Pharmacokinetic Bioequivalence between Generic and Originator Orally Inhaled Drug Products: Validity of Administration of Doses above the Approved Single Maximum Dose.

Pharmacokinetic bioequivalence of orally inhaled drug products is a critical component of the US FDA's "weight of evidence" approach, and it can serve as the sole indicator of safety and effectiveness of follow-on inhalation products approved in Europe and some other geographic areas. The approved labels of the orally inhaled drug products recommend the maximum number of actuations that can be administered in a single dose on one occasion. This single maximum dose may consist of one or more inhalations depending upon the product. Bioequivalence studies for the inhalation drug product registrations in the US and EU have employed single and multiple actuation doses, in some cases over and above the approved single maximum labeled doses, thus, inconsistent with the approved labeling of the reference products. Pharmacokinetics of inhaled drug products after single and multiple doses may be different, with implications for bioequivalence determined at single and multiple doses. Scientific literature indicates that the relative bioavailability of the Test and Reference products may differ between administrations of doses in one and multiple inhalations. Multiple doses not only alter the pharmacokinetics but also may reduce the sensitivity of the bioassay to actual differences between the Test and Reference product performances. Ability of the pharmacokinetic bioassay to accurately determine the extent of difference between two products may also be substantially reduced at high doses. Therefore, in our opinion, pharmacokinetic bioequivalence to support regulatory approvals of inhalation products at doses above the recommended single maximum dose should be avoided. Furthermore, the bioequivalence of products (if any) established at doses exceeding the approved single maximum doses should be revisited to determine if the products maintain bioequivalence when evaluated at the clinically relevant single maximum doses.

Effective density of inhaled environmental and engineered nanoparticles and its impact on the lung deposition and dosimetry.

BACKGROUND: Airborne environmental and engineered nanoparticles (NPs) are inhaled and deposited in the respiratory system. The inhaled dose of such NPs and their deposition location in the lung determines their impact on health. When calculating NP deposition using particle inhalation models, a common approach is to use the bulk material density, ρb, rather than the effective density, ρeff. This neglects though the porous agglomerate structure of NPs and may result in a significant error of their lung-deposited dose and location. RESULTS: Here, the deposition of various environmental NPs (aircraft and diesel black carbon, wood smoke) and engineered NPs (silica, zirconia) in the respiratory system of humans and mice is calculated using the Multiple-Path Particle Dosimetry model accounting for their realistic structure and effective density. This is done by measuring the NP ρeff which was found to be up to one order of magnitude smaller than ρb. Accounting for the realistic ρeff of NPs reduces their deposited mass in the pulmonary region of the respiratory system up to a factor of two in both human and mouse models. Neglecting the ρeff of NPs does not alter significantly the distribution of the deposited mass fractions in the human or mouse respiratory tract that are obtained by normalizing the mass deposited at the head, tracheobronchial and pulmonary regions by the total deposited mass. Finally, the total deposited mass fraction derived this way is in excellent agreement with those measured in human studies for diesel black carbon. CONCLUSIONS: The doses of inhaled NPs are overestimated by inhalation particle deposition models when the ρb is used instead of the real-world effective density which can vary significantly due to the porous agglomerate structure of NPs. So the use of realistic ρeff, which can be measured as described here, is essential to determine the lung deposition and dosimetry of inhaled NPs and their impact on public health.

Assessment of seasonal variability of PM, BC and UFP levels at a highway toll stations and their associated health risks.

