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Aerosolization is a non-invasive approach in drug delivery for localized and systemic effect. Nanostructured lipid carriers (NLCs) are new generation versatile carriers, which offer protection from degradation and enhance bioavailability of poorly water soluble drugs. The aim of this study was to develop and optimize NLC formulations in combination with optimized airflow rates (i.e. 60 and 15 L/min) and choice of medical nebulizers including Air jet, Vibrating mesh and Ultrasonic nebulizer for superior aerosolization performance, assessed via a next generation impactor (NGI). Novel composition and combination of NLC formulations (F1 – F15) were prepared via ultrasonication method, employing five solid lipids (glycerol trimyristate (GTM), glycerol trilaurate (GTL), cetyl palmitate (CP), glycerol monostearate (GMS) and stearic acid (SA)); and three liquid lipids (glyceryl tributyrate (GTB), propylene glycol dicaprylate/dicaprate (PGD) and isopropyl palmitate (IPP)) in 1:3 w/w ratios (i.e. combination of one solid and one liquid lipid), with Beclomethasone dipropionate (BDP) incorporated as the model drug. Out of fifteen BDP-NLC formulations, the physicochemical properties of formulations F7, F8 and F10 exhibited desirable stability (one week at 25 °C), with associated particle size of ~241 nm, and >91% of drug entrapment. Post aerosolization, F10 was observed to deposit notably smaller sized particles (from 198 to 136 nm, 283 to 135 nm and 239 to 157 nm for Air jet, Vibrating mesh and Ultrasonic nebulizers, respectively) in all stages (i.e. from stage 1 to 8) of the NGI, when compared to F7 and F8 formulations. Six week stability studies conducted at 4, 25 and 45 °C, demonstrated F10 formulation stability in terms of particle size, irrespective of temperature conditions. Nebulizer performance study using the NGI for F10 identified the Air jet to be the most efficient nebulizer, depositing lower concentrations of BDP in the earlier stages (1–3) and higher (circa 82 and 85%) in the lateral stages (4–8) using 60 and 15 L/min airflow rates, when compared to the Vibrating mesh and Ultrasonic nebulizers. Moreover, at both airflow rates, the Air jet nebulizer elicited a longer nebulization time of ~42 min, facilitating aerosol inhalation for prophylaxis of asthma with normal tidal breathing. Based on characterization and nebulizer performance employing both 60 and 15 L/min airflow rates, the Air jet nebulizer offered enhanced performance, exhibiting a higher fine particle dose (FPD) (90 and 69 µg), fine particle fraction (FPF) (70 and 54%), respirable fraction (RF) (92 and 69%), and lower mass median aerodynamic diameter (MMAD) (1.15 and 1.62 µm); in addition to demonstrating higher drug deposition in the lateral parts of the NGI, when compared to its counterpart nebulizers. The F10 formulation used with the Air jet nebulizer was identified as being the most suitable combination for delivery of BDP-NLC formulations.

Aerosol inhalation delivery of cefazolin, a broad-spectrum first-generation cephalosporin antibiotic, was investigated. Inhalation system based on ultrasonic nebulizer was developed for the generation of dry cefazolin aerosol within mean particle diameter range 0.5–3.0 μm and mass concentration 0.01–3 μg/cm3. Pharmacokinetic measurements were carried out for the aerosolized form of cefazolin delivered in mice using nose-only chamber. Cefazolin concentrations in blood serum and in the lungs of mice were measured as a function of time by means of high performance liquid chromatography. Body-delivered dose depending on particle size, concentration and inhalation time as well as other pharmacokinetic parameters were determined. The antibacterial effect of aerosolized cefazolin was assessed through the aerosol inhalation treatment of mice infected with Klebsiella pneumoniae. Survival rate for infected mice after the treatment with cefazolin aerosol demonstrated high antibacterial efficiency of the inhalation delivery of cefazolin in comparison with intraperitoneal delivery.

The sudden expansion of gas at the outlet of the jet (pneumatic) nebulizer significantly reduces the temperature of the solution, which may provoke bronchospasm, therefore it is recommended to use modern pneumatic inhalers equipped with a thermostat or a universal thermal attachment that allow to obtain a higher temperature aerosol, i.e. thermo-aerosol. The research was carried out for model Newtonian fluids. The droplet diameters of the aerosol spray were investigated using a Spraytec aerosol particle size measurement system. Analysis of the obtained results showed that the increase in solution viscosity caused a decrease in mean droplet diameters and prolonged nebulization time. The analysis of experimental data made it possible to propose a correlation equation describing the mean diameter of the droplets depending on the properties of the liquid and the flow conditions in the thermostated medical nebulizer. The obtained data contributes to a better understanding of the complex liquid atomisation process and can be helpful in the design of medical nebulizers and pharmaceutical preparations.

