Preformulation research on the nasal preparation of mianserin hydrochloride
Objective To determine the equilibrium solubility,apparent oil-water partition coefficient(Papp)and solution chemical stability of mianserin hydrochloride(MIA),and to screen the optimal permeation enhancer of the drug absorption via nasal mucosa to provide a theoretical basis for MIA nasal preparation.Methods The concentration of MIA and its equilibrium solubility in various solvents were determined by HPLC.The Papp values of MIA in the n-octanol-water and n-octanol different pH buffer systems were measured with the shaking bottle method.The degradation percentage of MIA aqueous solution was also determined under different pHs and at various time intervals after it was placed at 80 ℃.Finally,the ideal permeation enhancer of MIA absorption across the nasal mucosa was sieved by Franz diffusion cell method,with in vitro sheep nasal mucosa as the test model.Results The equilibrium solubility of MIA in different solvents followed the order below:propylene glycol＞5％DM-β-CD＞5％HP-β-CD＞1％F68＞PEG400＞5％SBE-β-CD＞purified water.Meantime,the equilibrium solubility of MIA was larger at acidic or neutral pH media,but quite low at alkaline pH environment.In n-octanol different pH buffer systems,the Papp values of MIA generally increased with pH.MIA aqueous solution was less stable in acidic pHs below 6.0,and most stable at pH≥6.0.The candidate permeation enhancers all exhibited an obvious permeation-improving effect on MIA absorption through the nasal mucosa,but 5％DM-β-CD proved to be the strongest.Conclusion The three water-soluble β-CD derivatives all improve the solubility of MIA.The pH obviously affects the equilibrium solubility of the drug,its Papp and aqueous solution chemical stability.DM-β-CD may be an ideal solubilizing agent and permeation enhancer for MIA nasal preparation.
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