Kashapova Nadezda E, Kashapov Ruslan R, Ziganshina Albina Y, Nikitin Dmitry O, Semina Irina I, Salnikov Vadim V, Khutoryanskiy Vitaliy V, Moustafine Rouslan I, Zakharova Lucia Y
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, 8 Arbuzov Str., 420088 Kazan, Russia.
Department of Pharmacology, Kazan State Medical University, 49 Butlerov Str., 420012 Kazan, Russia.
Pharmaceutics. 2023 Mar 11;15(3):921. doi: 10.3390/pharmaceutics15030921.
In this study, a water-soluble form of haloperidol was obtained by coaggregation with calix[4]resorcinol bearing viologen groups on the upper rim and decyl chains on the lower rim to form vesicular nanoparticles. The formation of nanoparticles is achieved by the spontaneous loading of haloperidol into the hydrophobic domains of aggregates based on this macrocycle. The mucoadhesive and thermosensitive properties of calix[4]resorcinol-haloperidol nanoparticles were established by UV-, fluorescence and CD spectroscopy data. Pharmacological studies have revealed low in vivo toxicity of pure calix[4]resorcinol (LD is 540 ± 75 mg/kg for mice and 510 ± 63 mg/kg for rats) and the absence of its effect on the motor activity and psycho-emotional state of mice, which opens up a possibility for its use in the design of effective drug delivery systems. Haloperidol formulated with calix[4]resorcinol exhibits a cataleptogenic effect in rats both when administered intranasally and intraperitoneally. The effect of the intranasal administration of haloperidol with macrocycle in the first 120 min is comparable to the effect of commercial haloperidol, but the duration of catalepsy was shorter by 2.9 and 2.3 times ( < 0.05) at 180 and 240 min, respectively, than that of the control. There was a statistically significant reduction in the cataleptogenic activity at 10 and 30 min after the intraperitoneal injection of haloperidol with calix[4]resorcinol, then there was an increase in the activity by 1.8 times ( < 0.05) at 60 min, and after 120, 180 and 240 min the effect of this haloperidol formulation was at the level of the control sample.
在本研究中，通过将在上缘带有紫精基团且在下缘带有癸基链的杯[4]间苯二酚进行共聚集以形成囊泡状纳米颗粒，从而获得了一种水溶性形式的氟哌啶醇。基于这种大环化合物，氟哌啶醇通过自发负载到聚集体的疏水区域中来实现纳米颗粒的形成。通过紫外光谱、荧光光谱和圆二色光谱数据确定了杯[4]间苯二酚 - 氟哌啶醇纳米颗粒的粘膜粘附性和热敏性。药理学研究表明，纯杯[4]间苯二酚的体内毒性较低（小鼠的半数致死量为540±75mg/kg，大鼠为510±63mg/kg），且对小鼠的运动活动和心理情绪状态没有影响，这为其在有效药物递送系统设计中的应用开辟了可能性。与杯[4]间苯二酚一起配制的氟哌啶醇在大鼠经鼻内给药和腹腔内给药时均表现出致僵作用。在最初的120分钟内，经鼻内给予与大环化合物结合的氟哌啶醇的效果与市售氟哌啶醇的效果相当，但在180分钟和240分钟时，僵住症的持续时间分别比对照组短2.9倍和2.3倍（P<0.05）。在腹腔注射与杯[4]间苯二酚结合的氟哌啶醇后10分钟和30分钟，致僵活性有统计学意义的降低，然后在60分钟时活性增加1.8倍（P<0.05），在120分钟、180分钟和240分钟后，这种氟哌啶醇制剂的效果与对照样品相当。
