Aerosol Delivery System Research Articles

Dry Powder Aerosol Delivery Systems: Current and Future Research Directions

Development of dry powder aerosol delivery system involves powder production, formulation, dispersion, delivery, and deposition of the powder aerosol in the airways. Insufficiency of conventional powder production by crystallization and milling has led to development of alternative techniques. Over the last decade, performance of powder formulations has been improved significantly through the use of engineered drug particles and excipient systems which are (i) of low aerodynamic diameters (being porous or of low particle density), and/or (ii) less cohesive and adhesive (via corrugated surfaces, low bulk density, reduced surface energy and particle interaction, hydrophobic additives, and fine carrier particles). Early insights into particle forces and surface energy that help explain the improvement have been provided by analytical techniques such as the atomic force microscopy (AFM) and inverse gas chromatography (IGC). Relative humidity is critical to the performance of dry powder inhaler (DPI) products via capillary force and electrostatic interaction. Electrostatic charge of different particle size fractions of an aerosol can now be measured using a modified electrical low-pressure impactor (ELPI). Compared with powders, much less work has been done on the inhaler devices at the fundamental level. Most recently, computational fluid dynamics has been applied to understand how the inhaler design (such as mouthpiece, grid structure, air inlet) affects powder dispersion. The USP throat is known to under-represent the oropharyngeal deposition of DPI aerosols. Studies using magnetic resonance imaging (MRI) model casts have been undertaken to explain the inter- and intra- subject variation in oropharyngeal deposition. Most of the lung deposition studies performed on commercial products did not allow a thorough understanding of the determinants affecting in vivo lung deposition. A more systematic approach would be necessary to build a useful database on the dependence of lung deposition on the breathing parameters, inhaler design, and powder formulation properties.

177 Delivery of tobramycin via the I-nebTM adaptive aerosol delivery (AADO) system and the Pari LC Plus® nebulizer

177 Delivery of tobramycin via the I-nebTM adaptive aerosol delivery (AADO) system and the Pari LC Plus® nebulizer

The 15th International Society of Aerosols in Medicine Congress

This international meeting brought together ∼ 250 delegates from the pharmaceutical industry, academia, hospitals and government agencies, to discuss the latest research and development on areas related to inhalation aerosols. Fundamental science and applied research encompassing both the biological and physicochemical aspects were presented. There was a wide range of topics covered, from immune modulation to pharmaceutical regulatory issues, including aerosol clearance; industry innovations; aerosols and in utero effects; technical advances in imaging; inhalation catastrophes; as well as recent advances and future directions in aerosol delivery systems. This biennial congress has provided an excellent forum for stimulating fruitful discussion of aerosols in medicine.

Pharmacokinetics and Acute Safety of Inhaled Testosterone in Postmenopausal Women

This was a preliminary feasibility study to assess the pharmacokinetics and acute safety of a single dose of orally inhaled testosterone via the AERx system, a novel handheld aerosol delivery system in postmenopausal women. Twelve postmenopausal women stabilized on oral estrogen therapy were treated with a single dose of testosterone (0.1, 0.2, or 0.3 mg) by inhalation. Plasma concentrations of sex steroids were measured between 1 and 360 minutes. Pulmonary and cardiovascular adverse events were monitored. Inhaled testosterone produced a dose-dependent increase in plasma total and free testosterone. At the highest dose (0.3 mg), total and free testosterone increased from baseline (mean +/- SD, 0.6 +/- 0.3 nmol/L, 2.5 +/- 1.0 pmol/L) to maximum levels of 62.6 +/- 20.4 nmol/L (total) and 168.2 +/- 50.2 pmol/L(free), occurring 1 to 2 minutes after dosing. A 2-compartment model best described the free and total testosterone pharmacokinetic profile. Dihydrotestosterone levels were higher than baseline at 60 minutes (P < .0002). Estradiol did not vary, but sex hormone binding globulin and albumin fell. There were no adverse events related to the treatment. Administration of inhaled testosterone is safe and achieves a supraphysiologic "pulse" kinetic profile of total and free testosterone with a rapid return to pretreatment levels.

