Nasal drug delivery devices: characteristics and performance in a clinical perspective-a review.

Nasal delivery is the logical choice for topical treatment of local diseases in the nose and paranasal sinuses such as allergic and non-allergic rhinitis and sinusitis. The nose is also considered an attractive route for needle-free vaccination and for systemic drug delivery, especially when rapid absorption and effect are desired. In addition, nasal delivery may help address issues related to poor bioavailability, slow absorption, drug degradation, and adverse events in the gastrointestinal tract and avoids the first-pass metabolism in the liver. However, when considering nasal delivery devices and mechanisms, it is important to keep in mind that the prime purpose of the nasal airway is to protect the delicate lungs from hazardous exposures, not to serve as a delivery route for drugs and vaccines. The narrow nasal valve and the complex convoluted nasal geometry with its dynamic cyclic physiological changes provide efficient filtration and conditioning of the inspired air, enhance olfaction, and optimize gas exchange and fluid retention during exhalation. However, the potential hurdles these functional features impose on efficient nasal drug delivery are often ignored. With this background, the advantages and limitations of existing and emerging nasal delivery devices and dispersion technologies are reviewed with focus on their clinical performance. The role and limitations of the in vitro testing in the FDA guidance for nasal spray pumps and pressurized aerosols (pressurized metered-dose inhalers) with local action are discussed. Moreover, the predictive value and clinical utility of nasal cast studies and computer simulations of nasal airflow and deposition with computer fluid dynamics software are briefly discussed. New and emerging delivery technologies and devices with emphasis on Bi-Directional™ delivery, a novel concept for nasal delivery that can be adapted to a variety of dispersion technologies, are described in more depth.

Nasal deposition and clearance in man: comparison of a bidirectional powder device and a traditional liquid spray pump.

BACKGROUND: Delivery of powder formulations to the nose is an attractive alternative for many drugs and vaccines. This study compared the regional nasal deposition and clearance patterns of lactose powder delivered by the OptiNose powder device (Opt-Powder; OptiNose US Inc., Yardley, PA, USA) to that of liquid aerosol administered via a traditional hand-actuated liquid spray pump (Rexam SP270, Rexam Pharma, France). METHODS: The study was an open-label, crossover design in seven healthy subjects (five females, two males). The regional nasal deposition and clearance patterns of the Opt-Powder device were compared to a traditional liquid spray pump by dynamic gamma camera imaging after administration of either (99m)Tc-labeled lactose powder or liquid (99m)Tc- diethelyne triamine pentaacetic acid-aerosol. The gamma camera images were scaled and aligned with sagittal magnetic resonance images to identify nasal regions. Possible deposition of radiolabeled material in the lungs following both methods of delivery was also evaluated. RESULTS: Both powder and spray were distributed to all of the nasal regions. The Opt-Powder device, however, achieved significantly larger initial deposition in the upper and middle posterior regions of the nose than spray (upper posterior region; Opt-Powder 18.3% ± 11.5 vs. Spray 2.4% ± 1.8, p<0.02; sum of upper and middle posterior regions; Opt-Powder 53.5% ± 18.5 vs. Spray 15.7% ± 13.8, p<0.02). The summed initial deposition to the lower anterior and posterior regions for spray was three times higher compared to Opt-Powder (Opt-Powder 17.4% ± 24.5 vs. Spray 59.4% ± 18.2, p<0.04). OptiNose powder delivery resulted in more rapid overall nasal clearance. No lung deposition was observed. CONCLUSIONS: The initial deposition following powder delivery was significantly larger in the ciliated mucosa of the upper and posterior nasal regions, whereas less was deposited in the lower regions. Overall nasal clearance of powder was slower initially, but due to retention in anterior nonciliated regions the overall nasal clearance after spray was slower.

A new method for scintigraphic quantification of deposition and clearance in anatomical regions of the human nose.

OBJECTIVES: To develop methods for absolute quantification of the deposition of 99mTc-labeled aerosols and powders in well-defined anatomical regions of the nose, and to enable accurate comparisons of different nasal administration techniques in the same individual. METHODS: The volunteer was seated and positioned relative to the scintillation camera field of view by means of a fixation frame. After nasal administration, a dynamic series of images was acquired for 32 min with a lateral direction of view. The images were corrected for photon attenuation by the use of a lateral transmission image acquired before the delivery of aerosols or powders. Marker images, obtained with a line source fixed to a balloon and kept for a short while against the palate as well as with a point source held on anatomical landmarks, were used to co-register the scintigraphic images to sagital sections through a three-dimensional magnetic resonance (MR)-image series. The MR set was used to define the inner nose contour and the nasal regions used for quantification. RESULT: Attenuation correction factors ranged from 1.1 to 1.7 in different parts of the nasal cavity. Alignment of the markers on the teeth and palate with the sagital MR images could be reproduced with accuracies of 1.2 and 1.7 mm, respectively. CONCLUSION: The new method provides reliable quantification of the deposition in anatomic regions that can be defined in MR images. Accurate co-registration and quantification are essential when comparing distribution and clearance patterns for different administration techniques.

Breath actuated device improves delivery to target sites beyond the nasal valve.

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.

Bi-directional nasal delivery of aerosols can prevent lung deposition.

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.

Nitric oxide (NO) and obstructive sleep apnea (OSA).

Nitric oxide (NO) and obstructive sleep apnea are inseparable. Obstructive sleep apnea could be described as the intermittent failure to transport the full complement of nasal NO to the lung with each breath. There NO matches perfusion to ventilation. NO is utilized by the efferent pathways that control the unequal, inspiratory battle between the pharyngeal dilators and the closing negative pressures induced by the thoracic musculature. Recurrent cortical arousals are a major short-term complication, and the return to sleep after each arousal uses NO. The long-term complications, namely hypertension, myocardial infarction, and stroke, might be due to the repeated temporary dearth of NO in the tissues, secondary to a lack of oxygen, one of NO's two essential substrates.