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Advanced Characterization of Inhalation Medicinal Products

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

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 24916

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Special Issue Editors

Prof. Dr. Fabio Sonvico

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Guest Editor

Interdept Ctr Biopharmanet TEC, Univ Parma, Parco Area delle Scienze 27-A, I-43124 Parma, Italy
Interests: pharmaceutical nanotechnology; nasal delivery; brain delivery; lung cancer; polysaccharides
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Francesca Buttini

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Guest Editor

Food and Drug Department, University of Parma, 43124 Parma, Italy
Interests: dry powder inhaler; particle engineering; inhalation therapy; high drug dose
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pulmonary drug delivery over the past twenty years has been demonstrated not only to be a valuable approach to treat a number of local diseases such as infections, asthma, and COPD but has shown great potential for drug delivery systemically thanks to its high surface area and the absorptive potential of the respiratory region of the lungs. This has presented the possibility to develop new and promising products for the delivery of small molecules, as well as peptide and proteins, for the treatment of clinically relevant diseases such as diabetes. However, the look for new therapeutic approaches has led to lead compounds that in comparison to those in the clinical use present some challenges such as lower aqueous solubility; poor permeability; and high dosages sometimes combined with challenging solid state properties impacting aerosol performances such as cohesiveness, hygroscopicity, and poor flowability. On the other side, more complex formulations are proposed, in some cases in view of providing a controlled release of drugs after lung deposition. In this scenario, the classic pharmacopoeial tests for inhalation products do not appear to be the set of tools appropriate to investigate and characterize such new products.

The aim of this Special Issue is to showcase a series of advanced approaches for the characterization of innovative products for pulmonary delivery, with special emphasis on issues related to aerosol performance, physico-chemical characterisation, dissolution studies, particle engineering, controlled release formulations, and the behavior of the product at biological interfaces. As Guest Editors, we cordially invite you to contribute a research paper or comprehensive review on any aspect related to this topic.

Prof. Dr. Fabio Sonvico
Prof. Dr. Francesca Buttini
Guest Editors

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Keywords

Pulmonary delivery
Dry powders inhalers
pMDI
Liposomes
Micelles
In vitro models of airways epithelia
Dissolution studies
Solid state characterization
Aerosol performance.

Published Papers (7 papers)

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Research

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18 pages, 3188 KiB

Open AccessArticle

RespiCell^TM: An Innovative Dissolution Apparatus for Inhaled Products

by Fabio Sonvico, Veronica Chierici, Giada Varacca, Eride Quarta, Davide D’Angelo, Ben Forbes and Francesca Buttini

Pharmaceutics 2021, 13(10), 1541; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101541 - 23 Sep 2021

Cited by 7 | Viewed by 3300

Abstract

To overcome some of the shortfalls of the types of dissolution testing currently used for pulmonary products, a new custom-built dissolution apparatus has been developed. For inhalation products, the main in vitro characterisation required by pharmacopoeias is the deposition of the active pharmaceutical ingredient in an impactor to estimate the dose delivered to the target site, i.e., the lung. Hence, the collection of the respirable dose (<5 µm) also appears to be an essential requirement for the study of the dissolution rate of particles, because it results as being a relevant parameter for the pharmacological action of the powder. In this sense, dissolution studies could become a complementary test to the routine testing of inhaled formulation delivered dose and aerodynamic performance, providing a set of data significant for product quality, efficacy and/or equivalence. In order to achieve the above-mentioned objectives, an innovative dissolution apparatus (RespiCell™) suitable for the dissolution of the respirable fraction of API deposited on the filter of a fast screening impactor (FSI) (but also of the entire formulation if desirable) was designed at the University of Parma and tested. The purpose of the present work was to use the RespiCell dissolution apparatus to compare and discriminate the dissolution behaviour after aerosolisation of various APIs characterised by different physico-chemical properties (hydrophilic/lipophilic) and formulation strategies (excipients, mixing technology). Full article

(This article belongs to the Special Issue Advanced Characterization of Inhalation Medicinal Products)

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22 pages, 33955 KiB

Open AccessArticle

Water Uptake by Evaporating pMDI Aerosol Prior to Inhalation Affects Both Regional and Total Deposition in the Respiratory System

by Victoria Legh-Land, Allen E. Haddrell, David Lewis, Darragh Murnane and Jonathan P. Reid

Pharmaceutics 2021, 13(7), 941; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13070941 - 24 Jun 2021