The Reno Aerosol Optics Study: An Evaluation of Aerosol Absorption Measurement Methods

The Reno Aerosol Optics Study (RAOS) was designed and conducted to compare the performance of many existing and new instruments for the in situ measurement of aerosol optical properties with a focus on the determination of aerosol light absorption. For this study, simple test aerosols of black and white particles were generated and combined in external mixtures under low relative humidity conditions and delivered to each measurement system. The aerosol mixing and delivery system was constantly monitored using particle counters and nephelometers to ensure that the same aerosol number concentration and amount reached the different instruments. The aerosol light-scattering measurements of four different nephelometers were compared, while the measurements of seven light-absorption instruments (5 filter based, 2 photoacoustic) were evaluated. Four methods for determining the aerosol light-extinction coefficient (3 cavity ring-down instruments and 1 folded-path optical extinction cell) were also included in the comparisons. An emphasis was placed on determining the representativeness of the filter-based light absorption methods, since these are used widely and because major corrections to the raw attenuation measurements are known to be required. The extinction measurement from the optical extinction cell was compared with the scattering measurement from a high-sensitivity integrating nephelometer on fine, nonabsorbing ammonium sulfate aerosols, and the two were found to agree closely (within 1% for blue and green wavelengths and 2% for red). The wavelength dependence of light absorption for small kerosene and diesel soot particles was found to be very near λ− 1, the theoretical small-particle limit. Larger, irregularly shaped graphite particles showed widely variable wavelength dependencies over several graphite runs. The light-absorption efficiency at a wavelength of 530 nm for pure kerosene soot with a number size distribution peak near 0.3 μ m diameter was found to be 7.5 ± 1.2 m2 g− 1. The two most fundamental independent absorption methods used in this study were photoacoustic absorption and the difference between suspended-state light extinction and scattering, and these showed excellent agreement (typically within a few percent) on mixed black/white aerosols, with the photoacoustic measurement generally slightly lower. Excellent agreement was also observed between some filter-based light-absorption measurements and the RAOS reference absorption method. For atmospherically relevant levels of the aerosol light-absorption coefficient (< 25 Mm− 1), the particle soot absorption photometer (PSAP) absorption measurement at mid-visible wavelengths agreed with the reference absorption measurement to within ∼ 11% for experiment tests on externally mixed kerosene soot and ammonium sulfate. At higher absorption levels (characterized by lower single-scattering albedo aerosol tests), this agreement worsened considerably, most likely due to an inadequate filter loading correction used for the PSAP. The PSAP manufacturer's filter loading correction appears to do an adequate job of correcting the PSAP absorption measurement at aerosol single-scattering albedos above 0.80–0.85, which represents most atmospheric aerosols, but it does a progressively worse job at lower single-scattering albedos. A new filter-based light-absorption photometer was also evaluated in RAOS, the multiangle absorption photometer (MAAP), which uses a two-stream radiative transfer model to determine the filter and aerosol scattering effects for a better calculation of the absorption coefficient. The MAAP absorption measurements agreed with the reference absorption measurements closely (linear regression slope of ∼ 0.99) for all experimental tests on externally mixed kerosene soot and ammonium sulfate.

Alternative Propellant Aerosol Delivery Systems

The year 2006 represents the 50th anniversary of the pressurized metered dose inhaler. With most technologies, 50 years represents a significant time span for technology evolution and modification, but with propellant-driven metered dose inhalers, the pace of change has been relatively slow. We are now in the era of alternative propellant aerosol delivery systems, but at this 50-year juncture, what are the characteristics of these systems and what are the prospects for future advances? This review will consider alternative propellant aerosol delivery systems broadly from their inception through future opportunities and challenges.

