Methods and bioavailability highly permeable compounds for treatment of viral diseases

Abstract

Methods and compounds are provided for treating viral infections by administering a high bioavailability, high permeability compound based on abamectin. The compounds, compositions, and methods provided are particularly useful for the treatment of severe acute respiratory syndrome coronavirus type 2, dengue virus, Chikungunya virus, yellow fever virus, Zika virus, and other viral infections.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 324,087, filed Mar. 27, 2022, and U.S. Provisional Patent Application No. 63 / 398,038, filed Aug. 15, 2022. The entire contents of the above applications are incorporated herein by reference. Technical Field

[0003] The present invention generally relates to methods and compounds for treating viral infections, particularly avermectin-based methods and compounds for treating infections by coronaviridae SARS-CoV-2, flaviviridae dengue and Zika, and togaviridae chikungunya virus. Background Art

[0004] Human coronaviruses were first discovered in the mid-1960s and are common viruses that most people are infected with at some point in their lives, typically causing mild to moderate upper respiratory and gastrointestinal diseases. A novel coronavirus called "Middle East Respiratory Syndrome Coronavirus" (MERS-CoV or MERS) was first reported in Saudi Arabia in 2012 and spread to several other countries. SARS-CoV, the coronavirus that causes Severe Acute Respiratory Syndrome (SARS), caused a global outbreak in 2002 and 2003.

[0005] Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a strain of coronavirus that causes COVID-19 (Coronavirus Disease 2019), a respiratory disease and the pathogen responsible for the ongoing COVID-19 pandemic. The World Health Organization declared the outbreak a Public Health Emergency of International Concern on Jan. 30, 2020, and a pandemic on Mar. 11, 2020. SARS-CoV-2 is a positive-sense single-stranded RNA virus that is infectious in humans.

[0006] As of December 2021, the number of cases continued to climb due to multiple factors, including new COVID-19 variants. As of Dec. 28, 2021, 282,790,822 people had been confirmed infected globally. As of Apr. 14, 2022, the global confirmed cases exceeded 500 million. Most cases are unconfirmed, and the Institute for Health Metrics and Evaluation estimated the true number of cases in early 2022 to be in the billions.

[0007] According to the World Health Organization (WHO), the increasing awareness of Aedes - transmitted viruses in recent years, especially chikungunya virus, Zika virus, and dengue virus, has become a global concern. Unfortunately, due to the lack of arbovirus disease surveillance and a comprehensive understanding of arboviral diseases, these diseases are hidden behind malaria. Underestimating arboviral diseases can lead to misdiagnosis and unnecessary medical costs, especially in febrile illnesses suspected of being malaria. Approximately 3.9 billion people from 120 different regions seem to be at risk of these three major arboviruses. Summary of the Invention

[0008] Technical Problem

[0009] Some compounds show antiviral activity in vitro, and some of them are used in disease treatment, but the treatment effect is sometimes insufficient. There are difficulties in increasing the bioavailability and permeability of drugs.

[0010] Ivermectin is a drug used to treat parasitic infections. In vitro, ivermectin has antiviral effects against several different RNA and DNA viruses. In vitro, ivermectin can inhibit the replication of RNA viruses such as Zika virus, dengue virus, yellow fever virus, West Nile virus, Hendra virus, Newcastle disease virus, Venezuelan equine encephalitis virus, chikungunya virus, forest virus, Sindbis virus, avian influenza A virus, porcine reproductive and respiratory syndrome virus, human immunodeficiency virus type 1, and severe acute respiratory syndrome coronavirus 2. In vitro, ivermectin can inhibit the replication of DNA viruses such as equine herpesvirus type 1, BK polyomavirus, pseudorabies virus, porcine circovirus type 2, and bovine herpesvirus type 1. In vitro, ivermectin can inhibit the replication of severe acute respiratory syndrome coronavirus 2 at concentrations of EC50 2.4 μM and EC90 5 μM.

[0011] The antiviral effect of ivermectin has been recorded:

[0012]

[0013]

[0014] The degree of inhibition of virus replication by ivermectin directly depends on the concentration of ivermectin in the cells. Once the concentration of ivermectin in the cells reaches the threshold concentration, each subsequent increase in the concentration of ivermectin in the body tissues will increase the inhibitory effect. Generally, the concentration of ivermectin in the body tissues is higher than that in the plasma. For example, the plasma - to - lung ratio of cattle is about 2.67, and that of humans is about 3.0.

[0015] Even a high dose of ivermectin in the form of a standard tablet at 600 μg / kg per day can only produce a pulmonary Cmax of 0.4 - 0.9 μM over 5 days, which is far below the concentration required to inhibit viral replication and cannot provide the concentration of ivermectin in body tissues necessary for effective inhibition of viral replication.

[0016] The technical problem is to provide a method for treating viral diseases in humans or mammals or animals or birds in need of treatment, including administering a therapeutically effective amount of an avermectin-based compound with high bioavailability and high permeability.

[0017] Problem solution

[0018] There are provided methods and compounds for pharmaceutical dosage forms for treating viral diseases, including administering a therapeutically effective amount of a compound. There is provided a method for treating viral diseases in a human or mammal or animal or bird in need of treatment, including administering a therapeutically effective amount of a FORMULA I compound, which is a high bioavailability and high permeability solid dispersion (or its solution or suspension), wherein the compound of FORMULA I is obtained by co-processing an API (active pharmaceutical ingredient guest drug compound) with a HOST substance

[0019] wherein the API is selected from avermectin / ivermectin and their derivatives;

[0020] wherein the HOST substance is selected from:

[0021] a) Polymers and oligomers and macrocyclic hosts, mainly organic polymers and oligomers, more mainly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, or mixtures thereof;

[0022] b) Substances that may contain large amounts of polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, which may be (but are not limited to) 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 large amounts of the substances specified in paragraph a), or mixtures thereof;

[0023] c) Synthetic polymers, mainly water-soluble polymers or mixtures thereof;

[0024] d) Polyols or mixtures thereof;

[0025] e) Glycosides or mixtures thereof;

[0026] f) Surfactants or mixtures thereof;

[0027] g) Acids or mixtures thereof;

[0028] h) Oxides and salts based on these oxides or mixtures thereof;

[0029] i) Copolymers of the polymers listed in paragraphs a) and c);

[0030] j) Methoxylated, ethoxylated, esterified, carboxylated, alkoxylated, acetylated, hydroxylated, hydrogenated, decarboxylated, amidated, oxidized, sulfated, amino acid derivatives, fermented, thermally modified, chemically modified, acid-modified derivatives and their esters, salts and any other chemical derivatives and mixtures thereof of the substances listed in paragraphs a)-i);

[0031] k) Any combination of the substances listed in paragraphs a)-j);

[0032] Wherein the combined treatment method is selected from methods for obtaining solid dispersions, including methods for obtaining solid dispersions such as solvent evaporation methods, low-temperature methods, melting methods, mechanochemical methods and other methods. As non-limiting examples, the methods that can be selected include:

[0033] a) High-energy stress grinding / crushing method;

[0034] b) High-energy stress grinding / crushing and solvent method;

[0035] c) Media grinding method;

[0036] d) Kneading method;

[0037] e) Hot melt method / melting method / fusion method;

[0038] f) Hot melt extrusion / thermal stage extrusion method;

[0039] g) Meltrex method;

[0040] h) Melt aggregation method;

[0041] i) High-pressure homogenization method;

[0042] j) Solvent evaporation method;

[0043] k) Spin coating thin film method;

[0044] l) Spray drying method;

[0045] m) Supercritical fluid (SCF) process method;

[0046] n) Low-temperature technology method;

[0047] o) Freeze-drying technology method;

[0048] p) Spray freezing into cryogenic fluid method;

[0049] q) Spray freezing into cryogenic liquid (SFL) method;

[0050] r) Spray freezing into liquid surface vapor (SFV / L) method;

[0051] s) Ultra-rapid freezing method;

[0052] t) Precipitation / coprecipitation method;

[0053] u) Microwave irradiation method;

[0054] v) Energy input method;

[0055] w) Thermal / shear energy input method;

[0056] x) Combined method.

[0057] On the other hand, a method for treating viral diseases is provided, which comprises administering to a human or mammal or animal or bird in need thereof a therapeutically effective amount of a FORMULA II compound (and its solutions, gels, colloids, sols, etc.), which compound 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, wherein the compound of FORMULA I is obtained by co-processing an API (active pharmaceutical ingredient guest drug compound) with a host substance,

[0058] wherein the solvent is usually water;

[0059] wherein the molecular information of the FORMULA II non-covalent complex is encoded by the following formula (the non-covalent complex of FORMULA II is):

[0060] GUEST(SOLVENT)m[HOST]n

[0061] wherein m is from 1 to 100;

[0062] wherein n is from 1 to 1000;

[0063] wherein the molecular information of GUEST is provided based on the InChI derived from the InChIKey, with each guest drug being indicated;

[0064] wherein the molecular information of SOLVENT is H2O if the solvent is water;

[0065] On the other hand, a pharmaceutical dosage form of FORMULA I is provided, having enhanced bioavailability and permeability, characterized in that it comprises a highly bioavailable and highly permeable solid dispersion or its aqueous solution or suspension, wherein the compound of FORMULAI is obtained by co-processing an API (active pharmaceutical ingredient guest drug compound) with a host substance.

[0066] On the other hand, there is provided a pharmaceutical dosage form of FORMULA II (and its solutions, gels, colloids, sols, etc.), 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, wherein the compound of FORMULA I is obtained by co-processing an API (active pharmaceutical ingredient, guest drug compound) with a host substance.

[0067] On the other hand, there is provided a method for manufacturing or preparing a pharmaceutical dosage form of FORMULA I with enhanced bioavailability and permeability, characterized in that it comprises a highly bioavailable and highly permeable solid dispersion or its aqueous solution or suspension, wherein the compound of FORMULA I is obtained by co-processing an API with a host substance.

[0068] In another aspect, there is provided a method for preparing or manufacturing a pharmaceutical dosage form of FORMULA II (and its solutions, gels, colloids, sols, etc.), 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, wherein the compound of FORMULA I is obtained by co-processing an API with a host substance.

[0069] In another embodiment, the method comprises administering a therapeutically effective amount of a combined pharmaceutical preparation (FORMULA III), which comprises:

[0070] a) a first pharmaceutical composition comprising a compound of FORMULA I-II, and

[0071] b) a second pharmaceutical composition comprising at least one additional therapeutic agent against antiviral activity, 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.

[0072] In another embodiment, the method comprises administering a therapeutically effective amount of a combined pharmaceutical preparation of FORMULA IV, in the form of a solution / emulsion / suspension, comprising:

[0073] a) a first pharmaceutical composition comprising a compound of FORMULA I-III, and

[0074] b) at least one of the following components:

[0075] (1) an oil phase containing plant or / and animal fats;

[0076] (2) one or more surfactants;

[0077] (3) one or more solvents;

[0078] (4) one or more gelling agents.

[0079] In another embodiment, the method comprises administering a therapeutically effective amount of the FORMULA V pharmaceutical composition, in the form of a food product or beverage, or a dietary supplement.

[0080] In another embodiment, a method of treating a viral disease in a human in need of treatment or in a mammal or animal or bird comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a FORMULA I-V compound and a pharmaceutically acceptable diluent or carrier.

[0081] In another embodiment, a method of treating a viral disease in a human in need of treatment or in a mammal or animal or bird comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a FORMULA I-V compound in combination with at least one additional therapeutic agent.

[0082] In another embodiment, the method comprises administering a therapeutically effective amount of a FORMULA I-V compound to a human in need thereof or to a mammal or animal or bird, or treating a disease in a human or mammal or animal or bird with a FORMULA I-V compound.

[0083] Advantages of the Invention

[0084] The advantageous effects of the patented invention provide a method for treating viral diseases in humans or mammals or animals or birds. BRIEF DESCRIPTION OF THE DRAWINGS

[0085] FIG. 1 Example of the chemical formula of a non-covalent complex of FORMULA II;

[0086] FIG. 2 Pharmacokinetic parameters after oral administration of ivermectin and a FORMULA I compound;

[0087] FIG. 3 Blood oxygen saturation before and after oral administration of a FORMULA I compound. DETAILED DESCRIPTION

[0088] The following description is intended to enable those skilled 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 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 spirit and scope of the invention. Accordingly, the invention is not limited to the embodiments shown, but is to be accorded the widest scope consistent with the claims.

[0089] I. Definitions

[0090] Unless otherwise specified, the term "treatment" as used herein refers to the elimination, alleviation, inhibition of progression, or prevention of the applicable disease or condition, or one or more symptoms of such disease or condition. The term "treatment" as used herein refers to the treatment act "cure" as defined directly above.

[0091] The term "therapeutically effective amount" as used herein refers to the amount of the compounds of FORMULA I-V present in the compositions described herein, which amount is necessary to provide the desired level of the drug in the secretions and tissues of the respiratory tract and lungs, or in the blood of the subject to be treated, to produce the desired physiological response or the desired biological effect under the selected route of administration. The exact amount depends on a variety of factors, such as the particular compound of FORMULA I-V, the specific activity of the composition, the delivery device used, the physical characteristics of the composition, its intended use, and patient considerations such as the severity of the disease state, patient compliance, etc., and can be readily determined by one of ordinary skill in the art based on the information provided herein.

[0092] The term "API" (Active Pharmaceutical Ingredient, Active Pharmaceutical Ingredient Guest Drug Compound, GUEST, Guest, Guest Molecular Drug, Guest Drug, Guest Drug Compound, Guest Compound, Guest Extract, Guest Bioactive Extract) is a compound with pharmaceutical activity and biological activity; if the selected API is in the free base form - the medicinal salts and medicinal esters or ethers of the base are also included; if the API is in the medicinal salt form - the free base, medicinal ester or ether of the salt, and other medicinal salts of the free base are also included; also included are racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, hydrates, hydrogens, isotopically labeled forms, prodrugs, or mixtures thereof.

[0093] The term "derivative" refers to derivatives of the API (Guest, Guest Molecular Drug, Guest Drug Compound, Guest Compound), such as racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, hydrogens, hydrates, isotopically labeled forms, prodrugs, medicinal salts, medicinal esters or ethers. If the API is present in the free base form, its derivatives are the medicinal salts and medicinal esters or ethers of the base. If the API is present in the medicinal salt form - the free base, medicinal ester or ether of the salt, and other medicinal salts of the free base also belong to derivatives. Derivatives can also be other obvious derivatives.

[0094] 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 through certain chemical or enzymatic pathways.

[0095] The term "avermectin" (IVM) as used in this document refers to 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 their pharmaceutically acceptable salts or esters or prodrugs or mixtures thereof.

[0096] II. Compounds of the present invention.

[0097] Certain embodiments of the present invention will now be described in detail, which are shown in the accompanying description, structures and formulas. Although the present invention will be described in conjunction with the listed embodiments, it should be understood that these embodiments are not intended to limit the present invention to these embodiments. On the contrary, the present invention is intended to cover all alternatives, modifications and equivalents within the scope of the present invention.

[0098] The compounds of the present invention may also exist in the form of physiologically acceptable salts. Examples of physiologically acceptable salts include salts derived from suitable bases, such as alkali metals or alkaline earth metals (e.g., Na+, K+, Ca+2, Mg+2, Li+), ammonium and NR4+ (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, phosphoric acid, nitric acid, etc.; (b) salts formed by organic acids, such as acetic acid, tartaric acid, maleic acid, fumaric acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc., oxalic acid, salicylic acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, succinic acid, isothionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, malonic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, pectic acid, 5-sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoic acid, pamoic acid, stearic acid, phthalic acid, D-mandelic acid, lactic acid, ethanesulfonic acid; and (c) salts formed by elemental anions, such as chlorine, bromine and iodine. Physiologically acceptable salts of hydroxy compounds include the anions of the compound combined with suitable cations (e.g., Na+ and NR4+). All these forms are within the scope of the present invention.

[0099] The compounds of the present invention have the ability to exist in multiple polymorphic or pseudopolymorphic forms. As used herein, polymorphism refers to the ability of a crystalline compound to exist in different crystal structures. Polymorphism can be caused by differences in crystal packing (packing polymorphism) or differences in packing between different conformations of the same molecule (conformational polymorphism). As used herein, crystal pseudopolymorphism refers to the ability of a compound hydrate or solvate to exist in different crystal structures. The pseudopolymorphs of the present invention may exist due to differences in crystal packing (packing pseudopolymorphism) or differences in packing between different conformations of the same molecule (conformational pseudopolymorphism). All of these forms are considered to be within the scope of the present invention.

[0100] The compounds of the present invention may also exist in the form of amorphous solids. As used herein, an amorphous solid refers to a solid in which the atoms do not have a long-range ordered arrangement. This definition also applies when the crystal size is two nanometers or less. Additives including solvents can be used to prepare the amorphous forms of the present invention. All of these forms are within the scope of the present invention.

[0101] When used for treatment, the active ingredient of the compounds of the present invention will be physiologically acceptable. However, non-physiologically acceptable ingredients may also be useful, for example, in the preparation or purification of physiologically acceptable compounds.

[0102] Finally, it should be expected that the compositions presented herein include non-ionized forms as well as zwitterionic forms of the compounds of the present invention, and stoichiometric combinations with compound-bound water (such as hydrates). All of these forms are within the scope of the present invention.

[0103] It should be noted that the scope of the present invention includes all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, and pseudopolymorphs of the compounds. All mixtures of these enantiomers and diastereomers are also within the scope of the present invention.

[0104] The compounds of the present invention may have chiral centers, such as chiral carbon or phosphorus atoms. Accordingly, the compounds of the present invention include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the present invention include optical isomers enriched or separated at some or all of the asymmetric chiral atoms. In other words, it can be seen from the figure that the chiral centers are presented in the form of chiral isomers or racemic mixtures. Racemic mixtures and mixtures of diastereomers, as well as individual optical isomers separated or synthesized from their enantiomeric or diastereomeric partners and substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the present invention. Racemic mixtures are separated into their individual, substantially optically pure isomers by known methods, such as separation of diastereomeric salts formed with an optically active excipient (such as an acid or a base), followed by reconversion to the optically active substance. In most cases, the desired optical isomers are synthesized by stereospecific reactions starting from the corresponding stereoisomers of the desired starting materials. All such forms are provided within the scope of the present invention.

[0105] The compounds of the present invention may exist as tautomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are within the scope of the present invention.

[0106] Any formula or structure herein is also intended to represent both unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures represented in the formulas provided herein, but with one or more atoms replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H (deuterium, D), 3H (tritium), 35S, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, and 125I, but are not limited thereto. Different isotopically labeled compounds of the present disclosure, such as those containing radioactive isotopes such as 3H, 13C, and 14C. All such forms are provided within the scope of the present invention. These isotopically labeled compounds are useful in metabolic studies, reaction kinetics studies, detection, or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue distribution analysis of drugs or substrates, or in the radiotherapy of patients. The present disclosure also includes compounds of FORMULA I, wherein 1 to n hydrogens attached to carbon atoms are replaced by deuterium, where n is the number of hydrogens in the molecule. These compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any FORMULA I compound when administered to mammals, particularly humans.

[0107] III. Key methods and concepts of the invention.

[0108] The solid dispersions of the present invention can be defined as the solid-state dispersion of one or more active ingredients (API) in an inert carrier or matrix (HOST) prepared by melting / fusion method, solvent method, melt-solvent method, mechanochemical treatment and other methods. The API drugs are hydrophobic in nature, while the matrix (HOST) is hydrophilic. The solid dispersions of the present invention can be molecular dispersions, simple eutectic mixtures, solid solutions, glass solutions and glass suspensions, mechanochemically obtained solid dispersions (including solid dispersions in the form of micro-machine complexes in which solid-phase fusion, mechanical synthesis, and mechanical activation processes have occurred), amorphous precipitates in crystal carriers, compound or complex formations. The solid dispersions of the present invention can be first-generation solid dispersions; second-generation solid dispersions; third-generation solid dispersions; fourth-generation solid dispersions. The solid dispersions of the present invention can be classified according to the physical state and molecular arrangement form of the API and the carrier: C-C type, C-A type, A-C type, A-A type, M-C type, M-A type.

[0109] Table 1. Classification according to the physical state and molecular arrangement of API and carrier (HOST)

[0110]

[0111]

[0112] Many analytical and instrumental techniques are used to characterize solid dispersions. The techniques used for characterization can be thermal analysis, spectroscopy, microscopy, microthermal analysis, macroscopic techniques, etc. A mere mixture of substances without treating the API and the carrier (HOST) will not yield the results brought about by solid dispersion. Solid dispersions are not mixtures in which synergists amplify each other's effects. Solid dispersions are not a kind of nanoparticles.

[0113] The non-covalent complexes of the present invention are molecular aggregates that have specific properties different from the environment as a whole, and their internal structure and form are determined by non-covalent interactions of atoms. This makes the non-covalent system different from molecular systems whose structures are mainly determined by covalent interactions. Non-covalent complexes are molecular complexes of two or more cations, anions or neutral molecules held together in a single system by hydrogen bonds, van der Waals interactions, donor-acceptor interactions, π-π interactions, ionic interactions, and hydrophobic interactions. Non-covalent complexes have the ability to form different structures while the chemical composition of the system remains unchanged. The non-covalent complexes of the present invention are composed of at least two different components, usually a matrix (HOST, host substance, "host", "host substance", "carrier", etc.) and a therapeutic agent (API, GUEST, active pharmaceutical ingredient, drug, guest, "guest drug", "guest drug compound", "guest substance", etc.). Many analytical and instrumental techniques are used to characterize non-covalent complexes (such as spectroscopy).

[0114] A treatment method is provided, which comprises administering a therapeutically effective amount of a solid dispersion to a patient in need (human, mammal, animal or bird), including: contacting an API and a matrix "HOST substance" under conditions sufficient to form a solid dispersion to form a solid dispersion; and (optionally) dissolving the solid dispersion in a solvent to form a liquid-dissolved non-covalent complex (forming a solution, gel, colloid, sol, suspension, etc.) under conditions sufficient to form a liquid-dissolved non-covalent complex.

[0115] On the other hand, a treatment method is provided, which comprises administering a therapeutically effective amount of a solid dispersion or a non-covalent complex to a patient in need (human, mammal, animal or bird), wherein the "carrier substance" (HOST substance) molecules of the solid dispersion or the non-covalent complex interact with the biological membrane of the organism, thereby improving the transfer of API molecules and ions through such a biological membrane; the permeability of the API in the form of a non-covalent complex is improved. Therefore, the scope of the present invention includes solid dispersions and non-covalent complexes having special permeability characteristics; solid dispersions and non-covalent complexes having high permeability.

[0116] On the other hand, a method for treating a viral disease is provided, which comprises administering a therapeutically effective amount of a solid dispersion or a non-covalent complex to a patient in need (human, mammal, animal or bird), wherein the solid dispersion or the non-covalent complex of the API has a higher bioavailability than the API itself.

[0117] On the other hand, a method for treating a viral disease is provided, which comprises administering a therapeutically effective amount of a solid dispersion or a non-covalent complex to a patient in need (human, mammal, animal or bird), wherein the solid dispersion or the non-covalent complex of the API has lower toxicity and cytotoxicity than the API itself.

[0118] In another aspect, a method for treating a viral disease is provided by administering a therapeutically effective amount of a solid dispersion or a non-covalent complex to a patient or mammal or animal or bird in need, wherein the solid dispersion or the non-covalent complex of the API has pharmacokinetic parameters different from those of the API itself.

[0119] In another aspect, a method for preparing or manufacturing the solid dispersion or the non-covalent complex of the present invention is provided.

[0120] The method for obtaining the solid dispersion of the present invention includes:

[0121] 1) Solvent evaporation and cryogenic methods;

[0122] 2) Melt method and hot-stage extrusion method;

[0123] 3) Mechanochemical methods (but not limited to other methods).

[0124] The particle size of the solid dispersion may vary depending on the equipment (such as nozzle size), equipment operating parameters, and the degree of grinding of the finished product. The typical particle size is 0.5 - 1000 microns, but it can exceed 1000 microns, and the obtained solid dispersion can also be ground to submicron size after being obtained.

[0125] The solvent evaporation method involves dissolving the API and the carrier (HOST substance) in a volatile solvent and then evaporating the solvent. In this method, thermal decomposition of the API or the carrier can be prevented because the evaporation of the organic solvent occurs at low temperatures. The differences in the solvent evaporation process are related to the solvent evaporation procedures, which typically include vacuum drying, heating the mixture on a hot plate, slowly evaporating the solvent at low temperature, using a rotary evaporator, nitrogen gas flow, spray drying, freeze drying, using supercritical fluids (SCF), and other types of solvent evaporation.

[0126] The melting method involves melting the API in the carrier (HOST substance) and then cooling and grinding the resulting product. During the melting process, the molecular mobility of the carrier is high enough to change the incorporation of the drug. A common modification of the melting stage is to suspend the API in the pre-melted carrier instead of having both the drug and the carrier in the molten state, thereby reducing the process temperature. To cool and solidify the molten mixture, various processes are used, such as stirring in an ice bath, spreading a thin layer on stainless steel and blowing cold air, curing on a petri dish at room temperature in a desiccator, spreading on dry ice, immersing in liquid nitrogen or storing in a desiccator, and other types of cooling. After cooling, the mixture must be ground for easy handling. However, the use of high temperatures and the possible degradation of some drugs during melting may be a limitation of this method. The possible incomplete miscibility between the drug and the carrier due to the high viscosity of the polymer carrier in the molten state is another limitation of this process. To avoid the limitations of the melting method, various modifications have been made to the original method, such as hot stage extrusion, Meltrex, melt aggregation, etc.

