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WO2023037254A1 - Methods and compounds for treating coronaviridae virus infections - Google Patents

Methods and compounds for treating coronaviridae virus infections Download PDF

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Publication number
WO2023037254A1
WO2023037254A1 PCT/IB2022/058395 IB2022058395W WO2023037254A1 WO 2023037254 A1 WO2023037254 A1 WO 2023037254A1 IB 2022058395 W IB2022058395 W IB 2022058395W WO 2023037254 A1 WO2023037254 A1 WO 2023037254A1
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mixtures
polysaccharides
acid
peg
avermectin
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WO2023037254A4 (en
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Kirill DIDENKO
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the invention relates generally to methods and compounds for treating Coronaviridae virus infections, particularly methods and compounds based on avermectins for treating SARS-CoV-2 virus.
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic.
  • COVID-19 coronavirus disease 2019
  • the World Health Organization declared the outbreak a Public Health Emergency of International Concern on 30 January 2020, and a pandemic on 11 March 2020.
  • SARS-CoV-2 is a positive-sense single-stranded RNA virus that is contagious in humans
  • Ivermectin is a medication used to treat parasite infestations.
  • ivermectin could inhibit the replication of severe acute respiratory syndrome coronavirus 2 with EC 50 2.4 pM and EC 90 5 pM.
  • the degree of inhibition of virus replication by ivermectin depends directly on the concentration of ivermectin in the body cells. Once the threshold concentration of ivermectin in the cells is reached, each subsequent increase in the concentration of ivermectin in the tissues of the body increases the inhibition.
  • body tissues have a higher concentration of ivermectin than plasma.
  • the plasma-to-lung ratio is approximately 2.67 for cattle, and 3.0 for human. Since the lungs are often affected by the infection, this ratio is favorable.
  • the technical problem is to provide a method for treating an Coronaviridae infection in a human in need thereof comprising administering a therapeutically effective amount of a avermectin-based bioavailable highly permeable compound.
  • a method for treating an Coronaviridae infection in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula I, that is a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof, where the compound of Formula I is obtained by co-treating avermectin with a host substance, wherein the avermectin is selected from: ivermectin (a mixture of avermectins), avermectin Ala, avermectin Alb, avermectin A2a, avermectin A2b, avermectin B 1 a, avermectin Bib, avermectin B2a, avermectin B2b or racemate, enantiomer
  • a medical dosage form of Formula I of enhanced bioavailability and permeability characterised in that it comprises a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof, where the compound of Formula I is obtained by co-treating avermectin with a host substance wherein the avermectin is selected from avermectins, wherein the host substance is selected from: a) polymers and oligomers, predominantly organic polymers and oligomers, even more predominantly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, or mixtures thereof; b) substances that may contain in significant amounts polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysacc
  • a method for preparing a medical dosage form of Formula I of enhanced bioavailability and permeability characterised in that it comprises a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof where the compound of Formula I is obtained by co-treating avermectin with a host substance wherein the avermectin is selected from avermectins, wherein the host substance is selected from: a) polymers and oligomers, predominantly organic polymers and oligomers, even more predominantly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, or mixtures thereof; b) substances that may contain in significant amounts polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sul
  • the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula II) comprising: a) a first pharmaceutical composition comprising a compound of Formula I, and b) a second pharmaceutical composition comprising at least one additional therapeutic agent active against infectious Coronaviridae viruses or agent that increases the antiviral activity of the Formula I component, or decreases the hepatotoxicity of the Formula I component, or increases the stability of the Formula I component.
  • a combination pharmaceutical agent of Formula II
  • a combination pharmaceutical agent comprising: a) a first pharmaceutical composition comprising a compound of Formula I
  • a second pharmaceutical composition comprising at least one additional therapeutic agent active against infectious Coronaviridae viruses or agent that increases the antiviral activity of the Formula I component, or decreases the hepatotoxicity of the Formula I component, or increases the stability of the Formula I component.
  • the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula III) in form of solution/emulsion/suspension of comprising: a) a first pharmaceutical composition comprising a compound of Formula I-II, and b) at least one of the following components:
  • oil phase containing vegetable or/and animal fats
  • the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula IV) in form of food product or beverage, or dietary supplement.
  • the method comprises treating a SARS-CoV-2 virus infection in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I-IV.
  • the method comprises treating a MERS virus infection in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I-IV.
  • the method comprises treating a SARS virus infection in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I-IV.
  • the method of treating a Coronaviridae infection in a human in need thereof comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a Formula I-IV compound in combination with a pharmaceutically acceptable diluent or carrier.
  • the method of treating a Coronaviridae infection in a human in need thereof comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a Formula I-IV compound in combination with at least one additional therapeutic agent.
  • the method comprises administering a therapeutically effective amount of compound of Formula I-IV to a mammal in need thereof.
  • a compound of Formula I-IV to treat a viral infection caused by an Coronaviridae virus.
  • Fig.1 Pharmacokinetic parameters after oral administration of Ivermectin and compound of Formula I.
  • Fig. 2 Blood oxygen saturation levels without treatment and after oral administration of compound of Formula I.
  • treatment means the abolition, relief, inhibition of the progression or prevention of the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the action of treatment as “treating" is defined directly above.
  • terapéuticaally effective amount is the amount of a compound of formula I-IV present in a composition described herein that is necessary to provide the desired level of the drug in the secretions and tissues of the respiratory tract and lungs or, alternatively, in the bloodstream of the subject to be treated to produce the expected physiological response or desired biological effect when such composition is administered in the selected route of administration.
  • the exact amount depends on a variety of factors, such as the specific compound of Formula I-IV, the specific activity of the composition, the delivery device used, the physical characteristics of the composition, its intended use, and patient considerations such as severity of the disease state, patient cooperation, etc., and can be readily determined by a person skilled in the art based on the information provided herein.
  • avermectin means avermectins and their derivatives such as: ivermectin, avermectin Ala, avermectin Alb, avermectin A2a, avermectin A2b, avermectin Bia, avermectin Bib, avermectin B2a, avermectin B2b or racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, hydrate or solvate thereof or a pharmaceutically acceptable salt or ester thereof or prodrug thereof or mixtures thereof.
  • a “prodrug” is defined in the pharmaceutical field as a biologically inactive derivative of a drug that, when introduced into the human body, is transformed into a biologically active parent drug according to some chemical or enzymatic pathway.
  • physiologically acceptable salts examples include salts derived from an appropriate base such as an alkali metal or alkaline earth metal (e g., Na+, K+, Ca+2, Mg+2, Li+), ammonium and NR4+ (where R is defined herein).
  • Physiologically acceptable salts of a nitrogen atom or amino group include (a) acid accession salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; (b) salts formed by organic acids, such as, for example, acetic acidtartaric acid, maleic acid, fumaric acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, iso-leucine, leucine and the like, oxalic acid, salicylic acid, gluconic acid, citric acid, malic acid ascorbic acid, benzoic acid, succinic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, malonic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluen
  • crystalline polymorphism refers to the ability of a crystalline compound to exist in different crystal structures. Crystalline polymorphism can result from differences in crystal packing (packing polymorphism) or from differences in packing between different conformers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism refers to the ability of a compound hydrate or solvate to exist in different crystal structures.
  • Pseudopolymorphs of the present invention may exist because of differences in crystal packing (packing pseudopolymorphism) or because of differences in packing between different conformers of the same molecule (conformational pseudopolymorphism). All such forms are considered to be within the scope of the invention.
  • the compounds of the invention can also exist as amorphous solids.
  • an amorphous solid is a solid in which there is no long-range ordering of atoms in the solid. This definition also applies when the crystal size is two nanometers or less.
  • Additives, including solvents, can be used to create the amorphous forms of the present invention. All such forms are contemplated within the scope of the invention.
  • the active ingredients of the compounds of the invention will be physiologically acceptable. Ingredients that are not physiologically acceptable, however, may also find use, such as in the preparation or purification of a physiologically acceptable compound.
  • compositions presented herein include the compounds of the invention in their non-ionized as well as zwitterionic forms, and combinations with stoichiometric amounts of water, as in hydrates. All such forms are contemplated within the scope of the invention.
  • the compounds of the invention can have chiral centers, such as chiral carbon or phosphorus atoms.
  • the compounds of the invention include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers.
  • the compounds of the invention include enriched or resolved optical isomers on any or all asymmetric chiral atoms.
  • the chiral centers evident from the figures are presented as chiral isomers or racemic mixtures. Racemic and diastereomeric mixtures as well as individual optical isomers isolated or synthesized essentially free from their enantiomeric or diastereomeric partners are within the scope of the invention.
  • Racemic mixtures are divided into their individual, essentially optically pure isomers by well-known methods, such as, for example, separation of diastereomeric salts formed with optically active excipients, such as acids or bases, followed by conversion back to optically active substances.
  • optically active excipients such as acids or bases
  • the desired optical isomer is synthesized by stereospecific reactions starting from the corresponding stereoisomer of the desired starting substance. All such forms are provided within the scope of the invention.
  • the compounds of the invention may in some cases exist as tautomeric isomers. While only one delocalized resonance structure may be depicted, all such forms are considered within the scope of the invention.
  • any formula or structure herein is also intended to represent unlabeled forms and isotopically labeled forms of compounds.
  • Isotopically labeled compounds have the structures represented in the formulas provided herein except that one or more atoms are replaced with an atom of a selected atomic mass or mass number.
  • isotopes that may be included in the compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine such as 2H (deuterium, D), 3H (tritium), SS, 13C, 14C, 1SN, 18F, 31P, 32P, 35S, 36C1 and 1251, but without limitation.
  • isotopically labeled compounds of the present disclosure such as those incorporating radioactive isotopes such as 3H, 13C and 14C. All such forms are provided within the scope of the invention.
  • Such isotopically labeled compounds can be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue distribution analyses of drugs or substrates, or in the radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • the disclosure also includes compounds of formula I in which 1 to n hydrogens attached to the carbon atom are substituted with deuterium, where n is the number of hydrogens in the molecule. These compounds exhibit increased resistance to metabolism and thus are useful for increasing the half-life of any compound of formula I when administered to a mammal, particularly a human.
  • a method for treating an Coronaviridae infection in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula I, that is a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof, where the compound of Formula I is obtained by co-treating avermectin with a host substance: wherein the avermectin is selected from (0.01-90% of the total weight of the Formula I): ivermectin, avermectin Ala, avermectin Alb, avermectin A2a, avermectin A2b, avermectin Bia, avermectin Bib, avermectin B2a, avermectin B2b or racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, hydrate
  • Polymers and oligomers predominantly organic polymers and oligomers, even more predominantly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, which may be (but are not exclusive to):
  • Hemicelluloses which can be arabanes, arabinans, galactans (galactosans), glucans, xylans, mannans, fructans, xyloglucans, arabinogalactans, arabinoxylans, glucomannans, galactomannans, galactoglucomannans, beta-glucans, galactogens, their mixtures, but not excluding other hemicelluloses, and mixtures thereof;
  • Sulfated polysaccharides and oligosaccharides which may be fucoidans, carrageenans or carrageenins, agaropectins, sea cucumber sulfated polysaccharides (SCSP), chondroitin sulfate, keratan sulfate, their mixtures, but not excluding other sulfated polysaccharides and oligosaccharides, and mixtures thereof;
  • polysaccharides and oligosaccharides storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages which may be (but are not exclusive to others): polysaccharides based on glucose, dextrose, galactose, mannose, arabinose, rhamnose, sucrose, maltose, lactose and their uronic acids, which may be methoxylated or acetylated, and their salts (gum, gummi); polyuronic acids and esters; gum, xanthan gum, oat gum, gellan gum, guar gum, carob gum, karaya gum, dammar gum, gummiarabica, tara gum, ghatti gum, british gum, agar, agar-agar, tragakant gum, conjac gum, velan gum, dutan gum; galacturonic acidbased polysacchari
  • a frequent but non-limiting example is dried brown or red algae such as kelp or focus;
  • Syntetic polymers predominantly water-soluble polymers which may be (but are not limited to): polymers and copolymers formed from acrylic acid, methacrylic acid, and/or esters thereof; polymethacrylates, Eudragit and their salts; polyacrylamides; poly(amidoamine)s, poly(propyleneimine)s, polyethylene glycols; polyvinyl alcohol; polyvinylpyrrolidone; acrylic polymers, cellulose acetate phthalate(s), copovidone(s), ethyl oleate, glycerol derivatives, glyceryl triacetate, polyethylene glycol(s) (PEG), PEG derivatives, polymethacrylates, propylene glycol, propylene glycol derivatives, povidone(s), polyvinylpyrrolidone(s) (PVP), polyvinyl acetate phthalate(s) (PVAP), hypromellose acetate succinate(s) (HPMCAS), hydroxypropy
  • Polyols which may be (but are not limited to): ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol, and mixtures thereof;
  • E. Saccharides which may be glucose, dextrose, galactose, mannose, arabinose, rhamnose, sucrose, maltose, lactose, ribose, and mixtures thereof;
  • Surfactants which may be (but are not limited to): anionic surfactants contained anionic functional groups at their head, such as sulfate, sulfonate, phosphate, carboxylates, carboxylate salts; alkyl sulfates; alkyl-ether sulfates; carboxylate-based fluorosurfactants; cationic surfactants; primary, secondary, or tertiary amines; permanently charged quaternary ammonium salts; zwitterionic (amphoteric) surfactants; zwitterionic surfactants which cationic part is based on primary, secondary, or tertiary amines or quaternary ammonium cations; sultaines; betaines; phospholipids;
  • Acids and salts based on these acids which may be (but are not limited to): citric acid, tartaric acid, succinic acid, phosphoric acid, aminoacids, acetate(s), sodium acetate, alginate(s), sodium alginate, glycyrrhizic acid and their salts, and mixtures thereof;
  • Oxides and salts based on these oxides which may be (but are not limited to): silicon dioxide, silicates, titanium dioxide, and mixtures thereof;
  • Copolymers of the polymers listed in paragraph A, C including alternating copolymers, random copolymers, block copolymers, graft copolymers, cross-linked modifications which may be (but are not limited to): methacrylic acid and ethyl acrylate copolymers; methacrylic acid copolymers; vinylpyrrolidone-vinyl acetate copolymers (PVPVA); polyvinylpolypyrrolidone (PVPP); PVA-PEG graft co-polymers; HPMC and PVA-PEG grafted copolymers; grafted polyvinylpyrrolidone-arabinogalactan copolymers; the graft copolymer has a) poly(vinyl acetate) and/or poly (vinyl alcohol) and/or poly(vinyl chloride) and poly(vinyl ester) on b) a polymer chain of polyethylene glycols, polyalkylene glycols,
  • Method 1 (Grinding/Milling With High Energy Stress): avermectin and the “host substance” are milled in a roller, ball, planetary, vibratory, jet, drum, medium-speed, impact-jet, centrifugal countercurrent, rotary, disintegrator, and other types of mills or other grinders.
  • the grinding process may produce particles of a size of mainly 0.01 to 100 microns, which are powders;
  • Grinding should be carried out to such a state that there are changes in the structure and properties of the ground substance so that it has increased bioavailability and permeability and bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion is formed. Grinding should cause structural changes such as defects, shears, increased deformation, associates. Grinding should occur under conditions of high energy stress, energy input. In the grinding process mechanoactivation must/may occur;
  • a solvent may be added to the grinding process, such as organic and inorganic solvents which may be (but are not limited to): water, hydrocarbons and their halogen derivatives, alcohols, esters and ethers, ketones, nitro compounds: 1,1,1 -tri chloroethane, 1,1,2- tri chloroethene, 1,1-dichloroethene, 1,2-dichloroethane, 1,2-di chloroethene, 1,2- dimethoxyethane, 1,2-propanedioi, 1,4-dioxane, 1 -butanol, 1 -pentanol, 1 -propanol, 2- butanol, 2-butanone, 2-ethoxy ethanol, 2-methoxy ethanol, 2-methyl-l -propanol, 2- methylpyridine, 2-methyl tetrahydrofuran, 2-nitropropane, 2-propanol, 3 -methyl- 1- butanol, 4-methyl-2-pentan
  • Method 2 rinding/Milling With High Energy Stress and Solvent: Avermectin and the “host substance” are wetted with a solvent, the wetted mass is dried and then ground in the same manner as described in Method 1.
  • the list of solvents used is the same as the solvents listed in Method 1;
  • Method 3 Media Milling: The “base component” is prepared by using high-shear media mills. The milling chamber charged with milling media, solvent, avermectin, and “host substance” is rotated at a very high-shear rate under controlled temperatures.
  • the milling medium is composed of glass, zirconium oxide, highly cross-linked polystyrene resin or other standart milling medium. High energy shear forces are generated as a result of the impaction of the milling media with the avermectin in the breaking of microparticulate avermectin into nanosized particles.
  • the list of solvents used is the same as the solvents listed in Method 1;
  • Method 4 (Kneading Method): This method is based on impregnating the “host substance” with a little amount of water or hydroalcoholic solutions to convert it into a paste. The avermectin is then added to the above paste and kneaded for a specified time. The kneaded mixture is then dried and passed through a sieve if required. On a laboratory scale, kneading can be achieved by using a mortar and pestle. On large scale, kneading can be done by utilizing extruders and other machines;
  • Method 5 Hot-Melt Method, Melting Method, Fusion Method: In this method, the physical mixture of avermectin and a “host substance” are heated directly until the two melt. The melted mixture is then cooled and solidified rapidly with rigorous stirring. The final solid mass is then crushed, pulverized, and sieved.
  • the melting method consists of melting the avermectin within the “host substance” followed by cooling and pulverization of the obtained product.
  • a common adaptation to the melting phase consists of suspending the avermectin in a previously melted “host substance”, instead of using both avermectin and “host substance” in the melted state, reducing, therefore, the process temperature.
  • Hot-Melt Extrusion is a modification of the Melting Method. Hot-melt extrusion is essentially the same as the melting method except that intense mixing of the components is induced by the extruder.
  • Hot-stage extrusion consists of the extrusion, at high rotational speed, of the avermectin and “host substance”, previously mixed, at melting temperature for a small period of time. The resulting product is then collected after cooling at room temperature and milled. A reduction in processing temperature can be achieved by the association of hot- stage extrusion with the use of carbon dioxide as a plasticizer;
  • Meltrex is a modification of the Melting Method.
  • Meltrex is a patented solid dispersion manufacturing process, also based on the melting process.
  • the crucial elements in the Meltrex technology are the use of a special twin screw extruder and the presence of two independent hoppers in which the temperature can vary over a broad temperature range;
  • Melt agglomeration is a modification of the Melting Method. Melt agglomeration allows the preparation of solid dispersions in conventional high shear mixers. It is made by adding the molten “host substance” containing the avermectin to the heated excipients, by adding the molten “host substance” to a heated mixture of avermectin and excipients, or by heating a mixture of the avermectin, “host substance” and excipients to a temperature within or above the melting range of the “host substance”. It is also possible to produce stable solid dispersions by melt agglomeration in a rotary processor;
  • Method 9 High-Pressure Homogenization: In this method, the suspension of an avermectin and “host substance” is forced under pressure through a nanosized aperture valve of a high-pressure homogenizer;
  • Method 10 Solvent Evaporation Method: In this method dissolved both the avermectin and the “host substance” in a common solvent and then evaporate the solvent to produce a solid solution.
  • a basic process of preparing solid dispersions of this type consists of dissolving the avermectin and the polymeric “host substance” in a common solvent or solvents mixture (the list of solvents used is the same as the solvents listed in Method 1). Normally, the resulting films are pulverized and milled. The use of the “host substances” partially suspended, instead of dissolved, was also can be used. Solvent evaporation procedure usually include vacuum drying, heating of the mixture on a hot plate, slow evaporation of the solvent at low temperature, the use of a rotary evaporator, a stream of nitrogen, or other drying procedure;
  • Spin-coated films Method is a modification of the Solvent Evaporation Method, which consists of dissolving avermectin and “host substance” in a common solvent that is dropped onto a clean substrate highly spinned. The solvent is evaporated during spinning;
  • Spray-drying is a modification of the Solvent Evaporation Method. It consists of dissolving or suspending the avermectin and “host substance”, then spraying it into a stream of heated airflow to remove the solvent;
  • Supercritical Fluid Process is a modification of the Solvent Evaporation Method. In this method, the avermectin particles are solubilized within the SCF (usually carbon dioxide).
  • SCF processing can be used to address individual aspects, such as precipitation with a compressed antisolvent process (PCA), solution enhanced dispersion by SCF (SEDS), supercritical antisolvent processes (SAS), the rapid expansion of supercritical solutions (RESS), gas anti-solvent recrystallization (GAS), and aerosol supercritical extraction system (ASES).
  • PCA compressed antisolvent process
  • SEDS solution enhanced dispersion by SCF
  • SAS supercritical antisolvent processes
  • RES rapid expansion of supercritical solutions
  • GAS gas anti-solvent recrystallization
  • ASES aerosol supercritical extraction system
  • the technique consists of dissolving the avermectin and the “host substance” in a common solvent that is introduced into a particle formation vessel through a nozzle, simultaneously with CO2.
  • the solvent is rapidly extracted by the SCF, resulting in the precipitation of solid dispersion particles on the walls and bottom of the vessel;
  • Method 14 Cryogenic Techniques are methods in which a solution of avermectin and “host substance” in a common solvent is frozen before a low- temperature solvent evaporation procedure.
  • the common solvent can be the same as in the Solvent Evaporation Method. Freezing of the solution can occur after injection.
  • the type of injection device can be a capillary, rotary, pneumatic, ultrasonic nozzle, or other types of the injection device. The location of the nozzle can be above or under the cryogenic liquid level.
  • the composition of cryogenic liquid can be hydrofluoroalkanes, fluorocarbons, N2, Ar, 02, organic solvents, or other types of cryogenic liquid.
  • dry powder can be obtained by various drying processes like spray freeze drying, atmospheric freeze drying, vacuum freeze drying, lyophilization, or other low-temperature drying processes.
  • the list of common solvents used is the same as the solvents listed in Method 1;
  • Lyophilization Method is a modification of the Cryogenic Techniques.
  • the common solvent from the solution is eliminated through a primary freezing and subsequent drying of the solution containing both avermectin and “host substance” at reduced pressure.
  • the basic freeze-drying process consists of dissolving the avermectin and “host substance” in a common solvent, which is immersed in cryogenic liquid until it is fully frozen. Then, the frozen solution is further lyophilized;
  • Method 16 (Spray Freezing onto Cryogenic Fluids): This Method is a modification of the Cryogenic Techniques. In this technique, the avermectin and the “host substance” were dissolved in a common solvent and atomized above the surface of a boiling agitated cryogenic liquid refrigerant;
  • Method 17 Spray Freezing into Cryogenic Liquids (SFL): This Method is a modification of the Cryogenic Techniques. It incorporates direct liquid-liquid impingement (by spraying) between the solution and cryogenic liquid to provide intense atomization into microdroplets. The frozen particles are then lyophilized to obtain dry and free-flowing micronized powders.