Intra-Subject Variability in Lung Dose in Healthy Volunteers Using Five Conventional Portable Inhalers

High intra-subject variability in lung dose achieved when using aerosol delivery systems may impact on the efficacy of treatment in clinical practice. While the dose delivered by metered dose inhalers (pMDIs) is highly reproducible when tested in vitro, the variability in dose delivered to the lungs is known to be high. It has been suggested that newer delivery systems such as dry powder inhalers (DPIs) or breath actuated pMDIs significantly reduce the intra-subject variability in lung dose, but this remains untested. The 30-min urinary salbutamol technique was used to assess intra-subject variability in lung dose for five portable inhaler devices. Thirteen healthy adult subjects inhaled salbutamol from five different devices. Each device was used at five separate study days, a total of 25 visits. The devices studied were the Evohaler pMDI, a pMDI with Volumatic (pMDI + HC), the Easibreath, the Accuhaler and the Turbohaler. Subjects inhaled 400 microg of salbutamol and produced a urine sample exactly 30 min later. Quantities of salbutamol contained in the urine were determined using an HPLC technique. The mean coefficient of variation (CV% and range) for lung dose were 31.8% (20.1-87.4) for the pMDI + HC, Easi-breathe 35.9% (10.4-66.2), Accuhaler 40.4% (15.6-75.2), Turbohaler 42.4% (20.7-74.2), and 52.0% (27.1-49.3) for the pMDI alone. There was no significant statistical significant difference between any of the devices. In seven of 13 subjects, the greatest lung dose was achieved with the Volumatic. The observed intra-subject in health volunteers is similar to the reported intra-subject variability of bioavailability for a number of oral medications. Though there was trend towards higher variability when using the pMDI, this was not statistically significant and was largely attributable to one subject in with a poor technique.

Intra-Subject Variability in Lung Dose in Healthy Volunteers Using Five Conventional Portable Inhalers

High intra-subject variability in lung dose achieved when using aerosol delivery systems may impact on the efficacy of treatment in clinical practice. While the dose delivered by metered dose inhalers (pMDIs) is highly reproducible when tested in vitro, the variability in dose delivered to the lungs is known to be high. It has been suggested that newer delivery systems such as dry powder inhalers (DPIs) or breath actuated pMDIs significantly reduce the intrasubject variability in lung dose, but this remains untested. The 30-min urinary salbutamol technique was used to assess intra-subject variability in lung dose for five portable inhaler devices. Thirteen healthy adult subjects inhaled salbutamol from five different devices. Each device was used at five separate study days, a total of 25 visits. The devices studied were the Evohaler pMDI, a pMDI with Volumatic (pMDI + HC), the Easibreath, the Accuhaler and the Turbohaler. Subjects inhaled 400 µg of salbutamol and produced a urine sample exactly 30 min later. Quantities of salbutamol contained in the urine were determined using an HPLC technique. The mean coefficient of variation (CV% and range) for lung dose were 31.8% (20.1–87.4) for the pMDI + HC, Easi-breathe 35.9% (10.4–66.2), Accuhaler 40.4% (15.6–75.2), Turbohaler 42.4% (20.7–74.2), and 52.0% (27.1–49.3) for the pMDI alone. There was no significant statistical significant difference between any of the devices. In seven of 13 subjects, the greatest lung dose was achieved with the Volumatic. The observed intra-subject in health volunteers is similar to the reported intra-subject variability of bioavailability for a number of oral medications. Though there was trend towards higher variability when using the pMDI, this was not statistically significant and was largely attributable to one subject in with a poor technique.

Matching the device to the patient.

Aerosol therapy is complex, especially in young children, and can only succeed when the physician has detailed knowledge about: aerosol characteristics of the various aerosol delivery systems; the pathophysiology of the lung disease; the skills of the patient in various age groups. Only when this knowledge is available the appropriate delivery device for the child can be selected and the proper instructions can be given. Most aerosol delivery devices are not primarily developed for use in children. Particle size characteristics of most delivery systems are suboptimal for children since they deliver only a low mass of extra fine aerosol particles.

Bacterial agents used for bioterrorism.