[0127] The mechanochemical method for obtaining solid dispersions involves mechanical processing under conditions of high-intensity mechanical treatment (e.g., in a planetary or other type of mill), where processes of solid-phase fusion, mechanical synthesis, and mechanical activation between components occur, including the formation of microcomposites, where the processes of mechanochemical solid-phase fusion / melting, mechanical synthesis, and mechanical activation of the API with the HOST substance occur. When the components are mixed, reactions occur in the solid phase, forming a product with a high contact surface and an extremely high concentration of various defects. An interfacial surface required for physical-chemical interactions is formed. Under these conditions, the characteristic time of mass transfer between the reagents is reduced for physical-chemical reactions to occur. While comminuting and forming the solid dispersion obtained mechanochemically, additional structural defects are generated in the mixture components. In a macroscopic approximation, the activation energy barrier for chemical interactions is reduced. Generally, the longer the mechanical processing time, the higher the bioavailability and permeability of the resulting solid dispersion, while the particle size remains almost unchanged.

[0128] At the initial stage of mechanochemical processing, the initial collisions of powder particles with the spheres result in plastic deformation and flattening of the particles. The continuous plastic deformation is accompanied by an increase in the ratio of the particle surface area to its volume. During the deformation of the particles, the pure inner layer of the API is opened and comes into close contact with the pure layer of another component, leading to a welding process. The accompanying plastic deformation hardening reaches a critical value, and the formed object is broken. Then, the three processes of plastic deformation, welding, and fracture of the processed particles are repeatedly parallel many times. During this process, the material acquires a layered, distorted structure. At the end of the initial fusion stage, a hybrid heterogeneous system called a mechanical composite is formed. The mechanical composite has a morphologically metastable structure with a high density of phase interfaces between the initial components, providing a developed contact surface and a high concentration of defects due to a large number of atoms on the surface and near the surface layer. Such a system has a large amount of stored energy, which, together with the extremely large contact surface between the components, provides a high reactivity of the system. At the same time, although the contact surface of the reagents in the matrix is almost perfect, a large number of inclusions of the more brittle component in contact with the plastic reagent in the volume of the mechanical composite are still visible.

[0129] The mechanochemical processing method leads to the same results as other methods but excludes the use of toxic solvents or the process of thermal degradation of the API.

[0130] In the present invention, solid dispersions with high bioavailability and non-covalent complexes with high bioavailability are obtained and used. High bioavailability for the solid dispersions and non-covalent complexes means at least one of the following:

[0131] 1) The absolute or relative bioavailability of the solid dispersion or non-covalent complex of the API is higher than that of the API itself;

[0132] 2) The concentration of the API and / or its metabolites in blood, organs or tissues, the maximum plasma concentration, pharmacokinetic parameters, etc. are higher for the solid dispersion or non-covalent complex of the API than for the API itself.

[0133] The release rate of the API molecule from the non-covalent complex may play an important role in increasing bioavailability.

[0134] Non-covalent complexes play a particularly important role in biological systems, such as the transfer of molecules and ions across biological membranes. Highly permeable solid dispersions or non-covalent complexes are obtained and used in the present invention. High permeability for the solid dispersion or non-covalent complex means at least one of the following:

[0135] 1) The transfer of the API molecule, ion, metabolite across the biological membrane / cell membrane is better for the solid dispersion or non-covalent complex of the API than for the API itself;

[0136] 2) The transfer of the API molecule, ion, metabolite across the Caco-2 cell line layer or other cell line layers (such as the intestinal epithelial cell layer, etc.) is better for the solid dispersion or non-covalent complex of the API than for the API itself;

[0137] 3) The intestinal permeability of the solid dispersion or non-covalent complex of the API is better than that of the API itself;

[0138] 4) The permeability is increased according to the method for determining permeability in the biopharmaceutics classification system.

[0139] Within the scope of the present invention, an increase in the permeability and absorption of the API in the solid dispersion or non-covalent complex is achieved through the following mechanisms (but not limited to other mechanisms for increasing permeability):

[0140] 1) Due to the interaction of the membrane with the carrier substance (HOST) molecule, blocking / reducing the activity of CYP3A4 and / or P-glycoprotein, blocking / reducing the activity of other transmembrane carrier proteins, transporters, enzymes, etc.;

[0141] 2) Due to the interaction of the carrier substance (HOST) molecule with the membrane, blocking / reducing the activity of CYP3A4 and / or P-glycoprotein, blocking / reducing the activity of other transmembrane protein transporters, transporters, enzymes, etc., this adhesion may lead to an interaction with the transporter region located outside the cell membrane and block the action of the transmembrane transporter;

[0142] 3) Due to the incorporation of the carrier substance (HOST) molecule into the membrane rather than due to adhesion, resulting in a change in the cell membrane structure;

[0143] 4) Due to the direct action of the carrier substance (HOST) molecules on the intestinal epithelial cell membrane: This may include altering the properties of the lipid bilayer, the density of cell-cell contacts, or inhibiting transmembrane proteins involved in multidrug resistance;

[0144] 5) Due to changes in the hydrophilicity and hydrophobicity of the non-covalent complex, paracellular transport of the non-covalent complex may occur;

[0145] 6) Other changes in the membrane structure and properties caused by other mechanisms contribute to increasing its permeability.

[0146] Carriers play a major role in the formulation of solid dispersions. They can be hydrophilic, hydrophobic, or swellable upon water absorption. Depending on their properties, they can be used as release retardants or release enhancers. The dissolution characteristics of drug molecules also depend on the nature of the carrier. The criteria for selecting the carrier (HOST) are as follows:

[0147] a. It should be water-soluble or swellable and soluble in various solvents.

[0148] b. It should be economical, pharmacologically inert, and non-toxic.

[0149] c. It should be heat-resistant.

[0150] d. Chemically compatible with the drug.

[0151] e. Water-soluble and water-insoluble carriers must prevent the recrystallization tendency through hydrogen bond interaction and help maintain a supersaturated state after dissolution (spring and parachute effects).

[0152] Due to their diverse pharmaceutical applications, availability, biocompatibility, non-toxicity, and chemical inertness, polymers of plant origin are used in the present invention and are more favored compared to synthetic polymers. Polysaccharides are one of the most abundant industrial raw materials and are used due to their sustainability, biosafety, and biodegradability. Natural gums are metabolic by-products of plants and come from various parts of plants such as seeds, fruits, and cut tree trunks (gummy exudates), etc.

[0153] Natural polysaccharides are biodegradable and biocompatible materials for drug delivery systems. However, these materials have some limitations, such as uncontrolled hydration rates, viscosity changes during the shelf life, and microbial contamination. Therefore, in order to overcome these problems, some improvements have been made. The improvements can be carried out by physical modification and chemical modification. Physical modification methods include the use of dry heat, microwave technology, ultraviolet light, and gamma radiation. Chemical modification includes carboxymethylation / carboxyethylation, in which the free -OH groups are replaced, thus improving the solubility of the drug in water. Generally, modifying natural carriers by heating methods results in changes in their physical properties such as viscosity, density, swelling index, water - holding capacity, flow properties, etc. Due to these property changes, the modified natural carriers obtain improved results in use. The carboxymethylation of natural carriers increases their hydrophilicity and makes them more soluble in aqueous systems.

[0154] There is provided a method of treating a viral disease in a human or a mammal or an animal or a bird in need thereof, comprising administering a therapeutically effective amount of a compound of FORMULA I, which is a highly bioavailable and highly permeable solid dispersion (or a solution or suspension thereof), wherein the compound of FORMULA I is obtained by co - processing an API compound with a HOST substance,

[0155] wherein the medical condition or disease or disorder or syndrome of the human is selected from those listed in the International Classification of Diseases and Related Health Problems (including ICD - 9, ICD - 10, ICD - 10 - CM, ICD - 11, ICD - 11 - CM, etc.);

[0156] and / or the medical condition or disease or disorder or syndrome of the human is selected from those listed in the Diagnostic and Statistical Manual of Mental Disorders, including DSM - IV, DSM - 5, DSM - 5 - TR, etc.;

[0157] and / or the medical condition or disease or disorder or syndrome of the human is selected from those starting with MeSH codes C01 - C25 in the Medical Subject Headings;

[0158] and / or the medical condition or disease or disorder or syndrome of the human is selected from the conditions published by the Genetic and Rare Diseases Information Center;

[0159] and / or a medical condition or disease or disorder or syndrome / infection of a human being caused by a virus; including those caused by RNA viruses, DNA viruses, and retroviruses; including those caused by viruses of the domains double-stranded deoxyribonucleic acid viruses, single-stranded deoxyribonucleic acid viruses, adenoviruses, nucleoviruses, riboviruses, variola deoxyribonucleic acid viruses; including those caused by dsDNA viruses, ssDNA viruses, dsRNA viruses, (+)ssRNA viruses, (-)ssRNA viruses, ssRNA-RT viruses, dsDNA-RT viruses; including viral infections or viral diseases caused by viruses of the families Coronaviridae, Flaviviridae, Herpesviridae, Orthomyxoviridae, Paramyxoviridae, Polyomaviridae, Retroviridae, Togaviridae; including viral infections or viral diseases caused by severe acute respiratory syndrome coronavirus, severe acute respiratory syndrome coronavirus 2, dengue virus, West Nile virus, yellow fever virus, Zika virus, bovine alphaherpesvirus 1, influenza A virus, Hendra virus, BK polyomavirus, human immunodeficiency virus type 1, chikungunya virus, forest virus, Sindbis virus, Venezuelan equine encephalitis virus, but not excluding viral infections or viral diseases caused by viruses of other families; including human adenovirus, Junin arenavirus, Lassa virus, lymphocytic choriomeningitis virus, Machupo virus, Pichinde virus, porcine reproductive and respiratory syndrome virus / porcine arterivirus type 1, human astrovirus, hantavirus, Crimean-Congo hemorrhagic fever virus, Dugbe virus, Bunyamwera virus, La Crosse bunyavirus, snowshoe hare bunyavirus, Potosi fever virus, Rift Valley fever virus, Naples phlebotomus fever virus (Toscana virus), Sicilian phlebotomus fever virus, Uukuniemi virus, Norwalk virus, Southampton virus, Sapporo virus, porcine circovirus type 2, human coronavirus, Middle East respiratory syndrome coronavirus, human circovirus, Ebola virus, Lake Victoria Marburg virus, Japanese encephalitis virus, Langat virus, louping ill virus, Saint Louis encephalitis virus, tick-borne Powassan virus, tick-borne encephalitis virus, hepatitis C virus, hepatitis G / hepatitis E 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 alphaherpesvirus 1, equine herpesvirus 1 (EHV-1), pseudorabies virus, rubella virus, influenza B virus, influenza C virus, influenza A virus, Torii virus, human papillomavirus (16, 18), human papillomavirus type 2, human papillomavirus type 1, Nipah virus, measles virus, human parainfluenza virus, mammalian orthopneumovirus 5 (simian virus 5), mumps virus, Newcastle disease virus, adeno-associated virus, human parvovirus B19, encephalomyocarditis virus, picornavirus A type,Coxsackie virus, echovirus, human enterovirus (68, 70), poliovirus, hepatitis A virus, Aichi virus, roseovirus type A, rhinovirus, salivirus type A, human respiratory syncytial virus, JC polyomavirus, KI polyomavirus, Merkel cell polyomavirus, WU polyomavirus, BK polyomavirus, molluscum contagiosum virus, vaccinia virus, horsepox virus, vaccinia vaccine virus, smallpox virus, Yaba monkey tumor virus, Yaba-like disease virus, smallpox, aphthous ulcer virus, rotavirus type A, rotavirus type B, orivirus, Colorado tick fever virus, rotavirus type C, banner virus, human T-lymphotropic virus, human immunodeficiency virus Trapped virus, Eastern chimpanzee simian foamy virus, simian foamy virus, human immunodeficiency virus type 1 / 2, Australian bat rabies virus, Duvenhach virus, Lagos bat virus, Mokola virus, rabies virus, Chandipura virus, Isfahan virus, vesicular stomatitis virus, European bat rabies virus, Bama Forest virus, Eastern equine encephalitis virus, Mayaro virus, Nyongyon virus, Ross River virus, Heron Mountain virus, Western equine encephalitis virus, Rubella virus, Hepatitis D virus, Convoluted toroidal virus, Human rhinovirus, Murray Valley encephalitis virus, Oropok virus, Monkeypox virus, New York virus, Puumala virus, Seoul virus, but conditions caused by other viruses are not excluded;

[0160] The API compound is selected from ivermectin or avermectin and its derivatives (each API has a serial number and an InChIKey, which are indicated in brackets after the API (guest molecule drug) name, first the InChIKey and then the serial number); the API is selected from the following:

[0161] Ivermectin (SPBDXSGPUHCETR-JFUDTMANSA-N or

[0162] AZSNMRSAGSSBNP-ZLRQRZFZSA-N,1); Abamectin A1a

[0163] (AFSHKCWTGFDXJR-SQOHEDJBSA-N,2); Avermectin A1b

[0164] (MNRHCELBXZARFX-OVBDMLLUSA-N,3); Avermectin A2a

[0165] (JVGWUGTWQIAGHJ-DFAYUBCLSA-N,4); Abamectin A2b

[0166] (QUTFLJHOCPQPEW-WUSILSRKSA-N,5); Avermectin B1a

[0167] (AZSNMRSAGSSBNP-XPNPUAGNSA-N,6); Avermectin B1b

[0168] (VARHUCVRRNANBD-PVVXTEPVSA-N,7); Avermectin B2a

[0169] (CWGATOJEFAKFBK-QJDTYEMPSA-N,8); Avermectin B2b

[0170] (ZPAKHHSWIYDSBJ-YAGODIQJSA-N,9) or its racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, hydrate or solvate, or its pharmaceutically acceptable salt or ester, or its prodrug or a mixture thereof;

[0171] The serial number is used to abbreviate the API, and the InChIKey is used to obtain the molecular information of the API. For example, for GUEST3 - "3" is the serial number of the compound Avermectin A1b, and GUEST3 represents Avermectin A1b, whose InChIKey is MNRHCELBXZARFX-OVBDMLLUSA-N. Based on this InChIKey, the molecular information InChI of Avermectin A1b (GUEST3) can be obtained:

[0172] 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;

[0173] Therefore, GUEST1 - GUEST3 represent all guest molecule drugs with serial numbers 1 - 3, namely: GUEST1, GUEST2, GUEST3.

[0174] If the selected API is in the free base form - also includes the medicinal salts, esters or ethers of the base. If the selected API is in the medicinal salt form - also includes the free base of the salt, its medicinal esters or ethers and other medicinal salts of the free base. Also includes its racemates, enantiomers, diastereoisomers, tautomers, polymorphs, pseudopolymorphs, hydrates or prodrugs or mixtures thereof.

[0175] Therefore, the API is selected from GUEST1 - 9.

[0176] The weight of the API is 0.01 - 90% of the total weight of FORMULA I.

[0177] Wherein, the HOST substance is selected from the following (accounting for 10 - 99.99% of the total weight of FORMULA I):

[0178] A. Polymers, oligomers and macrocyclic hosts, mainly organic polymers and oligomers, more mainly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, but not limited to the following:

[0179] A.1. Hemicelluloses, which can be arabinan, arabinogalactan, galactan, glucan, xylan, mannan, fructan, xyloglucan, arabinogalactan, arabinoxylan, glucomannan, galactomannan, galactoglucomannan, Β - glucan, glycogen, their mixtures, but does not exclude other hemicelluloses and their mixtures;

[0180] A.2. Sulfated polysaccharides and oligosaccharides, which can be fucoidan, carrageenan or carrageenans, agaropectin, sea cucumber sulfated polysaccharide (SCSP), chondroitin sulfate, keratan sulfate, their mixtures, but does not exclude other sulfated polysaccharides and oligosaccharides and their mixtures;

[0181] A.3. Polysaccharides and oligosaccharides, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages can be (but not limited to):

[0182] Polysaccharides based on glucose, β-D-glucose, galactose, mannose, arabinose, rhamnose, sucrose, maltose, lactose and their uronic acids, which may be methoxylated or acetylated, and their salts (gums, gum arabic); polyuronic acids and their 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-agar, tragacanth, konjac gum, welan gum, rhodymenan; galacturonic acid-based polysaccharides with rhamnose, arabinose, xylose and fructose and their salts as side chains (pectin, pectinate, calcium pectate); pectin from beet, carrot, pepper, pumpkin, eggplant, sunflower, apple, quince, cherry, plum, pear, citrus, undaria; modified pectin, modified citrus pectin; acidic polysaccharides - i.e. polysaccharides containing carboxyl, phosphate and / or sulfate ester groups; psyllium husk, psyllium seed gum; soybean hemicellulose; galacturonic acid, homogalacturonic acid, polygalacturonic acid and their salts, rhamnogalacturonic acid, rhamnogalactose; callose, fucoidan, chrysolaminarin, thermogel polysaccharide; inulin, guar, dextran, pullulan; agarose, galactooligosaccharides (oligogalactosyl lactose, oligogalactose, oligolactose or trans-galactooligosaccharides), xylooligosaccharides, fructooligosaccharides, isomaltooligosaccharides; alginic acid and its salts alginate, propylene glycol alginate; arabinan, arabic acid and their salts; cellulose, cellulose polymers, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose (HPMC), methyl ethyl cellulose, ethyl hydroxyethyl cellulose, cross-linked sodium carboxymethyl cellulose, carboxymethyl cellulose and its salts; starch, starch, starch 1500G, soluble starch, modified starch, hydroxyethyl starch, cationic starch, acid-treated starch, alkali-modified starch, bleached starch, oxidized starch, enzyme-treated starch, mono starch 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 adipate, acetylated distarch glycerol, distarch glycerol, hydroxypropyl starch, hydroxypropyl distarch glycerol, hydroxypropyl distarch phosphate, hydroxypropyl distarch glycerol, sodium octenyl succinate starch, acetylated oxidized starch; dextrin, maltodextrin, cyclodextrin, starch dextrin, polydextrose; amylopectin, amylose, glycogen; chitosan, chitin; pullulan, glucuronoxylan, methylglucuronoxylan, glycosaminoglycan, mucopolysaccharide, heparin / heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid, hyaluronic acid and their mixtures, but not limited to other polysaccharides and oligosaccharides, hemicellulose, storage polysaccharides, sulfated polysaccharides and oligosaccharides, mucilage and their mixtures;

[0183] A.4. The macrocyclic host can be (but is not limited to): cyclodextrin, cucurbit[n]uril, calix[n]arene, pillararene, crown ether, cyclophane, cryptand;

[0184] B. Substances that may contain large amounts (more than 5% by weight) of polysaccharides and oligosaccharides, hemicellulose, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectin, gums, mucilages, which can be (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 containing large amounts of the substances described in section A, parts of the processed plants or algae or animals or fungi, and mixtures thereof. A common but not limited example is dried brown or red algae, such as kelp or laminaria;

[0185] C. Synthetic polymers, mainly water-soluble polymers, can be (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; polyvinylpyrrolidones; acrylic polymers, cellulose acetate phthalate, copovidone, ethyl oleate, glycerol derivatives, glyceryl triacetate, polyethylene glycol (PEG), PEG derivatives, polymethacrylates, propylene glycol, propylene glycol derivatives, povidone, polyvinylpyrrolidone (PVP), cellulose acetate phthalate (PVAP), hypromellose acetate succinate (HPMCAS), hypromellose acetate succinate (HPMCAS), hypromellose phthalate (HPMCP), cellulose acetate butyrate phthalate, cellulose acetate hydrogen phthalate, cellulose acetate propionate phthalate, cellulose acetate phthalate, cellulose acetate tricarboxylate, hypromellose phthalate, hypromellose acetate, dioxypropylmethylcellulose succinate, carboxymethylethylcellulose, hypromellose 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-50AAS-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-MSDDs, HPMCAS-MG, HPMCP(HP 55), HPMCP-HP55, HPMCPh, hypromellose phthalate HP-50, Imwitor, Imwitor 742, Klucel HPC, Kolhdon 17PF, Kollicoat, Kollicoat IR, Kollicoat MAE, Kollicoat MAE 100, Kollicoat MAE 100P,Kollicoat Protect, Kollidon (Povidone), Kollidon 12pf, Kollidon 12 / 17PF, Kollidon 30, Kollidon 30 / 90, Kollidon90, Kollidon CL-F, Kollidon CL-SF, Kollidon K30, Kollidon SR, Kollidon SR, Kollidon SR (PVAc), Kollidon V64 / Fine, Kollidon VA 64, Kollidon VA 64 (Copovidone), Kollidon VA64, Kolliphor, Kolliphor EL, Kolliphor EL / ELP, Kolliphor HS15, Kolliphor P 188, Kolliphor P188 / 407, Kolliphor P 188 / micro, Kolliphor P 407, Kolliphor P 407 / micro, Kolliphor PS20, Kolliphor PS 60, Kolliphor PS 80, Kolliphor RH 40, Kolliphor SLS, Kolliphor SLS / fine, Kollisolv, Kollisolv GTA, Kollisolv PEG 1450, Kollisolv PEG 300, Kollisolv PEG 3350, Kollisolv PEG 400, Kollisolv PEG E 300, Kollisolv PEG E 400, Kollisolv PEG grade (Polyethylene Glycol), Kolliwax, Kolliwax GMS II, Kolliwax SA, Labrasol, Lactose 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 SDDs, PVP-VA, PVP-VA 64,PVP-VA SDD, palm stearyl polyester amide (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), polyethylene oxide (PEO) (3400, 10000, 20000), polyethylene glycol stearate, Shin-Etsu AQOAT, Soluplus, Solutol, sucrose laurate, tocopheryl polyethylene glycol 1000 succinate (TPGS), vitamin E TPGS, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), isomaltitol (Galen IQ 810), but other synthetic polymers and their mixtures are not excluded;

[0186] D. The polyol can be (but is not limited to): ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, heptitol, isomaltitol, maltitol, lactitol, maltotriitol, maltotetraitol, polymannitol and their mixtures.

[0187] E. The glycoside can be glucose, β-D-glucose, galactose, mannose, arabinose, rhamnose, sucrose, maltose, lactose, L-ribose and their mixtures;

[0188] F. The surfactant can be (but is not limited to): anionic surfactants containing anionic functional groups in their heads, such as sulfates, sulfonates, phosphates, carboxylates, carboxylate-based fluorosurfactants, cationic surfactants, primary, secondary or tertiary amines, permanently charged quaternary ammonium salts, amphoteric (zwitterionic) surfactants, amphoteric surfactants with a cationic moiety based on primary, secondary or tertiary amines or quaternary ammonium cations, betaines, phospholipids, amphoteric surfactants of the tertiary amine oxide structural type, nonionic surfactants, ethoxylates, fatty alcohol ethoxylates, alkylphenol ethoxylates (APEs or APEOs), fatty acid ethoxylates, special ethoxylated fatty esters and oils, ethoxylated amines and / or fatty acid amides, 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 polyglycosides, ammonium lauryl sulfate, sodium lauryl sulfate, sodium dodecyl sulfate, sodium laureth sulfate, sodium lauryl polyoxyethylene ether sulfate, laureth sulfate, Triton (sodium dioctyl sulfosuccinate) and its salts, perfluorooctane sulfonates (PFOS), perfluorobutane sulfonates, alkylaryl ether phosphates, alkyl ether phosphates, sodium stearate, sodium lauroyl sarcosinate, perfluorononanoates, perfluorooctanoates, octenidine dihydrochloride, cetyltrimethylammonium bromide (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyloctadecylammonium chloride, octadecyl dimethylammonium bromide (DODAB), CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate), coconut amidopropyl hydroxysultaine, cocamidopropyl betaine, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, sphingomyelin, lauryldimethylamine oxide, myristamine oxide, narrow range ethoxylates, octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether, nonoxynol, polyethylene glycol monooctyl phenyl ether, polyethoxylated tallow amine, coconut amide monoethanolamine, coconut amide diethanolamine, poloxamer, glycerol monostearate, monoglyceryl laurate, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, Tween, Tween 20, Tween 40, Tween 60, Tween 80, decyl glucoside, Span, Span 20, Span 40, Span 80, dodecyl glucoside, octyl glucoside, poloxamer, poloxamer 188, poloxamer 407, polyethylene glycol stearate, myrj 52, deoxycholic acid, bile acids, pluronic, pluronic F-127, pluronic P85, pluronic f68, gelucire, gelucire 44 / 14, lecithin, polysorbates, polysorbate 80, plasdone-s630, pluronic-f68, inutecsp1, Compritol 888ato, tocopheryl polyethylene glycol succinate, polyoxyethylated castor oil, polyoxyethylated glyceryl esters, lauroyl diglycerides, and mono- and di-fatty acid esters of low molecular weight polyethylene glycols and mixtures thereof;

[0189] G. Acids and salts based on these acids can be (but are not limited to): citric acid, tartaric acid, succinic acid, phosphoric acid, amino acids, acetate, sodium acetate anhydrous, alginate, sodium alginate, glycyrrhizic acid and its salts and mixtures;

[0190] H. Oxides and salts based on these oxides can be (but are not limited to): silica, silicate, titanium dioxide and mixtures thereof;

[0191] I. Copolymers of the polymers listed in paragraphs A and C, including alternating copolymers, random copolymers, block copolymers, graft copolymers, crosslinked modifiers, and these copolymers can include (but are not limited to):

[0192] Methacrylic acid-ethyl acrylate copolymer; methacrylic acid copolymer; vinyl pyrrolidone-vinyl acetate copolymer (PVPVA); polyvinyl polyvinyl pyrrolidone (PVPP); PVA-PEG graft copolymer; HPMC and PVA-PEG graft copolymer; graft copolymer of polyvinyl pyrrolidone-arabinogalactan; graft copolymer having a) poly(vinyl acetate) and / or poly(vinyl alcohol) and / or poly(vinyl chloride) and poly(vinyl ester) on the polymer chain of b) polyethylene glycol, polyalkylene glycol, polypropylene glycol, polyisobutylene glycol or polymethylpentanediol; graft copolymer having polyvinyl acetate and / or hydrolyzed polyvinyl acetate (polyvinyl alcohol) groups on polyalkylene oxide (preferably polyethylene oxide); vinyl pyrrolidone-vinyl acetate copolymer; vinyl pyrrolidone-vinyl acetate copolymer-64+; vinyl pyrrolidone-vinyl acetate VA 64; polymethacrylate-based copolymers including anionic, cationic and neutral copolymers based on methacrylic acid and methacrylic acid / acrylate and their salts, esters or other derivatives and mixtures thereof;

[0193] J. Methoxylated, ethoxylated, esterified, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, decarboxylated, amide, oxidized, sulfated, amino acid derivatives, fermented, thermally modified, chemically modified, acid-modified derivatives and their esters and ethers, salts and any other chemical derivatives and mixtures thereof of the substances specified in A-I;

[0194] K. Any combination of the substances specified in items A-J;

[0195] Among them, the combined treatment method is selected from the following methods (but not limited to other methods, and these methods should result in the formation of a solid dispersion with high bioavailability):

[0196] Method 1 (High-energy stress grinding or milling; mechanochemical method): "API" and "host substance" are ground in a roller, ball, planetary, vibration, jet, drum, medium-speed, impact jet, centrifugal countercurrent, rotary, disintegrator and other types of mills or other grinders. The grinding process can produce particles, mainly sized from 1 to 1000 microns, which are powders. The grinding should be carried out to a state where the structure and properties of the ground substance are changed to increase its bioavailability and permeability and to form a highly bioavailable and highly permeable solid dispersion. The grinding should cause structural changes such as defects, increased deformation, and aggregates. During the grinding process, solid-phase fusion, mechanical synthesis, and mechanochemical activation processes must occur, including the formation of microcomposites, in which the mechanochemical solid-phase fusion, mechanical synthesis, and mechanochemical activation processes of the API substance and the host substance have occurred. When the components are mixed, reactions occur in the solid phase to form a product with a high contact surface and an extremely high concentration of various defects.

