Optimizing Spray-Dried Porous Particles for High Dose Delivery with a Portable Dry Powder Inhaler

This manuscript critically reviews the design and delivery of spray-dried particles for the achievement of high total lung doses (TLD) with a portable dry powder inhaler. We introduce a new metric termed the product density, which is simply the TLD of a drug divided by the volume of the receptacle it is contained within. The product density is given by the product of three terms: the packing density (the mass of powder divided by the volume of the receptacle), the drug loading (the mass of drug divided by the mass of powder), and the aerosol performance (the TLD divided by the mass of drug). This manuscript discusses strategies for maximizing each of these terms. Spray drying at low drying rates with small amounts of a shell-forming excipient (low Peclet Number) leads to formation of higher density particles with high packing densities. This enables ultrahigh TLD (>100 mg of drug) to be achieved from a single receptacle. Emptying of powder from capsules is directly proportional to the mass of powder in the receptacle, requiring an inhaled volume of about 1 L for fill masses between 40 and 50 mg and up to 3.2 L for a fill mass of 150 mg.

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Optimizing Spray-Dried Porous Particles for High Dose Delivery with a Portable Dry Powder Inhaler

Pharmaceutics ◽

10.3390/pharmaceutics13091528 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1528

Author(s):

Yoen-Ju Son ◽

Danforth P. Miller ◽

Jeffry G. Weers

Keyword(s):

Drug Loading ◽

Dry Powder Inhaler ◽

High Dose ◽

Dose Delivery ◽

Dry Powder ◽

Product Density ◽

Aerosol Performance ◽

Drying Rates ◽

Shell Forming ◽

Spray Dried

This manuscript critically reviews the design and delivery of spray-dried particles for the achievement of high total lung doses (TLD) with a portable dry powder inhaler. We introduce a new metric termed the product density, which is simply the TLD of a drug divided by the volume of the receptacle it is contained within. The product density is given by the product of three terms: the packing density (the mass of powder divided by the volume of the receptacle), the drug loading (the mass of drug divided by the mass of powder), and the aerosol performance (the TLD divided by the mass of drug). This manuscript discusses strategies for maximizing each of these terms. Spray drying at low drying rates with small amounts of a shell-forming excipient (low Peclet number) leads to the formation of higher density particles with high packing densities. This enables ultrahigh TLD (>100 mg of drug) to be achieved from a single receptacle. The emptying of powder from capsules is directly proportional to the mass of powder in the receptacle, requiring an inhaled volume of about 1 L for fill masses between 40 and 50 mg and up to 3.2 L for a fill mass of 150 mg.

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Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Pharmaceutics ◽

10.3390/pharmaceutics12111002 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1002

Author(s):

Sawittree Sahakijpijarn ◽

Chaeho Moon ◽

John J. Koleng ◽

Dale J. Christensen ◽

Robert O. Williams

Keyword(s):

Thin Film ◽

Drug Loading ◽

Dry Powder Inhaler ◽

Drug Dissolution ◽

Outpatient Basis ◽

Dry Powder ◽

Aerosol Performance ◽

Thin Film Freezing

Remdesivir exhibits in vitro activity against SARS-CoV-2 and was granted approval for emergency use. To maximize delivery to the lungs, we formulated remdesivir as a dry powder for inhalation using thin film freezing (TFF). TFF produces brittle matrix nanostructured aggregates that are sheared into respirable low-density microparticles upon aerosolization from a passive dry powder inhaler. In vitro aerodynamic testing demonstrated that drug loading and excipient type affected the aerosol performance of remdesivir. Remdesivir combined with optimal excipients exhibited desirable aerosol performance (up to 93.0% FPF< 5 µm; 0.82 µm mass median aerodynamic diameter). Remdesivir was amorphous after the TFF process, which benefitted drug dissolution in simulated lung fluid. TFF remdesivir formulations are stable after one month of storage at 25 °C/60% relative humidity. An in vivo pharmacokinetic evaluation showed that TFF remdesivir–leucine was poorly absorbed into systemic circulation while TFF remdesivir-Captisol® demonstrated increased systemic uptake compared to leucine. Remdesivir was hydrolyzed to the nucleoside analog GS-441524 in the lung, and levels of GS-441524 were greater in the lung with leucine formulation compared to Captisol®. In conclusion, TFF technology produces high-potency remdesivir dry powder formulations for inhalation that are suitable to treat patients with COVID-19 on an outpatient basis and earlier in the disease course where effective antiviral therapy can reduce related morbidity and mortality.

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Effect of Dosing Cup Size on the Aerosol Performance of High-Dose Carrier-Based Formulations in a Novel Dry Powder Inhaler

Journal of Pharmaceutical Sciences ◽

10.1016/j.xphs.2018.09.033 ◽

2019 ◽

Vol 108 (2) ◽

pp. 949-959

Author(s):

Stewart Yeung ◽

Daniela Traini ◽

Alan Tweedie ◽

David Lewis ◽

Tanya Church ◽

...

