Method for preparing formulations for the treatment of viral diseases and compounds with high permeability and bioavailability

Abstract

The present invention provides methods and compounds for treating (or for use in preparing formulations for treating) viral infections by administering highly penetrant, bioavailable avermectin-based compounds. The provided compounds, compositions, and methods are particularly useful for treating SARS-coronavirus 2, dengue virus, chikungunya, yellow fever, Zika virus, and other viral infections.

Description

[Technical field]

[0001] The present invention generally relates to methods and compounds for treating (or for use in the manufacture of pharmaceutical dosage forms for treating) viral infections, in particular, to avermectin-based methods and compounds for treating SARS-CoV-2 of the Coronaviridae family, Dengue and Zika of the Flaviviridae family, and Chikungunya virus infections of the Togaviridae family. [Background technology]

[0002] First identified in the mid-1960s, human coronaviruses are common viruses that infect most people at some point in their lives and typically cause mild to moderate upper respiratory and gastrointestinal illness. A novel coronavirus, called "Middle East respiratory syndrome coronavirus" (MERS-CoV or MERS), was first reported in Saudi Arabia in 2012 and has since spread to several other countries. SARS-CoV, the coronavirus that causes severe acute respiratory syndrome (SARS), was first recognized in China in 2002 and caused global outbreaks 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 disease that is the cause of the ongoing COVID-19 pandemic. First identified in Wuhan, Hubei province, China, the World Health Organization declared the outbreak a Public Health Emergency of International Concern on January 30, 2020, and a pandemic on March 11, 2020. SARS-CoV-2 is a positive-sense, single-stranded RNA virus that is transmissible to humans.

[0004] In December 2021, the number of cases continued to rise due to several factors, including new COVID-19 variants. As of December 28, 2021, 282,790,822 people have been confirmed infected worldwide. As of April 14, 2022, there have been over 500 million confirmed cases worldwide. Most cases are unconfirmed, and the Institute for Health Metrics and Evaluation estimates that the true number of cases could be in the billions as of early 2022.

[0005] According to the World Health Organization (WHO), in recent years, increased awareness of Aedes-borne viruses, especially Chikungunya virus, Zika virus, as well as Dengue virus, have become a global concern around the world. Unfortunately, due to lack of vector-borne disease surveillance, there is no comprehensive knowledge of arbovirus infections, and therefore these lurk behind malaria. Underestimation of arbovirus infections may lead to misdiagnosis and unnecessary medical costs, especially in febrile illnesses suspected to be malaria. Approximately 3.9 billion people in about 120 different regions appear to be at risk from these three major arboviruses. Summary of the Invention [Problem to be solved by the invention]

[0006] Although several compounds have shown antiviral activity in vitro and some of them have been used to treat the disease, the efficacy of the treatment is sometimes insufficient. Improving the bioavailability and permeability of the drugs remains a challenge.

[0007] Ivermectin is a drug used to treat parasitic infections. In vitro, ivermectin exhibits antiviral effects against several different RNA and DNA viruses. In vitro, ivermectin can inhibit the replication of RNA viruses such as Zika, dengue virus, yellow fever, West Nile virus, Hendra virus, Newcastle virus, Venezuelan equine encephalitis virus, chikungunya, Semliki Forest virus, Sindbis virus, avian influenza A virus, porcine reproductive and respiratory syndrome virus, human immunodeficiency virus type 1, and SARS coronavirus 2. In vitro, ivermectin can inhibit the replication of DNA viruses such as equine herpesvirus 1, BK polyomavirus, Aujeszky's disease, porcine circovirus 2, and bovine herpesvirus 1. In vitro, ivermectin can inhibit the replication of SARS coronavirus 2 at concentrations of EC 50 2.4 μM and EC 90 5 μM.

[0008] [Table 1] The degree of inhibition of viral replication by ivermectin is directly dependent on the intracellular ivermectin concentration. Once a threshold concentration of ivermectin is reached in cells, any subsequent increase in ivermectin concentration increases inhibition in body tissues. Generally, body tissues have higher ivermectin concentrations than plasma. For example, the plasma-to-lung ratio is approximately 2.67 in cattle and 3.0 in humans.

[0009] High doses of ivermectin in standard tablet form at 600 μg / kg / day for 5 days result in a lung Cmax of 0.4-0.9 μM, which is much lower than the concentration required to inhibit viral replication and does not provide the concentrations of ivermectin in body tissues required to effectively inhibit viral replication.

[0010] The technical problem is to provide a method for treating a viral disease in a human or mammal or animal or bird in need thereof by administering a therapeutically effective amount of a bioavailable and highly permeable avermectin compound. [Means for solving the problem]

[0011] Methods and compounds for treatment (or for use in the manufacture of a formulation for treating a viral disease) are provided, comprising administering a therapeutically effective amount of the compound. A method is provided for administering a therapeutically effective amount of a compound of FORMULA I (or a solution or suspension thereof) to a human or mammal or animal or bird in need of a viral disease, where the compound of FORMULA I is obtained by co-processing an API (active ingredient guest drug compound) with a HOST substance. The API will be selected from avermectin / ivermectin and its derivatives; The HOST substance is selected from: a) organic polymers and oligomers, mainly polymers and oligomers based on macrocyclic hosts, also mainly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, GUM, mutilations, or mixtures thereof; b) Substances which may contain significant quantities of polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, GUM, mutilations, from plants or algae or animals or fungi, parts of plants or algae or animals or fungi, processed plants or algae or animals or fungi, or parts of processed plants or algae or animals or fungi containing significant quantities of the foregoing substances, or mixtures thereof; c) synthetic polymers, mainly water-soluble polymers or mixtures thereof; d) polyols or mixtures thereof; e) sugars 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 described in a) and c); j) methoxylated, ethoxylated, esterified, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, decarboxylated, amide, oxidized, sulfation, amino acid derived, fermentation, thermally modified, chemically modified, acid modified derivatives of the substances specified in a)-i) and their esters, salts and other chemical derivatives, and mixtures thereof; k) any combination of the substances specified in a)-j); The co-processing method is selected from the methods for obtaining solid dispersions, which include solvent evaporation method, low-temperature method, melting method, mechanochemical method, etc., and can be selected from the following methods as non-limiting examples: a) Milling / powdering using high energy stress methods; b) Milling / pulverization using high energy stress and solvent methods; c) Media grinding method; d) kneading method; e) Hot melt / melt / fusion process; f) Hot melt extrusion / high temperature extrusion method; g) Meltrex process; h) Melt agglomeration method; i) High pressure homogenization method; j) Solvent evaporation method; k) spin-coated film method; l) Spray drying method; m) Supercritical fluid (SCF) processing; n) cryogenic techniques; o) Freeze-drying technology method; p) spray freezing into cryogenic fluids; q) Spray Freezing into Cryogenic Liquids (SFL); r) Spray freezing of vapor onto liquid (SFV / L); s) ultra-rapid freezing; t) Precipitation / coprecipitation methods; u) Microwave irradiation method; v) Energy input method; w) heat / shear energy input method; x) Combination method.

[0012] In another aspect, a method is provided for the treatment (or use in the manufacture of a formulation for the treatment) of humans or mammals or animals or birds with a viral disease, comprising administering a therapeutically effective amount of a compound of FORMULA II (and solutions, gels, colloids, SOLs, etc. thereof), i.e. a highly bioavailable and highly permeable non-covalent complex, obtained by adding a solvent to a highly bioavailable and highly permeable solid dispersion of FORMULA I, which compound of FORMULA I is obtained by processing an API (active ingredient guest drug compound) with a host substance. Here, the solvent is usually water; Here, the molecular information of the non-covalent complex of FORMULA II is encoded by the following formula (non-covalent complex of FORMULA II): GUEST (SOLVENT)m [HOST]n where m is 1 to 100; where n is 1 to 1000; Here, the molecular information of GUEST is given based on the InChI derived from the InChIKey shown for each guest drug; Here, if the solvent is water, the molecular information of SOLVENT is H2O;

[0013] In another aspect, medical dosage forms of FORMULA I are provided, characterized by enhanced bioavailability and permeability, comprising a highly bioavailable and highly permeable solid dispersion or an aqueous solution or suspension thereof, wherein the FORMULA I compound is obtained by processing an API (active ingredient guest drug compound) with a host substance.

[0014] In another aspect, medical dosage forms of FORMULA II (and solutions, gels, colloids, SOLs, etc.) are provided, which are highly bioavailable and highly permeable non-covalent complexes obtained by adding a solvent to the highly bioavailable and highly permeable solid dispersions of FORMULA I, and the FORMULA I compounds are obtained by processing API (active ingredient guest drug compound) with a host substance.

[0015] In another aspect, a method is provided for preparing or manufacturing a pharmaceutical dosage form of FORMULA I characterized by enhanced bioavailability and permeability, comprising a highly bioavailable and highly permeable solid dispersion or an aqueous solution or suspension thereof, the FORMULA I compound being obtained by processing an API with a host substance.

[0016] In another aspect, a method is provided for preparing or manufacturing a pharmaceutical dosage form of FORMULA II (and solutions, gels, colloids, SOLs, etc. thereof) obtained by adding a solvent to a highly bioavailable and highly permeable solid dispersion of FORMULA I, the FORMULA I compound being obtained by co-processing an API with a host material.

[0017] In another embodiment, the method comprises administering a therapeutically effective amount of a pharmaceutical combination (FORMULA III) comprising: a) a first pharmaceutical composition comprising a compound of FORMULA I-II, and b) a second pharmaceutical composition comprising at least one additional therapeutic agent having activity against viruses, or an agent that increases the antiviral activity of the FORMULA I-II component, or an agent that reduces the hepatotoxicity of the FORMULA I-II component, or an agent that increases the stability of the FORMULA I-II component.

[0018] In another embodiment, the method comprises administering a therapeutically effective amount of FORMULA IV in the form of a solution / emulsion / suspension. a) a first pharmaceutical composition comprising a compound of FORMULA I-III, and b) at least one of the following ingredients: (1) an oil phase containing vegetable or animal fat; (2) one or more surfactants; (3) one or more solvents; (4) One or more gelling agents.

[0019] In another embodiment, the method comprises administering a therapeutically effective amount of a formulation of FORMULA V in the form of a food product or beverage, or dietary supplement.

[0020] In another embodiment, a method for the treatment of a viral disease in humans or mammals or animals or birds in need thereof comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a FORMULA IV compound in combination with a pharma- ceutical acceptable diluent or carrier.

[0021] In another embodiment, a method for treating a viral disease in a human or mammal or animal or bird in need thereof comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a FORMULA IV compound and at least one additional therapeutic agent.

[0022] In another embodiment, the method comprises administering a therapeutically effective amount of a compound of FORMULA IV to a human or mammal or animal or bird in need thereof, or using a compound of FORMULA IV for treating a disease in a human or mammal or animal or bird. Effect of the Invention

[0023] The advantageous effect of the patented invention is to provide a method for the treatment of a viral disease in a human or mammal or animal or bird in need thereof or a method for producing a formulation for the treatment. [Brief description of the drawings]

[0024] [Figure 1]An example of one of the chemical formulas for a non-covalent complex in FORMULA II. [Diagram 2] Pharmacokinetic parameters after oral administration of ivermectin and FORMULA I compounds. [Diagram 3] Blood oxygen saturation without treatment and after oral administration of compounds of FORMULA I. BEST MODE FOR CARRYING OUT THEINVENTION

[0025] The following description is provided to enable one of ordinary skill in the art to make and use the invention, and is provided in the context of a particular application and its requirements. Various modifications to the disclosed embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other embodiments and applications without departing from the scope of the invention. Thus, it is not intended that the present invention be limited to the embodiments shown, but is to be accorded the widest scope consistent with the claims. I. Definition

[0026] The term "treatment" as used herein, unless otherwise specified, means the abolition, alleviation, inhibition of 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 directly refers to the act of "treating" as defined above. Treatment also means "for use in the manufacture of a pharmaceutical form for treating."

[0027] As used herein, the term "therapeutically effective amount" means the amount of compound of FORMULA IV present in the compositions described herein, which is necessary to provide a desired level of drug in the respiratory and pulmonary secretions and tissues, or in the bloodstream of a treated subject, when the composition is administered by a selected route of administration, to produce an expected physiological response or a desired biological effect. The exact amount will depend on a variety of factors, including the specific compound of FORMULA IV, the specific activity of the composition, the delivery device used, the physical characteristics of the composition, the intended use, and patient considerations, such as the severity of the disease state, patient cooperation, and can be readily determined by one of skill in the art based on the information provided herein.

[0028] The term "API" (Active Ingredient, Active Ingredient Guest Drug Compound, GUEST, Guest, Guest Drug, Guest Drug Compound, Guest Compound, Guest Extract, Guest Bioactive Extract) means a pharmacologically and biologically active compound. If the selected API is in the form of a free base, it also includes pharmaceutical salts and pharmaceutical esters or ethers of that base. If the API is in the form of a pharmaceutical salt, it also includes the free base, pharmaceutical esters or ethers of that salt, and other pharmaceutical salts of that free base. It also includes racemates, optical isomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, hydrates, hydrides, isotopically labeled forms, prodrugs or mixtures thereof.

[0029] The term "derivatives of an API (guest, guest drug, guest drug compound, guest compound)" means derivatives such as racemates, optical isomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, hydrides, hydrates, isotopically labeled forms, prodrugs, pharmaceutical salts, drug esters or ethers, etc. If the API is in the form of a free base, the derivatives are pharmaceutical salts and drug esters or ethers of that base. If the API is in the form of a pharmaceutical salt, the free base, drug esters or ethers of that salt, and other pharmaceutical salts of the free base are also derivatives. Derivatives also include other obvious derivatives.

[0030] The term "prodrug" is defined in the pharmaceutical field as a biologically inactive derivative of an API that, when introduced into the human body, is converted into a biologically active drug by following some chemical or enzymatic pathway.

[0031] The term "avermectin (IVM)" as used herein means avermectin and its derivatives, such as: ivermectin and avermectin (A1a, A1b, A2a, A2b, B1a, B1b, B2a, B2b) or their racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, hydrides or solvates or pharma- ceutically acceptable salts or esters or prodrugs or mixtures thereof. II. Compounds of the Invention

[0032] Certain embodiments of the present invention are described in detail below. Examples of the embodiments are illustrated in the accompanying description, structures, and formulas. It is to be understood that the invention is described in conjunction with these embodiments, but is not limited thereto. Rather, the present invention is intended to encompass all alternatives, modifications, and equivalents falling within the scope of the present invention.

[0033] The compounds of the present invention may also be in the form of physiologically acceptable salts. Examples of physiologically acceptable salts include salts derived from suitable bases such as alkali metals or alkaline earth metals (e.g., Na+, K+, Ca+2, Mg+2, Li+), ammonium and NR4+ (where R is defined herein). Physiologically acceptable salts of nitrogen atoms or amino groups include (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, orthophosphoric acid, nitric acid, and the like; (b) acid addition salts formed with inorganic acids such as acetic acid, tartaric acid, maleic acid, fumaric acid, lysine, arginine, 2-aminoglutaric acid, glycine, serine, threonine, alanine, isoleucine, leucine, and the like, oxalic acid, salicylic acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, succinic acid, isethionic acid, lactobionic acid, β-D-glucopyranose pentakis[3,4-dihydro- and (c) salts formed with organic acids such as 5-[(3,4,5-trihydroxybenzoyl)oxy]benzoate, 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 the like; and (c) salts formed with elemental anions such as chloride, bromide, and iodine. Physiologically acceptable salts of hydroxy compounds include combinations of the anion of the compound with suitable cations (e.g., Na+ and NR4+). All of these forms are considered to be within the scope of the present invention.

[0034] The compounds of the present invention have the ability to exist as various polymorphs or pseudopolymorphs. Crystalline polymorphism, as used herein, 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 differences in packing between different conformers of the same molecule (conformational polymorphism). Crystalline pseudopolymorphism, as used herein, refers to the ability of a compound hydrate or solvate to exist in different crystal structures. Pseudopolymorphs of the present invention can exist due to differences in crystal packing (packing pseudopolymorphism) or differences in packing between different conformers of the same molecule (conformational pseudopolymorphism). All of these forms are considered within the scope of the present invention.

[0035] The compounds of the present invention may also exist as amorphous solids. Amorphous solids, as used herein, refer to solids in which there is no long-range order of atoms in the solid. This definition also applies when the crystal size is 2 nanometers or less. Additives, including solvents, can be used to create the amorphous forms of the present invention. All such forms are considered to be within the scope of the present invention.

[0036] For therapeutic use, the active ingredients of the compounds of the invention must be physiologically acceptable, however, ingredients that are not physiologically acceptable may be used in the preparation or purification of an acceptable compound.

[0037] Finally, it is anticipated that the compositions presented herein will include compounds of the invention in non-ionized and zwitterionic forms, including forms associated with stoichiometric amounts of water, such as hydrates, and all of these forms are contemplated as being within the scope of the present invention.

[0038] It should be noted that all enantiomers, diastereomers and racemic mixtures, tautomers, polymorphs and pseudopolymorphs of the compounds are included within the scope of the present invention. All mixtures of these enantiomers and diastereomers are included within the scope of the present invention.

[0039] The compounds of the present invention may have chiral centers (e.g., chiral carbon or phosphorus atoms). Thus, the compounds of the present invention include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. The compounds of the present invention also include enriched or resolved forms of optical isomers at any or all asymmetric chiral atoms. In other words, the chiral centers shown in the figures are presented as chiral isomers or racemic mixtures. Racemic and diastereomeric mixtures, as well as isolated or synthesized individual optical isomers substantially free from their enantiomeric or diastereomeric partners, are also within the scope of the present invention. Racemic mixtures are resolved into individual, substantially optically pure isomers by well-known methods, such as separation of diastereomeric salts formed with optically active excipients (e.g., acids or bases), followed by reconversion to optically active substances. In many cases, the desired optical isomers are synthesized by stereospecific reactions starting from the corresponding stereoisomers of the desired starting materials. All of these forms are provided within the scope of the present invention.

[0040] The compounds of the present invention may in some cases exist as tautomers, and all of these forms are considered within the scope of the invention, even if only one delocalized resonance structure is depicted.

[0041] Any formula or structure shown herein is intended to represent the compound in unlabeled and isotopically labeled form. Isotopically labeled compounds have the structure shown in the formula provided herein, except that one or more atoms are replaced with an atom of selected atomic weight or mass number. Examples of isotopes that may be included in the compounds included in this disclosure include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine isotopes (e.g., 2H (deuterium, D), 3H (tritium), 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl and 125I, etc.). Different isotopically labeled compounds of the present disclosure, such as those incorporating radioisotopes such as 3H, 13C and 14C. All of these forms are provided within the scope of the present invention. These isotopically labeled compounds are useful for metabolic studies, kinetic studies, detection or imaging techniques (e.g., positron emission tomography (PET) or single photon emission computed tomography (SPECT)), drug or substrate tissue distribution analysis, or radiotherapy of patients. The present disclosure also includes compounds of FORMULA I in which 1 to n hydrogens attached to a carbon atom are replaced with deuterium, where n is the number of hydrogens in the molecule. These compounds have increased resistance to metabolism and are therefore useful for extending the half-life of any compound of FORMULA I, particularly when administered to humans. III. Main Method and Concept of the Invention

[0042] The solid dispersion of the present invention can be defined as one or more active ingredients (API) dispersed in an inert carrier or matrix (HOST) in the solid state, prepared by melting / fusion method, solvent method, melting solvent method, mechanochemical processing and other methods. The solid dispersion of the present invention can exist in the form of molecular dispersion, simple eutectic mixture, solid solution, glass solution and glass suspension, mechanochemically obtained solid dispersion (including the form of micromechanocomposite subjected to solid phase fusion, mechanosynthesis, mechanoactivation process), amorphous precipitation in crystalline carrier, compound or complex formation. The solid dispersion of the present invention can exist in the form of first generation solid dispersion, second generation solid dispersion, third generation solid dispersion, fourth generation solid dispersion. The solid dispersion of the present invention can exist in the form of class CC, class CA, class AC, class AA, class MC, class MA based on the physical state and molecular arrangement of the active ingredient and carrier (HOST). [Table 2] Many analytical and instrumental techniques are used to characterize solid dispersions. Techniques used for characterization include thermal analysis, spectroscopy, microscopy, microthermal analysis, and macroscopic techniques. Creating a mixture of substances without processing the API and carrier (HOST) will not result in a solid dispersion. A solid dispersion is not a mixture of synergistic agents that amplify each other's effects. A solid dispersion is not a type of nanoparticle.

[0043] The noncovalent complexes of the present invention are molecular assemblies whose internal structure and morphology are determined by the noncovalent interactions of atoms, with specific properties that are distinct from the environment as a whole. This differs from molecular systems whose structure is determined primarily by covalent interactions. A noncovalent complex is a molecular complex of two or more cationic, anionic, or neutral molecules held within a single system by hydrogen bonds, van der Waals interactions, donor-acceptor interactions, π-π interactions, ionic interactions, and hydrophobic interactions. A noncovalent complex has the ability to form different structures while the chemical composition of the system remains unchanged. A noncovalent complex of the present invention is generally composed of at least two distinct components: a matrix (HOST, HOST substance, “host”, “host substance”, “carrier”, etc.) and a therapeutic agent (API, active ingredient, drug, guest, “guest drug”, “guest drug compound”, “guest substance”, etc.). Many analytical and instrumental techniques (e.g., spectroscopy) are used to characterize noncovalent complexes.

[0044] Provided is a method for treating a disease (and for use in making a dosage form for treating) by administering a therapeutically effective amount of a solid dispersion to a human, mammal, animal, or bird in need thereof, comprising: contacting an API with a matrix "HOST material" to form a solid dispersion under conditions sufficient to form a solid dispersion, and (optionally) dissolving the solid dispersion in a solvent to form a liquid soluble non-covalent complex under conditions sufficient to form a liquid soluble non-covalent complex (forming a solution, gel, colloid, SOL, suspension, etc.).

[0045] In another aspect, a method for treating a disease (and for use in manufacturing a dosage form for treating) is provided by administering a therapeutically effective amount of the solid dispersion or non-covalent complex to a human, mammal, animal, or bird in need thereof. In this method, the "carrier substance" (HOST substance) molecules of the solid dispersion or non-covalent complex interact with a biological membrane of the organism, improving the movement of the API molecules and ions across this biological membrane. The permeability of the API is improved in the form of the non-covalent complex. Thus, the scope of the present invention includes solid dispersions and non-covalent complexes with special permeability properties. Highly permeable solid dispersions and non-covalent complexes are included, such as highly permeable solid dispersions and non-covalent complexes.

[0046] In another aspect, there is provided a method for treating (and for use in preparing a dosage form for treating) a viral disease by administering a therapeutically effective amount of the solid dispersion or non-covalent complex to a human, mammal, animal, or bird in need thereof, wherein the solid dispersion or non-covalent complex of the API has a higher bioavailability than the API itself.

[0047] In another aspect, there is provided a method for treating (and for use in preparing a dosage form for treating) a viral disease by administering a therapeutically effective amount of the solid dispersion or non-covalent complex to a human, mammal, animal, or bird in need thereof, where the solid dispersion or non-covalent complex of the API has lower toxicity and cytotoxicity than the API itself.

[0048] In another aspect, a method for treating a viral disease (and producing a therapeutic formulation) is provided, in which a therapeutically effective amount of a solid dispersion or non-covalent complex is administered to a human or mammal, animal or bird in need thereof, where the solid dispersion or non-covalent complex of an API is shown to have different pharmacokinetic parameters than the API itself.

[0049] In another aspect, there is provided a method for preparing or manufacturing the solid dispersion or non-covalent complex of the invention.

[0050] Methods for obtaining the solid dispersion of the present invention include: 1) Solvent evaporation and low temperature methods; 2) Melt method and hot extrusion method; 3) Mechanochemical methods (but not excluding other methods). The particle size of the solid dispersion depends on the type of equipment (e.g. nozzle size), the operating parameters of the equipment, and the degree of grinding of the final product; typical particle sizes are between 0.5 and 1000 microns, but can exceed 1000 microns; the resulting solid dispersion can also be ground to submicron sizes.

[0051] Solvent evaporation is a method in which the API and carrier (HOST substance) are dissolved in a volatile solvent and then the solvent is evaporated. In this method, the evaporation of the organic solvent is carried out at a low temperature, which can prevent thermal decomposition of the API and carrier. The differences in the solvent evaporation process are usually related to the solvent evaporation procedure, which includes vacuum drying, heating the mixture on a heating plate, slow evaporation of the solvent at low temperature, use of a rotary evaporator, nitrogen flow, spray drying, freeze drying, use of supercritical fluids (SCF), and other solvent evaporation methods.

[0052] The melting method is a method in which the API is melted in a carrier (HOST material) and then cooled and the resulting product is milled. In the melting process, the molecular mobility of the carrier is high, which can alter the drug uptake. A common adaptation of the melting step is to reduce the process temperature by suspending the API in a pre-melted carrier instead of using both the drug and carrier in the molten state. To cool and solidify the molten mixture, ice bath stirring, stainless steel thin layer spreading with cold air, solidification on a petri dish at room temperature in a desiccator, plate spreading on solid carbon dioxide, immersion in liquid nitrogen, storage in a desiccator, and other cooling methods were used. After cooling, the mixture needs to be milled for handling. However, the use of high temperatures and the possibility that some drugs may be degraded by the melting process can be limitations of this method. The inability to obtain complete miscibility between the drug and carrier due to the high viscosity of the polymeric carrier in the molten state is also a limitation of this process. To circumvent the limitations of the melting method, several modifications such as hot stage extrusion, Meltrex, and melt agglomeration were introduced into the original method.

[0053] The mechanochemical method for obtaining solid dispersions involves intensive mechanical processing, for example in planetary mills or other types of mills, under conditions in which the processes of solid-state fusion, mechanosynthesis, mechanoactivation occur between the components, including the formation of microcomposites, in which the processes of mechanochemical solid-state fusion / melting, mechanosynthesis, mechanoactivation of API and HOST substances occur, the mixing of the components leads to reactions in the solid phase, forming products with a high contact area and extremely high concentrations of various types of defects. The formation of interfacial surfaces necessary for the realization of physicochemical interactions takes place. Under these conditions, the characteristic time of mutual movement of reagents for the progression of physicochemical reactions is reduced. Simultaneously with the milling and the formation of the mechanochemically obtained solid dispersion, additional structural defects are created in the mixture components. In a macroscopic approximation, the activation barrier of chemical interactions is reduced. Usually, the longer the mechanical processing time, the higher the bioavailability and permeability of the resulting solid dispersion, and the particle size may remain almost unchanged.

[0054] In the initial stage of mechanochemical processing, the initial collision of the powder particles with the balls causes the plastic deformation of the particles and their flattening. Continuing plastic deformation is accompanied by an increase in the ratio of the surface area to the volume of the particles. During the deformation process of the particles, the internal layers of the pure API are exposed and come into intimate contact with the pure layers of the other components, giving rise to the welding process. When the accompanying plastic deformation hardening reaches a critical value, the formed object is destroyed. The three processes of plastic deformation, welding and destruction of the processed particles are then repeated many times in parallel. In this process, the material acquires a layered and twisted structure. At the end of the initial fusion stage, a mixed heterophase system is formed, called a mechanocomposite. Mechanocomposites have a morphologically metastable structure with a high density of interfacial boundaries between the initial components, and many atoms are present in the surface and near-surface layers, providing a developed contact surface where many defects are present in high concentration. Such a system has a large amount of stored energy, which, coupled with the very large contact surface between the components, provides a high reactivity of the system. At the same time, despite the almost complete contact surface of the reagents in the matrix, large inclusions of more brittle components in contact with the plastic reagents can be observed in the volume of the mechanocomposite.

[0055] Mechanochemical processing methods yield similar results to other methods but exclude toxic solvents and the thermal degradation process of the API.

