Study Of MPEG-b-PCL-b-PAA/PMAA Micelles For Oral Administration

Polymeric micelles are thermodynamically stable system formed by amphiphilic polymer.They can increase the solubility of water-insoluble drugs,enhance drug's permeability through biomembrane,and strengthen drug efficacy.Because of the various composition and properties of polymers,polymeric micelles with pH-or thermo-sensitivity as well as mucosa adhesion have appeared.These functionalized micelles can change the release profile of drugs in gastrointestinal tract and enhance the bioavailability.Both of polyethylene glycol and polycaprolactone are FDA approved polymers with biocompatibility,and PCL can be degraded in organism.Among many amphiphilic polymers,mPEG-b-PCL has been researched widely and deeply.A new type of mPEG-b-PCL with pH sensitive groups was synthesized in this paper.Polyacrylic acid and polymethylacrylic acid were polymerized at the terminal of PCL block of mPEG-b-PCL to produce a tri-block polymer mPEG-b-PCL-b-PAA/PMAA.Based on the solubilizing ability of mPEG-b-PCL and pH sensitivity of PAA/PMAA,mPEG-b-PCL-b-PAA/PMAA micelles were studied as carriers of water-insoluble drugs for oral administration.Ring opening polymerization method was employed to synthesize mPEG-b-PCL,and the characterization was carried out by GPC,qH NMR and FT-IR.Eight mPEG-b-PCLs with different length of hydrophilic and hydrophobic blocks were obtained by changing the feed ratio of mPEG and ?-CL.Drug loading ability of mPEG-b-PCL micelles was studied using nifedipine as the model drug.The results showed that mPEG114 based polymeric micelles have greater drug content than mPEG45 based.And with the same hydrophilic block,on increasing the length of the hydrophobic block,drug-loading content increased initially but then decreased,peaking at mPEG:?-CL=5:7(w:w).After all,four mPEG-b-PCLs synthesized by feed ratio of 5:5 and 5:7(w:w)(mPEG:?-CL)were chosen to be polymerized with t-BA and t-BMA by atom transfer radical polymerization(ATRP).The successful synthesis of mPEG-b-PCL-b-PAA/PMAA was approved by the results of GPC,1H NMR and FT-IR.To study the drug loading ability of mPEG-b-PCL-b-PAA/PMAA,four water-insoluble drugs were loaded.The maximun drug loading content for nifedipine,fenobrate,itraconazole and paclitaxel was 3.43%,6.07%,0.21%and 0.93%,respectively.Based on the experiment results,molecular dynamics simulation and docking calculation were combined to study drug-polymer interactions.Binding energy between drug and polymeric assembly,type of hydrophobic block in polymer,size of drug molecular,nature of drugs' surface,logP value of drug as well as distribution of binding sites were discussed to discover the mechanism of drug loading of polymeric micelles and analyze the factors impacting drug loading content.We hope it can provide a foundation to quantitative design and research of polymeric micelles as drug carriers.As a result,between the same drug and different polymers,the higher the binding energy,the higher the drug loading content for the polymer.Furthermore,for the model drugs,high hydrophobic value,small molecular volume and lipophilic surface may help them loading into micelles.Additionally,separated distribution of binding sites of drug in polymers is also good for drug loading content.The in vitro drug release of nifedipine from mPEG-b-PCL-b-PAA/PMAA micelles was studied in different PBS with series of pH values.In PBS pH 7.4,about 90%of drug released within 4 hrs from mPEG-b-PCL-b-PAA/PMAA micelles while only 60%released from mPEG-b-PCL micelles.Besides,the size of mPEG-b-PCL-b-PAA/PMAA micelles also increased as pH value increased.It can be proved that due to the introduction of PAA/PMAA,mPEG-b-PCL-b-PAA/PMAA micelles exhibited pH sensitivity to some extent.Everted gut sac model was employed to study the in vitro transportation and mucosa adhesion of nifedipine mPEG-b-PCL-b-PAA/PMAA micelles.The transfer quantity of micelles is higher than nifedipine tablets,and mPEG-b-PCL-b-PAA/PMAA micelles exhibited obvious adhesion in mucosa of intestine.The pharmacokinetics of nifedipine in mPEG114-b-PCL44-b,PMAA27 and mPEG114-b-PCL61-b-PAA27 micelles was studied in Wistar rats,and the results were compared with nifedipine tablets.AUC(0-12h)and Cmax of micelles have statistical significance improvement compared with those of tablets.The relative bioavailabilities of mPEG114-b-PCL44-b-PMAA27 and mPEG114-b-PCL61-b-PAA27 were 296%and 287%,respectively.Compared with bi-block polymeric micelles,AUC(0-12h),Tmax and t1/2z of mPEG-b-PCL-b-PAA/PMAA nifedipine micelles all increased to a certain degree,but there was not statistic significant.mPEG-b-PCL-b-PAA/PMAA micelles can improve the solubility of water-insoluble drug in gastrointestinal tract,and drug can be accumulated in mucosa because of adhesion brought by PAA/PMAA.And it is helpful for absorption of drug.Our study suggested that polymeric micelles can be used as a promising carrier in oral administration for water-insoluble drugs.