Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

Background and objectives
Background and objectives
The most popular nasal drug delivery is nasal application of topical decongestants or antiinflammatory
drugs, to treat rhinitis or allergy related symptoms. In addition, for transmucosal nasal
absorbed drugs the nasal route provides direct access to the systemic blood circulation. For drugs
with constricted oral bioavailability, due to degradation in the intestinal tract or hepatic first-pass
effect, transmucosal nasal delivery is an interesting alternative to intravenous and intramuscular
drug administration. A challenge in transmucosal nasal drug delivery is the limited volumetric
capacity of the nasal cavities. Therefore, the entire dose, preferably administered in solution, has to
be instilled in a limited volume. Consequently, solubility of the drug is one of the critical parameters
in transmucosal nasal drug delivery.
Midazolam is a benzodiazepine used for the treatment of anxious patients undergoing diagnostic or
surgical procedures (procedural anxiolysis and/or sedation in adults and children) and the
treatment of seizures (epileptic or febrile). These therapeutic indications are clinical situations, in
which drug administration is potentially difficult and rapid onset of therapeutic effect absolutely
desirable. Intranasal administration of midazolam has been of particular interest, because of the
rapid and reliable onset of therapeutic effect and the convenience of administration. Due to low
midazolam concentration, the commercially available preparation for intravenous administration
(Dormicum ® , Roche) is not optimal for transmucosal nasal midazolam delivery. For the optimization
of transmucosal nasal midazolam delivery minimized administration volumes are essential to
reduce the risk of swallowing the administered preparation. Therefore, nasal preparations with
enhanced midazolam concentrations need to be provided.
The aim of Project I was the development and in vitro characterization of preparations for
transmucosal nasal midazolam delivery. Several solubilization enhancers were evaluated to reduce
the administration volume. For the developed midazolam preparations stability testing was
performed.
The purpose of Project II was the pharmacokinetic characterization of the developed preparations
for transmucosal nasal midazolam delivery. The influence of the vehicle, namely RMβCD
(solubilization enhancer) and chitosan hydrochloride (penetration enhancer) on pharmacokinetic
profile of nasally delivered midazolam was assessed.
In a multicenter trial (Project III) two midazolam preparations for transmucosal nasal midazolam
delivery were compared in anxious and/or claustrophobic patients undergoing MRI examination.
The objectives of this thesis were to provide preparations for transmucosal nasal midazolam
delivery (Project I), to assess the pharmacokinetic characteristics of nasally applied midazolam
(Project II), and to compare the benefit of two nasal midazolam preparations for procedural
anxiolysis in anxious patients undergoing MRI examinations (Project III).
Katja Suter-Zimmermann Page 7 of 188 University of Basel, 2008