Bacterial pathogens and their products are potential agents of biological terrorism and biological warfare. These agents can be deployed through simple aerosol delivery systems and thereby cause widespread disease and death. This report is a review of bacterial species that have been employed for development of biological terrorism, relying on a system for classification of their threat developed by the Centers for Disease Control. Physicians must understand how to recognize early signs and symptoms caused by bacterial agents. Clinical findings often seen on presentation are emphasized along with a summary of therapeutic approaches. Initiation of immediate therapy and supportive care provides the best chance for survival from these potentially lethal and devastating infections. A high index of suspicion must be maintained, especially in the setting of a sudden influx of cases with what are often relatively nonspecific symptoms.

Topical lidocaine–prilocaine spray for the treatment of premature ejaculation: a proof of concept study

Premature ejaculation (PE) is the most common sexual dysfunction in men. Since heightened sensitivity of the glans is implicated in PE, it seems reasonable that reducing this sensitivity could have a delaying effect on intravaginal ejaculation latency time (IVELT) without adversely affecting the sensation of ejaculation. We have developed a local anesthetic combination, in a metered-dose aerosol delivery system, that delivers lidocaine and prilocaine in base form without organic solvents. The drug can be easily removed prior to vaginal penetration, circumventing the need for a condom that most patients find undesirable. Herein, we report on a prospective open-label pilot study investigating the safety and efficacy of this novel delivery system for topical local anesthetic to the glans penis aimed at prolonging the IVELT in patients who self-reported having PE. This was an open-label prospective pilot study. The lidocaine-prilocaine (LP) aerosol delivered 7.5 mg lidocaine and 2.5 mg prilocaine, both in base form, per actuation. A total of 14 men who had been referred to urology clinics with the problem of PE were recruited. Consent was obtained from both subjects and their partners. Couples were asked to time their IVELT without treatment on one encounter, and then on five subsequent encounters were asked to apply the spray to the glans penis, leave on for 10-15 min, wipe off carefully before intercourse. The IVELT was timed with a stopwatch and then both partners were asked to rate their individual satisfaction relative to baseline without treatment. They were also asked to document any adverse events or comments. In all, 11 patients completed the study. The average IVELT increased from 1 min:24 s to 11 min:21 s (P=0.008) representing an average eight-fold increase. No subjects experienced a decrease in IVELT. The average satisfaction score for both subjects and partners was 1.0; on a scale where -1 was worse, 0 the same, +1 better and +2 much better. Topical LP spray, applied to the glans penis 15 min before intercourse, prolongs ejaculation time significantly and improves sexual satisfaction in both men with PE and their partners. The glandular numbness, noticed in only two cases, did not adversely affect the quality of the orgasm. Occasionally, a patient reported difficulty maintaining an erection while waiting the required 15 min between application of the spray and the initiation of intercourse.

Feasibility of aerosol vaccination in humans.

The feasibility of using aerosol vaccines to achieve mass and rapid immunization, especially in developing countries and disaster areas, is being assessed on the basis of current available information. The aerosol mode of vaccine introduction, which best follows the natural route of many infections, may first lead to development of immunity at the portal of entry, and may also induce a more generalized defense. The recommended optimal way of introducing an aerosol vaccine is nasal breathing, which is more suitable for geriatric and pediatric populations, permits use of greater antigen volumes, and allows easier monitoring of results. Technical requirements for ideal aerosol vaccines and delivery systems, possible adverse effects, and cost-effectiveness are other issues addressed. Several thousand human subjects have been aerosol-vaccinated over a period of many years in Russia with live-attenuated strains against many diseases. Extensive field trials in South America with aerosolized live-attenuated measles vaccine have also been successful, and excellent results have been reported with pilot projects employing inactivated or live-attenuated aerosol influenza A vaccine. We conclude that aerosol immunization seems a promising method of vaccination. Although some basic information is still lacking, this method has already been used successfully in large populations and has therefore passed the phase of initial feasibility evaluation.

Aerosol gene therapy.

