Development and Evaluation of Inhalable Dry Powder Formulations

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 18761

Special Issue Editors


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Guest Editor
Center for Translational Science, Florida International University (FIU), 11350 SW Village Parkway, CTS 314, Port Saint Lucie, FL 34987, USA
Interests: respiratory drug delivery; inhalation aerosol medicine; lung surfactant; targeted drug delivery systems; controlled release drug delivery; sustained-release peptide injectibles; CNS peptide therapeutics nose-to-brain delivery

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Guest Editor
Center for Translational Science, Florida International University (FIU), 11350 SW Village Parkway, CTS 321, Port Saint Lucie, FL 34987, USA
Interests: pulmonary delivery; dry powder inhalations; targeted drug delivery systems; particle engineering; spray drying; surface characterization; physicochemical characterization; respirable size particle dissolution

Special Issue Information

Dear Colleagues,

Respiratory drug delivery is an important route for the administration of treatment and prevention of diseases of the respiratory tract (nasal and pulmonary regions), and for delivering drugs non-invasively to the central nervous system (CNS). Pulmonary drug delivery has recently gained a significant importance in the therapeutic field due to the various advantages, such as pain-free administration, targeted drug delivery with minimum systemic exposure, rapid onset of action, reduced enzymatic degradation, high drug-concentrations in the lungs, and avoidance of hepatic first-pass metabolism compared to the other conventional routes of administration. Formulations including biologicals have shown an increased stability when they are in solid-state rather than liquid formulations, making dry powder inhalers (DPIs) the more preferred formulation for pulmonary drug delivery. The aerodynamic diameter, along with other features of the particles, plays a key role in the deposition of aerosols in the lungs; therefore, it is important to engineer the particles using the right technique. This Special Issue focuses on the design and development of innovative dry powder formulations as inhalation aerosols by the lung and nasal routes of administration.

Prof. Dr. Heidi M. Mansour
Dr. Basanth Babu Eedara
Guest Editors

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Keywords

  • respiratory delivery
  • dry powder inhalation
  • particle engineering design
  • physicochemical characterization
  • aerosolization
  • lung delivery
  • nasal delivery

Published Papers (9 papers)