  • Method 18 (Spray Freezing into Vapor over Liquid (SFV/L): This Method is a modification of the Cryogenic Techniques. Freezing of avermectin solutions in cryogenic fluid vapors and subsequent removal of frozen solvent. During SFV/L the atomized droplets typically start to freeze in the vapor phase before they contact the cryogenic liquid. As the solvent freezes, the avermectin becomes supersaturated in the unfrozen regions of the atomized droplet.
  • Method 19 (Ultra-Rapid Freezing): This Method is a modification of the Cryogenic Techniques. Application of avermectin solution to the solid surface of the cryogenic substrate leads to instantaneous freezing and subsequent lyophilization.
  • Method 20 (Precipitation Technique, Co-precipitation Method): In the precipitation method the avermectin is dissolved in a solvent, which is then added to Non-solvent to precipitate the crystals. Non-solvent is added dropwise to the avermectin and “host substance” solution, under constant stirring. In the course of the non-solvent addition, the avermectin and “host substance” are co-precipitated to form micro-particles. In the end, the resulted micro-particle suspension is filtered and dried. The list of solvents used is the same as the solvents listed in Method 1.
  • Method 21 (Microwave Irradiation Method): This method involves the microwave irradiation reaction between avermectin and complexing agent using a microwave oven.
  • the avermectin and “host substance” in a definite molar ratio are dissolved in a mixture of water and/or organic solvent in a specified proportion into a container.
  • the mixture is reacted in the microwave oven.
  • an adequate amount of solvent mixture is added to the above reaction mixture to remove the residual uncomplexed free avermectin and “host substance”.
  • the precipitate so obtained is separated using a filter, and dried.
  • the list of solvents used is the same as the solvents listed in Method 1.
  • Method 22 comprises the step of exposing a host substance and a avermectin to an energy input until a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion is formed of the avermectin as amorphous material entrapped in the host substance.
  • Method 23 (Heat/Shear Energy Input Method): Method comprises the step of exposing a host substance and a avermectin to an energy input, whereby the energy input is heat and/or shear forces, until a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion is formed of the avermectin as amorphous material entrapped in the host substance.
  • Method 24 This method includes any combination of Methods 1-23.
  • Methods 1-24 should lead to the formation bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion.
  • a medical dosage form of Formula I of enhanced bioavailability and permeability characterised in that it comprises a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof, where the compound of Formula I is obtained by co-treating avermectin with a host substance wherein the avermectin is selected from avermectins, wherein the host substance is selected from: a) polymers and oligomers, predominantly organic polymers and oligomers, even more predominantly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, or mixtures thereof; b) substances that may contain in significant amounts polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysacc
  • a method for preparing a medical dosage form of Formula I of enhanced bioavailability and permeability characterised in that it comprises a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof where the compound of Formula I is obtained by co-treating avermectin with a host substance wherein the avermectin is selected from avermectins, wherein the host substance is selected from: a) polymers and oligomers, predominantly organic polymers and oligomers, even more predominantly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, or mixtures thereof; b) substances that may contain in significant amounts polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sul
  • Formula I also includes aqueous solutions or suspensions of Formula I as they are naturally formed in the stomach and intestines of a human or mammal when taken orally at the expense of the water naturally contained in the stomach and intestines as well as the water with which Formula I is ingested. Also solutions or suspensions of Formula I may be obtained by prestirring Formula I in a container with a liquid containing water.
  • the method comprises treating a SARS-CoV-2 virus infection in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I.
  • the method comprises treating a SARS-CoV-2 virus infection in caused by a SARS-CoV-2 virus caused by a strain selected from SARS-CoV-2 strains virus infection in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I.
  • the method comprises treating a MERS virus infection in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I.
  • the method comprises treating a SARS virus infection in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I.
  • the method comprises treating a alpha coronaviruses 229E (HCoV-229E), NL63 (HCoV-NL63, New Haven coronavirus), beta coronaviruses OC43 (HCoV-OC43), HKU1 virus infections in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I.
  • HCV-229E alpha coronaviruses 229E
  • NL63 HoV-NL63, New Haven coronavirus
  • beta coronaviruses OC43 HCoV-OC43
  • HKU1 virus infections in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I.
  • the method comprises administering a therapeutically effective amount of compound of Formula I to a mammal in need thereof.
  • compositions of the invention are also used in combination with other active ingredients.
  • another active therapeutic agent is active against infections caused by Coronaviridae family viruses, in particular infections caused by SARS-CoV-2.
  • Non-limiting examples of such other active therapeutic agents are niclosamide, remdesivir, nitazoxanide, chloroquine, lopinavir, ritonavir, hydroxychloroquine and mixtures thereof.
  • the compounds and compositions of the present invention are also intended for use in the general care of patients with Coronaviridae viral infections, including nutrition, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and/or antifungal prophylaxis, antipyretics and analgesics, antiemetics (such as metoclopramide) and/or anti-diarrheals vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatories (such as ibuprofen), pain medications, and medications for other common conditions in the patient population, such as antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin) or shigellosis.
  • any compound of the invention with one or more additional active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient.
  • the combination therapy may be administered as simultaneous or sequential administration.
  • sequential administration the combination may be administered in two or more injections.
  • Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are simultaneously present in the patient.
  • Co-administration comprises administering single doses of the compounds of the invention before or after administering single doses of one or more other active therapeutic agents, for example, administering the compounds of the invention within seconds, minutes or hours after administering one or more other active therapeutic agents.
  • a single dose of the compound of the invention may be administered first, followed by a single dose of one or more other active therapeutic agents within seconds or minutes.
  • a single dose of one or more other therapeutic agents may be administered first, followed by a single dose of the compound of the invention within seconds or minutes.
  • Combination therapy can provide "synergism” and "synergy", i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects occurring when the compounds are used separately.
  • Synergistic effects can be achieved when the active ingredients are (1) combined and administered or delivered simultaneously in a combination drug; (2) delivered alternately or in parallel as separate drugs; or (3) by some other scheme.
  • drugs are alternated, a synergistic effect may be achieved when the compounds are administered or delivered sequentially, for example, in separate tablets, pills, or capsules, or when different injections are given in separate syringes.
  • each active ingredient is administered sequentially, that is, serially, whereas in combination therapy the effective doses of two or more active ingredients are administered together.
  • Synergistic antiviral effect means an antiviral effect that exceeds the predicted purely additive effect of the individual compounds of the combination.
  • kits comprising a compound selected from the group of each of the formulas provided herein and each subgroup and embodiments thereof, including Formula II, Formula II, Formula IV.
  • the kit includes a compound of Formula I.
  • Each of the individual kits described herein may include a label and/or instructions for administering the compound to treat a disease or condition in a subject (e.g., human) in need thereof.
  • the disease or condition is a human viral infection of the Coronaviridae family, including SARS-CoV-2 viral infection.
  • each individual kit may also contain instructions for administering additional medical agents in combination with a compound of Formula I to treat a disease or condition in a subject (e g., human) in need thereof.
  • the disease or condition is a human viral infection of the Coronaviridae family, including SARS-CoV-2 viral infection.
  • the kit includes individual dosage units of the compound described herein. Examples of individual doses may include tablets, tablets, capsules, filled syringes or syringe cartridges, IV bags, etc., each containing a therapeutically effective amount of the compound in question.
  • the kit may contain a single dosage unit, and in other embodiments, the kit may contain multiple dosage units, such as the number of dosage units required for a particular regimen or period.
  • the product container may be a vial, jar, ampule, preloaded syringe, blister pack, tin, can, bottle, box, or intravenous bag.
  • certain embodiments of the invention provide for the use of a compound selected from each of claims I-IV herein in the preparation of a medicament for use in the treatment of Coronaviridae infection in humans.
  • the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula II) comprising: a) a first pharmaceutical composition comprising a compound of Formula I (is 0.01-99.99% of the total weight of the Formula II), and b) a second pharmaceutical composition comprising at least one additional therapeutic agent active against infectious Coronaviridae viruses or agent that increases the antiviral activity of the Formula I component, or decreases the hepatotoxicity of the Formula I component, or increases the stability of the Formula I component (0.01-99.99% of the total weight of the composition) which may be (but are not limited to): ivermectin, niclosamide, remdesivir, nitazoxanide, chloroquine, lopinavir, ritonavir, hydroxychloroquine, vegetable or animal fats, ethyl alcohol, water, glycerin, propylene glycol, triethylene glycol, dimethylsulfoxide, solvents, betaine
  • juss regdanvimab, ruxolitinib, saline, selamectin, silmitasertib, suramin, tannic acid, tenofovir disoproxil, valproic acid, amentoflavone, pristimerin, ribavirin, indinavir, saquinavir, cryptospirolepine, rhoifolin, pectolinarin, tamoxifen, 6-gingerol, theaflavin, oleuropein, etoposide, genistein, ibuprofen, paclitaxel, sertraline, tacrolimus, puerarin, limonin, obacunone, amprenavir, velpatasvir, ursolic acid, daidzein, sesamin, astragalin, gilteritinib, baicalein, caffeic acid, amitriptyline, apalutamide,
  • the method of treating a Coronaviridae infection in a human in need thereof comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a Formula I compound in combination with at least one additional therapeutic agent.
  • a method of treating Coronaviridae infection in a person in need thereof includes administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of compound of formula VII in combination with at least one additional therapeutic agent such as (but not limited to) intravenous or intramuscular forms of thiamine, vitamin C, vitamin D, glutanione, S-adenosylmethionine, cysteine, N- acetylcysteine.
  • additional therapeutic agent such as (but not limited to) intravenous or intramuscular forms of thiamine, vitamin C, vitamin D, glutanione, S-adenosylmethionine, cysteine, N- acetylcysteine.
  • the compounds of the present invention are formulated with common carriers and excipients, which are selected according to common practice. Tablets will contain excipients, glydants, fillers, binders, and the like. Aqueous formulations are prepared in sterile form, and if they are not intended to be administered orally, they are usually isotonic. All formulations optionally contain excipients, such as those described in Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethyl cellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is usually between 7 and 10. In some embodiments of the invention, the pH of the formulations varies from about 2 to about 5, but is usually about 3 to 4.
  • compositions of the invention include at least one active ingredient, as defined above, together with one or more acceptable carrier(s) for it and, optionally, other therapeutic ingredients, in particular additional therapeutic ingredients, which are discussed herein.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the composition and physiologically harmless to the recipient.
  • compositions include those suitable for the above-mentioned routes of administration.
  • the compositions may be conveniently presented in unit dose form and may be prepared by any of the methods well known in the pharmaceutical art.
  • the methods and compositions are generally described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa ). Such methods involve the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then shaping the product if necessary,.
  • Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient can be administered as a bolus, electuary or paste.
  • Tablets are made by compression or molding, optionally with one or more additional ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine an active ingredient in a free-flowing form, such as a powder or granules, further mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded tablets can be made by molding in a suitable machine a mixture of a powdered active ingredient moistened with an inert liquid diluent.
  • the tablets may additionally be coated with a shell or pellets and optionally formulated to allow slow or controlled release of the active ingredient therefrom.
  • the compositions are preferably applied in the form of an ointment or cream containing the active ingredient(s) in an amount, for example, from 0.075 to 20% wt. (including the active ingredient(s) in a range of 0.1% to 20% in 0.1% wt. increments, e.g., 0.6% wt., 0.7% wt., etc.), more preferably from 0.2 to 15% wt. and most preferably from 0.5 to 10% wt.
  • the active ingredients may be used with a paraffin or water-miscible ointment base.
  • the active ingredients may be formulated as a cream with an oil-in-water type cream base.
  • the aqueous phase of the cream base may include, if desired, at least 30% wt. of a polyhydric alcohol, that is, an alcohol with two or more hydroxyl groups, such as propylene glycol, butane- 1,3 -diol, mannitol, sorbitol, glycerol, polyethylene glycol (including PEG 400) and mixtures thereof.
  • a polyhydric alcohol that is, an alcohol with two or more hydroxyl groups, such as propylene glycol, butane- 1,3 -diol, mannitol, sorbitol, glycerol, polyethylene glycol (including PEG 400) and mixtures thereof.
  • Compositions for topical use may preferably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • dermal penetration enhancers are dimethyl sulfoxide and related analogues.
  • the oil phase of emulsions of the present invention can be composed of known ingredients in a known manner.
  • the phase may comprise an emulsifier alone (otherwise referred to as emulsifier), preferably it comprises a mixture of at least one emulsifier with a fat or oil or with a fat and oil.
  • the hydrophilic emulsifier is preferably included together with a lipophilic emulsifier, acting as a stabilizer. Also preferably both oil and fat are included.
  • Emulsifier(s) with or without stabilizer(s) together constitute the so-called emulsifying wax, and the wax together with oil and fat constitute the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream compositions.
  • Emulsifiers and emulsion stabilizers appropriate for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • Other emulsifiers and emulsion stabilizers appropriate for use in the formulation of the invention include Tween® 80.
  • the choice of suitable oils or fats for the formulation is determined by achieving the desired cosmetic properties.
  • the cream may be a non-greasy, non-staining and washable product with a suitable consistency to avoid leakage from tubes or other containers.
  • compositions include a combination together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • the pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended route of administration.
  • the compositions may be prepared, for example, tablets, trochets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.
  • Formulations intended for oral use may be made according to any method known in the art for making pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavorings, colorings, and preservative agents, to provide a palatable preparation.
  • Tablets containing the active ingredient in a mixture with a nontoxic pharmaceutically acceptable excipient that is suitable for tablet production are acceptable.
  • excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as com starch or alginic acid; binding agents such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated using known methods, including microencapsulation, to delay breakdown and adsorption in the gastrointestinal tract and thereby provide sustained action over an extended period.
  • a time delayed material such as glyceryl monostearate or glyceryl dystearate alone or with a wax, for example, may be used.
  • Products for oral use can also be designed as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, such as calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent such as calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions according to the invention contain active materials mixed with excipients suitable for making aqueous suspensions.
  • excipients may include a suspending agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum, and dispersing or wetting agents such as naturally occurring phosphatide (such as lecithin), an alkylene oxide condensation product with a fatty acid (e.g., polyoxyethylene stearate), an ethylene oxide condensation product with a long-chain aliphatic alcohol (e.g., hepta dekaethylene acetanol), an ethylene oxide condensation product with a partial ester derived from a fatty acid and hexitol anhydride (e.g., polyoxyethylene sorbitan monoleate).
  • a suspending agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium al
  • the aqueous suspension can also contain one or more preservatives such as ethyl- or n-propyl p-hydroxy- benzoate, one or more colorants, one or more flavorings, and one or more sweeteners such as sucrose or saccharin.
  • preservatives such as ethyl- or n-propyl p-hydroxy- benzoate
  • colorants such as ethyl- or n-propyl p-hydroxy- benzoate
  • sweeteners such as sucrose or saccharin.
  • Other non-limiting examples of suspending agents include Cyclodextrin and Captisol.
  • Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • a thickening agent such as beeswax, solid paraffin or cetyl alcohol may be contained in the oral suspension.
  • Sweeteners, such as those described above, and flavorings may be added to produce a palatable oral preparation. These compositions may be preserved by adding an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the invention applicable for preparing an aqueous suspension by adding water, include the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are examples of those disclosed above. Additional excipients, such as sweetening, loosening and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention can also be presented as oil-in- water emulsions.
  • the oil phase can be a vegetable oil such as olive or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof.
  • emulsifiers include gum of natural origin such as acacia gum and tragacanth gum, phosphatides of natural origin such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsion can also contain sweeteners and flavorings. Syrups and elixirs may contain sweetening agents such as glycerin, sorbitol, or sucrose. These formulations can also contain a demulgent, preservative, flavoring, or coloring agent.
  • the pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oily suspension.
  • This suspension may be prepared according to the prior art using suitable dispersing or wetting agents and suspending agents as mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 -butanediol or prepared as a lyophilized powder.
  • Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile fixed oils are usually used as a solvent or suspension medium.
  • Any tasteless fixed oil can be used for this purpose, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid, can also be used to prepare injectable preparations.
  • acceptable vehicles and solvents that can be used are water, isotonic Ringer's solution, isotonic sodium chloride solution and hypertonic sodium chloride solution.
  • a time-release formulation intended for oral administration to humans may contain from about 1 to 1000 mg of the active ingredient combined with an appropriate and convenient amount of carrier material, which may be from about 5 to about 95% of the total amount of the composition (weight weight).
  • the pharmaceutical composition may be prepared so as to provide an easily measurable amount for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to about 500 pg of active ingredient per milliliter of solution to provide an infusion of a suitable volume at a rate of about 30 ml/hr.
  • Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially in an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such compositions in a concentration of from 0.5 to 20%, more preferably from 0.5 to 10% and especially about 1.5% w/w.
  • Formulations suitable for topical use in the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; lozenges containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be in the form of a suppository with a suitable base including, for example, cocoa butter or salicylate.
  • Formulations suitable for intrapulmonary or nasal administration have particle sizes, for example, in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35, etc., which are administered by rapid inhalation through the nasal passage or inhalation through the mouth to reach the alveolar sacs.
  • Suitable compositions include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for administration as an aerosol or dry powder may be prepared according to conventional methods and may be delivered together with other therapeutic agents, such as compounds previously used to treat or prevent Coronaviridae infections, as described below.
  • Formulations suitable for vaginal administration may be in the form of pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be suitable.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous sterile solutions for injection, which may contain antioxidants, buffers, bacteriostatics and solvents that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending and thickening agents.
  • the formulations are presented in single or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use.
  • a sterile liquid carrier such as water for injection
  • Extemporaneous injectable solutions and suspensions are made from sterile powders, pellets, and tablets described earlier.
  • Preferred single-dose preparations are preparations containing a daily dose or a single daily subdose, as described above, or an appropriate fraction of the active ingredient.
  • compositions of the present invention may include other agents common in the art, taking into account the type of composition in question, for example, compositions suitable for oral use can include flavorings.
  • the invention also provides veterinary compositions comprising at least one active ingredient, as defined above, together with a veterinary carrier for it.
  • Veterinary carriers are materials useful for administering the composition and may be solids, liquids, or gases that are inert or acceptable in veterinary medicine and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.
  • controlled-release compositions containing as an active ingredient one or more compounds of the invention
  • the release of the active ingredient is controlled and regulated to provide less frequent dosing or to improve the pharmacokinetic or toxicity profile of that active ingredient.
  • the method of treating a Coronaviridae infection in a human in need thereof comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a Formula I/II compound in combination with a pharmaceutically acceptable diluent or carrier.
  • the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula III) in form of solution/emulsion/suspension of comprising: a) a first pharmaceutical composition comprising a compound of Formula VII, and b) at least one of the following components:
  • oil phase containing vegetable or/and animal fats
  • Formula III can be a true solution or colloidal solution, emulsion, solid or liquid dispersion, suspension, emulsion-suspension form, gas cocktail, foam, sol, gel, paste, their mixture.
  • a Formula III can be prepared by mixing, homogenizing, dispersing, and emulsifying the constituent components.
  • the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula III variant A) comprising:
  • one or more gelling agents (0-99.9% by weight) include (but are not limited to): alginate, pectin, carrageenan, gellan, gelatin, agar, modified starch, methyl cellulose, and hydroxypropylmethylcellulose.
  • the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula III variant B) comprising:
  • one or more gelling agents (0-99.9% by weight) include (but are not limited to): alginate, pectin, carrageenan, gellan, gelatin, agar, modified starch, methyl cellulose, and hydroxypropylmethylcellulose.
  • the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula III variant C) comprising:
  • one or more gelling agents (0-99.9% by weight) include (but are not limited to): alginate, pectin, carrageenan, gellan, gelatin, agar, modified starch, methyl cellulose , and hydroxypropylmethylcellulose.
  • the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula III variant D) comprising:
  • one or more gelling agents (0-99.9% by weight) include (but are not limited to): alginate, pectin, carrageenan, gellan, gelatin, agar, modified starch, methyl cellulose, and hydroxypropylmethylcellulose.
  • the active compounds of Formula I-III can be administered/can be in form of foods, food additives, edible soluble films, drinks, medicinal agents, and feeds for domestic and wild animals.
  • the drinks may be non-alcohol drinks or alcohol drinks.
  • non-alcohol drinks include carbonated drinks, noncarbonated drinks (such as fruit juice, and nectar), soft drinks, sports drinks, tea, coffee, and hot chocolate.
  • the alcohol drinks may be in the form of, for example, beer, low-malt beer, third-category beer, sake, wine, champagne, liqueur, or medicated liquor.
  • the active compound may be in the form of, for example, a tablet, a capsule formulation, a solid agent (such as a powder and a granule) dissolved in drinks, a semi-solid such as jelly, a liquid (such as drinking water), and a high- concentration solution diluted before use.
  • a solid agent such as a powder and a granule
  • a semi-solid such as jelly
  • a liquid such as drinking water
  • a high- concentration solution diluted before use a high- concentration solution diluted before use.
  • Optional components such as vitamins, carbohydrates, dyes, and flavoring agents commonly added to food may be appropriately mixed.
  • the food may be given in any form, including a liquid and a solid.
  • the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula IV) in form of food product or beverage, or dietary supplement.
  • a combination pharmaceutical agent of Formula IV
  • the compounds of Formula I-IV described herein may be administered (e.g., orally) in the form of a solid or liquid dosage form.
  • the compounds may be coated in a material to protect them from the action of acids and other natural conditions which may inactivate the compounds.
  • the compounds may be formulated as aqueous solutions, liquid dispersions, (ingestible) tablets, buccal tablets, troches, capsules, elixirs, powders, granules, ointments, adhesive skin patches, sprays, suspensions, syrups, and wafers.
  • the dosage forms may include pharmaceutically acceptable excipients, diluents, and/or carriers known in the art, such as binders, disintegrating agents, emulsifiers, lubricants, flavorants, antioxidants, and preservatives.
  • Liquid dosage forms may include diluents such as saline or an aqueous buffer.
  • any route of administration Formula I-IV may be selected for use in the methods described herein.
  • the route of administration may be selected from oral, nasal, topical, buccal, rectal, vaginal, ophthalmic, subcutaneous, intramuscular, intraperitoneal, epidural, intravenous, intraarterial, intratumoral, spinal, intrathecal, intra-articular, intra-arterial , sub -arachnoid, sublingual, oral mucosal, pulmonary, bronchial, lymphatic, intra-uterine, subcutaneous, intratumor, integrated on an implantable device, intradural, intracortical, intradermal, dermal, epidermal, transdermal, vaginal, rectal, ocular (for examples through the conjunctiva), intraocular, uretal, and parenteral.
  • compounds of the present invention may be administered at any time to a person who may be in contact with people suffering from Coronaviridae infection or already suffering from Coronaviridae infection.
  • the compounds of the present invention can be administered prophylactically to people in contact with people suffering from Coronaviridae infection.
  • the compounds of the present invention can be administered to people who test positive for Coronaviridae infection but do not yet have symptoms of Coronaviridae infection.
  • the compounds of the present invention can be administered to people after symptoms of Coronaviridae infection appear.
  • the effective dose of the active ingredient depends at least on the nature of the disease being treated, the toxicity, whether the compound is used prophylactically (lower doses) or against an active viral infection, the method of delivery and the pharmaceutical formulation, and is determined by the physician using routine dose escalation studies. It can be expected to range from about 0.0001 to about 100 mg/kg body weight per day; typically from about 0.01 to about 10 mg/kg body weight per day; more typically from about 0.01 to about 5 mg/kg body weight per day; most typically from about 0.2 to about 1 mg/kg body weight per day.
