The Preparation And Pharmacokinetic Studies Of Paclitaxel Nanosuspension

Improving indissolvable drugs into druggability was a major problem in pharmaceutics.Number of approaches were available for addressing the issues of low aqueous solubility currently.such as,the synthesis of water soluble prodrugs,adding solvents or surfactants,medicine micronizing,drug dispersion incarrier,package and microemulsion technologies,et al.But theses technologies were not applicable to all the drugs.Nanosuspension were defined as unique liquid submicron colloidal dispersions of nanosized pure drug particles that were stabilized by a suitable polymer or surfactant.Nanosuspension can improve the druggability of insoluble drugs by improving the solubility,chemical stability and reducing the use of additives,which provided a new approach for the development and application of the insoluble drugs formulation.Insoluble drugs paclitaxel,the model drug in this research,was made into PTX-Nanos,using polyamino acid as stabilizer which had a good biocompatibility.The physicochemical property,pharmacokinetics and tissue distribution in vivo were studied.In this research,we prepared a good biocompatibility amphiphilic block copolymer poly(L-phenylalanine)-b-poly(L-aspartic acid)(PPA-PAA)as a stabilizer;The preparation methods,preparation process and formulation were studied.The methods of microprecipitation,ultrasonic,microprecipitation combined with high pressure homogenization were used to prepare PTX nanosuspensions.To optimize the best formulations and preparation process,the influences of some factors on particle size and stability of PTX-Nanos were studied,such as stirring speed,homogenization pressure,homogenization times and dosages of stabilizer,drug concentration,theratio of drug and stabilizer.Freeze-drying was used to solidify nanosuspension and effect of the type and usage amount of cryoprotectants on the redispersibility of nanosuspension were explored.Analysis method was developed to determine the concentration of PTX in PTX-Nanos;The pharmaceutical properties of PTX-Nanos were characterized,its physical stability and in vitro dissolution were investigated;The pharmacokinetics study and tissue distribution of PTX-Nanos and commercial injection formulation(PTX-Injection)were researched,evaluating the characteristic of the two formulations in pharmacokinetics.Results showed that PTX-Nanos was manufactured successfully by microprecipitationhigh-pressure homogenization method,using homemade PPA-PAA as stabilizer,TPGS as an auxiliary stabilizer.Agitation speed of stabilizer solution was 1500 rpm,homogeneous pressure was 1000 bar,the cycle of homogeneous was 25 times,drug concentration was 2mg·m L-1,the ratio of PPA-PAA and TPGS was 1:1,the ratio of drug and stabilizer was 2:1.Size of PTX-Nanos was230 nm,polydispersity index(PDI)was less than 0.2,the value of Zeta potential was about 30 m V;5% mannitol was used as protective agent and the appearance of freeze-dried powder prepared by freeze-drying was good.The freeze-dried powder had good redispersibility without a significant change in parameters after redispersion;TEM and SEM images confirmed that PTX-Nanos had a rod-like morphology.Compared with coarse PTX,PTX-Nanos had a uniform distribution and particle size of which reduced significantly.XRD and DSC results showed that crystalline form of drug was changed into amorphous from crystalization after preparation;Stability test showed that there was no significant change in particle size when PTX-Nanos was diluted 200 times or placed a week later at 4℃.The in vitro dissolution rate of PTX from nanosuspensions was significantly increased compared with coarse PTX,which was favorable for the rapid absorption of the drug;The result of pharmacokinetics showed that compared with the PTX-Injection,PTX-Nanos can reduce the time of drug distribution,prolong elimination time and mean residence time,has a certain sustained-release effect.The result of tissue distribution showed that PTX-Nanos was mainly absorbed by liver and spleen,which was very low in heart and kidney,this can reduce the toxicity of drugs in the heart and kidney,which has a certain clinic significance to reduce the toxic and side effects of paclitaxel.