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WO2025088452A1 - Substance artificielle et son procédé de préparation - Google Patents

Substance artificielle et son procédé de préparation Download PDF

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Publication number
WO2025088452A1
WO2025088452A1 PCT/IB2024/060256 IB2024060256W WO2025088452A1 WO 2025088452 A1 WO2025088452 A1 WO 2025088452A1 IB 2024060256 W IB2024060256 W IB 2024060256W WO 2025088452 A1 WO2025088452 A1 WO 2025088452A1
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Prior art keywords
iterations
iteration
initial substance
solvent
sample
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Inventor
Oleg Ilyich EPSHTEIN
Tarasov Sergey ALEKSANDROVICH
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Priority claimed from RU2023127192A external-priority patent/RU2023127192A/ru
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Publication of WO2025088452A1 publication Critical patent/WO2025088452A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/249—Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0004—Homeopathy; Vitalisation; Resonance; Dynamisation, e.g. esoteric applications; Oxygenation of blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2833—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against MHC-molecules, e.g. HLA-molecules
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • This invention relates to the field of pharmaceutics, namely, to a method for preparation of a product possessing a biological activity due to an activating or suppressing effect on various physicochemical or biological processes involving the initial substance used for product preparation, or its molecular target.
  • the author of the invention found out that as a result of vibration influence and joint incubation of the initial substance without multiple dilution (transfer of a part of the previous dilution to the subsequent one) makes it possible to obtain products (artificial substances) that have a modifying effect and exhibit biological activity.
  • the author also developed a method for separating the obtained products into fractions possessing inherent modified physicochemical properties, including, among others, a specific modifying effect on the initial substances from which they were obtained. The obtained fractions also exert pharmacological and biological activity.
  • This invention had a technical purpose of developing a product exhibiting biological activity, and separating the obtained product into fractions possessing a biological efficacy determined by the initial substance and the target molecules associated with it.
  • the claimed invention s technical solution consists in developing a method of obtaining a product (artificial substance) that possesses a biological (therapeutic) activity and includes multiple successive external vibration treatment of vials with activated initial substance or a processed solvent and a neutral solvent, optionally followed by incubation of vials in close contact to each other.
  • the technical solution also consists in separating the obtained product into fractions by evaluating their physicochemical properties and/or determination of their modifying action on target molecules predetermined by the initial substance and assessed by known analytical methods [RU2643934, 2643936],
  • the method of obtaining a product which is a series of processed solvents - iterations, possessing an activating or suppressing effect on various physicochemical or biological processes involving the initial substance used for product obtaining or molecular target associated with this initial substance, by multiple successive external vibration treatment of the initial substance.
  • Multiple successive external vibration treatment of the initial substance is a process including: a) external vibration treatment of vials containing the initial substance and neutral solvent to obtain form neutral solvent the first processed solvent (artificial object) - iteration zero; b) external vibration effect on vials containing the previous iteration and neutral solvent to obtain from neutral solvent the processed solvent - subsequent iteration; c) successive multiple repetitions of step b) using the processed solvent obtained at the previous step and a neutral solvent to obtain a series of processed solvents representing the final product.
  • a product which is a series of processed solvents - iterations, obtained by the method possessing an activating or suppressing effect on various physicochemical or biological processes involving the initial substance used for product obtaining or molecular target associated with this initial substance.
  • the processed solvents obtained as a result of external vibration treatment of vials containing a neutral solvent and the activated initial substance or a previously obtained in the same way another processed solvent exert biological and/or chemical activity, including a modifying effect characteristic of gradualized products.
  • the iterations can be separated and classified into fractions, where each fraction possessing a specific set of measured properties by which they differ from the neutral solvent.
  • the obtained fractions can exert a modifying action aimed at one or more initial substances and/or target molecules, and can exert a distant action by modifying the physicochemical properties of the initial substances and/or its molecular target in a similar way as highly diluted substance solutions (gradualized products).
  • a "fraction ’ (artificial substance or artificial material object) is understood to be a processed solvent (iteration), wherein each fraction has modified physicochemical properties and/or exhibits a modifying action directed at a target molecule predetermined by the initial substance, or a combination of modified physicochemical properties and modifying action on the initial substance and the target molecule. Fraction constitutes one or more processed solvent - iterations.
  • the fraction has biological activity determined by the initial substance and the chemical, biological and physical processes involving this initial substance, since the fraction possessing specific physicochemical properties regulates (by activating or suppressing) the physicochemical and biological processes involving the initial substance or its target molecule.
  • the fraction regulates processes that are carried out in different phases of these processes.
  • the claimed invention presents a method for obtaining the product, including:
  • the method for preparing of iterations can also be accompanied by incubation of the vials with the initial substance/activated initial substance/processed solvent and neutral solvent at a small distance for 1 minute to 24 hours at room temperature, after external vibration influence. ‘Incubation’ refers to the process of holding the tubes together for a period of time.
  • the resulting series of iterations can be used both in a mixture, exhibiting biological or chemical effect, including the modifying action characteristic of gradualized products, or be separated into fractions having inherent physicochemical properties and biological and/or chemical activity.
  • a series of iterations can be obtained from an individual activated initial substance, a neutral initial substance, or from a combination of initial substances.
  • the time of external vibration treatment and incubation depends on the amount of initial substance and solvent and is selected from the specified range individually in each specific case. Test tubes and vials are placed next to each other, closely or at a distance.
  • the present invention can also be implemented as follows:
  • C12 dilution is a solution obtained by 12 successive dilutions of one part of the starting stock solution of antibodies to IFN-gamma with a concentration of 3.0 mg/ml in 99 parts of a neutral solvent in separate containers, which is equivalent to C12 dilution. Similar procedures using the appropriate dilution factor are performed to obtain C30, C50, C200 and other dilutions.
  • the present invention s method of separating obtained iterations into fractions includes the following phases:
  • the iterations or dilutions are classified into four fractions depending on the presence of altered physicochemical properties and/or modifying action: the first fraction has neither specific physicochemical properties nor modifying action (‘native’ fraction; the second fraction has specific physicochemical properties, but no modifying action (‘semi-native’ fraction); the third fraction has no specific physicochemical properties, but exerts a modifying action (‘semi-active’ fraction); the fourth fraction has specific physicochemical properties and exerts modifying action (‘active’ fraction).
  • External vibration treatment is understood as horizontal or vertical mechanical shaking or their combination, or shaking using acoustics and microfluidics methods [RU2724254], or electromagnetic, ultrasound influence or other rhythmic physical action.
  • the fraction’s modifying effect on the target molecule is understood to be the effect exerted by the fraction on the parameters of the target molecule, namely, a change in the basic properties of the substance (target molecule) inside or outside the body after the fractions are administered.
  • a target molecule is understood to be the initial substance or a compound that is tropic to it, based on the ligand/ substrate principle, e.g., an antigen and its antibody.
