COVID-19 : novel thin-film-freezing technology to deliver remdesivir through dry powder inhalation


The only antiviral drug currently used to treat SARS-CoV-2, the coronavirus that causes COVID-19, is remdesivir, but administering it is invasive and challenging.

Scientists at The University of Texas at Austin are hoping to change that by using their novel thin-film-freezing technology to deliver remdesivir through dry powder inhalation, potentially making treatment more potent, easier to administer and more broadly available.

A team of researchers in UT Austin’s Division of Molecular Pharmaceutics and Drug Delivery, led by Robert O. (Bill) Williams III, has investigated varying methods of drug delivery to repurpose existing drugs into more efficacious forms.

Earlier this year, the team focused on niclosamide, confirmed to exhibit antiviral efficacy in COVID-19 infected cells. Since then, remdesivir has emerged as the only available antiviral treatment for coronavirus.

Remdesivir is authorized for emergency use in adult and pediatric patients hospitalized with severe disease. Originally developed to treat the Ebola virus disease, remdesivir has shown promising results treating COVID-19 in the human airway epithelial cells.

However, limited effective delivery methods have hindered efforts to provide widespread treatment to a broad range of patients exhibiting life-threatening symptoms.

“Unfortunately, remdesivir is not suitable for oral delivery since the drug is mostly metabolized by the body,” Williams said.

“Intramuscular injection also faces challenges, since release rates from the muscles can vary widely.”

To provide remdesivir for other patients beyond the most severely ill, more convenient and accessible dosage forms for different routes of administration must be quickly developed and tested so patients have more options to get treated.

One way to overcome the poor absorption rates of remdesivir is to deliver it directly to the infection site. The research team, which includes Sawittree Sahakijpijarn, Chaeho Moon and John J. Koleng, has developed inhaled forms of remdesivir for protecting and treating the respiratory mode of infection, including an amorphous brittle matrix powder made by thin-film freezing.

Not only would this delivery method allow for wider distribution of an essential antiviral in the fight against COVID-19, it could also make remdesivir more effective.

“If patients can avoid a hospital visit to begin remdesivir treatment, it can lessen the current strains on our health system, lower cost and provide fewer points of contact with those who are still contagious,” Williams said.

“More widely available early stage intervention methods could significantly lesson symptoms before they become potentially life-threatening, providing more hospital beds and ventilators to those who need them the most.”

TFF Pharmaceuticals Inc. has acquired the patents regarding thin-film freezing and inhalation.

The UT researchers’ findings were recently published as a preprint in bioRxiv. Upon final study results, the team will submit its full findings for peer review and publication.

The feasibility to deliver remdesivir via different administration routes (e.g., intravenous (IV) injection, intramuscular (IM) injection and oral administration) has been investigated (3).

Unfortunately, remdesivir is not suitable for oral delivery since the drug is mostly metabolized and cleared by first-pass metabolism, resulting in poor hepatic stability and poor bioavailability (3).

The delivery of remdesivir by the IM route also faces the challenge of variable release from muscle and slow acting of the active compound in peripheral blood mononuclear cells (3).

Therefore, remdesivir is administrated by IV injection since this route allows wide distribution to most tissues including kidney, kidney medulla, and liver (3).

For IV administration, remdesivir was developed in two dosage forms, a concentrate solution intended for dilution and administration by infusion and a lyophilized powder for reconstitution and dilution intended for administration by infusion (3).

Since remdesivir is practically insoluble in water, both formulations contain sulfobutylether-beta-cyclodextrin (SBECD) as a solubility enhancer (3). Since the excipient, SBECB, is cleared by the kidneys, remdesivir is contradicted in patients with several renal impairment (3).

A pharmacokinetic study showed that both formulations are interchangeable based on similar plasma concentrations (3).

Lyophilized remdesivir powder is stable when stored below 30 °C and has a shelf-life of 51 months, while remdesivir concentrate solution for dilution requires the product to be stored at freezing storage conditions (−25 °C to −10 °C) for a shelf-life of 48 months (3).

