Design and Characterization of Maltoheptaose-b-Polystyrene Nanoparticles, as a Potential New Nanocarrier for Oral Delivery of Tamoxifen.

Tamoxifen citrate (TMC), a non-steroidal antiestrogen drug used for the treatment of breast cancer, was loaded in a block copolymer of maltoheptaose-b-polystyrene (MH-b-PS) nanoparticles, a potential drug delivery system to optimize oral chemotherapy. The nanoparticles were obtained from self-assembly of MH-b-PS using the standard and reverse nanoprecipitation methods. The MH-b-PS@TMC nanoparticles were characterized by their physicochemical properties, morphology, drug loading and encapsulation efficiency, and release kinetic profile in simulated intestinal fluid (pH 7.4). Finally, their cytotoxicity towards the human breast carcinoma MCF-7 cell line was assessed. The standard nanoprecipitation method proved to be more efficient than reverse nanoprecipitation to produce nanoparticles with small size and narrow particle size distribution. Moreover, tamoxifen-loaded nanoparticles displayed spherical morphology, a positive zeta potential and high drug content (238.6 ± 6.8 µg mL-1) and encapsulation efficiency (80.9 ± 0.4 %). In vitro drug release kinetics showed a burst release at early time points, followed by a sustained release profile controlled by diffusion. MH-b-PS@TMC nanoparticles showed higher cytotoxicity towards MCF-7 cells than free tamoxifen citrate, confirming their effectiveness as a delivery system for administration of lipophilic anticancer drugs.

Evaluation of the Physico-mechanical Properties and Electrostatic Charging Behavior of Different Capsule Types for Inhalation Under Distinct Environmental Conditions.

Capsule-based dry powder inhaler (DPI) products can be influenced by a multitude of interacting factors, including electrostatic charging. Tribo-charging is a process of charge transfer impacted by various factors, i.e., material surface characteristics, mechanical properties, processing parameters and environmental conditions. Consequently, this work aimed to assess how the charging behavior of capsules intended for inhalation might be influenced by environmental conditions. Capsules having different chemical compositions (gelatin and hydroxypropyl methylcellulose (HPMC)) and distinct inherent characteristics from manufacturing (thermally and cold-gelled) were exposed to various environmental conditions (11%, 22% and 51% RH). Their resulting properties were characterized and tribo-charging behavior was measured against stainless steel and PVC. It was observed that all capsule materials tended to charge to a higher extent when in contact with PVC. The tribo-charging of the thermally gelled HPMC capsules (Vcaps® Plus) was more similar to the gelatin capsules (Quali-G™-I) than to their HPMC cold-gelled counterparts (Quali-V®-I). The sorption of water by the capsules at different relative humidities notably impacted their properties and tribo-charging behavior. Different interactions between the tested materials and water molecules were identified and are proposed to be the driver of distinct charging behaviors. Finally, we showed that depending on the capsule types, distinct environmental conditions are necessary to mitigate charging and assure optimal behavior of the capsules.

100 Years of Drug Delivery to the Lungs.

Inhalation therapy is one of the oldest approaches to the therapy of diseases of the respiratory tract. It is well recognised today that the most effective and safe means of treating the lungs is to deliver drugs directly to the airways. Surprisingly, the delivery of therapeutic aerosols has a rich history dating back more than 2,000 years to Ayurvedic medicine in India, but in many respects, the introduction of the first pressurised metered-dose inhaler (pMDI) in 1956 marked the beginning of the modern pharmaceutical aerosol industry. The pMDI was the first truly portable and convenient inhaler that effectively delivered drug to the lung and quickly gained widespread acceptance. Since 1956, the pharmaceutical aerosol industry has experienced dramatic growth. The signing of the Montreal Protocol in 1987 to reduce the use of CFCs as propellants for aerosols led to a surge in innovation that resulted in the diversification of inhaler technologies with significantly enhanced delivery efficiency, including modern pMDIs, dry powder inhalers and nebuliser systems. There is also great interest in tailoring particle size to deliver drugs to treat specific areas of the respiratory tract. One challenge that has been present since antiquity still exists, however, and that is ensuring that the patient has access to the medication and understands how to use it effectively. In this article, we will provide a summary of therapeutic aerosol delivery systems from ancient times to the present along with a look to the future.

