• Assessment of Bioequivalence in Nasal Sprays Containing Suspension Formulations

      Jin, Feiyan; Dalby, Richard N. (2010)
      FDA's draft guidance "Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (2003)" recommends that the bioequivalence (BE) of nasal suspension products should be established not only by a battery of in vitro tests but also clinical studies. However, locally acting solutions do not necessitate a clinical comparison. The different requirements for nasal solution and suspension formulations are based on the assumptions that in vitro studies are more sensitive indicators of drug delivery to nasal cavity than are clinical studies, and that the drug particle size distributions (PSDs) in suspension formulations may potentially affect the rate and extent of drug availability to nasal sites of action and to the systemic circulation. So the difficulty in establishing the BE of nasal spray suspension products through expensive clinical trials have become a long-standing challenge for the generic pharmaceutical industry and subsequently few generic nasal suspension products have been approved compared to the nasal solutions. Whether the sizes and shapes of primary drug particles in nasal suspensions influence drug absorption in local nasal passage was investigated in this project through 1) In vitro tests including viscosity measurement, spray weight testing, droplet size distribution characterization, spray pattern and plume geometry studies; 2) In vitro drug absorption studies such as drug uptake and transport in a human bronchial epithelium cell line Calu-3 cells, and dissolution tests in beakers and the USP apparatus II with a sensitive and robust LC/MS/MS assay method; 3) In vitro anti-inflammatory activity evaluation using necrosis factor κB reporter plasmids and nitrite measurement. Results showed that the sizes of primary drug particles in the small range with Dv50s of 2.13-3.35 µm did not influence the in vitro performances of nasal suspension formulations. Smaller particles (Dv50=1.58 µm) and spherical particles (Dv50=3.87 µm) exhibited slightly higher or lower dissolution rate differences which was nevertheless not reflected in the in vitro characterization tests, drug uptake, transport and in vitro efficacy studies. This project suggested that nasal suspension spray products containing primary drug particles with different sizes and shapes in the relevant range may not affect the drug absorption and in vivo BE studies may potentially be waived once the drug particle size and shape design space is defined.
    • Development of a Novel Color Based Method for Assessing Deposition Patterns of Nasal Sprays and Nebulized Aerosols

      Kundoor, Vipra; Dalby, Richard N. (2010)
      Aqueous nasal sprays are widely used to treat patients with local diseases such as allergic rhinitis. Several nasally administered corticosteroid products are nearing patent expiration and are candidates for generic copies, which is driving interest in how bioequivalence will be established - possibly using clinical and scintigraphic methods, but these methods each have specific limitations, as does the existing practice of measuring spray pattern and plume geometry which have proven difficult to correlate with nasal deposition. To overcome these limitations this thesis focused on designing a simple and inexpensive method that allows simulation of nasal anatomy and airflow, and is able to visualize and quantify deposition patterns of nasal sprays. Initially, we used the method to compare deposition patterns of different nasal sprays and different nasal drug delivery devices. Results showed that lower viscosity formulations provided greater coverage than the higher viscosity formulation and the nebulizer covered a greater surface area than the spray pump we evaluated. We also systematically investigated the effect of various formulation and patient related factors, and inspiratory flow rate on nasal deposition pattern and the results obtained showed that inspiratory flow rate did not have a significant effect whereas formulation and patient related factors had a significant effect on deposition pattern. Since bioequivalence of nasal sprays is carried out using in vitro studies, we compared the method to laser based systems which are used to measure spray pattern and plume geometry and we found that both the methods yielded similar results. We also evaluated the use of the method on cascade impactor stages (to detect droplet deposition) and on model faces fitted with facemasks (to quantify unintended facial and ocular droplet deposition associated with nebulizer use). It revealed that impactor temperature does have an effect on the size of nebulized droplets and facemask design had a significant effect on unintended facial and ocular deposition of nebulized droplets. This thesis demonstrates that this approach can be used as an alternative tool to justifiably establish in vitro bioequivalence of nasally administered, locally acting drug solutions and also provide a scientific rationale for justifying patient instructions for use.
    • Development of a patient inhalation training tool and use of simulated inhalations to study dry powder inhaler performance realistically in vitro

