ABSTRACT
Bidirectional nasal drug delivery is a new administration principle with improved deposition pattern that may increase nasal drug uptake. Twelve healthy subjects were included in this open, non-randomized 3-way crossover study: midazolam (3.4 mg) intravenously (1 mg mL (-1)), or nasally by bidirectional or traditional spray (2 x100 microL of a 17 mg mL(-1) nasal midazolam formulation). The primary outcome was bioavailability. Blood samples were drawn for 6 h for determination (gas-chromatography-mass-spectrometry) of midazolam and 1-OH-midazolam. Pharmacokinetic calculations were based on non-compartmental modelling, sedation assessed by a subjective 0-10 NRS-scale, and nasal dimensions by non-invasive acoustic rhinometry. Mean bioavailabilities were 0.68-0.71, and Tmax 15 min for the sprays, which also were bioequivalent (ratio geometric means (90%) CI: 97.6% (90% CI 83.5; 113.9)). Sedation after bidirectional spray followed intravenous sedation closely, while sedation after the traditional spray was less pronounced. A negative correlation between Cmax and smallest cross-sectional area was seen. Adverse effects such as local irritation did not differ significantly between the sprays. Apparently bidirectional delivery did not increase systemic bioavailability of midazolam. We cannot disregard that only the traditional spray caused less sedation than intravenous administration. This finding needs to be confirmed in trials designed for this purpose.
Subject(s)
Hypnotics and Sedatives/administration & dosage , Hypnotics and Sedatives/pharmacokinetics , Midazolam/administration & dosage , Midazolam/pharmacokinetics , Administration, Intranasal , Adolescent , Adult , Area Under Curve , Biological Availability , Cross-Over Studies , Female , Humans , Hypnotics and Sedatives/blood , Hypnotics and Sedatives/pharmacology , Male , Midazolam/blood , Midazolam/pharmacology , Middle Aged , Rhinometry, AcousticABSTRACT
OBJECTIVES: The objective was to compare nasal deposition patterns achieved with a conventional hand actuated spray pump and a novel breath actuated bidirectional prototype device housing the same spray pump (OptiMist, OptiNose AS, Oslo, Norway). STUDY DESIGN AND METHODS: The bidirectional delivery device exploits the posterior connection between the nasal passages persisting when the velum automatically closes during oral exhalation. The deposition and clearance patterns achieved with the two devices were compared in nine healthy subjects by scintigraphy after administration of Tc-aerosols. RESULTS: Compared with traditional spray pump delivery, the OptiMist device provided significantly (P < .004) larger initial and cumulative deposition (area under the deposition vs. time curve) in the upper posterior segment of the nasal passage, housing the sinus ostia and the olfactory region, and significantly lower deposition (P < .004) in the anterior segment, lined by nonciliated squamous epithelium. Furthermore, intersubject reproducibility of the initial and cumulative deposition was higher for the OptiMist device both in the upper posterior segment and the entire nose. CONCLUSIONS: Compared with a spray pump, the novel breath actuated bidirectional device provides significantly larger deposition in the clinically important regions beyond the nasal valve and reduced anterior deposition. These striking differences provide new opportunities for improved therapy of chronic rhinosinusitis and polyposis as well as extended use of the nose for delivery of drugs from the nose into the brain.
Subject(s)
Aerosols/administration & dosage , Nasal Cavity/diagnostic imaging , Nebulizers and Vaporizers , Respiration , Administration, Intranasal , Adult , Aged , Equipment Design , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Nasal Cavity/anatomy & histology , Radionuclide Imaging , Radiopharmaceuticals/administration & dosage , Reference Values , Technetium Tc 99m Pentetate/administration & dosageABSTRACT
Nasal delivery of drugs and vaccines has important advantages compared to injection and oral administration, and is being considered for a widening range of vaccines and substances with topical and systemic action. Traditional nasal delivery technologies are, however, trapped in the dilemma between achieving improved nasal distribution and limiting deposition in the lower airways. The novel bi-directional nasal delivery concept takes advantage of the posterior connection between the nasal passages persisting when the soft palate automatically closes during oral exhalation. Exhalation into the delivery device triggers release of liquid or powder particles into an airflow, which enters one nostril via a sealing nozzle and exits through the other nostril. In a study of 16 healthy subjects using 99mTc labeled nebulized particles with a mean particle size of 3.5 microm, delivery with this novel concept showed no or minimal lung deposition (0.8 +/- 2.0% (range -4.1% to 5.6%) for bi-directional delivery, whereas significant fractions were deposited in the lungs in all 16 subjects (mean 22.3 +/- 8.1%, range 12.2-39.3%) following conventional nasal inhalation (p < 0.0005). In the latter case, the fraction deposited in the lungs correlated significantly (r2 = 0.47, p < 0.004) with the volume of the nasal passages. The bi-directional nasal delivery concept minimizes the risks and problems related to lung deposition occurring during conventional nasal inhalation from a nebulizer and opens up a new range of opportunities for nasal delivery of drugs and vaccines.