Intranasal delivery of nebulized drugs with the consideration of the nasal anatomy is not adequately studied. The objective of this study was to evaluate nasal and paranasal drug delivery with nebulizers, with and without pulsating airflow, in three anatomically-different nasal models in different age groups, considering normal and bidirectional breathing techniques. Anatomically-accurate nasal models of 2-, 5-, and 50-year old subjects were developed and tested to quantify sub-regional deposition of an aqueous solution of a model drug, nebulized with PARI SinuStar™ and Sinus™ nebulizers. Paranasal delivery was significantly enhanced using pulsating nebulization under bidirectional breathing administration technique for all subjects (p 0.05). Airway morphology resulted in significantly different drug delivery efficiency (p 0.05). Use of a modified nasal adaptor enhanced the inhaled dose and resulted in significantly higher percent recovery, 68.41±13.56%, compared to the standard design,10.35±1.75%. In the adult subject, paranasal delivery was equal to 19.34±1.21%, and 5.99±0.95% using PARI Sinus™ nebulizer, with and without pulsating airflow, respectively. In the pediatric subjects, pulsating paranasal delivery was 12.80±0.28%, but without pulsating airflow no drug reached the target. This study confirmed that bidirectional breathing and pulsating airflow are beneficial for improved paranasal aerosol delivery in children similar to previous findings for adults.

Coenzyme Q10 (CoQ10) is a poorly-water soluble compound that is being investigated for the treatment of carcinomas. The aim of this study was to investigate the feasibility of preparing phospholipid-stabilized dispersions of the anticancer agent for continuous pulmonary delivery using a vibrating-mesh nebulizer. We determined the physicochemical properties (drug particle size distribution in dispersion, zeta potential, surface tension, and rheology) and compared the aerosolization profiles (nebulization performance, aerodynamic drug deposition and total emitted dose) of dispersions of CoQ10 prepared with different phospholipids. The hydrodynamic sizes of the drug particles in dispersion were primarily in the submicron range, but formulations with drug particle sizes greater than the aperture size of the nebulizer presented superior aerosolization profiles. At high shear rates, certain formulations presented increased shear-thickening behavior, which was connected to a decrease in mass and drug output over time, and with decreased aerodynamic and geometric sizes. Other formulations presented shear-thinning behavior and showed similarly high drug depositions. In this investigation, we found that dispersed formulations of CoQ10 presented different in vitro performance for pulmonary delivery based on their rheological behavior. In conclusion, this characterization methodology provides an innovative approach to screen formulations of poorly-water soluble compounds for continuous (no clogging) active vibrating-mesh nebulization.

The evaluation of particle size recommended in the pharmacopeias requires a constant flow rate, and the method for pediatric inhaled drugs is the same as for adult drugs. In this study, the aerosol concentration and particle size distribution (PSD) were measured under a realistic breathing pattern and constant flow. Two types of nebulizer (i.e., breath-enhanced nebulizer and vibrating-mesh nebulizer) and two formulations (i.e., budesonide suspension and albuterol solution) were chosen for comparison. The aerosol concentration under the realistic pattern was not constant, which was different from the result at constant flow. The changing trend of aerosol concentration varied with the operation process of each device. The aerosol concentration profile was similar between budesonide suspension and albuterol solution. As to the PSD, as inspiratory flow increased, the X50 (50% undersize) increased with all nebulizers but Omron microAir NE-U22 nebulizer. There was good agreement between X50 obtained under the realistic inhalation patterns and their equivalent average flow rates by Bland-Altman analysis, although the X50 obtained under the realistic inhalation pattern was greater than value at constant flow. The agreement of the two breath-enhanced jet nebulizers was better than that of the vibrating-mesh nebulizers. The X50 of budesonide was not equal to that of albuterol when using the same nebulizer. Interestingly, a significant difference was observed in the X50 and Span when comparing the results of PSD under adult and child breathing patterns. Furthermore, all vibrating-mesh nebulizers produced aerosol droplets having larger mean diameter and narrower size distribution than those of the air-jet nebulizers. We conclude that it will be more conducive to the evaluation of particle size to use a laser diffractometer under a realistic pattern and make up for the shortcomings of cascade impactors. The effects of flow pattern, nebulizer and formulation should be taken into account in the evaluation of the qualities of nebulizer products in pharmaceutical practice.

It was previously demonstrated that the loss of infectivity of a myovirus PEV44 after jet nebulization was closely related to a change in bacteriophage (phage) structure. In this follow-up study, we further examined the impact of jet nebulization on tailed phages, which constitute 96% of all known phages, from three different families, Podoviridae (PEV2), Myoviridae (PEV40) and Siphoviridae (D29). Transmission electron microscopy (TEM) identified major changes in phage structures after jet nebulization, correlating with their loss of infectivity. For the podovirus PEV2, jet nebulization had a negligible impact on activity (0.04 log10¬ pfu/mL loss) and structural change. On the other hand, the proportion of intact phages in the nebulised samples dropped from 50% to ~27% for PEV40 and from 15% to ~2% for D29. Phage deactivation of PEV40 measured by the TEM structural damage (0.52 log10¬ pfu/mL) was lower than that obtained by plaque assay (1.02 log10 pfu/mL), but within the range of variation (± 0.5 log10 pfu/mL). However, TEM quantification considerably underestimated the titer reduction of D29 phage, ~ 2 log pfu/mL lower than that obtained in plaque assay (3.25 log10 pfu/mL). In conclusion, nebulisation-induced titre loss was correlated with morphological damage to phages and in particular, the tail length may be an important consideration for selection of phages in inhaled therapy using jet nebulization. This work was financially supported by the Australian Research Council (Discovery Project DP150103953). The authors acknowledge the facilities and technical assistance of the Australian Microscopy and Microanalysis Research Facility at the Australian Centre for Microscopy

