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WO2022122175A1 - Composition antivirale comprenant du ciste et dispositif médical pour son administration - Google Patents

Composition antivirale comprenant du ciste et dispositif médical pour son administration Download PDF

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Publication number
WO2022122175A1
WO2022122175A1 PCT/EP2020/085858 EP2020085858W WO2022122175A1 WO 2022122175 A1 WO2022122175 A1 WO 2022122175A1 EP 2020085858 W EP2020085858 W EP 2020085858W WO 2022122175 A1 WO2022122175 A1 WO 2022122175A1
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Prior art keywords
composition
extract
cistus
antiviral
medical device
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Ceased
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PCT/EP2020/085858
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English (en)
Inventor
Ondrej Michlo
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HERB-PHARMA AG
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HERB-PHARMA AG
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Priority to PCT/EP2020/085858 priority Critical patent/WO2022122175A1/fr
Publication of WO2022122175A1 publication Critical patent/WO2022122175A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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

Definitions

  • the object of the present invention relates to an antiviral composition and a medical device for the administration of this composition.
  • the composition of the present invention is useful against the SARS-CoV-2 coronavirus, that is, in the treatment or prophylaxis of the COVID-19 viral disease.
  • the composition contains Cistus extract, Echinacea purpurea extract, and optionally Citrus bioflavonoid complex and.
  • the present invention further relates to a medical device which is suitable for the administration of the composition according to the present invention.
  • SARS-CoV-2 coronavirus strain (hereinafter referred to as SARS-CoV-2) is one of the major plagues worldwide in 2020.
  • SARS-CoV-2 coronavirus is a member of the large family of coronaviruses, that can infect people and some animals, as well.
  • the number of the registered infected people around the globe has exceeded 65 million and more than 1.5 million people have already died due to this highly infectious pathogen since 2019 until the filing date of the present patent application [WHO Coronavirus Disease (COVID-19) Dashboard (online) . World Health Organization, 2020 (retrieved on 2020-11-26) . Retrieved from ⁇ https://covidl9.who.int/>] .
  • COVID-19 spreads easily from person to person according to the examples below: spread between people who are in close contact; through respiratory droplets produced when an infected person coughs, sneezes, breathes, sings or talks; less common ways COVID-19 can spread by airborne transmission or with contaminated surfaces
  • Centers for Disease Control and Prevention online ) . National Center for Immuni zation and Respiratory Diseases (NCIRD) , Division of Viral Diseases , 2020 ( retrieved on 2020- 11- 13 ) . Retrieved from ⁇ https : / /www . cdc . gov/ coronavirus/ 2019-ncov/pr event- get ting- sick/ index . html>] .
  • the respiratory droplets can cause infection by the SARS-CoV-2 coronavirus when these droplets are inhaled or deposited on mucous membranes , such as those that line the inside of the nose and mouth that is why covering mouth and nose with mask in public places or transport and shopping malls nowadays is obligatory in almost every country .
  • Regular hand washing, cleaning frequently touched surfaces , keeping social distance and strengthening the immune system are also recommended .
  • the 21 st century' s most severe pandemic outbreak is still going on, civilization is vulnerable to this respiratory disease without any safe preventive vaccination, furthermore people with health problems and/or the olds are particularly af fected .
  • Herbs and generally plants with natural active substances often have antibacterial and antiviral ef fects that can be used for the prophylaxis and treatment of diseases caused by such microorganisms .
  • These herbs and plants serve as an excellent source of biodiversity for discovering novel antivirals , revealing new structure-activity relationships , and developing ef fective protective/ therapeutic strategies against viral infections .
  • Many natural products and herbal ingredients are observed to possess robust antiviral activity and their discoveries can further help develop derivatives and therapeutic leads [ Lin, et al . , Journal of Traditional and Complementary Medicine ; 2014 , 4 , 24-35 ] .
  • Alcoholic extracts of ginger are active against bacteria that infect the intestinal tract (for example: Salmonella typhimurium, Escherichia coli etc.) and respiratory tract (such as Streptococcus pneumoniae and Haemophilus influenzae etc.) [Monterey Bay Spice Company Newsletter Archive, Infection-Fighting Herbs (online) . Linda B. White, M.D., 2020 (retrieved on 2020-11-13) . Retrieved from ⁇ https://www.herbco.com/t-herbs-infection.aspx>] .