[0197] Solvents, such as organic and inorganic solvents, may be added during the grinding process, and may include (but are not limited to):

[0198] Water, hydrocarbons and their halogen derivatives, alcohols, esters and ethers, ketones, nitro compounds: 1,1,1-trichloroethane; 1,1,2-trichloroethylene; 1,1-dichloroethylene; 1,2-dichloroethane; 1,2-dichloroethylene; 1,2-dimethoxyethane;1,2 - propylene glycol, 1,4 - dioxane, n - butanol, 1 - pentanol, n - propanol, sec - butanol, 2 - butanone, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, 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, tribromomethane, bromooctane, butanol, butanone, butyl acetate, butylbenzene, carbon disulfide, carbon tetrachloride, carbon tetrachloride, ethylene glycol monoethyl ether acetate, acetic acid, chlorobenzene, chloroform, chloroform, chlorohexane, cumene, cyclohexane, cyclohexanol, cyclohexanone, cyclopentane, cyclopentanes, decalin, decane, decanol, dibromoethane, dibutyl ether, dichlorobenzene, difluorobenzene, dichloroethane, dichloromethane, diethylene glycol, diethyl ether, diethylene glycol dimethyl ether, isopropyl ether, ethylene glycol dimethyl ether, dimethyl acetate, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, dimethylpyridine, dimethyl sulfoxide, dioxane, dioxane (1,4 - dioxane), dodecane, esters, ethyl tert - butyl ether, ethylene glycol, ethanol, ethers, phenetole, ethyl acetate, ethyl acetoacetate, ethanol, ethyl acetate, ethylbenzene, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, ethylene glycol monobutyl ether, ethylene glycol, diethyl ether, ethyl formate, fluorobenzene, fluorooctane, formamide, formic acid, freon, furfural, glacial acetic acid, glycerol, ethylene glycol ethers, halogenated benzenes, n - heptane, heptanes, heptanol, hexadecane, iodohexadecane, hexamethylphosphoramide, tris(dimethylamino)phosphine (hmpt), n - hexane, isohexane, hexanol, isopentanol, iodobenzene, isobutanol, isobutyl acetate, isooctane, isopropanol, isopropyl acetate, cumene, cymene, m - cresol, mesitylene, formic acid, methanol, methoxyethanol, methyl acetate, methyl ethyl ketone, methyl tert - butyl ether, methyl tert - butyl ether, methyl butyl ketone, methylcyclohexane, dichloromethane, methyl ethyl ketone, N - methylformamide, methyl isobutyl ketone, miscellaneous solvents, chlorobenzene, morpholine, m - xylene, N,N - dimethylacetamide, N,N - dimethylformamide, n - pentanol, n - butyl acetate, nitrobenzene, nitroethane, nitromethane, N - methyl - 2 - pyrrolidone (nmp), N - methylpyrrolidone, n - octanol, nonane, nonanol, octane, octanol, o - dichlorobenzene, o - nitrotoluene, o - xylene, pentadecane, n - pentane, pentane, pentanol, perchloroethylene, perfluorobenzene, naphtha, phenol, phenyl ether, propanol, propoxypropane, propyl acetate, propylene glycol monomethyl ether, p - xylene, pyridine, sec - butanol, sec - butylbenzene, sulfolane, tert - butanol, tert - butanol, tert - butylbenzene, tert - butyl methyl ether, tetrachloroethane, tetrachloroethylene, carbon tetrachloride, tetrahydrofuran, tetrahydrothiophene dioxide, tetralin, toluene, tributyl phosphate, trichloroethane, trifluorotoluene, trichloroethylene, triethylamine, trimethylbenzene, trimethylpentane, undecane, xylene, xylenes, 2,2,4 - trimethylpentane and its mixtures;

[0199] Method 2 (High-energy stress grinding or milling with solvent; mechanochemical method with solvent): The "API" and "host substance" are wetted with a solvent, the wetted material is dried, and then ground in the same manner as in Method 1. The list of solvents used is the same as the solvents listed in Method 1;

[0200] Method 3 (Media milling method): A high-shear media mill is used to prepare the solid dispersion. The grinding chamber containing the grinding media, solvent, "API", and "host substance" is rotated at a very high shear rate at a controlled temperature. The grinding media consists of glass, zirconia, highly cross-linked polystyrene resin, or other standard grinding media. The high-energy shear force is generated due to the impact of the grinding media with the "API" and "host substance". The list of solvents used is the same as the solvents listed in Method 1;

[0201] Method 4 (Kneading method): This method is based on impregnating the "host substance" with a small amount of water or a water-alcohol solution to convert it into a paste. Then the "API" is added to the above paste and kneaded for a specified period of time. Then the kneaded mixture is dried and sieved as required. At the laboratory scale, kneading can be carried out using a mortar and pestle. At the large scale, kneading can be carried out using an extruder and other machines;

[0202] Method 5 (Hot melt method, melting method, fusion method): In this method, a physical mixture of the "API" and "host substance" is directly heated until both are melted. Then the molten mixture is rapidly cooled and solidified by vigorous stirring. The final solid mass is then crushed, pulverized, and sieved. The melting method involves melting the "API" within the "host substance" and then cooling and pulverizing the resulting product. Common modifications in the melting stage include suspending the "API" in the pre-melted "host substance" instead of using the "API" and "host substance" in the molten state, thereby reducing the process temperature. To cool and solidify the molten mixture, several processes are employed, such as stirring in an ice bath, coating on a thin stainless steel layer and then passing through a cold air stream, solidifying on a petri dish at room temperature in a desiccator, coating on dry ice, immersion in liquid nitrogen, or storing in a desiccator or other cooling methods. After cooling, the mixture must be pulverized for processing. Dispersion techniques can also be used;

[0203] Method 6 (Hot melt extrusion method, hot-stage extrusion method): Hot melt extrusion is a modification of the melting method. Hot melt extrusion is essentially the same as the melting method, except that intense mixing is introduced through an extruder. Hot-stage extrusion involves extruding the pre-mixed "API" and "host substance" at the melting temperature for a short period of time at a high rotational speed. Then the resulting product is collected and ground after cooling at room temperature. By combining hot-stage extrusion with the use of carbon dioxide as a plasticizer, the processing temperature can be reduced;

[0204] Method 7 (Meltrex method): Meltrex is an improvement of the melting method. Meltrex is a patented solid dispersion manufacturing process based on a melting process. The key elements of the Meltrex technology are the use of a special twin-screw extruder and the presence of two independent hoppers, the temperatures of which can vary over a wide temperature range;

[0205] Method 8 (molten aggregation method): Molten aggregation is an improvement of the melting method. Molten aggregation allows the preparation of solid dispersions in a conventional high-shear mixer. This step is completed by adding the molten "API" containing "host substance" to the heated excipient, or adding the molten "host substance" to the heated mixture of "API" and excipient, or heating the mixture of "API", "host substance" and excipient to a temperature within or above the melting range of the "host substance". Stable solid dispersions can also be produced by the molten aggregation method in a rotary processor;

[0206] Method 9 (high-pressure homogenization): In this method, a suspension of "API" and "host substance" passes through the microporous or sub-microporous valve of a high-pressure homogenizer under pressure;

[0207] Method 10 (solvent evaporation method): In this method, "API" and "HOST substance" are dissolved in a common solvent, and then the solvent is evaporated to produce a solid solution. The basic process for preparing or manufacturing such solid dispersions includes dissolving "API" and the polymer "host substance" in a common solvent or solvent mixture (the list of solvents used is the same as the solvents in Method 1). Usually, the resulting film is crushed and / or ground. A partially suspended rather than dissolved "host substance" can also be used. Solvent evaporation procedures usually include vacuum drying, heating the mixture on a hot plate, slowly evaporating the solvent at a low temperature, using a rotary evaporator, a nitrogen stream or other drying procedures;

[0208] Method 11 (spin coating film method): The spin coating film method is a modified version of the solvent evaporation method, which includes dissolving "API" and "HOST substance" in a common solvent, and then dropping it on a clean substrate rotating at a high speed. The solvent evaporates during rotation;

[0209] Method 12 (spray drying method): Spray drying is a modified version of the solvent evaporation method. The process includes dissolving or suspending "API" and "host substance", and then spraying it into a heated gas stream to remove the solvent;

[0210] Method 13 (Supercritical Fluid (SCF) Process): The supercritical fluid process is a modified version of the solvent evaporation method. In this method, the "API" particles are dissolved in an SCF (usually carbon dioxide). Several SCF processing methods can be used to address individual aspects, such as the compressed antisolvent process (PCA), SCF solution enhanced dispersion (SEDS), supercritical antisolvent process (SAS), rapid expansion of supercritical solutions (RESS), gas antisolvent recrystallization (GAS), and aerosol supercritical extraction system (ASES). In the modification of this method, the technique involves dissolving the "API" and "HOST substance" in a common solvent and introducing them simultaneously with CO2 through a nozzle into a particle formation vessel. When the solution is sprayed, the solvent is rapidly extracted by the SCF, causing solid dispersion particles to precipitate on the walls and bottom of the vessel;

[0211] Method 14 (Cryogenic Technology): The cryogenic method is a method of dissolving the "API" and "HOST substance" in a common solvent prior to a cryogenic solvent evaporation procedure. The common solvent can be the same as in the solvent evaporation method. The solution can be frozen after injection. The injection device can be a capillary, rotary, pneumatic, ultrasonic nozzle, or other type of injection device. The position of the nozzle can be above or below the cryogenic liquid surface. The composition of the cryogenic liquid can be hydrofluoroalkane, fluorocarbon, N2, Ar, O2, organic solvent, or other types of cryogenic liquids. After cryogenic treatment, dry powder can be obtained through various drying processes such as spray freeze-drying, atmospheric freeze-drying, vacuum freeze-drying, lyophilization, or other cryogenic drying processes. The list of common solvents used is the same as the solvents in Method 1;

[0212] Method 15 (Lyophilization / Freeze-Drying Technology): The lyophilization method is a modification of the cryogenic technology. In this technology, the common solvent in the solution is removed by primary freezing and subsequent drying of the solution containing the "API" and "HOST substance" under reduced pressure. The basic freeze-drying process involves dissolving the "API" and "HOST substance" in a common solvent and then immersing it in a cryogenic liquid until it is completely frozen. Then, the frozen solution is further lyophilized;

[0213] Method 16 (Spray Freezing onto a Cryogenic Liquid): This method is a modification of the cryogenic technology. In this technology, the "API" and "HOST substance" are dissolved in a common solvent and atomized onto the surface of a boiling and agitated cryogenic liquid refrigerant;

[0214] Method 17 (Spray Freezing into a Cryogenic Liquid (SFL)): This method is a modification of the cryogenic technology. It combines direct liquid-liquid impingement (through spraying) between the solution and the cryogenic liquid to provide intense droplet atomization. Then, the frozen particles are lyophilized to obtain dry and free-flowing micropowder;

[0215] Method 18 (Spray Freezing into Vapor above Liquid (SFV / L)): This method is a modification of cryogenic technology. The “API” solution is frozen in the cryogenic liquid vapor and then the frozen solvent is removed. During the SFV / L process, the atomized droplets usually start to freeze in the vapor phase before contacting the cryogenic liquid. When the solvent freezes, the “API” becomes supersaturated in the unfrozen regions of the atomized droplets;

[0216] Method 19 (Ultra-rapid Freezing): This method is a modification of cryogenic technology. The “API” solution is applied to the solid surface of a cryogenic substrate, resulting in instant freezing and subsequent lyophilization;

[0217] Method 20 (Precipitation Technique, Co-precipitation Method): In the precipitation method, the “API” is dissolved in a solvent and then added to a non-solvent to precipitate the crystals. While stirring continuously, the non-solvent is dropped into the solution of “API” and “HOST Substance”. During the addition of the non-solvent, the “API” and “HOST Substance” co-precipitate to form microparticles. Finally, the resulting microparticle suspension is filtered and dried. The list of solvents used is the same as those listed in Method 1.

[0218] Method 21 (Microwave Radiation Method): This method involves a microwave radiation reaction between the “API” and the complexing agent using a microwave oven. The “API” and “HOST Substance” are dissolved in a mixture of water and / or organic solvents in a certain proportion to a container at a certain molar ratio. The mixture reaction is carried out in a microwave oven. After the reaction is completed, an appropriate amount of solvent mixture is added to the above reaction mixture to remove the remaining uncomplexed free “API” and “HOST Substance”. The resulting precipitate is separated by filtration and dried. The list of solvents used is the same as those listed in Method 1.

[0219] Method 22 (Energy Input Method): This method includes exposing the HOST Substance and the “API” to energy input until a highly bioavailable and highly permeable solid dispersion is formed in which the “API” is trapped as an amorphous material in the HOST Substance.

[0220] Method 23 (Thermal / Shear Energy Input Method): This method includes exposing the HOST Substance and the “API” to energy input, where the energy input is heat and / or shear force, until a highly bioavailable and highly permeable solid dispersion is formed in which the “API” is trapped as an amorphous material in the HOST Substance.

[0221] Method 24 (Combination Method): This method includes any combination of Methods 1 - 23.

[0222] Methods 1 - 24 should result in the formation of highly bioavailable solid dispersions.

[0223] In another aspect, there is provided a method for treating a disease (a human disease or a mammalian, animal or avian disease), which comprises administering a therapeutically effective amount of a compound of FORMULA II (and its solutions, gels, colloids, sols, etc.), which compound 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, wherein the compound of FORMULA I is obtained by co-processing an API compound with a HOST substance,

[0224] wherein 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 in the aforementioned method (the same as in (III.I. section));

[0225] wherein the API compound is selected from GUEST1-9 (the same API as selected in the method of (III.I. section));

[0226] wherein the molecular information of the non-covalent complex of FORMULA II is encoded by the formula (the non-covalent complex of FORMULA II is):

[0227] [GUEST]k[HOST]n(SOLVENT)m

[0228] where k is from 1 to 100;

[0229] where m is from 1 to 10000;

[0230] where n is from 1 to 10000;

[0231] wherein the molecular information of GUEST is based on the InChI representation derived from the InChIKey, indicating the InChIKey of each API in parentheses after the API name, at the first position before the serial number (in (III.I. section)). The molecular information of the API compound can be used alone or, on this basis, the molecular information of pharmaceutically acceptable salts, esters, ethers, free bases, and other pharmaceutically acceptable salts of the free base can be obtained by a person skilled in the art;

[0232] wherein the molecular information of HOST represents the molecular information of the polymer monomer; or the smallest representable part of the copolymer chain (defining the copolymer); or a compound selected from the HOST substance at the molecular level (if the HOST substance does not exist in polymer form) and can be obtained by a person skilled in the art;

[0233] wherein the molecular information of SOLVENT is H2O if the solvent is water, but other physiologically acceptable solvents can also be used, and the molecular information can be obtained by a person skilled in the art;

[0234] Figure 1 shows an example of the chemical formula of a FORMULA II non-covalent complex based on abamectin B1a and pectin.

[0235] In another aspect, a method for treating a disease is provided, wherein the solid dispersion of FORMULA I is encoded by the following formula (the solid dispersion of FORMULA I is):

[0236] GUESTk HOSTn

[0237] where k is 0.0001 - 0.9 and n is 0.1 to 0.9999, and the solid dispersion is a C-C type, C-A type, A-C type, A-A type, M-C type, M-A type solid dispersion containing one, two or more phases (single phase or phase mixture).

[0238] In another aspect, solid dispersions, non-covalent complexes, polymer complexes and biopolymers can be obtained by other methods when energy is supplied in other ways, such as (but not limited to) electromagnetic radiation, heat, mechanical action, sound, or in any way described in scientific and patent literature. As a non-limiting example, examples of exposure to mechanical and acoustic effects are given. A non-covalent complex obtained by the interaction of an aqueous solution of a HOST substance and an API under mechanical acoustic and ethanol precipitation conditions. The mechanical acoustic effect can be carried out at a rotor speed of 100 - 10000 rpm in a rotary pulsation device.

[0239] In another aspect, it is possible to use various other combination methods described in scientific and patent literature to obtain solid dispersions and non-covalent complexes, polymer complexes and biopolymers. As a non-limiting example, the HOST substance is placed in a flask and completely dissolved in ethanol. Then the API is added to the flask. Water is slowly added and stirred on a magnetic stirrer at 40 - 80 °C for several hours. Then the alcohol part is treated under vacuum on a rotary evaporator. The water part is dried by a freeze dryer.

[0240] In another aspect, a method for treating viral diseases is provided, wherein any form of solid dispersion, non-covalent complex, polymer complex and biopolymer described in scientific and patent literature, and obtained by any method described in scientific and patent literature.

[0241] In another aspect, a method for treating any viral disease caused by any virus is provided.

[0242] Another aspect provides a pharmaceutical dosage form of FORMULA I, which has enhanced bioavailability and permeability, and is characterized in that it comprises a highly bioavailable and highly permeable solid dispersion or its aqueous solution or suspension, wherein the compound of FORMULA I is obtained by co-processing "API" with a HOST substance.

[0243] Wherein the list of API compounds, the list of HOST substances, and the co-processing method are the same as those in part (III.I.).

[0244] Another aspect provides a pharmaceutical dosage form of FORMULA II (as well as its solutions, gels, colloids, sols, etc.), which is a highly bioavailable and highly permeable non-covalent complex obtained by adding a solvent to the highly bioavailable and highly permeable solid dispersion of FORMULA I, wherein the compound of FORMULA I is obtained by co-processing an API compound with a HOST substance.

[0245] Wherein the solvent is usually water, and the molecular information of the solvent is H2O, but other physiologically acceptable solvents or their mixtures can also be used;

[0246] Wherein the list of API compounds, the list of HOST substances, the co-processing method, and the molecular information of the non-covalent complex of FORMULA II are the same as those in part (III.II.).

[0247] Another aspect provides a method for preparing or manufacturing a pharmaceutical dosage form of FORMULA I, which has enhanced bioavailability and permeability, and is characterized in that it comprises a highly bioavailable and highly permeable solid dispersion or its aqueous solution or suspension, wherein the compound of FORMULA I is obtained by co-processing "API" with a HOST substance.

[0248] Wherein the list of API compounds, the list of HOST substances, and the co-processing method are the same as those in part (III.I.).

[0249] Another aspect provides a method for preparing or manufacturing a pharmaceutical dosage form of FORMULA II, which has a highly bioavailable and highly permeable non-covalent complex, obtained by adding a solvent to the highly bioavailable and highly permeable solid dispersion of FORMULA I, wherein the compound of FORMULA I is obtained by co-processing an API compound with a HOST substance.

[0250] Wherein the solvent is usually water, and the molecular information of the solvent is H2O, but other physiologically acceptable solvents or their mixtures can also be used;

[0251] The API compound list, HOST substance list, combined treatment method, and molecular information of the non-covalent complex of FORMULA II are the same as those in section (III.II.).

[0252] The pharmaceutical dosage form can be used for a wide range of active pharmaceutical or bioactive compounds with low water solubility and dissolution rate, covering the following categories: angiotensin-converting enzyme inhibitors, adenohypophyseal hormones, adrenergic nerve blockers, adrenocortical steroids, adrenocortical steroid biosynthesis inhibitors, α-adrenergic agonists, α-adrenergic antagonists, selective α2-adrenergic agonists, analgesics, antipyretics and anti-inflammatory drugs, androgens, anesthetics, anti-addiction agents, anti-androgens, antiarrhythmic drugs, anti-asthma drugs, anticholinergics, anticholinesterases, anticoagulants, antidiabetic drugs, antidiarrheals, antidiuretics, antiemetics and prokinetics, antiepileptic drugs, anti-estrogens, antifungal drugs, antihypertensive drugs, antimicrobials, anti-migraine drugs, antimuscarinics, antineoplastic drugs, antiparasitic drugs, anti-Parkinson drugs, antiplatelet drugs, antiprogesterones, antithyroid drugs, antitussives, antiviral drugs, atypical antidepressants, azaspirodecanediones, barbiturates, benzodiazepines classes, benzothiadiazines, β-adrenergic agonists, β-adrenergic antagonists, selective β1-adrenergic receptor antagonists, selective β2-adrenergic receptor agonists, bile salts, drugs affecting body fluid volume and composition, butyrophenones, drugs affecting calcification, calcium channel blockers, cardiovascular drugs, catecholamines and sympathomimetics, cholinergic receptor agonists, cholinesterase reactivators, dermatological drugs, diphenylbutylpiperidines, diuretics, ergot alkaloids, estrogens, ganglionic blockers, ganglionic stimulants, hydantoins, drugs for gastric acid control and peptic ulcer treatment, hematopoietic drugs, histamine, histamine antagonists, 5-hydroxytryptamine antagonists, drugs for treating hyperlipoproteinemia, hypnotics and sedatives, immunosuppressants, laxatives, methylxanthines, monoamine oxidase inhibitors, neuromuscular blockers, organic nitrates, opioid analgesics and antagonists, pancreatic enzymes, phenothiazines, progesterones, prostaglandins, drugs for treating mental disorders, retinoids, sodium ion channel blockers, drugs for treating spasm and acute muscle spasm, succinimides, thioxanthenes, thrombolytics, thyroid drugs, tricyclic antidepressants, organic compound tubular transport inhibitors, drugs affecting uterine motility, vasodilators, vitamins, etc., used alone or in combination. Although this list is exhaustive, it is not intended to cover all types.

[0253] III. Combination therapy

[0254] The compositions of the present invention can also be used in combination with other active ingredients. Non-limiting examples of these other active therapeutic agents include niclosamide, remdesivir, nitazoxanide, chloroquine, lopinavir, ritonavir, hydroxychloroquine, and mixtures thereof. The compounds and compositions of the present invention are also intended for the comprehensive care of patients' diseases, including nutrition, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory drugs (such as ibuprofen), analgesics, and drugs for other common diseases in the patient population, such as antimalarials (including artemether and artesunate-fluorfenuramide combination therapy), typhoid (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or shigellosis.

[0255] Any compound of the present invention can also be combined with one or more additional active therapeutic agents in a unified dosage form for simultaneous or sequential administration to a patient. The combination therapy can be administered as simultaneous or sequential dosing. In the case of sequential dosing, the combination therapy can be administered by two or more injections.

[0256] The combined administration of a compound of the present invention with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of a compound of the present invention with one or more other active therapeutic agents such that a therapeutically effective amount of the compound of the present invention and one or more other active therapeutic agents is present in the patient's body simultaneously.

[0257] Co-administration includes administering a single dose of a compound of the present invention before or after administering one or more other active therapeutic agents, for example, administering a compound of the present invention within seconds, minutes, or hours after administering one or more other active therapeutic agents. For example, a single dose of a compound of the present invention can be administered first, and then a single dose of one or more other active therapeutic agents can be administered within seconds or minutes. Alternatively, a single dose of one or more other therapeutic agents can be administered first, and then a single dose of a compound of the present invention can be administered within seconds or minutes. In some cases, it may be necessary to administer a single dose of a compound of the present invention first, and then, after several hours (e.g., 1 - 12 hours), administer a single dose of one or more other active therapeutic agents. In other cases, it may be necessary to administer a single dose of one or more other active therapeutic agents first, and then, after several hours (e.g., 1 - 12 hours), administer a single dose of a compound of the present invention.

