Development of Neutralizing Multimeric Nanobody Constructs Directed against IL-13: From Immunization to Lead Optimization.

IL-13 is a pleiotropic cytokine mainly secreted by Th2 cells. It reacts with many different types of cells involved in allergy, inflammation, and fibrosis, e.g., mastocytes, B cells, and fibroblasts. The role of IL-13 in conditions involving one or several of these phenotypes has therefore been extensively investigated. The inhibition of this cytokine in animal models for various pathologies yielded highly promising results. However, most human trials relying on anti-IL-13 conventional mAbs have failed to achieve a significant improvement of the envisaged disorders. Where some studies might have suffered from several weaknesses, the strategies themselves, such as targeting only IL-13 using conventional mAbs or employing a systemic administration, could be questioned. Nanobodies are recombinant Ag-binding fragments derived from the variable part of H chain-only Abs occurring in Camelidae. Thanks to their single-domain structure, small size (≈15 kDa), good stability, and solubility, they can be engineered into multispecific constructs for combined therapies or for use in new strategies such as formulations for local administration, e.g., pulmonary administration. In this study, we describe the generation of 38 nanobodies that can be subdivided into five CDR3 families. Nine nanobodies were found to have a good affinity profile (KD = 1-200 nM), but none were able to strongly inhibit IL-13 biological activity in vitro (IC50 > 50 µM: HEK-Blue IL-13/IL-4 cells). Multimeric constructs were therefore designed from these inhibitors and resulted in an up to 36-fold improvement in affinity and up to 300-fold enhancement of the biological activity while conserving a high specificity toward IL-13.

In vitro and in vivo local tolerability of a synergistic anti-tuberculosis drug combination intended for pulmonary delivery.

A drug combination, vancomycin (VAN) plus tetrahydrolipstatin (THL), has demonstrated an effective synergistic action in vitro against Mycobacterium tuberculosis (Mtb). The poor oral bioavailability of VAN and THL and the predominant tropism of Mtb infection to the lungs make their pulmonary administration very attractive. To evaluate their local tolerability, bronchial cells, alveolar cells and monocytes were exposed to concentrations around and above their minimal inhibitory concentration (MIC). The VAN had no inhibitory activity on the tested human cell lines, even at a concentration 125 times higher than its MIC, whereas the THL, alone or in combination with VAN, presented a cytostatic action. Monolayer epithelium showed no significant irreversible damage at concentrations up to 100 times the combination MIC. BALB/cAnNRj mice exposed to concentration of 50 times the combination MIC delivered endotracheally 3 times a week for 3 weeks showed no clinical signs or significant weight loss. The increase of proinflammatory biomarkers (i.e., IL-1, IL-6, TNF-α and proportion of inflammatory cells) and cytotoxicity in bronchoalveolar lavage fluid (BALF) were non-significant. Lung histopathology did not show significant tissue damage. The VAN/THL combination at doses up to 50 times the combination MIC is found to be thus well tolerated by pulmonary route. This study is a promising result and encouraging further investigations of pulmonary administration of VAN/THL combination as dry powder for anti-tuberculosis treatment.

Tumor Targeting by Peptide-Decorated Gold Nanoparticles.

Cancer remains one of the most important challenges in biomedical sciences. Chemotherapeutic agents are very potent molecules that exhibit a significant level of toxicity in numerous tissues of the body, particularly in those characterized by high proliferative activity, such as the bone marrow. The scenario is even more complex in the case of the central nervous system, and in particular brain tumors, where the blood brain barrier limits the efficacy of drug therapies. Integrins, transmembrane proteins widely expressed in different types of cancer (glioblastoma, melanoma, and breast cancer), regulate the angiogenic process and play a pivotal role in tumor growth and invasion. Here, we report a nanotechnology strategy based on the use of AuNPs decorated with an arginine-glycine-aspartic acid-like peptide for the diagnosis and treatment of cancer. Two hours after administration in mice, the accumulation of the peptide-decorated NPs in the subcutaneous tumor was ∼4-fold higher than that of uncoated particles and ∼1.4-fold higher than that of PEGylated particles. Also, in the case of the intracranial tumor model, interesting results were obtained. Indeed, 2 h after administration, the amount of peptide-decorated particles in the brain was 1.5-fold that of undecorated particles and 5-fold that of PEGylated particles. In conclusion, this preliminary study demonstrates the high potential of this carrier developed for diagnostic and therapeutic applications.

