Menzel Claudia, Jelkmann Max, Laffleur Flavia, Bernkop-Schnürch Andreas
Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Int J Pharm. 2017 Jan 30;517(1-2):196-202. doi: 10.1016/j.ijpharm.2016.11.055. Epub 2016 Nov 24.
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 HO as an oxidizing agent Xan-Cys-MNA showed unlike Xan-Cys no increase in viscosity, indicating high stability towards oxidation. Addition of CaCl 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.
本研究的目的是为液体鼻腔剂型建立一种新型聚合物辅料，该辅料具有增粘特性、改善的粘膜粘附性以及在溶液中对氧化的稳定性。为实现这一目标，首先通过二硫键交换反应将2-巯基烟酸与L-半胱氨酸偶联，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主链上。对所得共轭物进行了偶联配体的量、原位胶凝行为、粘膜粘附特性以及对氧化的稳定性等方面的表征。此外，研究了预活化聚合物对猪鼻上皮细胞纤毛摆动频率（CBF）的影响。结果表明，每克聚合物连接了252.52±20.54μmol的配体。在聚合物主链上未检测到游离巯基，表明完全预活化。聚合物-粘液混合物的流变学研究表明，与硫醇化黄原胶（Xan-Cys）和未改性黄原胶（Xan）相比，完全预活化的黄原胶（Xan-Cys-MNA）的粘膜粘附性提高了1.7倍和2.5倍。拉伸力评估报告显示，与Xan-Cys和Xan相比，Xan-Cys-MNA的总粘附功（TWA）高2.87倍和5.11倍，最大分离力高1.63倍和2.41倍。在作为氧化剂的HO存在下，Xan-Cys-MNA与Xan-Cys不同，粘度没有增加，表明对氧化具有高稳定性。向Xan-Cys-MNA溶液中添加CaCl导致粘度降低，但总粘度仍然较高。CBF研究结果证明了新型共轭物的鼻腔安全性。根据这些结果，完全预活化的硫醇化黄原胶似乎是一种有前途的鼻腔剂型辅料，以提高药物生物利用度。
