WO2023100080A1 - Composition pharmaceutique liquide antivirale contre le sars-cov-2 - Google Patents

Composition pharmaceutique liquide antivirale contre le sars-cov-2 Download PDF

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Publication number
WO2023100080A1
WO2023100080A1 PCT/IB2022/061555 IB2022061555W WO2023100080A1 WO 2023100080 A1 WO2023100080 A1 WO 2023100080A1 IB 2022061555 W IB2022061555 W IB 2022061555W WO 2023100080 A1 WO2023100080 A1 WO 2023100080A1
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composition
iodine
sodium
stability
cov
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PCT/IB2022/061555
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English (en)
Spanish (es)
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Rafael CASTELLANOS BUENO
Cristhiam Alexis GONZÁLEZ RODRÍGUEZ
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Quifarmedical Company S.A.S.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
    • A61K31/79—Polymers of vinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present disclosure is related to the field of medicinal chemistry, particularly to the development of effective medicaments for the treatment of infectious diseases caused by viruses.
  • the disclosure refers to a liquid pharmaceutical composition that comprises iodinated active agents and is effective against infection caused by the SARS-CoV-2 virus.
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus type-2
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus type-2
  • Iodinated compounds correspond to one of the best known and most commonly used antiseptics, given their germicidal and virucidal properties.
  • US patent 1,903,614 refers to disinfectant solutions and, specifically, to aqueous solutions of free iodine in a solvent that in turn is an aqueous solution of sodium iodide, potassium iodide and calcium iodide.
  • patents WO 2000/06202 and WO 2001/78751 refer to drugs to treat diseases of a viral and bacterial nature in mammals, where said drugs comprise as active agent, iodine, potassium or sodium iodide, lithium chloride, a water soluble gel-forming synthetic polymer or natural polymers, mono and oligosaccharides.
  • Such medicaments can be used in the treatment of diseases such as AIDS, herpes simplex, and encephalocarditis.
  • composition described in the present disclosure offers the therapeutic advantage and safety to mitigate the mortality generated by this pandemic.
  • iodinated compositions are taught in the state of the art, there is no known composition comprising a complex of sodium iodide, potassium iodide and inorganic iodine, which is stable, safe, can be administered orally and is effective. for the treatment of viral infections such as COVID19.
  • the present disclosure refers to a liquid pharmaceutical composition that comprises iodinated active agents and is effective against infection caused by the SARS-CoV-2 virus.
  • the composition comprises inorganic iodine, sodium iodide, potassium iodide, and pharmaceutically acceptable excipients.
  • FALLENVIR® the antiviral drug registered under the trademark FALLENVIR® was obtained.
  • FIG 1 Degradation of iodine in the composition as a function of pH
  • A. Composition E2505211; B.: Composition E2505212; C.: Composition E2505213; D.: Composition E2505218; E. Composition E2505219.
  • FIG 2 Density variation A.: Composition E2505211; B.: Composition E2505212; C.: Composition E2505213; D.: Composition E2505218; E.: Composition E2505219.
  • FIG 3. Degradation of iodine A.: Composition E2505211; B.: Composition E2505212; C.: Composition E2505213; D.: Composition E2505218; E.: Composition E2505219.
  • FIG 4 Kinetics of iodine stability in compositions stored in glass and plastic containers, at temperatures of 40, 60 and 70°C.
  • FIG. 5 Mean cell viability against different dilutions of the composition
  • FIG. 6 Mean percentage of antiviral activity of the composition
  • FIG. 7 Mean SARS-CoV-2 viral titer after treatment with each of the dilutions of the composition: 1:512, 1:1024, 1:2048 and 1:4096.
  • FIG 8 Plating test of the treatment with the different dilutions of the composition.
  • FIG 9 Evolution of biological markers (ferritin and D-dimer) post-treatment
  • FIG. Evolution of biological markers (PCR, LDH and ESR) post-treatment
  • the present development corresponds to a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising inorganic iodine, sodium iodide, potassium iodide, and pharmaceutically acceptable excipients.
