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首页> 外文期刊>Journal of pharmaceutical sciences. >A formulation strategy for gamma secretase inhibitor ELND006, a BCS class II compound: Development of a nanosuspension formulation with improved oral bioavailability and reduced food effects in dogs
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A formulation strategy for gamma secretase inhibitor ELND006, a BCS class II compound: Development of a nanosuspension formulation with improved oral bioavailability and reduced food effects in dogs

机译：γ分泌酶抑制剂ELND006（一种BCS II类化合物）的配方策略：开发一种纳米混悬剂，可改善口服生物利用度并降低狗食影响

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摘要

ELND006 is a novel gamma secretase inhibitor previously under investigation for the oral treatment of Alzheimer's disease. ELND006 shows poor solubility and has moderate to high permeability, suggesting it is a Biopharmaceutics Classification System Class II compound. The poor absolute oral bioavailability of the compound in fasted dogs (F ～11%) is attributed to poor aqueous solubility. In addition, inhibiting amyloid precursor protein but not Notch cleavage is an important goal for gamma secretase inhibitors; therefore, significant variation in bioavailability resulting from food consumption is a potential liability for this class of compounds. The objective of the present study was to determine if an ELND006 nanocrystalline formulation would offer improved and predictable pharmacokinetics. ELND006 was formulated as a nanosuspension with a mean particle size of less than 200nm, which was stable in particle size and crystallinity for over 1 year. In addition, ELND006 nanosuspension exhibited rapid dissolution in comparison with reference active pharmaceutical ingredient (API). The in vivo performance of the ELND006 nanosuspension was tested in fed and fasted beagle dogs and compared with a gelatin capsule containing reference API. The results show that nanosizing ELND006 profoundly improved the oral bioavailability and virtually eliminated variation resulting from food intake.
机译：ELND006是一种新型的γ分泌酶抑制剂，先前正在研究中用于口服治疗阿尔茨海默氏病。 ELND006的溶解度差，并且具有中等到高的渗透性，表明它是生物制药分类系统II类化合物。该化合物在禁食犬中的绝对绝对口服生物利用度差（F〜11％）是由于水溶性差。另外，抑制淀粉样前体蛋白而不是Notch裂解是γ分泌酶抑制剂的重要目标。因此，食用食物引起的生物利用度的显着变化是这类化合物的潜在责任。本研究的目的是确定ELND006纳米晶制剂是否可以提供改善的和可预测的药代动力学。 ELND006被配制成平均粒径小于200nm的纳米悬浮液，其粒径和结晶度稳定超过1年。另外，与参考活性药物成分（API）相比，ELND006纳米混悬液表现出快速溶解。在喂食和禁食的比格犬中测试了ELND006纳米混悬剂的体内性能，并与含有参考API的明胶胶囊进行了比较。结果表明，纳米化ELND006大大改善了口服生物利用度，实际上消除了食物摄入引起的变化。

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