New Folate-Grafted Chitosan Derivative To Improve Delivery of Paclitaxel-Loaded Solid Lipid Nanoparticles for Lung Tumor Therapy by Inhalation.

Inhaled chemotherapy for the treatment of lung tumors requires that drug delivery systems improve selectivity for cancer cells and tumor penetration and allow sufficient lung residence. To this end, we developed solid lipid nanoparticles (SLN) with modified surface properties. We successfully synthesized a new folate-grafted copolymer of polyethylene glycol (PEG) and chitosan, F-PEG-HTCC, with a PEG-graft ratio of 7% and a molecular weight range of 211-250 kDa. F-PEG-HTCC-coated, paclitaxel-loaded SLN were prepared with an encapsulation efficiency, mean diameter, and zeta potential of about 100%, 250 nm, and +32 mV, respectively. The coated SLN entered folate receptor (FR)-expressing HeLa and M109-HiFR cells in vitro and M109 tumors in vivo after pulmonary delivery. The coated SLN significantly decreased the in vitro half-maximum inhibitory concentrations of paclitaxel in M109-HiFR cells (60 vs 340 nM, respectively). We demonstrated that FR was involved in these improvements, especially in M109-HiFR cells. After pulmonary delivery in vivo, the coated SLN had a favorable pharmacokinetic profile, with pulmonary exposure to paclitaxel prolonged to up to 6 h and limited systemic distribution. Our preclinical findings therefore demonstrated the positive impact of the coated SLN on the delivery of paclitaxel by inhalation.

Safe lipid nanocapsule-based gel technology to target lymph nodes and combat mediastinal metastases from an orthotopic non-small-cell lung cancer model in SCID-CB17 mice.

The purpose of this study is the assessment of gel technology based on a lauroyl derivative of gemcitabine encapsulated in lipid nanocapsules delivered subcutaneously or intravenously after dilution to (i) target lymph nodes, (ii) induce less systemic toxicity and (iii) combat mediastinal metastases from an orthotopic model of human, squamous, non-small-cell lung cancer Ma44-3 cells implanted in severe combined immunodeficiency mice. The gel technology mainly targeted lymph nodes as revealed by the biodistribution study. Moreover, the gel technology induced no significant myelosuppression (platelet count) in comparison with the control saline group, unlike the conventional intravenous gemcitabine hydrochloride treated group (P<0.05). Besides, the gel technology, delivered subcutaneously twice a week, was able to combat locally mediastinal metastases from the orthotopic lung tumor and to significantly delay death (P<0.05) as was the diluted gel technology delivered intravenously three times a week. FROM THE CLINICAL EDITOR: Lung cancer is one of the leading causes of mortality worldwide. A significant proportion of patients with this disease have lymph node metastasis. In this study, the authors investigated the use of lipid nanocapsules, loaded with the lipophilic pro-drug gemcitabine for targeting tumors in lymph nodes after subcutaneous injection. This delivery method was shown to be effective in controlling tumor progression and may be useful in future clinical use.

Cyclic versus hemi-bastadins. pleiotropic anti-cancer effects: from apoptosis to anti-angiogenic and anti-migratory effects.

Bastadins-6, -9 and -16 isolated from the marine sponge Ianthella basta displayed in vitro cytostatic and/or cytotoxic effects in six human and mouse cancer cell lines. The in vitro growth inhibitory effects of these bastadins were similar in cancer cell lines sensitive to pro-apoptotic stimuli versus cancer cell lines displaying various levels of resistance to pro-apoptotic stimuli. While about ten times less toxic than the natural cyclic bastadins, the synthetically derived 5,5'-dibromohemibastadin-1 (DBHB) displayed not only in vitro growth inhibitory activity in cancer cells but also anti-angiogenic properties. At a concentration of one tenth of its in vitro growth inhibitory concentration, DBHB displayed actual antimigratory effects in mouse B16F10 melanoma cells without any sign of cytotoxicity and/or growth inhibition. The serum concentration used in the cell culture media markedly influenced the DBHB-induced antimigratory effects in the B16F10 melanoma cell population. We are currently developing a specific inhalation formulation for DBHB enabling this compound to avoid plasmatic albumin binding through its direct delivery to the lungs to combat primary as well as secondary (metastases) tumors.