Currently, remdesivir is administered by injection into a vein as an infusion to treat patients with COVID-19 only in hospitals. However, due to the pandemic, many patients are not able to be hospitalized, and they do not have access to injectable administration of remdesivir.

To provide remdesivir for other patients besides those most severely ill, more convenient and accessible dosage forms for different routes of administration must be quickly developed and tested so that patients have more options to get treated.

Intriguing strategies for future improvement of remdesivir include the development of inhaled dry powder of remdesivir for direct administration to the primary site of infection, the lungs.

The mechanism of coronavirus infection is mostly in the respiratory tract, especially in the deep lungs. Hence, the inhalation route must be immediately pursued as the most promising route of administration to maximize direct delivery to the target site without first-pass metabolism, boost local antiviral activity in the lungs, and limit the potential for systemic side effects (15).

In addition, the cost of the drug can be reduced, and the supplies of the drug can be maximized, thus treating more patients due to less dose required by inhalation as compared to injectable forms.

The treatment cost can also be decreased when administered by inhalation, since patients may not need to visit hospitals as is required to administer the IV injectable dose. Therefore, more affordable and early stage treatment can be provided to patients with inhaled remdesivir.

Nebulization of the current IV formulation in a diluted form is a potential method of pulmonary administration; however, the drug is prone to degrade by hydrolysis in aqueous solution to form the nucleoside monophosphate, which has difficulty penetrating cell membranes, thereby minimizing the antiviral activity in the lung cells (16).

Another concern is the use of sulfobutylether-beta-cyclodextrin (SBECD) as an excipient in inhalation dosage forms. Although cyclodextrin is not an excipient in an approved FDA inhaled product (17), several papers have investigated the use cyclodextrin in inhaled formulations. Tolman et al. (18, 19) previously demonstrated that aerosolized voriconazole nebulized solution that contained a diluted form of the commercially available Vfend®, an IV voriconazole dosage form containing SBECD, is capable of producing clinically relevant lung tissue and plasma concentrations of the drug in animals.

However, in this form, voriconazole in lung tissue was not able to be detected 6-8 h after administration of a single inhaled dose in the animal study by Tolman et al. (18), while voriconazole dry powder lasted longer in the lungs (up to 24 h) in an animal study by Beinborn et al (20).

Therefore, a dry powder formulation for inhalation can be more favorable with a smaller number of daily doses.
The advantages of dry powders for inhalation over liquids administered by nebulizers are not limited only to improve the stability of the drug during inhalation, but also dry powder inhalers provide the ease of maintenance and having a short administration time (21).

The inconvenience of nebulized inhalation solutions includes the use of a large nebulizer device requiring power and water, user manipulation for cleaning and operating, and long nebulization times.

Also, the cost per dose and initial cost of the nebulizer are higher than a DPI device (21). Hence, dry powder inhalation is an ideal dosage form for the treatment of COVID-19 in an outpatient setting, which would minimize the risk of spreading the virus to healthcare professionals.

Although several techniques have been used to prepare inhalable powders, including mechanical milling and spray drying, the advantages of thin film freezing (TFF) over other techniques rely on the ability to produce aerosolizable particles composed of brittle matrix, nanostructured aggregates.

These are high surface area powders that are ideally suited for dry powder inhalation. TFF employs ultra-rapid freezing (on the order of 10,000 K/sec) such that precipitation (either as a crystalline nanoaggregate or amorphous solid dispersion) and particle growth of the dissolved solute can be prevented (22).

Subsequently, nanostructured aggregates are formed as a low-density brittle matrix powder (23), which is efficiently sheared into respirable low-density microparticles by a dry powder inhaler upon inhalation by the patient (24).

Despite a large geometric diameter (>10 microns), low- density microparticles composed of these nanostructured aggregates can be delivered to the deep lung with optimal aerodynamic diameters of <3 to 4 microns (24).

Additionally, it has been reported that the engineered particles with a geometric diameter greater than 10 microns can extend drug retention time in the lungs due to the ability of the deposited particles to escape from macrophage phagocytosis (25).