  • the specific physicochemical properties are understood to be a manifestation of activated initial substance’s or processed solvent’s physicochemical properties that statistically significant differ from the initial substance’s or neutral solvent’s physicochemical properties.
  • Water, aqueous-alcohol solution, lactose or any pharmaceutically acceptable solvent or filler can be used as a neutral solvent.
  • Any compound with known biological or pharmaceutical activity including low-molecular compounds, high-molecular compounds (e.g. natural, monoclonal or polyclonal antibodies), biologically active substances, organic or inorganic compounds, synthetic medicinal products, a neutral solvent, a neutral carrier processed by energy influence with transformed oscillations of bioelectric potentials of nervous tissue or brain [RU 2678979], gradualized products and neutral solvent may be used as initial substance.
  • the initial substance may be used in different physical forms: in solid form (e.g. a crystalline structure), in liquid form (e.g. a solution), or in gaseous form.
  • solid form e.g. a crystalline structure
  • liquid form e.g. a solution
  • gaseous form e.g. a gaseous form
  • the initial substance may be a solid substance, a solution or a gradualized product (ultra-high dilution of the initial substance).
  • the concentration of the initial substance in the vial may range from 1 pg/ml to 10 mg/ml, and is selected empirically in each specific case.
  • the claimed method also may use two or more initial substances.
  • the procedure may use the initial substance, or the activated initial substance obtained by preliminary external vibration treatment and joint incubation with one or more other initial substances by the procedure described above (step a).
  • Some examples of the implementation of this invention may include various fractions and serial numbers of iterations obtained from the initial substance or activated product that may be selected from antibodies to IFN-gamma, S-100B, histamine, bradykinin, morphine, prostate-specific antigen (PSA), tumor necrosis factor (TNF), insulin receptor, endothelial NO synthase, CD4, b2-microglobulin, HLA-DRB1.
  • PSA prostate-specific antigen
  • TNF tumor necrosis factor
  • CD4 b2-microglobulin
  • HLA-DRB1 b2-microglobulin
  • the initial substance may be also selected from phenobarbital, diazepam, sildenafil, paracetamol, morphine, diclofenac, prednisolone, sulpiride, metformin, semaglutide, glucose, cisplatin etc., or their release-active form (gradualized products).
  • biological activity consisting in antiviral, antibacterial and immunomodulatory action, or in the treatment of pathological immune reactions is based on antibodies to IFN-gamma as initial substance;
  • the treatment for acute or chronic diseases of the respiratory system and cough syndrome is based on the antibodies to bradykinin or histamine as initial substance;
  • the treatment for impaired immune homeostasis is based on the antibodies to CD4 as initial substance;
  • the effect on the central and peripheral nervous system, mental disorders, neuroses or psychoses, and mental balance recovery is based on antibodies to S100 calcium -binding protein B (S-100B) as initial substance;
  • the treatment for vascular tone impairments, neurotropic effect, anti-inflammatory and antiallergic effect, and the treatment for endothelial dysfunction is based on antibodies to endothelial NO synthase as initial substance;
  • the pharmacological effect aimed at treating erectile dysfunction and prostate gland disorders, and the treatment of genitourinary system is based on antibodies to PSA as initial substance; inhibiting
  • the claimed method for preparing the product may also include an additional phase of external physical treatment at the stage of joint incubation, which increases the modifying action exerted by the final product (iteration or fraction).
  • external treatment may be selected from electromagnetic radiation, geomagnetic radiation, IR radiation, temperature influence, etc.
  • the claimed product presented as a mixture of processed solvents (artificial substance) or as a fraction can be used as an independent medicinal product both in liquid form as a solution, and in solid medicinal form as a pharmaceutical composition containing the technologically necessary (effective) amount of a neutral carrier saturated with the claimed product or a combination of the claimed product with an active substance, and pharmaceutically acceptable additives including lactose, microcrystalline cellulose, magnesium stearate and others, and prepared as described in W02007105981 (Al), 20.09.2007.
  • the claimed product can also be used as a specific fraction exerting a certain biological activity and consisting of a mixture of different iterations (activated solvents obtained at different stages of sequential activation series with external vibration treatment and joint incubation), and as a combination of several fractions.
  • the claimed product can be used as a combination of different fractions exerting different modifying effects and/or physicochemical properties, but representing iterations (activated solvents) with the same serial number, prepared from one activated substance.
  • Example 1 Example of the process for preparing iterations, using antibodies to IFN-gamma as initial substance.
  • processed solvent 1 (iteration 1)
  • a vial with purified water (neutral solvent) in a comparable volume was placed close to the vial with activated initial substance 1.
  • the filled vials were subjected to vibration together, on a vortex at 3000 rpm for 10 seconds, then left to incubate at room temperature for 1 minute.
  • the vial with the initial purified water after the activation process was taken as processed solvent 1 - iteration 1 (Ii).
  • a vial with purified water (neutral solvent) in a comparable volume was placed close to the vial with iteration 1.
  • the filled vials were subjected to vibration together, on a vortex at 3000 rpm for 10 seconds, then left to incubate at room temperature for 1 minute.
  • the vial with the initial purified water after the activation process was taken as processed solvent 2 - iteration 2 (12).
  • each of the processed solvents exhibits specific physicochemical properties that may be assessed by known analytical methods and represent a basis for classifying the obtained activated initial substances (iterations) into fractions (groups), and exerts a specific modifying action directed at the target molecules. 2) Methods for testing processed solvents.
  • the conductometry method was used to assess the physicochemical properties of a series of processed solvents.
  • SEC specific electrical conductivity
  • step 1 21 iterations (processed solvents) were prepared.
  • the conductometry method demonstrated that the processed solvents (iterations) 4, 11, 14, 17 had significant differences compared to the water sample.
  • the intrinsic electromagnetic radiation of the iterations was assessed using the radiometry method with a special installation consisting of a Faraday cage (an aluminum frame covered with a copper mesh), a tripod bearing a detector fixed with a clamp, a thermoshaker (BIO SAN PST-60HL-4) for heating the samples, and a TES-92 electromagnetic radiation (EMR) detector (TES Electrical Electronic Corp., Taiwan), for detecting the EMR flux density in the range from 1 pW/m 2 to 30.93 W/m 2 and a frequency range from 50 MHz to 3.5 GHz.
  • EMR electromagnetic radiation
  • the maximum average value (MAX AVG) was used as measurement mode.
  • test sample (10 ml) was placed in a Petri dish, then the Petri dish with the sample was placed on a thermoshaker, and the sample was heated to a temperature of 37 ⁇ 1°C. After that, the detector was placed at a distance of 0.5 cm above the sample, and the Petri dish was uncovered. The measurements were performed for 10 min, with the Faraday cage closed. After 10 min, the maximum average value of EMR flux density was recorded on the device display.