  • the composition has been found to be effective against infection caused by the SARS-CoV-2 virus.
  • the composition corresponds to the antiviral medication registered under the trademark FALLENVIR®.
  • composition presents advantages in different chemical, physical, biological and pharmacological aspects, since it allows to overcome stability problems of the active ingredients used, during processing and storage. Likewise, the pharmacotechnical characteristics of the composition allow it to be administered orally, oropharyngeal, nasal or topical.
  • composition disclosed here corresponds to an essential drug, given the world events that have occurred as a consequence of the COVID 19 pandemic that we are currently facing, where the variants of SARS-CoV-2 are dynamic and change their structure. , as well as its pathogenicity and/or speed of contagion. It has been found that the composition of the present development has the capacity to affect the viruses in their capsid, as well as to inhibit or destroy their structures made up of sugars, lipids and proteins, such as glycoproteins (for example neuraminidases, hemagglutinin, spike protein), etc In addition, it exerts an alteration of the viral genetic material that can inactivate its pathogenic activity.
  • glycoproteins for example neuraminidases, hemagglutinin, spike protein
  • composition reaches the lung thanks to its union in the lactoperoxidase - halide system, its virucidal or antiviral effect is confirmed both by in vitro studies and in vivo studies and experience, supported by monitoring the behavior of paraclinical tests such as C-reactive protein, D-dimer, ferritin, and the follow-up or clinical evolution of patients whose 6-day treatment is sufficient, effective, and safe, demonstrating that after 3 days the patient begins to improve clinically, showing recovery and progress behavior in its infectious state.
  • paraclinical tests such as C-reactive protein, D-dimer, ferritin
  • compositions by the oral (systemic) route, its first-pass metabolism, its affinity for ACE 2 receptors, its binding in the lactoperoxidase-halide system in lung cells, its rapid absorption and its distribution in the human organism make it a first-choice medicine to combat the infection generated by SARS Cov2, taking into account that it generates its antiviral activity in the biological points where the virus replicates, lodges and causes damage in the body. Specifically, it reaches these targets, exercising its therapeutic action in a precise, effective and safe manner. Therefore, the composition offers 4 flanks of biological activity that generate a clinical response in the infected patient regarding its effectiveness and safety.
  • a liquid composition corresponds to a liquid pharmaceutical form that includes, without limitation, solutions, suspensions, or emulsions.
  • the composition that is described corresponds to an aqueous or hydroalcoholic solution, suitable for administration by oral, oropharyngeal, nasal or topical routes.
  • the composition is administered orally.
  • the composition comprises inorganic iodine, sodium iodide and potassium iodide.
  • the inorganic iodine, sodium iodide and potassium iodide they are each in a range of 1 to 10% w/v.
  • the inorganic iodine, sodium iodide and potassium iodide are in the range of 1 to 5% w/v, each.
  • the composition comprises pharmaceutically acceptable excipients selected from the group consisting of stabilizers, flavors, sweeteners, solvents, and preservatives.
  • the composition may comprise a complexant.
  • the stabilizers are selected, without being limited to sodium citrate, citric acid, ascorbic acid, sodium bisulfite, sodium metabisulfite or other compounds of a similar chemical nature.
  • the stabilizer is selected from sodium citrate, citric acid and ascorbic acid.
  • the stabilizer is sodium citrate, citric acid or a mixture thereof.
  • the stabilizer can be found in a range between 0.05% to 10% w/v or between 0.1 to 5% w/v. In a more particular modality, the stabilizer is between 0.1 to 2% w/v.
  • the composition includes flavors, which are selected from but not limited to artificial berry flavor, artificial peach flavor, and artificial strawberry flavor.
  • flavors which are selected from but not limited to artificial berry flavor, artificial peach flavor, and artificial strawberry flavor.
  • the flavoring is artificial flavor of red fruits.
  • the sweeteners are selected from, without being limited to, sorbitol, sodium saccharin, sodium cyclamate, aspartame, sucralose, mannitol, or other compounds of a similar chemical nature.
  • the sweetener is sorbitol, sodium saccharin, aspartame, sucralose, or a mixture thereof.
