Advanced nebulizer designs employing vibrating mesh/aperture plate technologies for aerosol generation

Recent technological advances and improved nebulizer designs have overcome many limitations of jet nebulizers. Newer devices employ a vibrating mesh or aperture plate (VM/AP) for the generation of therapeutic aerosols with consistent, increased efficiency, predominant aerosol fine particle fractions, low residuals, and the ability to nebulize even microliter volumes. These enhancements are achieved through several different design features and include improvements that promote patient compliance, such as compact design, portability, shorter treatment durations, and quiet operation. Current VM/AP devices in clinical use are the Omron MicroAir, the Nektar Aeroneb, and the Pari eFlow. However, some devices are only approved for use with specific medications. Development of "smart nebulizers" such as the Respironics I-neb couple VM technologies with coordinated delivery and optimized inhalation patterns to enhance inhaled drug delivery of specialized, expensive formulations. Ongoing development of advanced aerosol technologies should improve clinical outcomes and continue to expand therapeutic options as newer inhaled drugs become available.     

Lactose characteristics and the generation of the aerosol

The delivery efficiency of dry-powder products for inhalation is dependent upon the drug formulation, the inhaler device, and the inhalation technique. Dry powder formulations are generally produced by mixing the micronised drug particles with larger carrier particles. These carrier particles are commonly lactose. The aerosol performance of a powder is highly dependent on the lactose characteristics, such as particle size distribution and shape and surface properties. Because lactose is the main component in these formulations, its selection is a crucial determinant of drug deposition into the lung, as interparticle forces may be affected by the carrier-particle properties. Therefore, the purpose of this article is to review the various grades of lactose, their production, and the methods of their characterisation. The origin of their adhesive and cohesive forces and their influence on aerosol generation are described, and the impact of the physicochemical properties of lactose on carrier-drug dispersion is discussed in detail.     

Assessment of antibiotic aerosol generation using commercial jet nebulizers.

The performance of 14 commercial jet nebulisers has been assessed; Unineb, Suremist (Unimed (UK) Ltd), Micro-Cirrus (Intersurgical Ltd), Pulmo-Neb (DeVilbiss Health Care UK Ltd), Side-Stream (Medic-Aid Ltd), Micro-Neb III (Lifecare Ltd), RespirGard (Marquest Medical Products Inc), Aeromist, Venticaire (S and W Vickers Ltd), Up-Draft II, Ava-Neb, Up-Draft (Hudson Respiratory Care Inc), Bennett/Twin, Raindrop (Puritan-Bennett Corporation). The units were operated with a high flow compressor (Maxi III, Medix Ltd) at 101/min. Performance was assessed by measuring the fraction of the initial mass of drug released as an aerosol and nebulisation time for initial drug volume of 2-6mls, and the mass median diameter and mass fraction of the aerosol in particles < 5.17 microns diameter. The Side-Stream nebuliser gave the best performance, although incorporation of a filter to trap exhaled antibiotic may prove difficult. The Micro-Cirrus generated a particularly fine aerosol. The Raindrop nebuliser performed well, while the Up-Draft II nebulised efficiently but was associated with extended nebulisation times which may limit its utility.     

New advances in aerosolised drug delivery: vibrating membrane nebuliser technology

Innovative nebuliser systems bear the potential to greatly improve and expand the administration of therapeutic aerosols for the treatment of respiratory diseases. Exploiting the technology of a microperforated vibrating membrane offers a close control of the droplet size that is being generated and targeted to reach the lower airways, with little oropharyngeal deposition, thereby reducing undesired side effects. The greatly improved efficiency of such devices, as exemplified by the eFlow nebuliser (PARI), provides further advantages for the patient. A high respirable fraction due to the precisely defined perforations, low residual losses and the high liquid output rate combine to produce a highly efficient and fast administration of inhaled medications. Portability, ease of handling and noiseless operation have a positive effect on patient compliance, control of the therapy by the physician and the therapy costs.     

Factors influencing the in vitro deposition of tobramycin aerosol: a comparison of an ultrasonic nebulizer and a high-frequency vibrating mesh nebulizer.

