Hydrofluoroalkane Research Articles

Pharmaceutical, Clinical, and Regulatory Challenges of Reformulating Pressurized Metered-Dose Inhalers to Reduce Their Environmental Impact.

The chlorofluorocarbons (CFCs) that were used as propellants in early pressurized metered-dose inhalers (pMDIs) had substantial ozone-depleting potential. Following the Montreal Protocol in 1987, the manufacture of a range of ozone-depleting substances, including CFCs, was gradually phased out, which required the propellants used in pMDIs to be replaced. Current pMDIs use hydrofluoroalkanes (HFAs) as propellants, such as 1,1,1,2-tetrafluoroethane (HFA-134a). Although these HFAs have no ozone-depleting potential, they have a high global warming potential (GWP), and consequently, their use is being phased down. One option for the discontinuation of HFA use in inhalers would be to discontinue all pMDIs, switching patients to dry powder inhalers (DPIs). However, a switch from pMDIs to DPIs may not be a clinically appropriate option for some patients; furthermore, the full lifecycle carbon footprint and the overall environmental impact of different inhalers should be considered. An alternative is therefore to reformulate the current HFA pMDIs to use low-GWP propellants, such as 1,1-difluoroethane (HFA-152a). This article summarizes the various steps and challenges associated with this change, illustrated using data from the inhaled triple combination of beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide, a complex formulation of three molecules in a solution that contains liquid-phase propellant.

Pressurized metered-dose inhalers using next-generation propellant HFO-1234ze(E) deposit negligible amounts of trifluoracetic acid in the environment

Pressurized metered-dose inhalers (pMDIs) deliver life-saving medications to patients with respiratory conditions and are the most used inhaler delivery device globally. pMDIs utilize a hydrofluoroalkane (HFA), also known as an F-gas, as a propellant to facilitate the delivery of medication into the lungs. Although HFAs have minimal impact on ozone depletion, their global warming potential (GWP) is more than 1,000 times higher than CO2, bringing them in scope of the F-Gas Regulation in the European Union (EU). The pharmaceutical industry is developing solutions, including a near-zero GWP “next-generation propellant,” HFO-1234ze(E). At the same time, the EU is also evaluating a restriction on per-and polyfluoroalkyl substances (PFAS) under the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) regulation. Trifluoroacetic acid (TFA) is a persistent PFAS and a potential degradation product of HFO-1234ze(E). We quantified yield of TFA from HFO-1234ze(E) using a computational model under Europe-relevant atmospheric conditions. The modeling suggests that most HFO-1234ze(E) degrades into formyl fluoride within 20 days (≥85%) even at the highest examined altitude. These results suggest that TFA yield from HFO-1234ze(E) varies between 0%–4% under different atmospheric conditions. In 2022, France represented the highest numbers of pMDI units sold within the EU, assuming these pMDIs had HFO-1234ze(E) as propellant, we estimate an annual rainwater TFA deposition of ∼0.025 μg/L. These results demonstrate negligible formation of TFA as a degradation product of HFO-1234ze(E), further supporting its suitability as a non-persistent, non-bioaccumulative, and non-toxic future propellant for pMDI devices to safeguard access for patients to these essential medicines.

The Study of Spray-Freeze-Drying Technique for Development of Novel Combination pMDIs, Part II: In Vitro and In Vivo Evaluations

AbstractThe mometasone furoate (MF) and formoterol fumarate dihydrate (FF) inhalable microparticles prepared by different methods, such as micronized active pharmaceutical ingredients (APIs), microparticles of APIs prepared by spray-freeze drying technique (SFD APIs), and phospholipid microparticles of APIs prepared by SFD (SFD Lip-APIs), showed different inhaled drug delivery characteristics. Study on the physicochemical characteristics of those microparticles and the effect of matrix excipients on pharmacokinetic (PK) behaviors of inhalable microparticles is helpful for the development of new methods for inhalable microparticles with excellent performance of inhalation characteristics. In this study, the crystal state of the microparticles was investigated by powder X-ray diffraction and differential scanning calorimetry. The density was investigated by a bulk density method. The suspension and dispersion characteristics were determined by observing its state in hydrofluoroalkane (HFA). Meanwhile, the PK behaviors of SFD Lip-APIs in beagle dogs were also investigated by airway administration to evaluate the effect of phospholipids on drug release. The results indicated that the presence of phospholipids prevents the formation of solid bridges bonding to each other during SFD of pure drug solutions. In comparison to the conventional micronized microparticles, inhalable drug–phospholipid microparticles were easily dispersed and suspended in HFA. The embedded drugs were in a crystal state that endowed a better physical stability, and most interestingly, have similar PK behavior to the control (a mixed solution of MF/FF), suggesting that the phospholipids, as matrix excipients, had no effect on absorption. Given above, our designed SFD phospholipid microparticles may represent an efficient carrier for pulmonary delivery of MF and FF for further clinical treatment.

