不同比例三联抗结核药物复合缓释材料的释药性能观察

Sustained-release composite of triple anti-uberculosis drugs: release property in different drug proportion

中文关键词:  脊柱结核  抗结核药  聚乳酸-羟基乙酸  缓释材料  配方

英文关键词:Spinal tuberculosis  Anti-uberculosis drugs  Poly lactic-co-glycolic acid  Release material  Best formula

中文摘要:

  【摘要】 目的：观察不同比例三联抗结核药物复合缓释材料在模拟体液中的药物释药性能。方法：以聚乳酸-羟基乙酸（PLGA）作为载体，采用双乳、喷涂、冷冻干燥溶剂挥发法制备不同比例抗结核药物的复合缓释材料：A组，异烟肼（INH，H）∶利福平（RFP，R）∶吡嗪酰胺（PZA，Z）=15∶15∶30；B组，H∶R∶Z=20∶30∶50；C组，H∶R∶Z=30∶30∶120；D组，H∶R∶Z=80∶120∶250。药物总质量与PLGA之比为1∶5。扫描电子显微镜（SEM）观察HRZ/PLGA复合缓释材料的表面形态，高效液相色谱法（HPLC）检测其在模拟体液中H、R、Z三种药物的释放浓度，计算药物累计释放量及释放率，分析其体外缓释性能。结果：A组和B组缓释材料表面分散均匀，空隙规则、分布均匀，直径分别为23.07±0.38μm和25.67±1.26μm；C组和D组缓释材料分散欠均匀，空隙不规则、分布欠均匀，直径分别为31.25±1.98μm和45.67±3.26μm。A组H、R、Z分别于42d、56d、42d的累计缓释度超过50%，于70d时的阶段释药量分别为157.43±057μg、129.29±0.14μg、196.43±0.28μg，浓度分别为28.486μg/ml、23.525μg/ml、39.265μg/ml。B组H、R、Z分别于35d、42d、35d的累计缓释度超过50%，于70d时阶段释药量分别为9.89±0.96μg、21.71±0.42μg、51.12±0.87μg，浓度分别为1.789μg/ml、1.618μg/ml、10.242μg/ml。C组H、R、Z分别于21d、35d、42d的累计缓释度均超过50%，于70d时阶段释药量分别为1.76±0.49μg、8.43±0.31μg、81.14±0.58μg，浓度分别为0.352μg/ml、1.618μg/ml、10.242μg/ml。D组H、R、Z分别于28d、42d、35d的累计缓释度均超过50%，于70d时阶段释药量分别为1.71±0.21μg、14.01±0.42μg、65.57±0.26μg，浓度分别为0.312μg/ml、2.128μg/ml、13.516μg/ml。70d时A组三种药物浓度均大于各自的10倍最低抑菌浓度（MIC），且A组分散均匀，空隙规则、分布均匀，直径约为23.07±0.38μm，三种药物在不同的时间段释放行为不相同，前14d药物缓释规律按Higuchi方程拟合最好，即前14d三种药物按照扩散的形式进行缓释，14d后三种药物按照零级动力学缓释曲线释放，即等量缓释。其余3组均有药物未达到10倍MIC。结论：复合HRZ/PLGA缓释材料具有优良的载药及药物缓释效果，是一种理想的复合药物缓释系统，其中H∶R∶Z=15∶15∶30的HRZ/PLGA缓释材料为较佳配方。

英文摘要:

  【Abstract】 Objectives: To observe the drug release property of sustained-release composite prepared by different proportion of triple anti-tuberculosis drugs in simulated body fluid, and to determine the optimum drug proportion of the sustained-release composite. Methods: The anti-tuberculosis drug sustained-release composite was prepared by multiple emulsion technique, vacuum-dried and spray-dried with poly lactic-co-glycolic acid(PLGA) as carrier: group A, isoniazid(H)∶rifampicin(R)∶pyrazinamide(Z)=15∶15∶30; group B, H∶R∶Z=20∶30∶50; group C, H∶R∶Z=30∶30∶120; group D, H∶R∶Z=80∶120∶250. The quality ratio of total drug and PLGA was 1∶5. The morphological characteristics of HRZ/PLGA were observed by scanning electron microscopy(SEM). Drug concentration and cumulative release of H, R, Z in HRZ/PLGA sustained-release composite were detected by HPLC in simulated body, the cumulative release amount and release rate were calculated, and the sustained-releases property was analyzed in vitro. Results: In group A, at the 42nd, 56th and 42nd day, cumulative release of H, R and Z were all higher than 50%. At the 70th day, stage release amount of H, R and Z was 157.43±057μg, 129.29±0.14μg, 196.43±0.28μg. And released concentration of H, R and Z was 28.486μg/ml, 23.525μg/ml, 39.265μg/ml. In group B, at the 35th, 42nd and 35th day, cumulative releases of H, R and Z were all higher than 50%. At the 70th day, stage release amount of H, R and Z was 9.89±0.96μg, 21.71±0.42μg, 51.12±0.87μg. And released concentration of H, R and Z was 21.789μg/ml, 1.618μg/ml, 10.242μg/ml. In group C, at the 21st, 35th and 42nd day, cumulative releases of H, R and Z were all higher than 50%. At the 70th day, stage release amount of H, R and Z was 1.76±0.49μg, 8.43±0.31μg, 81.14±0.58μg. And released concentration of H, R and Z was 0.352μg/ml, 1.618μg/ml, 10.242μg/ml. In group D, at the 28th, 42nd and 35th day, cumulative releases of H, R and Z were all higher than 50%. At the 70th day, stage release amount of H, R and Z was 1.71±0.21μg, 14.01±0.42μg, 65.57±0.26μg. And released concentration of H, R and Z was 0.312μg/ml, 2.128μg/ml, 13.516μg/ml. According to the HRZ/PLGA sustained- release composite achieving the longest sustained time, the drug concentration of H, R, Z was greater than the 10MIC respectively. In group A, at the 70th day, the concentrations of three anti-uberculosis drugs were all higher than 10 times of MIC at the same time, showing the best drugs proportion(H∶R∶Z=15∶15∶30) of the sustained-release composite in this study. Group A had satisfactory dispersion, regular pores and even distribution, with the pore diameter of 23.07±0.38μm. Within the first 14 days, the drug release best fitted in the Higuchi equation, suggesting HRZ sustained release in form of diffusion. After the first 14 days, HRZ release displayed zero order release kinetics, suggesting isometric sustained release. Conclusions: HRZ/PLGA sustained-release composite as an ideal drug delivery system, has excellent effect of drug loading and drug release. H∶R∶Z=15∶15∶30 is the best formula of the HRZ/PLGA sustained-release composite.