  • the prepared processed solvents representing a series of iterations Ii- I21 were classified into the following fractions using the above methods: fractions with altered physicochemical properties and exhibiting a modifying effect (14, 6, 11, 13, 14, 15, 16); fractions with altered physicochemical properties, not exhibiting a modifying effect (117, 20); fractions without altered physicochemical properties but exhibiting a modifying effect (17, 9, 18, 21); fractions without altered physicochemical properties, not exhibiting a modifying effect (II, 2, 3, 5, 8, 10, 12, 19).
  • Example 2 The antiviral activity of the sample prepared by the claimed method was assessed using a model of influenza infection induced in mice by inoculating influenza A/California/04/2009pndm (H1N1) virus adapted to mice at an infection dose causing death in 80% of the animals.
  • H1N1 influenza A/California/04/2009pndm
  • This study used 6-8-week-old sexually mature female Balb/c mice weighing 12-14 g.
  • the animal facility has a veterinary certificate of compliance with veterinary requirements, rules and regulations issued by State Veterinary Surveillance.
  • each animal was assigned an individual number from 1 to 15 in each group. Animals were randomized by weight, and marked using eosin staining. The card on the cage in which the animals were kept indicated the study name, group number and administered substance.
  • Sample 1 was prepared with the product prepared by the claimed method, using purified water as neutral solvent and initial substance. This sample belonged to the fraction that had no specific physicochemical properties or modifying effect (‘native’ fraction). The iteration was applied to lactose granules, and then dissolved in purified water (5% w/v).
  • Tamiflu comparison drug
  • the activity of the compounds in a model of influenza pneumonia in mice was assessed by the following criteria: i. animal survival rate, ii. increase in mean survival duration (MSD), iii. pathogen replication in the lungs, virus titer
  • the mortality rate was calculated as the ratio of the number of dead animals to the total number of infected mice in the group.
  • the virus titer was assessed as follows. On day 4 after influenza virus infection, 5 mice in each group were humanely sacrificed, then their lungs were removed under sterile conditions, homogenized, and resuspended in 1 ml of cold sterile 0.01 M PBS.
  • the suspension was cleared of cell debris by centrifugation at 2000 g for 10 min.
  • 0.1 ml of the supernatant was used to assess the infectious titer of the virus in the MDCK cell culture.
  • the resulting samples were stored at 4°C for no more than a week before experiments.
  • MDCK cells were seeded in 96-well Costar plates at an average density of 30,000-35,000 cells per well and grown in Minimum Eagle medium (MEM) supplemented with 5% fetal calf serum, 10 mM glutamine, and antibiotics (penicillin 100 lU/ml and streptomycin 100 pg/ml) until a complete monolayer was formed. Before infection with the virus, the cell culture was washed twice with serum -free MEM.
  • MEM Minimum Eagle medium
  • Tenfold dilutions of each virus sample from the lungs were prepared in the medium supplemented with L-(tosylamido-2-phenyl)ethyl chloromethyl ketone-treated trypsin (2 pg/ml). The resulting dilutions were used to infect the monolayers in 4 wells of a 96-well plate. After incubation at 37°C in an atmosphere containing 5% CO2 for 72 h, the cells were washed three times with PBS and fixed with 10% formaldehyde solution at a temperature of 18-23 °C for 5 min.
  • the average virus titer in the lungs on the 4 th day after infection with the influenza A/California/04/09pndm (H1N1) virus was 7.8 1g TCID50/0.1 ml (or 8.25 1g TCID50/0.1 ml by the median values), which was a cause for animals’ death from viral pneumonia or their illness.
  • Sample 1 proved to be effective.
  • the treatment with this sample reduced the animals’ mortality by 60%, increasing their life expectancy by 1.25 times (vs virus control, p> 0.05).
  • Treatment with Sample 1 also suppressed virus replication in the animals’ lungs by more than 2 logTCIDso/O.l ml (p> 0.05) compared to the virus control: 5.85 logTCIDso/O. l ml vs 7.8 logTCIDso/0.1 ml in the virus control group (or 5.5 vs 8.25 logTCIDso/O. l ml median values, Table 1).
  • the Sample 1 exhibited similar pharmacological activity with the comparison drug Tamiflu (no statistically significant difference), the administration of which led to 60% survival of animals (p> 0.05), and increased their life expectancy to 14 days (p ⁇ 0.05 vs virus control).
  • the virus titer in the lungs of infected animals treated with Tamiflu was 5.4 logTCIDso/0.1 ml vs 7.8 logTCIDso/0.1 ml in the virus control group.
  • Example 3 Assessment of efficacy of the product prepared by the claimed method on the model of insomnia.
  • the rats obtained from the laboratory animal nursery were kept in individual transparent polycarbonate rodent cages with natural corn cob granulate bedding Rehofix (OOO Rettenmayer Rus, Russia). The bedding was changed once a week.
  • the cages were located in racks supplied with affluent ventilation device Bio.V.S. Vent II (Bioscape (EHRET), Germany). The cages were changed once a week.
  • the corticographic electrodes were made of nichrome wire with 0.5 mm diameter (for the recording and reference electrodes) and 0.16 mm diameter (for the grounding electrode).
  • the wires were insulated using heat-shrinkable tubing, the recording (non-insulated) part being approximately 1 mm long. All electrodes were connected in a socket on a BLS-8 cable, at 2.54 mm intervals.
  • the animals were pre-anesthetized with chloral hydrate (400 mg/kg). Before the operation, oftagel (Santen OY, Finland) was applied to the animals’ eyes to prevent cornea from drying. After preparing the skull surface (removing the muscles, fascia and periosteum, and coagulating the bleeding areas), holes of the appropriate diameters were drilled for the electrodes and fixing screws (drill insertion depth up to 1 mm). To prevent the brain from heating, holes were drilled in short intervals. Then, corticographic electrodes were implanted.
  • the coordinates of the electrodes were located using the stereotaxic atlas of the rat brain by G. Paxinos, C. Watson.
  • the recording electrodes were distributed evenly and symmetrically over the surface of the cerebral hemispheres.
  • the reference electrode was installed in the nasal bone, and the ground electrode was placed under the skin in the neck area.
  • the skull structures were additionally fixated using Villacryl C dental plastic (Zhermack, Italy). After this, the skin incision was sutured, then the sutures and the adjacent area were treated with antiseptic.
  • the rats were kept in individual cages with free access to water and food throughout the study period. The condition of the animals was monitored immediately after recovery from anesthesia and then daily in the morning and evening; the sutures were treated with iodine solution if necessary.
  • the animals were administered bicillin-3 (500 U/100 g intramuscularly) immediately after the surgery.
  • the rats were administered saline subcutaneously for the first 3 days after the surgery. For pain relief, ketoprofen was injected at a dose of 5 mg/kg for 3 days after the surgery.