Inhalable chitosan microparticles for simultaneous delivery of isoniazid and rifabutin in lung tuberculosis treatment.

The direct delivery of antibiotics to the lung has been considered an effective approach to treat pulmonary tuberculosis, which represents approximately 80% of total cases. In this sense, this work aimed at producing inhalable chitosan microparticles simultaneously associating isoniazid and rifabutin, for an application in pulmonary tuberculosis therapy. Spray-dried chitosan microparticles were obtained with adequate flow properties for deep lung delivery (aerodynamic diameter of 4 µm) and high drug association efficiencies (93% for isoniazid and 99% for rifabutin). The highest concentration of microparticles that was tested (1 mg/mL) decreased the viability of macrophage-differentiated THP-1 cells to around 60% after 24 h exposure, although no deleterious effect was observed in human alveolar epithelial (A549) cells. The release of LDH was, however, increased in both cells. Chitosan microparticles further evidenced capacity to activate macrophage-like cells, inducing cytokine secretion well above basal levels. Moreover, the propensity of macrophages to internalize microparticles was demonstrated, with uptake levels over 90%. Chitosan microparticles also inhibited bacterial growth by 96%, demonstrating that the microencapsulation preserved drug antibacterial activity in vitro. Overall, the obtained data suggest the potential of chitosan microparticles for inhalable lung tuberculosis therapy.

Dry powder inhaler of colistimethate sodium for lung infections in cystic fibrosis: optimization of powder construction.

Colistimethate sodium (CMS) for treatment of lung infections in cystic fibrosis patient was transformed into a dry powder for inhalation by spray drying. Design of Experiment was applied for understanding the role of the spray-drying process parameters on the critical quality attributes of the CMS spray-dried (SD) powders and agglomerates thereof. Eleven experimental SD microparticle powders were constructed under different process conditions according to a central composite design. The SD microparticles were then agglomerated in soft pellets. Eleven physico-chemical characteristics of SD CMS microparticle powders or agglomerates thereof were selected as critical quality attributes. The yield of SD process was higher than 75%. The emitted fraction of agglomerates from RS01 inhaler was 75-84%, and the fine particle fraction (particles <5 µm) was between 58% and 62%. The quality attributes of CMS SD powders and respective agglomerates that were significantly influenced by spray-drying process parameters were residual solvent and drug content of the SD microparticles as well as bulk density and respirable dose of the agglomerates. These attributes were also affected by the combination of the process variables. The air aspiration rate was found as the most positively influential on drug and solvent content and respirable dose. The residual solvent content significantly influenced the powder bulk properties and aerodynamic behavior of the agglomerates, i.e. quality attributes that govern drug metering in the device and the particles lungs deposition. Agglomerates of CMS SD microparticles, in combination with RS01 DPI, showed satisfactory results in terms of dose emitted and fine particle fraction.

Lipid-core nanocapsules are an alternative to the pulmonary delivery and to increase the stability of statins.

Aims: Lipid-core nanocapsules (LNCs) loaded with simvastatin (SV, SV-LNC) or lovastatin (LV, LV-LNC) were formulated for pulmonary administration. Methods: The LNC suspensions were characterized physicochemically, their stability was evaluated, and drug delivery by the pulmonary route was tested in vitro. Results: The loaded LNCs had a particle size close to 200 nm, a low polydispersity index, and a zeta potential around -20 mV. The encapsulation efficiency was high for SV (99.21 ± 0.7%) but low for LV (20.34 ± 1.2%). SV release from nanocapsules was slower than it was from SV in solution, with a monoexponential release profile, and the drug emitted and aerosol output rate was higher for SV-LNCs (1.58 µg/s) than for SV in suspension (0.54 µg/s). Conclusions: SV-LNCs had a median aerodynamic diameter of 3.51 µm and a highly respirable fraction (61.9%), indicating that nanoparticles are a suitable system for efficient delivery of simvastatin to the lung.

Spray-dried fucoidan microparticles for pulmonary delivery of antitubercular drugs.

