WO2022034557A1 - Compositions anti-virales d'inhalation orale et intraveineuse et procédés associés - Google Patents

Compositions anti-virales d'inhalation orale et intraveineuse et procédés associés Download PDF

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Publication number
WO2022034557A1
WO2022034557A1 PCT/IB2021/057499 IB2021057499W WO2022034557A1 WO 2022034557 A1 WO2022034557 A1 WO 2022034557A1 IB 2021057499 W IB2021057499 W IB 2021057499W WO 2022034557 A1 WO2022034557 A1 WO 2022034557A1
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pharmaceutical composition
mammal
metal
prevention
treatment
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PCT/IB2021/057499
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English (en)
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Archana PALIKA
Akram RAHIMI
Sreenath BOLISETTY
Raffaele Mezzenga
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Bluact Technologies Gmbh
Eth Zurich
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Publication of WO2022034557A1 publication Critical patent/WO2022034557A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1716—Amyloid plaque core protein
    • 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
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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

  • Viruses essentially consist of genetic material, a protein capsid and the outer envelopes (in case of enveloped viruses). They cannot live in an inanimate environment but are dependent on favorable conditions in living host cells to replicate. Many viral infections eventually result in the death of the host cell of any host organism, including microorganisms, plants, and animals, including human beings. Viral epidemics for instance caused by smallpox or poliovirus are well documented and history has seen many viral epidemics. The 1918 influenza pandemic is the last great pandemic responsible for the death of several tens of millions of people across the planet. More recent viral epidemics include the AIDS, SARS (2002), Swine flu (2009), Ebola (2013) and the recent outbreak of COVID-19 (2019-2020).
  • Favilavir which is sold under the brand name Avigan®, is an antiviral drug that was approved in Japan in 2014 to treat influenza, and currently also approved for treating COVID-19 in some countries.
  • Some anti-flu drugs such as oseltamivir, laninamivir, peramivir and zanamivir have been applied for the treatment of COVID-19 patients. However, these drugs are not very effective against SARS-Cov-2.
  • Remdesivir Another anti-viral drug, Remdesivir showed efficacy by resisting two viruses similar to Covid-19, SARS- CoV and MERS-CoV, in animals.
  • Clinical trials of Remdesivir have officially started in a number of hospitals in Wuhan to test its efficacy against COVID-19 and has been shown to have some benefits in shortening the hospitalization time in some patients.
  • arbidol an antiinfluenza drug targeting the viral hemagglutinin (HA) is being used in a clinical trial against COVID-19.
  • Chloroquine phosphate an old drug for the treatment of malaria, has been shown to have apparent efficacy and acceptable safety against COVID-19 associated pneumonia.
  • viruses largely depend on the biosynthetic machinery of infected cells for their replication, the specificity of antiviral drugs is far from ideal, resulting in general intrinsic toxicity associated with such treatment. Additionally, many viruses mutate rapidly due to error- prone replication machinery; therefore, they often develop resistance. As discussed above, additionally, numerous antiviral drugs have proven to exhibit toxicity. The antiviral drugs often cannot be active for the broad spectrum of viral infections and it is difficult for the drugs to pass the phase 3 clinical trials.
  • An aspect of the present disclosure is generally directed to a pharmaceutical composition for the prevention or treatment of a viral infection in a mammal, typically a human, that includes hybrid antiviral metal-associated amyloid fibrils comprising metal nanoparticles on a surface of amyloid fibrils where the pharmaceutical composition is an intravenous pharmaceutical composition or inhalation composition.
  • Another aspect of the present disclosure is generally directed to a pharmaceutical composition for the prevention or treatment of a viral infection in a mammal that includes a hybrid antiviral metal-associated amyloid fibril comprising metal nanoparticles on a surface of an amyloid fibril where the pharmaceutical composition is not a buccally administered composition or an enterically administered composition.
  • Yet another aspect of the present disclosure is generally directed to a method of treating a mammal infected or at risk of being infected with a virus that includes the step of intravenously administering a pharmaceutical composition having hybrid antiviral metal- associated amyloid fibrils that include metal nanoparticles on a surface of amyloid fibrils.
