鼓室注射地塞米松原位凝胶的体内分布及药动学研究

In vivo Distribution and Pharmacokinetics of Dexamethasone Sodium Phosphate Thermosensitive in situ Gel Following Intratympanic Injection

目的研究鼓室注射(intratympanicinjection,IT)地塞米松磷酸钠(DSP)温度敏感原位凝胶的体内分布特征,探讨载药凝胶经圆窗膜吸收的规律,为其临床应用提供理论依据。方法制备DSP温度敏感原位凝胶。建立在外淋巴(perilymph,PL)、脑脊液(cerebrospinalfluid,CSF)和血中DSP及地塞米松(Dex)的HPLC测定方法。经鼓室注射DSP凝胶,并与溶液剂相比较,测定药物的体内分布和在PL中的药代动力学参数。结果鼓室注射DSP原位凝胶,Dex在内耳组织的局部生物利用度显著提高,AUC是静脉注射溶液的593.7倍;药物作用时间明显延长,同鼓室注射溶液相比,t1/2高28.6倍,MRT增加了近5倍。而且,当采用鼓室注射时,药物在体内其他部位分布甚少,在血和CSF中的浓度均远远低于PL。结论经鼓室给药的DSP原位凝胶对耳蜗具有明显的定位释药作用和缓释效果。

Objective To investigate the absorption and distribution of DSP （Dexamethasone sodium phosphate ）-loaded thermosensitive in situ gel following IT（intratympanic injection） in guinea pig and provide rationale for clinical application. Methods DSP-loaded thermosensitive in situ gel was prepared by using poloxamer 407 as matrix. The HPLC assays for the determination of DSP and dexamethasone （Dex） in perilymph （PL）, cerebrospinal fluid （CSF） and plasma were developed, respectively. DSP-loaded gel and solution were administered after IT or IV （intravenous injection）. PL, CSF and plasma were collected periodically. The concentrations of DSP and Dex were measured by HPLC, and were used to estimate in vivo distribution and pharmacokinetic parameters of Dex in the inner ear. Results The AUC （area under curve） and t1/2 of Dex in PL following IT DSP-loaded gel were 593.7-and 28.6-fold higher than those following N DSP solution. Moreover, DSP-loaded gel following IT extended the mean residence time （MRT） by nearly 5 times, compared with the solution. After IT, the concentration levels of Dex in CSF and plasma were much lower than that in PL. Conclusion DSP thermosensitive in situ gel following IT has significant cochlea-oriented and sustained-release effect.