Pulmonary tuberculosis accounts for 80% of cases and the delivery of antitubercular drugs into the lungs allows targeting the infected organ and, possibly, reducing systemic drug toxicity. This work aimed at using fucoidan as matrix of inhalable microparticles that associate two first-line antitubercular drugs, for an application in pulmonary tuberculosis therapy. Fucoidan is composed of fucose and sulphated sugar residues, moieties described as being recognised by surface receptors of alveolar macrophages, which host mycobacteria. Inhalable fucoidan microparticles loaded with antitubercular drugs were successfully produced with high association efficiencies of either isoniazid (95%) or rifabutin (81%). The microparticles evidenced no cytotoxicity on lung epithelial cells (A549). However, rifabutin-loaded microparticles showed a certain degree of toxicity on macrophage-like cells (THP-1) at the highest tested concentration (1 mg/mL). Furthermore, microparticles showed favourable aerodynamic properties for deep lung delivery (MMAD 2.0-3.8 µm) and, thus, show potential for an application as inhalable tuberculosis therapy.

Dry powders for the inhalation of ciprofloxacin or levofloxacin combined with a mucolytic agent for cystic fibrosis patients.

OBJECTIVE: This study aimed to design and characterize an inhalable dry powder of ciprofloxacin or levofloxacin combined with the mucolytics acetylcysteine and dornase alfa for the management of pulmonary infections in patients with cystic fibrosis. METHODS: Ball milling, homogenization in isopropyl alcohol and spray drying processes were used to prepare dry powders for inhalation. Physico-chemical characteristics of the dry powders were assessed via thermogravimetric analysis, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry and scanning electron microscopy. The particle size distribution, dissolution rate and permeability across Calu-3 cell monolayers were analyzed. The aerodynamic parameters of dry powders were determined using the Andersen cascade impactor (ACI). RESULTS: After the micronization process, the particle sizes of the raw materials significantly decreased. X-ray and DSC results indicated that although ciprofloxacin showed no changes in its crystal structure, the structure of levofloxacin became amorphous after the micronization process. FT-IR spectra exhibited the characteristic peaks for ciprofloxacin and levofloxacin in all formulations. The dissolution rates of micro-homogenized and spray-dried ciprofloxacin were higher than that of untreated ciprofloxacin. ACI results showed that all formulations had a mass median aerodynamic diameter less than 5 µm; however, levofloxacin microparticles showed higher respirability than ciprofloxacin powders did. The permeability of levofloxacin was higher than those of the ciprofloxacin formulations. CONCLUSION: Together, our study showed that these methods could suitably characterize antibiotic and mucolytic-containing dry powder inhalers.

Multivariate Analysis of Effects of Asthmatic Patient Respiratory Profiles on the In Vitro Performance of a Reservoir Multidose and a Capsule-Based Dry Powder Inhaler.

PURPOSE: The aim of this work was to evaluate the effect of two different dry powder inhalers, of the NGI induction port and Alberta throat and of the actual inspiratory profiles of asthmatic patients on in-vitro drug inhalation performances. METHODS: The two devices considered were a reservoir multidose and a capsule-based inhaler. The formulation used to test the inhalers was a combination of formoterol fumarate and beclomethasone dipropionate. A breath simulator was used to mimic inhalatory patterns previously determined in vivo. A multivariate approach was adopted to estimate the significance of the effect of the investigated variables in the explored domain. RESULTS: Breath simulator was a useful tool to mimic in vitro the in vivo inspiratory profiles of asthmatic patients. The type of throat coupled with the impactor did not affect the aerodynamic distribution of the investigated formulation. However, the type of inhaler and inspiratory profiles affected the respirable dose of drugs. CONCLUSIONS: The multivariate statistical approach demonstrated that the multidose inhaler, released efficiently a high fine particle mass independently from the inspiratory profiles adopted. Differently, the single dose capsule inhaler, showed a significant decrease of fine particle mass of both drugs when the device was activated using the minimum inspiratory volume (592 mL).

Accessorized DPI: a Shortcut towards Flexibility and Patient Adaptability in Dry Powder Inhalation.