  • the sweetener is sodium saccharin.
  • the sweetener is in a range between 0.1 to 5% w/v or between 0.1 to 3% w/v. In a more particular modality, the sweetener is in a range between 0.1 to % w/v.
  • Solvents are selected from propylene glycol, glycerin, sorbitol, purified water, propylene glycol, dextrose, saline, or mixtures thereof. In a particular embodiment the solvent is sorbitol. In another particular embodiment, the solvent is a mixture of water and propylene glycol. In another particular embodiment, the solvent is a mixture of water and sorbitol. The solvent is in a range between 20 and 70% w/v or between 30 and 60%. In a more particular modality, the solvent is in a range between 35 to 50% w/v.
  • preservatives are selected without being limited to citric acid, sodium citrate, sodium benzoate, or a mixture thereof.
  • the preservative is sodium benzoate.
  • the preservative is present in the composition in a range between 0.1 to 10% w/v or 0.1 to 5% w/v.
  • the composition includes a complexing agent, which corresponds to polyvinylpyrrolidone, selected from PVP of different molecular weight, without being limited to PVP K17, PVP K30 or PVP K90.
  • the composition comprises PVP K30.
  • the PVP is in a range between 0.1% to 5% p/v or between 0.5% to 2% p/v. In a more particular modality, the PVP is 1% w/v.
  • iodine compounds The stability of iodine compounds is of great importance particularly because it is necessary to be sure that the iodinated solution contains the pharmaceutically active amount, and that this is preserved throughout the shelf life of the product. In addition, it is required to comply with current regulations (Decree 677 of 1995) that governs this type of product.
  • iodine, hypoiodous acid (HOI) and its conjugate acid (FhOI ' ) in aqueous media have antimicrobial and virucidal activity, in the degradation reaction of iodine in water these two acids are transient in the process and hence the importance of keeping iodine stabilized in order to maintain virucidal activity.
  • Another strategy to stabilize the iodine consists of controlling the pH, the ionic strength and the use of viscosity modifier excipients present in the composition, without modifying the concentrations of metallic (inorganic) iodine and iodides so as not to alter the therapeutic effect.
  • compositions inhibit blocking the interaction between SARS CoV2 and erythrocytes, preventing or inhibiting rapid viral replication.
  • the composition inhibits hemagglutination induced by the interaction of erythrocytes and the SARS CoV2 virus, since the iodide ions create a barrier that prevents the interaction between the erythrocytes and the SARS CoV2 virus, since the specific binding site for sialic acid is blocked, thus preventing the glycosylation of these proteins by host cell carbohydrates.
  • hemagglutination damage to the molecular structure of red blood cells and therefore the formation of thrombi will be avoided.
  • Iodine exerts an inhibitory activity because free iodine binds to sialic acid receptors (sialyloligosaccharide receptors) which prevents the virus from binding to the host cell, preventing viral replication and therefore exposing the virus to be recognized by the host's immune system.
  • sialic acid receptors sialyloligosaccharide receptors
  • iodine interacts and inactivates the S (spike) protein.
  • Iodine possesses appropriate pharmacokinetic properties for clinical use, since water-soluble iodine salts, such as potassium iodide, sodium iodide, exhibit approximately 100% gastrointestinal absorption after ingestion. Once absorbed, it is rapidly distributed through the extracellular fluid, and can even cross the placental barrier, being secreted in breast milk. The extracellular fluid distributes iodine to tissues other than the thyroid, such as the mammary gland, salivary glands, and gastric mucosa. Elimination occurs mainly through the urine and in small amounts through saliva, milk, sweat, bile, and feces. Additionally, iodine can be distributed through the interstitial spaces, passing biological barriers, reaching the whole body.
  • water-soluble iodine salts such as potassium iodide, sodium iodide
  • the iodine complex has an effect on the respiratory system since it reaches the lung, an important target of SARS CoV2.
