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

2020 ◽  
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.

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

Pharmaceutics ◽  
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.

scholarly journals In Vitro and In Vivo Performance of Dry Powder Inhalation Formulations: Comparison of Particles Prepared by Thin Film Freezing and Micronization

2014 ◽  
Vol 15 (4) ◽  
pp. 981-993 ◽  
Author(s):  
Yi-Bo Wang ◽  
Alan B. Watts ◽  
Jay I. Peters ◽  
Sha Liu ◽  
Ayesha Batra ◽  
...  
Keyword(s):  
Thin Film ◽  
Dry Powder Inhalation ◽  
Dry Powder ◽  
Thin Film Freezing

In Vitro and In Vivo Performance of Novel Spray Dried Andrographolide Loaded Scleroglucan Based Formulation for Dry Powder Inhaler

2017 ◽  
Vol 14 (7) ◽  
Author(s):  
Ashwin Jagannath Mali ◽  
Chellampillai Bothiraja ◽  
Ravindra Nandlal Purohit ◽  
Atmaram Pandurang Pawar
Keyword(s):  
Dry Powder Inhaler ◽  
Dry Powder ◽  
Spray Dried

scholarly journals Understanding Carrier Performance in Low-Dose Dry Powder Inhalation: An In Vitro–In Silico Approach

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 297
Author(s):  
Joana T. Pinto ◽  
Inês Cachola ◽  
João F. Pinto ◽  
Amrit Paudel
Keyword(s):  
Particle Size ◽  
In Silico ◽  
Low Dose ◽  
Drug Product ◽  
Dry Powder Inhaler ◽  
Dry Powder ◽  
Bulk Properties ◽  
Pbpk Models

The use of physiologically based pharmacokinetic (PBPK) models to support drug product development has become increasingly popular. The in vitro characterization of the materials of the formulation provides valuable descriptors for the in silico prediction of the drug’s pharmacokinetic profile. Thus, the application of an in vitro–in silico framework can be decisive towards the prediction of the in vivo performance of a new medicine. By applying such an approach, this work aimed to derive mechanistic based insights into the potential impact of carrier particles and powder bulk properties on the in vivo performance of a lactose-based dry powder inhaler (DPI). For this, a PBPK model was developed using salbutamol sulphate (SS) as a model drug and the in vitro performance of its low-dose blends (2% w/w) with different types of lactose particles was investigated using different DPI types (capsule versus reservoir) at distinct airflows. Likewise, the influence of various carrier’s particle and bulk properties, device type and airflow were investigated in silico. Results showed that for the capsule-based device, low-dose blends of SS had a better performance, when smaller carrier particles (Dv0.5 ≈ 50 μm) with about 10% of fines were used. This resulted in a better predicted bioavailability of the drug for all the tested airflows. For the reservoir type DPI, the mean particle size (Dv0.5) was identified as the critical parameter impacting performance. Shear cell and air permeability or compressibility measurements, particle size distribution by pressure titration and the tensile strength of the selected lactose carrier powders were found useful to generate descriptors that could anticipate the potential in vivo performance of the tested DPI blends.

scholarly journals Design and Comprehensive Characterization of Tetramethylpyrazine (TMP) for Targeted Lung Delivery as Inhalation Aerosols in Pulmonary Hypertension (PH): In Vitro Human Lung Cell Culture and In Vivo Efficacy

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 427
Author(s):  
Priya Muralidharan ◽  
Maria F. Acosta ◽  
Alexan I. Gomez ◽  
Carissa Grijalva ◽  
Haiyang Tang ◽  
...  
Keyword(s):  
Human Lung ◽  
Antioxidant Properties ◽  
Dry Powder Inhaler ◽  
Chinese Herbs ◽  
Dry Powder ◽  
Comprehensive Characterization ◽  
Spray Dried