The aim of the study was to elaborate recommendations for inhalation during mechanical ventilation that could optimize delivery. Delivery of aerosols in vitro from nebulizers during mechanical ventilation is dependent on the dimensions of the ventilator circuit, the nebulizer type, and the ventilator settings. A review of the literature shows that some ventilator settings have a larger influence on the amount of aerosol delivered than others. It has been shown in an in vitro model that the factors influencing delivered aerosol are the ventilator flow rate, the diameter of the endotracheal tube, and the time spent in inspiration (all p < 0.05). Two different nebulizer types were used in the study: an ultrasonic nebulizer (SUN 345) and a high-frequency vibrating mesh nebulizer (Aeroneb Pro). No difference in the amount delivered was seen with different nebulizer types (p = 0.215). For optimizing the amount delivered, the largest possible flow, endotracheal tube, and time spent in inspiration should be used.     

Dry powder aerosol generation in different environments: Performance comparisons of albuterol,albuterol sulfate,albuterol adipate and albuterol stearate

Aerosols formed by three salts and the free base of albuterol were compared following their formation from similarly micronized crystalline powders held in a model dry powder inhaler (DPI) under varying environmental conditions. Aqueous solubility at 22°C was the greatest for albuterol adipate diethanolate (353 mg/ml), followed by albuterol sulfate (250 mg/ml), albuterol free base (15.7 mg/ml) and albuterol stearate (0.6 mg/ml). Temperature and relative humidity (RH) of the air drawn through the inhaler was systematically varied in the range 20–45°C and 30–95% RH. Several inhaler performance outcomes were compared statistically between physical forms and across the applied environmental conditions. Significant differences (P < 0.05) existed between powder forms with respect to emptying of the metering disk, inhaler emptying, powder deaggregation, fine particle dose (mass < 6.4 μm aerodynamic diameter), and each compound's susceptibility to temperature and relative humidity. The free base emptied poorly from the inhaler compared to all salt forms. Inhaler emptying for all four compounds was unaffected by temperature and humidity over most environments tested (P > 0.05) although only albuterol adipate diethanolate and albuterol sulfate were insensitive at 94% RH and 45°C. At 20°C and 50% RH, the fine particle percent of the emitted doses [mean (experimental range)] were 77.7 (7.3)%, 63.6 (4.2)%, 9.0 (1.8)% and 55.7 (3.4)% for the free base, sulfate, adipate diethanolate and stearate salts of albuterol, respectively. Fine particle doses and percents of albuterol and albuterol sulfate decreased progressively with increasing relative humidity and temperature while albuterol adipate diethanolate and albuterol stearate aerosol performance remained largely unaffected; these latter salts showed changes in fine particle percents only at 45°C and 95% RH although the adipate diethanolate deaggregated very poorly under all conditions. Overall, albuterol stearate, the most hydrophobic salt, emptied and aerosolized best from the inhaler and showed least sensitivity to temperature and humidity. Neither solubility nor moisture sorption correlated directly with inhaler performance in high humidity environments, showing that the multiplicity of factors controlling the quality of the emitted aerosol from DPIs prevents straightforward prediction of optimal physical forms and mandates their experimental review. Nevertheless, salt selection is an important area to screen as new compounds are developed for inhalation and DPI device performance continues to improve.     

Use of the next generation pharmaceutical impactor for particle size distribution measurements of live viral aerosol vaccines.

Aerosol administration of live measles vaccine virus has proven to be extremely efficacious in field trials using an industrial compressor coupled to a disposable nebulizer (IPI). To develop a new system for administration, it is necessary to characterize the operating characteristics of the old system. There are no standardized techniques for measuring particle size of live biological agents. This study evaluated the Next Generation Pharmaceutical Impactor's (NGI) ability to particle size wet aerosols in an effort to measure the particle size distribution of live measles vaccine from the IPI nebulizer. As a control albuterol was aerosolized using a Pari LC Star, since the soluble albuterol is evenly distributed throughout the droplets and laser diffraction measurements should agree with those from the NGI, as long as the NGI is cooled to prevent heat transfer to the aerosol. Albuterol was also used as a control for the IPI using quantitative ultraviolet spectrophotometry. There was close agreement in MMD (mean +/- 95% CI) for the LC Star, measured by laser diffraction (3.24 +/- 0.06 microm) and the NGI (2.93 +/- 0.22 microm) and the IPI (4.26 +/- 0.17 and 4.26 +/- 0.24 microm, respectively). For the measles vaccine assayed for plaque forming units, there were significant differences between the NGI MMD (6.14 +/- 0.39 microm) compared to laser diffraction (4.95 +/- 0.16 microm) indicating that the vaccine is not evenly distributed among the droplets of various sizes. This is likely clumping of the virus due to gelatin in the formulation. These data indicate that the NGI is capable of particle sizing live biological agents.     