Gene therapy is a novel field of medicine that holds tremendous therapeutic potential for a variety of human diseases. Targeting of therapeutic gene delivery vectors to the lungs can be beneficial for treatment of various pulmonary diseases such as lung cancer, cystic fibrosis, pulmonary hypertension, alpha-1 antitrypsin deficiency, and asthma. Inhalation therapy using formulations delivered as aerosols targets the lungs through the pulmonary airways. The instant access and the high ratio of the drug deposited within the lungs noninvasively are the major advantages of aerosol delivery over other routes of administration. Delivery of gene formulations via aerosols is a relatively new field, which is less than a decade old. However, in this short period of time significant developments in aerosol delivery systems and vectors have resulted in major advances toward potential applications for various pulmonary diseases. This article will review these advances and the potential future applications of aerosol gene therapy technology.

Heliox improves aerosol deposition and tidal volume in a model of acute airway obstruction

Heliox has been reported to reduce work of breathing and to improve aerosol deposition in patients with acutely obstructed airways. We wanted to evaluate the effects of an aerosol delivery system (Aerogen, Inc, Mountain View, CA, USA) with a prototype heliox delivery system (Datex-Ohmeda, Inc, Madison, WI, USA) incorporating an electronic demand valve with an active exhalation valve, and its impact on aerosol deposition and tidal volume (Vt).

A Widely Available Method for the Assessment of Aerosol Delivery in Cystic Fibrosis

Whilst nebulisers are commonly used in the treatment of cystic fibrosis (CF), nebulised aerosol lung deposition in individual patients is not routinely assessed in clinical practice. The present study was designed to evaluate whether a comparative measurement of aerosol lung deposition from nebulisers using a widely available scintigraphic method could be employed to assist the selection of the best system for individual patients. Lung deposition of the radiolabelled aerosol from the Pari LC Plus (Pari Medical Ltd) nebuliser and the HaloLite Adaptive Aerosol Delivery (AAD®) system (Profile Therapeutics Ltd) was measured using planar scintigraphy in 10 healthy volunteers and 6 CF patients. The HaloLite AAD® delivered on average 2.1 times ( P=0.003) as much aerosol to the lungs compared with Pari LC Plus. Only two subjects had higher lung deposition from Pari LC Plus than HaloLite AAD® system. There was marked inter-individual variation in the deposition pattern in CF patients. The aerosol deposition from HaloLite AAD® had higher central distribution than that obtained with the Pari LC Plus. The overall intersubject variability of the delivered dose was 56% with Pari LC Plus and 24% with HaloLite AAD® ( P<0.05). The measurement of aerosol deposition from nebulisers can be performed using a simple and widely available methodology, and may improve nebuliser selection in CF patients.

Aerosol delivery of virulent Mycobacterium bovis to cattle

Setting: Although animal models of aerosol inoculation of Mycobacterium tuberculosis and M. bovis have been reported using laboratory animals, a model of aerosol delivery of M. bovis to cattle has not been reported previously. Objective: Develop and characterize a model of aerosol delivery of M. bovis to cattle, and compare the distribution of lesions in cattle infected with either of two different strains of M. bovis, one isolated from cattle (HC2005T), and the other isolated from white-tailed deer (1315). Design: Cattle ( n=20, female and castrated males) aged 4 months, were infected with 1×10 3 ( n=5) or 1×10 5 ( n=5) colony-forming units (CFU) of M. bovis 1315 or 1×10 3 ( n=5) or 1×10 5 ( n=5) CFU of M. bovis HC2005T. Calves were infected using a commercially available aerosol delivery system. One hundred fifty-five days after infection, calves were euthanized, examined and tissues collected for microscopic analysis and bacteriologic culture. Results: Nineteen of 20 calves developed tuberculosis. Typical tuberculous lesions were most pronounced in the lungs and tracheobronchial and mediastinal lymph nodes. Conclusion: The system described provides a reliable method of aerosol delivery of M. bovis to cattle. Lesion distribution suggests that the aerosolized inoculum was delivered deep into pulmonary alveoli and thus represents true aerosol exposure. Disease was more severe in groups receiving the highest dose of either inoculum strain; however, differences between strains were not seen. Published by Elsevier Science Ltd.

