Formulations generated from ethanol-based proliposomes for delivery via medical nebulizers

Multilamellar and oligolamellar liposomes were produced from ethanol-based soya phosphatidyl-choline proliposome formulations by addition of isotonic sodium chloride or sucrose solutions. The resultant liposomes entrapped up to 62% of available salbutamol sulfate compared with only 1.23% entrapped by conventionally prepared liposomes. Formulations were aerosolized using an air-jet nebulizer (Pari LC Plus) or a vibrating-mesh nebulizer (Aeroneb Pro small mesh, Aeroneb Pro large mesh, or Omron NE U22). All vibrating-mesh nebulizers produced aerosol droplets having larger volume median diameter (VMD) and narrower size distribution than the air-jet nebulizer. The choice of liposome dispersion medium had little effect on the performance of the Pari nebulizer. However, for the Aeroneb Pro small mesh and Omron NE U22, the use of sucrose solution tended to increase droplet VMD, and reduce aerosol mass and phospholipid outputs from the nebulizers. For the Aeroneb Pro large mesh, sucrose solution increased the VMD of nebulized droplets, increased phospholipid output and produced no effect on aerosol mass output. The Omron NE U22 nebulizer produced the highest mass output (approx. 100%) regardless of formulation, and the delivery rates were much higher for the NaCl-dispersed liposomes compared with sucrose-dispersed formulation. Nebulization produced considerable loss of entrapped drug from liposomes and this was accompanied by vesicle size reduction. Drug loss tended to be less for the vibrating-mesh nebulizers than the jet nebulizer. The large aperture size mesh (8 mum) Aeroneb Pro nebulizer increased the proportion of entrapped drug delivered to the lower stage of a twin impinger. This study has demonstrated that liposomes generated from proliposome formulations can be aerosolized in small droplets using air-jet or vibrating-mesh nebulizers. In contrast to the jet nebulizer, the performance of the vibrating-mesh nebulizers was greatly dependent on formulation. The high phospholipid output produced by the nebulizers employed suggests that both air-jet and vibrating-mesh nebulization may provide the potential of delivering liposome-entrapped or solubilized hydrophobic drugs to the airways.     

A study of the effects of sodium halides on the performance of air-jet and vibrating-mesh nebulizers

The influence of sodium halide electrolytes on aerosols generated from the Aeroneb Pro vibrating mesh nebulizer and the Sidestream air-jet nebulizer has been evaluated. Fluids with a range of concentrations of Na halides (i.e. NaF, NaCl, NaBr and NaI) were used as nebulizer solutions and their effect on aerosol properties such as total aerosol output, fine particle fraction (FPF), volume median diameter (VMD) and predicted regional airway deposition were investigated. For both nebulizers, the inclusion of electrolyte significantly enhanced the aerosol properties compared with HPLC grade (deionized) water. Aerosol output, FPF and aerosol fraction less than 2.15 μm were directly proportional to electrolyte concentration. Furthermore, the proportion of aerosols that are likely to deposit in the oropharyngeal region, and the VMD of the droplets were inversely related to the electrolyte concentration for both nebulizers. In general, the inclusion of electrolytes had a greater impact on the aerosol properties of the vibrating-mesh nebulizer. In the Aeroneb Pro, NaI 2.0% (w/v) was the optimum solution as it generated the highest aerosol output, FPF and output fraction below 2.15 μm with the lowest VMD and minimal predicted oropharyngeal deposition. This was attributed to the polarizing ability of iodide ions present in the largest quantity at the air–water interface. This study has shown that the Aeroneb Pro vibrating-mesh device demonstrated greatly enhanced aerosol properties when halides were included in the nebulizer solutions.     