Cited by 7 | Viewed by 2885

Abstract

As pulmonary drug deposition is a function of aerosol particle size distribution, it is critical that the dynamics of particle formation and maturation in pMDI sprays in the interim between generation and inhalation are fully understood. This paper presents an approach to measure the evaporative and condensational fluxes of volatile components and water from and to solution pMDI droplets following generation using a novel technique referred to as the Single Particle Electrodynamic Lung (SPEL). In doing so, evaporating aerosol droplets are shown capable of acting as condensation nuclei for water. Indeed, we show that the rapid vaporisation of volatile components from a volatile droplet is directly correlated to the volume of water taken up by condensation. Furthermore, a significant volume of water is shown to condense on droplets of a model pMDI formulation (hydrofluoroalkane (HFA), ethanol and glycerol) during evaporative droplet ageing, displaying a dramatic shift from a core composition of a volatile species to that of predominantly water (non-volatile glycerol remained in this case). This yields a droplet with a water activity of 0.98 at the instance of inhalation. The implications of these results on regional and total pulmonary drug deposition are explored using the International Commission of Radiological Protection (ICRP) deposition model, with an integrated semi-analytical treatment of hygroscopic growth. Through this, droplets with water activity of 0.98 upon inhalation are shown to produce markedly different dose deposition profiles to those with lower water activities at the point of inspiration. Full article

(This article belongs to the Special Issue Advanced Characterization of Inhalation Medicinal Products)

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15 pages, 3950 KiB

Open AccessArticle

Inhalable Protein Powder Prepared by Spray-Freeze-Drying Using Hydroxypropyl-β-Cyclodextrin as Excipient

by Jason C. K. Lo, Harry W. Pan and Jenny K. W. Lam

Pharmaceutics 2021, 13(5), 615; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13050615 - 24 Apr 2021

Cited by 12 | Viewed by 3045

Abstract

The prospect of inhaled biologics has garnered particular interest given the benefits of the pulmonary route of administration. Pertinent considerations in producing inhalable dry powders containing biological medicines relate to aerosol performance and protein stability. Spray-freeze-drying (SFD) has emerged as an established method to generate microparticles that can potentially be deposited in the lungs. Here, the SFD conditions and formulation composition were evaluated using bovine serum albumin (BSA) as a model protein and 2-hydroxypropyl-beta-cyclodextrin (HPβCD) as the protein stabilizer. A factorial design analysis was performed to investigate the effects of BSA content, solute concentration of feed solution, and atomization gas flow rate on dispersibility (as an emitted fraction), respirability (as fine particle fraction), particle size, and level of protein aggregation. The atomization gas flow rate was identified as a significant factor in influencing the aerosol performance of the powder formulations and protein aggregation. Nonetheless, high atomization gas flow rate induced aggregation, highlighting the need to further optimize the formulation. Of note, all the formulations exhibited excellent dispersibility, while no fragmentation of BSA occurred, indicating the feasibility of SFD and the promise of HPβCD as an excipient. Full article

(This article belongs to the Special Issue Advanced Characterization of Inhalation Medicinal Products)

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15 pages, 3366 KiB

Open AccessArticle

In-Depth Comparison of Dry Particle Coating Processes Used in DPI Particle Engineering

by Nicholas Bungert, Mirjam Kobler and Regina Scherließ

Pharmaceutics 2021, 13(4), 580; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13040580 - 19 Apr 2021

Cited by 15 | Viewed by 2966

Abstract

High-shear mixer coatings as well as mechanofusion processes are used in the particle-engineering of dry powder inhalation carrier systems. The aim of coating the carrier particle is usually to decrease carrier–drug adhesion. This study comprises the in-depth comparison of two established dry particle coating options. Both processes were conducted with and without a model additive (magnesium stearate). In doing so, changes in the behaviour of the processed particles can be traced back to either the process or the additive. It can be stated that the coarse model carrier showed no significant changes when processed without additives. By coating the particles with magnesium stearate, the surface energy decreased significantly. This leads to a significant enhancement of the aerodynamic performance of the respective carrier-based blends. Comparing the engineered carriers with each other, the high-shear mixer coating shows significant benefits, namely, lower drug–carrier adhesion and the higher efficiency of the coating process. Full article

(This article belongs to the Special Issue Advanced Characterization of Inhalation Medicinal Products)

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16 pages, 6924 KiB

Open AccessArticle

Aerosolized In Vivo 3D Localization of Nose-to-Brain Nanocarrier Delivery Using Multimodality Neuroimaging in a Rat Model—Protocol Development

by Michael C. Veronesi, Brian D. Graner, Shih-Hsun Cheng, Marta Zamora, Hamideh Zarrinmayeh, Chin-Tu Chen, Sudip K. Das and Michael W. Vannier

