Studies On Intranasal Brain Drug Targeting Delivery System For Galanthamine Hydrobromide

An anti-AD drug, galanthamine hydrobromide was select as our research project. The stability and the influence of galanthamine hydrobromide on nasal mucosa were studied. Then the concentration of galanthamine hydrobromide in brain after intranasal and intravenous administration at different time was determined. Finally the formulation of galanthamine hydrobromide hydrogel was developed and a spray was prepared.First, the stability of galanthamine hydrobromide, and its influence on nasal mucosa were determined. Galanthamine hydrobromide was stable in solution of pH5.0～6.5 and this pH range was chosen as the pH range of galanthamine hydrobromide. The influence of galanthamine hydrobromide on nasal mucosa was light, and the drug was suitable for intranasal administration.To increase the settling time of galanthamine hydrobromide in nasal cavity, hydrogels were used. Second, the characteristics, pH, the weight of each spray and the influence on cilia of several hydrogels, CMCNa, HPMC, PEG and PVP were investigated and HPMC was selected. Influence of several absorption enhancers on nasal mucosa was studied and the nasal toxicity of 0.1%EDTA and 5%2-HP-β-CD were more slight. Benzalkonium bromide was selected as antiseptics after the determination of nasal toxicity.Third, a HPLC analysis method was developed to investigate the distribution of galanthamine hydrobromide into brain and plasma. The methodology of HPLC analysis in rat brain and plasma was studied. SD rats (250g～280g) were used in the study. Galanthamine hydrobromide was then administered by intragastric administration, intranasal administration and intravenous injection(8 mg·kg^-1). At different timepoints post dose, blood and brain were collected. The AUC values of brain after intranasal administration were about 3.2 and 2.2 times of those after intragastric and intravenous administration, respectively. However, the AUC values in plasma obtained after intranasal administration were about 0.54 and 0.21 times of those after intragastric and intravenous administration, respectively. The influence of hydrogels and absorption enhancers on nasal absorption was investigated. HPMC has the effect of sustained release and the concentrations in brain were the highest after 2-HP-β-CD added.Finally, the influence of pH, concentration of HPMC and concentration of 2-HP-β-CD on the release of galanthamine hydrobromide hydrogel were studied and the formulation was determined. Then a galanthamine hydrobromide spray was prepared. A HPLC analysis method was developed and the stability of galanthamine hydrobromide hydrogel was studied. The hydrogel was stable in light but unstable in heat and the hydrogel should be stored at low temperature.