  • the oral administration of the composition, its oral, pharyngeal, and gastrointestinal transit and its affinity with the lactoperoxidase-hyalide system directly facilitates contact with the angiotensin-converting enzyme 2 (ANG2) receptors in the lung, the place where defenses are activated. of the respiratory tract and where the SARS COV2 virus binds with great affinity with human host cells and generates viral replication and as a side effect decreases inflammation and alleviates respiratory distress. It has been observed that after 2 hours of oral administration, the composition improves O2 saturation. In addition, Since the major route of elimination (80%) of the composition is renal, this prevents SARS-CoV2 from generating renal deposits.
  • ANG2 angiotensin-converting enzyme 2
  • the present disclosure also relates to the use of the composition as a medicament useful against various viral infections including, but not limited to infections caused by influenza (MYXOVIRUS), SARS-CoV-2, MERS-CoV, Flaviviridae dengue virus having four distinct but closely related serotypes: DEN-1, DEN-2, DEN-3, and DEN-4, chikungunya virus (CHIKV), Ebola virus (EVD), and HIV.
  • MYXOVIRUS infections caused by influenza
  • SARS-CoV-2 SARS-CoV-2
  • MERS-CoV Flaviviridae dengue virus having four distinct but closely related serotypes: DEN-1, DEN-2, DEN-3, and DEN-4, chikungunya virus (CHIKV), Ebola virus (EVD), and HIV.
  • composition is useful as a medicament against SARS-CoV-2.
  • the composition can be administered to the patient via the oral, oropharyngeal, nasal, or topical routes.
  • the composition is administered orally, gargling before proceeding to swallow the composition.
  • the gargles should have a time interval between two to five seconds, and should only be done in the first administration of the medication.
  • the composition must be administered as follows:
  • DAY 4 TO DAY 6 (1 drop x every 10 kilograms of weight) Dilute the liquid composition in half a glass of water (100 to 150ml), rinse the mouth together with gargles for a maximum of 5 seconds each gargle. Swallow the composition only when performing the first rinse. Do this three (3) times a day.
  • Example 1 Compositions The compositions shown in Table 2 were obtained.
  • Table 3 describes the composition that was subjected to the accelerated pre-stability test.
  • a solution H was prepared that comprises potassium iodide and polyvinylpyrrolidone-k30 in a mixture of water with propylene glycol
  • a solution K was prepared where sodium iodide and metallic iodine were diluted in a fraction of propylene glycol
  • both solutions were mixed, taking into account that solution H was added to solution K
  • the iodine-PVP complex (Formula 1) was obtained, which allows the stabilization of the element in the solution and also achieves a controlled release of iodine over time.
  • Table 3. Qualitative and quantitative composition of the iodine-PVP complex.
  • Table 4 describes the results obtained in the accelerated pre-stability test in an amber glass container at 70°C for the composition of Table 3.
  • Table 5 shows the results obtained in the prediction of stability at 30 °C and 5 °C of the composition of the iodine-PVP complex. It is estimated that the product in the most demanding prediction conditions would have a useful life of 72 and 407 days at 30°C and 5°C, respectively.
  • compositions E2505211 to E2505219 were not successful in terms of the stability of the active ingredient in oral solutions.
  • a new composition with greater projection is formulated according to the preliminary tests, listed in Table 11, which corresponds to the composition with greater projection.
  • This composition does not generate complexes with iodine or other reactions different from the degradation reaction in water described above, With these modifications to the environment, the aim is to slow down degradation for as long as possible.
  • Validation Table 13 describes the optimized composition, which was again subjected to a 70°C accelerated pre-stability test to validate the previous information.
  • the degradation percentage of this composition stored at 70°C for four days was 8.8%, a value outside the permitted degradation range of the iodinated solution, but which allows the Q10 acceleration factor to be used as a stability prediction strategy. of the product, as was done in the previously described complexation strategy.
  • Table 14 shows the results obtained in the prediction of stability at 30 °C and 5 °C of the optimized composition. It is estimated that the product in the most demanding prediction conditions would have a useful life of 48 and 272 days at 30°C and 5°C respectively. Table 14. Stability prediction using the acceleration factor Q10
  • the stability of iodine in solution is evaluated under two conditions relevant to the final product, temperature and the container used.
