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Background Aerosol and droplet production is inherent to dentistry. Potential for COVID-19 spread through aerosols and droplets characterizes dentistry as having a high risk of experiencing viral transmission, with necessity for aerosol and droplet mitigation. Methods Simulations of restorative treatment were completed on a dental manikin with a high-speed handpiece and high-volume evacuation suction. Variable experimental conditions with use of an extraoral vacuum suction at different distances from the simulated patient's mouth and different vacuum settings were tested to evaluate extraoral suction ability for droplet reduction. Results Using the extraoral suction unit during dental procedure simulations reduced droplet spatter at the dentist’s eye level, as well as the level of the simulated patient's mouth. When the extraoral suction unit was used at level 10 and 4 inches from the simulated patient's mouth, less spatter was detected. Conclusions Extraoral suction units are an effective method of reducing droplet spatter during operative dental procedures and can be useful in helping reduce risk of experiencing COVID-19 spread during dental procedures. Practical Implications During the pandemic, dentistry and its aerosol-generating procedures were placed on hold. The process to getting back to patient care is multifactorial, including personal protective equipment, patient screening, and mitigating aerosol spread.

Aerosols encompass a wide range of products and applications ranging from simple topical and toiletry products to inhaled therapeutics for chronic conditions to deliver potent medications for local and systemic actions. The various modes of delivery include pressurized metered-dose inhalers (pMDIs), nebulized systems, and dry-powder inhalation (DPI) systems as well as intranasally delivered products. This chapter gives an account of different aerosolized systems w.r.t. the components, formulation, manufacturing, and characterization. The patient (human) factors to be considered, namely, the patient–device interface, important for successful therapy, and outcomes are also included.

Electronic nicotine delivery systems (ENDS) are prefilled, battery-operated products intended to deliver nicotine to the user via an inhaled complex aerosol formed by heating a liquid composed of propylene glycol and glycerol, also referred to as vegetable glycerin and collectively called e-liquid, that contains nicotine and various flavor ingredients. Since their introduction in 2006, the number of ENDS on the market has increased exponentially. Despite their growing ubiquity, the possible health risks associated with ENDS use remain poorly understood. One potential concern is the presence of toxic metals in the e-liquid and aerosol. Herein, we report the evaluation of the metal content in the e-liquids from a series of commercially available cigalike ENDS brands (various flavors) determined using inductively coupled plasma mass spectrometry (ICP-MS) following e-liquid extraction. Each brand of cigalike ENDS was purchased at least three times at retail outlets in the Baltimore, Maryland metropolitan region over a period of six months (September 2017 to February 2018). This allowed for comparison of batch-to-batch variability. Several potentially toxic metals, including lead, chromium, copper, and nickel were detected in the e-liquids. In addition, high variability in metal concentrations within and between brands and flavors was observed . The internal assembled parts of each cartridge were analyzed by X-ray imaging, before dissembling so that the materials used to manufacture each cartridge could be evaluated to determine the metals they contained. Following washing to remove traces of e-liquid, lead, chromium, copper and nickel were all detected in the cigalike ENDS prefilled cartridges, suggesting one potential source for the metals found in the e-liquids. Collectively, these findings can inform further evaluation of product design and manufacturing processes, including quantification of metal concentrations in e-liquids over foreseeable storage times, safeguards against high concentrations of metals in the e-liquid before and after aerosolization (by contact with a metal heating coil), and control over batch-to-batch variability.

To systematically evaluate the effect of formulation- and administration-related variables on nasal spray deposition using a nasal cast. Deposition pattern was assessed by uniformly coating a transparent nose model with Sar-Gel®, which changes from white to purple on contact with water. Sprays were subsequently discharged into the cast, which was then digitally photographed. Images were quantified using Adobe® Photoshop. The effects of formulation viscosity (which influences droplet size), simulated administration techniques (head orientation, spray administration angle, spray nozzle insertion depth), spray pump design and metering volume on nasal deposition pattern were investigated. There was a significant decrease in the deposition area associated with sprays of increasing viscosity. This appeared to be mediated by an increase in droplet size and a narrowing of the spray plume. Administration techniques and nasal spray pump design also had a significant effect on the deposition pattern. This simple color-based method provides quantitative estimates of the effects that different formulation and administration variables may have on the nasal deposition area, and provides a rational basis on which manufacturers of nasal sprays can base their patient instructions or post approval changes when it is impractical to optimize these using a clinical study.