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Research

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12 pages, 2716 KiB  
Article
Spray-Dried Inhalable Microparticles Combining Remdesivir and Ebselen against SARS-CoV-2 Infection
by Tushar Saha, Shubhra Sinha, Rhodri Harfoot, Miguel E. Quiñones-Mateu and Shyamal C. Das
Pharmaceutics 2023, 15(9), 2229; https://doi.org/10.3390/pharmaceutics15092229 - 29 Aug 2023
Cited by 1 | Viewed by 1400
Abstract
There is a continuous effort to develop efficient treatments for coronavirus disease 2019 (COVID-19) and other viral respiratory diseases. Among the different strategies, inhaled treatment is considered one of the most logical and efficient approaches to treating COVID-19, as the causative “SARS-CoV-2 virus [...] Read more.
There is a continuous effort to develop efficient treatments for coronavirus disease 2019 (COVID-19) and other viral respiratory diseases. Among the different strategies, inhaled treatment is considered one of the most logical and efficient approaches to treating COVID-19, as the causative “SARS-CoV-2 virus RNA” predominantly infects the respiratory tract. COVID-19 treatments initially relied on repurposed drugs, with a few additional strategies developed during the last two years, and all of them are based on monotherapy. However, drug combinations have been found to be more effective than monotherapy in other viral diseases such as HIV, influenza, and hepatitis C virus. In the case of SARS-CoV-2 infection, in vitro studies have shown synergistic antiviral activity combining remdesivir with ebselen, an organoselenium compound. Therefore, these drug combinations could ensure better therapeutic outcomes than the individual agents. In this study, we developed a dry powder formulation containing remdesivir and ebselen using a spray-drying technique and used L-leucine as an aerosolization enhancer. The prepared dry powders were spherical and crystalline, with a mean particle size between 1 and 3 µm, indicating their suitability for inhalation. The emitted dose (ED) and fine particle fraction (FPF) of remdesivir- and ebselen-containing dry powders were ~80% and ~57% when prepared without L-leucine. The ED as well as the FPF significantly increased with values of >86% and >67%, respectively, when L-leucine was incorporated. More importantly, the single and combinational dry powder of remdesivir and ebselen showed minimal cytotoxicity (CC50 > 100 μM) in Calu-3 cells, retaining their anti-SARS-CoV-2 properties (EC50 2.77 to 18.64 μM). In summary, we developed an inhalable dry powder combination of remdesivir and ebselen using a spray-drying technique. The spray-dried inhalable microparticles retained their limited cytotoxicity and specific antiviral properties. Future in vivo studies are needed to verify the potential use of these remdesivir/ebselen combinational spray-dried inhalable microparticles to block the SARS-CoV-2 replication in the respiratory tract. Full article
(This article belongs to the Special Issue Development and Evaluation of Inhalable Dry Powder Formulations)
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21 pages, 8549 KiB  
Article
Designing Aerosol Therapies Based on the Integrated Evaluation of In Vitro, In Vivo, and In Silico Data
by Margaret Bourlon, Yu Feng and Lucila Garcia-Contreras
Pharmaceutics 2023, 15(6), 1695; https://doi.org/10.3390/pharmaceutics15061695 - 09 Jun 2023
Viewed by 1158
Abstract
Despite the advantages of the pulmonary route of administration and inhalable dosage forms, other routes of administration and dosage forms are often considered first to treat lung diseases. This occurs, in part, due to the perceived limitations of inhaled therapies resulting from the [...] Read more.
Despite the advantages of the pulmonary route of administration and inhalable dosage forms, other routes of administration and dosage forms are often considered first to treat lung diseases. This occurs, in part, due to the perceived limitations of inhaled therapies resulting from the improper design and interpretation of their in vitro and in vivo evaluation. The present study outlines the elements that should be considered in the design, performance, and interpretation of the results of the preclinical evaluation of novel inhaled therapies. These elements are illustrated using an optimized model poly(lactic-co-glycolic) acid (PLGA) microparticle (MP) formulation to optimize the site of MPs deposition. The different expressions of MP size were determined, and their aerosol performance in devices used for animal (Microsprayer® and Insufflator®) and human studies (nebulizer and DPIs) was assessed using inertial impaction. Radiolabeled MPs were delivered to the lungs of rats by spray instillation to determine their site of deposition using single-photon emission computed tomography (SPECT) imaging. Recommendations to optimize the in vitro determinations are given, as well as suggestions to evaluate and interpret in vivo data in the context of the anatomy and physiology of the animal model and the corresponding in vitro data. Recommendations for the proper selection of in vitro parameters to inform in silico modeling are also given, as well as their integration with in vivo data. Full article
(This article belongs to the Special Issue Development and Evaluation of Inhalable Dry Powder Formulations)
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17 pages, 1786 KiB  
Article
Effect of Inhalation Profile on Delivery of Treprostinil Palmitil Inhalation Powder
by Helena Gauani, Thomas Baker, Zhili Li, Vladimir S. Malinin, Walter R. Perkins, Eugene J. Sullivan and David Cipolla
Pharmaceutics 2023, 15(3), 934; https://doi.org/10.3390/pharmaceutics15030934 - 14 Mar 2023
Cited by 1 | Viewed by 1866
Abstract
Treprostinil palmitil (TP), a prodrug of treprostinil, is being developed as an inhalation powder (TPIP) for the treatment of patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension due to interstitial lung disease (PH-ILD). In ongoing human clinical trials, TPIP is administered via [...] Read more.