Electronic cigarette liquid and device parameters and aerosol characteristics: A survey of regular users

IntroductionElectronic cigarettes are widely variable devices, typically with user definable liquid and device parameters. Yet, little is known about how regular users manipulate these parameters. There is also limited understanding of what factors drive electronic cigarette use and liquid purchasing, and whether two common ingredients, propylene glycol and vegetable glycerin, alter the subjective effects of these devices.MethodsDuring the spring of 2016 522 adults, who reported daily use of electronic cigarettes containing nicotine, completed a survey on electronic cigarettes. Survey questions included an electronic cigarette dependence questionnaire, questions on tobacco and electronic cigarette use, and device and liquid preferences.ResultsFifty-nine percent of respondents reported using another tobacco product, which was positively associated with level of nicotine dependence. On average, devices were set to 28.3 (SD = 24.2) watts. Ability to change device voltage, and level of resistance typically used, was significantly associated with level of nicotine dependence. Amount of liquid consumed, nicotine concentration, and milligrams of nicotine used per week, were positively associated with nicotine dependence. Participants rated ‘good taste’ as the most important consideration when using and purchasing liquids, and propylene glycol is associated with undesirable effects and vegetable glycerin with desirable effects.ConclusionsThese data indicate that electronic cigarette users utilize a wide range device parameter settings and liquid variables, and that individuals with greater nicotine dependence favor voltage control devices, and lower resistance heating elements. Taste is a key factor for electronic cigarette selection, and concentrations of propylene glycol and vegetable glycerin may have a significant impact on the reinforcing effects of liquids.     

Nebulization performance of biodegradable sildenafil-loaded nanoparticles using the Aeroneb Pro: formulation aspects and nanoparticle stability to nebulization

Polymeric nanoparticles meet the increasing interest for drug delivery applications and hold great promise to improve controlled drug delivery to the lung. Here, we present a series of investigations that were carried out to understand the impact of formulation variables on the nebulization performance of novel biodegradable sildenafil-loaded nanoparticles designed for targeted aerosol therapy of life-threatening pulmonary arterial hypertension. Narrowly distributed poly(D,L-lactide-co-glycolide) nanoparticles (size: ～200 nm) were prepared by a solvent evaporation technique using poly(vinyl alcohol) (PVA) as stabilizer. The aerodynamic and output characteristics using the Aeroneb Pro nebulizer correlated well with the dynamic viscosity of the employed fluids for nebulization. The nebulization performance was mainly affected by the amount of employed stabilizer, rather than by the applied nanoparticle concentration. Nanoparticles revealed physical stability against forces generated during aerosolization, what is attributed to the adsorbed PVA layer around the nanoparticles. Sildenafil was successfully encapsulated into nanoparticles (encapsulation efficiency: ～80%). Size, size distribution and sildenafil content of nanoparticles were not affected by nebulization and the in vitro drug release profile demonstrated a sustained sildenafil release over ～120 min. The current study suggests that the prepared sildenafil-loaded nanoparticles are a promising pharmaceutical for the therapy of pulmonary arterial hypertension.     

The twin impinger: a simple device for assessing the delivery of drugs from metered dose pressurized aerosol inhalers

The development is described of the twin impinger, a two-stage separation device for assessing the drug delivery from metered dose inhalers and other oral inhalation delivery devices. The discharged aerosol is fractionated by firing through a simulated oropharynx and then through an impinger stage of defined aerodynamic particle size cut-off characteristics. The fine (pulmonary) fraction which penetrates is collected by a lower impinger. It is demonstrated that this device is able to assess individually the fine particle delivery of both components of two-drug aerosols. Formulations showing undue agglomeration or serious crystal growth of drug are readily detected. The twin impinger is shown to be a valuable device for routine quality assessment of aerosols during product development, stability testing and for quality assurance and comparison of commercial products.     

Cyclosporin A aerosol improves the anticancer effect of paclitaxel aerosol in mice.