Nebulization of Active Pharmaceutical Ingredients with the eFlow®rapid: Impact of Formulation Variables on Aerodynamic Characteristics

Nebulization of active pharmaceutical ingredient (API) solutions is a well-established means to achieve pulmonary drug deposition. The current study identified the impact of formulation variables on the aerosolization performance of the eFlow®rapid with special respect to optimized lung application. API formulations (including excipient-supplemented samples) were investigated for physicochemical properties, then nebulized using vibrating-mesh technology. The generated aerosol clouds were analyzed by laser diffraction. Aerosol deposition characteristics in the human respiratory tract were estimated using an algebraic model. Remarkable effects on aerosolization performance [i.e., mass median aerodynamic diameter (MMAD)] of API solutions were obtained when the sample conductivity (by API concentration and type, sodium chloride addition) and dynamic viscosity (by application of sucrose and poly(ethylene glycol) 200) were elevated. A similar influence was observed for a decline in surface tension (by ethanol addition). Thus, a defined adjustment of formulation parameters allowed for a decrease of the MMAD from ∼8.0 μm to values as small as ∼3.5 μm. Consequently, the pattern and efficiency of aerosol deposition in the human respiratory tract were improved. In conclusion, identification of physicochemical variables and their way of influencing vibrating-mesh nebulization has been provided to deliver a platform for tailoring aerosol characteristics and thus, advancing pulmonary therapy. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2585–2589, 2014     

Making Concentrated Antibody Formulations Accessible for Vibrating-Mesh Nebulization

Despite the significant interest in therapeutic antibodies for the treatment of airway diseases, no study addressed the challenge, which can arise when such formulations need to be made accessible for nebulization in concentrated (viscous) form. By (1) determining the maximum viscosity, which can still be atomized by vibrating-mesh technology and (2) supplementing the antibody formulation under investigation with at least 1 excipient, which decreases the viscosity under that specific threshold value of the utilized inhaler (and maintains the stability of the formulation), it should be possible to nebulize concentrated antibody formulations. Using sucrose as a viscosity enhancer, the viscosity threshold value amounted to ∼6 mPa*s for the eFlow^®rapid device (output rate of <0.1 g/min). When a supplementation of a concentrated model antibody formulation (125 mg/mL) with specific amounts of lysine (≥50 mM) and arginine (≥20 mM) led to the desired drop in viscosity (to <5.5 mPa*s), the previously non-nebulizable formulation (no measurable aerosol output) was made accessible for vibrating-mesh nebulization (output rate of up to ∼0.5 g/min, droplet diameter of <5 μm). The stability of the current antibody formulation was not adversely affected when nebulized in the presence of lysine and arginine. Overall, the presented results will help increase the understanding on how to aerosolize concentrated protein formulations by vibrating-mesh technology.     

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.

     

Characterization of nebulized buparvaquone nanosuspensions—effect of nebulization technology

The poorly soluble drug buparvaquone is proposed as an alternative treatment of Pneumocystis carinii pneumonia (PCP) lung infections. Physically stable nanosuspensions were formulated in order to deliver the drug at the site of infection using nebulization. The aerosolization characteristics of two buparvaquone nanosuspensions were determined with commercial jet and ultrasonic nebulizer devices. Aerosol droplet size distribution was determined with laser diffractometry (LD). Nebulization of the nanosuspensions and dispersion media surfactant solutions produced aerosol droplets diameters in the range from 3 to 5 μm for Respi-jet Kendall, Pari Turbo Boy system and Multisonic nebulizers and particles around 9–10 μm with Omron U1. Fractions of the nanosuspensions from the nebulizer reservoir and of aerosol produced were collected to investigate changes in the size of the drug nanocrystals influenced by the nebulization technology. Comparisons were performed measuring the drug nanocrystals with photon correlation spectroscopy (PCS) and LD of the samples. Drug particle aggregates were detected in the fractions of aerosol collected from jet nebulizers. Nebulizer technology (jet vs. ultrasonic) showed influence on the stability of the drug particle size distribution of buparvaquone nanocrystals during the nebulization time evaluated.     

Nebulizers for drug delivery to the lungs

Introduction: Nebulizers are the oldest modern method of delivering aerosols to the lungs for the purpose of respiratory drug delivery. While use of nebulizers remains widespread in the hospital and home setting, certain newer nebulization technologies have enabled more portable use. Varied fundamental processes of droplet formation and breakup are used in modern nebulizers, and these processes impact device performance and suitability for nebulization of various formulations.

Areas covered: This review first describes basic aspects of nebulization technologies, including jet nebulizers, various high-frequency vibration techniques, and the use of colliding liquid jets. Nebulizer use in hospital and home settings is discussed next. Complications in aerosol droplet size measurement owing to the changes in nebulized droplet diameters due to evaporation or condensation are discussed, as is nebulization during mechanical ventilation.

