School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, Queensland 4102, Australia.
Medicines Management Unit, Department of Health, Northern Territory Government, Royal Darwin Hospital, 105 Rocklands Drive, Tiwi, Northern Territory 0810, Australia.
Mol Pharm. 2022 Nov 7;19(11):4055-4066. doi: 10.1021/acs.molpharmaceut.2c00513. Epub 2022 Sep 23.
Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia. However, it causes many adverse drug reactions (ADRs), which lead to poor treatment outcomes. Nose-to-brain (N2B) drug delivery offers a promising approach to reduce peripheral ADRs by minimizing systemic drug exposure. The aim of the present study was to develop and characterize clozapine-loaded nanoemulsion sol-gel (CLZ-NESG) for intranasal administration using high energy sonication method. A range of oils, surfactants, and cosurfactants were screened with the highest clozapine solubility selected for the development of nanoemulsion. Pseudoternary phase diagrams were constructed using a low-energy (spontaneous) method to identify the microemulsion regions (i.e., where mixtures were transparent). The final formulation, CLZ-NESG (pH 5.5 ± 0.2), comprising 1% / clozapine, 1% / oleic acid, 10% / polysorbate 80/propylene glycol (3:1), and 20% / poloxamer 407 (P407) solution, had an average globule size of ≤30 nm with PDI 0.2 and zeta potential of -39.7 ± 1.5 mV. The cumulative drug release of clozapine from the nanoemulsion gel at 34 °C (temperature of nasal cavity) after 72 h was 38.9 ± 4.6% compared to 84.2 ± 3.9% with the control solution. The permeation study using sheep nasal mucosa as diffusion barriers confirmed a sustained release of clozapine with 56.2 ± 2.3% cumulative drug permeated after 8 h. Additionally, the histopathological examination found no severe nasal ciliotoxicity on the mucosal tissues. The thermodynamic stability studies showed that the gel strength and viscosity of CLZ-NESG decreased after temperature cycling but was still seen to be in "gel" form at nasal temperature. However, the accelerated storage stability study showed a decrease in drug concentration after 3 months, which can be expected at elevated stress conditions. The formulation developed in this study showed desirable physicochemical properties for intranasal administration, highlighting the potential value of a nanoemulsion gel for improving drug bioavailability of clozapine for N2B delivery.
氯氮平是治疗抵抗性精神分裂症最有效的抗精神病药物。然而，它会引起许多药物不良反应（ADR），导致治疗效果不佳。鼻内（N2B）药物传递通过最大限度地减少全身药物暴露，提供了一种减少外周 ADR 的有前途的方法。本研究的目的是使用高能超声法开发和表征载氯氮平纳米乳凝胶（CLZ-NESG）用于鼻内给药。筛选了一系列油、表面活性剂和共溶剂，选择具有最高氯氮平溶解度的油进行纳米乳的开发。使用低能量（自发）方法构建伪三元相图，以确定微乳液区域（即混合物透明的区域）。最终配方 CLZ-NESG（pH5.5±0.2），包含 1%/氯氮平、1%/油酸、10%/聚山梨酯 80/丙二醇（3:1）和 20%/泊洛沙姆 407（P407）溶液，平均粒径为≤30nm，PDI 为 0.2，Zeta 电位为-39.7±1.5mV。在 34°C（鼻腔温度）下，纳米乳凝胶中氯氮平的累积释放率在 72 h 后为 38.9±4.6%，而对照溶液为 84.2±3.9%。使用绵羊鼻黏膜作为扩散屏障的渗透研究证实，氯氮平持续释放，8 h 后累积药物渗透 56.2±2.3%。此外，组织病理学检查发现黏膜组织上没有严重的鼻纤毛毒性。热力学稳定性研究表明，CLZ-NESG 的凝胶强度和粘度在温度循环后降低，但在鼻腔温度下仍呈“凝胶”形式。然而，加速储存稳定性研究表明，在 3 个月后药物浓度下降，在高压力条件下可以预期。本研究开发的制剂具有用于鼻内给药的理想理化性质，突出了纳米乳凝胶在改善氯氮平经 N2B 传递的药物生物利用度方面的潜在价值。
