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WO2022108471A1 - Agent pour le traitement et la prévention d'infections virales respiratoires aiguës - Google Patents

Agent pour le traitement et la prévention d'infections virales respiratoires aiguës Download PDF

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Publication number
WO2022108471A1
WO2022108471A1 PCT/RU2020/000623 RU2020000623W WO2022108471A1 WO 2022108471 A1 WO2022108471 A1 WO 2022108471A1 RU 2020000623 W RU2020000623 W RU 2020000623W WO 2022108471 A1 WO2022108471 A1 WO 2022108471A1
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WO
WIPO (PCT)
Prior art keywords
agent
drops
alloferon
influenza
spray
Prior art date
Application number
PCT/RU2020/000623
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English (en)
Russian (ru)
Inventor
Герман Петрович БЕККЕР
Борис Алексеевич НИКОНОВ
Original Assignee
Герман Петрович БЕККЕР
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Герман Петрович БЕККЕР filed Critical Герман Петрович БЕККЕР
Priority to PCT/RU2020/000623 priority Critical patent/WO2022108471A1/fr
Publication of WO2022108471A1 publication Critical patent/WO2022108471A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • SUBSTANCE invention relates to medicine and pharmaceutical industry and concerns an antiviral drug for the prevention and treatment of influenza and other respiratory viral infections.
  • ARVI Acute respiratory viral infections
  • ARVI includes diseases caused by influenza viruses, rhinoviruses, adenoviruses, parainfluenza viruses, etc.
  • adamantane derivatives act on the M2 protein of the influenza virus, which forms ion channels, oseltamivir (Tamiflu) and zanamivir (Relenza) are neuraminidase inhibitors.
  • Entrance gates for respiratory viruses are epithelial cells of the upper respiratory tract - the nose, trachea, bronchi. In these cells, the virus multiplies and leads them to destruction and death. Therefore, it is advisable to deliver an antiviral drug capable of influencing virus replication directly to these entrance gate.
  • the preparation for administration into the nose can be nasal drops, into the trachea or bronchi by a spray.
  • the inner surface of the nasal cavity is rich in blood vessels; therefore, the intranasal application of drugs is practically bioequivalent to the injection route of administration.
  • antiviral drugs in nasal form, and most of them contain interferons as an active ingredient. These are Grippferon, Nazoferon and other drugs based on interferon-alpha, Ingaron based on interferon-gamma. In addition to them, there are several nasal immunomodulatory drugs used in the treatment of influenza and SARS. These are Timogen, Imunofan, T13.
  • Alloferons A family of peptides with antiviral action is known - Alloferons (Chernysh S.I., Kim Su Ying, Becker G.P., Makhaldiani N., Hoffmann J., Bule F., RF Patent No. 2172322 "Alloferons - immunomodulatory peptides").
  • the mechanism of action of alloferons consists in the induction of the synthesis of endogenous interferons and the activation of the natural killer system.
  • Peptide Alloferon is registered as a pharmaceutical substance (P N002830/02-240510) and is produced by Russian enterprises.
  • an antiviral drug "Allokin-alpha, lyophilisate for preparing a solution for subcutaneous administration, 1 mg" (P N002829/01-210610) was created.
  • the drug has found wide application in clinical practice in the treatment of papillomavirus infections and herpes.
  • the mechanism of antiviral action of Alloferon is universal, which should ensure its effectiveness against influenza viruses and other acute respiratory viral infections.
  • Allokin-alpha is indeed highly effective against SARS, including bird flu (H5N1).
  • H5N1 bird flu
  • the fact that it is used in the form of injections significantly limits its use for such massive infections as SARS. These infections require drugs in forms convenient for use by a wide range of ordinary consumers.
  • Sprays and drops are liquid dosage forms for repeated use. Since nasal preparations are used repeatedly, air and, of course, microorganisms inevitably get into them during use. Due to this circumstance, special requirements are imposed on drugs for intranasal use. niya. One of these is to ensure their stability, both the chemical stability of the active substance and the stability of the composition in relation to microflora. In order to suppress undesirable effects, stabilizers and preservatives (antiseptics) are introduced into nasal preparations. The former provide the chemical stability of the active components, the latter prevent the reproduction of microorganisms. In addition to stabilizers and antiseptics, they may include substances that increase the permeability of the mucous membrane and substances that increase the viscosity of the system.
  • Thymogen which is based on the peptide alpha-glutamyl-tryptophan, is used intramuscularly, as well as in the form of a spray.
  • the drug is a solution of the peptide in 0.9% sodium chloride solution using benzalkonium chloride as a preservative.
  • the drug Timogen practically does not contain auxiliary components that could increase its effectiveness when administered intranasally.
  • the antiviral agent contains interferon, a biocompatible polymer and a buffer mixture.
