缓释双药物载体制备与性能

Dual-drug sustained-release carrier: Preparation and performance

背景:骨结核患者常规用药,病灶处结核药物的有效浓度低,治疗效果差。目的:制备一种可直接植入骨结核病灶内的,且具有在骨结核周围组织能够长期保持一定的抗结核药物浓度,起到提高骨结核的治愈率有效治疗的新型生物材料。方法:采用乳剂-溶剂挥发法制备利福平-聚乳酸-羟基乙酸共聚物微球和异烟肼-聚乳酸-羟基乙酸共聚物微球,利用生物黏合剂α-氰基丙烯酸烷基酯将2种微球加工成长效缓释双组分药物载体,观察缓释双药物载体体外释药特性;然后将缓释双药物载体置入兔股骨转子间骨缺损部位,观察载药缓释载体植入后不同时间点药物释放浓度、组织相容性及骨缺损的愈合情况。结果与结论:利福平-聚乳酸-羟基乙酸微球平均粒径(240±13)μm,载药率为(26±1.5)%。异烟肼-聚乳酸-羟基乙酸微球平均粒径(250±10)μm,载药率为(28±1.8)%。利福平、异烟肼,90d体外累积释放率可达到80%和90%。90d体内释放利福平和异烟肼的浓度可达(0.5±0.4)和(0.6±0.3)μg/g。缓释双药物载体置入兔股骨转子间骨缺损部位可见筋膜、肌纤维之间出现少量中性粒细胞浸润,59d后肌肉组织中性粒细胞明显减少,X射线平片显示骨缺损明显缩小。提示该载体能够长时间保持骨结核周围组织中一定的药物浓度,弥补血中药物浓度不足,有望在骨结核手术治疗中提供一种新型的双药物缓释载体。

BACKGROUND： During conventional treatment for bone tuberculosis, there is a low effective concentration of anti-tuberculosis drugs, and the therapeutic effect is poor. OBJECTIVE：To develop a new biomaterial as a slow-release artificial carrier that can be directly implanted into the surrounding tissue of bone tuberculosis, maintain a certain anti-tuberculosis drug concentration for a long time, thereby playing an effective therapeutic action. METHODS：Rifampicin/polylactic acid/glycolic acid microspheres and isoniazid/polylactic acid/glycolic acid microspheres were prepared using the emulsion-solvent evaporation method. Usingα-cyanoacrylate, a biological adhesive, two kinds of microspheres were processed into a long-term slow-release bicomponent drug carrier. Then, in vitro release characteristics of the dual-drug sustained-release carrier were observed. After that, the dual-drug sustained-release carrier was implanted into rabbit intertrochanteric femur bone defects for observing drug release concentrations, histocompatibility and bone defect healing at different time points after drug delivery carrier implantation. RESULTS AND CONCLUSION：For rifampicin/polylactic acid/glycolic acid microspheres, the mean particle size was （240±13）μm, and the drug loading load rate was （26±1.5）%. For isoniazid/polylactic acid/glycolic acid microspheres, the mean particle size was （250±10）μm, and drug loading rate was （28±1.8）%. The in vitro cumulative release rate could reach 80%for rifampicin and 90%for isoniazid at day 90. The in vivo released concentration of rifampicin and isoniazid within 90 days was （0.5±0.4） and （0.6±0.3）μg/g, respectively. There were a smal amount of infiltrated neutrophils between the fascia and muscle fibers after the drug delivery carrier was implanted, and the amount of neutrophils in the muscle were reduced significantly at day 59. X-ray plain film showed that bone defects decreased obviously in size. These findings indicate that this dual-drug sustained-release carrier can maintain a certain anti-tuberculosis drug concentration in the surrounding tissues of bone tuberculosis, which is expected to provide a new type of dual-drug delivery carrier in the surgical treatment of bone tuberculosis.