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20 pages, 3695 KiB

Open AccessArticle

Manipulation of Spray-Drying Conditions to Develop an Inhalable Ivermectin Dry Powder

by Tushar Saha, Shubhra Sinha, Rhodri Harfoot, Miguel E. Quiñones-Mateu and Shyamal C. Das

Pharmaceutics 2022, 14(7), 1432; https://doi.org/10.3390/pharmaceutics14071432 - 08 Jul 2022

Cited by 8 | Viewed by 3148

SARS-CoV-2, the causative agent of COVID-19, predominantly affects the respiratory tract. As a consequence, it seems intuitive to develop antiviral agents capable of targeting the virus right on its main anatomical site of replication. Ivermectin, a U.S. FDA-approved anti-parasitic drug, was originally shown [...] Read more.

SARS-CoV-2, the causative agent of COVID-19, predominantly affects the respiratory tract. As a consequence, it seems intuitive to develop antiviral agents capable of targeting the virus right on its main anatomical site of replication. Ivermectin, a U.S. FDA-approved anti-parasitic drug, was originally shown to inhibit SARS-CoV-2 replication in vitro, albeit at relatively high concentrations, which is difficult to achieve in the lung. In this study, we tested the spray-drying conditions to develop an inhalable dry powder formulation that could ensure sufficient antiviral drug concentrations, which are difficult to achieve in the lungs based on the oral dosage used in clinical trials. Here, by using ivermectin as a proof-of-concept, we evaluated spray-drying conditions that could lead to the development of antivirals in an inhalable dry powder formulation, which could then be used to ensure sufficient drug concentrations in the lung. Thus, we used ivermectin in proof-of-principle experiments to evaluate our system, including physical characterization and in vitro aerosolization of prepared dry powder. The ivermectin dry powder was prepared with a mini spray-dryer (Buchi B-290), using a 2³ factorial design and manipulating spray-drying conditions such as feed concentration (0.2% w/v and 0.8% w/v), inlet temperature (80 °C and 100 °C) and presence/absence of L-leucine (0% and 10%). The prepared dry powder was in the size range of 1–5 μm and amorphous in nature with wrinkle morphology. We observed a higher fine particle fraction (82.5 ± 1.4%) in high feed concentration (0.8% w/v), high inlet temperature (100 °C) and the presence of L-leucine (10% w/w). The stability study conducted for 28 days confirmed that the spray-dried powder was stable at 25 ± 2 °C/<15% RH and 25 ± 2 °C/ 53% RH. Interestingly, the ivermectin dry powder formulation inhibited SARS-CoV-2 replication in vitro with a potency similar to ivermectin solution (EC₅₀ values of 15.8 µM and 14.1 µM, respectively), with a comparable cell toxicity profile in Calu-3 cells. In summary, we were able to manipulate the spray-drying conditions to develop an effective ivermectin inhalable dry powder. Ongoing studies based on this system will allow the development of novel formulations based on single or combinations of drugs that could be used to inhibit SARS-CoV-2 replication in the respiratory tract. Full article

(This article belongs to the Special Issue Dry Powders for Inhalation: Formulation Design and Quality Assessment)

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15 pages, 5699 KiB

Open AccessArticle

Experimental Evaluation of Dry Powder Inhalers during Inhalation and Exhalation Using a Model of the Human Respiratory System (xPULM™)

by Richard Pasteka, Lara Alina Schöllbauer, Joao Pedro Santos da Costa, Radim Kolar and Mathias Forjan

Pharmaceutics 2022, 14(3), 500; https://doi.org/10.3390/pharmaceutics14030500 - 24 Feb 2022

Cited by 6 | Viewed by 2345

Abstract

Dry powder inhalers are used by a large number of patients worldwide to treat respiratory diseases. The objective of this work is to experimentally investigate changes in aerosol particle diameter and particle number concentration of pharmaceutical aerosols generated by four dry powder inhalers [...] Read more.

