The aim of the present study was to establish a novel polymeric excipient for liquid nasal dosage forms exhibiting viscosity increasing properties, improved mucoadhesion and stability towards oxidation in solution. In order to achieve this goal, 2-mercaptonicotinic acid was first coupled to l-cysteine by disulfide exchange reaction and after purification directly attached to the polymeric backbone of xanthan gum by carbodiimide mediated amide bond formation. The resulting conjugate was characterized with respect to the amount of coupled ligand, the in situ gelling behavior, mucoadhesive properties and stability towards oxidation. Furthermore, the influence of preactivated polymers on ciliary beat frequency (CBF) of porcine nasal epithelial cells was investigated. Results showed, that 252.52±20.54μmol of the ligand was attached per gram polymer. No free thiol groups could be detected on the polymeric backbone indicating entire preactivation. Rheological investigations of polymer mucus mixtures revealed a 1.7-fold and 2.5-fold enhanced mucoadhesion of entirely preactivated xanthan (Xan-Cys-MNA) compared to thiolated xanthan (Xan-Cys) and unmodified xanthan (Xan). Tensile force evaluation reported a 2.87 and 5.11-fold higher total work of adhesion (TWA) as well as a 1.63 and 2.41-fold higher maximum detachement force of Xan-Cys-MNA compared to Xan-Cys and Xan. In the presence of H2O2 as an oxidizing agent Xan-Cys-MNA showed unlike Xan-Cys no increase in viscosity, indicating high stability towards oxidation. Addition of CaCl2 to Xan-Cys-MNA solutions caused a decrease in viscosity at nevertheless higher total viscosity. Results from CBF studies proved nasal safety for the novel conjugate. According to these results, entirely preactivated thiolated xanthan gum seems to be a promising excipient for nasal dosage forms in order to improve drug bioavailability.

译文

本研究的目的是建立一种用于液体鼻剂型的新型聚合物赋形剂,该剂型具有增加粘度的特性,改善的粘膜粘附性和对溶液中氧化的稳定性。为了实现这一目标,首先通过二硫键交换反应将2-巯基丙酸与l-半胱氨酸偶联,并在纯化后通过碳二亚胺介导的酰胺键形成直接连接到黄原胶的聚合物骨架上。所得缀合物的特征在于偶联配体的量,原位胶凝行为,粘膜粘附特性和对氧化的稳定性。此外,还研究了预活化聚合物对猪鼻腔上皮细胞睫状搏动频率 (CBF) 的影响。结果表明,每克聚合物连接252.52 ± 20.54 μ mol配体。在聚合物骨架上未检测到游离的硫醇基团,表明完全预活化。聚合物粘液混合物的流变学研究表明,与硫醇化的黄烷 (Xan-Cys-MNA) 和未改性的黄烷 (Xan) 相比,完全预活化的黄烷 (Xan-Cys-MNA) 的粘膜粘附增强了1.7倍和2.5倍。与Xan-Cys和Xan相比,拉伸力评估报告的粘附力总功 (TWA) 高2.87 5.11倍,Xan-Cys-MNA的最大分离力1.63 2.41倍。在H2O2作为氧化剂的存在下,Xan-Cys-MNA与Xan-Cys不同,粘度没有增加,表明氧化的稳定性很高。在Xan-Cys-MNA溶液中添加CaCl2会导致总粘度较高的情况下粘度降低。CBF研究的结果证明了新型结合物的鼻安全性。根据这些结果,为了提高药物的生物利用度,完全预活化的硫醇化黄原胶似乎是鼻剂型的有希望的赋形剂。

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