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Rain Jõgi,1 Leena Mattila,2 Mikko Vahteristo,3 Aino Takala,2 Satu Lähelmä,4 Ville A Vartiainen,2 Ari Lindqvist5 1Tartu University Hospital, Lung Clinic, Tartu, Estonia; 2Medical Affairs, Orion Corporation, Espoo, Finland; 3Research Unit of Pulmonary Diseases, Helsinki University Hospital and Helsinki University, Helsinki, Finland; 4Inhalation Platform, Orion Corporation, Espoo, Finland; 5Biostatistics and Data Analytics, Orion Corporation, Espoo, FinlandCorrespondence: Rain JõgiTartu University Hospital, Lung Clinic, Riia 167, Tartu, 50104, EstoniaTel +372 5331 8918Email Rain.Jogi@kliinikum.eeIntroduction: Achieving correct inhalation technique through an inhaler to ensure effective drug delivery is key to managing symptoms in patients with chronic obstructive pulmonary disease (COPD). However, many patients struggle to use their inhalers correctly, with the resultant reduction in therapeutic benefit. Consequently, appropriate inhaler choice is important to maximize clinical benefit. The primary objective of this study was to characterize inspiratory flow parameters across two Easyhaler® inhalers and the HandiHaler® inhaler in patients with COPD and healthy volunteers.Methods: In this randomized, open-label, crossover study, subjects (100 patients with COPD; 100 healthy volunteers) were trained to perform inhalations of placebo powder via two variants of Easyhaler and placebo capsules via the HandiHaler inhalers. Subjects then performed three placebo inhalations through each inhaler in a random sequence. Inspiratory flow parameters were assessed, including peak inspiratory flow (PIF), for each inhaler. A parallel sub-study was conducted in patients with COPD from the main study to assess correct use of the inhalers, patient’s preference, ability to learn to use the inhalers, and the feasibility of the In-Check Dial device to measure PIF values.Results: Mean PIF rates and inspiratory volumes through the three inhalers were similar between patients with COPD and healthy volunteers, and all subjects achieved the 30 L/min PIF required for effective use of Easyhaler. Almost 70% of the 88 patients enrolled in the sub-study used the Easyhaler and HandiHaler inhalers without errors. The Easyhaler was preferred by 51% of patients, while 25% favored the HandiHaler. Teaching the use of both inhalers to almost 70% of patients was very easy. The In-Check Dial PIF values and those obtained via spirometry were strongly correlated (p< 0.0001) for all three inhalers.Conclusion: The respiratory performance of patients with COPD does not appear to be a limiting factor in the use of Easyhaler.Keywords: COPD, crossover study, Easyhaler, HandiHaler, dry powder inhaler, peak inspiratory flow

Background: To evaluate whether patients of varying ages and lung function with asthma or those with chronic obstructive pulmonary disease (COPD) can achieve sufficient inspiratory flows for effective use of the fixed-dose combination of salmeterol-fluticasone propionate and budesonide-formoterol dispensed with the Easyhaler (R) (EH) device-metered, multi-dose dry powder inhaler (DPI). Methods: A pooled analysis of two randomized, multicenter, crossover, open-label studies (NCT01424137; NCT009849061) was conducted to characterize inspiratory flow parameters across the EH, Seretide Diskus (DI) and Symbicort Turbuhaler (TH) inhalers in patients with asthma and/or COPD of varying severity. The primary endpoint was peak inspiratory flow (PIF) rate through the EH. Results: The intent-to-treat population comprised 397 patients; 383 patients were included in the per protocol (PP) population. The mean PIF (standard deviation) values through the EH in patients = 18 years of age with asthma and in those with COPD, were similar: 61.4 (11.5), 69.7 (13.5), and 61.9 (13.2) L/min, respectively. These flow rates correspond to pressure drops of 5.05 (1.80), 6.52 (2.34) and 5.19 (2.07) kPa, respectively. In total, 380 (99.2%) of patients in the PP population were able to generate a PIF rate through the EH of >= 30 L/min, which is required to enable consistent dose delivery from the DPI; there was a moderate direct association between age and PIF in younger patients with asthma, but this was inverse and less apparent in adult patients with asthma and/or those with COPD. Height and weight were also moderately correlated with PIF. Stronger associations with PIF were observed for some lung function parameters, particularly native PIF and forced inspiratory vital capacity. Conclusions: Over 99% of patients with asthma and/or COPD were able to inhale through the EH with an adequate PIF rate, irrespective of age, or severity of airway obstruction. This confirms that patients with asthma and/or COPD can achieve inspiratory flows via the EH DPI that are sufficient for its effective use.