  • the obtained records were analyzed using the Neuron-Spectr.NET software (Neurosoft, Russia). The ratio of theta and delta rhythm indices was calculated. Delta rhythms are characteristic of a state of slow-wave sleep, sedation, and varying degrees of metabolic/dyscirculatory disorders. Increased theta rhythm activity, especially in the leads above the hippocampus, indicates an increase in search and exploration activity.
  • Group 2 rats had a statistically significantly reduced ratio of theta and delta rhythms in all leads compared to the control group (p ⁇ 0.01 for all leads).
  • test product reliably improved the ratio of theta / delta rhythm indices in animals with insomnia, which approached the values in the control group consisting of healthy animals. Based on EEG examination, it can be concluded that the test product manufactured using the claimed method proved to be more effective than the control samples.
  • Type 1 ultrapure water with a resistivity of 18.2 MQxcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • SevenCompact S230 conductometer Metaltler Toledo, USA
  • For liquids, automatic pipettes of different volumes (Eppendorf, Germany; Socorex, Switzerland) and measuring glassware of accuracy class A (Borosil, India; Steklopribor, Ukraine) were used.
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages. A 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (L) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • test samples inhibited [3H]pentazocine standard radioligand binding to human recombinant sigma 1 receptor.
  • thermohygrometer IVA-6N OOO NPK Microfor, Russia
  • temperature was 22 ⁇ 3 °C
  • humidity was 20-70 %.
  • Vials made of transparent borosilicate glass 60, 500 ml, Glastechnik Grafenroda, Germany) were used for the preparation of iterations.
  • Millipore was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • For liquids automatic pipettes of different volumes (Eppendorf, Germany; Socorex, Switzerland) and measuring glassware of accuracy class A (Borosil, India; Steklopribor, Ukraine) were used. Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA).
  • a calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as L. Then, the second iteration (L) was obtained from L in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • Sigma-1 receptor is an intracellular receptor localized in the cells of the central nervous system, the cells of most peripheral tissues, and in immune-competent cells. By controlling the homeostasis of intracellular calcium, this receptor regulates intracellular signaling cascades leading to the activation of the transcription factors and to the transcription of a whole family of genes. Sigma-1 receptor is involved in the pathogenesis of various diseases, including infections and neurodegenerative disorders. Thus, drugs that affect this receptor and the effectiveness of ligands interaction with it can be considered effective for the treatment of neuroinfections, neurodegenerative and other diseases.
  • potentiated distilled water mixture of homeopathic dilutions C12+C30+C50
  • potentiated water was used as a control.
  • test samples inhibited [ 3 H]pentazocine standard radioligand binding to the recombinant human sigma 1 receptor and thus can be used as an effective medicine for the treatment of neuroinfections, neurodegenerative and other diseases, in particular, for the treatment of multiple sclerosis.
  • Example 6 Effect on phagocytic activity of neutrophils.
  • Type 1 ultrapure water with a resistivity of 18.2 M xcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (L) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • Phagocytic activity was assessed by the ability of these cells to absorb a 24h culture of S. aureus strain 209 (microbial suspension concentration 100 million/mL). In this case, the percentage of neutrophils that absorbed microbes (phagocytic index - PI), and the average number of staphylococci absorbed by one cell (phagocytic number - PN) were taken into account.
  • Example 7 Evaluation of antiretroviral activity of the iterations.
  • thermohygrometer IVA-6N OOO NPK Microfor, Russia
  • temperature was 22 ⁇ 3 °C
  • humidity was 20-70 %.
  • Vials made of transparent borosilicate glass 60, 500 ml, Glastechnik Grafenroda, Germany) were used for the preparation of iterations.
  • Type 1 ultrapure water with a resistivity of 18.2 MQxcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • SevenCompact S230 conductometer Metaltler Toledo, USA
  • For liquids, automatic pipettes of different volumes (Eppendorf, Germany; Socorex, Switzerland) and measuring glassware of accuracy class A (Borosil, India; Steklopribor, Ukraine) were used.
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (I2) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • the iteration 12 prepared from a solution of polyclonal antibodies to CD4 receptor (1.8 mg/mL) was used.
  • the iteration activity was assessed by the following methods.
  • Human peripheral blood macrophages were obtained from human peripheral blood mononuclear cells that were isolated from the blood of two healthy seronegative donors using Ficoll-Hypaque density gradient centrifugation. Human peripheral blood mononuclear cells were grown for 3 days in RPMH640 medium (DIFCO) supplemented with 10% fetal calf serum , 1% antibiotic solution (PSN Gibco containing 50 pg/mL penicillin, 50 pg/mL streptomycin and 100 pg/mL neomycin), 15 ng/mL GM-CSF (granulocyte-macrophage colony-stimulating factor).
  • DIFCO RPMH640 medium
  • antibiotic solution PSN Gibco containing 50 pg/mL penicillin, 50 pg/mL streptomycin and 100 pg/mL neomycin
  • 15 ng/mL GM-CSF granulocyte-macrophage colony-stimulating factor
  • the cells were then placed in cultural plates (150,000 cells/well in a 48-well plate) and grown for 7 days with 1 ng/mL GM-CSF and 10 ng/mL M-CSF (macrophage colony-stimulating factor) to allow the cells to fully differentiate into macrophages.
  • the cells were infected with the HIV-l-Ba-L strain by adding 100 pL of HIV-l-Ba-L strain inoculum, equivalent to a dose of 1000 TCID50 (the dose that infects 50% of tissue culture cells).
  • TCID50 the dose that infects 50% of tissue culture cells.
  • the test samples were added to the wells 24 hours before infecting the cells with HIV-l-Ba-L strain, and on days 3, 7, 10, 14, and 17 after infection. On days 3, 7, 10, 14, and 17 after cell infection, the supernatant was collected and used to assess the effect of the products on inhibiting HIV replication.
  • the samples were diluted with RPMI1640 medium (DIFCO) to achieve a final volume of 250 pL before adding them to wells containing 750 pL of cell culture.
  • the ULD of AB to CD4 was diluted in RPMI1640 medium (DIFCO) by 8 times (dilution ratio 1/8), CD4 + ULD of AB to IFN-y with its individual components included in its composition.
  • the comparison drug azidothymidine was diluted in RPMI1640 medium (DIFCO) to achieve a concentration of 8 nM.
  • the efficacy of the test samples was measured by the inhibition of HIV replication, which was assessed by the enzymatic activity of HIV reverse transcriptase in supernatants of human peripheral blood macrophages using the HIV RT RetroSys kit manufactured by INNOVAGEN (lot 10-059C). To calculate the inhibition percentage of HIV replication, the supernatant of cells, to which the test samples were not added, was used as a control (Tables 11 and 12).