[0056] Bioavailable solid dispersions and bioavailable non-covalent complexes are obtained and used in the present invention. Bioavailable with respect to solid dispersions and non-covalent complexes means at least one of the following: 1) Higher absolute and relative bioavailability of the solid dispersion or noncovalent complex than the API itself; 2) The concentrations, Cmax, AUC and other pharmacokinetic parameters of the solid dispersion or noncovalent complex of the API and / or its metabolites in blood, organs or tissues are higher than those of the API itself. The release rate of API molecules from non-covalent complexes can play an important role in increasing bioavailability.

[0057] Non-covalent complexes play a particularly important role in biological systems, such as the transfer of molecules and ions through biological membranes. In the present invention, highly permeable solid dispersions or non-covalent complexes are obtained and used. Highly permeable with respect to a solid dispersion or non-covalent complex means at least one of the following: 1) The transport of API molecules, ions, and metabolites across biological / cellular membranes is improved in solid dispersions or non-covalent complexes of the API compared to the API itself; 2) The transfer of API molecules, ions, or metabolites across a Caco-2 cell line layer or other cell line layer (e.g., an intestinal epithelial cell layer) is improved for solid dispersions or non-covalent complexes of the API compared to the API itself; 3) A solid dispersion or noncovalent complex of the API has improved intestinal permeability compared to the API itself; 4) increased permeability based on the method used to determine permeability in the Biopharmaceutical Classification System.

[0058] Within the scope of the current invention, increased permeability and absorption of an API from a solid dispersion or non-covalent complex is achieved by the following mechanisms (without excluding other mechanisms of increasing permeability): 1) Carrier substance (HOST) molecules interact with membranes, thereby blocking / reducing the activity of CYP3A4 and / or P-glycoprotein, and as a result blocking / reducing the activity of other transmembrane carrier proteins, transporters, enzymes, etc.; 2) To block / reduce the activity of CYP3A4 and / or P-glycoprotein and to block / reduce the activity of other transmembrane protein transporters, transporters, enzymes, etc. by attaching carrier substance (HOST) molecules to the cell layer. Such attachment may cause an interaction with the transporter domains located on the outer side of the cell membrane and block the action of the transmembrane transport proteins; 3) due to structural changes in the cell membrane after incorporation of the carrier substance (HOST) molecule into the membrane, not due to attachment; 4) by direct action of carrier substance (HOST) molecules on the intestinal epithelial cell membrane: it can cause changes in the lipid bilayer properties, the density of cell-cell contacts, or inhibition of transmembrane proteins of multidrug resistance; 5) changes in the hydrophilicity and hydrophobicity of noncovalent complexes may result in alterations in the paracellular transport of noncovalent complexes; 6) Other changes in membrane structure and properties through other mechanisms that contribute to increased permeability.

[0059] Carriers play a major role in the formulation of solid dispersions. Carriers can be either hydrophilic, hydrophobic, or water-swellable. Depending on the properties of the carrier, it can be used as a release retarder or release enhancer. Also, the solubility properties of the drug molecule depend on the nature of the carrier. The selection criteria for the carrier (HOST) are: 1) It dissolves or swells in water and dissolves in a variety of solvents. 2) It is economical, pharmacologically inactive, and non-toxic. 3) It is heat stable. 4) Be chemically compatible with the drug. Water-soluble and water-insoluble carriers prevent the tendency to recrystallize through hydrogen bonding interactions and maintain a state of supersaturation after dissolution (spring and parachute effect). [0059a] Plant-derived polymers are used in diverse pharmaceutical applications and current inventions due to their easy availability, biocompatibility, non-toxicity, and chemical inertness. Polysaccharides are one of the most abundant industrial raw materials and are used for their sustainability, biosafety, and biodegradability. Natural rubber is a metabolic by-product of plants that is obtained from different parts of the plant, such as the seeds, fruits, and incised stems (rubbery exudates).

[0060] Natural polysaccharides are biodegradable, biocompatible materials used in drug delivery systems. However, these materials have limitations such as uncontrolled hydration rate, viscosity change during storage period, and microbial contamination. Hence, several modifications have been made to overcome these issues. Modifications can be done in terms of physical and chemical modification. Physical methods of modification include the use of dry heat, microwave techniques, UV and gamma radiation. Meanwhile, chemical modifications include carboxymethylation / carbomoylethylation, which results in the replacement of free -OH groups, improving the water solubility of the drug. Generally, natural carriers modified using heating methods undergo changes in their physical properties such as viscosity, density, swelling index, water holding capacity, and flow properties. The changes in these properties have provided excellent results in the case of modified natural carriers. Carboxymethylation of natural carriers increases their hydrophilicity and improves their solubility in aqueous systems. III.I. Section

[0061] A method is provided for the treatment of (and use in the manufacture of a formulation form for the treatment of) a human or mammal or animal or bird having a viral disease comprising administering a therapeutically effective amount of a FORMULA I compound (a highly bioavailable and highly permeable solid dispersion (or a solution or suspension thereof)) of a FORMULA I compound obtained by co-processing an API compound with a HOST substance. wherein a person's medical condition or disease or disorder or syndrome is selected from those listed in The International Statistical Classification of Diseases and Related Health Problems (including ICD-9, ICD-10, ICD-10-CM, ICD-11, ICD-11-CM, etc.); and / or a person's medical condition or disease or disorder or syndrome is selected from those listed in The Diagnostic and Statistical Manual of Mental Disorders (including DSM-IV, DSM-5, DSM-5-TR, etc.); and / or a person's medical condition or disease or disorder or syndrome is selected from those MeSH codes beginning with C01-C25 listed under Medical Subject Headings; and / or a person's medical condition or disease or disorder or syndrome is selected from conditions published in the Genetic and Rare Diseases (GARD) Information Centre; and / or the human medical condition or disease or disorder or syndrome / infection is one caused by a virus; including those caused by RNA viruses, DNA viruses, reverse transcription viruses; including those caused by viruses belonging to the Duplodonaviria, Monodonaviria, Adnaviria, Ribodiviria, Riboviria, and Baridnaviria kingdoms; including viral infections or diseases caused by dsDNA viruses, ssDNA viruses, dsRNA viruses, (+)ssRNA viruses, (-)ssRNA viruses, ssRNA-RT viruses, dsDNA-RT viruses; including viral infections or diseases caused by viruses in the Coronaviridae, Flaviviridae, Herpesviridae, Orthomyxoviridae, Paramyxoviridae, Polyomaviridae, Retroviridae, and Togaviridae families, but not to the exclusion of other virus families; human SARS coronavirus, SARS coronavirus 2, dengue virus, West Nile virus, yellow fever virus, Zika virus, bovine herpes virus Virus infections or diseases caused by influenza virus type 1, influenza A virus, Hendra virus, BK polyomavirus, human immunodeficiency virus type 1, chikungunya virus, Semliki Forest virus, Sindbis virus, Venezuelan equine encephalitis virus, but not by human adenovirus, Junin arenavirus, Lassa virus, lymphocytic choriomeningitis virus, Machupo virus, Pichinde virus, porcine reproductive and respiratory syndrome virus (PRRSV) / beta arterivirus suiid 1, human astrovirus, Hantaan virus, Crimean-Congo hemorrhagic fever virus, Dugbe virus, Bunyamwela virus, La Crosse bunyavirus, Snowshoe Hare bunyavirus, Punta Toro phlebovirus, Rift Valley fever virus, Neapolitan sandfly fever phlebovirus (Tuscan virus), Sicilian sandfly fever virus, Ukuniemi virus, Norwalk virus, Southampton virus, Sapporo virus, Porcine circovirus 2, Human coronavirus, MERS coronavirus, Human Torovirus, Ebola virus, Lake Victoria Marburg virus,Japanese encephalitis virus, Langat virus, Looping-Ile virus, St. Louis encephalitis virus, Tick-borne Pawassan virus, Tick-borne encephalitis virus, Hepatitis C virus, Hepatitis G virus / Hepatitis B virus, Hepatitis E virus, Human cytomegalovirus, Simian herpesvirus, Epstein-Barr virus, Human herpesvirus 8, Human herpesvirus 6, Human herpesvirus 7, Human herpesvirus 1, Human herpesvirus 2, Varicella-zoster virus, Bovine herpesvirus 1, Equine herpesvirus 1 (EHV-1), Pseudomonas aeruginosa, Pseudorabies virus, rubella virus, influenza B virus, influenza C virus, influenza A virus, Dori virus, human papillomavirus (16, 18), human papillomavirus 2, human papillomavirus 1, Nipah virus, measles virus, human parainfluenza, mammalian orthorubular virus 5 (simian virus 5), mumps virus, Newcastle, adeno-associated virus, human parvovirus B19, encephalomyocarditis virus, cosavirus A, coxsackievirus, echovirus, human enterovirus (6 8, 70), poliovirus, hepatitis A virus, Aichi virus, rosavirus A, rhinovirus, sarivirus A, human respiratory syncytial virus, JC polyomavirus, KI polyomavirus, Merkel cell polyomavirus, WU polyomavirus, BK polyomavirus, molluscum contagiosum virus, cowpox virus, horsepox virus, vaccinia virus, variola virus, yaba monkey tumor virus, yaba-like disease virus, smallpox, orf virus, rotavirus A, rotavirus B, orbivirus, coltivirus, rotavirus C, vancomycin virus, serovar I, serovar V, serovar I ... navirus, human T-lymphotropic virus, human immunodeficiency virus, eastern chimpanzee simian foamy virus, simian foamy virus, human immunodeficiency virus type 1 / 2, Australian bat rabies virus, Dubenhage virus, Lagos bat virus, Mokola virus, rabies virus, Chandipura virus, Isfahan virus, vesicular stomatitis virus, European bat rabies virus, Barmah Forest virus, eastern equine encephalitis virus, Mayaro virus, O'nyong-nyong virus, Rossliva virus, Sagiyama virus, western equine encephalitis virus,Caused by rubella virus, hepatitis D virus, hepatitis E virus, Torqueten virus, human rhinovirus, Murray Valley encephalitis virus, Oropouch virus, Empox virus, New York virus, Puumala virus, Seoul virus, but not to the exclusion of other viruses; The API compounds are selected from ivermectin or avermectin and their derivatives (each API has a sequential number and an InChIKey, which are given in parentheses after the name of the API (guest drug) with the InChIKey first and the sequential number second). The APIs are selected from: Ivermectin (SPBDXSGPUHCETR-JFUDTMANSA-N or AZSNMRSAGSSBNP-ZLRQRZFZSA-N, 1); Avermectin A1a (AFSHKCWTGFDXJR-SQOHEDJBSA-N, 2); Avermectin A1b (MNRHCELBXZARFX-OVBDMLLUSA-N, 3); Avermectin A2a (JVGWUGTWQIAGHJ-DFAYUBCLSA-N, 4); Avermectin A2b (QUTFLJHOCPQPEW-WUSILSRKSA-N, 5); Avermectin B1a (AZSNMRSAGSSBNP-XPNPUAGNSA-N, 6); Avermectin B1b (VARHUCVRRNANBD-PVVXTEPVSA-N, 7); Avermectin B2a (CWGATOJEFAKFBK-QJDTYEMPSA-N, 8);Avermectin B2b (ZPAKHHSWIYDSBJ-YAGODIQJSA-N, 9) or its racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, hydrates or solvates, or pharmaceutical salts, esters, prodrugs, or mixtures thereof; The sequence number is used to abbreviate the API, and the InChIKey is used to retrieve the molecular information of the API. For example, in the case of GUEST3 - "3" is the sequence number of the compound avermectin A1b, and GUEST3 means avermectin A1b whose InChIKey is MNRHCELBXZARFX-OVBDMLLUSA-N. Based on this InChIKey, the molecular information of avermectin A1b (GUEST3) can be retrieved by InChI can be derived: InChI = 1S / C48H72O14 / c1-25(2)41-28(5)17-18-47(62-41)23-34-20-33(61-47)16-15-27(4)42(59-39-22-37(53-10)44(31(8)57-39)60-38-21-36(52-9)40(49)30(7)56-38)26(3)13-12-14-32-24-55-45-43(54-11)29(6 )19-35(46(50)58-34)48(32,45)51 / h12-15,17-19,25-26,28,30-31,33-45,49,51H,16,20-24H2,1-11H3 / b13-12+ ,27-15+,32-14+ / t26-,28-,30-,31-,33+,34-,35-,36-,37-,38-,39-,40-,41+,42-,43+,44-,45+,47+,48+ / m0 / s1; Thus, GUEST1-GUEST3 means all guest drugs with sequence numbers 1-3, i.e.: GUEST1, GUEST2, GUEST3. If the selected API is in the form of a free base - also includes pharmaceutical salts and pharmaceutical esters or ethers of that base.If the API is in the form of a pharmaceutical salt - also includes the free base of that salt, pharmaceutical esters or ethers of that salt, and other pharmaceutical salts of that free base.Also includes racemates, optical isomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, hydrates or prodrugs, or mixtures thereof. Therefore, the API is selected from GUEST1-9. The weight of API is 0.01-90% of the total weight of FORMULA I. wherein the HOST substance is selected from the following (10-99.99% of the total weight of FORMULA I): A. Polymers and oligomers, macrocyclic hosts, primarily organic polymers and oligomers, further primarily polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mutilations, including, but not limited to: A.1. Hemicelluloses, including, but not limited to, araban, arabinan, galactan (galactosan), glucan, xylan, mannan, fructan, xyloglucan, arabinogalactan, arabinoxylan, glucomannan, galactomannan, galactoglucomannan, β-glucan, galactogens, mixtures thereof, other hemicelluloses and mixtures thereof; A.2. Sulfated polysaccharides and oligosaccharides, including, but not limited to, fucoidan, carrageenan or carrageenin, agaropectin, sea cucumber sulfated polysaccharides (SCSP), chondroitin sulfate, keratan sulfate, mixtures thereof, other sulfated polysaccharides and oligosaccharides and mixtures thereof; A.3. Polysaccharides and oligosaccharides, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mutilations include (but are not limited to): 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 (gums, gummies); polyuronic acids and esters; gums, xanthan gum, oat gum, gellan gum, guar gum, carob gum, karaya gum, dammar gum, gum arabic, tara gum, ghatti gum, British gum, agar, agar, tragacanth gum, konjac gum, verum gum, dutan gum; galacturonic acid-based polysaccharides with rhamnose, arabinose, xylose and fructose side chains and their salts (pectin, pectic acid, pectates); pectins from beets, carrots, peppers, pumpkins, eggplants, sunflowers, apples, quince, cherries, plums, pears, citrus fruits, zosterin; Modified pectin, modified citrus pectin; acidic polysaccharides - i.e. polysaccharides containing carboxyl, phosphate and / or sulfate groups; psyllium husk, psyllium; soybean hemicellulose; galacturon, homogalacturon, polygalacturonic acid and its salts, rhamnogalacturonan, rhamnogalactan; callose, laminaran, chrysolaminarin, curdlan; inulin, guar gram, dextran, pullulan; agarose, galactooligosaccharides (oligogalactosyllactose, oligogalactose, oligolactose or transgalactooligosaccharides), xylooligosaccharides, fructooligosaccharides, isomaltooligosaccharides; alginic acid and its salts, alginates, propylene glycol alginate; arabin, D-arabinonic acid and its salts; Cellulose, cellulosic polymers, methylcellulose, ethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate, hypromellose, hydroxypropylmethylcellulose (HPMC), methylethylcellulose, ethylhydroxyethylcellulose, croscarmellose, carboxymethylcellulose and its salts;Starch, Starches, Starch 1500G, Soluble Starch, Modified Starch, Hydroxyethyl Starch, Cationic Starch, Acid Treated Starch, Alkaline Modified Starch, Bleached Starch, Oxidized Starch, Enzyme Treated Starch, Monostarch Phosphate, Distarch Glycerol, Distarch Phosphate, Phosphorylated Distarch Phosphate, Acetylated Distarch Phosphate, Starch Acetate Esterified with Acetic Anhydride, Starch Acetate Esterified with Vinyl Acetate, Acetylated Distarch Dipate, Acetylated Distarch Glycerol, Distarch Glycerin, Hydroxypropyl Starch, Hydroxypropyl Distarch Glycerin, Hydroxypropyl Distarch Phosphate, Hydroxypropyl Distarch Glycerol, Starch Sodium Octenyl Succinate, Acetylated Oxidized Starch; Dextrin, Maltodextrin, Cyclodextrin, Amylodextrin, Polydextrose; amylopectin, amylose, glycogen; chitosan, chitin; pullulan, glucuronaraboxylan, methyl-glucuronaraboxylan, glycosaminoglycans, mucopolysaccharides, heparin / heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid, hyaluronic acid and mixtures thereof, but not excluding other polysaccharides and oligosaccharides, hemicellulose, storage polysaccharides, sulfated polysaccharides and oligosaccharides, mutilase and mixtures thereof; A.4. Macrocyclic hosts include, but are not limited to: cyclodextrins, cucurbit[n]urils, calix[n]arenes, pyrarenes, crown ethers, cyclophanes, cryptands; B. Substances which may contain significant amounts (5% or more) of polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums and mutilations include, but are not limited to, plants or algae or animals or fungi, parts thereof, processed plants or algae or animals or fungi, parts of processed plants or algae or animals or fungi containing significant amounts of the substances specified in paragraph A, and mixtures thereof. Frequent but non-limiting examples include dried brown and red algae such as kelp and foci.C. Synthetic Polymers, primarily water-soluble polymers, which may include (but are not limited to): polymers and copolymers formed from acrylic acid, methacrylic acid, and / or their esters; polymethacrylates, Eudragit and its salts; polyacrylamides; polyamidoamines, polypropyleneimines, polyethylene glycols; polyvinyl alcohols; polyvinylpyrrolidone; acrylic polymers, cellulose acetate phthalate; copovidone; ethyl oleate, glycerol derivatives, triacetin, polyethylene glycol (PEG), PEG derivatives, polymethacrylates, propylene glycol, propylene glycol derivatives, povidone, polyvinylpyrrolidone (PVP), vinyl acetate. Polyvinyl phthalate (PVAP), Hypromellose acetate succinate (HPMCAS), Hydroxypropyl methylcellulose acetate succinate (HPMCAS), Hypromellose phthalate (HPMCP), Cellulose butyrate phthalate, Cellulose hydrogen phthalate, Cellulose propionate phthalate, Polyvinyl acetate phthalate, Cellulose acetate phthalate, Cellulose acetate trimellitate, Hydroxypropyl methylcellulose phthalate, Hydroxypropyl methylcellulose acetate, Dioxypropyl methylcellulose succinate, Carboxymethylethylcellulose, Hydroxypropyl methylcellulose acetate succinate, Avicel, Avicel PH101, Avicel PH102, Benecel, Brij, Brij 30, Brij 35, Capryol, Cavamax, Cavasol and Cavitron, HPpCD, Cyclodextrin, Compritol 888 ATO, Cremophor, Cremophor EL, Cremophor RH40, DiCal Dihydrate, Epoxidized Palm Oil (Epo), Eudragit, Eudragit E, Eudragit EPO, Eudragit L100, Eudragit L100-55, Eudragit S100, Gelucire, Gelucire 44 / 14, HP-50 AAS-LF, HP-55AAS-MF, HPMC(p-606), HPMC-E, HPMC-F, HPMC-K, HPMCAS-H, HPMCAS-L, HPMCAS-M, HPMCAS SDD, HPMCAS(AS-MG), HPMCAS-M SDD, HPMCAS-MG, HPMCP(HP). 55) HPMCP-HP55 HPMCPh HP-50 Imwitor Imwitor 742 Klucel HPC Kolhdon PF、Kollicoat、Kollicoat IR、Kollicoat MAE、Kollicoat MAE 100、Kollicoat MAE 100P、Kollicoat Protect、Kollidon(ポビドン)、Kollidon 12 pf、Kollidon 12 / 17PF、Kollidon 30、Collision 30 / 90、Collision 90、Collision CL-F、Collision CL-SF、Collision K30、Collision SR、Collision SR、Collision SR(PVAc)、Collision V64 / Fine、Collision VA 64、Collision VA 64(コポビドン) Kollidon VA64, Kolliphor, 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、Kolliphor Solv GTA、Collision Solver PEG 1450、Collision Solver PEG 300、Collision Solver PEG 3350、Collision Solver PEG 400、Collision Solver PEG E 300、Collision Solver PEG E 400、Collision Solver PEG (PEG) Kolliwax, Kolliwax GMS II, KolliwaxSA, Labrasol, Lactose 310 Mono, Lactose FF316, Laurogucol, Maisine, Miglyol, Myrj, 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, 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 SDD, PVP-VA, PVP-VA 64, PVP-VA SDD, Palm Stearin Polyesteramide (PSPEA), Peceol, Pectin, Plasdone, 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, Soluplus, Solutol, Sucrose Laurate, Tocopheryl PEG 1000 Succinate (TPGS), Vitamin E TPGS, d-α-Tocopherol Polyethylene Glycol 1000 Succinate (TPGS), Isomalt (Galen IQ 810), not excluding other synthetic polymers and mixtures thereof; D. Polyols can include (but are not limited to): ethylene glycol, glycerol, erythritol, D-threitol, arabitol, ribitol, mannitol, sorbitol, galactitol, rhodiitol, D-iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetriitol, polyglycitol, and mixtures thereof; E. The sugars can be glucose, dextrose, galactose, mannose, arabinose, rhamnose, sucrose, maltose, lactose, ribose, and mixtures thereof. F. Surfactants include, but are not limited to, anionic surfactants containing an anionic functional group at the head, such as sulfates, sulfonates, phosphates, carboxylates, carboxylate salts; alkyl sulfates; alkyl ether sulfates; carboxylate-based fluorosurfactants; cationic surfactants; primary, secondary, or tertiary amines; permanently charged quaternary ammonium salts; amphoteric (amphoteric) surfactants; amphoteric surfactants in which the cationic moiety is based on a primary, secondary, or tertiary amine or a quaternary ammonium cation; sultaines; betaines; phospholipids; amphoteric surfactants of the tertiary amine oxide structure type; nonionic surfactants; ethoxylates; fatty alcohol ethoxylates; alkylphenol ethoxylates (APES or APEOs); fatty acid ethoxylates; specialty ethoxylated fatty acid esters and oils; ethoxylated amines and / or fatty acid amides; end-capped 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 dodecyl sulfate; Sodium dodecyl ethoxy sulfate; Sodium dodecyl sulfate; Sodium laureth sulfate; Sodium 2-{2-[2-(tetradecyloxy)ethoxy]ethoxy}ethyl sulfate; Dioctyl sodium sulfosuccinate (docusate) and its salts; Heptadecafluoro-1-octanesulfonate (PFOS); Nonafluorobutanesulfonate; Alkyl aryl ether phosphates; Alkyl ether phosphates; Sodium stearate; Sodium N-lauroyl sarcosinate; Pentadecafluorooctanoate; Heptadecafluorononanoate; Octenidine dihydrochloride; Hexadecyltrimethylammonium bromide (CTAB); Cetylpyridinium chloride (CPC); Benzalkonium chloride (BAC); Solamine (BZT); Dimethyldioctadecylammonium chloride; Dimethyldioctadecylammonium bromide (DODAB); CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate);Cocamidopropyl hydroxysultaine; Cocamidopropyl betaine; O-(1-O,2-O-distearoyl-L-glycero-3-phospho)serine; 2-[(1-O,2-O-diacetyl-L-glycero-3-phospho)oxy]ethanamine; Phosphatidylcholine; Sphingomyelin; Dodecyldimethylamine N-oxide; Tetradecyldimethylamine oxide; Narrow range ethoxylates; Octaethylene glycol monododecyl ether; Pentaethylene glycol monododecyl ether; Nonylphenol ethoxylates; Triton X-15; Polyethoxylate tallowamine; Cocamide monoethanolamine; Cocamide diethanolamine; Poloxamer; Aquacera; 1-Monolaurin; Sorbitan monolaurate; Sorbitan monostearate; Sorbitan tristearate; Tween; Tween 20; Tween 40; Tween 60; Tween 80; Decyl-D-glucoside; Span; Sorbitan monolaurate; Span 40; 1,4-anhydro-D-glucitol 6-oleate; Dodecyl D-glucopyranoside; Octyl D-glucopyranoside; Poloxamer; Poloxamer 188; Poloxamer 407; Polyoxyethylene stearate; Montyl; Deoxycholic acid; Bile acids; Pluronic; Pluronic F-127; Pluronic P85; Pluronic F68; Gelucire; Gelucire 44 / 14; Lecithins; Polysorbates; Polysorbate 80; Plasdone-S630; Pluronic-F68; Inutec SP1; Glyceryl behenate; Tocopherol polyethylene glycol succinate; Polyoxyethylenated castor oil; polyoxyethylenated glycerides; lauroyl macroglycerides; mono- and di-fatty acid esters of low molecular weight polyethylene glycols; and mixtures thereof. G. Acids and salts based on these acids can be (but are not limited to) citric acid, tartaric acid, succinic acid, orthophosphoric acid, amino acids, acetate salts, sodium acetate, alginates, sodium alginate, glycyrrhizin and its salts, and mixtures thereof. H. The oxides and salts based on these oxides can be, but are not limited to, silica, silicates, titanium(IV) oxide, and mixtures thereof. I. Copolymers of the polymers described in A and C include, but are not limited to, alternating copolymers, random copolymers, block copolymers, graft copolymers, and crosslinked modifications: Methacrylic acid and ethyl acrylate copolymers;Methacrylic acid copolymers;Vinylpyrrolidone-vinyl acetate copolymer (PVPVA);Polyvinylpolypyrrolidone (PVPP);PVA-PEG graft copolymers;HPMC and PVA-PEG graft copolymers;Grafted polyvinylpyrrolidone-arabinogalactan copolymers;The graft copolymers have a) poly(vinyl acetate) and / or poly(vinyl alcohol) and / or poly(vinyl chloride) and poly(vinyl ester) on a polymer chain of b) polyethylene glycol, polyalkylene glycol, polypropylene glycol, polyisobutylene glycol or polymethylpentene glycol;The graft copolymers have polyvinyl acetate and / or hydrolyzed 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 copolymers include anionic, cationic and neutral copolymers based on methacrylic acid and methacrylic / acrylic esters, as well as their salts, esters or other derivatives and mixtures thereof; J. Methoxylated, ethoxylated, esterified, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, decarboxylated, amide, oxidized, sulfation, amino acid derived, fermented, thermally modified, chemically modified, acid modified derivatives of substances specified in AI and their esters and ethers, salts, and other chemical derivatives, and mixtures thereof; K. Any combination of substances specified in AJ; wherein the co-processing method is selected from the following methods, without excluding other methods that lead to the formation of a bioavailable solid dispersion: Method 1 (Crushing or milling with high energy stress; mechanochemical method): "API" and "HOST substance" are crushed by roller, ball, planetary, vibration, jet, drum, medium speed, impact jet, centrifugal counterflow, rotary, disintegrator, and other types of mills or other crushers. The crushing process mainly produces particles with a size of 1-1000 microns, which is powder. The crushing should be carried out to a state where the structure and properties of the crushed substance are changed, the bioavailability and permeability are improved, and a solid dispersion with high bioavailability and high permeability is formed. The crushing should cause structural changes such as defects, increased deformation, and associates. In the crushing process, one of the processes of solid-phase fusion, mechanosynthesis, and mechanoactivation of API substance and HOST substance occurs, and the mixture of the components causes a reaction in the solid phase to form a product with a high contact area and extremely high concentration of various types of defects. Organic and inorganic solvents may be added to the milling process, including but not limited to: Water, hydrocarbons and their halogenated derivatives, alcohols, esters and ethers, ketones, nitro compounds: 1,1,1-trichloroethane; 1,1,2-trichloroethene; 1,1-dichloroethene; 1,2-dichloroethane; 1,2-dichloroethene; 1,2-dimethoxyethane; 1,2-propanediol; 1,4-dioxane; 1-butanol; 1-pentanol; 1-propanol; 2-butanol; 2-butanone; 2-ethoxyethanol; 2-methoxyethanol; 2-methyl-1-propanol; 2-methylpyridine; 2-methyltetrahydrofuran; 2-Nitropropane;2-Propanol;3-Methyl-1-butanol;4-Methyl-2-pentanone;Acetic acid;Acetic anhydride;Acetone;Acetonitrile;Acetophenone;Ammonia;Aniline;Anisole;Benzene;Benzonitrile;Benzyl alcohol;Bromoethane;Bromoform;1-Bromooctane;Butanol;Butanone;Butyl acetate;Butylbenzene;Bromide;Carbon tetrachloride;Ethyl acetate;2-Ethoxyethyl acetate;Acetic acid;Chlorobenzene;Chloroform;1-Chlorohexane;Cumene; Cyclohexane;Cyclohexanol;Cyclohexanone;Cyclopentane;Decalin;Decane;Decanol;1,1-Dibromoethane;Dibutyl ether;Dichlorobenzene;1,2-Difluorobenzene;1,1-Dichloroethane;Methylene chloride;Diethylene glycol;Diethyl ether;Diglyme (diethylene glycol dimethyl ether);Diisopropyl ether;1,2-Dimethoxyethane;Dimethyl acetate;2-Thiapropane 2-oxide (dimethyl sulfoxide);Dimethylacetamide;Dimethylformamide;2,3-Dimethyl Pyridine;1,4-dioxane;Dodecane;Esters;Ethyl tert-butyl ether;Ethylene glycol;Ethanol;Ethers;Phenetole;Ethyl acetate (ethyl acetoate);Ethyl acetoacetate;Ethanol;Ethylbenzene;2-ethoxyethanol;2-methoxyethanol;2-butoxyethanol;Ethylene glycol;Ethyl ether;Ethyl formate;Fluorobenzene;Fluorooctane;Formamide;Formic acid;Furon;Furfural;Acetic acid (glacial acetic acid);Glycerol;Glycol ethers;Halobenzenes;Heptane;Heptane;1-Heptanol;Hexadecane;Hexadecyl iodide;Hexamethylphosphoric triamide;Tris(dimethylamino)phosphine;Hexane;2-Methylpentane (Hexane);Hexanol;Isoamyl alcohol;Phenyl iodine (III);Isobutanol;Isobutyl acetate;Isooctane;Propol (Isopropanol);Isopropyl acetate;Cumene (Isopropylbenzene);p-Cymene (Isopropyltoluene);m-Cresol;Mesitylene;Formic acid;Hydroxymethylidyne radical (methanol);2-Methoxy Ethanol;Methyl acetate;Methyl ethyl ketone;Methyl tert-butyl ether;Methyl isobutyl ketone;Methylcyclohexane;Methylene chloride;N-Methylformamide;Methyl isobutyl ketone;Other solvents;Monochlorobenzene;Morpholine;m-Xylene;Dimethylacetamide;Dimethylformamide;1-Pentanol;Butyl acetate;Nitrobenzene;Nitroethane;Nitromethane;N-Methylpyrrolidone;1-Octanol;Nonane;1-Nonanol;Octane;1-Octanol;o-Dichlorobenzene; o-Nitrotoluene;o-Xylene;Pentadecane;Pentane;Pentane;1-Pentanol;Tetrachloroethylene;Hexafluorobenzene;Petroleum ether;Phenol;Diphenyl ether;Propanol;Dipropyl ether;Propyl acetate;1-Methoxy-2-propanol;p-Xylene;1H-Pyridine (Pyridine);sec-Butanol;sec-Butylbenzene;Sulfolane;t-Butyl alcohol;t-Butyl alcohol;t-Butylbenzene;Methyl tert-butyl ether;1,1,2,2-Tetrachloroethylene ethane;tetrachloroethylene;tetrachlorocarbon (tetra);tetrahydrofuran;sulfolane (tetrahydrothiophene dioxide);tetralin;benzylidine radical (toluene);tributyl phosphate;1,1,1-trichloroethane;(trifluoromethyl)benzene;trichloroethylene;triethylamine;1,2,3-trimethylbenzene;2,2-dimethylhexane (trimethylpentane);undecane;o-xylene;xylene;isooctane (2,2,4-trimethylpentane);and mixtures thereof; Method 2 (grinding or milling with high energy stress and solvent; mechanochemical method with solvent): The "API" and "HOST material" are wetted with a solvent, the wet material is dried and ground in the same manner as in method 1. The list of solvents used is the same as the solvents listed in method 1; Method 3 (Media Milling): Solid dispersions are prepared using a high shear media mill. The milling chamber is filled with grinding media, solvent, "API", and "host substance" and rotated at very high shear rates under controlled temperatures. The grinding media consists of glass, zirconium oxide, highly cross-linked polystyrene resin, or other standard grinding media. High energy shear forces are generated by the collision of the grinding media with the "API" and "host substance". The list of solvents used is the same as those listed in Method 1. Method 4 (Mixing Method): This method is based on making a paste of the "host substance" with a small amount of water or water-alcoholic solution. The "API" is then added to the above paste and mixed for a given time. The mixed mixture is dried and sieved if necessary. In laboratory scale, mixing can be done using a mortar and pestle. In large scale, mixing can be done with the help of extruders or other machines. Method 5 (Hot Melt Method, Melt Method, Fusion Method): In this method, a physical mixture of the "API" and the "host substance" is melted by direct heating. The molten mixture is rapidly cooled and solidified. The final solid mass is crushed, powdered, and sieved. The melt method involves melting the "API" in the "host substance" followed by cooling and grinding the resulting product. A common adaptation of the melting step involves suspending the "API" in a pre-melted "host substance" instead of using both the "API" and the "host substance" in the molten state, which reduces the process temperature. To cool and solidify the molten mixture, methods such as ice bath stirring, thin layer spreading on stainless steel exposed to cold air, solidification on a petri dish at room temperature in a desiccator, spreading on a plate on dry ice, immersion in liquid nitrogen, or storage in a desiccator were used. After cooling, the mixture needs to be crushed for handling. KinetiSol® dispersion technology can also be used. Method 6 (Hot Melt Extrusion, Hot Stage Extrusion): Hot melt extrusion is a modification of the melt method. Hot melt extrusion is essentially the same as the melt method, except that the intensive mixing of the components is promoted by the extruder. Hot stage extrusion involves extruding a premixed "API" and "host substance" at their melting point for a short period of time and at high rotational speeds. The resulting product is cooled at room temperature and ground. A reduction in processing temperature is possible by combining hot stage extrusion with the use of carbon dioxide as a plasticizer. Method 7 (Meltrex process): Meltrex is a modification of the melt process. Meltrex is a patented solid dispersion manufacturing process based on the melt process. The key elements of the Meltrex technology are the use of a special twin-screw extruder and the presence of two independent hoppers in which the temperature can be varied over a wide range. Method 8 (Melt Agglomeration): Melt agglomeration is a modification of the melting method. Melt agglomeration allows the preparation of solid dispersions in a conventional high shear mixer. This is done by adding a molten "host substance" containing the "API" to a warmed excipient, by adding a molten "host substance" to a heated mixture of "API" and excipients, or by heating a mixture of "API", "host substance" and excipients to a temperature within or above the melting point of the "host substance". It is also possible to produce stable solid dispersions by performing melt agglomeration in a rotary processor. Method 9 (High Pressure Homogenization): In this method, a suspension of the “API” and “host substance” is passed under pressure through micro- or sub-micro-sized restrictors in a high pressure homogenizer. Method 10 (Solvent Evaporation): In this method, the "API" and "HOST" are dissolved in a common solvent, followed by evaporation of the solvent to produce a solid solution. The basic process for preparing or manufacturing this type of solid dispersion involves dissolving the "API" and the polymeric "HOST" in a common solvent or solvent mixture (the list of solvents used is the same as that listed in Method 1). The resulting film is usually milled and / or powdered. The "HOST" can also be used partially suspended rather than dissolved. Solvent evaporation procedures usually include vacuum drying, heating the mixture on a hot plate, slowly evaporating the solvent at low temperature, using a rotary evaporator, a stream of nitrogen, or other drying procedures. Method 11 (Spin-coated film method): The spin-coated film method is a modification of the solvent evaporation method, in which the "API" and "HOST substance" are dissolved in a common solvent and then dropped onto a clean substrate rotating at high speed. The solvent evaporates during the rotation. Method 12 (Spray Drying): Spray drying is a modification of the solvent evaporation method, in which the API and HOST substance are dissolved or suspended and then sprayed into a heated air stream to remove the solvent. Method 13 (Supercritical Fluid (SCF) Process): The supercritical fluid process is a modification of the solvent evaporation method. In this method, the "API" particles are dissolved in the SCF (usually carbon dioxide). Several SCF processing methods can be used to address individual aspects, including the compressed antisolvent process (PCA), solution-enhanced dispersion with SCF (SEDS), supercritical antisolvent process (SAS), rapid expansion of supercritical solutions (RESS), gas antisolvent recrystallization (GAS), and aerosol supercritical extraction system (ASES). In a modification of this method, the "API" and the "HOST material" are dissolved in a common solvent and introduced into the particle generation vessel through a nozzle simultaneously with CO2. When the solution is atomized, 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 Technique): The cryogenic method is a method in which the solutions of the "API" and the "HOST substance" are dissolved in a common solvent and frozen before the cryogenic solvent evaporation procedure. The common solvent can be the same as that used in the solvent evaporation method. Freezing of the solution may be performed after injection. The type of injection device can be capillary, rotary, pneumatic, ultrasonic nozzle, or other types of injection devices. The nozzle position can be above or below the level of the cryogenic liquid. The composition of the cryogenic liquid can be hydrofluoroalkane, fluorocarbon, N2, Ar, O2, organic solvent, or other types of cryogenic liquid. After the cryogenic treatment, dry powder can be obtained by various drying processes such as spray freeze drying, atmospheric freeze drying, vacuum freeze drying, lyophilization, and other cryogenic drying processes. The list of common solvents used is the same as that listed in Method 1. Method 15 (Lyophilization / Freeze-drying technique): Lyophilization is a modification of cryogenic technique. In this technique, the common solvent in the solution is removed by primary freezing and subsequent drying under low pressure. The basic freeze-drying process begins with dissolving the "API" and "HOST substance" in a common solvent and immersing them in a cryogenic liquid until they are completely frozen. The frozen solution is then further freeze-dried. Method 16 (Spray Freezing into Cryogenic Fluid): This method is a modification of the cryogenic technique, in which the "API" and "HOST" substances are dissolved in a common solvent and sprayed onto the surface of a boiling, agitated cryogenic liquid refrigerant. Method 17 (Cooling to cryogenic liquid by freeze atomization (SFL)): This method is a modification of the cryogenic technique. It incorporates direct liquid-liquid collision (by atomization) between the solution and the cryogenic liquid, providing intense atomization into microdroplets. The frozen particles are then freeze-dried to obtain a flowable fine powder. Method 18 (Freeze Spray to Vapor on Liquid (SFV / L)): This method is a modification of the cryogenic technique. It involves freezing the "API" solution in the vapor of a cryogenic fluid and then removing the frozen solvent. During SFV / L, the sprayed droplets typically start to freeze in the vapor phase before contacting the cryogenic liquid. As the solvent freezes, the unfrozen regions of the droplet become supersaturated with the "API". Method 19 (Ultra-rapid freezing): This method is a modification of cryogenic techniques. The "API" solution is applied to the solid surface of a cryogenic substrate, where it freezes instantly and is then freeze-dried. Method 20 (Precipitation, Co-precipitation): In the precipitation method, the "API" is dissolved in a solvent and then added to a non-solvent to precipitate the crystals. The non-solvent is added dropwise to the "API" and "HOST" solution under constant stirring. During the process of adding the non-solvent, the "API" and "HOST" co-precipitate to form microparticles. Finally, the resulting microparticle suspension is filtered and dried. The list of solvents used is the same as that listed in Method 1. Method 21 (Microwave Irradiation Method): In this method, the microwave irradiation reaction between the "API" and the complexing agent is carried out using a microwave heating device. The "API" and the "HOST substance" are dissolved in a mixture of water and / or organic solvent in a specific molar ratio and placed in a container in a specific ratio. This mixture is reacted in a microwave heating device. After the reaction is completed, an appropriate amount of a solvent mixture is added to the above reaction mixture to remove the residual uncomplexed "API" and "HOST substance". The resulting precipitate is filtered and dried. The list of solvents used is the same as that listed in Method 1. Method 22 (Energy Input Method): This method involves exposing a HOST substance and an “API” to an energy input to form a highly bioavailable and permeable solid dispersion in which the “API” is entrapped within the HOST substance as an amorphous material. Method 23 (Heat / Shear Energy Input Method): This method involves exposing the HOST material and the "API" to an energy input, where the energy input is heat and / or shear force, until a highly bioavailable and permeable solid dispersion of the "API" is formed as an amorphous material entrapped within the HOST material. Method 24 (Combination Method): This method involves any combination of Methods 1-23. Methods 1-24 should lead to the formation of solid dispersions with high bioavailability. Section III.II.