Pulmonary application of drug-loaded polymeric nanosuspensions is achieved by vibrating-mesh nebulizers, which allow for an output of intact nanocarriers from the nebulizer reservoir. However, adequate aerosol droplet sizes are a prerequisite for an efficient pulmonary deposition. The current study discloses experimental findings useful to optimize the aerodynamic characteristics of formulations atomized by the vibrating-mesh nebulizers Aeroneb® Pro and eFlow®rapid. Parameters with significant influence on the aerosol droplet diameter were identified by a statistical design analysis rating size results from laser diffraction. Subsequently, the effect of selected biocompatible solutes on the aerodynamic performance of nebulized formulations was studied and correlated with their physicochemical properties. Vibrating-mesh generated aerosols were significantly affected by the dynamic viscosity and conductivity of the applied formulation. Consequently, an increase in viscosity enhancer (sucrose and poly(ethylene glycol)) or electrolyte (NaCl and CaCl2) content caused the droplet diameter to decrease. Similarly, purified nanosuspensions revealed a considerable decline in aerosol particle size upon excipient addition. However, coating of polymeric nanoparticles with poloxamer and poly(vinyl alcohol) was necessary to avoid electrolyte-induced nanoparticle aggregation. Overall, the current study emphasizes that supplementation of nanosuspensions with biocompatible solutes is an excellent means to tailor the characteristics of aerosols generated by vibrating-mesh technology.

Aerosolization of aqueous formulations is of special interest for inhalative drug delivery, where an adequate nebulizer performance represents a prerequisite for improving pulmonary therapy. The present study investigated the interplay of output rate and aerodynamic characteristics of different excipient-based formulations and its impact on the atomization process by vibrating-mesh technology (i.e. eFlow®rapid). Output rate and aerodynamic characteristics were manipulated by both dynamic viscosity and conductivity of the applied formulation. Supplementation with sucrose and sodium chloride caused a decline (down to ∼0.2 g/min) and elevation (up to ∼1.0 g/min) of the nebulizer output rate, respectively. However, both excipients were capable of decreasing the aerodynamic diameter of produced aerosol droplets from >7.0 μm to values of ≤5.0 μm. Thus, the correlation of output rate and aerodynamic characteristics resulted in linear fits of opposite slopes (R2 > 0.85). Finally, the overall number of delivered aerosol droplets per time was almost constant for sucrose (≤1 × 108 droplets/s), while for sodium chloride a concentration-dependent increase was observed (up to ∼3 × 108 droplets/s). Overall, the current findings illustrated the influence of formulation parameters on the aerosolization process performed by vibrating-mesh technology. Moreover, concentration and charge distribution of aerosol populations supposedly modify the final characteristics of the delivered aerosols.

This study intended to investigate the in vivo pulmonary fate of intratracheally dosed nanosuspensions of fluticasone propionate (FP). Three FP suspensions, including a microsuspension and two nanosuspensions with different dissolution profiles, were prepared and they exhibited comparable aerodynamic performances after nebulization via a jet nebulizer. Following intratracheal administration to rats, the microsuspension underwent extensive mucociliary clearance, leading to a limited absorption time whereas the nanosuspensions decreased the mucociliary clearance and allowed dissolution rate-limiting and extended pulmonary absorption, resulting in prolonged pulmonary retention and long-acting anti-inflammatory efficacy in a lipopolysaccharide induced lung injury model. Delaying the FP dissolution of a nanosuspension by phospholipid coating increased AUC value in lung tissues to 1.72-fold of a conventional nanosuspension, but led to a decreased pharmacological efficacy. This study demonstrated that inhalable nanosuspensions were a feasible means for the sustained pulmonary delivery of FP and the local anti-inflammatory efficacy was highly dependent on the dissolution profiles.

Several aerosol production systems have been used for aerosol insulin production. However; since the first studies several new models of jet-nebulizers and ultrasound nebulizers have been introduced in the market.Three different models of jet-nebulizers (different brands, same properties) and three different ultrasound nebulizers (different brands, same properties). Six residual cups (2 small ≤ 6 ml and 3 large ≤ 8 ml) were used for the jet-nebulizers. The ultrasound nebulizers were used with their facemasks or with their inlets which were included in the purchase package.Ultrasound nebulizers; LANTUS produces by far the lowest mean droplets (2.44) half the size of the other two drugs (4.43=4.97). GIMA nebulizer is the most efficient producing one third of the droplet size of SHIMED and one second of EASYNEB (2.063.156.62). Finally, the 4 ml loading concentration is more suitable for supporting the production of smaller droplets (3.654.24). Drugs and nebulizers act interactively yielding very large droplets when ACTRAPID and HUMULIN are administered in joint with SHIMED nebulizer (9.59=7.72). Jet-nebulizers; HUMULIN again is the least preferred insulin since it hardly reaches the low but equal performance of others at the loading level of 6 ml. Residual cups E and B produce uniquely lower mean droplets at loading level 6.Ultrasound nebulizers; the best suggested combination should be LANTUS insulin, GIMA nebulizer administered at loading dose of 4 ml jet-nebulizers. A global review can give the best combination: the lowest mean droplets are produced when the drugs LANTUS (mostly) and ACTRAPID are administered, applying the SUNMIST nebulizer in concert with residual cup B at loading levels of 6 ml.

