Sandri Giuseppina, Bonferoni Maria Cristina, Chetoni Patrizia, Rossi Silvia, Ferrari Franca, Ronchi Celestino, Caramella Carla
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Pavia, Pavia, Italy.
Eur J Pharm Biopharm. 2006 Jan;62(1):59-69. doi: 10.1016/j.ejpb.2005.07.002. Epub 2005 Sep 12.
Aim of the work was to develop mucoadhesive eyedrops containing tetrahydrozoline hydrochloride (TZ), a decongestant drug, and based on a ternary interaction drug-polymer-polymer. The anionic polymers assessed were the anionic hyaluronic acid (HA) and polyacrylic acid (PAA), the cationic chitosan (HCS) and the polyelectrolyte gelatin (G). Formulations based on the ternary systems TZ/G/HA, TZ/HCS/HA, TZ/G/PAA and TZ/HCS/PAA at the stoichiometry ratios between cationic and anionic polymers and containing a 10 and 20 fold excess of the anionic polymers were prepared. The formulations were characterized for in vitro mucoadhesive and release properties. The ex vivo/in vivo residence properties were assessed for the formulations that combined the better in vitro mucoadhesive and release properties. The physical stability of the formulations selected was determined following steam sterilization and storage at 25 and 40 degrees C. The synergistic effect of G with HA and PAA improves the mucoadhesion of the formulations while the interaction of HCS with HA and PAA is likely to produce higher neutralization of the anionic polymer charge and minor chain flexibility resulting in a limited mucoadhesion improvement. Both G and HCS participate to control drug release. The selected formulations demonstrate to possess consistency (viscosity) sensitive to the ions of the medium, and probably for this reason the ex vivo/in vivo residence properties could not directly correlated to mucoadhesion and to drug release control properties. However, the formulations are able to maintain levels of TZ detectable until 20 min after the instillation in rabbits, while TZ was not detectable since 3 min after instillation of the drug solution. The physical stability, following steam sterilization and storage, the low viscosity combined with good residence time in conjunctival sac make the TZ/G/20HA the more promising formulation.
本研究的目的是开发一种含有盐酸四氢唑啉（TZ）的粘膜粘附性眼药水，TZ是一种减充血剂药物，该眼药水基于药物 - 聚合物 - 聚合物的三元相互作用。评估的阴离子聚合物有阴离子透明质酸（HA）和聚丙烯酸（PAA），阳离子壳聚糖（HCS）和聚电解质明胶（G）。制备了基于三元体系TZ/G/HA、TZ/HCS/HA、TZ/G/PAA和TZ/HCS/PAA的配方，其中阳离子和阴离子聚合物的化学计量比以及阴离子聚合物过量10倍和20倍的情况均有涉及。对这些配方的体外粘膜粘附性和释放特性进行了表征。对于体外粘膜粘附性和释放特性较好的配方，评估了其离体/体内滞留特性。对所选配方进行蒸汽灭菌并在25℃和40℃下储存后，测定其物理稳定性。G与HA和PAA的协同作用改善了配方的粘膜粘附性，而HCS与HA和PAA的相互作用可能会使阴离子聚合物电荷产生更高的中和作用，并使链的柔韧性降低，从而导致粘膜粘附性改善有限。G和HCS都参与了药物释放的控制。所选配方表现出对介质离子敏感的稠度（粘度），可能正因如此，离体/体内滞留特性与粘膜粘附性和药物释放控制特性无法直接相关。然而，这些配方能够在兔眼滴注后20分钟内维持可检测到的TZ水平，而滴注药物溶液后3分钟就检测不到TZ了。经过蒸汽灭菌和储存后的物理稳定性、低粘度以及在结膜囊中良好的滞留时间，使得TZ/G/20HA成为最有前景的配方。