Reducing carbon footprint of inhalers: analysis of climate and clinical implications of different scenarios in five European countries

BackgroundInhaled therapies are key components of asthma and chronic obstructive pulmonary disease (COPD) treatments. Although the use of pressurised metered-dose inhalers (pMDIs) accounts for <0.1% of global greenhouse gas emissions,...

Water Uptake by Evaporating pMDI Aerosol Prior to Inhalation Affects Both Regional and Total Deposition in the Respiratory System.

As pulmonary drug deposition is a function of aerosol particle size distribution, it is critical that the dynamics of particle formation and maturation in pMDI sprays in the interim between generation and inhalation are fully understood. This paper presents an approach to measure the evaporative and condensational fluxes of volatile components and water from and to solution pMDI droplets following generation using a novel technique referred to as the Single Particle Electrodynamic Lung (SPEL). In doing so, evaporating aerosol droplets are shown capable of acting as condensation nuclei for water. Indeed, we show that the rapid vaporisation of volatile components from a volatile droplet is directly correlated to the volume of water taken up by condensation. Furthermore, a significant volume of water is shown to condense on droplets of a model pMDI formulation (hydrofluoroalkane (HFA), ethanol and glycerol) during evaporative droplet ageing, displaying a dramatic shift from a core composition of a volatile species to that of predominantly water (non-volatile glycerol remained in this case). This yields a droplet with a water activity of 0.98 at the instance of inhalation. The implications of these results on regional and total pulmonary drug deposition are explored using the International Commission of Radiological Protection (ICRP) deposition model, with an integrated semi-analytical treatment of hygroscopic growth. Through this, droplets with water activity of 0.98 upon inhalation are shown to produce markedly different dose deposition profiles to those with lower water activities at the point of inspiration.

Effects of Shake-Actuation Delay on Delivered Dose and Aerosol Characteristics of an Albuterol Suspension From a Pressurized Metered-Dose Inhaler.

Suspensions delivered via a pressurized metered-dose inhaler (pMDI) require shaking the canister before actuation to prevent drug sedimentation. We hypothesized that a shake-actuation delay of an albuterol hydrofluoroalkane (HFA) pMDI will increase and decrease delivered dose (DOSE) at the beginning and end of the canister's life, respectively, and that aerosol characteristics will remain unchanged with the delay. Albuterol HFA pMDIs (90 µg/actuation, 200 doses) operated with and without a 30-s shake-actuation delay, and with and without a valved holding chamber (VHC), were studied. Ten puffs, with a 30-s interval between puffs and 5s of shaking, were actuated into a drug-recovery apparatus. Inhalers were studied throughout their entire life (from 200 doses to 0 remaining doses). Particle size analysis was performed with cascade impaction at the beginning, middle, and end of the canister's life. Albuterol mass was determined via spectrophotometry (276 nm). Mean (99% CI) delivered dose without shake-actuation delay was 100.4% (98.1-102.9%) of the nominal dose. Mean (99% CI) delivered dose with a VHC without a shake-actuation delay was 48.6% (46.2-50.9%) of the nominal dose. The shake-actuation delay increased and decreased delivered dose at the beginning and end of the canister's life, respectively, irrespective of VHC use. Decline in delivered dose began when 110-120 doses remained in the canister. Aerosol characteristics remained constant throughout the canister's life except for the amount of drug captured by the impactor for the pMDI with delay and the pMDI/VHC with delay. Adding a VHC to a pMDI operated with a delay increased fine-particle fraction and decreased the amount of drug captured by the impactor at the middle and at the end of the canister's life. A 30-s shake-actuation delay of an albuterol HFA pMDI increased and decreased delivered dose at the beginning and end of canister's life, respectively. Particle size characteristics at the end of the canister's life changed when the pMDI and pMDI/VHC were operated with a shake-actuation delay. Patients should re-shake the pMDI if it is not actuated immediately after shaking the canister.

