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Assessment of new-generation high-power electronic nicotine delivery system as thermal aerosol generation device for inhaled bronchodilators
International Journal of Pharmaceutics 518 (2017) 264–269
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International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Assessment of new-generation high-power electronic nicotine delivery system as thermal aerosol generation device for inhaled bronchodilators Jérémie Pourcheza,b,c,* ,1, Fabien de Oliveiraa,b,c,d,1, Sophie Perinel-Rageyb,c,e, Thierry Bassetb,c,f , Jean-Michel Vergnonb,c,g , Nathalie Prévôta,b,c,d a
Ecole Nationale Supérieure des Mines de Saint-Etienne, CIS-EMSE, SAINBIOSE, F-42023 Saint Etienne, France INSERM, U1059, F-42023 Saint Etienne, France c Université de Lyon, F-69000 Lyon, France d CHU Saint-Etienne, Department of Nuclear Medicine, F-42055 Saint-Etienne, France e CHU Saint-Etienne, Medical-Surgical Intensive Care Unit, F-42055 Saint-Etienne, France f CHU de Saint-Etienne, Laboratoire de Pharmacologie Toxicologie, F-42055 Saint-Etienne, France g CHU Saint-Etienne, Department of Chest Diseases and Thoracic Oncology, F-42055 Saint-Etienne, France b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 November 2016 Received in revised form 29 December 2016 Accepted 3 January 2017 Available online 4 January 2017
Purpose: A need remains for alternative devices for aerosol drug delivery that are low cost, convenient and easy to use for the patient, but also capable of producing small-sized aerosol particles. This study investigated the potential of recent high power electronic nicotine delivery systems (ENDS) as aerosol generation devices for inhaled bronchodilators. Methods: The particle size distribution was measured using a cascade impactor. The delivery of terbutaline sulfate, a current bronchodilator used for asthma or COPD therapy by inhalation, was studied. This drug was quantified by liquid chromatography coupled with tandem mass spectrometry. Results: The particle size distribution in terms of mass frequency (in two ways, gravimetrically and quantitatively through drug assay on each stage) and the terbutaline sulfate concentration in the aerosol were elucidated. The mass median aerodynamic diameter (MMAD) and the drug delivery rose when the power level increased, to reach 5.6 0.4 mg/puff with a MMAD of 0.78 0.03 mm at 25 W. Conclusion: New generation high-power ENDS are very efficient to generate carrier-droplets in the submicron range containing drug molecules with a constant drug concentration whatever the sizefractions. ENDS appear to be highly patient-adaptive. © 2017 Elsevier B.V. All rights reserved.
Keywords: Aerosol Bronchodilator ENDS Electronic cigarette Thermal aerosol generation
1. Introduction Drugs can be delivered to the human body through a variety of routes such as oral intake, parenteral administration or inhalation. The pulmonary route has proven to be effective in local and systemic delivery of miscellaneous medications to treat pulmonary but also non-pulmonary diseases. A pulmonary drug administration requires a successful interaction between the pharmaceutical formulation, the patient and the aerosol device. In the last decade, various innovations have been devoted to develop aerosol technologies generating smaller airborne particles
* Corresponding author at: Ecole Nationale Supérieure des Mines de Saint Etienne 158 cours Fauriel, 42023 Saint Etienne Cedex 2, France. E-mail address: [email protected] (J. Pourchez). 1 Authors contributed equally to this work. http://dx.doi.org/10.1016/j.ijpharm.2017.01.009 0378-5173/© 2017 Elsevier B.V. All rights reserved.
(Albuquerque-Silva et al., 2014; Leclerc et al., 2014; Perinel et al., 2016) compared to usual devices used in clinical practice like nebulizers, pressurized metered-dose inhalers and drypowder inhalers. These technological breakthroughs aim at improving the drug delivery via the deep lung for systemic administration (e.g. insulin delivery), or local administration in patients suffering from obstructive lung diseases like asthma, cystic fibrosis and chronic obstructive pulmonary disease (COPD) (Dolovich et al., 2005; Sims, 2011). However, it remains a need for an alternative means of generating aerosols for drug delivery that is low cost, convenient and easy to use for the patient, and capable of producing small-sized aerosol particles with aerodynamic diameter ranging from 500 nm to 1 mm. Smokers of tobacco have implicitly found out that aerosols from thermal generation can reach the alveoli and are at least partially deposited upon inhalation. From a pharmaceutical perspective, of
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course smoking has never been considered as a viable drug delivery process because of uncontrolled production of numerous carcinogens, and also because of lack of consistent or desirable aerosol particle size. But new aerosol devices, electronic nicotine delivery systems (ENDS), have appeared on the market for a decade already. Currently, they are regulated as general consumer products and not as medical devices. The popularity of these devices has dramatically increased since approximately 2009. They have become a widespread smoking reduction or cessation tool (“E-cigarettes,” n.d.; Fagerstrom et al., 2015). The ENDS market has grown from several thousand users in 2006 to several million worldwide in 2016. Basically, ENDS are battery-powered personal vaporizers. The physic principle shared by all ENDS is an electrically-powered heating element which enables to vaporize a liquid solution so that aerosol is produced for the user to inhale. Therefore, ENDS are undoubtedly thermal aerosol generation devices. They exhibit a close working principle to that of some medical devices, already on the drug delivery technology market for various clinical applications like schizophrenia or bipolar disorder in adults, the delivery of anti-panic or anti-migraine agents (Ibrahim et al., 2015; Rabinowitz et al., 2006, 2004). The refill liquid used in ENDS contains nicotine, humectants (i.e. glycerol and propylene glycol) and other ingredients in small quantities (water, ethanol, flavorings, etc.). Since its emergence the ENDS industry continuously evolved. Nowadays new generation of high-power ENDS perfectly demonstrate that they can deliver very high levels of aerosol nicotine (Farsalinos et al., 2016, 2014). Their effectiveness in delivering a drug (i.e. nicotine) for systemic administration thanks to small-sized aerosol particles, their capacity in developing userfriendly and customer-oriented technology, make ENDS a potential promising aerosol device for clinical purposes. In this frame, this study proposes to assess the potential of newgeneration high-power ENDS as aerosol generation device for inhaled therapy. As a proof of concept in order to emphasize the main advantages and drawbacks of this class of devices, this work focuses on the delivery of an inhaled bronchodilator. To the best of authors’ knowledge, this paper studies for the first time: the thermal stability of a drug after ENDS vaporization (i.e. to proceed at the vaporization of a bronchodilator without thermal degradation), the aerosol features (i.e. according to usual standards in the aerosol therapy field: mass median aerodynamic diameter (MMAD), cumulative and frequency mass distributions vs. aerodynamic diameters), the aerosol output (defined as the mass of fluid and the mass of drug contained in aerosol for different size fractions) using recent ENDS technology. 2. Materials and methods 2.1. Materials A recent high-power ENDS was used (purchased in March 2016 from a local store and online distributor). This ENDS model is made up of a variable lithium-ion battery (iStick TC40W, Eleaf) and an atomizer (GS Tank, Eleaf). Equipped with an internal 2600 mAh battery, the variable wattage can be adjusted up to 40 W (W) of vaping power. The variable wattage/voltage resistance range is 0.15–3.55 ohm. It corresponds to the working range of the battery device. The GS-Tank is a recently engineered atomizer. It presents a resistance of 0.15 ohm, a liquid capacity of 3 mL and requires maximum push power ranging up to 40 W. The amount of airflow can easily be adjusted by the control ring on the atomizer base. Prior to perform particle size assessments, batteries were fully charged, the maximum air inflow position was fixed, and the value of the electrical resistance was checked. Atomizers were changed regularly to avoid biases due to the use of degraded and/or dirty
