JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY Volume 29, Number 1, 2016 ª Mary Ann Liebert, Inc. Pp. 30–35 DOI: 10.1089/jamp.2014.1179
A Proof-of-Principle Setup for Delivery of Relenza (Zanamivir) Inhalation Powder to Intubated Patients Sharon Shui Yee Leung, PhD, Thaigarajan Parumasivam, MSc, Patricia Tang, PhD, and Hak-Kim Chan, PhD, DSc
Abstract
Background: A fatal incident was reported when a mechanical ventilated patient received nebulization of a reconstituted Relenza formulation. We propose a delivery system to introduce Relenza and other inhalation dry powders to intubated patients to avoid accidental fatalities in the future. Methods: This is a bench study demonstrating the feasibility of a delivery system to introduce dry powder of Relenza to intubated patients. A dry powder inhaler placed within a delivery chamber was actuated by compressing a ventilation bag to disperse powder into a tracheal tube. The performance of two inhalers, a Diskhaler and an OsmohalerTM, were compared. The effects of the length and size of the tracheal tube on the powder output and sizing of emitted powder were investigated using the more efficient OsmohalerTM. Results: The efficiency of Osmohaler in delivering Relenza to the distal end [delivered dose¼30.2 – 0.2% and fine particle fraction (FPF)¼14.5 – 1.7%] was significantly higher than the Diskhaler (delivered dose¼18.1 – 4.7% and FPF¼3.4 – 2.1%). While no differences in the delivered dose and FPF were observed between the tracheostomy and endotracheal tubes of the same internal diameter, a larger endotracheal tube (9.0 mm internal diameter) gave a 6% higher FPF compared with the smaller counterpart (7.0 mm internal diameter). Conclusion: The dry powder delivery system has been demonstrated to be capable of delivering Relenza formulation to the distal end of tracheal tubes with a reasonable delivered dose and FPF. It would be necessary for further investigation into incorporating the proposed powder delivery system within a mechanical ventilator, as well as animal and clinical studies to prove its applicability to deliver zanamivir dry powder to ventilated influenza patients in the intensive care setting. Key words: dry powder inhaler, endotracheal tube, influenza virus A (H1N1), tracheostomy tube, ventilated patients
severe ventilator occlusion occurred transiently during the ninth nebulization. Following the incident, health care practitioners are reminded that the Relenza formulation is not intended to be reconstituted in any liquid formulation and is not recommended for use in a nebulizer or mechanical ventilator.(3) This means Relenza Diskhaler is ruled out for the treatment in intubated influenza patients, which may result in suboptimal treatment. Recently, the potential influences of the use of nebulization and active humidification on the resistance of expiratory filter have been demonstrated.(3,4) Hence, there is recommendation that the expiratory filter should be replaced either if the expiratory resistance increases or every 24 hours.(3–5)
Introduction
P
atients infected with influenza A (H1N1) can develop severe, rapidly progressing respiratory failure that requires invasive ventilation and makes treatment difficult.(1) An intubated patient who had received reconstituted Relenza (zanamivir) solutions died by asphyxiation because the solubilized lactose obstructed the expiratory filter of the ventilator.(2) Kiatboonsri et al.(2) conducted an in vitro experiment to verify the lactose hypothesis by connecting the ventilator to a test lung and a pressure manometer. Significant retardation of expiratory flow and airway pressure was observed from the sixth dose of zanamivir nebulization, and
Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia. *Correspondence: Hak-Kim Chan (
[email protected])
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DELIVERY OF RELENZA POWDER
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FIG. 1. Schema of the dry powder delivery system (the tracheal tube was used in its natural curve configuration as it was supplied). Adapted from Tang et al.(9) Zanamivir is one of the four approved neuraminidase inhibitors and can be used alone or in combination for the treatment and prophylaxis of uncomplicated influenza A and B.(6) Though an aqueous saline solution of zanamivir is currently in clinical development for intravenous administration in patients with severe influenza,(7) the lactose powder formulation of zanamivir marketed as Relenza Diskhaler for inhalation is currently the only approved product for delivering zanamivir. In addition, laninamivir, which is currently approved in Japan only, is another neuraminidase inhibitor available as a dry powder inhaler. Therefore, there is a need to develop a dry powder delivery system for patients who are incapable of administering the Relenza and other dry powder formulations via inhalation. Everard et al.