According to a recent study by Longest et al., computational models demonstrated that nanoaggregates are favorable for higher drug absorption efficiency and dose uniformity in the lungs, compared to microparticles (26).

Furthermore, TFF can produce amorphous high surface area powders with submicron primary particles, which can enhance the dissolution rate and subsequently improve the bioavailability of poorly water-soluble drugs like remdesivir in the lungs (27).

This work aims to apply the TFF technology to develop remdesivir dry powder formulations for inhalation administered by a commercially available dry powder inhaler.

We hypothesize that the ultra- rapid freezing rate of the TFF technology will produce low-density, high porosity brittle matrix powders of remdesivir, which are aerosolizable by the shear forces generated from the passive dry powder inhaler, and thus allow high doses of remdesivir to be administered to the lung.

Thin film freezing can produce high potency remdesivir dry powders for inhalation with high aerosol performance

We investigated the feasibility of thin film freezing to prepare inhalable remdesivir powder formulations. Different excipients including Captisol®, mannitol, lactose, and leucine were selected in this study.

Mannitol and lactose are presently contained in FDA approved inhalation dosage forms, while leucine has gained more interest for pulmonary delivery.

Captisol® was selected in this study since it is a solubilizer used in both the solution concentrate for dilution and infusion and the lyophilized powder for reconstitution/dilution and infusion (3).

The RS00 high resistance monodose DPI is a capsule-based DPI device that is available for commercial product development, and it functions to disperse powder based on impaction force.

A previous study confirms that this impact-based DPI can disperse low-density brittle matrix powder made by TFF into respirable particles better than a shear-based DPI (e.g., Handihaler®) (28).

Another study also evaluated the performance of different models of monodose DPI (RS01 and RS00) on the aerosol performance of brittle matrix powders containing voriconazole nanoaggregates prepared by TFF (29).

It was shown that the RS00 device exhibited better powder shearing and deaggregation through smaller

holes of the capsule created by the piercing system of the RS00 device (29). Therefore, the RS00 high resistance Plastiape® DPI was selected in this study.

We found that excipient type and drug loading affect the aerosol performance of TFF remdesivir. Overall, the aerosol performance of TFF remdesivir powders increased as the drug loading was increased.

This trend is obvious for the Captisol®-, lactose-, and mannitol-based formulations when the drug loading was increased from 20% to 50%. Furthermore, high potency TFF remdesivir powder without excipients (F14 and F15) also exhibited high FPF and small MMAD, which indicates remdesivir itself has a good dispersing ability without the need of a dispersing aid when prepared using the TFF process.

This shows the TFF technology can be used to minimize the need of excipient(s) in the formulation, thus maximizing the amount of remdesivir being delivered by dry powder inhalation.

Although the aerosol performance of leucine-based formulations did not significantly change when the drug loading was increased from 20% to 80%, these formulations exhibited superior aerosol performance compared to other excipient-based formulations.

This is likely attributed to the surface modifying properties of leucine. Several papers report that leucine can minimize the contact area and distance between particles (30, 31). This decreases Van der Waal forces between drug particles and subsequently increases aerosol performance.

Additionally, different cosolvent systems affected the aerosol performance of TFF remdesivir powders. The formulation prepared in a 1,4-dioxane/water cosolvent system (F15) exhibited smaller MMAD and higher FPF than the formulation prepared in an acetonitrile/water cosolvent system (F14).

This agrees with SEM figures showing that F15 has smaller nanostructured aggregates than F14. This is possibly due to the difference in viscosity of the solvent. The viscosity of ACN/water (50/50 v/v) was lower than that of 1,4-dioxane/water (50/50 v/v) (0.81 vs. 1.62 mPa·s) (32, 33).

Our results agree with the previous studies by Beinborn et al. (34) and Moon et al. (29) showing that the viscosity of the solvent system has an impact on the aerosol performance of TFF powder.

The higher viscosity of the cosolvent minimizes the movement of molecules during the ultra-rapid freezing step, resulting in more homogenous distribution in the frozen state (29).

