低玻璃化转变温度药物辛伐他汀的喷雾干燥无定形固体分散体：体外和体内评价
Spray-dried amorphous solid dispersions of simvastatin, a low tg drug: in vitro and in vivo evaluations.
作者信息
Ambike Anshuman A, Mahadik K R, Paradkar Anant
机构信息
Department of Pharmaceutics, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Erandwane, Pune, 411 038, Maharashtra, India.
出版信息
Pharm Res. 2005 Jun;22(6):990-8. doi: 10.1007/s11095-005-4594-z. Epub 2005 Jun 8.
PURPOSE
To obtain free flowing, stable, amorphous solid dispersions (SDs) of simvastatin (SIM), a drug with relatively lower glass transition temperature (T(g)) by spray drying technique, and to perform comparative in vivo study in rats, which could justify the improvement in rate and extent of in vitro drug release.
METHODS
Dichloromethane suspensions of SIM either alone or in combination with PVP (1:1 or 1:2 parts by weight) were spray dried with proposed quantity of Aerosil 200 (1:1, 1:1:1, 1:2:2 parts by weight of SIM, Aerosil 200 and PVP, respectively). SDs were characterized initially in comparison with pure drug and corresponding physical mixtures in same ratios by drug content, saturation solubility, SEM, DSC, XRPD, IR, and in vitro drug release. SD 1:2:2 was further subjected to accelerated stability testing and checked for in vitro drug release and presence of crystallinity using DSC and XRPD. In addition, improvement in rate and extent of in vitro drug release from SD 1:2:2 was justified by in vivo study in rats.
RESULTS
Combination of SD and surface adsorption techniques has been attempted to overcome the limitations of spray drying technique for amorphization of low T(g) drugs. Based on powder characteristics, drug content, saturation solubility, and feasibility of processing into tablets; SD 1:2:2 was selected as the optimized formulation. During initial characterization, SEM, DSC, and XRPD analyses confirmed the presence of amorphous form in SD 1:2:2. IR spectroscopy revealed possibility of hydrogen bonding interaction between SIM and PVP in SDs. Also, there was dramatical improvement in rate and extent of in vitro drug release of SD 1:2:2. Insignificant decrease in dissolution was observed with no evidence of crystallinity during accelerated stability studies of SD 1:2:2. Moreover in vivo study in rats also justified the improvement in therapeutic efficacy of SD 1:2:2 over pure SIM.
CONCLUSIONS
Thus, present study demonstrates high potential of spray drying technique for obtaining stable amorphous SDs of low T(g) drugs.
目的
通过喷雾干燥技术获得具有良好流动性、稳定性的辛伐他汀（SIM）无定形固体分散体（SDs），辛伐他汀是一种玻璃化转变温度（T(g)）相对较低的药物，并在大鼠中进行比较体内研究，以证明体外药物释放速率和程度的改善。
方法
将SIM单独或与聚乙烯吡咯烷酮（PVP）（重量比1:1或1:2）的二氯甲烷悬浮液与规定量的Aerosil 200（分别为SIM、Aerosil 200和PVP重量比1:1、1:1:1、1:2:2）一起进行喷雾干燥。最初通过药物含量、饱和溶解度、扫描电子显微镜（SEM）、差示扫描量热法（DSC）、X射线粉末衍射（XRPD）、红外光谱（IR）以及体外药物释放，将SDs与相同比例的纯药物和相应物理混合物进行比较来表征。SD 1:2:2进一步进行加速稳定性试验，并使用DSC和XRPD检查体外药物释放和结晶度的存在情况。此外，通过大鼠体内研究证明了SD 1:2:2体外药物释放速率和程度的改善。
结果
尝试将SD技术与表面吸附技术相结合，以克服喷雾干燥技术对低T(g)药物非晶化的局限性。基于粉末特性、药物含量、饱和溶解度以及压片加工的可行性，选择SD 1:2:2作为优化制剂。在初始表征期间，SEM、DSC和XRPD分析证实SD 1:2:2中存在无定形形式。红外光谱显示SDs中SIM和PVP之间可能存在氢键相互作用。此外，SD 1:2:2的体外药物释放速率和程度有显著提高。在SD 1:2:2的加速稳定性研究中，观察到溶出度无显著下降，且无结晶度证据。此外，大鼠体内研究也证明了SD 1:2:2相对于纯SIM的治疗效果有所改善。
结论
因此，本研究证明了喷雾干燥技术在获得低T(g)药物稳定无定形SDs方面具有很高的潜力。
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