As a part of their occupation, workers at toll stations are exposed to traffic emissions during the working shift, which sometimes stretches to 12 h. To assess the exposure and subsequent health risk of these workers, a study was performed on a highway toll station in India. PM1, PM2.5, PM10, BC and UFP concentration were determined inside a toll collectors' cabin and outside in a free-flowing traffic section (125 m from the toll cabin). The concentrations varied in the following range: PM1 (40.69-226.13 µg m-3), PM2.5 (49.71-247.36 µg m-3), PM10 (83.15-458.14 µg m-3) and BC (2.1-87.5 µg m-3) and UFP: 101-53705 pt cm-3. The mean concentration inside the cabin was 1.34 (PM1), 1.35 (PM2.5), 1.16 (PM10) and 2.91 (BC) times the concentration outside for the summer season. The corresponding levels in the winter season were 1.14 (PM1), 1.11 (PM2.5), 1.11 (PM10), 2.50 (BC) and 1.82 (UFP). In addition to the exhaust emission, the non-exhaust emissions such as resuspension of crustal particles, fly ash and bioaerosols were identified. Using the Multiple Path Particle Dosimetry model for two groups - adults (18-21 years) and adults (21+ years), it was estimated that the pulmonary deposition of in-cabin workers were 50% (PM2.5) -75% (PM1) higher than the workers outside the cabin. Particle mass deposition was found to be higher for adults (21+ years) than adults (18-21 years) for both the seasons. The study quantitatively assessed the health risk faced by the workers in terms of exposure concentration and deposition in respiratory tract. More such studies at different traffic mix and climate can provide better estimates of health risk of toll workers that can be used to devise appropriate strategies for control of it.

Dry Powder Formulations for Inhalation Require a Smaller Aerodynamic Diameter for Usage at High Altitude.

BACKGROUND: High Altitude Pulmonary Edema (HAPE) seriously threatens the health of people at high altitudes. There are drug treatments for HAPE, and dry powder formulations (DPFs) represent a rapid and accessible delivery vehicle for these drugs. However, there are presently no reports on the inhalability of DPFs in low-pressure environments. Given the reduced atmospheric pressure typical at high altitudes, conventional DPFs might not be suitable for inhalation. Therefore, it is necessary to elucidate the deposition behaviors of dry powder in the respiratory tract at low pressure, as well as to improve their pulmonary deposition efficiency via adjustments to their formulation and design. METHODS: The effect of air pressure, inspiratory velocity, and particle properties (such as size, density, and aerodynamic diameter) on pulmonary deposition of DPFs was calculated by a computational fluid dynamics (CFD)-coupled discrete phase model. DPFs of various aerodynamic diameters were prepared by spray drying, and the inhalability of these DPFs in a low-pressure environment was evaluated in mice. Finally, a mouse model of HAPE was established, and the treatment of HAPE by nifedipine-loaded DPFs with small aerodynamic diameter was validated. RESULTS: CFD results showed that low pressure decreased the deposition of DPFs in the lungs. At 0.5 standard atmosphere, DPFs with aerodynamic diameter of ∼2.0 µm could not enter the lower respiratory tract; however, a decrease in the physical diameter, density, and, consequently, the aerodynamic diameter of the DPFs was able to enhance pulmonary deposition of these powders. To validate the CFD results, three kinds of dry powder with aerodynamic diameters of 0.66, 0.98, and 2.00 µm were prepared by spray drying. Powders with smaller aerodynamic diameter could be inhaled into the lungs of mice more effectively, and, consequently could ameliorate the progression of HAPE more effectively than conventional powders. These results were consistent with the CFD results. CONCLUSIONS: Low atmospheric pressure can prevent the pulmonary deposition of DPFs at high altitudes. Compared with conventional DPFs, powders with smaller aerodynamic diameter can be effectively inhaled at these pressures and thus might be more suitable for the treatment the HAPE.

A path forward in the development of new aerosol drug delivery devices for pediatrics.

Inhaled medications are widely accepted as being the optimal route for treating pediatric respiratory diseases, a leading cause of hospitalization and death. Despite jet nebulizers being the preferred inhalation device for neonates and infants, current devices face performance issues with most of the drug never reaching the target lung location. Previous work has aimed to improve pulmonary drug deposition, yet nebulizer efficiency remains low. The development of an inhalant therapy that is efficacious and safe for pediatrics depends on a well-designed delivery system and formulation. To accomplish this, the field needs to rethink the current practice of basing pediatric treatments on adult studies. The rapidly evolving pediatric patient (i.e. neonates to eighteen) needs to be considered because they are different from adults with respect to airway anatomy, breathing patterns, and adherence. Previous research approaches to improve deposition efficiency have been limited due to the complexity of combining physics, which drives aerosol transport and deposition, and biology, especially within the area of pediatrics. To address these critical knowledge gaps, we need a better understanding of how patient age and disease state affect deposition of aerosolized drugs. The complexity of the multiscale respiratory system makes scientific investigation very challenging. The authors have simplified the complex problem into five components with these three areas as ones to address first: how the aerosol is (i) generated in a medical device, (ii) delivered to the patient, and (iii) deposited inside the lung. In this review, we discuss the technological advances and innovations made from experiments, simulations, and predictive models in each of these areas. In addition, we discuss the impact on patient treatment efficacy and recommend a clinical direction, with a focus on pediatrics. In each area, a series of research questions are posed and steps for future research to improve efficacy in aerosol drug delivery are outlined.