[0062] In another aspect, there is provided a method for treating (and for use in preparing a dosage form for) a disease in a human, mammal, animal, or bird in need thereof, comprising administering a therapeutically effective amount of a compound of FORMULA II (and solutions, gels, colloids, SOLs, etc. thereof), which is a highly bioavailable and highly permeable non-covalent complex obtained by adding a solvent to a highly bioavailable and highly permeable solid dispersion of FORMULA I, which is obtained by co-processing the API compound with a HOST substance. The list of diseases, the list of API compounds, the list of HOST substances, and the list of co-processing methods are the same as those described above (same as

[0061] (III.I. Section)). The API compound was selected from GUEST 1-9 (the same as the API selected in Method

[0061] (III.I. Section)), The molecular information of the non-covalent complexes in FORMULA II is encoded by the following formula (non-covalent complexes in FORMULA II): [GUEST]k [HOST]n (SOLVENT)m where k ranges from 1 to 100. m ranges from 1 to 10,000. n ranges from 1 to 10,000. The molecular information of the GUEST is provided based on the InChI derived from the InChIKey shown in parentheses after the name of the API compound and in the first position before the sequence number (in

[0061] (III.I. Section)). The molecular information of the API compound can be used by itself or based on it (by the skilled person) to obtain molecular information of pharmaceutical salts, esters, ethers, free bases and other pharmaceutical salts of these free bases. The molecular information of the HOST represents the molecular information of the monomers of the polymer, the smallest representable portion of the copolymer chain (which defines the copolymer) or the molecule (if the HOST material is not in a polymeric form), of a compound selected from the HOST material, and can be obtained by a skilled person. The molecular information for SOLVENT is HO when the solvent is water, but other physiologically acceptable solvents can be used and their molecular information can be obtained by a skilled practitioner. [Figure 1] shows an example of the chemical formula of a non-covalent complex of avermectin B1a and FORMULA II based on pectin. Section III.

[0063] In another aspect, there is provided a method for the treatment (and use in the manufacture of a formulation for the treatment) of a disease, wherein a solid dispersion of FORMULA I is encoded by the formula: GUESTk HOSTn where k is 0.0001-0.9, n is 0.1-0.9999, and the solid dispersion is in the form of a Class CC, Class CA, Class AC, Class AA, Class MC, Class MA solid dispersion, and contains one, two or more phases (single phase or mixture of phases).

[0064] In another aspect, other methods are provided for obtaining solid dispersions, non-covalent complexes, complexes with macromolecules and biopolymers. These may be performed by providing energy by any means, including but not limited to electromagnetic radiation, heat, mechanical action, sound. As non-limiting examples, examples of exposure by mechanical and acoustic influences are given. Non-covalent complexes obtained by interaction of aqueous solutions of HOST substances and APIs are obtained under conditions of mechano-acoustic and precipitation with ethanol. Mechano-acoustic effects can be performed in a rotary pulsating device with rotor speeds of 100-10000 rpm.

[0065] In another aspect, various combinatorial methods for obtaining solid dispersions and non-covalent complexes, complexes with macromolecules and biopolymers, which are described in patent and scientific literature, are provided. As a non-limiting example, the HOST substance is placed in a flask and completely dissolved in ethanol. The API is then added to the flask. Water is slowly added to the solution and stirred on a magnetic stirrer at 40-80°C for several hours. The alcohol portion is then removed under vacuum in a rotary evaporator. The aqueous portion is freeze-dried in a freeze dryer.

[0066] In another aspect, there is provided a method for treating a viral disease (and for use in the manufacture of a formulation for the treatment), using any form of solid dispersion, non-covalent complex, complex with a polymer and biopolymer described in the scientific and patent literature, obtained by any method described in the scientific and patent literature.

[0067] In another aspect, there is provided a method for treating (and for use in the manufacture of a pharmaceutical formulation for the treatment of) any viral disease caused by any virus.

[0068] In another aspect, there is provided a medical dosage form of FORMULA I having enhanced bioavailability and permeability, comprising a highly bioavailable and highly permeable solid dispersion or an aqueous solution or suspension thereof, the FORMULA I compound being obtained by co-processing the "API" with a HOST substance. Here, the list of API compounds, the list of HOST substances, and the list of co-processing methods are the same as those in Method

[0061] (Section III.I.).

[0069] In another aspect, there is provided a medical dosage form of FORMULA II (including its solutions, gels, colloids, SOLs, etc.), a non-covalent complex with high bioavailability and permeability, obtained by adding a solvent to the solid dispersion of FORMULA I with high bioavailability and permeability, and the FORMULA I compound is obtained by co-processing the API compound with a HOST substance. Here, the solvent is usually water and the molecular information of that solvent is HO, but other physiologically acceptable solvents or mixtures thereof can also be used. Here, the list of API compounds, the list of HOST substances, the list of co-processing methods, and the molecular information of non-covalent complexes in FORMULA II are the same as in Method

[0062] (Section III.II.).

[0070] In another aspect, there is provided a method for preparing or manufacturing a medical dosage form of FORMULA I having enhanced bioavailability and permeability (and a method for producing a therapeutic dosage form using the same), which comprises a highly bioavailable and highly permeable solid dispersion or an aqueous solution or suspension thereof, the FORMULA I compound being obtained by co-processing an "API" with a HOST substance. Here, the list of API compounds, the list of HOST substances, and the list of co-processing methods are the same as those in Method

[0061] (Section III.I.).

[0071] In another aspect, there is provided a method for preparing or manufacturing a medical dosage form (and using the same to manufacture a therapeutic dosage form) of FORMULA II (including its solutions, gels, colloids, SOLs, etc.), a non-covalent complex with high bioavailability and permeability, which is obtained by adding a solvent to a solid dispersion of FORMULA I with high bioavailability and permeability, and the FORMULA I compound is obtained by co-processing the API compound with a HOST substance. Here, the solvent is usually water and the molecular information of that solvent is HO, but other physiologically acceptable solvents or mixtures thereof can also be used. Here, the list of API compounds, the list of HOST substances, the list of co-processing methods, and the molecular information of non-covalent complexes in FORMULA II are the same as in Method

[0062] (Section III.II.).

[0072] Pharmaceutical dosage forms are available for a wide range of poorly water-soluble and slowly dissolving active ingredients or biologically active compounds, including the following groups: angiotensin-converting enzyme inhibitors, anterior pituitary hormones, adrenergic neuron blockers, corticosteroids, corticosteroid biosynthesis inhibitors, α-adrenergic agonists, α-adrenergic receptor blockers, selective α2-adrenergic agonists, analgesics, antipyretics, analgesics, anti-inflammatory drugs, androgens, anesthetics, anti-addictions, antiandrogens, antiarrhythmics, antiasthmatics, anticholinergic ... Antiprandials, anticoagulants, antidiabetics, antidiarrheals, antidiuretics, antiemetics and prokinetics, antiepileptics, antiestrogens, antifungals, antihypertensives, antibacterials, antimigraine drugs, antimuscarinics, antineoplastics, antiparasitics, antiparkinsonian drugs, antiplatelet drugs, antiprogestins, antithyroid drugs, antitussives, antivirals, atypical antidepressants, azaspirodecanediones, barbiturates, benzodiazepines, benzothiadiazides, β-adrenergic agonists, β-adrenergic blockers, selective β1-adrenergic blockers, selective β2-adrenergic Agonists, bile salts, drugs affecting body fluid volume and composition, butyrophenones, drugs affecting calcification, calcium antagonists, cardiovascular drugs, catecholamines and sympathomimetics, cholinergic agonists, cholinesterase reactivators, dermatological drugs, diphenylbutylpiperidines, diuretics, ergotamine alkaloids, estrogens, ganglionic blockers, ganglionic stimulants, hydantoins, gastric acid suppressants and drugs for treating peptic ulcers, hematopoietic drugs, histamine, histamine antagonists, 5-hydroxytryptamine antagonists, drugs for treating hyperlipidemia, hypnotics and sedatives , immunosuppressants, laxatives, methylxanthines, monoamine oxidase inhibitors, neuromuscular blocking agents, organic nitrates, opioid analgesics and antagonists, pancreatic enzymes, phenothiazines, progestins, prostaglandins, drugs for treating psychiatric disorders, retinoids, sodium channel blockers, drugs for treating spasticity and acute muscle spasms, succinimides, thioxanthines, thrombolytics, thyroid drugs, tricyclic antidepressants, organic ductal transport inhibitors, drugs affecting uterine motility, vasodilators, vitamins, etc., used alone or in combination in the manufacture of medical dosage forms. This list is extensive but is not intended to be exhaustive. IV. Combination Therapy

[0073] The compositions of the present invention may also be used in combination with other active therapeutic agents, non-limiting examples of which include niclosamide, remdesivir, nitazoxanide, chloroquine, lopinavir, ritonavir, hydroxychloroquine, and mixtures thereof. The compounds and compositions of the invention are also intended for use in the general care of patients, including nutrition, antibiotic (including metronidazole and cephem antibiotics such as ceftriaxone or cefuroxime) and / or antifungal prophylaxis, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatories (such as ibuprofen), analgesics, and medications for other common conditions in patient populations, such as antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid (quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephem antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin) or dysentery.

[0074] The compounds of the invention may also be combined 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. For sequential administration, the combination therapy may be administered as two or more injections.

[0075] Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to the administration of a compound of the invention and one or more other active therapeutic agents, either simultaneously or sequentially, such that therapeutically effective amounts of the compound of the invention and the one or more other active therapeutic agents are present in the patient at the same time.

[0076] Concomitant administration includes administering a single dose of a compound of the invention before or after a single dose of one or more other active therapeutic agents. For example, administration of a compound of the invention can occur within seconds, minutes, or hours after administration of one or more other active therapeutic agents. For example, a single dose of a compound of the invention can be administered first, followed within seconds or minutes by a single dose of one or more other active therapeutic agents. Alternatively, a single dose of one or more other active therapeutic agents can be administered first, followed within seconds or minutes by a single dose of a compound of the invention. In some cases, it may be desirable to administer a single dose of a compound of the invention first, followed several hours (e.g., 1-12 hours) later by a single dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a single dose of one or more other active therapeutic agents first, followed several hours (e.g., 1-12 hours) later by a single dose of a compound of the invention.

[0077] Combination therapy can provide "synergism" and "synergistic effects"; that is, the effect achieved when the active ingredients are used together exceeds the sum of the effects achieved when the compounds are used separately. Synergistic effects may be achieved when the active ingredients are (1) administered or delivered together in a combination drug, (2) delivered alternately or in parallel as separate drugs, or (3) delivered by other methods. Synergistic effects may be achieved when drugs are delivered in an alternating fashion, for example when the compounds are administered sequentially in separate tablets, pills, or capsules, or when they are injected separately in different syringes. In general, alternating deliveries provide an effective dose of each active ingredient sequentially, i.e., consecutively, whereas combination therapy provides effective doses of two or more active ingredients together. Synergistic antiviral effects refer to antiviral effects that are greater than the purely additive effects of the individual compounds of the combination.

[0078] Kits containing a compound of FORMULA IV are also provided. In some embodiments of the invention, individual kits are provided that contain compounds selected from each of the formula groups and subgroups and embodiments thereof provided herein, including FORMULA II, FORMULA III, FORMULA IV, and FORMULA V. In one aspect, the kit contains a compound of FORMULA I. Each individual kit described herein may include a label and / or instructions on how to administer the compound to treat a disease or condition in a subject (e.g., a human) in need of the compound. In some embodiments of the invention, the disease or condition is a human viral infection. In other embodiments of the invention, each individual kit may also include instructions on how to administer an additional pharmaceutical agent in combination with a compound of FORMULA I to treat a human disease or condition. In some embodiments of the invention, the disease or condition is a human viral infection. In each of the embodiments presented herein, there are alternative embodiments in which the kit includes individual dosage units of the compound described herein. Examples of individual dosages include 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 includes a single dosage unit, while in other embodiments, the kit may include multiple dosage units as required for a particular regimen or time period.

[0079] In certain embodiments, the product container may include a vial, bottle, ampoule, preloaded syringe, blister pack, can, bottle, box, or intravenous bag.

[0080] Also provided in certain embodiments of the invention is the use of a compound selected from each of FORMULA I-II set forth herein in the manufacture of a medicament for use in treating a disease in humans. Section IV.I.