      Li, Zhili; Dalby, Richard N. (2002)
      Patients find metered dose inhalers difficult to use correctly. A computerized training tool to detect and immediately respond to common problems, such as, inadequate coordination between inhalation and actuation, was developed. Pressure, force and acceleration transducers mounted on a placebo MDI, and a C program written to acquire these signals, was used to deliver situation-specific, real time feed back on the performance of five volunteers. A computer interface provided pop-up instructions in response to the volunteer's inhalation profile, actuation force, shaking intensity and their temporal relationship. Improvements in technique were realized, and the system proved capable of recording inspiratory profile parameters. A method of reproducing recorded inhalation profiles was validated, and applied to in vitro testing of a Rotahaler dry powder inhaler. The performance of passive DPIs is known to be dependent on inhalation profile, but clinical studies have little power to discriminate the influence of specific breathing patterns on lung deposition. An electronic valve and computerized control system were used to generate a series of simulated inhalation profiles. Four liters of air, at a peak flow rate of 30, 60 or 100 L/min, was drawn through a preloaded Rotahaler. Peak flow was achieved instantaneously (USP method) or linearly approached over 0.1, 0.5, 1, 2 or 3 seconds. The amount and particle size of albuterol and lactose exiting Rotahaler was simultaneously determined by laser diffraction and inertial impaction. Rapidly imposed, higher flow rates drawn through the DPI induced more emptying and smaller emitted drug and carrier particles sizes. The USP method of instantaneously reaching the peak flow rate yielded maximal powder emptying and minimum particle size. Area under the laser obscuration versus time plot was found to correlate to total powder emptying. This relationship was used to demonstrate that most powder leaves a DPI before the peak flow rate is achieved. A correlation between the fine particle fraction of albuterol (obtained from cascade impaction) and the volume mean diameter (of lactose and albuterol) obtained from laser diffraction was established. This work represents a step towards applying realistic inhalation profiles to both established inertial, and more convenient laser based aerosol evaluation techniques.
    • Effervescent Aerosols: A Novel Formulation Technology for Solution and Suspension-type Metered Dose Inhalers

      Kelkar, Mukul Sunil; Dalby, Richard N.; 0000-0002-5087-4051 (2016)
      Pressurized metered dose inhalers are complex drug delivery systems which have revolutionized the treatment of asthma and chronic obstructive pulmonary disease since the 1950s. Since the early 1990s, solution and suspension metered dose inhalers have been formulated using HFA-134a and HFA-227 as the propellants of choice, along with other excipients such as ethanol and oleic acid. Performance of an inhaler is partially dependent upon the size of particles it generates, which is partially dictated by intra-canister pressure. In this dissertation, a novel method of formulation of inhalers- the "effervescent aerosol technology" has been introduced. A propellant consisting of HFA-134a containing dissolved carbon dioxide has been used to formulate solution and suspension inhalers. We hypothesized that dissolution of carbon dioxide in HFA-134a will lead to higher degree of aerosol particle size reduction upon actuation, caused due to the process of effervescence i.e. escape of dissolved carbon dioxide from HFA -134a droplet. Since this is a novel technology, the initial part of the dissertation tested the hypothesis in a custom-designed pressure vessel capable of holding and spraying solution inhaler formulations. Particle size analysis was done using Malvern Spraytec®, a laser diffractometry instrument. Formulations prepared using a mixture of HFA-134a and carbon dioxide showed significantly lower particle sizes compared to analogous, pressure-controlled formulations. In the later part of the dissertation, a method to transfer the formulation from the pressure vessel to commercially viable canisters has been described. Further laser diffractometry experiments showed that solution and suspension inhalers prepared using effervescent aerosol technology consistently produce particles with significantly lower particle sizes than HFA-134a-only inhalers. Cascade impaction testing showed that inhalers prepared using a mixture of HFA-134a and carbon dioxide cause significantly lower throat deposition and show improvements in other crucial performance parameters, when compared to HFA-134a-only formulations. Additionally, spray characterization studies such as spray force and plume geometry have also been conducted. This thesis demonstrates that using a combination propellant of liquefied HFA-134a and dissolved CO2 to prepare solution and suspension-type metered dose inhalers is a viable formulation strategy to achieve improved inhaled drug delivery.
    • Evaluation of a Device Modification and Hand-Related Variability on the Performance of Nasal Sprays and Metered Dose Inhalers

