Miro A, Quaglia F, Sorrentino U, La Rotonda M I, D'Emmanuele Di Villa Bianca R, Sorrentino R
Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy.
Eur J Pharm Sci. 2004 Sep;23(1):57-64. doi: 10.1016/j.ejps.2004.05.008.
This study was carried out with the aim to optimize the pharmacological profile of gliquidone (GLI)--a poorly bioavailable hypoglycaemic agent sparingly soluble in water--through complexation with cyclodextrins. In order to increase the apparent solubility of GLI, two cyclodextrins, namely beta-cyclodextrin (betaCD) and hydroxypropyl-beta-cyclodextrin (HPbetaCD), were tested. The effect of cyclodextrin addition on the aqueous solubility of GLI was evaluated by the phase solubility method at different pH values. The amount of GLI in solution increased upon CD addition according to A type plots. The aqueous solubility of GLI was enhanced more at higher pH values and using HPbetaCD. On the basis of its performance, HPbetaCD was selected as host to prepare GLI oral formulations. GLI/HPbetaCD solid systems were prepared at 1:2 molar ratio by co-grinding, spray-drying and freeze-drying and characterized by DSC, FTIR and X-ray powder diffractometry. Powders were amorphous and showed an improved dissolution rate in comparison with GLI. GLI/HPbetaCD co-ground and freeze-dried products were the most interesting systems, since they dissolved 62 and 94% of total drug after 15 min, respectively. The hypoglycaemic effect of the most rapidly dissolving binary systems was evaluated after oral administration in fasted rats by measuring plasma glucose level in the time interval 0.5-36 h and compared to free GLI. Our findings indicate that cyclodextrin-containing formulations not only provide an onset of hypoglycaemic effect faster than GLI, but also enhance significantly the pharmacological effect due to improved biopharmaceutics. The association GLI/HPbetaCD allows a reduction of the oral dose and is expected to provide a better control over drug side effects, contributing to improve safety and efficacy of GLI.
本研究旨在通过与环糊精络合来优化格列喹酮（GLI）的药理特性，GLI是一种生物利用度差且在水中微溶的降血糖药物。为了提高GLI的表观溶解度，测试了两种环糊精，即β-环糊精（βCD）和羟丙基-β-环糊精（HPβCD）。通过相溶解度法在不同pH值下评估环糊精添加对GLI水溶解度的影响。根据A类曲线，添加环糊精后溶液中GLI的量增加。在较高pH值下使用HPβCD时，GLI的水溶解度提高得更多。基于其性能，选择HPβCD作为主体来制备GLI口服制剂。通过共研磨、喷雾干燥和冷冻干燥以1:2的摩尔比制备GLI/HPβCD固体体系，并通过差示扫描量热法（DSC）、傅里叶变换红外光谱法（FTIR）和X射线粉末衍射法进行表征。粉末为无定形，与GLI相比，其溶解速率有所提高。GLI/HPβCD共研磨和冷冻干燥产品是最具吸引力的体系，因为它们在15分钟后分别溶解了62%和94%的总药物。在禁食大鼠口服给药后，通过测量0.5 - 36小时时间间隔内的血浆葡萄糖水平，评估了溶解最快的二元体系的降血糖作用，并与游离GLI进行比较。我们的研究结果表明，含环糊精的制剂不仅比GLI更快地产生降血糖作用，而且由于生物药剂学的改善，还显著增强了药理作用。GLI/HPβCD的结合允许减少口服剂量，并有望更好地控制药物副作用，有助于提高GLI的安全性和有效性。