Expert opinion: While the limelight may often appear to be focused on other delivery devices, such as pressurized metered dose and dry powder inhalers, the ease of formulating many drugs in water and delivering them as aqueous aerosols ensures that nebulizers will remain as a viable and relevant method of respiratory drug delivery. This is particularly true given recent improvements in nebulizer droplet production technology.     

Preparation and characterization of magnetizable aerosols

Magnetizable aerosols can be used for inhalative magnetic drug targeting in order to enhance the drug concentration at a certain target site within the lung. The aim of the present study was to clarify how a typical ferrofluid can be atomized in a reproducible way. The influence of the atomization principle, the concentration of magnetic nanoparticles within the carrier liquid and the addition of commonly used pharmaceutical excipients on the aerosol droplet size were investigated. Iron oxide (magnetite) nanoparticles were synthesized by alkaline precipitation of mixtures of iron(II)- and iron(III)-chloride and coated with citric acid. The resulting ferrofluid was characterized by photon correlation spectroscopy and vibrating sample magnetometry. Two different nebulizers (Pari Boy and eFlow) with different atomization principles were used to generate ferrofluid aerosols. A range of substances that influence the surface tension, viscosity, density or vapor pressure of the ferrofluid were added to investigate their impact on the generated aerosol droplets. The particle size was determined by laser diffraction. A stable ferrofluid with a magnetic core diameter of 10.7 ± 0.45 nm and a hydrodynamic diameter of 124 nm was nebulized by Pari Boy and eFlow. The aerosol droplet size of Pari Boy was approximately 2.5 μm and remained unaffected by the addition of substances that changed the physical properties of the solvent. The droplet size of aerosols generated by eFlow was approximately 5 μm. It was significantly reduced by the addition of Cremophor RH 40, glycerol, polyvinyl pyrrolidone and ethanol.     

A new approach to characterise pharmaceutical aerosols: Measurement of aerosol from a single dose aqueous inhaler with an optical particle counter

An in-line sampling system with dilution units for aqueous droplet aerosols from single dose inhalers (Berodual Respimat^®, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany) for an optical particle counter is described. The device has been designed to interface with a white light aerosol spectrometer (welas^® digital 2100, Palas^® GmbH, Germany) that allows the time-resolved measurement of highly concentrated aerosols. Performance of the sampling system with regard to the measured particle size distribution (PSD) is compared to Next Generation Impactor (NGI) and to laser diffraction measurements (Sympatec Inhaler and open bench). Optimal settings of the sampling system lead to PSDs that correspond well to those measured by the evaporation minimising NGI approach (15 L/min, cooled) and laser diffraction. The better accuracy of the new dilution unit in presence of an additional aerosol sampling filter in comparison to a previously described aerosol sampling system is shown for different settings of the sampling system. This allows a more precise quantification of the delivered drug amount which is also well correlated to the aerosol volume measured by the welas^® system. In addition, using time-resolved welas^® measurements provides insight into droplet size, evaporation and size changes of aerosol clouds delivered by liquid inhalers.     

In vitro characterization of nebulizer delivery of liposomal amphotericin B aerosols

Pharmaceutical aerosols have the potential to prevent pulmonary infectious diseases. Liposomal amphotericin B (LAMB, Ambisome^?, Astellas Pharma US, Deerfield, IL, USA) is approved as an intravenous infusion for empiric treatment of presumed fungal infections in neutropenic, febrile patients, as well as patients infected with Aspergillus, Cryptococcus, and other fungal pathogens. In this study, four different nebulizers were tested for their ability to deliver LAMB in aerodynamic droplet-size ranges relevant to lung deposition by an inertial sampling technique Mass median aerodynamic diameter (MMAD) and fine particle fraction percent <3.3 μm (FPF_3.3) and <5.8 μm (FPF_5.8) were determined by cascade impaction during a 2?min sampling period for each of three trials of all nebulizers. The MMADs for all nebulizers ranged from 1.72?±?0.11 μm to 2.89?±?0.12 μm; FPF_3.3 and FPF_5.8 were approximately 80% and 90%, respectively. Although all nebulizers appear acceptable for delivery of LAMB, the Pari LC Star and the Aeroeclipse II were considered the best in terms of delivery of aerosol efficiently and the proportion suitable for lung deposition. Additional research on pulmonary delivery and clinical tolerability is warranted.     