The hygroscopic properties of an aerosol originating from a nebulizer solution can affect the extent of peripheral deposition within the respiratory tract, which in turn affects drug efficacy of drugs delivered to the lungs. Thus, the ability to tailor the degree and rate of hygroscopic growth of an aerosol produced by a nebulizer through modification of the formulation would serve to improve drug efficacy through targeted lung deposition. In this study, the kinetic and thermodynamic hygroscopic properties of sodium chloride aerosol mixed with commercially available Pluronic polymers, specifically F77 and F127, are reported using three complementary single aerosol analysis techniques, specifically aerosol optical tweezers, a double ring electrodynamic balance and a concentric cylinder electrodynamic balance. The F77 polymer is shown to have a predictable effect on the hygroscopic properties of the aerosol: the ability of the droplet to uptake water from the air depends on the solute weight percent of sodium chloride present in a linear dose dependant manner. Unlike the smaller F77, a non-linear relationship was observed for the larger molecular weight F127 polymer, with significant suppression of hygroscopic growth (>50% by mass) for solution aerosol containing even only 1 wt% of the polymer and 99 wt% sodium chloride. The suppression of growth is shown to be consistent with the formation of mixed phase aerosol particles containing hydrophilic inorganic rich domains and hydrophobic polymer rich domains that sequester some of the inorganic component, with the two phases responding to changes in relative humidity independently. This independence of coupling with the gas phase is apparent in both the equilibrium state and the kinetics of water evaporation/condensation. By starting with a saline nebulizer solution with a concentration of F127 ∼10 −2 mM, a 12% reduction in the radius of all aerosol produced at a relative humidity (RH) of 84% is possible. The difference in diameter is RH dependent, and may be much greater at higher humidities. These findings suggest that the addition of μM concentrations of larger Pluronic polymers to nebulizer formulations may greatly reduce the size of aerosols produced.

The aerosol properties of niosomes were studied using Aeroneb Pro and Omron MicroAir vibrating-mesh nebulizers and Pari LC Sprint air-jet nebulizer. Proniosomes were prepared by coating sucrose particles with Span 60 (sorbitan monostearate), cholesterol and beclometasone dipropionate (BDP) (1:1:0.1). Nano-sized niosomes were produced by manual shaking of the proniosomes in deionized water followed by sonication (median size 236nm). The entrapment of BDP in proniosome-derived niosomes was higher than that in conventional thin film-made niosomes, being 36.4% and 27.5% respectively. All nebulizers generated aerosols with very high drug output, which was 83.6% using the Aeroneb Pro, 85.5% using the Pari and 72.4% using the Omron. The median droplet size was 3.32μm, 3.06μm and 4.86μm for the Aeroneb Pro, Pari and Omron nebulizers respectively and the "fine particle fraction" (FPF) of BDP was respectively 68.7%, 76.2% and 42.1%. The predicted extrathoracic deposition, based on size distribution of nebulized droplets was negligible for all devices, suggesting all of them are potentially suitable for pulmonary delivery of niosomes. The predicted drug deposition in the alveolar region was low using the Omron (3.2%), but greater using the Aeroneb Pro (17.4%) and the Pari (20.5%). Overall, noisome-BDP aerosols with high drug output and FPF can be generated from proniosomes and delivered using vibrating-mesh or air-jet nebulizers.

Phosphodiesterase type 5 (PDE-5) inhibitors - among which sildenafil citrate (SC) - play a primary role in the treatment of pulmonary hypertension (PH). Yet, SC can be only administered orally or parenterally with lot of risks. Targeted delivery of SC to the lungs via inhalation/nebulization is mandatory. In this study, solid lipid nanoparticles (SLNs) loaded with SC were prepared and characterized in terms of colloidal, morphological and thermal properties. The amount of drug loaded and its release behavior were estimated as a function of formulation variables. The potential of lipid nanocarriers to retain their properties following nebulization and autoclaving was investigated. In addition, toxicity aspects of plain and loaded SLNs on A549 cells were studied with respect to concentration. Spherical SLNs in the size range (100-250nm) were obtained. Particles ensured high encapsulation efficiency (88-100%) and sustained release of the payload over 24h. Cell-based viability experiments revealed a concentration-dependant toxicity for both plain and loaded SLNs recording an IC50 of 516 and 384μg/mL, respectively. Nebulization with jet nebulizer and sterilization via autoclaving affected neither the colloidal stability of SLNs nor the drug entrapment, proving their potential as pulmonary delivery system. Interaction of SLNs with mucin was a function of the emulsifier coating layer. Results yet seeking clinical evidence - might give promises of new therapy for PH of higher safety, better performance and higher patient compliance.

