Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.8, and C-3.7), differing only in type and composition of lactose fines, exhibited median mass aerodynamic diameter (MMAD) of 4.5 µm (A-4.5), 3.8 µm (B-3.8), and 3.7 µm (C-3.7) and varied in dissolution rates (A-4.5 slower than B-3.8 and C-3.7). In vitro total lung dose (TLDin vitro) was determined as the average dose passing through three anatomical mouth-throat (MT) models and yielded dose normalization factors (DNF) for each DPI formulation X (DNFx = TLDin vitro,x/TLDin vitro,A-4.5). The DNF was 1.00 for A-4.5, 1.32 for B-3.8, and 1.21 for C-3.7. Systemic PK after inhalation of 500 µg FP was assessed in a randomized, double-blind, four-way crossover study in 24 healthy volunteers. Peak concentrations (Cmax) of A-4.5 relative to those of B-3.8 or C-3.7 lacked bioequivalence without or with dose normalization. The area under the curve (AUC0-Inf) was bio-IN-equivalent before dose normalization and bioequivalent after dose normalization. Thus, PK could detect differences in pulmonary available dose (AUC0-Inf) and residence time (dose-normalized Cmax). The differences in dose-normalized Cmax could not be explained by differences in in vitro dissolution. This might suggest that Cmax differences may indicate differences in regional lung deposition. Overall this study supports the use of PK studies to provide relevant information on the pulmonary performance characteristics (i.e., available dose, residence time, and regional lung deposition).

CFD Guided Optimization of Nose-to-Lung Aerosol Delivery in Adults: Effects of Inhalation Waveforms and Synchronized Aerosol Delivery.

PURPOSE: The objective of this study was to optimize nose-to-lung aerosol delivery in an adult upper airway model using computational fluid dynamics (CFD) simulations in order to guide subsequent human subject aerosol delivery experiments. METHODS: A CFD model was developed that included a new high-flow nasal cannula (HFNC) and pharmaceutical aerosol delivery unit, nasal cannula interface, and adult upper airway geometry. Aerosol deposition predictions in the system were validated with existing and new experimental results. The validated CFD model was then used to explore aerosol delivery parameters related to synchronizing aerosol generation with inhalation and inhalation flow rate. RESULTS: The low volume of the new HFNC unit minimized aerosol transit time (0.2 s) and aerosol bolus spread (0.1 s) enabling effective synchronization of aerosol generation with inhalation. For aerosol delivery correctly synchronized with inhalation, a small particle excipient-enhanced growth delivery strategy reduced nasal cannula and nasal depositional losses each by an order of magnitude and enabled ~80% of the nebulized dose to reach the lungs. Surprisingly, nasal deposition was not sensitive to inhalation flow rate due to use of a nasal cannula interface with co-flow inhaled air and the small initial particle size. CONCLUSIONS: The combination of correct aerosol synchronization and small particle size enabled high efficiency nose-to-lung aerosol delivery in adults, which was not sensitive to inhalation flow rate.

Team teaching with pharmacy practice and pharmaceutics faculty in a nonsterile compounding laboratory course to increase student problem-solving skills.

BACKGROUND AND PURPOSE: Combining pharmaceutics and pharmacy practice into nonsterile compounding is ideal to increase problem-solving skills. The objectives of this activity were to: (1) create a nonsterile compounding activity through a team-teaching collaboration, (2) increase students' independent problem-solving skills to compound a nonsterile natural product, and (3) assess student and faculty perceptions of the learning activity. EDUCATIONAL ACTIVITY AND SETTING: The activity was created, implemented, and assessed using a team-teaching technique between pharmacy practice and pharmaceutics faculty. The first week students were tasked with extraction of an active ingredient from a natural product, and the second week students independently compounded a nonsterile product using the concentrated extract. Faculty and students were asked to give their perceptions of the activity. FINDINGS: The activity has been taught to two cohorts of elective students. Students from both cohorts (n = 57) independently created a nonsterile compound, scoring an average (standard deviation) of 8.1 (1) and 8.6 (0.9) out of 10 points on their graded products for the 2018 and 2019 elective, respectively. Faculty collaboration and team-teaching adjustments to the content resulted in increased student performance (p = 0.0392). Student feedback on the activity was overwhelmingly positive. Faculty appreciated the collaborative approach and improved the course activity together. SUMMARY: A team-teaching approach created an activity that focused on elements of both pharmaceutics and pharmacy practice. Students developed problem-solving abilities by creating their own independent nonsterile compounded natural product. The collaboration between faculty was positive and well received by students.

In Vitro Measurement of Regional Nasal Drug Delivery with Flonase,® Flonase® Sensimist,™ and MAD Nasal™ in Anatomically Correct Nasal Airway Replicas of Pediatric and Adult Human Subjects.