Dry powder inhalers are used by a large number of patients worldwide to treat respiratory diseases. The objective of this work is to experimentally investigate changes in aerosol particle diameter and particle number concentration of pharmaceutical aerosols generated by four dry powder inhalers under realistic inhalation and exhalation conditions. To simulate patients undergoing inhalation therapy, the active respiratory system model (xPULM™) was used. A mechanical upper airway model was developed, manufactured, and introduced as a part of the xPULM™ to represent the human upper respiratory tract with high fidelity. Integration of optical aerosol spectrometry technique into the setup allowed for evaluation of pharmaceutical aerosols. The results show that there is a significant difference (p < 0.05) in mean particle diameter between inhaled and exhaled particles with the majority of the particles depositing in the lung, while particles with the size of (>0.5 μm) are least influenced by deposition mechanisms. The fraction of exhaled particles ranges from 2.13% (HandiHaler^®) over 2.94% (BreezHaler^®), and 6.22% (Turbohaler^®) to 10.24% (Ellipta^®). These values are comparable to previously published studies. Furthermore, the mechanical upper airway model increases the resistance of the overall system and acts as a filter for larger particles (>3 μm). In conclusion, the xPULM™ active respiratory system model is a viable option for studying interactions of pharmaceutical aerosols and the respiratory tract regarding applicable deposition mechanisms. The model strives to support the reduction of animal experimentation in aerosol research and provides an alternative to experiments with human subjects. Full article

(This article belongs to the Special Issue Dry Powders for Inhalation: Formulation Design and Quality Assessment)

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16 pages, 5192 KiB

Open AccessArticle

Inhalable, Spray-Dried Terbinafine Microparticles for Management of Pulmonary Fungal Infections: Optimization of the Excipient Composition and Selection of an Inhalation Device

by Khaled Almansour, Iman M. Alfagih, Alhassan H. Aodah, Fawaz Alheibshy, Raisuddin Ali, Turki Al Hagbani and Mustafa M.A. Elsayed

Pharmaceutics 2022, 14(1), 87; https://doi.org/10.3390/pharmaceutics14010087 - 30 Dec 2021

Cited by 2 | Viewed by 2322

Abstract

Terbinafine is a broad-spectrum antifungal agent with therapeutic potential against pulmonary aspergillosis. The main aim of the current study was to investigate the potential of l-leucine, alone and in combination with mannitol, to improve the performance of spray-dried terbinafine microparticles for inhalation. [...] Read more.

Terbinafine is a broad-spectrum antifungal agent with therapeutic potential against pulmonary aspergillosis. The main aim of the current study was to investigate the potential of l-leucine, alone and in combination with mannitol, to improve the performance of spray-dried terbinafine microparticles for inhalation. The study also aimed to investigate the potential of the low resistance Cyclohaler^® and the high resistance Handihaler^® as inhalation devices for spray-dried microparticles. To this end, eight powder inhalation formulations of terbinafine were prepared by nano spray drying via a factorial experimental design. The formulations were evaluated in vitro for their potential to deliver the antifungal drug to the lungs using the Cyclohaler^® and the Handihaler^®. Leucine was superior as an excipient to mannitol and to mixtures of leucine and mannitol. Using leucine as an excipient resulted in formulations with fine particle fractions of up to 60.84 ± 0.67% w/w and particle mass median aerodynamic diameters of down to 1.90 ± 0.20 μm, whereas using mannitol as an excipient resulted in formulations with fine particle fractions of up to 18.75 ± 3.46% w/w and particle mass median aerodynamic diameters of down to 6.79 ± 0.82 μm. When leucine was used as an excipient, using 50% w/w rather than 25% w/w ethanol in water as a spray solvent enhanced the dispersibility of the particles, with a mean absolute increase in the formulation fine particle fraction of 9.57% w/w (95% confidence interval = 6.40–12.73% w/w). This was potentially underlain by enrichment of the particle surfaces with leucine. The Cyclohaler^® outperformed the Handihaler^® as an inhalation device for the developed formulations, with a mean absolute increase in the fine particle fraction of 9.17% w/w (95% confidence interval = 8.17–10.16% w/w). Full article

(This article belongs to the Special Issue Dry Powders for Inhalation: Formulation Design and Quality Assessment)

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23 pages, 7744 KiB

Open AccessArticle

Comparative Assessment of In Vitro and In Silico Methods for Aerodynamic Characterization of Powders for Inhalation

by Jelisaveta Ignjatović, Tijana Šušteršič, Aleksandar Bodić, Sandra Cvijić, Jelena Đuriš, Alessandra Rossi, Vladimir Dobričić, Svetlana Ibrić and Nenad Filipović

Pharmaceutics 2021, 13(11), 1831; https://doi.org/10.3390/pharmaceutics13111831 - 02 Nov 2021

Cited by 5 | Viewed by 2329

Abstract

In vitro assessment of dry powders for inhalation (DPIs) aerodynamic performance is an inevitable test in DPI development. However, contemporary trends in drug development also implicate the use of in silico methods, e.g., computational fluid dynamics (CFD) coupled with discrete phase modeling (DPM). [...] Read more.