This March 2009 Workshop Summary Report was sponsored by Product Quality Research Institute (PQRI) based on a proposal by the Inhalation and Nasal Technology Focus Group (INTFG) of the American Association of Pharmaceutical Scientists (AAPS). Participants from the pharmaceutical industry, academia and regulatory bodies from the United States, Europe, India, and Brazil attended the workshop with the objective of presenting, reviewing, and discussing recommendations for demonstrating bioequivalence (BE) that may be considered in the development of orally inhaled drug products and regulatory guidances for new drug applications (NDAs), abbreviated NDAs (ANDAs), and postapproval changes. The workshop addressed areas related to in vitro approaches to demonstrating BE, biomarker strategies, imaging techniques, in vivo approaches to establishing local delivery equivalence and device design similarity. The workshop presented material that provided a baseline for the current understanding of orally inhaled drug products (OIPs) and identified gaps in knowledge and consensus that, if answered, might allow the design of a robust, streamlined method for the BE assessment of locally acting inhalation drugs. These included the following: (1) cascade impactor (CI) studies are not a good 2 predictor of the pulmonary dose; more detailed studies on in vitro/in vivo correlations (e.g., suitability of CI studies for assessing differences in the regional deposition) are needed; (2) there is a lack of consensus on the appropriate statistical methods for assessing in vitro results; (3) fully validated and standardized imaging methods, while capable of providing information on pulmonary dose and regional deposition, might not be applicable to the BE of inhaled products mainly due to the problems of having access to radiolabeled innovator product; (4) if alternatives to current methods for establishing local delivery BE of OIPs cannot be established, biomarkers (pharmacodynamic or clinical endpoints) with a sufficiently steep dose-response need to be identified and validated for all relevant drug classes; and (5) the utility of pharmacokinetic studies for evaluating "local pulmonary delivery" equivalence deserves more attention. A summary of action items for seminars and working groups to address these topics in the future is also presented.

To develop a simple and inexpensive method to visualize and quantify droplet deposition patterns. Deposition pattern was determined by uniformly coating the nose model with Sar-Gel® (a paste that changes from white to purple on contact with water) and subsequently discharging sprays into the nose model. The color change was captured using a digital camera and analyzed using Adobe® Photoshop. Several tests were conducted to validate the method. Deposition patterns of different nasal sprays (Ayr, Afrin, and Zicam) and different nasal drug delivery devices (Afrin nasal spray and PARI Sinustar nasal nebulizer) were compared. We also used the method to evaluate the effect of inhaled flow rate on nasal spray deposition. There was a significant difference in the deposition area for Ayr, Afrin, and Zicam. The deposition areas of Afrin nasal spray and PARI Sinustar nasal nebulizer (2 min and 5 min) were significantly different. Inhaled flow rate did not have a significant effect on the deposition pattern. Lower viscosity formulations (Ayr, Afrin) provided greater coverage than the higher viscosity formulation (Zicam). The nebulizer covered a greater surface area than the spray pump we evaluated. Aerosol deposition in the nose model was not affected by air flow conditions.

Objectives: This safety study of terameprocol (also called M4N, EM-1421) daily vaginal application in healthy women explores its potential application as a microbicide in interrupting human immunodeficiency virus sexual transmission and additional interruption of human papillomavirus and herpes simplex virus transmission. Methods: A double-blind placebo controlled phase I repeat dose tolerability and pharmacokinetic, crossover study of 90 mg terameprocol (2% w/w ointment) administered intravaginally for 7 consecutive days in healthy female subjects. The pharmacokinetics after administration was examined on days 1 and 7 of dosing. Subjects underwent vaginal examination following the 6-hour pharmacokinetic sample on day 7 of each study period. Results: Recruitment started January 2006 and ended May 2006, and 14 subjects completed the study. Median age was 24 years. No treatment-related serious adverse events were reported, and there were a total of 17 treatment-emergent adverse events (AE) reported by 11 participants. The most common AE was headache. Terameprocol was not detectable in serum in pharmacokinetic samples. Conclusions: Terameprocol was well tolerated at a 90 mg dose (2% wt/wt) administered vaginally daily for 7 days. No serious adverse events occurred and any AEs were mild. The excellent safety profile supports future clinical trial to evaluate the application of intravaginal terameprocol in women.

Objectives. Terameprocol (M4N, EM-1421) is a novel transcription inhibitor that selectively interferes with HPV viral genes E6/E7 with Sp1-dependent promoters, and induces apoptosis by inactivation of the CDC2/cyclin B complex (maturation promoting factor)and production and phosphorylation of survivin. This trial was designed to define the maximum tolerated dose (MTD), dose-limiting toxicity and determine the pharmacokinetic profiles of intravaginal terameprocol in women with HPV-linked cervical squamous intraepithelial neoplasia. Methods. An open label, dose escalation Phase I/II clinical trial enrolled women with biopsy confirmed CIN 1, 2 or 3. Terameprocol (45 or 90 mg) was physician-administered directly to the cervix uteri in 3 once weekly applications. The pharmacokinetics after administration were examined on Day 1 of dosing. Patients underwent colposcopic examinations, HPV testing, biomarker assessments, cytology and cervical punch biopsy. Results. Recruitment ended March 30, 2006 and 7 patients were enrolled. Median age was 24 years. There were no serious adverse events (SAEs) and possible treatment-related Adverse Events (AEs) reported were mild and self-limiting. There was no detectable absorption of terameprocol from the vaginal ointment application. Conclusions. Terameprocol in 1% and 2% vaginal ointment use in Phase I/II trials with women with HPV-linked cervical intraepithelial neoplasia has an excellent safety profile, no SAEs reported and mild, self-limiting treatment-related AEs. There was no detectable absorption of terameprocol. These data support the continued evaluation of terameprocol in in vitro and animal efficacy models followed by definitive human Phase II clinical trials in CIN.