PURPOSE: In this work, a novel powder dispersion add-on device, the AOS (Axial Oscillating Sphere), was studied in conjunction with commercially available DPI devices to improve the powder dispersion. METHODS: An ordered mixture of formoterol fumarate and lactose was selected. We studied in two laboratories located at different altitudes the dispensing and dispersion of the drug at different flow rates, paying particular attention to a number of metrics of Fine Particle Dose (FPD). RESULTS: Two novel findings emerged from the data collected. First, the aerosol quality, measured as fine particle dose, can be increased by adding the accessory promoting the dispersion and de-aggregation of the formulation. The second finding was that, albeit the emitted dose was independent of altitude, the drug/lactose carrier DPI aerosolizing performance changed with the altitude of testing. In particular, fine particle dose depended on both altitude and device configuration. The RS01 inhaler without the AOS accessory used at higher altitude gave the lowest FPD values. By combining the AOS accessory with the DPI, however, the performance dependence on altitude/atmospheric pressure was essentially removed. CONCLUSIONS: Increasing inhaler performance can be achieved using an add-on accessory that enhances aerosol dispersion and minimizes flow rate dependency.

Floating modular drug delivery systems with buoyancy independent of release mechanisms to sustain amoxicillin and clarithromycin intra-gastric concentrations.

Release modules of amoxicillin and clarithromycin combined in a single dosage form designed to float in the gastric content and to sustain the intra-gastric concentrations of these two antibiotics used for the eradication of Helicobacter pylori have been studied. The modules having a disc shape with curved bases were formulated as hydrophilic matrices. Two modules of clarithromycin were assembled by sticking the concave base of one module to the concave base of the other, creating an internal void chamber. The final dosage form was a floating assembly of three modules of clarithromycin and two of amoxicillin in which the drug release mechanism did not interfere with the floatation mechanism. The assembled system showed immediate in vitro floatation at pH 1.2, lasting 5 h. The in vitro antibiotics release profiles from individual modules and assembled systems exhibited linear release rate during buoyancy for at least 8 h. The predicted antibiotic concentrations in the stomach maintained for long time levels significantly higher than the respective minimum inhibitory concentrations (MIC). In addition, an in vivo absorption study performed on beagle dogs confirmed the slow release of clarithromycin and amoxicillin from the assembled system during the assembly's permanence in the stomach for at least 4 h.

Long-acting inhaled medicines: Present and future.

Inhaled medicines continue to be an essential part of treatment for respiratory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. In addition, inhalation technology, which is an active area of research and innovation to deliver medications via the lung to the bloodstream, offers potential advantages such as rapid onset of action, enhanced bioavailability, and reduced side effects for local treatments. Certain inhaled macromolecules and particles can also end up in different organs via lymphatic transport from the respiratory epithelium. While the majority of research on inhaled medicines is focused on the delivery technology, particle engineering, combination therapies, innovations in inhaler devices, and digital health technologies, researchers are also exploring new pharmaceutical technologies and strategies to prolong the duration of action of inhaled drugs. This is because, in contrast to most inhaled medicines that exert a rapid onset and short duration of action, long-acting inhaled medicines (LAIM) improve not only the patient compliance by reducing the dosing frequency, but also the effectiveness and convenience of inhaled therapies to better manage patients' conditions. This paper reviews the advances in LAIM, the pharmaceutical technologies and strategies for developing LAIM, and emerging new inhaled modalities that possess a long-acting nature and potential in the treatment and prevention of various diseases. The challenges in the development of the future LAIM are also discussed where active research and innovations are taking place.

The role of airways microbiota on local and systemic diseases: a rationale for probiotics delivery to the respiratory tract.

INTRODUCTION: Recent discoveries in the field of lung microbiota have enabled the investigation of new therapeutic interventions involving the use of inhaled probiotics. AREAS COVERED: This review provides an overview of what is known about the correlation between airway dysbiosis and the development of local and systemic diseases, and how this knowledge can be exploited for therapeutic interventions. In particular, the review focused on attempts to formulate probiotics that can be deposited directly on the airways. EXPERT OPINION: Despite considerable progress since the emergence of respiratory microbiota restoration as a new research field, numerous clinical implications and benefits remain to be determined. In the case of local diseases, once the pathophysiology is understood, manipulating the lung microbiota through probiotic administration is an approach that can be exploited. In contrast, the effect of pulmonary dysbiosis on systemic diseases remains to be clarified; however, this approach could represent a turning point in their treatment.

Development of inhalation powders containing lactic acid bacteria with antimicrobial activity against Pseudomonas aeruginosa.

