Gabriele Meyer

Pulsating aerosols for drug delivery to the sinuses in healthy volunteers

Objective: Approximately 10 to 15 percent of the European and U.S. population have chronic rhinosinusitis, but effective treatment remains a challenge. There has been limited success using topical drug delivery to the nose and the paranasal cavities/sinuses, in part because most nasally administered aerosol drug formulations are efficiently filtered at the nasal valve and fail to reach the osteomeatal area and sinuses. Study Design: Feasibility study. Setting: Nuclear medicine department. Subjects and Methods: Pulsating airflows were applied to the nasal cavity and sinus ventilation was studied in five healthy human volunteers using dynamic 81mKr-gas gamma camera imaging. Furthermore, deposition and retention of 99mTc-DTPA radiolabeled aerosols delivered by nasal pump sprays or by pulsating aerosols was assessed in each volunteer over a 24-hour period. Results: Only the pulsating airflow demonstrated efficient 81mKr-gas ventilation of the paranasal sinuses. No drug was deposited into the sinuses using nasal pump sprays, but up to 6.5 percent of the nasally administered drug was deposited into the sinuses using pulsating airflow. Clearance kinetics of the drug was reduced after pulsating aerosol delivery compared to nasal pump sprays. Residence time of the drug at the site of deposition was up to three-fold longer with pulsating aerosol delivery than with nasal pump sprays. Conclusion: Our data support the hypothesis that topical drug delivery in relevant quantities to the nose and osteomeatal areas, including the paranasal sinuses, is possible using pulsating airflows. Furthermore, the frequency of drug applications may be reduced due to a delayed clearance and longer residence time.

Left-to-Right Asymmetry of Aerosol Deposition after Shallow Bolus Inhalation Depends on Lung Ventilation

BACKGROUND After shallow bolus inhalation of radiolabeled aerosols, gamma camera imaging has shown a left-right asymmetry, with a higher fraction of deposited particles in the left lung. It was not clear, however, whether this phenomenon was an effect of asymmetry in lung ventilation or aerosol deposition efficiency. METHODS Lung ventilation and aerosol deposition was studied after shallow bolus inhalation and gamma camera imaging in nine healthy nonsmokers and 10 asymptomatic smokers. A 100-mL (81m)Kr-gas boli were administered within the Fowler and within the phase-1 dead space, respectively. In addition, 1-L full breaths of 81m-Kr-gas were inhaled. For aerosol deposition subjects inhaled 100-mL boli of 100-nm diameter radiolabeled carbon particles with shallow and deep penetration. Left-to-right (L/R) and central-to-peripheral (C/P) activity distribution of the lung was analyzed. RESULTS None of the parameters analyzed were significantly different between nonsmokers and smokers. The full-breath 81m-Kr-gas inhalation revealed a similar activity distribution over the left and right lungs, according to their respective volumes (L/R ratio = 0.84 +/- 0.04; mean +/- SE). In contrast, the shallow bolus inhalation of 81m-Kr-gas to the phase-1 dead space revealed more activity in the left lung (L/R ratio = 1.49 +/- 0.15, normalized to full-breath Kr-gas L/R). This same left-right asymmetry was observed for the aerosol after shallow bolus inhalation (L/R ratio = 1.69 +/- 0.15), and there was no significant difference between Kr-gas and aerosol L/R ratio. C/P activity ratios of bolus inhalation to the phase-1 dead space were 1.71 +/- 0.19 and 1.79 +/- 0.15 (normalized to full-breath Kr-gas C/P) for gas and aerosol, respectively, and correlated with the L/R ratios. CONCLUSIONS The data show that the asymmetry in shallow aerosol bolus deposition is primarily determined by lung ventilation. The reason for this asymmetry is unclear.

Nasal High Flow Reduces Dead Space

Clearance of expired air in upper airways by nasal high flow (NHF) can be extended below the soft palate and de facto causes a reduction of dead space. Using scintigraphy, the authors found a relationship between NHF, time, and clearance. Direct measurement of CO2 and O2 in the trachea confirmed a reduction of rebreathing, providing the actual data on inspired gases, and this can be used for the assessment of other forms of respiratory support.

Ventilation and aerosolized drug delivery to the paranasal sinuses using pulsating airflow - a preliminary study.

BACKGROUND Although there is a high incidence of nasal disorders including chronic sinusitis, there is limited success in the topical drug delivery to the nose and the paranasal sinuses. This is caused by the nose being an efficient filter for inhaled aerosol particles and the paranasal sinuses being virtually non-ventilated. METHOD The objective of this study was to visualize the efficiency of sinus ventilation in healthy volunteers using dynamic 81mKr-gas imaging in combination with pulsating airflows. Furthermore, the deposition and retention of 99mTc-DTPA aerosol particles was assessed. RESULTS The ventilation of the maxillary and frontal sinuses could be visualized by gamma camera imaging during pulsating airflow. In addition, using pulsating airflow, between 3% and 5% of nasally deposited aerosols penetrated into the paranasal sinuses while during application without pulsation aerosol deposition was below 1%. Furthermore pulsation increased aerosol deposition in the nasal airways by a factor of three. CONCLUSIONS The study demonstrates the high efficiency of a pulsating airflow in paranasal sinus ventilation and aerosolized drug delivery. This proves that topical drug delivery to the paranasal sinuses in relevant quantities is possible and indicates further clinical studies are necessary.

Drug delivery to paranasal sinuses using pulsating aerosols.

Chronic rhinosinusitis (CRS) is the major disorder of the upper airways, affecting about 10-15% of the total population. Topical treatment regimens show only modest efficacy, because drug delivery to the posterior nose and paranasal sinuses is still a challenge. Therefore, there is a high rate of functional endoscopic sinus surgery in CRS patients. Most nasally administered aerosolized drugs, like nasal pump sprays, are efficiently filtered by the nasal valve and do not reach the posterior nasal cavity and the sinuses, which are poorly ventilated. However, as highlighted in this review, sinus ventilation and paranasal aerosol delivery can be achieved by using pulsating airflow, offering new topical treatment options for nasal disorders. Radioaerosol inhalation and imaging studies in nasal casts and in healthy volunteers have shown 4-6% of the nasally administered dose within the sinuses. In CRS patients, significant aerosol deposition in the sinus cavities was reported before sinus surgery. After surgery, deposition increased to the amount observed in healthy volunteers. In addition, compared with nasal pump sprays, retention kinetics of the radiolabel deposited in the nasal cavity was prolonged, both in healthy volunteers and in CRS patients. These efficiencies may be sufficient for topical aerosol therapies of sinus disorders and, due to the prolonged retention kinetics, may reduce application modes, but have to be proven in future clinical trials. Pulsating aerosols may offer additional new topical treatment options of nasal and sinus disorders before as well as after surgery.