Preparation Of Danshen Inhalation Powder And Its Pharmacodynamics For Idiopathic Pulmonary

Objective:Salvianolic acids and tanshinones, the major extractions of Salviae Miltiorrhizae radix et rhizoma, were both displayed significant anti-pulmonary fibrosis effects. The aim of this study was to formulatethe Salvia Miltiorrhiza powder for inhalation with narrow drug particle size distribution, good liquidity and high lung deposition rate. The Salvia Miltiorrhiza powder for inhalation was dosed through the pulmonary drug delivery to increase the local concentration of salvianolic acids and tanshinones and enhance the efficacy for idiopathic pulmonary fibrosis (IPF), in the expectation of providing new ideas and methods for researching and developing safe, effective and convenient drugs for IPF treatment.Methods:salvianolic acids, which were purified with macroporous resin, and tanshinones were co-micronized to formulate salvianolic acids-tanshinones composite powder using a planetary ball mill. The micronization process parameters were optimized by central composite design (CCD) and response surface methodology (RSM). Treatment time, rotation speed and the ball/sample weight ratio were selected as the independent variables, and the volume fraction of particle size in 1-5μm was set as the dependent variable. The powder properties were characterized by scanning electron microscopy (SEM), laser diffraction and X-ray powder diffraction (XRPD). The powder flow and hygroscopicity were evaluated by the determination of repose angle, compressibility index and critical relative humidity (CRH). The Salvia Miltiorrhiza powder for inhalation was prepared by blending the salvianolic acids-tanshinones composite powder with coarse lactose and micronized lactose. Formulation and preparing process was optimized through completely randomalized design to obtain better in vitro inhalation behavior and fluidity.The pulmonary fibrosis model was established by intratracheal instillation of bleomycin. The salvianolic acids-tanshinones composite powder was dosed through the pulmonary drug delivery. The effect of treatment was evaluated by pathomorphology, fibrosis score, the contents of hydroxyproline (HYP) and transforming growth factor-β1 (TGF-β1)in lung tissue of rats.Results:The best purification process of salvianolic acids involved D101 macroporous resin, ratio of diameter to height of resin column 1:3,24.3 mg·mL-1 drug solution at a loading rate of 1 mL·min-1 with a volume of 3BV, absorption time of 3h,6 BV water washing, and 40% ethanol washing at a washing rate of mL·min-1 with a volume of 7 BV.The purity of salvianolic acid B and salvianolic acids were 79.3% and 101.2% and the transfer rate were 73.6% and 68.7% respectively.The salvianolic acids and the tanshinoneswere mixed and grinded by wet ball milling with particle size distribution in 1-5 microns volume percentage as an index. the best preparation process which optimized by CCD-RSM for:take 80% salvianolic acids 4.565 g,60% tanshinones 2.435 g (salvianolic acids:tanshinones= 5:2), in 100 mL stainless steel ball grinding jar, grinding media for the stainless steel grinding ball (Φ 5:Φ3=1:8), ratio of grinding media to drug 17.5(g·g-1), add cyclohexane 7 g, ball grinding time 3.5 h, rotating speed of 250 r·min-1, then dry the suspension by rotary evaporation.The salvianolic acids-tanshinones composite powder which was produced in optimal conditions had a narrow and unimodal particle size distribution and a smaller D50 of 2.33μm. The volume fraction of particle size in 1-5μm was 80.82%.The compressibility index was 50.60°±1.13° and critical relative humidity (CRH) was 77%.Mixingthe salvianolic acids-tanshinones composite powderwithcoarse carrier lactose can effectively improve the dispersion and fluidity of powder and affect its in vitro inhalation behavior.Fluidity and fine particle dose as indexes, the optimum formulation was the salvianolic acids-tanshinones composite powder: coarsecarrier lactose:micronized lactose= 1:6:0.37.The Salvia Miltiorrhiza powder for inhalation has good in vitro inhalation behavior with repose angle of 52.46°,compressibility index of34.00%, salvianolic acid B and tanshinone Ⅱ A delivery rate of 80.24% and 85.70% and fine particle doses of 40.81% and 45.30% respectively.Through pulmonary drug delivery device targeted delivery of salvianolic acids-tanshinones composite powder to rat lungs.Conclusions:This study indicate that the grinding method using a planetary ball mill is useful to reduce the drug particles size below 10μm and prepares composite drug powders for dry powder inhalation. CCD-RSM is suitable for process optimization of salvianolic acids-tanshinones composite powder.Add coarse carrier lactose and micronized lactose in composite powder can effectively improve the dispersion and fluidity of composite powder. The Salvia Miltiorrhiza powder for inhalation has good in vitro inhalation behavior and dispersion performance.