A Single Inhaler Combining a Corticosteroid and Long-Acting Beta-2 Agonist for Maintenance with Additional Doses for Reliever Therapy (SMART): Obstacles for Asthma Patients in the USA.

A Single Inhaler Combining a Corticosteroid and Long-Acting Beta-2 Agonist for Maintenance with Additional Doses for Reliever Therapy (SMART): Obstacles for Asthma Patients in the USA.

Consequences of not-shaking and shake-fire delays on the emitted dose of some commercial solution and suspension pressurized metered dose inhalers

ABSTRACT Background Pressurized metered-dose inhalers (pMDIs) include hydrofluoroalkane (HFA) propellant to generate a drug aerosol upon actuation and drugs can be formulated as solution or suspension. Suspended particles can cream or sediment depending on density differences between drug and propellant and shaking the pMDI is an essential step to ensure a uniform drug dose release. Research design and methods The effect of the delay (0, 10, 30, 60 seconds) in pMDI actuation after shaking and the effect of no-shaking during the canister life on the emitted dose (ED) for commercial solution and suspension pMDIs was investigated. Results The ED for solutions was unaffected by no-shaking or by the progressive increasing delay in actuation after shaking (between 77% and 97%). For all the suspension products, shaking was demonstrated to be critical to assure the close to nominal drug delivery. In detail, the actuation delay after shaking led to an increase up to 380% or a drop to 32% of ED in relation to the label claim with high variability. Conclusion The drug delivered can vary widely for no-shaking and over different shake-fire delays with suspension pMDIs while solution formulations appear to remain stable.

Green respiratory healthcare: need for proportionality

The Montreal Protocol on Substances That Deplete the Ozone Layer was an example of an amazing international collaboration that has already led to improvements in the ozone layer, although the...

Long-term safety and efficacy studies of epinephrine HFA metered-dose inhaler (Primatene® Mist): a two-stage randomized controlled trial

Objective: A new epinephrine hydrofluoroalkane (HFA) asthma metered-dose inhaler (MDI) was reformulated to replace the previously marketed epinephrine chlorofluorocarbon (CFC) MDI. In addition to the HFA propellant change, several enhanced modifications (i.e. changed from solution to suspension, 43% dose reduction, etc.) were made to the formulation of epinephrine HFA MDI. This study evaluates the 6-month long-term safety and efficacy profile of the new epinephrine HFA MDI.Method: The long-term safety study consists of two 3-month, multi-center, double- or evaluator-blinded, parallel-group, placebo, and active controlled stages. In each stage, subjects aged ≥12 years with intermittent or mild-to-moderate persistent asthma were randomized to receive epinephrine HFA (2 × 125 mcg/inhalation), placebo HFA, or epinephrine CFC (2 × 220 mcg/inhalation). Bronchodilator efficacy was assessed in Stage 1 and was determined primarily by the change in the forced expiratory volume in 1 s (ΔFEV1) at Week 12, relative to the same day baseline.Results: The primary efficacy endpoint (AUC0-6hrs of %ΔFEV1 at Week 12) for epinephrine HFA (47.3 ± 54.2) closely paralleled those for the active control, epinephrine CFC (41.0 ± 43.4). Both groups were found to be overall comparable in bronchodilator efficacy. Both also showed low incidence rates of AEs with tremor being most commonly reported for epinephrine HFA. All AEs found were non-serious and non-significant. The observed changes in vital signs, ECG, serum glucose, and potassium were minimal and not clinically relevant.Conclusion: This study demonstrated that the new epinephrine HFA is overall comparable, in both safety and efficacy, to the previous epinephrine CFC.