  • Peppermint is commonly added to teas, extracts, and tinctures meant to naturally treat viral infections via its active components, including menthol and rosmarinic acid which have antiviral and anti-inflammatory activity [Healthline Media a Red Ventures Company, Infection-Fighting Herbs (online) . Jillian Kubala, MS, RD, 2019 (retrieved on 2020-11-13) . Retrieved from ⁇ https://www.healthline.com/nutrition/antiviral-herbs>] . Green tea's major phenolic compounds called catechins exhibit antiviral and antimicrobial activities [Yasmin, A. R., Chia, S. L., Looi, Q. H., Omar, A. R., Noordin, M.
  • Plant-derived polyphenols have been shown to be strong antioxidants with potential health benefits as they are able to protect the heart, support the biological activity of vitamin C, protect from premature skin ageing, and bind viruses and bacteria [Urquiaga, I., Leighton, F. Plant polyphenol antioxidants and oxidative stress. Biol. Res. 2000, Vol. 33 No.2, pages 55 and 64.] .
  • Cistus plant (about twenty species are known in the Cistus genus) is used for producing a composition for the prophylaxis and/or treatment of viral cold infections caused by rhinoviruses, adenoviruses or coronaviruses.
  • a preferred embodiment according to this disclosure is in the form of an extract from the Cistus plant and the composition is administered orally or topically.
  • Cistus creticus i.e. pink rockrose
  • Cistus creticus is rich in polyphenols, its antiviral activity is long known.
  • Cistus creticus contains a large number of polar compounds which bind well to the surface of viruses and cells, break down their protein shell, that increases their direct antiviral effect. Its main compounds are flavan-3-ols and proanthocyanidins, the monomer phenolic compounds' total content is under 2%, the polymer components are dominants, especially proanthocyanidins which molecular weight range between 500 to 1200 Da. Because of the active components' high molecular weight, they cannot enter the cell by either active nor passive transport that is why Cistus creticus extract is preferably used topically as antiviral agents, e.g. as an aerosol or oral spray. Due to this direct effect on pathogens it does not lead to antiviral drug resistance. Said active components are present in the alcoholic or aqueous extract of Cistus creticus .
  • Echinacea varieties are suitable for the treatment of diseases caused by viruses or bacteria affecting the respiratory system.
  • One possible embodiment is when Echinacea extract is combined with Cistus incanus extract.
  • a composition described in FR2948570A1 published patent application relates more specifically to compositions comprising an extract of the fruit of Citrus medica L. var Risso, and their uses, particularly in the field of human and animal health as well as in the agriculture and food sector. It describes twenty-five new compositions comprising an extract of the fruit of Citrus medica L. var Risso and one or more other plant extracts including cinnamon. The description also discloses the use of the mentioned compositions for the preparation of an anti-allergic, anti fungal , antibacterial , antiparasitic, anti-arthropod, anthelmintic and/or antiviral composition .
  • Other plant extracts include among others Ci stus ladaniferus .
  • This preparation comprises an extract of at least one type of Echinacea .
  • One possible preparation according this invention can also be combined with at least one further active substance , for example with a Ci stus incanus extract , a neuraminidase inhibitor and/or an M2 inhibitor .
  • Ci stus is used for producing a composition or a preparation for the prophylaxis and/or treatment of colds ( flu-like infections ) caused by rhinoviruses , adenoviruses or coronaviruses .
  • the disclosed composition is administered in the form of a tablet , an extract (most preferred form is the dry extract ) , further it can be administered in the form of emulsions , ointments , gels , creams for topical application, an aerosol or room spray .
  • the use of Ci stus according this invention is not restricted only to people , it is also suitable for animals , particularly mammals , such as pets or livestock .
  • the FR2877576A1 patent application relates to a pharmaceutical composition used to stimulate the proli feration and activation of mast cells . It relates more particularly to the pharmaceutical compositions used to ampli fy the immune response following the introduction of infectious agents into the human or animal body . Ci stus ladaniferus and also citrus derivatives are mentioned in this document as natural ingredients which can be extracted by distillation .