A scintigraphy study of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler in patients with moderate-to-very severe chronic obstructive pulmonary disease.

BACKGROUND: Triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting ß2-agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 µg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD. METHODS: This phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 µg per actuation) radiolabeled with technetium­99­pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs. RESULTS: The mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64). CONCLUSIONS: Radiolabeled BGF 320/18/9.6 µg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045.

Guia prático de aerossolterapia na criança e no adolescente: Documento conjunto da Associação Brasileira de Alergia e Imunologia e Sociedade Brasileira de Pediatria / Practical guide to aerosol therapy in children and adolescents: Joint document from the Brazilian Association of Allergy and Immunology and the Brazilian Society of Pediatrics

A via inalatória é a mais adequada para o tratamento das doenças respiratórias. Muitos fatores influenciam na deposição pulmonar do fármaco inalado, e, consequentemente, no sucesso terapêutico, desde fatores relacionados ao indivíduo, como questões anatômicas das vias aéreas, dinâmica respiratória, doença de base e técnica correta, até situações relacionadas às questões aerodinâmicas das partículas que compõem o aerossol, como o tamanho (diâmetro aerodinâmico mediano de massa) e a homogeneidade das partículas (desvio padrão geométrico). Nos últimos anos os dispositivos inalatórios se aperfeiçoaram, buscando atender às características necessárias que garantam uma deposição pulmonar satisfatória dos fármacos. A escolha do dispositivo inalatório deve ser individualizada, e o conhecimento das particularidades de cada dispositivo e das vantagens e desvantagens instrumentaliza o profissional na decisão, e impacta diretamente no sucesso terapêutico da medicação utilizada.

The inhalation route is the most adequate for the treatment of respiratory diseases. Many factors influence pulmonary deposition of the inhaled drug and, consequently, therapeutic success. They include individual factors such as airway anatomy, respiratory dynamics, underlying disease, and correct technique, as well as factors related to the aerodynamics of aerosol particles such as size (mass median aerodynamic diameter) and homogeneity of the particles (geometric standard deviation). In recent years, inhalation devices have improved to comply with the necessary characteristics that guarantee a satisfactory pulmonary deposition of drugs. The choice of the inhalation device must be individualized, and the knowledge about the features of each device and their advantages and disadvantages instrumentalizes health professionals in the decision and impacts directly the therapeutic success of the medication used.

Estimates of carbon nanotube deposition in the lung: improving quality and robustness.

Carbon nanotube (CNT) in vivo inhalation studies are increasingly providing estimates of the quantity of material deposited in the lung, generally estimated using standard formulae and pulmonary deposition models. These models have typically been developed and validated using data from studies using sphere-like particles. Given the importance of particle morphology to pulmonary deposition, the appropriateness of such an approach was explored to identify any potential limitations. Aerosolized CNT particles typically form 'fiber-like' and/or 'broadly spherical' agglomerates. A review of currently used deposition models indicates that none have been directly validated against results for CNT, however, models for spherical particles have been extensively validated against a wide range of particle sizes and materials and are thus expected to provide reasonable estimates for most 'broadly spherical' CNT particles, although experimental confirmation of this would be of benefit, especially given their low density. The validation of fiber deposition models is significantly less extensive and, in general, focused on larger particles, e.g. asbestos. This raises concerns about the accuracy of deposition estimates for 'fiber-like' CNT particles and recommendations are made for future research to address this. An appreciation of the uncertainties on CNT deposition estimates is important for their interpretation and thus it is recommended that model sensitivity and uncertainty assessments be undertaken. Issues surrounding the measurement and derivation of model input data are also addressed, including instrument responses and particle density assessment options. Recommendations are also made for aerosol characterization to 'future-proof' CNT inhalation studies regarding advances in deposition modeling and toxicological understanding.