(8) proposed the use of an adaptor that could contain a Turbohaler and be inserted in a ventilator circuit to introduce budesonide dry powder to intubated patients and showed a 30% delivered dosed. However, they highlighted that air humidification could reduce the drug delivery for their system. We have developed a simple delivery system to introduce mannitol to intubated patients with high delivered dose obtained (50%–60%).(9) The safety of this method to delivery mannitol at doses of 160 mg and 320 mg to improve sputum clearance of intubated patients was demonstrated in a clinical study.(10) In the present work, we intend to investigate the feasibility of this in-line dry powder delivery system to deliver lactose carrier-based Relenza formulation to intubated patients. The introduction of DPIs to intubated patients may offer more clinical options and enable treatment optimization. Materials and Methods Materials
Relenza Rotadisk containing a powder mixture of 5 mg zanamivir and 20 mg lactose with the Diskhaler inhalation device (GlaxoSmithKline, Brentford, England, United Kingdom)
was purchased commercially and used prior to its labeled expiry date. A high efficiency dry powder inhaler, OsmohalerTM (Pharmaxis, Sydney, NSW, Australia), was also employed in this study. Prior to testing, the Relenza powder was transferred from a Rotadisk blister to a hydroxypropyl methylcellulose (HPMC) size 3 capsule which fits into the Osmohaler. This study used one Portex tracheostomy tube of 7.0 mm i.d. and 115 mm in length and two endotracheal tubes of 7.0 and 9.0 mm i.d. and 300 mm in length (Smiths Medical, Norwell, Massachusetts, USA), which are commonly used in adult patients. Experimental setup
The proposed powder delivery system used to deliver Relenza dry powder to intubated patients will require them to be disconnected from the ventilator temporarily. The setup (Fig. 1) was detailed in Tang et al.(9) In brief, a standard adult manual ventilation bag of 1500 mL bag volume (Mayo Health Care, Sydney, NSW, Australia) with a PEEP valve set at a value of 20 cm H2O was used to aerosolize Relenza powders. Airflow pattern during the bagging procedure was monitored by a flowmeter (Model 4040, TSI Inc, Shoreview, Minnesota, USA) connected to an oscilloscope. The inhalation device was contained within a delivery chamber to allow positive pressure ventilation. A duckbill valve assembled with an exhale diverter (donated by Royal Prince Alfred Hospital, Sydney, Australia) was used to connect the delivery chamber to the tracheal tube, which would prevent the patient’s moist exhaled air from entering the inhaler in a clinical setting. Before runs, the tracheal tube was humidified until the ‘‘rain-down’’ condition was observed using a jet nebulizer to mimic condensation in the tube in vivo. The humidified tracheal tubes were expected to avoid powder bouncing within the tracheal tube, which may create artifacts in the dispersion results. It is recognized that there is increasing awareness of the formation of biofilm in the tracheostomy tubes. Inglis et al. (1993) demonstrated that the biofilm in endotracheal
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tube was not formed along the tube, but towards the tracheobronchial tree due to the positive pressure ventilation.(11) Together with the difficulty of simulating the biofilm model, the presence of biofilm was not considered in the present study. A T-junction was connected between the United States Pharmacopeia (USP) throat and the tracheal tube to allow air drawn through the open port of the T-junction for particle sizing using a multi-stage liquid impinger (MSLI, Copley Scientific, Colwick, Nottingham, UK). Powder dispersion
