美金刚长效注射剂的制备及其评价

Preparation and evaluation of long-acting injectable formulations of memantine

为了降低盐酸美金刚给药频率,提高阿尔茨海默病患者治疗顺应性和连续性,采用难溶性盐技术制备了一系列美金刚难溶性盐纳米混悬型长效注射剂,包括美金刚油酸盐(Mem-Ole)、美金刚硬脂酸盐(Mem-Pal)、美金刚棕榈酸盐(Mem-Pal)和美金刚双羟萘酸盐(Mem-Pam),并对其结构、溶解特性和缓释性能进行了表征。结果表明,与美金刚相比,4种盐在模拟体液中溶解度分别降低了95. 1%、96. 2%、96. 7%和99. 6%,其中Mem-Pam在p H 5~8的模拟体液中溶解度均低于0. 07 mg/m L。与美金刚纳米混悬剂相比,4种难溶性盐纳米混悬剂释药速度显著降低,释药速度由大到小依次为:Mem-Ste、Mem-Pal≈Mem-Ole、Mem-Pam,其中Mem-Pam可缓释7 d,并呈现近零级释药特征(y=0. 549 9x+7. 594 2,r=0. 988 3)。实验结果表明,Mem-Pam具有优良的缓释性能,有望在体内缓释7 d并获得平稳的血药浓度。

In order to improve the compliance of patients with Alzheimer′s disease and maintain the continuity of treatment by reducing administration frequency of memantine hydrochloride,a series of memantine long-acting nanosuspension-based injectable formulations were prepared using a hydrophobic salt formation method.Four hydrophobic salt forms of memantine were prepared,including memantine oleate(Mem-Ole),memantine stearate(Mem-Ste),memantine palmitate(Mem-Pal)and memantine pamoate(Mem-Pam).The salt forms of memantine were characterized using fourier transform infrared(FTIR)spectroscopy,proton nuclear magnetic resonance(1 H NMR)spectroscopy and powder X-ray diffraction(PXRD)analysis.The equilibrium solubilities of different salt forms of memantine and the in vitro drug release of long-acting injectable formulations were investigated.In comparison with memantine alone,the equilibrium solubilities of Mem-Ole,Mem-Ste,Mem-Pal and Mem-Pam in simulated body fluid were decreased by 95.1%、96.2%、96.7%and 99.6%,respectively.Meanwhile,the equilibrium solubilities of Mem-Pam in simulated body fluid with pH ranging from 5 to 8 were all lower than 0.07 mg/mL.The order of the in vitro drug release rate of the four long-acting injectable formulations with nanosuspensions of memantine was Mem-Ste>Mem-Pal≈Mem-Ole>Mem-Pam>Memantine.The Mem-Pam nanosuspensions could sustain drug release for seven days and exhibited a zero-order drug release profile(y=0.549 9 x+7.594 2,r=0.988 3).In conclusion,injectable Mem-Pam nanosuspensions showed desired drug release behavior and might potentially be applied in vivo for a week with a steady plasma drug concentration-time profile.