This research investigated the impact of the full range of in vitro spray characterization tests described in the FDA Draft Bioequivalence Guidance on nasal deposition pattern, pharmacokinetics, and biological response to nicotine administered by two aqueous nasal spray pumps in human volunteers. Nicotine was selected as a model drug (even though it is not locally acting) based on its ability to alter cardiac function and available plasma assay. Significant differences in pump performance-including mean volume diameters, spray angle, spray width, and ovality ratios-were observed between the two pumps. There were no significant differences in deposition pattern, or pharmacokinetic or pharmacodynamic response to the nasally administered nicotine. Although there were statistical differences in the in vitro tests between the two pumps, these differences did not result in significant alterations in the site of droplet deposition within the nose, the rate and extent of nicotine absorption, or the physiologic response it induced. These results suggest that current measures of in vitro performance, particularly spray angle and spray pattern (ovality), may not be clinically relevant. Additional research is needed to define what spray pump characteristics are likely to produce differences in deposition pattern and drug response.

This study was conducted to evaluate the effect of formulation variables and breathing patterns on aerosol distribution in the nasal cavity. Placebo nasal spray formulations containing 0.25% w/v Avicel CL611 (viscosity = 4 cP) and 2% w/v methylcellulose (MC; viscosity = 18.2 cP) were radiolabeled with 99mTechnicium. Following spraying into a silicone nose model, through which air was drawn at one of three constant rates (0, 10, and 20 L/min) or one of two breathing profiles (representing fast and slow inhalations), aerosol deposition in the model was quantified by gamma scintigraphy. Regional deposition was expressed as horizontal[inner, middle (h), outer] and vertical distribution [upper, middle (v), lower] in the nose model. Compared to 2% MC, Avicel CL611 significantly increased aerosol deposition in the middle (h) region of the nasal cavity under all breathing conditions, and in the inner region at 0 and 20 L/min and with a slow inhalation. The different breathing rates showed no effect on deposition of 2% MC. However, 10 L/min significantly increased the upper deposition of Avicel compared to 0 and 20 L/min. Nasal sprays with a low viscosity provided greater surface coverage of the nasal mucosa than higher viscosity formulations. Changes in breathing profiles did not affect aerosol deposition in this nose model.

Purpose. To correlate the surface energy of active and carrier components in an aerosol powder to in vitro performance of a passive dry powder inhaler.

Purpose. To determine whether deposition pattern is related to in vitromeasurements of droplet size, plume geometry, and spray pattern between two different nasal spray pumps believed to have different performance characteristics.

Study objective: To determine if aerosolizedmedications can be targeted to deposit in the smaller, peripheralairways or the larger, central airways of adult cystic fibrosis (CF)patients by varying particle size and inspiratory flow rate. Design: Randomized clinical trial. Setting: Outpatient research laboratory. Patients: Nine adult patients with CF. Interventions: Patients inhaled an aerosol comprised of3.68 ± 0.04 μm saline solution droplets (two visits) or1.01 ± 0.2 μm saline solution droplets (two visits) for 30 s, starting from functional residual capacity and breathing at a slow orfaster inspiratory flow rate. On all visits, the saline solution wasadmixed with the radioisotope 99m Tc. Immediately afterinhalation, a gamma camera recorded the deposition pattern of theradioaerosol in the lungs. Deposition images were analyzed in terms of the inner:outer zone (I: O) ratio, a measure of deposition in an innerzone (large, central airways) vs an outer zone (small airways andalveoli). Measurements and results: For the 3.68-μmaerosol, I: O ratios averaged 2.29 ± 1.45 and 2.54 ± 1.48(p > 0.05), indicating that aerosol distribution within the lungswas unchanged while breathing at 12 ± 2 L/min vs 31 ± 5 L/min, respectively. For the 1.01-μm aerosol, I: O ratios averaged2.09 ± 0.96 and 3.19 ± 1.95 (p Conclusions: These resultssuggest that the targeted delivery of an aerosol to the smaller, peripheral airways or the larger, central airways of adult CF patientsmay be achieved by generating an aerosol comprised of approximately1.0-μm particles and inspiring from functional residual capacity atapproximately 18 L/min and ∼ 38 L/min, respectively.

