Tetradrine-tanshinone ? A-PLGA Microspheres Prepared By The SPG Membrane Emulsification Method

Microspheres, so called Multiphase dispersed system, are formed when drugs are distributed or absorbed in high polymer materials, of which the average size ranged from1to500?m, even with nano-size. Oweing to its potential to improve the solubility and distribution behavior of drugs, these microspheres with drugs were usually made in suspensions by injection or oral administration. Narrowly size distributed droplet size was required due to its strongly influence in improve drug loading efficiency?drug release in vitro and drug efficiency in vivo from the microspheres. However, microspheres prepared by conventional mechanical stirring, homogenization or ultrasonication method showed bigger droplet size and broader size distribution with low drug encapsulation efficiency. The stability and reproducibility of these emulsions were uncontrollable yet, SPG membrane emulsification method indeed can avoid these problems and show great advantage to prepare monodispersed microspheres with high drug encapsulation efficiency and stability.ObjiectiveResearch about Tetradrine-PLA microspheres with lung targeting potential have been successfully parapared in this program with SPG membrane emulsification method. According to a larger amount of study stastcics, this paper choose Tanshinone IIA to cooperate with Tetradrine, thus to treat silicosis together, and reduce irritation and liver damage from Tetrandrine injection. However, Tetradrine and Tanshinone IIA were kinds of BCS class II drugs which have low aqueous solubility, resulting in its low oral bioavailability and efficacy stability, what's more, Tanshinone IIA are applied in tanshinone IIA sulfonate injection for the treatment of cardiovascular disease, but studies have shown that the pharmacological effects betwwen pharmacological tanshinone IIA sulfonate and tanshinone IIA were in great difference. In order not to change the structure of tanshinone IIA, this paper tried to dispersed these two drugs in the same polymers to improve the solubility and realized the cooperation energy with SPG membrane emulsification method, this paper were looking forword to achieve the prescription decomposited and integrated from a "complex-simple-complex" direction. MethodsBased on single factor experiments, response surface method (RSM) was used to establish the mathematical model with SPG membrane emulsification technique to obtain the optimum conditions of Tanshinone IIA microspheres and Tetradrine-Tanshinone IIA microspheres. These microspheres were characterized in terms of drug loading efficiency, drug encapsulation efficiency, and polydispersity coefficient (PDI). The distributed behavior of these two drugs were observed by a series of mehods, such as scanning electron microscope, laser diffraction particle size analyzer, Infrared ectrography, DSC204differntial scanning calorimeter,XRD-6000intelligent X-ray dirrfactometer etc.Then the amount of organic solvent residual in the composite microspheres was measured by gas chromatography, and the amount of emulsifiers and stabilizers were measured by UV photometer. Futhermore in vitro and in vivo study of the composite microspheres was investigated.ResultsNarrowly size-distributed Tanshinone IIA-PLGA microspheres were obtained with a loading efficiency of1.20%and a high drug encapsulation efficiency of89.75%, an average diameter of2.338?m,PDI was0.328at the optimized condition. And Tetradrine-Tanshinone IIA-PLGA microspheres obtained at the optimized condition showed an average diameter of2.787?m withPDI of0.164, the totall drug loading efficiency of7.85%(7.21%of Tetradrine,0.64%of Tanshinone IIA), totall drug encapsulation efficiency of89.75%(88.55%of Tetradrine,46.86%of Tanshinone IIA)Both Tetradrine and Tanshinone IIA were highly dispersed in the PLGA polymers without crystals when the composite microspheres were observed in these methods above.Results of in vitro release showed that The total amount of cumulative release of these composite microspheres within24h was barely6.21%, and was84.10%after17days,(the amount of cumulative release of tetrandrine and Tanshinone IIA within24h was6.44%,3.60%, respectively. The amount of cumulative release of tetrandrine and Tanshinone IIA after17days was89.02%,21.24%, respectively). Then in vivo release behavior of the formulation was in correlation with Riger-Peppas models. While the residual amount of dichloromethane in the composite microspheres was87.9ppm (which was much less than the standard of600ppm in the Chinese Pharmacopoeia of2010version). The residual amount of polyethylene glycol4000was0.22%, and the residual amount of polyvinyl alcohol was0.24%.Injecting with the same dose of Tetrandrine-Tanshinone IIA-PLGA microspheres and bulk drugs group by the tail vein of rats. The in vivo pharmacokinetic results showed no significant difference between the two groups; however, results of the tissue distribution showed that both Tetrandrine and Tanshinone IIA in microspheres distributed highly in lungs of rats than the bulk drugs group, and showed obviously sustained release in lungs. The concentration of Tetrandrine in microspheres was0.12,1.56,4.76,8.48,9.07times higher than bulk drugs group in0.25,1,2,8,24h, respectively. What's more, Tetrandrine in bulk drugs group could not be detected after24h, while Tetrandrine in microspheres could still be detected after48h; Similarly, the concentration of Tanshinone IIA in microspheres was0.20,3.16,4.53,6.08,5.96times higher than bulk drugs group in0.25,1,2,8,24h, respectively.Conclusions:It is feasible to prepare uniform-sized Tetrandrine-Tashinone IIA-PLGA microspheres with high encapsulation efficiency by the SPG membrane emulsification technique SPG membrane emulsification technique. On one hind, this kind of composite microspheres could initially make the two ingridients acieve synchronous behaviors, on the other hand, the obtained microspheres were safer with low toxicity, in vitro stuy showed that they could reduce the burst release, in vivo study showed sustained release and lung-targeting potential. This study could be applied in other anti-tumor Chinese medicine compound preparation and provides a new idea and methods for the traditional Chinese medicine applying in DDS.