[0258] Combination therapies can provide “synergy” and “synergistic effects”, i.e., when the active ingredients are used together, the effect achieved is greater than the sum of the effects when these compounds are used alone. Synergistic effects can be achieved when the active ingredients (1) are combined and administered or delivered simultaneously in a combination drug; (2) are delivered alternately or in parallel as separate drugs; or (3) by other regimens. When the drugs are used alternately, synergistic effects can be achieved when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or in separate syringes for different injections. Generally, in alternation, the effective doses of each active ingredient are administered sequentially, i.e., continuously, while in combination therapy, the effective doses of two or more active ingredients are administered together. A synergistic antiviral effect means an antiviral effect that exceeds the pure additive effect of the individual compounds in the combination.

[0259] Kits containing compounds of FORMULA I-V are also provided. In some embodiments of the present invention, a single kit is provided, containing compounds selected from each of the formulas provided herein, and each of its subgroups and embodiments, including FORMULA II, FORMULA II, FORMULA IV, FORMULA V. In one aspect, the kit includes a compound of FORMULA I. Each individual kit described herein may include a label and / or instructions for administering to a subject in need (e.g., a human) to treat a disease or disorder. In some embodiments of the present invention, the disease or disorder is a human viral infection. In other embodiments of the present invention, each individual kit may further contain instructions for administering additional pharmaceutical agents in combination with the compound of FORMULA I to treat a disease or disorder in a subject in need (e.g., a human). In some embodiments of the present invention, the disease or disorder is a human viral infection. In each embodiment provided herein, there is also an embodiment in which the kit includes separate dosage units of the compounds described. Examples of separate dosages may include tablets, tablets, capsules, prefilled syringes or syringe cartridges, intravenous infusion bags, etc., each containing a therapeutically effective amount of the relevant compound. In some embodiments, the kit may contain a single dosage unit, while in other embodiments, the kit may contain multiple dosage units, e.g., the number of dosage units required for a particular regimen or period.

[0260] In certain embodiments, the product container can be a vial, jar, ampoule, prefilled syringe, blister pack, tin can, bottle, box or intravenous infusion bag.

[0261] Furthermore, certain embodiments of the present invention provide the use of a compound selected from each of FORMULA I-II herein in the preparation of a medicament for treating human diseases.

[0262] In another embodiment, the method comprises administering a therapeutically effective amount of a combined pharmaceutical preparation (FORMULA III), which comprises:

[0263] a) a first pharmaceutical composition comprising a compound of FORMULA I-II (0.01-99.99% of the total weight of FORMULA III), and

[0264] b) a second pharmaceutical composition comprising at least one additional therapeutic agent against an infectious virus, or an agent that enhances 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 enhances the stability of the FORMULA I-II component (0.01-99.99% of the total weight of the composition), which may include (but is not limited to):

[0265] (-)-Carbavir; (-)-Carbovir triphosphate; (-)-Epicatechin; (-)-Epicatechin gallate; (+)-12-Oxocannanolide A; (+)-Catechin, Catechol, Catechuic acid, Pyrocatechol; (+ / -)-Trans-U-50488 mesylate; (5E)-2-Amino-5-(furan-2-ylmethylene)-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]triazin-5,7-dione; 1,3-Diphenylguanidine; 1,4-Tetramethylenediamine; 1,4-Dicaffeoylquinic 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-Benzothiazolyl-N-morpholinyl sulfide; 2-(Sec-butyldithio)-1H-imidazole; 2,3,5,6-Tetrakis(furan-2-yl)pyrazine; 2',3'-Dideoxy-3'-thiacytidine; 2',3'-Dideoxyadenosine; 2,3-Bis(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-methyl-9H-xanthen-3-one; 2-[(E)-2-(Furan-2-yl)vinyl]quinoline; 2-[2-(4-Nonylphenoxy)ethoxy]ethanol; 20R-Dexycamptothecin; 2-Aminophenanthrene-9,10-dione; 2be2; 2'-C-Methyladenosine; 2'-C-Methylcytidine; 2'-C-Methylguanosine; 2-Deoxy-2,3-dehydro-N-acetylneuraminic acid; 2'-Deoxy-2'-fluoro-2'-C-methylcytidine; 2'-Deoxy-5-[(3-pyrenyl)ethynyl]uridine; 2'-Deoxycytidine; 2'-Deoxyguanosine monohydrate; 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-Thiophene-2-carboxylic acid; 3-Ethyl-2-[3-(3-ethyl-3H-benzothiazol-2-ylidene)-2-methylprop-1-enyl]benzothiazolium iodide; 3,3'-Diindolylmethane;3,4,5,6-Tetramethylphenanthrene-9,10-dione; 3,6-Propanediamine, sulfate (2:1); 3,6-Bis(furan-2-yl)-1,2,4,5-tetrazine; 3-Anilino-6-bromo-isoindole; 3'-Azido-2',3'-dideoxyguanosine; 3-Phenylsulfonyl-5-chloroindole-2-carboxamide; 3gi5; 3-m-Hydroxybenzoic acid; 3-Methyl-cyclic sulfonate-d4TMP; 4-(4-Methylanilino)-1,2-naphthoquinone; 4',6-Dichloroflavan; 4,7-Epoxyhexahydro-3a,7a-dimethylisobenzofuran-1,3-dione; 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; 2'-Deoxy-4'-C-ethynyl-2-fluoroadenosine; 4-p-Hydroxybenzoic acid; 4-p-Methoxyphenol; 4-Methyl-DCK; 4-Morpholino-1,2-naphthoquinone; 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; 6-119-19-7; 6-Azauridine; 6-Benzyl-1-benzyloxymethyl-5-isopropyluracil; 6-Hydroxydopamine hydrobromide; 6-Methyl-2-(phenylazo)-3-pyridinol; 7-[6-(Benzimidazol-1-yl)hexyloxy]chromen-2-one; 7-Amino-6-methoxy-2-methyl-5,8-quinolinedione; 7-Aminocephalosporanic acid; 7-Deaza-2'-C-ethynyl-adenosine; 7-Deaza-2'-C-methyladenosine; 7-Ethyl-10-hydroxycamptothecin; 8-Aminoquinoline-5,6-dione; 8-Hydroxy-2-methylquinazolin-4(3H)-one; 8-Hydroxyquinoline;

[0266] 8-OH-Dpat (8-Hydroxy-2-(dipropylamino)tetralin); 9,10-Phenanthrenequinone; 9-Aminoacridine; 9-Aminocamptothecin;

[0267] 9VR1J6U4XG; A43D; A-790742; A-837093; Abacavir; AG221 Mesylate; Epalrestat; ABT-072; Abt-737; Abt-751; Acetazolamide; Acetylcysteine; Acetylpeptidase Inhibitor; Acetylshikonin; Acridine Yellow; Aclidinium Bromide; Hyperoside; Acyclovir; Adefovir; Adam II; Adastit; Adefovir; Adefovir Dipivoxil; Adenine; Adenosine; Adenosine-5'-Monophosphate Monohydrate; Adenosine Monophosphate; Adenosine-5'-Diphosphate; Adenosine-5'-Triphosphate; Adiphenine Hydrochloride; Adipic Acid; Agelastatin; Afimoxifene; AG14361; Albendazole; Albendazole Oxide; Alogliptin; Alendronate; Alfuzosin; Alfuzosin Hydrochloride; Allibendol; Alisertib; Aliskiren; Alaprevir; Allethrin; Alectinib; Alosetron Hydrochloride; Aloxiprin; α-D-Galactopyranose; α-D-Mannose-6-Phosphate; α-Hederin; α-Ketoamide Inhibitor 11R; α-L-Arabinopyranose; α-Maltotriose; α-Mangostin; Alprenolol; Alprenolol Hydrochloride; Apludil; Atiprimone; Estratetraenol; Altretamine; Alverine; Alverine Citrate; Avermectin; Avosentan; Amantadine; Amantadine Hydrochloride; Amaranthus; AMD 3465; Adefovir; AMG-131; AMG-232; AMG-900; Amiloride Hydrochloride; Aminocaproic Acid; Amiodarone; Amiodarone Hydrochloride; Amitriptyline; Amitriptyline Hydrochloride; Amlexanox; Amlodipine; Amlodipine Besylate; Amodiaquine Hydrochloride; Amodiaquine; Amonafide; Amorolfine; Amoxapine; Amoxicillin; Amphotericin B; Ampicillin Impurity; Amprenavir; Amrubicin; Amsacrine; Amsacrine Hydrochloride; Amuvatinib; Anacetrapib; Anagrelide; Ancitabine Hydrochloride; S-3-(4-Acetylaminophenoxy)-2-Hydroxy-2-Methyl-N-(4-Nitro-3-Trifluoromethylphenyl)Propanamide; Andrographolide; Androsterone; Androstanone; Anethole Trithione; Sophoramine; Anidulafungin; Benzethidine; Anisomycin; Antazoline Hydrochloride; Anthralin; Antimycin A1; Antipyrine; Apalutamide; Apatinib; Apigenin; Apremilast; Apitolisib; Apixaban; Alavero; Aplaviroc Hydrochloride; Apomorphine; Aprepitant; Arcitabine; Arachidonic Acid; Arbidol; Arctigenin; Aripiprazole; Artemether; Artemisinin; Artesunate; Aspartame; Acetylsalicylic Acid; Astemizole; Astrinic Acid; ASTX660; Anaprevir; AT9283; Ataciguat; Ataluren; Atazanavir; Atevirdine; Atipamezole; Atomoxetine; Atomoxetine Hydrochloride; Atopaxar; Atorvastatin; Atrosab; Aurintricarboxylic Acid; AV-412 Free Base; Avamimet; AVN-944; AVP-13358; Axitinib;AZ-960; Azacitidine; Azapyrimidine; Azatadine; Azathioprine; Azd4547; AZD8330; Azelaic acid; Azelastine hydrochloride; Azelastine hydrochloride; Amlodipine besylate; Azithromycin; Azoxystrobin; Azvudine; B5R5IQ1D64; Baicalein; Baicalin; Bakuchiol; Balofloxacin; Baloxavir; Baloxavir marboxil; Methylbardoxolone; Baricitinib; Balmasept; Bay 41-2272; BAY 41-4109; Bazedoxifene; Bazedoxifene acetate; Bdcrb; Belatacept; Beclomethasone; Belinostat; Belladonna alkaloids; Benazepril hydrochloride; Bendamustine; Benidipine hydrochloride; Benperidol; Benserazide; Benserazide hydrochloride; Bentazepam; Benzamidine; Benzbromarone; Benzenesulfonamide; Benzethonium chloride; Benzalkonium chloride; Beclidonium; Benzoic acid; Benzophenone; Benzotropine; Benzatropine; Benzydamine; Benzydamine hydrochloride; Benzyl p-hydroxybenzoate; Benzyl benzoate; Benzyl dimethyl (tridecyl) ammonium chloride; Benzapril; Berbamine; Berberine hydrochloride; Coptisine; Bictegravir; Bezosertib; Bessifovir; β-Carotene; β-Cyclodextrin; β-D-Ribopyranose; beta-Escin; β-Lactose; 3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione; β-L-Arabinose; Betaxolol; Betazole hydrochloride; Betulinol; Betulinic acid; Brivanib alaninate; Bexarotene; BGT-226 free base; BI 2536; Bictegravir; Bifemelane; Bifonazole; BILR-355; Binoldrin; Biotin; Biperiden; Biperiden hydrochloride; Fesoterodine; Bis (2-ethylhexyl) phthalate; Bisphenamide; Bis (maleimidohexanoic acid) ester; Benfotiamine; Bisoprolol fumarate; Bisphenol A; Bisphenol A diglycidyl ether; Bithionol; Bitolterol; Bunaprolene; Boceprevir; Boldine; Bortezomib; Boscalid; Bosutinib; Brivudin; Brevetoxin A; Buquinolate; Brilliant green; Brincidofovir; Brinzolamide impurity A; Brivaracetam; 1-[[4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]oxy]-2-propanol L-alanine ester; Bromovinyldeoxyuridine; Bromodiphenhydramine; Bromfenac; Bromhexine hydrochloride; Bromocriptine; Bromperidol; Brompheniramine maleate; Bucindolol; Budesonide; Bumetanide; Bunamidine hydrochloride; Buparlisib; Buparvaquone; Bupranolol; Bupropion hydrochloride; Buspirone; Dibucaine; Butenafine; Butoconazole; Butoconazole nitrate; Butriptyline; BX-912; Direct Blue 53; C188-9; Cabergoline; Cabotegravir; Cabozantinib; 3,4-Dihydroxycinnamic acid (Caffeic acid); Caffeine; Calanolide A; (+)-Calophyllolide; Calicheamicin; Calcitriol; Capuramycin; Cambridge Chemical No. 6798241; Camostat; Camptothecin; Camylofin; Candesartan cilexetil; Canertinib; Cannabinol; Canrenone;Carbiverine; Carpiverine; Capsaicin; Captopril; Carbamazepine; Bethanechol; Carbetapentane citrate; Clemastine fumarate; Carbovir; Carboxyamidotriazole; Carboxy-N,N,N-trimethylammonium methane; Carfilzomib; Carmofur; Carphenazine di-malonate; Carprofen; Carvedilol; Caspofungin; Cbr15S3hnj; Cbz-1Nal-Leucine-Alanine ((S)-2-oxopyrrolidin-3-yl)-aldehyde; Cbz-Alanyl-Valyl-Phenylalanyl-alcohol; CC-401; CCT129202; Cediranib; Cefaclor; Cefazolin sodium; Cefixime EP impurity C; Cefotaxime sodium; Cefotiam hydrochloride; Cefoxitin sodium; Cefuroxime sodium; Celastrol; Celecoxib; Selgocivir; TAK-652; Senicriviroc mesylate; Sensipar; Cephalothin acid; Cefapirin sodium; Stephania tetrandra S. Moore; Ceritinib; Cetylammonium chloride; N,N,N-trimethyl-1-tetradecylammonium bromide; Cetrimonium bromide; Cetylpyridinium bromide; Cetylpyridinium chloride; Hexadecylpyridinium chloride; Cetylpyridinium; Chelerythrine; Chelerythrine chloride; Dicaffeoyl tartaric acid; Chidamide; Chikv-IN-2; CHIR-124; Chlorambucil; Chlorcyclizine; Chlorcyclizine hydrochloride; Chlordiazepoxide; Chlorhexidine hydrochloride; Chlorogestin acetate; Chlorogenic acid; Chloroquine; Chloroquine monophosphate; Chloroquine phosphate; Clioquinol; Chlorpheniramine maleate; Chlorpromazine; Chlorpromazine hydrochloride; Chlorprothixene; Chlorprothixene; Clioquinol; Chlortetracycline; Chlortetracycline hydrochloride; Aureomycin hydrochloride; Cholesterol; Choline; (+)-Catechin; Ciclesonide; Ciclopirox; Ciclopirox; Cyclosporine; Cidofovir dihydrate; Cilnidipine; Siluprevir; Parathyroid hormone hydrochloride; Cinnarizine; Ciprofloxacin hydrochloride; Cisapride; Cisapride; Citalopram; Citalopram hydrobromide; Citric acid; Cladribine; Clemastine; Clemastine fumarate; Pyrazolopyrimidine; Clevudine; Clevudine; Climbazole; Clinofibrate; Clobetasol propionate; Clobetasone butyrate; Clofarabine; Clofazimine; DDT; Chlorinated tert-octylphenol; Clomifene; Clomifene; Clomifene citrate; Clomipramine; Clomipramine hydrochloride; Cloperastine hydrochloride; N-[3-(2,4-dichlorophenoxy)propyl]-N-methyl-2-propynamine hydrochloride; Cloprostenol; Closantel; Chlorprothixene; Clotrimazole; Clozapine; Cndac; Codeine hydrochloride; Colchicine; Polymyxin methanesulfonate; Combivir; Combretastatin A4; Congo red; Cormethasone; Copanlisib; Cordycepin; Costunolide; Cozaar; CP-673451; CP-91149; [1-[2-[5-(3-methyloxetan-3-ylmethoxy)benzimidazol-1-yl]quinolin-8-yl]piperidin-4-yl]amine; Cladanimod; CTS-1027; CU-3; Cudc-101; CUDC-427; Curcumin; Cvt-313;CX-5461; Cyclizine; Cyclizine Dihydrochloride; Cyclobenzaprine; Cyclobenzaprine Hydrochloride; Ciclguanil; 1-(4-Chlorophenyl)-6,6-dimethyl-1,3,5-triazinane-2,4-diamine Hydrochloride; Actidione; Cyclophosphamide; CycloSal-d4TMP; Cycloserine; Cyproheptadine; Cyproheptadine Hydrochloride; Cyproterone Acetate; Cysteamine Hydrochloride; Cysteine; Cytarabine; Cytarabine Hydrochloride; Cytisine; Dabigatran Etexilate Mesylate; Dabrafenib; Dacarbazine; Daktawe; Actinomycin; Dacotolisib; Daidzein; Danazol; Danicamtiv; Danoprevir; Darolutamide; Daphnetin; Dapivirine; Daprodustat; Dapoxetine; Darifenacin Hydrobromide; Darunavir; Dasabuvir; Dasatinib; Daunorubicin; Daunorubicin Hydrochloride; D-Cellobiose; Decitabine; Deferasirox; Desferrioxamine; Delanzomib; Delapril Hydrochloride; Delavirdine; Delavirdine Mesylate; Delobuvir; Demeclocycline; Demeclocycline Hydrochloride; Deoxycholic Acid; Dequalinium Chloride; Dequalinium Chloride; Deracoxib; Drenorpholine; Desacetylvinblastine Amide; Reserpine; Desipramine; Nortriptyline Hydrochloride; Deslanoside; Desloratadine; Dexamethane; Dexamethasone Isonicotinate; Dexbrompheniramine Maleate; S-(+)-Chlorpheniramine Maleate; D-Adefovir; Desogestrel Acetamide; D-Galactose; DHAD; Diacerein; Diazepam; Clopamide; Dibenzepin; Dibenzepin Hydrochloride; Cocaine Hydrochloride; Dichlorophen; Dichlorphenamide; Diclofenac; Diclofenac Sodium; Dicloxacillin Sodium Monohydrate; Dicumarin; Dicyclomine; Dicyclomine Hydrochloride; Didanosine; 3,5-D-Dehydrothymidine Cyclophosphate; 2,3-Diphenylbutadiene; Diethylstilbestene; Diflunisal; Digitoxin; Digoxinigenin; Digoxin; Dihydroergocryptine; Dihydroergocristine Mesylate; Ergotamine; Doxazosin Impurity F; 3-Dihydroxypyrimidinecarboxamide; Diltiazem; (2R-trans)-3-(Acetyloxy;

[0268] (base)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one monohydrochloride; dimethyldioctylammonium chloride; dinaciclib; diosmetin; dioxybenzone; dipentamethylenethiuram disulfide; diperodon; dipipanone hydrochloride; diphenhydramine; diphenidol; diphenylpyraline hydrochloride; dipyridamole; dipyridodiazepinone derivative No. 42; dipyrithione; disodium hydrogen phosphate; disulfiram; dizan; dizocilpine maleate; Dmipopmt; Dmp-323; docetaxel; docosahexaenoic acid; dofetilide; dolutegravir; dolutegravir sodium; domiphen; domperidone impurity C; donepezil hydrochloride; dopamine hydrochloride; dopaxamine; 1-[2-(4-methylphenyl)-5-tert-butylpyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea; doramectin; doravirine; doripenem; dorzolamide; dovitinib; doxazosin; doxazosin mesylate; doxepin hydrochloride; doxercalciferol (hectorol); doxorubicin; doxorubicin hydrochloride; doxycycline; doxylamine succinate; DPC-082; DPC-961; hexahydrofenine hydrochloride; droloxifene; ultraviolet absorber UV-P; dronabinol; dronedarone; dronedarone hydrochloride; droperidol; drospirenone; drostanolone propionate; D-serine; D-tartaric acid; duloxetine; duloxetine hydrochloride; dyclonine hydrochloride; dydrogesterone; dynamex; E100; ebastine; ebselen; econazole nitrate; ecopipam; edaravone trimer; edoxudine; efavirenz; RAD-1901; eclipta; elaidic acid; elbasvir; elisomol; eletriptan; eltoprazine; ellagic acid; ellipticine; eltrombopag; elvitegravir; elvucitabine; enbucrilate; emedastine difumarate; emivirine; emodin; enrasafen; emtricitabine; indomethacin cyclotrimethylene citrate;

[0269] (Z)-N-Demethyl-4-hydroxytamoxifen; Endoxifen; Enfuvirtide; Enoxam; Enoximone; Glycyrrhetinic acid; Ansulizole; Ensovip; Entecavir; Entecavir triphosphate; Enzastaurin; Eperisone hydrochloride; Ephedrine sulfate; Epigallocatechin; Epigallocatechin gallate; Epinephrine; Epinephrine tartrate; Epirubicin; Epirubicin hydrochloride; Eprazinone hydrochloride; Ergocalciferol; Erlotinib; Itibrutinib; Erythromycin; Erythromycin estolate; Erythromycin propionate; Escitalopram oxalate; Esculetin; Esmolol hydrochloride; α-Estradiol; Estradiol acetate; Estradiol cypionate; Estragole; Estramustine; Estriol; Estrone; Rivanol; Ethacrynic acid; Ethanol; Ethinylestradiol; Ethoxybenzamide; Promethazine hydrochloride; Ethoxyquin; Ethoxzolamide; Ethyl gallate; Ethyl nitrite; Ethylestrenol; Etodolac; Etoposide; Etravirine; Etravirine impurity 5; Azocarmine; Everolimus; Isarulen; Exenatide; Exemestane; Etobenzanid; Ezetimibe; F2-NH-DABO 9d; Faldaprevir; Famciclovir; Farglitazar; Fasudil; Favipiravir; Febuxostat; Felodipine; Fenbendazole; Fenbufen; Anhydrous phenoxymethylpenicillin; Fenoldopam; Fenoldopam mesylate; Fenoverine; Fileritinib; Facitabine; Fialuridine; Fibfabprone; Fidaxomicin; Figlatir; Filibuvir; Firoxolamine; Fimepinostat; Fingolimod; Phentermine hydrochloride; Fisostat; 3,3',4',7-Tetrahydroxyflavone; 2,6-Anthracenediol; Flavone; (-)-2-(2-Chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4H-1-benzopyran-4-one hydrochloride; Flecainide; Chlorhexidine acetate; 5-Fluoro-2'-deoxyuridine; Fludarabine; Flufenamic acid; Flumequine; Flunarizine; Flunarizine hydrochloride; Fluorescein; 5-Fluorouracil; Fluoxetine; Fluoxetine hydrochloride; Flupenthixol; Flupenthixol dihydrochloride; Fluphenazine; Fluphenazine hydrochloride; Flupirtine; Flupirtine maleate; Flurazepam; Flurbiprofen; Paroxetine impurity C; Flutamide; Fluticasone propionate; Fluvastatin; Sodium fluvastatin; Fluvoxamine; Fluvoxamine maleate; D-Folic acid; Furitinib; Formononetin; 7-[(2S,3S,4R,5R)-3,4-Dihydroxy-5-(hydroxymethyl)-2-pyrrolidinyl]-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; Forskolin; Fosamax; Foscarnet; Foscarnet sodium; Futibatinib; Fulvestrant; Furosemide; Furazolidone; Sodium fusidate; Fusidate; Galantamine; Galidesivir; Gallic acid; Phloretin; Tannic acid; γ-Aminobutyric acid; Oryzanol; Ganciclovir; Ganetespib; Gatifloxacin; GC376 sodium; Gdc-0152; Gefitinib; Geldanamycin; Gemcitabine; Gemcitabine hydrochloride; Genistein; Gentian violet; Gentian violet cation; Gestrinone;Gilteritinib; Gemcitabine; Givinostat Hydrochloride Monohydrate; Clfenamic Acid Hydrochloride; Glecaprevir; Glesatinib; Gliclazide; Glipizide; Gliquidone; Glutamic Acid; Glutamine; Glutaric Acid; Glutathione; Glibenclamide; Glycine, N-[(iminophosphonoamino)methyl]-N-methyl-; Glycopyrronium Bromide; Glycyrrhizic Acid; GNF-Pf-159; GNF-Pf-2335; GNF-Pf-4300; GNF-Pf-888; Go-6976; Golvatinib; Gossypol; Gossypol Acetate; Gossypol Hexaacetate; Granisetron; Grazoprevir; Guaiol; 4-Imidazoleacetic Acid Hydrochloride; Guanidino-Oseltamivir Carboxylic Acid; Guanidino-Tamiphosphate; Guanosine; GW0742; GW4511; GW678248; H-Alanyl-Lysyl-Valyl-Threonyl-Methionyl-Threonyl-Cysteinyl-Seryl-Alanyl-Seryl-OH; Halcinonide; Halofantrine; Halofantrine Hydrochloride; Haloperidol; Haloxon; Harmaline; Harmine Hydrochloride (hydrate); Harringtonine; HBF-0259; HDP-HPMPA; Fucoxanthin 8-1; Hematoxylin Hydrate; Hesperidin; Hexachlorophene; 4,4'-Dihydroxy-Γ,Δ-diphenylhexane, 4,4'-DIHYDROXY-Γ,Δ;