      Doughty, Diane; Dalby, Richard N. (2010)
      Drug delivery to the nose and lungs using nasal sprays and metered dose inhalers (MDIs) is complicated by a reliance on the formulation, device, and patient to generate droplets or particles within a suitable particle size range so that drug deposits at an appropriate location. Many properties of the formulation, device, and patient have been investigated for their role in nasal spray and MDI performance. However, no published works have studied the influence of the dip tube during emptying of the nasal spray, or how patient-relevant hand technique affects nasal sprays or MDIs. Therefore, the purpose of this work is to investigate the effects of a flexible dip tube modification on emptying characteristics of nasal sprays, and to evaluate the influence of hand technique on nasal sprays and MDIs. The number of full sprays and the number of sprays in the tail-off period generated at thirty degrees to the vertical by flexible and rigid dip tubes were determined in five over-the-counter nasal sprays. Results showed that flexible dip tubes were able to generate significantly more sprays before the tail-off period in four of the five nasal sprays tested. Three of the five nasal sprays showed significantly fewer sprays in the tail-off period when flexible dip tubes were used in place of their rigid counterparts. Hand data recorded from adults and children were used to conduct in vitro tests on nasal sprays using force-controlled and velocity-controlled actuators. Variability in hand spraying led to significant differences in patient-relevant actuator settings between the adult and pediatric groups. Also, a significantly decreased spray weight was recorded in children compared to adults. While variability among participants was high, only actuation force, force rise time, and compression velocity resulted in significantly different in vitro test results. Although hand variability was high when adults sprayed two MDIs, the variability in the recorded spray weight was low. This suggests that hand technique does not play a dominant role in the resultant dose and/or spray characteristics, as long as the participant is able to apply enough force to the MDI to compress the valve spring and release the product.
    • Functionality testing used to rationally assess performance of a model respiratory solution or suspension in a nebulizer

      Tiano, Susan L.; Dalby, Richard N. (1995)
      There are currently no USP performance standards for nebulizers and their associated respiratory solutions. This research sought to establish reliable methodologies for comparing total aerosolized output (TO), output rate (OR) and fine droplet fraction (FDF) between an air-jet and an ultrasonic nebulizer. The nebulized output of an aqueous 0.08% w/v fluorescein solution was collected in a total output collection device and four inertial samplers over 0.5, 2 and 5 minutes. Increases in airflow rate to the air-jet nebulizer resulted in significant increases in output rate and variability. However, no practical increases in fine droplet fraction for the air-jet nebulizer were observed. The determination of fine droplet fraction from an ultrasonic nebulizer was found to be prone to sampler overloading. Results among the impactors showed similar trends, but the data was not interchangeable. Using the validated methods established for characterizing a respiratory solution, a model suspension containing 0.1% w/v fluorescein (to estimate droplet deposition) and known quantities of 1, 3 and 6 mum latex spheres (representing insoluble drug particles) was aerosolized from an air-jet and an ultrasonic nebulizer to determine if differences in the aerosolization mechanism affected droplet and sphere deposition. Nebulized output was collected in a modified Andersen impactor. Samples were analyzed spectrophotometrically and by a Coulter Counter to estimate droplet and sphere deposition, respectively. Theoretical mathematical predictions were compared to experimental findings. Significant differences between nebulizers were observed. In the ultrasonic nebulizer, 99% of the spheres were not aerosolized, which the model did not predict. However, the results more closely followed the model for the air-jet nebulizer, since a substantial fraction of the spheres appeared in the aerosolized output. Any attempt to regulate nebulizer performance standards should consider that dissolved drug or droplet deposition patterns do not necessarily reflect those of undissolved drug particles. This research highlighted several justifications for reliably evaluating nebulizer output characteristics. The presented methods provide a rational basis to evaluate performance of nebulizers and their associated respiratory solutions or suspensions.
    • Optimizing pulmonary drug delivery using spacer devices in conjunction with pressurized metered dose inhalers

      Somaraju, Shailaja; Dalby, Richard N. (1999)
      Spacers are commonly prescribed for use with pressurized metered dose inhalers (MDIs), in the hope of increasing the total drug dose inhaled by a patient. The effect of spacer geometry, size, design and mode of use on the quality of aerosol output was critically examined to assess the validity of typical in-vitro test protocols used by spacer manufacturers to document spacer performance. (1) A pilot clinical study showed that patients induced delays between actuation and the onset of inhalation, even after extensive training on AeroChamber, ACE and OptiHaler spacers. Total drug output (TDO) from these spacers was reduced substantially when such delays were simulated in-vitro. (2) AeroChamber and OptiChamber (differently sized spacers with mouthpiece valves) were tested with Ventolin, Beclovent and Intal to determine TDO and fine particle dose (FPD). OptiChamber yielded a higher TDO and FPD, which was less sensitive to actuation-inhalation delays than AeroChamber. Spacer size and valve design were found to affect performance. (3) Spacers 2 to 8 inches long, with internal diameters of 1 to 2.5 inches were tested with Ventolin and Intal. For Ventolin, the 2.5 inch spacer gave the highest TDO and FPD of all the lengths tested. Length had a minimal effect. Drug output from Intal was affected by both spacer length and width. (4) Sites of maximum drug loss within these spacers were determined by building equivalently sized spacers from interlocking rings. Ventolin deposition was concentrated 1 to 2 inches from the actuator spray nozzle, while almost uniform Intal distribution was observed along the spacer length. (2) and (3) suggest that all spacer-MDI combinations may not function equivalently. Determining spacer performance under ideal in-vitro conditions, and ignoring patient use scenarios can potentially over estimate spacer efficiency. All valved spacers do not perform identically and larger spacers do not always enhance dose delivery. There are significant differences in meaningful performance parameters of marketed spacers deemed equivalent by the United States Food and Drug Administration. Spacer performance with one inhaler may not be indicative of all inhaled medications.
    • Realistic evaluation of metered dose inhalers alone or in association with add-on devices