  • Example 8 Investigation of the efficacy of iteration derived from polyclonal antibodies to human IFN-gamma in influenza infection in mice.
  • thermohygrometer IVA-6N OOO NPK Microfor, Russia
  • temperature was 22 ⁇ 3 °C
  • humidity was 20-70 %.
  • Vials made of transparent borosilicate glass 60, 500 ml, Glastechnik Grafenroda, Germany) were used for the preparation of iterations.
  • Type 1 ultrapure water with a resistivity of 18.2 M xcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (h) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • the iteration 14 prepared from a solution of polyclonal antibodies to IFN-gamma (2.1 mg/mL) was used.
  • the iterations activity was assessed by the following methods.
  • the test samples were administered to 32 mice intragastrically at 0.2 mL/mouse (daily dose 0.4 mL/mouse) for 5 days before infection and for 8 days after infection.
  • the comparison drug oseltamivir was administered to 32 mice intragastrically 1 hour before infection at a dose of 20 mg/kg, then twice daily at 10 mg/kg (0.2 mL/mouse) for 5 days after infection; starting from Day 6 after infection, the animals were administered distilled water twice daily at 0.2 mL/mouse instead of oseltamivir.
  • 20 mice were administered distilled water intragastrically twice daily at 0.2 mL/mouse.
  • the influenza virus titer in the lungs was assessed on days 2, 4, 6, 8 after infection.
  • Table 14 Dynamics of influenza virus replication in the lungs of mice administered iteration of antibodies to IFN-gamma vs. oseltamivir, when infected with 10LD50 strain of influenza A/California/07/2009(HlNl)v virus.
  • the claimed product has high antiviral efficacy in the treatment of influenza A/H1N1 caused by the strain A/Califomia/07/2009(HlNl)v, not inferior to the reference drug for the treatment of influenza A, oseltamivir.
  • Example 9 Study of the efficacy of the iterations in influenza infection in mice.
  • thermohygrometer IVA-6N OOO NPK Microfor, Russia
  • temperature was 22 ⁇ 3 °C
  • humidity was 20-70 %.
  • Vials made of transparent borosilicate glass 60, 500 ml, Glastechnik Grafenroda, Germany) were used for the preparation of iterations.
  • Type 1 ultrapure water with a resistivity of 18.2 MQxcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • SevenCompact S230 conductometer Metaltler Toledo, USA
  • For liquids, automatic pipettes of different volumes (Eppendorf, Germany; Socorex, Switzerland) and measuring glassware of accuracy class A (Borosil, India; Steklopribor, Ukraine) were used.
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (L) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • the iteration 15 prepared from a solution of polyclonal antibodies to TNF-a (2.5 mg/mL) and iteration 2 prepared from a solution of polyclonal antibodies to CD4 receptor (3.0 mg/mL) were used.
  • the activity of the iterations was assessed by the following methods.
  • influenza A/California/07/2009swl H1N1
  • 10LD50 the dose infecting 50% of tissue culture cells
  • test samples were added to the drinking bowls of the animals in the appropriate experimental groups. The drinking bowls were freely accessible.
  • the drug was administered for 5 days after infection with A/Califomia/07/2009swl (H1N1) influenza virus.
  • the mice were administered distilled water instead of oseltamivir, intragastrically at 0.2 mL/mouse twice daily (daily dose 0.4 mL/mouse) for 4 days before infection and starting from day 6 after infection.
  • Results [000186] The results of the study of the test samples’ antiviral activity are presented in Table 16. The statistical significance of differences between the experimental groups and the control group (distilled water) was calculated using the nonparametric chi-square criterion.
  • Example 10 Antituberculosis activity of the claimed product against Mycobacterium tuberculosis caused in guinea pigs.
  • Type 1 ultrapure water with a resistivity of 18.2 M xcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (U) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • the iteration 6 prepared from a 1.8 mg/mL solution of monoclonal antibodies to HLA-DRB1 (Sample 1) and the iteration 10 prepared from 3.1 mg/mL solution of monoclonal antibodies to P2-microglobulin (MG) (Sample 2) were used.
  • the activity of the iterations was assessed by the following methods.
  • the study also assessed the product of technologically processing the initial substance of antibodies to HLA-DRB1 by method of successive multiple dilutions, in aqueous-alcoholic dilution C12C150 at a ratio of 2:3, monoclonal antibodies to HLA-DRB1 (Sample 3), and the product of technologically processing the initial substance of antibodies to [32-MG by the method of successive multiple dilutions, in aqueous dilution C12C150 at a ratio of 2:3, and monoclonal antibodies to [32-MG (Sample 4).
  • the study products were administered to guinea pigs orally using a needle free syringe, at a total amount of 8 mL/kg twice a day for 5 days before infection and six days a week (daily, except Sunday) for 2 months after infection.
  • the dose of the products was titrated once a week based on the results of weighing the animals.
  • Water-starch suspension of isoniazid was administered to the animals at the same time and in the same way as the test samples. Isoniazid was administered at a dose of 10 mg/kg of body weight, in 0.4 mL of water-starch gruel.
  • Example 11 Experimental study of hypotensive effect of the claimed product.
  • Type 1 ultrapure water with a resistivity of 18.2 M xcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • SevenCompact S230 conductometer Metaltler Toledo, USA
  • For liquids, automatic pipettes of different volumes (Eppendorf, Germany; Socorex, Switzerland) and measuring glassware of accuracy class A (Borosil, India; Steklopribor, Ukraine) were used.
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (h) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • the iteration 6 prepared from 2.0 mg/mL solution of monoclonal antibodies to C-terminal fragment of ATI angiotensin II receptor (Sample 1) and the iteration 3 prepared from 2.5 mg/mL solution of monoclonal antibodies to endothelial NO synthase (Sample 2) and iteration 11, obtained from a solution containing 1 : 1 mixture of monoclonal antibodies to the C-terminal fragment of ATI of angiotensin II receptor at a concentration of 2.0 mg/ml and monoclonal antibodies to endothelial NO synthase at a concentration of 2.5 mg/ml (Sample 3) were used in this study.
  • the activity of the iterations was assessed by the following methods:
  • mice were administered the test samples orally at 2-2.5 mL/kg once a day for 28 days.
  • animals were administered the comparison drug Losartan orally at 4-5 mL/kg (10 mg/kg) once a day.
  • Group 5 was administered distilled water at 5 mL/kg.
  • the control group animals were administered distilled water at 5 mL/kg orally, once a day for 28 days.
  • SBP systolic blood pressure
  • test samples (Samples 1-5), compared to control sample.
  • the test samples are not inferior in efficacy to the well-known and widely used antihypertensive drug Losartan.
  • Example 12 Study of antidiabetic activity of drugs in a model of spontaneous insulin-independent, non-overweight diabetes mellitus in rats.