Inhaled dry powder cisplatin increases antitumour response to anti-PD1 in a murine lung cancer model.

Despite advances in targeted therapies and immunotherapy in lung cancer, chemotherapy remains the backbone of treatment in most patients at different stages of the disease. Inhaled chemotherapy is a promising strategy to target lung tumours and to limit the induced severe systemic toxicities. Cisplatin dry powder for inhalation (CIS-DPI) was tested as an innovative way to deliver cisplatin locally via the pulmonary route with minimal systemic toxicities. In vivo, CIS-DPI demonstrated a dose-dependent antiproliferative activity in the M109 orthotopic murine lung tumour model and upregulated the immune checkpoint PD-L1 on lung tumour cells. Combination of CIS-DPI with the immune checkpoint inhibitor anti-PD1 showed significantly reduced tumour size, increased the number of responders and prolonged median survival over time in comparison to the anti-PD1 monotherapy. Furthermore, the CIS-DPI and anti-PD1 combination induced an intra-tumour recruitment of conventional dendritic cells and tumour infiltrating lymphocytes, highlighting an anti-tumour immune response. This study demonstrates that combining CIS-DPI with anti-PD1 is a promising strategy to improve lung cancer therapy.

Development of a new indole derivative dry powder for inhalation for the treatment of biofilm-associated lung infections.

The aim of this work was to produce an inhalable dry powder formulation of a new anti-biofilm compound (SC38). For this purpose, chitosan was used as a polymeric carrier and l-leucine as a dispersibility enhancer. SC38 was entrapped by spray-drying into previously optimized chitosan microparticles. The final formulation was fully characterized in vitro in terms of particle morphology, particle size and distribution, flowability, aerodynamic properties, anti-biofilm activity and effects on lung cell viability. The SC38-loaded chitosan microparticles exhibited favorable aerodynamic properties with emitted and respirable fractions higher than 80 % and 45 % respectively. The optimized formulation successfully inhibited biofilm formation at microparticle concentrations starting from 20 µg/mL for methicillin-sensitive and 100 µg/mL for methicillin-resistant Staphylococcus aureus and showed a relatively safe profile in lung cells after 72 h exposure. Future in vivo tolerability and efficacy studies are needed to unravel the potential of this novel formulation for the treatment of difficult-to-treat biofilm-mediated lung infections.

Trivanillic polyphenols with anticancer cytostatic effects through the targeting of multiple kinases and intracellular Ca2+ release.

Cancer cells exhibit de-regulation of multiple cellular signalling pathways and treatments of various types of cancers with polyphenols are promising. We recently reported the synthesis of a series of 33 novel divanillic and trivanillic polyphenols that displayed anticancer activity, at least in vitro, through inhibiting various kinases. This study revealed that minor chemical modifications of a trivanillate scaffold could convert cytotoxic compounds into cytostatic ones. Compound 13c, a tri-chloro derivative of trivanillic ester, displayed marked inhibitory activities against FGF-, VEGF-, EGF- and Src-related kinases, all of which are implicated not only in angiogenesis but also in the biological aggressiveness of various cancer types. The pan-anti-kinase activity of 13c occurs at less than one-tenth of its mean IC(50) in vitro growth inhibitory concentrations towards a panel of 12 cancer cell lines. Of the 26 kinases for which 13c inhibited their activity by >75%, eight (Yes, Fyn, FGF-R1, EGFR, Btk, Mink, Ret and Itk) are implicated in control of the actin cytoskeleton organization to varying degrees. Compound 13c accordingly impaired the typical organization of the actin cytoskeleton in human U373 glioblastoma cells. The pan-anti-kinase activity and actin cytoskeleton organization impairment provoked by 13c concomitantly occurs with calcium homeostasis impairment but without provoking MDR phenotype activation. All of these anticancer properties enabled 13c to confer therapeutic benefits in vivo in a mouse melanoma pseudometastatic lung model. These data argue in favour of further chemically modifying trivanillates to produce novel and potent anticancer drugs.

New respirable and fast dissolving itraconazole dry powder composition for the treatment of invasive pulmonary aspergillosis.

