DEVELOPMENT OF MIDAZOLAM SUBLINGUAL TABLETS - IN-VITRO STUDY

Midazolam is a benzodiazepine with short elimination half-life, used a s induction or continuous agent for general anesthesia. At present, on ly injectable solution is available from French hospital pharmacies. T he aim of the study is the development of 5 mg midazolam sublingual ta blets to realize a short general anesthesia without intravenous or int ramuscular injection. Incorporation of citric acid in the tablet formu lation leads to an increase of dissolution rates of active drug, but a decrease of diffusion through lipid membranes is observed with 10 mg of citric acid when using the Dibbern's Resomat three phases apparatus . One explanation of this result is that midazolam (pKa = 6.1) in pres ence of 10 mg of citric acid is ionised. The ionised form, more hydrop hilic, cannot cross the artificial lipid membrane and therefore the di ffusion decreases. On the other hand, the decrease of diffusion's rate , when pH increases, is explained by the precipitation of midazolam at pH higher than 6. A compromise between dissolution and diffusion resu lts leads us to choose the sublingual formulation containing 5 mg of c itric acid per tablet.