  • Type 1 ultrapure water with a resistivity of 18.2 M xcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (L) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • mice Male GK/Par rats weighing 283-314 g were divided into 7 groups of 12 animals each.
  • the experimental groups animals were administered the iteration of piR AB (Sample 1) or the iteration of eNOs AB (Sample 2) at a dose of 2.5 mL/kg.
  • the animals were also administered activated/potentiated forms of piR AB (Sample 3), eNOS AB (Sample 4) at a dose of 2.5 mL/kg/day (diluted with distilled water to 5 mL/kg/day).
  • the original substances were used in homeopathic dilutions C12, C30, C200.
  • Positive control group animals were administered Rosiglitazone at a dose of 5 mg/kg/day.
  • Control animals were administered distilled water or 1% CMC solution (Rosiglitazone solvent) in equivalent doses. All samples were administered once daily, intragastrically, for 4 weeks.
  • the basal level of fasting glucose in the blood plasma was assessed twice a week, before administering the products.
  • the effect of the products on the rate of glucose disposal was also assessed in oral glucose tolerance test (2 g glucose / kg body weight) on the day before the first administration of the products (DO), on the first day after administration (DI) and on the day of the last administration of the products (D28) at 12:00.
  • Type 1 ultrapure water with a resistivity of 18.2 MQxcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • SevenCompact S230 conductometer Metaltler Toledo, USA
  • For liquids, automatic pipettes of different volumes (Eppendorf, Germany; Socorex, Switzerland) and measuring glassware of accuracy class A (Borosil, India; Steklopribor, Ukraine) were used.
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as L. Then, the second iteration (L) was obtained from L in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • Macrophages from intact C57B1/6 mice (4* 10 5 cells/well in 50 pL) and a murine macrophage leukemia cell line, hereinafter RAW 264.7 (5* 10 4 cells/well in 50 pL) were used in the experiment. Both cultures were provided by the Research Institute of Pharmacology and Regenerative Medicine (Tomsk, Russia) and cultured under standard conditions in a CO2 incubator (5%) at 37°C.
  • Three groups of mouse-derived macrophages and three groups of RAW 264.7 cells were treated with three different test samples (one of which was a placebo i.e. purified water) at 1/5 of the total volume per well (20 pL of sample + 80 pL of culture medium), followed by 48-hour incubation. The intact group treated with the medium only (100 pL) served as a control.
  • the MTT assay was performed according to the manufacturer's instructions. 17 pL of MTT solution (2 mg/mL) were added to 96-well plates with cells so that the final MTT concentration in each well was 200 pg/mL. The plates were then incubated for 4 hours at 37°C. The supernatants were removed and 50 pL of DMSO solution was added. Optical density (OD) was measured on a microplate reader at a wavelength of 540 nm. The results are presented as a percentage of the metabolic activity of intact control.
  • Example 14 Study of the antinociceptive effect.
  • Type 1 ultrapure water with a resistivity of 18.2 M xcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (U) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • mice Fifteen minutes after the last injection of test samples, the mice were subcutaneously injected with 20 pL of 2% formalin solution into the plantar surface of the left hind paw using a 100 pL Hamilton syringe connected to a 30-gauge needle. A mouse was placed in a transparent observation chamber. After a 5-min adaptation period, the intensity of the pain response was assessed for the next 50 minutes (5 consecutive 10-min intervals) by the latency of the first pain response, the number of episodes of licking or twitching the injected paw.
  • Example 15 Effectiveness of the claimed product in the treatment of influenza virus.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • a SevenCompact S230 conductometer Metal Organic Chemical Vapor
  • a SevenCompact S220 pH meter Metal Organic Chemical Vapor
  • For liquids automatic pipettes of different volumes (Eppendorf, Germany; Socorex, Switzerland) and measuring glassware of accuracy class A (Borosil, India; Steklopribor, Ukraine) were used. Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA).
  • a calibrated laboratory timer Traceable VWR, USA was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (L) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • Lactose powder was coated with the samples using the fluidized bed saturation method.
  • mice were administered Tamiflu (Hoffmann-La Roche) orally 4 hours before infection (20 mg/kg/day, divided into 2 doses), then the dosing was repeated for 4 days.
  • the mice in Groups 2 and 3 were administered the test samples (dissolved in purified water) intragastrically at 20 mL/kg/day 3 days before infection and for 6 days after infection.
  • the mice in Group 4 were administered a placebo (intact lactose dissolved in purified water).
  • the mice in Group 5 were administered distilled water based on the dosing regimen used for the test samples.
  • mice were anesthetized with ether and then infected intranasally with mouse-adapted influenza A/California/04/2009 (HlNlpdm2009) virus (provided by the WHO National Influenza Center, A. Smorodintsev Research Institute of Influenza, Ministry of Health of the Russian Federation, St. Russia).
  • HlNlpdm2009 mouse-adapted influenza A/California/04/2009 virus
  • test samples for the murine influenza model were provided as lactose- based powder in Falcon polypropylene tubes. Prior to intragastric administration, the test samples were dissolved in purified water by the following procedure: 1.25 g of the test sample was placed in a sterile polypropylene tube, and then purified water (15 mL) was added. The polypropylene tube containing the diluted test sample was gently mixed by inversion. Additional 10 mL of purified water was then added to the resulting solution (total 25 mL). The resulting solutions were mixed prior to each administration.
  • Example 16 Effect of the claimed product on the toxic dose of paracetamol.
  • thermohygrometer IVA-6N OOO NPK
  • Type 1 ultrapure water with a resistivity of 18.2 M xcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the 1 mg/mL stock solution of paracetamol was prepared by adding 5 mL of a freshly opened Paracetamol-Alium solution for infusions (OOO PFK ALIUM, Russia) with a concentration of 10 mg/mL to 45 mL of purified water, then mixing by inverting the bottle ten times.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (L) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • the fertilized eggs were incubated under controlled conditions in a solution of test samples (2 mL per well) or paracetamol (500 mg/1). The incubation solutions were renewed daily. Larval viability was recorded as the main indicator of toxicity after 24, 48, 72, 96 and 120 h of incubation.
  • Example 17 Study of the ability to counteract the development of metabolic syndrome and pathological fat formation in mice.
  • Type 1 ultrapure water with a resistivity of 18.2 MQxcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (U) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • mice in HFD groups received standard synthetic complete food, manufactured at the research center according to the recipe AIN-93G, with the addition of rendered pork fat (lard).
  • the drinking water for the animals in HFD groups was replaced with an 8% fructose solution.
  • Animals of the first and second groups received standard synthetic complete food and water throughout the study.
  • Experimental samples were administered to animals orally in the form of an aqueous solution daily for 10 weeks immediately from the start of the experimental diet-induced metabolic syndrome modeling. [000337] During the experiment, the body weight and body weight gain of laboratory animals in the control and experimental groups, as well as indicators of food and water consumption were monitored.