Assessment of regional lung ventilation in dog lungs with Gd-DTPA aerosol ventilation MR imaging

Gd-DTPA aerosol ventilation MR imaging was obtained using a modified aerosol delivery system with an aerosol reservoir to non-invasively assess regional lung ventilation in dogs.Seven anesthetized, spontaneously breathing normal dogs inhaled 200 mmol Gd/l Gd-DTPA aerosol produced by an ultrasonic nebulizer, using an open-circuit aerosol delivery system with or without an aerosol reservoir. Fast gradient-echo MR images were sequentially acquired with an interval time of 1 min for 25 min before and after aerosol inhalation. The aerosol study was also performed using the aerosol delivery system with an aerosol reservoir in the same 7 dogs after airway obstruction with a balloon catheter, and in another 7 dogs after pulmonary arterial embolization with enbucrilate. An i.v. Gd-DTPA-enhanced dynamic MR study after i.v. bolus injection of a 0.1 mmol/kg dose of Gd-DTPA was combined to assess regional lung perfusion. Lung enhancement effect was evaluated by time-signal intensity curves and the subtracted ventilation- and perfusion-weighted images.With or without the aerosol reservoir, the normal dog lungs were gradually and gravity-dependently enhanced with time after aerosol inhalation. The use of the aerosol reservoir, however, showed significantly greater lung enhancement without a significant increase in breathing rate and with minimal reduction in PaO2 of less than 5 mm Hg in these animals. The enhancement effect of i.v. injection of Gd-DTPA at pulmonary arterial perfusion phase was significantly greater compared to that of Gd-DTPA aerosol throughout the normal lungs, and the subtracted ventilation-weighted and perfusion-weighted images showed homogeneous but gravity-dependent aerosol deposition and perfusion. These images clearly defined the regionally matched perfusion-ventilation deficits in the lung regions distal to bronchial obstruction in all the airway obstruction dogs, and the regionally mismatched perfusion-ventilation in the embolized regions of all the pulmonary arterial embolization animals.Gd-based aerosol can non-invasively image regional lung ventilation in spontaneously breathing animals, using an adequate aerosol delivery system. The combined use of Gd-DTPA perfusion MR imaging may be acceptable for defining regionally impaired lung function associated with acute airway obstruction and pulmonary arterial embolization.

Regional lung functional impairment in acute airway obstruction and pulmonary embolic dog models assessed with gadolinium-based aerosol ventilation and perfusion magnetic resonance imaging.

Gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA)-based aerosol ventilation and perfusion magnetic resonance (MR) images were used to define regional functional impairment in acute airway obstruction (AO) and pulmonary embolic (PE) dog models. The aerosol study was performed in 10 anesthetized normal dogs in a supine position during 20-minute spontaneous inhalation of an aerosol of 100- or 200-mmol-Gd/L Gd-DTPA solute produced by an ultrasonic nebulizer in an open-circuit delivery system, combined with a dynamic perfusion study after a 3-second intravenous bolus injection of a 0.1 mmol/kg dose of Gd-DTPA. These MR studies were also performed in the same 10 dogs approximately 30 minutes after obstructing the segmental (n = 6) or lobar (n = 4) bronchus with a balloon catheter, and in another six dogs after segmental (n = 6) and lobar (n = 4) pulmonary arterial embolization with enbucrilate. Regional lung enhancement was assessed on time-signal intensity (SI)-curves and ventilation- and perfusion-weighted images produced by a subtraction technique. The normal lungs were gradually and gravity-dependently enhanced with time after Gd-DTPA aerosol inhalation regardless of the respiratory SI changes, except for three animals with the fastest breathing rate. The averaged maximal relative lung SI increase against the baseline in the successful animals was significantly greater in the slowly and deeply breathing animals than in the fast and shallow breathing animals, regardless of the difference in Gd-concentration (100 mmol Gd/L: 153.3% +/- 69.7% vs. 54.2% +/- 23%; P < 0.001; and 200 mmol Gd/L: 189.7% +/- 68.0% vs. 75.6% +/- 42.2%; P < 0.0001, respectively). There was an additional enhancement of 382% +/- 101 in the ventral lung and 722% +/- 160 in the dorsal lung on the pulmonary arterial phase perfusion image even in the slowly and deeply breathing animals who inhaled 200-mmol-Gd/L aerosol, and the enhancement effect was significantly greater compared with that with the aerosol (P < 0.0001). The ventilation- and perfusion-weighted images clearly defined the regionally matched perfusion-ventilation deficits in all the AO models, and the regionally mismatched perfusion-ventilation in all the PE models. Gd-based aerosol can provide efficient lung enhancement in spontaneously and adequately breathing animals, using a relatively noninvasive aerosol delivery system. The combined use of Gd-based perfusion MR imaging may be acceptable for defining regionally impaired function associated with acute AO and PE.