Aerosols were delivered to the tracheal tube by compressing the ventilation bag in a reproducible manner to generate positive pressure airflow. In the clinical setting, various flow patterns may be generated depending on the operators and patients. In the present study, we reproduced air flow patterns as they are performed by an experienced Intensive Care physiotherapist in Royal Prince Alfred Hospital (Sydney, Australia). The acceleration (fa) and peak flow (fp) were 4.26 L/s2 and 116 L/min, respectively, for endotracheal tube experiments. The tracheostomy tube experiments used a flow pattern of fa = 8.99 L/s2 and fp = 100 L/min detailed in Tang et al.(9) With the two patterns used, the tidal volume and inspiratory time were 670 mL and 0.7 sec for endotracheal tube experiments, and 580 mL and 0.7 sec for the tracheostomy tube experiments, respectively. These values are close to the traditional tidal volume of 10– 12 mL/kg body mass for ventilated patients.(12) Airflow through the impinger was set at 125 L/min to avoid aerosols bouncing out of the MSLI during the inflation of the ventilation bag. The cut-off diameters of the impinger stages were calculated as being inversely proportional to the square root of the flow rate,(13) giving values of 9.0, 4.7, 2.1, and 1.2 lm for stages 1–4, respectively. During the in vitro testing, the exhalation outlet of the duckbill valve assembly was blocked to avoid the capsule from spinning when the
vacuum pump was turned on for the MSLI sizing. In the in vivo setting, this exhalation outlet will leave open to allow patient to exhale. One blister/capsule was dispersed to compare the performance of the two inhaler devices using a tracheostomy tube of 7.0 mm internal diameter and 115 mm in length. The more efficient Osmohaler was selected to examine the influences of different tracheal tubes. These experiments were conducted by dispersing two capsules consecutively because the recommended treatment dose for flu is two inhalations (one blister per inhalation) twice daily. All measurements were performed in triplicate to ascertain the consistency of the delivered dosage and fine particle fraction (FPF) defined as particles smaller than 5 lm. Zanamivir deposited on different locations of the setup were assayed by high-pressure liquid chromatography (HPLC). The HPLC system consisted of a CBM-20A controller, LC-20AT pump, SPD-20A UV/VIS detector, SIL20A HT autosampler, and LCSolution software for control and analysis (Shimadzu, Kyoto, Japan). Samples (100 lL) were injected into a Nova-Pak C18 (4 lm particle size, 3.9 mm x 150 mm, Waters, MA, USA) with a 50% water– acetonitrile mixture as the mobile phase at a flow rate of 1mL/min. Zanamivir was analyzed using a wavelength of 230 nm with an average retention time of 4 minutes. The delivered dose was calculated as the amount of drug delivered to the distal end of the tracheal tube, including the T-junction, USP throat, and the MSLI stages. Results Performance of Inhalers
The proposed dry powder system was able to actuate both the Diskhaler and Osmohaler and empty most of the powder from the Rotadisk or the capsule within six puffs of the ventilation bag. The performance of the Diskhaler and Osmohaler in delivering Relenza powders is compared in
FIG. 2. Comparasion of the dispersion profiles of the Diskhaler and the OsmohalerTM using a tracheostomy tube of 7.0 mm internal diameter and 115 mm in length. (* denotes a statistically significant difference defined as p < 0.05).
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FIG. 3. The effect of dose regime on the dispersion profiles using an Osmohaler and a tracheostomy tube of 7.0 mm internal diameter and 115 mm in length. (* denotes a statistically significant difference defined as p < 0.05).
Figure 2. The efficiencies of the two inhalers in dispersing the lactose–zanamivir formulation were distinct. The deposition of zanamivir on the duckbill valve was two times higher when a Diskhaler was used (31.6 – 4.5%). Together with the high deposition inside the 7.0 mm tracheostomy tube (34.7 – 6.3%), only 18.1 – 4.66% of zanamivir powder was delivered to the distal end and a low FPF (3.4 – 2.1%) was obtained with the Diskhaler. In contrast, the Osmohaler was able to deliver a much higher dose ( p = 0.02) of 30.5 – 0.2%, despite a higher device retention. Dispersion with the Osmohaler also yielded a higher FPF (14.5 – 1.7%) than that obtained for the Diskhaler ( p < 0.01). This demonstrated that the Osmohaler is more efficient in dispersing
Relenza powder and may be a more suitable device for the proposed system. Effect of number of capsules
The recommended dose of Relenza Diskhaler is two blisters twice a day for flu treatment, and two blisters once daily for flu prevention. Therefore, two capsules were dispersed in sequence to understand the influence of the dose regime on the dispersion efficiency (Fig. 3). The device retention was lower when two capsules were dispersed, which could possibly be accounted by the increased number of actuations (12 puffs for two capsules and 6 puffs for one
FIG. 4. Comparison of the performance of the tracheostomy and endotracheal tubes using an Osmohaler. (* denotes a statistically significant difference defined as p < 0.05).
