The purpose of this study was to develop an extended-release(ER) matrix tablet that shows robust dissolution properties able to account for the variability of pH and mechanical stress in the GI tract using a combinati...The purpose of this study was to develop an extended-release(ER) matrix tablet that shows robust dissolution properties able to account for the variability of pH and mechanical stress in the GI tract using a combination of enteric polymer and hydrophilic polymer. Hypromellose acetate succinate(HPMCAS) and hydroxypropylcellulose(HPC) were selected as ER polymers for the ER matrix tablet(HPMCAS/HPC ER matrix tablet). Oxycodone hydrochloride was employed as a model drug. Dissolution properties of the HPMCAS/HPC ER matrix tablets were evaluated and were not affected by the pH of the test medium or paddle rotating speed.In a USP apparatus 3(bio-relevant dissolution method), dissolution profiles of the HPMCAS/HPC ER matrix tablets containing oxycodone hydrochloride were similar to that of the reference product(OxyC ontin). Moreover, in vivo performance after oral administration of the HPMCAS/HPC ER matrix tablets to humans was simulated by GastroP lus based on dissolution profiles from the USP apparatus 3. The plasma concentration-time profile simulated was similar to that of the reference product. These results suggest that the combination of HPMCAS and HPC shows a robust dissolution profile against pH and paddle rotating speed and indicates the appropriate extended-release profile in humans.展开更多
Hypromellose acetate succinate(HPMCAS) microparticles containing the poorly-water soluble drug celecoxib(CEL) were prepared by electrospraying intended for oral drug delivery. Various solvent mixtures with different s...Hypromellose acetate succinate(HPMCAS) microparticles containing the poorly-water soluble drug celecoxib(CEL) were prepared by electrospraying intended for oral drug delivery. Various solvent mixtures with different solubility for CEL and HPMCAS were used to induce changes in the polymer structural conformation of the microparticles. The performance of the prepared microparticles was evaluated by studying the solid state from, particle size and morphology, radial drug distribution and drug release. CEL was amorphous in all electrosprayed HPMCAS microparticles. The particle size and morphology was dependent on the solubility of HPMCAS in the solvent mixture used with poorer solvents resulting in smaller microparticles with rougher appearance. The CEL distribution on the particles surface was relatively homogeneous and similar for all microparticles. Drug release from the microparticles was observed at a higher rate depending on the solubility of HPMCAS in the solvent used for electrospraying, and in all cases an at least 4-fold higher rate was observed compared with the crystalline drug. Drug precipitation from the supersaturated solution was inhibited by HPMCAS for all microparticles based on its parachute effect while crystalline CEL did not reach supersaturation. This study demonstrated that electrospraying can be used to produce microparticles with tailored properties for pharmaceutical application by adjusting solvent selection.展开更多
分别以聚维酮K29/32、共聚维酮S-630、聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)以及3个规格的醋酸羟丙甲纤维素琥珀酸酯(HPMCAS,规格L、M和H)为载体材料,采用喷雾干燥技术制备依非韦伦固体分散体。以120 min 的动力...分别以聚维酮K29/32、共聚维酮S-630、聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)以及3个规格的醋酸羟丙甲纤维素琥珀酸酯(HPMCAS,规格L、M和H)为载体材料,采用喷雾干燥技术制备依非韦伦固体分散体。以120 min 的动力溶解度为指标考察,筛选出增溶效果和抑晶效果较优的载体材料,并用全因子设计优化喷雾干燥的工艺参数。通过差示扫描量热(DSC)法、X射线粉末衍射(XRPD)法和红外光谱(FT-IR)法对优化所得的固体分散体进行物相鉴别。结果表明,L规格的HPMCAS 增溶效果最好;依非韦伦与HPMCAS L 的质量比为1∶3时制得的固体分散体在pH6.8 磷酸盐缓冲溶液中120min 的动力溶解度达到(955.97±5.13)μg/ml,比原料药提高了约66.7 倍;喷雾干燥工艺参数中泵的流速越慢、氮气流量越大,制得的固体分散体动力溶解度越高。DSC 和XRPD 结果表明依非韦伦以无定形分散在载体材料中,FT-IR 显示依非韦伦与载体材料分子之间以氢键结合。加速试验[40℃、相对湿度75%]结果表明HPMCAS L 固体分散体在6个月内较稳定;大鼠体内药动学试验表明,该固体分散体的cmax 和AUC0→t分别为原料药的1.98 和1.79 倍。本试验表明以HPMCAS L为载体制备的依非韦伦固体分散体可显著提高药物的溶解度和口服生物利用度。展开更多