      Hsu, Wenchi; Dalby, Richard N. (2012)
      A pressurized metered dose inhaler (MDI) is a type of medical device designed to deliver multiple, individually precise doses of finely dispersed drugs to the lungs via the oral inhalation route. As documented by numerous studies, a significant drawback of MDIs is the use of incorrect techniques by patients. The effects of improper use and subsequent inadequate dosing can lead to a host of clinical problems ranging from sub-optimal therapeutic outcomes to emergency room admissions or mortality. All these outcomes also place a financial burden on society due to increased medical costs and decreased productivity from missed days at school or work. In an attempt to improve therapeutic outcome, MDIs were instrumented with a differential pressure transducer, load cell and accelerometer to facilitate simultaneous capture and display of inhaled flow rate, applied finger-force on canister, and shaking in real-time plots. A biofeedback function for inhaled flow rate was also included. Once developed, the instrumented MDI was used to train pediatric patient volunteers recruited from a predefined high risk population for asthma-related complications. The instrumented MDI was shown to be an effective training aid for significantly improving inhaler techniques. Improving inhaler techniques, as demonstrated by real-time collection of shaking, actuation, and inhalation profiles based on actual patient use, is an important step to reducing incidences of preventable therapeutic deficiencies or failures due to inhaler misuse. In addition to training alone, another way to facilitate correct MDI use is to deploy add-on devices such as dose counters, valved holding chambers, and facemasks. However, there is no generally acceptable or agreed upon methodology for evaluating these products. To that end, test methods were developed which consisted of using a force-instrumented MDI to evaluate dose counter accuracy, and using a novel soft anatomical model face-based test fixture with adjustable settings to evaluate valved holding chambers with facemasks under realistic simulated use conditions.
    • Use of simulated inhaled volumes, flow rates and flow rate ramps to evaluate in vitro dry powder inhaler performance

      Chavan, Varsha S.; Dalby, Richard N. (2001)
      Dry Powder Inhalers (DPIs) utilize a patient's inspiratory maneuver to entrain and deaggregate a powder forming an inhalation aerosol. United States Pharmacopoeia (USP) DPI methods replicate the peak rate a patient might achieve, but do not account for how this peak is approached. This research developed a simple, robust system to simulate different rates of rise (ramps) to a final peak inspiratory flow rate. Ramps were programmed to reach 30, 60, 90 and 120 L/min over 100 ms, 500 ms, 1, 2 and 3 s. Using this computerized system, it was demonstrated that peak flow rate, the rate at which that flow rate was achieved and carrier particle size, influenced powder emptying from three passive DPIs. Generally, powder emptying increased as ramp steepness increased---this being most evident at 30 L/min. Greater emptying was usually facilitated by larger carrier particles using all ramps and peak flows. The USP method of instantaneous peak flow rate generation produced more emptying than even the steepest ramp, and may therefore overestimate powder emptying during use. While maximized powder emptying is a prerequisite of optimized dose delivery, a meaningful determination of Fine Particle Fraction (FPF), the fraction of the aerosolized output likely to reach the lungs, is more critical to therapeutic outcome. A semi-automated system was developed permitting ramped air flow through a DPI while maintaining a relatively constant air flow through an inertial impactor. This system suggested that a steeper rate of rise in air flow elicited a higher FPF compared to a shallower ramp at test flow rates of 30 and 60 Umin. FPF determined by the USP method was higher than the ramp method at these flow rates. There were no significant differences in FPF when a 2 and 4 L inhaled volume were compared. This research highlights the limitations of two existing compendial tests when applied to therapeutic aerosols generated from DPIs, and provides a basis and apparatus for evaluating in vitro DPI performance more realistically. It also illustrates the potential dangers in using in vitro tests to infer in vivo performance in the absence of valid correlations.