Treprostinil palmitil (TP), a prodrug of treprostinil, is being developed as an inhalation powder (TPIP) for the treatment of patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension due to interstitial lung disease (PH-ILD). In ongoing human clinical trials, TPIP is administered via a commercially available high resistance (HR) RS01 capsule-based dry powder inhaler (DPI) device manufactured by Berry Global (formerly Plastiape), which utilizes the patient’s inspiratory flow to provide the required energy to deagglomerate and disperse the powder for delivery to their lungs. In this study, we characterized the aerosol performance of TPIP in response to changes in inhalation profiles to model more realistic use scenarios, i.e., for reduced inspiratory volumes and with inhalation acceleration rates that differ from those described in the compendia. The emitted dose of TP for all combinations of inhalation profiles and volumes ranged narrowly between 79 and 89% for the 16 and 32 mg TPIP capsules at the 60 LPM inspiratory flow rate but was reduced to 72–76% for the 16 mg TPIP capsule under the scenarios at the 30 LPM peak inspiratory flow rate. There were no meaningful differences in the fine particle dose (FPD) at all conditions at 60 LPM with the 4 L inhalation volume. The FPD values for the 16 mg TPIP capsule ranged narrowly between 60 and 65% of the loaded dose for all inhalation ramp rates with a 4 L volume and at both extremes of ramp rates for inhalation volumes down to 1 L, while the FPD values for the 32 mg TPIP capsule ranged between 53 and 65% of the loaded dose for all inhalation ramp rates with a 4 L volume and at both extremes of ramp rates for inhalation volumes down to 1 L for the 60 LPM flow rate. At the 30 LPM peak flow rate, the FPD values for the 16 mg TPIP capsule ranged narrowly between 54 and 58% of the loaded dose at both extremes of the ramp rates for inhalation volumes down to 1 L. Based on these in vitro findings, the TPIP delivery system appears not to be affected by the changes in inspiratory flow profiles or inspiratory volumes that might be expected to occur in patients with PAH or PH associated with underlying lung conditions such as ILD. Full article
(This article belongs to the Special Issue Development and Evaluation of Inhalable Dry Powder Formulations)
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24 pages, 2543 KiB  
Article
Impact of Leucine and Magnesium Stearate on the Physicochemical Properties and Aerosolization Behavior of Wet Milled Inhalable Ibuprofen Microparticles for Developing Dry Powder Inhaler Formulation
by Shahjabeen Sharif, Saiqa Muneer, Emad L. Izake and Nazrul Islam
Pharmaceutics 2023, 15(2), 674; https://doi.org/10.3390/pharmaceutics15020674 - 16 Feb 2023
Cited by 1 | Viewed by 1626
Abstract
This study investigated the development and characterization of leucine and magnesium stearate (MgSt) embedded wet milled inhalable ibuprofen (IBF) dry powder inhaler (DPI) formulations. IBF microparticles were prepared by a wet milling homogenization process and were characterized by SEM, FTIR, DSC, XRD and [...] Read more.
This study investigated the development and characterization of leucine and magnesium stearate (MgSt) embedded wet milled inhalable ibuprofen (IBF) dry powder inhaler (DPI) formulations. IBF microparticles were prepared by a wet milling homogenization process and were characterized by SEM, FTIR, DSC, XRD and TGA. Using a Twin-Stage Impinger (TSI), the in vitro aerosolization of the formulations with and without carrier lactose was studied at a flow rate of 60± 5 L/min and the IBF was determined using a validated HPLC method. The flow properties were determined by the Carr’s Index (CI), Hausner Ratio (HR) and Angle of Repose (AR) of the milled IBF with 4–6.25% leucine and leucine containing formulations showed higher flow property than those of formulations without leucine. The fine particle fraction (FPF) of IBF from the prepared formulations was significantly (p = 0.000278) higher (37.1 ± 3.8%) compared to the original drug (FPF 3.7 ± 0.9%) owing to the presence of leucine, which enhanced the aerosolization of the milled IBF particles. Using quantitative phase analysis, the XPRD data revealed the crystallinity and accurate weight percentages of the milled IBF in the formulations. FTIR revealed no changes of the structural integrity of the milled IBF in presence of leucine or MgSt. The presence of 2.5% MgSt in the selected formulations produced the highest solubility (252.8 ± 0.6 µg/mL) of IBF compared to that of unmilled IBF (147.4 ± 1.6 µg/mL). The drug dissolution from all formulations containing 4–6.25% leucine showed 12.2–18.6% drug release in 2.5 min; however, 100% IBF dissolution occurred in 2 h whereas around 50% original and dry milled IBF dissolved in 2 h. The results indicated the successful preparation of inhalable IBF microparticles by the wet milling method and the developed DPI formulations with enhanced aerosolization and solubility due to the presence of leucine may be considered as future IBF formulations for inhalation. Full article
(This article belongs to the Special Issue Development and Evaluation of Inhalable Dry Powder Formulations)
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26 pages, 11280 KiB  
Article
On the Physical Stability of Leucine-Containing Spray-Dried Powders for Respiratory Drug Delivery
by Mani Ordoubadi, Kimberly B. Shepard, Hui Wang, Zheng Wang, Amanda M. Pluntze, Joseph P. Churchman and Reinhard Vehring
Pharmaceutics 2023, 15(2), 435; https://doi.org/10.3390/pharmaceutics15020435 - 28 Jan 2023
Cited by 6 | Viewed by 1966
Abstract
Carrier-free spray-dried dispersions for pulmonary delivery, for which the demand is growing, frequently require the incorporation of dispersibility-enhancing excipients into the formulations to improve the efficacy of the dosage form. One of the most promising of such excipients, L-leucine, is expected to be [...] Read more.