  • a daily candidate dose for an adult with a body weight of about 70 kg would be from about 1 mg to 1000 mg, preferably from 5 mg to 500 mg, and may take the form of a single or multiple dose. All dosages are given for an equivalent amount of pure avermectin.
  • the effective dose of the compound of the present invention for treating Coronaviridae infection may depend on whether it is used prophylactically or to treat a person already suffering from Coronaviridae infection. Moreover, the dose may depend on whether the person suffering from Coronaviridae infection is not yet showing symptoms or is already showing symptoms of Coronaviridae infection. People who test positive for Coronaviridae infection and people with symptoms of Coronaviridae infection may require higher doses for treatment compared to people receiving preventive treatment
  • any suitable time period for administration of the compounds of the present invention is contemplated.
  • the administration may be from 1 day to 100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80 or 90 days. Admission may also last from 1 week to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 weeks. Longer periods of administration are also suggested.
  • the timing of administration may depend on whether the compound is administered prophylactically or to treat a person suffering from Coronaviridae infection.
  • prophylactic administration may be for a period of time while the person is in constant contact with other people suffering from Coronaviridae infection and for a suitable period of time after the last contact with the person suffering from Coronaviridae infection.
  • the period of use may be any length of time necessary to treat the patient and a suitable period of time after a negative test for Coronaviridae infection to ensure that Coronaviridae infection will not return.
  • Ivermectin of pharmaceutical grade CAS Number 70288-86-7, was purchased from Aecochem Corp., Xiamen, China. Apple pectin was purchased from Ronas Chemicals Ind. Co., Ltd., Chengdu, China. All other chemicals were of analytical grade and used without further purification.
  • Method 1 was used to obtain compounds of Formula 1.
  • the roller ball mill was used to carry out mechanochemical synthesis of nanocomposite/solid dispersions. Processing mode: rotational speed of the drive - 400 rpm, rotational speed of the grinding jar -100 rpm, grinding jar volume - 2000 ml, grinding media - steel balls (diameter 12 mm, 800 g/load), processing time ranging from 2 to 24 h. Samples are loose powders (particle size from 0.1 - 10 microns). Compositions and results of obtaining bioavailable nanocomposites with Formula I are shown in Table 1.
  • Method 10 was used to obtain compounds of Formula 1.
  • Acetone or ethyl alcohol (rectified 96%) was used as organic solvents: 40-70 parts of the solvent per 100 parts of the polymer and avermectin mixture taken in gram-equivalent quantities.
  • the named solvents dissolve the polymer host. After thoroughly stirring in a mortar the polymer with avermectin moistened with solvent, a dough-like mass is formed, which is dried with evaporation of the solvent. Ball mills or other grinders can be used for grinding the dried polymer mass, and the particle size of the polymer product should not exceed 5-9 microns.
  • Compositions and results of obtaining bioavailable nanocomposites with Formula I are shown in Table 2.
  • Method 6 was used to obtain compounds of Formula 1.
  • Ivermectin and PVA- polypropylene glycol graft co-polymers were used to create a solid dispersion.
  • Hot stage extrusion was performed with a co-rotating, fully intermeshing conical mini twin screw extruder. The temperature was set at 195° C, the screw rate varied from 90 to 105 rpm. A load of 7.5 g per run was fed manually; after feeding the internal circulation time was 5 min. The extrudates were collected after cooling at ambient temperature on a conveyer belt. Extruded samples were subsequently milled for 4 min with a laboratory mill and sieved to exclude particles >400 pm.
  • Free ivermectin substance was processed in planetary mill, the parameters were as follows: weight of the material - 5 g, grinding jar volume - 200 mb, grinding media - steel balls (diameter 8 mm, 90.0 g load), processing time - 20 minutes.
  • Compound of Formula I was treated according to Example I N> l .
  • Ivermectin concentrations in blood plasma were analyzed according to the method Na-Bangchang, K., High-performance liquid chromatographic method for the determination of ivermectin in plasma, Southeast Asian J Trop Med Public Health, 2006 Sep, 37(5):848-58, PMID: 17333725.
  • the internal standard (m oxidectin) was separated from ivermectin on a Hypersil Gold C18 column (150 x 4.6 mm, 5 pm particle size), with retention time of 3.7 and 7.0 minutes, respectively. Fluorescence detection was set at an excitation and emission wavelength of 365 and 475 nm, respectively.
  • the mobile phase consisted of acetonitrile, methanol and distilled water (50:45:5, v/v/v), running through the column at a flow rate of 1.5 ml/minute.
  • the chromatographic analysis was operated at 25°C.
  • Sample preparation (100 pl plasma) was done by a single stepprotein precipitation with acetonitrile, followed by derivatization with 100 pl of N-methylimidazole solution in acetonitrile (1:1, v/v) and 150 pl of trifluoroacetic anhydrous solution in acetonitrile (1:2, v/v). Calibration curve over the concentration range of 20-8,000 ng/ml plasma was linearwith correlation coefficient better than 0.995.
  • Another aspect of the invention relates to methods of inhibiting viral infections, comprising the step of treating a sample or subject suspected of needing such inhibition with a composition of the invention.
  • samples suspected of containing a virus include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like.
  • biological material samples blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like
  • laboratory samples food, water, or air samples
  • bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like.
  • samples will be suspected of containing an organism which induces a viral infection, frequently a pathogenic organism such as a tumor virus.
  • Samples can be contained in any medium including water and organic solvent ⁇ water mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures.
  • the anti-virus activity of a compound of the invention after application of the composition can be observed by any method including direct and indirect methods of detecting such activity. Quantitative, qualitative, and semi quantitative methods of determining such activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
  • the antiviral activity of a compound of the invention can be measured using standard screening protocols that are known.
  • the antiviral activity of a compound can be measured using the several general protocols.
  • SARS-CoV-2 viral load from nasopharyngeal swabs was quantified from samples stored at -40°C until use.
  • Viral RNA was isolated using the QIAamp Viral RNA Mini Kit (Qiagen, Hilden, Germany) from stored samples.
  • RT-qPCR Quantitative reverse transcriptase PCR
  • This assay included measurement of the housekeeping gene as an internal control and normalizer.
  • the cycle threshold (Ct) of the housekeeping gene was used to correct the specific SARS-CoV-2 Ct according to the number of cells in the sample. Therefore, viral load measurements were expressed in loglO copies per reaction.
  • Names of compounds of the present disclosure are provided using ACD/Name software for naming chemical compounds (Advanced Chemistry Development, Inc., Toronto, Canada). Other compounds or radicals may be named with common names or systematic or non- systematic names.
  • the compounds of the present invention can be prepared by methods known to one of skill in the art.
  • Buonfrate, D High-dose ivermectin for early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial, International Journal of Antimicrobial Agents, https://doi.Org/10.1016/j.ijantimicag.2021.106516

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Abstract

Provided are methods and compounds for treating Coronaviridae virus infections by administering avermectin-based bioavailable highly permeable nanocomposites or solid dispersions or aqueous solutions, suspensions or emulsions thereof. The compounds, compositions, and methods provided are particularly useful for the treatment of SARS-CoV-2 virus infection.

Description

TITLE OF THE INVENTION: METHODS AND COMPOUNDS FOR TREATING CORONA VIRIDAE VIRUS INFECTIONS
CROSS-REFERENCES TO RELATED APPLICATIONS
This patent application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 63/241,541, filed Sep. 08, 2021. The foregoing applications are incorporated herein by reference in their entireties.
FIELD OF THE INVENTION
[0001] The invention relates generally to methods and compounds for treating Coronaviridae virus infections, particularly methods and compounds based on avermectins for treating SARS-CoV-2 virus.
BACKGROUND OF THE INVENTION
[0002] Human coronaviruses, first identified in the mid-1960s, are common viruses that infect most people at some time in their life, generally causing mild to moderate upper respiratory and gastrointestinal tract illnesses. The novel coronavirus referred to as “Middle East Respiratory Syndrome Coronavirus” (MERS-CoV or MERS) was first reported in Saudi Arabia in 2012 and has spread to several other countries. SARS-CoV, the coronavirus responsible for Severe Acute Respiratory Syndrome (SARS) was first recognized in China in 2002 and led to a worldwide outbreak in 2002 and 2003.
[0003] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. First identified in the city of Wuhan, Hubei, China, the World Health Organization declared the outbreak a Public Health Emergency of International Concern on 30 January 2020, and a pandemic on 11 March 2020. SARS-CoV-2 is a positive-sense single-stranded RNA virus that is contagious in humans
[0004] In December 2021, the number of cases continued to climb due to several factors, including new COVID-19 variants. As of that 28 December, 282,790,822 individuals worldwide had been confirmed as infected. As of 14 April 2022, over 500 million cases were confirmed globally. Most cases are unconfirmed, with the Institute for Health Metrics and Evaluation estimating the true number of cases as of early 2022 to be in the billions. SUMMARY OF THE INVENTION
Technical Problem
[0005] Ivermectin is a medication used to treat parasite infestations. In vitro, ivermectin could inhibit the replication of severe acute respiratory syndrome coronavirus 2 with EC 50 2.4 pM and EC 90 5 pM. The degree of inhibition of virus replication by ivermectin depends directly on the concentration of ivermectin in the body cells. Once the threshold concentration of ivermectin in the cells is reached, each subsequent increase in the concentration of ivermectin in the tissues of the body increases the inhibition. Generally, body tissues have a higher concentration of ivermectin than plasma. As an example, the plasma-to-lung ratio is approximately 2.67 for cattle, and 3.0 for human. Since the lungs are often affected by the infection, this ratio is favorable.
[0006] Even a high dose of the standard tablet form of ivermectin of 600 pg/kg/day during x5 days has been shown to produce a lung Cmax of 0.4-0.9 pM and viral load reduction 14% which is much less than its in vitro EC 50 2.4 pM and EC 90 5 pM. These relatively high doses of the standard tablet form of ivermectin do not provide the concentration of ivermectin in body tissues necessary to effectively inhibit viral replication. All current studies of ivermectin are limited to doses for which the Cmax in the lungs is less than EC 5.
[0007] The technical problem is to provide a method for treating an Coronaviridae infection in a human in need thereof comprising administering a therapeutically effective amount of a avermectin-based bioavailable highly permeable compound.
Solution to Problem
[0008] Provided are methods and compounds for the treatment of infections caused by the Coronaviridae virus family. Provided is a method for treating an Coronaviridae infection in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula I, that is a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof, where the compound of Formula I is obtained by co-treating avermectin with a host substance, wherein the avermectin is selected from: ivermectin (a mixture of avermectins), avermectin Ala, avermectin Alb, avermectin A2a, avermectin A2b, avermectin B 1 a, avermectin Bib, avermectin B2a, avermectin B2b or racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, hydrate or solvate thereof or a pharmaceutically acceptable salt or ester thereof or prodrug thereof or mixtures thereof; wherein the host substance is selected from: a) polymers and oligomers, predominantly organic polymers and oligomers, even more predominantly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, or mixtures thereof; b) substances that may contain in significant amounts polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, which may be (but are not limited to) plants or algae or animal or fungi, parts of plants or algae or animal or fungi, processed plants or algae or animal or fungi, processed parts of plants or algae or animal or fungi containing in significant amounts the substances specified in paragraph a), or mixtures thereof; c) syntetic polymers, predominantly water-soluble polymers or mixtures thereof; d) polyols or mixtures thereof; e) saccharides or mixtures thereof; f) surfactants or mixtures thereof; g) acids or mixtures thereof; h) oxides and salts based on these oxides or mixtures thereof; i) copolymers of the polymers listed in paragraph a) and c) j) methoxylated, ethoxylated, esterificated, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, decarboxylated, amide, oxidized, sulfated, aminoacid derivatives, fermented, thermally modified, chemically modified, acid modified derivatives of the substances specified in a)-i), and their esters, salts, and any other chemical derivatives, and mixtures thereof; k) any combination of substances specified in paragraph a)-j); wherein co-treating method is selected from: a) grinding/milling with high energy stress method; b) grinding/milling with high energy stress and solvent method; c) media milling method; d) kneading method; e) hot-melt method/melting method/fusion method; f) hot-melt extrusion/hot-stage extrusion method; g) meltrex method; h) melt agglomeration method; i) high-pressure homogenization method; j) solvent evaporation method; k) spin-coated films method; l) spray-drying method; m) supercritical fluid (SCF) process method; n) cryogenic techniques method; o) lyophilization/freeze-drying technique method; p) spray freezing onto cryogenic fluids method; q) spray freezing into vryogenic liquids (SFL) method; r) spray freezing into vapor over liquid (SFV/L) method; s) ultra-rapid freezing method; t) precipitation/co-precipitation method; u) microwave irradiation method; v) energy input method; w) heat/ shear energy input method; x) combined method.
[0009] Provided a medical dosage form of Formula I of enhanced bioavailability and permeability characterised in that it comprises a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof, where the compound of Formula I is obtained by co-treating avermectin with a host substance wherein the avermectin is selected from avermectins, wherein the host substance is selected from: a) polymers and oligomers, predominantly organic polymers and oligomers, even more predominantly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, or mixtures thereof; b) substances that may contain in significant amounts polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, which may be (but are not limited to) plants or algae or animal or fungi, parts of plants or algae or animal or fungi, processed plants or algae or animal or fungi, processed parts of plants or algae or animal or fungi containing in significant amounts the substances specified in paragraph a), or mixtures thereof; c) syntetic polymers, predominantly water-soluble polymers or mixtures thereof; d) polyols or mixtures thereof; e) saccharides or mixtures thereof; f) surfactants or mixtures thereof; g) acids or mixtures thereof; h) oxides and salts based on these oxides or mixtures thereof; i) copolymers of the polymers listed in paragraph a) and c) j) methoxylated, ethoxylated, esterificated, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, decarboxylated, amide, oxidized, sulfated, aminoacid derivatives, fermented, thermally modified, chemically modified, acid modified derivatives of the substances specified in a)-i), and their esters, salts, and any other chemical derivatives, and mixtures thereof; k) any combination of substances specified in paragraph a)-j); wherein co-treating method is selected from: a) grinding/milling with high energy stress method; b) grinding/milling with high energy stress and solvent method; c) media milling method; d) kneading method; e) hot-melt method/melting method/fusion method; f) hot-melt extrusion/hot-stage extrusion method; g) meltrex method; h) melt agglomeration method; i) high-pressure homogenization method; j) solvent evaporation method; k) spin-coated films method; l) spray-drying method; m) supercritical fluid (SCF) process method; n) cryogenic techniques method; o) lyophilization/freeze-drying technique method; p) spray freezing onto cryogenic fluids method; q) spray freezing into vryogenic liquids (SFL) method; r) spray freezing into vapor over liquid (SFV/L) method; s) ultra-rapid freezing method; t) precipitation/co-precipitation method; u) microwave irradiation method; v) energy input method; w) heat/ shear energy input method; x) combined method.
[0010] Provided a method for preparing a medical dosage form of Formula I of enhanced bioavailability and permeability characterised in that it comprises a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof where the compound of Formula I is obtained by co-treating avermectin with a host substance wherein the avermectin is selected from avermectins, wherein the host substance is selected from: a) polymers and oligomers, predominantly organic polymers and oligomers, even more predominantly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, or mixtures thereof; b) substances that may contain in significant amounts polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, which may be (but are not limited to) plants or algae or animal or fungi, parts of plants or algae or animal or fungi, processed plants or algae or animal or fungi, processed parts of plants or algae or animal or fungi containing in significant amounts the substances specified in paragraph a), or mixtures thereof; c) syntetic polymers, predominantly water-soluble polymers or mixtures thereof; d) polyols or mixtures thereof; e) saccharides or mixtures thereof; f) surfactants or mixtures thereof; g) acids or mixtures thereof; h) oxides and salts based on these oxides or mixtures thereof; i) copolymers of the polymers listed in paragraph a) and c) j) methoxylated, ethoxylated, esterificated, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, decarboxylated, amide, oxidized, sulfated, aminoacid derivatives, fermented, thermally modified, chemically modified, acid modified derivatives of the substances specified in a)-i), and their esters, salts, and any other chemical derivatives, and mixtures thereof; k) any combination of substances specified in paragraph a)-j); wherein co-treating method is selected from: a) grinding/milling with high energy stress method; b) grinding/milling with high energy stress and solvent method; c) media milling method; d) kneading method; e) hot-melt method/melting method/fusion method; f) hot-melt extrusion/hot-stage extrusion method; g) meltrex method; h) melt agglomeration method; i) high-pressure homogenization method; j) solvent evaporation method; k) spin-coated films method; l) spray-drying method; m) supercritical fluid (SCF) process method; n) cryogenic techniques method; o) lyophilization/freeze-drying technique method; p) spray freezing onto cryogenic fluids method; q) spray freezing into vryogenic liquids (SFL) method; r) spray freezing into vapor over liquid (SFV/L) method; s) ultra-rapid freezing method; t) precipitation/co-precipitation method; u) microwave irradiation method; v) energy input method; w) heat/ shear energy input method; x) combined method.
[0011] In another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula II) comprising: a) a first pharmaceutical composition comprising a compound of Formula I, and b) a second pharmaceutical composition comprising at least one additional therapeutic agent active against infectious Coronaviridae viruses or agent that increases the antiviral activity of the Formula I component, or decreases the hepatotoxicity of the Formula I component, or increases the stability of the Formula I component. [0012] In another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula III) in form of solution/emulsion/suspension of comprising: a) a first pharmaceutical composition comprising a compound of Formula I-II, and b) at least one of the following components:
(1) oil phase containing vegetable or/and animal fats;
(2) one or more surfactants;
(3) one or more solvents;
(4) one or more gelling agents.
[0013] In another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula IV) in form of food product or beverage, or dietary supplement.
[0014] In another embodiment, the method comprises treating a SARS-CoV-2 virus infection in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I-IV.
[0015] In another embodiment, the method comprises treating a MERS virus infection in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I-IV.
[0016] In another embodiment, the method comprises treating a SARS virus infection in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I-IV.
[0017] In another embodiment, the method of treating a Coronaviridae infection in a human in need thereof comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a Formula I-IV compound in combination with a pharmaceutically acceptable diluent or carrier.
[0018] In another embodiment, the method of treating a Coronaviridae infection in a human in need thereof comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a Formula I-IV compound in combination with at least one additional therapeutic agent.
[0019] In another embodiment, the method comprises administering a therapeutically effective amount of compound of Formula I-IV to a mammal in need thereof.
[0020] In another embodiment, provided is the use of a compound of Formula I-IV to treat a viral infection caused by an Coronaviridae virus.
Advantageous Effects of Invention
[0021] The advantageous effect of the patented invention provides a method of treating Coronaviridae infection in humans. BRIEF DESCRIPTION OF DRAWINGS
[0022]
Fig.1 Pharmacokinetic parameters after oral administration of Ivermectin and compound of Formula I.
Fig. 2 Blood oxygen saturation levels without treatment and after oral administration of compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
[0023] The term "treatment" as used herein, unless otherwise specified, means the abolition, relief, inhibition of the progression or prevention of the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The term "treatment," as used herein, refers to the action of treatment as "treating " is defined directly above.
[0024] The term "therapeutically effective amount," as used herein, is the amount of a compound of formula I-IV present in a composition described herein that is necessary to provide the desired level of the drug in the secretions and tissues of the respiratory tract and lungs or, alternatively, in the bloodstream of the subject to be treated to produce the expected physiological response or desired biological effect when such composition is administered in the selected route of administration. The exact amount depends on a variety of factors, such as the specific compound of Formula I-IV, the specific activity of the composition, the delivery device used, the physical characteristics of the composition, its intended use, and patient considerations such as severity of the disease state, patient cooperation, etc., and can be readily determined by a person skilled in the art based on the information provided herein.
[0025] The term “avermectin”, as used herein, means avermectins and their derivatives such as: ivermectin, avermectin Ala, avermectin Alb, avermectin A2a, avermectin A2b, avermectin Bia, avermectin Bib, avermectin B2a, avermectin B2b or racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, hydrate or solvate thereof or a pharmaceutically acceptable salt or ester thereof or prodrug thereof or mixtures thereof.
[0026] A “prodrug” is defined in the pharmaceutical field as a biologically inactive derivative of a drug that, when introduced into the human body, is transformed into a biologically active parent drug according to some chemical or enzymatic pathway.
II. Compounds of the Present Invention:
[0027] Reference will now be made in detail to certain embodiments of the invention, examples of which are shown in the accompanying description, structures, and formulas. Although the invention will be described in connection with the embodiments listed, it will be understood that they are not intended to limit the invention to these embodiments. Rather, the invention is intended to encompass all alternatives, modifications, and equivalents that may be included within the scope of the present invention. [0028] The compounds of the present invention may also exist in the form of physiologically acceptable salts. Examples of physiologically acceptable salts include salts derived from an appropriate base such as an alkali metal or alkaline earth metal (e g., Na+, K+, Ca+2, Mg+2, Li+), ammonium and NR4+ (where R is defined herein). Physiologically acceptable salts of a nitrogen atom or amino group include (a) acid accession salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; (b) salts formed by organic acids, such as, for example, acetic acidtartaric acid, maleic acid, fumaric acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, iso-leucine, leucine and the like, oxalic acid, salicylic acid, gluconic acid, citric acid, malic acid ascorbic acid, benzoic acid, succinic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, malonic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3 -naphthoate, pamoate, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid,; and (c) salts formed from element anions, e.g., chlorine, bromine, and iodine. Physiologically acceptable salts of a hydroxy group compound include the anion of said compound in combination with a suitable cation such as Na+ and NR4+. All such forms are contemplated within the scope of the invention.
[0029] Compounds of the invention have the ability to exist as various polymorphs or pseudopolymorphs. As used in this document, crystalline polymorphism refers to the ability of a crystalline compound to exist in different crystal structures. Crystalline polymorphism can result from differences in crystal packing (packing polymorphism) or from differences in packing between different conformers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism refers to the ability of a compound hydrate or solvate to exist in different crystal structures. Pseudopolymorphs of the present invention may exist because of differences in crystal packing (packing pseudopolymorphism) or because of differences in packing between different conformers of the same molecule (conformational pseudopolymorphism). All such forms are considered to be within the scope of the invention.
[0030] The compounds of the invention can also exist as amorphous solids. As used herein, an amorphous solid is a solid in which there is no long-range ordering of atoms in the solid. This definition also applies when the crystal size is two nanometers or less. Additives, including solvents, can be used to create the amorphous forms of the present invention. All such forms are contemplated within the scope of the invention.
[0031] For therapeutic use, the active ingredients of the compounds of the invention will be physiologically acceptable. Ingredients that are not physiologically acceptable, however, may also find use, such as in the preparation or purification of a physiologically acceptable compound.
[0032] Lastly, it is to be expected that the compositions presented herein include the compounds of the invention in their non-ionized as well as zwitterionic forms, and combinations with stoichiometric amounts of water, as in hydrates. All such forms are contemplated within the scope of the invention.