On the contrary, the lower-viscosity solvent allows molecules to move more easily, which increases the chance of molecular aggregation and subsequently decreases the aerosol performance (29).

Physical and chemical stability of remdesivir dry powder produced using TFF

Both XRD diffractograms and DSC thermograms showed that remdesivir was amorphous after the TFF process. An amorphous form of the drug generally provides for faster dissolution rate than its crystalline form.

Since the drug needs to be absorbed and then penetrate through the cell membrane before it is hydrolyzed to nucleoside monophosphate, TFF remdesivir powders may provide benefits for the dissolution of the deposited powder in the lung fluid that leads to improvement in the bioavailability and efficacy of the drug when administered by inhalation.

One concern related to the amorphous drug is physical instability due to its high energy state. According to criteria described in Wyttenbach et al., our study confirmed that remdesivir is categorized as a class III glass-forming drug (i.e., it is a stable glass former) (35), because no crystallization peak was observed in both the cooling and heating cycles on DSC. This provides evidence that TFF remdesivir can maintain its physical stability during storage.

In addition to the physical stability, remdesivir, as a prodrug, is prone to degrade by hydrolysis in aqueous solution. Since an organic/water cosolvent system is required to dissolve the drug and excipients in the TFF process, chemical stability is another concern during preparation.

NMR spectra demonstrated that remdesivir did not chemically degrade as a result of the TFF process. Even though remdesivir was exposed to binary solvent systems consisting of water during the process, the entire TFF process used to produce remdesivir dry powder inhalation formulations did not induce chemical degradation of the parent prodrug.


