Regulatory Affairs Department, Al Andalous for Pharmaceutical Industries, Giza, Egypt.
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Int J Nanomedicine. 2023 Mar 27;18:1577-1595. doi: 10.2147/IJN.S403707. eCollection 2023.
The research objective is to design intranasal brain targeted CLZ loaded lecithin based polymeric micelles (CLZ- LbPM) aiming to improve central systemic CLZ bioavailability.
In our study, intranasal CLZ loaded lecithin based polymeric micelles (CLZ- LbPM) were formulated using soya phosphatidyl choline (SPC) and sodium deoxycholate (SDC) with different CLZ:SPC:SDC ratios via thin film hydration technique aiming to enhance drug solubility, bioavailability and nose to brain targeting efficiency. Optimization of the prepared CLZ-LbPM using Design-Expert® software was achieved showing that M6 which composed of (CLZ:SPC: SDC) in respective ratios of 1:3:10 was selected as the optimized formula. The optimized formula was subjected to further evaluation tests as, Differential Scanning Calorimetry (DSC), TEM, in vitro release profile, ex vivo intranasal permeation and in vivo biodistribution.
The optimized formula with the highest desirability exhibiting (0.845), small particle size (12.23±4.76 nm), Zeta potential of (-38 mV), percent entrapment efficiency of > 90% and percent drug loading of 6.47%. Ex vivo permeation test showed flux value of 27 μg/cm².h and the enhancement ratio was about 3 when compared to the drug suspension, without any histological alteration. The radioiodinated clozapine ([I] iodo-CLZ) and radioiodinated optimized formula ([I] iodo-CLZ-LbPM) were formulated in an excellent radioiodination yield more than 95%. In vivo biodistribution studies of [I] iodo-CLZ-LbPM showed higher brain uptake (7.8%± 0.1%ID/g) for intranasal administration with rapid onset of action (at 0.25 h) than the intravenous formula. Its pharmacokinetic behavior showed relative bioavailability, direct transport percentage from nose to brain and drug targeting efficiency of 170.59%, 83.42% and 117% respectively.
The intranasal self-assembling lecithin based mixed polymeric micelles could be an encouraging way for CLZ brain targeting.
本研究旨在设计一种新型的载氯氮平（CLZ）的脑靶向大豆卵磷脂基聚合物胶束（CLZ-LbPM），以提高 CLZ 的中枢系统生物利用度。
在本研究中，我们采用薄膜水化法，使用大豆卵磷脂（SPC）和脱氧胆酸钠（SDC），通过不同的 CLZ：SPC：SDC 比例，制备载 CLZ 的脑靶向大豆卵磷脂基聚合物胶束（CLZ-LbPM），以提高药物的溶解度、生物利用度和鼻内递药至脑的效率。采用 Design-Expert®软件对所制备的 CLZ-LbPM 进行优化，结果表明，CLZ：SPC：SDC 比例分别为 1：3：10 的 M6 被选为最优配方。对最优配方进行进一步的评价试验，包括差示扫描量热法（DSC）、透射电镜（TEM）、体外释放曲线、离体鼻内渗透和体内分布。
最优配方具有最高的理想值（0.845）、较小的粒径（12.23±4.76nm）、-38mV 的 Zeta 电位、>90%的包封效率和 6.47%的载药量。离体鼻内渗透试验显示，与药物混悬液相比，通量值为 27μg/cm².h，增强比约为 3，且无组织学改变。放射性碘标记氯氮平（[I]碘代-CLZ）和放射性碘标记优化配方（[I]碘代-CLZ-LbPM）的放射性碘标记产率均超过 95%。[I]碘代-CLZ-LbPM 的体内分布研究表明，与静脉注射配方相比，其经鼻给药后具有更高的脑摄取（7.8%±0.1%ID/g）和快速起效（在 0.25 小时）。其药代动力学行为显示相对生物利用度、从鼻内直接转运至脑的百分比和药物靶向效率分别为 170.59%、83.42%和 117%。
载 CLZ 的脑靶向自组装大豆卵磷脂基混合聚合物胶束可能是一种有前途的方法。
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