Pulmonary deposition of budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler formulated using co-suspension delivery technology in healthy male subjects.

This gamma scintigraphy imaging study assessed pulmonary, extrathoracic and regional lung deposition patterns of a radiolabelled inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist triple fixed-dose combination budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF 320/14.4/10 µg), delivered by pressurised metered dose inhaler (pMDI) using innovative co-suspension delivery technology (Aerosphere™). In this Phase I, randomised, single-centre, single-dose, two-period, crossover study (NCT03740373), 10 healthy male adults received two actuations of BGF MDI (160/7.2/4.8 µg per actuation) radiolabelled with 99mTc, not exceeding 5 MBq per actuation. Immediately following each inhalation, subjects performed a 10- or 3-second breath-hold, then exhaled into an exhalation filter. The primary objective was to assess the pulmonary deposition of BGF MDI following the 10-second breath-hold. The secondary objectives were to assess deposition after the 3-second breath-hold and lung regional and extrathoracic deposition after each breath-hold length. Imaging of the lungs, stomach, head and neck was recorded by gamma scintigraphy immediately after exhalation. The mean BGF MDI emitted dose deposited in the lungs was 37.7% for the 10-second breath-hold and 34.5% for the 3-second breath-hold. Emitted dose detected in the exhalation filter was ≤0.4% for both breath-hold lengths. The mean normalised peripheral/central ratio was 0.65 and 0.75 for the 10- and 3-second breath-holds, respectively, while the standardised central/peripheral ratios were 1.79 and 1.40, respectively. There were no new or unexpected safety findings. In conclusion, BGF MDI was efficiently deposited in the central and the peripheral regions of the lungs, with similar regional deposition patterns following a 10- and 3-second breath-hold.

Preparation of berberine hydrochloride dry powder inhalation and its effect on Staphylococcus aureus pneumonia / 中草药

Objective: To prepare berberine hydrochloride dry powder inhalation, and investigate its pharmacological effect on Staphylococcus aureus pneumonia after pulmonary administration. Methods: Berberine hydrochloride dry powder by spray drying and the experimental conditions was optimized by orthogonal experiment. The lung deposition, fluidity and appearance were characterized. The pharmacodynamic effects of the preparations on S. aureus pneumonia were performed with SD rats. Results: A berberine hydrochloride dry powder was prepared at an inlet temperature of 130 ℃ with a gas volume flow of 610 L/h and a feed volume flow of 3 mL/min. The berberine hydrochloride dry powder had a lung deposition rate (FPF) of 76.4% and an aerodynamic diameter of 4.61 μm. The stability index (SI) ≈ 1, the aeration energy ratio (AR) = 1.76 > 1, and the inflation energy (AE10) = 2.1 mJ < 10 mJ. Through the pharmacodynamic evaluation of S. aureus, we can know that the berberine hydrochloride dry powder inhalation effectively improved the pathological state of pneumonia rats, and significantly reduced (P < 0.05) the number of WBC, neutrophils, and the expression of inflammatory factors (TNF-α, IL-1β, and IL-6) in pneumonia rats. Conclusion: Berberine hydrochloride dry powder inhalation can directly reach the lesion site through pulmonary administration, so it has significant therapeutic effect on S. aureus pneumonia.

Influence of airborne particulates on respiratory tract deposition of inhaled toluene and naphthalene in the rat.