Environmental impacts of healthcare and pharmaceutical products: Influence of product design and consumer behaviour

Healthcare and pharmaceutical products are used widely but their environmental impacts are still largely unknown. This paper provides an insight into the influence of product design and consumer behaviour on the environmental impacts of the use and end-of-life of some healthcare and pharmaceutical products, with the aim of identifying improvement opportunities. The influence of product design is assessed through two types of asthma inhaler: hydrofluoroalkane (HFA) and dry-powder devices. Consumer behaviour is examined by considering the use of toothpaste and consumption of nutritional drinks. The results indicate that the use and end-of-life stages contribute significantly (∼90%) to the carbon footprint of HFA inhalers, estimated at 26.9 kg CO2/100 doses. The carbon footprint of dry-powder inhalers is 10 times smaller (2.7 kg CO2/100 doses). Product design innovations to eliminate HFA propellants could save over 13 Mt CO2 eq./y globally. The use stage is also the main hotspot for most other environmental impacts across the products considered in the study. The contribution of end-of-life stage is significant for eutrophication and some toxicity-related impacts for inhalers and toothpaste. The impacts of toothpaste and nutritional drinks are highly influenced by consumer behaviour during the use stage. For example, using cold instead of warm water for teeth brushing and a tumbler instead of leaving the tap running would reduce the carbon footprint from the use of toothpaste by 57 times and water consumption by 20 times. These findings highlight that both design innovations and changes in consumer behaviour play a significant role in addressing global environmental challenges. Therefore, in addition to environmental improvements through product development and supply change management, healthcare companies should also focus on providing consumer guidance to help lower the environmental impacts of their products.

In vitro evaluation of aerosol drug delivery with and without high flow nasal cannula in children.

To quantify aerosol delivery with or without a high flow nasal cannula (HFNC) in place using pressurized metered-dose inhaler (pMDI) and jet nebulizer (JN) with facemask in a simulated spontaneously breathing pediatric lung model. An upper airway model of a 9-month-old infant (Sophia Anatomical Infant Nose-Throat) with an absolute filter distal to the trachea was connected to a breathing simulator to simulate pediatric parameters (tidal volume = 100 mL, respiratory rate = 30 breaths/min, and I:E ratio = 1:1.4). Oxygen at 3 L/min was administered through an infant HFNC (Fisher & Paykel Healthcare Ltd, Auckland, New Zealand) attached to the nares of the model. Albuterol sulfate (2.5 mg/3 mL) was delivered with JN attached to an aerosol facemask and powered by air at 8 L/min. Ventolin Hydrofluoroalkane (HFA) (360 μg) was administered using pMDI connected to a valved holding chamber (VHC) with a facemask. Aerosol was administered to the model with and without HFNC in the nares (n = 3). Drug was eluted from the filter and quantified using spectrophotometry. Independent t tests were performed for data analysis (P < .05). Aerosol deposition was greater without HFNC (6.05% ± 1.53% and 39.54% ± 8.98% for JN and pMDI/VHC, respectively) than with HFNC using JN (2.91% ± 0.23%; P = .024) and pMDI/VHC (6.04% ± 0.28%; P = .003). Delivery efficiency of pMDI/VHC was greater than JN with or without nasal cannula in place (P = .0001 and .003, respectively). Aerosol administered via facemask over HFNC was less efficient than removing HFNC during administration. When delivering medical aerosol by facemask, the benefit of increased aerosol delivery must be weighed against the changes in oxygen delivery and risk of lung derecruitment when nasal prongs are removed.

The Effect of a Holding Chamber on Albuterol Metered-Dose Inhaler Product Differences

JL Johnson, D Guthrie, J Hyde, T Hanson, K Karlage, PB Myrdal. Ann Allergy Asthma Immunol. 2016;117(3):246–250 To investigate the differences in 3 albuterol sulfate metered-dose inhaler (MDI) products and their particle size. The study also evaluated if use of a valved holding chamber (VHC) would impact drug delivery and/or diminish systemic adverse effects. The study did not use human subjects, but rather examined Ventolin hydrofluoroalkane (HFA), Proventil HFA, and ProAir HFA, the 3 racemic albuterol sulfate pressurized MDI products available in the United States. The experimental design involved a nonviable 8-stage Anderson Cascade Impactor (ACI) with a US Pharmacopeia (USP) throat model with a mean (SD) airflow rate of 28.3 (0.5) mL/min. Each of the 3 albuterol MDI products …