Comparison of nebulized particle size distribution with Malvern laser diffraction analyzer versus Andersen cascade impactor and low-flow Marple personal cascade impactor.

Particle size of nebulized aerosols can be measured directly using laser diffraction or by evaluating aerodynamic properties by cascade impaction. As of today, there are no generally accepted standards for measuring particle size distribution from nebulizers. Laser diffraction has been questioned because of potential evaporative losses of the small particles at the edge of the plume, causing an apparent shift in the particle size distribution and thus a larger mass median diameter (MMD). When particle-sizing wet aerosols, cascade impaction may give rise to an apparent shift in the distribution, resulting in a smaller mass median aerodynamic diameter (MMAD) due to evaporative losses of aerosol droplets as they enter the impactor at ambient temperature. The modified low-flow Marple 296 Personal Cascade Impactor (MPCI) is currently being proposed as the European standard for wet aerosol analysis to minimize evaporative losses during sampling. The present study compared the particle size distribution of salbutamol and sodium cromoglycate aerosols nebulized by the Pari LC Star, using laser diffraction (Malvern Mastersizer X; MMX) and cascade impaction (Andersen Cascade Impactor [ACI] and the commercially available MPCI), which was either at ambient temperature or cooled to the nebulized aerosol temperature (10 degrees C). MMDs obtained with the MMX were virtually identical to the MMADs measured with both impactors when cooled with no significant differences in geometric standard deviation (sigma(g)). When the impactors were operated at ambient temperature, MMADs were smaller (18 to 30%) with a significantly larger sigma(g) (p < 0.05) compared to the MMX. These findings suggest that droplet distribution data for wet aerosol where evaporation process has not been minimized must be viewed with caution. There was no evidence suggesting a significant evaporative loss of small droplets from the edge of the plume during laser particle sizing. The MPCI does not minimize evaporative losses of aerosol particles during sampling.     

<Emphasis Type="BoldItalic">In Vitro</Emphasis> Performance Testing of the Novel Medspray® Wet Aerosol Inhaler Based on the Principle of Rayleigh Break-up

Purpose

A new inhaler (Medspray®) for pulmonary drug delivery based on the principle of Rayleigh break-up has been tested with three different spray nozzles (1.5; 2.0 and 2.5 μm) using aqueous 0.1% (w/w) salbutamol and 0.9% (w/w) sodium chloride solutions.

Materials and methods

Particle size distributions in the aerosol were measured with the principles of time of flight (APS) and laser diffraction (LDA).

Results

The Medspray® inhaler exhibits a highly constant droplet size distribution in the aerosol during dose emission. Droplets on the basis of Rayleigh break-up theory are monodisperse, but due to some coalescence the aerosols from the Medspray® inhaler are slightly polydisperse. Mass median aerodynamic diameters at 60 l.min^?1 from APS are 1.42; 1.32 and 1.27 times the theoretical droplet diameters (TD’s) and median laser diffraction diameters are 1.29; 1.14 and 1.05 times TD for 1.5; 2.0 and 2.5 μm nozzles (TD: 2.84; 3.78 and 4.73 μm respectively).

Conclusions

The narrow particle size distribution in the aerosol from the Medspray® is highly reproducible for the range of flow rates from 30 to 60 l.min^?1. The mass median aerodynamic droplet diameter can be well controlled within the size range from 4 to 6 μm at 60 l.min^?1.

     

Characterization of nebulized buparvaquone nanosuspensions--effect of nebulization technology

The poorly soluble drug buparvaquone is proposed as an alternative treatment of Pneumocystis carinii pneumonia (PCP) lung infections. Physically stable nanosuspensions were formulated in order to deliver the drug at the site of infection using nebulization. The aerosolization characteristics of two buparvaquone nanosuspensions were determined with commercial jet and ultrasonic nebulizer devices. Aerosol droplet size distribution was determined with laser diffractometry (LD). Nebulization of the nanosuspensions and dispersion media surfactant solutions produced aerosol droplets diameters in the range from 3 to 5 microm for Respi-jet Kendall, Pari Turbo Boy system and Multisonic nebulizers and particles around 9-10 microm with Omron U1. Fractions of the nanosuspensions from the nebulizer reservoir and of aerosol produced were collected to investigate changes in the size of the drug nanocrystals influenced by the nebulization technology. Comparisons were performed measuring the drug nanocrystals with photon correlation spectroscopy (PCS) and LD of the samples. Drug particle aggregates were detected in the fractions of aerosol collected from jet nebulizers. Nebulizer technology (jet vs. ultrasonic) showed influence on the stability of the drug particle size distribution of buparvaquone nanocrystals during the nebulization time evaluated.     

