Development And Mechanism Of In Vitro Release Measurement Of Lipid Drug Delivery Preparation

The lipid drug delivery preparations were widely applied to anesthesia and cancer therapy because of advantages of increasing lipophilic drug solubility and stability,decreasing adverse drug reaction.The lipid drug delivery preparations,especially lipid complex injection,consist of multiple functional pharmaceutical excipients.Thus,it was lack of the studies and standards about in vitro release measurement in pharmacopeia,in vitro-in vivo cocorrelation assessment method and drug release mechanism studies.Compared with oral solid preparations and general injections,the consistency evaluation of lipid preparations represented by lipid emulsions and liposome faced huge challenges.This paper had conducted a series of research on development of in vitro release measurement for propofol emulsions and liposome with different formulations and technologies,and proposed a novel method,resin adsorption method,for determining in vitro release rate.Compared to dialysis techniques and centrifugalization,the resin adsorption method was able to quickly separate free drugs,reduce the measurement time and cost,and can better distinguish propofol fat emulsions or liposome with different formulations and technologies.And the physical model was establish for simulating their release behavior.The main research contents of this thesis are as follows:1.Due to the high lipophilicity,volatility and easy oxidation of propofol,dialysis techniques by using conventional release mediums(PBS solution,SDS PBS solution,glycerin PBS solution)could not determine the in vitro release rate of propofol emulsion.While the positive dialysis could distinguish the release profiles of different formulations and technologies emulsions by using 50% ethanol as release medium.Decreasing the oil content or increasing homogeneous times would accelerate the propofol emulsion release rate,but whether propofol emulsion was flushed into nitrogen had no effect on in vitro release profile.2.Ultrafiltration centrifugation method could not completely separate free propofol due to the adsorption of emulsion to free propofol.Thus,it was not suitable for measuring the propofol emulsion in vitro release rate.Then the microcolumn centrifugation method was studied.For the microcolumn centrifugation method,the adsorption capacity of macroporous resin was too strong which resulted in the macroporous resin adsorbed the propofolencapsulated in the emulsion and caused error.So the microcolumn centrifugation method was not suitable for determining the release rate of propofol fat emulsion.3.Two online monitoring methods,turbidity method and pH colorimetry,were studied.For turbidity method,the propofol fat emulsion dilution time was effect the release profile,while the propofol content had no effect on the release profile.Turbidity method was not reproducible due to the large fluctuation of release rates data.pH colorimetry was not suitable for determining the in vitro release rate of propofol fat emulsion because propofol was a weak acid which could not change the pH of the release medium.4.The emulsion release rate was determined by resin adsorption.The agitation speed,AB-8 resin content,the soybean oil content and particle size of emulsion would effect the propofol emulsion in vitro release profile.The amount of 4w /v% AB-8 macroporous resin was suitable to determined in vitro propofol emulsion release rate.Increasing the amount of soybean oil content of emulsion or reducing the particle size will accelerate the release process.However,the propofol content of emulsion had little effect on the release profile.Thus,the resin adsorption could be used to distinguish the release profile of different formulations and technologies emulsions.In this paper,the physical model of in vitro release of resin adsorption method was established,and the factors affecting the in vitro release rate of propofol fat emulsion were stirring angular velocity,propofol adsorption constant,propofol oil-water partition coefficient and resin maximum adsorption propofol concentration.5.It was investigated whether the resin adsorption method was suitable for liposome.The liposoluble MD and water-soluble OMT were selected as drug models.The HSPC liposome and sodium alginate and chitosan layer self-assembled liposome had a significant sustained release effect.There was no differences between in vitro release rates of liposome coated with different concentrations PEG,while the PEG increased the liposome particle size.Compared with the positive dialysis and reverse dialysis,the resin adsorption method had a faster rate of separating the free drug and the liposome,and the release rate was higher at the equilibrium.The resin adsorption method had a great applicability when the MD concentration in release medium was over the MD sink condition.A physical model of liposome in vitro release was established,and the theoretical liposome release rate was simulated and error of resin adsorption method were corrected.In addition,the in vitro release of oxymatrine liposome showed that the resin adsorption method had good applicability for the water-soluble alkaloids,and the release rate was slower than MD-HSPC liposome.Therefore,the resin adsorption method was a simpler and more accurate method for determining the in vitro release rate of emulsion and liposome than the dialysis method.