[0270] -Diphenylhexane; Hexylcaine hydrochloride; Hexylresorcinol; Histamine; Histidine; HIV-1 Inhibitor-43; Humidine bromide; Honokiol; Hpmpa; Huperzine A; Hydergine; Hydrocortisone aceponate; Hydrocortisone acetate; 1,4-Benzenediol; Hydroxychloroquine; Hydroxychloroquine sulfate; Hydroxyflutamide; Hydroxyprogesterone; Hydroxyprogesterone caproate; Hydroxytyrosol; Hydroxyurea; Hydroxyzine; Hydroxyzine pamoate; Hyoscyamine; Hypericin; Hyperoside; Hypoxanthine; Ibrutinib; Ibufenac; Ibuprofen; IC9564; Anhydroicaritin; ICG-001; Elosulfase alfa; Idarubicin; Idarubicin hydrochloride; Idarsartan; Idazoxan; Idelalisib; Idoxuridine; Ideronel; Ifenprodil; Iloperidone; Imatinib; Imatinib mesylate; Diminazene; Imipramine; Imipramine hydrochloride; Imiquimod; Imperatorin; Inalivisoprosin; INCB-9471; Indibulin; Indinavir; Indinavir sulfate; Indiplon; Indirubin; Indobufen; Indocyanine green; Indole-3-methanol; Indomethacin; Indoprofen; Indoramin hydrochloride; Ingenol-3-O-angelate; Inosine; Inositol; Invirase; INX-08189; Iodoacetamide; Iodoquinolone; Iodoflutamide; iOWH-032; Ipatrimox; Ipriflavone; Irbesartan; Irinotecan; Irinotecan hydrochloride; Iloprost; Isoconazole; Isocycloheximide; Isoliquiritigenin; Isoorientin; Disopyramide; Isopropylunoprostone; Isoquercitrin; Isocoumarin; Purified Patent Blue Violet; Isothymoleon; Isotretinoin; Isradipine; Istatod; Istradefylline; ITD-1; Itraconazole; Itraconazole; Ivacaftor; Ivermectin; Ixazomib; JE-2147; JNJ-7706621; Kaempferol; Carafate; Clarani; Ketanserin; Ketoconazole; Ketorolac; Ketorolac tromethamine; Ketotifen; Ketotifen fumarate; 6-Furfurylaminopurine; KNI-1931; Ksc-16-200S2C; Ku-0063794; Kyotorphin 272; L-685434; Labetalol; Lamividine; Lanatoside C; Laninamivir; Laninamivir octanoate; Lansoprazole; Lapatinib; Laropiprant; Narasin; LCL161; Ledipasvir; Leflunomide; Lenalidomide; LEO 275; Lercanidipine; Lercanidipine hydrochloride; Lesivirin; Letaraxel; Letermovir; Leucine; Methylene blue; Levorphanol; Levobupivacaine hydrochloride; Levodopa; Levofloxacin; Levomethadyl acetate hydrochloride; Levodopex; Levosimendan; Levothyroxine; Recilibin; L-Glutamic acid hydrochloride; Lickfiren; Lidoflazine; Lifitegrast sodium; Ligustroside B; Linoleic acid;Cis-3-[8-amino-1-(2-phenyl-7-quinolinyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutanol; Lisinopril; Sodium triiodothyronine; Liquiritigenin; Liranaftate; Lithocholic acid; Lobeline; Ledoxin; Lofepramine hydrochloride; Lofexidine; Lomefloxacin; Lomefloxacin hydrochloride; Lomerizine hydrochloride; Lomibuvir; Lonafarnib; Loperamide oxide; Loperamide hydrochloride; Lopinavir; Loratadine; Lorcaserin; Lorlatinib; Ornithine; Lornoxicam; Lovastatin; Loviride; Loxapine; Flupentixol succinate; L-tartaric acid; Lucanthone hydrochloride; Luliconazole; Lumacaftor; Lumefantrine; Lumicitabine; NVP-AUY922; Ruxolitinib; Luteolin; Lynestrenol; Lysergic acid diethylamide; Lysine; Magnolol; Malachite green oxalate; Maleic acid; Malonic acid; SF-6847; Marotilate; Manidipine; Manidipine dihydrochloride; Maprotiline; Maprotiline hydrochloride; Maraviroc; Madepude; Maribavir; Mesopuco; Matrine; Maxacalcitol; MC-1220; Mebendazole; Mepivacaine hydrochloride; Mecamylamine; Embitropin; Meclizine hydrochloride; Mechlortetracycline sulfosalicylate; Melphalan; Medroxyprogesterone; Mefenamic acid; Flumequine hydroxypiperidine; Mefloquine hydrochloride; Melitracen hydrochloride; Melphalan; 3,5-dimethyladamantylamine; Memantine hydrochloride; Menadione; Menadione sodium bisulfite; Meptazinol hydrochloride; Mepyramine; Mequitazine; 2,7-dibromo-4-hydroxymercurifluorescein disodium salt; Mercaptopurine; Mericitabine; Merimorexdb; Mesalazine; Mesoridazine; Mestranol; MET kinase inhibitor; Metarrestin; Methysergide; Methacycline; Methacycline hydrochloride; Methadone hydrochloride; Methapyrilene hydrochloride; Methazolamide; Methdilazine hydrochloride; Methionine; Methythiazide hydrochloride; Methotrexate; Methyl methanesulfonate; Methyl-2-pyrrolidone, 17b; Methyldopa; Methyldopa monohydrate; Methylene blue; Methylene blue cation; Methylergonovine; Methylprednisolone; Methysergide; Methysergide maleate; Metildigoxin; Methythiazide hydrochloride; Metolazone; Chlorphenamidine; Mevastatin; Mianserin; Mianserin hydrochloride; Mibefradil; Mibefradil; Mitchelamine B; Miconazole; Miconazole nitrate; Midostaurin; Mifepristone; Micyclil; 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 free base; MK-944a; ML322; ML355; MLN8054; Mozobil; Mocravimod; Morolimus; Mometasone furoate; 4-benzyloxyphenol; Montelukast sodium; Ethmozine; Morin; Morphine sulfate; Mofedisin; Mosapride citrate; Motesanib; Moxisylyte disodium; Mosapramine;Moxifloxacin Hydrochloride; Mozavavir; 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-Methoxynonyl-deoxynojirimycin Hydrochloride; Naftifine Hydrochloride; Nafudil; Naloxone; Naltrexone; Nannamycin; Naphazoline Hydrochloride; Naproxen; Naratriptan; Naringenin; Narlaprevir; Vinorelbine; Navitoclax; NBD-14270; NCGC00090797-11;

[0271] NCGC00179454-04; Nebivolol; Nefazodone; Nefazodone Hydrochloride; Nefopam; Nefopam Hydrochloride; Nelfinavir Mesylate; Nelfinavir Mesylate; Neomycin; Nesbuvir; N-Ethylmaleimide; Netilmicin; Nevirapine; Isonicotinyl Hydrazide; Nicardipine; Nicardipine Hydrochloride; Nicergoline; Nickel Dibutyldithiocarbamate; Niclosamide; Nicotine; Nifedipine; Flunixin; Nitrofurfuroyl Hydrazide; Nimesulide; Nimodipine; Nimustine Hydrochloride;

[0272] (3E)-1-(2-Chloroacetyl)-2,3-dihydro-3-(methoxyphenylmethylene)-2-oxo-1H-indole-6-carboxylic Acid Methyl Ester; Niraparib; Nisoldipine; Antioxidant 4010NA; Nitazoxanide; Nitrendipine; Nitrofurantoin; Nitrofurazone; 5-Nitro-8-hydroxyquinoline; N-Methylpyrimidone, 17; Nocodazole; Norvasan; Nomifensine; Norcantharidin; Nordihydroguaiaretic Acid; Norepinephrine; Norethisterone Enanthate; Norfloxacin; Acetophenone; North Methanecarbonyl Thymidine; Nortriptyline; Nortriptyline; Novobiocin; N-Phenylanthranilic Acid; NSC158393; NSC351815; NSC640065; NSC651084; NSC666863; NSC697445; N-tert-Butylisoquinoline; Nucleoside Zinc; Nabilone; Nystatin (Fungicidin); Nystatin A1; O6-Benzylguanine; Octocrylene; Odanacatib; Amoxicillin Impurity I; Olanzapine; Oleanolic Acid; Oleic Acid; Oripavine; Omacetaxine Methylsuccinate; Omadacycline; Obeticholic Acid; (R)-Omeprazole; Omipalisib; Onalespib; Vincristine; Ondansetron; ONO-5334; Xiton; Oprea1_836388;

[0273] ONX0912; O-Tolylhistamine; O-Tolylhistamine Hydrochloride; Oseltamivir; Oseltamic Acid; Oseltamivir Phosphate;

[0274] Osi-027; Osi-930; Osimertinib; Ospemifene; Osthole; Otamixaban; Otilonium bromide; Otilonium bromide; Ouabain; Ouabain; Oxaloacetic acid; Oxalic acid standard solution; Oxatomide; Oxycaine; Oxfendazole; Oxibendazole; Oxiconazole nitrate; Oxprenolol hydrochloride; Closantel; Oxymatrine; Xylometazoline; Xylometazoline hydrochloride; Methandienone; Hydroxybenzobutyryl ketone; Oxyclipine hydrochloride; Oxytetracycline; Oxytetracycline dihydrate; Oxytetracycline hydrochloride; Paclitaxel; Paclitaxel (Taxol); Palbociclib; Paritaprevir; Palmitic acid; Palonosetron hydrochloride; Pamigrel; Panobinostat; Papaverine; Papaverine hydrochloride; Paritaprevir; Paritaprevir dihydrate; Paroxetine; Paroxetine hydrochloride; Parthenolide; Parthenolide; Parthenolide; Pasiniazid; Paromomycin; Pazopanib; Pazopanib hydrochloride; PD0166285; PDK1 inhibitor AR-12; Piperazine; Pecacetamol; Pemetrexed impurity; Bambuterol sulfate; Penciclovir; Penfluridol; Pentamidine; Pentoxifylline; Aprotinin A; Peramivir; Phenothiazine; Pergolide mesylate; Perhexiline maleate; Perazine; Perospirone hydrochloride; Perphenazine; PF-00562271 free base; PF-03882845; PF-04217903; PF-04691502; PF-3758309; PF-46396;

[0275] PF-477736; pf74; PH-797804; Pha-665752; PHA-793887; phenazopyridine; phenazopyridine hydrochloride; phenelzine; phenformin hydrochloride; phenol; phenoxybenzamine; ethylbenzcoumarol; phentolamine; phentolamine mesylate; phenylalanine; phenylbutazone; phorbol 12-myristate 13-acetate; methyl phosphonate formate; phosphoric acid; phthalic acid; physostigmine; phytic acid; PI-103; picropodophyllotoxin; paritaprevir; polydatin; meropenem; GDC-0941; picofibrate; 2-amino-N-[3-[N-[3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl]aminosulfonyl]phenyl]-2-methylpropanamide; mepazine; pimethixene maleate; pimobendan; VX-787; pimozide; pinaverium bromide; pindolol; pipothiazine; piredoxine hydrochloride; pirarubicin; pirfenidone; pemetrexed; pirindol mesylate; pyrazinamide; pivampicillin; pivmecillinam hydrochloride; pizotifen; pizotifen malate; PL-100; cisplatin; pleconaril; plerixafor; plerixafor octahydrochloride; plumbagin; PLX-4720; Pnu-103017; boceprevir; podophyllotoxin; ponatinib; posaconazole; padigatram; pradimicin A; pradimicin S; pralatrexate; pramipexole hydrochloride; promecaine hydrochloride; pranlukast; praziquantel; prazosin; prazosin hydrochloride; procort; prednisolone aceponate; prednisone; prasterone; prenylamine lactate; GS-5806; Prima-1met; primaquine; primaquine phosphate; primidone; propantheline bromide; procainamide hydrochloride; prochlorperazine; prochlorperazine edisylate; prochlorperazine; procyclidine hydrochloride; pyridine-3,6-diamine; progesterone; proguanil hydrochloride; promazine; promazine hydrochloride; promethazine; promethazine hydrochloride; pronethalol; propafenone; propafenone hydrochloride; proxymetacaine hydrochloride; propidium iodide; dextropropoxyphene hydrochloride; propranolol hydrochloride; propyl gallate; ptilosarcine; prevastatin; prothionamide; protoporphyrin; protriptyline; pucrutamide; psi 7851; psi-352938; pterostilbene; PU-H71; puromycin dihydrochloride hydrate; purpurogallin; pyrantel pamoate; pyrazinamide; pyridoxal; pyridoxine; N-[(4-methoxyphenyl)methyl]-N-(2-pyridyl)-N’,N’-dimethyl-ethylenediamine maleate; pyrimethamine; pyrithione; pyronaridine phosphate; pyrophosphoric acid; N-hydroxy-N'-3-pyridyl octanediamide; pyrrole-A; pyruvate; pyrvinium pamoate; Q9LK8R766M; quercetin; quercetin dihydrate; quercitrin; quinine chloride; quinacrine dihydrochloride hydrate; quinine chloride dihydrochloride dihydrate; quinestrol; quinidine; quinidine hydrochloride monohydrate; quinine; quinine sulfate; quisinostat; R-82913; rabeprazole sodium; labesertib; racecadotril; ridipravir; RAF265;Iodoetheramide; Larimetinib; Raloxifene; Raloxifene Hydrochloride; Raltegravir; Raltegravir Potassium Salt; Raltitrexed; Larutide; Ramosetron Hydrochloride; Rapacuronium Bromide; Ravidasvir; Rebastinib; Reboxetine Mesylate; Regorafenib; Remdesivir; Rescinnamine; Reserpine; Resiniferatoxin; Resmetirom; Resorcinol; Resveratrol; Retigabine; Retinol; Rimidlovir Sodium Dihydrate; Ribavirin; Vitamin B2; Ricolinostat; Rifabutin; Relatlimab; Rilmenidine; Rilpivirine; Riluzole; Rimantadine; Rimantadine Hydrochloride; Rimonabant; Risperidone; Rita; Ritanserin; Ritonavir; Rivaroxaban; Revesiclib; RO4929097; Rofecoxib; Noprilan; Rolitetracycline; Rosmarinic Acid; Rotenone; Rotigotine; Mallotusapetalusin; Roxadustat; RSV604; Ruboxistaurin; Salidroside; Rucaparib; Lupinavir; Rutaecarpine; Rutin; Ruxolitinib; Saccharin; S-Adenosyl-DL-Methionine; Safinamide; Salicylic Acid; Salinomycin Sodium; Salinomycin Sodium; Salmeterol; Salmeterol Xinafoate; Sancycline; Sanguinarine; Sanguinarine Chloride; Sapanisertib; Sapitinib; Saponarin; Isocoumarin; Saquinavir; Saquilarvir; Seclatinib; Sarafloxacin; Saricycline; Sarpogrelate; Sarpogrelate Hydrochloride; SB-505124; SB-743921; Sch 58261; Scy-635; SD-06; sd146; Sebacic Acid; Secnidazole; Secoisolariciresinol; Securinine; Celocipar; Selisistat; Simanib; Sennoside A, Analytical Standard; Sensit; Sepantronium; Sermetacin; 5-Hydroxytryptamine Hydrochloride; Sertaconazole Nitrate; Sertindole; Sertraline; Sertraline Hydrochloride; SGI-1776; Sgx-523; Sibutramine; Silybin; Silmetitracitinib; Silymarin; Simeprevir; Simvastatin; Sinefungin; Xinnaikang; Sinomenine; Sirolimus; Sisunatovir; Sitagliptin; SNS-032; SNX-2112; Snx-5422; Sodium Hydroxide; Sodium Hypochlorite; Sofalcone; Sofosbuvir; Solifenacin Hydrochloride; Sophoridine; Sorafenib; Sorafenib; Sorivudine; Sotalac; Sovaprevir; Spironolactone; Streptonigrin; Stavudine; Stavudine Triphosphate; Stearic Acid; Streptomycin; Staurosporine; SU9516; Succinic Acid; Succinylcholine; Sufentanil Citrate; Sulbactam Acid; Sulconazole Nitrate; Sulfadiazine; Sulfamethazine Sodium; Sulfamethoxazole; Sulfapyridine; Sulfasalazine; Surindac Sulfonate; Sultiam; Sumatriptan; Sunitinib; Sunitinib Malate; Suprofen; Suramin; Suramin (Sodium Salt); Gentiamarin; Tacrine; Tacrine Hydrochloride Monohydrate; Tak-285; N-(4-(2-Ethyl-4-(3-Methylphenyl)Thiazol-5-Yl)Pyridin-2-Yl)Benzamide; TAK-733; TAK-901; Talinolol; Tapermod; Tavaborole; Avianca Ecuador;Tamibarotene; Tamiphosphor; Tamoxifen; Tamoxifen Citrate; Tandutinib; Tanespimycin; Naringenin; Tanshinone I; Tanshinone IIA; Tanespite; N-[2-[[4-[2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]carbamoyl]-4,5-dimethoxyphenyl]quinoline-3-carboxamide; Tauroursodeoxycholic Acid; Taxifolin; Tazarotene; Tazobactam Sodium; TCRB; Tecovirimat; Tegaserod; Tegaserod Maleate; Telbivudine; Telaprevir (VX-950); Telithromycin; Telmisartan; Telotristat; Ethyl Telotristat; Temsirolimus; Temixovir; Tenofovir; Tenofovir Alafenamide; Tenofovir Alafenamide Fumarate; Tenofovir Diphosphate; Tenofovir Disoproxil; Tenofovir Disoproxil Fumarate; Tenofovir Isonixil; Tepotinib; Tepoxalin; Terameprocol; Terazosin; Terazosin Hydrochloride; Terbinafine; Terbinafine Hydrochloride; Itraconazole; Terfenadine; Teriflunomine; Trodiline Hydrochloride; Tesaglitazar; Paramomycin; Testosterone; Testosterone Propionate; Tetrabenazine; Tetracaine Hydrochloride; Tetracycline Hydrochloride; Tetradecylthioacetic Acid; Tetramethylthiourea Monosulfide; Tetrandrine; TG101209; TGX-221; Thioperamide; Theophylline; Thiabendazole; Thiamine Diphosphate; Thiamine; Thiazolebenzimidazole; Thimerosal Sodium; Thioctic Acid; thio-DABO 3s; thio-DABO 3t; thio-DABO 3w; Thioguanine; Thioridazine; Thioridazine Hydrochloride; Thiosangivamycin; Thiram; Ammonium Bromide Tongzuo; beta-Thymidine; Thymidine-5'-Triphosphate; Thymol; Tiagabine Hydrochloride; Tiaprofenic Acid; Tibo; Tibolone; Tilorone Hydrochloride; Tinidazole; Tiopronin; Tiothixene; Tioxolone; Tipifarnib; Tiprasidine; Telaprevir; Telarcicab; Telavapril; Tivozanib; Tizanidine; Thiazolidine; TMC 126; TMC647055; Tobramycin; Tolcapone; Tolnaftate; Toluidine Blue; Tolterodine; Toltrazuril; Tolvaptan; Tomivosertib; Topiramate; Topotecan; Topotecan Hydrochloride; Toremifene; Toremifene Citrate; Torasemide; Tauzasertib; Trabectedin; 4-(Aminomethyl)cyclohexanecarboxylic Acid; Tranilast; Cis-Flupenthixol; Trazodone; Trehalose; Tratriciclib; Tretinoin; Triamterene; Tribromsalan; Trichlorfon; Trichostatin A; Troxacitabine Phosphate; Troxacitabine Phosphate; Triclabendazole; Triclocarban; Triclosan; Trifluoperazine; Trifluoperazine Hydrochloride; Triflupromazine; Triflupromazine Hydrochloride; Trifluorothymidine; Triglycidyl Isocyanurate; Trihexyphenidyl Hydrochloride; Trimethoprim; Trimetrexate; Trimipramine; Trimipramine Maleate; Tripalmitol; Tripelennamine Citrate; Triprolidine; Triprolidine Hydrochloride; Tripterygium Wilfordii Hook F; Tromethamine; Tropisetron; Trovafloxacin Mesylate; Trivudine; Trixacalid; Acridine Yellow Hydrochloride; Tryptamine; Tryptophan;TSAO-m3T;

[0276] Tsao-T; TTP-8307; tuberculocidin; TYA5; tyrosine; tyrosine kinase inhibitor B42; epsilonercept; UC-781; UK-201844; ulixertinib; urodenafil; UMI-77; uprifosbuvir; uracil; urapidil hydrochloride; urea-PETT derivative 13; uric acid; uridine; uridine 5'-triphosphate; uridine-5'-monophosphate; ursolic acid; US9107954, maraviroc; vadadustat; 2,5-hexanediol theophylline; famciclovir; deracoxib; valganciclovir; valine; faropenem pivoxil; valproic acid; valpromide; valrubicin; vandetanib; vanrelvir; vanoserine; vanoxerine dihydrochloride; vaparitaprevir; vardenafil; varenicline; valinomycin; valitinib; vatalanib; vatalanib; VCH759; vedolizumab; vinblastine; veliflapon; veliparib; velpatasvir; venetoclax; venlafaxine; verapamil; verapamil hydrochloride; vidofludimus; vigantolimod; viclevir; vidarabine; vidofluradimod; vinblastine; vincristine; vinorelbine tartrate; vinpocetine; vindoline; vitamin B12; vitamin E; vitexin; vorasertib; vorinostat; voxilaprevir; VRX-480773; 6-[(aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3-pyridinecarboxamide; warfarin; wedelolactone; Win vi; Win-54954; WIN61209; xanthine; cevipatril; XV638; Y-27632 dihydrochloride; methysticin; zileuton; zalcitabine; zaleplon; zaltoprofen; zanamivir hydrate; zeaxanthin; zidovudine; zidovudine monophosphate; zimeldine hydrochloride; zemeldine; 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one; ziprasidone hydrochloride monohydrate; zireovir; Z-leucine-leucine-leucinal; Z-L-phenylalanine chloromethyl ketone; zofenopril; zolpidem; zolquidar; zuclopenthixol trihydrochloride; zotepine; 2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine; vegetable or animal fat; ethanol; water; glycerol; propylene glycol; triethylene glycol; dimethyl sulfoxide; solvent; betaine hydrochloride; octanoic acid; monolauric acid; glycerol monolaurate; undecylenic acid (undecenoic acid); croton bark extract; cat's claw extract; garlic extract; black walnut hull extract; catalase; lipase; alpha-amylase; pectinase; beta-glucanase; cellulase; alpha-galactosidase; amylase; invertase; xylanase; hemicellulase; or other enzymes; black cumin oil; Nigella sativa; oregano oil; essential oil; lactoferrin; colloidal silver; vitamin C; benfotiamine; thiamine zinc sulfate; allithiamine; vitamin D; vitamin A; iodine; melatonin; fenofibrate; glycine;N-acetylcysteine; lipoic acid; S-adenosyl-L-methionine; silymarin extract; grape seed extract; carnitine; anti-androgen; bromhexine; cannabidiol; convalescent plasma; ensovibep; famotidine; iota-carrageenan; metformin; molnupiravir; bamlanivimab / etesevimab; bebtelovimab; casirivimab / imdevimab; sotrovimab; tizazumab / silgamivab; nitric oxide; Paxlovid; peginterferon lambda; povidone iodine; prucalopride; camostat mesilate; fosudil; Glycyrrhiza glabra; Glycyrrhiza glabra; Artemisia annua; hesperidin; arbidol hydrochloride; kaempferol 3-O-rutinoside; catechin; epigallocatechin-3-gallate; nafamostat; nafamostat mesilate; nafamostat mesylate; omega-3; DHA / EPA; xylitol; xlear; APN01; alunalpha; soluble ACE2; rhace2-apn01; hydrogen peroxide; glyceryl laurate; propolis; atovaquone; fenofibrate; fucoidan; hypochlorous acid; pomegranate; pomegranate; punicalagin; pomegranate tannin; urolithin A; rosuvastatin; selenium; theaflavin-3,3'-digallate; cryptojaponol; losartan; myricitrin; chrysin; ro-0622; azd7442; tizazumab; silgamivab; cetirizine; ct-p59; darolutamide; doxycycline; masitinib; neem; neem; ridanvimab; normal saline; selamectin; tannic acid; valproic acid; taxusflavone; plagiochiline A; cryptospirolactone; rhoifolin; cirsimaritin; 6-gingerol; theaflavin; oleuropein; tacrolimus monohydrate; puerarin; limonin; obacunone; sesamin; astragalin; Alpinia katsumadai; aprotinin; Withania somnifera; Withania somnifera; bedaquiline; bergapten; boswellic acid; canakinumab; chlorpheniramine; chlorpheniramine; chlorhexidine; clarithromycin; Echinacea angustifolia extract; enzalutamide; forsythoside A; glycine; Griffithsin; Huashi Baidu; Jingsi herbal tea; JinHua QingGan; jt001(vv116); lenzilumab; Lianhua Qingwen capsule; noq19; phosphodiesterase type 5 inhibitor; Pleurotus ostreatus; Rheum palmatum; s-S-217622; tafenoquine; tofacitinib; virgin coconut oil; Xuanfei Baidu; moxidectin; thymol quinone; baicalein E; butylidenephthalide; igustin; micafungin; emetine; polymyxin e; glycyrrhizic acid; crocin; cryptoestrogen; biscryptopine; herbacetin; cycloeucalenol; campesterol; cyanidin 3-O-glucoside; afatinib; nilotinib; scedapin c; quinadoline B; afidopyropen; rhein; artesunate; bufalin; hydralazine; phenytoin; propylthiouracil; sulindac; theobromine; tigluticib; binimetinib; ergotamine; taraxerol; dioscin D; estrone-2,3-quinone; hinokiflavone; ginkgetin; dequinadoline A; natamycin; cyanidin 3-O-rutinoside; quercetin 3-o-rutinoside; forsythin;Conivaptan; Aloesin; Gingerol; Tinosporide; Sesamol; Sesamin; Ephedrine; Solanine; Donepezil; VBY-825; Psoralidin; Cryptotanshinone; Fangchinoline; Z-FA-FMK; Allicin; Pravastatin; Ramipril; Dihydromyricetin; Scutellarein; Corilagin; Isorhamnetin; Nystatin; Anakinra; Tocilizumab; Dacel; Sinigrin; Glabridin; Gemtuzumab; Kin1901; Infliximab; Lorlizumab; PA14; Pro-140; Velocix; Tocilizumab; Proanthocyanidin; Α-Hederin; Ferulic acid; Anthocyanidin; Anthocyanin 5-O-β-D-glucoside; Cyanidin-3-O-glucoside; Lambda-carrageenan; 4'-Fluorouridine; 76clabs; 8G3; A6-001; AGP-14; AGP-15; Acarbose;