The objective of this study was to assess the effect of cyclosporin A liposome aerosol on the anticancer activity of paclitaxel (PTX) liposome aerosol against renal cell carcinoma (Renca) pulmonary metastases in mice. Cyclosporin A (CsA) was administered as a liposome aerosol for one-half hour before starting one-half hour treatment with PTX liposome aerosol (CsA/PTX), and in a second groups of animals cyclosporin A liposome aerosol was given before PTX for one-half hour and also later by mixing a second dose of cyclosporin A aerosol with PTX aerosol and extending the treatment period to one hour (CsA/PTX + CsA). In one experiment, PTX and CsA/PTX aerosols were significantly more effective compared to untreated controls against renal cell cancer as measured by lung weights and tumor surface areas. CsA/PTX was significantly better that PTX alone as measured by lung weights and tumor area. In a second experiment, tumor areas of PTX and CsA/PTX treated mice were significantly reduced compared to untreated controls and CsA/PTX treated mice had significantly smaller tumor areas than PTX treated mice. In contrast, tumor numbers were not significantly fewer than controls in either therapeutic group. In a third experiment, tumor numbers and tumor areas were significantly fewer in mice treated with CsA/PTX and CsA/PTX + CsA compared to untreated controls. Mice treated with CsA/PTX + CsA had significantly fewer tumors and less tumor area than mice receiving CsA/PTX. While PTX treated mice were not different than untreated controls with respect to tumor numbers or tumor volumes, PTX treated mice had significantly greater tumor numbers and tumor areas than CsA/PTX and CsA/PTX + CsA treated mice. Co-administration of CsA with PTX demonstrated significant dose dependent anticancer effects against renal cell pulmonary metastases in mice. Toxicity manifested by weight loss was associated with the highest dose of CsA.     

The development of a novel high-dose pressurized aerosol dry-powder device (PADD) for the delivery of pumactant for inhalation therapy.

The performance of a novel dry powder inhaler designed to deliver exceptionally high doses was investigated using pumactant as a model powder. Pumactant (a synthetic lung surfactant consisting of a phospholipid mixture), with a 90th percentile particle size of 2.92 microm is highly cohesive, has a high moisture affinity (6.2% w/w at 45% RH), and is predominantly amorphous. The device (pressurized aerosol dry-powder delivery [PADD]) utilizes pressurized gas to aerosolize a powder bed from a reservoir and delivers it through a conventional mouthpiece. The influence of loaded dose on dry powder delivery and can pressure on aerosolization efficiency was investigated. Analysis of the delivered dose studies suggested a linear relationship between loaded dose and delivered dose (R(2) = 0.96, for loaded doses of 0-250 mg), with a delivery efficiency of 70%. Analysis of the aerosolization efficiency using a Marple Miller type impactor suggested fine particle fractions (particles with an aerodynamic diameter of <5 microm) of approximately 30% using canister pressures of 8-14 bars. These results indicate that the PADD device may be a useful tool in delivering high-dose medicaments, as a carrier-free formulation, to the deep lung.     

SPECT-CT Comparison of Lung Deposition using a System combining a Vibrating-mesh Nebulizer with a Valved Holding Chamber and a Conventional Jet Nebulizer: a Randomized Cross-over Study

Purpose

To compare in vivo the total and regional pulmonary deposition of aerosol particles generated by a new system combining a vibrating-mesh nebulizer with a specific valved holding chamber and constant-output jet nebulizer connected to a corrugated tube.

Methods

Cross-over study comparing aerosol delivery to the lungs using two nebulizers in 6 healthy male subjects: a vibrating-mesh nebulizer combined with a valved holding chamber (Aerogen Ultra®, Aerogen Ltd., Galway, Ireland) and a jet nebulizer connected to a corrugated tube (Opti-Mist Plus Nebulizer®, ConvaTec, Bridgewater, NJ). Nebulizers were filled with diethylenetriaminepentaacetic acid labelled with technetium-99 m (^99mTc-DTPA, 2 mCi/4 mL). Pulmonary deposition of ^99mTc-DTPA was measured by single-photon emission computed tomography combined with a low dose CT-scan (SPECT-CT).

Results

Pulmonary aerosol deposition from SPECT-CT analysis was six times increased with the vibrating-mesh nebulizer as compared to the jet nebulizer (34.1?±?6.0% versus 5.2?±?1.1%, p?<?0.001). However, aerosol penetration expressed as the three-dimensional normalized ratio of the outer and the inner regions of the lungs was similar between both nebulizers.

Conclusions

This study demonstrated the high superiority of the new system combining a vibrating-mesh nebulizer with a valved holding chamber to deliver nebulized particles into the lungs as comparted to a constant-output jet nebulizer with a corrugated tube.