Ultradeformable liposomes are stress-responsive phospholipid vesicles that have been investigated extensively in transdermal delivery. In this study, the suitability of ultradeformable liposomes for pulmonary delivery was investigated. Aerosols of ultradeformable liposomes were generated using air-jet, ultrasonic or vibrating-mesh nebulizers and their stability during aerosol generation was evaluated using salbutamol sulphate as a model hydrophilic drug. Although delivery of ultradeformable liposome aerosols in high fine particle fraction was achievable, the vesicles were very unstable to nebulization so that up to 98% drug losses were demonstrated. Conventional liposomes were relatively less unstable to nebulization. Moreover, ultradeformable liposomes tended to aggregate during nebulization whilst conventional vesicles demonstrated a "size fractionation" behaviour, with smaller liposomes delivered to the lower stage of the impinger and larger vesicles to the upper stage. A release study conducted for 2 h showed that ultradeformable liposomes retained only 30% of the originally entrapped drug, which was increased to 53% by inclusion of cholesterol within the formulations. By contrast, conventional liposomes retained 60-70% of the originally entrapped drug. The differences between ultradeformable liposomes and liposomes were attributed to the presence of ethanol or Tween 80 within the elastic vesicle formulations. Overall, this study demonstrated, contrary to our expectation, that materials included with the aim of making the liposomes more elastic and ultradeformable to enhance delivery from nebulizers were in fact responsible for vesicle instability during nebulization and high leakage rates of the drug.

Amphotericin B (AmB) lipid nanoemulsions were prepared and characterized and their suitability for pulmonary delivery via nebulization was evaluated. AmB nanoemulsions were prepared by sonicating and vortexing the drug with two commercially available lipid nanoemulsions: the Intralipid(®) or Clinoleic(®). Loading the nanoemulsions with the drug slightly increased the size of the lipid droplets and did not affect the zeta potential of the nanoemulsions. The loading efficiency of AmB was found to be 87.46±2.21% in the Intralipid(®) nanoemulsions and 80.7±0.70% in the Clinoleic(®) formulation. This respectively corresponded to 21.86 mg and 20.19 mg of AmB being successfully loaded in the nanoemulsions. On aerosolization using a Pari Sprint jet nebulizer, both nanoemulsions produced very high drug output which was approximately 90% for both formulations. Using the two-stage impinger, the Clinoleic(®) emulsion had higher fine particle fraction (FPF) than the Intralipid(®), since the Clinoleic(®) displayed higher deposition of AmB in the lower impinger stage (exceeding 80%), compared to 57% for the Intralipid(®). Overall, the ease of preparation of the AmB lipid nanoemulsions, along with their in vitro nebulization performance suggest that lipid nanoemulsions could be successful nanocarriers for delivery of AmB to the peripheral respiratory airways.

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.

PURPOSE: To quantify the amount of aerosol deposited in different parts of the airways with a commercially available nasal sonic jet nebulizer (NJN) using a sound effect, and to compare its performance with a new nasal mesh nebulizer (NMN). METHODS: Seven healthy non-smoking male volunteers aged 21-36 years with a mean weight of 77±10 kg were included in this single-center study. Both nebulizer systems were loaded with (99m)Tc-DTPA and scintigraphies were performed with a gamma camera. Particle size distribution of the aerosols produced by the two nebulizer systems was measured. RESULTS: There was no statistical difference between the two nebulizers in terms of fraction of particles smaller than 5 μm (44±4% vs 45±2%) (p>0.9). Aerosol deposition in the nasal region was 73±10% (% of aerosol deposited in airways) with the NJN, and 99±3% with the NMN (p=0.01). Total nasal deposition was 9.6±1.9% of the nebulizer charge with the NJN and 28.4±8.9% with the NMN (p=0.01). 0.5±0.3% of the nebulizer charge was deposited in the maxillary sinuses with the NJN, compared to 2.2±1.6% with the NMN (p=0.01). CONCLUSION: Although the two nebulizers had the same particle size, NMN significantly improved aerosol deposition in nasal cavity and prevents deposition into the lungs.

Whilst some proteins can be effectively administered to the lungs using a nebulizer, others, such as lactate dehydrogenase (LDH) are degraded during air-jet nebulization. In order to deliver LDH by nebulization a protective delivery system or carrier may therefore be appropriate. The aim of this study was to produce and characterize a formulation of LDH, which retains enzyme activity during nebulization. Chitosan, a biocompatible, biodegradable and bioadhesive polysaccharide polymer, was included in the formulations studied as a potential protective agent. Complexes of LDH with chitosan of different molecular weights and concentrations were assessed for size, zeta potential, aerosol droplet size and delivery from a jet nebulizer. The highest molecular weight chitosan had the greatest complex size and a net positive charge of +29.7mV. Jet nebulization resulted in aerosol droplets with median size in the range 2.36-3.52μm. Nebulization of LDH solution resulted in enzyme denaturation and reduced activity. The stability of LDH was greatly improved in formulations with chitosan; with greater than 50% total LDH available in a nebulizer delivered to the lower stage of a two-stage impinger, with up to 62% retained enzyme activity. The nonionic surfactant Tween 80 also improved the stability of LDH to nebulization and had an additive protective effect when included, with chitosan, in formulations. These findings suggest chitosan may be a useful excipient in the preparation of stable protein formulations for jet nebulization.