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coil. In our study, all combinations of vaping parameters were carefully adjusted to avoid the dry puff phenomenon. The human control feedback of a regular vaper was used to be certain of the absence of unpleasant taste using the ENDS (which proves that the dry puff phenomenon occurs). For all experiments the power level of the battery was fixed at 12.5 W, 18 W or 25 W. 2.2. Refill liquid composition The composition of the refill liquid used corresponded to a 80% PG + 20% VG base (noted 80 PG/20VG); PG referred to propylene glycol, and VG referred to vegetable glycerin. This formulation was home-made in the laboratory from commercial nicotine-free solutions (purchased in March 2016 from a local store, 100-VG and 100-PG base, A&L company, France). It is important to underline that both formulations of refill liquid used for this study were flavor-free. Although the nominal capacity of the tank-type atomizer is 3 mL, only 2.4 mL of the prepared solution was used to avoid potential overfilling. The drug chosen for this study was a solution of terbutaline sulfate (5 mg/2 mL, Bricanyl1) usually employed to fill nebulizers for pulmonary administration (composition of the commercial product: water, terbutaline sulfate and excipients such as sodium chloride, sodium EDTA or E385, hydrochloric acid or E507). Terbutaline sulfate is a b2 adrenergic receptor agonist used as bronchodilator. Therapeutic indications of terbutaline sulfate are the treatment or prevention of bronchospasm (wheezing, chest tightness, trouble breathing) in patients with lung conditions such as asthma, bronchitis, COPD or emphysema. A dilution of 12.5% of the terbutaline sulfate solution with 87.5% of the 80 PG/20VG solution was carried out. Thus, a concentration of terbutaline sulfate equal to 0.3125 mg/mL was used to fill the tank-atomizer of the ENDS. 2.3. Particle size distribution: mass distribution and MMAD Aerosol particle sizing was defined in terms of Mass Median Aerodynamic Diameter (MMAD). Aerodynamic particle size distribution was measured using a cascade impactor, where the aerosolized particles are impacted on different stages depending on their inertia in relation to their aerodynamic diameter. This device allows simultaneous measurements of the aerodynamic size and the mass of aerosol in the different size ranges. The DLPI set-up was used (Low-Pressure Impactor; Dekati Ltd, Finland) to quantify the aerosol output and the particle size distribution of aerosol generated by high-power ENDS. The DLPI allows the collection of nebulized particles from 7 nm to 10 mm into 12 size fractions and operated with an air flow of 10 L min 1. An in-house interface was designed to introduce quickly and reproducibly a well-controlled volume and duration puff into the inlet of the impactor. This interface was composed of a 3L syringe (3 L spirometry calibration syringe, Hans-Rudolph, USA) connected to both the ENDS and the DLPI cascade impactor. Aerosol sampling was carried out considering 4-s puff with a flow rate of 500 mL/s and a dilution ratio of 1.5 (i.e. the aerosol was produced in the 3 L syringe applying an inhaling flow rate of 500 mL/s for 4 s to reach a volume of 2 L of aerosol diluted in 1 L of air). 6 syringes of 3 L (2 L of aerosol diluted with 1 L of air) were successively introduced to the impactor. All parameters were chosen from results performed during previous works (Pourchez et al., 2016; Prévôt et al., 2016). Particularly, high flow rate is needed when we introduce aerosol generated by ENDS to the DLPI cascade impactor. This flow rate is totally unrealistic (i.e. no human can apply such a high flow rate). However, previous studies (Pourchez et al., 2016; Prévôt et al., 2016) showed no significant impact on MMAD of this high flow rate (for a dilution ratio of 1.5) compared to highly realistic puffing
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behavior (i.e. 4-s puff and 55 mL per puff). After each DLPI experiment, each stage corresponding to a well-defined aerodynamic size-fraction was weighted using an electronic precision balance (Adventurer Pro, OHAUS, USA) and then rinsed with 1.6 mL of deionized water into appropriate volumetric flasks. Liquids were then assayed for drug concentration. Experiments were performed in triplicate for 3 power levels of the ENDS (12.5 W, 18 W, 25 W). 2.4. Assessment of emitted drug mass per puff An important output consists in measuring the content of terbutaline sulfate per puff of aerosol emitted by the ENDS. As cascade impactors experiments (see previous section) do not used realistic puffing behavior (experimental procedure using high flow rate and aerosol dilution ratio of 1.5 which is only validated for MMAD measurement, not for the aerosol output), a biological air sampler set-up (Coriolis micro, Bertin instruments) was used to assess the terbutaline sulfate emitted dose under realistic puffing behavior. This device is an air sampler for bio-contamination assessment, mainly dedicated to air quality control and air quality monitoring in environmental and pharmaceutical research. Based on a wet cyclonic technology, combined to a high air flow rate, this set-up offers high efficient particles collection in short times. Aerosol sampling generated by the ENDS was carried out considering 50 puffs (2 series of 25 puffs) with given features: 4-s puff, volume of 55 mL per puff, inter-puff duration of 30 s, interseries duration of 300 s (25 puffs per series). An in-house interface was designed for puffing. Puffs were performed using a 60 mL syringe connected to both the ENDS and the biological air sampler set-up through a 3 ways valve. The airflow rate of the Coriolis air sampler was 300 L/min. At the end of the experiment, the sample liquid output collected in the Coriolis air sampler set-up was rinsed with 1.5 mL of deionized water into appropriate volumetric flasks. Liquids were then assayed for terbutaline sulfate dosage. The emitted drug mass per puff was simply obtained knowing the aerosol sample ratio using the Coriolis set-up for our experimental conditions. This ratio was calculated by dividing the total mass of aerosol generated by the ENDS (obtained from the refill liquid mass loss during the 50 puffs experiments using an electronic precision balance, Adventurer Pro, OHAUS, USA) by the mass of condensate aerosol liquid collected using the Coriolis air sampler set-up (condensate aerosol liquid collected was weighted using an electronic precision balance, Adventurer Pro, OHAUS, USA). Of course the mass of condensate aerosol collected was lower than the mass of aerosol generated by the ENDS due to condensation and loss in the walls of the tubing and syringe of the experimental set-up as well as evaporation phenomenon occurring inside the Coriolis air sampler (from this initial inlet connected to the syringe to the final Coriolis air sampler collecting tube). Experiments were performed in triplicate for 3 power levels of ENDS (12.5 W, 18 W, 25 W).
