Fisher A, Watling M, Smith A, Knight A
Archimedes Development Limited, Albert Einstein Center, Nottingham Science and Technology Park, Nottingham, NG7 2TN, UK.
Int J Clin Pharmacol Ther. 2010 Feb;48(2):138-45. doi: 10.5414/cpp48138.
To optimize the absorption profile and reduce C(max), three new fentanyl nasal spray formulations have been developed: fentanyl pectin (FPNS), fentanyl chitosan (FChNS) and fentanyl in chitosan-poloxamer 188 (FChPNS). The venous pharmacokinetic profiles and tolerability of these formulations were assessed and compared with oral transmucosal fentanyl citrate (OTFC) lozenge.
This randomized, open-label, crossover study was conducted in opioid-naïve, healthy adult volunteers. Subjects were dosed under naltrexone blockade on four occasions with three nasal sprays (100 microg in 100 microl) and OTFC 200 microg. Fentanyl venous plasma concentrations were measured up to 24 h post-dose. Tolerability was assessed by clinical nasal assessments and a nasal reactogenicity questionnaire.
18 subjects were enrolled and completed the study. The mean dose-normalized AUC(0-infinity) for each nasal formulation was significantly higher (p < 0.05) compared with OTFC. Bioavailability compared with OTFC was significantly greater for all nasal fentanyl formulations (FPNS 132.4%, FChNS 154.1%, FChPNS 122.3%). Median tmax (FPNS 0.33 h, FChNS 0.17 h, FChPNS 0.26 h) were significantly (p < 0.001) reduced (OTFC 1.5 h) and mean C(max) significantly increased with all nasal formulations compared with OTFC. Nasal reactogenicity symptom incidence was lowest for the FPNS formulation (FPNS 2, FChNS 28 and FChPNS 45).
All nasal formulations demonstrated significantly increased systemic exposure and reduced times to peak plasma values compared with OTFC. The FPNS formulation exhibited the most favorable nasal and general tolerability profiles. It appears suitable for further investigation in breakthrough cancer pain management.
为优化吸收曲线并降低C(max)，已研发出三种新型芬太尼鼻喷雾剂制剂：芬太尼果胶（FPNS）、芬太尼壳聚糖（FChNS）和壳聚糖-泊洛沙姆188中的芬太尼（FChPNS）。评估了这些制剂的静脉药代动力学曲线和耐受性，并与口服透粘膜芬太尼柠檬酸盐（OTFC）含片进行比较。
本随机、开放标签、交叉研究在未使用阿片类药物的健康成年志愿者中进行。受试者在纳曲酮阻断下分四次接受三种鼻喷雾剂（100微升中含100微克）和200微克OTFC给药。在给药后24小时内测量芬太尼静脉血浆浓度。通过临床鼻腔评估和鼻腔反应原性问卷评估耐受性。
18名受试者入组并完成研究。与OTFC相比，每种鼻用制剂的平均剂量标准化AUC(0-无穷大)显著更高（p < 0.05）。与OTFC相比，所有鼻用芬太尼制剂的生物利用度显著更高（FPNS 132.4%，FChNS 154.1%，FChPNS 122.3%）。中位达峰时间（FPNS 0.33小时，FChNS 0.17小时，FChPNS 0.26小时）显著（p < 0.001）缩短（OTFC为1.5小时），与OTFC相比，所有鼻用制剂的平均C(max)显著升高。FPNS制剂的鼻腔反应原性症状发生率最低（FPNS为2例，FChNS为28例，FChPNS为45例）。
与OTFC相比，所有鼻用制剂均显示全身暴露显著增加，血浆峰值时间缩短。FPNS制剂表现出最有利的鼻腔和总体耐受性特征。它似乎适合在癌症突破性疼痛管理中进行进一步研究。