Background Surface tension of aqueous solutions has a great impact on the resulting size of the produced aerosol droplets. Nevertheless, little attention has been drawn so far to the drug output of surface active substances during nebulization. Methods Six nebulizers with three different nebulization mechanisms were operated on the breath simulator and the dependence between the type of aerolisation mechanism, concentration of surface active substance and output rate was investigated. Results The results of this study confirm that surface active substances significantly affect nebulization. During ultrasonic nebulization of surface active substances a decrease of the residual drug concentration occurs. Simultaneously, higher amounts of aerosolized substance were observed in in vitro studies. These findings were dependent on the saturation of the liquid–air interface with molecules of a surface active substance. During jet nebulization, nevertheless, the process of an incorporation of substance molecules into aerosol droplets is associated with a strong solvent evaporation from the reservoir. In this case the resulting residual concentration and the aerosolized substance amount are dependent on the outbalancing of either an up-concentration of the surface active substance in the reservoir or rate of solvent evaporation. Vibrating membrane mechanism to nebulize solutions were observed to have minimal effects on the aerosolized substance quantity and residual concentration during nebulization. Conclusions Following conclusions for an efficient nebulization delivery of drugs with surface activity with respect to optimal delivery device can be made. Generally, ultrasonic devices produce higher drug output rates within shorter periods of time as compared to jet and vibrating membrane nebulizers. Accordingly, prescription instructions have to be adjusted to these findings. The study also emphasizes that aqueous nebulizer solutions should preferably be prescribed in conjunction with a specific nebulizer which has been tested in vitro and been used in in vivo studies, rather than to let patients choose their delivery device themselves.

Mathematical models are available which predict aerosol deposition in the respiratory system assuming that the aerosol concentration and size are constant during inhalation. In this study, we constructed a sinusoidal breathing model to calculate the aerosol concentration produced by a nebulizer as a function of inhalation time. The laser diffraction technique (Spraytec, Malvern Instruments Ltd., Malvern, UK) was used to validate this model as it allows the aerosol concentration and particle size to be measured in real time. Each nebulizer was attached to a special glass measurement cell and a sine-wave pump. Two standard jet nebulizers (Mistyneb and Microneb), two breath-enhanced jet nebulizers (Pari LC+ and Atomisor NL9M) and three mesh nebulizers (Eflow, Aeroneb Go and Aeroneb Pro with Idehaler) were characterized. Results obtained were consistent in terms of curve profile between the proposed model and the laser diffraction measurements. The standard jet and mesh nebulizers produced significant variations in aerosol concentration during inhalation, whereas the breath-enhanced jet nebulizers produced a constant aerosol concentration. All of the nebulizers produced a relatively constant particle size distribution. Our findings confirm that the concentration observed during inhalation is often not constant over time. The laser diffraction method allows the concentration and size of particles for each unit volume of air inhaled to be measured and could therefore be used to predict the aerosol deposition pattern more precisely.

Nebulized treatment is an important delivery option for the young, elderly, and those with severe chronic respiratory disease, but there is a lack of new nebulized drug products being produced for these patients, leading to the potential for under-treatment. This communication describes a new drug development paradigm as a timely solution to this issue. Often, drug development is initiated with nebulizers in the early stages, to provide cheaper and faster drug development, and then switched to inhaler devices in later clinical trials to address the majority of patients. However, the waste of resource on parallel development of the inhaler can be large due to the high early attrition rate of new drug development. The new paradigm uses the nebulizer to continue drug development through to market, and initiates inhaler development after completion of the riskier early phase studies. New drug safety and efficacy can be assessed faster and more efficiently by using a nebulized formulation rather than developing an inhaler. The results of calculations of expected net present value showed that the new paradigm produced higher expected net present values than the conventional model over a range of economic scenarios. This new paradigm could therefore provide improved returns on investments, as well as more modern drugs in nebulized form for those patients unable to use inhalers.

Nebulizer drug output rate increases during the nebulization. For unvented jet nebulizers, a physical and mathematical model based on the efficiency of the nebulization process is presented for this phenomenon. Formulas are derived for the cumulative drug output and the drug output rate of the nebulization process. The model is compared with the model proposed by Coates et al. [J. Aerosol. Med. 11 (1998) 101]. Both models are supported by experimental literature data. Both models predict the experimental values well but the proposed model allows more easy prediction of the influence of small changes in the nebulization conditions and the calculation of the cumulative drug output for a related process. From literature data it is shown that the efficiency of an unvented jet nebulization process of diluted aqueous solutions is relatively insensitive to small changes in the concentration as well as to small changes in aspiration flow but is sensitive to the humidity of the compressor gas only. © 2003 Elsevier Science B.V. All rights reserved.

The inhalation of tobramycin is part of current cystic fibrosis (CF) therapy. Local therapy with inhaled antibiotics has demonstrated improvements in pulmonary function. Current inhalation therapy is limited by the available drug formulations in combination with the nebulization time. The aim of this study is to develop a highly concentrated tobramycin solution for inhalation. Several tobramycin solutions, ranging from 5 to 30% (m/v), were compared after aerosolation with a jet and with an ultrasonic nebulizer. Laser diffraction and cascade impactor analysis were used for characterization of the aerosolized solutions. The output rate was determined in volume and mass output per minute. From the output rate measurements, it was concluded that a 20% tobramycin solution is the optimal and maximal concentration to be aerosolized. The jet nebulizer was most suitable. Using the jet nebulizer and the 20% solution, it is possible to administer a dosage of 1000 mg tobramycin by inhalation within 30 min. Copyright (C) 1999 Elsevier Science B.V.

