Manfred Keller

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.

Nasally inhaled pulsating aerosols: lung, sinus and nose deposition.

OBJECTIVESnTopical delivery of drugs to the sinuses is challenging and requires also particular administration manoeuvres from the patient. This study was conducted to investigate 1) the delivery efficiency of a pulsating aerosol (Vibrent prototype device) to the sinuses and the nose, 2) the aerosol fraction that will deposit in the lungs and 3) potential differences regarding sinus and nasal deposition ratio when comparing aerosol administration during two different administration routes.nnnMETHODSnAn open label deposition study in healthy volunteers was conducted using 99mTc-DTPA radiolabeled pulsating aerosols in comparison to nasal pump sprays. Deposition and retention of pulsating aerosols was assessed by gamma camera imaging during spontaneous nasal breathing and during closed soft palate administration.nnnRESULTSnAerosol administration during nasal breathing vs. application with closed soft plate results in significant lung, nasal and sinus deposition. No significant differences were observed for nasal clearance. In comparison, drug delivery using nasal pump sprays resulted in non-significant sinus, 100 % nasal and non-significant lung deposition. The clearance kinetics after nasal pump spray delivery was significantly accelerated.nnnDISCUSSIONnThe standard application mode of pulsation aerosols with closed soft palate results in negligible lung deposition and therefore limits drug delivery to the nasal cavity only, minimizing unwanted side effects. Administration during spontaneous nasal breathing shows only 10% lung deposition, which is tolerable during drug administration. Relevant paranasal sinus deposition is noted during both application modes and clearance kinetics remains essentially unchanged. In contrast, nasal pump sprays do not show sinus drug delivery and nasal drug residence time is shortened.nnnCONCLUSIONnPulsating aerosols offer advantageous topical nasal and sinus drug delivery options.

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

BACKGROUNDnAlthough 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.nnnMETHODnThe 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.nnnRESULTSnThe 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.nnnCONCLUSIONSnThe 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.

Impact of Nasal Drug Delivery System on Mucociliary Clearance

Objective: Aerosolized drugs are predominantly delivered by nasal sprays, but they target the anterior nose only, and the administered drug is rapidly cleared. Studies with pulsating aerosols showed improved sinonasal deposition. This study compared clearance kinetics and cumulative dose after nasal spray and pulsating aerosol delivery. Method: Open label deposition study in 15 healthy volunteers using radiolabeled pulsating aerosols generated by a Vibrent nebulizer in comparison to nasal pump sprays. Nasal deposition and retention was assessed by gamma camera imaging at various time intervals over 24-hours in the entire nose and in specified ROIs. Results: Nasal pump spray vs pulsating aerosol application resulted in a nasal deposition of 100% vs 70 ± 16%. Conclusion: As found in earlier studies, nasal clearance of pulsating aerosols is significantly retarded compared with nasal sprays, causing prolonged drug residence time in the nose. Our data suggest that this effect may be related to the small droplet size and pulsations rather than deposition in certain nasal regions.

R457 – Paranasal Aerosol Delivery of Budesonide Using PARI VibrENT

Problem Nasal sprays containing inhaled corticosteroids are widely used for the treatment of chronic, allergic and acute sinusitis. However, nasal sprays deposit mainly on the nasal valve and on the anterior portion of the nose, and are rapidly cleared from there. Clinical efficacy data are equivocal which might be caused by the inability of nasal sprays to reach into the posterior regions of the nose. Hence, a drug delivery system such as the PARI VibrENT designed to target the deep nose and the paranasal cavities via a pulsating aerosol may offer substantial benefits. Methods Nebulization efficiency was investigated by a novel cast deposition model of the upper airway including paranasal sinuses developed by PARI GmbH (Munich, Germany). 0.5 mL of a captisol enabled budesonide inhalation solution (CBIS, 480 μg Budesonide/ml) was completely aerosolized into each nostril. Consequently, in total 1 ml or 480 μg of Budesonide were administered in about 3 minutes. Sinus deposition was measured by extracting the deposited drug with a defined volume of solvent and assayed by HPLC. Results The mean values are as follows: the mean paranasal deposition was 15.9% of the initially charged budesonide amount. Only about 2% of the initial budesonide charge remained in the nebulizer, whereas 57.7% deposited in the nasal cavity, 15.2 % were expelled and 90.8 % of the drug was recovered. Deposition in the single sinus cavities ranged from 0.1% up to 7% depending significantly on sinus volume (p<0.01) and ostium diameter (p<0.01). Conclusion Relevant drug amounts could be delivered by the VibrENT into the nose and paranasal cavities of the nasal cast. Sinus deposition depends on its anatomy and was highest with ostium diameters from 1.5 to 3 mm. Significance Significant sinus deposition of abudesonide solution may be attainable through the use of the VibrENT nebulizer system. Clinical studies are warranted.