Background: Use of drug delivery devices between nebulizers, dry powder inhalers (DPIs), or metered dose inhalers (MDIs), for treating patients with asthma and chronic obstructive pulmonary disease (COPD), is based on patients' capability of coordinating the inhalation maneuver and achieving sufficient airflow. There are limited data available with regard to how patients meet the requirements of successful inhalation performance, and how the concept of inspiratory lungpower could be applied. The aim of this work was to study the patient inspiratory airflow profile performance in large data sets. We analyzed how the Kamin-Haidl inhalation criteria were met by patients with DPIs such as Easyhaler for combination therapy (EH-combi), Easyhaler for monotherapy (EH-mono), Diskus, and Turbuhaler (TH), and applied peak lungpower instead of peak inspiratory flow rate as an indicator of patient performance. Materials and Methods: Data sets gathered in two previous studies for DPIs, that is, EH-combi, EH-mono, Diskus, and TH, were used to analyze how inspiratory lungpower representing inspiratory muscle power, flow acceleration, and volume after peak met the inhalation criteria. The measured patient airflow profiles through inhalers were assessed for patients with asthma or COPD. Results: Based on the Kamin-Haidl inhalation criteria, successful inhalation requirements were met with EH-combi in 96.1% and with EH-mono in 92.6% of patients. The success rates were 89.5% and 84.6% with Diskus and TH, respectively, (p

BACKGROUND: To evaluate whether patients of varying ages and lung function with asthma or those with chronic obstructive pulmonary disease (COPD) can achieve sufficient inspiratory flows for effective use of the fixed-dose combination of salmeterol-fluticasone propionate and budesonide-formoterol dispensed with the Easyhaler(®) (EH) device-metered, multi-dose dry powder inhaler (DPI). METHODS: A pooled analysis of two randomized, multicenter, crossover, open-label studies (NCT01424137; NCT009849061) was conducted to characterize inspiratory flow parameters across the EH, Seretide Diskus (DI) and Symbicort Turbuhaler (TH) inhalers in patients with asthma and/or COPD of varying severity. The primary endpoint was peak inspiratory flow (PIF) rate through the EH. RESULTS: The intent-to-treat population comprised 397 patients; 383 patients were included in the per-protocol (PP) population. The mean PIF (standard deviation) values through the EH in patients

Dry powder inhalers (DPIs) have about 20-fold lower carbon footprint (CO2FP) than metered dose inhalers (MDIs) with estimates of CO2FP between 1.5 and 6 kg CO2e for a 200-dose DPI. GSK’s Carbon Trust-verified analysis including Relvar and Seretide Accuhaler is about 1 kg CO2e/inhaler, and Product Carbon Footprint analysis of Spiriva Respimat 0.780 kg CO2e. Still, limited data is available on CO2FP and Life Cycle Assessment (LCA) of different types of DPIs. We conducted a Cradle-to-Grave (CTG) CO2FP analysis and LCA of four different Easyhaler® (EH) products available for the treatment of asthma and COPD (budesonide-formoterol; salmeterol-fluticasone; salbutamol, and formoterol EH). In-depth data collection from Orion in-house data, suppliers, and reference databases was conducted in 2019. Analyses were performed by ISO14001:2015 and 9001:2015 certified Carbon Footprint Ltd. The total CTG life cycle emissions for one EH (average) was 0.588 kg CO2e (range 0.514–0.664 kg). Emissions from manufacture accounted for 60% (range 54–65%). In comparison, emissions from distribution accounted for less than 2%, indicating that most potential for improvement lies in manufacture processes. Patients with asthma or COPD, and treating physicians alike, are increasingly aware of climate change and this affects even their treatment choices. When considering the climate impact of inhalation therapy, DPIs, like EH, have a minimal carbon footprint compared with MDI.

