Design, Synthesis Of Phospholipids’ Compounds And Their Applications In Establishment Of Drugs Permeation Model

Drug permeation is one of popular research topics in terms of drug development. Caco-2 cellular model is the most commonly used one to evaluate the drug permeation ability in vitro. However, the studies on in vitro un-cellular model remain limited. The Parallel Artificial Membrane Permeability (PAMPA) model, an in vitro phospholipids membrane drug permeation model, was first introduced by Kansy et al. In 1998, which provided a novel method for testing drug permeation ability. Due to its obvious advantages such as fast, convenient and low cost, PAMPA model aroused lots of interestes of researchers, different PAMPA models were produced in the last decade.So far, most of compounds used in these PAMPA models, however, are either natural phospholipids’compounds or those extracted from tissue cells Different from those work, artifical phospholipids compounds and their phospholipids membranes were prepared in this thesis. The pemeation rule of drugs on different synthetic phospholipids membranes was studied, the chemical morphous of phospholipids membranes was characterized and the impact of outer operating conditions, such as pemeation time and pH gradient, on drug permeation was also evqluqted. The main obtained results were outlined as follows,1. A series of different chemical structural phospholipids compounds was synthesized. The chemical structures of both these compounds and their precurosors were supported by IR, NMR, MS, and elemental analysis.2. The phospholipids membranes were prepared via self-assembling these synthetic compounds onto hydrophobic supported materials under saturated humidity and at room temperature. Water contact angle analysis showed that the surface of phospholipids membranes displayed good hydrophilicity; SEM study indicated that the surface of three phospholipids membranes were more integrated and a layer continuous phospholipids membranes were observed on the surface of hydrophobic supported material from the transverse section of membranes; AFM showed that the membrane surface were composed by many bilayers of phospholipids, instead of only one bilayer; DSC manifected that three phospholipids membrane had very low Tc temperature and showed curmbly mobile phase under the experimental condition. In conclusion, the chemical morphous of three phospholipids membrane with different length of carbon chain prepared in this thesis were composed by irregular multilayer phospholipids qnd the surface of these membranes were uneven and hydrophilic.3. Fifteen model drugs were chosen for testing the impact of time on drug permeation in different artificial phospholipids membranes. The results showed that the effective permeation rate (Pe) first rised with the permeation time, and then droped down slowly after the max value; but the residual drug coefficient first decreased, and then increased after the mix value. The length of hydrophoblic carbon chain of phospholipids affected the drug permeation, although limited. Compared with Fa, those artificial phospholipids membranes have good correlation on passive permeation drugs.4. Fifteen model drugs were chosen for testing the impact of pH gradient on drug permeation in different artificial phospholipids membranes. The study showed that Pe was dependent on pKa. As far as mono-weak acid electrolytes drugs is concerned, when pH<pKa, Pe maintained invariably; when pH>pKa, Pe decreased with the increase of pH. As for mono-weak base electrolytes drugs, it was just opposite, when pH<pKa, Pe increased with the increasing of pH; when pH>pKa, Pe was constant. As tp multi-electrolytes drugs, it behaved depending on different pKa values. Moreover, the length of carbon chain had little effect on drug permeation within different pH gradient.The drug permeation model established in this thesis may have the potential to predict drug permeation ability in earlier phase of drug development, to evaluate many non-ideal drugs, to cut down the cost of drug development, and therefore, in a sense, it is important to new drug research.