  • mice of all groups were subjected to humane euthanasia by CO2 asphyxia with immediate collection of blood serum for biochemical analyzes and epididymal adipose tissue for histological examination.
  • all generally accepted standards of experimental ethics were observed (Directive 2010/63/EU of the European Parliament and of the council on the protection of animals used for scientific purposes, September 22, 2010).
  • Sample 1 (iteration No. 6 of purified water) demonstrated the ability to counteract the development of metabolic syndrome and pathological fat formation in mice, while Sample 3 (iteration No. 4 of semaglutide) increased the epididymal fat weight gain.
  • the blinded randomised comparative clinical trial determined the efficacy and safety of the claimed medicinal product - native fraction of iterations of phenobarbital, in the form of oral lozenge tablets in the treatment of sleep disorders and insomnia.
  • the AEs resolved with recovery. In the opinion of the study physicians, there was no causal relationship of the AEs with the intake of the investigational comparator drug in all cases.
  • the comparative clinical study determined the efficacy and safety of the claimed medicinal product, made in the form of oral drops of native fraction of iterations of benzodiazepine, in the treatment of sleep disorders and insomnia.
  • Table 31 Change in scores on the Sleepiness and Sleep Quality Questionnaire after 1 day of therapy with native fraction of iterations of benzodiazepine and a comparison drug
  • Type 1 ultrapure water with a resistivity of 18.2 MQxcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as L. Then, the second iteration (L) was obtained from L in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • Sample 1 was administered to 11 rats intragastrically at a dose of 5 ml/kg/day for 7 days. In the control group 10 rats were intragastrically administered purified water at a dose of 5 ml/kg/day for 7 days. [000391] Behavioral responses of rats using the indicated test were examined before administration of Sample 1 or control and the day after the last administration of Sample 1 or control (values on day 8).
  • the “Elevated Cross Maze” test setup consists of 4 sleeves 0.5 m long and 10 cm wide, fastened together at right angles. Two opposite arms are surrounded on three sides by 40 cm high walls, the other two are open. The maze is located 0.5 m above the floor and its entire surface is evenly illuminated by two fluorescent lamps (20 W) located 60 cm above the level of the arms. Animals were placed on the central platform of the maze with their tails facing the open arm and the latent period of the animal's exit from the central platform, the time of staying in the open and closed arms, and the number of hanging off the edges of the maze were visually evaluated for 3 minutes.
  • Type 1 ultrapure water with a resistivity of 18.2 MQxcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (U) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration. [000403] In this study, we used the mixture (1 : 1 v/v) of I5 (iteration No. 5) and I7 (iteration No. 7) both obtained using diclofenac solution as initial substance (3 pg/ml) (hereinafter referred to as Sample 1). The activity of iteration was determined by methods listed in Table 34.
  • the aim of the study was to investigate anti-inflammatory activity of the claimed preparation in a study model of carrageenan-induced inflammation in rats in comparison with the anti-inflammatory drug indomethacin (Merck, USA).
  • Group 3 male Wistar rats, received indomethacin intragastrically at a dose of 10 mg/kg (in 7.5 ml/kg/day of purified water).
  • the anti-inflammatory effect was assessed by the reduction of edema and expressed as a percentage of control.
  • Statistical analysis of the results was performed using the Kraskell-Wallis test with Tukey's post-hoc test. Differences were considered statistically significant at p ⁇ 0.05.
  • the claimed drug which is a mixture (1 : 1 v/v) of 15 (iteration No. 5) and 17 (iteration No. 7) both obtained using diclofenac solution as initial substance (1 mg/ml), showed a pronounced anti-inflammatory activity in modeling carrageenan-induced inflammation in rats, reducing the mass of paw swelling.
  • Example 22 Aqueous iterations, metformin iterations, and glucose iterations affect the rate of glucose utilization in mice
  • Type 1 ultrapure water with a resistivity of 18.2 M xcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (U) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • Aqueous metformin iterations (Active and Native) were administered intragastrically in the volume of 10 ml/kg for three days, with the last administration after the first glucose measurement and 30 minutes before the glucose load. The next blood glucose measurement was performed 15 minutes after glucose solution administration. A total of 4 time points were used for measurement: fasting, 15, 30, and 60 minutes after administration. Metformin (MF, single oral administration at a dose of 350 mg/kg) was used as a reference drug.
  • Glucose levels were measured using a Contour TS glucometer and test strips (Ascensia Diabetes, Basel, Switzerland). The animal was placed under the grate with its tail stretched between the bars, and one of the lateral tail veins was punctured with a lancet The blood drop was collected on a test strip, the result was read and recorded in the protocol.
  • AUC area under the curve
  • Table 39 Area under the curve of the blood glucose level after administration of metformin iterations.
  • Example 23 Evaluating the effects of iterations on physico-chemical processes involving the substance used to produce the iterations.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • a SevenCompact S230 conductometer Metal Organic Chemical Vapor
  • a SevenCompact S220 pH meter Metal Organic Chemical Vapor
  • For liquids automatic pipettes of different volumes (Eppendorf, Germany; Socorex, Switzerland) and measuring glassware of accuracy class A (Borosil, India; Steklopribor, Ukraine) were used. Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA).
  • a calibrated laboratory timer Traceable VWR, USA was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (L) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • test sample sodium thiosulfate iteration
  • This reaction causes the solution to become cloudy and yellow colored: finely dispersed colloidal sulfur is formed, due to which the rate of the reaction can be estimated by the change in turbidity of the solution over time.
  • Na2S2C>3 (0.1 M) solution was diluted 2-fold with the test sample to a concentration of 0.05 M. Dilution was performed in 20 mL glass vials by adding 2.5 mL of each solution.
  • Table 41 presents the results of the effect of the test sample on the decomposition rate of sodium thiosulfate. When Sample 1 was added, an increase in the chemical reaction rate by 8.2% was observed compared to the neutral carrier (purified water) (p ⁇ 0.05).
  • Type 1 ultrapure water with a resistivity of 18.2 M xcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo) and pH using a SevenCompact S220 pH meter (Mettler Toledo).
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA).
  • a calibrated laboratory timer (Traceable, VWR) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of obtaining iterations included several stages.
  • a vial with a capacity of 60 ml with a freshly prepared stock solution of the initial substance in a volume of 50 ml and a vial with a capacity of 500 ml with neutral carrier (purified water) in a volume of 480 ml were rotated on a vortex for 10 seconds at 3000 rpm in close contact. After this, both vials were incubated for 1 minute at room temperature in close contact.
  • 480 ml of iteration 0 (Io) was obtained.
  • Group 2 Control. Animals were intragastrically injected with purified water at a rate of 10 ml/kg for 5 days using an atraumatic metal probe.
