Summary
Midazolam is a benzodiazepine with short elimination half-life, used as induction or continuous agent for general anesthesia. At present, only injectable solution is available from French hospital pharmacies. The aim of the study is the development of 5 mg midazolam sublingual tablets to realize a short general anesthesia without intravenous or intramuscular injection.
Incorporation of citric acid in the tablet formulation 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 presence of 10 mg of citric acid is ionised. The ionised form, more hydrophilic, cannot cross the artificial lipid membrane and therefore the diffusion 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 results leads us to choose the sublingual formulation containing 5 mg of citric acid per tablet.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Klotz U., Reimann I.W. (1984): Chronopharmacokinetic study with prolonged infusion of midazolam. Clin. Pharmacol. 9, 469–474.
Puglisi C.V., Pao, J., Ferrara F.J., De Silva J.A. (1985): Determination of midazolam (Versed®) and its metabolites in plasma by high performance liquid chromatography. J. Chromatogr. 344, 199–209.
Smith M.T., Eadie M.J., Rourke O., Brophy T. (1981): The pharmacokinetics of midazolam in man. Eur. J. Clin. Pharmacol., 19(4), 271–278.
Schutz H. (1989): Benzodiazepine II. In: Handbook, basic data, analytical methods pharmacokinetics and comprehensive literature. Berlin: Springer Verlag.
Garzone P.D., Kroboth P.D. (1989): Pharmacokinetics of the newer benzodiazepines. Clin. Pharmacokinet, 16, 6, 337–364.
Fujii J., Inotsume N., Nakano M. (1988): Relative bioavailability of midazolam following sublingual versus oral administration in healthy volunteers. J. Pharmacobio-Dyn., 11, 206–209.
Alfonso-Echeverri E., Troutman K.C., George W., (1990): Absorption and elimination of Midazolam by submucosal and Intramuscular routes. Anesth. Prog., 37, 277–281.
Ridley D., Washington N., Wilson C.G. (1991): Drug delivery to the buccal and nasal cavities, anatomical and physiological considerations. In: buccal and Nasal administration as an alternative to parental administration. European symposium APGI Paris, Ed. de Sant, Minutes: Paris, 13–28.
Barthélémy C., Lefebvre C., Guyot-Hermann A-M. (1986): Conception et_tude d'une nouvelle membrane pour simuler l'absorption passive. Il Farmaco, 41, 11, 363–376.
Barth_l_my C., Lef_bvre C., Guyot-Hermann A-M. (1987): Utilisation of non polar membranes to simulate passive diffusion of drugs through biological membranes. Chimica Oggi, 11, 15–21.
Ritschel W.A. (1973): Biopharmaceutical Development and Evaluation of Oral DosageForms. In: applied biopharmaceutics II, Ed. College of Pharmacy: University of Cincinnati, Chap. 23, 1037–1059.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Odou, P., Barthelemy, C. & Robert, H. Development of midazolam sublingual tablets: in vitro study. European Journal of Drug Metabolism and Pharmacokinetics 23, 87–91 (1998). https://doi.org/10.1007/BF03189320
Issue Date:
DOI: https://doi.org/10.1007/BF03189320