Introduction: Ziprasidone (ZP) is a novel atypical antipsychotic agent effective in the treatment of positive and negative symptoms of schizophrenia with low chances for extrapyramidal side effects (EPs) and cognitive deficits. ZP possesses poor oral bioavailability (∼ 50%), short biological half-life (∼ 2.5 h) and due to extensive first-pass metabolism, a repeated dose is administered which makes the therapy non-adherent, leading to patient non-compliance. Therefore, this is a first report of developing parenteral ZP loaded sustained release phospholipid based phase-transition system (ZP-LPS).
Methods: The ZP-LPS system was formulated by mixing of biocompatible materials including phospholipid E 80, medium chain triglyceride (MCT) and ethanol. Optimization was done by aqueous titration method using pseudo-ternary phase diagram and dynamic rheological measurements. In vivo depot formation was confirmed by gamma scintigraphy after subcutaneous injection. Biodegradation and biocompatibility studies were performed for its safety evaluation. Finally, the efficacy of the formulation was assessed by Morris water maze (MWM) test and dizocilpine (MK-801) was used to induce schizophrenia in Sprague-Dawley rats.
Results: Optimized ZP-LPS showed rapid gelation (2 min), highest change in viscosity (∼ 48000 mPa.s) and sustained release of ZP over a period of 1 month. Gamma scintigraphy depicted that the low-viscosity ZP-LPS system undergo rapid in situ gelation. Biodegradation and biocompatibility studies revealed gradual degradation in size of depot over a period of 28 days without any inflammation at the injection site. In MWM test, escape latency, time spent and total distance in target quadrant were significantly improved (p < 0.001) in the ZP-LPS group in comparison to the MK-801 group when evaluated at day 0, day 7 and day 28. However, significant improvement (p < 0.001) was observed only at day 0 in ZP suspension group.
Conclusion: The overall result indicates that the novel ZP-LPS system is safe, biodegradable, and effective for the management of schizophrenia.

Keywords: Gamma scintigraphy, lipid phase-transition, Morris Water Maze (MWM) test, phospholipid, schizophrenia, ziprasidone (ZP)


中文翻译：

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齐拉西酮的肠外持续释放脂质相变系统：精神分裂症治疗的制造和评价。

简介：齐拉西酮 (ZP) 是一种新型非典型抗精神病药物，可有效治疗精神分裂症的阳性和阴性症状，且锥体外系副作用 (EPs) 和认知缺陷的可能性较低。ZP 的口服生物利用度差（~ 50%），生物半衰期短（~ 2.5 h），并且由于广泛的首过代谢，重复给药导致治疗不依从，导致患者不依从。因此，这是开发肠外载有 ZP 的缓释磷脂基相变系统 (ZP-LPS) 的第一份报告。
方法：ZP-LPS 系统通过混合生物相容性材料（包括磷脂 E 80、中链甘油三酯 (MCT) 和乙醇）配制而成。通过使用伪三元相图和动态流变测量的水滴定法进行优化。皮下注射后通过伽马闪烁显像证实体内贮库形成。对其安全性评估进行了生物降解和生物相容性研究。最后，通过莫里斯水迷宫 (MWM) 试验评估制剂的功效，并使用地佐西平 (MK-801) 在 Sprague-Dawley 大鼠中诱导精神分裂症。
结果：优化的 ZP-LPS 表现出快速凝胶化（2 分钟）、粘度变化最大（~ 48000 mPa.s）和 ZP 在 1 个月内的持续释放。伽马闪烁显像描绘了低粘度 ZP-LPS 系统经历快速的原位凝胶化。生物降解和生物相容性研究表明，在 28 天的时间内，贮库的大小逐渐下降，而注射部位没有任何炎症。在 MWM 测试中，与 MK-801 组相比，在第 0 天、第 7 天和第 28 天进行评估时，ZP-LPS 组的逃逸潜伏期、目标象限花费的时间和总距离显着改善 (p < 0.001)。然而，仅在 ZP 悬浮组的第 0 天观察到显着改善 (p < 0.001)。
结论：总体结果表明，新型 ZP-LPS 系统安全、可生物降解且对精神分裂症的治疗有效。

关键词：伽马闪烁显像，脂质相变，莫里斯水迷宫（MWM）试验，磷脂，精神分裂症，齐拉西酮（ZP）