[0081] In another embodiment, the method includes administering a therapeutically effective amount of a combination pharmaceutical (of FORMULA III). The combination pharmaceutical includes: a) a first pharmaceutical composition comprising a compound of FORMULA I-II (0.01-99.99% of the total weight of FORMULA III); and b) A second pharmaceutical composition (0.01-99.99% of the total weight of the composition) comprising an additional therapeutic agent having activity at least against the infectious virus, or an agent that increases the antiviral activity of the FORMULA I-II component, or an agent that reduces the hepatotoxicity of the FORMULA I-II component, or an agent that increases the stability of the FORMULA I-II component. This may include (but is not limited to): (Note: Internationally registered names of chemical compounds and medicines may be written in English. This includes INN (International Nonproprietary Name) - WHO International Nonproprietary Name Programme and Pharmaceutical Classification (https: / / www.who.int / teams / health-product-and-policy-standards / inn) and IUPAC (International Union of Pure and Applied Chemistry) names.) (-)-Carbovir; (-)-Carbovir triphosphate; (-)-Epicatechin; (-)-Epicatechin gallate; (+)-12-Oxocalanolide A; (+)-Catechin Hydrate; (+ / -)-trans-U-50488 methanesulfonate salt; (5E)-2-amino-5-(furan-2-ylmethylidene)-1,3-thiazol-4-one; (Melle-4)cyclosporin; (r)-Mandelic acid; (R,R)-asenapine; (S)-(-)-Propranolol hydrochloride; (S)-(+)-rolipram; 1-(Furan-2-ylmethyl)-1,3-diazinane-2,4,6-trione; 1,10-Phenanthroline; 1,10-Phenanthroline-5,6-dione; 1,3,6-Trimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione; 1,3-Diphenylguanidine; 1,4-Diaminobutane; 1,4-Dicaffeylquinic acid; 1,8-Dihydroxy-4,5-dinitroanthraquinone; 1,9-Pyrazoloanthrone; 10-Hydroxycamptothecin; 1-Amino-8-methoxybenzo[f]quinazoline-7,10-dione; 1-Chloro-2,4-dinitrobenzene; 1-Deoxynojirimycin; 1-Hexadecyl-3-methylimidazolium bromide; 2-(1-Naphthylsulfonyl)-6-aminobenzonitrile; 2-(3,4-Dichlorophenoxy)-5-nitrobenzonitrile; 2-(Morpholinothio)benzothiazole; 2-(Sec-butyldisulfanyl)-1h-imidazole; 2,3,5,6-Tetrakis(furan-2-yl)pyrazine;2',3'-Dideoxy-3'-thiacytidine; 2',3'-Dideoxyadenosine; 2,3-Di-furan-2-yl-quinoxaline-6-carboxylic acid; 2,3-Dihydroxy-5-isopropylcyclohepta-2,4,6-trienone; 2,3-Dihydroxypropyl octanoate; 2,3-Dimercaptosuccinic acid; 2,6,7-Trihydroxy-9-methylxanthen-3-one; 2-[(E)-2-(furan-2-yl)ethenyl]quinoline; 2-[2-(4-Nonylphenoxy)ethoxy]ethanol; 20R-Camptothecin; 2-Aminophenanthrene-9,10-dione; 2be2; 2'-C-methyladenosine; 2'-C-methylcytidine; 2'-C-methylguanosine; 2-Deoxy-2,3-dehydro-n-acetyl-neuraminic acid; 2'-deoxy-2'-fluoro-2'-C-methylcytidine; 2'-Deoxy-5-[(perylen-3-yl)ethynyl]uridine; 2'-Deoxycytidine; 2'-Deoxyguanosine; 2'-Deoxyuridine; 2-Fluoroadenosine; 2-Hydroxy-N'-(2-hydroxybenzoyl)benzohydrazide; 2i0a; 2i0d; 2-Iminobiotin; 2MD; 2-Methoxyestradiol; 2-Methyl-6-(phenylethynyl)pyridine; 2nmw; 2-Phosphoglycolic Acid; 2-Thiophenecarboxylic acid; 3,3'-Diethyl-9-methylthiacarbocyanine iodide; 3,3'-Diindolylmethane; 3,4,5,6-Tetramethylphenanthrene-9,10-dione; 3,6-Acridinediamine, sulfate (2:1);3,6-Bis(furan-2-yl)-1,2,4,5-tetrazine; 3-Anilino-6-bromo-isocarbostyril; 3'-Azido-2',3'-dideoxyguanosine; 3-Benzenesulfonyl-5-chloroindole-2-carboxamide; 3gi5; 3-Hydroxybenzoic acid; 3-Me-CycloSal-d4TMP; 4-(4-Toluidino)-1,2-naphthalenedione; 4',6-Dichloroflavan; 4,7-Epoxyisobenzofuran-1,3-dione, hexahydro-3a,7a-dimethyl-; 4-[(4-Methylbenzyl)amino]phenol; 4-[3-Hydroxyanilino]-6,7-dimethoxyquinazoline; 4-[4-(4-Hydroxyphenyl)hex-3-en-3-yl]phenol; 4-{[2-(Benzyloxy)benzyl]amino}phenol; 4'-Azidocytidine; 4E1RCat; 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine; 4-Hydroxybenzoic acid; 4-Methoxyphenol; 4-Methyl-DCK; 4-Morpholin-4-ylnaphthalene-1,2-dione; 4-Phenylbutyric acid; 558447-26-0; 5-Bromo-2'-deoxyuridine; 5-Chloro-8-hydroxyquinoline; 6-(4-Tert-butylphenoxy)pyridin-3-amine; 6-(cyclohexylmethoxy)-9H-purin-2-amine; 6,7-Bis(3-hydroxyphenyl)pteridine-2,4-diamine; 6,7-Dimethoxy-2-phenylquinoxaline; 6-Amino-7-bromo-5,8-quinolinedione; 6-Anilino-4-hydroxynaphthalene-2-sulphonic acid; 6-Azauridine;6-Benzyl-1-benzyloxymethyl-5-isopropyl uracil; 6-Hydroxydopamine hydrobromide; 6-Methyl-2-(phenylazo)-3-pyridinol; 7-[6-(Benzimidazol-1-yl)hexoxy]chromen-2-one; 7-Amino-6-methoxy-2-methyl-5,8-quinolinedione; 7-Aminocephalosporanic acid; 7-Deaza-2'-C-acetylene-adenosine; 7-Deaza-2'-C-methyladenosine; 7-Ethyl-10-hydroxycamptothecin; 8-Aminoquinoline-5,6-dione; 8-Hydroxy-2-methylquinazolin-4(3H)-one; 8-Hydroxyquinoline; 8-OH-Dpat; 9,10-Phenanthrenequinone; 9-Aminoacridine; 9-Aminocamptothecin; 9VR1J6U4XG; A43D; A-790742; A-837093; Abacavir; Abemaciclib; Abexinostat; ABT-072; Abt-737; Abt-751; Acelarin; Acenocoumarol; Acetazolamide; Acetophenazine maleate; Acetylcholine; Acetylcysteine; Acetylpepstatin; Acetylshikonin; Acriflavine; Acrisorcin; Acteoside; Acyclovir; Adafosbuvir; Adam ii; Adavosertib; Adefovir; Adefovir dipivoxil; Adenine; Adenosine; Adenosine 5'-monophosphate monohydrate; Adenosine monophosphate; Adenosine-5'-diphosphate; Adenosine-5'-triphosphate; Adiphenine hydrochloride;Adipic acid; Afegostat; Afimoxifene; AG14361; Albendazole; Albendazole oxide; Aleglitazar; Alendronic acid; Alfuzosin; Alfuzosin hydrochloride; Alibendol; Alisertib; Aliskiren; Alisporivir; Allethrin; Allitinib; Alosetron hydrochloride; Alovudine; Alpha-D-Galactopyranose; alpha-D-mannose 6-phosphate; alpha-Hederin; alpha-Ketoamide inhibitor 11r; alpha-L-arabinopyranose; alpha-Maltotriose; alpha-Mangostin; Alprenolol; Alprenolol hydrochloride; Alprostadil; Alsterpaullone; Altrenogest; Altretamine; Alverine; Alverine citrate; Alvespimycin; Alvocidib; Amantadine; Amantadine hydrochloride; Amaranth; AMD 3465; Amdoxovir; AMG-131; AMG-232; AMG-900; Amiloride; Aminocaproic acid; Amiodarone; Amiodarone hydrochloride; Amitifadine; Amitriptyline; Amitriptyline hydrochloride; Amlexanox; Amlodipine; Amlodipine besylate; Amodiaquin dihydrochloride dihydrate; Amodiaquine; Amonafide; Amorolfine; Amoxapine; Amoxicillin; Amphotericin b; Ampicillin; Amprenavir; Amrubicin; Amsacrine;Amsacrine hydrochloride; Amuvatinib; Anacetrapib; Anagrelide; Ancitabine hydrochloride; Andarine; Andrographolide; Androstanolone; Androsterone; Anethole trithione; Angustibalin; Anidulafungin; Anileridine; Anisomycin; Antazoline hydrochloride; Anthralin; antimycin A1; Antipyrine; Apalutamide; Apatinib; Apigenin; Apilimod; Apitolisib; Apixaban; Aplaviroc; Aplaviroc hydrochloride; Apomorphine; Aprepitant; Apricitabine; Arachidonic acid; Arbidol; Arctigenin; Aripiprazole; Artemether; Artemisinin; Artesunic acid; Aspartame; Aspirin; Astemizole; Asterric acid; ASTX660; Asunaprevir; AT9283; Ataciguat; Ataluren; Atazanavir; Atevirdine; Atipamezole; Atomoxetine; Atomoxetine hydrochloride; Atopaxar; Atorvastatin; Atrasentan; Aurintricarboxylic acid; AV-412 free base; Avasimibe; AVN-944; AVP-13358; Axitinib; AZ-960; Azacitidine; Azaribine; Azatadine; Azathioprine; Azd4547; AZD8330; Azelaic acid; Azelastine; Azelastine hydrochloride; Azelnidipine; Azithromycin; Azoxystrobin; Azvudine;B5R5IQ1D64; Baicalein; Baicalin; Bakuchiol; Balofloxacin; Baloxavir; Baloxavir marboxil; Bardoxolone methyl; Baricitinib; Batimastat; Bay 41-2272; BAY 41-4109; Bazedoxifene; Bazedoxifene acetate; Bdcrb; Beclabuvir; Beclomethasone; Belinostat; Belladonna total alkaloids; Benazepril hydrochloride; Bendamustine; Benidipine hydrochloride; Benperidol; Benserazide; Benserazide hydrochloride; Bentamapimod; Benzamidine; Benzbromarone; Benzenesulfonamide; Benzethonium chloride; Benzethonium; Benziodarone; Benzoic acid; Benzophenone; Benztropine; Benztropine mesylate; Benzydamine; Benzydamine hydrochloride; Benzyl 4-hydroxybenzoate; Benzyl benzoate; Benzyldimethyl(tridecyl)ammonium chloride; Bepridil; Berbamine; Berberine chloride; Berberine; Bersacapavir; Berzosertib; Besifovir; Beta-Carotene; beta-CYCLODEXTRIN; beta-D-Ribopyranose; beta-Escin; beta-Lactose; beta-Lapachone; beta-L-Arabinose; Betaxolol; Betazole hydrochloride; Betulin; Betulinic acid; Bevirimat; Bexarotene; BGT-226 free base;BI 2536; Bictegravir; Bifemelane; Bifonazole; BILR-355; Binodrenal; Biotin; Biperiden; Biperiden hydrochloride; Birinapant; Bis(2-ethylhexyl) phthalate; Bisbenzimide; Bishelenalinyl malonate; Bisibutiamine; Bisoprolol fumarate; Bisphenol a; Bisphenol a diglycidyl ether; Bithionol; Bitolterol; Blonanserin; Boceprevir; Boldine; Bortezomib; Boscalid; Bosutinib; Brecanavir; Brefeldin a; Brequinar; Brilliant green; Brincidofovir; Brinzolamide; Brivanib; Brivanib alaninate; Brivudine; Bromazine; Bromfenac; Bromhexine hydrochloride; Bromocriptine; Bromperidol; Brompheniramine maleate; Bucindolol; Budesonide; Bumetanide; Bunamidine hydrochloride; Buparlisib; Buparvaquone; Bupranolol; Bupropion hydrochloride; Buspirone; Butacaine; Butenafine; Butoconazole; Butoconazole nitrate; Butriptyline; BX-912; C.I. Direct blue 53; C188-9; Cabergoline; Cabotegravir; Cabozantinib; Caffeic acid; Caffeine; Calanolide; Calanolide a; Calcimycin; Calcitriol; Calpeptin; Cambridge id 6798241; Camostat;Camptothecin; Camylofin; Candesartan cilexetil; Canertinib; Cannabinol; Canrenone; Capivasertib; Capravirine; Capsaicin; Captopril; Carbamazepine; Carbamylcholine; Carbetapentane; Carbetapentane citrate; Carbinoxamine maleate; Carbodine; Carboxyamidotriazole; carboxy-N,N,N-trimethylmethanaminium; Carfilzomib; Carmofur; Carphenazine dimaleate; Carprofen; Carvedilol; Caspofungin; Cbr15S3hnj; Cbz-1Nal-Leu-Ala((S)-2-oxopyrrolidin-3-yl)-al; Cbz-Ala-Val-Phe-ol; CC-401; CCT129202; Cediranib; Cefaclor; Cefazolin sodium; Cefixime; Cefotaxime sodium; Cefotiam hydrochloride; Cefoxitin sodium; Cefuroxime sodium; Celastrol; Celecoxib; Celgosivir; Cenicriviroc; Cenicriviroc mesylate; Censavudine; Cephalothin; Cephapirin sodium; Cepharanthine; Ceritinib; Cetalkonium chloride; Cetrimide; Cetrimonium bromide; Cetylpyridinium bromide; Cetylpyridinium chloride; Cetylpyridinium chloride monohydrate; Cetylpyridinium; Chelerythrine chloride; Chelerythrine; Chicoric acid; Chidamide; Chikv-IN-2; CHIR-124;Chlorambucil; Chlorcyclizine; Chlorcyclizine hydrochloride; Chlordiazepoxide; Chlorhexidine hcl; Chlormadinone acetate; Chlorogenic acid; Chloroquine; Chloroquine monophosphate; Chloroquine phosphate; Chloroxine; Chlorpheniramine maleate; Chlorpromazine; Chlorpromazine hydrochloride; Chlorprothixen; Chlorprothixene; Chlorquinaldol; Chlortetracycline; Chlortetracycline hcl; Chlortetracycline hydrochloride; Cholesterol; Choline; Cianidanol; Ciclesonide; Ciclopirox; Ciclopirox olamine; Ciclosporin; Cidofovir; Cilnidipine; Ciluprevir; Cinacalcet hydrochloride; Cinnarizine; Ciprofloxacin hydrochloride; Cisapride; Cisapride; Citalopram; Citalopram hydrobromide; Citric acid; Cladribine; Clemastine; Clemastine fumarate; Clemizole; Clevudine; Clevudine; Climbazole; Clinofibrate; Clobetasol propionate; Clobetasone butyrate; Clofarabine; Clofazimine; Clofenotane; Clofoctol; Clomifene; Clomiphene; Clomiphene citrate; Clomipramine; Clomipramine hydrochloride; Cloperastine hydrochloride;Clorgyline hydrochloride; Clorsulon; Closantel; Clothiapine; Clotrimazole; Clozapine; Cndac; Codeine hydrochloride; Colchicine; Colistinmethanesulfonic acid; Combivir; Combretastatin A4; Congo red; Conjuncain; Copanlisib; Cordycepin; Costatolide; Cozaar; CP-673451; CP-91149; Crenolanib; Cridanimod; CTS-1027; CU-3; ; Cudc-101; CUDC-427; Curcumin; Cvt-313; CX-5461; Cyclizine; Cyclizine dihydrochloride; Cyclobenzaprine; Cyclobenzaprine hydrochloride; Cycloguanil; Cycloguanil hydrochloride; Cycloheximide; Cyclophosphamide; CycloSal-d4TMP; Cycloserine; Cydectin; Cynarine; Cyproheptadine; Cyproheptadine hydrochloride; Cyproterone acetate; Cysteamine hydrochloride; Cysteine; Cytarabine; Cytarabine hydrochloride; Cytisine; Dabigatran etexilate mesylate; Dabrafenib; Dacarbazine; Daclatasvir; Dactinomycin; Dactolisib; Daidzein; Danazol; Daniquidone; Danoprevir; Danusertib; Daphnetin; Dapivirine; Daporinad; Dapoxetine; Darifenacin hydrobromide; Darunavir; Dasabuvir; Dasatinib; Daunorubicin; Daunorubicin hydrochloride; D-Cellobiose; Decitabine; Deferasirox; Deferoxamine mesylate; Delanzomib; Delapril hydrochloride; Delavirdine; Delavirdine mesylate; Deleobuvir; Demeclocycline; Demeclocycline hydrochloride; Deoxycholic acid; Dequalinium chloride; Dequalinium; Deracoxib; Derenofylline;Desacetylvinblastine amide; Deserpidine; Desipramine; Desipramine hydrochloride; Deslanoside; Desloratadine; Dexamethasone; Dexamethasone isonicotinate; Dexbrompheniramine maleate; Dexchlorpheniramine maleate; Dexelvucitabine; Dexnorgestrel acetime; D-Galactose; DHAD; Diacerein; Diazepam; Diazoxide; Dibenzepin; Dibenzepin hydrochloride; Dibucaine; Dichlorophen; Dichlorphenamide; Diclazuril; Diclofenac; Diclofenac sodium; Dicloxacillin sodium monohydrate; Dicumarol; Dicyclomine; Dicyclomine hydrochloride; Didanosine; Didehydrothymidine-cyclic-benzophosphate, 3,5-D; Dienestrol; Diethylstilbestrol; Diflunisal; Digitoxin; Digoxigenin; Digoxin; Dihydroergocristine; Dihydroergocristine mesylate; Dihydroergotamine; Dihydrotachysterol; Dihydroxypyrimidine carboxamide, 3; Diltiazem; Diltiazem hydrochloride; Dimethyldioctylammonium chloride; Dinaciclib; Diosmetin; Dioxybenzone; Dipentamethylenethiuram disulfide; Diperodon; Diperodon hydrochloride; Diphenhydramine; Diphenidol;Diphenylpyraline hydrochloride; Dipyridamole; Dipyridodiazepinone deriv. 42; Dipyrithione; Disodium hydrogen phosphate; Disulfiram; Dizan; Dizocilpine maleate; Dmipopmt; Dmp-323; Docetaxel; Docosahexaenoic acid; Dofetilide; Dolutegravir; Dolutegravir sodium; Domiphen bromide; Domperidone; Donepezil hydrochloride; Dopamine hydrochloride; Dopexamine; Doramapimod; Doramectin; Doravirine; Doripenem; Dorzolamide; Dovitinib; Doxazosin; Doxazosin mesylate; Doxepin hydrochloride; Doxercalciferol (hectorol); Doxorubicin; Doxorubicin hydrochloride; Doxycycline hydrochloride; Doxylamine succinate; DPC-082; DPC-961; Drofenine hydrochloride; Droloxifene; Drometrizole; Dronabinol; Dronedarone; Dronedarone hydrochloride; Droperidol; Drospirenone; Drostanolone propionate; D-serine; d-Tartaric acid; Duloxetine; Duloxetine hydrochloride; Dyclonine hydrochloride; Dydrogesterone; Dynamax; E100; Ebastine; Ebselen; Econazole nitrate; Ecopipam; Edaravone; Edoxudine; Efavirenz; Elacestrant; Elacridar;Elaidic acid; Elbasvir; Elesclomol; Eletriptan; Eliprodil; Ellagic acid; Ellipticine; Eltrombopag; Elvitegravir; Elvucitabine; Embelin; Emedastine difumarate; Emivirine; Emodin; Emricasan; Emtricitabine; Enclomiphene citrate; Endoxifen; Endurobol; Enfuvirtide; Enobosarm; Enoximone; Enoxolone; Ensulizole; Ensovibep; Entecavir; Entecavir triphosphate; Entinostat; Enviroxime; Enzastaurin; Eperisone hydrochloride; Ephedrine sulfate; Epigallocatechin; Epigallocatechin gallate; Epinephrine; Epinephrine hydrogen tartrate; Epirubicin; Epirubicin hydrochloride; Eprazinone dihydrochloride; Ergocalciferol; Erlotinib; Erteberel; Erythromycin; Erythromycin estolate; Erythromycin propionate; Escitalopram oxalate; Esculetin; Esmolol hydrochloride; Estradiol; Estradiol acetate; Estradiol cypionate; Estragole; Estramustine; Estriol; Estrone; Ethacridine lactate monohydrate; Ethacrynic acid; Ethanol; Ethinyl estradiol; Ethopabate; Ethopropazine hydrochloride; Ethoxyquin; Ethoxzolamide; Ethyl gallate;Ethyl nitrite; Ethylestrenol; Etofenamate; Etoposide; Etravirine; Etravirine impurity 5; Evans blue; Everolimus; Exaluren; Excenel; Exemestane; Exifone; Ezetimibe; F2-NH-DABO 9d; Faldaprevir; Famciclovir; Farglitazar; Fasudil; Favipiravir; Febuxostat; Felodipine; Fenbendazole; Fenbufen; Fenobam anhydrous; Fenoldopam; Fenoldopam mesylate; Fenoverine; Fenretinide; Fiacitabine; Fialuridine; Fiboflapon; Fidaxomicin; Filgotinib; Filibuvir; Filociclovir; Fimepinostat; Fingolimod; Fipexide hydrochloride; Firsocostat; Fisetin; Flavin mononucleotide; Flavone; Flavopiridol hydrochloride; Flecainide; Flecainide acetate; Floxuridine; Fludarabine; Flufenamic acid; Flumequine; Flunarizine; Flunarizine hydrochloride; Fluorescein; Fluorouracil; Fluoxetine; Fluoxetine hydrochloride; Flupentixol; Flupentixol dihydrochloride; Fluphenazine; Fluphenazine hydrochloride; Flupirtine; Flupirtine maleate; Flurazepam; Flurbiprofen; Fluspirilene; Flutamide; Fluticasone propionate; Fluvastatin; Fluvastatin sodium;Fluvoxamine; Fluvoxamine maleate; Folic acid; Foretinib; Formononetin; Forodesine; Forskolin; Fosamax; Foscarnet; Foscarnet sodium; Fostamatinib; Fulvestrant; Furosemide; Furoxone; Fusidate sodium; Fusidic acid; Galantamine; Galidesivir; Gallic acid; Galloflavin; Gallotannin; Gamma-Aminobutyric Acid; gamma-Oryzanol; Ganciclovir; Ganetespib; Gatifloxacin; GC376 sodium; Gdc-0152; Gefitinib; Geldanamycin; Gemcitabine; Gemcitabine hydrochloride; Genistein; Gentian violet; Gentian violet cation; Gestrinone; Gilteritinib; Gimatecan; Givinostat hydrochloride monohydrate; Glafenine hydrochloride; Glecaprevir; Glesatinib; Gliclazide; Glipizide; Gliquidone; Glutamic acid; Glutamine; Glutaric acid; Glutathione; Glyburide; Glycine, N-[imino(phosphonoamino)methyl]-N-methyl-; Glycopyrrolate; Glycyrrhizic acid; GNF-Pf-159; GNF-Pf-2335; GNF-Pf-4300; GNF-Pf-888; Go-6976; Golvatinib; Gossypol; Gossypol acetic acid; Gossypol hexaacetate; Granisetron; Grazoprevir; Guaiazulene; Guanabenz acetate;Guanidino-Oseltamivir Carboxylicacid; Guanidino-Tamiphosphor; Guanosine; GW0742; GW4511; GW678248; H-Ala-Lys-Val-Thr-Met-Thr-Cys-Ser-Ala-Ser-OH; Halcinonide; Halofantrine; Halofantrine hydrochloride; Haloperidol; Haloxon; Harmaline; Harmine; Harmine hydrochloride; Harringtonine; HBF-0259; HDP-HPMPA; Helioxanthin 8-1; Hematoxylin; Hesperetin; Hexachlorophene; Hexestrol; Hexylcaine hydrochloride; Hexylresorcinol; Histamine; Histidine; HIV-1 inhibitor-43; Homidium bromide; Honokiol; Hpmpa; Huperzine a; Hydergine; Hydrocortisone; Hydrocortisone acetate; Hydroquinone; Hydroxychloroquine; Hydroxychloroquine sulfate; Hydroxyflutamide; Hydroxyprogesterone; Hydroxyprogesterone caproate; Hydroxytyrosol; Hydroxyurea; Hydroxyzine; Hydroxyzine pamoate; Hyoscyamine; Hypericin; Hyperoside; Hypoxanthine; Ibrutinib; Ibufenac; Ibuprofen; IC9564; Icaritin; ICG-001; Icosapent; Idarubicin; Idarubicin hydrochloride; Idasanutlin; Idazoxan; Idelalisib; Idoxuridine; Idronoxil; Ifenprodil; Iloperidone;Imatinib; Imatinib mesylate; Imidocarb; Iminostilbene; Imipenem; Imipramine; Imipramine hydrochloride; Imiquimod; Imperatorin; Inarigivir soproxil; INCB-9471; Indibulin; Indinavir; Indinavir sulfate; Indiplon; Indirubin; Indobufen; Indocyanine green; Indole-3-carbinol; Indomethacin; Indoprofen; Indoramin hydrochloride; Ingenol mebutate; Inosine; Inositol; Invokana; INX-08189; Iodoacetamide; Iodoquinol; Iofetamine; iOWH-032; Ipatasertib; Ipriflavone; Irbesartan; Irinotecan; Irinotecan hydrochloride; Irosustat; Isoconazole; Isocycloheximide; Isoliquiritigenin; Isoorientin; Isopropamide; Isopropyl unoprostone; Isoquercetin; Isoreserpin; Isosulfan blue; Isothymonin; Isotretinoin; Isradipine; Istodax; Istradefylline; ITD-1; Itraconazole; Itraconazolum [latin]; Ivacaftor; Ivermectin; Ixazomib; JE-2147; JNJ-7706621; Kaempferol; Kalafungin; Kenpaullone; Ketanserin; Ketoconazole; Ketorolac; Ketorolac tromethamine; Ketotifen; Ketotifen fumarate; Kinetin; KNI-1931; Ksc-16-200S2C; Ku-0063794;Kynostatin 272; L-685434; Labetalol; Lamivudine; Lanatoside c; Laninamivir; Laninamivir octanoate; Lansoprazole; Lapatinib; Laropiprant; Lasalocid sodium; LCL161; Ledipasvir; Leflunomide; Lenvatinib; LEO 275; Lercanidipine; Lercanidipine hydrochloride; Lersivirine; Lestaurtinib; Letermovir; Leucine; Leucomethylene blue; Levallorphan; Levobupivacaine hydrochloride; Levodopa; Levofloxacin; Levomethadyl acetate hydrochloride; Levonordefrin; Levosimendan; Levothyroxine; Lexibulin; L-Glutamic acid hydrochloride; Licofelone; Lidoflazine; Lificiguat; Ligustrinin b; Linoleic acid; Linsitinib; Liothyronine; Liothyronine sodium; Liquiritigenin; Liranaftate; Lithocholic acid; Lobeline; Lodosyn; Lofepramine hydrochloride; Lofexidine; Lomefloxacin; Lomefloxacin hydrochloride; Lomerizine hydrochloride; Lomibuvir; Lonafarnib; Loperamide; Loperamide hydrochloride; Lopinavir; Loratadine; Lorcaserin; Lorlatinib; L-ornithine; Lornoxicam; Lovastatin; Loviride; Loxapine; Loxapine succinate;L-Tartaric acid; Lucanthone hydrochloride; Luliconazole; Lumacaftor; Lumefantrine; Lumicitabine; Luminespib; Lusutrombopag; Luteolin; Lynestrenol; Lysergide; Lysine; Magnolol; Malachite green oxalate; Maleic acid; Malonic acid; Malonoben; Malotilate; Manidipine; Manidipine dihydrochloride; Maprotiline; Maprotiline hydrochloride; Maraviroc; Mardepodect; Maribavir; Masoprocol; Matrine; Maxacalcitol; MC-1220; Mebendazole; Mebeverine hydrochloride; Mecamylamine; Mechlorethamine hydrochloride; Meclizine hydrochloride; Meclocycline sulfosalicylate; Medphalan; Medroxyprogesterone; Mefenamic acid; Mefloquine; Mefloquine hydrochloride; Melitracen hydrochloride; Melittin; Melphalan; Memantine; Memantine hydrochloride; Menadione; Menadione sodium bisulfite; Meptazinol hydrochloride; Mepyramine; Mequitazine; Merbromin; Mercaptopurine; Mericitabine; Merimepodib; Mesalamine; Mesoridazine; Mestranol; Met kinase inhibitor; Metarrestin; Metergoline; Methacycline; Methacycline hydrochloride;Methadone hydrochloride; Methapyrilene hydrochloride; Methazolamide; Methdilazine hydrochloride; Methionine; Methixene hydrochloride; Methotrexate; Methyl methanesulfonate; methyl-2-pyrrolidinone, 17b; Methyldopa; Methyldopa sesquihydrate; Methylene blue; Methylene blue cation; Methylergonovine; Methylprednisolone; Methysergide; Methys; ergide maleate; Metildigoxin; Metixene hydrochloride; Metolazone; Metoprine; Mevastatin; Mianserin; Mianserin hydrochloride; Mibefradil; Mibefradil dihydrochloride; Michellamine b; Miconazole; Miconazole nitrate; Midostaurin; Mifepristone; Milciclib; Miltefosine; Minocycline hydrochloride; Minoxidil; Mitomycin c; Mitotane; Mitoxantrone; Mitoxantrone hydrochloride; Mizolastine; MK-1107; MK-2206; MK-3281; MK-4965; MK-5108; MK-6186; MK-7445; MK-8245; MK-8325 free base; MK-944a; ML322; ML355; MLN8054; Mocetinostat; Mocravimod; Momelotinib; Mometasone furoate; Monobenzone; Montelukast sodium; Moricizine; Morin; Morphine sulfate; Morphothiadin; Mosapride citrate; Motesanib; Moxalactam disodium; Moxaverine; Moxifloxacin hydrochloride; Mozenavir; Mthpc; Mupirocin; Mycophenolate mofetil; Mycophenolic acid; Myricetin; N-(1,3-benzothiazol-2-yl)-2-methoxybenzamide; N-(1,4-dioxonaphthalen-2-yl)benzamide; N-(1H-benzimidazol-2-yl)-2-fluorobenzamide; N-(1H-benzimidazol-2-yl)-2-methoxybenzamide;N-(2,6-Dichlorobenzylidene)-N'-amidinohydrazine; N-9-Methoxynonyldeoxynojirimycin hydrochloride; Naftifine hydrochloride; Naftopidil; Naloxone; Naltrexone; Nanaomycin; Naphazoline hydrochloride; Naproxen; Naratriptan; Naringenin; Narlaprevir; Navelbine; Navitoclax; NBD-14270; NCGC00090797-11; NCGC00179454-04; Nebivolol hcl; Nefazodone; Nefazodone hydrochloride; Nefopam; Nefopam hydrochloride; Nelfinavir; Nelfinavir mesylate; Neomycin; Nesbuvir; N-ethylmaleimide; Netilmicin; Nevirapine; Nialamide; Nicardipine; Nicardipine hydrochloride; Nicergoline; Nickeldibutyldithiocarbamate; Niclosamide; Nicotine; Nifedipine; Niflumic acid; Nifuroxazide; Nimesulide; Nimodipine; Nimustine