In vitro characterization of nebulizer delivery of liposomal amphotericin B aerosols

Pharmaceutical aerosols have the potential to prevent pulmonary infectious diseases. Liposomal amphotericin B (LAMB, Ambisome, Astellas Pharma US, Deerfield, IL, USA) is approved as an intravenous infusion for empiric treatment of presumed fungal infections in neutropenic, febrile patients, as well as patients infected with Aspergillus, Cryptococcus, and other fungal pathogens. In this study, four different nebulizers were tested for their ability to deliver LAMB in aerodynamic droplet-size ranges relevant to lung deposition by an inertial sampling technique Mass median aerodynamic diameter (MMAD) and fine particle fraction percent <3.3 μm (FPF(3.3)) and <5.8 μm (FPF(5.8)) were determined by cascade impaction during a 2 min sampling period for each of three trials of all nebulizers. The MMADs for all nebulizers ranged from 1.72 ± 0.11 μm to 2.89 ± 0.12 μm; FPF(3.3) and FPF(5.8) were approximately 80% and 90%, respectively. Although all nebulizers appear acceptable for delivery of LAMB, the Pari LC Star and the Aeroeclipse II were considered the best in terms of delivery of aerosol efficiently and the proportion suitable for lung deposition. Additional research on pulmonary delivery and clinical tolerability is warranted.     

Nebulizer-compatible liquid formulations for aerosol pulmonary delivery of hydrophobic drugs: glucocorticoids and cyclosporine

This review discusses pulmonary delivery of glucocorticoids and cyclosporine in pharmaceutically acceptable organic solvents and liposomes, as well as in micellar solutions and microemulsions, by means of liquid aerosols generated by nebulizers. The review points out the importance of a variety of parameters for successful treatment of immunologically mediated lung diseases by inhalation of drug containing aerosols with particular references to physico-chemical properties of formulations, aerosol parameters, pharmacokinetics, and lung deposition in experimental animals and humans. The prospects for the use of these types of formulations for clinical treatment of asthma, lung transplant rejection processes and other lung diseases are summarized.     

Lung Deposition of Droplet Aerosols in Monkeys

Nonhuman primates are often the animal models of choice to study the infectivity and therapy of inhaled infectious agents. Most animal models for inhaled infectious diseases use aerosol/droplets generated by an atomization technique such as a Collison nebulizer that produces particles in the size range of 1 to 3 μm in diameter. There are few data in the literature on deposition patterns in monkeys. Our study was designed to measure the deposition pattern in monkeys using droplets having diameters of 2 and 5 μm using an exposure system designed to expose monkeys to aerosols of infectious agents. Six cynomolgus monkeys were exposed to droplets. The aerosol solution was generated from a Vero cell supernate containing DMEM + 10% fetal bovine serum tagged with Tc-99m radiolabel. Collison and Retec nebulizers were used to generate small and large droplets, respectively. The particle size (as determined from a cascade impactor) showed an activity median aerodynamic diameter (AMAD) of 2.3 and 5.1 μm for the Collison and Retec nebulizer, respectively. The animals were anesthetized, placed in a plethysmography box, and exposed to the aerosol. The deposition pattern was determined using a gamma camera. Deposition in the head airways was 39% and 58% for 2.3- and 5.1-μm particle aerosols, respectively, whereas the deposition in the deep lung was 12% and 8%, respectively. This information will be useful in developing animal models for inhaled infectious agents.     

