An emerging terpolymeric nanoparticle pore former as an internal recrystallization inhibitor of celecoxib in controlled release amorphous solid dispersion beads:Experimental studies and molecular dynamics analysis  

作　　者：Jamie Anne Lugtu-Pe Xuning Zhang Sako Mirzaie Hao Han R.Chang Nour AL-Mousawi Kuan Chen Yongqiang Li Anil Kane Daniel Bar-Shalom Xiao Yu Wu 

机构地区：[1]Advanced Pharmaceutics and Drug Delivery Laboratory,Leslie Dan Faculty of Pharmacy,University of Toronto,Toronto M5S 3M2,Canada [2]Candoo Pharmatech Company Inc.,Mississauga L5N 5M1,Canada [3]Department of Pharmacy,University of Copenhagen,Copenhagen DK-2100,Denmark [4]Patheon by Thermo Fisher Scientific,Toronto Region Operations(TRO),Mississauga L5N 3X4,Canada

出　　处：《Acta Pharmaceutica Sinica B》2024年第6期2669-2684,共16页药学学报（英文版）

基　　金：supported in part by an Ontario Research Fund-Research Excellence(ORF-RE)grant(Ontario,Canada)in partnership with Patheon by Thermo Fisher Scientific,Natural Sciences and Engineering Research Council(NSERC)of Canada Discovery Grant and Equipment Grants to Xiao Yu Wu,University of Toronto(Canada),Leslie Dan Faculty of Pharmacy Dean's Fund to Jamie Anne Lugtu-Pe,University of Toronto(Canada),Mitacs Accelerate Internship sponsored by Candoo Pharmatech Company Inc.to Xuning Zhang(Canada),NSERC CREATE ContRoL program support to Sako Mirzaie and Hao Han R.Chang(Canada),Ontario Graduate Scholarship(OGS)to Hao Han R.Chang(Canada),and Pharmaceutical Sciences graduate department scholarships to Hao Han R.Chang and Kuan Chen,University of Toronto(Canada).

摘　　要：Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution rate.However,most new chemical entities exhibit poor water solubility,and hence are exempt from such benefits.Although combining drug amorphization with controlled release formulation is promising to elevate drug solubility,like other supersaturating systems,the problem of drug recrystallization has yet to be resolved,particularly within the dosage form.Here,we explored the potential of an emerging,non-leachable terpolymer nanoparticle(TPN)pore former as an internal recrystallization inhibitor within controlled release amorphous solid dispersion(CRASD)beads comprising a poorly soluble drug(celecoxib)reservoir and insoluble polymer(ethylcellulose)membrane.Compared to conventional pore former,polyvinylpyrrolidone(PVP),TPN-containing membranes exhibited superior structural integrity,less crystal formation at the CRASD bead surface,and greater extent of celecoxib release.All-atom molecular dynamics analyses revealed that in the presence of TPN,intra-molecular bonding,crystal formation tendency,diffusion coefficient,and molecular flexibility of celecoxib were reduced,while intermolecular H-bonding was increased as compared to PVP.This work suggests that selection of a pore former that promotes prolonged molecular separation within a nanoporous controlled release membrane structure may serve as an effective strategy to enhance amorphicity preservation inside CRASD.

关 键 词：Controlled release amorphous solid dispersion Poorly soluble drug Internal recrystallization Membrane-reservoir coated beads Molecular dynamics simulation Effect of pore formers Terpolymer nanogel Drug-polymer interactions 

分 类 号：R943[医药卫生—药剂学]