In vitro assessment of dry powders for inhalation (DPIs) aerodynamic performance is an inevitable test in DPI development. However, contemporary trends in drug development also implicate the use of in silico methods, e.g., computational fluid dynamics (CFD) coupled with discrete phase modeling (DPM). The aim of this study was to compare the designed CFD-DPM outcomes with the results of three in vitro methods for aerodynamic assessment of solid lipid microparticle DPIs. The model was able to simulate particle-to-wall sticking and estimate fractions of particles that stick or bounce off the inhaler’s wall; however, we observed notable differences between the in silico and in vitro results. The predicted emitted fractions (EFs) were comparable to the in vitro determined EFs, whereas the predicted fine particle fractions (FPFs) were generally lower than the corresponding in vitro values. In addition, CFD-DPM predicted higher mass median aerodynamic diameter (MMAD) in comparison to the in vitro values. The outcomes of different in vitro methods also diverged, implying that these methods are not interchangeable. Overall, our results support the utility of CFD-DPM in the DPI development, but highlight the need for additional improvements in these models to capture all the key processes influencing aerodynamic performance of specific DPIs. Full article

(This article belongs to the Special Issue Dry Powders for Inhalation: Formulation Design and Quality Assessment)

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16 pages, 3709 KiB

Open AccessArticle

Roflumilast Powders for Chronic Obstructive Pulmonary Disease: Formulation Design and the Influence of Device, Inhalation Flow Rate, and Storage Relative Humidity on Aerosolization

by Mohammad A. M. Momin, Bishal Raj Adhikari, Shubhra Sinha, Ian Larson and Shyamal C. Das

Pharmaceutics 2021, 13(8), 1254; https://doi.org/10.3390/pharmaceutics13081254 - 13 Aug 2021

Cited by 7 | Viewed by 3199

Abstract

Roflumilast is currently administered orally to control acute exacerbations in chronic obstructive pulmonary disease (COPD). However, side effects such as gastrointestinal disturbance and weight loss have limited its application. This work aimed to develop an inhalable roflumilast formulation to reduce the dose and [...] Read more.

Roflumilast is currently administered orally to control acute exacerbations in chronic obstructive pulmonary disease (COPD). However, side effects such as gastrointestinal disturbance and weight loss have limited its application. This work aimed to develop an inhalable roflumilast formulation to reduce the dose and potentially circumvent the associated toxicity. Roflumilast was cospray-dried with trehalose and L-leucine with varied feed concentrations and spray-gas flow rates to produce the desired dry powder. A Next-Generation Impactor (NGI) was used to assess the aerosolization efficiency. In addition, different devices (Aerolizer, Rotahaler, and Handihaler) and flow rates were used to investigate their effects on the aerosolization efficiency. A cytotoxicity assay was also performed. The powders produced under optimized conditions were partially amorphous and had low moisture content. The powders showed good dispersibility, as evident by the high emitted dose (>88%) and fine particle fraction (>52%). At all flow rates (≥30 L/min), the Aerolizer offered the best aerosolization. The formulation exhibited stable aerosolization after storage at 25 °C/15% Relative Humidity (RH) for one month. Moreover, the formulation was non-toxic to alveolar basal epithelial cells. A potential inhalable roflumilast formulation including L-leucine and trehalose has been developed for the treatment of COPD. This study also suggests that the choice of device is crucial to achieve the desired aerosol performance. Full article

(This article belongs to the Special Issue Dry Powders for Inhalation: Formulation Design and Quality Assessment)

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17 pages, 11369 KiB

Open AccessArticle

Stability and In Vitro Aerodynamic Studies of Inhalation Powders Containing Ciprofloxacin Hydrochloride Applying Different DPI Capsule Types

by Edit Benke, Patrícia Varga, Piroska Szabó-Révész and Rita Ambrus

Pharmaceutics 2021, 13(5), 689; https://doi.org/10.3390/pharmaceutics13050689 - 11 May 2021

Cited by 6 | Viewed by 2846

Abstract

In the case of capsule-based dry powder inhalation systems (DPIs), the selection of the appropriate capsule is important. The use of gelatin, gelatin-PEG, and HPMC capsules has become widespread in marketed capsule-based DPIs. We aimed to perform a stability test according to the [...] Read more.