Secretion of mucins from airway epithelial cells has been studied almost exclusively using in vitro cell culture systems. Our understanding of in vivo secretion is greatly limited due to the unavailability of both suitable model systems and adequate assays. It has been reported that ATP induces mucin release from the cultured primary tracheal surface epithelial cell, but there is no clear demonstration of the effect of ATP on mucin release in vivo, which is important to understand the mechanism of mucin release in vivo and also to devise means for regulation of mucin release. The objective of this experiment was to see if inhaled ATP could stimulate airway mucin release in intact rats using both enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. The results were: (1) a new monoclonal antibody (mAbRT03) developed against purified rat mucins specifically recognized high-molecular-mass mucins; (2) ELISA results with conventional gel-filtration assay results are virtually superimposable; (3) inhalation of ATP in intact rats resulted in a dose-independent increase in the amount of mucins in the tracheal lavage fluid with a concomitant decrease in the number of mucin-positive cells in the trachea. We conclude that extracellular ATP can stimulate mucin release from the airway in vivo, and the present rat inhalation system combined with ELISA of the airway secretions should serve a useful model for studying the pharmacology of airway mucin secretion in vivo.

Background: Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. Objective: We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. Methods: Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at ~30 L/min or ~70 L/min. Percent decreases in FEV 1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. Results: Mean (± SD) allergen-induced decrease in FEV 1 was 5.4% ± 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV 1 after faster inhalation of CS with 12.6% ± 11% ( p 1 and skew values for the two breathing maneuvers were significantly correlated. Conclusion: These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.

To determine if patient-related variability for adults and children recorded during hand spraying of Flonase with an instrumented nasal spray results in significant differences in spray weight, droplet size or spray pattern.Settings derived from adult and pediatric participants hand-spraying nasal sprays were implemented into force and velocity-controlled automated actuators. Spray weight, droplet size distribution and spray pattern tests were performed using iterations of actuation force (AF) and force rise, hold and fall times. Travel, actuation velocity and release velocity settings were also investigated.The variability measured in adult-derived actuator settings did not result in any differences in spray weight, but pediatric participants spraying with low AF and/or compression velocity (CV) were predicted to receive a partial dose or no dose at all under some circumstances. Droplet size characteristics were sensitive to the hand-based variability, with actuation force, force rise time and CV hand-related settings all resulting in significant differences in the droplet size.This study demonstrated how variability in hand spraying by adults and pediatric patients could result in differences in nasal spray characteristics, thus demonstrating the importance of monitoring how the prospective patient groups are likely to use a nasal spray.

Dry powder aerosol performance of albuterol and albuterol sulfate from a model dry powder inhaler (DPI) was studied under varying environmental conditions using a twin stage impinger (TSI). Pure micronized drug was metered into the DPI and the loaded inhaler inserted into the inlet of the TSI housed in a pre-equilibrated environmental chamber. After 3 min, the drug was aerosolized at 60 1/min for 20 s. Washings from the DPI and TSI were analyzed by UV spectroscopy. Temperature and relative humidity (RH) were varied (20, 30 and 45°C; 30–95% RH). Drug collected in stage 2 of the TSI was expressed as fine particle dose or fine particle percent of either the loaded dose or the amount emitted from the mouthpiece of the DPI. These values decreased with increasing relative humidity for both albuterol and albuterol sulfate at any given temperature with differences being more marked at higher temperatures. For example, at 30°C, the mean(experimental range) fine particle percent of the emitted dose of albuterol sulfate was 59.4(3.1) and 35.8(5.7)% at 43 and 85% RH, respectively, n = 3 (p < 0.05). Increasing temperature also resulted in diminished aerosol performance. These differences were more marked for albuterol sulfate. The fine particle percent of the emitted dose of albuterol base was always greater than that of albuterol sulfate under similar environmental conditions. The reverse was true when fine particle percents of the loaded dose were considered because only 32 +- 6.6% of the loaded albuterol was emitted from the inhaler as compared to 58.5 +- 6.3% of albuterol sulfate mean +- SD, n = 27). There is a need, in some circumstances, to define specific ranges of temperature and humidity for the testing of dry powder aerosols.