OBJECTIVE: Most studies report that inhaled volatile and semivolatile organic compounds (VOCs/SVOCs) tend to deposit in the upper respiratory tract, while ultrafine (or near ultrafine) particulate matter (PM) (∼100 nm) reaches the lower airways. The objective of this study was to determine whether carbon particle co-exposure carries VOCs/SVOCs deeper into the lungs where they are deposited. MATERIALS AND METHODS: Male Sprague-Dawley rats were exposed by inhalation (nose-only) to radiolabeled toluene (20 ppm) or naphthalene (20 ppm) on a single occasion for 1 h, with or without concurrent carbon particle exposure (∼5 mg/m3). The distribution of radiolabel deposited within the respiratory tract of each animal was determined after sacrifice. The extent of adsorption of toluene and naphthalene to airborne carbon particles under the exposure conditions of the study was also assessed. RESULTS: We found that in the absence of particles, the highest deposition of both naphthalene and toluene was observed in the upper respiratory tract. Co-exposure with carbon particles tended to increase naphthalene deposition slightly throughout the respiratory tract, whereas slight decreases in toluene deposition were observed. Few differences were statistically significant. Naphthalene showed greater adsorption to the particles compared to toluene, but overall the particle-adsorbed concentration of each of these compounds was a small fraction of the total inspired concentration. CONCLUSIONS: These studies imply that at the concentrations used for the exposures in this study, inhaled carbon particles do not substantially alter the deposition of naphthalene and toluene within the respiratory tract.

Gamma scintigraphic pulmonary deposition study of glycopyrronium/formoterol metered dose inhaler formulated using co-suspension delivery technology.

This gamma scintigraphy imaging study was the first to assess pulmonary and extrathoracic deposition and regional lung deposition patterns of a radiolabelled long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10µg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6µg), delivered by pressurized metered dose inhaler (pMDI) using novel co-suspension delivery technology. In this Phase I, randomized, single-centre, single-blind, single-dose, two-treatment, crossover, placebo-controlled study (PT003020), 10 healthy male adults received two actuations of GFF pMDI (7.2/5.0µg per actuation) and placebo pMDI (containing phospholipid-based porous particles without active pharmaceutical ingredient), both radiolabelled with 99mTc, up to 5MBq per actuation. Gamma scintigraphy images of lungs, stomach, head and neck were recorded. In addition, images of the actuators after use, collected mouth washings and exhalation filters were acquired. On average, 38.4% of the emitted dose of radiolabelled GFF pMDI, and 32.8% of radiolabelled placebo pMDI, was deposited in the lungs. The percentage emitted dose detected in the oropharyngeal and stomach regions was 61.4% and 66.9% for radiolabelled GFF pMDI and placebo pMDI, respectively. For both treatments, ≤0.25% of the emitted dose was detected in the exhalation filter. The normalized outer/inner ratio was 0.57 and 0.59 for radiolabelled GFF pMDI and placebo pMDI, respectively, and the standardized central/peripheral ratio was 1.85 and 1.94 respectively, indicating delivery of both co-suspension delivery technology formulations throughout the airways. There were no new or unexpected safety findings. In conclusion, both formulations were efficiently and uniformly deposited in the lungs with similar regional deposition patterns, oropharyngeal and stomach deposition, exhalation fraction and actuator-recovered dose.

Nebulised antibiotherapy: conventional versus nanotechnology-based approaches, is targeting at a nano scale a difficult subject?

Nebulised antibiotics offer great advantages over intravenously administered antibiotics and other conventional antibiotic formulations. However, their use is not widely standardized in the current clinical practice. This is the consequence of large variability in the performance of nebulisers, patient compliance and a deficiency of robust preclinical and clinical data. Nebulised antibiotherapy may play a significant role in future pulmonary drug delivery treatments as it offers the potential to achieve both a high local drug concentration and a lower systemic toxicity. In this review, the physicochemical parameters required for optimal deposition to the lung in addition to the main characteristics of currently available formulations and nebuliser types are discussed. Particular attention will be focused on emerging nanotechnology based approaches which are revolutionizing inhaled therapies used to treat both infections and lung cancer. Promising carriers such as Trojan-Horse microparticles, liposomes, polymeric and lipid nanoparticulate systems have been investigated and proposed as viable options. In order to achieve site-specific targeting and to optimize the PK/PD balance critical nanoscale design parameters such as particle size, morphology, composition, rigidity and surface chemistry architecture must be controlled. Development of novel excipients to manufacture these nanomedicines and assessment of their toxicity is also a keystone and will be discussed in this review.