Forteen commercially available jet and ultrasonic nebulizers were investigated with the aim to select the most suitable type of apparatus for the inhalation of a 10% tobramycin solution. Two different techniques for measurement of particle size distribution were evaluated: laser diffraction and cascade impactor analysis. The final selection of the nebulizers is based on particle size distribution, output and stable performance during nebulization. All 14 nebulizers (eight jet and six ultrasonic) were filled with a solution of 10% m/v tobramycin (as sulphate) in water. The volume in the tested devices ranged from 4.5 to 10 ml (=450-1000 mg tobramycin) in accordance with the prescribed usage by the suppliers. The nebulizers were connected with a special designed adapter to a laser diffraction analyser in order to measure particle size distribution of the aerosol. Inhalation was simulated with a static flow of 40 l/min. The particle size distribution (expressed as X-10, X-50, and X-90) was determined after 10 s, 1.5, 3, 4.5, 6, 9 and 12 min of nebulization. Furthermore, the tobramycin solutions were assayed for tobramycin content before and after nebulization. For all nebulizers, the mean particle size distribution, depicted as X-50, was within the range of 1-5 mm. There were no relevant differences between the nebulizers in concentration or particle size distribution during nebulization. The output of the nebulizers is a result of both nebulization and evaporation. The output, expressed as volume of tobramycin solution, ranged from 0.06 to 0.50 ml/min. The output of tobramycin ranged from 1.2 to 39.5 mg/min. For clinical practice 300-600 mg have to be nebulized within 20-30 min. Lt was concluded that only three jet nebulizers [Porta-Neb Sidestream (PNS), Porta-Neb Ventstream (PNV) and Pariboy Pari LC + (PLC)] have a reasonable output and an acceptable particle size distribution for the administration of a 10% tobramycin solution in the therapeutic dosage range. (C) 1999 Elsevier Science B.V. All rights reserved.

Aerosolized IFN-gamma is very unstable. We have improved the stability of IFN-gamma in the jet nebulizer by adding small liposomes. Aerosolized IFN-gamma was recovered in PBS solution by bubbling and its concentration was determined. After nebulization for 30 min, aerosolized IFN-gamma was detected only 0.4+/-0.2% of the initial amount in the PBS solution and 3.1+/-0.7% in the reservoir. On the other hand, the addition of small liposomes (HSPC/DSPG=10/1 (molar ratio), 45+/-24 nm) in the nebulizer increased the stability of IFN-gamma, 27.2+/-4.7% of the initial amount in the PBS solution and 25.7+/-12.6% in the reservoir. The present study also examined the effects of composition and concentration of liposomes on the stabilization of aerosolized IFN-gamma. Liposome prepared from distearoyl phosphatidylcholine (DSPC) or hydrogenated soy phosphatidylcholine (HSPC) was very effective for stabilization of aerosolized IFN-gamma (DSPC/DPPG=10/1, HSPC/DSPG=10/1). HSPC/DSPG liposome was efficient at the concentration higher than 12.5 micromols/ml for the stabilization of 5x10(5) JRU/ml of IFN-gamma. In considering the mechanism of this stabilization, the results of gel filtration chromatography suggest that IFN-gamma is inactivated by polymerization or aggregation in nebulization, while the inactivation is suppressed by liposomes due to their adsorption to IFN-gamma.

The phase-out of chlorofluorocarbons (CFCs) has spurred the development of alternative pulmonary drug delivery systems to pressurized metered dose inhalers (MDIs), such as dry powder inhalers and pocket size nebulizers. Reformulation of CFC-MDIs with hydrofluoroalkanes (HFAs) 134a and 227 is also an opportunity to improve these widely accepted systems with respect to ease of handling, compliance, dosing, and more reliable and efficient lung deposition. MDIs have the advantage to protect the drug substance from external parameters such as temperature and humidity and to meter and de-agglomerate the drug independent from patients inspiratory flow rates. Novel formulation technologies combined with improved valves and actuators should help to overcome dose uniformity and priming problems and will increase the percentage of fine particles capable of reaching the deeper regions of the lungs. Spacer mouthpieces can reduce the cold freon effect and undesired oropharyngeal deposition caused by the rapid evaporation of the propellant and plume velocity of the aerosol cloud. More advanced delivery devices may allow the patient to inhale at predetermined flow rates (fast/slow) to target the deposition of fine drug particles (1-6 microm) to specific sites into the lungs. Breath-actuated devices make these systems more effective and patient friendly. The above features in combination with numerical counters showing the remaining number of shots, and built-in blocking mechanisms to avoid tail-off dependent dose uniformity problems of the last labeled shots, should help to improve both acceptance and compliance of pMDIs compared to other inhalation devices. However, only those inhalation systems, which are accepted and appreciated by patients and offering an ambulatory treatment at reasonable cost, will be successful in a more and more competitive market. These issues must be considered in the development of future devices and formulations.