NANO-VESICLES OF SALBUTAMOL SULPHATE IN METERED DOSE INHALERS: FORMULATION, CHARACTERIZATION AND IN VITRO EVALUATION

Objective: The present work was aimed to prepare niosomes entrapping salbutamol sulphate (SS) using reversed phase evaporation method (REV).Methods: Niosomes were prepared by mixing span 60 and cholesterol in 1:1 molar ratio in chloroform, SS in water was then added to organic phase to form niosomal SS. Formulations after evaporation of chloroform, freeze centrifuged then lyophilized, were evaluated for particles size, polydispersity index (Pdi), zeta-potential, morphology, entrapment efficiency (EE%) and in vitro release. For pulmonary delivery; metered dose inhalers (MDI) were prepared by suspending SS niosomes equivalent to 20 mg SS in hydrofluoroalkane (HFA). The metered valve was investigated for leakage rate, the total number of puffs/canister, weight/puff, dose uniformity and particle size.Results: The results showed spherical niosomes with 400-451 nm particles that entrapped 66.19% of SS. 76.54±0.132% SS release from niosomes that showed a controlled release profile for 8h. The leakage test was not exceeding 4 mg/3 d, the number of puffs were up to 200puffs/canister, the dose delivered/puff was 0.1 mg and 0.64-4.51μm niosomal aerosol.Conclusion: The results indicate an encouraging strategy to formulate a controlled drug delivery by entrapping (SS) in niosomes which could be packaged into (MDI) that met the requirements of (USP) aerosols guidelines which offering a novel approach to respiratory delivery.

Nanoparticles of pH-Responsive, PEG-Doxorubicin Conjugates: Interaction with an in Vitro Model of Lung Adenocarcinoma and Their Direct Formulation in Propellant-Based Portable Inhalers.

Pulmonary administration of polymer drug conjugates is of great potential clinical significance for treating lung cancer as such regimen significantly increases local drug concentrations while decreases systemic and local side effects. In this work, we demonstrate that nanoparticles prepared with methoxypoly(ethylene glycol) (mPEG)-doxorubicin (DOX) conjugates (mPEG-DOX) that have a pH-sensitive imine bond (Schiff base) can at the same time work as efficient carriers for DOX to kill cancer cells and also as a strategy to directly formulate nanoparticles in propellant-based inhalers. Nanoparticles prepared by precipitation in water had a diameter in the range between 100 and 120 nm. We investigated the effects of molecular weight (MW) of mPEG (1K, 2K, and 5K Da) on the in vitro release kinetics, cellular internalization, and cytotoxicity on in vitro model of lung adenocarcinoma and aerosol characters. It is observed that the DOX released from mPEG-DOX nanoparticles was significantly accelerated in acidic environment, pH 5.5 (endosomal/lysosomal pH) in comparison with pH 7.4 (physiological pH), as designed. Release of DOX from mPEG1K-DOX nanoparticles was significantly greater than those from mPEG2K and mPEG5K counterparts. In vitro cytotoxicity of nanoparticles followed the sequence of mPEG1K-DOX > free DOX > mPEG2K-DOX ≫ mPEG5K-DOX, a trend closely following their rate and extent of cellular internalization. mPEG-DOX nanoparticles with mPEG1K and mPEG2K were directly dispersed in hydrofluoroalkane (HFA), while a trace of ethanol was required to disperse mPEG5K-DOX nanoparticles in HFA. These pMDI formulations with high physical stability in HFAs display superior aerosol characteristics conducive to deep lung deposition. The fine particle fractions of these formulations ranged from 40-60%, higher than those of commercial products. Such formulations prepared from nanoparticles of pH-sensitive PEG-drug conjugates may also be envisioned to be extended to formulate other hydrophobic drugs for local delivery with propellant-based inhalers to other pulmonary disorders, thus broadening the impact of the proposed strategy.