Keyword(s):

Dry Powder Inhaler ◽

High Dose ◽

Dry Powder ◽

Aerosol Performance

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Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

10.1101/2020.07.26.222109 ◽

2020 ◽

Cited By ~ 1

Author(s):

Sawittree Sahakijpijarn ◽

Chaeho Moon ◽

John J. Koleng ◽

Dale J. Christensen ◽

Robert O. Williams

Keyword(s):

Thin Film ◽

Drug Loading ◽

Dry Powder Inhaler ◽

Drug Dissolution ◽

Outpatient Basis ◽

Dry Powder ◽

Aerosol Performance ◽

Thin Film Freezing

AbstractRemdesivir exhibits in vitro activity against SARS-CoV-2 and was granted approval for Emergency Use. To maximize delivery to the lungs, we formulated remdesivir as a dry powder for inhalation using thin film freezing (TFF). TFF produces brittle matrix nanostructured aggregates that are sheared into respirable low-density microparticles upon aerosolization from a passive dry powder inhaler. In vitro aerodynamic testing demonstrated that drug loading and excipient type affected the aerosol performance of remdesivir. Remdesivir combined with optimal excipients exhibited desirable aerosol performance (up to 93.0% FPF; 0.82μm MMAD). Remdesivir was amorphous after the TFF process, which benefitted drug dissolution in simulated lung fluid. TFF remdesivir formulations are stable after one-month storage at 25 °C/60%RH. In vivo pharmacokinetic evaluation showed that TFF-remdesivir-leucine was poorly absorbed into systemic circulation while TFF-remdesivir-Captisol® demonstrated increased systemic uptake compared to leucine. Remdesivir was hydrolyzed to the nucleoside analog GS-441524 in lung, and levels of GS-441524 were greater in lung with the leucine formulation compared to Captisol®. In conclusion, TFF technology produces high potency remdesivir dry powder formulations for inhalation suitable to treat patients with COVID-19 on an outpatient basis and earlier in the disease course where effective antiviral therapy can reduce related morbidity and mortality.

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Flow and Particle Modelling of Dry Powder Inhalers: Methodologies, Recent Development and Emerging Applications

Pharmaceutics ◽

10.3390/pharmaceutics13020189 ◽

2021 ◽

Vol 13 (2) ◽

pp. 189

Author(s):

Zhanying Zheng ◽

Sharon Shui Yee Leung ◽

Raghvendra Gupta

Keyword(s):

Dry Powder Inhaler ◽

Research Direction ◽

Particle Methods ◽

Future Research ◽

High Dose ◽

Dry Powder ◽

Multi Scale ◽

Wide Range ◽

Computational Fluid Dynamics Cfd ◽

Discrete Element Methods

Dry powder inhaler (DPI) is a device used to deliver a drug in dry powder form to the lungs. A wide range of DPI products is currently available, with the choice of DPI device largely depending on the dose, dosing frequency and powder properties of formulations. Computational fluid dynamics (CFD), together with various particle motion modelling tools, such as discrete particle methods (DPM) and discrete element methods (DEM), have been increasingly used to optimise DPI design by revealing the details of flow patterns, particle trajectories, de-agglomerations and depositions within the device and the delivery paths. This review article focuses on the development of the modelling methodologies of flow and particle behaviours in DPI devices and their applications to device design in several emerging fields. Various modelling methods, including the most recent multi-scale approaches, are covered and the latest simulation studies of different devices are summarised and critically assessed. The potential and effectiveness of the modelling tools in optimising designs of emerging DPI devices are specifically discussed, such as those with the features of high-dose, pediatric patient compatibility and independency of patients’ inhalation manoeuvres. Lastly, we summarise the challenges that remain to be addressed in DPI-related fluid and particle modelling and provide our thoughts on future research direction in this field.

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Influence of Humidity on the Electrostatic Charge and Aerosol Performance of Dry Powder Inhaler Carrier based Systems

Pharmaceutical Research ◽

10.1007/s11095-006-9218-8 ◽

2007 ◽

Vol 24 (5) ◽

pp. 963-970 ◽

Cited By ~ 77

Author(s):

Paul M Young ◽

Adrian Sung ◽

Daniela Traini ◽

Philip Kwok ◽

Herbert Chiou ◽

...

Keyword(s):

Dry Powder Inhaler ◽

Electrostatic Charge ◽

Dry Powder ◽

Aerosol Performance

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Development of cefdinir loaded Functionalized carbon Nanotubes dry powder Inhaler for the Treatment of cystic Fibrosis

Research Journal of Pharmacy and Technology ◽

10.52711/0974-360x.2021.00666 ◽

2021 ◽

pp. 3839-3845

Author(s):

Krishnat D. Dhekale ◽

Ravindra N. Kamble

Keyword(s):

Carbon Nanotubes ◽

Cystic Fibrosis ◽

Drug Loading ◽

Dry Powder Inhaler ◽

Dry Powder ◽

Efficient Treatment ◽

Multi Walled Carbon Nanotubes ◽

Stable Product ◽

Lung Infections ◽

Walled Carbon Nanotubes

A dry-powder inhaler (DPI) carries medication to lungs as a dry powder, useful against respiratory diseases. The current research was endeavoured to examine the capabilities of Multi-walled carbon nanotubes (MWCNT) as a pulmonary transporter for directing cefdinir to cystic fibrosis (CF). Functionalized MWCNTs were loaded with cefdinir to formulate DPI (F-CEF FMWCNTs DPI) having efficient treatment against lung infections and were evaluated successfully. The outcomes demonstrated that cefdinir loaded FMWCNTs were non-toxic and accomplished 79.73 % entrapment with better flow properties. The optimized formulation had Mass Median Aerodynamic Diameter (MMAD), Fine particle fraction (FPF), and particle size of 3.45±0.09 μm, 58.52±1.06%, 5.25 ± 0.03 μm (CEF FMWCNT DPI) and 4. 29±0.16μm 38.74±1.02%, 7.54 ± 0.02 μm (C-DPI) respectively. The loaded nanotubes showed 72. 63 % release after 15 hours in a controlled manner. The outcome of work recognized a unique, simple, and stable product having improved drug loading and increased dispersibility of carbon nanotubes (CNTs) thus improved bioavailability at a lung infection place with less adverse actions.

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