Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS, V. L. Mehta Road, Vile Parle (W), Mumbai 400056, India.
Mol Pharm. 2024 May 6;21(5):2534-2543. doi: 10.1021/acs.molpharmaceut.4c00085. Epub 2024 Mar 28.
The aim of the present study was to develop and evaluate intranasal formulations of the thermoreversible fluoxetine cubosomal in situ gel. This gel was intended for permeation and bioavailability enhancement to target the brain effectively by bypassing the blood-brain barrier (BBB). Fluoxetine-loaded cubosomes were prepared by the homogenization method followed by the cold method approach to develop in situ gel. Fluoxetine-loaded cubosomes displayed a higher encapsulation efficiency (82.60 ± 1.25%) than fluoxetine. This might be due to the solubilizing activity of the polymer to cause partitioning of the lipophilic drug into the aqueous phase during the change from the cubic gel phase to cubosomes. In vitro analysis of fluoxetine-loaded cubosomal in situ gel showed a sustained release profile (93.22 ± 2.47%) due to limited diffusion of fluoxetine. The formation of strong affinity bonds of the drug with GMO (drug transporter) decreased the drug release in comparison to that with fluoxetine-loaded cubosomes (90.68 ± 1.74%). The ex vivo drug release profile revealed the drug release of 96.31 ± 2.88% by the end of 24 h. This is attributed to the higher capability of the intranasal cubosomal in situ gel to prolong the retention and enable better permeation through the nasal mucosa. In male Wistar rats, in vivo biodistribution studies for cubosomal in situ gel administered via the intranasal route at a dose of 3.5 mg/kg demonstrated an increase in pharmacokinetic parameters like the AUC (406 ± 75.35 μg/mL), (368.07 ± 0.23 μg/mL), (4 h), and (14.06 h). The mucoadhesive nature of the in situ gel led to an increase in the residence time of the gel in the nasal mucosa. The biodistribution study of intranasal in situ cubosomal gel improved the bioavailability 2.21-fold in comparison to that with the cubosomal dispersion but 2.83-fold in comparison to that with the drug solution. Therefore, fluoxetine-loaded cubosomal in situ gel proved as a promising carrier for effective transportation of fluoxetine via the intranasal route with significant brain bioavailability.
本研究旨在开发并评价氟西汀立方体温敏原位凝胶的鼻腔制剂。该凝胶旨在通过绕过血脑屏障（BBB），有效靶向大脑，以增强渗透和生物利用度。氟西汀负载的立方脂质体通过匀浆法和冷法制备原位凝胶。氟西汀负载的立方脂质体显示出比氟西汀更高的包封效率（82.60±1.25%）。这可能是由于聚合物的增溶作用，导致疏脂性药物在从立方凝胶相转变为立方脂质体时分配到水相中。体外分析表明，由于氟西汀的扩散受限，氟西汀负载的立方脂质体原位凝胶呈现出持续释放的特点（93.22±2.47%）。药物与 GMO（药物转运体）形成强亲和键，降低了药物释放，与氟西汀负载的立方脂质体（90.68±1.74%）相比。体外药物释放曲线显示，24 小时结束时药物释放 96.31±2.88%。这归因于鼻腔立方体温敏原位凝胶能够延长滞留时间并更好地透过鼻黏膜的更高能力。在雄性 Wistar 大鼠中，经鼻给予 3.5mg/kg 剂量的立方体温敏原位凝胶的体内生物分布研究表明，药代动力学参数如 AUC（406±75.35μg/mL）、 （368.07±0.23μg/mL）、 （4h）和 （14.06h）增加。原位凝胶的粘膜粘附性质导致凝胶在鼻黏膜中的停留时间延长。与立方脂质体分散体相比，鼻腔原位立方脂质体凝胶的生物分布研究将生物利用度提高了 2.21 倍，与药物溶液相比，生物利用度提高了 2.83 倍。因此，氟西汀负载的立方体温敏原位凝胶证明是一种有前途的载体，可通过鼻腔途径有效输送氟西汀，并具有显著的脑生物利用度。
