Aceclofenac is a new generational Non-Steroidal Anti-Inflammatory Drug (NSAID), and is considered a better alternative to the popular pain-killer diclofenac, as it overcomes some of the adverse gastrointestinal and ca...Aceclofenac is a new generational Non-Steroidal Anti-Inflammatory Drug (NSAID), and is considered a better alternative to the popular pain-killer diclofenac, as it overcomes some of the adverse gastrointestinal and cardiac side effects associated with the latter. However, the bioavailability of the drug remains limited due to low aqueous solubility (0.058 μg/mL) and poor dissolution characteristics. Hence, improving its dissolution characteristics is of prime significance in order to establish its optimal therapeutic efficacy. In an effort to tackle this issue, we report the use of novel Soluplus®-based nanocomposites, prepared from emulsion templates, as effective drug loading agent for aceclofenac. Nanoemulsion templates were prepared by high-shear homogenization using a probe sonicator. The emulsions were subsequently lyophilized to obtain free flowing powders. The amorphization of the drug with increasing polymer content was clearly observed from powder X-ray diffractogram, while the drug-polymer interaction was explored by FTIR spectroscopy. The phase purity and homogeneity of the formulation was characterized using Differential Scanning Calorimetry. The dissolution profiles of the formulations were established by an USP paddle apparatus. Phase solubility study was conducted to evaluate the effect of polymer concentration on aqueous solubility of aceclofenac. The values of Gibbs-free energy (ΔG°tr) associated with the aqueous solubility of aceclofenac in the presence of Soluplus was used to optimize the polymer content. The in vitro dissolution rates of aceclofenac from the nanoparticles were significantly higher compared to the pure drug. Thus, Soluplus nanoparticles provide promising formulations for the improvement of the dissolution profiles and thus, the bioavailability, of aceclofenac.展开更多
Increasing the degree of supersaturation of drugs and maintaining their proper stability are very important in improving the oral bioavailability of poorly soluble drugs by a supersaturated drug delivery system(SDDS)....Increasing the degree of supersaturation of drugs and maintaining their proper stability are very important in improving the oral bioavailability of poorly soluble drugs by a supersaturated drug delivery system(SDDS). In this study, we reported a complex system of Soluplus–Copovidone(Soluplus–PVPVA)loaded with the model drug silybin(SLB) that could not only maintain the stability of a supersaturated solution but also effectively promote oral absorption. The antiprecipitation effect of the polymers on SLB was observed using the solvent-shift method. In addition, the effects of the polymers on absorption were detected by cellular uptake and transport experiments. The mechanisms by which the Soluplus–PVPVA complex promotes oral absorption were explored by dynamic light scattering, transmission electron microscopy, fluorescence spectra and isothermal titration calorimetry analyses. Furthermore, a pharmacokinetic study in rats was used to demonstrate the advantages of the Soluplus–PVPVA complex. The results showed that Soluplus and PVPVA spontaneously formed complexes in aqueous solution via the adsorption of PVPVA on the hydrophilichydrophobic interface of the Soluplus micelle, and the Soluplus–PVPVA complex significantly increased the absorption of SLB. In conclusion, the Soluplus–PVPVA complex is a potential SDDS for improving the bioavailability of hydrophobic drugs.展开更多
The presence of residual water may deteriorate the performance of amorphous solid dispersions prepared by ball milling,affecting molecular mobility,crystallinity,particle size and finally,the drug dissolution rate.As ...The presence of residual water may deteriorate the performance of amorphous solid dispersions prepared by ball milling,affecting molecular mobility,crystallinity,particle size and finally,the drug dissolution rate.As the stability of these metastable systems depend on both formulation and process variables,the aim of this study was to assess for the first time,the impact that the polymer load and the rotational speed applied upon high energy ball milling could have on the performance of binary co-milled solid dispersions composed of tadalafil(a hydrophobic crystalline drug)and Soluplus(an amphiphilic,hygroscopic amorphous polymer).Each of these variables was tested at three levels.Scanning electron microscopy,laser diffraction and X-ray powder diffraction were used to analyze morphology,particle size distribution and crystallinity of ball milled formulations respectively.Dissolution studies were also carried out.Advanced tools of applied physics,namely solid state 1H NMR and relaxometry were used to assess the structure and water mobility upon gaseous phase hydration on storage.It was shown that both tested variables determined the particle size of the formulation.When the rotational speed of 400 rpm was used,all solid dispersion were XRD-amorphous,but to ensure the immediate release of tadalafil its micellar solubilization in Soluplus was necessary.While the formulation was exposed to water vapor,the hydration level increased with an increasing polymer load as well.Hence,the rotational speed governed the space available for the adsorption of water molecules and their organization in a monolayer or multilayers.Such behavior may have impact on the kinetics of the amorphous drug recrystallization,and finally deteriorate its dissolution.展开更多
文摘Aceclofenac is a new generational Non-Steroidal Anti-Inflammatory Drug (NSAID), and is considered a better alternative to the popular pain-killer diclofenac, as it overcomes some of the adverse gastrointestinal and cardiac side effects associated with the latter. However, the bioavailability of the drug remains limited due to low aqueous solubility (0.058 μg/mL) and poor dissolution characteristics. Hence, improving its dissolution characteristics is of prime significance in order to establish its optimal therapeutic efficacy. In an effort to tackle this issue, we report the use of novel Soluplus®-based nanocomposites, prepared from emulsion templates, as effective drug loading agent for aceclofenac. Nanoemulsion templates were prepared by high-shear homogenization using a probe sonicator. The emulsions were subsequently lyophilized to obtain free flowing powders. The amorphization of the drug with increasing polymer content was clearly observed from powder X-ray diffractogram, while the drug-polymer interaction was explored by FTIR spectroscopy. The phase purity and homogeneity of the formulation was characterized using Differential Scanning Calorimetry. The dissolution profiles of the formulations were established by an USP paddle apparatus. Phase solubility study was conducted to evaluate the effect of polymer concentration on aqueous solubility of aceclofenac. The values of Gibbs-free energy (ΔG°tr) associated with the aqueous solubility of aceclofenac in the presence of Soluplus was used to optimize the polymer content. The in vitro dissolution rates of aceclofenac from the nanoparticles were significantly higher compared to the pure drug. Thus, Soluplus nanoparticles provide promising formulations for the improvement of the dissolution profiles and thus, the bioavailability, of aceclofenac.