Asthma pressurised metered dose inhaler performance: propellant effect studies in delivery systems

BackgroundCurrent pressurised metered dose asthma inhaler (pMDI) propellants are not inert pharmacologically as were previous chlorofluorocarbons, have smooth muscle relaxant‚ partial pressure effects in the lungs and inhaled hydrofluoroalkane 134a (norflurane) has anaesthetic effects. Volumes of propellant gas per actuation have never been measured.MethodsIn-vitro studies measured gas volumes produced by pMDIs on air oxygen (O2) levels in valved holding chambers (VHC) and the falls in O2% following actuation into lung ventilator delivery devices.ResultsVolumes of propellant gas hydrofluoroalkane (HFA) 134a and 227ea and redundant chlorofluorocarbons (CFC) varied from 7 ml per actuation from a small salbutamol HFA inhaler to 16 ml from the larger. Similar-sized CFC pMDI volumes were 15.6 and 20.4 ml. Each HFA salbutamol inhaler has 220 full volume discharges; total volume of gas from a small 134a pMDI was 1640 ml, and large 3885 ml. Sensing the presence of liquid propellant by shaking was felt at the 220th discharge in both large and small inhalers. Because of a partial pressure effect, VHC O2% in air was reduced to 11% in the smallest 127 ml volume VHC following 10 actuations of a large 134a salbutamol inhaler. The four ventilator delivery devices studied lowered 100% oxygen levels to a range of 93 to 81% after five actuations, depending on the device and type of pMDI used.ConclusionPressurised inhaler propellants require further study to assess smooth muscle relaxing properties.

Real-world health care utilization in asthma patients using albuterol sulfate inhalation aerosol (ProAir ® HFA) with and without integrated dose counters.

BackgroundAccurate tracking of the administered dose of asthma rescue inhalers is critical for optimal disease management and is related to reductions in rates of unscheduled health care utilization in asthma patients. There are few published data on the real-world impact of rescue inhalers with integrated dose counters (IDCs) on health care resource utilization (HRU) for asthma patients. This study evaluates HRU among users of ProAir® hydrofluoroalkane (HFA) (albuterol sulfate inhalation aerosol), with IDC versus without IDC, in asthma patients.MethodsThis was a retrospective administrative claims study of asthma patients receiving a new prescription for albuterol inhalation aerosol without IDC during 2 years (January 2011–December 2012) or with IDC during the first full year after IDC implementation in the USA (July 2013–July 2014). Six months of continuous enrollment with medical and prescription drug benefits were required before and after the first prescription during the study period. Data on respiratory-related hospitalizations and emergency department (ED) visits were collected during the follow-up period.ResultsA total of 135,305 (32%) patients used albuterol inhalation aerosol with IDC, and 287,243 (68%) patients received albuterol inhalation aerosol without IDC. After adjusting for baseline confounding factors, the odds ratio (OR) for experiencing a respiratory-related hospitalization (OR=0.92; 95% confidence interval [CI] 0.88–0.96) or ED visit (OR=0.92; 95% CI 0.90–0.94) was significantly lower among patients using albuterol inhalation aerosol with IDC versus without IDC.ConclusionIn a real-world setting, asthma patients using ProAir HFA with IDC experienced significantly fewer hospitalizations and ED visits compared with patients using ProAir HFA without IDC. Dosage information provided by IDCs may allow providers to better understand patients’ disease severity and aid in titrating controller medications and also decrease the likelihood that the canister will be empty when needed, thereby enhancing disease management and reducing HRU.

Erratum to: Comparative lung bioavailability of fluticasone/salmeterol via a breath-actuated spacer and conventional plastic spacers.

This study compares the in vivo relative lung bioavailability of Hydrofluoroalkane (HFA) Seretide delivered via unprimed and unwashed Aerochamber Plus (AP) or Volumatic (VM) spacers, a integrated breath-actuated vortex Synchro-Breathe (SB) device and an Evohaler pMDI (EH) device using adrenal suppression and early fall in serum potassium (K) as surrogates for respirable dose.Seventeen healthy volunteers completed this randomised double-blind, double-dummy crossover study. Single doses of placebo/Seretide 250 (total dose ex valve fluticasone 2000 mcg/salmeterol 200 mcg) were administered via the devices. Overnight urinary cortisol/creatinine (OUCC) and serum K were measured at baseline and after each dose.Significant suppression of OUCC and K occurred from baseline with the SB, AP and VM but not with the EH devices. The geometric mean fold suppression (95% confidence interval, p) was: EH, 1.59 (0.80-3.14, p=0.40); AP, 4.26 (3.01-6.02, p<0.001); VM, 3.11 (1.99-4.78, p<0. 001); SB, 3.29 (2.04-5.24, p<0.001). For K, the arithmetic mean fall (mmol/l) (95% confidence interval; p) was: EH, -0.10 (-0.25-0.05, p=0.18); AP, -0.23 (-0.41 to -0.04, p=0.02); VM, -0.22 (-0.44 to -0.01, p=0.04); SB, -0.28 (-0.42 to -0.13, p=0.001).The breath-actuated SB device was comparable to 'out of the box' small and large volume spacers and produced similar improvements in relative systemic lung bioavailability for fluticasone and salmeterol.