Deposition and clearance studies are used during product development and in fundamental research. These studies mostly involve radionuclide imaging, but pharmacokinetic methods are also used to assess the amount of drug absorbed through the lungs, which is closely related to lung deposition. Radionuclide imaging may be two-dimensional (gamma scintigraphy or planar imaging), or three-dimensional (single photon emission computed tomography and positron emission tomography). In October 2009, a group of scientists met at the "Thousand Years of Pharmaceutical Aerosols" conference in Reykjavik, Iceland, to discuss future research in key areas of pulmonary drug delivery. This article reports the session on "Deposition, imaging and clearance." The objective was partly to review our current understanding, but more importantly to assess "what remains to be done?" A need to standardize methodology and provide a regulatory framework by which data from radionuclide imaging methods could be compared between centers and used in the drug approval process was recognized. There is also a requirement for novel radiolabeling methods that are more representative of production processes for dry powder inhalers and pressurized metered dose inhalers. A need was identified for studies to aid our understanding of the relationship between clinical effects and regional deposition patterns of inhaled drugs. A robust methodology to assess clearance from small conducting airways should be developed, as a potential biomarker for therapies in cystic fibrosis and other diseases. The mechanisms by which inhaled nanoparticles are removed from the lungs, and the factors on which their removal depends, require further investigation. Last, and by no means least, we need a better understanding of patient-related factors, including how to reduce the variability in pulmonary drug delivery, in order to improve the precision of deposition and clearance measurements.

To determine and compare patient-relevant settings for automated nasal spray actuation stations from adult and pediatric hand data.Twenty adults and 20 pediatric participants were asked to spray Flonase(®) Nasal Spray six times in a Hand Actuation Monitor, which records force and displacement data in 5-ms increments. Settings for force- and velocity-controlled actuation stations were determined from the data using a predefined set of calculations.For force-controlled settings, hand spraying by children resulted in lower actuation forces, and longer force rise, hold and fall times. Pediatric velocity-controlled actuator settings were lower for travel, compression velocity, and release velocity compared with adults. The pediatric spray weight recorded during hand spraying was significantly lower than the spray weight generated by adult participants. Adult participants were able to generate full sprays with each attempt, whereas 11 out of 120 actuations performed by pediatric participants resulted in partial and 'no spray' events. No differences in spray weight were detected in participants who chose to actuate the nasal spray using both hands.A predefined set of calculations was used to determine patient-relevant settings from force and displacement hand data for force- and velocity-controlled automated actuation stations. This study determined and quantified, for the first time, the differences in hand spraying between adults and children.

The objective of this investigation was to develop an inexpensive and uncomplicated color-based method to rapidly assess undesirable facial and ocular deposition of aerosolized droplets on the surface of a 3D rigid replica of a 4-year-old child's face.Sar-Gel(®), which changes color on contact with water, was evenly coated on the face model through which air was drawn using two breathing patterns (representing moderate and shallow inhalations) or a constant rate of 0, 10, and 20 L/min. A standard and two proprietary (one shaped to resemble a fish face, the other shaped to resemble a dragon face) pediatric facemasks were evaluated. A nebulizer was charged with 3 mL of normal saline before connection to the facemask. The mask was held in contact with the face using 300 g-F determined by instrumenting the mounting strap using a force gauge. The nebulizer was operated for 5 minutes. The region of color change was captured using a digital camera and analyzed using Adobe(®) Photoshop.Facial and ocular deposition with all the facemasks was affected by breathing pattern. Compared to the standard and dragon masks, the fish mask resulted in significantly reduced facial and ocular deposition at all breathing patterns.This simple screening method allows quantification of droplet deposition outside the facemask and may be a useful tool for designing masks that result in reduced facial and ocular deposition.

Left to right: Badrul Chowdhury (US FDA), John Hall (Quintiles and John Hall Consulting Limited), Gaetano Brambrilla (Chiesi Farmaceutici), Richard Ahrens (University of Iowa), Caroline Vanneste (H...

Several potential replacements for chlorofluorocarbons (CFCs) in metered-dose inhalers (MDIs) are flammable. The flammability hazard associated with their use was assessed using a range of MDIs containing 0–100% (w/w) n-butane (flammable) in HFC-134a (nonflammable) fitted with either 25-, 63-, or 100-µl metering valves or continuous valves. In flame projection tests each MDI was fired horizontally into a flame, and the ignited flume length emitted from the MDI was measured. Flame projections of ≥60 cm were produced by all formulations fitted with continuous valves which contained ≥40% (w/w) n-butane in HFC-134a. Using metering valves the maximum flame projection obtained was 30 cm. This was observed with a formulation containing 90% (w/w) n-butane in HFC-134a and a 100-µl valve. For a particular formulation, smaller metering valves produced shorter flame projections. Because many MDIs are used in conjunction with extension devices, the likelihood of accidental propellant vapor ignition was determined in Nebuhaler and Inspirease reservoirs and a Breathancer spacer. Ignition was predictable based on propellant composition, metered volume, number of actuations, and spacer capacity. Calculated n-butane concentrations in excess of the lower flammability limit [LFL; 1.9% (v/v)] but below the upper flammability limit [UFL; 8.5% (v/v)] were usually predictive of flammability following ignition by a glowing nichrome wire mounted inside the extension device. No ignition was predicted or observed following one or two 25-µl actuations of 100% n-butane into large volume Nebuhaler (750 ml) or Inspirease (660 ml) devices. Additionally, several other formulations containing lower proportions of n-butane also remained nonflammable, due to failure to reach the LFL. In the small-volume Breathancer spacer (140 ml), nonflammability was usually due to n-butane exceeding its UFL. In this situation further dilution during respiration could result in a flammable mixture. Using a carefully selected propellant blend, metering volume, and spacer design, environmentally acceptable flammable propellants may have considerable utility in MDIs reformulated without CFCs.

