Eichenbaum G, Pollock-Dove C, Nguyen J, Li S, Evans J, Borghys H, Kennis L, Dong L, van Osdol W, Dai W, Scicinski J, Chen J, Xu Y, Ashton D, Mackie C, Megens A
Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey 08869, USA.
J Pharm Sci. 2006 Apr;95(4):883-95. doi: 10.1002/jps.20550.
In this paper, we present a preclinical approach for evaluating the feasibility of applying controlled-release (CR) oral drug delivery to increase the duration of exposure and lower the C(max) of compounds in a lead series of short half-life atypical antipsychotics. Three lead compounds in the series had demonstrated potential pharmacological benefits for the treatment of psychosis, in preclinical studies. However, the compounds showed evidence of insufficient half-lives to enable a once-a-day (QD) product using immediate-release (IR) oral delivery. To evaluate and compare the potential for oral CR delivery to extend the duration of action and thereby enable QD administration, the in vitro solubility and permeability, and the duodenal and colonic absorption of three compounds in the series were measured. Based on the results, one candidate was selected for advancement that showed moderate in vitro solubility, but had the highest in vitro permeability and ratio of colonic to duodenal bioavailability (0.9) in the rat. The results from this study provided evidence that a CR drug delivery system could be used to extend the duration of exposure of the compounds in the series and a scientific basis for selecting one of the three compounds as a candidate.
在本文中，我们提出了一种临床前方法，用于评估应用控释（CR）口服给药来延长暴露时间并降低一系列短效非典型抗精神病药物先导化合物的C(max)的可行性。在临床前研究中，该系列中的三种先导化合物已证明对治疗精神病具有潜在的药理益处。然而，这些化合物显示出半衰期不足的证据，无法使用速释（IR）口服给药实现每日一次（QD）的产品。为了评估和比较口服CR给药延长作用时间从而实现QD给药的潜力，我们测量了该系列中三种化合物的体外溶解度和渗透性，以及十二指肠和结肠的吸收情况。基于这些结果，选择了一个候选物进行进一步研究，该候选物在体外溶解度中等，但在大鼠中具有最高的体外渗透性以及结肠与十二指肠生物利用度之比（0.9）。这项研究的结果提供了证据，表明CR药物递送系统可用于延长该系列化合物的暴露时间，并为从三种化合物中选择一种作为候选物提供了科学依据。