Factors DeterminingIn VitroLung Deposition of Albuterol Aerosol Delivered by Ventolin Metered-Dose Inhaler

The effectiveness of metered-dose inhalers (MDIs) in delivering medication to the lungs highly depends on its correct usage technique. Current guidelines state optimal technique for high lung deposition should include a slow inhalation (>5 seconds) at an inspiratory flow rate of 30 L/min and inhaler actuation at the start of inhalation. However, these recommendations were based on clinical studies using CFC (chlorofluorocarbon)-MDIs and in vitro studies of HFA (hydrofluoroalkane)-MDIs using idealized MDI techniques of uniform inhalation and actuation, disregarding the nonuniform techniques of actual patients. To better understand the effects of time-varying MDI usage parameters on lung deposition of aerosol delivered by an HFA-MDI, we conducted an in vitro study modeled on real-life variable inspiratory flow and actuation techniques recorded from 15 subjects with asthma/chronic obstructive pulmonary disease (COPD). We developed a model representing the time-varying inspiratory flow waveforms and actuation timings based on 43 MDI techniques recorded from patients. Furthermore, we constructed an in vitro experimental setup using a mouth-throat cast, programmable MDI actuator, and breath simulator to evaluate lung deposition for the MDI techniques derived from our model. High inspiratory flow rates, 60-90 L/min, consistently resulted in high in vitro lung deposition (>40%) of aerosol (albuterol delivered from Ventolin HFA-MDI) compared to 30 L/min when MDI actuation occurred in the first half of inhalation. Also, positive coordination resulted in higher in vitro lung deposition compared with negative or zero coordination (actuating before or at the start of inspiration). Furthermore, variation in coordination affected lung deposition more significantly (23%) than flow rate or duration of inspiration (≤5%). In an in vitro experimental model based on inhalation data from patients with asthma and COPD, we demonstrated that aerosol lung deposition emitted from Ventolin HFA-MDI is most optimal for MDI actuation in the first half of inspiration at high flow rates (60-90 L/min).

Comparison of Pharmacokinetic and Pharmacodynamic Effects of Two Hydrofluoroalkane Formulations of Salmeterol

Introduction: To compare the Pharmacokinetic (PK) and Pharmacodynamic (PD) effects of two Hydrofluoroalkane (HFA) formulations of salmeterol xinafoate (Test HFA formulation, Cipla Ltd., India; Reference HFA formulation, Allen and Hanburys, UK) administered using pressurized metered dose inhalers. Methods: Three separate randomized, crossover, PK studies and one PD study comparing the efficacy and safety of the two HFA formulations of salmeterol xinafoate (25 μg per actuation) in healthy subjects were conducted. The PK assessments of the two formulations were done without charcoal blockade, with charcoal blockade, and with a Volumatic spacer device using a single dose. A PD study was also conducted to evaluate the systemic exposure of the two formulations using three different doses (50 μg, 150 μg and 300 μg). Results: In the PK study without charcoal, the 90% CI for the difference between the two formulations for AUC0-t was within the bioequivalence limits of 80-125%; however, Cmax marginally exceeded the upper bioequivalence limit to 136%. In the PK study with charcoal, the 90% CI for the difference between the two formulations for Cmax was within the bioequivalence limits of 80-125%; however, AUC0-t marginally exceeded the upper bioequivalence limit to 128%. The impact of marginally higher systemic exposure was therefore further evaluated in the PD study. The PD study confirmed there were no greater systemic safety effects of the test formulation on the primary PD endpoints such as heart rate and serum potassium as well as on other safety PD endpoints such as blood glucose and QTc interval. The PK study with spacer demonstrated bioequivalence between the test and reference formulations. Both formulations were safe and well tolerated. Conclusion: The test HFA formulation of salmeterol was therapeutically equivalent to the reference HFA formulation of salmeterol when used with and without a spacer.