Standard solutions were prepared by serial dilutions in water at concentration levels of 0.25, 2.5, 25 and 250 g/L. Samples were stored at 20 C until analysis. Liquid chromatography was performed using an Acquity ultra-performance liquid chromatograph system using an UPLC HSS-T3 C18 column (Waters, France). The mobile phase was a mix of A: distilled water containing 0.1% formic acid and B: acetonitrile containing 0.1% formic acid. The gradient was 0–0.1 min: 10% B; 0.1–0.4 min: linear from 10 to 90% B; 0.4–1.2 min: 90% B; 1.20 min return to initial conditions until 1.3 min. The flow rate was 0.5 mL/min. The liquid chromatograph system was coupled to a Xevo TQS Micro triple quadrupole mass spectrometer (Waters, France). The instrument was equipped with an electrospray ionization source. The analytes were detected in multiple reaction monitoring mode using the positive ionization mode. The system control and data acquisition were performed using MassLynx V4.1 software (Waters, France). 3. Results 3.1. Impact of the ENDS power level on the drug delivery Table 1 summarizes particle size data and the delivery of aerosol terbutaline sulfate obtained for all experimental conditions. First of all, spectra allowing the terbutaline sulfate dosage indicated that the drug vaporization occurred without thermal degradation of the terbutaline sulfate whatever the power levels used (i.e. no degradation products were detected). Fig. 1 shows the drug delivery vs. the ENDS power level ranging from 12.5 W to 25 W. A linear correlation (y = 0.34x 2.85, R2 = 1.00, Fig. 1) was clearly identified indicating that the higher the power level, the higher the delivery of aerosol bronchodilator, showing a concentration of terbutaline sulfate in the aerosol up to 5.6 0.4 mg/puff at 25 W. These findings highlighted that, for a given initial drug concentration (the un-puffed liquid), a patient could very easily vary the drug mass delivery (for a same number of puffs) by simply adjusting the ENDS power level (variable wattage function of ENDS
2.5. Terbutaline sulfate dosage Primary stock solutions of terbutaline sulfate (1 g/L) were prepared in water and stored at 20 C. Working solutions were prepared freshly on each day of analysis as serial dilutions in water.
Fig. 1. Impact of the power level (ranging from 12.5 to 25 W) on the drug delivery (expressed in mg of terbutaline sulfate/puff generated by the ENDS).
Table 1 Summary of the size distribution data and the drug delivery. Experiments were performed in triplicate. MMAD referred to the Mass Median Aerodynamic Diameter. Power level of the battery
MMAD of refill liquid (mm)
MMAD of terbutaline sulfate (mm)
Delivery of terbutaline sulfate (mg/puff)
Concentration of aerosol terbutaline sulfate (mg/mL)
Mass loss of ENDS after 50 puffs (mg)
12.5 W 18 W 25 W
0.56 0.03 0.74 0.08 0.77 0.02
0.55 0.03 0.71 0.06 0.78 0.03
1.3 0.2 3.5 0.2 5.6 0.4
0.25 0.04 0.34 0.01 0.33 0.03
284 1 540 19 920 24
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can be easily activated by using battery button to change settings in a single step). Besides, the concentration of aerosol terbutaline sulfate was measured after 50 puffs (Fig. 2). The concentration of aerosol terbutaline sulfate slightly rose when the ENDS power level increased. Furthermore, from the power level of 18 W, the concentration of aerosol drug reached similar value to the initial drug concentration of the liquid (i.e. the un-puffed liquid) used to fill the tank-atomizer of the ENDS. For example, the aerosol drug concentration was 0.33 0.03 mg/mL at 25 W (compared to 0.3125 mg/mL initially, Fig. 2 and Table 1). 3.2. Aerosol features of ENDS for inhaled bronchodilator Fig. 3 demonstrates that a perfect matching between the frequency mass distribution of the airborne refill liquid and the aerosol drug was observed for a given power level at 25 W. Similar results were obtained at 12.5 W and 18 W (data not shown). This finding leads to indicate that:
Fig. 3. DLPI Impactor-collected data showing the frequency mass distribution for a power level fixed at 25 W. Mass of airborne refill liquid in grey (expressed in%). Mass of drug in black (expressed in%).
(i) There is not empty airborne carrier generated by recent highpower ENDS (i.e. droplet of refill liquid without terbutaline sulfate). (ii) The drug concentration inside droplets of refill liquid, whatever the aerodynamic size-fractions in the submicron range, is constant. Besides, Figs. 4 and 5 show impactor-collected data by means of frequency mass distribution. Three levels of ENDS power were investigated. Results highlighted a gradual transition of a dominant mode mainly distributed from 382 nm at 12.5 W to 613 nm at 25 W whatever the mass distribution considered (i.e. mass distribution of airborne refill liquid in Fig. 4 or mass distribution of aerosol drug in Fig. 5). The transition from 613 nm to 949 nm seems to occur at a lower power level than 18 W. As a result, a slight increase of the MMAD (expressed in term of MMAD of refill liquid or MMAD of aerosol drug) was noticed when the power level rose (Table 1). For example the aerosol drug MMAD increased from 0.55 0.03 mm at 12.5 W to 0.77 0.02 mm at 25 W. Therefore, these findings indicate that, for a given drug concentration of the un-puffed refill liquid, a patient could very easily vary the aerodynamic features of the aerosol drug in the submicron range by simply adjusting the ENDS power level.
Fig. 4. DLPI Impactor-collected data showing the impact of the power level (ranging from 12.5 to 25 W) on the frequency mass distribution of airborne refill liquid (expressed in%).
Fig. 5. DLPI Impactor-collected data showing the impact of the power level (ranging from 12.5 to 25 W) on the frequency mass distribution of drug (expressed in%).
4. Discussion 4.1. Impact of aerosol sampling and low pressure impactor on the MMAD calculation
Fig. 2. Impact of the power level on the concentration of aerosol drug (bar graph) expressed in mg of terbutaline sulfate per mL of refill liquid.
Determination of particle size distribution of ENDS aerosol is an experimental challenge because of the high hygroscopicity and
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volatility nature of the particulate matter (composed largely from propylene glycol, glycerin and water). Sizing techniques requiring a high degree of aerosol dilution are expected to result in significant particle evaporation, and then to induce potential bias with the alteration of the particle size distribution from that provided to the vaper. Besides, the ENDS aerosol exhibits a dynamic behavior after puffing and during inhalation. Both the size particle distribution and the number particle concentration are expected to evolve because the aerosol is subject to condensational growth, particulate matter evaporation, coagulation and particle deposition. To address these obstacles, we have taken special care with the development of a measurement strategy to limit as much as possible experimental biases by particles evaporation and particles coagulation. However, we must underline that a possible evaporation of aerosol droplets during sampling can always occur. Therefore, MMAD measured in the proposed tests, using low pressure cascade impactor, may not absolutely correspond to MMAD happening under humid physiological conditions. 4.2. Safety assessment of ENDS: a limit on its use for pharmaceutical purposes? Despite a steep increase in market penetration, safety assessment of ENDS remains an issue (“E-cigarettes,” n.d.). Used as a smoking reduction or cessation tool, the main toxicological issues concern: the inhaled nicotine (Benowitz and Burbank, 2016; Bhatnagar, 2016; Grana et al., 2014; Schraufnagel et al., 2014), inhaled flavor additives (Grana et al., 2014; Schraufnagel et al., 2014), inhaled metallic nanoparticles potentially generated by some ENDS devices (Williams et al., 2013), inhaled aldehydes inadvertently produced when solvents are heated (Drummond and Upson, 2014; Grana et al., 2014), inhaled propylene glycol (PG) composing the refill liquid (Callahan-Lyon, 2014; Grana et al., 2014; Schraufnagel et al., 2014; Varlet et al., 2015). All things considered, from a pharmaceutical perspective of the ENDS use to delivery bronchodilators, it seems crucial to consider: (i) Appropriate solvents compared to ENDS used for smoking reduction or cessation purpose, i.e. nicotine-free and flavorfree. The safety issue about PG-containing solvents appears uncertain even if PG has been used as carrier for inhalation medications (Niven et al., 2011; Wang et al., 2007). (ii) Recent tank-atomizer ENDS under appropriate combination of experimental parameters (power of the battery, atomizer design) to limit or avoid aldehydes and nanoparticles emissions in the produced aerosol.
