设计基于纤维素醚的环丙沙星大分子前药用于延长释放和提高生物利用度。
Design of cellulose ether-based macromolecular prodrugs of ciprofloxacin for extended release and enhanced bioavailability.
机构信息
Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistan.
Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistan.
出版信息
Int J Biol Macromol. 2018 Jul 1;113:719-728. doi: 10.1016/j.ijbiomac.2018.02.142. Epub 2018 Feb 24.
The present study reveals the syntheses of hydroxypropylcellulose‑(HPC) and hydroxyethylcellulose‑(HEC) based macromolecular prodrugs (MPDs) of ciprofloxacin (CIP) using homogeneous reaction methodology. Covalently loaded drug content (DC) of each prodrug was quantified using UV-Vis spectrophotometry to determine degree of substitution (DS). HPC-ciprofloxacin (HPC-CIP) conjugates showed DS of CIP in the range 0.87-1.15 whereas HEC-ciprofloxacin (HEC-CIP) conjugates showed DS range 0.51-0.75. Transmission electron microscopy revealed that HPC-CIP conjugate 2 and HEC-CIP conjugate 6 self-assembled into nanoparticles of 150-300 and 180-250nm, respectively. Size exclusion chromatography revealed HPC-CIP conjugate 2 and HEC-CIP conjugate 6 as monodisperse systems. In vitro drug release studies indicated 15 and 43% CIP release from HPC-CIP conjugate 2 after 6h in simulated gastric and simulated intestinal fluids (SGF and SIF), respectively. HEC-CIP conjugate 6 showed 16% and 46% release after 6h in SGF and SIF, respectively. HPC-CIP conjugate 2 and HEC-CIP conjugate 6 exhibited half-lives of 10.87 and 11.71h, respectively with area under the curve values of 164 and 175hμgmL, respectively, indicating enhanced bioavailability and improved pharmacokinetic profiles in animal model. Equal antibacterial activities to that of unmodified CIP confirmed their competitive efficacies. Cytotoxicity studies supported their non-toxic nature and biocompatibility.
本研究采用均相反应法合成了羟丙基纤维素（HPC）和羟乙基纤维素（HEC）为载体的环丙沙星（CIP）大分子前药（MPD）。采用紫外分光光度法（UV-Vis spectrophotometry）定量测定每个前药的载药量（DC），以确定取代度（DS）。HPC-环丙沙星（HPC-CIP）缀合物的 CIP 取代度（DS）范围为 0.87-1.15，而 HEC-环丙沙星（HEC-CIP）缀合物的 DS 范围为 0.51-0.75。透射电子显微镜（TEM）显示，HPC-CIP 缀合物 2 和 HEC-CIP 缀合物 6 自组装成 150-300nm 和 180-250nm 的纳米粒子。尺寸排阻色谱（Size exclusion chromatography）表明，HPC-CIP 缀合物 2 和 HEC-CIP 缀合物 6 为单分散体系。体外药物释放研究表明，在模拟胃液（SGF）和模拟肠液（SIF）中，HPC-CIP 缀合物 2 在 6h 时分别释放 15%和 43%的 CIP。HEC-CIP 缀合物 6 在 SGF 和 SIF 中分别在 6h 时释放 16%和 46%的 CIP。HPC-CIP 缀合物 2 和 HEC-CIP 缀合物 6 的半衰期分别为 10.87h 和 11.71h，曲线下面积（AUC）值分别为 164hμgmL 和 175hμgmL，表明在动物模型中具有增强的生物利用度和改善的药代动力学特征。与未修饰的 CIP 相比，具有相当的抗菌活性，证实了它们的竞争疗效。细胞毒性研究支持它们的非毒性和生物相容性。
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