文摘The purpose of this study was to develop an extended-release(ER) matrix tablet that shows robust dissolution properties able to account for the variability of pH and mechanical stress in the GI tract using a combination of enteric polymer and hydrophilic polymer. Hypromellose acetate succinate(HPMCAS) and hydroxypropylcellulose(HPC) were selected as ER polymers for the ER matrix tablet(HPMCAS/HPC ER matrix tablet). Oxycodone hydrochloride was employed as a model drug. Dissolution properties of the HPMCAS/HPC ER matrix tablets were evaluated and were not affected by the pH of the test medium or paddle rotating speed.In a USP apparatus 3(bio-relevant dissolution method), dissolution profiles of the HPMCAS/HPC ER matrix tablets containing oxycodone hydrochloride were similar to that of the reference product(OxyC ontin). Moreover, in vivo performance after oral administration of the HPMCAS/HPC ER matrix tablets to humans was simulated by GastroP lus based on dissolution profiles from the USP apparatus 3. The plasma concentration-time profile simulated was similar to that of the reference product. These results suggest that the combination of HPMCAS and HPC shows a robust dissolution profile against pH and paddle rotating speed and indicates the appropriate extended-release profile in humans.
基金the Danish Council for Inde-pendent Research(Grant No.DFF-12-131927)for financial sup-port of this project
文摘Hypromellose acetate succinate(HPMCAS) microparticles containing the poorly-water soluble drug celecoxib(CEL) were prepared by electrospraying intended for oral drug delivery. Various solvent mixtures with different solubility for CEL and HPMCAS were used to induce changes in the polymer structural conformation of the microparticles. The performance of the prepared microparticles was evaluated by studying the solid state from, particle size and morphology, radial drug distribution and drug release. CEL was amorphous in all electrosprayed HPMCAS microparticles. The particle size and morphology was dependent on the solubility of HPMCAS in the solvent mixture used with poorer solvents resulting in smaller microparticles with rougher appearance. The CEL distribution on the particles surface was relatively homogeneous and similar for all microparticles. Drug release from the microparticles was observed at a higher rate depending on the solubility of HPMCAS in the solvent used for electrospraying, and in all cases an at least 4-fold higher rate was observed compared with the crystalline drug. Drug precipitation from the supersaturated solution was inhibited by HPMCAS for all microparticles based on its parachute effect while crystalline CEL did not reach supersaturation. This study demonstrated that electrospraying can be used to produce microparticles with tailored properties for pharmaceutical application by adjusting solvent selection.
文摘考察了基于盐酸度洛西汀肠溶微丸的3种胶囊剂[原研制剂欣百达？,以醋酸羟丙甲基纤维素琥珀酸酯（HPMCAS）为肠溶包衣材料,以及2种仿制制剂（分别以HPMCAS和甲基丙烯酸树脂Eudragit L30D-55为肠溶包衣材料）]在加速试验（40℃、相对湿度75%）中的稳定性。将3种胶囊剂分别于加速条件放置6个月,考察试验期间3种制剂的药物含量、微丸尺寸和形态以及释放特性稳定性。结果显示,原研制剂及2种仿制制剂在加速试验期间药物含量均大于95%、微丸尺寸和形态无明显变化,提示两种肠溶材料均与药物有良好的化学相容性,物理性质稳定;但采用Eudragit L30D-55的仿制制剂2中药物含量在6个月时有轻微下降。通过相似因子（？2）判断,3种制剂在加速试验期间药物释放特性保持稳定,但仿制制剂2在p H 6.8磷酸盐缓冲溶液中释放不完全。因此,本试验提示在开发高质量盐酸度洛西汀肠溶微丸仿制制剂中HPMCAS是更好的肠溶辅料。
