Development Of Gefitinib Loaded PLLA Dry Powder Inhalation

Gefitinib(Gefitinib,GFB),a selective epidermal growth factor receptor tyrosine kinase inhibitor,is suitable for the previously treated with chemotherapy,or the local late chemotherapy,or the metastatic non-small cell lung cancer.However,some limitations in clinical applications were found because of its poor solubility,high binding to human hemoglobin,low bioavailability and larger side effects.Therefore,it would be a great significance to improve the water solubility of GFB and to reduce the binding degree of hemoglobin and reduce the side effects.In this paper,the supercritical anti-solvent(SAS)technology was selected to prepare GFB@PLLA microspheres,the mixed solvent ethanol(EtOH)/dichloromethane(DCM)was used as the GFB and PLLA solvent system,while the supercritical carbon dioxide(scCO2)as the anti-solvent.GFB@PLLA microspheres with smaller particle size(1~5?m)were prepared by adjusting the parameters during the SAS process.The prepared samples were characterized by a series of characterization,such as particle size distribution(PSD),scanning electron microscopy(SEM),X-ray diffraction(XRD),differential scanning calorimetry(DSC)and Fourier transform infrared spectroscopy(FT-IR),in vitro release and cytotoxicity,etc.The optimal GFB@PLLA micro-particles blended with the anhydrous lactose sieved using the200 mesh in different proportions,then the powder properties of the blended powders were measured by homemade two-stage impinge.The results show that the GFB@PLLA particles,with drug loading 15.82%,mean size2.48?m and higher encapsulation rate 94.91%,were prepared using the SAS technology at the optimal conditions.The experimental results of XRD,DSC and FT-IR showed that when the GFB@PLLA particles with higher drug loading,the GFB was loaded in PLLA with a new polymorph that difference from the crystal type of raw GFB;while the GFB was loaded in PLLA in an amorphous state when the drug loading was lower.The results of the in vitro anti-tumor activity showed that the GFB@PLLA particles prepared by SAS were better than raw GFB.Finally,the optimal GFB@PLLA particles were blended with the sieved anhydrous lactose at the mass ratio 1:1,and the powder properties of the blended powders were measured.The results showed that the average value of CI is 9.69,the angle of repose(?)is 23°,the emited dose(ED)is 96.64%,the effective deposition in the lung is 20.06%,and the fine particle fraction(FPF)is 40.62% meeting the requirements of dry powder inhalation.