[0033] It should be noted that all enantiomers, diastereomers and racemic mixtures, tautomers, polymorphs, pseudopolymorphs of compounds are included in the scope of the present invention. All mixtures of such enantiomers and diastereomers are included in the scope of the present invention.
[0034] The compounds of the invention can have chiral centers, such as chiral carbon or phosphorus atoms. Thus, the compounds of the invention include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. Additionally, the compounds of the invention include enriched or resolved optical isomers on any or all asymmetric chiral atoms. Other words, the chiral centers evident from the figures are presented as chiral isomers or racemic mixtures. Racemic and diastereomeric mixtures as well as individual optical isomers isolated or synthesized essentially free from their enantiomeric or diastereomeric partners are within the scope of the invention. Racemic mixtures are divided into their individual, essentially optically pure isomers by well-known methods, such as, for example, separation of diastereomeric salts formed with optically active excipients, such as acids or bases, followed by conversion back to optically active substances. In most cases, the desired optical isomer is synthesized by stereospecific reactions starting from the corresponding stereoisomer of the desired starting substance. All such forms are provided within the scope of the invention.
[0035] The compounds of the invention may in some cases exist as tautomeric isomers. While only one delocalized resonance structure may be depicted, all such forms are considered within the scope of the invention.
[0036] Any formula or structure herein is also intended to represent unlabeled forms and isotopically labeled forms of compounds. Isotopically labeled compounds have the structures represented in the formulas provided herein except that one or more atoms are replaced with an atom of a selected atomic mass or mass number. Examples of isotopes that may be included in the compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine such as 2H (deuterium, D), 3H (tritium), SS, 13C, 14C, 1SN, 18F, 31P, 32P, 35S, 36C1 and 1251, but without limitation. Different isotopically labeled compounds of the present disclosure, such as those incorporating radioactive isotopes such as 3H, 13C and 14C. All such forms are provided within the scope of the invention. Such isotopically labeled compounds can be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue distribution analyses of drugs or substrates, or in the radioactive treatment of patients. The disclosure also includes compounds of formula I in which 1 to n hydrogens attached to the carbon atom are substituted with deuterium, where n is the number of hydrogens in the molecule. These compounds exhibit increased resistance to metabolism and thus are useful for increasing the half-life of any compound of formula I when administered to a mammal, particularly a human.
[0037] Provided is a method for treating an Coronaviridae infection in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula I, that is a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof, where the compound of Formula I is obtained by co-treating avermectin with a host substance: wherein the avermectin is selected from (0.01-90% of the total weight of the Formula I): ivermectin, avermectin Ala, avermectin Alb, avermectin A2a, avermectin A2b, avermectin Bia, avermectin Bib, avermectin B2a, avermectin B2b or racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, hydrate or solvate thereof or a pharmaceutically acceptable salt or ester thereof or prodrug thereof or mixtures thereof; wherein the host substance is selected from (10-99.99% of the total weight of the Formula I):
A. Polymers and oligomers, predominantly organic polymers and oligomers, even more predominantly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, which may be (but are not exclusive to):
A.l. Hemicelluloses, which can be arabanes, arabinans, galactans (galactosans), glucans, xylans, mannans, fructans, xyloglucans, arabinogalactans, arabinoxylans, glucomannans, galactomannans, galactoglucomannans, beta-glucans, galactogens, their mixtures, but not excluding other hemicelluloses, and mixtures thereof;
A.2. Sulfated polysaccharides and oligosaccharides which may be fucoidans, carrageenans or carrageenins, agaropectins, sea cucumber sulfated polysaccharides (SCSP), chondroitin sulfate, keratan sulfate, their mixtures, but not excluding other sulfated polysaccharides and oligosaccharides, and mixtures thereof;
A.3. Polysaccharides and oligosaccharides, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages which may be (but are not exclusive to others): polysaccharides based on glucose, dextrose, galactose, mannose, arabinose, rhamnose, sucrose, maltose, lactose and their uronic acids, which may be methoxylated or acetylated, and their salts (gum, gummi); polyuronic acids and esters; gum, xanthan gum, oat gum, gellan gum, guar gum, carob gum, karaya gum, dammar gum, gummiarabica, tara gum, ghatti gum, british gum, agar, agar-agar, tragakant gum, conjac gum, velan gum, dutan gum; galacturonic acidbased polysaccharides with side chains of rhamnose, arabinose, xylose and fructose and their salts (pectins, pectates, pectinates); pectin, pectins of beets, carrots, peppers, pumpkins, eggplant, sunflower, apples, quinces, cherries, plums, pears, citrus, zosterin; modified pectins, modified citrus pectin; acidic polysaccharides - i.e. e. polysaccharides containing carboxyl groups, phosphate groups and/or sulfuric ester groups; plantain husk, psyllium; soybean hemicellulose; galacturones, homogal ctur ones, polygalacturonic acids and their salts, rhamnogal acturonan, rhamnogalactans; calloses, laminarins, chrysolaminarins, curdlans; inulins, guars, dextrans, pullulans; agaroses, galacto-oligosaccharides (oligogalactosyllactose, oligogalactose, oligolactose or transgalactooligosaccharides), xylooligosaccharides, fructooligosaccharides, isomaltooligosaccharide; alginic acid and its salts alginates, propylene glycol alginate; arabin, arabic acid and its salts; cellulose, cellulosic polymers, methylcellulose, ethylcellulose, hydroxypropylcellulose(s) (HPC), hydroxypropylmethylcellulose acetate succinate, hypromellose(s), hydroxypropylmethylcellulose(s) (HPMC), methylethylcellulose, ethylhydroxyethylcellulose, croscaramellose, carboxymethylcellulose and its salts; starch, starch(es), starch 1500G, soluble starch, modified starches, hydroxyethyl starch, cationic starch, acid-treated starch, alkaline modified starch, bleached starch, oxidized starch, enzyme treated starch, monostarch phosphate, distarch glycerol, distarch phosphate, phosphated distarch phosphate, acetylated distarch phosphate, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated distarch adipate, acetylated distarch glycerol, distarch glycerine, hydroxy propyl starch, hydroxy propyl di starch glycerine, hydroxy propyl di starch phosphate, hydroxy propyl distarch glycerol, starch sodium octenyl succinate, acetylated oxidised starch; dextrin(s), maltodextrins, cyclodextrins, amylodextrins, polydextroses; amylopectin, amylose, glycogen; chitosan, chitins; pullulans, glucuronoaraboxylans, methyl-glucuronoaraboxylans, glycosaminoglycans, mucopolysaccharides, heparin/heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronan, hyaluronic acid and mixtures thereof, but not excluding other polysaccharides and oligosaccharides, hemicelluloses, stored polysaccharides, sulfated polysaccharides and oligosaccharides, mucilages and mixtures thereof;
B. Substances that may contain in significant amounts (more than 5% wt ) polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, which may be (but are not limited to) plants or algae or animal or fungi, parts of plants or algae or animal or fungi, processed plants or algae or animal or fungi, processed parts of plants or algae or animal or fungi containing in significant amounts the substances specified in paragraph A, and mixtures thereof. A frequent but non-limiting example is dried brown or red algae such as kelp or focus; C. Syntetic polymers, predominantly water-soluble polymers which may be (but are not limited to): polymers and copolymers formed from acrylic acid, methacrylic acid, and/or esters thereof; polymethacrylates, Eudragit and their salts; polyacrylamides; poly(amidoamine)s, poly(propyleneimine)s, polyethylene glycols; polyvinyl alcohol; polyvinylpyrrolidone; acrylic polymers, cellulose acetate phthalate(s), copovidone(s), ethyl oleate, glycerol derivatives, glyceryl triacetate, polyethylene glycol(s) (PEG), PEG derivatives, polymethacrylates, propylene glycol, propylene glycol derivatives, povidone(s), polyvinylpyrrolidone(s) (PVP), polyvinyl acetate phthalate(s) (PVAP), hypromellose acetate succinate(s) (HPMCAS), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hypromellose phthalate(s) (HPMCP), cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, Avicel(s), Avicel PH101, Avicel PH102, Benecel(s), Brij(s), Brij 30, Brij 35, Capryol(s), Cavamax(s), Cavasol(s) and Cavitron(s) HPpCD cyclodextrins, Compritol 888 ATO, Cremophor(s), Cremophor EL, Cremophor RH40, DiCai Dihydrate, epoxidized palm oil (Epo), Eudragit(s), Eudragit E, Eudragit EPO, Eudragit LI 00, Eudragit LI 00-55, Eudragit S100, Gelucire(s), Gelucire 44/14 , HP-50 AAS-LF, HP-55 AAS-MF, HPMC(p- 606), HPMC-E, HPMC-F, HPMC-K, HPMCAS-H, HPMCAS-L, HPMCAS-M, HPMCAS SDD, HPMCAS(AS-MG), HPMCAS-M SDDs, HPMCAS-MG, HPMCP (HP 55), HPMCP-HP55, HPMCPh, hypromellose phthalate HP-50, Imwitor(s), Imwitor 742, Klucel HPC, Kolhdon 17 PF, Kollicoat(s), Kollicoat IR, Kollicoat MAE, Kollicoat MAE 100, Kollicoat MAE 100P , Kollicoat Protect, Kollidon(s) (povidone(s)), Kollidon 12 pf, Kollidon 12/17PF, Kollidon 30, Kollidon 30/90, Kollidon 90, Kollidon CL-F, Kollidon CL-SF, Kollidon K30, Kollidon SR, Kollidon SR, Kollidon SR(PVAc), Kollidon V64/Fine, Kollidon VA 64, Kollidon VA 64 (copovidone), Kollidon VA64, Kolliphor(s), Kolliphor EL, Kolliphor EL/ELP, Kolliphor HS15, Kolliphor P 188, Kolliphor P 188/407, Kolliphor P 188/micro, Kolliphor P 407, Kolliphor P 407/micro, Kolliphor PS 20, Kolliphor PS 60, Kolliphor PS 80, Kolliphor RH 40, Kolliphor SLS, Kolliphor SLS/fine, Kollisolv(s), Kollisolv GTA, Kollisolv PEG 1450, Kollisolv PEG 300, Kollisolv PEG 3350, Kollisolv PEG 400, Kollisolv PEG E 300, Kollisolv PEG E 400, Kollisolv PEG grades (polyethylene glycol), Kolliwax(s), Kolliwax GMS II, Kolliwax SA, Labrasol(s), Lactose 310 Mono, Lactose FF316, Laurogucol(s), Maisine(s), Miglyol(s), Myrj(s), Myrj 52, PEG 1000, PEG 10000, PEG 1500, PEG 2000, PEG 20000, PEG 3000, PEG 400, PEG 4000, PEG 600, PEG 6000, PEG 800 , PEG 8000 , Pharmacoat(s), PVP K-12 , PVP K-120 , PVP K-15, PVP K-17, PVP K-30, PVP K-60, PVP K-90, PVP SDD, PVP VA64 SDDs, PVP-VA, PVP-VA 64, PVP-VA SDD, Palm stearin based polyesteramide (PSPEA), Peceol(s), pectin(s), Plasdone(s), Plasdone K povidone, Plasdone K-12 povidone, Plasdone K-29/32 povidone, Plasdone K-90 povidone, Plasdone S, Plasdone S-630 copovidone, poly(2-ethyl-2-oxazoline), poly(ethylene oxide) (PEO) (3400, 10000, 20000), polyoxyethylene stearate, Shin-Etsu AQOAT(s), Soluplus(es), Solutol(s), sucrose laurate, tocopheryl PEG 1000-succinate (TPGS), vitamin E TPGS, d-a-tocopherol polyethylene glycol 1000 succinate (TPGS), Isomalt (Galen IQ 810), but not excluding other synthetic polymers and mixtures thereof;
D. Polyols which may be (but are not limited to): ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol, and mixtures thereof;
E. Saccharides which may be glucose, dextrose, galactose, mannose, arabinose, rhamnose, sucrose, maltose, lactose, ribose, and mixtures thereof; F. Surfactants which may be (but are not limited to): anionic surfactants contained anionic functional groups at their head, such as sulfate, sulfonate, phosphate, carboxylates, carboxylate salts; alkyl sulfates; alkyl-ether sulfates; carboxylate-based fluorosurfactants; cationic surfactants; primary, secondary, or tertiary amines; permanently charged quaternary ammonium salts; zwitterionic (amphoteric) surfactants; zwitterionic surfactants which cationic part is based on primary, secondary, or tertiary amines or quaternary ammonium cations; sultaines; betaines; phospholipids; zwitterionic surfactants of the tertiary amine oxides structural type; non-ionic surfactants; ethoxylates; fatty alcohol ethoxylates; alkylphenol ethoxylates (apes or apeos); fatty acid ethoxylates; special ethoxylated fatty esters and oils; ethoxylated amines and/or fatty acid amides; terminally blocked ethoxylates; fatty acid esters of polyhydroxy compounds; fatty acid esters of glycerol; fatty acid esters of sorbitol; fatty acid esters of sucrose; alkyl polyglucosides; ammonium lauryl sulfate; sodium lauryl sulfate; sodium dodecyl sulfate; sodium laureth sulfate; sodium lauryl ether sulfate; sodium myreth sulfate; docusate (dioctyl sodium sulfosuccinate) and their salts; perfluorooctanesulfonate (pfos); perfluorobutanesulfonate; alkyl-aryl ether phosphates; alkyl ether phosphates; sodium stearate; sodium lauroyl sarcosinate; perfluorononanoate; perfluorooctanoate; octenidine dihydrochloride; cetrimonium bromide (ctab); cetylpyridinium chloride (cpc); benzalkonium chloride (bac); benzethonium chloride (bzt); dimethyl dioctadecyl ammonium chloride; dioctadecyldimethylammonium bromide (dodab); chaps (3-[(3-cholamidopropyl)dimethylammonio]-l-propanesulfonate); cocamidopropyl hydroxysultaine; cocamidopropyl betaine; phosphatidylserine; phosphatidylethanolamine; phosphatidylcholine; sphingomyelins; lauryldimethylamine oxide; myristamine oxide; narrow-range ethoxylates; octaethylene glycol monododecyl ether; pentaethylene glycol monododecyl ether; nonoxynols; triton x-100; polyethoxylated tallow amine; cocamide monoethanolamine; cocamide diethanolamine; poloxamers; glycerol monostearate; glycerol monolaurate; sorbitan monolaurate; sorbitan monostearate; sorbitan tristearate; tween(s), tween 20; tween 40; tween 60; tween 80; decyl glucoside; span(s), span 20, span 40, span 80; lauryl glucoside; octyl glucoside; poloxamer(s), pol oxamer 188, poloxamer 407, polyoxyethylene stearate, myrj 52, deoxycholic acid, bile acids, pluronic(s), pluronic F-127, pluronic P85, pluronic f68, gelucire(s), gelucire 44/14, lecithins, polysorbates, polysorbate 80, plasdone-s630, pluronic-f68, inutec spl, compritol 888 ato, tocopherol polyethylene glycol succinate, polyoxyethylated castor oil, polyoxyethylated glycerides, lauroyl macroglycerides, and mono- and di-fatty acid esters of low molecular weight polyethylene glycols; and mixtures thereof;
G. Acids and salts based on these acids which may be (but are not limited to): citric acid, tartaric acid, succinic acid, phosphoric acid, aminoacids, acetate(s), sodium acetate, alginate(s), sodium alginate, glycyrrhizic acid and their salts, and mixtures thereof;
H. Oxides and salts based on these oxides which may be (but are not limited to): silicon dioxide, silicates, titanium dioxide, and mixtures thereof;
I. Copolymers of the polymers listed in paragraph A, C including alternating copolymers, random copolymers, block copolymers, graft copolymers, cross-linked modifications which may be (but are not limited to): methacrylic acid and ethyl acrylate copolymers; methacrylic acid copolymers; vinylpyrrolidone-vinyl acetate copolymers (PVPVA); polyvinylpolypyrrolidone (PVPP); PVA-PEG graft co-polymers; HPMC and PVA-PEG grafted copolymers; grafted polyvinylpyrrolidone-arabinogalactan copolymers; the graft copolymer has a) poly(vinyl acetate) and/or poly (vinyl alcohol) and/or poly(vinyl chloride) and poly(vinyl ester) on b) a polymer chain of polyethylene glycols, polyalkylene glycols, polypropylene glycols, polyisobutylene glycols orpolymeth- ylpentene glycols, graft copolymer polyvinyl acetate and/or hydrolysed polyvinyl acetate (polyvinyl alcohol) groups on a polyalkylene oxide (preferably polyethylene oxide); vinylpyrrolidone-vinyl acetate copolymers; vinylpyrrolidone-vinyl acetate copolymer- 64+; vinylpyrrolidone-vinyl acetate VA 64; polymethacrylate-based copolymers includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters their salts, esters or other derivatives and mixtures thereof;
J. Methoxylated, ethoxylated, esterificated, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, decarboxylated, amide, oxidized, sulfated, aminoacid derivatives, fermented, thermally modified, chemically modified, acid modified derivatives of the substances specified in A-I, and their esters, salts, and any other chemical derivatives, and mixtures thereof;
K. Any combination of substances specified in items A-J; wherein co-treating method is selected from (but not excluding other methods, which should lead to the formation bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion):
Method 1 (Grinding/Milling With High Energy Stress): avermectin and the “host substance” are milled in a roller, ball, planetary, vibratory, jet, drum, medium-speed, impact-jet, centrifugal countercurrent, rotary, disintegrator, and other types of mills or other grinders. The grinding process may produce particles of a size of mainly 0.01 to 100 microns, which are powders;
Grinding should be carried out to such a state that there are changes in the structure and properties of the ground substance so that it has increased bioavailability and permeability and bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion is formed. Grinding should cause structural changes such as defects, shears, increased deformation, associates. Grinding should occur under conditions of high energy stress, energy input. In the grinding process mechanoactivation must/may occur;
A solvent may be added to the grinding process, such as organic and inorganic solvents which may be (but are not limited to): water, hydrocarbons and their halogen derivatives, alcohols, esters and ethers, ketones, nitro compounds: 1,1,1 -tri chloroethane, 1,1,2- tri chloroethene, 1,1-dichloroethene, 1,2-dichloroethane, 1,2-di chloroethene, 1,2- dimethoxyethane, 1,2-propanedioi, 1,4-dioxane, 1 -butanol, 1 -pentanol, 1 -propanol, 2- butanol, 2-butanone, 2-ethoxy ethanol, 2-methoxy ethanol, 2-methyl-l -propanol, 2- methylpyridine, 2-methyl tetrahydrofuran, 2-nitropropane, 2-propanol, 3 -methyl- 1- butanol, 4-methyl-2-pentanone, acetic acid, acetic anhydride, acetone, acetonitrile, acetophenone, ammonia, aniline, anisole, benzene, benzonitrile, benzylalcohol, bromoethane, bromoform, bromooctane, butanol, butanone, butylacetate, butylbenzene, carbon disulfide, carbontetrachloride, carbontet, cellosolve acetate, cetic acid, chlorobenzene, chloroform, chloroform, chlorohexane, cumene, cyclohexanes cyclohexane, cyclohexanol, cyclohexanone, cyclopentane, cyclopentanes, decalin, decane, decanol, dibromoethane, dibutylether, dichlorobenzene, di fluorobenzene, dichloroethane, dichloromethane, diethyleneglycol, diethylether, diglyme (diethylene glycoldimethyl ether), diisopropylether, dimethoxyethane, dimethyl acetate, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, dimethylpyridine, dimethylsulfoxide, dioxane, di oxanes (1.4 dioxane), dodecane, esters, etbe, ethanediol, ethanol, ether(s), ethoxybenzene, ethyl acetate, ethyl acetoacetate, ethyl alcohol, ethylacetate, ethylbenzene, ethylene glycol ethyl ether, ethylene glycol methyl ether , ethylene glycol monobutyl ether, ethyleneglycol, ethylether, ethylformate, fluorobenzene, fluoroctane, formamide, formic acid, freon, furfuraldehyde, glacial acetic acid, glycerin, glycol ethers, halobenzenes, heptane, heptanes, heptanol, hexadecane, hexadecyliodide, hexamethylphosphoramide, hexamethylphosphorous triamide (hmpt), hexane, hexanes, hexanol, i-amyl alcohol, iodobenzene, isobutanol, isobutyl acetate, isooctane, isopropanol, isopropyl acetate, isopropylbenzene, isopropyl toluene, mcresol, mesitylene, methanoic acid, methanol, methoxyethanol, methyl acetate, methyl ethyl ketone, methyl t-butyl ether, methyl tert butyl ether, methylbutyl ketone, methylcyclohexane, methylenechloride, methylethyl ketone, methylformamide, methylisobutyl ketone, miscellaneous solvents, monochlorobenzene, morpholine, m-xylene, n,n- dimethylacetamide, n,n-dimethylformamide, n-amyl alcohol, n-butyl acetate, nitrobenzene, nitroethane, nitromethane, n-methyl-2-pyrrolidinone(nmp), n- methylpyrrolidone, n-octanol, nonane, nonanol, octane, octanol, odichlorobenzene, onitrotoluene, o-xylene, pentadecane, pentane, pentanes, pentanol, perchloroethylene, perfluorobenzene, petroleum ether (ligroine), phenol, phenylether, propanol, propoxypropane, propyl acetate, propylene glycol methyl ether , p-xylene, pyridine, secbutanol, secbutylbenzene, sulfolane, t-butanol, t-butyl alcohol, tbutylbenzene, tertbutylmethylether, tetrachloroethane, tetrachloroethylene, tetrachloromethane, tetrahydrofuran, tetrahydrothiophenedioxide, tetralin, toluene, tributylphosphate, tri chloroethane, trifluoromethylbenzene , trichloroethylene, triethylamine, trimethylbenzene, trimethylpentane, undecane, xylene, xylenes, 2,2,4-trimethyl pentane, and mixtures thereof;
Method 2 (Grinding/Milling With High Energy Stress and Solvent): Avermectin and the “host substance” are wetted with a solvent, the wetted mass is dried and then ground in the same manner as described in Method 1. The list of solvents used is the same as the solvents listed in Method 1;
Method 3 (Media Milling): The “base component” is prepared by using high-shear media mills. The milling chamber charged with milling media, solvent, avermectin, and “host substance” is rotated at a very high-shear rate under controlled temperatures. The milling medium is composed of glass, zirconium oxide, highly cross-linked polystyrene resin or other standart milling medium. High energy shear forces are generated as a result of the impaction of the milling media with the avermectin in the breaking of microparticulate avermectin into nanosized particles. The list of solvents used is the same as the solvents listed in Method 1;
Method 4 (Kneading Method): This method is based on impregnating the “host substance” with a little amount of water or hydroalcoholic solutions to convert it into a paste. The avermectin is then added to the above paste and kneaded for a specified time. The kneaded mixture is then dried and passed through a sieve if required. On a laboratory scale, kneading can be achieved by using a mortar and pestle. On large scale, kneading can be done by utilizing extruders and other machines;
Method 5 (Hot-Melt Method, Melting Method, Fusion Method): In this method, the physical mixture of avermectin and a “host substance” are heated directly until the two melt. The melted mixture is then cooled and solidified rapidly with rigorous stirring. The final solid mass is then crushed, pulverized, and sieved. The melting method consists of melting the avermectin within the “host substance” followed by cooling and pulverization of the obtained product. A common adaptation to the melting phase consists of suspending the avermectin in a previously melted “host substance”, instead of using both avermectin and “host substance” in the melted state, reducing, therefore, the process temperature. To cool and solidify the melted mixture, several processes such as ice bath agitation, stainless steel thin layer spreading followed by a cold draught, solidification on petri dishes at room temperature inside a desiccator, spreading on plates placed over dry ice, immersion in liquid nitrogen or stored in a desiccators or other cooling method were used After cooling, the mixture must be pulverized regarding its handling; Method 6 (Hot-Melt Extrusion, Hot-stage extrusion): Hot-Melt Extrusion is a modification of the Melting Method. Hot-melt extrusion is essentially the same as the melting method except that intense mixing of the components is induced by the extruder. Hot-stage extrusion consists of the extrusion, at high rotational speed, of the avermectin and “host substance”, previously mixed, at melting temperature for a small period of time. The resulting product is then collected after cooling at room temperature and milled. A reduction in processing temperature can be achieved by the association of hot- stage extrusion with the use of carbon dioxide as a plasticizer;
Method 7 (Meltrex Method): Meltrex is a modification of the Melting Method. Meltrex is a patented solid dispersion manufacturing process, also based on the melting process. The crucial elements in the Meltrex technology are the use of a special twin screw extruder and the presence of two independent hoppers in which the temperature can vary over a broad temperature range;
Method 8 (Melt agglomeration Method): Melt agglomeration is a modification of the Melting Method. Melt agglomeration allows the preparation of solid dispersions in conventional high shear mixers. It is made by adding the molten “host substance” containing the avermectin to the heated excipients, by adding the molten “host substance” to a heated mixture of avermectin and excipients, or by heating a mixture of the avermectin, “host substance” and excipients to a temperature within or above the melting range of the “host substance”. It is also possible to produce stable solid dispersions by melt agglomeration in a rotary processor;
Method 9 (High-Pressure Homogenization): In this method, the suspension of an avermectin and “host substance” is forced under pressure through a nanosized aperture valve of a high-pressure homogenizer;
Method 10 (Solvent Evaporation Method): In this method dissolved both the avermectin and the “host substance” in a common solvent and then evaporate the solvent to produce a solid solution. A basic process of preparing solid dispersions of this type consists of dissolving the avermectin and the polymeric “host substance” in a common solvent or solvents mixture (the list of solvents used is the same as the solvents listed in Method 1). Normally, the resulting films are pulverized and milled. The use of the “host substances” partially suspended, instead of dissolved, was also can be used. Solvent evaporation procedure usually include vacuum drying, heating of the mixture on a hot plate, slow evaporation of the solvent at low temperature, the use of a rotary evaporator, a stream of nitrogen, or other drying procedure;
Method 11 (Spin-coated films Method): Spin-coated films method is a modification of the Solvent Evaporation Method, which consists of dissolving avermectin and “host substance” in a common solvent that is dropped onto a clean substrate highly spinned. The solvent is evaporated during spinning;
Method 12 (Spray-drying Method): Spray-drying is a modification of the Solvent Evaporation Method. It consists of dissolving or suspending the avermectin and “host substance”, then spraying it into a stream of heated airflow to remove the solvent;
Method 13 (Supercritical Fluid (SCF) Process): Supercritical Fluid Process is a modification of the Solvent Evaporation Method. In this method, the avermectin particles are solubilized within the SCF (usually carbon dioxide). Several methods of SCF processing can be used to address individual aspects, such as precipitation with a compressed antisolvent process (PCA), solution enhanced dispersion by SCF (SEDS), supercritical antisolvent processes (SAS), the rapid expansion of supercritical solutions (RESS), gas anti-solvent recrystallization (GAS), and aerosol supercritical extraction system (ASES). In this method modification, the technique consists of dissolving the avermectin and the “host substance” in a common solvent that is introduced into a particle formation vessel through a nozzle, simultaneously with CO2. When the solution is sprayed, the solvent is rapidly extracted by the SCF, resulting in the precipitation of solid dispersion particles on the walls and bottom of the vessel;
Method 14 (Cryogenic Techniques): Cryogenic methods are methods in which a solution of avermectin and “host substance” in a common solvent is frozen before a low- temperature solvent evaporation procedure. The common solvent can be the same as in the Solvent Evaporation Method. Freezing of the solution can occur after injection. The type of injection device can be a capillary, rotary, pneumatic, ultrasonic nozzle, or other types of the injection device. The location of the nozzle can be above or under the cryogenic liquid level. The composition of cryogenic liquid can be hydrofluoroalkanes, fluorocarbons, N2, Ar, 02, organic solvents, or other types of cryogenic liquid. After cryogenic processing, dry powder can be obtained by various drying processes like spray freeze drying, atmospheric freeze drying, vacuum freeze drying, lyophilization, or other low-temperature drying processes. The list of common solvents used is the same as the solvents listed in Method 1;
Method 15 (Lyophilization/Freeze-Drying Technique): Lyophilization Method is a modification of the Cryogenic Techniques. In this technique, the common solvent from the solution is eliminated through a primary freezing and subsequent drying of the solution containing both avermectin and “host substance” at reduced pressure. The basic freeze-drying process consists of dissolving the avermectin and “host substance” in a common solvent, which is immersed in cryogenic liquid until it is fully frozen. Then, the frozen solution is further lyophilized;
Method 16 (Spray Freezing onto Cryogenic Fluids): This Method is a modification of the Cryogenic Techniques. In this technique, the avermectin and the “host substance” were dissolved in a common solvent and atomized above the surface of a boiling agitated cryogenic liquid refrigerant;
Method 17 (Spray Freezing into Cryogenic Liquids (SFL)): This Method is a modification of the Cryogenic Techniques. It incorporates direct liquid-liquid impingement (by spraying) between the solution and cryogenic liquid to provide intense atomization into microdroplets. The frozen particles are then lyophilized to obtain dry and free-flowing micronized powders.