This is the first study reporting on the design and development innovative inhaled formulations of the novel natural product antioxidant therapeutic, tetramethylpyrazine (TMP), also known as ligustrazine. TMP is obtained from Chinese herbs belonging to the class of Ligusticum. It is known to have antioxidant properties. It can act as a Nrf2/ARE activator and a Rho/ROCK inhibitor. The present study reports for the first time on the comprehensive characterization of raw TMP (non-spray dried) and spray dried TMP in a systematic manner using thermal analysis, electron microscopy, optical microscopy, and Raman spectroscopy. The in vitro aerosol dispersion performance of spray dried TMP was tested using three different FDA-approved unit-dose capsule-based human dry powder inhaler devices. In vitro human cellular studies were conducted on pulmonary cells from different regions of the human lung to examine the biocompatibility and non-cytotoxicity of TMP. Furthermore, the efficacy of inhaled TMP as both liquid and dry powder inhalation aerosols was tested in vivo using the monocrotaline (MCT)-induced PH rat model.

scholarly journals Inhaled ciprofloxacin-loaded poly(2-ethyl-2-oxazoline) nanoparticles from dry powder inhaler formulation for the potential treatment of lower respiratory tract infections

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261720
Author(s):  
Mohammad Zaidur Rahman Sabuj ◽  
Tim R. Dargaville ◽  
Lisa Nissen ◽  
Nazrul Islam
Keyword(s):  
Respiratory Tract ◽  
Lower Respiratory Tract ◽  
Respiratory Tract Infections ◽  
Drug Loading ◽  
Dry Powder Inhaler ◽  
Pulmonary Delivery ◽  
Lower Respiratory Tract Infections ◽  
Dry Powder ◽  
Tract Infections

Lower respiratory tract infections (LRTIs) are one of the fatal diseases of the lungs that have severe impacts on public health and the global economy. The currently available antibiotics administered orally for the treatment of LRTIs need high doses with frequent administration and cause dose-related adverse effects. To overcome this problem, we investigated the development of ciprofloxacin (CIP) loaded poly(2-ethyl-2-oxazoline) (PEtOx) nanoparticles (NPs) for potential pulmonary delivery from dry powder inhaler (DPI) formulations against LRTIs. NPs were prepared using a straightforward co-assembly reaction carried out by the intermolecular hydrogen bonding among PEtOx, tannic acid (TA), and CIP. The prepared NPs were characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction analysis (PXRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The CIP was determined by validated HPLC and UV spectrophotometry methods. The CIP loading into the PEtOx was between 21–67% and increased loading was observed with the increasing concentration of CIP. The NP sizes of PEtOx with or without drug loading were between 196–350 nm and increased with increasing drug loading. The in vitro CIP release showed the maximum cumulative release of about 78% in 168 h with a burst release of 50% in the first 12 h. The kinetics of CIP release from NPs followed non-Fickian or anomalous transport thus suggesting the drug release was regulated by both diffusion and polymer degradation. The in vitro aerosolization study carried out using a Twin Stage Impinger (TSI) at 60 L/min air flow showed the fine particle fraction (FPF) between 34.4% and 40.8%. The FPF was increased with increased drug loading. The outcome of this study revealed the potential of the polymer PEtOx as a carrier for developing CIP-loaded PEtOx NPs as DPI formulation for pulmonary delivery against LRTIs.

scholarly journals Development of Dry Powder Inhaler Containing Prothionamide-PLGA Nanoparticles Optimized Through Statistical Design: In-vivo Study

2017 ◽  
Vol 4 (1) ◽  
pp. 30-40 ◽  
Author(s):  
Sujit K. Debnath ◽  
Saisivam Srinivasan ◽  
Monalisha Debnath
Keyword(s):  
Particle Size ◽  
Drug Release ◽  
Dry Powder Inhaler ◽  
Burst Release ◽  
Dry Powder ◽  
Box Behnken Design ◽  
Pulmonary Administration ◽  
Aerodynamic Particle Size