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capsule), emptying more powder out of the device. However, the increase was offset by the higher deposition on the duckbill valve, resulting in only a 5.4 % overall enhancement ( p < 0.03) in the delivered dose and no changes in the FPF. After this preliminary analysis of dosage amounts, all tests were performed with two-capsule dispersion. Effect of tracheal tube dimensions
Figure 4 shows the effects of the lengths (300 mm for endotracheal tube vs. 150 mm for tracheostomy tube) and tube internal diameters (7.0 mm vs. 9.0 mm) of the tracheal tubes on the dispersion performance using an Osmohaler. Similar deposition profiles were observed between the endotracheal and tracheostomy tubes of same interanl diameters (7.0 mm). Hence, similar delivered dose (32.9 – 2.9%) and FPF (13.6 – 3.4%) were obtained for these two tubes. Though the dispersion via the larger endotracheal tube (9 mm) had no significant difference in the delivered dose (35.7 – 3.0%) compared with the smaller counterpart, it yielded a significantly higher ( p < 0.02) FPF (13.6 – 2.0%). Discussion
The delivered dose and FPF of zanamivir using the Osmohaler were approximately half of the values reported in Tang et al.(9) when mannitol powder was dispersed. This variation may be attributed to the different nature of the drug formulations, where mannitol is a pure drug powder and Relenza contains lactose particles as a carrier. The much higher deposition of zanamivir inside the duckbill valve when the Diskhaler was use was most likely attributed to its low efficiency in dispersing the zanamivir from the lactose surface when compared with the Osmohaler. In the clinical setting, the tracheal tube will bypass the larynx, hence all the powder exiting the tube will deposit into the lungs. The delivered dose obtained by the proposed dry powder delivery system using the Relenza Diskhaler (18.1%) was comparable to the total lung dose obtained for healthy adults of 8%–21%.(14) In contrast, the system coupled with the Osmohaler was able to deliver even a higher dose (30.5%). This may potentially lead to improved clinical outcomes or a reduction in the amount of medication required. In an in vitro study, Ari et al.(15) demonstrated that jet nebulized aerosol therapy through a tracheostomy tube was more efficient than an endotracheal tube of the same internal diameter. Thus, when an endotracheal tube (300 mm in length) was used, a reduction is expected in the total delivered dose to the distal end. This is because aerosols are more likely to impact onto the tube surface due to the longer length, and yield a higher deposition inside the endotracheal tube. However, this is not the case for the present dry powder delivery system, where the deposition inside the endotracheal tube is insignificantly different from that in the tracheostomy tube. Similar observations were reported in our previous work(9) when mannitol dry powder was dispersed. This is possibly due to fine powders dispersed by the Osmohaler were able to follow the airflow without impacting onto the tube surface and/or powders deposited inside the tube got pushed out of the tube during the bagging procedures. The similar tube deposition also resulted in a comparable delivered dose and FPF between the two tubes (Fig. 4).
LEUNG ET AL.