Method 18 (Spray Freezing into Vapor over Liquid (SFV/L)): This Method is a modification of the Cryogenic Techniques. Freezing of avermectin solutions in cryogenic fluid vapors and subsequent removal of frozen solvent. During SFV/L the atomized droplets typically start to freeze in the vapor phase before they contact the cryogenic liquid. As the solvent freezes, the avermectin becomes supersaturated in the unfrozen regions of the atomized droplet.
Method 19 (Ultra-Rapid Freezing): This Method is a modification of the Cryogenic Techniques. Application of avermectin solution to the solid surface of the cryogenic substrate leads to instantaneous freezing and subsequent lyophilization.
Method 20 (Precipitation Technique, Co-precipitation Method): In the precipitation method the avermectin is dissolved in a solvent, which is then added to Non-solvent to precipitate the crystals. Non-solvent is added dropwise to the avermectin and “host substance” solution, under constant stirring. In the course of the non-solvent addition, the avermectin and “host substance” are co-precipitated to form micro-particles. In the end, the resulted micro-particle suspension is filtered and dried. The list of solvents used is the same as the solvents listed in Method 1.
Method 21 (Microwave Irradiation Method): This method involves the microwave irradiation reaction between avermectin and complexing agent using a microwave oven. The avermectin and “host substance” in a definite molar ratio are dissolved in a mixture of water and/or organic solvent in a specified proportion into a container. The mixture is reacted in the microwave oven. After the reaction completes, an adequate amount of solvent mixture is added to the above reaction mixture to remove the residual uncomplexed free avermectin and “host substance”. The precipitate so obtained is separated using a filter, and dried. The list of solvents used is the same as the solvents listed in Method 1.
Method 22 (Energy Input Method): Method comprises the step of exposing a host substance and a avermectin to an energy input until a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion is formed of the avermectin as amorphous material entrapped in the host substance.
Method 23 (Heat/Shear Energy Input Method): Method comprises the step of exposing a host substance and a avermectin to an energy input, whereby the energy input is heat and/or shear forces, until a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion is formed of the avermectin as amorphous material entrapped in the host substance.
Method 24 (Combined method): This method includes any combination of Methods 1-23.
Methods 1-24 should lead to the formation bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion.
[0038] Provided a medical dosage form of Formula I of enhanced bioavailability and permeability characterised in that it comprises a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof, where the compound of Formula I is obtained by co-treating avermectin with a host substance wherein the avermectin is selected from avermectins, wherein the host substance is selected from: a) polymers and oligomers, predominantly organic polymers and oligomers, even more predominantly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, or mixtures thereof; b) substances that may contain in significant amounts polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, which may be (but are not limited to) plants or algae or animal or fungi, parts of plants or algae or animal or fungi, processed plants or algae or animal or fungi, processed parts of plants or algae or animal or fungi containing in significant amounts the substances specified in paragraph a), or mixtures thereof; c) syntetic polymers, predominantly water-soluble polymers or mixtures thereof; d) polyols or mixtures thereof; e) saccharides or mixtures thereof; f) surfactants or mixtures thereof; g) acids or mixtures thereof, h) oxides and salts based on these oxides or mixtures thereof; i) copolymers of the polymers listed in paragraph a) and c) j) methoxylated, ethoxylated, esterificated, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, decarboxylated, amide, oxidized, sulfated, aminoacid derivatives, fermented, thermally modified, chemically modified, acid modified derivatives of the substances specified in a)-i), and their esters, salts, and any other chemical derivatives, and mixtures thereof; k) any combination of substances specified in paragraph a)-j); wherein co-treating method is selected from: a) grinding/milling with high energy stress method; b) grinding/milling with high energy stress and solvent method; c) media milling method; d) kneading method; e) hot-melt method/melting method/fusion method; f) hot-melt extrusion/hot-stage extrusion method; g) meltrex method; h) melt agglomeration method; i) high-pressure homogenization method; j) solvent evaporation method; k) spin-coated films method; l) spray-drying method; m) supercritical fluid (SCF) process method; n) cryogenic techniques method; o) lyophilization/freeze-drying technique method; p) spray freezing onto cryogenic fluids method; q) spray freezing into vryogenic liquids (SFL) method; r) spray freezing into vapor over liquid (SFV/L) method; s) ultra-rapid freezing method; t) precipitation/co-precipitation method; u) microwave irradiation method; v) energy input method; w) heat/ shear energy input method; x) combined method.
[0039] Provided a method for preparing a medical dosage form of Formula I of enhanced bioavailability and permeability characterised in that it comprises a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof where the compound of Formula I is obtained by co-treating avermectin with a host substance wherein the avermectin is selected from avermectins, wherein the host substance is selected from: a) polymers and oligomers, predominantly organic polymers and oligomers, even more predominantly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, or mixtures thereof; b) substances that may contain in significant amounts polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, which may be (but are not limited to) plants or algae or animal or fungi, parts of plants or algae or animal or fungi, processed plants or algae or animal or fungi, processed parts of plants or algae or animal or fungi containing in significant amounts the substances specified in paragraph a), or mixtures thereof; c) syntetic polymers, predominantly water-soluble polymers or mixtures thereof; d) polyols or mixtures thereof; e) saccharides or mixtures thereof; f) surfactants or mixtures thereof; g) acids or mixtures thereof; h) oxides and salts based on these oxides or mixtures thereof; i) copolymers of the polymers listed in paragraph a) and c) j) methoxylated, ethoxylated, esterificated, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, decarboxylated, amide, oxidized, sulfated, aminoacid derivatives, fermented, thermally modified, chemically modified, acid modified derivatives of the substances specified in a)-i), and their esters, salts, and any other chemical derivatives, and mixtures thereof; k) any combination of substances specified in paragraph a)-j); wherein co-treating method is selected from: a) grinding/milling with high energy stress method; b) grinding/milling with high energy stress and solvent method; c) media milling method; d) kneading method; e) hot-melt method/melting method/fusion method; f) hot-melt extrusion/hot-stage extrusion method; g) meltrex method; h) melt agglomeration method; i) high-pressure homogenization method; j) solvent evaporation method; k) spin-coated films method; l) spray-drying method; m) supercritical fluid (SCF) process method; n) cryogenic techniques method; o) lyophilization/freeze-drying technique method; p) spray freezing onto cryogenic fluids method; q) spray freezing into vryogenic liquids (SFL) method; r) spray freezing into vapor over liquid (SFV/L) method; s) ultra-rapid freezing method; t) precipitation/co-precipitation method; u) microwave irradiation method; v) energy input method; w) heat/ shear energy input method; x) combined method.
[0040] Formula I also includes aqueous solutions or suspensions of Formula I as they are naturally formed in the stomach and intestines of a human or mammal when taken orally at the expense of the water naturally contained in the stomach and intestines as well as the water with which Formula I is ingested. Also solutions or suspensions of Formula I may be obtained by prestirring Formula I in a container with a liquid containing water.
[0041] In another embodiment, the method comprises treating a SARS-CoV-2 virus infection in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I.
[0042] In another embodiment, the method comprises treating a SARS-CoV-2 virus infection in caused by a SARS-CoV-2 virus caused by a strain selected from SARS-CoV-2 strains virus infection in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I. [0043] In another embodiment, the method comprises treating a MERS virus infection in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I.
[0044] In another embodiment, the method comprises treating a SARS virus infection in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I.
[0045] In another embodiment, the method comprises treating a alpha coronaviruses 229E (HCoV-229E), NL63 (HCoV-NL63, New Haven coronavirus), beta coronaviruses OC43 (HCoV-OC43), HKU1 virus infections in a human in need thereof by administering a therapeutically effective amount of a compound of Formula I.
[0046] In another embodiment, the method comprises administering a therapeutically effective amount of compound of Formula I to a mammal in need thereof.
[0047] In another embodiment, provided is the use of a compound of Formula I to treat a viral infection caused by an Coronaviridae virus. in. Combination Therapy
[0048] The compositions of the invention are also used in combination with other active ingredients. For the treatment of infections caused by Coronaviridae family viruses, preferably another active therapeutic agent is active against infections caused by Coronaviridae family viruses, in particular infections caused by SARS-CoV-2. Non-limiting examples of such other active therapeutic agents are niclosamide, remdesivir, nitazoxanide, chloroquine, lopinavir, ritonavir, hydroxychloroquine and mixtures thereof. The compounds and compositions of the present invention are also intended for use in the general care of patients with Coronaviridae viral infections, including nutrition, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and/or antifungal prophylaxis, antipyretics and analgesics, antiemetics (such as metoclopramide) and/or anti-diarrheals vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatories (such as ibuprofen), pain medications, and medications for other common conditions in the patient population, such as antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin) or shigellosis.
[0049] It is also possible to combine any compound of the invention with one or more additional active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient. The combination therapy may be administered as simultaneous or sequential administration. In case of sequential administration the combination may be administered in two or more injections.
[0050] Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are simultaneously present in the patient.
[0051] Co-administration comprises administering single doses of the compounds of the invention before or after administering single doses of one or more other active therapeutic agents, for example, administering the compounds of the invention within seconds, minutes or hours after administering one or more other active therapeutic agents. For example, a single dose of the compound of the invention may be administered first, followed by a single dose of one or more other active therapeutic agents within seconds or minutes. Alternatively, a single dose of one or more other therapeutic agents may be administered first, followed by a single dose of the compound of the invention within seconds or minutes. In some cases, it may be desirable to first administer a single dose of the compound of the invention and then, after a few hours (e.g., 1-12 hours), administer a single dose of one or more other active therapeutic agents. In other cases, it may be desirable to first administer a single dose of one or more other active therapeutic agents and then administer a single dose of the compound of the invention a few hours later (e g., 1-12 hours).
[0052] Combination therapy can provide "synergism" and "synergy", i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects occurring when the compounds are used separately. Synergistic effects can be achieved when the active ingredients are (1) combined and administered or delivered simultaneously in a combination drug; (2) delivered alternately or in parallel as separate drugs; or (3) by some other scheme. When drugs are alternated, a synergistic effect may be achieved when the compounds are administered or delivered sequentially, for example, in separate tablets, pills, or capsules, or when different injections are given in separate syringes. In general, in alternation, the effective dose of each active ingredient is administered sequentially, that is, serially, whereas in combination therapy the effective doses of two or more active ingredients are administered together. Synergistic antiviral effect means an antiviral effect that exceeds the predicted purely additive effect of the individual compounds of the combination.
[0053] A kit comprising a compound of Formula I-IV is also provided. In some embodiments of the invention, individual kits are provided comprising a compound selected from the group of each of the formulas provided herein and each subgroup and embodiments thereof, including Formula II, Formula II, Formula IV. In one aspect, the kit includes a compound of Formula I. Each of the individual kits described herein may include a label and/or instructions for administering the compound to treat a disease or condition in a subject (e.g., human) in need thereof. In some embodiments of the invention, the disease or condition is a human viral infection of the Coronaviridae family, including SARS-CoV-2 viral infection. In other embodiments of the invention, each individual kit may also contain instructions for administering additional medical agents in combination with a compound of Formula I to treat a disease or condition in a subject (e g., human) in need thereof. In some embodiments of the invention, the disease or condition is a human viral infection of the Coronaviridae family, including SARS-CoV-2 viral infection. In each of the embodiments presented herein, there is another embodiment in which the kit includes individual dosage units of the compound described herein. Examples of individual doses may include tablets, tablets, capsules, filled syringes or syringe cartridges, IV bags, etc., each containing a therapeutically effective amount of the compound in question. In some embodiments, the kit may contain a single dosage unit, and in other embodiments, the kit may contain multiple dosage units, such as the number of dosage units required for a particular regimen or period.
[0054] In certain embodiments, the product container may be a vial, jar, ampule, preloaded syringe, blister pack, tin, can, bottle, box, or intravenous bag.
[0055] Also, certain embodiments of the invention provide for the use of a compound selected from each of claims I-IV herein in the preparation of a medicament for use in the treatment of Coronaviridae infection in humans.
