Preparation Of Nintedanib Solid Dispersion And Its Evaluation In Vitro And In Vivo

Background:Nintedanib is a small molecule tyrosine kinase receptor inhibitor and belongs to the biopharmaceutics classification system（BCS）class II or class IV drugs.This drug was first approved by FDA in 2014 for the treatment of idiopathic pulmonary fibrosis,which only could be treated by lung transplantation medically.Due to the low solubility in intestinal tract,the bioavailability of nintedanib is only 4.7%,which seriously affects its clinical application.Purpose:To maintain the supersaturated state of the drug in intestinal tract,the amorphous solid dispersions were prepared by screening suitable polymers,thereby improving the absorption of the drug in the intestinal tract and increasing its bioavailability.Methods:（1）The HPLC analysis method for nintedanib was established and validated.The solubility and oil-water distribution coefficient of nintedanib at different p H values were determined.Based on the results of simulated dissolution and solubility of nintedanib in intestinal tract,the solubilizing properties of various polymers were investigated and suitable polymers were screened.（2）We investigated the supersaturated crystal inhibition capacity of the selected four polymers.The four polymers were used as carriers to prepare solid dispersions with different proportions by a solvent evaporation method.The obtained solid dispersions were characterized by scanning electron microscopy（SEM）,differential scanning calorimetry（DSC）,X-ray diffraction（XRD）,and Fourier transform infrared spectroscopy（FT-IR）.We also explored the intermolecular interaction between the drug and polymers by molecular docking method.Moreover,the dissolution performance of different solid dispersions in vitro was further studied,and their stability was investigated to determine the optimal prescription of solid dispersions.（3）A method for the determination of nintedanib in rat plasma by LC-MS/MS was established and validated.The bioavailability of the screened solid dispersion was evaluated in rats.Results:（1）The HPLC analysis method of nintedanib showed high precision and good linearity in the range of 1～100μg/m L.The solubility of nintedanib was high in an acidic environment and low in an alkaline environment,indicating a high p H dependence of nintedanib.Moreover,the experimental results of simulated dissolution and solubilization of nintedanib in different polymer solutions showed that Eudragit L100,Eudragit L100 55,HPMCAS MG and HPMCAS LG possess solubilization effects.（2）The crystal inhibition capacity of the four polymers follows as:Eudragit L100>Eudragit L100 55>HPMCAS MG>HPMCAS LG.The physical characterization results showed that the drug existed in an amorphous state,and there was molecular interaction between the drug and polymers.Besides,the results of in vitro dissolution tests showed that the solid dispersion with a ratio of nintedanib to Eudragit L100（1:5）showed good enteric dissolution properties and it helped to promote the maintenance of drug supersaturated solution.The prepared solid dispersion showed good stability for 10 days at 60℃and 92.5%humidity.（3）The established LC-MS/MS method for the determination of nintedanib in rat plasma presented good linearity in the range of 1～500 ng,and its precision and recovery met the methodological requirements.The pharmacokinetic study in rats showed that the AUC and C_max of solid dispersion with a ratio of nintedanib to Eudragit L100（1:5）were 2.45 times and 1.49 times that of active pharmaceutical ingredient（API）,respectively.These findings indicated that the preparation of nintedanib as solid dispersion could significantly improve drug oral bioavailability.Conclusion:The solid dispersion prepared with the ratio of nintedanib to Eudragit L100of 1:5 can significantly increase the drug dissolution in the intestinal tract and effectively improve the oral bioavailability of nintedanib.This study laid a foundation for the research and development of new nintedanib formulations and provided a useful reference for improving the oral bioavailability of other poorly soluble drugs.