Can extraoral suction units minimize droplet spatter during a simulated dental procedure?

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.

Cigalike electronic nicotine delivery systems e-liquids contain variable levels of metals.

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.

Clinical implications of the tiotropium/olodaterol inhaler for patients with chronic obstructive pulmonary disease.

Oral inhalation is the recommended delivery method of medications for the treatment of patients with chronic obstructive pulmonary disease (COPD). However, patients may struggle when using the various available inhaler platforms, and, as a result, may fail to achieve the benefit of the prescribed medication. Propellant-based, pressurized metered-dose inhaler and powder-based, dry powder inhaler devices are currently the most commonly prescribed delivery systems. Each of these devices has its own advantages and challenges. The Respimat® Soft Mist™ inhaler (SMI) (Boehringer Ingelheim) is a delivery system that incorporates features intended to improve orally inhaled drug delivery to these patients. These features include simple device actuation, patient inspiratory effort-independent aerosol generation, and a slower spray emission with a longer spray duration, helping to mitigate issues with precise aerosol release and breath coordination. We review the clinical trials assessing lung deposition, efficacy, and safety, and patient satisfaction for the Respimat® SMI. These data indicate that the Respimat® SMI is a device capable of delivering a consistent, clinically effective dose of medication that patients can use and prefer, which may provide significant clinical benefits for patients with COPD.

Automated actuation of nasal spray products: effect of hand-related variability on the in vitro performance of Flonase nasal spray.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Effect of formulation- and administration-related variables on deposition pattern of nasal spray pumps evaluated using a nasal cast.

PURPOSE: To systematically evaluate the effect of formulation- and administration-related variables on nasal spray deposition using a nasal cast. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Automated actuation of nasal spray products: determination and comparison of adult and pediatric settings.

OBJECTIVE: To determine and compare patient-relevant settings for automated nasal spray actuation stations from adult and pediatric hand data. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Development of Respimat(®) Soft Mist™ Inhaler and its clinical utility in respiratory disorders.

The Respimat(®) Soft Mist™ Inhaler (SMI) (Boehringer Ingelheim International GmbH, Ingelheim, Germany) was developed in response to the need for a pocket-sized device that can generate a single-breath, inhalable aerosol from a drug solution using a patient-independent, reproducible, and environmentally friendly energy supply. This paper describes the design and evolution of this innovative device from a laboratory concept model and the challenges that were overcome during its development and scaleup to mass production. A key technical breakthrough was the uniblock, a component combining filters and nozzles and made of silicon and glass, through which drug solution is forced using mechanical power. This allows two converging jets of solution to collide at a controlled angle, generating a fine aerosol of inhalable droplets. The mechanical energy comes from a spring which is tensioned by twisting the base of the device before use. Additional features of the Respimat(®) SMI include a dose indicator and a lockout mechanism to avoid the problems of tailing-off of dose size seen with pressurized metered dose inhalers. The Respimat(®) SMI aerosol cloud has a unique range of technical properties. The high fine particle fraction allied with the low velocity and long generation time of the aerosol translate into a higher fraction of the emitted dose being deposited in the lungs compared with aerosols from pressurized metered dose inhalers and dry powder inhalers. These advantages are realized in clinical trials in adults and children with obstructive lung diseases, which have shown that the efficacy and safety of a pressurized metered dose inhaler formulation of a combination bronchodilator can be matched by a Respimat(®) SMI formulation containing only one half or one quarter of the dose delivered by a pressurized metered dose inhaler. Patient satisfaction with the Respimat(®) SMI is high, and the long duration of the spray is of potential benefit to patients who have difficulty in coordinating inhalation with drug release.

Assessment of facial and ocular deposition of nebulized aerosol using a color-based method.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Use of flexible weighted nasal spray dip tubes to improve product performance.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Assessment of nasal spray deposition pattern in a silicone human nose model using a color-based method.

PURPOSE: To develop a simple and inexpensive method to visualize and quantify droplet deposition patterns. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Phospholipid-induced in vivo particle migration to enhance pulmonary deposition.

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 analysis and prediction of functional robustness of inhaler devices.

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.

Positive expiratory pressure changes aerosol distribution in patients with cystic fibrosis.

HYPOTHESIS: We hypothesized that aerosol distribution in the lungs of patients with cystic fibrosis changes with positive expiratory pressure (PEP). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Drug delivery to the nasal cavity: in vitro and in vivo assessment.

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.

Allergen challenge and deposition of nedocromil sodium in asthma.

We examined whether the acute protective effect of nedocromil sodium aerosol could be enhanced by increasing the deposition uniformity of the drug in the lungs of adult patients with allergic asthma. Ten patients with mild-to-moderate asthma were challenged with the same doses of allergen on two occasions in a randomized manner. Thirty minutes before these challenges, patients inhaled 4 mg nedocromil sodium, admixed with the radioisotope (99m)technetium. Radiolabeled drug was inhaled during slow (25.4 +/- 4.6 L/min) and faster (58.0 +/- 7.3 L/min) inhalations from a 700 ml holding chamber. Percent changes in FEV(1) at the same top dose of allergen on the two treatment visits were compared. Lung deposition fraction (LDF) and indices of distribution uniformity, quantified from gamma camera images, were also compared. Acute protection against allergen challenge was similar and complete after slow or faster inspiration of nedocromil sodium. Mean (+/- SD) allergen-induced changes in FEV(1) were -1.05 +/- 2.78% and -0.39 +/- 2.80%, respectively, compared to -26.30 +/- 8.49% on a screening challenge (no drug). Mean LDF was also similar on the two visits, averaging 16.4 +/- 4.6% and 16.1 +/- 7.2% of administered drug, respectively. Distribution of nedocromil sodium was most uniform after slow inspiration, but increased uniformity was not related to enhanced protection. Complete protection against acute bronchoconstriction induced by inhaled allergen can be obtained with 4 mg of nedocromil sodium aerosol, inhaled from a large volume holding chamber, 30 min before the exposure, and at inspiratory flow rates between approximately 20-60 L/min. Protection does not appear to be enhanced by increased uniformity of drug distribution within the lungs.