[0056] In another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula II) comprising: a) a first pharmaceutical composition comprising a compound of Formula I (is 0.01-99.99% of the total weight of the Formula II), and b) a second pharmaceutical composition comprising at least one additional therapeutic agent active against infectious Coronaviridae viruses or agent that increases the antiviral activity of the Formula I component, or decreases the hepatotoxicity of the Formula I component, or increases the stability of the Formula I component (0.01-99.99% of the total weight of the composition) which may be (but are not limited to): ivermectin, niclosamide, remdesivir, nitazoxanide, chloroquine, lopinavir, ritonavir, hydroxychloroquine, vegetable or animal fats, ethyl alcohol, water, glycerin, propylene glycol, triethylene glycol, dimethylsulfoxide, solvents, betaine hydrochloride, caprilic acid, monolauric acid, monolaurin (glyceryl monolaurate), undecenoic acid (undecylenic acid), pau p'arco bark extract, cat's claw extract, garlic extract, black walnut shell extract, catalase enzyme, lipase, glucoamylase, pectinase, beta-glucanase, cellulase, alpha-galactosidase, amylase, invertase, xylanase, hemicellulase, or other enzymes, black cumin oil, nigella sativa, oregano oil, essential oils, lactoferrin, colloid silver, vitamin C, thiamine, benfothiamine, sulbutiamine, allithiamine, vitamin D, vitamin A, zinc salts, iodine, melatonin, phenofibrate, curcumin, quercetin, resveratrol, lysine, glycine, glutathione, N- acetylcysteine, cysteine, lipoic acid, S-adenosyl-L-methionine, milk thistle extract, grape seed extract, carnitine, antiandrogens, aspirin, bromhexine, budesonide, cannabidiol, colchicine, convalescent plasma, ensovibep, famotidine, favipiravir, fluvoxamine, iota-carrageenan, metformin, molnupiravir, bamlanivimab/etesevimab, bebtelovimab, casirivimab/imdevimab, sotrovimab, tixagevimab/cilgavimab, nitric oxide, paxlovid, peginterferon lambda, povidone- iodine, proxalutamide, camostat (camostat mesilate, camostat mesylate), foistar, glycyrrhiza glabra, liquorice, glycyrrhizic acid, amantadine, artemisia annua, amodiaquine, artemisinin, rutin, hesperidin, hesperetin, luteolin, baricitinib, arbidol, umifenovir, fluoxetine, kaempferol, kaempferol 3-o-rutinoside, catechin, epigallocatechin, epigallocatechin gallate, epigallocatechin-3 -gallate, myricetin, andrographolide, atorvastatin, indomethacin, nafamostat, nafamostat mesilate, nafamostat mesylate, omega 3, dha/epa, xylitol, xlear, ellagic acid, apnOl, alunacedase alfa, soluble ace2, rhace2-apn01, azelastine, baicalin, cetyl pyridinium chloride, estradiol, hydrogen peroxide, loratadine, methylene blue, monolaurin, propolis, sofosbuvir, darunavir, galidesivir, cepharanthine, hypericin, spironolactone, apigenin, emodin, apilimod, atovaquone, ciclesonide, daclatasvir, fenofibrate, fucoidan, hypochlorous acid, methotrexate, nicotine, pomegranate, punica granatum, punicalagin, punicalan, urolithin a, rosuvastatin, selenium, theaflavin-3,3’-digallate, dexamethasone, boceprevir, paritaprevir, cryptoquindoline, losartan, myricitrin, amiodarone, simeprevir, berberine, chrysin, digoxin, atazanavir, azvudine, ro-0622, azd7442, tixagevimab, cilgavimab, azithromycin, carvedilol, cetirizine, ct-p59, disulfiram, darolutamide, doxycycline, fostamatinib, masitinib, naproxen, neem, azadirachta indica a. juss, regdanvimab, ruxolitinib, saline, selamectin, silmitasertib, suramin, tannic acid, tenofovir disoproxil, valproic acid, amentoflavone, pristimerin, ribavirin, indinavir, saquinavir, cryptospirolepine, rhoifolin, pectolinarin, tamoxifen, 6-gingerol, theaflavin, oleuropein, etoposide, genistein, ibuprofen, paclitaxel, sertraline, tacrolimus, puerarin, limonin, obacunone, amprenavir, velpatasvir, ursolic acid, daidzein, sesamin, astragalin, gilteritinib, baicalein, caffeic acid, amitriptyline, apalutamide, apixaban, aframomum melegueta, aprotinin, ashwagandha, withania somnifera, bedaquiline, bergamottin, boswellic acids, calpeptin, canakinumab, chlorpheniramine, chlorphenamine, chlorhexidine, desloratadine, clarinex, diphenhydramine, doramectin, doxazosin, echinacea purpurea, enzalutamide, forsythoside a, glycine, griffithsin, hydroxyurea, huashibaidu, jing si herbal tea, jinhua qinggan, jtOOl (vvl l6), lenzilumab, lianhua qingwen, nelfinavir, noql9, panobinostat, paroxetine, phosphodiesterase enzyme type 5 inhibitors, pleurotus ostreatus, rheum palmatum, s-217622, tafenoquine, tofacitinib, virgin coconut oil, xuanfeibaidu, zinc pyrithione, berbamine, moxidectin, thymoquinone, xanthoangelol e, tingenone, iguesterin, micafungin, ombitasvir, tipranavir, glecaprevir, emetine, colistin, ebselen, lonafamib, glycyrrhizin, crocin, cryptomi srine, biscryptolepine, herbacetin, cycloeucalenol, campesterol, cyanidin-3-o-glucoside, afatinib, nilotinib, scedapin c, quinadoline b, decitabine, gemcitabine, afzelin, rhein, artesunate, bufalin, camptothecin, capsaicin, chlorpromazine, cyclophosphamide, dasatinib, doxorubicin, flutamide, folic acid, hydralazine, isotretinoin, leflunomide, morin, naringenin, phenytoin, propylthiouracil, pterostilbene, reserpine, simvastatin, sirolimus, sorafenib, sulindac, tretinoin, verapamil, vincristine, bicuculline, ledipasvir, tideglusib, bemcentinib, ergotamine, taraxerol, diosbulbinoside d, estrone-2, 3 -quinone, hinokiflavone, ginkgetin, norquinadoline a, natamycin, raltegravir, dolutegravir, cyanidin 3-o-rutinoside, quercetin 3-o-rutinoside, magnolol, phillyrin, conivaptan, aloesin, gingerol, tinocordiside, sesaminol, sesamolin, ephedrine, solanine, donepezil, vby-825,, omipalisib, psoralidin, cryptotanshinone, tetrandrine, fangchinoline, z-fa- fmk, imatinib, duloxetine, allicin, ezetimibe, pravastatin, ramipril, abemaciclib, dihydromyricetin, scutellarein, corilagin, ouabain, isorhamnetin, nystatin, sunitinib, anakinra, eculizumab, dieckol, sinigrin, glabridin, gimsilumab, kinl901, infliximab, leronlimab, pal4, pro- 140, vyrologix, tocilizumab, procyanidin, a-hederin, ferulic acid, cyanidin, cyanidin 5-o-P- d-glucoside, cyanidin 3-o-glucoside, chi orogenic acid, gallic acid, k-carrageenan, 4'- fluorouridine, 76clabs, 8g3, a6-001, agp-14, agp-15, amodiaquine, acarbose, ard-61, arq ajib, arylazothiazolimines, aviptadil, ayurcov, beauvericin, bifonazole, bismuth subsalicylate, bis- thiadiazoles, blue light, brazilin, breathing exercises, brii- 196/brii- 198, bromelain, bucillamine, c60 fullerene, camellia sinensis, cd24fc, chlorine dioxide, chyawanprash, clevudine, clitoria tematea, asian pigeonwings, bluebellvine, blue pea, butterfly pea, cordofan pea, darwin pea, clofoctol, codivir, copper(ii) gluconate, clsp-2, ctb-ace2 gum, cysteamine, d-a-tocopherol polyethylene glycol succinate, tpgs, dfo, diammonium glycyrrhizinate, dimethyl sulfoxide, darunavir ethanolate, ebastine, eklc4, engineered ace2, enoxaparin, epicatechin, fbr-002, estrogen, ethoxzolamide, ethyl lauroyl arginine, exo-cd24, evusheld, tixagevimab, cilgavimab, ferrocene derivatives, fl ovid-20, gancao-banxia, gb-1, green tea, hanshi zufei, heparin, hinokitiol, homo-harringtonine, honey, hydroxyzine, inm005, interferon-k (interferon lamba), isoprinosine, js016, kabasura kudineer, kalmegh, kinetin, led spirulina, levamisole, levilimab, 1- glutamine, ly2835219, mani dipine, manuka honey, maoto, mesencure, metformin glycinate, mi-1851, montelukast, multimeric soluble ace2, n-acetylglucosamine, natto extract, naphthoquine, niacinamide, nicotinamide mononucleotide, opaganib, oseltamivir, oxygenozone immunoceutical therapy, palmitoylated ace2, pamapimod, pegylated interferon alpha-2b, peg ifn-a2b, pentosan polysulfate, pioglitazone, phoxwell, phthalocyanine, porphyridium sp., pranayama, probenecid, propolis sulabiroin-a, pyramax, pyronaridine-artesunate, pyrimidine, pyronaridine, q34, quinine, raloxifene, rd-xl9, rejuveinix, riboflavin, sabizabulin, saliravira, sarbd-1, sars-block, schaftoside, sea cucumber sulfated polysaccharide, scsp, seraph 100 microbind affinity filter, serratiopeptidase, serratia e-15 protease, serralysin, serratiaprotease, serrapeptase, shallot, si-fOl 9, silibinin, sngOOl, spirulina, sodium bicarbonate, stenoparib, sti- 9167, thymic peptides, tollovir, toremifene, tpntl, tranilast, trisb92, urtica dioica agglutinin, zinv03977803, znonps, znsec-humicin, z-veid-fmk, minocycline, coclobine, dieckol 1, celastrol, 3-isotheaflavin-3 gallate, dihydrotanshinone i, citriquinochroman, holyrine b, proximicin c, pityriacitrin b, anthrabenzoxocinone, penimethavone a, maraviroc, valrubicin, icatibant, bepotastine, epirubicin, epoprostenol, vapreotide, aprepitant, caspofungin, perphenazine, hrsace2, tegobuvir, olysio, filibuvir, alisporivir, allyl disulphide, allyl trisulphide, digitoxigenin, tenufolin, pavetannin cl, lianhuaqingwen, dorzolamide, deptropine, neostigmine bromide, ethotoin, hydrocotarnine, ampyrone, withanolide b, lurasidone, lumacaftor, perfenazine, benserazide, isocarboxazide, cryptophycin 1, cryptophycin 52, deoxycylindrospermopsin, anatibant, pilaralisib, zabofoxacin, tiracizine, picotamide, cilazapril, indisulam, ziprasidone, propadimine, phenformin, torososide b, covitris2020, chlovid2020, silybin, licoleafol, mitomycin c, gardenin a, 6-paradol, psiadia punctulata, tanshinone-i, mangiferin, y-mangostin, 3,3'-diindolylmethane, 4-hydroxy-2-nonenal, acetaldehyde, aflatoxin- bl, aica-ribonucleotide, alitretinoin, alpha-tocopherol, azacitidine, azathioprine, belinostat, benazepril, benzopyrene, bezafibrate, bisphenol-a, bortezomib, bucladesine, buspirone, buthionine-sulfoximine, cadmium-chloride, caffeine, carbamazepine, carbon-tetrachloride, celecoxib, ciglitazone, cisplatin, clodronic-acid, clofibrate, clozapine, colforsin, corticosterone, coumestrol, cycloheximide, cytarabine, dactinomycin, daunorubicin, deguelin, dichloroacetic- acid, diclofenac, dieldrin, diethylstilbestrol, dimethylnitrosamine, dinoprost, entinostat, estriol, ethinyl-estradiol, fenretinide, fluorouracil, fulvestrant, fumonisin-bl, furan, gefitinib, glafenine, glucosamine, haloperidol, ifosfamide, indole-3 -carbinol, ionomycin, irinotecan, levofloxacin, lithium-chloride, mercaptopurine, methapyrilene, methimazole, methoxychlor, mevalonic acid, mifepristone, nimesulide, norepinephrine, ochratoxin-a, olanzapine, omeprazole, orphenadrine, oxidopamine, pentachlorophenol, phenethyl-isothiocyanate, pifithrin, pilocarpine, pirinixic acid, piroxicam, progesterone, pyrazol anthrone, ranitidine, rimonabant, rosiglitazone, rotenone, sulfasalazine, tamibarotene, testosterone, tetrachloroethylene, tetracycline, thapsigargin, theophylline, topotecan, tributyltin, trichloroethylene, trichostatin-a, triclosan, troglitazone, tunicamycin, tyrphostin-ag-1478, urethane, valdecoxib, vancomycin, vorinostat, wortmannin, zearalenone, zidovudine, zinc32960814, zincl2006217, zinc03231196, nigricanoside a, nigricanoside b, callophysin a, gallocatechin, hyperin, lupinifolin, viomycin, capastat, demethoxycurcumin, bisdemethoxycurcumin, scuteliarin, alloyohimbine gummadiol, asparagamine a, vincapusine, oxytetracycline, naringin, kanamycin, cefpiramide, salvianolic acid b, teniposide, benzoylgedunin, 6-deaminosinefungin, unii-o9h5kyl Isv, cephalosporin derivatives, neomycin, tcm5280805, tcm5280445, tcm5280343, tcm5280863, tcm5458190, quinadoline, polyketide isochaetochromin dl, O-hydroxyusambarensine, 6-oxoisoiguesterin, 22-hydroxyhopan3-one, grazopavir, mfcd00832476, mfcd02180753, pacritinib, a3659, a3777, leucopelargonidin, taxifolin, eriodictyol, enterodiol, naringen, flemiflavanone d, euchrestaflavanone a, triamterene, estrone, azadirachtin-h, azadirachtin-i, azadirachtin-q, sn00334175, sn00162745, alphaspinasterol, gycyrrhizin, azadirachtani, mycophenolic acid, kushenol-w, 6-azauridine, cyanidin 5-o-P-d-glucoside, morelloflavone, methylochnaflavon, isoginkget, sciadopitysin, podocarpusflavone a, cryptomerin, cytochalasin z8, leucal, zanamivir, penciclovir, etravirine, p-coumaric acid, ketazolam, methylnaltrexone, ethynodiol diacetate, petunidin 3, 5 -odi glucoside, delphinidin 3-o-rutinoside, grazoprevir, las 51620435, las 51620429, rosoxacin, levomefolic, etodolac, tenofovir, tinofoviralafenamide, ornipressin, otosiban, lanreotide, argiprestocin, demoxytocin, carbetocin, lypressin, examorelin, polymyxin bl, verbascoside, abrisapogenol g, kaempferol-3-o-rutinoside, hederagenin, abrusoside a, robustaflavone, agathisflavone, swertianolin, ononin, pedunculoside, imperialine, peimisine, batatasin i, pomiferin, coumarin, rhodionin, aloin, sarsasapogenin, silydianin, rutaecarpine, morusin, a-mangostin, yohimibine, coclaurine, strychnine, myristicin, medicarpin, coptisine, tiliroside, glabrone, lignans, gastrodin, cordycepin, ajugol, evodiamine, nuciferine, cynarin, betulin, gramine, narciclasine, vitexin, protopanaxatriol, karanjin, gigantol, harsingar, nictoflorin, lupeol, aloevera, aloenin, giloy, sitosterol, nimbin, ginger, shogaol, cyanin, medicagol, faradiol, flavanthrin, withanoside v, somniferine, vicenin, isorientin, sesamolinol, ellipticine, ecteinascidin, homoharringtonine, dolastatin, halichondrin, plicamycin, arvoside, nicotiflorin, kaempferol sulphates, quercetin-3 -o-glucuronide, isorhamnetin-3-o-glucoside, narcissin, calendula glycoside b, lauruside, miricetine-3 -glucoside, cordifoliside, anthraquinones, emodine 8-glucosides, acetoside, lisinopril, deoxynortryptoquivaline, thalimonine, sophaline, tomatidine, 1 O-hydroxyusambarensine, stychnopentamine, usambarensine, vanillin, crambescidin 786, crambescidin 826, sepiapterin, tetrodotoxin, caulerpin, lutein, galanthamine, nomilin, deacetylnomilin, ichangin, amyrin, 24-dimethylene cycloartenol, isoiguesterin, lentinula edodes, agaricus bisporus, jmx0286, jmx0301, jmx0941, erythromycin, chloramphenicol, mpi43, mpi44, mpi46, keigairengyoto, shosaikotokakikyosekko, kakkontokasenkyushin'i, vuwcov059, vwcov267, vuwcov270, 4- hydroxycordoin, mallotophilippen d, 3'-(3-methyl-2-butenyl)-4'-o-P-d-glucopyranosyl-4,2'- dihydroxychalcone, lefamulin, cefixime, cefpodoxime, ciprofloxacin, sparfloxacin, moxifloxacin, tbaj-876, (s)-crizotinib, spermidine, spermine, mk-2206, saffron, mdl-28170, z Ivg chn2, ono 5334, mln-3897, tipifamib, salinomycin, bavachin, tanshinone iia, isobavachalcone, lycorine hydrochloride, lycorine, bufotaline, cinobufagin, periplocoside, veratridine, coniferyl aldehyde, cornuside, brusatol, momordinic, roburicacid, hruceine a, isoalantolactone, oridonin, dehydrocostus lactone, alantolactone, dehydrodiisoeugenol, liensinine, isoliensinine, vps34-inl, stf-62247, mcoppb, gw 803430, amodiaquine dihydrochloride, n-methyl spiperone, clemastine fumarate, gmc 2-29, lu ae58054, chlorprothixene, methdilazine, methotrimeprazine maleate, piperacetazine, difeterol, loperamide, naltrindole isothiocyanate, aml241, cpdd, sb 271046, gmc 2-113, caa-0225, cathepsin inhibitor 1, z-gly-leu-phechloromethyl ketone, balicatib, calpain inhibitor i, berzosertib, ikk-2 inhibitor viii, nsc 33994, alpha-l-arabinopyranose, ml414, itlt dihydrochloride, s-15176 difumarate, jtv519 hemifumarate, rescimetol, trifluomeprazine 2- butenedioate, asteriscunolide d, genz-123346, maprotiline, deserpidine, melitracen, dlunarizine, proglumetacin, dmp 777, dexanabinol, trifluoperazine 2hcl, thioridazine hcl, bicalutamide, cinnamaldehyde, piperine, zingeberene, gr 127935, diazepam, levetiracetam, sotalol, tolterodine, oxazepam, thiamazole, hydroxycarbamide, clonazepam, meloxicam, temazepam, anastrozole, rivaroxaban, perindopril, silodosin, lorazepam, pramipexole, bupropion, venlafaxine, bisoprolol, aripiprazole, linagliptin, clopidogrel, allopurinol, indapamide, chlortalidone, nifedipine, warfarin, phylloflavan, milk thistle, ilexin b, isosilybin b, spiperone, vitamin bl2, vitamin b9, vitamin kl, vitamin k2, vitamin e, oleanderolide, proceragenin a, balsaminone a, anacardic acid, aloeresin d, tcid, dihydrokaempferol, dihydroquercetin, myricentin, isoquercitrin, pc000550, pc000361, pc000558, pc000573, grl0617, mefloquine, brequinar, dipyridamole, quercetagetin, glycycrrhizin, 59-tetrahydrocannabinol, arteether, dihydroartemisinin, arteannuin, cannabidinol, punicalin, panduratin a, andrographis paniculata, zingiber officinale, boesenbergia rotunda, Scutellaria baicalensis, pomegranate peel extract, zinc000013444414, zinc000137976768, zinc000143375720, diosmin, apiin, okadaic acid, p- 57as3, concanamycin a, amphotericin b, oleandrin, gitoformate, eprinomectin, beta-escin, fiisicoccin, perilla aldehyde, perillyl alcohol, cidofovir, valaciclovir, tazarotene, hydroquinone, bromocriptine, acyclovir, finasteride, betamethasone, clonidine, somatotropin, nitisinone, tadalafil, vinblastine, pyrimethamine, pentamidine, etacrynic acid, proguanil, everolimus, tamsulosin, rifapentine, terbinafine, fluvastatin, cyclosporine, hydrocortisone, pentoxifylline, nitrogen, arginine, abatacept, interferon beta-la, thalidomide, crizanlizumab, nitroglycerin, fluorescein, captopril, brexanolone, omalizumab, siltuximab, propranolol, interferon beta-lb, prednisone, prednisolone, methylprednisolone, torin-2, rapamycin, radotinib, thiostrepton, cl- amidine, bb-cl-amidine, broussoflavan a, hygromycin b, nabiximols, abyssinone ii, procynidin bl, indigo blue, crytospirolepine, lO'-hydroxyusambaresine, strychnopentamine, usararotenoid a, 12a-epi-milletosin, torchnil, febcin, pibrentasvir, 5-chloro-omega-hydroxy-l-o- methyl emodin, cystodion e, jql, zbc260, zafirlukast, pranlukast, canderastan cilexetil, saquanivir, boron citrate, oleoylethanolamide, liquiritin, laminarin, eckol, trifucol, -d- galactose, K-carrageenan, cl35-ls/cl44-ls, sab-185, vir-7831/vir-7832, covi-amg/covi-drops, covi -guard, 2-deoxy-d-glucose, dnl758, lanadelumab, abivertinib, bld-2660, pemziviptadil, artesunate/pyronaridine, carragelose, at-527, ptc299, brilacidin, saracatinib, erlotinib, osimertinib, pictilisib, dinaciclib, cigb-325, sb203580, ralimetinib, mapkl3-in-l, arry-797, tofacitinibfedratinib, mpro 13b, gc-373, gc-376, mpro n3, bosutinib, clofazimine, domperidone, entecavir, fedratinib, ipratropium bromide, lomitapide, metoclopramide, slra, thioguanine, sitagliptin, dihydroergotamine, crinine, il exsaponin b2, strictinin, zinc000027215482, zinc000252515584, loniflavone, 2 -o-ribose methyltransferase, tirucallin a, zinc000253504770, zinc000253504766, triamcinolone, amoxicillin, hydrochlorothiazide, terflavin a, chebulagic acid, chebulinic acid, coumaroylquinic acids, sinapoyl d glucoside, tetra-o-galloyl-P-d-glucose, methyl rosmarinates, cosmosiin, dihydronitidine, lectin, digitoxigenine, calarene, amaranthin, diarylheptanoids, indigo, aloe emodin, dihydrocelastrol, phyllaemblinol, isocolumbin, magnoflorine, piperolactam a, withanone, biflavone, cinnamic amides, agomelatine, ramelteon, immunoglobulin, ifn-pia, ifn-pib, interleukin-2, cynk-001, baloxavir marboxil, asc09, danoprevir, cobicistat, carrimycin, dihydroartemisinine, piperaquine, fingolimod, piclidenoson, cflOl, nivolumab, obtivo, meplazumab, jakotinib, tj003234, tozumab, adamumab, ravulizumab, alxnl210, clazakizumab, avdoralimab, iph5401, ly3127804, ifx-1, bevacizumab, valsartan, 7-hydroxy staurosporine, bafetinib, emtricitabine, adefovir, tenofovir alafenamide, abacavir, ganciclovir, didanosine, delavirdine, pirfenidone, p-glucan, p-coumaroyltriacetic acid lactone, zinc02111387, zinc02122196, sn00074072, zinc04090608, xuebijing, lung cleansing and detoxifying decoction, etanercept, ibrutinib, enalapril, telmisartan, oroxylin a, irisolidone, anhydrosafflor yellow b, euchrenone, uncaric acid, demethylzeylasteral, maslinic acid, atractyl enolide iii, astragaloside iv, daturaolone, cucurbitacin g 2-glucoside, citronellol, limonene, salvianolic acid, neochlorogenic acid, kobophenol a, bis-demethoxycurcumin, 3- viniferin, pseudoephedrine, methylephedrine, speciophylline, uncarine f, anisodamine, forsythoside i, amygdalin, urso-deoxycholic acid, withanolide a, [3-sitosterol, famesiferol b, amlodipine, dexchlorpheniramine, tanshinones, isatis indigotica root, rhizoma cibotii, torreya nucifera, shuang huang lian, estragole, eugenol, ubiquinone, flecainide, poly-methoxyflavones, poly-hydroxyflavones, meamsitrin, 3-o-[3-d-glucoside, benzoic acid, biorobin, delphinidin, galangin, isoferulic acid, dithymoquinone, negillicine, negillidine, mucl, a-lactalbumin, or mixtures thereof.
[0057] In another embodiment, the method of treating a Coronaviridae infection in a human in need thereof comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a Formula I compound in combination with at least one additional therapeutic agent.
[0058] In another embodiment, a method of treating Coronaviridae infection in a person in need thereof includes administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of compound of formula VII in combination with at least one additional therapeutic agent such as (but not limited to) intravenous or intramuscular forms of thiamine, vitamin C, vitamin D, glutanione, S-adenosylmethionine, cysteine, N- acetylcysteine. iv Pharmaceutical Formulations
[0059] The compounds of the present invention are formulated with common carriers and excipients, which are selected according to common practice. Tablets will contain excipients, glydants, fillers, binders, and the like. Aqueous formulations are prepared in sterile form, and if they are not intended to be administered orally, they are usually isotonic. All formulations optionally contain excipients, such as those described in Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethyl cellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is usually between 7 and 10. In some embodiments of the invention, the pH of the formulations varies from about 2 to about 5, but is usually about 3 to 4.
[0060] Although the active ingredients may be administered separately, it may be preferable to present them as pharmaceutical compositions. Compositions of the invention, whether for veterinary or human use, include at least one active ingredient, as defined above, together with one or more acceptable carrier(s) for it and, optionally, other therapeutic ingredients, in particular additional therapeutic ingredients, which are discussed herein. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the composition and physiologically harmless to the recipient.
[0061] The compositions include those suitable for the above-mentioned routes of administration. The compositions may be conveniently presented in unit dose form and may be prepared by any of the methods well known in the pharmaceutical art. The methods and compositions are generally described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa ). Such methods involve the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then shaping the product if necessary,. [0062] Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can be administered as a bolus, electuary or paste.
[0063] Tablets are made by compression or molding, optionally with one or more additional ingredients. Compressed tablets can be prepared by compressing in a suitable machine an active ingredient in a free-flowing form, such as a powder or granules, further mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets can be made by molding in a suitable machine a mixture of a powdered active ingredient moistened with an inert liquid diluent. The tablets may additionally be coated with a shell or pellets and optionally formulated to allow slow or controlled release of the active ingredient therefrom.
[0064] For infections of the eyes or other external tissues, such as the mouth and skin, the compositions are preferably applied in the form of an ointment or cream containing the active ingredient(s) in an amount, for example, from 0.075 to 20% wt. (including the active ingredient(s) in a range of 0.1% to 20% in 0.1% wt. increments, e.g., 0.6% wt., 0.7% wt., etc.), more preferably from 0.2 to 15% wt. and most preferably from 0.5 to 10% wt. When formulated as an ointment, the active ingredients may be used with a paraffin or water-miscible ointment base. As an alternative, the active ingredients may be formulated as a cream with an oil-in-water type cream base.
[0065] Optionally, the aqueous phase of the cream base may include, if desired, at least 30% wt. of a polyhydric alcohol, that is, an alcohol with two or more hydroxyl groups, such as propylene glycol, butane- 1,3 -diol, mannitol, sorbitol, glycerol, polyethylene glycol (including PEG 400) and mixtures thereof. Compositions for topical use may preferably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Among examples of such dermal penetration enhancers are dimethyl sulfoxide and related analogues.
[0066] The oil phase of emulsions of the present invention can be composed of known ingredients in a known manner. Although the phase may comprise an emulsifier alone (otherwise referred to as emulsifier), preferably it comprises a mixture of at least one emulsifier with a fat or oil or with a fat and oil. The hydrophilic emulsifier is preferably included together with a lipophilic emulsifier, acting as a stabilizer. Also preferably both oil and fat are included. Emulsifier(s) with or without stabilizer(s) together constitute the so-called emulsifying wax, and the wax together with oil and fat constitute the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream compositions.
[0067] Emulsifiers and emulsion stabilizers appropriate for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. Other emulsifiers and emulsion stabilizers appropriate for use in the formulation of the invention include Tween® 80.
