Academic Unit of Diabetes, Endocrinology and Reproduction, University of Sheffield, Sheffield, UK (M.D., R.J.R); Diurnal Ltd, Cardiff, UK (M.W., H.H.); National Institutes of Health Clinical Center and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA (D.M.); Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, UK (W.A.).
Clin Endocrinol (Oxf). 2014 Apr;80(4):554-561. doi: 10.1111/cen.12316. Epub 2013 Sep 20.
It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified-release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multiparticulate technology.
Screening by in vitro dissolution profiles, pharmacokinetic (PK) testing in dexamethasone-suppressed dogs and humans, and comparison with a reference population.
Field laboratories and clinical research facility.
Formulations were generated using an enteric (delayed release) design configuration with an extended (sustained release) dissolution profile. In vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained-release functionality. PK characterization of DIURF-006 showed that, despite absence of a sustained-release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n = 16) receiving a twice-daily 'toothbrush' regimen (20 mg at 23:00 h and 10 mg at 07:00 h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 h * nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8·5 h vs clock time 08:12 h for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89%, and cortisol levels increased linearly with doses between 5 and 30 mg.
A multiparticulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a 'toothbrush' regimen provides physiological cortisol exposure.
目前使用氢化可的松替代疗法无法模拟肾上腺功能不全患者的皮质醇昼夜节律。先前使用改良释放技术的尝试均未成功。我们的目标是开发使用多颗粒技术重现皮质醇昼夜节律的氢化可的松制剂。
通过体外溶解曲线筛选、地塞米松抑制的狗和人体内的药代动力学（PK）测试以及与参考人群进行比较。
现场实验室和临床研究设施。
使用肠溶（延迟释放）设计配置和延长（持续释放）溶解曲线生成制剂。体外溶解证实了氢化可的松的延迟和持续释放。然而，在狗和人中，持续释放导致生物利用度降低。开发了一种制剂 DIURF-006，它保持了延迟释放但省略了持续释放功能。DIURF-006 的 PK 特征表明，尽管没有持续释放成分，但吸收足够持续，可提供延长的氢化可的松吸收。在接受每日两次“牙刷”方案（23:00 时 20 毫克，07:00 时 10 毫克）的地塞米松抑制志愿者（n=16）中，DIURF-006 使皮质醇水平与生理皮质醇水平相似：DIURF-006 与生理，几何均数 AUC 5610 与 4706 h * nmol/l，几何均数 Cmax 665 与 594 nmol/l，中位数 Tmax 8.5 h 与生理时钟时间 08:12 h 时的峰值皮质醇。DIURF-006 与氢化可的松的相对生物利用度为 89%，皮质醇水平在 5 至 30 毫克剂量之间呈线性增加。
具有肠溶包衣的多颗粒口服氢化可的松制剂仅提供延迟和持续吸收，并且当以“牙刷”方案给药时提供生理皮质醇暴露。