Background: The majority of current nasal delivery devices, commercialized for children, are developed for adults. Differences in the dose reaching the target are expected due to significant differences between the pediatric and adult nasal airway geometries and their inhalation patterns. This study aims to compare the efficacy of most common nasal drug delivery devices in terms of regional delivery of suspension and solution formulations in pediatric and adult subjects. Methods: Anatomically correct nasal models of 2-, 5-, and 50-year old subjects were developed to evaluate regional nasal delivery of suspensions of fluticasone propionate and fluticasone furoate delivered with Flonase® and Flonase® Sensimist™, respectively, and the delivery of an aqueous solution of a model drug, administered with MAD Nasal™. Relevant inhalation patterns were considered for each nasal airway geometry. Controlled administration methods were used, and all contributing parameters, including particle size, velocity, and plume geometry, are reported. Results: Regional deposition patterns resulting from Flonase® Sensimist™ and Flonase® were not significantly different in each replica (p > 0.05), despite their different plume geometry and droplet size distributions. However, there was a significant difference in deposition of nasal sprays between the pediatric (2- and 5-year old) and adult models (p < 0.05), while no statistical differences were found between the two pediatric models (p > 0.05). The MAD atomizer resulted in different deposition patterns in all three subjects (p < 0.05). Conclusion: Nasal sprays are not adequate delivery devices for pediatric population, due to the narrower nasal passage and greater anterior deposition (∼60%). MAD atomizer resulted in significantly less anterior deposition (∼10%-15%) compared to the nasal pumps, but there was ∼30% run off to the throat. An in vitro platform incorporating anatomically correct nasal geometries and inhalation patterns can guide the development of age-appropriate nasal drug delivery devices.

Development of a High-Flow Nasal Cannula and Pharmaceutical Aerosol Combination Device.

Background: Aerosol drug delivery to the lungs is known to be very inefficient during all forms of noninvasive ventilation, especially when the aerosol is administered simultaneously with high-flow nasal cannula (HFNC) therapy. The objective of this study was to develop a new combination device based on vibrating mesh nebulizers that can provide continuously heated and humidified HFNC therapy as well as on-demand pharmaceutical aerosols with high efficiency. Methods: The combination device implemented separate mesh nebulizers for generating humidity (humidity nebulizer) and delivering the medical aerosol (drug nebulizer). Nebulizers were actuated in an alternating manner with the drug nebulizer delivering the medication during a portion of an adult inhalation cycle. Aerosol entered a small-volume mixing region where it was combined with ventilation gas flow and then entered a heating channel to produce small particles that are desirable for nose-to-lung administration and potentially excipient enhanced growth delivery. Three assessment methods (analytical calculations, computational fluid dynamics [CFD] simulations, and in vitro experiments in three-dimensional [3D] printed devices) were used to improve the mixer-heater design to minimize depositional drug losses, maintain a small device volume, ensure sufficient droplet evaporation, and control the outlet thermodynamic conditions. Results: For an initial configuration (Design 1), good agreement in performance metrics was found using the three assessment methods. Based on insights gained from the CFD simulations of Design 1, two new designs were developed and produced with 3D printing. Experimental analysis indicated that the new designs both achieved <5% depositional loss in the mixer-heater even with cyclic operation and sufficiently dried the aerosol from an initial size of 5.3 µm to an outlet size of ∼1.0 µm. A combination of the applied methods indicated that the desired thermodynamic conditions of HFNC therapy were also met. Conclusions: Multiple methodological approaches were used concurrently to develop a new combination device for administering HFNC therapy and simultaneous on-demand pharmaceutical aerosols to the lungs with high efficiency. The use of a small-volume mixer-heater (<100 mL), synchronization of the drug nebulizer with inhalation, and small outlet particle size should enable high efficiency lung delivery of the aerosol.

In Vitro Tests for Aerosol Deposition. VI: Realistic Testing with Different Mouth-Throat Models and In Vitro-In Vivo Correlations for a Dry Powder Inhaler, Metered Dose Inhaler, and Soft Mist Inhaler.

Background:In vitro-in vivo correlations (IVIVC) for lung deposition may be established by testing inhalers in vitro with realistic mouth-throat (MT) models and inhalation profiles (IP). This study was designed to compare the currently available MT models and their ability to predict in vivo lung deposition. Methods: Budelin® Novolizer®, Ventolin® Evohaler®, and Respimat® fenoterol were chosen to represent a dry powder inhaler (DPI), metered dose inhaler (MDI), and soft mist inhaler (SMI) in tests using eight MT models: small, medium, and large Virginia Commonwealth University (VCU) models; small, medium, and large oropharyngeal consortium (OPC) models, the medium adult Alberta Idealized Throat (AIT), and the United States Pharmacopeia (USP) Induction Port, with IPs that simulated those used by volunteers in lung scintigraphy studies. Drug deposition in MT was compared across the models, and IVIVCs evaluated by comparing values for total lung dose in vitro (TLDin vitro) to those reported in the clinic. Results: MT deposition was dependent on both the flow condition and MT geometry for all the inhalers, while the deposition rank order was independent of both factors. The overall ranking was USP

Predicting Pulmonary Pharmacokinetics from In Vitro Properties of Dry Powder Inhalers.