  • interferon contains genetically engineered interferon, and also additionally contains an antioxidant with the following content of components in 1 ml of the buffer mixture: genetically engineered interferon, ME 1000-500000; biocompatible polymer, g 0.005-0.714; antioxidant, g 0.0001-0.0006.
  • the agent contains alpha, beta or gamma interferon.
  • the product obtained has a viscosity of (1.1-30.0)»10-3. It contains Trilon B as an antioxidant. It contains polyvinylpyrrolidone and/or polyethylene oxide as a biocompatible polymer. Moreover, polyvinylpyrrolidone and polyethylene oxide are taken in a ratio of 1:1-50.
  • the antiviral agent provides prolonged contact with the nasal mucosa and action at the site of the primary introduction and reproduction of the virus, as well as good absorption.
  • the essence of the prototype is also that it includes substances that increase the bioavailability of the active ingredient for the body, namely: disodium edetate (trilon B) as chemical stabilizer and additives that increase the viscosity of the solution.
  • the technical problem of the prototype is the lack of therapeutic efficacy of the drug due to the limited permeability of interferons through the nasal mucosa.
  • the low bioavailability of interferons with intranasal administration is due to their large molecular weight.
  • the objective of the invention is to eliminate these problems and create a drug in the form of a spray or nasal drops, which has a pronounced antiviral activity.
  • the technical result of the invention is a drug with high antiviral activity in the form of a spray or drops applied intranasally.
  • the drug is a medicinal and prophylactic protection against SARS.
  • influenza A and B viruses it has been proved that the proposed agent has a high protective effect against acute respiratory viral infections (ARVI.
  • the specified technical result is achieved due to the fact that the declared agent for the treatment and prevention of acute respiratory viral infections in the form of a spray or nasal drops, characterized in that it contains Alloferon oligopeptide at a concentration of at least 0.01%, osmotically active substances, acceptable stabilizers and antiseptics.
  • polyhydric alcohols selected from the range: 1,2-propylene glycol, glycerin, low molecular weight polyethylene glycols (PEG) at a concentration of up to 5%.
  • xylometazoline hydrochloride or its analogue which provide a vasoconstrictive effect, is additionally introduced into its composition.
  • a method for preparing the developed agent consisting in the fact that the calculated amounts are successively dissolved in purified water with stirring. properties of benzalcolnium chloride (in the form of a 2% solution), disodium edatate and sodium chloride, after their complete dissolution, an osmotically active substance and Alloferon are introduced, purified water is added to a predetermined value, filtered through a filter with a pore size of 0.4 ⁇ m; the resulting solution is packaged in glass vials, dosing pumps (spray) or nozzles (drops) are inserted and sealed.
  • benzalcolnium chloride in the form of a 2% solution
  • disodium edatate and sodium chloride after their complete dissolution, an osmotically active substance and Alloferon are introduced, purified water is added to a predetermined value, filtered through a filter with a pore size of 0.4 ⁇ m; the resulting solution is packaged in glass vials, dosing pumps (
  • the essence of the invention lies in the fact that the agent contains Alloferon oligopeptide in combination with excipients.
  • the solution to the problem and the technical result is a composition containing at least 0.01% of Alloferon oligopeptide and excipients.
  • the composition adopted by us contains up to 5% polyhydric alcohols: 1,2-propylene glycol, glycerin or low molecular weight polyethylene glycols (PEG), which, by increasing the permeability of the mucous membrane, perform a transport function for the active substance.
  • PEG polyethylene glycols
  • Their use increases the viscosity of the composition, which provides better wetting of the nasal cavity and, accordingly, greater availability of Alloferon.
  • Their bacteriostatic action is also known.
  • As a standard preservative it is permissible to use benzalkonium chloride or phenylethyl alcohol at a concentration of 0.02%.
  • the function of a chemical stabilizer can be performed by disodium edetate.
  • Respiratory viral infections are usually accompanied by symptoms of acute inflammatory processes in the nose and nasopharynx.
  • vasoconstrictive substances are used that increase vascular tone and relieve swelling of the mucosa in the affected area.
  • the standard vasoconstrictor components used in respiratory diseases are xylometazoline and its derivatives. Their introduction in the amount of 0.05% allows you to achieve the desired result.
  • Evaluation of the effectiveness of the proposed agent in relation to SARS was performed on the examples of influenza A and influenza B viruses.
  • the assessment was carried out both in therapeutic - use after infection, and therapeutic and prophylactic - use before and after infection, schemes.