Background With rising concern on the global warming potential of propellants in pressurized metered dose inhalers (pMDIs) it has become increasingly important to identify patients who are able to safely switch from pMDI to dry powder inhaler (DPI). Clinicians have been concerned whether patients with COPD can achieve sufficient inspiratory flow rates (PIFR) through DPIs due to the devices internal resistance. Aim To study PIFR through Easyhaler® inhalers (EH-mono and -combi) and Handihaler® (HH) and to evaluate suitability of In-Check Dial® training device in inhaler selection. Methods Subjects used the inhalers as instructed by manufacturers and pneumotachograph was used to record inspiratory profiles. PIFR was also measured with In-Check Dial using resistance settings of the inhalers. Results 100 healthy volunteers and 100 patients with COPD were recruited in Finland and Estonia. Patients were classified to GOLD groups A(20 patients), B(58), C(8), and D(14). All subjects were able to achieve required PIFR (≥30 L/min) with EH. One COPD patient and one healthy volunteer did not archieve 30 L/min flow rate with HH device. The distributions of PIFRs are presented in the table 1. Patients showed lower PIF with In-Check Dial than with the inhalers. The difference was 3.0 (SD 8.5) L/min, 8.0 (SD 7.5) L/min, and 8.1 (SD 7.8) L/min for EH-mono, EH-combi and HH, respectively. Conclusions Patient performance is not a limiting factor for use of DPI for vast majority of patients with COPD. In this study In-Check Dial underestimated the PIFR for these inhalers, but it correctly classified the PIFR to be in the appropriate range in all cases.

Dry powder inhalers (DPIs) have about 20-fold lower carbon footprint (CO2FP) than metered dose inhalers (MDIs) with estimates of CO2FP between 1.5 and 6kg CO2e for a 200-dose DPI. GSK’s Carbon Trust-verified analysis including Relvar and Seretide Accuhaler is about 1kg CO2e/inhaler, and Product Carbon Footprint analysis of Spiriva Respimat 0.780kg CO2e. Still, limited data is available on CO2FP and LCA of different types of DPIs. We conducted a CTG CO2FP analysis and LCA of four different Easyhaler® (EH) products available for the treatment of asthma and COPD (budesonide-formoterol; salmeterol-fluticasone; salbutamol, and formoterol EH). In-depth data collection from Orion in-house data, suppliers, and reference databases was conducted in 2019. Analyses were performed by ISO14001:2015 and 9001:2015 certified Carbon Footprint Ltd. The total CTG life cycle emissions for one EH (average) was 0.588kg CO2e (range 0.514-0.664kg). Emissions from manufacture accounted for 60% (range 54-65%). In comparison, emissions from distribution accounted for less than 2%, indicating that most potential for improvement lies in manufacture processes. Patients with asthma or COPD, and treating physicians alike, are increasingly aware of climate change and this affects even their treatment choices. When considering the climate impact of inhalation therapy, DPIs, like EH, have a minimal carbon footprint compared with MDI.