PURPOSE: Novel itraconazole (ITZ)-based dry powders for inhalation (DPI) were optimized for aerodynamic and dissolution properties and contained excipients that are acceptable for inhalation. METHODS: The DPI were produced by spray drying solutions. The drug content, crystallinity state, and morphological evaluation of the dry powders were determined by high performance liquid chromatography, powder X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy, respectively. A particle size analysis was conducted using laser light scattering. The aerodynamic behaviors of the powders were characterized by impaction tests. ITZ dissolution rates were evaluated using a dissolution method adapted to inhaled products. RESULTS: The DPI presented very high fine particle fractions that ranged from 46.9% to 67.0% of the nominal dose. The formulations showed very fast dissolution rates compared to unformulated crystalline ITZ with the possibility of modulating the dissolution rate by varying the quantity of phospholipids (PL) incorporated. ITZ remained amorphous while the mannitol was crystalline. The α, ß and δ-mannitol polymorph ratios varied depending on the formulation compositions. CONCLUSION: This formulation strategy could be an attractive alternative for treating invasive pulmonary aspergillosis. The ITZ and PL content are key characteristics because of their influence on the dissolution rate and aerosol performance.

Optimization of Long-Acting Bronchodilator Dose Ratios Using Isolated Guinea Pig Tracheal Rings for Synergistic Combination Therapy in Asthma and COPD.

The co-administration of a long-acting ß2-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), has been shown to be beneficial in the management of non-communicable chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The resulting relaxation of the airways can be synergistically enhanced, reducing symptoms and optimizing lung function. This provides an insight into more effective treatments. In this study, the LABAs formoterol fumarate dihydrate (FOR) and indacaterol maleate (IND) were each associated with tiotropium bromide monohydrate (TIO) to assess their synergistic potential. This was done using an appropriate ex vivo model of isolated perfused guinea pig tracheal rings, and pharmacological models of drug interaction. Among the dose ratios studied for both types of combination, a higher synergistic potential was highlighted for FOR/TIO 2:1 (w/w). This was done through three steps by using multiple additions of drugs to the organ baths based on a non-constant dose ratio and then on a constant dose ratio, and by a single addition to the organ baths of specific amounts of drugs. In this way, the synergistic improvement of the relaxant effect on the airways was confirmed, providing a basis for improving therapeutic approaches in asthma and COPD. The synergy found at this dose ratio should now be confirmed on a preclinical model of asthma and COPD by assessing lung function.

Temozolomide-based dry powder formulations for lung tumor-related inhalation treatment.

PURPOSE: Temozolomide dry powder formulations for inhalation, performed with no excipient or with a lipid or lactose coating, have been evaluated. METHODS: The particle size of raw temozolomide in suspension was reduced by a high-pressure homogenizing technique, and the solvent was evaporated by spray-drying to obtain a dry powder. The physicochemical properties of this powder were evaluated and included its crystalline state, thermal properties, morphology, particle size and moisture and drug content, and these properties were determined by X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, laser light scattering, thermogravimetric analysis and high-performance liquid chromatography, respectively. The aerodynamic properties and release profiles were also evaluated using a multistage liquid impinger and a modified USP type 2 dissolution apparatus adapted for inhaler products, respectively. RESULTS: The dry powder inhalation formulations had a high temozolomide content that ranged from 70% to 100% in the crystalline state and low moisture content. Aerodynamic evaluations showed high fine-particle fractions of up to 51% related to the metered dose. The dissolution profile revealed a similarly fast temozolomide release from the formulations. CONCLUSIONS: Dry temozolomide powder formulations, based on the use of acceptable excipients for inhalation and showing good dispersion properties, represent an attractive alternative for use in local lung cancer therapy.

Inhaled cytotoxic chemotherapy: clinical challenges, recent developments, and future prospects.