OBJECTIVES: The aim of the project was to develop and characterise powders containing a probiotic (Lactiplantibacillus plantarum [Lpb. plantarum], Lacticaseibacillus rhamnosus, or Lactobacillus acidophilus) to be administered to the lung for the containment of pathogen growth in patients with lung infections. METHODS: The optimised spray drying process for the powder manufacturing was able to preserve viability of the bacteria, which decreased of only one log unit and was maintained up to 30 days. RESULTS: Probiotic powders showed a high respirability (42%-50% of particles had a size < 5 µm) suitable for lung deposition and were proven safe on A549 and Calu-3 cells up to a concentration of 107 colony-forming units/mL. The Lpb. plantarum adhesion to both cell lines tested was at least 10%. Surprisingly, Lpb. plantarum powder was bactericidal at a concentration of 106 colony-forming units/mL on P. aeruginosa, whereas the other two strains were bacteriostatic. CONCLUSION: This work represents a promising starting point to consider a probiotic inhalation powder a value in keeping the growth of pathogenic microflora in check during the antibiotic inhalation therapy suspension in cystic fibrosis treatment regimen. This approach could also be advantageous for interfering competitively with pathogenic bacteria and promoting the restoration of the healthy microbiota.

Cyclosporine A micellar nasal spray characterization and antiviral action against SARS-CoV-2.

The upper airways represent the point of entrance from where Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection spreads to the lungs. In the present work, α-tocopheryl-polyethylene-glycol succinate (TPGS) micelles loaded with cyclosporine A (CSA) were developed for nasal administration to prevent or treat the viral infection in the very first phases. The behavior of the micelles in presence of simulated nasal mucus was investigated in terms of stability and mucopenetration rate, evidencing long-term stability and fast diffusion across the glycoproteins matrix. Moreover, the spray characteristics of the micellar formulation and deposition profile in a silicon nasal model were studied using three nasal spray devices. Results allowed to identify the nasal spray pump (BiVax, Aptar) able to provide the wider and uniform deposition of the nasal cavity. The cyclosporine A micelles antiviral activity against SARS-CoV-2 was tested on the Omicron BA.1 variant using Vero E6 cells with protocols simulating treatment before, during and after the infection of the upper airways. Complete viral inactivation was observed for the cyclosporine-loaded micelles while a very low activity was evidenced for the non-formulated drug, suggesting a synergistic activity of the drug and the formulation. In conclusion, this work showed that the developed cyclosporine A-loaded micellar formulations have the potential to be clinically effective against a wide spectrum of coronavirus variants.

Novel Dry Hyaluronic Acid-Vancomycin Complex Powder for Inhalation, Useful in Pulmonary Infections Associated with Cystic Fibrosis.

Polyelectrolyte-drug complexes are interesting alternatives to improve unfavorable drug properties. Vancomycin (VAN) is an antimicrobial used in the treatment of methicillin-resistant Staphylococcus aureus pulmonary infections in patients with cystic fibrosis. It is generally administered intravenously with a high incidence of adverse side effects, which could be reduced by intrapulmonary administration. Currently, there are no commercially available inhalable formulations containing VAN. Thus, the present work focuses on the preparation and characterization of an ionic complex between hyaluronic acid (HA) and VAN with potential use in inhalable formulations. A particulate-solid HA-VAN25 complex was obtained by spray drying from an aqueous dispersion. FTIR spectroscopy and thermal analysis confirmed the ionic interaction between HA and VAN, while an amorphous diffraction pattern was observed by X-ray. The powder density, geometric size and morphology showed the suitable aerosolization and aerodynamic performance of the powder, indicating its capability of reaching the deep lung. An in vitro extended-release profile of VAN from the complex was obtained, exceeding 24 h. Microbiological assays against methicillin-resistant and -sensitive reference strains of Staphylococcus aureus showed that VAN preserves its antibacterial efficacy. In conclusion, HA-VAN25 exhibited interesting properties for the development of inhalable formulations with potential efficacy and safety advantages over conventional treatment.

Lung-to-Heart Nano-in-Micro Peptide Promotes Cardiac Recovery in a Pig Model of Chronic Heart Failure.

