that are formed by dispersion and digestion of the formulation together with the species produced by incorporation of lipid digestion products into endogenous solubilising species including BS, PL and Ch mixed micelles reflect the solubilisation capacity of the intestine digestion,which can easily transferred the drug into the aqueous phase. In this case, the intestine digestion plays a key role in the distribution and absorption of the lipid formulationsTo indomethacin as a model drug,in vitro lipolysis model can be carried out as an in vitro test using a pH-stat to maintain pH,using the lipase-colipase content of porcine pancreatin to serve as model for human pancreatic juice and providing a sink for solubilization of degradation products by being added the bile salt-lecithin mixed micelles to the reaction mixture,which can be used to simulate the physiological environment of intestinal; The influence of intestinal digestion on the drug molecular state of the lipid formulations(TypeⅠ,TypeⅡ,TypeⅢA,TypeⅢB,TypeⅣ) could be studied; Having been used the conductivity meter and the optical microscopy during the intestinal digestion process, the influence of intestinal digestion on the micromorphology of the lipid formulations and the drug molecular state correlation with the micromorphology has be also investigated; based on the characteristics of the lipid formulations,Having been used the grey relational analysis and the Box-Behnken response surface design,an optimizal new lipolysis-absorption model can be established and the the parameters of the model was be analyzed;The screened lipid formulations through conventional methods(pseudo-ternary phase diagram, solubility, self-emulsifying performance and size)has been also evaluated by this new lipolysis-absorption model;To the pharmacokinetics of the lipid formulations as the parameters in vivo,to the absorption datas from the lipolysis-absorption model or the classical everted gut sac method as the parameters in vitro,the disparation of in vivo-in vitro correlation be investigated by a point to point relatived level method;The correlation among the absorption curve in vitro from the lipolysis-absorption model, the drug molecular state after intestinal digestion and bioavailability of the lipid formulations in vivo could be also researched.The study showed that a more significant solubilization was in the aqueous phase from the lipid formulations than digestion buffer, NaTDC/PC and the lipid formulations dispersed by NaTDC/PC,indicating that intestinal digestion has significant solubilization at fed state or at fasted state. Solubilization of aqueous phase is TypeⅠ>TypeⅡ>TypeⅢA> TypeⅢB>TypeⅣ,while the amounts of drug in the aqueous phase is TypeⅢA> TypeⅣ> TypeⅢB> TypeⅡ>TypeⅠ;In the fast digestion,the rule of lipolysis rate of the lipid formulations is TypeⅠ>TypeⅡTypeⅢA>TypeⅢB>TypeⅣ. There has a inconsistency among the solubilization trend of the aqueous phase to drug,the lipolysis rate and the drug distribution after intestinal digestion, indicating that the higher lipolysis rate and the higher solubilization of aqueous phase are better for drug dissolving,but there are some key factors which can be determined by the difference between the structure and the properties from lipid formulations during the intestinal digestion process,such as the generation and the change of micromorphology.The changes of micromorphology of the lipid formulations during the intestine digestion process has been studied.The conductivity was first increased and then decreased.after that it was increased to the extreme large,and slowly decreases at last(except for Type III A).The suddenly change of conductivity has occurred in the rapid digestion period.in that this phenomenon reflected that there may be a liquid crystal phase in the digestion process.The duration of sudden drop in conductivity during the fast digestion period is TypeⅠ>TypeⅡ>TypeⅢB>TypeIV,while TypeⅢA has not happened the phenomenon of sudden drop in conductivity during the fast digestion period. Furthermore.the duration of the liquid phase in the lipid formulations during the digestion process was was investigated by microscope as TypeⅠ>TypeⅡ>TypeⅢB>TypeⅣ,showing that there is a strong evidence on the conductivity datas.The study also found that the duration of the liquid crystal phase that generated from the digestion process is inversely proportional to the amounts of drug in the aqueous phase,indicating that the production of liquid crystal phase during the intestinal digestion may prevents the drug distributing into the aqueous phase.A new lipolysis-absorption model was successfully established and optimized.and the intestinal tissue culture medium(at fasted state) are Trizma mealate 50 mM,NaCl 150 mM,PC 1.25 mM,NaTDC 5 mM,K+ 3.7 mM,Ca2+ 5 mM,D-glucose 12.06mM, Pancreatin 4938.34TBU and pH7.37;The study showed that the changes of pH,D-glucose concentration and pancreatin concentration all have significant effects on the activity of intestinal tissue,while the changes of the Ca2+ concentration and pancreatin concentration have significant effects on the release of fatty acid.From the surface analysis,the increasing of D-glucose concentration could stepped significantly down the decay of the intestinal activity; With the increasing of pH and pancreatin concentration, intestinal activity decay rate is increased at first and then decreased.However, with the increasing of pH and pancreatin concentration, the release of fatty acid from lipid digestion system is increasing.The optimum lipid formulations screened by pseudo-ternary phase diagram, solubility, self-emulsifying performance and size were Labrafac@Lipohile wl1349,Cremophor RH40,Transcutol P=10:67.5:22.5or20:60:20.But the use of a new lipolysis-absorption model to evaluate the prescription, the optimum lipid formulations were Labrafac@Lipohile wl1349,Cremophor RH40,Transcutol P=20:60:20or40:45:15. These differents results from the two evaluation methods,suggesting that the conventional evaluation and screening method of lipid formutaions only investigates the physical properties in vitro,but not exactly reflects the status of drug in vivo.However,this new mode is making up for the inadequacy of conventional methods.and can more accurately evaluate and screen the lipid formutations.The intestinal absorption of the lipid formulations was studied by lipolysis-absorption model,and the cumulative absorption rate at 2hours is TpyeⅢA>TpyeⅣ> TpyeⅢB>TpyeⅡ>TpyeⅠ.This result has a positive correlation with the drug distribution in the aqueous phase and also has a well relevance with the changes of micromorphology during the intestinal digestion process.This indicated that TpyeⅢA is the best for drug distribution and absorption ability to IMC during the intestinal digestion. And there is a close ship between the the changes of micromorphology and drug distribution and absorption during the intestinal digestion process(such as liquid crystal).Furthermore, there has a inconsistency between the absorption datas from classical everted gut sac method and drug distribution datas from the in vitro lipolysis,which reflects the weightiness of intestinal digestion.For the lipid formulations.in vivo-in vitro correlation study of cumulative absorption rate in vitro and absorption percentage in vivo,there was an extremely significant correlation between the cumulative absorption rate in vitro from lipolysis-absorption model(fa) and absorption percentage in vivo(Pa) at fasted state(P<0.01),While there was only a significant correlation between fa and Pa at fed state(P<0.05).However, there was no significant correlation between fa from classical everted gut sac method and Pa.These results demonstrated that there was a significance influence of intestinal digestion on the drug distribution and absorption ability of the lipid formulations.In present work, To indomethacin as a model drug, the intestinal lipolytic behavioral regularities of the lipid formulations were investigated and the intestinal absorptive regularities of the lipid formulations were also successfully studied by a new optimization lipolysis-absorption model,which would be important scientific significance and application value on the development of lipid formulations.In the future, further investigations are necessary to research the influence of different oil-water partition coefficient,pH drugs on the intestinal lipolytic behavior of lipid formulations.and the influence of different structure lipid materials on the changes of the microstructure of lipid formulations during the intestinal digestion process.