Transmucosal nasal drug delivery is a drug delivery option for challenging clinical situations where common drug administrations (e.g., intravenous, intramuscular, or oral) are inapplicable. For drugs with constricted oral bioavailability, due to degradation in the intestinal tract or hepatic first-pass metabolism, transmucosal nasal delivery is a convenient alternative to intravenous and intramuscular drug administration. The considerable blood flow, actually responsible for breath conditioning, benefits efficient systemic drug uptake and provides direct access to the systemic circulation for transmucosal absorbed drugs. Often, in nasal drug delivery the limited nasal capacity is disregarded and the instilled volumes exceed the limited capacity of the nose. Consequently, the administered preparations are partially swallowed and resulting pharmacokinetic characteristics refer to a combination of transmucosal nasal and gastrointestinal drug absorption. Due to low midazolam concentration, the commercially available preparations for intravenous administration (e.g. Dormicum , Roche) is inappropriate for transmucosal nasal midazolam delivery. For the optimization of transmucosal nasal midazolam delivery minimized administration volumes are essential to prevent swallowing of nasally administered preparations. Therefore, nasal preparations with enhanced midazolam concentrations need to be provided. In Project I different preparations for transmucosal nasal midazolam delivery were developed. The impact of vehicle and application modality on the pharmacokinetics of nasally applied midazolam was studied by administration of the developed preparations to healthy volunteers (Project II). The benefit of two nasal midazolam preparations for procedural anxiolysis in anxious patients undergoing MRI examinations was compared (Project III). Project I: Midazolam solubilization with RMβCD (randomized methylated-β-cyclodextrin, a cyclodextrin derivative) facilitated compounding of midazolam preparations adjusted to the limited volumetric capacity of the nose. RMβCD (added in equimolar or higher concentration to solubilize midazolam) reduced midazolam release in drug release studies with semi-permeable cellophane membranes (in vitro). Stability data affirmed shelf life of at leastmonths for RMβCD containing nasal midazolam preparations. Addition of chitosan hydrochloride (penetration enhancer) affected midazolam stability; therefore shelf life of the chitosan containing nasal midazolam preparation was reduced. The developed preparations for transmucosal nasal midazolam delivery were the basis to study the influence of the vehicle and the application modality on pharmacokinetics and systemic bioavailability of nasally applied midazolam (Project II).ududProject II: Pharmacokinetic characteristics following nasal application of 1 mg midazolamud(Preparation 1, 2, and 3) and 3 mg midazolam (Preparation 4 and 5) were compared withudpharmacokinetic characteristics of 1 mg i.v. administered midazolam (Dormicum®, Roche). Theudimpact of RMbCD (solubilizer), chitosan hydrochloride (penetration enhancer) and the applicationudmodality (one- versus two-sided nasal administration) was investigated in this open-label study withudhealthy volunteers. Volunteers were asked to describe nasal midazolam administration and toudclassify local irritation after nasal midazolam administration. Pharmacologic effects were assessedudby computer-controlled self-adjusting reaction time test (CRTT, recording reaction time andudinterstimulus interval) and visual analog scale (VAS). Blood samples were serially obtained untilud6 hours after midazolam administration. Serum concentrations of midazolam and two metabolitesud(a-hydroxymidazolam and 4-hydroxymidazolam) were quantified by liquid chromatography-massudspectrometry (LC-MS). Non-compartment and two-compartment pharmacokinetic modeling wasudperformed to estimate pharmacokinetic parameters. Bioequivalence testing was performedudaccording to the requirements of EMEA (European Agency for the Evaluation of MedicinaludProducts).udSystemic bioavailability of nasally applied midazolam ranged from 78% (Preparation 5) to 93%ud(Preparation 2), differences of bioavailability were not significant. After nasal administration of 1 mgudmidazolam by Preparation 1, 2, and 3 mean Cmax was, 28.1 ± 9.1 mg/l, 30.1 ± 6.6 mg/l andud28.9 ± 5.4 mg/l, respectively. After nasal administration of 3 mg midazolam by Preparation 4 and 5udCmax was, 72.6 ± 18.2 mg/l, and 82.2 ± 15.8 mg/l, respectively. Following nasal midazolamudadministration tmax was between 7.1 ± 0.6 minutes (Preparation 5) and 11.7 ± 2.4 minutesud(Preparation 4). All tested nasal administration modalities to deliver 1 mg midazolam provedudbioequivalence. For Preparation 4 and Preparation 5 bioequivalence was not confirmed. The serumudconcentration time profiles of the midazolam metabolites (a-hydroxymidazolam and 4-udhydroxymidazolam) demonstrated exclusive transmucosal absorption of nasally appliedudmidazolam. Swallowing of nasally delivered preparations was prevented and hepatic first-passudeffect successfully circumvented. Consequently, the assessed pharmacokinetic parametersudcharacterized pure transmucosal nasal midazolam delivery.udNeither RMbCD (equimolar to midazolam) nor application modality (one- or two-sided) changedudabsorption kinetics of nasally administered midazolam, whereas chitosan hydrochloride promotedudabsorption of nasally applied midazolam. Significant higher midazolam serum concentrations wereudachieved faster. The outcome of the pharmacokinetic study emphasizes the decisive role ofudminimized nasal application volume to prevent swallowing of nasally applied preparations and toudprovide for exclusive transmucosal midazolam absorption.ududProject III: In this randomized multicenter trial with 110 anxious and/or claustrophobic patientsudundergoing MRI examinations, two nasal preparations for low-dose midazolam delivery,udMidazolam MD Nasal Spray 5 mg/ml (MD) and Midazolam UD Nasal Spray 1 mg (UD), wereudcompared. Nasal administration of 1 mg or 2 mg midazolam was provided before MRI examination.udWithin both groups anxiety reduction was significant, but there was no difference in anxietyudreduction between the MD and UD group. Local irritation following administration of UD nasal sprayudwas slightly more intense than local irritation after administration of MD nasal spray.udNasal delivery of low-dose midazolam is a safe therapy to provide procedural anxiolysis in patientsudundergoing MRI examinations. The two compared low-dose midazolam preparations forudtransmucosal nasal delivery of midazolam proved therapeutic equivalence. Hence, anxious and/orudclaustrophobic patients equally benefit from procedural anxiolysis during MRI examinationsudfollowing administration of low-dose midazolam by MD nasal spray or UD nasal spray. Concerningudconvenient handling, administration to laying patients, and hygienic aspects the new midazolamudnasal spray (UD) is superior to the commonly used midazolam multidose nasal spray (MD).udOverall, the presented nasal preparations facilitated characterization of exclusive transmucosaludnasal absorbed midazolam. In vivo neither RMbCD (equimolar to midazolam) nor administrationudmodality changed the pharmacokinetic profile of nasally applied midazolam. Chitosanudhydrochloride promoted nasal midazolam absorption but clinical relevance (e.g., for the treatmentudof status epilepticus) is to be verified in further clinical investigations. High systemic bioavailabilityudof nasally applied midazolam demonstrated the veritable potential of transmucosal nasal druguddelivery as alternative to invasive drug administration.ud
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