Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA; College of Pharmacy, Roseman University of Health Sciences, South Jordan, UT, USA.
Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA.
Int J Pharm. 2018 Jul 10;545(1-2):113-116. doi: 10.1016/j.ijpharm.2018.04.040. Epub 2018 Apr 20.
N-Acetyl-l-cysteine (NAC) commonly used as an antidote in acetaminophen poisoning has shown promise in the treatment of neurological disorders such as cerebral palsy (CP). However, NAC suffers from drawbacks such as poor oral bioavailability and suboptimal blood-brain-barrier (BBB) permeability limiting its clinical success. It was previously demonstrated that intravenous administration of dendrimer-NAC (D-NAC) conjugates have shown significant promise in the targeted treatment of neuroinflammation, in multiple preclinical models. Development of an oral formulation of D-NAC may open new administrative routes for this compound. Here, we report the gastrointestinal stability, in vitro transepithelial permeability, and in vivo oral absorption and pharmacokinetics in rats of a pediatric formulation of D-NAC containing Capmul MCM (glycerol monocaprylate) as a penetration enhancer. D-NAC was stable for 6 h in all five simulated gastrointestinal fluids with no signs of chemical degradation. The apparent permeability (P) of D-NAC increased 9-fold in the formulation containing Capmul. The area under the curve [AUC] of D-NAC with Capmul increased by 47% when compared to D-NAC alone. These results indicate that an oral pediatric formulation containing D-NAC and Capmul can be an effective option for the treatment of neuroinflammation.
N-乙酰-L-半胱氨酸（NAC）通常用作对乙酰氨基酚中毒的解毒剂，已显示出在治疗脑瘫（CP）等神经疾病方面的潜力。然而，NAC 存在口服生物利用度差和血脑屏障（BBB）通透性不佳等缺点，限制了其临床应用。先前的研究表明，静脉注射树枝状大分子-NAC（D-NAC）缀合物在多种临床前模型中对神经炎症的靶向治疗显示出了显著的前景。开发 D-NAC 的口服制剂可能为该化合物开辟新的给药途径。在这里，我们报告了含有 Capmul MCM（甘油单辛酸酯）作为渗透增强剂的儿科用 D-NAC 制剂的胃肠道稳定性、体外跨上皮通透性以及在大鼠体内的口服吸收和药代动力学。在所有五种模拟胃肠道液中，D-NAC 稳定 6 小时，没有化学降解的迹象。在含有 Capmul 的制剂中，D-NAC 的表观渗透系数（P）增加了 9 倍。与单独使用 D-NAC 相比，含 Capmul 的 D-NAC 的 AUC 增加了 47%。这些结果表明，含有 D-NAC 和 Capmul 的儿科口服制剂可能是治疗神经炎症的有效选择。