In addition, Figure 4 depicts the influence of the internal diameter of the endotracheal tube on the powder delivery. While the delivered dose remained similar, an increase in the FPF was observed for the larger endotracheal tube (9.0 mm i.d.). As the internal diameter increases, the flow velocity decreases, and hence the likelihood of powder impaction on the tube surface should reduce. However, the increased tube surface area of the larger tracheal tube may also increase the incidence of powder impaction and deposition. As a result, the total amount of drug deposited inside the tube is a balance of these two phenomena. As seen in Figure 4, the deposition inside the larger endotracheal tube was found to be similar to that inside the smaller one, leading to a comparable delivered dose between the two tubes. The FPF for the 9.0 mm endotracheal tube was significantly higher with a value of 20.4 – 2.0% compared with that obtained with the 7.0 mm counterpart. Also, the FPF was only slightly lower than that the in vitro value reported by Kamiya(16) at 90 L/min (FPF < 5.2lm * 23%). The difference in the FPF was attributed to the higher deposition on stage 4 and the filter of the MSLI. It was also noted that the depositions on the T-junction and stage 1 were lower in the larger endotracheal tube dispersion. These observations suggested an increased number of large particles were deposited on the 9.0 mm endotracheal tube while the smaller particles were able to follow the airflow and travel to the distal end. For patients with severe acute respiratory distress syndrome, a lower tidal volume is 6 mL/kg body mass (300– 400 mL) would be more beneficial.(17) In our previous study,(9) the effect of different air flow patterns on the delivered dose and fine particle fraction of mannitol for mucus clearance was investigated. The flow acceleration ranged 4.07–9.68 L/sec2 and the peak flow ranged 87–133 L/min, which were the extreme conditions recorded from patients during manual hyperinflation. It was found that there was a slight increase in the delivered dose with no significant difference in the FPF when the peak flow rate from 100 to 133 L/min. There was no significant difference in both the delivered dose and FPF when the acceleration decreased from 9.68 to 4.07 L/sec2. Therefore, even though the bagging procedure may differ among operators, it may not have a significant influence on the delivered dose and FPF. Similarly, reducing the tidal volume during the bagging procedure for these patients is not expected to have significant impacts on our findings. Conclusion
The in vitro results demonstrated the feasibility of the proposed delivery system to introduce Relenza dry powder to intubated patients using both the Diskhaler and the Osmohaler. The Osmohaler was better than Diskhaler in dispersing the lactose-based zanamivir powder formulation using the proposed delivery system. The dose delivered to the distal end could reach up to 35%, with a favorable FPF of 13.6%–20.4%. Drug delivery through the endotracheal tube was found to be comparably efficient to the tracheostomy tube of the same internal diameter. Though the internal diameter of the endotracheal tube did not play a role in determining the total delivered dose, a higher FPF was obtained using the larger endotracheal tube. This in-line dry
DELIVERY OF RELENZA POWDER
powder delivery system offers a possible option for critically ill patients with influenza who cannot receive the Relenza Diskhaler by inhalation. It is recognized that there is potential risk of disconnecting the ventilator from the patients with H1N1 respiratory infection, especially those suffering from severe hypoxemic respiratory failure. However, given the relatively simple delivery mechanism of the proposed dry powder delivery system, it has the potential to be incorporated within a mechanical ventilator, hence eliminating the need to disconnect patients from the ventilation machine for administration of powdered drugs. Further animal and clinical studies offer the potential to see Relenza and other DPI products being introduced into ventilated patients, giving clinicians more options in patient care.
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8.
9.
10.
Acknowledgments
This study was funded by a grant from the Australian Research Council (DP110105161). Thaigarajan Parumasivam is a recipient of a Malaysian Government scholarship. Authors are thankful for Kevin Samnick for his helpful comments and suggestions. The authors are grateful to one of the reviewers for the valuable comments related to the clinical aspects.
11. 12.
Author Disclosure Statement
Sharon Shui Yee Leung, Patricia Tang, and Hak-Kim Chan are employees of the University of Sydney, Faculty of Pharmacy, NSW, Australia. Thaigarajan Parumasivam is a postgraduate student at the University of Sydney, Faculty of Pharmacy, NSW, Australia, supervised by Hak-Kim Chan. The study was funded by a grant from the Australian Research Council.
13. 14.
15.
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Received on September 8, 2014 in final form, February 13, 2015 Reviewed by: David Cipolla Stephan Ehrmann
Address correspondence to: Hak-Kim Chan, PhD Faculty of Pharmacy The University of Sydney Sydney, NSW 2006 Australia E-mail:
[email protected]