[0277] ard-61; ARQ AJīB; Arylazothiazolimine; Aveyparotide; AYURCOV; Beauvericin; Bismuth subsalicylate; Bisthiadiazole; Blue light; Sappanin; Breathing exercises; brii-196 / brii-198; Bromelain; Bucillamine; C60 Fullerene; Camellia sinensis; cd24fc; Chlorine dioxide; Chivapraside; Clitoria ternatea; Clitoria ternatea; Clitoria cyanantha; Clitoria pea; Butterfly pea; Codovan bean; Darwin pea; codivir; Copper gluconate; clsp-2; ctb-ace2 glue; Cysteamine; d-α-Tocopheryl polyethylene glycol succinate; tpgs; dfo; Diammonium glycyrrhizinate; Dimethyl sulfoxide; Darunavir ethanolate; ek1c4; Engineered ACE2; Enoxaparin; Epicatechin; fbr-002; Estrogen; Ethyl lauroyl arginate; Exogenous CD24; Evosudil; Tizazumab; Sigavumab; Iron sandwich compound derivative; flovid-20; Glycyrrhiza glabra and Pinellia ternata; gb-1; Green tea; Han Shi Zufei; Heparin; Hinokitiol; Demethyl homoharringtonine; Honey; inm005; Interferon-λ (Interferon lambda); Isoprinosine; js016; Kabasura kudineer; Andrographis paniculata; Spirulina maxima; Levamisole; Revilimab; L-Glutamine; ly2835219; Manuka honey; Mahuang decoction; Mesenchymal stem cells; Metformin glycinate; mi-1851; Montelukast; Polymeric soluble ACE2; N-Acetylglucosamine; Natto extract; Naphthoquine; Nicotinamide; Nicotinamide mononucleotide; Opaganib; Oxygen-ozone immunotherapy; Palmitoylated ACE2; PAMAPIMOD; Pegylated interferon α-2b; peg ifn-α2b; Pentosan polysulfate; Pioglitazone; Phoxwell; Phthalocyanine; Rhodophyta; Breathing regulation method; Probenecid; Propolis Rabiloin A; Nima; Artesunate-pyronaridine; Pyrimidine; q34; rd-x19; Rejuveinix; Sabizabulin; Sarelivira; sarbd-1; sars-block; Anisodine; Sea cucumber sulfated polysaccharide; scsp; Serratia protease; Serratia E-15 protease; Venomase; Serratia protease; Fibrinase; Allium ascalonicum; si-f019; sng001; Spirulina; Sodium bicarbonate; Stemparyb; sti-9167; Thymosin; Tolvaptan; tpnt1; trisb92; Urtica agglutinin; zinv03977803; znonps; znsec-humicin; z-veid-fmk; Minocycline; Theobromine; Diker 1; 3-Isoflavone-3-gallate; Dihydrotanshinone I; Citrus quinosene; Saintcyclin B; Nearpurpurin C; Pityrocitrin B; Anthrabenzoxanthone; Penicillone A; Icatibant; Betastine; Epoprostenol; Vapreotide; hrsace2; Olysio; Allyl disulfide; Allyl trisulfide; Digoxigenin;Tianluling; Caesalpinia tannin C1; Lianhua Qingwen; Diprotopine; Neostigmine Bromide; Ethotoin; Hydrocotarnine; 4-Aminoantipyrine; Vitamin B; Lurasidone; Perphenazine; Isocarboxazid; Cryptophytin 1; Cryptophytin 52; Deoxycylindrospermopsin; Anatibant; Zaborafloxacin; Tirazosin; Picolamide; Cilazapril; N-(3-Chloro-1H-indol-7-yl)-1,4-benzenedisulfonamide; Pradimicin; Phenformin; Toroside B; Covitris2020; Chlovid2020; Silybin; Licofelone; Phytin A; 6-Capsaicinol; Centipeda minima; Tanshinone-i; Mangiferin; γ-Mangostin; 4-Hydroxy-2-nonenal; Acetaldehyde; Aflatoxin B1; AICA-Ribonucleotide; Acitretin; α-Tocopherol; ENT-Benazepril; Benzo[a]pyrene; Bezafibrate; Bisphenol A; Dibutyryl Cyclic Adenosine Monophosphate; Buthionine-Sulfoximine; Cadmium Chloride; Carbon Tetrachloride; Clidazoline; Cisplatin; Chloroformic Acid; Clofibrate; Clonidine; Adrenalone; Comestrol; Tephrosin; Dichloroacetic Acid; Dieldrin; Dimethylnitrosamine; Dinoprost; Ethinylestradiol; Fumitremorgin B1; Furan; Chlorfenamic Acid; Glucosamine; Ifosfamide; Ionomycin; Lithium Chloride; Methapyrilene; Methimazole; Methoxychlor; Mevalonic Acid; Ochratoxin A; Dopamine Hydrochloride; Pentachlorophenol; Phenethyl Isothiocyanate; Piperficine; Pilocarpine; Piroxicam; Pyrazolanthrone; Ranitidine; Rosiglitazone; Tetrachloroethylene; Tetracycline; Toxiferine; Tributyltin Compounds; Trichloroethylene; Trichostatin A; Tunicamycin; Tyrosine Kinase Inhibitor AG-1478; Ethyl Carbamate; Vancomycin; Wortmannin; Zearalenone; zinc32960814; zinc12006217; zinc03231196; Seneciphylloside A; Seneciphylloside B; Calophycin A; Catechuic Acid; Hyperoside; Lupinine; Viomycin; Capastat; Demethoxycurcumin; Bisdemethoxycurcumin; Scutellarin; Synthetic Yohimbine Gum Alcohol; Asparagine A; Vinpocetine; Naringin; Kanamycin Base; Cefpiramide; Salvianolic Acid B; Teniposide; Benzoylgedunin; 6-Deaminoadenosin; unii-o9h5ky11sv; Cephalosporin Derivative; tcm5280805; tcm5280445; tcm5280343; tcm5280863; tcm5458190; Quinadoline; Polyketide Isocoumarin D1; 0-Hydroxyusambarine; 6-Oxo-isogorgosterol; 22-Hydroxyhopane-3-one; Glazoprevir; mfcd00832476; mfcd02180753; Pacritinib; a3659; a3777; Rutin; Eriodictyol; Enterodiol; Naringenin; Freymiflavone D; Eucryphin A; Azadirachtin H; Azadirachtin I; Azadirachtin Q; sn00334175; sn00162745; Alpha-Sitosterol;Glycyrrhizic acid; Azadirachtin; Kushenol-W; Cyanidin 5-O-β-D-glucoside; Mollflavone; Methylflavone; Isoginkgetin; Sciadopitysin; Podocarpusflavone A; Cryptomeresin; Cytosporin Z8; Levocabastine; p-Coumaric acid; Ketorolac tromethamine; Methylnaltrexone; Dienogest; Petunidin 3,5-diglucoside; Anemonin 3-O-rutinoside; las 51620435; las 51620429; Roxithromycin; Levoleucovorin; Etodolac; Tenofovir alafenamide; Ornithine vasopressin; Otilonium bromide; Lanreotide; Argipressin; Demoxytocin; Carbetocin acetate; Lysine vasopressin; Ecopipam; Polymyxin B1; Acteoside; Abrus saponol G; Kaempferol-3-O-rutinoside; Hederagenin; Abruside A; Robustaflavone; Agathisflavone; Sweroside; Ononin; Ilexsaponin A1; Peimine; Peiminine; Dioscin I; Maclurin; Coumarin; Salidroside; Aloe-emodin; Timosaponin AIII; Silybinin; Moracin M; α-Luteolin; Yohimbine; Linderalactone; Brucine sulfate; Myristicin; Methysticin; Coptisine; Tiliroside; Glabrone; Lignan; Gastrodin; Leonuride A; Evodiamine; Nuciferine; Cynarin; Gramine; Narcissin; Protopanaxatriol; Dryocrassin ABBA; Megastigmane; Halosaline; Nicotiflorin; Lupeol; Aloe; Aloe-emodin; Gloiosporone; Sitosterol; Azadirachtin; Ginger; Gingerol; Anthocyanin; Medicagol; Faradiol; Flavonearsenate; Withanoside V; Somniferine; Vicenin-2; Isocamphane; Sesamolinol; Ecabet sodium; Homoharringtonine; Dorastatin; Spongistatin; Plicamycin; Alvodine; Nicotiflorin; Kaempferol sulfate; 2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-4-oxo-4H-1-benzopyran-3-yl-β-D-glucuronide; Isorhamnetin-3-O-glucoside; Narcissoside; Calenduloside B; Lauryl glucoside; Quercetin-3-glucoside; Cordifolioside; Anthraquinone; Emodin 8-glucoside; Hyperoside; Lisinopril; Deoxynortestosterone; Telithromycin; Sophorine; Solanine; 10-Hydroxyusambarensine; Strychnopentamine; Usambarine; Vanillin; Clambesidin 786; Clambesidin 826; Tetrahydrobiopterin; Tetrodotoxin; Bryostatins; Lutein; Galantamine; Nomilin; Deacetylnomilin; Ichangensin; Amyrin; 24-Dimethylenecycloartanol; Isogustine; Lentinus edodes; Agaricus bisporus; jmx0286; jmx0301; jmx0941; DL-Chloramphenicol; mpi43; mpi44; mpi46; Keigairengyoto; Sho-saiko-to plus kiyaku-sekko; Kakkontokasenkyushin'i; vuwcov059; vuwcov267; vuwcov270; 4-Hydroxyisoledene; Mallotusphilippensis 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; Crocus sativa oil; MDL-28170; Z-LVG-CHN2; ONO 5334; MLN-3897; Psoralen; Isopsoralen; Lycorine hydrochloride; Lycorine hydrochloride; Bufotalin; Venenum Bufonis; Periplocin; Veratridine / Veratrine I; Coniferyl aldehyde; Macrocarpioside; Bruceolide; Kochioside IC; Roburic acid; Holotox A; Isotumerone; Rubescensin; Dehydrocostus lactone; Costunolide; Dehydrodiisoeugenol; Liensinine; Isoliensinine; VPS34-IN1; STF-62247; MCoPPB; GW803430; Amodiaquine dihydrochloride; N-Methylspiperone; GMC 2-29; LU AE58054; Medirazine; Levomepromazine; Difetorone; Naltrexone isothiocyanate; AM1241; CPDD; SB 271046; GMC 2-113; CAA-0225; Caspase inhibitor 1; Z-Gly-Leu-Phe chloromethyl ketone; Baricitinib; Calpain inhibitor I; IKK-2 inhibitor VIII; NSC 33994; ML414; IT1T dihydrochloride; S-15176 difumarate; JTV519 fumaric acid hemisalt; Resmetirom; Trifluoperazine 2-butenedioate; Asterin D; N-[(1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl]nonanamide; Merianthrene; Disuprazine; Proglicmetazine; DMP777; HU-211; Trifluoperazine dihydrochloride; Thioridazine hydrochloride; Bicalutamide; Cinnamaldehyde; Piperine; Zingiberene; GR;

[0278] 127935; Levetiracetam; Sotalol; Oxazepam; Methimazole; Hydroxycarbamide; Clonazepam; Meloxicam; Temazepam; Anastrozole; Perindopril; Silodosin; Lorazepam; Bupropion; Bisoprolol; Linagliptin; S-Chloropyridinyl N-Oxide; Allopurinol; Indapamide; Chlorthalidone; Phloretin; Silybum marianum; Isoliquiritigenin B; Isosilybin B; Spiropiperone; Vitamin B9; Vitamin K; Vitamin K2; Oleandrin; Pro-Fibrogen A; Cucurbitacin A; Jambulic acid; Aloenin D; 4,5,6,7-Tetrachloroindan-1,3-dione; Auraptene; Dihydroquercetin; Quercetin; Isoquercitrin; pc000550; pc000361; pc000558; pc000573; grl0617; Quercetin; Glycyrrhizic acid; Δ9-Tetrahydrocannabinol; Artemether; Dihydroartemisinin; Artemisinin II; Cannabidiol; Punicalagin; Panduratin A; Andrographis paniculata; Ginger; Boesenbergia rotunda; Scutellaria baicalensis; Punica granatum extract; zinc000013444414; zinc000137976768; zinc000143375720; Diosmin; Apigenin; Okadaic acid; p-57as3; Concanavalin A; Oleandrin; Methyl gitolate; Ivermectin; Fumitremorgin; Perillaldehyde; Perilla alcohol; Valacyclovir; Finasteride; Betamethasone; Clonidine; Growth hormone; Nitisinone; Cialis; Ethacrynic acid; Chloroguanide; Tamsulosin; Rifapentine; Cyclosporine; Nitrogen; Arginine; Abatacept; Interferon β-1a; Thalidomide; Crisaborole; Nitroglycerin; Brexanolone; Omalizumab; Cetuximab; Propranolol; Interferon β-1b; Prednisolone; Torin-2; Rapamycin; Radotinib; Thiostrepton; Cl-Chloramidine; CS-2826; Ficus flavan A; Hygromycin B; Nabisimus; Abixicin II; Procyanidin B1; Indigo; Cryptospirolactone; 10'-Hydroxyusambarensine; Strychnopentamine; Usaralocarpin A; 12α-Epi-Millettosone; Tokinol; Fibuxine; 5-Chloro-ω-hydroxy-1-O-methylrhein; Cystine E; jq1; zbc260; Candesartan cilexetil; Saquinavir; Boron citrate; Oleoylethanolamide; Liquiritin; Laminarin; Eckloniaol; Trifluorocortol; 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; Ranizumab; Abivertinib; bld-2660; Pemizivipirdil; Artesunate / Piroxicam; Carrageenan dew; at-527; ptc299; Bulyric acid; cigb-325; sb203580; mapk13-in-1; arry-797; Tofacitinib; mpro 13b; gc-373;GC-376; mpron3; fedratinib; ipratropium bromide; lomitapide; metoclopramide; S1RA; crinine; ilexsaponin B2; yan glycoside; zinc000027215482; zinc000252515584; gentioflavone; 2'-O-ribomethyltransferase; boswellic acid A; zinc000253504770; zinc000253504766; triamcinolone; hydrochlorothiazide; theaflavin A; chebulinic acid; chebulilinic acid; coumaroylquinic acid; sinapoyl D-glucoside; tetra-O-galloyl-β-D-glucose; methyl rosmarinate; hibiscus grandiflorus glycoside; dihydroserinol; lectin; digitoxigenin; carene; amaranth; diarylheptanoids; indigo; aloe-emodin; dihydrotriptolide; philambine; isolimonicin; magnoflorine; piperolactam A; vetanon; biflavonoid; cinnamamide; agomelatine; ramelteon; immunoglobulin; IFN-β1a; IFN-β1b; interleukin-2; cynk-001; asc09; cobicistat; calicheamicin; dihydroartemisinin; piperaquine; piclinaldazone; cf101; nivolumab; obinutuzumab; mepolizumab; jackatinib; tj003234; tocilizumab; adalimumab; ravulizumab; ALXN1210; clazakizumab; afutuzumab; iph5401; ly3127804; ifx-1; bevacizumab; valsartan; 7-hydroxyellipticine; baricitinib; β-glucan; p-coumaroyl triacetate lactone; zinc02111387; zinc02122196; sn00074072; zinc04090608; Xuebijing; Qingfei Paidu Decoction; etanercept; enalapril; oroxylin A; irilone; crocin B anhydride; eucangongone; ulcaic acid; demethylzeylasteral; maslinic acid; atractylenolide III; astragaloside IV; mandelon; cucurbitacin G 2-glucoside; citronellol; limonene; salvianolic acid A; neochlorogenic acid; artemisia alcohol A; bisdemethoxycurcumin; δ-viniferin; pseudoephedrine; methylephedrine; special leaf alkaloid; ukarine F; anisodamine; forsythoside I; amygdalin; ursodeoxycholic acid; withania somnifera extract A; β-sitosterol; farnesol B; desloratadine; tanshinone; isatis root; rhizome of cibotium barometz; torreya nucifera; Shuanghuanglian; eugenol; ubiquinone; polymethoxyflavone; polyhydroxyflavone; melcytin; 3-O-β-D-glucoside; kaempferol 3-O-robinobioside; delphinidin; galangin; isoferulic acid; thymol; nigellicin; nigellidine; MUC1; α-lactalbumin; monoclonal antibody; or its derivatives; or its mixtures.;

[0279] In alternative embodiments, additional therapeutic agents can be formulated in any manner and can be applied in a variety of forms, including nanoparticles, polymeric nanoparticles (PNPs), liposomes, lyophilized liposomes, micelles, polymeric micelles, niosomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), nanoemulsions, emulsions, self-emulsifying nano drug delivery systems (SNEDDS), nanocrystals, cocrystals, mesoporous silica nanoparticles (MSNs), dendrimers, superspreaders, solid dispersions, non-covalent complexes, polymer complexes, biopolymer complexes, solutions, oleaginous / oil solutions, cosolvent solutions, surfactant / surfactant solutions, solubilizer solutions, polymorphs, lipid-based systems, gels, colloids, sols, or any form described in the scientific and patent literature and obtained in any manner described in the scientific and patent literature.

[0280] In alternative embodiments, the synergistic effect of FORMULA I-III can be achieved by various forms of niclosamide, remdesivir, etc. Other synergists can be found in the scientific and patent literature.

[0281] In alternative embodiments, additional agents such as verapamil, polyoxylated castor oil derivatives, the emulsifiers Cremophor RH 60 and Tween 80, grapefruit juice, etc. (other agents can be found in the scientific and patent literature), which are regulators of CYP3A4 and P-glycoprotein and can increase the absorption of FORMULA I-III compounds, can also be included.

[0282] In another aspect, a method for treating a viral disease in a human in need of treatment or in a mammal or an animal or a bird is provided, comprising administering a therapeutically effective amount of a stable aqueous formulation comprising avermectin, a surfactant, and a cosolvent.

[0283] In another aspect, a method for treating a viral disease in a human in need of treatment or in a mammal or an animal or a bird is provided, comprising administering a therapeutically effective amount of a stable formulation comprising an avermectin solution in an oleaginous / oil or an avermectin emulsion.

[0284] In another embodiment, a method for treating a disease in a human in need of treatment or in a mammal or an animal or a bird comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a FORMULA I-II compound in combination with at least one additional therapeutic agent.

[0285] In another embodiment, a method of treating a disease in a human in need of treatment or in a mammal, animal or bird comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a compound of FORMULA I-III and at least one additional therapeutic agent such as, but not limited to, thiamine, vitamin C, vitamin D, glutathione, S-adenosylmethionine, cysteine, N-acetylcysteine in intravenous or intramuscular form.

[0286] IV. Formulations and Pharmaceutical Compositions

[0287] The compounds of the present invention are formulated with common carriers and excipients, which are selected according to conventional practice. Tablets will contain excipients, preservatives, fillers, binders, etc. Aqueous formulations are prepared in a sterile form and are usually isotonic if they are not intended for oral administration. All formulations optionally contain excipients such as those described in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, sugars such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc. The pH of the formulations ranges from about 3 to about 11, but is usually between 7 and 10. In some embodiments of the present invention, the pH of the formulations ranges from about 2 to about 5, but is usually between 3 and 4.

[0288] While the active ingredients may be administered alone, it is preferred to present them as pharmaceutical compositions. The compositions of the present invention, whether for veterinary or human use, include at least one active ingredient, as described above, together with one or more acceptable carriers and optionally contain other therapeutic ingredients, particularly other therapeutic ingredients discussed herein. The carrier must be "acceptable", i.e., compatible with the other ingredients of the composition and physiologically harmless to the recipient.

[0289] These compositions include compositions suitable for the above-described routes of administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. These methods and compositions are generally described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). These methods involve bringing the active ingredient into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then shaping if necessary.

[0290] Formulations of the present invention suitable for oral administration may be presented in discrete unit forms such as capsules, sachets or tablets, each 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 an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may be administered as a bolus, paste or cream.

[0291] Tablets are made by compression or molding, optionally with the addition of one or more additional ingredients. Compressed tablets can be prepared by compressing the active ingredient in free-flowing form, such as a powder or granules, in a suitable machine, further mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets can be made by molding a mixture of powdered active ingredient moistened with an inert liquid diluent in a suitable machine. Tablets can additionally be coated with a shell or pellet and optionally formulated in a form that allows for slow or controlled release of the active ingredient.

[0292] For infections of the eye or other external tissues (such as the oral cavity and skin), the composition is preferably applied in the form of an ointment or cream containing the active ingredient, for example, in an amount of from 0.075 to 20% wt. (including the active ingredient in the range of 0.1% to 20% in 0.1% wt. increments, for example, 0.6% wt., 0.7% wt., etc.), more preferably from 0.2 to 15% wt., and most preferably from 0.5 to 10% wt. When formulated as an ointment, the active ingredient can be used with paraffin or a water-soluble ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base.

[0293] Optionally, the aqueous phase of the cream base can include (if desired) at least 30% wt. of a polyol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol (including PEG400) and mixtures thereof. The composition for topical use can preferably include a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and its analogs.

[0294] The oil phase of the emulsion of the present invention can be composed of known ingredients in a known manner. Although this phase can contain only an emulsifier (or emulsifying agent), preferably it contains at least one emulsifier together with a fat or oil or a mixture containing both a fat and an oil. Hydrophilic emulsifiers are preferably used together with lipophilic emulsifiers as stabilizers. It is also preferred to contain both oil and fat at the same time. The emulsifier (with or without a stabilizer) together constitutes a so-called emulsifying wax, and the emulsifying wax together with the oil and fat constitutes a so-called emulsifying ointment base, which forms the oily dispersed phase of the cream composition.

[0295] Emulsifiers and emulsion stabilizers suitable for the formulations of the present invention include 60, 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. Other emulsifiers and emulsion stabilizers suitable for the formulations of the present invention include 80.

[0296] The choice of oil or fat suitable for the formulation depends on achieving the desired cosmetic properties. Creams can be non-greasy, non-staining and washable products with an appropriate consistency to avoid leakage from tubes or other containers. Straight-chain or branched-chain alkyl esters, mono- or di-esters, such as diisoadipate, isocetostearate, propylene glycol dicaprylate, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixture of branched-chain esters known as Crodamol CAP, the latter three being preferred. They can be used alone or in combination, depending on the desired properties. As an alternative, high-melting-point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can also be used.

[0297] According to the present invention, the pharmaceutical composition comprises a combination with one or more pharmaceutically 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 can be prepared, for example, as tablets, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft gelatin capsules, syrups or elixirs. The formulations for oral use can be prepared by any method known in the pharmaceutical art, and such compositions can contain one or more excipients, including sweetening agents, flavoring agents, coloring agents and preservatives, to provide a palatable preparation. Tablets containing the active ingredient admixed with non-toxic pharmaceutically acceptable excipients suitable for tablet production are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate 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 gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated using known methods, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. Delayed-release materials such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with waxes.

[0298] The products for oral use can also be designed as hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is admixed with a water or oil medium such as peanut oil, liquid paraffin or olive oil.

[0299] The aqueous suspension according to the present invention comprises an active material mixed with excipients suitable for preparing an aqueous suspension. These excipients may include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic, and dispersing or wetting agents such as naturally occurring phospholipids (such as lecithin), condensation products of alkyl oxides with fatty acids (such as polyethylene glycol stearate), condensation products of ethylene oxide with long-chain fatty alcohols (such as heptadecaethylene glycol), condensation products of ethylene oxide with partial esters of fatty acids and hexitol anhydrides (such as polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or propyl p-hydroxybenzoate, one or more colorants, one or more flavorings, and one or more sweeteners such as sucrose or saccharin. Other non-limiting examples of suspending agents include cyclodextrin and Captisol.

[0300] The oily suspension can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. A thickening agent such as beeswax, solid paraffin or cetyl alcohol can be included in the oral suspension. Sweeteners and flavorings as described above can be added to make a palatable oral preparation. These compositions can be preserved by adding an antioxidant such as ascorbic acid.

[0301] The dispersible powders and granules of the present invention, suitable for preparing or manufacturing an aqueous suspension by adding water, comprise an active ingredient mixed with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are those exemplified above. Additional excipients such as sweeteners, disintegrants and colorants may also be present.

[0302] The pharmaceutical composition of the present invention may also be presented as a water-in-oil emulsion. The oil phase may 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 gums of natural origin such as gum arabic and gum tragacanth, phospholipids of natural origin such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings. Syrups and elixirs may contain sweeteners such as glycerol, sorbitol or sucrose. These formulations may also contain a lubricant, a preservative, a flavoring or a colorant.

[0303] The pharmaceutical composition of the present invention can be a sterile injectable preparation, such as a sterile aqueous injection solution or an oily suspension. This suspension can be prepared using the above-mentioned suitable dispersants or wetting agents and suspending agents according to the prior art. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Acceptable carriers and solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, a sterile fixed oil is usually used as a solvent or suspension medium. Any odorless fixed oil can be used for this purpose, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injectable preparations. Acceptable carriers and solvents that can be used include water, isotonic Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0304] The amount of the active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the recipient and the specific route of administration. For example, a human sustained-release formulation intended for oral administration may contain about 1 to 1000 milligrams of the active ingredient, combined with a suitable and convenient amount of carrier material, which can account for about 5% to about 95% (by weight) of the total amount of the composition. The pharmaceutical composition can be prepared into a dosage amount convenient for measurement. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 picograms of the active ingredient per milliliter of solution, providing an appropriate infusion volume at a rate of about 30 milliliters per hour.