  • Another aspect of the present disclosure is generally directed toward a method of treating a mammal infected or at risk of being infected with a virus that includes the step of inhaling a pharmaceutical composition into the lungs of the mammal where the pharmaceutical composition includes hybrid antiviral metal-associated amyloid fibrils having metal nanoparticles on a surface of amyloid fibrils.
  • FIG. 1 is a schematic process for the synthesis of the amyloid-iron hydroxide nanoparticles.
  • FIG. 2A is a graphical depiction of the incubation of Phi6 Bacteriophages with -lac Amyloid fibrils, Fe nanoparticles and -lac Amyloid iron hydroxide particle hybrids.
  • FIG. 2B is a graphical depiction of the incubation of Influenza A virus with -lac Amyloid fibrils, Fe nanoparticles and -lac amyloid iron hydroxide particle hybrids.
  • FIG. 3 is a graphical depiction of the incubation of Phi6 bacteriophage with -lac Amyloid fibrils and -lac Amyloid iron hydroxide and iron oxide nanoparticles.
  • a stated range of "1 to 10" should be considered to include any and all sub-ranges beginning with a minimum value of 1 or more and ending with a maximum value of 10 or less (e.g., 1 to 6.1, or 2.3 to 9.4), and to each integer (1, 2, 3, 4, 5, 6, 7, 8, 9, 10) contained within the range.
  • the singular forms "a,” “an” and “the” include plural reference unless the context clearly dictates otherwise. All combinations of method steps or process steps as used herein can be performed in any order, unless otherwise specified or clearly implied to the contrary by the context in which the referenced combination is made.
  • the anti-viral compositions of the present disclosure may also be substantially free of any ingredient or feature described herein, provided that the remaining composition still contains all of the required ingredients or features as described herein.
  • the term "substantially free” means that the selected composition contains less than a functional amount of the optional ingredient, typically less than 1%, including less than 0.5%, including less than 0.1%, and also including zero percent, by weight of such optional or selected essential ingredient.
  • the present disclosure is generally directed to the use of hybrid antiviral metal- associated amyloid fibrils to treat mammals, in particular humans, infected with one or more types of viruses.
  • the pharmaceutical compositions of the present disclosure while typically used to treat someone suffering from a viral infection, it is presently believed that the pharmaceutical compositions may also be administered to prevent infection.
  • the hybrid antiviral metal-associated amyloid fibrils of the present disclosure surprisingly synergistically work to destroy and significantly reduce or eliminate viruses coming into contact with the hybrid antiviral metal-associated amyloid fibrils of the present disclosure.
  • the hybrid antiviral metal-associated amyloid fibrils of the present disclosure work synergistically to treat various viruses.
  • the hybrid antiviral metal-associated fibrils include amyloid fibrils having one or more anti-viral metal components bound to or carried by the amyloid fibrils.
  • the network of hybrid antiviral metal-associated amyloid fibrils of the present disclosure cause viruses coming into contact with the hybrid antiviral metal-associated amyloid fibrils to be killed or otherwise eliminated/inactivated viruses when the hybrid antiviral metal-associated amyloid fibrils are administered intravenously and/or by inhalation into the respiratory systems.
  • the amount of virus is dramatically reduced and, in many instances, lowered to non-detectable levels, which are levels not achieved by the use of amyloid fibrils or the metal particles alone.
  • the antiviral metal-associated hybrid amyloid fibrils of the present disclosure can be incorporated into each of the following: (1) intravenous compositions for administration to a patient or person; and (2) an inhaled composition for administration to a patient or person; and (3) methods of treating or preventing viral infections by administration of either or both of the intravenous composition(s) and/or the inhaled composition.
  • the compositions will include the virucidal hybrid antiviral metal-associated amyloid fibrils.
  • the virucidal hybrid antiviral metal-associated amyloid fibrils material of the present disclosure is typically a metal-associated hybrid amyloid fibril material usually composed of food-grade milk protein fibrils modified on their surface by metal particles, typically metal nanoparticles, more typically, iron oxide nanoparticles or iron hydroxide nanoparticles, most typically iron oxide nanoparticles.
  • metal nanoparticles typically, iron oxide nanoparticles or iron hydroxide nanoparticles, most typically iron oxide nanoparticles.