4.3. ENDS: a possible device for inhaled bronchodilators? This work studied the delivery of inhaled bronchodilator using new-generation high-power ENDS technology. The main advantages of ENDS for inhaled bronchodilator therapy, compared to the usual aerosol devices (pressurized metered-dose inhalers or pMDI, nebulizers, dry-powder inhalers or DPI), are to produce smaller aerosol particles (MMAD in the 0.5–0.8 mm range) with the possibility for the patient (with a same device and a given initial drug concentration in the un-puffed liquid) to vary both the content of bronchodilator delivery per puff as well as the aerodynamic size of the airborne carrier. Thus, ENDS appears to be highly patient-adaptive aerosol devices in good accordance with the concept of personalized medicine. The main advantage of ENDS is to be efficient for patients of disparate anatomy or lung function (e.g. using smaller particle size for children or for patients with highly obstructive diseases) and/or to be adjusted depending on the illness evolution (e.g. variation of aerosol drug dose per puff
as a function of pathology changes during the treatment time). The patient could also modify the dose by adjusting the puff duration without changing the power. Besides, at the same time we should notice that this could lead to easier misuse ENDS by uneducated patients. So there needs to be some education, because the easy manipulation and use of ENDS technology could be a huge advantage, but could also create some problems. All things considered, a main drawbacks regard the thermal stability of drugs, which can be aerosolized using ENDS. The best drug candidates for such systems are those which are thermally stable and with low-melting points. Another possible limitation is that respiratory smooth muscles are not located in deep lungs but generally in the central lungs. Therefore, the ENDS device may not necessary target the desired regions of the lungs in the case of bronchodilators administration. The very small airways are devoid of smooth bronchial fibers and therefore they are a priori insensitive to beta2-agonist drug. Nevertheless a usual micronsize aerosol leads to a very central deposition, generally until the 5th or 6th orders of bronchi. On the contrary, small airborne particles generated by ENDS allow guaranteeing a more homogeneous aerosol deposition, especially in already small bronchi (e.g. children) or in asthma and COPD exacerbation where larger particles usually are blocked in proximal bronchi. In the case of inhaled corticosteroids, the impact of small airborne particles (e.g. generated by ENDS) on the lung periphery is even more straightforward. Furthermore, an important parameter to compare the ENDS performance to other aerosol devices is the drug delivery potential. Important factors influencing the total dose delivered to patients airways include the initial volume fill, the efficiency by which nebulized aerosol is made available for patient inhalation, and the “dead” volume left in the nebulizer on cessation of operation (Force et al., 2001). It is commonly accepted that the drug dose inhaled using a nebulizer is in the 5–40% range of the initial drug introduced into the device. In these conditions, the patient could inhale approximately 250 mg to 2 mg of terbutaline sulfate. At the maximum power level tested in this study, an emitted dose of approximately 280 mg can be obtained for 50 ENDS puffs. Consequently, this result show quite similar emitted dose between nebulization and ENDS. Moreover, we must keep in mind that the initial terbutaline sulfate concentration used to fill the ENDS in this study is 8 times lower than the usual nominal concentration used for nebulization (0.3125 mg/mL vs. 2.5 mg/mL). In a next future, the enhancement of the emitted dose of bronchodilator using ENDS could be quite easily achieved by increasing the power level of the ENDS and/or the initial drug concentration of the un-puffed refill liquid. The same reasoning can be proposed for another terbutaline sulfate aerosol device, the Bricanyl Turbuhaler (labeled as a nominal dose of 500 mg terbutaline sulfate per puff, AstraZeneca, UK). The emitted dose of terbutaline sulfate from the Turbuhaler at different inhalation flows is in the 21.4%–77.3% range (Abdelrahim, 2010). The amounts are expressed as a% of the 500 mg terbutaline sulfate nominal dose. So the emitted dose of sulfate terbutaline can be estimated ranging from 107 to 386 mg matching 20–70 puffs using ENDS in the experimental conditions (not optimal) tested in this work. All things considered, the doses of inhaled bronchodilator enable to be delivered with new generation high-power ENDS are quite relevant compared to existing aerosol devices. 4.4. ENDS: a possible device for systemic drug delivery? The lungs can also be used as a pathway for systemic drug delivery. Although a variety of pulmonary delivery systems are used in current clinical practice, the efficiency of their delivery of
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particles to the deep lung is limited. Recently, a new approach to generate aerosols has been introduced, the thermal aerosol generation (Ibrahim et al., 2015; Rabinowitz et al., 2006, 2004). The process involves heating a thin film of drug, enabling its flash vaporization with minimal decomposition, to form a vapor that then cools and condenses into particles in the 1 mm–3 mm range. ENDS appear as a category of devices with a close working principle compared to thermal aerosol medical devices already on the market. ENDS have proven their potential to produce high level of active substance in the aerosol (such as nicotine). ENDS could be a promising tool to deliver thermally stable systemic drugs. 5. Conclusion This study investigated the potential of recent high power ENDS as aerosol generation devices for inhaled bronchodilators. Results showed that new generation high-power ENDS are very efficient to generate carrier-droplets in the submicron range containing bronchodilators with a constant drug concentration whatever the size-fractions. Moreover, MMAD and the drug delivery significantly rise when the power level increases from 12.5 to 25 W. Therefore, ENDS appears as highly patient-adaptive device. In fact, MMAD and drug emitted can be easily self-adjusted by the patient thanks to ENDS electronic function. In other words, for the first time an aerosol generation device allows to change both MMAD and the amount of drug emitted, with a same device and a given nominal drug concentration. These findings provide a better understanding of how a drug can be delivered from the refill liquid to the aerosol using recent ENDS technology. Nowadays, the main drawbacks to consider ENDS as a medical device in the aerosol therapy field remains the choice of drug with well-adapted thermal behavior. Acknowledgements & disclosures There is no source of support for this study (grants, gift, equipment or drugs) to declare. The authors are independent from tobacco industry and declare no financial relationships with any organizations that might have an interest in the submitted work. In particular, we do not have a source of support to declare from the company that sells the electronic cigarette used in the submitted work. However, some authors declare links of interest with pharmacy and medical devices industries. J. Pourchez has received research grants outside the submitted work from Pari GmbH and Laboratoires CERES; J.M. Vergnon has received research and educational grants outside the submitted work from Novatech SA, Boehringer Ingelheim, Olympus, Pentax and Astra Zeneca. References Abdelrahim, M.E., 2010. Emitted dose and lung deposition of inhaled terbutaline from Turbuhaler at different conditions. Respir. Med. 104, 682–689. Albuquerque-Silva, I., Vecellio, L., Durand, M., Avet, J., Le Pennec, D., de Monte, M., Montharu, J., Diot, P., Cottier, M., Dubois, F., Pourchez, J., 2014. Particle deposition in a child respiratory tract model: in vivo regional deposition of fine and ultrafine aerosols in baboons. PLoS One 9, e95456.
