Abstract
Midazolam (MDZ) is a short acting benzodiazepine not only used in treatment of pediatric status epilepticus but also is the most common preoperative sedative-agent in many surgical processes especially in children. According to MDZ hydrophobic characteristics at physiological-pH, its commercial parenteral aqueous solution is formulated in acidic pH that may cause pain and inflammation at administration-site. Alternatively, it is administered orally especially in children, however its bitter taste results low patient-compliance. Nasal route shows better acceptance than oral route. Considering fast clearance and frequent administration of nasal solutions, the mucoadhesive gels are considerable. According to MDZ poor aqueous solubility at physiologic pH (≈6) and nasal dose volume limitation, MDZ solubility enhancement techniques evaluation seems to be necessary in mucoadhesive gel formulation. Solubilized MDZ gel at physiologic pH -as a replacement of commercial acidic parenteral formulations- not only can improve MDZ residence-time in nasal-cavity but also reduces nasal administered volume. In this study, thermosensitive Poloxamer407 used as in situ gel-forming agent in various concentrations in presence of different solubility enhancers such as propylene glycol (P.G), polyethylene glycol400 (PEG400) and β-cyclodextrin (β-CD) in various amounts. MDZ solubility and gelation properties of different gel formulations were evaluated. Results showed Poloxamer gel containing P.G, enhanced MDZ solubility at nasal physiologic-pH up to 15.1 fold. Optimized nasal gel formulation indicated acceptable gelation-temperature (34±0.5 °C), gelation-capacity (1.5±0.10 min) with shearthinning pattern, which released MDZ within 1hour. Rat nasal histopathological showed no damage within 3 hours after nasal administration of MDZ nasal-gel. Stability tests of MDZ nasal-gel were acceptable over 90 days.
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Parhizkar, E., Emadi, L. & Alipour, S. Development and evaluation of midazolam in situ nasal gel properties in presence of solubility enhancers at cilia-friendly pH. Macromol. Res. 25, 255–261 (2017). https://doi.org/10.1007/s13233-017-5031-y
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DOI: https://doi.org/10.1007/s13233-017-5031-y