Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States.
Section of Oral Medicine, University of Connecticut Health Center, Farmington, CT 06030, United States.
Int J Pharm. 2021 Feb 15;595:120225. doi: 10.1016/j.ijpharm.2021.120225. Epub 2021 Jan 21.
Localized delivery to oral mucositis ulcerations requires specialized dosage forms, (e.g. in situ forming gels) delivered to the site in relatively low volumes. However, this is challenging for drugs with low solubility such as Bupivacaine γ-Linoleate (Bup-γL). The objective of this study is to develop an in situ forming gel with enhanced loading of Bup-γL for oral mucositis pain control. Two co-solvents (PEG400 and ethanol) and eight solubilizers (Tween 80, sodium lauryl sulfate, Cremophor® RH40, Cremophor® EL, Kolliphor® HS 15, Soluplus®, PEG 3350 and PEG8000) were screened for their capability to solubilize Bup-γL. Among all tested solubilizers, sodium lauryl sulfate (SLS) showed the highest solubilizing capacity (8.83 ± 0.94 mg/mL). This was considered to be a consequence of the similarity between the structure of SLS and Bup-γL. On the addition of SLS to the in situ forming gels, the drug loading was enhanced from ~6.5 to ~10.5 mg/ml. The formulations were characterized for their gelation temperature, rheological properties, in vitro drug release and short-term storage stability. The gelation temperatures of the in situ forming gel formulations were significantly reduced with enhanced drug loading. The in vitro drug release profiles showed good fit to both the first order and the Higuchi models. Formulations with SLS demonstrated sustained drug release (time to plateau ~7 h) compared with formulations without SLS (time to plateau ~3.5 h). This study offers an effective strategy to enhance drug loading of in situ forming gels. The enhanced drug loading will reduce the dosing volume and as such is expected to reduce any unwanted numbing of the healthy mucosa.
局部递送至口腔黏膜炎溃疡需要特殊的剂型（例如原位形成凝胶），以相对较低的体积递送至该部位。然而，对于溶解度低的药物（如布比卡因 γ-亚麻酸（Bup-γL））来说，这是具有挑战性的。本研究的目的是开发一种具有增强的 Bup-γL 载药量的原位形成凝胶，以控制口腔黏膜炎疼痛。两种共溶剂（PEG400 和乙醇）和八种增溶剂（Tween 80、十二烷基硫酸钠、Cremophor® RH40、Cremophor® EL、Kolliphor® HS 15、Soluplus®、PEG 3350 和 PEG8000）被筛选用于其溶解 Bup-γL 的能力。在所有测试的增溶剂中，十二烷基硫酸钠（SLS）显示出最高的增溶能力（8.83±0.94mg/mL）。这被认为是 SLS 与 Bup-γL 结构相似的结果。在向原位形成凝胶中加入 SLS 时，药物载药量从约 6.5mg/ml 增强至约 10.5mg/ml。对凝胶的胶凝温度、流变学特性、体外药物释放和短期储存稳定性进行了表征。随着药物载药量的增加，原位形成凝胶制剂的胶凝温度显著降低。体外药物释放曲线与一级和 Higuchi 模型均良好拟合。与不含 SLS 的制剂（达到平台期的时间约为 3.5 小时）相比，含有 SLS 的制剂表现出持续的药物释放（达到平台期的时间约为 7 小时）。本研究提供了一种有效提高原位形成凝胶药物载药量的策略。增加的药物载药量将减少给药体积，从而减少对健康黏膜的不必要麻木。