Idiopathic pulmonary fibrosis (IPF) is a lung parenchymal disease of unknown cause usually occurring in older adults. It is a chronic and progressive condition with poor prognosis and diagnosis is largely clinical. Currently, there exist few biomarkers that can predict patient outcome or response to therapies. Together with lack of markers, the need for novel markers for the detection and monitoring of IPF, is paramount. We have performed label-free plasma proteomics of thirty six individuals, 17 of which had confirmed IPF. Proteomics data was analyzed by volcano plot, hierarchical clustering, Partial-least square discriminant analysis (PLS-DA) and Ingenuity pathway analysis. Univariate and multivariate statistical analysis overlap identified haptoglobin-related protein as a possible marker of IPF when compared to control samples (Area under the curve 0.851, ROC-analysis). LXR/RXR activation and complement activation pathways were enriched in t-test significant proteins and oxidative regulators, complement proteins and protease inhibitors were enriched in PLS-DA significant proteins. Our pilot study points towards aberrations in complement activation and oxidative damage in IPF patients and provides haptoglobin-related protein as a new candidate biomarker of IPF.

The aim of this work was to study the antifibrotic effect of pulmonary administration of tilorone to lung fibrosis. L-leucine coated tilorone particles were prepared and their aerosolization properties were analyzed using two dry powder inhalers (Easyhaler and Twister). In addition, the biological activity and cell monolayer permeation was tested. The antifibrotic effect of tilorone delivered by oropharyngeal aspiration was studied in vivo using a silica-induced model of pulmonary fibrosis in mice in a preventive setting. When delivered from the Easyhaler in an inhalation simulator, the emitted dose and fine particle fraction were independent from the pressure applied and showed dose repeatability. However, with Twister the aerosolization was pressure-dependent indicating poor compatibility between the device and the formulation. The formulation showed more consistent permeation through a differentiated Calu-3 cell monolayer compared to pristine tilorone. Tilorone decreased the histological fibrosis score in vivo in systemic and local administration, but only systemic administration decreased the mRNA expression of type I collagen. The difference was hypothesized to result from 40-fold higher drug concentration in tissue samples in the systemic administration group. These results show that tilorone can be formulated as inhalable dry powder and has potential as an oral and inhalable antifibrotic drug.

Patient’s adherence and ability to correctly perform the inhalation maneuver are challenges often discussed when sufficient control over asthma or COPD is not achieved. Dry powder inhalers (DPIs) rely on patient generated energy to aerosolize the formulation. Inspiratory flow rate is used to evaluate whether the patient is able to use DPIs. However, the power generation is a function of both flow rate and inhaler resistance and hence flow rate alone does not describe the physics involved in the powder deagglomeration nor does it describe the patients ability to inhale sufficiently. We used modified ‘Inhalation Manouvre Quality’ –requirements1 to assess how asthma (n=724) and COPD (n=244) patients performed with various DPIs. The airflow profiles of asthma and COPD were assessed for lungpower, flow acceleration and inspiratory volume after peak flow rate. The unit conversion from peak inspiratory flow rate to lungpower was conducted using device resistances found in literature. 96.1% (n=383), 92.6% (n=202), 89.5% (n=202) and 84.6% (n=181) of the patients met the requirements for successful inhalation for Easyhaler combi (for combination therapy), Easyhaler mono (for monotherapy), Diskus and Turbuhaler respectively (figure 1). The mean lungpower values varied between 7.18W and 9.65W for the four devices while the minimum power threshold calculated from the minimum flow rate was 0.58W, 1.15W, 0.29W and 4.36W for Easyhaler combi, Easyhaler mono, Diskus and Turbuhaler, respectively. In terms of lungpower, the poorest performing patients were COPD patients using Diskus. In this patient group 10th percentile cut off was 1.29W, which is sufficient for all the studied DPIs except for Turbuhaler. For large majority of respiratory patients DPIs provide a feasible treatment option. The Turbuhaler requires largest lungpower and performed worst likely due to its built-in deagglomeration system that requires large flow rates to operate properly.1 As for other inhalers, the lungpower requirement did not significantly limit the performance in any patient group. Reference Haidl P, Heindl S, Siemon K, Bernacka M, Cloes RM. Inhalation device requirements for patients’ inhalation maneuvers. Respir Med 2016;118:65–75. doi:10.1016/j.rmed.2016.07.013

