In vitro cell compatibility and antibacterial activity of microencapsulated doxycycline designed for improved localized therapy of septic arthritis
In vitro cell compatibility and antibacterial activity of microencapsulated doxycycline designed for improved localized therapy of septic arthritis
复制标题
DOI：
10.1093/jac/dkm491
复制
发表时间：
2008-02-01
影响因子：
5.2
通讯作者：
Gander, Bruno A.
中科院分区：
文献类型：
--
作者：
Haerdi-Landerer, M. Christina;Suter, Maja M.;Gander, Bruno A.
目的：对于大动物化脓性关节炎的治疗，局部应用抗生素作为缓释系统可能是一种适当的手段，以达到高的局部生物活性和低的全身副作用和药物残留。在这项研究中，多西环素微球的开发和测试在体外的药物释放特性，适用于关节内应用和抗菌activity.Methods：开发的缓释系统实现了微囊化的药物到聚（丙交酯-共-乙交酯）微球通过一种新的超声雾化方法。通过HPLC在预定时间点从分散在洗脱介质中的微球评价药物洗脱。通过评估促炎细胞因子mRNA的表达和一氧化氮（NO）的产生，在培养的牛滑膜细胞上测试关节组织相容性。最后，用暴露于微球悬浮后第1、7和12天取样的释放介质的革兰氏阴性和革兰氏阳性细菌评估释放的抗生素的抗微生物活性。适当尺寸的微球，多西环素在水性环境中充分稳定和药物释放（25 mg微球在4 mL培养基中）高于通常在牛和马关节中分离的细菌的MIC。虽然细胞因子mRNA表达反映了优异的组织相容性，但NO的结果产生了矛盾的结果。释放介质的抗微生物测试证明完全匹配的非胶囊化，游离多西环素的活性，在literation.Conclusions：新开发的多西环素输送系统达到了目标规格，并准备在体内测试。
Objectives: For the treatment of septic arthritis in large animals, the local application of antibiotics as a slow release system may be an appropriate means to reach high local bioactivity and low systemic side effects and drug residues. In this study, doxycycline microspheres were developed and tested in vitro for their drug-release properties, suitability for intra-articular application and antimicrobial activity.Methods: The development of a slow release system was achieved by microencapsulation of the drug into poly(lactide-co-glycolide) microspheres by a novel ultrasonic atomization method. Drug elution was evaluated from microspheres dispersed in elution medium at pre-defined time points by HPLC. Joint-tissue compatibility was tested on cultured bovine synoviocytes by evaluating the expression of pro-inflammatory cytokine mRNA and the production of nitric oxide (NO). Finally, the antimicrobial activity of the released antibiotic was assessed with Gram-negative and Gram-positive bacteria exposed to release medium sampled at days 1, 7 and 12 after microsphere suspension.Results: An adequate size of the microspheres, sufficient stabilization of doxycycline in aqueous environment and drug release (25 mg microspheres in 4 mL medium) above MIC for bacteria usually isolated in bovine and equine joints were obtained over 15 days. Although the cytokine mRNA expression reflected the excellent tissue compatibility, the results with NO yielded contradictory results. Antimicrobial tests of the release medium proved to match perfectly the activity of non-encapsulated, free doxycycline as reported in the literature.Conclusions: The newly developed doxycycline delivery system achieved the target specifications and is ready for in vivo testing.