  • the nontoxic, metal-associated hybrid amyloid fibrils of the present disclosure can effectively inactivate the enveloped viruses such as HBV, HCV, HIV, influenza and coronaviruses in vitro and it is presently believed that they can do so in vivo as well.
  • the studies employed in the case of the present disclosure included testing on an enveloped bacteriophage Phi6, which has been accepted by the research community as a surrogate for the enveloped viruses (influenza virus and coronaviruses). Initially, these hybrid materials were tested for enveloped phi6 - bacteriophages and then for Influenza viruses. The hybrid material of various concentrations of 2.6 mg/ml to the virus concentration range of 10 4 -10 7 pfu/ml were incubated; all the phi6 and influenza viruses were inactivated by 100%. Since these are made with food-grade materials, these antiviral materials are environmental-friendly.
  • amyloid fibrils may be produced by heating the two wt. % of purified beta-lactoglobulin (BLG) protein monomer (pH 2) at 90° C. for 5 h. (scale bar is 100 nm).
  • BLG beta-lactoglobulin
  • metal particles may be bound or otherwise associated with the amyloid fibrils, but the metal particles are more typically, nanoparticles and most typically, iron nanoparticles.
  • Iron nanoparticles typically iron hydroxide or iron oxide nanoparticles, have each been found to be particularly effective to reduce significantly viral presence when used in association with amyloid fibrils. Iron hydroxide is more sustainable food-grade material compared to other nanoparticles discussed herein.
  • a blend of different nanoparticles could also be used and a mix of different metal particles associated with and/or bonded to the amyloid fibrils to create the hybrid antiviral metal-associated amyloid fibrils material of the present disclosure.
  • the antiviral metal-associated amyloid fibril material effectively inactivates viruses, in particular enveloped viruses such as HBV, HCV, HIV, influenza. It is presently believed that the protein fibrils play a major role in binding strongly to the virus to the outer lipid membrane, leading to multivalent binding with the consequent inactivation of the virus. As shown in FIGS. 2A-B, and FIG. 3, protein fibrils or iron hydroxide nanoparticles alone do not have significant virucidal properties, but the hybrid antiviral metal-associated amyloid fibrils material of the present disclosure generates a synergistic effect leading to outstanding virucidal properties.
  • Iron nanoparticles may be synthesized onto amyloid fibrils by in situ chemical reduction of FeCh-BHjO to obtain iron -lactoglobulin fibrils (i.e. the composite materials comprising amyloid fibrils and nanoparticulate mineral compounds located on the surface of said amyloid fibrils). 0.45 wt. percent of amyloid fibrils may be mixed with 0.015M FeCh-BHjO salt solutions. Iron III ions binding to amyloid fibrils are then chemically reduced by NaBH4 and/or NaOH. (scale bar is 100 nm).
  • the present disclosure provides for the use of hybrid antiviral metal-associated amyloid fibrils having amyloid fibrils bound with antiviral metals that work synergistically to deactivate viral components where the antiviral metal is most typically an iron nanoparticle chemically engaged or bound to at least the surface of the amyloid fibrils.
  • the hybrid antiviral metal-associated amyloid fibrils of the present disclosure may be included as an active ingredient in a pharmaceutical composition, in particular, an intravenous composition or an inhaler.
  • the hybrid antiviral metal-associated amyloid fibrils may be the only active or work in conjunction with one or more additional active antiviral pharmaceutical active such as antiviral drugs that employ small molecules (for example, nucleoside analogues and peptidomimetics), proteins were able to stimulate the immune response (for example, interferon), and oligonucleotides (for example, fomivirsen).
  • additional active antiviral pharmaceutical active such as antiviral drugs that employ small molecules (for example, nucleoside analogues and peptidomimetics), proteins were able to stimulate the immune response (for example, interferon), and oligonucleotides (for example, fomivirsen).
  • the hybrid antiviral metal- associated amyloid fibrils may also be combined with Favilavir, which is sold under the brand name Avigan®, oseltamivir, laninamivir, peramivir, and/or remdesivir.
  • hybrid antiviral metal-associated amyloid fibrils of the present disclosure typically contain both amyloid fibrils and one or more nanoparticulate minerals located on the surface of the amyloid fibrils.