hydrochloride; Nintedanib; Niraparib; Nisoldipine; N-Isopropyl-N'-phenyl-p-phenylenediamine; Nitazoxanide; Nitrendipine; Nitrofurantoin; Nitrofurazone; Nitroxoline; N-Methylpyrimidone, 17; Nocodazole; Nolvasan; Nomifensine maleate; Norcantharidin; Nordihydroguaiaretic acid; Norepinephrine; Norethisterone enanthate;Norfloxacin; Normethadone; North-methanocarbathymidine; Nortriptyline; Nortriptyline hydrochloride; Novobiocin; N-phenylanthranilic acid; NSC158393; NSC351815; NSC640065; NSC651084; NSC666863; NSC697445; N-tert-butyl isoquine; Nucleozin; Nylidrin; Nystatin (fungicidin); Nystatin A1; o6-Benzylguanine; Octocrylene; Odanacatib; Ofloxacin; Olanzapine; Oleanolic acid; Oleic acid; Olprinone; Omacetaxine mepesuccinate; Omadacycline; Ombitasvir; Omeprazole; Omipalisib; Onalespib; Oncovin; Ondansetron; ONO-5334; Opipramol; Oprea1_836388; Oprozomib; Orphenadrine; Orphenadrine hydrochloride; Oseltamivir; Oseltamivir acid; Oseltamivir phosphate; Osi-027; Osi-930; Osimertinib; Ospemifene; Osthole; Otamixaban; Otilonium bromide; Otilonium; Ouabain; Ouabain octahydrate; Oxalacetic acid; Oxalic acid; Oxatomide; Oxethazaine; Oxfendazole; Oxibendazole; Oxiconazole nitrate; Oxprenolol hydrochloride; Oxyclozanide; Oxymatrine; Oxymetazoline; Oxymetazoline hydrochloride; Oxymetholone; Oxyphenbutazone;Oxyphencyclimine hydrochloride; Oxytetracycline; Oxytetracycline dihydrate; Oxytetracycline hydrochloride; Paclitaxel; Paclitaxel (taxol); Palbociclib; Palinavir; Palmitic acid; Palonosetron hydrochloride; Pamicogrel; Panobinostat; Papaverine; Papaverine hydrochloride; Paritaprevir; Paritaprevir dihydrate; Paroxetine; Paroxetine hydrochloride; Parthenolide; Parthenolide; Parthenolide; Pasiniazid; Paxlovid; Pazopanib; Pazopanib hydrochloride; PD0166285; PDK1 inhibitor AR-12; Pecazine; Pectamol; Pemetrexed; Penbutolol sulfate; Penciclovir; Penfluridol; Pentamidine; Pentoxifylline; Pepstatin; Peramivir; Perazine; Pergolide mesylate; Perhexiline; Perhexiline maleate; Periciazine; Perospirone hydrochloride; Perphenazine; PF-00562271 free base; PF-03882845; PF-04217903; PF-04691502; PF-3758309; PF-46396; PF-477736; pf74; PH-797804; Pha-665752; PHA-793887; Phenazopyridine; Phenazopyridine hydrochloride; Phenelzine; Phenformin hydrochloride; Phenol; Phenoxybenzamine; Phenprocoumon;Phentolamine; Phentolamine mesylate; Phenylalanine; Phenylbutazone; Phorbol 12-myristate 13-acetate; Phosphonatoformate; Phosphoric acid; Phthalic acid; Physostigmine; Phytic acid; PI-103; Piboserod; Pibrentasvir; Piceid; Picropodophyllin; Pictilisib; Pifoxime; Pilaralisib; Pimethixene; Pimethixene maleate; Pimobendan; Pimodivir; Pimozide; Pinaverium bromide; Pindolol; Piperacetazine; Piperidolate hydrochloride; Pirarubicin; Pirfenidone; Piritrexim; Pirlindole mesylate; Pirodavir; Pivampicillin; Pivmecillinam hydrochloride; Pizotifen; Pizotifen malate; PL-100; Platinum, diamminedichloro-; Pleconaril; Plerixafor; Plerixafor octahydrochloride; Plumbagin; PLX-4720; Pnu-103017; Pocapavir; Podofilox; Ponatinib; Posaconazole; Pradigastat; Pradimicin a; Pradimicin s; Pralatrexate; Pramipexole; Pramoxine hydrochloride; Pranlukast; Praziquantel; Prazosin; Prazosin hydrochloride; Precose; Prednisolone tebutate; Prednisone; Preladenant; Prenylamine lactate; Presatovir; Prima-1met; Primaquine;Primaquine phosphate; Prinaberel; Proadifen hydrochloride; Procainamide hydrochloride; Prochlorperazine; Prochlorperazine edisylate; Prochlorperazine maleate; Procyclidine hydrochloride; Proflavine; Progesterone; Proguanil hydrochloride; Promazine; Promazine hydrochloride; Promethazine; Promethazine hydrochloride; Pronetalol; Propafenone; Propafenone hydrochloride; Proparacaine hydrochloride; Propidium iodide; Propoxyphene hydrochloride; Propranolol hydrochloride; Propyl gallate; Proscillaridin; Prostratin; Protionamide; Protoporphyrin ix; Protriptyline; Proxalutamide; psi 7851; psi-352938; Pterostilbene; PU-H71; Puromycin dihydrochloride; Purpurogalline; Pyrantel pamoate; Pyrazinamide; Pyridoxal; Pyridoxine; Pyrilamine maleate; Pyrimethamine; Pyrithione; Pyronaridine; Pyrophosphoric acid; Pyroxamide; Pyrrollo-A; Pyruvate; Pyrvinium pamoate; Q9LK8R766M; Quercetin; Quercetin dihydrate; Quercitrin; Quinacrine; Quinacrine dihydrochloride; Quinacrine dihydrochloride dihydrate; Quinestrol;Quinidine; Quinidine hydrochloride monohydrate; Quinine; Quinine sulfate dihydrate; Quisinostat; R-82913; Rabeprazole sodium; Rabusertib; Racecadotril; Radalbuvir; RAF265; Rafoxanide; Ralimetinib; Raloxifene; Raloxifene hydrochloride; Raltegravir; Raltegravir potassium; Raltitrexed; Raluridine; Ramosetron hydrochloride; Rapacuronium bromide; Ravidasvir; Rebastinib; Reboxetine mesylate; Regorafenib; Remdesivir; Rescinnamine; Reserpine; Resiniferatoxin; Resiquimod; Resorcinol; Resveratrol; Retigabine; Retinol; Riamilovir sodium dihydrate; Ribavirin; Riboflavin; Ricolinostat; Rifabutin; Rilematovir; Rilmenidine; Rilpivirine; Riluzole; Rimantadine; Rimantadine hydrochloride; Rimonabant; Risperidone; Rita; Ritanserin; Ritonavir; Rivaroxaban; Riviciclib; RO4929097; Rofecoxib; Rolipram; Rolitetracycline; Rosmarinic acid; Rotenone; Rotigotine; Rottlerin; Roxadustat; RSV604; Ruboxistaurin; Rubschisandrin; Rucaparib; Rupintrivir; Rutaecarpine; Rutin; Ruxolitinib; Saccharin;S-Adenosyl-DL-methionine; Safinamide; Salicylic acid; Salinomycin; Salinomycin sodium; Salmeterol; Salmeterol xinafoate; Sancycline; Sanguinarine; Sanguinarium chloride; Sapanisertib; Sapitinib; Saponaretin;homovitexin; Saquinavir; Saquinavir mesylate; Saracatinib; Sarafloxacin; Sarecycline; Sarpogrelate; Sarpogrelate hydrochloride; SB-505124; SB-743921; Sch 58261; Scy-635; SD-06; sd146; Sebacic acid; Secnidazole; Secoisolariciresinol; Securinine; Selexipag; Seliciclib; Semaxanib; Sennoside a, analytical standard; Sensit; Sepantronium; Serdemetan; Serotonin hydrochloride; Sertaconazole nitrate; Sertindole; Sertraline; Sertraline hydrochloride; SGI-1776; Sgx-523; Sibutramine; Silibinin; Silmitasertib; Silymarin; Simeprevir; Simvastatin; Sinefungin; Sinequan; Sinomenine; Sirolimus; Sisunatovir; Sitagliptin; SNS-032; SNX-2112; Snx-5422; Sodium hydroxide; Sodium hypochlorite; Sofalcone; Sofosbuvir; Solifenacin hydrochloride; Sophoridine; Sorafenib; Sorafenib tosylate; Sorivudine;Sotradecol; Sovaprevir; Spironolactone; Staurosporine; Stavudine; Stavudine triphosphate; Stearic acid; Streptomycin; Stubomycin; SU9516; Succinic acid; Succinylcholine; Sufentanil citrate; Sulbactam; Sulconazole nitrate; Sulfadiazine; Sulfamethazine sodium; Sulfamethoxazole; Sulfapyridine; Sulfasalazine; Sulindac sulfone; Sultiame; Sumatriptan; Sunitinib; Sunitinib malate; Suprofen; Suramin; Suramin (sodium salt); Swertiamarin; Tacrine; Tacrine hydrochloride monohydrate; Tak-285; Tak-715; TAK-733; TAK-901; Talinolol; Talmapimod; Talviraline; Tame; Tamibarotene; Tamiphosphor; Tamoxifen; Tamoxifen citrate; Tandutinib; Tanespimycin; Tangeretin; Tanshinone i; Tanshinone iia; Tanzisertib; Tariquidar; Tauroursodeoxycholic acid; Taxifolin; Tazarotene; Tazobactam sodium; TCRB; Tecovirimat; Tegaserod; Tegaserod maleate; Tegobuvir; Telaprevir; Telbivudine; Telinavir; Telmisartan; Telotristat; Telotristat ethyl; Temoporfin; Temsavir; Tenofovir; Tenofovir alafenamide;Tenofovir alafenamide fumarate; Tenofovir diphospahte; Tenofovir disoproxil; Tenofovir disoproxil fumarate; Tenofovir exalidex; Tepotinib; Tepoxalin; Terameprocol; Terazosin; Terazosin hydrochloride; Terbinafine; Terbinafine hydrochloride; Terconazole; Terfenadine; Teriflunomide; Terodiline hydrochloride; Tesaglitazar; Tesmilifene; Testosterone; Testosterone propionate; Tetrabenazine; Tetracaine hydrochloride; Tetracycline hydrochloride; Tetradecylthioacetic acid; Tetramethylthiuram monosulfide; Tetrandrine; TG101209; TGX-221; Thenalidine; Theophylline; Thiabendazole; Thiamine diphosphate; Thiamine; Thiazolobenzimidazole; Thimerosal; Thioctic acid; thio-DABO 3s; thio-DABO 3t; thio-DABO 3w; Thioguanine; Thioridazine; Thioridazine hydrochloride; Thiosangivamycin; Thiram; Thonzonium bromide; Thymidine; Thymidine-5'-triphosphate; Thymol; Tiagabine hydrochloride; Tiaprofenic acid; Tibo; Tibolone; Tilorone dihydrochloride; Tioconazole; Tiopronin; Tiotixene; Tioxidazole; Tioxolone;Tipifarnib; Tiplasinin; Tipranavir; Tiratricol; Tivirapine; Tivozanib; Tizanidine; Tizoxanide; TMC 126; TMC647055; Tobramycin; Tolcapone; Tolnaftate; Tolonium chloride; Tolterodine; Toltrazuril; Tolvaptan; Tomivosertib; Topiramate; Topotecan; Topotecan hydrochloride; Toremifene; Toremifene citrate; Torsemide; Tozasertib; Trabectedi; n; Tranexamic acid; Tranilast; trans-Flupentixol; Trazodone; Trehalose; Tretazicar; Tretinoin; Triamterene; Tribromsalan; Trichlorfon; Trichostatin a; Triciribine; Triciribine phosphate; Triclabendazole; Triclocarban; Triclosan; Trifluoperazine; Trifluoperazine hydrochloride; Triflupromazine; Triflupromazine hydrochloride; Trifluridine; Triglycidyl isocyanurate; Trihexyphenidyl hydrochloride; Trimethoprim; Trimetrexate; Trimipramine; Trimipramine maleate; Triparanol; Tripelennamine citrate; Triprolidine; Triprolidine hydrochloride; Triptil; Troglitazone; Tromethamine; Tropisetron; Trovafloxacin mesylate; Trovirdine; Troxatyl; Trypaflavine hydrochloride; Tryptamine; Tryptophan; TSAO-m3T; Tsao-T; TTP-8307; Tubercidin; TYA5; Tyrosine; Tyrphostin B42; Ubenimex; UC-781; UK-201844; Ulixertinib; Ulodesine; UMI-77; Uprifosbuvir; Uracil; Urapidil hydrochloride; urea-PETT deriv. 13; Uric acid; Uridine; Uridine 5'-triphosphate; Uridine-5'-monophosphate; Ursolic acid; US9107954, maraviroc;Vadadustat; Vadimezan; Valacyclovir; Valdecoxib; Valganciclovir; Valine; Valopicitabine; Valproate; Valpromide; Valrubicin; Vandetanib; Vaniprevir; Vanoxerine; Vanoxerine dihydrochloride; Vapendavir; Vardenafil; Varenicline; Variamycin; Varlitinib; Vatalanib; Vatalanib dihydrochloride; VCH759; Vch759;vch 759; Vedroprevir; Velban; Veliflapon; Veliparib; Velpatasvir; Venetoclax; Venlafaxine; Verapamil; Verapamil hydrochloride; Verdinexor; Vergentan; Vesatolimod; Vicriviroc; Vidarabine; Vidofludimus; Vinblastine; Vincristine; Vinorelbine tartrate; Vinpocetine; Visudyne; vitamin B12; Vitamin e; Vitexin; Volasertib; Vorinostat; Voxilaprevir; VRX-480773; VX-702; Warfarin; Wedelolactone; Win vi; Win-54954; WIN61209; Xanthine; Xevinapant; XV638; Y-27632 dihydrochloride; Yangonin; Zafirlukast; Zalcitabine; Zaleplon; Zaltoprofen; Zanamivir; Zeaxanthin; Zidovudine; Zidovudine monophosphate; Zimeldine hydrochloride; Zimelidine dihydrochloride; Ziprasidone; Ziprasidone hydrochloride monohydrate;Ziresovir; Z-Leu-leu-leu-al; Z-L-Phe chloromethyl ketone; Zofenoprilat; Zolpidem; Zosuquidar; Zosuquidar trihydrochloride; Zotatifin; Zotepine; ZSTK474; 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; benfothiamine; sulbutiamine; allithiamine; vitamin D; vitamin A; iodine; melatonin; phenofibrate; glycine; N-acetylcysteine; lipoic acid; S-adenosyl-L-methionine; milk thistle extract; grape seed extract; carnitine; antiandrogens; bromhexine;cannabidiol; convalescent plasma; ensovibep; famotidine; 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; artemisia annua; hesperidin; umifenovir; kaempferol 3-o-rutinoside; catechin; epigallocatechin-3-gallate; nafamostat; nafamostat mesilate; nafamostat mesylate; omega 3; dha / epa; xylitol; xlear; apn01; alunacedase alfa; soluble ace2; rhace2-apn01; hydrogen peroxide; monolaurin; propolis; atovaquone; fenofibrate; fucoidan; hypochlorous acid; pomegranate; punica granatum; punicalagin; punicalan; urolithin a; rosuvastatin; selenium; theaflavin-3,3’-digallate; cryptoquindoline; losartan; myricitrin; chrysin; ro-0622; azd7442; tixagevimab; cilgavimab; cetirizine; ct-p59; darolutamide; doxycycline; masitinib; neem;azadirachta indica a. juss; regdanvimab; saline; selamectin; tannic acid; valproic acid; amentoflavone; pristimerin; cryptospirolepine; rhoifolin; pectolinarin; 6-gingerol; theaflavin; oleuropein; tacrolimus; puerarin; limonin; obacunone; sesamin; astragalin; aframomum melegueta; aprotinin; ashwagandha; withania somnifera; bedaquiline; bergamottin; boswellic acids; canakinumab; chlorpheniramine; chlorphenamine; chlorhexidine; clarinex; echinacea purpurea; enzalutamide; forsythoside a; glycine; griffithsin; huashibaidu; jing si herbal tea; jinhua qinggan; jt001 (vv116); lenzilumab; lianhua qingwen; noq19; phosphodiesterase enzyme type 5 inhibitors; pleurotus ostreatus; rheum palmatum; s-217622; tafenoquine; tofacitinib; virgin coconut oil; xuanfeibaidu; moxidectin; thymoquinone; xanthoangelol e; tingenone; iguesterin; micafungin; emetine; colistin; glycyrrhizin; crocin; cryptomisrine; biscryptolepine; herbacetin; cycloeucalenol; campesterol; cyanidin-3-o-glucoside; afatinib; nilotinib;scedapin c; quinadoline b; afzelin; rhein; artesunate; bufalin; hydralazine; phenytoin; propylthiouracil; sulindac; bicuculline; tideglusib; bemcentinib; ergotamine; taraxerol; diosbulbinoside d; estrone-2,3-quinone; hinokiflavone; ginkgetin; norquinadoline a; natamycin; cyanidin 3-o-rutinoside; quercetin 3-o-rutinoside; phillyrin; conivaptan; aloesin; gingerol; tinocordiside; sesaminol; sesamolin; ephedrine; solanine; donepezil; vby-825,; psoralidin; cryptotanshinone; fangchinoline; z-fa-fmk; allicin; pravastatin; ramipril; dihydromyricetin; scutellarein; corilagin; isorhamnetin; nystatin; anakinra; eculizumab; dieckol; sinigrin; glabridin; gimsilumab; kin1901; infliximab; leronlimab; pa14; pro-140; vyrologix; tocilizumab; procyanidin; α-hederin; ferulic acid; cyanidin; cyanidin 5-o-β-d-glucoside; cyanidin 3-o-glucoside; λ-carrageenan; 4'-fluorouridine; 76clabs; 8g3; a6-001; agp-14; agp-15; acarbose; ard-61; arq ajib; arylazothiazolimines; aviptadil; ayurcov; beauvericin;bismuth subsalicylate; bis-thiadiazoles; blue light; brazilin; breathing exercises; brii-196 / brii-198; bromelain; bucillamine; c60 fullerene; camellia sinensis; cd24fc; chlorine dioxide; chyawanprash; clitoria ternatea; asian pigeonwings; bluebellvine; blue pea; butterfly pea; cordofan pea; darwin pea; codivir; copper(ii) gluconate; clsp-2; ctb-ace2 gum; cysteamine; d-α-tocopherol polyethylene glycol succinate; tpgs; dfo; diammonium glycyrrhizinate; dimethyl sulfoxide; darunavir ethanolate; ek1c4; engineered ace2; enoxaparin; epicatechin; fbr-002; estrogen; ethyl lauroyl arginine; exo-cd24; evusheld; tixagevimab; cilgavimab; ferrocene derivatives; flovid-20; gancao-banxia; gb-1; green tea; hanshi zufei; heparin; hinokitiol; homo-harringtonine; honey; inm005; interferon-λ (interferon lamba); isoprinosine; js016; kabasura kudineer; kalmegh; led spirulina; levamisole; levilimab; l-glutamine; ly2835219; manuka honey; maoto; mesencure; metformin glycinate; mi-1851; montelukast;multimeric soluble ace2; n-acetylglucosamine; natto extract; naphthoquine; niacinamide; nicotinamide mononucleotide; opaganib; oxygen-ozone immunoceutical therapy; palmitoylated ace2; pamapimod; pegylated interferon alpha-2b; peg ifn-α2b; pentosan polysulfate; pioglitazone; phoxwell; phthalocyanine; porphyridium sp.; pranayama; probenecid; propolis sulabiroin-a; pyramax; pyronaridine-artesunate; pyrimidine; q34; rd-x19; rejuveinix; 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-f019; sng001; spirulina; sodium bicarbonate; stenoparib; sti-9167; thymic peptides; tollovir; tpnt1; trisb92; urtica dioica agglutinin; zinv03977803; znonps; znsec-humicin; z-veid-fmk; minocycline; coclobine; dieckol 1; 3-isotheaflavin-3 gallate; dihydrotanshinone i; citriquinochroman; holyrine b; proximicin c;pityriacitrin b; anthrabenzoxocinone; penimethavone a; icatibant; bepotastine; epoprostenol; vapreotide; hrsace2; olysio; allyl disulphide; allyl trisulphide; digitoxigenin; tenufolin; pavetannin c1; lianhuaqingwen; deptropine; neostigmine bromide; ethotoin; hydrocotarnine; ampyrone; withanolide b; lurasidone; perfenazine; isocarboxazide; cryptophycin 1; cryptophycin 52; deoxycylindrospermopsin; anatibant; zabofoxacin; tiracizine; picotamide; cilazapril; indisulam; propadimine; phenformin; torososide b; covitris2020; chlovid2020; silybin; licoleafol; gardenin a; 6-paradol; psiadia punctulata; tanshinone-i; mangiferin; γ-mangostin; 4-hydroxy-2-nonenal; acetaldehyde; aflatoxin-b1; aica-ribonucleotide; alitretinoin; alpha-tocopherol; benazepril; benzopyrene; bezafibrate; bisphenol-a; bucladesine; buthionine-sulfoximine; cadmium-chloride; carbon-tetrachloride; ciglitazone; cisplatin; clodronic-acid; clofibrate; colforsin; corticosterone; coumestrol; deguelin; dichloroacetic-acid; dieldrin;dimethylnitrosamine; dinoprost; ethinyl-estradiol; fumonisin-b1; furan; glafenine; glucosamine; ifosfamide; ionomycin; lithium-chloride; methapyrilene; methimazole; methoxychlor; mevalonic acid; ochratoxin-a; oxidopamine; pentachlorophenol; phenethyl-isothiocyanate; pifithrin; pilocarpine; pirinixic acid; piroxicam; pyrazolanthrone; ranitidine; rosiglitazone; tetrachloroethylene; tetracycline; thapsigargin; tributyltin; trichloroethylene; trichostatin-a; tunicamycin; tyrphostin-ag-1478; urethane; vancomycin; wortmannin; zearalenone; zinc32960814; zinc12006217; zinc03231196; nigricanoside a; nigricanoside b; callophysin a; gallocatechin; hyperin; lupinifolin; viomycin; capastat; demethoxycurcumin; bisdemethoxycurcumin; scutellarin; alloyohimbine gummadiol; asparagamine a; vincapusine; naringin; kanamycin; cefpiramide; salvianolic acid b; teniposide; benzoylgedunin; 6-deaminosinefungin; unii-o9h5ky11sv; cephalosporin derivatives; tcm5280805; tcm5280445; tcm5280343; tcm5280863;tcm5458190; quinadoline; polyketide isochaetochromin d1; 0-hydroxyusambarensine; 6-oxoisoiguesterin; 22-hydroxyhopan3-one; grazopavir; mfcd00832476; mfcd02180753; pacritinib; a3659; a3777; leucopelargonidin; eriodictyol; enterodiol; naringen; flemiflavanone d; euchrestaflavanone a; azadirachtin-h; azadir; achtin-i; azadirachtin-q; sn00334175; sn00162745; alphaspinasterol; gycyrrhizin; azadirachtani; kushenol-w; cyanidin 5-o-β-d-glucoside; morelloflavone; methylochnaflavon; isoginkget; sciadopitysin; podocarpusflavone a; cryptomerin; cytochalasin z8; leucal; p-coumaric acid; ketazolam; methylnaltrexone; ethynodiol diacetate; petunidin 3,5-odiglucoside; delphinidin 3-o-rutinoside; las 51620435; las 51620429; rosoxacin; levomefolic; etodolac; tinofoviralafenamide; ornipressin; otosiban; lanreotide; argiprestocin; demoxytocin; carbetocin; lypressin; examorelin; polymyxin b1; 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; morusin; α-mangostin; yohimibine; coclaurine; strychnine; myristicin; medicarpin; coptisine; tiliroside; glabrone; lignans; gastrodin; ajugol; evodiamine; nuciferine;cynarin; gramine; narciclasine; protopanaxatriol; karanjin; gigantol; harsingar; nictoflorin; lupeol; aloevera; aloenin; giloy; sitosterol; nimbin; ginger; shogaol; cyanin; medicagol; faradiol; flavanthrin; withanoside v; somniferine; vicenin; isorientin; sesamolinol; 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; 10-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; chloramphenicol; mpi43; mpi44;mpi46; keigairengyoto; shosaikotokakikyosekko; kakkontokasenkyushin'i; vuwcov059; vwcov267; vuwcov270; 4-hydroxycordoin; mallotophilippen d; 3'-(3-methyl-2-butenyl)-4'-o-β-d-glucopyranosyl-4,2'-dihydroxychalcone; lefamulin; cefpodoxime; ciprofloxacin; sparfloxacin; moxifloxacin; tbaj-876; (s)-crizotinib; spermidine; spermine; saffron; mdl-28170; z lvg chn2; ono 5334; mln-3897; bavachin; 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-in1; stf-62247; mcoppb; gw 803430; amodiaquine dihydrochloride; n-methylspiperone; gmc 2-29; lu ae58054; methdilazine; methotrimeprazine maleate; difeterol; naltrindole isothiocyanate; am1241; cpdd; sb 271046; gmc 2-113; caa-0225; cathepsin inhibitor 1; z-gly-leu-phechloromethyl ketone; balicatib;calpain inhibitor i; ikk-2 inhibitor viii; nsc 33994; ml414; it1t dihydrochloride; s-15176 difumarate; jtv519 hemifumarate; rescimetol; trifluomeprazine 2-butenedioate; asteriscunolide d; genz-123346; melitracen; dlunarizine; proglumetacin; dmp 777; dexanabinol; trifluoperazine 2hcl; thioridazine hcl; bicalutamide; cinnamaldehyde; piperine; zingeberene; gr 127935; levetiracetam; sotalol; oxazepam; thiamazole; hydroxycarbamide; clonazepam; meloxicam; temazepam; anastrozole; perindopril; silodosin; lorazepam; bupropion; bisoprolol; linagliptin; clopidogrel; allopurinol; indapamide; chlortalidone; phylloflavan; milk thistle; ilexin b; isosilybin b; spiperone; vitamin b9; vitamin k1; vitamin k2; oleanderolide; proceragenin a; balsaminone a; anacardic acid; aloeresin d; tcid; dihydrokaempferol; dihydroquercetin; myricentin; isoquercitrin; pc000550; pc000361; pc000558; pc000573; grl0617; quercetagetin; glycycrrhizin; δ9-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; oleandrin; gitoformate; eprinomectin; fusicoccin; perilla aldehyde; perillyl alcohol; valaciclovir; finasteride; betamethasone; clonidine; somatotropin; nitisinone; tadalafil; etacrynic acid; proguanil; tamsulosin; rifapentine; cyclosporine; nitrogen; arginine; abatacept; interferon beta-1a; thalidomide; crizanlizumab; nitroglycerin; brexanolone; omalizumab; siltuximab; propranolol; interferon beta-1b; prednisolone; torin-2; rapamycin; radotinib; thiostrepton; cl-amidine; bb-cl-amidine; broussoflavan a; hygromycin b; nabiximols; abyssinone ii; procynidin b1; indigo blue; crytospirolepine; 10'-hydroxyusambaresine; strychnopentamine; usararotenoid a; 12α-epi-milletosin; torchnil; febcin;5-chloro-omega-hydroxy-1-o-methylemodin; cystodion e; jq1; zbc260; canderastan cilexetil; saquanivir; boron citrate; oleoylethanolamide; liquiritin; laminarin; eckol; trifucol; β-d-galactose; κ-carrageenan; c135-ls / c144-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; cigb-325; sb203580; mapk13-in-1; arry-797; tofacitinibfedratinib; mpro 13b; gc-373; gc-376; mpro n3; fedratinib; ipratropium bromide; lomitapide; metoclopramide; s1ra; crinine; ilexsaponin b2; strictinin; zinc000027215482; zinc000252515584; loniflavone; 2'-o-ribose methyltransferase; tirucallin a; zinc000253504770; zinc000253504766; triamcinolone; hydrochlorothiazide; terflavin a; chebulagic acid; chebulinic acid; coumaroylquinic acids; sinapoyl d glucoside; tetra-o-galloyl-β-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-β1a; ifn-β1b; interleukin-2; cynk-001; asc09; cobicistat; carrimycin; dihydroartemisinine; piperaquine; piclidenoson; cf101; nivolumab; obtivo; meplazumab; jakotinib; tj003234; tozumab; adamumab; ravulizumab; alxn1210; clazakizumab; avdoralimab; iph5401; ly3127804; ifx-1; bevacizumab; valsartan; 7-hydroxystaurosporine; bafetinib; β-glucan; p-coumaroyltriacetic acid lactone; zinc02111387; zinc02122196; sn00074072; zinc04090608; xuebijing; lung cleansing and detoxifying decoction; etanercept; enalapril; oroxylin a; irisolidone; anhydrosafflor yellow b; euchrenone; uncaric acid; demethylzeylasteral; maslinic acid; atractylenolide iii; astragaloside iv; daturaolone; cucurbitacin g 2-glucoside; citronellol; limonene; salvianolic acid; neochlorogenic acid; kobophenol a;bis-demethoxycurcumin; δ-viniferin; pseudoephedrine; methylephedrine; speciophylline; uncarine f; anisodamine; forsythoside i; amygdalin; urso-deoxycholic acid; withanolide a; torreya nucifera; shuang huang lian; eugenol; ubiquinone; poly-methoxyflavones; poly-hydroxyflavones; mearnsitrin; 3-o-β-d-glucoside; biorobin; delphinidin; galangin; A monoclonal antibody; or a derivative thereof; or a mixture thereof; Section IV.II.