  1. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU) [Internet]. Johns Hopkins University. 2020 [cited July 19, 2020].
  2. Singhal T. A Review of Coronavirus Disease-2019 (COVID-19). Indian J Pediatr. 2020;87(4):281-6.
  3. Summary on compassionate use: Remdesivir Gilead. European Medicines Agency; 2020 03 April 2020.
  4. Ko WC, Rolain JM, Lee NY, Chen PL, Huang CT, Lee PI, et al. Arguments in favour of remdesivir for treating SARS-CoV-2 infections. Int J Antimicrob Agents. 2020;55(4):105933.
  5. Amirian SE, Levy JK. Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses. One Health. 2020;9:100128.
  6. Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531(7594):381-5.
  7. Gordon CJ, Tchesnokov EP, Feng JY, Porter DP, Gotte M. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol Chem. 2020;295(15):4773-9.
  8. Williamson B, Feldmann F, Schwarz B, Meade-White K, Porter D, Schulz J, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. BioRxiv. 2020.
  9. Lo MK, Jordan R, Arvey A, Sudhamsu J, Shrivastava-Ranjan P, Hotard AL, et al. GS- 5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci Rep. 2017;7:43395-.
  10. Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018;9(2).
  11. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020.
  12. Ferner RE, Aronson JK. Remdesivir in covid-19. BMJ. 2020;369:m1610.
  13. Mild/moderate 2019-nCoV remdesivir RCT – Full Text View – [Internet]. 2020 [cited May 1, 2020].
  14. Severe 2019-nCoV remdesivir RCT – Full Text View – 2020 [Internet]. 2020 [cited May 1, 2020].
  15. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. British Journal of Clinical Pharmacology. 2003;56(6):588-99.
  16. Sun D. Remdesivir for Treatment of COVID-19: Combination of Pulmonary and IV Administration May Offer Aditional Benefit. AAPS J. 2020;22(4):77.
  17. Inactive Ingredient Search for Approved Drug Products [Internet]. U.S. Food and Drug Administration. 2020 [cited July 19, 2020]. Available from:
  18. Tolman JA, Nelson NA, Son YJ, Bosselmann S, Wiederhold NP, Peters JI, et al. Characterization and pharmacokinetic analysis of aerosolized aqueous voriconazole solution. Eur J Pharm Biopharm. 2009;72(1):199-205.
  19. Tolman JA, Nelson NA, Bosselmann S, Peters JI, Coalson JJ, Wiederhold NP, et al. Dose tolerability of chronically inhaled voriconazole solution in rodents. Int J Pharm. 2009;379(1):25-31.
  20. Beinborn NA, Du J, Wiederhold NP, Smyth HD, Williams RO, 3rd. Dry powder insufflation of crystalline and amorphous voriconazole formulations produced by thin film freezing to mice. Eur J Pharm Biopharm. 2012;81(3):600-8.
  21. Gardenhire DS, Burnett D, Strickland S, Myers TR. A guide to aerosol delivery devices for respiratory therapists. American Association for Respiratory Care2017.
  22. Overhoff KA, Johnston KP, Tam J, Engstrom J, Williams RO. Use of thin film freezing to enable drug delivery: a review. Journal of Drug Delivery Science and Technology. 2009;19(2):89-98.
  23. Wang YB, Watts AB, Williams RO. Effect of processing parameters on the physicochemical and aerodynamic properties of respirable brittle matrix powders. Journal of Drug Delivery Science and Technology. 2014;24(4):390-6.
  24. Watts AB, Wang YB, Johnston KP, Williams RO, 3rd. Respirable low-density microparticles formed in situ from aerosolized brittle matrices. Pharm Res. 2013;30(3):813- 25.
  25. Wang YB, Watts AB, Peters JI, Liu S, Batra A, Williams RO, 3rd. In vitro and in vivo performance of dry powder inhalation formulations: comparison of particles prepared by thin film freezing and micronization. AAPS PharmSciTech. 2014;15(4):981-93.
  26. Longest PW, Hindle M. Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid Particles after Deposition. Pharm Res. 2017;34(10):2049-65.
  27. Overhoff KA, Engstrom JD, Chen B, Scherzer BD, Milner TE, Johnston KP, et al. Novel ultra-rapid freezing particle engineering process for enhancement of dissolution rates of poorly water-soluble drugs. Eur J Pharm Biopharm. 2007;65(1):57-67.
  28. Sahakijpijarn S, Moon C, Ma X, Su Y, Koleng JJ, Dolocan A, et al. Using thin film freezing to minimize excipients in inhalable tacrolimus dry powder formulations. International Journal of Pharmaceutics. 2020;586:119490.
  29. Moon C, Sahakijpijarn S, Koleng JJ, Williams RO. Processing design space is critical for voriconazole nanoaggregates for dry powder inhalation produced by thin film freezing. Journal of Drug Delivery Science and Technology. 2019;54.
  30. Paajanen M, Katainen J, Raula J, Kauppinen EI, Lahtinen J. Direct evidence on reduced adhesion of Salbutamol sulphate particles due to L-leucine coating. Powder Technology. 2009;192(1):6-11.
  31. Mangal S, Park H, Nour R, Shetty N, Cavallaro A, Zemlyanov D, et al. Correlations between surface composition and aerosolization of jet-milled dry powder inhaler formulations with pharmaceutical lubricants. Int J Pharm. 2019;568:118504.
  32. Thompson JW, Kaiser TJ, Jorgenson JW. Viscosity measurements of methanol-water and acetonitrile-water mixtures at pressures up to 3500 bar using a novel capillary time-of- flight viscometer. J Chromatogr A. 2006;1134(1-2):201-9.
  33. Besbes R, Ouerfelli N, Latrous H. Density, dynamic viscosity, and derived properties of binary mixtures of 1,4 dioxane with water at T=298.15 K. Journal of Molecular Liquids. 2009;145(1):1-4.
  34. Beinborn NA, Lirola HL, Williams RO, 3rd. Effect of process variables on morphology and aerodynamic properties of voriconazole formulations produced by thin film freezing. Int J Pharm. 2012;429(1-2):46-57.
  35. Wyttenbach N, Kuentz M. Glass-forming ability of compounds in marketed amorphous drug products. Eur J Pharm Biopharm. 2017;112:204-8.

More information: Chaeho Moon et al. Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing, (2020). DOI: 10.1101/2020.07.26.222109



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