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Impact of power level and refill liquid composition on the aerosol output and particle size distribution generated by recent high-power ecigarette device. J. Aerosol Med. Pulm. Drug Deliv. Submitted. Prévôt, N., de Oliveira, F., Wintzer, L., Perinel-Ragey, S., Basset, T., Vergnon, J.-M., Pourchez, J., 2016. Nicotine delivery from the refill liquid to the aerosol via highpower e-cigarette device. J. Aerosol Med. Pulm. Drug Deliv. Submitted. Rabinowitz, J.D., Wensley, M., Lloyd, P., Myers, D., Shen, W., Lu, A., Hodges, C., Hale, R., Mufson, D., Zaffaroni, A., 2004. Fast onset medications through thermally generated aerosols. J. Pharmacol. Exp. Ther. 309, 769–775. Rabinowitz, J.D., Lloyd, P.M., Munzar, P., Myers, D.J., Cross, S., Damani, R., Quintana, R., Spyker, D.A., Soni, P., Cassella, J.V., 2006. Ultra-fast absorption of amorphous pure drug aerosols via deep lung inhalation. J. Pharm. Sci. 95, 2438–2451. 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International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Assessment of new-generation high-power electronic nicotine delivery system as thermal aerosol generation device for inhaled bronchodilators Jérémie Pourcheza,b,c,* ,1, Fabien de Oliveiraa,b,c,d,1, Sophie Perinel-Rageyb,c,e, Thierry Bassetb,c,f , Jean-Michel Vergnonb,c,g , Nathalie Prévôta,b,c,d a
Ecole Nationale Supérieure des Mines de Saint-Etienne, CIS-EMSE, SAINBIOSE, F-42023 Saint Etienne, France INSERM, U1059, F-42023 Saint Etienne, France c Université de Lyon, F-69000 Lyon, France d CHU Saint-Etienne, Department of Nuclear Medicine, F-42055 Saint-Etienne, France e CHU Saint-Etienne, Medical-Surgical Intensive Care Unit, F-42055 Saint-Etienne, France f CHU de Saint-Etienne, Laboratoire de Pharmacologie Toxicologie, F-42055 Saint-Etienne, France g CHU Saint-Etienne, Department of Chest Diseases and Thoracic Oncology, F-42055 Saint-Etienne, France b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 November 2016 Received in revised form 29 December 2016 Accepted 3 January 2017 Available online 4 January 2017
Purpose: A need remains for alternative devices for aerosol drug delivery that are low cost, convenient and easy to use for the patient, but also capable of producing small-sized aerosol particles. This study investigated the potential of recent high power electronic nicotine delivery systems (ENDS) as aerosol generation devices for inhaled bronchodilators. Methods: The particle size distribution was measured using a cascade impactor. The delivery of terbutaline sulfate, a current bronchodilator used for asthma or COPD therapy by inhalation, was studied. This drug was quantified by liquid chromatography coupled with tandem mass spectrometry. Results: The particle size distribution in terms of mass frequency (in two ways, gravimetrically and quantitatively through drug assay on each stage) and the terbutaline sulfate concentration in the aerosol were elucidated. The mass median aerodynamic diameter (MMAD) and the drug delivery rose when the power level increased, to reach 5.6 0.4 mg/puff with a MMAD of 0.78 0.03 mm at 25 W. Conclusion: New generation high-power ENDS are very efficient to generate carrier-droplets in the submicron range containing drug molecules with a constant drug concentration whatever the sizefractions. ENDS appear to be highly patient-adaptive. © 2017 Elsevier B.V. All rights reserved.
Keywords: Aerosol Bronchodilator ENDS Electronic cigarette Thermal aerosol generation
1. Introduction Drugs can be delivered to the human body through a variety of routes such as oral intake, parenteral administration or inhalation. The pulmonary route has proven to be effective in local and systemic delivery of miscellaneous medications to treat pulmonary but also non-pulmonary diseases. A pulmonary drug administration requires a successful interaction between the pharmaceutical formulation, the patient and the aerosol device. In the last decade, various innovations have been devoted to develop aerosol technologies generating smaller airborne particles
* Corresponding author at: Ecole Nationale Supérieure des Mines de Saint Etienne 158 cours Fauriel, 42023 Saint Etienne Cedex 2, France. E-mail address: [email protected] (J. Pourchez). 1 Authors contributed equally to this work. http://dx.doi.org/10.1016/j.ijpharm.2017.01.009 0378-5173/© 2017 Elsevier B.V. All rights reserved.
(Albuquerque-Silva et al., 2014; Leclerc et al., 2014; Perinel et al., 2016) compared to usual devices used in clinical practice like nebulizers, pressurized metered-dose inhalers and drypowder inhalers. These technological breakthroughs aim at improving the drug delivery via the deep lung for systemic administration (e.g. insulin delivery), or local administration in patients suffering from obstructive lung diseases like asthma, cystic fibrosis and chronic obstructive pulmonary disease (COPD) (Dolovich et al., 2005; Sims, 2011). However, it remains a need for an alternative means of generating aerosols for drug delivery that is low cost, convenient and easy to use for the patient, and capable of producing small-sized aerosol particles with aerodynamic diameter ranging from 500 nm to 1 mm. Smokers of tobacco have implicitly found out that aerosols from thermal generation can reach the alveoli and are at least partially deposited upon inhalation. From a pharmaceutical perspective, of
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course smoking has never been considered as a viable drug delivery process because of uncontrolled production of numerous carcinogens, and also because of lack of consistent or desirable aerosol particle size. But new aerosol devices, electronic nicotine delivery systems (ENDS), have appeared on the market for a decade already. Currently, they are regulated as general consumer products and not as medical devices. The popularity of these devices has dramatically increased since approximately 2009. They have become a widespread smoking reduction or cessation tool (“E-cigarettes,” n.d.; Fagerstrom et al., 2015). The ENDS market has grown from several thousand users in 2006 to several million worldwide in 2016. Basically, ENDS are battery-powered personal vaporizers. The physic principle shared by all ENDS is an electrically-powered heating element which enables to vaporize a liquid solution so that aerosol is produced for the user to inhale. Therefore, ENDS are undoubtedly thermal aerosol generation devices. They exhibit a close working principle to that of some medical devices, already on the drug delivery technology market for various clinical applications like schizophrenia or bipolar disorder in adults, the delivery of anti-panic or anti-migraine agents (Ibrahim et al., 2015; Rabinowitz et al., 2006, 2004). The refill liquid used in ENDS contains nicotine, humectants (i.e. glycerol and propylene glycol) and other ingredients in small quantities (water, ethanol, flavorings, etc.). Since its emergence the ENDS industry continuously evolved. Nowadays new generation of high-power ENDS perfectly demonstrate that they can deliver very high levels of aerosol nicotine (Farsalinos et al., 2016, 2014). Their effectiveness in delivering a drug (i.e. nicotine) for systemic administration thanks to small-sized aerosol particles, their capacity in developing userfriendly and customer-oriented technology, make ENDS a potential promising aerosol device for clinical purposes. In this frame, this study proposes to assess the potential of newgeneration high-power ENDS as aerosol generation device for inhaled therapy. As a proof of concept in order to emphasize the main advantages and drawbacks of this class of devices, this work focuses on the delivery of an inhaled bronchodilator. To the best of authors’ knowledge, this paper studies for the first time: the thermal stability of a drug after ENDS vaporization (i.e. to proceed at the vaporization of a bronchodilator without thermal degradation), the aerosol features (i.e. according to usual standards in the aerosol therapy field: mass median aerodynamic diameter (MMAD), cumulative and frequency mass distributions vs. aerodynamic diameters), the aerosol output (defined as the mass of fluid and the mass of drug contained in aerosol for different size fractions) using recent ENDS technology. 2. Materials and methods 2.1. Materials A recent high-power ENDS was used (purchased in March 2016 from a local store and online distributor). This ENDS model is made up of a variable lithium-ion battery (iStick TC40W, Eleaf) and an atomizer (GS Tank, Eleaf). Equipped with an internal 2600 mAh battery, the variable wattage can be adjusted up to 40 W (W) of vaping power. The variable wattage/voltage resistance range is 0.15–3.55 ohm. It corresponds to the working range of the battery device. The GS-Tank is a recently engineered atomizer. It presents a resistance of 0.15 ohm, a liquid capacity of 3 mL and requires maximum push power ranging up to 40 W. The amount of airflow can easily be adjusted by the control ring on the atomizer base. Prior to perform particle size assessments, batteries were fully charged, the maximum air inflow position was fixed, and the value of the electrical resistance was checked. Atomizers were changed regularly to avoid biases due to the use of degraded and/or dirty