Objective:The objective of the present work was to formulate Prothionamide (PTH) nanoparticles using Poly lactic co-glycolic acid (PLGA), optimized by Box-Behnken Design and further modification to dry powder inhaler followed byin-vivostudy.Methods:Poly-lactic co-gycolic acid (PLGA), a biodegradable polymer was used to coat Prothionamide by solvent evaporation technique. Formulation was optimized using Box-Behnken Design. Response surface curve and desirability factors helped in the selection of optimum formulation of PTH nanoparticles. Dry powder inhaler was prepared by adding inhalable grade lactose to optimize PTH nanoparticles. Mass median aerodynamic diameter (MMAD) was carried out using Andersen Cascade Impactor (ACI) to demonstrate its suitability in the pulmonary administration.In-vitrodrug release of dry powder inhaler was carried out in simulated lungs fluid. Correlationin-vitrotoin-vivowas established after performing animal experiment.Results:FTIR study reveals no chemical interaction between PTH, lactose and PLGA as the principle peaks was retained with same intensity in the physical mixture. Scanning electron microscope showed the spherical shape and aerodynamic particle size was found to be 1.69µm. Drug release study showed initial burst release followed by zero order release.In-vivomodel confirmed the presence of PTH after 24h. Aerodynamic particle size and the release profile revealed the suitability of PTH loaded nanoparticles containing dry powder inhaler for the pulmonary administration.Conclusion:Prepared DPI containing PTH nanoparticles can improve in the management of tuberculosis by increasing PTH residency in the lungs tissue for prolong period of time.

Nano-Liposomal Dry Powder Inhaler of Amiloride Hydrochloride

2006 ◽  
Vol 6 (9) ◽  
pp. 3001-3009 ◽  
Author(s):  
Mahavir Bhupal Chougule ◽  
Bijay Kumar Padhi ◽  
Ambikanandan Misra
Keyword(s):  
Cystic Fibrosis ◽  
Drug Release ◽  
Phosphate Buffer ◽  
Dry Powder Inhaler ◽  
Dry Powder ◽  
Phosphate Buffer Saline ◽  
Amiloride Hydrochloride ◽  
Spray Dried

The purpose of this study was to encapsulate Amiloride Hydrochloride into nano-liposomes, incorporate it into dry powder inhaler, and to provide prolonged effective concentration in airways to enhance mucociliary clearance and prevent secondary infection in cystic fibrosis. Liposomes were prepared by thin film hydration technique and then dispersion was passed through high pressure homogenizer to achieve size of nanometer range. Nano-liposomes were separated by centrifugation and were characterized. They were dispersed in phosphate buffer saline pH 7.4 containing carriers (lactose/sucrose/mannitol), and glycine as anti-adherent. The resultant dispersion was spray dried. The spray dried powders were characterized and in vitro drug release studies were performed using phosphate buffer saline pH 7.4. in vitro and in vivo drug pulmonary deposition was carried out using Andersen Cascade Impactor and by estimating drug in bronchial alveolar lavage and lung homogenate after intratracheal instillation in rats respectively. Nano-liposomes were found to have mean volume diameter of 198 ± 15 nm, and 57% ± 1.9% of drug entrapment. Mannitol based formulation was found to have low density, good flowability, particle size of 6.7 ± 0.6 μm determined by Malvern MasterSizer, maximum fine particle fraction of 67.6 ± 0.6%, mean mass aerodynamic diameter 2.3 ± 0.1 μm, and geometric standard deviation 2.4 ± 0.1. Developed formulations were found to have prolonged drug release following Higuchi's Controlled Release model and in vivo studies showed maximal retention time of drug of 12 hrs within the lungs and slow clearance from the lungs. This study provides a practical approach for direct lung delivery of Amiloride Hydrochloride encapsulated in liposomes for controlled and prolonged retention at the site of action from dry powder inhaler. It can provide a promising alternative to the presently available nebulizers in terms of prolonged pharmacological effect, reducing systemic side effects such as potassium retention due to rapid clearance of the drug from lungs in patients suffering from cystic fibrosis.

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