  • each female rat that was to receive test samples was removed from the holding cage and the animal's paw was placed on a small platform under a cone-shaped pusher in an appropriate manner.
  • the researcher then used a foot pedal to gradually increase the pressure on the rat's paw until it resisted and the paw jerked back.
  • the researcher released the pedal and the level of pressure at which the animal felt pain was recorded on a measuring scale (in g/mm2) using an analgesimeter (Ugo Basile, Italy).
  • the hot/cold plate apparatus (UgoBasile, Italy) consists of a thermostatically controlled, electrically heated surface surrounded by a transparent cylinder 15 cm in diameter.
  • Temperature sensitivity was determined by the occurrence of motor responses of restlessness to thermal irritation: paw licking and jumping. For this purpose, a temperature of 55°C was set on the apparatus. At the moment the animal was placed on the plate, the "start" button on the instrument panel was pressed and the latent period (in seconds) of the nociceptive response in the animal was determined. That is, the time interval from the moment the animal was placed on the hot plate to the moment it licked its hind leg and jumped up was recorded. After these behavioural responses, the timer of the apparatus was stopped, the latency period was recorded and the animal was removed from the hot surface of the apparatus.
  • Type 1 ultrapure water with a resistivity of 18.2 M *cm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • SevenCompact S230 conductometer Metaltler Toledo, USA
  • For liquids, automatic pipettes of different volumes (Eppendorf, Germany; Socorex, Switzerland) and measuring glassware of accuracy class A (Borosil, India; Steklopribor, Ukraine) were used.
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as Ii. Then, the second iteration (U) was obtained from Ii in a similar manner. The procedure was repeated the required number of times to obtain the final iteration. [000492] In this study, we used I4 (iteration No. 4) obtained using Prednisolone (Sigma, USA) solution as initial substance (100 pg/ml) (hereinafter referred to as Sample 1). The activity of iteration was determined by methods listed in Table 46.
  • Sensitisation schedule HS at 1/10 dilution was administered p/v 0.3 ml once daily, 5 times with an interval of 4 days.
  • the permissive HS of drug at 1/10 dilution was administered intravenously, 0.5 ml, on day 7 after the last sensitising injection.
  • Sample 1 Control (purified water) and HS were administered as follows:
  • HS sensitisation was performed p/k 0.3 ml; from day 1 to day 10 - administration of Sample 1 (0.2 ml per os); on day 23 (on day 7 after the last HS administration) - administration of a permissive dose of HS and recording of the results.
  • HS sensitisation was performed p/k 0.3 ml; from day 1 to day 10 - administration of Control (0.2 ml per os); on day 23 (on day 7 after the last HS administration) - administration of a permissive dose of HS and recording of the results.
  • HS sensitisation was carried out p/k 0.3 ml; from the 14th to the 23rd day - administration of Samplel (0.2 ml per os); on the 23rd day (on the 7th day after the last HS administration) - administration of the authorising dose of HS and recording of the results.
  • Table 48 Mean IIEF-5 scores in drug/placebo groups, before and after 4 weeks of therapy.
  • VAS pain severity decreased by 31.5 ⁇ 14.3 and 10.8 ⁇ 11.6 points in the drug and placebo groups, respectively, after 8 weeks of treatment.
  • the differences between baseline and post-treatment scores were statistically significant in both groups (p ⁇ 0.0001). The differences between the groups were also significant (p ⁇ 0.0001).
  • Example 28 In vitro evaluation of the antitumour activity of the claimed drug against mastocytoma P-815.
  • Type 1 ultrapure water with a resistivity of 18.2 MQxcm (Milli-Q Integral 5, Millipore) was used as the neutral carrier for the preparation of iterations, as well as the solvent for all other reagents used in this work.
  • the quality of purified water was monitored daily by measuring resistivity using a SevenCompact S230 conductometer (Mettler Toledo, USA) and pH using a SevenCompact S220 pH meter (Mettler Toledo, USA).
  • Dry reagents were weighed using an analytical balance of accuracy class I (Pioneer PA214C, Ohaus, USA). A calibrated laboratory timer Traceable (VWR, USA) was used to measure all incubation periods. Vibration was performed using a shaker (vortex) MS 3 basic (IKA-Werke, Germany) with a standard insert.
  • the process of preparing iterations included several stages.
  • a 60 mL vial containing a 50 mL of the initial substance (purified water or metformin solution) and a 500 mL vial containing 480 mL of purified water (neutral carrier) were rotated on a vortex for 10 seconds at 3000 rpm in close contact with each other. Thereafter, both vials were incubated for 1 minute at room temperature in close contact. Using the above-described procedure, 480 ml of iteration No.O (zero iteration) was obtained.
  • the vial with iteration No.O (480 mL) was placed next to a new 500 mL vial with 480 mL neutral carrier and rotated on a vortex for 10 seconds at 3000 rpm in close contact. Both vials were then incubated for 1 minute at room temperature in close contact. After the above-described procedure, the exposed neutral carrier was taken as L. Then, the second iteration (L) was obtained from L in a similar manner. The procedure was repeated the required number of times to obtain the final iteration.
  • the cell concentration and viability were counted before seeding the cells onto the plates.
  • the cell concentration for seeding was 5xl0 4 cells/well.
  • the P-815 cell line was cultured in DMEM and EFV medium (containing a mixture of antibiotic and antifungal agent, sodium pyruvate and glutamine) at 37°C and 5% CO2.
  • DMEM and EFV medium containing a mixture of antibiotic and antifungal agent, sodium pyruvate and glutamine
  • MTT (3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) solution (Serva, USA) was added to the wells at a final concentration of 200 pg/ml. The supernatant was then removed from the wells and the precipitate was dissolved with dimethyl sulfoxide (Sigma, USA). The absorbance of the resulting solutions was measured using a Titertek Multiscan MCC spectrophotometer (Labsystems, Finland) at a wavelength of 540 nm.
  • Sample 1 demonstrated the ability to inhibit the metabolic activity of tumour cells compared to placebo.

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Abstract

La présente invention se rapporte au domaine des produits pharmaceutiques, à savoir un procédé d'obtention d'un produit, qui est une série de solvants traités, présentant un effet d'activation ou de suppression sur divers processus physico-chimiques ou biologiques impliquant la substance initiale utilisée pour l'obtention du produit ou la cible moléculaire qui lui est associée, par de multiples traitements vibratoires externes successifs de la substance initiale à un produit obtenu par ce procédé, et la séparation du produit en fractions, constituant un ou plusieurs solvants traités, possédant des propriétés physico-chimiques intrinsèques et régulant les processus physico-chimiques et biologiques impliquant la substance initiale ou sa molécule cible.
PCT/IB2024/060256 2023-10-24 2024-10-18 Substance artificielle et son procédé de préparation Pending WO2025088452A1 (fr)

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