[0068] The choice of suitable oils or fats for the formulation is determined by achieving the desired cosmetic properties. The cream may be a non-greasy, non-staining and washable product with a suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain alkyl esters, mono- or dibasic, such as di-isoadipate, isocetyl stearate, propylene glycol coconut fatty acid diester, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixture of branched chain esters known as Crodamol CAP, the latter three being preferred. They may be used alone or in combination depending on the desired properties As an alternative, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
[0069] According to the present invention, pharmaceutical compositions include a combination together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended route of administration. For oral administration, the compositions may be prepared, for example, tablets, trochets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Formulations intended for oral use may be made according to any method known in the art for making pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavorings, colorings, and preservative agents, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with a nontoxic pharmaceutically acceptable excipient that is suitable for tablet production are acceptable. Such excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as com starch or alginic acid; binding agents such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated using known methods, including microencapsulation, to delay breakdown and adsorption in the gastrointestinal tract and thereby provide sustained action over an extended period. A time delayed material such as glyceryl monostearate or glyceryl dystearate alone or with a wax, for example, may be used.
[0070] Products for oral use can also be designed as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, such as calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
[0071] Aqueous suspensions according to the invention contain active materials mixed with excipients suitable for making aqueous suspensions. Such excipients may include a suspending agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum, and dispersing or wetting agents such as naturally occurring phosphatide (such as lecithin), an alkylene oxide condensation product with a fatty acid (e.g., polyoxyethylene stearate), an ethylene oxide condensation product with a long-chain aliphatic alcohol (e.g., hepta dekaethylene acetanol), an ethylene oxide condensation product with a partial ester derived from a fatty acid and hexitol anhydride (e.g., polyoxyethylene sorbitan monoleate). The aqueous suspension can also contain one or more preservatives such as ethyl- or n-propyl p-hydroxy- benzoate, one or more colorants, one or more flavorings, and one or more sweeteners such as sucrose or saccharin. Other non-limiting examples of suspending agents include Cyclodextrin and Captisol.
[0072] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. A thickening agent such as beeswax, solid paraffin or cetyl alcohol may be contained in the oral suspension. Sweeteners, such as those described above, and flavorings may be added to produce a palatable oral preparation. These compositions may be preserved by adding an antioxidant such as ascorbic acid.
[0073] Dispersible powders and granules of the invention, applicable for preparing an aqueous suspension by adding water, include the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are examples of those disclosed above. Additional excipients, such as sweetening, loosening and coloring agents, may also be present. [0074] The pharmaceutical compositions of the invention can also be presented as oil-in- water emulsions. The oil phase can be a vegetable oil such as olive or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Appropriate emulsifiers include gum of natural origin such as acacia gum and tragacanth gum, phosphatides of natural origin such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweeteners and flavorings. Syrups and elixirs may contain sweetening agents such as glycerin, sorbitol, or sucrose. These formulations can also contain a demulgent, preservative, flavoring, or coloring agent.
[0075] The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension may be prepared according to the prior art using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 -butanediol or prepared as a lyophilized powder. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as a solvent or suspension medium. Any tasteless fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, can also be used to prepare injectable preparations. Among the acceptable vehicles and solvents that can be used are water, isotonic Ringer's solution, isotonic sodium chloride solution and hypertonic sodium chloride solution.
[0076] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the recipient and the particular route of administration. For example, a time-release formulation intended for oral administration to humans may contain from about 1 to 1000 mg of the active ingredient combined with an appropriate and convenient amount of carrier material, which may be from about 5 to about 95% of the total amount of the composition (weight weight). The pharmaceutical composition may be prepared so as to provide an easily measurable amount for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to about 500 pg of active ingredient per milliliter of solution to provide an infusion of a suitable volume at a rate of about 30 ml/hr.
[0077] Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially in an aqueous solvent for the active ingredient. The active ingredient is preferably present in such compositions in a concentration of from 0.5 to 20%, more preferably from 0.5 to 10% and especially about 1.5% w/w.
[0078] Formulations suitable for topical use in the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; lozenges containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.
[0079] Formulations for rectal administration may be in the form of a suppository with a suitable base including, for example, cocoa butter or salicylate.
[0080] Formulations suitable for intrapulmonary or nasal administration have particle sizes, for example, in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35, etc., which are administered by rapid inhalation through the nasal passage or inhalation through the mouth to reach the alveolar sacs. Suitable compositions include aqueous or oily solutions of the active ingredient. Formulations suitable for administration as an aerosol or dry powder may be prepared according to conventional methods and may be delivered together with other therapeutic agents, such as compounds previously used to treat or prevent Coronaviridae infections, as described below.
[0081] Formulations suitable for vaginal administration may be in the form of pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be suitable.
[0082] Formulations suitable for parenteral administration include aqueous and nonaqueous sterile solutions for injection, which may contain antioxidants, buffers, bacteriostatics and solvents that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending and thickening agents.
[0083] The formulations are presented in single or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Extemporaneous injectable solutions and suspensions are made from sterile powders, pellets, and tablets described earlier. Preferred single-dose preparations are preparations containing a daily dose or a single daily subdose, as described above, or an appropriate fraction of the active ingredient.
[0084] It is important to note that in addition to the ingredients especially mentioned above, the compositions of the present invention may include other agents common in the art, taking into account the type of composition in question, for example, compositions suitable for oral use can include flavorings.
[0085] The invention also provides veterinary compositions comprising at least one active ingredient, as defined above, together with a veterinary carrier for it.
[0086] Veterinary carriers are materials useful for administering the composition and may be solids, liquids, or gases that are inert or acceptable in veterinary medicine and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.
[0087] Compounds of the invention are used to make controlled-release pharmaceutical compositions containing as an active ingredient one or more compounds of the invention ("controlled-release compositions") in which the release of the active ingredient is controlled and regulated to provide less frequent dosing or to improve the pharmacokinetic or toxicity profile of that active ingredient.
[0088] In another embodiment, the method of treating a Coronaviridae infection in a human in need thereof comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a Formula I/II compound in combination with a pharmaceutically acceptable diluent or carrier.
[0089] In another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula III) in form of solution/emulsion/suspension of comprising: a) a first pharmaceutical composition comprising a compound of Formula VII, and b) at least one of the following components:
(1) oil phase containing vegetable or/and animal fats;
(2) one or more surfactants;
(3) one or more solvents;
(4) one or more gelling agents. [0090] Formula III can be a true solution or colloidal solution, emulsion, solid or liquid dispersion, suspension, emulsion-suspension form, gas cocktail, foam, sol, gel, paste, their mixture. A Formula III can be prepared by mixing, homogenizing, dispersing, and emulsifying the constituent components.
[0091] In another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula III variant A) comprising:
(a) oil phase containing vegetable or/and animal fats or/and lecithin 1-99.999% by weight
(b) a compound of Formula I/I I or/and avermectin 0.001-99% by weight
(c) (optional) one or more surfactants 0-70% by weight (physiologically acceptable surfactant selected from the surfactants listed in paragraph [0037] F).
(d) (optional) one or more solvents 0-99.9% by weight (physiologically acceptable solvent selected from the solvents listed in paragraph [0037] Method 1).
(e) (optional) one or more gelling agents (0-99.9% by weight) include (but are not limited to): alginate, pectin, carrageenan, gellan, gelatin, agar, modified starch, methyl cellulose, and hydroxypropylmethylcellulose.
[0092] In another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula III variant B) comprising:
(a) (optional) oil phase containing vegetable or/and animal fats or/and lecithin 0-99.999% by weight
(b) a compound of Formula I/I I or/and avermectin 0.001-99% by weight
(c) (optional) one or more surfactants 0-70% by weight (physiologically acceptable surfactant selected from the surfactants listed in paragraph [0037] F).
(d) one or more solvents 5-99.9% by weight (physiologically acceptable solvent selected from the solvents listed in paragraph [0037] Method 1).
(e) (optional) one or more gelling agents (0-99.9% by weight) include (but are not limited to): alginate, pectin, carrageenan, gellan, gelatin, agar, modified starch, methyl cellulose, and hydroxypropylmethylcellulose.
[0093] In another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula III variant C) comprising:
(a) oil phase containing vegetable or/and animal fats or/and lecithin 1-99.999% by weight
(b) a compound of Formula I/I I or/and avermectin 0.001-99% by weight
(c) (optional) one or more surfactants 0-70% by weight (physiologically acceptable surfactant selected from the surfactants listed in paragraph [0037] F).
(d) one or more solvents 1-99.9% by weight (physiologically acceptable solvent selected from the solvents listed in paragraph [0037] Method 1).
(e) (optional) one or more gelling agents (0-99.9% by weight) include (but are not limited to): alginate, pectin, carrageenan, gellan, gelatin, agar, modified starch, methyl cellulose , and hydroxypropylmethylcellulose.
[0094] In another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula III variant D) comprising:
(a) (optional) oil phase containing vegetable or/and animal fats or/and lecithin 0-99.999% by weight (b) a compound of Formula I/I I or/and avermectin 0.001-99% by weight
(c) one or more surfactants 0.05-70% by weight (physiologically acceptable surfactant selected from the surfactants listed in paragraph [0037] F).
(d) (optional) one or more solvents 0-99.9% by weight (physiologically acceptable solvent selected from the solvents listed in paragraph [0037] Method 1).
(e) (optional) one or more gelling agents (0-99.9% by weight) include (but are not limited to): alginate, pectin, carrageenan, gellan, gelatin, agar, modified starch, methyl cellulose, and hydroxypropylmethylcellulose.
[0095] The active compounds of Formula I-III can be administered/can be in form of foods, food additives, edible soluble films, drinks, medicinal agents, and feeds for domestic and wild animals. The drinks may be non-alcohol drinks or alcohol drinks. Examples of non-alcohol drinks include carbonated drinks, noncarbonated drinks (such as fruit juice, and nectar), soft drinks, sports drinks, tea, coffee, and hot chocolate. The alcohol drinks may be in the form of, for example, beer, low-malt beer, third-category beer, sake, wine, champagne, liqueur, or medicated liquor. For use as a food material or food additive (e.g., human food or animal food, such as a dog or cat food or feed for poultry, cows, or pigs), the active compound may be in the form of, for example, a tablet, a capsule formulation, a solid agent (such as a powder and a granule) dissolved in drinks, a semi-solid such as jelly, a liquid (such as drinking water), and a high- concentration solution diluted before use. Optional components, such as vitamins, carbohydrates, dyes, and flavoring agents commonly added to food may be appropriately mixed. The food may be given in any form, including a liquid and a solid.
[0096] In another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent (of Formula IV) in form of food product or beverage, or dietary supplement. v. Routes of Administration
[0097] The compounds of Formula I-IV described herein may be administered (e.g., orally) in the form of a solid or liquid dosage form. In both, the compounds may be coated in a material to protect them from the action of acids and other natural conditions which may inactivate the compounds. The compounds may be formulated as aqueous solutions, liquid dispersions, (ingestible) tablets, buccal tablets, troches, capsules, elixirs, powders, granules, ointments, adhesive skin patches, sprays, suspensions, syrups, and wafers. The dosage forms may include pharmaceutically acceptable excipients, diluents, and/or carriers known in the art, such as binders, disintegrating agents, emulsifiers, lubricants, flavorants, antioxidants, and preservatives. Liquid dosage forms may include diluents such as saline or an aqueous buffer.
[0098] Any route of administration Formula I-IV may be selected for use in the methods described herein. For instance, the route of administration may be selected from oral, nasal, topical, buccal, rectal, vaginal, ophthalmic, subcutaneous, intramuscular, intraperitoneal, epidural, intravenous, intraarterial, intratumoral, spinal, intrathecal, intra-articular, intra-arterial , sub -arachnoid, sublingual, oral mucosal, pulmonary, bronchial, lymphatic, intra-uterine, subcutaneous, intratumor, integrated on an implantable device, intradural, intracortical, intradermal, dermal, epidermal, transdermal, vaginal, rectal, ocular (for examples through the conjunctiva), intraocular, uretal, and parenteral. An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally. A preferred route of administration is oral. [0099] In the methods of the present invention for treating Coronaviridae infection, compounds of the present invention may be administered at any time to a person who may be in contact with people suffering from Coronaviridae infection or already suffering from Coronaviridae infection. In some embodiments, the compounds of the present invention can be administered prophylactically to people in contact with people suffering from Coronaviridae infection. In some embodiments of the invention, the compounds of the present invention can be administered to people who test positive for Coronaviridae infection but do not yet have symptoms of Coronaviridae infection. In some embodiments of the invention, the compounds of the present invention can be administered to people after symptoms of Coronaviridae infection appear.
[0100] The effective dose of the active ingredient depends at least on the nature of the disease being treated, the toxicity, whether the compound is used prophylactically (lower doses) or against an active viral infection, the method of delivery and the pharmaceutical formulation, and is determined by the physician using routine dose escalation studies. It can be expected to range from about 0.0001 to about 100 mg/kg body weight per day; typically from about 0.01 to about 10 mg/kg body weight per day; more typically from about 0.01 to about 5 mg/kg body weight per day; most typically from about 0.2 to about 1 mg/kg body weight per day. For example, a daily candidate dose for an adult with a body weight of about 70 kg would be from about 1 mg to 1000 mg, preferably from 5 mg to 500 mg, and may take the form of a single or multiple dose. All dosages are given for an equivalent amount of pure avermectin.
[0101] The effective dose of the compound of the present invention for treating Coronaviridae infection may depend on whether it is used prophylactically or to treat a person already suffering from Coronaviridae infection. Moreover, the dose may depend on whether the person suffering from Coronaviridae infection is not yet showing symptoms or is already showing symptoms of Coronaviridae infection. People who test positive for Coronaviridae infection and people with symptoms of Coronaviridae infection may require higher doses for treatment compared to people receiving preventive treatment
[0102] Any suitable time period for administration of the compounds of the present invention is contemplated. For example, the administration may be from 1 day to 100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80 or 90 days. Admission may also last from 1 week to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 weeks. Longer periods of administration are also suggested. The timing of administration may depend on whether the compound is administered prophylactically or to treat a person suffering from Coronaviridae infection. For example, prophylactic administration may be for a period of time while the person is in constant contact with other people suffering from Coronaviridae infection and for a suitable period of time after the last contact with the person suffering from Coronaviridae infection. For people already suffering from Coronaviridae infection, the period of use may be any length of time necessary to treat the patient and a suitable period of time after a negative test for Coronaviridae infection to ensure that Coronaviridae infection will not return.
VI. Examples
A. Preparation of Compounds
Example 1.
[0103] Ivermectin of pharmaceutical grade, CAS Number 70288-86-7, was purchased from Aecochem Corp., Xiamen, China. Apple pectin was purchased from Ronas Chemicals Ind. Co., Ltd., Chengdu, China. All other chemicals were of analytical grade and used without further purification.
[0104] Method 1 was used to obtain compounds of Formula 1. The roller ball mill was used to carry out mechanochemical synthesis of nanocomposite/solid dispersions. Processing mode: rotational speed of the drive - 400 rpm, rotational speed of the grinding jar -100 rpm, grinding jar volume - 2000 ml, grinding media - steel balls (diameter 12 mm, 800 g/load), processing time ranging from 2 to 24 h. Samples are loose powders (particle size from 0.1 - 10 microns). Compositions and results of obtaining bioavailable nanocomposites with Formula I are shown in Table 1.
Table 1. Compounds of Formula I obtained in Example 1.
Figure imgf000035_0001
Example 2.
[0105] Method 10 was used to obtain compounds of Formula 1. Acetone or ethyl alcohol (rectified 96%) was used as organic solvents: 40-70 parts of the solvent per 100 parts of the polymer and avermectin mixture taken in gram-equivalent quantities. The named solvents dissolve the polymer host. After thoroughly stirring in a mortar the polymer with avermectin moistened with solvent, a dough-like mass is formed, which is dried with evaporation of the solvent. Ball mills or other grinders can be used for grinding the dried polymer mass, and the particle size of the polymer product should not exceed 5-9 microns. Compositions and results of obtaining bioavailable nanocomposites with Formula I are shown in Table 2.
Table 2. Compounds of Formula I obtained in Example 2.
Figure imgf000035_0002
Example 3.
[0106] Method 6 was used to obtain compounds of Formula 1. Ivermectin and PVA- polypropylene glycol graft co-polymers were used to create a solid dispersion. Hot stage extrusion was performed with a co-rotating, fully intermeshing conical mini twin screw extruder. The temperature was set at 195° C, the screw rate varied from 90 to 105 rpm. A load of 7.5 g per run was fed manually; after feeding the internal circulation time was 5 min. The extrudates were collected after cooling at ambient temperature on a conveyer belt. Extruded samples were subsequently milled for 4 min with a laboratory mill and sieved to exclude particles >400 pm.
B. Bioavailability study
Example 4. Study of ivermectin concentration in the blood plasma of cattle
[0107] Free ivermectin substance was processed in planetary mill, the parameters were as follows: weight of the material - 5 g, grinding jar volume - 200 mb, grinding media - steel balls (diameter 8 mm, 90.0 g load), processing time - 20 minutes. Compound of Formula I was treated according to Example I N> l .
[0108] Cattle were divided into 2 groups of 1 animals each. Free Ivermectin (IVM) and compound of Formula I were orally administered to starving cattle. Blood samples were withdrawn from the jugular vein at appropriate time intervals after administration (0, 4, 20 h).
[0109] Ivermectin concentrations in blood plasma were analyzed according to the method Na-Bangchang, K., High-performance liquid chromatographic method for the determination of ivermectin in plasma, Southeast Asian J Trop Med Public Health, 2006 Sep, 37(5):848-58, PMID: 17333725.
[0110] The internal standard (m oxidectin) was separated from ivermectin on a Hypersil Gold C18 column (150 x 4.6 mm, 5 pm particle size), with retention time of 3.7 and 7.0 minutes, respectively. Fluorescence detection was set at an excitation and emission wavelength of 365 and 475 nm, respectively. The mobile phase consisted of acetonitrile, methanol and distilled water (50:45:5, v/v/v), running through the column at a flow rate of 1.5 ml/minute. The chromatographic analysis was operated at 25°C. Sample preparation (100 pl plasma) was done by a single stepprotein precipitation with acetonitrile, followed by derivatization with 100 pl of N-methylimidazole solution in acetonitrile (1:1, v/v) and 150 pl of trifluoroacetic anhydrous solution in acetonitrile (1:2, v/v). Calibration curve over the concentration range of 20-8,000 ng/ml plasma was linearwith correlation coefficient better than 0.995.
[0111] All the blood samples were centrifuged at 3000 rpm for 15 min to obtain serum. Cattle plasma samples (100 pL each) were placed in 1.5 mL Eppendorf tubes, and then the samples underwent protein precipitation. The samples were vortexed for 1 min and centrifuged at 13,400 rpm for 10 min 20 pL of the supernatant was injected into the HPLC.
[0112] Pharmacokinetic parameters of Ivermectin and compound of Formula I are shown in Fig. 1 and in Table 3. The results provide evidence of a substantial increase in the bioavailability and permeability of compound of Formula I. Oral administration of formula I 600 pg/kg IVM results in an excess of EC 50 2.4 pM for SARS-CoV-2.
Table 3. Pharmacokinetic parameters (ivermectin concentrartion) after oral administration of Ivermectin and compound of Formula I.
Figure imgf000036_0001
Figure imgf000037_0001
C. Antiviral Activity
[0113] Another aspect of the invention relates to methods of inhibiting viral infections, comprising the step of treating a sample or subject suspected of needing such inhibition with a composition of the invention.
[0114] Within the context of the invention samples suspected of containing a virus include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like. Typically the sample will be suspected of containing an organism which induces a viral infection, frequently a pathogenic organism such as a tumor virus. Samples can be contained in any medium including water and organic solvent\water mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures.
[0115] If desired, the anti-virus activity of a compound of the invention after application of the composition can be observed by any method including direct and indirect methods of detecting such activity. Quantitative, qualitative, and semi quantitative methods of determining such activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
[0116] The antiviral activity of a compound of the invention can be measured using standard screening protocols that are known. For example, the antiviral activity of a compound can be measured using the several general protocols.
Example 5. Blood oxygen saturation levels in humans study
[0117] The blood oxygen saturation levels of one symptomatic male patient and another symptomatic male patient who tested positive for SARS-CoV-2 was measured. Compound of Formula I was treated according to Example 1 3.
[0118] Humans were divided into 2 groups of 1 human in each. Compound of Formula I was administered orally 600 pg/kg (per pure ivermectin) to human in Group 2. Blood oxygen saturation levels were withdrawn at appropriate time intervals after administration (0, 24, 48, 72, 96h).
[0119] Changes in oxygen saturation levels for each study group on Day 0-4 are shown in Table 4 and FIG. 2. As shown in Table 4 and in FIG. 2, people who received compound Formula I showed a recovery in saturation levels associated with SARS-CoV-2 infection compared with those who did not receive treatment. As shown in FIG. 2, infectious virus was significantly reduced in people who received Formula I compound on days 1 and 2 after infection compared to untreated individuals. These data indicate that the Formula I compound reduces SARS-CoV-2 replication in the lungs.
Table 4. Blood oxygen saturation levels without treatment and after oral administration of compound of Formula I.
Figure imgf000038_0001
Example 6. SARS-CoV-2 viral load in humans study
[0120] The viral load of a symptomatic male patient who tested positive for SARS-CoV- 2 was measured. Compound of Formula I was treated according to Example 2 N° 2.
[0121] The SARS-CoV-2 viral load from nasopharyngeal swabs was quantified from samples stored at -40°C until use. Viral RNA was isolated using the QIAamp Viral RNA Mini Kit (Qiagen, Hilden, Germany) from stored samples.
[0122] Quantitative reverse transcriptase PCR (RT-qPCR) targeting the SARS-CoV-2 N- gene was then performed. The standard curve consisted of in vitro transcribed viral RNA serially diluted in a matrix of cellular RNA from nasopharyngeal negative samples.
[0123] This assay included measurement of the housekeeping gene as an internal control and normalizer. The cycle threshold (Ct) of the housekeeping gene was used to correct the specific SARS-CoV-2 Ct according to the number of cells in the sample. Therefore, viral load measurements were expressed in loglO copies per reaction.
[0124] The logic viral load before oral administration of Formula I compound was 6.3 copies per mL, and logic viral load 24 hours after administration 1200 pg/kg (per pure ivermectin) of Formula I was 5.1 copies per mL. The loglO viral load was significantly different between the start of treatment (loglO 6.3 copies per mL), and 24 hours after the start of treatment (loglO 5.1 copies per mL). These data suggest that compound of Formula I reduces replication of SARS-CoV-2.
Table 5. Viral load levels before and 24 h after oral administration of compound of Formula I 1200 pg/kg.
Figure imgf000038_0002
Figure imgf000039_0001
VII. Concluding remarks
[0125] Names of compounds of the present disclosure are provided using ACD/Name software for naming chemical compounds (Advanced Chemistry Development, Inc., Toronto, Canada). Other compounds or radicals may be named with common names or systematic or non- systematic names.
[0126] When trade names are used herein, applicants intend to independently include the trade name product and the active pharmaceutical ingredient(s) of the trade name product.
[0127] The compounds of the present invention can be prepared by methods known to one of skill in the art.
[0128] The invention has been described with reference to various specific and preferred embodiments and techniques. However, one skilled in the art will understand that many variations and modifications may be made while remaining within the spirit and scope of the invention.