INTRODUCTION: Since 1968, inhaled chemotherapy has been evaluated and has shown promising results up to phase II but has not yet reached the market. This is due to technological and clinical challenges that require to be overcome with the aim of optimizing the efficacy and the tolerance of drug to re-open new developments in this field. Moreover, recent changes in the therapeutic standard of care for treating the patient with lung cancer also open new opportunities to combine inhaled chemotherapy with standard treatments. AREAS COVERED: Clinical and technological concerns are highlighted from the reported clinical trials made with inhaled cytotoxic chemotherapies. This work then focuses on new pharmaceutical developments using dry powder inhalers as inhalation devices and on formulation strategies based on controlled drug release and with sustained lung retention or based on nanomedicine. Finally, new clinical strategies are described in regard to the impact of the immunotherapy on the patient's standard of care. EXPERT OPINION: The choice of the drug, inhalation device, and formulation strategy as well as the position of inhaled chemotherapy in the patient's clinical care are crucial factors in optimizing local tolerance and efficacy as well as in its scalability and applicability in clinical practice.

The combination of an innovative dry powder for inhalation and a standard cisplatin-based chemotherapy in view of therapeutic intensification against lung tumours.

Cisplatin is one of the most commonly used chemotherapy in lung cancer despite its high nephrotoxicity leading to an administration only every 3-4 weeks. This study is the first report of a preclinical investigation of therapeutic intensification combining a cisplatin dry powder for inhalation (CIS-DPI) with an intravenous (iv) cisplatin-based treatment. CIS-DPI with 50% cisplatin content (CIS-DPI-50) was developed using lipid excipients through scalable processes (high-speed and high-pressure homogenization and spray-drying). CIS-DPI-50 showed good aerodynamic performance (fine particle fraction of ~ 55% and a mass median aerodynamic particle size of ~ 2 µm) and a seven-fold increase and decrease in Cmax in the lungs and in plasma, respectively, in comparison with an iv cisplatin solution (CIS-iv) in healthy mice. Finally, the addition of CIS-DPI-50 to the standard cisplatin/paclitaxel iv doublet increased the response rate (67% vs 50%), decreased the tumour growth and prolonged the median survival (31 vs 21 days), compared to the iv doublet in the M109 lung carcinoma model tending to demonstrate a therapeutic intensification of cisplatin.

Simple di- and trivanillates exhibit cytostatic properties toward cancer cells resistant to pro-apoptotic stimuli.

A series of 33 novel divanillates and trivanillates were synthesized and found to possess promising cytostatic rather than cytotoxic properties. Several compounds under study decreased by >50% the activity of Aurora A, B, and C, and WEE1 kinase activity at concentrations <10% of their IC(50) growth inhibitory ones, accounting, at least partly, for their cytostatic effects in cancer cells and to a lesser extent in normal cells. Compounds 6b and 13c represent interesting starting points for the development of cytostatic agents to combat cancers, which are naturally resistant to pro-apoptotic stimuli, including metastatic malignancies.

How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods.

Nasal delivery offers many benefits over other conventional routes of delivery (e.g. oral or intravenous administration). Benefits include, among others, a fast onset of action, non-invasiveness and direct access to the central nervous system. The nasal cavity is not only limited to local application (e.g. rhinosinusitis) but can also provide direct access to other sites in the body (e.g. the central nervous system or systemic circulation). However, both the anatomy and the physiology of the nose impose their own limitations, such as a small volume for delivery or rapid mucociliary clearance. To meet nasal-specific criteria, the formulator has to complete a plethora of tests, in vitro and ex vivo, to assess the efficacy and tolerance of a new drug-delivery system. Moreover, depending on the desired therapeutic effect, the delivery of the drug should target a specific pathway that could potentially be achieved through a modified release of this drug. Therefore, this review focuses on specific techniques that should be performed when a nasal formulation is developed. The review covers both the tests recommended by regulatory agencies (e.g. the Food and Drug Administration) and other complementary experiments frequently performed in the field.

The Position of Inhaled Chemotherapy in the Care of Patients with Lung Tumors: Clinical Feasibility and Indications According to Recent Pharmaceutical Progresses.

Despite new treatment modalities, including targeted therapies and checkpoint inhibitors, cytotoxic chemotherapy remains central in the care of patients with lung tumors. Use of the pulmonary route to deliver chemotherapy has been proved to be feasible and safe in phase I, Ib/IIa and II trials for lung tumors, with the administration of drug doses to the lungs without prior distribution in the organism. The severe systemic toxicities commonly observed with conventional systemic chemotherapy are consequently reduced. However, development has failed in phase II at best. This review first focuses on the causes of failure of inhaled chemotherapy. It then presents new promising technologies able to take up the current challenges. These technologies include the use of a dry powder inhaler or a smart nebulizer with advanced drug formulations such as controlled-release formulations and nanomedicine. Finally, the potential position of inhaled chemotherapy in patient care is discussed and some indications are proposed based on the literature.