R458 – Drug Delivery to the Sinuses- Basics and Aerosol Dynamics

Problem Drug delivery to the sinuses via aerosols appears to be a very difficult task, since the paranasal cavities are virtually non-vented cavities. However, there is a scientifically traceable approach to transport aerosol to the sinuses via pressure differences using so-called “vibrating” or “sonic” aerosols which suggests that pressure fluctuations increase aerosol diffusion and ventilate dead spaces by flow induction. Methods The influence of droplet size, vibration frequency and flow rate on drug delivery to the nasal and paranasal cavities was studied in a human nasal cast model (NC). One ml of a Levofloxacin solution (100 mg/ml) was aerosolized into the NC by a VibrENT prototype nebulizer generating a slow, high density aerosol (MMD = 3.7μm) via a perforated vibrating membrane in connection with an adjustable pulsation source. Results Total paranasal cavity deposition was highest (-20 % of label claim) configured with ostia of 1 and 3 mm in diameter and sinus volumes of 7, 12 and 23 ml when VibrENT was operated at flow rates below 3 1/min and a pulsation frequency of 36 Hz. Delivery efficiency decreased at higher frequencies, higher flow rates and with larger aerosol droplets. Omission of pulsation resulted in no paranasal deposition and a drop in nasal cavity deposition from more than 50% to about 6%. Drug deposition to the sinuses is also significantly (p<0.01) affected by the ostium diameter and sinus volume, being lowest (∼0.2 %) at a large ostium diameter (6 mm) and a low sinus volume (7 ml). Conclusion It is possible to deliver aerosol to the sinuses but physical boundary conditions like pulsation frequency, aerosol size and flow rate have to be considered for an efficient transport as well as sinus anatomy. PARI VibrENT addresses these requirements. Significance Efficient drug transport to the sinuses enables novel therapeutic approaches.

R155: A Novel Pulsating Device to Increase Human Sinus Ventilation

by AR. RESULTS: The nasal resistances were 2.02 1.43 Pa?cm3?s-1 in OSA and 0.64 0.57 in normals with p 0.001. The nasal volumes measured by AR were 4.90 2.75 ml in OSA and 6.08 1.96 in normals. There was a near significant difference between two groups in the nasal volume measurements (p 0.0448). CONCLUSION: OSA patients have more congested nasal airways during sleep compared to the non-apneas. Nasal resistance measurement appears more sensitive in detecting the nasal patency in OSA patient than AR measurement. SIGNIFICANCE: Detection of nasal patency is helpful in diagnosis and treatment of OSA.

R104: Delivery of Flutide Nasal Spray vs. Aerosol via PARI VibrENT

PROBLEM: This in vitro study was conducted to investigate the delivery efficiency and deposition pattern of Flutide® nasal spray against a fluticasone-propionate (FP) suspension and novel aqueous FP-solution using an aerosol compressor/nebulizer (VibrENT) for paranasal sinus and nasal deposition. METHODS: Nebulization efficiency was investigated by a novel cast deposition model of the upper airway including paranasal sinuses developed by PARI GmbH (Munich, Germany). For experiments using Flutide® nasal spray (GSK, Munich, Germany), the model was connected to a PARI breath simulator and 2 puffs each (100 g) were fired in each nostril of the model. Either 2000 g/2mL (Flutide forte®, GSK, Munich, Germany) or 455 g/2ml of a novel aqueous FP solution (PARI, Munich, Germany) was aerosolized for 4 minutes in both the left and right nostril using the VibrENT nebulizer/ compressor system (Pari, Munich, Germany). Sinus deposition was measured by extracting the deposited drug with a defined volume of solvent and assayed by HPLC. RESULTS: Nasal deposition was 66.8 ug (3.2%) for the suspension, 28.4 ug (6.2%) for the solution, and 193 ug (96.5%) for the spray. Sinus deposition was 38.7 ug (1.9%) for the suspension, 29.0 ug (6.4%) for the solution, and 0.93 ug (0.5%) for the spray. CONCLUSION: Results indicate that only one-third of a novel FP-solution is needed to obtain a comparable paranasal deposition compared to the approved product Flutide® forte suspension. As expected the nasal spray showed negligible sinus deposition. Deposition from the VibrENT nebulizer system showed significant deposition into the sinuses favoring the solution over the suspension. SIGNIFICANCE: Significant sinus deposition of a fluticisone solution may be attainable through the use of the VibrENT nebulizer system. Clinical studies are warranted.