  • the nanoparticles may be the same or a combination of different nanoparticles.
  • amyloid fibrils is generally known in the field to describe a specific type of protein aggregates and particularly describes fibrils made by proteins or peptides prevalently found in beta-sheet secondary structure. Accordingly, the term amyloid fibrils exclude native proteins. Particularly suitable amyloid fibrils used to produce the hybrid antiviral metal- associated amyloid fibrils of the present disclosure are amyloid fibrils from -lactoglobulin, an inexpensive milk protein with natural reducing effects, which proves to act as an anti-oxidizing nanocarrier and colloidal stabilizer for nanoparticulate minerals, such as nanoparticulate iron compounds. The amyloid fibrils are typically obtained from globular proteins, most typically food grade globular proteins.
  • Some globular proteins that may be used to form the amyloid fibrils of the present disclosure may be from any one or combination of the following globular proteins: beta-lactoglobulin (BLG), whey, lysozyme, bovine serum albumin, soy proteins, ovalbumin and combinations or mixtures thereof.
  • beta-lactoglobulin is most typically preferred. It is most typically preferred because of inexpensive, readily available and highly robustness to form the amyloid fibrils. Positive charge groups available on the surface of the beta-lactoglobulin fibrils will bind the iron ions and in situ synthesis of the nanoparticles.
  • the solution of protein fibrils coated by iron hydroxide nanoparticles can be obtained via a simple in situ binding process by initial mixing of amyloid fibrils solution with an aqueous solution of FeCh-BHjO.
  • the nucleation and growth of the iron hydroxide nanoparticles onto the amyloid fibrils surface is achieved by a simple change in pH, allowing the conversion of iron ion precursors into the strongly bound nanoparticles.
  • These hybrid protein fibrils show the outstanding antiviral capability when tested in the water against several enveloped viruses.
  • the amyloid fibrils typically have a high aspect ratio, preferably with ⁇ 10 nm in diameter and >1 pm in length.
  • the amyloid fibrils have a highly charged surface.
  • highly charged surfaces are generally known in the field and particularly describes surfaces showing electrophoretic mobility of the order 2 pm-cm/V-s at pH 2. Accordingly, amyloid fibrils having electrophoretic mobility of the order 1-4 pm-cm/V-s at pH 2 are preferred.
  • Amyloid fibrils that may be used in the context of the present disclosure include, but are not limited to, the amyloid fibrils disclosed in US Patent Application Publication No. 2017/0096349 Al, the entire disclosure of which is hereby incorporated by reference herein.
  • iron nanoparticles whether from iron elementally, iron hydroxide or iron oxide
  • the resulting composite material forms a stable protein-iron colloidal dispersion.
  • the iron nanoparticle and amyloid composites show high antiviral capability. Formation of the composites from iron hydroxide and iron oxide may be formed in the manner described below.
  • Iron oxide particles in the case of the present disclosure may be produced by mixing the iron chloride FeCh dissolved salt solution to the amyloid fibrils, further iron ions converted to iron oxide nanoparticles by the Sodium Borohydride (NaBF ). NaOH adjusts the pH to pH7 for the virus incubation studies.
  • NaBF Sodium Borohydride
  • Nanoparticulate minerals are defined both by particle size and chemical composition of the particles.
  • particles of 5-100 nm size are particularly useful in the context of the present disclosure.
  • the particle size may vary, depending on the mineral.
  • a preferred range of the particles is from about 2 to about 100 nm.
  • a typical range of the particles is from about 3 to about 100 nm.
  • iron oxide and iron hydroxide nanoparticles have all been shown to synergistically dramatically reduce and eliminate to an undetectable level of various bacteria and viruses. [0033] Broadly speaking, it is believed that any non-toxic metal may be used, but currently preferred are iron nanoparticles.
  • the term minerals shall particularly include compounds selected from the group consisting of salts, oxides and hydroxides.
  • the metal nanoparticles are predominantly located on the surface of the amyloid fibrils, such as at least 80%, more typically, at least 90% of the nanoparticles, and most typically at least 95% of the nanoparticles are located on the surface (with respect to the total amount of nanoparticles present in the composite). Particularly preferably, all nanoparticles are present on the surface of the amyloid fibrils. It was surprisingly found that the amyloid fibrils and metal nanoparticles of the composite material synergistically interact to eliminate viruses in vitro. It is presently believed that when administered intravenously and/or via respiration/inhalation, viral reduction and elimination may also be achieved for any virus contacting the hybrid material of the present disclosure.