The purpose of this study was to assess the feasibility of hydroxypropyl-β-cyclodextrin as a solubilizer for the corticosteroids prednisolone and fludrocortisone acetate in dry powder inhalation formulations. The dry particles were simultaneously produced and coated with nanosized L-leucine crystals using an aerosol flow reactor method. The aerosolization performances of carrier-free powders were studied using Easyhaler® and Twister™ at 2 and 4 kPa pressure drops over the inhalers. Drug permeation properties of the formulations were tested across a Calu-3 cell monolayer. Toxicity and reactive oxygen species induction were tested against Calu-3 and A549 cell lines. The hydroxypropyl-β-cyclodextrin in the powders promoted the dissolution of fludrocortisone the most, followed by that of prednisolone. Fine particle fractions were 52–70% from emitted doses which showed good repeatability with a coefficient variation of 0.9–0.17. In addition, hydroxypropyl-β-cyclodextrin enhanced the permeation of the corticosteroids. The powders showed no statistically significant toxicity nor reactive oxygen species induction in the tested cell lines. This study demonstrated the preparation and function of fine powder formulations which combine improved dissolution of poorly soluble drugs with good aerosolization performance. These results are expected to promote particle engineering as a way to develop new types of therapeutic pulmonary powders.

Malignant mesothelioma is an aggressive cancer with poor prognosis. It is characterized by prominent extracellular matrix, mesenchymal tumor cell phenotypes and chemoresistance. In this study, the ability of pirfenidone to alter mesothelioma cell proliferation and migration as well as mesothelioma tumor microenvironment was evaluated. Pirfenidone is an anti-fibrotic drug used in the treatment of idiopathic pulmonary fibrosis and has also anti-proliferative activities. Mesothelioma cell proliferation was decreased by pirfenidone alone or in combination with cisplatin. Pirfenidone also decreased significantly Transwell migration/invasion and 3D collagen invasion. This was associated with increased BMP pathway activity, decreased GREM1 expression and downregulation of MAPK/ERK and AKT/mTOR signaling. The canonical Smad-mediated TGF-β signaling was not affected by pirfenidone. However, pirfenidone blocked TGF-β induced upregulation of ERK and AKT pathways. Treatment of mice harboring mesothelioma xenografts with pirfenidone alone did not reduce tumor proliferation in vivo. However, pirfenidone modified the tumor microenvironment by reducing the expression of extracellular matrix associated genes. In addition, GREM1 expression was downregulated by pirfenidone in vivo. By reducing two major upregulated pathways in mesothelioma and by targeting tumor cells and the microenvironment pirfenidone may present a novel anti-fibrotic and anti-cancer adjuvant therapy for mesothelioma.

Idiopathic pulmonary fibrosis (IPF) is a severe progressive fibrotic lung disease. During the past few years two orally administered drug candidates (pirfenidone and nintedanib) for slowing the progression of IPF were approved for clinical practice. Our research group discovered a potential antifibrotic drug, tilorone, using a high throughput screening and …