Carrier-free spray-dried dispersions for pulmonary delivery, for which the demand is growing, frequently require the incorporation of dispersibility-enhancing excipients into the formulations to improve the efficacy of the dosage form. One of the most promising of such excipients, L-leucine, is expected to be approved for inhalation soon and has been studied exhaustively. However, during stability, small fibers protruding from the particles of leucine-containing powders have occasionally been observed. To clarify the origin of these fibers and assess their potential influence on the performance of the powders, three different classes of spray-dried leucine-containing formulation systems were studied over an 8-month accelerated stability program. These systems consisted of a large molecule biologic (bevacizumab) in conjunction with a glass former (trehalose), an amorphous small-molecular mass active (moxidectin), and a crystallizing active (mannitol). It was determined that the appearance of the fibers was due to the presence of small quantities of leucine in higher energy states, either because these were amorphous or present as a less stable crystalline polymorph. It was further shown that the growth of these leucine fibers caused no significant physicochemical instability in the powders. Nor, more importantly, did it decrease their aerosol performance in a dry powder inhaler or reduce the concentration of their active pharmaceutical ingredients. Full article
(This article belongs to the Special Issue Development and Evaluation of Inhalable Dry Powder Formulations)
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18 pages, 4923 KiB  
Article
In Silico Quantification of Intersubject Variability on Aerosol Deposition in the Oral Airway
by Azadeh A. T. Borojeni, Wanjun Gu, Bahman Asgharian, Owen Price, Andrew P. Kuprat, Rajesh K. Singh, Sean Colby, Richard A. Corley and Chantal Darquenne
Pharmaceutics 2023, 15(1), 160; https://doi.org/10.3390/pharmaceutics15010160 - 03 Jan 2023
Cited by 5 | Viewed by 2036
Abstract
The extrathoracic oral airway is not only a major mechanical barrier for pharmaceutical aerosols to reach the lung but also a major source of variability in lung deposition. Using computational fluid dynamics, deposition of 1–30 µm particles was predicted in 11 CT-based models [...] Read more.
The extrathoracic oral airway is not only a major mechanical barrier for pharmaceutical aerosols to reach the lung but also a major source of variability in lung deposition. Using computational fluid dynamics, deposition of 1–30 µm particles was predicted in 11 CT-based models of the oral airways of adults. Simulations were performed for mouth breathing during both inspiration and expiration at two steady-state flow rates representative of resting/nebulizer use (18 L/min) and of dry powder inhaler (DPI) use (45 L/min). Consistent with previous in vitro studies, there was a large intersubject variability in oral deposition. For an optimal size distribution of 1–5 µm for pharmaceutical aerosols, our data suggest that >75% of the inhaled aerosol is delivered to the intrathoracic lungs in most subjects when using a nebulizer but only in about half the subjects when using a DPI. There was no significant difference in oral deposition efficiency between inspiration and expiration, unlike subregional deposition, which shows significantly different patterns between the two breathing phases. These results highlight the need for incorporating a morphological variation of the upper airway in predictive models of aerosol deposition for accurate predictions of particle dosimetry in the intrathoracic region of the lung. Full article
(This article belongs to the Special Issue Development and Evaluation of Inhalable Dry Powder Formulations)
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15 pages, 3653 KiB  
Article
Preparation and Evaluation of Mucus-Penetrating Inhalable Microparticles of Tiotropium Bromide Containing Sodium Glycocholate
by Yong-Bin Kwon, Ji-Hyun Kang, Young-Jin Kim, Dong-Wook Kim, Sung-Hoon Lee and Chun-Woong Park
Pharmaceutics 2022, 14(7), 1409; https://doi.org/10.3390/pharmaceutics14071409 - 05 Jul 2022
Cited by 1 | Viewed by 1914
Abstract
This study aimed to prepare mucus-penetrating inhalable microparticles for dry powder inhalers and to evaluate their applicability in an asthma-induced rat model. Microparticles were prepared from water solutions containing tiotropium bromide, L-leucine, and sodium glycocholate (NaGc) as permeation enhancers using the spray drying [...] Read more.
This study aimed to prepare mucus-penetrating inhalable microparticles for dry powder inhalers and to evaluate their applicability in an asthma-induced rat model. Microparticles were prepared from water solutions containing tiotropium bromide, L-leucine, and sodium glycocholate (NaGc) as permeation enhancers using the spray drying method. Four formulations (SDL1, SDL2, SDL3, and SDL4) were used, depending on the various NaGc concentrations. Tiotropium microparticles were characterized by standard methods. Additionally, an asthma-induced rat model was used to confirm the effects of the formulations on lung function. Tiotropium microparticles with NaGc resulted in formulations with a more corrugated morphology and smaller particle size distribution than those without NaGc. SDL 1 had a rough surface with irregular morphology, and SDL 2, 3, and 4 had a corrugated morphology. All SDL formulations had an aerodynamic size of <3 µm. The microparticles with a corrugated morphology aerosolized better than SDL1 microparticles. The apparent permeability coefficient (Papp) values of SDL3 and SDL4 were significantly higher than those for raw tiotropium. In an in vivo study using an asthma-induced rat model, the specific airway resistance (Sraw), airway wall thickness, and mean alveolus size recovered to those of the negative control group in the SDL4 formulation. Full article
(This article belongs to the Special Issue Development and Evaluation of Inhalable Dry Powder Formulations)
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Review

