Amorphous solid dispersion(ASD)is one of the most effective approaches for delivering poorly soluble drugs.In ASDs,polymeric materials serve as the carriers in which the drugs are dispersed at the molecular level.To p...Amorphous solid dispersion(ASD)is one of the most effective approaches for delivering poorly soluble drugs.In ASDs,polymeric materials serve as the carriers in which the drugs are dispersed at the molecular level.To prepare the solid dispersions,there are many polymers with various physicochemical and thermochemical characteristics available for use in ASD formulations.Polymer selection is of great importance because it influences the stability,solubility and dissolution rates,manufacturing process,and bioavailability of the ASD.This review article provides a comprehensive overview of ASDs from the perspectives of physicochemical characteristics of polymers,formulation designs and preparation methods.Furthermore,considerations of safety and regulatory requirements along with the studies recommended for characterizing and evaluating polymeric carriers are briefly discussed.展开更多
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 he...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.展开更多
Amorphous solid dispersions(ASDs)are popular for enhancing the solubility and bioavailability of poorly water-soluble drugs.Various approaches have been employed to produce ASDs and novel techniques are emerging.This ...Amorphous solid dispersions(ASDs)are popular for enhancing the solubility and bioavailability of poorly water-soluble drugs.Various approaches have been employed to produce ASDs and novel techniques are emerging.This review provides an updated overview of manufacturing techniques for preparing ASDs.As physical stability is a critical quality attribute for ASD,the impact of formulation,equipment,and process variables,together with the downstream processing on physical stability of ASDs have been discussed.Selection strategies are proposed to identify suitable manufacturing methods,which may aid in the development of ASDs with satisfactory physical stability.展开更多
Water-insoluble materials containing amorphous solid dispersions(ASD)are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs.ASDs bas...Water-insoluble materials containing amorphous solid dispersions(ASD)are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs.ASDs based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers.For example,solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate)(PHEMA)can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble polymers.The creation of both immediate-and controlled-release ASD dosage forms is also achievable with the PHEMA based hydrogels.So far,ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability.This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers,and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.展开更多
基金the National Natural Science Foundation of China(No.81872813,22108313,82273880)Natural Science Foundation of Jiangsu Province(No.BK 20200573,BK 20200576)+1 种基金Fundamental Research Funds for the Central Universities(No 2632022ZD16)the Scientific Research Fund of Hunan Provincial Education Department(No.22B0820).
文摘Amorphous solid dispersion(ASD)is one of the most effective approaches for delivering poorly soluble drugs.In ASDs,polymeric materials serve as the carriers in which the drugs are dispersed at the molecular level.To prepare the solid dispersions,there are many polymers with various physicochemical and thermochemical characteristics available for use in ASD formulations.Polymer selection is of great importance because it influences the stability,solubility and dissolution rates,manufacturing process,and bioavailability of the ASD.This review article provides a comprehensive overview of ASDs from the perspectives of physicochemical characteristics of polymers,formulation designs and preparation methods.Furthermore,considerations of safety and regulatory requirements along with the studies recommended for characterizing and evaluating polymeric carriers are briefly discussed.
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).
文摘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.
基金supported,in whole or in part,by the Bill&Melinda Gates Foundation[No.OPP1159809,USA]supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award(No.R01AI132681,USA)
文摘Amorphous solid dispersions(ASDs)are popular for enhancing the solubility and bioavailability of poorly water-soluble drugs.Various approaches have been employed to produce ASDs and novel techniques are emerging.This review provides an updated overview of manufacturing techniques for preparing ASDs.As physical stability is a critical quality attribute for ASD,the impact of formulation,equipment,and process variables,together with the downstream processing on physical stability of ASDs have been discussed.Selection strategies are proposed to identify suitable manufacturing methods,which may aid in the development of ASDs with satisfactory physical stability.
基金This work was supported in part by funding from the Natural Sciences and Engineering Research Council of Canada(NSERC).D.D.S.was also supported by a University of Toronto Fellowship Award.
文摘Water-insoluble materials containing amorphous solid dispersions(ASD)are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs.ASDs based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers.For example,solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate)(PHEMA)can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble polymers.The creation of both immediate-and controlled-release ASD dosage forms is also achievable with the PHEMA based hydrogels.So far,ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability.This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers,and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.