基金supported by the National Natural Science Foundation of China (grant Nos. 81573378 and 81773651)the Shanghai Science and Technology Innovation Action Plan for Basic Research, China (No. 17430741500)
文摘Increasing the degree of supersaturation of drugs and maintaining their proper stability are very important in improving the oral bioavailability of poorly soluble drugs by a supersaturated drug delivery system(SDDS). In this study, we reported a complex system of Soluplus–Copovidone(Soluplus–PVPVA)loaded with the model drug silybin(SLB) that could not only maintain the stability of a supersaturated solution but also effectively promote oral absorption. The antiprecipitation effect of the polymers on SLB was observed using the solvent-shift method. In addition, the effects of the polymers on absorption were detected by cellular uptake and transport experiments. The mechanisms by which the Soluplus–PVPVA complex promotes oral absorption were explored by dynamic light scattering, transmission electron microscopy, fluorescence spectra and isothermal titration calorimetry analyses. Furthermore, a pharmacokinetic study in rats was used to demonstrate the advantages of the Soluplus–PVPVA complex. The results showed that Soluplus and PVPVA spontaneously formed complexes in aqueous solution via the adsorption of PVPVA on the hydrophilichydrophobic interface of the Soluplus micelle, and the Soluplus–PVPVA complex significantly increased the absorption of SLB. In conclusion, the Soluplus–PVPVA complex is a potential SDDS for improving the bioavailability of hydrophobic drugs.
文摘目的研究3种沉淀抑制剂(PPI)羟丙基甲基纤维素K4M(Hydroxypropyl methyl cellulose K4M,HPMC K4M)、醋酸羟丙甲纤维素琥珀酸酯MG(Hypromellose Acetate Succinate MG,HPMC AS MG)、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(Polyvinylpyrrolidone,Soluplus)对临床口服剂量下pH值诱导延胡索乙素(dl-THP)过饱和相行为的影响。方法绘制dl-THP的pH值-溶解度相图和p H值转换过程中的去过饱和曲线,用溶解度相图佐证dl-THP相行为,以质量浓度-时间曲线下面积和过饱和度为指标分析沉淀抑制剂对dl-THP相行为的影响;采用偏振光显微镜、差示扫描量热法分析沉淀性质。结果临床给药剂量下,dl-THP在pH值转换过程中最大过饱和度为3.93,随时间推移失去过饱和;HPMC K4M、HPMC AS MG、Soluplus在pH值转换180 min内均能维持过饱和度。HPMC K4M、HPMC AS MG、Soluplus在浓度5%时维持过饱和度分别为1.19、1.89、1.36,浓度20%时为1.30、2.35、1.86、浓度50%时为1.30、2.60、2.07。偏振光显微镜和差示扫描量热法结果表明产生结晶沉淀。结论沉淀抑制剂均能改善pH值诱导延胡索乙素过饱和相行为,且这种改善行为随沉淀抑制剂种类和浓度的不同而不同,HPMC AS MG作用效果最佳。
基金Sonata Bis (grant no.DEC-2019/34/E/NZ7/00245)financed by the National Science Centre in Polandsupport (grant no.7150/E-338/M/2017)financed by the Polish Ministry of Science and Higher Educationthe equipment purchased thanks to the financial support of the European Regional Development Fund in the framework of the Polish Innovation Economy Operational Program (contract no.POIG.02.01.00-12-023/08).
文摘The presence of residual water may deteriorate the performance of amorphous solid dispersions prepared by ball milling,affecting molecular mobility,crystallinity,particle size and finally,the drug dissolution rate.As the stability of these metastable systems depend on both formulation and process variables,the aim of this study was to assess for the first time,the impact that the polymer load and the rotational speed applied upon high energy ball milling could have on the performance of binary co-milled solid dispersions composed of tadalafil(a hydrophobic crystalline drug)and Soluplus(an amphiphilic,hygroscopic amorphous polymer).Each of these variables was tested at three levels.Scanning electron microscopy,laser diffraction and X-ray powder diffraction were used to analyze morphology,particle size distribution and crystallinity of ball milled formulations respectively.Dissolution studies were also carried out.Advanced tools of applied physics,namely solid state 1H NMR and relaxometry were used to assess the structure and water mobility upon gaseous phase hydration on storage.It was shown that both tested variables determined the particle size of the formulation.When the rotational speed of 400 rpm was used,all solid dispersion were XRD-amorphous,but to ensure the immediate release of tadalafil its micellar solubilization in Soluplus was necessary.While the formulation was exposed to water vapor,the hydration level increased with an increasing polymer load as well.Hence,the rotational speed governed the space available for the adsorption of water molecules and their organization in a monolayer or multilayers.Such behavior may have impact on the kinetics of the amorphous drug recrystallization,and finally deteriorate its dissolution.