  • the formulation described in Table 7 was stored in a glass container and in a plastic container number 7 (mixture of plastics), both presentations were subjected to storage at 40, 60 and 70 °C.
  • the percentage of iodine degradation at 21, 41, 71 and 89 hours was determined, to later calculate the value of the Q10 acceleration factor, which is used to rectify the stability predictions. presented in the validation section. Table 16 and Figure 4 present the results of the tests.
  • Cytotoxicity assay Cytotoxicity is determined by the MTT assay, which is based on the metabolic reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazole (MTT) bromide by the enzyme mitochondrial succinate-dehydrogenase in a blue compound (formazan), allowing to determine the mitochondrial functionality of the treated cells. This method is used to measure cell survival and antiviral activity; in this way, the amount of formazan is directly proportional to cell viability (Shen L., et al. High-throughput screening and identification of potent broad-spectrum inhibitors of coronaviruses. J. Virol. 2019;93).
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazole
  • cells are seeded at a density of IxlO 5 cells/well in a 96-well plate in 200 pL of DMEM (Dulbecco's Modified Eagle Medium) medium, with 10% FBS (fetal bovine serum) and they were cultivated for 24 hours at 37°C in an atmosphere of 5% CO2. Subsequently, the cells were treated with different concentrations of Composition A in triplicate. Forty-eight hours after the treatment, the supernatant was removed and the MTT solution (0.5 mg/mL) was added. After 2h of incubation, 130 pL/well of DMSO were added. The plates were shaken for 15 minutes and were finally read in a spectrophotometer at 550nm. Controls without treatment were also included, in which cell viability was determined as 100%.
  • DMEM Dynamic Eagle Medium
  • FBS fetal bovine serum
  • the antiviral activity of the composition was evaluated against the SARS-CoV-2 virus isolated in the VERO E6 cell line.
  • Cells isolated from the kidney epithelial cells of an African green monkey (VERO E6) were maintained in DMEM culture medium, supplemented with 5% SFB, in a 5% CO2 atmosphere and at a temperature of 37°C.
  • the titer of the SARS-CoV-2 virus isolated in the laboratory was determined by the plating technique and TCID50 (Tissue Culture Infectious Doses 50) in VERO E6 cells, following a protocol described in (Fan HH, et al., Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus (2019-nCoV) related coronavirus model. Chin. Med. J.). The title obtained was 4.21xl0 6 PFU (plaque-forming units)/mL.
  • VERO E6 cells were seeded in 96-well dishes, at a density of IxlO 5 cells/well in 1OOuL/well of DMEM, 2% SFB, 5% CO2 and 37°C, 24h before being used. On the day of the assay, non-cytotoxic dilutions of the composition were added to VERO E6 cells, in replicates of 3 wells, for 1 hour. Subsequently, the composition was removed and the cells were infected with the SARS-CoV-2 virus at an MOI (Multiplicity of infection) of 0.01 per Ih.
  • MOI Multiplicity of infection
  • the virus remnant that failed to enter the cells was removed and replaced with fresh culture medium and new dilutions of the composition.
  • a negative control (cells + DMEM) and a positive control (cells + DMEM + virus) were used.
  • A corresponds to the OD (optical density) of cells infected and treated with the composition
  • B to the OD of infected cells without treatment with the composition (positive infection control)
  • C to the OD of uninfected cells (negative control). of infection).
  • Figure 6 shows that treatment with the composition induced a mean percentage of antiviral activity of 14.2%, 16.8%, 14.4%, 18.3% and 18% in dilutions of 1:512, 1:1024, 1:2048, 1:4096 and 1:8192, respectively, which shows that the composition has a maximum antiviral activity of 18.3%, determined by assessing cell viability measured by the MTT assay. as control Positive for inhibition, chloroquine was used, which showed an average inhibition of 73% ( Figure 6).
  • the viral titer was determined by means of a plating assay, from the supernatants obtained in the antiviral assay.
  • the dilution used corresponds to the highest dilution in which antiviral activity was observed, in Example 4, comparing cells infected and treated with the compound vs infected cells without treatment with the compounds, and in which the cytotoxicity of the compound was less than twenty%.