     

Variation in pediatric aerosol delivery: importance of facemask.

We have quantified in vitro the influence of the facemask on the amount of drug delivered (e.g., inhaled mass) by jet nebulizer and pressurized metered dose inhaler (pMDI) valved holding chamber (VHC) combinations (non-detergent-coated and detergent-coated). Pediatric breathing patterns were used with a breathing simulator, which was connected to a face onto which each device was positioned. An inhaled mass filter interposed between the simulator and the face captured the aerosolized drug. Budesonide inhalation suspension (0.25 mg) was used with the jet nebulizers and fluticasone propionate (220 microg) pMDI with the VHCs. Maximal drug delivery was measured using constant flow through each device. Breathing pattern effects were assessed for sealed devices (no leaks) and with facemasks (possible leaks at the facemask). Inhaled mass from both nebulizers and pMDI VHCs was affected by breathing pattern, but compared to nebulizers the pMDI VHCs were significantly more variable and sensitive to several factors. The influence of VHC conditioning combined with effects of breathing pattern resulted in the inhaled mass ranging from 0.7 +/- 0.5 to 53.3 +/- 6.2%. Nebulizers were less variable (9.6 +/- 0.7 to 24.3 +/- 3.1%). Detergent coating of VHC markedly increased the inhaled mass and reproducibility of drug delivery (27.2 +/- 1.4 to 53.3 +/- 6.2%) for pMDI VHC combinations, but these effects were lost in the presence of facemasks. Using pediatric patterns of breathing, nebulizer/facemask combinations delivered 4.1 +/- 0.8 to 19.3 +/- 2.3% of the label dose while pMDI and detergent-coated VHC delivered 4.0 +/- 1.6 to 28.6 +/- 2.5%. Facemask seal is a key factor in drug delivery. Leaks around the facemask reduce drug delivery and for pMDI VHCs can negate effects of detergent coating.     

Sodium cromoglycate: spincaps or metered dose aerosol.

1 Sodium cromoglycate administered as a dry powder inhalation (20 mg/dose) via the Spinhaler was compared with a metered dose aerosol (2 mg/dose) in an eight week double dummy double blind crossover trial in 29 asthmatic children. 2 The powder formulation was associated with significantly less symptoms (night wheeze, night cough, day wheeze, day cough, activity) and bronchodilator intake; and significantly greater weight gain than aerosol therapy. There were no significant differences in morning or evening peak flow measurements on the two treatments. 3 The powder may be more effectively inhaled than the aerosol or the dose of the aerosol may not be large enough.     

Fluorocarbon aerosol propellants IX: adsorption on activated charcoal.

The adsorption of three commonly used fluorocarbons, trichloromonofluoromethane, dichlorodifluoromethane, and dichlorotetrafluoroethane, on activated charcoal was studied at 25 degrees. The adsorption versus pressure plots are consistent with the Brunauer, Emmett, and Teller (BET) type II and type IV isotherms, which can be explained as the condensation of the gaseous molecules in a wide range of pores in the activated charcoal. The monolayer capacity derived from the BET equation is discussed and used to estimate the volume of micropores present in the activated charcoal. Below the relative pressure of 0.01, the adsorption deviated from the BET plot. The deviation revealed that the adsorption capacity and adsorption potential at these lower pressures are greater than the extrapolated values. It is concluded that activated charcoal can be used effectively to remove propellants from the air in pollution control.     

Fluorocarbon aerosol propellants X: pharmacokinetics of dichlorotetrafluoroethane in dogs.

An intravenous dosage form of dichlorotetrafluoroethane, a common fluorocarbon aerosol propellant, was formulated in polyethylene glycol 400 for single dosing to unanesthetized dogs. A three-compartment open model was proposed for the disposition of this compound in dogs, with average half-lives of 1.3, 9.6, and 50.8 min for the three disposition phases. An analysis of tissue compartment distribution following a single dose showed that it took about 2 hr to achieve pseudo-distribution equilibration, following which more than 90% of the propellant remaining in the body was retained in the tissue compartments. Pulmonary clearance and volumes of distribution were calculated considering the first-pass effect through the lungs. The volume of distribution was approximately 10 times the body weight in terms of blood concentration, and about 84% of the propellant was cleared from the blood passing through the lungs in each cycle.