PURPOSE: The ability of two semi-mechanistic simulation approaches to predict the systemic pharmacokinetics (PK) of inhaled corticosteroids (ICSs) delivered via dry powder inhalers (DPIs) was assessed for mometasone furoate, budesonide and fluticasone propionate. METHODS: Both approaches derived the total lung doses and the central to peripheral lung deposition ratios from clinically relevant cascade impactor studies, but differed in the way the pulmonary absorption rate was derived. In approach 1, the rate of in vivo drug dissolution/absorption was predicted for the included ICSs from in vitro aerodynamic particle size distribution and in vitro drug solubility estimates measured in an in vivo predictive dissolution medium. Approach 2 derived a first order absorption rate from the mean dissolution time (MDT), determined for the test formulations in an in vitro Transwell® based dissolution system. RESULTS: Approach 1 suggested PK profiles which agreed well with the published pharmacokinetic profiles. Similarly, within approach 2, input parameters for the pulmonary absorption rate constant derived from dissolution rate experiments were able to reasonably predict the pharmacokinetic profiles published in literature. CONCLUSION: Approach 1 utilizes more complex strategies for predicting the dissolution/absorption process without providing a significant advantage over approach 2 with regard to accuracy of in vivo predictions.

In Vitro Tests for Aerosol Deposition. V: Using Realistic Testing to Estimate Variations in Aerosol Properties at the Trachea.

BACKGROUND: The dose and aerodynamic particle size distribution (APSD) of drug aerosols' exiting models of the mouth and throat (MT) during a realistic inhalation profile (IP) may be estimated in vitro and designated Total Lung Dose, TLDin vitro, and APSDTLDin vitro, respectively. These aerosol characteristics likely define the drug's regional distribution in the lung. METHODS: A general method was evaluated to enable the simultaneous determination of TLDin vitro and APSDTLDin vitro for budesonide aerosols' exiting small, medium and large VCU-MT models. Following calibration of the modified next generation pharmaceutical impactor (NGI) at 140 L/min, variations in aerosol dose and size exiting MT were determined from Budelin® Novolizer® across the IPs reported by Newman et al., who assessed drug deposition from this inhaler by scintigraphy. RESULTS: Values for TLDin vitro from the test inhaler determined by the general method were found to be statistically comparable to those using a filter capture method. Using new stage cutoffs determined by calibration of the modified NGI at 140 L/min, APSDTLDin vitro profiles and mass median aerodynamic diameters at the MT exit (MMADTLDin vitro) were determined as functions of MT geometric size across Newman's IPs. The range of mean values (n ≥ 5) for TLDin vitro and MMADTLDin vitro for this inhaler extended from 6.2 to 103.0 µg (3.1%-51.5% of label claim) and from 1.7 to 3.6 µm, respectively. CONCLUSIONS: The method enables reliable determination of TLDin vitro and APSDTLDin vitro for aerosols likely to enter the trachea of test subjects in the clinic. By simulating realistic IPs and testing in different MT models, the effects of major variables on TLDin vitro and APSDTLDin vitro may be studied using the general method described in this study.

In Vitro Tests for Aerosol Deposition. IV: Simulating Variations in Human Breath Profiles for Realistic DPI Testing.

BACKGROUND: The amount of drug aerosol from an inhaler that can pass through an in vitro model of the mouth and throat (MT) during a realistic breath or inhalation flow rate vs. time profile (IP) is designated the total lung dose in vitro, or TLDin vitro. This article describes a clinical study that enabled us to recommend a general method of selecting IPs for use with powder inhalers of known airflow resistance (R) provided subjects followed written instructions either alone or in combination with formal training. METHODS: In a drug-free clinical trial, inhaler-naïve, nonsmoking healthy adult human volunteers were screened for normal pulmonary function. IPs were collected from each volunteer inhaling through different air flow resistances after different levels of training. IPs were analyzed to determine the distribution of inhalation variables across the population and their dependence on training and airflow resistance. RESULTS: Equations for IP simulation are presented that describe the data including confidence limits at each resistance and training condition. Realistic IPs at upper (90%), median (50%), and lower (10%) confidence limits were functions of R and training. Peak inspiratory flow rates (PIFR) were inversely proportional to R so that if R was assigned, values for PIFR could be calculated. The time of PIFR, TPIFR, and the total inhaled volume (V) were unrelated to R, but dependent on training. Once R was assigned for a powder inhaler to be tested, a range of simulated IPs could be generated for the different training scenarios. Values for flow rate acceleration and depth of inspiration could also be varied within the population limits of TPIFR and V. CONCLUSIONS: The use of simulated IPs, in concert with realistic in vitro testing, should improve the DPI design process and the confidence with which clinical testing may be initiated for a chosen device.