Department of CEPIN, Institute of Nuclear Medicine and Allied Sciences (INMAS) Defence Research and Development Organisation, Ministry of Defence, Govt. of India, Timarpur, Delhi 110054, India; Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India; Department of Pharmaceutics, School of Pharmaceutical sciences, Delhi Pharmaceutical Science and Research University, Delhi 110017, India.
Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
Int J Pharm. 2021 Apr 15;599:120428. doi: 10.1016/j.ijpharm.2021.120428. Epub 2021 Mar 1.
Naloxone is an opioid receptor antagonist that can eradicate all pre-indications of the toxicity and inverse the opioid overdose. However, oral administration of naloxone offers limitations such as its extensive first-pass metabolism that results in poor therapeutic effects. In order to resolve this issue, we developed intranasal solid-lipid nanoparticles in which naloxone was incorporated for the higher brain disposition of naloxone with superior therapeutic effects for the reversal of toxicity of opioid overdose. The preparation of naloxone loaded solid-lipid nanoparticles was done by employing the solvent evaporation method. Later, the designed formulation was optimized by Quality by Design approach, specifically, Box-Behnken method. The composition of optimized formulation was Glyceryl monostearate as a solid lipid (40 mg), Pluronic127 (0.5%) and Tween 80 (0.1%) as a surfactant and co-surfactant, respectively. Furthermore, the characterization of optimized formulation was achieved in terms of particle size, PDI, zeta potential, entrapment efficiency, and drug loading which were 190.2 nm, 0.082, -16 mV, 95 ± 0.532% and 19.08 ± 0.106%, respectively. Afterwards, in vitro, ex vivo and in vivo experiments were performed in which higher drug release and superior drug uptake by nasal membrane were observed for naloxone-loaded solid-lipid nanoparticles, later it was confirmed by confocal microscopy of ex vivo nasal membrane tissue. The findings of gamma scintigraphy investigation exhibited better deposition of naloxone-loaded solid-lipid nanoparticles as compared to naloxone solution. Also, the better deposition of naloxone by gamma scintigraphy was further validated by the investigation through the biodistribution study. Additionally, the key findings of the pharmacokinetic study revealed C, T, AUC, AUC, T and K was found to be 163.95 ± 2.64 ng/ml, 240 ± 2.1 min, 17.75 ± 1.08 ng.hr/ml, 18.82 ± 2.51 ng.hr/ml, 70.71 ± 0.115 min, 0.098 ± 0.01 h respectively. Lastly, investigations such as weight variation and histopathological proved the plausible potential of naloxone-loaded solid-lipid nanoparticles in terms of safety as no toxicity was noticed even after the administration of the three-folds dose of the normal dose. Therefore, considering all these findings, it could be easy to say that these developed naloxone-loaded solid-lipid nanoparticles could be administrated via intranasal route and can act as successful novel nanoformulation for the effective treatment of opioid overdose.
纳洛酮是一种阿片受体拮抗剂，可消除所有毒性前指征并逆转阿片类药物过量。然而，纳洛酮的口服给药存在局限性，如广泛的首过代谢导致治疗效果不佳。为了解决这个问题，我们开发了鼻腔用固体脂质纳米粒，其中纳洛酮被包封，以便纳洛酮更好地分布到大脑中，从而对逆转阿片类药物过量的毒性具有更好的治疗效果。纳洛酮负载固体脂质纳米粒的制备采用溶剂蒸发法。随后，通过质量源于设计方法（特别是 Box-Behnken 法）对设计的配方进行了优化。优化配方的组成包括作为固体脂质的甘油单硬脂酸酯（40mg）、泊洛沙姆 127（0.5%）和吐温 80（0.1%），分别作为表面活性剂和助表面活性剂。此外，还对优化配方进行了特征描述，包括粒径、PDI、Zeta 电位、包封效率和载药量，分别为 190.2nm、0.082、-16mV、95±0.532%和 19.08±0.106%。随后，进行了体外、离体和体内实验，结果表明，纳洛酮负载固体脂质纳米粒具有更高的药物释放和更好的鼻腔膜吸收。随后通过离体鼻腔膜组织的共聚焦显微镜观察得到证实。γ闪烁显像研究的结果表明，与纳洛酮溶液相比，纳洛酮负载固体脂质纳米粒具有更好的沉积。此外，通过生物分布研究进一步验证了γ闪烁显像中纳洛酮更好的沉积。此外，药代动力学研究的主要发现表明，C、T、AUC、AUC、T 和 K 分别为 163.95±2.64ng/ml、240±2.1min、17.75±1.08ng.hr/ml、18.82±2.51ng.hr/ml、70.71±0.115min 和 0.098±0.01h。最后，体重变化和组织病理学等研究证明了纳洛酮负载固体脂质纳米粒具有良好的安全性潜力，即使给予正常剂量的三倍剂量，也没有观察到毒性。因此，考虑到所有这些发现，可以轻易地说，这些开发的纳洛酮负载固体脂质纳米粒可以通过鼻腔途径给药，并可以作为治疗阿片类药物过量的有效治疗的成功新型纳米制剂。