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coil. In our study, all combinations of vaping parameters were carefully adjusted to avoid the dry puff phenomenon. The human control feedback of a regular vaper was used to be certain of the absence of unpleasant taste using the ENDS (which proves that the dry puff phenomenon occurs). For all experiments the power level of the battery was fixed at 12.5 W, 18 W or 25 W. 2.2. Refill liquid composition The composition of the refill liquid used corresponded to a 80% PG + 20% VG base (noted 80 PG/20VG); PG referred to propylene glycol, and VG referred to vegetable glycerin. This formulation was home-made in the laboratory from commercial nicotine-free solutions (purchased in March 2016 from a local store, 100-VG and 100-PG base, A&L company, France). It is important to underline that both formulations of refill liquid used for this study were flavor-free. Although the nominal capacity of the tank-type atomizer is 3 mL, only 2.4 mL of the prepared solution was used to avoid potential overfilling. The drug chosen for this study was a solution of terbutaline sulfate (5 mg/2 mL, Bricanyl1) usually employed to fill nebulizers for pulmonary administration (composition of the commercial product: water, terbutaline sulfate and excipients such as sodium chloride, sodium EDTA or E385, hydrochloric acid or E507). Terbutaline sulfate is a b2 adrenergic receptor agonist used as bronchodilator. Therapeutic indications of terbutaline sulfate are the treatment or prevention of bronchospasm (wheezing, chest tightness, trouble breathing) in patients with lung conditions such as asthma, bronchitis, COPD or emphysema. A dilution of 12.5% of the terbutaline sulfate solution with 87.5% of the 80 PG/20VG solution was carried out. Thus, a concentration of terbutaline sulfate equal to 0.3125 mg/mL was used to fill the tank-atomizer of the ENDS. 2.3. Particle size distribution: mass distribution and MMAD Aerosol particle sizing was defined in terms of Mass Median Aerodynamic Diameter (MMAD). Aerodynamic particle size distribution was measured using a cascade impactor, where the aerosolized particles are impacted on different stages depending on their inertia in relation to their aerodynamic diameter. This device allows simultaneous measurements of the aerodynamic size and the mass of aerosol in the different size ranges. The DLPI set-up was used (Low-Pressure Impactor; Dekati Ltd, Finland) to quantify the aerosol output and the particle size distribution of aerosol generated by high-power ENDS. The DLPI allows the collection of nebulized particles from 7 nm to 10 mm into 12 size fractions and operated with an air flow of 10 L min 1. An in-house interface was designed to introduce quickly and reproducibly a well-controlled volume and duration puff into the inlet of the impactor. This interface was composed of a 3L syringe (3 L spirometry calibration syringe, Hans-Rudolph, USA) connected to both the ENDS and the DLPI cascade impactor. Aerosol sampling was carried out considering 4-s puff with a flow rate of 500 mL/s and a dilution ratio of 1.5 (i.e. the aerosol was produced in the 3 L syringe applying an inhaling flow rate of 500 mL/s for 4 s to reach a volume of 2 L of aerosol diluted in 1 L of air). 6 syringes of 3 L (2 L of aerosol diluted with 1 L of air) were successively introduced to the impactor. All parameters were chosen from results performed during previous works (Pourchez et al., 2016; Prévôt et al., 2016). Particularly, high flow rate is needed when we introduce aerosol generated by ENDS to the DLPI cascade impactor. This flow rate is totally unrealistic (i.e. no human can apply such a high flow rate). However, previous studies (Pourchez et al., 2016; Prévôt et al., 2016) showed no significant impact on MMAD of this high flow rate (for a dilution ratio of 1.5) compared to highly realistic puffing
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behavior (i.e. 4-s puff and 55 mL per puff). After each DLPI experiment, each stage corresponding to a well-defined aerodynamic size-fraction was weighted using an electronic precision balance (Adventurer Pro, OHAUS, USA) and then rinsed with 1.6 mL of deionized water into appropriate volumetric flasks. Liquids were then assayed for drug concentration. Experiments were performed in triplicate for 3 power levels of the ENDS (12.5 W, 18 W, 25 W). 2.4. Assessment of emitted drug mass per puff An important output consists in measuring the content of terbutaline sulfate per puff of aerosol emitted by the ENDS. As cascade impactors experiments (see previous section) do not used realistic puffing behavior (experimental procedure using high flow rate and aerosol dilution ratio of 1.5 which is only validated for MMAD measurement, not for the aerosol output), a biological air sampler set-up (Coriolis micro, Bertin instruments) was used to assess the terbutaline sulfate emitted dose under realistic puffing behavior. This device is an air sampler for bio-contamination assessment, mainly dedicated to air quality control and air quality monitoring in environmental and pharmaceutical research. Based on a wet cyclonic technology, combined to a high air flow rate, this set-up offers high efficient particles collection in short times. Aerosol sampling generated by the ENDS was carried out considering 50 puffs (2 series of 25 puffs) with given features: 4-s puff, volume of 55 mL per puff, inter-puff duration of 30 s, interseries duration of 300 s (25 puffs per series). An in-house interface was designed for puffing. Puffs were performed using a 60 mL syringe connected to both the ENDS and the biological air sampler set-up through a 3 ways valve. The airflow rate of the Coriolis air sampler was 300 L/min. At the end of the experiment, the sample liquid output collected in the Coriolis air sampler set-up was rinsed with 1.5 mL of deionized water into appropriate volumetric flasks. Liquids were then assayed for terbutaline sulfate dosage. The emitted drug mass per puff was simply obtained knowing the aerosol sample ratio using the Coriolis set-up for our experimental conditions. This ratio was calculated by dividing the total mass of aerosol generated by the ENDS (obtained from the refill liquid mass loss during the 50 puffs experiments using an electronic precision balance, Adventurer Pro, OHAUS, USA) by the mass of condensate aerosol liquid collected using the Coriolis air sampler set-up (condensate aerosol liquid collected was weighted using an electronic precision balance, Adventurer Pro, OHAUS, USA). Of course the mass of condensate aerosol collected was lower than the mass of aerosol generated by the ENDS due to condensation and loss in the walls of the tubing and syringe of the experimental set-up as well as evaporation phenomenon occurring inside the Coriolis air sampler (from this initial inlet connected to the syringe to the final Coriolis air sampler collecting tube). Experiments were performed in triplicate for 3 power levels of ENDS (12.5 W, 18 W, 25 W).