Pharmaceutics 2021, 13(3), 391; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13030391 - 15 Mar 2021

Cited by 7 | Viewed by 2599

Abstract

The fate of intranasal aerosolized radiolabeled polymeric micellar nanoparticles (LPNPs) was tracked with positron emission tomography/computer tomography (PET/CT) imaging in a rat model to measure nose-to-brain delivery. A quantitative temporal and spatial testing protocol for new radio-nanotheranostic agents was sought in vivo. LPNPs labeled with a zirconium 89 (⁸⁹Zr) PET tracer were administered via intranasal or intravenous delivery, followed by serial PET/CT imaging. After 2 h of continuous imaging, the animals were sacrificed, and the brain substructures (olfactory bulb, forebrain, and brainstem) were isolated. The activity in each brain region was measured for comparison with the corresponding PET/CT region of interest via activity measurements. Serial imaging of the LPNPs (100 nm PLA–PEG–DSPE+⁸⁹Zr) delivered intranasally via nasal tubing demonstrated increased activity in the brain after 1 and 2 h following intranasal drug delivery (INDD) compared to intravenous administration, which correlated with ex vivo gamma counting and autoradiography. Although assessment of delivery from nose to brain is a promising approach, the technology has several limitations that require further development. An experimental protocol for aerosolized intranasal delivery is presented herein, which may provide a platform for better targeting the olfactory epithelium. Full article

(This article belongs to the Special Issue Advanced Characterization of Inhalation Medicinal Products)

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18 pages, 6641 KiB

Open AccessArticle

Formulation and In Vitro and In Silico Characterization of “Nano-in-Micro” Dry Powder Inhalers Containing Meloxicam

by Petra Party, Csilla Bartos, Árpád Farkas, Piroska Szabó-Révész and Rita Ambrus

Pharmaceutics 2021, 13(2), 211; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13020211 - 03 Feb 2021

Cited by 20 | Viewed by 2578

Abstract

Pulmonary delivery has high bioavailability, a large surface area for absorption, and limited drug degradation. Particle engineering is important to develop inhalable formulations to improve the therapeutic effect. In our work, the poorly water-soluble meloxicam (MX) was used as an active ingredient, which could be useful for the treatment of non-small cell lung cancer, cystic fibrosis, and chronic obstructive pulmonary disease. We aimed to produce inhalable “nano-in-micro” dry powder inhalers (DPIs) containing MX and additives (poly-vinyl-alcohol, leucine). We targeted the respiratory zone with the microcomposites and reached a higher drug concentration with the nanonized active ingredient. We did the following investigations: particle size analysis, morphology, density, interparticular interactions, crystallinity, in vitro dissolution, in vitro permeability, in vitro aerodynamics (Andersen cascade impactor), and in silico aerodynamics (stochastic lung model). We worked out a preparation method by combining wet milling and spray-drying. We produced spherical, 3–4 µm sized particles built up by MX nanoparticles. The increased surface area and amorphization improved the dissolution and diffusion of the MX. The formulations showed appropriate aerodynamical properties: 1.5–2.4 µm MMAD and 72–76% fine particle fraction (FPF) values. The in silico measurements proved the deposition in the deeper airways. The samples were suitable for the treatment of local lung diseases. Full article

(This article belongs to the Special Issue Advanced Characterization of Inhalation Medicinal Products)

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Review

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20 pages, 1974 KiB

Open AccessReview

Current Perspective on Nasal Delivery Systems for Chronic Rhinosinusitis

by Junhu Tai, Kijeong Lee and Tae Hoon Kim

Pharmaceutics 2021, 13(2), 246; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13020246 - 10 Feb 2021

Cited by 12 | Viewed by 6694

Abstract

Chronic rhinosinusitis is an upper respiratory disease during which topical drug treatment via the nasal cavity is the most actively utilized therapeutic strategy. In addition to steroids, antibiotics, and antifungal agents, which are widely used in clinical practice, research on novel topical agents to improve the bacterial biofilm or mucociliary clearance remains ongoing. Moreover, owing to the complex structure of the nasal cavity, the effects of nasal drug delivery vary depending on factors related to delivery fluid dynamics, including device, volume, and compounds. In this article, we review methods and compounds that have been applied to chronic rhinosinusitis management and introduce recent advances and future perspectives in nasal drug delivery for upper respiratory diseases. Full article

(This article belongs to the Special Issue Advanced Characterization of Inhalation Medicinal Products)

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