Nasal spray performance attributes are related to the formulation, device, and patient, with the delivery of precise doses with minimal waste being key goals during product development, especially for potent and high cost drugs.We investigated the influence of replacing the traditional rigid dip tube with a weighted, flexible dip tube on spray weight and tail-off characteristics in five over-the-counter nasal sprays representing varying viscosities, metering chamber volumes, formulation volumes, and active ingredients. Nasal sprays were actuated in ways representative of patient use.Compared to inherently curved, rigid dip tubes that were actuated in their worst case orientation, we found that weighted, flexible dip tubes (that seek the lowest point in the bottle irrespective of orientation) significantly increase the number of full sprays (in four out of five products) and reduce the duration of the tail-off period (in three out of five products). Shaking significantly decreased the spray weight in Afrin, Rite Aid, and Zicam nasal sprays using the original rigid dip tubes, and Afrin, Nostrilla, and Rite Aid when flexible dip tubes were used.This study demonstrated that flexible dip tubes can improve the performance of many nasal sprays, and that shaking may have negative effects on spray weight uniformity.

Amount of drug actually reaching the target region in the lung following pulmonary inhalation is often estimated at less than 10% for older devices. Current particle and device engineering technologies have improved on this but still fail to recover the "wasted" fraction of the drug and deliver it deeper into the lungs, which is generally desirable. FDA has approved several exogenous surfactants for prophylaxis and rescue treatment of respiratory distress syndrome (RDS). Their approved mode of administration (intratracheal instillation) and site of action (alveolar spaces) suggest that the phospholipids in the exogenous surfactants can spread from the trachea to alveolar air spaces and exert advantageous effects. We investigated whether in vivo lung migration of particles based on this phenomenon was possible and could be quantified based on changes in total and regional deposition of fluorescently labeled latex beads, utilized as an insoluble drug model. Following intranasal administration of beads, migration to rodent lungs was monitored upon intranasal instillation of Survanta (exogenous surfactant) or saline (control). After intranasal instillation approximately 12% of beads were found to migrate to the lung, and total lung deposition increased by approximately 10% on administration of Survanta or saline (control). After intranasal administration approximately 1% of beads in the lung were found to migrate to peripheral regions of the lungs, and a four- to six-fold increase in peripheral lung deposition was observed after Survanta instillation, compared to the saline control, which was determined to be independent of dose and volume of Survanta instillate in the range we studied. The in vivo rodent studies provided support for the idea that intranasally administered particles deposited in non-target lung locations may be translocated to peripheral sites in the lung therapeutically after surfactant application.

The studies described in this paper were undertaken to develop a method for the quick analysis and prediction of robustness of inhaler devices, and to define a standard among inhaler devices against which the structural integrity of new innovations could be judged. In addition, an effort was made to correlate mechanical properties with product performance metrics. The effect of mechanical stresses, alone and in combination with elevated temperatures, on the in vitro performance of pressurized metered dose inhalers (pMDIs) was investigated. The innovator pMDI devices (Ventolin HFA, GlaxoSmithKline) tested proved to be functionally robust in response to extreme mechanical stresses, suggesting that they are appropriate standards on which acceptance criteria for new devices should be defined. The actuator seat where the valve stem is inserted was identified as the critical area of the pMDI. A comparison of innovator vs. generic albuterol MDIs revealed that generic products approved as "equivalent " to the innovator products by current standards are not necessarily equivalent in ruggedness. Finite-element models of the actuator seat of Ventolin HFA (polypropylene) and QVAR 40 (high-density polyethylene) (3M Healthcare Ltd.) capable of predicting mechanical failure of MDIs were established. The material properties as well as the actuator design influenced the operational limit of MDIs. Stress analysis using finite-element modeling could be effectively used for the selection of the optimal design and appropriate materials of construction, which could lead to the development of robust inhalers while shortening the product development cycle.