Standard solutions were prepared by serial dilutions in water at concentration levels of 0.25, 2.5, 25 and 250 g/L. Samples were stored at 20 C until analysis. Liquid chromatography was performed using an Acquity ultra-performance liquid chromatograph system using an UPLC HSS-T3 C18 column (Waters, France). The mobile phase was a mix of A: distilled water containing 0.1% formic acid and B: acetonitrile containing 0.1% formic acid. The gradient was 0–0.1 min: 10% B; 0.1–0.4 min: linear from 10 to 90% B; 0.4–1.2 min: 90% B; 1.20 min return to initial conditions until 1.3 min. The flow rate was 0.5 mL/min. The liquid chromatograph system was coupled to a Xevo TQS Micro triple quadrupole mass spectrometer (Waters, France). The instrument was equipped with an electrospray ionization source. The analytes were detected in multiple reaction monitoring mode using the positive ionization mode. The system control and data acquisition were performed using MassLynx V4.1 software (Waters, France). 3. Results 3.1. Impact of the ENDS power level on the drug delivery Table 1 summarizes particle size data and the delivery of aerosol terbutaline sulfate obtained for all experimental conditions. First of all, spectra allowing the terbutaline sulfate dosage indicated that the drug vaporization occurred without thermal degradation of the terbutaline sulfate whatever the power levels used (i.e. no degradation products were detected). Fig. 1 shows the drug delivery vs. the ENDS power level ranging from 12.5 W to 25 W. A linear correlation (y = 0.34x 2.85, R2 = 1.00, Fig. 1) was clearly identified indicating that the higher the power level, the higher the delivery of aerosol bronchodilator, showing a concentration of terbutaline sulfate in the aerosol up to 5.6 0.4 mg/puff at 25 W. These findings highlighted that, for a given initial drug concentration (the un-puffed liquid), a patient could very easily vary the drug mass delivery (for a same number of puffs) by simply adjusting the ENDS power level (variable wattage function of ENDS
2.5. Terbutaline sulfate dosage Primary stock solutions of terbutaline sulfate (1 g/L) were prepared in water and stored at 20 C. Working solutions were prepared freshly on each day of analysis as serial dilutions in water.
Fig. 1. Impact of the power level (ranging from 12.5 to 25 W) on the drug delivery (expressed in mg of terbutaline sulfate/puff generated by the ENDS).
Table 1 Summary of the size distribution data and the drug delivery. Experiments were performed in triplicate. MMAD referred to the Mass Median Aerodynamic Diameter. Power level of the battery
MMAD of refill liquid (mm)
MMAD of terbutaline sulfate (mm)
Delivery of terbutaline sulfate (mg/puff)
Concentration of aerosol terbutaline sulfate (mg/mL)
Mass loss of ENDS after 50 puffs (mg)
12.5 W 18 W 25 W
0.56 0.03 0.74 0.08 0.77 0.02
0.55 0.03 0.71 0.06 0.78 0.03
1.3 0.2 3.5 0.2 5.6 0.4
0.25 0.04 0.34 0.01 0.33 0.03
284 1 540 19 920 24
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can be easily activated by using battery button to change settings in a single step). Besides, the concentration of aerosol terbutaline sulfate was measured after 50 puffs (Fig. 2). The concentration of aerosol terbutaline sulfate slightly rose when the ENDS power level increased. Furthermore, from the power level of 18 W, the concentration of aerosol drug reached similar value to the initial drug concentration of the liquid (i.e. the un-puffed liquid) used to fill the tank-atomizer of the ENDS. For example, the aerosol drug concentration was 0.33 0.03 mg/mL at 25 W (compared to 0.3125 mg/mL initially, Fig. 2 and Table 1). 3.2. Aerosol features of ENDS for inhaled bronchodilator Fig. 3 demonstrates that a perfect matching between the frequency mass distribution of the airborne refill liquid and the aerosol drug was observed for a given power level at 25 W. Similar results were obtained at 12.5 W and 18 W (data not shown). This finding leads to indicate that:
Fig. 3. DLPI Impactor-collected data showing the frequency mass distribution for a power level fixed at 25 W. Mass of airborne refill liquid in grey (expressed in%). Mass of drug in black (expressed in%).
(i) There is not empty airborne carrier generated by recent highpower ENDS (i.e. droplet of refill liquid without terbutaline sulfate). (ii) The drug concentration inside droplets of refill liquid, whatever the aerodynamic size-fractions in the submicron range, is constant. Besides, Figs. 4 and 5 show impactor-collected data by means of frequency mass distribution. Three levels of ENDS power were investigated. Results highlighted a gradual transition of a dominant mode mainly distributed from 382 nm at 12.5 W to 613 nm at 25 W whatever the mass distribution considered (i.e. mass distribution of airborne refill liquid in Fig. 4 or mass distribution of aerosol drug in Fig. 5). The transition from 613 nm to 949 nm seems to occur at a lower power level than 18 W. As a result, a slight increase of the MMAD (expressed in term of MMAD of refill liquid or MMAD of aerosol drug) was noticed when the power level rose (Table 1). For example the aerosol drug MMAD increased from 0.55 0.03 mm at 12.5 W to 0.77 0.02 mm at 25 W. Therefore, these findings indicate that, for a given drug concentration of the un-puffed refill liquid, a patient could very easily vary the aerodynamic features of the aerosol drug in the submicron range by simply adjusting the ENDS power level.
Fig. 4. DLPI Impactor-collected data showing the impact of the power level (ranging from 12.5 to 25 W) on the frequency mass distribution of airborne refill liquid (expressed in%).
Fig. 5. DLPI Impactor-collected data showing the impact of the power level (ranging from 12.5 to 25 W) on the frequency mass distribution of drug (expressed in%).
4. Discussion 4.1. Impact of aerosol sampling and low pressure impactor on the MMAD calculation
Fig. 2. Impact of the power level on the concentration of aerosol drug (bar graph) expressed in mg of terbutaline sulfate per mL of refill liquid.
Determination of particle size distribution of ENDS aerosol is an experimental challenge because of the high hygroscopicity and
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volatility nature of the particulate matter (composed largely from propylene glycol, glycerin and water). Sizing techniques requiring a high degree of aerosol dilution are expected to result in significant particle evaporation, and then to induce potential bias with the alteration of the particle size distribution from that provided to the vaper. Besides, the ENDS aerosol exhibits a dynamic behavior after puffing and during inhalation. Both the size particle distribution and the number particle concentration are expected to evolve because the aerosol is subject to condensational growth, particulate matter evaporation, coagulation and particle deposition. To address these obstacles, we have taken special care with the development of a measurement strategy to limit as much as possible experimental biases by particles evaporation and particles coagulation. However, we must underline that a possible evaporation of aerosol droplets during sampling can always occur. Therefore, MMAD measured in the proposed tests, using low pressure cascade impactor, may not absolutely correspond to MMAD happening under humid physiological conditions. 4.2. Safety assessment of ENDS: a limit on its use for pharmaceutical purposes? Despite a steep increase in market penetration, safety assessment of ENDS remains an issue (“E-cigarettes,” n.d.). Used as a smoking reduction or cessation tool, the main toxicological issues concern: the inhaled nicotine (Benowitz and Burbank, 2016; Bhatnagar, 2016; Grana et al., 2014; Schraufnagel et al., 2014), inhaled flavor additives (Grana et al., 2014; Schraufnagel et al., 2014), inhaled metallic nanoparticles potentially generated by some ENDS devices (Williams et al., 2013), inhaled aldehydes inadvertently produced when solvents are heated (Drummond and Upson, 2014; Grana et al., 2014), inhaled propylene glycol (PG) composing the refill liquid (Callahan-Lyon, 2014; Grana et al., 2014; Schraufnagel et al., 2014; Varlet et al., 2015). All things considered, from a pharmaceutical perspective of the ENDS use to delivery bronchodilators, it seems crucial to consider: (i) Appropriate solvents compared to ENDS used for smoking reduction or cessation purpose, i.e. nicotine-free and flavorfree. The safety issue about PG-containing solvents appears uncertain even if PG has been used as carrier for inhalation medications (Niven et al., 2011; Wang et al., 2007). (ii) Recent tank-atomizer ENDS under appropriate combination of experimental parameters (power of the battery, atomizer design) to limit or avoid aldehydes and nanoparticles emissions in the produced aerosol.