  • the dynamic viscosity of the compositions at a temperature of 20°C in the case of using 1,2-propylene glycol was 1.05 ⁇ 0.02 cP; for glycerin 1.14 ⁇ 0.03 cP, for PEG-400 - 1.31 ⁇ 0.03 cP.
  • the viscosity of the tested compositions was determined by the capillary method using an Ubbelohde viscometer.
  • Example 3 Induction of type 1 interferons.
  • compositions were administered to mice once intranasally in a volume of 0.1 ml, which corresponds to 10 ⁇ g for composition 1 and 50 ⁇ g for composition 2.
  • a positive control used cycloferon at a dose of 500 mcg administered intraperitoneally.
  • the control group received 0.1 ml of 0.9% sodium chloride solution intranasally. The results are presented in table 1.
  • compositions caused a significant increase in the concentration of interferons in the blood serum with maxima 6 and 24 hours after the administration of the drugs.
  • Composition 2 showed a particularly high level of induction of interferons. The maximum level of induction occurs 24 hours after their administration.
  • Composition 1 causes a weaker, however, significant increase in the induction of interferons. Both compositions at a dose of 10 to 50 ⁇ g cause an induction of interferons in excess of that caused by cycloferon at a dose of 500 ⁇ g.
  • compositions for intranasal administration are effective inducers of type 1 interferons.
  • Example 4 Antiviral activity of the drug on the model of experimental lethal influenza infection in white mice caused by influenza A virus. Therapeutic scheme for the use of the drug.
  • a model of a lethal influenza infection was used on white outbred mice of both sexes weighing 10-12 g obtained from the Rappolovo nursery.
  • compositions prepared according to examples 1 and 2 were used in the study.
  • the mice were divided into 2 parts of 5 groups each: The first part was intended for the study with a ten-fold lethal dose of the virus 10 LD 50 , the second - with a single lethal dose of 1 LD S0 .
  • the virus was administered to animals intranasally under light ether anesthesia.
  • test compositions were administered to animals according to the general scheme for two parts: 1/ 0.1 ml of composition 1 (dose 10 ⁇ g) intranasally once 30 minutes after infection, 2/ 0.1 ml of composition 2 (dose 50 ⁇ g) intranasally once after 30 minutes after infection, 3/ composition 1 four times in 30 minutes and then 1, 2 and 3 days after infection, 4/ positive control - subcutaneously four times the drug "Allokin-alpha" in 0.9% sodium chloride solution at a dose of 25 mcg, 5/ control - intranasally 0.1 ml of 0.9% sodium chloride solution.
  • N15 is the number of animals in the group that died within 15 days after infection
  • N is the total number of animals in the group
  • IP Ms-Me/Msx100%, where Ms and Me are lethality expressed as a percentage in the control and experimental groups, respectively.
  • Example 5 Antiviral activity of the drug on the model of experimental lethal influenza pneumonia in white mice caused by the influenza A virus.
  • a model of a lethal influenza infection was used on outbred mice of both sexes weighing 10–12 g obtained from the Rappolovo nursery.
  • mice were divided into 3 groups - two experimental and one control.
  • the virus was administered to animals intranasally under light ether anesthesia at a dose of 1 LD 50 .
  • compositions 1 and 2 prepared according to examples 1 and 2 were used.
  • the compositions were administered to mice intranasally in an amount of 0.1 ml (doses of 10 and 50 ⁇ g, respectively, of the composition) according to the following scheme relative to the date of infection: 1/ day before infection , 2/ 30 minutes before infection, 3/ 30 minutes after infection, 4/ then after 1, 2 and 3 days. Animals were observed for up to 15 days; the period during which 100% lethality of animals is observed in experimental influenza.
  • mice were injected intranasally with 0.1 ml of 0.9% sodium chloride solution.
  • Table 3 The protective effect of the developed agent on the model of experimental lethal influenza infection in white mice caused by the influenza A virus when using a treatment-and-prophylactic regimen using a single lethal dose of 1 LD 50 . influenza A.
  • Table data. 3 show that the developed compositions have a high protective effect in the therapeutic and prophylactic scheme of application. Moreover, both compositions show effectiveness.
  • compositions based on the Alloferon oligopeptide when administered intranasally, are highly effective against the influenza A virus in both therapeutic and preventive treatment regimens.
  • Example 6 Antiviral activity of the drug on the model of experimental lethal influenza infection in white mice caused by influenza B virus. Treatment regimen for the use of the drug.
  • mice were infected intranasally with influenza B virus, strain B/Lee/40, taken at doses of the corresponding 3 and 30 LD 50 .
  • the mice were divided into 6 groups.
  • the study used composition 2, prepared according to example 2, which was administered intranasally in an amount of 0.05 ml at a dose of 25 ⁇ g according to the scheme: one day before infection, then after 1, 2, 4, 6 and 8 days.
  • Ribavirin at a dose of 30 ⁇ g administered intraperitoneally was used as a positive control.
  • the control group received intranasally 0.9% sodium chloride solution.