  • the ratio of both constituents may vary over a broad range, depending inter alia on the specific materials and the intended use.
  • Particularly preferred hybrid antiviral metal-associated amyloid fibrils are obtained when the ratio of amyloid fibrils to metal nanoparticles is in the range of from about 20/1 to about 1/1 (w/w), such as about 5/1.
  • An enveloped virus has an outer lipid layer of glycoprotein and lipoproteins.
  • Many enveloped viruses such as HBV, HCV, HIV, influenza, and coronaviruses, are pathogenic to humans and of clinical importance. Infectious diseases caused by enveloped viruses, such as influenza viruses and the coronaviruses are responsible for severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), cause thousands of deaths and billions of dollars of economic losses per year.
  • SARS severe acute respiratory syndrome
  • MERS Middle East respiratory syndrome
  • antiviral drugs are the only treatment option presently available and these are only limited to antiviral drugs that have received regulatory approval in a given country or jurisdiction, which are often quite limited or non-existent for certain viruses.
  • the hybrid antiviral metal-associated amyloid fibrils of the present disclosure typically include a non-toxic food grade protein fibril component containing iron particles, typically nanoparticles, thereon. It is presently believed that the metal particles, which are typically iron nanoparticles, will act as at least a moderate virucidal or a virucidal for a broad spectrum of enveloped viruses when administered in vivo via inhalation or intravenously. Administration buccally or enterically is not expected to be effective since the hybrid materials will breakdown too quickly and will not come into contact with the virus in the body in sufficient amounts to be effective when administered in these pathways.
  • the virucidal hybrid antiviral metal-associated amyloid fibrils of the present disclosure typically include the synergistic combination of food-grade milk protein fibrils modified on their surface by iron hydroxide nanoparticles.
  • This material can effectively inactivate the enveloped virus such as HBV, HCV, HIV, influenza and coronaviruses, such as COVID-19.
  • the protein fibrils play a major role in binding strongly to the virus to the outer lipid membrane of a virus. This leads to multivalent binding with the consequent inactivation of the virus.
  • the pharmaceutical products incorporating the hybrid antiviral metal-associated amyloid fibrils of the present disclosure are made with non-toxic, food-grade materials, these antiviral materials are environmentally friendly and would decompose within two years.
  • the hybrid antiviral metal-associated amyloid fibrils of the present disclosure act as virucidal for a broad spectrum of enveloped viruses.
  • the hybrid active ingredients of the present disclosure have the potential to effectively inactivating the enveloped virus such as HBV, HCV, HIV, influenza and various coronaviruses such as COVID-19.
  • Protein fibrils play a major role in binding strongly to the virus to the outer lipid membrane, leading to multivalent binding with the consequent inactivation of the virus.
  • Protein fibrils or iron hydroxide nanoparticles alone do not have any virucidal properties but the hybrid material generates a synergistic effect leading to outstanding virucidal properties.
  • the virucidal hybrid antiviral metal-associated amyloid fibrils material of the present disclosure may be administered via an inhalation device, in particular a metered dose inhaler (MDI).
  • the active ingredient of the present disclosure, the hybrid antiviral metal-associated amyloid fibrils, may be a powdered material.
  • the MDI typically will have a metering valve or valves. The basic function of the metering value is to ensure a consistent amount of the active is administered from the canister containing the active with each time the patient actuates the device. In a way, the MDI valve has two separate valves, one at either end of the metering chamber.
  • the exterior valve that seals the system from the exterior environment by being kept closed while the formulation to be administered is allowed into a metering chamber. Then the inner valve closes, which isolates the single dose of the correct volume. Once the correct volume has been received through the inner valve, the outer valve is then allowed to open and dispense the dose under the vapor pressure of its own propellant. The outer valve then recloses and the inner valve then reopens in the preparation of the next dose to be administered.
  • MDI metering valve devices of the present disclosure are typically a press-to-fire type design with a protruding male valve stem that is depressed inwards towards the canister to dispense a dose.