[0129] While the present invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. Thus, it is intended that the present invention covers the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents. The reference to weight percents includes the weight percent of the component in the completed Formula, unless noted otherwise.
[0130] Although the disclosed inventions are illustrated and described herein as embodied in one or more specific examples, it is nevertheless not intended to be limited to the details shown, since various modifications and structural changes may be made therein without departing from the scope of the inventions. In addition, various features from one of the embodiments may be incorporated into another of the embodiments. Accordingly, it is appropriate that the invention be construed broadly and in a manner consistent with the scope of the disclosure.
[0131] Having described preferred embodiments, it is believed that other modifications, variations and changes will be suggested to those skilled in the art in view of the teachings set forth herein. It is therefore to be understood that all such variations, modifications and changes are believed to fall within the scope of the present invention as defined by the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. VIII. CITATION LIST
Non Patent Literature
[0132] Na-Bangchang, K., High-performance liquid chromatographic method for the determination of ivermectin in plasma, Southeast Asian J Trop Med Public Health, 2006 Sep, 37(5), 848-58, PMID: 17333725
Lifschitz, A., Comparative distribution of ivermectin and doramectin to parasite location tissues in cattle, Veterinary Parasitology 87 (2000) 327-338, PMID: 10669102, doi: 10.1016/s0304-4017(99)00175-2
Jermain, B., Development of a minimal physiologically-based pharmacokinetic model to simulate lung exposure in humans following oral administration of ivermectin for COVID-19 drug repurposing. J Pharm Sci 2020, 109:3574-8, doi: 10.1016/j.xphs.2020.08.024
Caly, L., The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Research, doi: 10.1016/j . antiviral.2020.104787
Buonfrate, D , High-dose ivermectin for early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial, International Journal of Antimicrobial Agents, https://doi.Org/10.1016/j.ijantimicag.2021.106516

Claims

CLAIMS What is claimed is:
1. A method for treating an Coronaviridae infection in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula I, that is a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof, where the compound of Formula I is obtained by co-treating avermectin with a host substance wherein the avermectin is selected from: ivermectin (a mixture of avermectins), avermectin Ala, avermectin Alb, avermectin A2a, avermectin A2b, avermectin Bia, avermectin Bib, avermectin B2a, avermectin B2b or racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, hydrate or solvate thereof or a pharmaceutically acceptable salt or ester thereof or prodrug thereof or mixtures thereof; wherein the host substance is selected from:
A. Polymers and oligomers, predominantly organic polymers and oligomers, even more predominantly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, which may be (but are not exclusive to):
A. 1. Hemicelluloses, which can be arabanes, arabinans, galactans (galactosans), glucans, xylans, mannans, fructans, xyloglucans, arabinogalactans, arabinoxylans, glucomannans, galactomannans, galactoglucomannans, beta-glucans, galactogens, their mixtures, but not excluding other hemicelluloses, and mixtures thereof;
A.2. Sulfated polysaccharides and oligosaccharides which may be fucoidans, carrageenans or carrageenins, agaropectins, sea cucumber sulfated polysaccharides (SCSP), chondroitin sulfate, keratan sulfate, their mixtures, but not excluding other sulfated polysaccharides and oligosaccharides, and mixtures thereof;
A.3. Polysaccharides and oligosaccharides, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages which may be (but are not exclusive to others): polysaccharides based on glucose, dextrose, galactose, mannose, arabinose, rhamnose, sucrose, maltose, lactose and their uronic acids, which may be methoxylated or acetylated, and their salts (gum, gummi); polyuronic acids and esters; gum, xanthan gum, oat gum, gellan gum, guar gum, carob gum, karaya gum, dammar gum, gummiarabica, tara gum, ghatti gum, british gum, agar, agar-agar, tragakant gum, conjac gum, velan gum, dutan gum; galacturonic acidbased polysaccharides with side chains of rhamnose, arabinose, xylose and fructose and their salts (pectins, pectates, pectinates); pectin, pectins of beets, carrots, peppers, pumpkins, eggplant, sunflower, apples, quinces, cherries, plums, pears, citrus, zosterin; modified pectins, modified citrus pectin; acidic polysaccharides - i.e. e. polysaccharides containing carboxyl groups, phosphate groups and/or sulfuric ester groups; plantain husk, psyllium; soybean hemicellulose; galacturones, homogal acturones, polygalacturonic acids and their salts, rhamnogal acturonan, rhamnogalactans; calloses, laminarins, chrysolaminarins, curdlans; inulins, guars, dextrans, pullulans; agaroses, galacto-oligosaccharides (oligogalactosyllactose, oligogalactose, oligolactose or transgalactooligosaccharides), xylooligosaccharides, fructooligosaccharides, isomaltooligosaccharide; alginic acid and its salts alginates, propylene glycol alginate; arabin, arabic acid and its salts; cellulose, cellulosic polymers, methylcellulose, ethylcellulose, hydroxypropylcellulose(s) (HPC), hydroxypropylmethyl cellulose acetate succinate, hypromellose(s), hydroxypropylmethyl cellulose(s) (HPMC), methyl ethyl cellulose, ethylhydroxyethylcellulose, croscaramellose, carboxymethylcellulose and its salts; starch, starch(es), starch 1500G, soluble starch, modified starches, hydroxyethyl starch, cationic starch, acid-treated starch, alkaline modified starch, bleached starch, oxidized starch, enzyme treated starch, monostarch phosphate, distarch glycerol, distarch phosphate, phosphated distarch phosphate, acetylated distarch phosphate, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated distarch adipate, acetylated distarch glycerol, distarch glycerine, hydroxy propyl starch, hydroxy propyl distarch glycerine, hydroxy propyl distarch phosphate, hydroxy propyl distarch glycerol, starch sodium octenyl succinate, acetylated oxidised starch; dextrin(s), maltodextrins, cyclodextrins, amylodextrins, polydextroses; amylopectin, amylose, glycogen; chitosan, chitins; pullulans, glucuronoaraboxylans, methyl -glucuronoaraboxylans, glycosaminoglycans, mucopolysaccharides, heparin/heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronan, hyaluronic acid and mixtures thereof, but not excluding other polysaccharides and oligosaccharides, hemicelluloses, stored polysaccharides, sulfated polysaccharides and oligosaccharides, mucilages and mixtures thereof;
B. Substances that may contain in significant amounts (more than 5% wt.) polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, which may be (but are not limited to) plants or algae or animal or fungi, parts of plants or algae or animal or fungi, processed plants or algae or animal or fungi, processed parts of plants or algae or animal or fungi containing in significant amounts the substances specified in paragraph A, and mixtures thereof. A frequent but non-limiting example is dried brown or red algae such as kelp or focus;
C. Syntetic polymers, predominantly water-soluble polymers which may be (but are not limited to): polymers and copolymers formed from acrylic acid, methacrylic acid, and/or esters thereof; polymethacrylates, Eudragit and their salts; polyacrylamides; poly(amidoamine)s, poly(propyleneimine)s, polyethylene glycols; polyvinyl alcohol; polyvinylpyrrolidone; acrylic polymers, cellulose acetate phthalate(s), copovidone(s), ethyl oleate, glycerol derivatives, glyceryl triacetate, polyethylene glycol(s) (PEG), PEG derivatives, polymethacrylates, propylene glycol, propylene glycol derivatives, povidone(s), polyvinylpyrrolidone(s) (PVP), polyvinyl acetate phthalate(s) (PVAP), hypromellose acetate succinate(s) (HPMCAS), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hypromellose phthalate(s) (HPMCP), cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methyl cellulose succinate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, Avicel(s), Avicel PH101, Avicel PH102, Benecel(s), Brij(s), Brij 30, Brij 35, Capryol(s), Cavamax(s), Cavasol(s) and Cavitron(s) HPpCD cyclodextrins, Compritol 888 ATO, Cremophor(s), Cremophor EL, Cremophor RH40, DiCai Dihydrate, epoxidized palm oil (Epo), Eudragit(s), Eudragit E, Eudragit EPO, Eudragit LI 00, Eudragit L 100-55, Eudragit S100, Gelucire(s) , Gelucire 44/14 , HP-50 AAS-LF, HP-55 AAS-MF, HPMC(p-606), HPMC-E , HPMC-F , HPMC-K , HPMCAS-H, HPMCAS-L , HPMCAS- M , HPMCAS SDD , HPMCAS(AS-MG), HPMCAS-M SDDs, HPMCAS-MG, HPMCP (HP 55), HPMCP-HP55, HPMCPh, hypromellose phthalate HP-50, Imwitor(s), Imwitor 742, Klucel HPC, Kolhdon 17 PF, Kollicoat(s), Kollicoat IR, Kollicoat MAE, Kollicoat MAE 100, Kollicoat MAE 100P , Kollicoat Protect, Kollidon(s) (povidone(s)), Kollidon 12 pf, Kollidon 12/17PF, Kollidon 30, Kollidon 30/90, Kollidon 90, Kollidon CL-F, Kollidon CL-SF, Kollidon K30, Kollidon SR, Kollidon SR, Kollidon SR(PVAc), Kollidon V64ZFine, Kollidon VA 64, Kollidon VA 64 (copovidone), Kollidon VA64, Kolliphor(s), Kolliphor EL, Kolliphor EL/ELP, Kolliphor HS15, Kolliphor P 188, Kolliphor P 188/407, Kolliphor P 188/micro, Kolliphor P 407 , Kolliphor P 407/micro, Kolliphor PS 20, Kolliphor PS 60, Kolliphor PS 80, Kolliphor RH 40, Kolliphor SLS, Kolliphor SLS/fine, Kollisolv(s), Kollisolv GTA, Kollisolv PEG 1450, Kollisolv PEG 300, Kollisolv PEG 3350, Kollisolv PEG 400, Kollisolv PEG E 300, Kollisolv PEG E 400, Kollisolv PEG grades (polyethylene glycol), Kolliwax(s), Kolliwax GMS II, Kolliwax SA, Labrasol(s), Lactose 310 Mono, Lactose FF316, Laurogucol(s), Maisine(s), Miglyol(s), Myrj(s), Myrj 52, PEG 1000, PEG 10000, PEG 1500, PEG 2000, PEG 20000, PEG 3000, PEG 400, PEG 4000, PEG 600, PEG 6000, PEG 800 , PEG 8000 , Pharmacoat(s), PVP K-12 , PVP K-120 , PVP K-15, PVP K-17, PVP K-30, PVP K-60, PVP K-90, PVP SDD, PVP VA64 SDDs, PVP-VA, PVP-VA 64, PVP-VA SDD, Palm stearin based polyesteramide (PSPEA), Peceol(s), pectin(s), Plasdone(s), Plasdone K povidone, Plasdone K-12 povidone, Plasdone K-29/32 povidone, Plasdone K-90 povidone, Plasdone S, Plasdone S-630 copovidone, poly(2-ethyl-2-oxazoline), poly(ethylene oxide) (PEG) (3400, 10000, 20000), polyoxyethylene stearate, Shin-Etsu AQOAT(s), Soluplus(es), Solutol(s), sucrose laurate, tocopheryl PEG 1000-succinate (TPGS), vitamin E TPGS, d-a-tocopherol polyethylene glycol 1000 succinate (IPGS), Isomalt (Galen IQ 810), but not excluding other synthetic polymers and mixtures thereof;
D. Polyols which may be (but are not limited to): ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol, and mixtures thereof;
E. Saccharides which may be glucose, dextrose, galactose, mannose, arabinose, rhamnose, sucrose, maltose, lactose, ribose, and mixtures thereof;
F. Surfactants which may be (but are not limited to): anionic surfactants contained anionic functional groups at their head, such as sulfate, sulfonate, phosphate, carboxylates, carboxylate salts; alkyl sulfates; alkyl-ether sulfates; carboxylate-based fluorosurfactants; cationic surfactants; primary, secondary, or tertiary amines; permanently charged quaternary ammonium salts; zwitterionic (amphoteric) surfactants; zwitterionic surfactants which cationic part is based on primary, secondary, or tertiary amines or quaternary ammonium cations; sultaines; betaines; phospholipids; zwitterionic surfactants of the tertiary amine oxides structural type; non-ionic surfactants; ethoxylates; fatty alcohol ethoxylates; alkylphenol ethoxylates (apes or apeos); fatty acid ethoxylates; special ethoxylated fatty esters and oils; ethoxylated amines and/or fatty acid amides; terminally blocked ethoxylates; fatty acid esters of polyhydroxy compounds; fatty acid esters of glycerol; fatty acid esters of sorbitol; fatty acid esters of sucrose; alkyl polyglucosides; ammonium lauryl sulfate; sodium lauryl sulfate; sodium dodecyl sulfate; sodium laureth sulfate; sodium lauryl ether sulfate; sodium myreth sulfate; docusate (dioctyl sodium sulfosuccinate) and their salts; perfluorooctanesulfonate (pfos); perfluorobutanesulfonate; alkyl-aryl ether phosphates; alkyl ether phosphates; sodium stearate; sodium lauroyl sarcosinate; perfluorononanoate; perfluorooctanoate; octenidine dihydrochloride; cetrimonium bromide (ctab); cetylpyridinium chloride (cpc); benzalkonium chloride (bac); benzethonium chloride (bzt); dimethyl dioctadecyl ammonium chloride; dioctadecyldimethylammonium bromide (dodab); chaps (3-[(3-cholamidopropyl)dimethylammonio]-l-propanesulfonate); cocamidopropyl hydroxysultaine; cocamidopropyl betaine; phosphatidylserine; phosphatidylethanolamine; phosphatidylcholine; sphingomyelins; lauryldimethylamine oxide; myristamine oxide; narrow-range ethoxylates; octaethylene glycol monododecyl ether; pentaethylene glycol monododecyl ether; nonoxynols; triton x-100; polyethoxylated tallow amine; cocamide monoethanolamine; cocamide diethanolamine; poloxamers; glycerol monostearate; glycerol monolaurate; sorbitan monolaurate; sorbitan monostearate; sorbitan tristearate; tween(s), tween 20; tween 40; tween 60; tween 80; decyl glucoside; span(s), span 20, span 40, span 80; lauryl glucoside; octyl glucoside; poloxamer(s), poloxamer 188, poloxamer 407, polyoxyethylene stearate, myrj 52, deoxycholic acid, bile acids, pluronic(s), pluronic F-127, pluronic P85, pluronic f68, gelucire(s), gelucire 44/14, lecithins, polysorbates, polysorbate 80, plasdone-s630, pluronic-f68, inutec spl, compritol 888 ato, tocopherol polyethylene glycol succinate, polyoxyethylated castor oil, polyoxyethylated glycerides, lauroyl macroglycerides, and mono- and di-fatty acid esters of low molecular weight polyethylene glycols; and mixtures thereof;
G. Acids and salts based on these acids which may be (but are not limited to): citric acid, tartaric acid, succinic acid, phosphoric acid, aminoacids, acetate(s), sodium acetate, alginate(s), sodium alginate, glycyrrhizic acid and their salts, and mixtures thereof;
H. Oxides and salts based on these oxides which may be (but are not limited to): silicon dioxide, silicates, titanium dioxide, and mixtures thereof;
I. Copolymers of the polymers listed in paragraph A, C including alternating copolymers, random copolymers, block copolymers, graft copolymers, cross-linked modifications which may be (but are not limited to): methacrylic acid and ethyl acrylate copolymers; methacrylic acid copolymers; vinylpyrrolidone-vinyl acetate copolymers (PVPVA); polyvinylpolypyrrolidone (PVPP); PVA-PEG graft co-polymers; HPMC and PVA-PEG grafted copolymers; grafted polyvinylpyrrolidone-arabinogalactan copolymers; the graft copolymer has a) poly(vinyl acetate) and/or poly (vinyl alcohol) and/or poly(vinyl chloride) and poly(vinyl ester) on b) a polymer chain of polyethylene glycols, polyalkylene glycols, polypropylene glycols, polyisobutylene glycols orpolymeth- ylpentene glycols; graft copolymer polyvinyl acetate and/or hydrolysed polyvinyl acetate (polyvinyl alcohol) groups on a polyalkylene oxide (preferably polyethylene oxide); vinylpyrrolidone-vinyl acetate copolymers; vinylpyrrolidone-vinyl acetate copolymer- 64+; vinylpyrrolidone-vinyl acetate VA 64; polymethacrylate-based copolymers includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters their salts, esters or other derivatives and mixtures thereof;
J. Methoxylated, ethoxylated, esterificated, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, decarboxylated, amide, oxidized, sulfated, aminoacid derivatives, fermented, thermally modified, chemically modified, acid modified derivatives of the substances specified in A-I, and their esters, salts, and any other chemical derivatives, and mixtures thereof;
K. Any combination of substances specified in items A-J; wherein co-treating method is selected from: a) grinding/milling with high energy stress method; b) grinding/milling with high energy stress and solvent method; c) media milling method; d) kneading method; e) hot-melt method/melting method/fusion method; f) hot-melt extrusion/hot-stage extrusion method; g) meltrex method; h) melt agglomeration method; i) high-pressure homogenization method; j) solvent evaporation method; k) spin-coated films method; l) spray-drying method; m) supercritical fluid (SCF) process method; n) cryogenic techniques method; o) lyophilization/freeze-drying technique method; p) spray freezing onto cryogenic fluids method; q) spray freezing into vryogenic liquids (SFL) method; r) spray freezing into vapor over liquid (SFV/L) method; s) ultra-rapid freezing method; t) precipitation/co-precipitation method; u) microwave irradiation method; v) energy input method; w) heat/ shear energy input method; x) combined method.
2. A medical dosage form of Formula I of enhanced bioavailability and permeability characterised in that it comprises a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof, where the compound of Formula I is obtained by co-treating avermectin with a host substance wherein the avermectin is selected from avermectins, wherein the host substance is selected from: a) polymers and oligomers, predominantly organic polymers and oligomers, even more predominantly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, or mixtures thereof; b) substances that may contain in significant amounts polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, which may be (but are not limited to) plants or algae or animal or fungi, parts of plants or algae or animal or fungi, processed plants or algae or animal or fungi, processed parts of plants or algae or animal or fungi containing in significant amounts the substances specified in paragraph a), or mixtures thereof; c) syntetic polymers, predominantly water-soluble polymers or mixtures thereof; d) polyols or mixtures thereof; e) saccharides or mixtures thereof; f) surfactants or mixtures thereof; g) acids or mixtures thereof; h) oxides and salts based on these oxides or mixtures thereof; i) copolymers of the polymers listed in paragraph a) and c) j) methoxylated, ethoxylated, esterificated, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, decarboxylated, amide, oxidized, sulfated, aminoacid derivatives, fermented, thermally modified, chemically modified, acid modified derivatives of the substances specified in a)-i), and their esters, salts, and any other chemical derivatives, and mixtures thereof; k) any combination of substances specified in paragraph a)-j); wherein co-treating method is selected from: a) grinding/milling with high energy stress method; b) grinding/milling with high energy stress and solvent method; c) media milling method; d) kneading method; e) hot-melt method/melting method/fusion method; f) hot-melt extrusion/hot-stage extrusion method; g) meltrex method; h) melt agglomeration method; i) high-pressure homogenization method; j) solvent evaporation method; k) spin-coated films method; l) spray-drying method; m) supercritical fluid (SCF) process method; n) cryogenic techniques method; o) lyophilization/freeze-drying technique method; p) spray freezing onto cryogenic fluids method; q) spray freezing into vryogenic liquids (SFL) method; r) spray freezing into vapor over liquid (SFV/L) method; s) ultra-rapid freezing method; t) precipitation/co-precipitation method; u) microwave irradiation method; v) energy input method; w) heat/ shear energy input method; x) combined method.
3. A method for preparing a medical dosage form of Formula I of enhanced bioavailability and permeability characterised in that it comprises a bioavailable highly permeable nanocomposite or bioavailable highly permeable solid dispersion or aqueous solutions or suspensions thereof where the compound of Formula I is obtained by co-treating avermectin with a host substance wherein the avermectin is selected from avermectins, wherein the host substance is selected from: a) polymers and oligomers, predominantly organic polymers and oligomers, even more predominantly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, or mixtures thereof; b) substances that may contain in significant amounts polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, which may be (but are not limited to) plants or algae or animal or fungi, parts of plants or algae or animal or fungi, processed plants or algae or animal or fungi, processed parts of plants or algae or animal or fungi containing in significant amounts the substances specified in paragraph a), or mixtures thereof; c) syntetic polymers, predominantly water-soluble polymers or mixtures thereof; d) polyols or mixtures thereof; e) saccharides or mixtures thereof; f) surfactants or mixtures thereof; g) acids or mixtures thereof; h) oxides and salts based on these oxides or mixtures thereof; i) copolymers of the polymers listed in paragraph a) and c) j) methoxylated, ethoxylated, esterificated, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, decarboxylated, amide, oxidized, sulfated, aminoacid derivatives, fermented, thermally modified, chemically modified, acid modified derivatives of the substances specified in a)-i), and their esters, salts, and any other chemical derivatives, and mixtures thereof; k) any combination of substances specified in paragraph a)-j); wherein co-treating method is selected from: a) grinding/milling with high energy stress method; b) grinding/milling with high energy stress and solvent method; c) media milling method; d) kneading method; e) hot-melt method/melting method/fusion method; f) hot-melt extra si on/hot- stage extrusion method; g) meltrex method; h) melt agglomeration method; i) high-pressure homogenization method; j) solvent evaporation method; k) spin-coated films method; l) spray-drying method; m) supercritical fluid (SCF) process method; n) cryogenic techniques method; o) lyophilization/freeze-drying technique method; p) spray freezing onto cryogenic fluids method; q) spray freezing into vryogenic liquids (SFL) method; r) spray freezing into vapor over liquid (SFV/L) method; s) ultra-rapid freezing method; t) precipitation/co-precipitation method; u) microwave irradiation method; v) energy input method; w) heat/ shear energy input method; x) combined method.
4. The method of claim 1 wherein the compound is a compound of Formula II comprising: a) a first pharmaceutical composition comprising a compound of Formula I, and b) a second pharmaceutical composition comprising at least one additional therapeutic agent active against infectious Coronaviridae viruses or agent that increases the antiviral activity of the Formula I component, or decreases the hepatotoxicity of the Formula I component, or increases the stability of the Formula I component.
5. The method of claim 1 wherein the compound is a compound of Formula III in the form of solution/emulsion/suspension comprising: a) a first pharmaceutical composition comprising a compound of Formula I/H, and b) at least one of the following components:
(1) oil phase containing vegetable or/and animal fats;
(2) one or more surfactants;
(3) one or more solvents;
(4) one or more gelling agents.
6. The method of claim 1 wherein the compound is a compound of Formula IV in the form of a food product or beverage, or dietary supplement.
7. The method of claim 1 wherein the Coronaviridae infection is caused by a SARS-CoV-2 virus
8. The method of claim 1 wherein the Coronaviridae infection is caused by a MERS virus.
9. The method of claim 1 wherein the Coronaviridae infection is caused by a SARS virus.
10 The method of claim 1 further comprising administering a pharmaceutically acceptable diluents, carrier or excipient.
11 The method of claim 1 further comprising administering a compound in combination with at least one additional therapeutic agent.
12 The method of claim 1 further comprising administering a compound to a mammal in need thereof.
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