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

English Keywords:Spinal tuberculosis  Anti-uberculosis drugs  Poly lactic-co-glycolic acid  Release material  Best formula

English Abstract:

  【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.