[0082] In alternative embodiments, the additional therapeutic agent may be formulated in any manner and applied in the form of nanoparticles, polymeric nanoparticles (PNPs), liposomes, lyophilized liposomes, micelles, polymeric micelles, niosomes, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), nanoemulsions, emulsions, self-nanoemulsifying drug delivery systems (SNEDDS), nanocrystals, cocrystals, mesoporous silica nanoparticles (MSN), dendrimers, ultrafine dispersions, solid dispersions, non-covalent complexes, complexes with macromolecules, complexes with biopolymers, solutions, solutions in fats / oils, solutions with cosolvents, solutions with surfactants / surfactants, solutions with solubilizing agents, polymorphs, lipid-based systems, gels, colloids, SOL, or any form described in the scientific and patent literature and obtained by any manner described in the scientific and patent literature.

[0083] In alternative embodiments, the synergistic effects of FORMULA I-III can be achieved with different forms of niclosamide, remdesivir, etc. Other synergistic agents can be found in the scientific and patent literature.

[0084] In alternative embodiments, additional agents such as verapamil, polyethoxylated castor oil derivatives, the emulsifiers Cremophor RH 60 and Tween 80, grapefruit juice (other agents can be found in the scientific and patent literature), as modulators of CYP3A4 and P-glycoprotein, can increase the absorption of FORMULA I-III compounds.

[0085] In another aspect, there is provided a method for treating (and for use in preparing a formulation for treatment of) a viral disease comprising administering to a human or mammal or animal or bird in need thereof a therapeutically effective amount of a stabilized aqueous formulation comprising an avermectin, a surfactant and a co-solvent.

[0086] In another aspect, there is provided a method for treating (and for use in preparing a formulation for treatment of) a viral disease comprising administering to a human or mammal or animal or bird in need thereof a therapeutically effective amount of a stabilized formulation comprising an avermectin solution or avermectin emulsion in fat / oil.

[0087] In another embodiment, there is provided a method for treating a disease (and for use in manufacturing a formulation for treatment) comprising administering to a human or mammal or animal or bird in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a FORMULA I-II compound and at least one additional therapeutic agent.

[0088] In another embodiment, there is provided a method for treating a disease (and for use in manufacturing a formulation for treatment) comprising administering to a human or mammal or animal or bird in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of FORMULA I-III compound and at least one additional therapeutic agent (including but not limited to intravenous or intramuscular thiamine, vitamin C, vitamin D, glutathione, S-adenosylmethionine, cysteine, acetylcysteine, etc.). V. Formulations and Pharmaceutical Compositions

[0089] The compounds of the invention are formulated with common carriers and excipients, which are selected according to common practice. Tablets include excipients, glidants, fillers, binders, etc. Aqueous formulations are prepared under sterile conditions and are usually isotonic if not intended for oral administration. All formulations optionally include excipients such as those described in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc. The pH of the formulations ranges from approximately 3 to 11, but is usually between 7 and 10. In some embodiments of the invention, the pH of the formulations ranges from about 2 to about 5, but is usually about 3 to 4.

[0090] The active ingredients may be administered separately, but may be more desirable to present as a pharmaceutical composition. The compositions of the present invention, whether for veterinary or human use, comprise at least one active ingredient as defined above, one or more suitable acceptable carriers therefor, and optionally other therapeutic ingredients, particularly the additional therapeutic ingredients discussed herein. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition and physiologically harmless to the recipient.

[0091] Compositions include those suitable for the above-mentioned routes of administration. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical art. These methods and compositions are generally described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methods include the step of bringing the active ingredient into association 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, if necessary, shaping the product.

[0092] Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, cachets or tablets containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as a water-in-oil or oil-in-water liquid emulsion. The active ingredient can be administered as a bolus, syrup or paste.

[0093] Tablets are manufactured by compression or molding and may optionally contain one or more additional ingredients. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form such as powder or granules in a suitable machine, which may further be mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets may be made by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. Tablets may be further coated with a shell or pellets, and may optionally be formulated to allow slow or controlled release of the active ingredient.

[0094] For infections of external tissues such as the eye, oral cavity, and skin, the composition is preferably applied in the form of an ointment or cream containing the active ingredient. For example, the active ingredient may be present in an amount of 0.075-20% wt. (ranging from 0.1% to 20% in 0.1% wt. increments, e.g., 0.6% wt., 0.7% wt., etc.), more preferably 0.2-15% wt., and most preferably 0.5-10% wt. When formulated as an ointment, the active ingredient may be used with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream using a water-in-oil cream base.

[0095] Optionally, the aqueous phase of the cream base may optionally contain at least 30% wt. of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups (e.g., propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol (including PEG 400) and mixtures thereof). Compositions for topical use may preferably contain a compound that enhances absorption or penetration of the active ingredient into the skin or other affected areas. Examples of such skin penetration enhancers include dimethylsulfoxide and related analogues.

[0096] The oil phase of the emulsion of the invention can be constituted by known ingredients in a known manner. The phase may consist of emulsifiers alone (also called emulsifiers), but preferably consists of at least one emulsifier and a fat or oil, or a mixture of fats and oils. A hydrophilic emulsifier is preferably included together with a lipophilic emulsifier and acts as a stabilizer. Also, preferably, both oils and fats are included. The emulsifiers (with or without stabilizers) constitute the so-called emulsifying waxes, which together with the oils and fats constitute the emulsifying ointment base and form the oily dispersed phase of the cream composition.

[0097] Emulsifiers and emulsion stabilizers suitable for formulation of the present invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium dodecyl sulfate. Other emulsifiers and emulsion stabilizers suitable for formulation of the present invention include Tween® 80.

[0098] The choice of oils and fats suitable for the formulation is determined by achieving the desired cosmetic properties. Creams are non-oily, non-staining, washable products and can have an appropriate viscosity to prevent leakage from tubes and other containers. Linear or branched alkyl esters, monobasic or dibasic (e.g. diisoadipate, isocetyl stearate, propylene glycol coconut fatty acid diester, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixture of branched esters known as clodamol CAP) are used. These may be used alone or in combination depending on the desired properties. Alternatively, high melting point lipids such as white soft paraffin or liquid paraffin or other mineral oils are used.

[0099] According to the present invention, a pharmaceutical composition is comprised in combination with one or more pharma- ceutically acceptable carriers or excipients and, optionally, other therapeutic agents. The pharmaceutical composition containing the active ingredient can be in any form suitable for the intended route of administration. For oral administration, the composition may be prepared, for example, as a tablet, troche, lozenge, suspension, dispersible powder or granule, emulsion, hard or soft capsule, syrup or elixir. Formulations intended for oral use are made by known methods for making pharmaceutical compositions and may include one or more agents, such as sweeteners, flavorings, coloring agents, preservatives, etc., to provide a palatably pleasing formulation. Tablets containing the active ingredient mixed with non-toxic, pharma- ceutically acceptable excipients are acceptable. Such excipients include, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; lubricants, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated using known methods, such as microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period, for example, a time delay material such as glyceryl monostearate or glyceryl distearate with a wax may be employed.

[0100] Products for oral use may be designed as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil vehicle such as peanut oil, liquid paraffin, or olive oil.

[0101] Aqueous suspensions according to the invention contain the active substance mixed with excipients suitable for producing aqueous suspensions. These excipients may include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and dispersing or wetting agents such as naturally occurring phospholipids (e.g. lecithin), alkylene oxide condensates with fatty acids (e.g. polyoxyethylene stearates), ethylene oxide condensates with long chain aliphatic alcohols (e.g. heptadecaethyleneacetanol), partial esters derived from fatty acids and ethylene oxide condensates with hexitol anhydrides (e.g. polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoates, colorants, flavorings, and sweeteners such as sucrose or saccharin. Other non-limiting examples of suspending agents include cyclodextrin and captisol.

[0102] Oily 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. Buccal suspensions can contain a thickening agent, such as beeswax, solid paraffin, or cetyl alcohol. Sweetening and flavoring agents, as mentioned above, can be added to make the buccal preparations palatable. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0103] The dispersible powders and granules of the present invention can be adapted to prepare or produce an aqueous suspension by the addition of water, containing the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents include those examples mentioned above. Additional excipients may also be included, such as sweetening, soothing and coloring agents.

[0104] The pharmaceutical compositions of the invention can also be presented as water-in-oil emulsions. The oil phase can be a vegetable oil, such as olive oil or peanut oil, a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents include naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phospholipids, such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate) or condensates with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsions can also contain sweetening and flavoring agents. Syrups and elixirs may contain sweetening agents, such as glycerol, sorbitol, or sucrose. These preparations can also contain a demulcent, preservative, flavoring, or coloring agent.

[0105] The pharmaceutical composition of the present invention may be in the form of a sterile injectable preparation. For example, it may be a sterile injectable aqueous or oleaginous suspension. This suspension may be prepared according to the conventional art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a diluent or solvent suitable for non-toxic enteral administration. For example, it may be prepared as a solution in 1,3-butanediol or as a lyophilized powder. Suitable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as a solvent or suspending medium. For this purpose, any flavorless fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may also be used to prepare the injectable preparation. Suitable vehicles and solvents that can be used include water, isotonic Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0106] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form varies depending on the subject and the particular route of administration. For example, a sustained release formulation intended for oral administration to humans can contain about 1 to 1000 mg of active ingredient combined with an appropriate and convenient amount of carrier material, which may be about 5 to about 95% (weight:weight) of the total weight of the composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion can contain about 3 to about 500 pg of active ingredient per milliliter of solution, and a suitable amount can be infused at a rate of about 30 ml per hour.

[0107] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient in such compositions is preferably present in a concentration of from 0.5 to 20%, more preferably from 0.5 to 10%, especially about 1.5% w / w.

[0108] Formulations suitable for topical use in the mouth include lozenges which comprise a flavored base containing the active ingredient (usually sucrose and gum acacia or resin tragacanth), lozenges which comprise the active ingredient in an inert base (e.g., gelatin and glycerol or sucrose and gum acacia), and mouthwashes which comprise the active ingredient in a suitable liquid carrier.

[0109] Formulations for rectal administration may be presented in the form of a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0110] Formulations suitable for pulmonary or nasal administration may, for example, have particle sizes in the range of 0.1 to 500 microns (e.g., 0.5, 1, 30, 35, etc.) and are administered by rapid inhalation through the nasal passages or by 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 administered together with other therapeutic agents, such as compounds previously used to treat or prevent viral infections or diseases as described below.

[0111] Formulations suitable for vaginal administration may be presented in the form of pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient a suitable carrier as known in the art.

[0112] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile solutions for injection which may contain antioxidants, buffers, bacteriostats and solvents which render the solution isotonic with the subject's blood, and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents.

[0113] The formulations may be presented in single- or multi-dose containers, such as sealed ampoules or vials, and may be stored in a lyophilized condition requiring only the addition of the sterile liquid carrier (e.g., water for injections) immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, pellets, and tablets as described above. Preferred unit-dose formulations are those containing a daily dose or daily sub-dose, as described above, or those containing an appropriate fraction of the active ingredient.

[0114] It is important to note that in addition to the ingredients specifically mentioned above, the compositions of the present invention may contain other agents common in the art, taking into account the type of composition in question, such as, for example, flavoring agents for compositions suitable for oral use.

[0115] The invention also provides a veterinary formulation comprising at least one active ingredient as defined above and a suitable veterinary carrier therefor.

[0116] Veterinary carriers are materials useful for administration of the compositions and may be solid, liquid, or gaseous, which are inert or acceptable in veterinary medicine and compatible with the active ingredient. These veterinary formulations may be administered orally, parenterally, or by any other desired route.

[0117] The compounds of the invention can be used to prepare controlled release formulations containing one or more compounds of the invention as an active ingredient ("controlled release formulations"), in which the release of the active ingredient is controlled and regulated, reducing dosing frequency or improving the pharmacokinetic or toxicity profile of the active ingredient.

[0118] In another embodiment, a method for treating a disease in a human in need thereof (and for use in preparing a formulation for treating such disease) comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a FORMULA I-III compound together with an effective amount of a pharma- ceutical acceptable diluent or carrier.

[0119] In yet another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical (in the form of FORMULA IV) in the form of a solution / emulsion / suspension, comprising: a) a first pharmaceutical composition comprising a compound of FORMULA I-III, and b) At least one of the following ingredients: (1) an oil phase containing vegetable or animal fat; (2) one or more surfactants; (3) one or more solvents; (4) One or more gelling agents.

[0120] FORMULA IV may be in the form of a true or colloidal solution, emulsion, solid or liquid dispersion, suspension, emulsion-suspension, gas cocktail, foam, sol, gel, paste, mixtures thereof. FORMULA IV may be prepared by mixing, homogenizing, dispersing, and emulsifying the components.

[0121] In yet another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical (FORMULA IV variant A) comprising: (a) 1-99.999% by weight of an oil phase containing vegetable or animal fat or lecithin (b) 0.001-99% by weight of a compound of Formula I-II or "API" (c) (Optional) 0-70% by weight of one or more surfactants (physiologically acceptable surfactants are selected from those listed in Section F (III.I. Section)). (d) (Optional) 0-99.9% by weight of one or more solvents (physiologically acceptable solvents are selected from those listed in Method 1 (Section III.I.)). (e) (Optional) One or more gelling agents (0-99.9% by weight) including, but not limited to, alginate, pectin, carrageenan, gellan gum, gelatin, agar, modified starch, methylcellulose, and hydroxypropyl methylcellulose.

[0122] In yet another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical (FORMULA IV variant B) comprising: (a) (Optional) 0-99.999% by weight of an oil phase containing vegetable or animal fat or lecithin (b) 0.001-99% by weight of a compound of Formula I-II or "API" (c) (Optional) 0-70% by weight of one or more surfactants (physiologically acceptable surfactants are selected from those listed in Section F (III.I. Section)). (d) 5-99.9% by weight of one or more solvents (physiologically acceptable solvents are selected from those listed in Method 1 (Section III.I.)). (e) (Optional) One or more gelling agents (0-99.9% by weight) including, but not limited to, alginate, pectin, carrageenan, gellan gum, gelatin, agar, modified starch, methylcellulose, and hydroxypropyl methylcellulose.

[0123] In yet another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical (FORMULA IV variant C) comprising: (a) 1-99.999% by weight of an oil phase containing vegetable or animal fat or lecithin (b) 0.001-99% by weight of a compound of Formula I-II or "API" (c) (Optional) 0-70% by weight of one or more surfactants (physiologically acceptable surfactants are selected from those listed in Section F (III.I. Section)). (d) 1-99.9% by weight of one or more solvents (physiologically acceptable solvents are selected from those listed in Method 1 (Section III.I.)). (e) (Optional) One or more gelling agents (0-99.9% by weight) including, but not limited to, alginate, pectin, carrageenan, gellan gum, gelatin, agar, modified starch, methylcellulose, and hydroxypropyl methylcellulose.

[0124] In yet another embodiment, the method comprises administering a therapeutically effective amount of a combination pharmaceutical (FORMULA IV variant D) comprising: (a) (optionally) 0-99.999% by weight of an oil phase containing vegetable or animal fat or lecithin; (b) 0.001-99% by weight of a compound of FORMULA I-II or "API"; (c) 0.05-70% by weight of one or more surfactants (physiologically acceptable surfactants are selected from those listed in

[0061] F (Section III.I.)); (d) (optionally) 0-99.9% by weight of one or more solvents (physiologically acceptable solvents are selected from those listed in Method 1 (Section III.I.)); (e) (Optional) One or more gelling agents (0-99.9% by weight) including, but not limited to, alginate, pectin, carrageenan, gellan gum, gelatin, agar, modified starch, methylcellulose, and hydroxypropyl methylcellulose.

[0125] The active compounds of FORMULA I-IV can be administered in the form of foods, food additives, edible soluble films, beverages, medicines, and livestock and wild animal feed. The beverages can be non-alcoholic or alcoholic drinks. Examples of non-alcoholic drinks include carbonated drinks, non-carbonated drinks (such as fruit juices and nectars), soft drinks, sports drinks, tea, coffee, and hot chocolate. The alcoholic drinks can be in the form of, for example, beer, low-malt beer, third beer, sake, wine, champagne, liqueurs, and medicinal liquor. When used in the form of food ingredients or food additives (e.g., human food or dog or cat feed, poultry, cow, and pig feed), the active compounds can be in the form of, for example, tablets, capsule formulations, solids (such as powders and granules) dissolved in the beverage, semi-solids such as jelly, liquids such as drinking water, and highly concentrated solutions diluted before use. Any ingredients commonly added to foods, such as vitamins, carbohydrates, pigments, and flavors, can be appropriately mixed. The foods can be given in both liquid and solid forms.

[0126] In another embodiment, the method comprises administering a therapeutically effective amount of the compounded pharmaceutical (FORMULA V) in the form of a food product or beverage, dietary supplement.

[0127] In another embodiment, the present invention provides pharmaceutical formulations or compositions for use in in vivo, in vitro or ex vivo methods for treating, preventing, reversing and / or ameliorating a medical condition, e.g., a disease, disorder, syndrome, infection.

[0128] In another embodiment, the pharmaceutical compositions provided herein or used to practice the methods provided herein can be administered enterally, topically, orally, or locally (by aerosol or transdermally). These pharmaceutical compositions can be formulated in any manner and administered in a variety of unit dosage forms depending on the condition or severity of the disease of the patient, the general health of each patient, the preferred method of administration, and the like. Details of formulation and administration techniques are fully described in the scientific and patent literature, see, for example, the latest issue of "Remington Pharmaceutical Sciences," Mark Publishing Co., Easton Pa. ("Remington"). For example, in another embodiment, these compositions of the invention are formulated in buffers, saline, powders, emulsions, vesicles, liposomes, nanoparticles, nanolipoparticles, and the like. In another embodiment, these compositions can be formulated in any manner and applied in a variety of concentrations and forms depending on the desired in vivo, in vitro, or ex vivo conditions, the desired method of in vivo, in vitro, or ex vivo administration, and the like. Details of in vivo, in vitro, or ex vivo formulation and administration techniques are fully described in the scientific and patent literature. The formulations and / or carriers used to practice the methods provided herein can be in any form suitable for in vivo, in vitro, or ex vivo application, such as tablets, pills, powders, capsules, liquids, gels, syrups, slurries, suspensions, and the like.

[0129] In alternative embodiments, the compositions can be formulated in any manner and applied in a variety of forms including solid dispersions, polymeric nanoparticles (PNPs), liposomes, micelles, niosomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), nanoemulsions, emulsions, self-nanoemulsifying drug delivery systems (SNEDDS), nanocrystals, mesoporous silica nanoparticles (MSNs) and dendrimers, and / or the following methods can be used: [Table 3] Or any method described in the scientific and patent literature can be applied. VI. Route of Administration

[0130] The FORMULA IV compounds described herein may be administered in solid or liquid dosage forms (e.g., orally). In either case, the compounds may be coated with materials to protect them from inactivation by acids and other natural conditions. 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. Dosage forms may include well-known pharma- ceutically acceptable excipients, diluents, and / or carriers, such as binders, disintegrants, emulsifiers, lubricants, flavorings, antioxidants, and preservatives. Liquid dosage forms may include diluents, such as saline or aqueous buffer solutions.

[0131] Any route of administration of FORMULA IV may be selected for use in the methods described herein. For example, the route of administration may be selected from oral, nasal, topical, buccal, rectal, vaginal, ophthalmic, subcutaneous, intramuscular, intraperitoneal, epidural, intravenous, intraarterial, intratumor, intraspinal, intrathecal, intraarticular, intraarterial, subarachnoid, sublingual, oral mucosal, pulmonary, bronchial, lymphatic, intrauterine, subcutaneous, intratumor, integrated into an implantable device, intradural, intracortical, intradermal, dermal, epidermal, transdermal, vaginal, rectal, ocular (e.g., through the conjunctiva), intraocular, ureteral, and parenteral. An advantage of the compounds of this invention is that they are orally bioavailable and can be administered orally. The preferred route of administration is oral.

[0132] In the methods of the invention for treating a viral infection (and for use in manufacturing a formulation for treating a viral infection), the compounds of the invention may be administered at any time to people who may come into contact with people suffering from a viral infection or to people who already have a viral infection. In some embodiments, the compounds of the invention may be administered prophylactically to people who are in contact with people suffering from a viral infection. In some embodiments of the invention, the compounds may be administered to people who have tested positive for a viral infection but have not yet developed symptoms of the viral infection. In some embodiments of the invention, the compounds may be administered to people after symptoms of a viral infection have developed.

[0133] The effective dose of the active ingredient is determined at least by the nature of the disease being treated, the toxicity, whether the compound is used prophylactically (low doses) or against an active viral infection, the method of administration and the formulation, and is determined by the physician using routine dose escalation studies. It is expected to range from about 0.0001 mg to about 100 mg per kg of body weight per day. Usually it ranges from about 0.01 mg to about 10 mg per kg of body weight per day. More commonly it ranges from about 0.01 mg to about 5 mg per kg of body weight per day. Most commonly it ranges from about 0.2 mg to about 1 mg per kg of body weight per day. For example, the candidate daily dose for an adult weighing about 70 kg is about 1 mg to 1000 mg, preferably 5 mg to 500 mg, and may be in single or multiple doses. All doses are given as the equivalent amount of pure "API".

[0134] The effective dose of the compounds of the present invention for treating a viral infection may vary depending on whether it is used prophylactically or to treat a person who already has a viral infection. Additionally, the dose may also vary depending on whether the person who has a viral infection is not yet symptomatic or is already showing symptoms of the viral infection. People who test positive for a viral infection and people who have symptoms of a viral infection may require higher doses than those receiving prophylactic treatment.

[0135] Any suitable period for administration of the compounds of the invention is contemplated. For example, administration may be for 1 to 100 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days, 50 days, 60 days, 70 days, 80 days or 90 days. Administration may also be for 1 week to 15 weeks, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks or 14 weeks. Longer administration periods are also proposed. The timing of administration may vary depending on whether the compound is administered prophylactically or to treat a person suffering from a viral infection. For example, prophylactic administration may be for a suitable period during contact with other people suffering from a viral infection and after the last contact with a person suffering from a viral infection. For people who already have a viral infection, the duration of use may be any length necessary to treat the patient and for an appropriate period following a negative test for the viral infection to ensure that the viral infection does not recur. VII. Working Examples A. Compound Preparation Example 1.

[0136] Pharmaceutical grade ivermectin (CAS number 70288-86-7) was purchased from Ecochem Co., Ltd., 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.

[0137] Method 1 was used to obtain compound FORMULA I. Mechanochemical synthesis of solid dispersions was performed using a roller ball mill. Processing mode: rotation speed of drive - 400 rpm, rotation speed of grinding jar - 100 rpm, volume of grinding jar - 2000 ml, grinding media - steel balls (diameter 12 mm, 800 g / load), processing time ranges from 2 to 24 hours. Samples are loose powders (particle size 0.1 - 10 microns). Preparation results of bioavailable solid dispersions with FORMULA I are shown in Table 2. [Table 4] Example 2.

[0138] Method 10 was used to obtain the compound FORMULA I. Acetone or ethanol (rectified 96%) was used as the organic solvent: 40-70 parts of solvent were used in equivalents per 100 parts of the mixture of polymer and avermectin. These solvents dissolve the polymer host. When the polymer and avermectin wetted with the solvent are thoroughly stirred in a mortar, a paste-like substance is formed, which is dried by evaporation of the solvent. A ball mill or other grinding machine can be used to grind the dried polymer mass, and the particle size of the polymer product should not exceed 5-9 microns. The results of the preparation of bioavailable nanocomposites with FORMULA I are shown in Table 3. [Table 5] Example 3.

[0139] Method 6 was used to obtain compound FORMULA 1. Ivermectin and PVA-polypropylene glycol graft copolymer were used to prepare solid dispersions. Hot stage extrusion was performed using a co-rotating, fully intermeshing conical mini twin screw extruder. The temperature was set at 195°C and the screw speed was varied from 90 to 105 rpm. A 7.5 g load was manually dosed per run with an internal circulation time of 5 min after dosing. The extrudates were collected after cooling at ambient temperature on a conveyor belt. The extrudate samples were then milled in a laboratory mill for 4 min and sieved to exclude particles >400 pm. B. Bioavailability Studies Example 4. Study of ivermectin concentration in bovine plasma

[0140] The free ivermectin material was processed in a planetary mill with the following parameters: weight of material - 5 g, volume of grinding jar - 200 mL, grinding media - steel balls (diameter 8 mm, load 90.0 g), processing time - 20 min. The compound of FORMULA I was processed according to Example 1 No. 1.

[0141] The cows were divided into two groups of one cow each. Free ivermectin (IVM) and FORMULA I compound were orally administered to the starved cows. Blood samples were taken from the jugular vein at appropriate time intervals (0, 4, and 20 hours) after administration.

[0142] Ivermectin concentrations in plasma were analyzed according to the method by 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.