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17 pages, 2253 KiB  
Review
Dry Powder Inhalation for Lung Delivery in Cystic Fibrosis
by Xiaoxuan Han, Danni Li, Felisa Reyes-Ortega and Elena K. Schneider-Futschik
Pharmaceutics 2023, 15(5), 1488; https://doi.org/10.3390/pharmaceutics15051488 - 13 May 2023
Cited by 1 | Viewed by 2011
Abstract
Pulmonary drug delivery has long been used for local and systemic administration of different medications used in acute and chronic respiratory diseases. Certain lung diseases, such as cystic fibrosis, rely heavily on chronic treatments, including targeted lung delivery. Pulmonary drug delivery possesses various [...] Read more.
Pulmonary drug delivery has long been used for local and systemic administration of different medications used in acute and chronic respiratory diseases. Certain lung diseases, such as cystic fibrosis, rely heavily on chronic treatments, including targeted lung delivery. Pulmonary drug delivery possesses various physiological advantages compared to other delivery methods and is also convenient for the patient to use. However, the formulation of dry powder for pulmonary delivery proves challenging due to aerodynamic restrictions and the lower tolerance of the lung. The aim of this review is to provide an overview of the respiratory tract structure in patients with cystic fibrosis, including during acute and chronic lung infections and exacerbations. Furthermore, this review discusses the advantages of targeted lung delivery, including the physicochemical properties of dry powder and factors affecting clinical efficacy. Current inhalable drug treatments and drugs currently under development will also be discussed. Full article
(This article belongs to the Special Issue Development and Evaluation of Inhalable Dry Powder Formulations)
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25 pages, 6160 KiB  
Review
In Vitro Dissolution and Permeability Testing of Inhalation Products: Challenges and Advances
by Ali Nokhodchi, Salonee Chavan and Taravat Ghafourian
Pharmaceutics 2023, 15(3), 983; https://doi.org/10.3390/pharmaceutics15030983 - 18 Mar 2023
Cited by 6 | Viewed by 3721
Abstract
In vitro dissolution and permeability testing aid the simulation of the in vivo behavior of inhalation drug products. Although the regulatory bodies have specific guidelines for the dissolution of orally administered dosage forms (e.g., tablets and capsules), this is not the case for [...] Read more.
In vitro dissolution and permeability testing aid the simulation of the in vivo behavior of inhalation drug products. Although the regulatory bodies have specific guidelines for the dissolution of orally administered dosage forms (e.g., tablets and capsules), this is not the case for orally inhaled formulations, as there is no commonly accepted test for assessing their dissolution pattern. Up until a few years ago, there was no consensus that assessing the dissolution of orally inhaled drugs is a key factor in the assessment of orally inhaled products. With the advancement of research in the field of dissolution methods for orally inhaled products and a focus on systemic delivery of new, poorly water-soluble drugs at higher therapeutic doses, an evaluation of dissolution kinetics is proving crucial. Dissolution and permeability testing can determine the differences between the developed formulations and the innovator’s formulations and serve as a useful tool in correlating in vitro and in vivo studies. The current review highlights recent advances in the dissolution and permeability testing of inhalation products and their limitations, including recent cell-based technology. Although a few new dissolution and permeability testing methods have been established that have varying degrees of complexity, none have emerged as the standard method of choice. The review discusses the challenges of establishing methods that can closely simulate the in vivo absorption of drugs. It provides practical insights into method development for various dissolution testing scenarios and challenges with dose collection and particle deposition from inhalation devices for dissolution tests. Furthermore, dissolution kinetic models and statistical tests to compare the dissolution profiles of test and reference products are discussed. Full article
(This article belongs to the Special Issue Development and Evaluation of Inhalable Dry Powder Formulations)
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