The last decade has seen developments in all categories of inhaler device. However, the underlying principles of aerosol delivery have changed little.Despite the numerous designs and configurations that may be employed to generate aerosols in therapeutically useful size ranges and concentrations (Chapters 9-11 and 14), there are only three basic categories of aerosol delivery systems for commercially marketed drug products. These are pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), and nebulizers. These three classes of devices do not represent optimal delivery systems in terms of their ability to produce monodisperse aerosols that can be precisely dosed in a single breath but rather are examples of delivery systems that achieve minimally acceptable characteristics in a simple, convenient, inexpensive, and portable format. To be acceptable for clinical use, an inhalation delivery system must meet certain criteria:1. It must generate an aerosol with most of the drug carrying particles less than 10m in size and ideally in the range 0.5-5m, the exact size depending on the intended application.

We hypothesized that aerosol distribution in the lungs of patients with cystic fibrosis changes with positive expiratory pressure (PEP).Eight patients were randomized to one of 2 conditions. On one study day, patients inhaled saline aerosol containing 99mtechnetium generated by a Pari LC Plus nebulizer and exhaled through a Pari PEP device. On another day, the same patients exhaled through a low-resistance Pari filter (no PEP). Afterwards, they underwent gamma-camera lung imaging. Images were analyzed for lung deposition fraction, expressed as a percent of the initial nebulizer activity, and deposition pattern, expressed in terms of inner-outer and apical-basal ratios.Lung deposition fraction was significantly lower with the Pari PEP device; the mean + SD deposition fraction was 6.10 + 3.05% (median 6.20%) with PEP, compared to 10.76 + 4.52% (median 10.32%) (p = 0.0078) without PEP. The inner-outer ratio was 2.01 + 0.69 (median 2.23) with PEP, which was significantly lower than without PEP (2.76 + 1.33, median 2.55) (p = 0.004). The apical-basal ratio was 0.82 + 0.31 (median 0.80) with PEP, which was not significantly different from no PEP (1.00 + 0.49, median 0.90).These results indicate that less aerosol is deposited in the lungs of patients with cystic fibrosis when the Pari LC Plus nebulizer is used with the Pari PEP device, as described in these experiments. Nevertheless, aerosol administration with this nebulizer and PEP device also results in a proportional redistribution of aerosol to the peripheral airways, compared to nebulization without the PEP device. The clinical relevance of this subtle redistribution of aerosol in cystic fibrosis patients will probably depend on the drug administered and disease severity.

Drugs are given intranasally for both local and systemic applications, and the use of the intranasal route is predicted to rise dramatically in the next 10 years. Nasal drug delivery may be assessed by a variety of means, but high reliance is often placed upon in vitro testing methodology (emitted dose, droplet or particle size distribution, spray pattern, and plume geometry). Spray pattern and plume geometry define the shape of the expanding aerosol cloud, while droplet size determines the likelihood of deposition within the nasal cavity by inertial impaction. Current FDA guidance recommends these methods as a means of documenting bioavailability (BA) and bioequivalence (BE) for topically acting solution formulations, because they can be performed reproducibly and are more discriminating among products. Nasal drug delivery in vivo may be determined by several radionuclide imaging methods: the two-dimensional imaging technique of gamma scintigraphy has been used most widely, but the three-dimensional method of positron emission tomography (PET) is being used increasingly often. In some situations a good in vitro/in vivo correlation (IVIVC) exists; for instance, negligible penetration into the lungs has been demonstrated in the case of nasal pump sprays delivering large droplets, while a clear difference may be shown in intranasal deposition between two aerosols with markedly different size distributions. However, recent studies have shown a poorer IVIVC for two similar nasal pump sprays, where significant differences in in vitro parameters were not reflected in differences in nasal deposition in vivo. It is suggested that radionuclide imaging data may have an important role to play as an adjunct to in vitro testing in BA and BE assessments and may provide a clearer understanding of the changes in in vitro parameters that are important for predicting differences in in vivo performance.

The humble origins of the propellant driven metered dose inhaler, as a response to a child's enquiry, initiated an industry which supplies approximately a half billion inhalers globally for the treatment of asthma. These inhalers fall into three major groups: nebulizers; propellant driven metered dose inhalers and dry powder inhalers. Each requires drug formulation, metering and device technology to be successful. In recent years there have been several new developments in the field including auxiliary systems to improve drug delivery from the device to the patient and new categories of device, notably single breath aqueous systems. As device technology improves and our understanding of the disease leads to new drugs the only barrier to therapy is the patient. Patient training and compliance will continue to be important factors in the success, or failure, of inhaled therapy and the role of health care professionals will depend on who sponsors their intervention.