  • a continuous aerosol inhaler device such as a home medicinal nebulizer may be used.
  • Aerosol inhalation has therefore the potential to maximize therapeutic effects and minimize side effects.
  • factors to consider for optimal treatment of the lungs include aerosol characteristics, breathing patterns, geometrical factors (lung morphology), disease state, pharmacokinetics, and drug-cell interactions. Aerosol characteristics are mainly determined by the drug formulation and the inhalation device. Not only the total pulmonary drug dose but also the regional deposition distribution of the lung- deposited aerosol is a key factor for the success of an inhalation therapy
  • the composition will have a target inhibitory concentration (IC) for antiviral applications of from about 10-1000pg/ml.
  • IC target inhibitory concentration
  • the breathing cycle losses are typically the following: inhalation is about 1/3 of the breathing cycle. Using a continuous aerosol source such as a medicinal nebulizer only about 30% of the nebulized substance is actually inhaled. Exhalation through the nose can be implemented as a method to deliver the hybrid antiviral metal-associated amyloid fibrils also to the nasal cavity when the nebulized inhalation is done orally.
  • the aerosol dosage is calculated using the following formula: (Aerosol dosage) - (Target IC [pg/ml]) * (Mucus Volume [ml])/(Tissue deposition fraction)/(lnhalation time losses)/ (colloid concentration [pg/ml]).
  • the dosage amount is from about 300pg to about lmg, taken over a period of 5 to 14 days.
  • the solvents for the inhaled composition may be water-based or alcohol aerosol compositions that can be administered directly into the lungs.
  • compositions of the present disclosure are administered and the following tissue deposition fraction observed: pharynx 30%, bronchial tree 30%, and alveoli 25%.
  • tissue deposition fraction observed: pharynx 30%, bronchial tree 30%, and alveoli 25%.
  • the hybrid antiviral metal-associated amyloid fibrils of the present disclosure may be incorporated into intravenous pharmaceutical compositions. Many factors such as size, shape, concentration, type of coating and form of administration may effect the iron nanoparticles' toxicity.
  • Inorganic nanoparticles in the bloodstream, and particularly iron oxide nanoparticles typically undergo a protein corona adsorption from plasma proteins. This general proteincorona formation is referred to as opsonization, which is the molecular mechanism whereby pathogenic molecules, microbes, or apoptotic cells (antigenic substances) are connected to antibodies, complements, or other proteins to attach to the cell surface receptors on phagocytes and NK cells.
  • the process is followed by recognition and uptake by macrophages of various organs, the last steps prior to elimination from the bloodstream. Size and charges of the nanoparticles are strongly influencing the residing time as well as the evacuation process. Large nanoparticles (>100 nm) accumulate in the liver and spleen, whereas nanoparticles smaller than 10 nm tend to be eliminated through the kidney. The charge of the nanoparticles is the other main factor. In general, positively charged particles tend to be easily taken up by macrophages and transported to the liver, whereas nanoparticles with negative charge feature low macrophage clearance.
  • the iron nanoparticles of the present disclosure with a size of from about or exactly 3 nm to about or exactly 100 nm are well tolerated and include a very favorable margin for safety between a diagnostic and any lethal dose amount when used.
  • the diagnostic dose depending on the specific application, is typically between about or exactly Spmol and about or exactly 800pmol (iron) per kilogram of body weight.
  • the approximate lethal dose is between 2mmol and 50mmol/kg body weight (in mice).
  • the carrier fluid is typically a saline solution of sodium chloride at about 0.9% concentration, which is close to the concentration in the blood (isotonic).

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Abstract

L'invention concerne une composition pharmaceutique pour la prévention ou le traitement d'une infection virale chez un mammifère qui comprend des fibrilles amyloïdes associées à un métal antiviral hybride ayant des nanoparticules métalliques sur une surface des fibrilles amyloïdes. La composition pharmaceutique est une composition pharmaceutique intraveineuse ou une composition d'inhalation et n'est pas administrée par voie buccale ou administrée par voie entérique.
PCT/IB2021/057499 2020-08-14 2021-08-13 Compositions anti-virales d'inhalation orale et intraveineuse et procédés associés WO2022034557A1 (fr)

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