Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

4. Compounding of nasal midazolam preparations
Due to the limited nasal capacity the whole midazolam dose has to be administered within 50 µl to
400 µl. To deliver therapeutic midazolam doses, nasal preparations with midazolam concentration,
exceeding solubility of midazolam in water need to be developed. For example, to deliver the dose
of 3 mg midazolam by instilling a volume of 100 µl, concentrations of 30 mg/ml midazolam are
required. Suitable solvents and solubilizers are needed to compound preparations for nasal
midazolam delivery. Table 4-1 lists some solubilizers, which have been described in literature to
solubilize midazolam for nasal administration.
Table 4-1: Different approaches to solubilize midazolam for nasal administration
Solubilizer
Propylene glycol 26%,
benzyl alcohol 1%
Midazolam
concentration
Comment
Reference
27.8 mg/ml 2% propylene glycol is isotonic with serum [Knoester
et al. 2002]
β-cyclodextrin 10 mg/ml Less nasal irritation compared with nasal
administration of Dormicum ® for injection
5mg/ml (Roche, Basel, Switzerland)
[Roelofse
et al. 2000]
Sulfobutylether-βcyclodextrin
(Captisol ® ,
CyDex, USA)
30 mg/ml, pH 3 Different cyclodextrin derivates were
investigated to solubilize midazolam. Above
pH 5 the maximal midazolam concentration is
5 mg/ml.
[Loftsson
et al. 2001]
4.2.2 Bio- and mucoadhesive excipients
Bioadhesion and mucoadhesion describe adhering of synthetic or natural macromolecules to
biological or mucosal surfaces. Most biological surfaces of interest for drug administration are
mucosal surfaces and the epithelial cells are covered with a mucus layer. Mucus is a complex
hydrated gel-like material containing the large glycoprotein mucin. The term mucoadhesion
describes molecules binding to a mucus layer, whereas bioadhesion describes the direct
interaction of macromolecules with the cell surfaces. But, these two mechanisms of adhesion can
hardly be differentiated; furthermore, many bioadhesives interact with biological surfaces by a
combination of these two mechanisms. The term specific bioadhesion refers to specific
interaction with defined structures. Specific bioadhesion is applied to target defined structures of
the cell surface [Woodley 2001].
The mechanism of non-specific bioadhesion is supposed to result form electrostatic interaction of
negatively charged cell surfaces and cationic macromolecules (e.g., chitosan see also chapter 4.4).
For anionic bioadhesive molecules, the interaction with the biologic surface is composed of
hydrophobic interaction, H-bonds, and Van der Waals interactions.
Addition of bioadhesive excipients to nasal preparation elongates the nasal residence time of
nasally delivered preparations. The prolonged residence time favors, complete release of the drug
from the preparation and thereby efficient transmucosal absorption [Dondeti et al., 1996].
Katja Suter-Zimmermann Page 32 of 186 University of Basel, 2008