[0143] The internal standard (moxidectin) was separated from ivermectin on a Hypersil Gold C18 column (150 x 4.6 mm, 5 μm particle size) with retention times of 3.7 and 7.0 min, respectively. Fluorescence detection was performed with excitation and emission wavelengths set at 365 and 475 nm, respectively. The mobile phase consisted of acetonitrile, methanol and distilled water (50:45:5, v / v / v) passed through the column at a flow rate of 1.5 ml / min. Chromatographic analysis was performed at 25oC. Sample preparation (100 μl plasma) was performed by single-step protein precipitation with acetonitrile, followed by derivatization with 100 μl of N-methylimidazole solution (1:1 in acetonitrile, v / v) and 150 μl of anhydrous trifluoroacetic acid solution (1:2 in acetonitrile, v / v). Calibration curves over the concentration range of 20-8,000 ng / ml plasma were linear with correlation coefficients of 0.995 or greater.

[0144] All blood samples were centrifuged at 3000 rpm for 15 min to obtain serum. Bovine plasma samples (100 μL each) were placed into 1.5 ml Eppendorf tubes, after which the samples underwent protein precipitation. The samples were vortexed for 1 min and then centrifuged at 13,400 rpm for 10 min. 20 μL of the supernatant was injected into the HPLC.

[0145] The pharmacokinetic parameters of ivermectin and FORMULA I compounds are shown in [Figure 2] and Table 4. The results show a significant increase in the bioavailability and permeability of FORMULA I compounds. Oral administration of FORMULA I 600 μg / kg IVM results in an EC50 of over 2.4 μM against SARS-CoV-2. [Table 6] C. Permeability Test Example 5. Permeability of solid dispersions or non-covalent complexes in Caco-2 cell line

[0146] The Caco-2 cell line is a standard in vivo model for evaluating drug permeability across the gastrointestinal wall. These cells retain almost complete morphofunctional properties inherent to intestinal epithelial cells, including the expression of multidrug resistance proteins such as P-glycoprotein. Data obtained in such experiments usually correlate well with the bioavailability of drugs in vivo.

[0147] Caco-2 cells were cultured in standard manner in Dulbecco's medium supplemented with 10% heat-inactivated bovine serum (FBS, USA). Permeability tests through Caco-2 cell monolayers were performed according to standard procedures. Transwell 12-well plates (Corning, USA) with 0.4 μm polyester membrane were used and cells were seeded at a density of 1x10^5 cells / well. Before the experiment, cells were grown in IMDM medium supplemented with 10% FBS. The medium was changed every 2 days. The integrity of the cell monolayer was evaluated by transepithelial electrical resistance (TEER) using a Millicell ERS-2 (Millipore, USA) at the beginning and end of the experiment. The substances under study (compounds of FORMULA I were processed according to Example 1 No. 2) were dissolved in Hanks' balanced salt solution (HBSS) at a concentration of 3 μM. Ivermectin was also dissolved in Hanks' balanced salt solution at a concentration of 3 μM.

[0148] The test solutions were added to the top of the wells and the bottom of the wells was filled with pure HBSS. The plates were incubated at 37.5 °C and agitated on an orbital shaker (100 rpm). 100 μL samples were taken from the bottom of the wells at 20, 40, 60, 80, 100, and 120 min. After sampling, the required volume was immediately replenished with fresh HBSS solution. The concentrations of the substances were determined by high-performance liquid chromatography on an Agilent 1200 HPLC equipped with a UV detector. The chromatographic analysis was performed on a reversed-phase column. The permeability coefficients were calculated according to formulas published in the literature. [Table 7] Therefore, the non-covalent ivermectin complex has better permeability than pure ivermectin. D. Toxicological studies Example 6. Toxicity of solid dispersions or non-covalent complexes

[0149] The compound of FORMULA I was treated according to Example 1 No. 2. The oral toxicity (against golden hamsters) results of the compound of FORMULA I showed LD50=340 mg / kg (for pure ivermectin) and LD50=62 mg / kg for pure ivermectin, i.e. the toxicity of compound I was reduced by 5.48 times. F. Spectroscopy Example 7. Spectroscopy of non-covalent complexes

[0150] The compound of Formula I was treated according to Example 1 No. 2. In the infrared spectrum of the obtained non-covalent complex, the frequency of the valence vibration of the OH group was observed as a broad shoulder, which indicates the presence of intermolecular hydrogen bonds during the complex formation. Based on the infrared spectroscopy analysis, it was confirmed that the non-covalent complex was stabilized by intermolecular hydrogen bonds.

[0151] To confirm the physicochemical values ​​and chemical structures of the noncovalent complexes and to analyze the formation of the major molecular ions more precisely, the mass spectra of the complexes were analyzed by liquid chromatography-mass spectrometry with TOF LC-MS (Agilent Technologies). Analysis of the mass spectra showed that besides the peaks belonging to the individual carrier and API components, peaks corresponding to various compositions of heterogeneous noncovalent structures were present. Ions corresponding to the molecular ions of the noncovalent complexes were present in the mass spectra, indicating that the carrier and API molecules formed noncovalent complexes by mutual noncovalent interactions. G. Antiviral Activity

[0152] Another aspect of the invention relates to a method of inhibiting a viral infection, comprising treating a sample or subject suspected of needing treatment with a composition of the invention. Samples suspected of containing a virus include organisms, tissues or cell cultures, biological samples (such as blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.), laboratory samples, food, water or air samples, bioproduct samples such as extracts of cells (especially recombinant cells that synthesize a glycoprotein of interest), etc. Typically, the sample is suspected of containing an organism such as a pathogen that causes a viral infection. The sample can be in any medium, such as water or an organic solvent\water mixture. Samples include organisms such as humans and manmade materials such as cell cultures.

[0153] If desired, the antiviral activity of the compound of the present invention can be observed by any method, including the method of detecting its activity directly and indirectly.Measurement of its activity by quantitative, qualitative and semi-quantitative methods is considered.Usually, any of the screening methods described above is applied, but other methods such as observing the physiological characteristics of an organism can also be applied.

[0154] The antiviral activity of the compounds of the invention can be measured using known standard screening protocols. For example, the antiviral activity of a compound can be measured using several common protocols. Example 8. Blood oxygen saturation studies in humans

[0155] Blood oxygen saturation was measured in one symptomatic male patient who tested positive for SARS-CoV-2 and another symptomatic male patient. Compound FORMULA I was treated according to Example 1, No. 3.

[0156] Humans were divided into two groups, one in each group. Compound FORMULA I was administered orally to humans in group 2 at 600 μg / kg (as pure ivermectin). Blood oxygen saturation was measured at appropriate time intervals after administration (0, 24, 48, 72, and 96 hours).

[0157] The changes in oxygen saturation for each study group are shown in Table 6 and Figure 3. As shown in Table 6 and Figure 3, those who received the compound FORMULA I showed a recovery in saturation associated with SARS-CoV-2 infection compared to those who did not receive treatment. As shown in Figure 3, those who received the FORMULA I compound on days 1 and 2 post-infection had a significant reduction in infectious virus compared to those who did not receive treatment. These data indicate that the FORMULA I compound reduces SARS-CoV-2 replication in the lungs. [Table 8] Example 9. SARS-CoV-2 viral load study in humans

[0158] The viral load was measured in a symptomatic male patient who tested positive for SARS-CoV-2. Compound FORMULA I was treated according to Example 2 No. 2.

[0159] SARS-CoV-2 viral load from nasopharyngeal swabs was quantified from samples stored at −40°C until use. Viral RNA was isolated from stored samples using the QIAamp viral RNA mini kit (Qiagen, Hilden, Germany).

[0160] Quantitative reverse transcription polymerase chain reaction (RT-qPCR) targeting the SARS-CoV-2 N gene was performed. The standard curve consisted of in vitro transcribed viral RNA serially diluted into a matrix of cellular RNA from nasopharyngeal negative samples.

[0161] The assay included the measurement of a housekeeping gene as an internal control and normalization factor. 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. Thus, the viral load measurement was expressed as log 10 copies per reaction.

[0162] The log10 viral load before oral administration of the FORMULA I compound was 6.3 copies / mL, and 24 hours after administration of 1200 μg / kg (pure ivermectin equivalent) of FORMULA I, the log10 viral load was 5.1 copies / mL. The log10 viral load was significantly different between the start of treatment (log10 6.3 copies / mL) and 24 hours after the start of treatment (log10 5.1 copies / mL). These data suggest that the FORMULA I compound reduces SARS-CoV-2 replication. [Table 9] Example 10. Patient Study

[0163] Dengue, chikungunya, yellow fever and Zika are common in the tropics, South and Central America, Mexico (including the states of Veracruz, Jalisco, Chiapas, Oaxaca and Quintana Roo) and the Caribbean. The viruses are transmitted by female Aedes aegypti and Aedes albopictus mosquitoes.

[0164] A 38-year-old man tested positive for the NS1 antigen test, which detects the nonstructural NS1 protein of the dengue virus. Symptoms included high fever of 40°C / 104°F, severe headache, nausea, and myalgia. The patient was orally administered FORMULA I compound (obtained according to Example 1 No. 2) in a mixture of 300 ml of water at 800 μg / kg of pure ivermectin equivalent. The patient's fever gradually subsided, his myalgia resolved, and after another 2 days the symptoms of the disease disappeared. VIII. Conclusion

[0165] Naming of compounds in this disclosure is provided using ACD / Name software (Advanced Chemistry Development, Inc., Toronto, Canada) for naming of chemical compounds. Other compounds and radicals may be named by common names or systematic or non-systematic names. Internationally registered names of chemical compounds and pharmaceutical preparations may be written in English. This applies to recognized names such as INN (International Nonproprietary Name) - WHO International Nonproprietary Name Programme and Pharmaceutical Classification (https: / / www.who.int / teams / health-product-and-policy-standards / inn) and IUPAC (International Union of Pure and Applied Chemistry) names.

[0166] When trade names are used herein, Applicants intend to independently include the trade name products and the APIs of the trade name products.

[0167] The compounds of the invention can be prepared by methods known to those skilled in the art.

[0168] The invention has been described with reference to various specific preferred embodiments and techniques, but those skilled in the art will recognize that many variations and modifications are possible within the spirit and scope of the invention.

[0169] Although the present invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention. It is therefore intended that the present invention encompasses all such modifications and variations that come within the scope of the appended claims and their equivalents. References to weight percentages include the weight percentage of the component in the finished formula unless otherwise specified.

[0170] Although the disclosed invention has been illustrated and described as embodied in one or more specific examples, it is nevertheless not intended to be limited to the details shown. Various modifications and structural changes may be made without departing from the scope of the invention. Also, various features of one embodiment may be incorporated in other embodiments. It is therefore appropriate that the present invention be accorded the broadest possible interpretation consistent with the scope of the disclosure.

[0171] Having described a preferred embodiment, 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. All such modifications, variations and changes are therefore to be understood as being within the scope of the present invention as defined in the appended claims. Although specific terms have been employed, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. A non-covalent complex comprising a pharma- ceutical active ingredient (API, GUEST) (selected from the group consisting of ivermectin or avermectins) and a host substance, which meets any of the following criteria: A) The API is ivermectin B1a and the host substance is pectin, forming a complex represented by the following structure: 【Chemistry 1】 B) The API is ivermectin B1b and the host substance is pectin, forming a complex represented by the following structure: 【Chemistry 2】 C) The host material is pectin and the API is selected from the group of ivermectin and avermectin (A1a, A1b, A2a, A2b, B1a, B1b, B2a, B2b), including racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, hydrides, solvates, pharma- ceutically acceptable salts, esters, prodrugs, or mixtures or derivatives thereof, forming a complex represented by the following structure: 【Chemistry 3】 The formula of the complex can then be established by an expert based on the InChI key. where k ranges from 1 to 100, m ranges from 1 to 10,000, and n ranges from 1 to 10,000. For use in producing a pharmaceutical dosage form to treat a viral infection (by administering a therapeutically effective amount to a person in need thereof) or for use in producing or preparing a medical dosage form for use as an antiviral medication. Doses were calculated as pure ivermectin or pure avermectin and ranged from 10 μg / kg to 100 mg / kg; the dose provides an improved therapeutic effect (e.g., treatment can be achieved within 10 to 48 hours for certain viral infections that do not shorten the duration of illness with known methods and that typically take 12 days or more to treat); Non-covalent complexes have the properties of increased permeability (to the internal organs and tissues of the recipient) and bioavailability, And the therapeutic effect of the non-covalent complexes is enhanced by the increased permeability, allowing the required concentrations to be rapidly achieved in the patient's organs and tissues.

2. A non-covalent complex comprising a pharma- ceutical active ingredient (API, GUEST) (selected from the group consisting of ivermectin or avermectins) and a host substance, which meets any of the following criteria: A) The API is ivermectin B1a and the host substance is arabinogalactan, forming a complex represented by the following structure: 【Chemistry 4】 B) The API is ivermectin B1b and the host substance is arabinogalactan, forming a complex represented by the following structure: 【Chemistry 5】 C) The host substance is arabinogalactan and the API is selected from the group of ivermectin and avermectin (A1a, A1b, A2a, A2b, B1a, B1b, B2a, B2b), including racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, hydrides, solvates, pharma- ceutically acceptable salts, esters, prodrugs, or mixtures or derivatives thereof, and the formula of the complex can be established by an expert based on the InChI key. D) The API is ivermectin B1a and the host material is laminaran, forming a complex represented by the following structure: 【Chemistry 6】 E) The API is ivermectin B1b and the host material is laminaran, forming a complex represented by the following structure: 【Chemistry 7】 F) The host substance is laminaran and the API is selected from the group of ivermectin and avermectin (A1a, A1b, A2a, A2b, B1a, B1b, B2a, B2b), including racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, hydrides, solvates, pharma- ceutically acceptable salts, esters, prodrugs, or mixtures or derivatives thereof, and the formula of the complex can be established by an expert based on the InChI key. G) The API is ivermectin B1a and the host material is polyvinylpyrrolidone, forming a complex represented by the following structure: 【Chemistry 8】 H) The API is ivermectin B1b and the host material is polyvinylpyrrolidone, forming a complex represented by the following structure: 【Chemistry 9】 I) The host material is polyvinylpyrrolidone and the API is selected from the group of ivermectin and avermectin (A1a, A1b, A2a, A2b, B1a, B1b, B2a, B2b), including racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, hydrides, solvates, pharma- ceutically acceptable salts, esters, prodrugs, or mixtures or derivatives thereof, and the formula of the complex can be established by an expert based on the InChI key. J) The API is ivermectin B1a and the host substance is glycyrrhizin, and the complex is represented by the following structure: 【Chemistry 10】 Form the body: K) The API is ivermectin B1b and the host substance is glycyrrhizin, forming a complex represented by the following structure: 【Chemistry 11】 L) The host substance is glycyrrhizin and the API is selected from the group of ivermectin and avermectin (A1a, A1b, A2a, A2b, B1a, B1b, B2a, B2b), including racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, hydrides, solvates, pharma- ceutically acceptable salts, esters, prodrugs, or mixtures or derivatives thereof, and the formula of the complex can be established by an expert based on the InChI key. Here, k ranges from 1 to 100, m ranges from 1 to 10000, n ranges from 1 to 10000, and n1, n2 range from 1 to 10000. For use in producing a pharmaceutical dosage form to treat a viral infection (by administering a therapeutically effective amount to a person in need thereof) or for use in producing or preparing a medical dosage form for use as an antiviral medication. Doses were calculated as pure ivermectin or pure avermectin and ranged from 10 μg / kg to 100 mg / kg; the dose provides an improved therapeutic effect (e.g., treatment can be achieved within 10 to 48 hours for certain viral infections that do not shorten the duration of illness with known methods and that typically take 12 days or more to treat); Non-covalent complexes have the properties of increased permeability (to the internal organs and tissues of the recipient) and bioavailability, And the therapeutic effect of the non-covalent complexes is enhanced by the increased permeability, allowing the required concentrations to be rapidly achieved in the patient's organs and tissues.

3. A method (co-processing method / solid dispersion technique) for modifying the properties of a compound (ivermectin, avermectin) to create a molecular / solid dispersion (using a compound of FORMULA I, ivermectin or avermectin (API, GUEST) as precursor, a HOST substance and, if necessary, other compounds) with properties that improve bioavailability and permeability (to the internal organs and tissues of the person receiving the drug) and using the compound (or an aqueous solution or suspension thereof) obtained in this way to produce a pharmaceutical form for the treatment of viral infections (by administering a therapeutically effective amount) or to produce or prepare a medical dosage form to be used as an antiviral drug, from 50 μg / kg to 250 mg / kg. in the range of dosages (calculated as pure ivermectin or pure avermectin) which improve the therapeutic effect (e.g., achieving a cure within 10-48 hours for certain viral infections which do not shorten the duration of the disease with known methods and which usually take 12 days or more to treat), the non-covalent complex has improved permeability (to the internal organs and tissues of the person receiving the drug) and bioavailability properties, and the therapeutic effect of the non-covalent complex is enhanced by the improved permeability and can rapidly achieve the required concentration in the patient's organs and tissues, Ivermectin, avermectin (API, GUEST) is selected from the following: Ivermectin and avermectin (A1a, A1b, A2a, A2b, B1a, B1b, B2a, B2b) or their racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, hydrides or solvates, or pharma- ceutically acceptable salts or esters, or prodrugs, or mixtures or derivatives thereof. wherein the HOST substance is selected from: A. Polymers and oligomers, primarily organic polymers and oligomers, further primarily polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, GUM, mutilations, including but not limited to: A.

1. Hemicelluloses are araban, arabinan, galactan (galactosan), glucan, xylan, mannan, fructan, xyloglucan, arabinogalactan, arabinoxylan, glucomannan, galactomannan, galactoglucomannan, β-glucan, galactogens, and mixtures thereof, but do not exclude other hemicelluloses and mixtures thereof; A.

2. Sulfated polysaccharides and oligosaccharides are fucoidan, carrageenan or carrageenin, agaropectin, sea cucumber sulfated polysaccharides (SCSP), chondroitin sulfate, keratan sulfate, and mixtures thereof, but do not exclude other sulfated polysaccharides and oligosaccharides, and mixtures thereof; A.

3. Polysaccharides and oligosaccharides, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums and mutilations which may include (but are not limited to): polysaccharides based on glucose, dextrose, galactose, mannose, arabinose, rhamnose, sucrose, maltose, lactose and their uronic acids, which may be methoxylated or acetylated, their salts (gums, gummies); polyuronic acids and esters; gums, xanthan gum, oat gum, gellan gum, guar gum, carob gum, karaya gum, damson gum. Rhus gum, gum arabic, gum tara, gum ghatti, gum british, agar, agar (agar), gum tragacanth, gum konjac, gum verum, gum dutan; galacturonic acid based polysaccharides and their salts having side chains of rhamnose, arabinose, xylose and fructose (pectin, pectic acid, pectates); pectins of beet, carrot, pepper, pumpkin, eggplant, sunflower, apple, quince, cherry, plum, pear, citrus, zosterin; modified pectins, modified citrus pectins; acidic polysaccharides, i.e. Polysaccharides containing carboxyl, phosphate and / or sulfate groups; psyllium husk; soybean hemicellulose; galacturon, homogalacturon, polygalacturonic acid and their salts, rhamnogalacturonan, rhamnogalactan; callose, laminaran, chrysolaminarin, curdlan; inulin, guar gram, dextran, pullulan; agarose, galactooligosaccharides (oligogalactosyllactose, oligogalactose, oligolactose or transgalactooligosaccharides), xylooligosaccharides, fructooligosaccharides. sugars, isomaltooligosaccharides; alginic acid and its salts; alginates, propylene glycol alginate; arabin, D-arabinonic acid and its salts; cellulose, cellulose-based polymers, methylcellulose, ethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate, hypromellose, hydroxypropylmethylcellulose (HPMC), methylethylcellulose, ethylhydroxyethylcellulose, croscarmellose, carboxymethylcellulose and its salts;Starch, Starches, Starch 1500G, Soluble Starch, Modified Starch, Hydroxyethyl Starch, Cationic Starch, Acid-Treated Starch, Alkaline-Modified Starch, Bleached Starch, Oxidized Starch, Enzyme-Treated Starch, Monostarch Phosphate, Distarch Glycerol, Distarch Phosphate, Phosphorylated Distarch Phosphate, Acetylated Distarch Phosphate, Starch Acetate Esterified with Acetic Anhydride, Starch Acetate Esterified with Vinyl Acetate, Acetylated Distarch Dipate, Acetylated Distarch Glycerol, Distarch Glycerin, Hydroxypropyl Starch, Hydroxypropyl Distarch Glycerin, Hydroxypropyl Distarch Glycerin starch octenylsuccinate, hydroxypropyl distarch glycerol, starch sodium octenylsuccinate, acetylated oxidized starch; dextrins, maltodextrin, cyclodextrin, amylodextrin, polydextrose; amylopectin, amylose, glycogen; chitosan, chitin; pullulan, glucuronaraboxylan, methyl-glucuronaraboxylan, glycosaminoglycans, mucopolysaccharides, heparin / heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid and mixtures thereof, but not excluding other polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, mutilation and mixtures thereof; A.

4. Macrocyclic hosts may include (but are not limited to): cyclodextrins, cucurbit[n]urils and calix[n]arenes, pyrarenes, crown ethers, cyclophanes, cryptands; B. Substances which may contain significant amounts (5% or more): Polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mutilations, which may include (but are not limited to) plants or algae or animals or fungi, parts of plants or algae or animals or fungi, processed plants or algae or animals or fungi, parts of processed plants or algae or animals or fungi containing significant amounts of the substances specified in paragraph A, and mixtures thereof. Common examples include dried brown or red algae, such as kelp or foci. C. Synthetic polymers, which may be primarily water-soluble polymers, including but not limited to: polymers and copolymers formed from acrylic acid, methacrylic acid, and / or their esters; polymethacrylates, methyl methacrylate and its salts; polyacrylamides; polyamidoamines, polypropyleneimines, polyethylene glycols; polyvinyl alcohols; polyvinylpyrrolidone; acrylic polymers, cellulose acetate phthalate, copovidone, ethyl oleate, glycerol derivatives, triacetin, polyethylene glycol (PEG), PEG derivatives, polymethacrylates, propylene glycol, propylene glycol derivatives, povidone, polyvinylpyrrolidone (PVP), vinyl acetate, cellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hypromellose phthalate (HPMCP), cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, vinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethylethylcellulose, hydroxypropyl methylcellulose acetate succinate, Avicel, Avicel PH101, Avicel PH102, Benecel, Brij, Brij 30, Brij 35, Capryol, Cavamax, Cavasol, Cavitron HPpCD Cyclodextrin, Compritol 888 ATO, Cremophor, Cremophor EL, Cremophor RH40, DiCal Dihydrate, Epoxidized Palm Oil (Epo), Methyl Methacrylate (Eudragit), Eudragit E, Eudragit EPO, Eudragit L100, Eudragit L100-55, Eudragit S100, Gelucire, Gelucire 44 / 14, HP-50 AAS-LF, HP-55AAS-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 HP-50 Imwitor Imwitor 742 Klucel HPC Kolhdon 17 PF Kollicoat MAE、Collicoat MAE 100、Collicoat MAE 100P、Collicoat Protect、Collidon(ポビドン)、Collision 12 pf、Collision 12 / 17PF、Collision 30、Collision 30 / 90、Collision 90、Collision CL-F、Collision CL-SF、Collision K30、Collision SR、Collision SR、Collision SR(PVAc)、Collision V64 / Fine、Collision VA 64、Collision VA 64(コポビドン) Kollidon VA64, Kolliphor, 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、Kolliphor Solv GTA、Collision Solver PEG 1450、Collision Solver PEG 300、Collision Solver PEG 3350、Collision Solver PEG 400、Collision Solver PEG E 300、Collision Solver PEG E 400、Collision Solver PEG Cotton, Kolliwax, Kolliwax GMS II, Kolliwax SA, Labrasol, Co.310Mono, Lactose FF316, Laurogucol, Maisine, Miglyol, Myrj, 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, 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 SDD, PVP-VA, PVP-VA 64, PVP-VA SDD, Palm Stearin Polyesteramide (PSPEA), Peceol, Pectin, Plasdone, 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, Soluplus, Solutol, sucrose laurate, tocopheryl PEG 1000 succinate (TPGS), vitamin E TPGS, d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS), Isomalt (Gallen IQ 810), other synthetic polymers and mixtures thereof; D. Polyols include, but are not limited to, ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, rhodiitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetriitol, polyglycitol, and mixtures thereof; E. Sugars include glucose, dextrose, galactose, mannose, arabinose, rhamnose, sucrose, maltose, lactose, ribose, and mixtures thereof; F. Surfactants include surfactants with anionic functional groups, including anionic surfactants (e.g. sulfates, sulfonates, phosphates, carboxylates, carboxylate salts); alkyl sulfates; alkyl ether sulfates; carboxylate-based fluorosurfactants; cationic surfactants; primary, secondary or tertiary amines; permanently charged quaternary ammonium salts; amphoteric surfactants; amphoteric surfactants in which the cationic moiety is based on a primary, secondary or tertiary amine or a quaternary ammonium cation; sultaines; betaines; phospholipids; amphoteric surfactants of the tertiary amine oxide structure type; Nonionic surfactants;Ethoxylates;Fatty alcohol ethoxylates;Alkylphenol ethoxylates (apes or apeos);Fatty acid ethoxylates;Special ethoxylated fatty acid esters and fats;Ethoxylated amines and / or fatty acid amides;End-closed 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 2-{2-[2-(tetradecyloxy)ethoxy]ethoxy}ethyl Sulfates; Dodecyl sodium sulfosuccinate and its salts; Heptadecafluoro-1-octanesulfonate (PFOS); Nonafluorobutanesulfonate; Alkyl aryl ether phosphates; Alkyl ether phosphates; Sodium stearate; Sodium N-lauroyl sarcosinate; Heptadecafluorononanoate; Pentadecafluorooctanoate; Octenidine dihydrochloride; Hexadecyltrimethylammonium bromide ( ctab); cetylpyridinium chloride (cpc); benzalkonium chloride (bac); solamin (bzt); dimethyldioctadecylammonium chloride; dimethyldioctadecylammonium bromide (dodab); CHAPS (3-[(3-cholamidopropyl)dimethylamonio]-1-propanesulfonate); cocamidopropyl hydroxysultaine; cocamidopropyl betaine; O-(1-O,2-O-distearoyl-L-glycero-3-phospho)serine;2-[(1-O,2-O-Diacetyl-L-glycero-3-phospho)oxy]ethanamine;Phosphatidylcholine;Sphingomyelin;Tetradecyldimethylamine oxide;Tetradecyldimethylamine oxide;Narrow range ethoxylate;Octaethylene glycol monododecyl ether;Pentaethylene glycol monododecyl ether;Nonylphenol ethoxylate;Triton X-15;Polyethoxylate tallowamine;Cocamide monoethanolamine;Cocamide diethanolamine;Poloxamer;Glycerol monostearate;1-Monolaurin ;Sorbitan monolaurate;Sorbitan monostearate;Sorbitan tristearate;Tween(s), Tween 20;Tween 40;Tween 60;Tween 80;Decyl-D-glucoside;Span(s),Sorbitan monolaurate, Tween 40,1,4-anhydro-D-glucitol 6-oleate;Dodecyl D-glucopyranoside;Octyl D-glucopyranoside;Poloxamer(s),Poloxamer 188,Poloxamer 407,Polyoxyethylene stearate,Montyl,Deoxycholic acid,Bile acid,Pluronic(s),Pluronic F-127, pluronic P85, pluronic f68, gelucire(s), gelucire 44 / 14, lecithin, polysorbates, polysorbate 80, plasdone-s630, pluronic-f68, inutec sp1, glyceryl behenate, tocopherol polyethylene glycol succinate, polyoxyethylated castor oil, polyoxyethylated glycerides, lauroyl macroglycerides, and mono- and di-fatty acid esters of low molecular weight polyethylene glycol; and mixtures thereof. G. Acids and salts based on these acids include, but are not limited to: citric acid, tartaric acid, succinic acid, orthophosphoric acid, amino acids, acetic acid (anion), sodium acetate, alginates, sodium alginate, glycyrrhizin and its salts, and mixtures thereof. H. Oxides and salts based on these oxides include, but are not limited to: silica, silicates, titanium(IV) oxide, and mixtures thereof. I. Copolymers of the polymers listed under A and C include alternating, random, block, graft, and crosslinked modifications, including, but not limited to, methacrylic acid and ethyl acrylate copolymers, methacrylic acid copolymers, vinylpyrrolidone-vinyl acetate copolymers (PVPVA), polyvinylpolypyrrolidone (PVPP), HPMC and PVA-PEG graft copolymers, grafted polyvinylpyrrolidone-arabinogalactan copolymers, graft copolymers having a) poly(vinyl acetate) and / or poly(vinyl alcohol) and / or poly(vinyl chloride) and poly(vinyl ester) on b) polyethylene glycol, polyalkylene glycol, polypropylene glycol, polyisobutylene glycol, or polymethylpentene glycol polymer chains; graft copolymers having polyvinyl acetate and / or hydrolyzed polyvinyl acetate (polyvinyl alcohol) groups on polyalkylene oxide (preferably polyethylene oxide); vinylpyrrolidone-vinyl acetate copolymers; vinylpyrrolidone-vinyl acetate copolymers-64+; vinylpyrrolidone-vinyl acetate copolymers VA. 64; Polymethacrylate copolymers include anionic, cationic and neutral copolymers based on methacrylic acid and methacrylic / acrylic esters, including their salts, esters and other derivatives and mixtures thereof. J. Methoxylated, ethoxylated, esterified, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, decarboxylated, amidated, oxidized, sulfation, amino acid derived, fermented, thermally modified, chemically modified, acid modified derivatives of the substances identified in AI and their esters, salts, other chemical derivatives, and mixtures thereof. K. Any combination of substances identified in AJ; Except for Kollicoat IR and similar PVA-PEG graft copolymers; wherein the co-processing method (solid dispersion preparation method) is selected from the following: a) Milling / powdering method using high energy stress method; b) Milling / powdering methods using high energy stress and solvent methods; c) Media grinding method; d) kneading method; e) Hot melt / melt / fusion process; f) Hot melt extrusion / high temperature extrusion method; g) Meltrex process; h) Melt agglomeration method; i) High pressure homogenization method; j) Solvent evaporation method; k) spin-coated film method; l) Spray drying method; m) Supercritical Fluid (SCF) processing; n) Low temperature techniques; o) Freeze-drying / freeze-drying technology method; p) Spray freezing into cryogenic fluids; q) Spray Freezing into Cryogenic Liquids (SFL); r) Spray freezing of vapor onto liquid (SFV / L); s) Ultra-rapid freezing; t) Precipitation / co-precipitation methods; u) Microwave irradiation method; v) Energy input method; w) heat / shear energy input methods; x) forming a solid dispersion by contacting the active ingredient with a matrix (host material) under conditions sufficient to form a solid dispersion; y) Combination method.