[0305] Formulations suitable for topical use in the eye also include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solution of the active ingredient. The concentration of the active ingredient in such a composition is preferably from 0.5% to 20%, more preferably from 0.5% to 10%, especially about 1.5% w / w.

[0306] Formulations suitable for topical use in the mouth include lozenges containing the active ingredient, usually made from a flavoring base of sucrose and gum arabic or tragacanth; lozenges containing the active ingredient made from an inert matrix of gelatin and glycerol or sucrose and gum arabic; and mouthwashes containing the active ingredient, with a suitable liquid carrier.

[0307] Formulations suitable for rectal administration can be in the form of suppositories, with a suitable matrix, including for example cocoa butter or salicylates.

[0308] Formulations suitable for pulmonary or nasal administration have a particle size, for example, in the range of 0.1 to 500 micrometers, such as 0.5, 1, 30, 35, etc., and reach the alveolar sacs by rapid inhalation through the nose or inhalation through the mouth. Suitable compositions include aqueous or oily solutions of the active ingredient. Formulations suitable for administration as an aerosol or dry powder can be prepared according to conventional methods and can be delivered together with other therapeutic agents, such as compounds for the treatment or prevention of viral infections or viral diseases, as described below.

[0309] Formulations suitable for vaginal administration may be in the form of vaginal suppositories, tampons, creams, gels, pastes, foams or sprays and, in addition to the active ingredient, contain carriers known in the art to be appropriate.

[0310] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile solutions for injection which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending and thickening agents.

[0311] These formulations are presented in single-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition immediately prior to use of a sterile liquid carrier, for example water for injection. Injectable solutions and suspensions prepared immediately before use are made from the sterile powders, granules and tablets described previously. Preferred single-dose preparations are those containing the daily dose or a sub-dose of the daily dose, as described above, or an appropriate fraction of the active ingredient.

[0312] It is important to note that, in addition to the ingredients specifically mentioned above, the compositions of the invention may also include other agents common in the art, taking into account the type of composition under discussion, for example compositions suitable for oral use may include flavorings.

[0313] The invention also provides veterinary compositions which comprise at least one active ingredient as described above, and a veterinary carrier therefor.

[0314] A veterinary carrier is a material for administering the composition which may be solid, liquid or gaseous and which is inert or acceptable in veterinary medicine and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

[0315] The compounds of the invention are used in the manufacture of controlled release formulations ("controlled release formulations") containing one or more compounds of the invention as active ingredient, in which the release of the active ingredient is controlled and regulated to provide less frequent dosing or to improve the pharmacokinetic or toxicological profile of that active ingredient.

[0316] In another embodiment, a method of treatment comprises administering a therapeutically effective amount of a pharmaceutical composition which comprises a combination of an effective amount of a compound of FORMULA I - III with a pharmaceutically acceptable diluent or carrier.

[0317] In another embodiment, the method comprises administering a therapeutically effective amount of a combined pharmaceutical formulation (FORMULA IV) in the form of a solution / emulsion / suspension which comprises:

[0318] a) A first pharmaceutical composition comprising compounds of FORMULA I-III, and

[0319] b) At least one of the following components:

[0320] (1) An oil phase containing vegetable and / or animal fats;

[0321] (2) One or more surfactants;

[0322] (3) One or more solvents;

[0323] (4) One or more gelling agents.

[0324] FORMULA IV may be in the form of a true solution or colloidal solution, emulsion, solid or liquid dispersion, suspension, emulsion-suspension, gas mixture, foam, sol, gel, paste, and mixtures thereof. FORMULA IV can be prepared by mixing, homogenizing, dispersing, and emulsifying the components.

[0325] In another embodiment, the method includes administering a therapeutically effective amount of a combined pharmaceutical preparation (FORMULA IV Variant A), which comprises:

[0326] (a) An oil phase containing vegetable and / or animal fats and / or lecithin, in a weight percentage of 1-99.999%

[0327] (b) Compounds of FORMULA I-II and / or "API", in a weight percentage of 0.001-99%

[0328] (c) (Optional) One or more surfactants, in a weight percentage of 0-70% (selected from the physiologically acceptable surfactants listed in F(III.I.Section))

[0329] (d) (Optional) One or more solvents, in a weight percentage of 0-99.9% (selected from the physiologically acceptable solvents listed in Method 1(III.I.Section))

[0330] (e) (Optional) One or more gelling agents, in a weight percentage of 0-99.9%, including but not limited to: alginate, pectin, carrageenan, gellan gum, gelatin, agar powder, modified starch, methylcellulose, and hydroxypropyl methylcellulose.

[0331] In another embodiment, the method includes administering a therapeutically effective amount of a combined pharmaceutical preparation (FORMULA IV Variant B), which comprises:

[0332] (a) (Optional) an oil phase containing vegetable and / or animal fat and / or lecithin, with a weight percentage of 0 - 99.999%

[0333] (b) A compound of FORMULA I-II and / or "API", with a weight percentage of 0.001 - 99%

[0334] (c) (Optional) one or more surfactants, with a weight percentage of 0 - 70% (selected from the physiologically acceptable surfactants listed in F(III.I.Section))

[0335] (d) one or more solvents, with a weight percentage of 5 - 99.9% (selected from the physiologically acceptable solvents listed in Method 1(III.I.Section))

[0336] (e) (Optional) one or more gelling agents, with a weight percentage of 0 - 99.9%, including but not limited to: alginate, pectin, carrageenan, gellan gum, gelatin, agar powder, modified starch, methylcellulose, and hydroxypropyl methylcellulose.

[0337] In another embodiment, the method includes administering a therapeutically effective amount of a combined pharmaceutical formulation (FORMULA IV variant C), which includes:

[0338] (a) an oil phase containing vegetable and / or animal fat and / or lecithin, with a weight percentage of 1 - 99.999%

[0339] (b) A compound of FORMULA I-II and / or "API", with a weight percentage of 0.001 - 99%

[0340] (c) (Optional) one or more surfactants, with a weight percentage of 0 - 70% (selected from the physiologically acceptable surfactants listed in F(III.I.Section))

[0341] (d) one or more solvents, with a weight percentage of 1 - 99.9% (selected from the physiologically acceptable solvents listed in Method 1(III.I.Section))

[0342] (e) (Optional) one or more gelling agents, with a weight percentage of 0 - 99.9%, including but not limited to: alginate, pectin, carrageenan, gellan gum, gelatin, agar powder, modified starch, methylcellulose, and hydroxypropyl methylcellulose.

[0343] In another embodiment, the method includes administering a therapeutically effective amount of a combined pharmaceutical formulation (FORMULA IV variant D), which includes:

[0344] (a) (Optional) An oil phase containing vegetable or / and animal fats or / and lecithin, with a weight percentage of 0 - 99.999%

[0345] (b) Compounds of FORMULA I-II or / and "API", with a weight percentage of 0.001 - 99%

[0346] (c) One or more surfactants, with a weight percentage of 0.05 - 70% (selected from the physiologically acceptable surfactants listed in F(III.I.Section))

[0347] (d) (Optional) One or more solvents, with a weight percentage of 0 - 99.9% (selected from the physiologically acceptable solvents listed in Method 1(III.I.Section))

[0348] (e) (Optional) One or more gelling agents, with a weight percentage of 0 - 99.9%, including but not limited to: alginates, pectins, carrageenans, gellan gums, gelatins, agar powders, modified starches, methylcellulose, and hydroxypropyl methylcellulose.

[0349] The active compounds of FORMULA I-IV can be administered / presented in the form of food, food additives, edible soluble films, beverages, pharmaceutical agents, and feeds for domestic and wild animals. The beverages can be non-alcoholic beverages or alcoholic beverages. Examples of non-alcoholic beverages include carbonated beverages, non-carbonated beverages (such as fruit juices and fruit juice drinks), soft drinks, sports drinks, tea, coffee, and hot chocolate. Alcoholic beverages can be, for example, beer, low-malt beer, third-class beer, sake, wine, champagne, liqueur, or medicinal liquor. When used as a food material or food additive (e.g., human food or animal food, such as dog or cat food or poultry, cow, or pig feed), the active compounds can be, for example, in the form of tablets, capsule preparations, solid agents dissolved in beverages (such as powders and granules), gel-like semi-solids, liquids (such as drinking water), and highly concentrated solutions to be diluted before use. Common food adjuncts such as vitamins, sugars, dyes, and flavorants can be appropriately mixed. The food can be given in any form, including liquids and solids.

[0350] In another embodiment, the method includes administering a therapeutically effective amount of a combined pharmaceutical preparation (FORMULA V) in the form of a food product, beverage, or dietary supplement.

[0351] In an alternative embodiment, the present invention provides pharmaceutical preparations or compositions for in vivo, in vitro, or ex vivo methods to treat, prevent, reverse, and / or improve medical conditions (e.g., diseases, disorders, syndromes, infections).

[0352] In alternative embodiments, the pharmaceutical compositions provided herein or for use in the methods provided herein can be administered parenterally, topically, orally, or locally, such as by aerosol or transdermal administration. These pharmaceutical compositions can be formulated in any manner and can be administered in various unit dosage forms depending on the condition or severity of the disease, the general medical condition of each patient, the preferred method of administration therefor, etc. Details regarding formulation and administration techniques are described in detail in the scientific and patent literature, see, for example, the latest version of Remington: The Science and Practice of Pharmacy, Mack Publishing Co., Easton, PA ("Remington"). For example, in alternative embodiments, these compositions of the present invention can be formulated in buffers, salt solutions, powders, emulsions, vesicles, liposomes, nanoparticles, nanolipid particles, etc. In alternative embodiments, these compositions can be formulated in any manner and can be applied in various concentrations and forms depending on the desired in vivo, in vitro, or ex vivo conditions, the desired in vivo, in vitro, or ex vivo method of administration, etc. Details regarding in vivo, in vitro, or ex vivo formulation and administration techniques are described in detail in the scientific and patent literature. The formulations and / or carriers for use in the methods provided herein can be in the form of tablets, pills, powders, capsules, liquids, gels, syrups, slurries, suspensions, etc., suitable for in vivo, in vitro, or ex vivo applications.

[0353] In alternative embodiments, the compositions can be formulated in any manner and can be applied in various forms, including solid dispersions, polymeric nanoparticles (PNPs), liposomes, micelles, niosomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), nanoemulsions, emulsions, self-emulsifying nano drug delivery systems (SNEDDS), nanocrystals, mesoporous silica nanoparticles (MSNs), and dendrimers; and / or using the following methods:

[0354] Physical modification: A) Particle size reduction

[0355] a) Micronization

[0356] b) Nanoparticle suspension,

[0357] B) Modification of crystallization habit

[0358] C) Solid dispersion

[0359] a) Eutectic mixture

[0360] b) Solid solution

[0361] c) Amorphous solid solution

[0362] d) Glass solution and glass suspension

[0363] e) Freezing techniques.

[0364] Chemical modification: A) Changing the pH,

[0365] B) Using buffers,

[0366] C) Derivatization,

[0367] D) Complexation,

[0368] E) Salt formation.

[0369] Miscellaneous methods: A) Supercritical fluid processes,

[0370] B) Using adjuvants such as surfactants, solubilizers, cosolvents, cosolubilizers, and novel excipients.

[0371] Or in any manner described in the scientific and patent literature.

[0372] V. Routes of administration

[0373] The compounds of FORMULA I-V described herein can be administered in solid or liquid dosage forms (e.g., orally). In both cases, the compound can be encapsulated in a material to protect it from acids and other natural conditions that may inactivate the compound. The compound can be made into aqueous solutions, liquid dispersions, (swallowable) tablets, buccal tablets, lozenges, capsules, elixirs, powders, granules, ointments, adhesive skin patches, sprays, suspensions, syrups, and wafers. These dosage forms can include pharmaceutically acceptable excipients, diluents, and / or carriers such as binders, disintegrants, emulsifiers, lubricants, flavorings, antioxidants, and preservatives. Liquid dosage forms can include diluents such as normal saline or aqueous buffers.

[0374] Any route of administration of FORMULA I-V can be selected in the methods described herein. For example, the route of administration can be selected from oral, nasal, topical, buccal, rectal, vaginal, ophthalmic, subcutaneous, intramuscular, intraperitoneal, epidural, intravenous, intraarterial, intratumoral, spinal, intrathecal, intra-articular, intraarterial, subarachnoid, sublingual, oral mucosa, pulmonary, bronchial, lymphatic, intrauterine, subcutaneous, intratumoral, integrated on an implantable device, intradural, intracortical, intradermal, cutaneous, epidermal, transdermal, vaginal, rectal, ocular (e.g., transconjunctival), intraocular, ureteral, and parenteral. An advantage of the compounds of the present invention is that they have high bioavailability and can be administered orally. The preferred route of administration is oral.

[0375] In the method for treating viral infections of the present invention, the compounds of the present invention can be administered at any time when contacting a person suffering from a viral infection or a person already infected with a virus. In some embodiments, the compounds of the present invention can be prophylactically administered to a person in contact with a person suffering from a viral infection. In some embodiments of the present invention, the compounds of the present invention can be administered to a person who tests positive but has no symptoms of viral infection. In some embodiments of the present invention, the compounds of the present invention can be administered after the appearance of symptoms of viral infection.

[0376] The effective dose of the active ingredient depends at least on the nature of the disease being treated, its toxicity, whether the compound is used prophylactically (lower dose) or to treat an active viral infection, the method of administration and the pharmaceutical formulation, and is determined by the doctor through conventional dose escalation studies. The expected range can be from about 0.0001 to about 100 mg / kg body weight per day; usually from about 0.01 to about 10 mg / kg body weight per day; more usually from about 0.01 to about 5 mg / kg body weight per day; most usually from about 0.2 to about 1 mg / kg body weight per day. For example, for an adult with a body weight of about 70 kg, the daily candidate dose is about 1 mg to 1000 mg, preferably 5 mg to 500 mg, and can be a single or multiple doses. All doses are based on the equivalent amount of pure "API".

[0377] The effective dose of the compounds of the present invention for treating viral infections may depend on whether it is used prophylactically or to treat a person already infected with a virus. In addition, the dose may also depend on whether the person infected with the virus has not yet shown symptoms or has already shown symptoms of viral infection. Persons who test positive and show symptoms of viral infection may require a higher dose of treatment, whereas the dose for those receiving prophylactic treatment may be lower.

[0378] Suitable dosing periods are conceivable. For example, the dosing time can be from 1 day to 100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80 or 90 days. The dosing time can also be from 1 week to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 weeks. Longer dosing periods are also recommended. The dosing time may depend on whether the compound is administered prophylactically or to treat a person infected with a virus. For example, prophylactic administration can be carried out during continuous contact with other persons infected with a virus and for an appropriate period of time after the last contact with the person infected with a virus. For a person already infected with a virus, the treatment time can be any duration required to treat the patient, as well as an appropriate period of time after testing negative for viral infection to ensure that the viral infection does not recur.

[0379] VI. Examples

[0380] A. Preparation of Compounds

[0381] Example 1.

[0382] Medicinal-grade ivermectin, CAS No. 70288-86-7, was purchased from Aecochem Co., Ltd., Xiamen, China. Apple pectin was purchased from Ronas Chemical Industry Co., Ltd., Chengdu, China. All other chemicals were of analytical grade and were not further purified.

[0383] The compound of FORMULA 1 was prepared by Method 1. Mechanochemical synthesis of the solid dispersion was carried out using a roller ball mill. Processing mode: driving speed was 400 rpm, grinding jar speed was 100 rpm, grinding jar volume was 2000 ml, grinding medium was steel balls (diameter 12 mm, loading amount 800 g), and the processing time varied from 2 to 24 hours. The sample was a loose powder (particle size from 0.1 to 10 microns). The compositions and results of obtaining highly bioavailable solid dispersions using FORMULA I are shown in Table 2.

[0384] Table 2. The compound of FORMULA I obtained in Example 1.

[0385]

[0386] Example 2.

[0387] The compound of FORMULA 1 was prepared by Method 10. Acetone or ethanol (refined 96%) was used as the organic solvent: 40 - 70 parts of the solvent were used per 100 parts of the polymer and avermectin mixture (calculated by gram equivalent). These solvents could dissolve the polymer matrix. After thoroughly stirring the polymer and avermectin wetted with the solvent in a mortar to form a dough-like substance, and after drying by solvent evaporation. The dried polymer substance could be ground using a ball mill or other grinding machines, and the particle size of the polymer product should not exceed 5 - 9 microns. The compositions and results of obtaining highly bioavailable nanocomposites using FORMULA I are shown in Table 3.

[0388] Table 3. The compound of FORMULA I obtained in Example 2.

[0389]

[0390] Example 3.

[0391] The compound of FORMULA 1 is obtained using Method 6. Ivermectin and PVA - polypropylene glycol graft copolymer are used to prepare a solid dispersion. Thermal stage extrusion is carried out using a co - rotating, fully meshing conical mini twin - screw extruder. The temperature is set at 195 °C, and the screw speed varies between 90 and 105 rpm. 7.5 grams are fed manually for each run; the internal circulation time after feeding is 5 minutes. The extrudate is collected after cooling to ambient temperature on a conveyor belt. The extruded samples are then ground in a laboratory mill for 4 minutes and sieved to remove particles with a particle size greater than 400 microns.

[0392] B. Bioavailability study

[0393] Example 4. Study of the concentration of ivermectin in bovine plasma

[0394] The free ivermectin substance is processed in a planetary ball mill with the following parameters: material weight - 5 grams, grinding jar volume - 200 ml, grinding medium - steel balls (diameter 8 mm, load 90.0 grams), processing time - 20 minutes. The compound of FORMULA I is processed according to Example 1 №1.

[0395] The cows are divided into 2 groups of 1 cow each. Free ivermectin (IVM) and the compound of FORMULA I are orally administered to the fasting cows. Blood samples are taken from the jugular vein at appropriate time intervals (0, 4, 20 hours) after administration.

[0396] The concentration of ivermectin in plasma is analyzed according to the method of Na - Bangchang, K. High - performance liquid chromatography (HPLC) is used to determine ivermectin in plasma, see Southeast Asian J Trop Med Public Health, September 2006, 37(5):848 - 58, PMID: 17333725.

[0397] The internal standard (moxidectin) and ivermectin are separated on a Hypersil Gold C18 column (150x4.6 mm, 5 - micron particle size) with retention times of 3.7 and 7.0 minutes respectively. Fluorescence detection is set with excitation and emission wavelengths of 365 and 475 nm respectively. The mobile phase consists of acetonitrile, methanol, and distilled water (50:45:5, v / v / v) and passes through the column at a flow rate of 1.5 ml / min. Chromatographic analysis is carried out at 25 °C. Sample preparation (100 μl plasma) is carried out by one - step protein precipitation with acetonitrile, followed by derivatization with an N - methylimidazole solution (1:1, v / v) in 100 μl acetonitrile and a trifluoroacetic acid anhydrous solution (1:2, v / v) in 150 μl acetonitrile. The calibration curve for a concentration range of 20 - 8,000 ng / ml plasma is linear with a correlation coefficient better than 0.995.

[0398] All blood samples were centrifuged at 3000 rpm for 15 minutes to obtain serum. Bovine plasma samples (100 μL each) were placed in 1.5 mL Eppendorf tubes and then subjected to protein precipitation. The samples were vortexed for 1 minute and then centrifuged at 13,400 rpm for 10 minutes. 20 μL of the supernatant was injected into the HPLC.

[0399] The pharmacokinetic parameters of ivermectin and the FORMULA I compound are shown in Figure 2 and Table 4. The results showed a significant increase in the bioavailability and permeability of the FORMULA I compound. Oral administration of FORMULA I 600 μg / kg IVM can exceed the EC 50 of SARS-CoV-2, which is 2.4 μM.

[0400] Table 4. Pharmacokinetic parameters after oral administration of ivermectin and the FORMULA I compound (ivermectin concentration)

[0401]

[0402] C. Permeability study

[0403] Example 5. Permeability of solid dispersions or non-covalent complexes on the Caco-2 cell line

[0404] The Caco-2 cell line is a standard in vitro model for evaluating the permeability of drugs through the gastrointestinal wall. These cells retain almost all the morphological and functional characteristics of intestinal epithelial cells, including the expression of multi-drug resistance proteins such as P-glycoprotein. Generally, the data obtained in such experiments has a good correlation with the bioavailability of drugs in vivo.

[0405] Caco-2 cells were cultured in Dulbecco's medium in a standard manner, supplemented with 10% heat-inactivated fetal bovine serum (FBS, USA). The permeability study through the Caco-2 cell monolayer was carried out according to the standard procedure. A Transwell 12-well plate (Corning, USA) containing a 0.4 μm polyester membrane was used, and the cells were seeded at a density of 1x105 cells per well. Before the experiment, the cells were grown in IMDM medium supplemented with 10% FBS. The medium was changed every two days. The integrity of the cell monolayer was evaluated by measuring the transepithelial electrical resistance (TEER) at the beginning and end of the experiment using a Millicell ERS-2 (Millipore, USA). The test substance (FORMULA I compound treated according to Example 1 No. 2) was dissolved in Hank's balanced salt solution (HBSS) at a concentration of 3 μM (calculated as pure IVM). Ivermectin was also dissolved in Hank's balanced salt solution at the same concentration of 3 μM.

[0406] The test solution was added to the top of the wells, and the bottoms of the wells were filled with pure HBSS. Then, the wells were incubated at 37.5 °C and shaken on an orbital shaker at 100 rpm. 100 μL samples were taken from the bottoms of the wells at 20, 40, 60, 80, 100, and 120 minutes. The required volume was immediately replenished with fresh HBSS solution after sampling. The substance concentration was determined by an Agilent 1200 high performance liquid chromatograph (equipped with an ultraviolet detector). Chromatographic analysis was performed on a reversed-phase column. The permeability coefficient was calculated according to the formula published in the literature.

[0407] Table 5. Comparison of the permeability of IVM non-covalent complexes through Caco-2 cell monolayers with pure IVM at similar points

[0408]

[0409] Therefore, the non-covalent ivermectin complex has better permeability than pure ivermectin.

[0410] D. Toxicity study

[0411] Example 6. Toxicity of solid dispersions or non-covalent complexes

[0412] The compounds of FORMULA I were processed according to Example 1 №2. The results of the oral toxicity (for Syrian hamsters) of the compounds of FORMULA I showed that the LD50 of pure ivermectin = 340 mg / kg, while the LD50 of pure ivermectin = 62 mg / kg, that is, the toxicity of the compounds of FORMULA I was reduced by 5.48 times.

[0413] F. Spectroscopy

[0414] Example 7. Spectroscopic analysis of non-covalent complexes

[0415] The compounds of FORMULA I were processed according to Example 1 №2. In the infrared spectrum of the obtained non-covalent complex, the valence vibration frequency of the hydroxyl group was manifested as a broad shoulder peak, which indicated the presence of intermolecular hydrogen bonds during the complex formation. Based on the infrared spectroscopic analysis, it was determined that the non-covalent complex was stable due to the presence of intermolecular hydrogen bonds.

[0416] To confirm the physicochemical values and chemical structure of the non-covalent complex and to more accurately analyze the formation of the main molecular ions, the mass spectrometry of the complex was analyzed by liquid chromatography-mass spectrometry (TOF LC-MS, Agilent Technologies). The mass spectrometry analysis showed that in addition to the peaks belonging to the individual carrier and API components, there were also peaks corresponding to various heterogeneous non-covalent structural compositions. The presence of ions corresponding to the molecular ions of the non-covalent complex in the mass spectrometry indicated that the carrier and API molecules formed a non-covalent complex due to mutual non-covalent interactions.

[0417] G. Antiviral activity

[0418] Another aspect of the present invention relates to methods for inhibiting viral infection, including treating a sample or a subject suspected of requiring such inhibition with a composition of the present invention. In the context of the present invention, samples suspected of containing a virus include natural or artificial materials such as organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.); laboratory samples; food, water or air samples; biological product samples such as cell extracts, especially recombinant cell extracts for synthesizing the required glycoproteins, etc. Generally, the sample will be suspected of containing an organism that induces viral infection, usually a pathogen such as an oncovirus. The sample can be contained in any medium, including water and organic solvent / water mixtures. Samples include organisms such as humans, as well as artificial materials such as cell cultures.

[0419] If desired, after application of the composition, the antiviral activity of the compounds of the present invention can be observed by any method, including methods for directly and indirectly detecting such activity. Methods for quantitatively, qualitatively and semi-quantitatively determining such activity are all contemplated. Generally, one of the above screening methods is applied, but any other method, such as observing the physiological characteristics of an organism, is also applicable.

[0420] The antiviral activity of the compounds of the present invention can be measured using known standard screening protocols. For example, several general protocols can be used to measure the antiviral activity of a compound.

[0421] Example 8. Human blood oxygen saturation study

[0422] The blood oxygen saturation of a symptomatic male patient and another symptomatic male patient who tested positive for SARS-CoV-2 was measured. The compound of FORMULA I was treated according to Example 1 №3.

[0423] Humans were divided into 2 groups, with 1 person in each group. The compound of FORMULA I of 600 μg / kg pure ivermectin was orally administered to the humans in the second group. Blood oxygen saturation was extracted at appropriate time intervals (0, 24, 48, 72, 96 hours) after administration.

