Goldsmith Sebastian D, McDowell Arlene
School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.
Pharmaceutics. 2018 Nov 18;10(4):240. doi: 10.3390/pharmaceutics10040240.
The nootropic drug aniracetam is greatly limited in its application by low aqueous solubility and a poor oral bioavailability. The primary aim of this study was to design a parenteral formulation of aniracetam that can be administered intravenously. Complexation of aniracetam with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was investigated as a strategy to enhance solubility. A phase solubility analysis was performed to quantify the extent of improvement. An 819% increase in the solubility of aniracetam was obtained, reaching 36.44 mg/mL. This marked increase enables aniracetam to exist in an aqueous solvent at levels sufficient for parenteral dosing. A stability test was then devised using a design of experiment approach. The aniracetam-HP-β-CD formulation was subjected to different relative humidity and temperature and cyclodextrin concentrations over a 12-week period. Key changes in FTIR vibrational frequencies suggest the benzene moiety of aniracetam was introduced into the hydrophobic cavity of HP-β-CD. These results are highly supportive of the formation of a predictable 1:1 molar stoichiometric inclusion complex, explaining the improvement seen in physiochemical properties of aniracetam following formulation with HP-β-CD. This novel formulation of aniracetam suitable for parenteral administration will have utility in future studies to further elucidate the pharmacokinetics of this drug.
促智药阿尼西坦因水溶性低和口服生物利用度差，其应用受到极大限制。本研究的主要目的是设计一种可静脉给药的阿尼西坦肠胃外制剂。研究了阿尼西坦与2-羟丙基-β-环糊精（HP-β-CD）的络合作用，以此作为提高溶解度的策略。进行了相溶解度分析以量化改善程度。阿尼西坦的溶解度提高了819%，达到36.44 mg/mL。这一显著提高使阿尼西坦能够以足以用于肠胃外给药的浓度存在于水性溶剂中。然后采用实验设计方法设计了稳定性试验。在12周的时间内，阿尼西坦-HP-β-CD制剂经受了不同的相对湿度、温度和环糊精浓度。傅里叶变换红外光谱（FTIR）振动频率的关键变化表明，阿尼西坦的苯部分被引入到HP-β-CD的疏水腔内。这些结果高度支持形成可预测的1:1摩尔化学计量包合物，解释了阿尼西坦与HP-β-CD配制成制剂后其理化性质的改善情况。这种适用于肠胃外给药的新型阿尼西坦制剂将在未来研究中用于进一步阐明该药物的药代动力学。