SPECT/CT study of bronchial deposition of inhaled particles. A human aerosol vaccination model against HPV.

AIMS: Vaccination by aerosol inhalation can be used to efficiently deliver antigen against HPV to mucosal tissue, which is particularly useful in developing countries (simplicity of administration, costs, no need for cold chain). For optimal immunological response, vaccine particles should preferentially be delivered to proximal bronchial airways. We aimed at quantifying the deposition of inhaled particles in central airways and peripheral lung, and to assess administration biosafety. Participants, methods: 20 healthy volunteers (13W/7M, aged 24±4y) performed a 10-min free-breathing inhalation of (99m)Tc-stannous chloride colloid aerosol (450 MBq) in a buffer solution without vaccinal particles using an ultrasonic nebulizer (mass median aerodynamic diameter 4.2 µm) and a double mask inside a biosafety cabinet dedicated to assess environmental particle release. SPECT/CT and whole-body planar scintigraphy were acquired to determine whole-body and regional C/P distribution ratio (central-to-peripheral pulmonary deposition counts). Using a phantom, SPECT sensitivity was calibrated to obtain absolute pulmonary activity deposited by inhalation. RESULTS: All participants successfully performed the inhalation that was well tolerated (no change in pulmonary peak expiratory flow rate, p = 0.9). It was environmentally safe (no activity released in the biosafety filter.) 1.3±0.6% (range 0.4-2.6%) of the total nebulizer activity was deposited in the lungs with a C/P distribution ratio of 0.40±0.20 (range 0.15-1.14). CONCLUSION: Quantification and regional distribution of inhaled particles in an aerosolized vaccine model is possible using radioactive particles. This will allow optimizing deposition parameters and determining the particles charge for active-particles vaccination.

The effect of body posture during medication inhalation on exercise induced bronchoconstriction in asthmatic children.

RATIONALE: Inhaling medication in a standard body posture leads to impaction of particles in the sharp angle of the upper airway. Stretching the upper airway by extending the neck in a forward leaning body posture may improve pulmonary deposition. A single dose of inhaled corticosteroids (ICS) offers acute, but moderate protection against exercise induced bronchoconstriction (EIB). This study investigated whether inhaling a single dose of ICS in a forward leaning posture improves this protection against EIB. METHODS: 32 Asthmatic children, 5-16 years, with EIB (Median fall in FEV1 or FEV0.5 30.9%) performed two exercise challenge tests (ECT's) with spirometry in a single blinded cross-over trial design. Children inhaled a single dose of 200 µg beclomethasone dipropionate (BDP) 4 h before the ECT, once in the standard posture and once with the neck extended in a forward leaning posture. Spirometry was also performed before the inhalation of the single dose of BDP. RESULTS: Inhalation of BDP in both body postures provided similar protection against EIB (fall in FEV1 or FEV0.1 in standard posture 16.7%; in forward leaning posture 15.1%, p = 0.83). Inhaling ICS in a forward leaning posture significantly delayed EIB compared to inhaling in the standard posture (respectively 2.5 min ± 1.0 min vs. 1.6 min ± 0.8 min; difference 0.9 min (95CI 0.25; 1.44 min); p = 0.01). CONCLUSION: Inhalation of a single dose BDP in both the forward leaning posture and the standard posture provided effective and similar protection against EIB in asthmatic children, but the forward leaning posture resulted in a delay of EIB. REGISTER: NTR3432 (www.trialregister.nl).

Lecithin/TPGS-based spray-dried self-microemulsifying drug delivery systems: In vitro pulmonary deposition and cytotoxicity.

