多西环素牙周缓释原位凝胶的制备和局部刺激性研究

Preparation and in Vivo Irritating Study of Doxycycline Hyclate in Situ Forming Sustained Release Injection

目的制备可注射多西环素牙周缓释原位凝胶并进行体内刺激性初步研究。方法采用可生物降解的聚乳酸-羟基乙酸共聚物(PLGA)和聚乳酸(PLA)为缓释材料、生物相容性N-甲基-2-吡咯烷酮(NMP)为溶剂制备了盐酸多西环素原位凝胶,采用正交实验优化处方并对凝胶的体外释放、流变学以及家兔体内刺激性进行考察。结果优化后的处方:聚合物为聚乳酸-羟基乙酸共聚物(Mn=10 000),聚合物浓度为25%,盐酸多西环素浓度为10%。按最优处方制备的盐酸多西环素原位凝胶在37℃条件下2 h突释20%,缓慢释放10 d,累计释放率达90%以上。体外以一级释放为主,符合Fick扩散机制。该凝胶接近于牛顿流体,具有良好的流变学特性,家兔牙龈刺激性实验表明无明显刺激性。结论本实验所制备的多西环素牙周缓释原位凝胶可生物降解、利于注射,有望为临床提供一种用于牙周局部给药的多西环素缓释剂型,以缓解牙周病带来的牙槽骨吸收以及牙齿松动甚至缺失等临床症状。

OBJECTIVE To optimize the formulation and study the irritation of doxycycline hyclate in situ forming sustained re- lease injection. METHODS Doxycycline in situ forming gel （DHISFG） was prepared by using biodegradable, biocompatible PLGA and PLA as materials, and non-toxic NMP as solvent. Orthogonal design was used to optimize the gel formulation. The in vitro drug re- lease, rheology and irritation were also studied. RESULTS The optimal formulation of DHISFG was PLGA （Mn = 10 000）-NMP- doxycycline hyclate =25： 65： 10. The drug release from the DHISFG was 20% within 2 hours and above 90% after 10 days sustained release. The in vitro release data fit the first release and Fick diffusion mechanism. Gingival irritation test of rabbit showed no irrita- tion. CONCLUSION The developed DHISFG which is degradable and easy to inject could provide a new sustained release formula- tion to relieve the symptoms of periodontal disease such as alveolar bone absorption and tooth loss.