BACKGROUND: The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking. OBJECTIVES: In this study, the authors sought to assess tolerability and efficacy of an inhalable lung-to-heart nano-in-micro technology (LungToHeartNIM) for cardiac-specific targeting of a mimetic peptide (MP), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF. METHODS: Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachypacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% ± 8%), animals were randomized and treatment was started after 4 weeks of tachypacing. HFrEF animals inhaled either a dry powder composed of mannitol-based microparticles embedding biocompatible MP-loaded calcium phosphate nanoparticles (dpCaP-MP) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment. RESULTS: DpCaP-MP inhalation restored systolic function, as shown by an absolute LVEF increase over the treatment period of 17% ± 6%, while reversing cardiac remodeling and reducing pulmonary congestion. The effect was recapitulated ex vivo in cardiac myofibrils from treated HF animals. The treatment was well tolerated, and no adverse events occurred. CONCLUSIONS: The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeutic peptide to the diseased heart.

Metered dose inhalers in the transition to low GWP propellants: what we know and what is missing to make it happen.

INTRODUCTION: The urgency to replace the propellants currently in use with the new sustainable ones has given rise to the need for investigation and reformulation of pMDIs. AREAS COVERED: The reformulation requires in-depth knowledge of the physico-chemical characteristics of the new propellants, which impact the atomization capacity and the plume geometry. Among the investigated propellants, HFA 152a, due to its lower vapor pressure and higher surface tension compared to HFA 134a, deliver larger particles and has a higher solvent capacity toward lipophilic drugs. On the other hand, HFO 1234ze has properties more similar to HFA 134a, but showed lower reproducibility of the generated spray, indicating a possible high susceptibility to variation in the consistency of the dose delivered. In addition, the device components currently in use are compatible with the new propellants. This allowed promising preliminary results in the re-formulation of pMDIs by academia and pharma companies. However, there is little information about the clinical studies required to allow the marketing of these new products. EXPERT OPINION: Overall, studies conducted so far show that the transition is technically possible, and the main obstacle will be represented by the investment required to put the product on the market.

Nasal delivery as a strategy for the prevention and treatment of COVID-19.

INTRODUCTION: The upper respiratory tract is a major route of infection for COVID-19 and other respiratory diseases. Thus, it appears logical to exploit the nose as administration site to prevent, fight, or minimize infectious spread and treat the disease. Numerous nasal products addressing these aspects have been considered and developed for COVID-19. AREAS COVERED: This review gives a comprehensive overview of the different approaches involving nasal delivery, i.e., nasal vaccination, barrier products, and antiviral pharmacological treatments that have led to products on the market or under clinical evaluation, highlighting the peculiarities of the nose as application and absorption site and pointing at key aspects of nasal drug delivery. EXPERT OPINION: From the analysis of nasal delivery strategies to prevent or fight COVID-19, it emerges that, especially for nasal immunization, formulations appear the same as originally designed for parenteral administration, leading to suboptimal results. On the other hand, mechanical barrier and antiviral products, designed to halt or treat the infection at early stage, have been proven effective but were rarely brought to the clinics. If supported by robust and targeted product development strategies, intranasal immunization and drug delivery can represent valid and sometimes superior alternatives to more conventional parenteral and oral medications.

The impact of possible improper use on the performance in vitro of NEXThaler in comparison with Ellipta inhaler.

The correct use of dry powder inhalers by the patients is essential to ensure effective treatment and management of the disease. The purpose of the work was to assess the consequence of inhaler misuse in terms of emitted dose and aerodynamic parameters. One reservoir multidose device (Foster-NEXThaler®) and one pre-dosed device (Relvar-Ellipta®), both sharing the "open, inhale and close" procedure, were the subject of the study. NEXThaler activated at different degrees of inclination showed a consistent dose delivery for both the drugs included in the formulation (beclometasone dipropionate/formoterol fumarate). Contrary, Ellipta showed a decrease of the emitted dose for both fluticasone furoate (FluF) and vilanterol trifenatate (VT) when the device was operated facing downward (-14% at 45° and -22% at 90°). Similarly, the delivered dose of NEXThaler was unaffected by an accidental fall, while Ellipta released FluF and VT doses 50% lower than control values. The presence of the dose protector in NEXThaler offers the advantage of retaining the powder if the inhaler is subjected to incorrect manipulations. Both products proved to be reliable in double activation. Finally, simulation exhalation conditions impaired, although not significantly, the aerodynamic profile of the two products.