The aim of the present work was to develop a new solid self-microemulsifying drug delivery system (SMEDDS) for the pulmonary delivery of the poorly water-soluble anti-cancer drug atorvastatin (AVT). Microemulsion (ME) was first developed using isopropyl myristate (IPM), a combination of 2 biocompatible surfactants: lecithin/d-α-tocopheryl polyethylene glycol succinate (TPGS) and ethanol as co-surfactant. Two types of lecithin with different phosphatidylcholine (PC) contents were compared. Phase diagram, physico-chemical characterization and stability studies were used to investigate ME region. Solid SMEDDS were then prepared by spray-drying the selected ME using a combination of carriers composed of sugars, leucine as dispersibility enhancer with or without polyethylene glycol (PEG) 6000. Yield, flow properties, particle size and in vitro pulmonary deposition were used to characterize the spray-dried powders. Reconstituted MEs were characterized in terms of morphology, particle size and size distribution. In vitro cytotoxicity study was undertaken on lung cancer cell line for the selected MEs and SD-SMEDDS formulae. Results showed that the most satisfactory MEs properties were obtained with 1:3 lecithin/TPGS, 1:1 lecithin/oil and 1:1 surfactant/co-surfactant ratios. A larger ME area was obtained with lecithin containing 100% PC compared to the less expensive lecithin containing 20% PC. By manipulating spray drying parameters, carrier composition and ratio of ME lipids to carrier, microparticles with more than 70% of respirable fraction could be prepared. The ME was efficiently recovered in simulated lung fluid even after removal of alcohol. The concurrent delivery of AVT with TPGS in solid SMEDDS greatly enhanced the cytotoxic activity on lung cancer cells.

Pharmacokinetic study for the establishment of bioequivalence of two inhalation treatments containing budesonide plus formoterol.

OBJECTIVES: The aim of this study was to compare lung deposition and assess the bioequivalence of two formulations containing budesonide and formoterol and being delivered via Elpenhaler and Turbuhaler, respectively. A pharmacokinetic (PK) study was conducted. METHODS: An open, randomized, two-sequence, two-period, crossover, single-dose study in 100 asthmatic patients under fasting conditions was performed. Wash out period was 6 days. Equivalence in lung deposition was assessed after a single inhalation of each treatment with concomitant oral administration of activated charcoal (40 g) to prevent gastrointestinal absorption of the drugs. Several PK parameters were estimated, the area under the drug concentration in plasma versus time curve (AUC0-t ) and the maximum drug concentration in plasma (Cmax ) being the primary response variables. Equivalent lung deposition was concluded if the 90% confidence interval (CI) for the Elpenhaler/Turbuhaler geometric mean ratio of AUC0-t and Cmax , for both drug substances fell within the regulatory limits (0.80-1.25). KEY FINDINGS: Acceptance criteria were met. Equivalent lung deposition can be concluded. No statistically significant differences between treatments in the incidence of adverse events were found. CONCLUSIONS: The formulations are bioequivalent regarding both rate and extent of absorption. The treatments were also well tolerated by the participating subjects.

Respiratory system deposition with a novel aerosol delivery system in spontaneously breathing healthy adults.

BACKGROUND: Intravenous magnesium sulfate (MgSO(4)) in children and adults with refractory acute asthma is effective, but therapy may be limited by systemic hypotension that might be avoided with the aerosol route. Inhaled MgSO(4) has a relatively high dose (volume) requirement. This, plus the use of inefficient delivery systems, may explain the lack of efficacy of inhaled MgSO(4) in some studies. An in vitro study suggested that the AeroNeb Go with the Idehaler Pocket and a face mask would deliver 16 mg/min of MgSO(4) to the respiratory system in older children, and approximately a fifth for toddlers, but no in vivo data exist. METHODS: Saline mixed with a radiolabel was used as a proxy for the 100 mg/mL MgSO(4) solution. In 5 adult males the rate of deposition was measured using nuclear medicine techniques. The radiolabel deposition below the vocal cords was converted to the rate of deposition of MgSO(4) and compared to the results from an in vitro model using adult respiratory patterns. RESULTS: The mean ± SD rate of deposition was 12.6 ± 1.9 mg/min. The reasons for this lower deposition, compared to the in vitro estimate, was most likely the exhalation of anatomical dead space aerosol, which would have been captured on the inspiratory filter in vitro. CONCLUSIONS: These in vivo data confirm the deposition data predicted in the in vitro study, although caution should be used in extrapolating the results to children. This device appears suitable for the clinical trial of inhaled MgSO(4) in children and adults with refractory asthma.