  • the title obtained is expressed in UFP/mL.
  • the average viral titer in the 1:512, 1:1024, 1:2048 and 1:4096 dilutions was 3.4 xlO 5 , 4.5 xlO 5 , 4.1 xlO 5 and 6.4xl0 5 PFU/mL , respectively, while the titer of the virus control (cells without treatment) was 9.4xl0 5 PFU/mL, which indicates that the inhibition percentage was 70%, 52%, 56% and 32%, respectively, with statistically significant differences between the 1:512 and 1:2048 dilutions compared to the virus control (p ⁇ 0.05) ( Figure 6 and 7). Therefore, a reduction in the viral titer and the number of infectious SARS-CoV-2 viral particles was observed when the virus was exposed to the dilutions of the composition.
  • An observational assay is carried out where the behavior of some inflammatory markers is evaluated in 19 patients with Covid-19 who were administered the iodinated composition of Example 1 orally 3 times a day for 5 days and the evolution of some inflammatory markers: C-reactive protein, ferritin, D-dimer, ESR, and LDH.
  • any decrease in inflammatory markers impacts the survival of patients with CO VID 19 in any of the three phases, Due to the decrease in the values of ferritin and D-dimer as presented after the administration of the liquid composition, it estimates a decrease in the predictors of mortality for the disease by COVID 19.
  • the iodinated composition studied presents a safe pharmacological alternative against clinical manifestations in mild and moderate phase by decreasing inflammatory markers: D-dimer and ferritin, reducing the mortality rate and additionally hospital interventions in emergency services and/or in the Intensive Care Unit (ICU).
  • ICU Intensive Care Unit

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Abstract

La présente divulgation concerne une composition pharmaceutique liquide comprenant de l'iode inorganique, du iodure de sodium, du iodure de potassium et des excipients pharmaceutiquement acceptables, ladite composition étant utilisée en tant que médicament antiviral contre le SARS-CoV-2.
PCT/IB2022/061555 2021-11-30 2022-11-29 Composition pharmaceutique liquide antivirale contre le sars-cov-2 WO2023100080A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1903614A (en) * 1930-12-15 1933-04-11 Iodine Educational Bureau Inc Disinfecting solution
WO2020232515A1 (fr) * 2019-06-10 2020-11-26 Firebrick Pharma Pty Ltd Prévention d'infection par des virus hautement pathogènes par application topique de povidone iodée sur des membranes muqueuses
WO2021198940A1 (fr) * 2020-03-31 2021-10-07 タイ ミン ファーマシューティカルズ ジェイエスシー Composition destinée à prévenir ou soigner une infection virale chronique ou aiguë et/ou une septicémie chez l'être humain ou chez l'animal

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HASSANDARVISH POUYA, TIONG VUNJIA, MOHAMED NURUL AZMAWATI, ARUMUGAM HARSHA, ANANTHANARAYANAN ABHISHEK, QASURI MURTAZA, HADJIAT YAC: "In vitro virucidal activity of povidone iodine gargle and mouthwash against SARS-CoV-2: implications for dental practice", BRITISH DENTAL JOURNAL : BDJ ; THE JOURNAL OF THE BRITISH DENTAL ASSOCIATION, NATURE PUBLISHING GROUP, BRITISH DENTAL ASSOCIATION, UK, UK , XP093071608, ISSN: 0007-0610, DOI: 10.1038/s41415-020-2402-0 *
PELLETIER JESSE S., TESSEMA BELACHEW, FRANK SAMANTHA, WESTOVER JONNA B., BROWN SETH M., CAPRIOTTI JOSEPH A.: "Efficacy of Povidone-Iodine Nasal and Oral Antiseptic Preparations Against Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2)", EAR, NOSE, AND THROAT JOURNAL., VENDOME GROUP, LLC, US, vol. 100, no. 2_suppl, 1 April 2021 (2021-04-01), US , pages 192S - 196S, XP093071602, ISSN: 0145-5613, DOI: 10.1177/0145561320957237 *

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