[0424] The change in oxygen saturation of each study group on days 0 - 4 is shown in Table 6 and Figure 3. As shown in Table 6 and Figure 3, the people who received the compound of FORMULA I showed a recovery of the saturation level related to SARS-CoV-2 infection compared to those who did not receive treatment. As shown in Figure 3, the people who received the compound of FORMULA I had significantly reduced infectious virus on days 1 and 2 after infection. These data show that the compound of FORMULA I reduced the replication of SARS-CoV-2 in the lungs.

[0425] Table 6. Blood oxygen saturation before treatment and after oral administration of FORMULA I compounds.

[0426]

[0427] Example 9. Human SARS-CoV-2 viral load study

[0428] The viral load of a symptomatic male patient tested positive for SARS-CoV-2 was measured. The compound of FORMULA I was processed according to Example 2 №2.

[0429] Before use, the SARS-CoV-2 viral load in nasopharyngeal swab samples stored at -40 °C was quantified. Viral RNA was isolated from the stored samples using the QIAamp Viral RNA Mini Kit (Qiagen, Hilden, Germany).

[0430] Then, quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) targeting the SARS-CoV-2 N gene was performed. The standard curve was constructed by serial dilution of in vitro transcribed viral RNA in a cellular RNA matrix, and the cellular RNA was from nasopharyngeal negative samples.

[0431] This assay included measurement of a housekeeping gene as an internal control and normalization gene. The cycle threshold (Ct) of the housekeeping gene was used to correct the specific SARS-CoV-2 Ct value according to the number of cells in the sample. Therefore, the viral load measurement results were expressed as log10 copies per reaction.

[0432] Before oral administration of the FORMULA I compound, the log10 value of the viral load was 6.3 copies / mL, and 24 hours after oral administration of 1200 μg / kg (per pure ivermectin) of FORMULA I, the log10 value of the viral load was 5.1 copies / mL. The log10 value of the viral load at the start of treatment (6.3 copies / mL) was significantly different from the log10 value of the viral load 24 hours after the start of treatment (5.1 copies / mL). These data indicate that the compound of FORMULA I can reduce the replication of SARS-CoV-2.

[0433] Table 7. Viral load levels before and 24 hours after oral administration of 1200 μg / kg FORMULA I compound.

[0434] Patient 1, log10 copies per ml, Compound of Formula I, 1200 μg / kg (per pure ivermectin) 0h 6.3 24h 5.1

[0435] Example 10. Patient study

[0436] Dengue, chikungunya, yellow fever, and Zika are common in the tropics, South and Central America, Mexico (including Veracruz, Jalisco, Chiapas, Oaxaca, and Quintana Roo), and the Caribbean. The virus is transmitted by female Aedes aegypti and Aedes albopictus mosquitoes.

[0437] A 38-year-old male tested positive for NS1, which detects the non-structural NS1 protein of the dengue virus. Symptoms included a high fever of 40 °C / 104 °F, severe headache, nausea, and muscle aches. The patient was orally administered a compound of FORMULA I (obtained according to Example 1 No. 2) mixed with 300 ml of water at a dose of 800 μg / kg of pure ivermectin. The compound was administered orally. The patient's fever gradually subsided, muscle pain recovered, and the illness disappeared after another 2 days.

[0438] VII. Conclusions

[0439] The names of the compounds of the present disclosure are provided using ACD / Name software for naming compounds (Advanced Chemistry Development, Inc., Toronto, Canada). Other compounds or radicals may be named using common names or systematic or non-systematic names.

[0440] When trade names are used herein, the applicant intends to independently include the trade name product and its API.

[0441] The compounds of the present invention can be prepared by methods known to those skilled in the art.

[0442] The present invention has been described with reference to various specific and preferred embodiments and techniques. However, those skilled in the art will understand that many changes and modifications can be made without departing from the spirit and scope of the invention.

[0443] Although the present invention has been described in detail and with reference to its specific embodiments, it is obvious to those skilled in the art that various changes and modifications can be made therein without departing from its spirit and scope. Accordingly, the present invention is intended to cover such modifications and variations provided that they are within the scope of the appended claims and their equivalents. Unless otherwise indicated, weight percentages refer to the weight percentages of the components in the finished formulation.

[0444] Although the disclosed invention has been illustrated and described herein as one or more specific examples, it is not intended to be limited to the details shown, since various modifications and structural changes can be made without departing from the scope of the invention. Additionally, the various features of one embodiment can be incorporated into another embodiment. Accordingly, it is appropriate that the present invention be broadly construed and consistent with the scope of the disclosure.

[0445] After describing the preferred embodiments, it is believed that other modifications, variations, and changes will occur to those skilled in the art in light of the teachings herein. Accordingly, it is to be understood that all such variations, modifications, and changes are considered to be within the scope of the invention as defined by the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. A method for treating viral diseases by administering a therapeutically effective amount of a solid dispersion to a human or mammal or animal or bird in need thereof, comprising: contacting an active pharmaceutical ingredient with a matrix "host substance" to form a solid dispersion under conditions sufficient to form the solid dispersion; and (optionally) dissolving the solid dispersion in a solvent to form a liquid-dissolved non-covalent complex (forming a solution, gel, colloid, sol, suspension, etc.) under conditions sufficient to form the liquid-dissolved non-covalent complex.

2. A method for treating viral diseases by administering a therapeutically effective amount of a solid dispersion or non-covalent complex to a human or mammal or animal or bird in need thereof, wherein the "host substance" molecules of the solid dispersion or non-covalent complex interact with the biological membrane of the organism, thereby improving the transport of molecular ions or metabolites of the active pharmaceutical ingredient through the biological membrane; the permeability of the active pharmaceutical ingredient in the non-covalent complex form is improved. Accordingly, the scope of the present invention includes solid dispersions and non-covalent complexes having special permeability characteristics (solid dispersions and non-covalent complexes having high permeability).

3. A method for treating viral diseases of a human or mammal or animal or bird in need thereof by administering a therapeutically effective amount of a stable aqueous preparation comprising abamectin, a solvent, a surfactant and a co-solvent or a stable preparation comprising a solution of abamectin in an oil / fat or an abamectin emulsion.

4. A method for treating viral diseases by administering a therapeutically effective amount of a solid dispersion or non-covalent complex to a human or mammal or animal or bird in need thereof, wherein the solid dispersion or non-covalent complex of the active pharmaceutical ingredient has a higher bioavailability than the active pharmaceutical ingredient itself.

5. A method for treating viral diseases by administering a therapeutically effective amount of a solid dispersion or non-covalent complex to a human or mammal or animal or bird in need thereof, wherein the solid dispersion or non-covalent complex of the active pharmaceutical ingredient has lower toxicity and cytotoxicity than the active pharmaceutical ingredient itself.

6. A method for treating a disease by administering a therapeutically effective amount of a solid dispersion or non-covalent complex to a human or mammal or animal or bird in need thereof, wherein the solid dispersion or non-covalent complex of the active pharmaceutical ingredient has pharmacokinetic parameters different from those of the active pharmaceutical ingredient itself.

7. A method for preparing the solid dispersion or non-covalent complex of the present invention.

8. The method for obtaining the solid dispersion of the present invention includes 1) solvent evaporation and low-temperature methods; 2) melting methods and hot-stage extrusion methods; 3) mechanochemical methods (but not limited to other methods). The particle size of the solid dispersion may vary depending on the equipment device (such as nozzle size), equipment operating parameters, and the degree of grinding of the finished product. The usual particle size is 0.5 - 1000 microns, but it can exceed 1000 microns, and the obtained solid dispersion can also be ground to sub-micron size after being obtained.

9. A method of treating a disease in a human or mammal or animal or bird in need thereof by administering a therapeutically effective amount of a FORMULA I compound, namely a highly bioavailable and highly permeable solid dispersion (or its solution or suspension), wherein the FORMULA I compound is obtained by co-processing a guest molecule drug compound with a host substance, wherein the guest molecule drug compound is selected from avermectins, which are given in section [0061], and may be represented as selected from guest molecule drugs (API, GUEST) with codes GUEST1-9 defined in [0061] or their derivatives; wherein, the HOST substance is selected from the following: A. Polymers and oligomers, mainly organic polymers and oligomers, more mainly polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages, and may include (but are not limited to): A.

1. Hemicelluloses, which may be arabinan, arabinan, galactan (galactan), glucan, xylan, mannan, fructan, xyloglucan, arabinogalactan, arabinoxylan, glucomannan, galactomannan, galactoglucomannan, Β-glucan, glycogen and their mixtures, but other hemicelluloses and their mixtures are not excluded; A.

2. Sulfated polysaccharides and oligosaccharides may be fucoidan, carrageenan or carrageenan, agar pectin, sea cucumber sulfated polysaccharide (SCSP), chondroitin sulfate, keratan sulfate and their mixtures, but other sulfated polysaccharides and oligosaccharides and their mixtures are not excluded; A.

3. Polysaccharides and oligosaccharides, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectins, gums, mucilages can be (but are not limited to others): polysaccharides based on glucose, BETA-D-glucose, galactose, mannose, arabinose, rhamnose, sucrose, maltose, lactose and their allantoinates, which can be methoxylated or acetylated polysaccharides and their salts (gums, gums); polyuronic acids and their 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 powder, agar, tragacanth gum, konjac gum, welan gum, rhodojaponin; galacturonan polysaccharides with side chains of rhamnose, arabinose, xylose and fructose and their salts (pectins, pectates, calcium pectate); pectins from beet, carrot, pepper, pumpkin, eggplant, sunflower, apple, quince, cherry, plum, pear, citrus, laminarin; modified pectins, modified citrus pectins; acidic polysaccharides - i.e., polysaccharides containing carboxyl, phosphate and / or sulfate ester groups; psyllium husk, psyllium seed gum; soybean hemicellulose; galacturonic acid, homogalacturonic acid, polygalacturonic acid and their salts, rhamnogalacturonic acid, rhamnogalactose; callose, fucoidan, chrysolaminarin, thermogel polysaccharide; inulin, guar, dextran, pullulan; agarose, galactooligosaccharides (oligogalactosyl lactose, oligogalactose, oligolactose or trans-galactooligosaccharides), xylooligosaccharides, fructooligosaccharides, isomaltooligosaccharides; alginic acid and its salts alginates, propylene glycol alginate; arabinan, arabic acid and their salts; cellulose, cellulose polymers, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose (HPC), hypromellose acetate succinate, hypromellose (HPMC), methyl ethyl cellulose, ethyl hydroxyethyl cellulose, sodium carboxymethyl cellulose crosslinked, carboxymethyl cellulose and its salts; starch, starch, starch 1500G, soluble starch, modified starch, hydroxyethyl starch, cationic starch, acid-treated starch, alkali-modified starch, bleached starch, oxidized starch, enzyme-treated starch, mono starch 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 adipate, acetylated distarch glycerol, distarch glycerol, hydroxypropyl starch, hydroxypropyl distarch glycerol, hydroxypropyl distarch phosphate, hydroxypropyl distarch glycerol, sodium starch octenyl succinate, acetylated oxidized starch; dextrin, maltodextrin, cyclodextrin, amylodextrin, polydextrin; amylopectin, amylose, glycogen; chitosan, chitin; pullulan polysaccharide, glucuronoxylan, methylglucuronoxylan, glycosaminoglycan, mucopolysaccharide, heparin / heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid, hyaluronic acid and their mixtures, but other polysaccharides and oligosaccharides, hemicelluloses, storage polysaccharides, sulfated polysaccharides and oligosaccharides, mucilages and their mixtures are not excluded; A.

4. The macrocyclic host can be (but is not limited to others): cyclodextrin, cucurbit[n]uril, calix[n]arene, pillararene, crown ether, cyclophane, cryptand; B. Substances that may contain a large amount (more than 5% wt.) of polysaccharides and oligosaccharides, hemicellulose, storage polysaccharides, sulfated polysaccharides and oligosaccharides, pectin, gum, mucilage may be (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 containing a large amount of the substances described in section A, parts of processed plants or algae or animals or fungi, and their mixtures. A common but not limited example is dried brown or red algae, such as kelp or seaweed. C. Synthetic polymers, mainly water-soluble polymers, can be (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; polyvinylpyrrolidones; acrylic polymers, cellulose acetate phthalate, copovidone, ethyl oleate, glycerol derivatives, triacetin, polyethylene glycol (PEG), polyethylene glycol derivatives, polymethacrylates, propylene glycol, 1,2-propylene glycol derivatives, povidone, polyvinylpyrrolidone (PVP), cellulose acetate phthalate (PVAP), hypromellose acetate succinate (HPMCAS), hypromellose acetate succinate (HPMCAS), hypromellose phthalate (HPMCP), cellulose acetate butyrate phthalate, cellulose acetate hydrogen phthalate, cellulose acetate propionate phthalate, cellulose acetate phthalate, cellulose acetate tricarboxylate, hypopropylmethylcellulose phthalate, hypromellose acetate, dioxypropylmethylcellulose succinate, carboxymethylethylcellulose, hypromellose acetate succinate, Avicel, Avicel PH101, Avicel PH102, Benecel, Brij, Brij 30, Brij 35, Capryol, Cavamax, Cavasol and CavitronHPpCD cyclodextrin, Compritol 888ATO, Cremophor, Cremophor EL, Cremophor RH40, DiCalDihydrate, epoxidized palm oil (Epo), Eudragit, Eudragit E, Eudragit EPO, Eudragit L100, Eudragit L100-55, Eudragit S100, Gelucire, Gelucire 44 / 14, HP-50AAS-LF, HP-55AAS-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, hypopropylmethylcellulose phthalate HP-50, Imwitor, Imwitor 742, Klucel HPC, Kolhdon 17PF, Kollicoat, Kollicoat IR, Kollicoat MAE, Kollicoat MAE 100, Kollicoat MAE100P, Kollicoat Protect, Kollidon (Povidone), Kollidon 12pf, Kollidon 12 / 17PF, Kollidon30, Kollidon 30 / 90, Kollidon 90, Kollidon CL-F, Kollidon CL-SF, Kollidon K30, Kollidon SR, Kollidon SR, Kollidon SR (PVAc), Kollidon V64 / Fine, Kollidon VA 64, Kollidon VA 64 (Copovidone), Kollidon VA64, Kolliphor, Kolliphor EL, Kolliphor EL / ELP, Kolliphor HS15, Kolliphor P 188, Kolliphor P188 / 407, Kolliphor P 188 / micro, Kolliphor P 407, Kolliphor P 407 / micro, Kolliphor PS20, Kolliphor PS 60, Kolliphor PS 80, Kolliphor RH 40, Kolliphor SLS, Kolliphor SLS / fine, Kollisolv, Kollisolv GTA, Kollisolv PEG 1450, Kollisolv PEG 300, Kollisolv PEG 3350, Kollisolv PEG 400, Kollisolv PEG E 300, Kollisolv PEG E 400, Kollisolv PEGgrades (Polyethylene Glycol), Kolliwax, Kolliwax GMS II, Kolliwax SA, Labrasol, Lactose310Mono, Lactose FF316, Laurogucol, Maisine, Miglyol, Myrj, Myrj 52, PEG 1000, PEG10000, 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, PVPK-60, PVP K-90, PVP SDD, PVP VA64 SDDs, PVP-VA, PVP-VA64, PVP-VA SDD, palm stearyl polyester amide (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), polyethylene oxide (PEO) (3400, 10000, 20000), polyethylene glycol stearate, Shin-Etsu AQOAT, Soluplus, Solutol, sucrose laurate, tocopheryl polyethylene glycol 1000 succinate (TPGS), vitamin E TPGS, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), isomaltitol (GalenIQ 810), but other synthetic polymers and their mixtures are not excluded; D. Polyols may include but are not limited to: ethylene glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, heptitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polymannitol, and their mixtures; E. Glycosides may include glucose, glucose, galactose, mannose, arabinose, rhamnose, sucrose, maltose, lactose, ribose, and their mixtures; F. Surfactants may include, but are not limited to: anionic surfactants containing anionic functional groups, 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; zwitterionic (amphoteric) surfactants; zwitterionic surfactants with a cationic moiety based on a primary, secondary or tertiary amine or a quaternary ammonium cation; betaines; phosphatidylcholines; zwitterionic surfactants of the tertiary amine oxide structural type; nonionic surfactants; ethoxylates; fatty alcohol ethoxylates; alkylphenol ethoxylates (APES or APEOS); fatty acid ethoxylates; special ethoxylated fatty esters and oils; ethoxylated amines and / or fatty acid amides; 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 polyglycosides; ammonium lauryl sulfate; sodium lauryl sulfate; sodium dodecyl sulfate; sodium laureth sulfate; sodium lauryl ether sulfate; Tween (sodium dioctyl sulfosuccinate) and its salts; perfluorooctane sulfonate (PFOS); perfluorobutane sulfonate; alkylaryl ether phosphates; alkyl ether phosphates; sodium stearate; sodium lauroyl sarcosinate; perfluorononanoate; perfluorooctanoate; octenidine dihydrochloride; cetyltrimethylammonium bromide (CTAB); cetylpyridinium chloride (CPC); benzalkonium chloride (BAC); benzethonium chloride (BZT); dimethyldioctadecylammonium chloride; dioctadecyldimethylammonium bromide (DODAB); CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate); coconutamidopropyl hydroxysultaine; cocamidopropyl betaine; phosphatidylserine; phosphatidylethanolamine; phosphatidylcholine; sphingomyelin; lauryldimethylamine oxide; myristamine oxide; narrow-range ethoxylates; octaethylene glycol monododecyl ether; pentaethylene glycol monododecyl ether; nonoxynol; polyethylene glycol monooctylphenyl ether; polyethoxylated tallow amine; coconut monoethanolamide; coconut diethanolamide; poloxamer; glyceryl monostearate; glycerol monolaurate; sorbitan monolaurate; sorbitan monostearate; sorbitan tristearate; Tween, Tween 20; Tween 40; Tween 60; Tween 80; decyl glucoside; Span, Span 20, Span 40, Span 80; dodecyl glucoside; octyl glucoside; poloxamer, poloxamer 188, poloxamer 407, polyethylene glycol stearate; Myrj52; deoxycholic acid; bile acids; Pluronic, Pluronic F-127, Pluronic P85, Pluronic f68; Gelucire, Gelucire 44 / 14; lecithin; polysorbate, polysorbate 80; Plasdone-s630; Pluronic-f68; Inutecsp1; Compritol 888ATO;Tocopheryl polyethylene glycol succinate; polyoxyethylated castor oil; polyoxyethylated glycerol esters; lauroyl diglycerol esters, and mono- and di-fatty acid esters of low molecular weight polyethylene glycols and mixtures thereof; G. Acids and salts based on these acids may include but are not limited to: citric acid, tartaric acid, succinic acid, phosphoric acid, amino acids, acetate, anhydrous sodium acetate, alginate, sodium alginate, glycyrrhizic acid and its salts, and their mixtures; H. Oxides and salts based on these oxides may include but are not limited to: silica, silicate, titanium dioxide, and their mixtures; I. Copolymers of the polymers listed in paragraphs A and C include alternating copolymers, random copolymers, block copolymers, graft copolymers, crosslinked modifiers, and may include but are not limited to: methyl methacrylate-ethyl acrylate copolymer; methacrylic acid copolymer; vinyl pyrrolidone-vinyl acetate copolymer (PVPVA); polyvinylpolypyrrolidone (PVPP); PVA-PEG graft copolymer; HPMC and PVA-PEG graft copolymer; graft polyvinyl pyrrolidone-arabic galactan copolymer; graft copolymers with a) polyvinyl acetate and / or polyvinyl alcohol and / or polyvinyl chloride and polyvinyl acetate on b) a polymer chain of polyethylene glycol, polyalkylene glycol, polypropylene glycol, polyisobutylene glycol, or polymethylpentene glycol; graft copolymers of polyvinyl acetate and / or hydrolyzed polyvinyl acetate (polyvinyl alcohol) groups on polyalkylene oxide (preferably polyethylene oxide); vinyl pyrrolidone-vinyl acetate copolymer; vinyl pyrrolidone-vinyl acetate VA 64; polymethacrylate-based copolymers include anionic, cationic, and neutral copolymers and their mixtures based on methacrylic acid and methacrylic acid / acrylate, their salts, esters, or other derivatives; J. Methoxylated, ethoxylated, esterified, carboxylated, alkoxylated, acetylated, hydroxylated, hydrated, decarboxylated, amidated, oxidized, sulfated, amino acid derivatives, fermented, heat-modified, chemically modified, acid-modified derivatives and their esters, salts, and any other chemical derivatives and their mixtures of the substances specified in A-I; Any combination of the substances specified in items K.A-J; wherein the combined treatment method (method for preparing a solid dispersion) is selected from: a) High-energy stress grinding / crushing method; b) High-energy stress grinding / crushing and solvent method; c) Media grinding method; d) Kneading method; e) Hot melt method / melting method / fusion method; f) Hot melt extrusion / thermal stage extrusion method; g) Meltrex method; h) Melt aggregation method; i) High-pressure homogenization method; j) Solvent evaporation method; k) Spin coating film method; l) Spray drying method; m) Supercritical fluid (SCF) process method; n) Low-temperature technology method; o) Freeze drying / freeze drying technology method; p) Spray freezing into cryogenic fluid method; q) Spray freezing into cryogenic liquid (SFL) method; r) Spray freezing into liquid surface vapor (SFV / L) method; s) Ultra-rapid freezing method; t) Precipitation / coprecipitation method; u) Microwave radiation method; v) Energy input method; w) Thermal / shear energy input method; x) Combined method.

10. A method for a viral disease in humans, mammals, animals or birds in need of treatment, comprising administering a therapeutically effective amount of a FORMULA II compound (and its solutions, gels, colloids, sols, etc.), which compound 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, wherein the compound of FORMULA I is obtained by jointly treating a guest molecule drug compound with a host substance, wherein the disease, host substance, and combined treatment method are the same as those in claim 1; wherein the guest molecule drug compound is selected from GUEST1-9 or its derivatives (the same as the guest molecule drug selected in claim 9); wherein the solvent is usually water, but other physiologically acceptable solvents and their mixtures can also be used; wherein the molecular information of the non-covalent complex of FORMULA II is encoded by FORMULA (the non-covalent complex of FORMULA II is): [GUEST]k[HOST]n(SOLVENT)m where k is from 1 to 100; where m is from 1 to 10,000; where n is from 1 to 10,000; wherein the molecular information of GUEST is based on the InChI derived from the InChIKey, which InChIKey is specified after the name of the guest molecule drug (at the position after the serial number in paragraph [0061]). The molecular information of the guest molecule drug compound can be used alone or based on the molecular information of its medicinal salts, esters, ethers, free bases, and other medicinal salts obtained (by a person skilled in the art) for these free bases; wherein the molecular information of HOST represents the molecular information of the polymer monomer of the "host substance"; or the smallest representable part of the copolymer of the "host substance" (defining the copolymer); or the molecule of the "host substance" (if the host substance is in the form of a single molecule) for a compound selected from the host substance and obtainable by a person skilled in the art; wherein the molecular information of SOLVENT is H2O if the solvent is water, but other physiologically acceptable solvents can also be used, and the molecular information can be obtained by a person skilled in the art.

11. A pharmaceutical dosage form of Formula I, having enhanced bioavailability and permeability, characterized in that it comprises a highly bioavailable and highly permeable solid dispersion or its aqueous solution or suspension, wherein the compound of Formula I is obtained by co-processing a "guest molecule drug" (API, GUEST) with a host substance, and wherein the guest molecule drug (API, GUEST) compound, the host substance, and the co-processing method are the same as those in claim 9.

12. A pharmaceutical dosage form of Formula II (and their solutions, gels, colloids, sols, etc.), which is a highly bioavailable and highly permeable non-covalent complex obtained by adding a solvent to the highly bioavailable and highly permeable solid dispersion of Formula I, wherein the compound of Formula I is obtained by co-processing a guest molecule drug (API, GUEST) compound with a host substance, and wherein the solvent, the guest molecule drug (API, GUEST) compound, the host substance, the co-processing method, and the molecular information of the non-covalent complex of Formula II are the same as those in claim 10.

13. A method for preparing a pharmaceutical dosage form of Formula I, having enhanced bioavailability and permeability, characterized in that it comprises a highly bioavailable and highly permeable solid dispersion or its aqueous solution or suspension, wherein the compound of Formula I is obtained by co-processing a "guest molecule drug" (API, GUEST) with a host substance, and wherein the guest molecule drug (API, GUEST) compound, the host substance, and the co-processing method are the same as those in claim 9.

14. A method for preparing a pharmaceutical dosage form of Formula II (and their solutions, gels, colloids, sols, etc.), which is a highly bioavailable and highly permeable non-covalent complex obtained by adding a solvent to the highly bioavailable and highly permeable solid dispersion of Formula I, wherein the compound of Formula I is obtained by co-processing a guest molecule drug (API, GUEST) compound with a host substance, and wherein the solvent, the guest molecule drug (API, GUEST) compound, the host substance, the co-processing method, and the molecular information of the non-covalent complex of Formula II are the same as those in claim 10.

15. The method of claims 9, 10, wherein the compound is a compound of 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 that is active against viral infections or increases the antiviral activity of the Formula I-II component, or reduces the hepatotoxicity of the Formula I-II component, or increases the stability of the Formula I-II component.

16. The method of claims 9, 10, wherein the compound is a compound 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 components: (1) An oil phase containing vegetable and / or animal fats; (2) One or more surfactants; (3) One or more solvents; (4) One or more gelling agents.

17. The method of claims 9, 10, wherein the compound is a compound of FORMULA V, in the form of a food product or beverage, or a dietary supplement.

18. The method of claims 9, 10, further comprising administering a pharmaceutically acceptable diluent, carrier or excipient.

19. The method of claims 9, 10, further comprising co-administering the compound with at least one additional therapeutic agent.

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