Abdulla Nourhan A, Balata Gehan F, El-Ghamry Hanaa A, Gomaa Eman
Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
Department of Pharmacy Practice, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt.
Saudi Pharm J. 2021 Dec;29(12):1466-1485. doi: 10.1016/j.jsps.2021.11.006. Epub 2021 Nov 15.
Limited solubility and hepatic first-pass metabolism are the main causes of low bioavailability of anti-schizophrenic drug, Clozapine (CZP). The objective of the study was to develop and validate nanoemulsion (NE) based gel of CZP for intranasal administration as an approach for bioavailability enhancement. Solubility of CZP was initially investigated in different oils, surfactants and co-surfactants, then pseudoternary phase diagrams were constructed to select the optimized ratio of oil, surfactant and co-surfactant. Clear and transparent NE formulations were characterized in terms of droplet size, viscosity, solubilization capacity, transmission electron microscopy, drug release and compatibility studies. Selected NEs were incorporated into different gel bases using combination of two thermosensitive polymers; Pluronic® F-127 (PF127) and F-68 (PF68). NE-based gels (NG) were investigated for gelation temperature, viscosity, gel strength, spreadability and stability. Moreover, selected NGs were evaluated for permeation, mucoadhesive strength and nasal ciliotoxicity. Peppermint oil, tween 80 and transcutol P were chosen for NE preparation owing to their maximum CZP solubilization. Clear NE points extrapolated from tween 80:transcutol P (1:1) phase diagram and passed dispersibility and stability tests, demonstrated globule size of 67.99 to 354.96 nm and zeta potential of -12.4 to -3.11 mV with enhanced CZP release (>90% in some formulations). After incorporation of the selected N3 and N9 formulations of oil:Smix of 1:7 and 2:7, respectively to a mixture of PF127 and PF68 (20:2% w/w), the resultant NG formulations exhibited optimum gelation temperature and viscosity with enhanced CZP permeation and retention through sheep nasal mucosa. Ciliotoxicity examinations of the optimum NGs displayed no inflammation or damage of the lining epithelium and the underlying cells of the nasal mucosa. In conclusion, NE-based gels may be a promising dosage form of CZP for schizophrenia treatment.
溶解性有限和肝脏首过代谢是抗精神分裂症药物氯氮平（CZP）生物利用度低的主要原因。本研究的目的是开发并验证基于纳米乳（NE）的氯氮平凝胶用于鼻腔给药，作为提高生物利用度的一种方法。首先在不同的油、表面活性剂和助表面活性剂中研究氯氮平的溶解度，然后构建伪三元相图以选择油、表面活性剂和助表面活性剂的最佳比例。对澄清透明的纳米乳制剂进行液滴大小、粘度、增溶能力、透射电子显微镜、药物释放和相容性研究等方面的表征。使用两种热敏聚合物（泊洛沙姆F-127（PF127）和F-68（PF68））的组合将选定的纳米乳掺入不同的凝胶基质中。对基于纳米乳的凝胶（NG）进行凝胶化温度、粘度、凝胶强度、铺展性和稳定性研究。此外，对选定的基于纳米乳的凝胶进行渗透、粘膜粘附强度和鼻纤毛毒性评估。由于薄荷油、吐温80和二甲基亚砜对氯氮平的增溶能力最强，因此选择它们用于制备纳米乳。从吐温80:二甲基亚砜（1:1）相图外推得到的澄清纳米乳点通过了分散性和稳定性测试，其液滴大小为67.99至354.96nm，zeta电位为-12.4至-3.11mV，氯氮平释放增强（某些制剂中>90%）。分别将选定的油:表面活性剂混合物比例为1:7和2:7的N3和N9纳米乳制剂掺入PF127和PF68（20:2%w/w）的混合物中后，所得的基于纳米乳的凝胶制剂表现出最佳的凝胶化温度和粘度，氯氮平通过绵羊鼻粘膜的渗透和滞留增强。对最佳基于纳米乳的凝胶的纤毛毒性检查显示鼻粘膜的衬里上皮和下层细胞没有炎症或损伤。总之，基于纳米乳的凝胶可能是用于治疗精神分裂症的氯氮平的一种有前景的剂型。