In the case of capsule-based dry powder inhalation systems (DPIs), the selection of the appropriate capsule is important. The use of gelatin, gelatin-PEG, and HPMC capsules has become widespread in marketed capsule-based DPIs. We aimed to perform a stability test according to the ICH guideline in the above-mentioned three capsule types. The results of the novel combined formulated microcomposite were more favorable than those of the carrier-free formulation for all capsule types. The use of HPMC capsules results in the greatest stability and thus the best in vitro aerodynamic results for both DPI powders after six months. This can be explained by the fact that the residual solvent content (RSC) of the capsules differs. Under the applied conditions the RSC of the HPMC capsule decreased the least and remained within the optimal range, thus becoming less fragmented, which was reflected in the RSC, structure and morphology of the particles, as well as in the in vitro aerodynamic results (there was a difference of approximately 10% in the lung deposition results). During pharmaceutical dosage form developments, emphasis should be placed in the case of DPIs on determining which capsule type will be used for specific formulations. Full article

(This article belongs to the Special Issue Dry Powders for Inhalation: Formulation Design and Quality Assessment)

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14 pages, 3186 KiB

Open AccessArticle

Optimization of Very Low-Dose Formulation of Vitamin D3 with Lyophilizate for Dry Powder Inhalation System by Simple Method Based on Time-of-Flight Theory

by Kahori Miyamoto, Misato Yanagisawa, Hiroaki Taga, Hiromichi Yamaji, Tomomi Akita and Chikamasa Yamashita

Pharmaceutics 2021, 13(5), 632; https://doi.org/10.3390/pharmaceutics13050632 - 29 Apr 2021

Cited by 2 | Viewed by 1749

Abstract

It has been previously reported that active vitamin D3 (VD3) is a candidate drug that can repair alveolar damage in chronic obstructive pulmonary disease at a very low dose. We herein report the optimization of a very low-dose formulation of VD3 for dry [...] Read more.

It has been previously reported that active vitamin D3 (VD3) is a candidate drug that can repair alveolar damage in chronic obstructive pulmonary disease at a very low dose. We herein report the optimization of a very low-dose formulation of VD3 for dry powder inhalation by a simple method based on time-of-flight (TOF) theory. As the preparation content of VD3 is very low, aerodynamic particle size distribution cannot be measured by pharmacopeial methods that require quantification of the main drug. Thus, a simple method based on TOF theory, which can measure aerodynamic particle size distribution without quantification, was used. The optimized formulation for an inhalation system using a lyophilized cake contained phenylalanine as the excipient (VD3 1 μg/vial + phenylalanine 0.3 mg/vial) and showed high performance with fine particle fraction ≤ 3 μm = 47.2 ± 4.4%. The difference between the results of pharmacopeial methods and simple method was examined using the formulation containing 10 µg/vial of VD3 and was within 5.0%. The preparation is expected to efficiently deliver VD3 to the lungs. Our simple method can optimize dry powder inhalation formulations more easily and rapidly even when the content of the main drug in a preparation is very low. Full article

(This article belongs to the Special Issue Dry Powders for Inhalation: Formulation Design and Quality Assessment)

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19 pages, 1957 KiB

Open AccessSystematic Review

Impact of Sex on Proper Use of Inhaler Devices in Asthma and COPD: A Systematic Review and Meta-Analysis

by Luigino Calzetta, Marina Aiello, Annalisa Frizzelli, Beatrice Ludovica Ritondo, Elena Pistocchini, Paola Rogliani and Alfredo Chetta

Pharmaceutics 2022, 14(8), 1565; https://doi.org/10.3390/pharmaceutics14081565 - 28 Jul 2022

Cited by 4 | Viewed by 2237

Abstract

Despite females being more often affected by asthma than males and the prevalence of COPD rising in females, conflicting evidence exists as to whether sex may modulate the correct inhaler technique. The aim of this study was to assess the impact of sex [...] Read more.

Despite females being more often affected by asthma than males and the prevalence of COPD rising in females, conflicting evidence exists as to whether sex may modulate the correct inhaler technique. The aim of this study was to assess the impact of sex on the proper use of inhaler devices in asthma and COPD. A pairwise meta-analysis was performed on studies enrolling adult males and females with asthma or COPD and reporting data of patients making at least one error by inhaler device type (DPI, MDI, and SMI). The data of 6,571 patients with asthma or COPD were extracted from 12 studies. A moderate quality of evidence (GRADE +++) indicated that sex may influence the correct use of inhaler device in both asthma and COPD. The critical error rate was higher in females with asthma (OR 1.31, 95%CI 1.14–1.50) and COPD (OR 1.80, 95%CI 1.22–2.67) using DPI vs. males (p < 0.01). In addition, the use of SMI in COPD was associated with a greater rate of critical errors in females vs. males (OR 5.36, 95%CI 1.48–19.32; p < 0.05). No significant difference resulted for MDI. In conclusion, choosing the right inhaler device in agreement with sex may optimize the pharmacological treatment of asthma and COPD. Full article

(This article belongs to the Special Issue Dry Powders for Inhalation: Formulation Design and Quality Assessment)

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