4. A non-covalent complex of ivermectin, avermectin (API, GUEST) and HOST substance with improved permeability and bioavailability properties (improved permeability and bioavailability to the internal organs and tissues of the person receiving the drug) for use in the manufacture of a pharmaceutical form for the treatment of viral infections, which is used as an antiviral drug for use in the manufacture or preparation of a medical dosage form for the treatment of viral infections in humans in need of treatment by administering a therapeutically effective amount; Doses of 10 μg / kg to 100,000 μg / kg (in terms of pure ivermectin or pure avermectin) This dosage improves therapeutic efficacy (e.g., treatment can be achieved within 10-48 hours for certain viral infections that cannot be shortened by known methods and that usually require treatment for 12 days or more), the non-covalent complex has permeability-enhancing (enhancing the ability of the drug to penetrate into the internal organs and tissues of the person receiving it) and bioavailability properties; The therapeutic effect of the non-covalent complex is enhanced by the increased permeability, which allows the required concentrations to be rapidly achieved in the patient's organs and tissues; GUEST is selected from: Ivermectin and avermectin (A1a, A1b, A2a, A2b, B1a, B1b, B2a, B2b) or their racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, hydrides or solvates, or pharma- ceutically acceptable salts or esters, or prodrugs, or mixtures, or derivatives thereof; The molecular information of the FORMULA II non-covalent complex is encoded by the following formula: [GUEST]k [HOST]n (SOLVENT)m where k ranges from 1 to 100; m ranges from 1 to 10000; n ranges from 1 to 10000; The molecular information of the GUEST is provided based on the InChI derived from the InChIKey shown in parentheses after the name of the guest drug compound, in the second position after the sequence number in paragraph [0061] (section III.I.). The molecular information of the guest drug compound can be used alone or based on it by a skilled technician to obtain molecular information of pharmaceutical salts, esters, ethers, free bases and other pharmaceutical salts of these free bases; The molecular information of the HOST represents the molecular information of the monomers of the "HOST substance" polymer; or represents the smallest representable portion of the "HOST substance" copolymer (defining that copolymer); or, if the HOST substance is in a monomolecular form, the compound representing the "HOST substance" molecule can be obtained by a skilled artisan; The molecular information for SOLVENT is H2O when the solvent is water, but other physiologically acceptable solvents can be used and molecular information can be obtained by a skilled technician; Alternatively, the formula of the complex can be established by an expert (skilled technician); The HOST substance is selected from the following: A. Polymers and oligomers, primarily organic polymers and oligomers, more specifically polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mutilations, which may include, but are not limited to: A.

1. Hemicelluloses include araban, arabinan, galactan (galactosan), glucan, xylan, mannan, fructan, xyloglucan, arabinogalactan, arabinoxylan, glucomannan, galactomannan, galactoglucomannan, β-glucan, galactogens, and mixtures thereof, but do not exclude other hemicelluloses and mixtures thereof; A.

2. Sulfated polysaccharides and oligosaccharides include fucoidan, carrageenan or carrageenin, agaropectin, sea cucumber sulfated polysaccharides (SCSP), chondroitin sulfate, keratan sulfate, and mixtures thereof, but do not exclude other sulfated polysaccharides and oligosaccharides, and mixtures thereof; A.

3. Polysaccharides and oligosaccharides, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mutilations, including polysaccharides and oligosaccharides based on glucose, dextrose, galactose, mannose, arabinose, rhamnose, sucrose, maltose, lactose and their uronic acids, which may be methoxylated or acetylated, their salts (gums, gummies), polyuronic acids and esters; gums, xanthan gum, oat gum, gellan gum, guar gum, carob gum, karaya gum, dammar gum, gum arabic, taraga gum, ghatti gum, British gum, agar, agar-agar, tragacanth gum, konjac gum, verum gum, dutan gum; galacturonic acid based polysaccharides and their salts (pectin, pectic acid, pectates) with side chains of rhamnose, arabinose, xylose, and fructose; pectins of beet, carrot, pepper, pumpkin, eggplant, sunflower, apple, quince, cherry, plum, pear, citrus, zosterin; modified pectins, modified citrus pectins; acidic polysaccharides, i.e. those with carboxyl, phosphate, and phosphate groups. polysaccharides containing and / or sulfate ester groups; psyllium husk; soybean hemicellulose; galactron, homogalactron, polygalacturonic acid and its salts, rhamnogalacturonan, rhamnogalactan; callose, laminaran, chrysolaminarin, curdlan; inulin, guar gram, dextran, pullulan; agarose, galactooligosaccharides (oligogalactosyllactose, oligogalactose, oligolactose or transgalactooligosaccharides), xylooligosaccharides, fructooligosaccharides, isomaltooligosaccharides; alginic acid and its salts, alginates, propylene glycol alginate; arabic, arabic acid and its salts; cellulose, cellulosic polymers, methylcellulose, ethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate, hypromellose, hydroxypropylmethylcellulose (HPMC), methylethylcellulose, ethylhydroxyethylcellulose, croscarmellose, carboxymethylcellulose and its salts;Starch, Starches, Starch 1500G, Soluble Starch, Modified Starch, Hydroxyethyl Starch, Cationic Starch, Acid-Treated Starch, Alkaline-Modified Starch, Bleached Starch, Oxidized Starch, Enzyme-Treated Starch, Monostarch Phosphate, Distarch Glycerol, Distarch Phosphate, Phosphorylated Distarch Phosphate, Acetylated Distarch Phosphate, Starch Acetate Esterified with Acetic Anhydride, Starch Acetate Esterified with Vinyl Acetate, Acetylated Distarch Dipate, Acetylated Distarch Glycerol, Distarch Glycerin, Hydroxypropyl Starch, Hydroxypropyl Distarch Glycerin, Hydroxypropyl Distarch Glycerin starch octenylsuccinate, hydroxypropyl distarchglycerol, starch sodium octenylsuccinate, acetylated oxidized starch; dextrin, maltodextrin, cyclodextrin, amylodextrin, polydextrose; amylopectin, amylose, glycogen; chitosan, chitin; pullulan, glucuronadoaraboxylan, methyl-glucuronadoaraboxylan, glycosaminoglycans, mucopolysaccharides, heparin / heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid and mixtures thereof, but not excluding other polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, mutilase and mixtures thereof; A.

4. Macrocyclic hosts include cyclodextrins, cucurbit[n]urils, calix[n]arenes, pyrarenes, crown ethers, cyclophanes, and cryptands, but do not exclude other macrocyclic hosts. B. Synthetic polymers, primarily water-soluble polymers, including but not limited to: polymers and copolymers formed from acrylic acid, methacrylic acid and / or their esters; polymethacrylates, methyl methacrylate and its salts; polyacrylamides; polyamidoamines, polypropyleneimines, polyethylene glycols; polyvinyl alcohols; polyvinylpyrrolidone; acrylic polymers, vinyl acetate phthalate, copovidone, ethyl oleate, glycerol derivatives, triacetin, polyethylene glycol (PEG), PEG derivatives, polymethacrylates, propylene glycol, propylene glycol derivatives, 1-vinyl-2-pyrrolidone, polyvinylpyrrolidone (PVP), vinyl acetate phthalates, PVAP, Hypromellose Acetate Succinate (HPMCAS), Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS), Hypromellose Phthalate (HPMCP), Cellulose Butyrate Phthalate, Cellulose Hydrogen Phthalate, Cellulose Propionate Phthalate, Vinyl Acetate Phthalate, Cellulose Acetate Phthalate, Cellulose Acetate Trimellitate, Hydroxypropyl Methylcellulose Phthalate, Hydroxypropyl Methylcellulose Acetate, Dioxypropyl Methylcellulose Succinate, Carboxymethyl Ethyl Cellulose, Hydroxypropyl Methylcellulose Acetate Succinate, Avicel, Avicel PH101, Avicel PH102, Benecel, Brij, Brij 30, Brij 35, Capryol, Cavamax, Cavasol and Cavitron, HPpCD Cyclodextrin, Glyceryl Behenate, Cremophor, Cremophor EL, Cremophor RH40, DiCal Dihydrate, Epoxidized Palm Oil (Epo), Methyl Methacrylate, Eudragit E, Eudragit EPO, Eudragit L100, Eudragit L100-55, Eudragit S100, Gelucire, 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, HPMCASSDD、HPMCAS(AS-MG)、HPMCAS-M SDDs、HPMCAS-MG、HPMCP (HP 55) HPMCP-HP55 HPMCPh HP-50 Imwitor Imwitor 742 Klucel HPC Kolhdon 17 PF Kollicoat MAE、Collicoat MAE 100、Collicoat MAE 100P、Collicoat Protect、Collidon(1-ビニ-2-ピリドン)、Collidon 12 pf、Collidon 12 / 17PF、Collidon 30、Collision 30 / 90、Collision 90、Collision CL-F、Collision CL-SF、Collision K30、Collision SR、Collision SR、Collision SR(PVAc)、Collision V64 / Fine、Collision VA 64、Collision VA 64(コポビドン) Kollidon VA64, Kolliphor, 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、Kolliphor Solv GTA、Collision Solver PEG 1450、Collision Solver PEG 300、Collision Solver PEG 3350、Collision Solver PEG 400、Collision Solver PEG E 300、Collision Solver PEG E 400、Collision Solver PEG diuretics, Kolliwax, Kolliwax GMS II, Kolliwax SA, Labrasol, β-sink 310 Mono, β-ラトース FF316, Laurogucol, Maisine Miglyol(s),Montyl(s),Montyl 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 polyesteramide (PSPEA),Monoolein(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-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS), Isomalt (Gallen IQ 810), but not excluding other synthetic polymers and mixtures thereof; C. Polyols include, but are not limited to, ethylene glycol, glycerol, erythritol, D-threitol, arabitol, ribitol, mannitol, sorbitol, galactitol, rhodiitol, D-iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol, and mixtures thereof. D. Sugars include α-D-glucopyranose, dextrose, galactose, D-mannopyranose, L-arabinose, rhamnose, sucrose, β-maltose, β-lactose, D-ribopyranose, and mixtures thereof. E. Surfactants may include (but are not limited to): anionic surfactants containing an anionic functional group, such as sulfates, sulfonates, phosphates, carboxylates, carboxylate salts; alkyl sulfates; alkyl ether sulfates; carboxylate-based fluorosurfactants; cationic surfactants; primary, secondary, or tertiary amines; permanently charged quaternary ammonium salts; amphoteric surfactants; amphoteric surfactants where the cationic moiety is based on a primary, secondary, or tertiary amine or a quaternary ammonium cation; sultaines; betaines; phospholipids; amphoteric boundaries of the tertiary amine oxide structure type. Surfactants;Nonionic surfactants;Ethoxylates;Fatty alcohol ethoxylates;Alkylphenol ethoxylates (apes or apeos);Fatty acid ethoxylates;Specialty ethoxylated fatty acid esters and oils;Ethoxylated amines and / or fatty acid amides;End-closed 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 dodecyl sulfate;Sodium laureth sulfate;Sodium lauryl sulfate;Sodium 2-{2-[2-(tetradecyloxy)ethoxy]ethoxy}ethyl Sulfates; docusate (dioctyl sodium sulfosuccinate) and its salts; perfluorooctanesulfonate (pfos); perfluorobutanesulfonate; alkylaryl ether phosphates; alkyl ether phosphates; sodium stearate; sodium N-lauroyl sarcosine; perfluorononanoate; perfluorooctanoate; octenidine dihydrochloride; hexadecyltrimethylammonium bromide (ctab); cetylpyridinium chloride (cpc); benzalkonium chloride (bac); solamin (bzt); dimethyldioctadecylammonium chloride; dimethyldioctadecylammonium bromide (dodab); chaps (3-[(3-cholamidopropyl)dimethylamonio]-1-propanesulfonate); cocamidopropyl hydroxysultaine; cocamidopropyl betaine; phosphatidylserine; phosphatidylethanolamine; phosphatidylcholine; sphingomyelin;Dodecyldimethylamine N-oxide;Tetradecyldimethylamine oxide;Narrow range ethoxylate;Octaethylene glycol monododecyl ether;Pentaethylene glycol monododecyl ether;Nonylphenol ethoxylate;Triton X-100;Polyethoxylate tallowamine;Cocamide monoethanolamine;Cocamide diethanolamine;Poloxamer;Glycerol monostearate;1-Monolaurin;Sorbitan monolaurate;Sorbitan monostearate;Sorbitan tristearate;tween,tween 20;tween 40;tween 60;tween 80;Decyl-D-glucoside;span,span 20;span 40;span 80;Dodecyl D-glucopyranoside;Octyl D-glucopyranoside;Poloxamer,Poloxamer 188,Poloxamer 407, polyoxyethylene stearates, montylic, deoxycholic acid, bile acids, pluronic, pluronic F-127, pluronic P85, pluronic F68, gelucire, gelucire 44 / 14, lecithin, polysorbates, polysorbate 80, plasdone-s630, pluronic-f68, inutec sp1, glyceryl behenate, 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. F. Acids and salts based on these acids, including but not limited to: citric acid, tartaric acid, succinic acid, orthophosphoric acid, amino acids, acetic acid, sodium acetate, alginates, sodium alginate, glycyrrhizic acid and its salts, and mixtures thereof; G. Copolymers of the polymers described in sections A and C include, but are not limited to, alternating, random, block, graft and crosslinked modifications of methacrylic acid and ethyl acrylate copolymers; methacrylic acid copolymers; vinylpyrrolidone-vinyl acetate copolymers (PVPVA); polyvinylpolypyrrolidone (PVPP); HPMC and PVA-PEG graft copolymers; grafted polyvinylpyrrolidone-arabinogalactan copolymers; graft copolymers having a) poly(vinyl acetate) and / or poly(vinyl alcohol) and / or poly(vinyl chloride) and poly(vinyl ester) on a polymer chain of b) polyethylene glycol, polyalkylene glycol, polypropylene glycol, polyisobutylene glycol or polymethylpentene glycol; graft copolymers having polyvinyl acetate and / or hydrolyzed 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 copolymers include anionic, cationic and neutral copolymers based on methacrylic acid and methacrylic / acrylic esters, their salts, esters or other derivatives and mixtures thereof; H. Methoxylated, ethoxylated, esterified, carboxylated, alkoxylated, acetylated, hydroxylated, hydrolyzed, decarboxylated, amidated, oxidized, sulfation, amino acid derived, fermented, thermally modified, chemically modified, acid modified derivatives of the following substances, and their esters, salts, and other chemical derivatives, and mixtures thereof: J. Any combination of substances specified in heading AH; However, this does not include Kollicoat IR and similar PVA-PEG graft copolymers; The preparation method is selected from the following: a) forming a liquid solubilized non-covalent complex under conditions sufficient to dissolve the solid dispersion (FORMULA I) in a solvent to form a liquid solubilized non-covalent complex (forming a solution, gel, colloid, SOL, suspension, etc.); b) Place the HOST substance in a flask and dissolve it completely in ethanol, then add the API and GUEST drugs to the flask. Slowly add water to the solution and stir for several hours; c) by other means of energy supply, such as electromagnetic radiation, heat, mechanical action, sound, or any of the methods described in the scientific and patent literature. As non-limiting examples, examples of exposure by mechanical and sound influences are given. Non-covalent complexes obtained by interaction of aqueous solutions of the HOST substance with the API and the GUEST drug, followed by precipitation of the obtained complex with ethanol.

5. A method for producing a dosage form for the treatment of a viral infection (in humans or mammals, animals or birds) or a method for producing or preparing a medical dosage form to be used as an antiviral drug, comprising the step of generating a solid dispersion or a non-covalent complex, in which a carrier (HOST) substance increases the permeability of the active ingredient (API, GUEST) by interacting with the biological membrane, improving the transfer of molecules, ions or metabolites of the API, GUEST through the biological membrane of an organism (resulting in a dosage form with improved therapeutic efficacy); and where the improved permeability allows the required concentration (EC (effective concentration) or IC (inhibitory concentration)) in the patient's organs and tissues to be reached more quickly.

6. A non-covalent complex or solid dispersion according to claims 1-5, wherein the non-covalent complex or solid dispersion has at least one altered property that enhances the therapeutic effect compared to pure ivermectin or pure avermectin: 1) It has higher bioavailability than pure ivermectin or pure avermectin; 2) has higher permeability than pure ivermectin or pure avermectin; 3) have lower toxicity or cytotoxicity than pure ivermectin or pure avermectin; 4) have different pharmacokinetic parameters than pure ivermectin or pure avermectin; 5) It has improved solubility over pure ivermectin or pure avermectin.

7. The method according to claims 1-5, wherein the non-covalent complex or solid dispersion has at least one altered property that enhances the therapeutic effect compared to pure ivermectin or pure avermectin: 1) It has higher bioavailability than pure ivermectin or pure avermectin; 2) has higher permeability than pure ivermectin or pure avermectin; 3) have lower toxicity or cytotoxicity than pure ivermectin or pure avermectin; 4) have different pharmacokinetic parameters than pure ivermectin or pure avermectin; 5) It has improved solubility over pure ivermectin or pure avermectin.

8. The non-covalent complex or solid dispersion of claims 1-7, wherein the non-covalent complex or solid dispersion is combined with at least one of the following: 1) Modulators of P-glycoprotein; 2) CYP3A4 modulators; 3) Ivermectin, an avermectin synergist; 4) quercetin and / or 2,3-dihydroquercetin and / or (4R,5S)-2,3,4,5,6-pentahydroxy-2-hexenoic acid 1,4-lactone; 5) additional therapeutic agents that demonstrate activity (in vitro, in vivo, in silico) against the infectious virus; 6) additional therapeutic agents that enhance the antiviral activity of the noncovalent complex; 7) additional therapeutic agents that reduce the hepatotoxicity of the noncovalent complex; 8) an additional therapeutic agent selected from those described in paragraph [0081] (Section IV.I.) or derivatives thereof; 9) niclosamide and / or nitazoxanide and / or melatonin; 10) Mebeverine hydrochloride; However, this does not include combinations with antibiotics (tetracycline, doxycycline, azithromycin) and zinc.

9. The method of claims 1-7, wherein the non-covalent complex or solid dispersion is combined with at least one of the following: 1) Modulators of P-glycoprotein; 2) CYP3A4 modulators; 3) Ivermectin, an avermectin synergist; 4) quercetin and / or 2,3-dihydroquercetin and / or (4R,5S)-2,3,4,5,6-pentahydroxy-2-hexenoic acid 1,4-lactone; 5) additional therapeutic agents that demonstrate activity (in vitro, in vivo, in silico) against the infectious virus; 6) additional therapeutic agents that enhance the antiviral activity of the noncovalent complex; 7) additional therapeutic agents that reduce the hepatotoxicity of the noncovalent complex; 8) an additional therapeutic agent selected from those described in paragraph [0081] (Section IV.I.) or derivatives thereof; 9) niclosamide and / or nitazoxanide and / or melatonin; 10) Mebeverine hydrochloride; However, this does not include combinations with antibiotics (tetracycline, doxycycline, azithromycin) and zinc.

10. The non-covalent complex or solid dispersion of claims 1-9 is used as a non-covalent complex or solid dispersion for the following purposes: 1) In the manufacture of pharmaceutical preparations for the treatment of viral infections in humans or mammals or animals or birds; 2) For the reduction of viral load in humans or mammals or animals or birds; 3) As an anticancer drug or anticancer pharmaceutical preparation; 4) ACE inhibitors, anterior pituitary hormones, adrenergic neuron blockers, corticosteroids, corticosteroid biosynthesis inhibitors, α-adrenergic agonists, α-adrenergic receptor blockers, selective α2-adrenergic agonists, analgesics, antipyretics, analgesics, anti-inflammatory drugs, androgens, anesthetics, antidependence drugs, antiandrogens, antiarrhythmic drugs, antiasthmatic drugs, anticholinergic drugs, anticholinesterase drugs, anticoagulants, antidiarrheals, antidiuretics, antiemetics and gastrointestinal motility enhancers, antiepileptic drugs, antiestrogens anti-inflammatory drugs, antifungals, antihypertensives, antibacterials, antimigraine drugs, antimuscarinics, antineoplastics, antiparasitic drugs, antiparkinsonian drugs, antiplatelet drugs, antiprogestins, antithyroid drugs, antitussives, antivirals, atypical antidepressants, azaspirodecanediones, barbiturates, benzodiazepines, benzothiadiazides, beta-adrenergic agonists, beta-adrenergic blocking agents, selective beta1-adrenergic blocking agents, selective beta2-adrenergic agonists, bile salts, agents affecting body fluid volume and composition, butyrophenones, Agents affecting calcification, Calcium antagonists, Cardiovascular drugs, Catecholamines and sympathomimetics, Cholinergic drugs, Cholinesterase reactivators, Dermatological drugs, Diphenylbutylpiperidines, Diuretics, Ergotamine alkaloids, Estrogens, Ganglionic blockers, Ganglionic stimulants, Hydantoins, Acid control and anti-ulcer drugs, Hematopoietic drugs, Histamine, Histamine antagonists, 5-hydroxytryptamine antagonists, Lipid-lowering drugs, Hypnotics and sedatives, Immunosuppressants, Laxatives, Methylxanthines , monoamine oxidase inhibitors, neuromuscular blocking agents, organic nitrates, opioid analgesics and antagonists, pancreatic enzymes, phenothiazines, progestins, prostaglandins, drugs for treating psychiatric disorders, retinoids, sodium channel blockers, drugs for treating spasticity and acute muscle spasms, succinimides, thioxanthines, thrombolytics, thyroid drugs, tricyclic antidepressants, ductal transport inhibitors of organic compounds, drugs affecting uterine motility, vasodilators, vitamins, etc. Although extensive, this list is not intended to be exhaustive.

11. The method of Claims 1-9 is for producing a pharmaceutical dosage form for treating a viral infection in humans or mammals or animals or birds, or for producing or preparing a medical dosage form for use as an antiviral drug, using the noncovalent complex or solid dispersion.

12. In accordance with Claims 1-11, if: A) When administering a therapeutically effective amount of a stabilized aqueous formulation containing avermectin or ivermectin, a solvent, a surfactant and a cosolvent; B) when administering a therapeutically effective amount of a solution of avermectin or ivermectin in a fat / oil or a stabilized formulation containing an avermectin or ivermectin emulsion; C) A therapeutically effective amount of a compound of FORMULA IV is administered in the form of a solution or emulsion or suspension, including: 1) a first pharmaceutical composition comprising a compound of FORMULA I-III; and 2) At least one of the following ingredients: a) an oil phase containing vegetable and / or animal fats; b) one or more surfactants; c) one or more solvents; d) one or more gelling agents; D) A therapeutically effective amount of a compound of FORMULA V is administered in the form of a food product or beverage, or dietary supplement; E) When used in combination with a pharma- ceutically acceptable diluent, carrier, or excipient; F) When a solid dispersion is administered instead of a non-covalent complex.

13. The method of claims 1-12, wherein the dose of the non-covalent complex or solid dispersion is greater than the following for each virus: 1) IC5 - 5% of the maximum inhibitory concentration of ivermectin or avermectin; 2) IC50 - half maximal inhibitory concentration of ivermectin or avermectin; 3) IC90 - 90% of the maximal inhibitory concentration of ivermectin or avermectin.

14. The non-covalent complex or solid dispersion of claims 1-13, wherein the carrier (HOST) is a polymer, a biopolymer or a synthetic polymer, or a methoxylated, ethoxylated, esterified, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, hydrated, decarboxylated, amide, oxidized, sulfated, amino acid derived, fermented, thermally modified, chemically modified, acid modified derivatives, esters and ethers, salts, other chemical derivatives, and mixtures thereof.

15. The method of claims 1-14, wherein the carrier (HOST) is a polymer, a biopolymer or a synthetic polymer, or a methoxylated, ethoxylated, esterified, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, hydrated, decarboxylated, amide, oxidized, sulfated, amino acid derived, fermented, thermally modified, chemically modified, acid modified derivatives, esters and ethers, salts, other chemical derivatives, and mixtures thereof.

16. The method of claims 1-15, wherein the mass ratio of ivermectin or avermectin to the polymer, biopolymer or synthetic polymer (HOST) is from 1:1 to 1:10000.

17. The non-covalent complex or solid dispersion of claims 1-15, wherein the mass ratio of ivermectin or avermectin to the polymer, biopolymer or synthetic polymer (HOST) is from 1:1 to 1:10000.

18. The method of claims 1-17, wherein the non-covalent complex or solid dispersion is administered in a composition that can be formulated and applied in various forms, including: polymeric nanoparticles (PNPs), liposomes, micelles, niosomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), nanoemulsions, emulsions, self-nanoemulsifying drug delivery systems (SNEDDS), nanocrystals, mesoporous silica nanoparticles (MSNs) and dendrimers; and / or using methods of physical, chemical or other modifications.

19. The method of claims 1-18 when used to treat a disease in humans or mammals, animals or birds.

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