Laboratory of Pharmaceutical Technology, University of Liège, 1 Avenue de l'Hôpital, 4000 Liège, Belgium.
J Control Release. 2009 Jun 5;136(2):110-6. doi: 10.1016/j.jconrel.2009.01.019. Epub 2009 Feb 5.
Cyclodextrins (CDs) are promising solubility enhancers for inhaled drug delivery. However, they have dose-dependent effects on the respiratory epithelium, which may have advantages for permeability enhancement but also gives rise to safety concerns. In this study, the methyl thiazol tetrazolium (MTT) assay was used to compare a new sparingly methylated beta-CD, Kleptose Crysmebeta (Crysmeb) with the more established CD derivatives hydroxypropyl-gamma-cyclodextrin (HPgammaCD), randomly methylated beta-cyclodextrin (Rameb) and hydroxypropyl-beta-cyclodextrin (HPbetaCD). The betaCD derivatives affected cell metabolism in A549 cells in a concentration dependent manner with LD(50) of 56, 31 and 11 mM obtained for HPbetaCD, Crysmeb and Rameb, respectively. Calu-3 cells were less susceptible to betaCD with an LD(50) of 25 mM being obtained for Rameb only. Permeability increases in Calu-3 cell layers were observed with betaCD derivatives and a concentration dependency shown. The mechanism of permeability enhancement and its reversibility was investigated. Rameb produced an irreversible loss of cell layer barrier function at > or = 25 mM, but perturbations of epithelial integrity were moderate and reversible in the case of HPbetaCD and Crysmeb (25-50 mM). Given its high solubilisation capacity, the low toxicity and transient absorption promoting properties, this study identifies Crysmeb as a promising adjuvant in formulations for inhalation.
环糊精（CDs）是一种很有前途的吸入式药物传递用增溶剂。然而，它们对呼吸上皮细胞有剂量依赖性的影响，这可能有利于渗透性增强，但也引起了安全性方面的担忧。在这项研究中，使用甲基噻唑四唑（MTT）测定法，将一种新型的低取代甲基-β-环糊精（Kleptose Crysmebeta，Crysmeb）与更成熟的 CD 衍生物羟丙基-γ-环糊精（HPgammaCD）、随机甲基-β-环糊精（Rameb）和羟丙基-β-环糊精（HPbetaCD）进行了比较。βCD 衍生物以浓度依赖性方式影响 A549 细胞的细胞代谢，HPbetaCD、Crysmeb 和 Rameb 的 LD50 分别为 56、31 和 11mM。Calu-3 细胞对βCD 的敏感性较低，仅 Rameb 的 LD50 为 25mM。在 Calu-3 细胞层中观察到βCD 衍生物的渗透性增加，并显示出浓度依赖性。研究了渗透性增强的机制及其可逆性。Rameb 在 >或=25mM 时产生了细胞层屏障功能的不可逆丧失，但在 HPbetaCD 和 Crysmeb（25-50mM）的情况下，上皮完整性的干扰是温和且可逆的。鉴于其高溶解能力、低毒性和促进短暂吸收的特性，本研究确定了 Crysmeb 是吸入制剂中一种很有前途的佐剂。