Impact of capsule type on aerodynamic performance of inhalation products: A case study using a formoterol-lactose binary or ternary blend.

The aerodynamic performance of a dry powder for inhalation depends on the formulation and the dry powder inhaler (DPI). In the case of capsule-based DPIs, the capsule also plays a role in the powder aerosolisation and the dispersion of the micronized drug during the inhalation. This study evaluated the impact of gelatine capsules (Quali-G™ and Hard Gelatine Capsules for DPIs), cold-gelled hypromellose (HPMC) capsules (Quali-V®-I and Vcaps®) and thermal-gelled HPMC capsules (Vcaps®Plus) from Qualicaps® and Capsugel® respectively, on the delivered dose (DD), fine particle dose (FPD), and capsule retention for formoterol-lactose binary and ternary blends. This study used a low resistance Axahaler® DPI based on the RS01 design (Plastiape, Italy). Similar trends were observed with the different capsule types that packaged both dry powder formulations. The highest DD and FPD and the lowest formoterol capsule retention were observed with cold-gelled HPMC capsules such as Quali-V-I® and Vcaps®, without significant differences between these capsules (p > 0.05, one-way ANOVA with Newman-Keuls post-hoc test) for both dry powders. Therefore, the capsule composition and manufacturing process have an influence on aerodynamic performance. In addition, the ternary blend showed higher DDs and FPDs but also higher capsule retention in comparison to the binary blend.

Chitosan-coated liposome dry-powder formulations loaded with ghrelin for nose-to-brain delivery.

The nose-to-brain delivery of ghrelin loaded in liposomes is a promising approach for the management of cachexia. It could limit the plasmatic degradation of ghrelin and provide direct access to the brain, where ghrelin's specific receptors are located. Anionic liposomes coated with chitosan in either a liquid or a dry-powder formulation were compared. The powder formulation showed stronger adhesion to mucins (89 ±â€¯4% vs 61 ±â€¯4%), higher ghrelin entrapment efficiency (64 ±â€¯2% vs 55 ±â€¯4%), higher enzymatic protection against trypsin (26 ±â€¯2% vs 20 ±â€¯3%) and lower ghrelin storage degradation at 25 °C (2.67 ±â€¯1.1% vs 95.64 ±â€¯0.85% after 4 weeks). The powder formulation was also placed in unit-dose system devices that were able to generate an appropriate aerosol characterized by a Dv50 of 38 ±â€¯6 µm, a limited percentage of particles smaller than 10 µm of 4 ±â€¯1% and a reproducible mass delivery (CV: 1.49%). In addition, the device was able to deposit a large amount of powder (52.04% w/w) in the olfactory zone of a 3D-printed nasal cast. The evaluated combination of the powder formulation and the device could provide a promising treatment for cachexia.

Proposed algorithm for healthcare professionals based on product characteristics and in vitro performances in different use conditions using formoterol-based marketed products for inhalation.

Healthcare professionals require an easy algorithm for selecting the most appropriate inhalation product for each patient at the beginning of a treatment. As a case study, we selected five marketed formoterol products: Foradil® and Formagal®, capsule-based dry powder inhalers (DPIs), Novolizer® Formoterol and Oxis®, reservoir-based DPIs and Formoair®, a pressurized metered dose inhaler. We generated an algorithm based on device properties (i.e. device handling, feedback and remaining dose/end of product indication) and in vitro aerodynamic performances (i) along the product use life in optimal conditions, (ii) at different airflows and (iii) after exposing pre-loaded doses to 40°C and 75% relative humidity for 4h. Based on these results, an algorithm was built where Formoair and Formagal can be proposed when there is high risk of humidity and for patients presenting suboptimal or optimal airflows. When no risk of humidity is present, Formoair, Foradil, Formagal and Novolizer Formoterol equipped with a trigger valve could be proposed for patients presenting suboptimal airflows. When no risk of humidity is present and for patients presenting optimal airflow, all products, including Oxis, could be proposed. Ultimately, the optimal inhalation product will be selected after checking the patient's preference and capacity for correct device handling and inhalation technique.