Controlled Preparation Of Nano-and Micro-structured Antiasthmatic Drug Particles And Their Application In Dry Powder Inhalation

The purpose of the thesis was to produce budesonide and salbutamol sulfate particles suitable for dry powder inhalation via high gravity controlled precipitation (HGCP) combined with spray drying. The feasibility, influencing factors of process, and in vitro evaluation of dry powder inhalation were investigated.Asthma is one of the high incidence diseases in the world. Currently, the annual sales of antiasthmatic drugs were estimated tens of billions of US dollars in global market, and RMB￥4.5～5.6billion in domestic market. Budesonide, an anti-inflammatory asthmatic drug and salbutamol sulfate, a bronchodilator drug were the most commonly used in the treatment of asthma, but now most of the domestic anti-asthmatic drug market was occupied by foreign brands. Consequently, they were recommended as key projects by the State Economic and Trade Commission, the State Pharmaceutical Board to development. Pulmonary delivery is the best way to treat asthma, because of effective deposition in the lower airways and deep lung, where drugs are most efficiently absorbed, the particle aerodynamic diameter (Dae) needs to be in the1～5μm range. It is testifying to the need of micronizing or nanosizing drugs for pulmonary delivery. Dry powder inhalation (DPI) has become more favorable owing to the prohibition of the CFC propellant in pMDI. Superior delivery efficiency may be achieved more cost-effectively by developing optimized particulate formulations for use with simple and user-friendly inhalers, which is synonymous with the controlled production of drug particles in ultra-fine size, narrow particle size distribution (PSD) and low bulk density. HGCP is an innovative and promising technology to produce ultra-fine particles with narrow PSD. Spray drying technology has been widely applied in the processing of pharmaceutical materials in industry. The drug particles can be granulated and dried simultaneously via spray drying. In light of the difference of crystallization process in the budesonide and salbutamol sulfate, HGAP and HGRP were employed to prepare their ultra-fine particles, respectively.Firstly, when budesonide particles were produced by HGAP, the influencing factors including the choice of solvent and antisolvent, the ratio of solvent to antisolvent, the incorporation time, the crystallization temperature and the mixing intensity, were studied. The results indicated that the elliptic flaky particles (average3μm in length,2μm in width, and200nm in thickness) could be obtained in the slurry under the optimal conditions, which were that the concentration of budesonide methanol was30mg·ml-1,the volume ratio of solution to water was1:7, the rotating speed of RPB was2840rpm, the incorporation time was5min, and the temperature was0℃. The specific surface area of such particles was7.24m2·g-1, which are twice as that of raw material. The recovery of the process was up to96.02%. The vacuum dried budesonide powder had the same chemical structure and crystal form analyzed by FT-IR and XRD. There were no free water, crystal water, and methanol residue in the powder characterized by DSC and gas phase chromatography.Salbutamol sulfate was prepared via HGRP by intense mixing of800ml10mg·ml-1isopropanol solution of salbutamol and8ml2.0mol·L-1sulfuric acid inside a RPB to form Salbutamol sulfate ultra-fine particles with0.98μm in volume median diameter. The reaction parameters were20℃,2840rpm of rotating speed and20min of incorporation time.Secondly, a mechanism model was proposed to explain the formation of porous spherical agglomerates by spray drying. According to the model, when the slurry that was consisting of submicron or nanosized primary particles was spray dried, the diameter of primary particles (dp), the solid concentration of the slurry (Φ), the spray drying temperature (T), and the droplet diameters (DD) were the key factors affecting on the size and morphology of PSA. The results indicated that2.90-μm budesonide and2.10-μm salbutamol sulfate PSA could be obtained under the optimal spray drying conditions. The specific surface areas of budesonide PSA and salbutamol sulfate PSA were8.71m2·g-1and24.7m2·g-1,respectively. Compared with the spherical particles spray dried from the solution, the PSA had the larger particle size, but more narrow PSD. In addition, the spherical particles spray dried from the solution were in amorphous form, which would lead to physical instability of the drug. Assessed by FT-IR and XRD, the spray drying process did not change the chemical structure and crystal form of both PSA.Among all the budesonide powders, the PSA powder had the highest aerosol performance when dispersed by the Aerolizer(?) at60L·min-1.The FPFemitted was82%, which was14%higher than PulmicortTM Turbuhaler(?). The flowability could be improved by blended with lactose as carrier. However, part of the fine PSA were deposited with big lactose particles on stage1of MSLI together, which leaded the decrease of FPFemitted.Due to the higher specific surface area, dispersion of the salbutamol sulfate PSA powder in MSLI gave the FPFloaded and FPFemitted of77%and86%by the Aerolizer(?) operating at60L·min-1, which were twice as those of the jet milled salbutamol sulfate. Moreover, the capsule and device retention of such powder was only10%, which indicated that compared with the jet milled salbutamol sulfate, the emitted dose of salbutamol sulfate PSA powder was increased from60%to90%.