Vintiloiu Anda, Lafleur Michel, Bastiat Guillaume, Leroux Jean-Christophe
Canada Research Chair in Drug Delivery, Faculty of Pharmacy, University of Montreal, PO Box 6128, Downtown Station, Montreal, QC, Canada H3C 3J7.
Pharm Res. 2008 Apr;25(4):845-52. doi: 10.1007/s11095-007-9384-3. Epub 2007 Aug 12.
To provide a simplified dosing schedule and potentially reduce side effects associated to peak plasma concentrations, an in situ-forming oleogel implant was studied for the sustained-release of rivastigmine.
The gel was prepared by dissolving 5-10% (w/w) N-stearoyl L: -alanine methyl ester (SAM) organogelator in safflower oil containing either dissolved rivastigmine or its dispersed hydrogen tartrate salt. Rheological analysis, differential scanning calorimetry, and infrared spectroscopy were carried out to assess the impact of drug incorporation on the oleogel; this was followed by in vitro and in vivo release studies.
A weakening of intermolecular interactions was suggested by gel-sol transition temperature drops of 10-15 degrees C upon incorporation of dissolved drug. Meanwhile, the dispersed drug salt induced minimal or no changes in transition temperature. Gels containing dispersed rivastigmine had the lowest burst in vitro (<15% in 24 h). In vivo, the 10% SAM formulation containing dispersed rivastigmine provided prolonged drug release within the therapeutic range for 11 days, with peak plasma levels well below the toxic threshold and up to five times lower than for the control formulation.
This study established SAM gels to be a promising option for sustained-release formulations in the treatment of Alzheimer's Disease.
为了提供一种简化的给药方案，并潜在地减少与血浆峰浓度相关的副作用，对原位形成的油凝胶植入物进行了研究，以实现卡巴拉汀的缓释。
通过将5 - 10%（w/w）的N - 硬脂酰 - L - 丙氨酸甲酯（SAM）有机凝胶剂溶解在含有溶解的卡巴拉汀或其分散的酒石酸氢盐的红花油中来制备凝胶。进行流变学分析、差示扫描量热法和红外光谱分析，以评估药物掺入对油凝胶的影响；随后进行体外和体内释放研究。
加入溶解药物后，凝胶 - 溶胶转变温度下降10 - 15摄氏度，这表明分子间相互作用减弱。同时，分散的药物盐对转变温度的影响最小或无影响。含有分散卡巴拉汀的凝胶在体外的突释最低（24小时内<15%）。在体内，含有分散卡巴拉汀的10% SAM制剂在治疗范围内提供了长达11天的药物缓释，血浆峰浓度远低于毒性阈值，比对照制剂低多达五倍。
本研究表明SAM凝胶是治疗阿尔茨海默病缓释制剂的一个有前景的选择。