Lung deposition of droplet aerosols in monkeys

Nonhuman primates are often the animal models of choice to study the infectivity and therapy of inhaled infectious agents. Most animal models for inhaled infectious diseases use aerosol/droplets generated by an atomization technique such as a Collison nebulizer that produces particles in the size range of 1 to 3 microm in diameter. There are few data in the literature on deposition patterns in monkeys. Our study was designed to measure the deposition pattern in monkeys using droplets having diameters of 2 and 5 microm using an exposure system designed to expose monkeys to aerosols of infectious agents. Six cynomolgus monkeys were exposed to droplets. The aerosol solution was generated from a Vero cell supernate containing DMEM + 10% fetal bovine serum tagged with Tc-99m radiolabel. Collison and Retec nebulizers were used to generate small and large droplets, respectively. The particle size (as determined from a cascade impactor) showed an activity median aerodynamic diameter (AMAD) of 2.3 and 5.1 microm for the Collison and Retec nebulizer, respectively. The animals were anesthetized, placed in a plethysmography box, and exposed to the aerosol. The deposition pattern was determined using a gamma camera. Deposition in the head airways was 39% and 58% for 2.3- and 5.1-microm particle aerosols, respectively, whereas the deposition in the deep lung was 12% and 8%, respectively. This information will be useful in developing animal models for inhaled infectious agents.     

A scattering methodology for droplet sizing of e-cigarette aerosols

Context: Knowledge of the droplet size distribution of inhalable aerosols is important to predict aerosol deposition yield at various respiratory tract locations in human. Optical methodologies are usually preferred over the multi-stage cascade impactor for high-throughput measurements of aerosol particle/droplet size distributions.

Objective: Evaluate the Laser Aerosol Spectrometer technology based on Polystyrene Sphere Latex (PSL) calibration curve applied for the experimental determination of droplet size distributions in the diameter range typical of commercial e-cigarette aerosols (147–1361?nm).

Materials and methods: This calibration procedure was tested for a TSI Laser Aerosol Spectrometer (LAS) operating at a wavelength of 633?nm and assessed against model di-ethyl-hexyl-sebacat (DEHS) droplets and e-cigarette aerosols. The PSL size response was measured, and intra- and between-day standard deviations calculated.

Results: DEHS droplet sizes were underestimated by 15–20% by the LAS when the PSL calibration curve was used; however, the intra- and between-day relative standard deviations were <?3%. This bias is attributed to the fact that the index of refraction of PSL calibrated particles is different in comparison to test aerosols. This 15–20% does not include the droplet evaporation component, which may reduce droplet size prior a measurement is performed. Aerosol concentration was measured accurately with a maximum uncertainty of 20%. Count median diameters and mass median aerodynamic diameters of selected e-cigarette aerosols ranged from 130–191?nm to 225–293?nm, respectively, similar to published values.

Discussion and conclusion: The LAS instrument can be used to measure e-cigarette aerosol droplet size distributions with a bias underestimating the expected value by 15–20% when using a precise PSL calibration curve. Controlled variability of DEHS size measurements can be achieved with the LAS system; however, this method can only be applied to test aerosols having a refractive index close to that of PSL particles used for calibration.     

Production of solid lipid nanoparticle suspensions using supercritical fluid extraction of emulsions (SFEE) for pulmonary delivery using the AERx system

The aims of the current work included: development of a new production method for nanoparticles of water-insoluble drugs in combination with lipids, characterization of the nanoparticles and development of lipid nanosuspension formulations, and investigation of the feasibility of delivering the nanosuspensions as aerosols for inhalation using Aradigm's AERx Single Dose Platform (SDP) with micron-sized nozzles and the all mechanical AERx Essence with sub-micron-sized nozzles. The continuous SFEE method was used for particle precipitation of solid lipid nanoparticles (SLN). The method allowed for production of stable particulate aqueous suspensions of a narrow size distribution, with a volume mean diameter below 30 nm (D99% cumulative volume below 100 nm). Thus the particle size obtained was significantly smaller than previously has been achieved by other techniques. The residual solvent content in the final suspension was consistently below 20 ppm. Drug loading values between 10-20% w/w drug were obtained for model compounds ketoprofen and indomethacin in formulation with lipids such as tripalmitin, tristearin and Gelucire 50/13. It was observed that the loading capacity achieved was higher than the thermodynamic limit of the solubility of the drugs in molten lipids. Lipid nanosuspension formulations were successfully aerosolized using both of the AERx systems. As measured by both cascade impactor and laser diffraction, the aerosol fine particle fraction (FPF) was comparable to drug solution formulations typically used in these devices; i.e., greater than 90% of the aerosol mass resided in particles less than 3.5 mum aerodynamic diameter.     

Nebulization of ultradeformable liposomes: The influence of aerosolization mechanism and formulation excipients

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 2h 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.