Preparation And Evaluation Of Chitosan Microspheres Containing Methotrexate For Delivery Into Brain Tissue By Intranasal Administration

Objects: Methotrexate was selected as the model drug for the study of microspheres for nose-to-brain administration. Drug delivery by the nasal route has recently received lots of attention. At present, the most important thing to deal with it is how to prolong the nasal residence time of drug. In our study, methotrexate, a widely used anticancer drug, was encapsulated into chitosan microspheres to increase the residence time in the nasal cavity and improve its absorption.Methods: On the basis of scientific literatures and pretesting, chitosan microspheres were prepared using spray-drying technique. We analyzed the formula factors and the process factors that had more influence to the evaluation indexes of microspheres. Then orthogonal design was used to select the optimal formula. In the course of that, the product yield and the entrapment efficiency of microspheres were selected as evaluation indexes. It was found that pump speed and the concentration of chitosan had much influence on indexes of microspheres. Chitosan microspheres made from the optimal formula had narrow size distribution. The average diameter was 4-5μm. And the methotrexate loaded chitosan microspheres showed a smooth surface, irregularly depressed shape and hollow inside. There was no free drug present on the surface. DSC results indicated that methotrexate was dispersed amorphously in the microspheres. The release profiles and mucoadhesive properties were affected by the drug loading and the molecular weight of chitosan employed. With the molecular weight of chitosan increased, the release of the drug decreased. Ritger-Peppas equation was introduced here to investigate the release mechanism of the methotrexate microspheres. Nasal ciliotoxity showed no cilia irritation for the microspheres and can be used in the nasal drug delivery. Influence parameter studies showed that the formulation of methotrexate was stable under high temperature and high light, but easy to absorb water under high humidity. Pharmacokinetics study indicated that following intravenous administration, few methotrexate could be detected by HPLC, however, when nasal dosing methotrexate solution and microspheres, they can reach the brain tissue via the nasal route. The AUC0-240 of the methotrexate microspheres in brain tissue was about 118% compared with methotrexate solution. The higher relative bioavailability was attributable to the prolonged retention with the nasal mucosa and permeation enhancement of Chitosan. It can be concluded that nasally administered MTX could markedly improve the bioavailability, and a fraction of the MTX dose could be transported directly from the nasal cavity into the brain tissue.