Miyamoto Kahori, Ishibashi Yuko, Akita Tomomi, Yamashita Chikamasa
Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
Pharmaceutics. 2021 Feb 7;13(2):233. doi: 10.3390/pharmaceutics13020233.
Ghrelin is the peptide that increases the hunger sensation and food intake and is expected to be clinically applied for treatment of diseases such as cachexia and anorexia nervosa. In the clinical application of ghrelin, injections are problematic in that they are invasive and inconvenient. Thus, we aimed to develop a formulation that can eliminate the need for injections and can be applied clinically. We prepared formulations of an hGhrelin derivative, in which the octanoyl group essential for expression of activity is modified to avoid rapid des-acylation, using lyophilizate for a dry powder inhalation (LDPI) system. The formulation of hGhrelin derivative was optimized by the addition of phenylalanine, of which the fine particle fraction of 5 µm or less was 41.7 ± 3.8%. We also performed pharmacokinetic/pharmacodynamic tests in monkeys using the optimum formulation that can be applied clinically. The absolute bioavailability of inhaled hGhrelin derivative with respect to that intravenously injected was 16.9 ± 2.6%. An increase in growth hormone was shown as an effect of the inhaled hGhrelin derivative similar to intravenous injection. The LDPI formulation can deliver the hGhrelin derivative systemically, and it is expected to be applied clinically as a substitute for injections.
胃饥饿素是一种能增强饥饿感和食物摄入量的肽，有望在临床上用于治疗恶病质和神经性厌食症等疾病。在胃饥饿素的临床应用中，注射存在问题，因为它们具有侵入性且不方便。因此，我们旨在开发一种无需注射且可临床应用的制剂。我们使用冻干粉末吸入（LDPI）系统制备了一种人胃饥饿素衍生物的制剂，其中对活性表达至关重要的辛酰基进行了修饰，以避免快速去酰化。通过添加苯丙氨酸对人胃饥饿素衍生物的制剂进行了优化，其5μm及以下的细颗粒部分为41.7±3.8%。我们还使用可临床应用的最佳制剂在猴子身上进行了药代动力学/药效学测试。吸入的人胃饥饿素衍生物相对于静脉注射的绝对生物利用度为16.9±2.6%。吸入的人胃饥饿素衍生物显示出与静脉注射类似的生长激素增加效应。LDPI制剂可以全身递送人胃饥饿素衍生物，有望作为注射的替代品临床应用。