4.3. ENDS: a possible device for inhaled bronchodilators? This work studied the delivery of inhaled bronchodilator using new-generation high-power ENDS technology. The main advantages of ENDS for inhaled bronchodilator therapy, compared to the usual aerosol devices (pressurized metered-dose inhalers or pMDI, nebulizers, dry-powder inhalers or DPI), are to produce smaller aerosol particles (MMAD in the 0.5–0.8 mm range) with the possibility for the patient (with a same device and a given initial drug concentration in the un-puffed liquid) to vary both the content of bronchodilator delivery per puff as well as the aerodynamic size of the airborne carrier. Thus, ENDS appears to be highly patient-adaptive aerosol devices in good accordance with the concept of personalized medicine. The main advantage of ENDS is to be efficient for patients of disparate anatomy or lung function (e.g. using smaller particle size for children or for patients with highly obstructive diseases) and/or to be adjusted depending on the illness evolution (e.g. variation of aerosol drug dose per puff
as a function of pathology changes during the treatment time). The patient could also modify the dose by adjusting the puff duration without changing the power. Besides, at the same time we should notice that this could lead to easier misuse ENDS by uneducated patients. So there needs to be some education, because the easy manipulation and use of ENDS technology could be a huge advantage, but could also create some problems. All things considered, a main drawbacks regard the thermal stability of drugs, which can be aerosolized using ENDS. The best drug candidates for such systems are those which are thermally stable and with low-melting points. Another possible limitation is that respiratory smooth muscles are not located in deep lungs but generally in the central lungs. Therefore, the ENDS device may not necessary target the desired regions of the lungs in the case of bronchodilators administration. The very small airways are devoid of smooth bronchial fibers and therefore they are a priori insensitive to beta2-agonist drug. Nevertheless a usual micronsize aerosol leads to a very central deposition, generally until the 5th or 6th orders of bronchi. On the contrary, small airborne particles generated by ENDS allow guaranteeing a more homogeneous aerosol deposition, especially in already small bronchi (e.g. children) or in asthma and COPD exacerbation where larger particles usually are blocked in proximal bronchi. In the case of inhaled corticosteroids, the impact of small airborne particles (e.g. generated by ENDS) on the lung periphery is even more straightforward. Furthermore, an important parameter to compare the ENDS performance to other aerosol devices is the drug delivery potential. Important factors influencing the total dose delivered to patients airways include the initial volume fill, the efficiency by which nebulized aerosol is made available for patient inhalation, and the “dead” volume left in the nebulizer on cessation of operation (Force et al., 2001). It is commonly accepted that the drug dose inhaled using a nebulizer is in the 5–40% range of the initial drug introduced into the device. In these conditions, the patient could inhale approximately 250 mg to 2 mg of terbutaline sulfate. At the maximum power level tested in this study, an emitted dose of approximately 280 mg can be obtained for 50 ENDS puffs. Consequently, this result show quite similar emitted dose between nebulization and ENDS. Moreover, we must keep in mind that the initial terbutaline sulfate concentration used to fill the ENDS in this study is 8 times lower than the usual nominal concentration used for nebulization (0.3125 mg/mL vs. 2.5 mg/mL). In a next future, the enhancement of the emitted dose of bronchodilator using ENDS could be quite easily achieved by increasing the power level of the ENDS and/or the initial drug concentration of the un-puffed refill liquid. The same reasoning can be proposed for another terbutaline sulfate aerosol device, the Bricanyl Turbuhaler (labeled as a nominal dose of 500 mg terbutaline sulfate per puff, AstraZeneca, UK). The emitted dose of terbutaline sulfate from the Turbuhaler at different inhalation flows is in the 21.4%–77.3% range (Abdelrahim, 2010). The amounts are expressed as a% of the 500 mg terbutaline sulfate nominal dose. So the emitted dose of sulfate terbutaline can be estimated ranging from 107 to 386 mg matching 20–70 puffs using ENDS in the experimental conditions (not optimal) tested in this work. All things considered, the doses of inhaled bronchodilator enable to be delivered with new generation high-power ENDS are quite relevant compared to existing aerosol devices. 4.4. ENDS: a possible device for systemic drug delivery? The lungs can also be used as a pathway for systemic drug delivery. Although a variety of pulmonary delivery systems are used in current clinical practice, the efficiency of their delivery of
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particles to the deep lung is limited. Recently, a new approach to generate aerosols has been introduced, the thermal aerosol generation (Ibrahim et al., 2015; Rabinowitz et al., 2006, 2004). The process involves heating a thin film of drug, enabling its flash vaporization with minimal decomposition, to form a vapor that then cools and condenses into particles in the 1 mm–3 mm range. ENDS appear as a category of devices with a close working principle compared to thermal aerosol medical devices already on the market. ENDS have proven their potential to produce high level of active substance in the aerosol (such as nicotine). ENDS could be a promising tool to deliver thermally stable systemic drugs. 5. Conclusion This study investigated the potential of recent high power ENDS as aerosol generation devices for inhaled bronchodilators. Results showed that new generation high-power ENDS are very efficient to generate carrier-droplets in the submicron range containing bronchodilators with a constant drug concentration whatever the size-fractions. Moreover, MMAD and the drug delivery significantly rise when the power level increases from 12.5 to 25 W. Therefore, ENDS appears as highly patient-adaptive device. In fact, MMAD and drug emitted can be easily self-adjusted by the patient thanks to ENDS electronic function. In other words, for the first time an aerosol generation device allows to change both MMAD and the amount of drug emitted, with a same device and a given nominal drug concentration. These findings provide a better understanding of how a drug can be delivered from the refill liquid to the aerosol using recent ENDS technology. Nowadays, the main drawbacks to consider ENDS as a medical device in the aerosol therapy field remains the choice of drug with well-adapted thermal behavior. Acknowledgements & disclosures There is no source of support for this study (grants, gift, equipment or drugs) to declare. The authors are independent from tobacco industry and declare no financial relationships with any organizations that might have an interest in the submitted work. In particular, we do not have a source of support to declare from the company that sells the electronic cigarette used in the submitted work. However, some authors declare links of interest with pharmacy and medical devices industries. J. Pourchez has received research grants outside the submitted work from Pari GmbH and Laboratoires CERES; J.M. Vergnon has received research and educational grants outside the submitted work from Novatech SA, Boehringer Ingelheim, Olympus, Pentax and Astra Zeneca. References Abdelrahim, M.E., 2010. Emitted dose and lung deposition of inhaled terbutaline from Turbuhaler at different conditions. Respir. Med. 104, 682–689. Albuquerque-Silva, I., Vecellio, L., Durand, M., Avet, J., Le Pennec, D., de Monte, M., Montharu, J., Diot, P., Cottier, M., Dubois, F., Pourchez, J., 2014. Particle deposition in a child respiratory tract model: in vivo regional deposition of fine and ultrafine aerosols in baboons. PLoS One 9, e95456.
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