Generation of Gelatin Aerosol Particles from Nebulized Solutions as Model Drug Carrier Systems

Purpose. Aerodynamically stable, nebulized aerosols are desirable to achieve optimum asthma therapy. Stabilizing droplet size using gel-forming polymers may assist in achieving this goal. Semisolid particles may be generated through aerosolization of a polymer solution. Gelatin was employed as a model polymer in a process optimization study using the marker, disodium fluorescein, and the drug, budesonide delivered from two commercially available air-jet nebulizers.Methods. The aerosol delivery system consisted of either of the air-jet nebulizers attached to a 30 cm drying column. The nebulizers employed were the Aerotech II and Salter SL8900. Two gelatin solutions (0.1 and 0.7%w/v) were evaluated following initial density and viscosity measurements. Particle characterization was conducted by scanning electron microscopy, eight-stage cascade impaction (CI), and phase-Doppler analysis. Disodium fluorescein (NaF, 5 and 7%w/v) and budesonide (B, 0.05%w/v) were added to the gelatin solutions in a 24-factorial design study and the follow-up drug formulation study, respectively. The factorial design experiment evaluated the influence of device, operating pressure, marker, and gelatin concentrations on mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF). Spectrophotometry of the CI samples was performed at wavelengths of 486 (NaF) and 254 (B) nm.Results. The factorial design experiment utilizing NaF showed that MMADs were not influenced significantly by the device, operating pressure, marker, or gelatin concentrations (p>0.05). However, FPFs were significantly influenced by marker concentration and device (p<0.05). In the presence of budesonide, the MMADs and FPFs for Aerotech and Salter, respectively, were: MMAD=1.39±0.30 μm and 1.75±0.63 μm, FPF=93.5±4% and 68.5±5%, (n=3). These values were consistent with those predicted in the designed experiment.Conclusions. A range of semisolid particle sizes were produced (1.3<MMAD<1.8 μm) for the 0.7%w/v gelatin formulation using different nebulizers. The budesonide formulation produced FPFs of 69–93%.

Factors affecting the deposition of aerosolized insulin.

The inhalation of insulin for absorption into the bloodstream via the lung seems to be a promising technique for the treatment of diabetes mellitus. A fundamental issue to be resolved in the development of such insulin aerosol delivery systems is their efficiency (measured, for example, in terms of the amount of insulin absorbed in the blood compared to the total amount loaded into an inhalation device). A primary factor that could cause inefficiency of insulin absorption is deposition in the nonalveolated airways with subsequent removal from the lung via mucociliary clearance. Thus, a better understanding of the spatial distribution of insulin particle deposition in the lung can give guidance to the optimization of inhalation therapy. A mathematical model was used to study factors affecting the disposition of aerosolized insulin. The model calculates the trajectories of inhaled particles in the lung and has been validated by data from human subject experiments. Computer simulations were performed describing a wide range of patient breathing maneuvers. The results indicate significant variations in particle deposition patterns within lungs for different tidal volumes, inspiratory flow rates, and breath hold times. These findings indicate that particle sizes and ventilatory parameters are significant factors determining locations of particle deposition within human lungs, and thus the absorption of insulin into the blood stream via alveloated airways. Mathematical modeling is a valuable technique to complement clinical studies in the targeted delivery of inhaled insulin.