The purpose of this study was to examine pirfenidone (PFD) as a potential new therapy for malignant pleural mesothelioma. PFD is an anti-fibrotic drug used to treat idiopathic pulmonary fibrosis (IPF). PFD reduces fibrous tissue formation e.g. by downregulating the production of fibroblasts and procollagens and inhibiting TGFß, TNFα and PDGF pathways. Since mesothelioma shares characteristics with IPF alongside with the activation of PI3K/Akt/mTOR, EGF, PDGF, HGF, VEGF, FGF and TGF-β pathways, we assessed the effect of PFD on mesothelioma cells in vitro and in vivo. In vitro studies were carried out using mesothelioma cell lines (JL-1, H2052, AB12) and primary mesothelioma cells. Cells treated with PFD and/or other agents (cisplatin, pemetrexed, MK-2206, PD98059, MG132) were subjected to cell viability assays, Transwell migration assays and 3D collagen or Matrigel growth and invasion assays. TGFβ/BMP, MAPK/Erk and Akt pathway activities were studied using luciferase reporter assays and human phospho-kinase array and validated with ELISA, RT-qPCR and Western blotting. For in vivo xenograft studies mice were injected subcutaneously with primary human mesothelioma cells expressing luciferase marker. Mice were treated with pirfenidone daily for 60 days and tumor growth was followed by bioluminescent imaging. Proliferation was studied by IHC. Differential gene expression in treated vs. untreated tumors was analyzed using RNA sequencing. We demonstrated that PFD treatment reduced significantly mesothelioma cell proliferation, migration and invasive growth in 3D in a concentration-dependent manner. The inhibitory effect of PFD increased when combined with cisplatin treatment in vitro. We also observed reduction of Akt and MAPK/Erk pathway activities and increase in BMP signaling in PFD treated tumor cells. Preliminary analyses of in vivo experiment revealed differential expression of multiple genes in pirfenidone treated vs. untreated tumors associated with a shift to more anti-fibrotic tumor microenvironment in PFD treated tumors. Expression profiles are currently under closer investigation. We identified pirfenidone as an inhibitor of mesothelioma invasive growth and showed that it has anti-fibrotic effects to tumor microenvironment. Since mesotheliomas are often inherently chemoresistant in fibrotic microenvironment, the use of pirfenidone could aid in overcoming chemoresistance by loosening ECM barrier for better drug penetration into the tumor tissue. Based on the current research we suggest that pirfenidone should be subjected to more intensive study as potential adjuvant-therapy for malignant mesotheliomas. Citation Format: Chang Li, Veronika Rezov, Emmi I. Joensuu, Ville Vartiainen, Mikko Rönty, Miao Yin, Marjukka Myllärniemi, Katri Koli. Pirfenidone as a new potential therapy for malignant mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-014.

The effect of three amino acid coatings ( l -leucine, l -valine and l -phenylalanine) on particle integrity, aerosolization properties, cellular interaction, cytocompatibility, and drug permeation properties of drug combination powder particles (beclomethasone dipropionate and salbutamol sulphate) for dry powder inhalation (DPI) was investigated. Particles with crystalline l -leucine coating resulted in intact separated particles, with crystalline l -valine coating in slightly sintered particles and with amorphous l -phenylalanine coating in strongly fused particles. The permeation of beclomethasone dipropionate across a Calu-3 differentiated cell monolayer was increased when compared with its physical mixture. Drug crystal formation was also observed on the Calu-3 cell monolayer. The l -leucine coated particles were further investigated for cytocompatibility in three human pulmonary (Calu-3, A549 and BEAS-2B) and one human macrophage (THP-1) cell lines, where they showed excellent tolerability. The l -leucine coated particles were also examined for their ability to elicit reactive oxygen species in pulmonary BEAS-2B and macrophage THP-1 cell lines. The study showed the influence of the amino acid coatings for particle formation and performance and their feasibility for combination therapy for pulmonary delivery.

Nanoconfined self-assemblies within aerosol nanoparticles and control of the secondary structures are shown here upon ionically complexing poly(L-lysine) (PLL) with dodecylbenzenesulfonic acid (DBSA) surfactant and using solvents chloroform, 1-propanol, or dimethylformamide. Different solvent volatilities and drying temperatures allowed tuning the kinetics of morphology formation. The supramolecular self-assembly and morphology were studied using cryo-TEM and SEM, and the secondary structures, using FT-IR. Highly volatile chloroform led to the major fraction of α-helical conformation of PLL(DBSA), whereas less volatile solvents or higher drying temperatures led to the increasing fraction of β-sheets. Added drugs budesonide and ketoprofen prevented β-sheet formation and studied PLL(DBSA)-drug nanoparticles were in the α-helical conformation. Preliminary studies showed that ketoprofen released with a slower rate than budesonide which was hypothesized to result from different localization of drugs within the PLL(DBSA) nanoparticles. These results instruct to prepare polypeptide aerosol nanoparticles with internal self-assembled structures and to control the secondary structures by aerosol solvent annealing, which we foresee to be useful, e.g., toward controlling the release of poorly soluble drug molecules.