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pulmonology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
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Abstract

L'invention se rapporte au domaine de la médecine et concerne une agent pharmaceutique pour le traitement et la prévention de la grippe et autres infections virales respiratoires aiguës (IVRA) sous forme nasale. Le résultat technique de la présente invention consiste en une préparation ayant une forte activité antivirale sous forme de spray ou de gouttes pour administration intranasale. Cette préparation consiste en un agent de traitement et de prévention pour la protection contre les IVRA. Par exemple, pour les virus de la grippe A et B, il a été démontré que cet agent possède une grande action de protection en ce qui concerne les infections virales respiratoires aiguës (IVRA). L'invention concerne essentiellement un agent sous forme de spray ou de gouttes nasales, dont la composition comprend un oligopeptide Allopheron en combinaison avec des agents stabilisants et antiseptiques. Cet agent est utilisé pour traiter et prévenir des infections virales respiratoires aiguës par administration intranasale.
PCT/RU2020/000623 2020-11-20 2020-11-20 Agent pour le traitement et la prévention d'infections virales respiratoires aiguës WO2022108471A1 (fr)

Priority Applications (1)

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PCT/RU2020/000623 WO2022108471A1 (fr) 2020-11-20 2020-11-20 Agent pour le traitement et la prévention d'infections virales respiratoires aiguës

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2212235C1 (ru) * 2001-12-24 2003-09-20 Закрытое акционерное общество "Брынцалов-А" Капли назальные бризолин, обладающие сосудосуживающим, противовоспалительным и противоотечным действием
RU2361593C2 (ru) * 2002-06-14 2009-07-20 Сипла Лимитед Комбинация азеластина и стероидов
RU2014136096A (ru) * 2014-09-05 2016-03-27 Общество с ограниченной ответственностью "Аллоферон" Лекарственное средство для лечения и профилактики заболеваний верхних и нижних дыхательных путей различной этиологии, его применение и метод лечения на его основе
RU2019112460A (ru) * 2019-04-24 2020-10-26 Герман Петрович Беккер Средство для лечения и профилактики острых респираторных вирусных инфекций (орви) и способ его приготовления

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2212235C1 (ru) * 2001-12-24 2003-09-20 Закрытое акционерное общество "Брынцалов-А" Капли назальные бризолин, обладающие сосудосуживающим, противовоспалительным и противоотечным действием
RU2361593C2 (ru) * 2002-06-14 2009-07-20 Сипла Лимитед Комбинация азеластина и стероидов
RU2014136096A (ru) * 2014-09-05 2016-03-27 Общество с ограниченной ответственностью "Аллоферон" Лекарственное средство для лечения и профилактики заболеваний верхних и нижних дыхательных путей различной этиологии, его применение и метод лечения на его основе
RU2019112460A (ru) * 2019-04-24 2020-10-26 Герман Петрович Беккер Средство для лечения и профилактики острых респираторных вирусных инфекций (орви) и способ его приготовления

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