As foam appears during solution constitution and nebulisation of alpha 1 protease inhibitor (alpha 1 PI), we selected in a previous work, antifoams likely to be associated with an alpha 1 PI solution to be nebulised: span 65 at a 0.025% concentration and cetyl alcohol at a 0.05% concentration associated with tyloxapol at 0.025% concentration. The purpose of this study was, on the one hand to study the influence of the formulation on nebulisation quality by relating physicochemical properties and nebulisation capacity, and on the other hand, to define the alpha 1 PI that will be retained for a clinical study. The properties of the different alpha 1 PI formulations are compared: surface tension, viscosity, time required to constitute the protein solution and pH. Nebulisation quality is evaluated under different operating conditions by measuring the droplet size, the quantity of alpha 1 PI nebulised, nebulisation time and the quantity of alpha 1 PI likely to reach the lungs which was subjected to statistical analysis. The statistical analysis of results indicates that the addition of the cetyl alcohol/tyloxapol mixture improves nebulisation effectiveness by significantly increasing the quantity of drug nebulised and therefore the quantity of alpha PI likely to reach the lungs. It is this formulation that will be retained for clinical trials. We check that the nebuliser and operating conditions influence all the parameters, that is to say the respirable fraction, the quantity nebulised and the nebulisation time. Although there is no interaction between the nebuliser and the formulation, nebulisation quality is the combined result of the formulation, the nebuliser and the operating conditions.

Multilamellar liposomes and latex spheres have been atomised using a range of jet and ultrasonic nebulisers. Studies with spheres indicated that relatively large particles can be delivered from nebulisers, although the smaller the suspended particle size, the more efficiently they are delivered from all nebulisers. The size of aerosols generated from liposome suspensions, as measured by laser diffraction, was determined by the lipid concentration and the nebuliser used, but was independent of liposome size and bilayer composition. Generation of aerosols by both jet and ultrasonic nebulisers resulted in damage to liposome structures, with a consequent reduction in the measured vesicle sizes. The Respirgard II jet nebuliser produced aerosols with the smallest median droplet size and caused the greatest damage to liposomes. However, the size of droplets produced by the nebuliser is not the only determinant of liposome stability during atomisation. Relatively fluid EggPC liposomes experienced the greatest disruption during nebulisation. Inclusion of cholesterol or DPPC in the liposome bilayers rendered them more resistant to the disruptive forces to which they were exposed during either jet or ultrasonic nebulisation.

Liposome-encapsulated ciprofloxacin (22.2 mg ciprofloxacin/ml) was nebulized in 25 nebulizers (five nebulizers from each of five nebulizer types). The aerosol was inhaled by a breath simulator (square wave pattern, 0.75 l tidal volume, 0.3 l/s inhalation flow rate) and inhaled droplet sizes were characterized using in-line phase Doppler anemometry. Filter collection combined with centrifugation, UV spectrophotometry and measurement of original entrapment efficiency using C14-radiolabelled ciprofloxacin was used to determine % encapsulation in the inhaled aerosol. Cascade impaction combined with chemical assay showed that encapsulated and free ciprofloxacin were homogeneously distributed among the inhaled droplet sizes. Combination of the above measurements with a mathematical lung deposition model allowed prediction of the amounts of encapsulated ciprofloxacin depositing in the tracheo-bronchial, alveolar and extrathoracic regions of the respiratory tract. The nebulizer types (Pari LC STAR, Pari LC+, Medix Sonix 2000, Hudson T-Updraft II, DeVilbiss Permaneb) differed by up to a factor of 30 in the amount of encapsulated ciprofloxacin depositing in the different regions of the lung (e.g. lung deposition of entrapped ciprofloxacin varied from 0.7% to 18.1% of total ciprofloxacin dose placed in the nebulizer). Much of this dramatic difference was due to the differing amounts of liposomal disruption, which varied among the different nebulizer types from no measurable disruption to nearly complete disruption.

The utilization of CsA–liposome for aerosol delivery by jet nebulizers has potential advantages for clinical development including: aqueous compatibility, sustained pulmonary release to maintain therapeutic drug levels and facilitated delivery to alveolar macrophages and pulmonary lymphocytes. Inhalation of cyclosporin A (CsA)–dilauroylphosphatidylcholine (DLPC) liposome aerosols will theoretically result in localized and sustained delivery of therapeutic CsA concentrations within the lung as an alternative to local immunotherapy for pulmonary diseases. In the lung, targeted delivery of therapeutic CsA concentrations would require lower dosages than via conventional intravenous or oral routes of administration. Potential benefits from targeted lung delivery could include reduced systemic toxicity and prolonged immunosuppressive activity. Aerosol delivery systems have been developed to deposit drugs directly onto pulmonary surfaces at the sites of disease within the lung. A novel HPLC method for tissue analysis of CsA–liposomes is developed and utilized with a solid-phase extraction method to measure CsA recovered from Balb/c mouse lung tissues. A concentrated formulation containing 5 mg CsA–37.5 mg DLPC/ml was nebulized with an Aerotech II nebulizer generating an aerosol particle size distribution (mass median aerodynamic diameter (MMAD)) of 1.7 μm and geometric standard deviation (GSD) of 2.0. After a 15-min aerosol exposure, little of no CsA was detected in the blood, liver, kidney or spleen. The lung contained the highest organ CsA levels with high immunosuppressive activity demonstrating effective pulmonary targeting of the CsA–DLPC liposome aerosol. The results of this system will be utilized as the experimental basis for future pharmacokinetic, toxicological, immunosuppression and other biological studies.