Metered-dose inhalers (MDIs) are an effective means of generating drug-containing aerosols targeted for delivery to intrapulmonary airways. Many problems associated with incorrect patient use of MDIs are mitigated by adding a valved spacer device to the inhaler mouthpiece. This in vitro study compared the efficiency of drug output through a new spacer device, OptiChamber (HealthScan Products Inc., Cedar Grove, NJ), to that of a device commercially available since the 1980s, AeroChamber (Monaghan Medical, Plattsburgh, NY). Testing utilized MDI formulations of albuterol, beclomethasone dipropionate, and cromolyn sodium. OptiChamber equaled or, in the majority of cases, exceeded AeroChamber in output of the three drugs at two simulated inspiratory flow rates. Drug output from OptiChamber was found to be less sensitive to changes in flow rate than that from AeroChamber. OptiChamber also showed less decrease in drug output than AeroChamber when time delays were introduced between MDI actuation and the start of a simulated inhalation. Mass median aerodynamic diameters of drugs exiting the two spacers were generally similar to those of drugs exiting the MDI alone. However, spacers were shown to nearly eliminate the output of large-size drug particles (>5.8 microm), which can result in oropharyngeal drug deposition. Emitted fine-particle drug (

Recent advances in structural elucidation of numerous natural peptides and proteins1, enhanced understanding of their role in several physiological processes, and the use of biotechnological techniques for their production have stimulated considerable interest in establishing peptides and proteins as therapeutic agents. A major problem, aside from proteolytic degradation and physical alteration of the protein molecule at the site of administration, is the slow rate of transport of macromolecules across membrane barriers into the systemic circulation.

The possibility of producing slowly dissolving albuterol salts was investigated as a potential means of extending the duration of action of the drug following aerosol delivery to the lung. Albuterol adipate and stearate were precipitated from alcoholic solutions of albuterol and adipic or stearic acids, respectively. Differential scanning calorimetry and hot stage microscopy showed that albuterol adipate and stearate produced single melting endotherms at 182 and 116 degrees C, respectively, which were distinct from those of albuterol (158 degrees C), adipic acid (152 degrees C), and stearic acid (70 degrees C). The aqueous solubilities of albuterol free base, sulfate, adipate, and stearate were 15.7, 250, 353, and 0.6 mg . mL-1, respectively, at room temperature. Only the solubilities of the adipate and the stearate increased significantly when the temperature was elevated to 37 degrees C (452.5 and 1.4 mg . mL-1, respectively). With a rotating disk dissolution method, albuterol free base, sulfate, and adipate were found to have intrinsic dissolution rates of 1.1, 20.4, and 24.0 mg . min-1 . cm-2, respectively, in pH 7.4 phosphate buffer at 37 degrees C. Albuterol stearate dissolved much more slowly and in a nonlinear fashion; this was explained by the deposition of a stearate-rich layer on the dissolving surface of the compacted salt.

Drugs are given intranasally for both local and systemic applications, and the use of the intranasal route is predicted to rise dramatically in the next 10 years. Nasal drug delivery may be assessed by a variety of means, but high reliance is often placed upon in vitro testing methodology (emitted dose, droplet or particle size distribution, spray pattern, and plume geometry). Spray pattern and plume geometry define the shape of the expanding aerosol cloud, while droplet size determines the likelihood of deposition within the nasal cavity by inertial impaction. Current FDA guidance recommends these methods as a means of documenting bioavailability (BA) and bioequivalence (BE) for topically acting solution formulations, because they can be performed reproducibly and are more discriminating among products. Nasal drug delivery in vivo may be determined by several radionuclide imaging methods: the two-dimensional imaging technique of gamma scintigraphy has been used most widely, but the three-dimensional method of positron emission tomography (PET) is being used increasingly often. In some situations a good in vitro/in vivo correlation (IVIVC) exists; for instance, negligible penetration into the lungs has been demonstrated in the case of nasal pump sprays delivering large droplets, while a clear difference may be shown in intranasal deposition between two aerosols with markedly different size distributions. However, recent studies have shown a poorer IVIVC for two similar nasal pump sprays, where significant differences in in vitro parameters were not reflected in differences in nasal deposition in vivo. It is suggested that radionuclide imaging data may have an important role to play as an adjunct to in vitro testing in BA and BE assessments and may provide a clearer understanding of the changes in in vitro parameters that are important for predicting differences in in vivo performance.

Baffles contained in conventional actuators may be a convenient alternative to some of the extension devices used presently with metered-dose inhalers (MDIs). Actuators were modified to determine whether baffles could be used to decrease the output of large “nonrespirable” droplets. These actuators were tested using a series of nonaqueous suspension aerosols containing 0.1 to 2.0% micronized disodium fluorescein (DF) as the model drug, stabilized by sorbitan trioleate in a constant blend of fluorocarbons 11, 12, and 114. A 25-µl metering volume was used throughout. Aerosol output was characterized by cascade impaction. Baffle size and position had pronounced effects on actuator retention and aerosol output. Increasing baffle size resulted in increased retention in the actuator. The total output of the MDI in the “respirable” range (aerodynamic diameter, Dae