  • the field of the US6447816B1 patent relates to the prevention of colds, flus, and diseases caused by other pathogens within the respiratory system of human beings by the inhalation of vapours from highly volatile essential oils such as eucalyptus oil and/or tea tree oil.
  • a thin anti-pathogenic layer is formed in the respiratory system that protects against infection for a certain duration of time following inhalation.
  • the list of essential oils consists some Citrus derivatives and the Cistus land!, var. pinene.
  • bactericide agents are listed in table I of this disclosure in combination with an anionic, cationic, non- anionic or amphoteric surface active agent or agents which have a (C12-) alkyl group as the longest alkyl chain attached to the hydrophilic moiety or moieties.
  • anionic, cationic, non- anionic or amphoteric surface active agent or agents which have a (C12-) alkyl group as the longest alkyl chain attached to the hydrophilic moiety or moieties.
  • Citrus bergamia melarosa Citrus medica acida
  • Cistus ladaniferus and Citrus auranti folia are mentioned among others.
  • CYSTUS052 was more effective in reducing the average duration and severity of symptoms in patients with infection of the upper respiratory tract than placebo.
  • the aim of the present invention is to provide an effective antiviral composition and medical device for its administration suitable for the prophylaxis and treatment of diseases caused by the SARS-CoV-2 coronavirus, especially for the treatment and prophylaxis of the COVID-19 viral disease.
  • the present invention was made in view of the prior art described above, and the object of the present invention is to provide a composition that can be used in the prophylaxis and treatment of COVID-19.
  • a further object of the present invention to provide said composition in a medical device suitable for the administration of said composition .
  • the solution of the present invention provides a composition that can be used alone or as an additive treatment to a drug treatment for the prophylaxis and treatment against COVID- 19 viral infections .
  • the use of composition of the present invention is without the risk of development of resistance due to its direct ef fect to the SARS-CoV-2 pathogen .
  • the present invention is based on the recognition that a Ci stus extract applied together with Echinacea purpurea extract , and optionally with Ci trus bioflavonoid complex show a synergistic ef fect , these ingredients have better overall ef fect than these components would have individually . Due to this synergy, a Ci stus extract , Echinacea purpurea extract , and optionally Ci trus bioflavonoid complex together have shown an antiviral activity against today' s most worrying virus strain, namely against SARS-CoV-2 .
  • the present invention relates to an antiviral composition, wherein said composition comprises a Ci stus extract , Echinacea purpurea extract , and optionally Ci trus bioflavonoid complex, and the composition inhibits the SARS-CoV-2 coronavirus .
  • the Ci stus extract is a Ci stus creti cus extract .
  • the solvent used for the preparation of the Ci stus extract is water and the solvent used for the preparation of the Echinacea purpurea extract is 70% ethanol .
  • the amount of the Ci stus extract is between 1 % and 49% of the total content of the composition
  • the Echinacea purpurea extract is between 1 % and 49% of the total content of the composition
  • the optional Ci trus bioflavonoid complex is between 1 % and 49% of the total content of the composition and .
  • composition of the present invention further comprises other antiviral agents known according to the state of the art .
  • the composition of the present invention further comprises excipients , like flavouring agents , colouring agents , pH adj usting agents , etc .
  • the present invention further relates to a medical device comprising the composition of the present invention .
  • the medical device is preferably a nasal spray, oral spray or solution .
  • the medical device is in the form of tablets or capsules .
  • % in the present speci fication is understood to mean mass percent (mass% ) , and in the case of ratios it is understood to mean the mass ratios of the individual components .
  • antiviral refers to such an agent that kills a virus or suppresses its ability to replicate and, hence, inhibits its capability to multiply and reproduce.
  • a virus is just genetic material, DNA or RNA, optionally with a few enzymes, wrapped in a protein coat.
  • a virus is technically not alive but can replicate by hijacking the machinery of the cell they infect which makes it hard to kill.
  • coronavirus which was denominated severe acute respiratory syndrome coronavirus 2 and defined as the causal agent of Coronavirus Disease 2019 (i.e. COVID-19) .
  • COVID-19 was declared a pandemic by the World Health Organization (WHO) in March 2020.
  • WHO World Health Organization
  • coronaviruses are enveloped viruses with a lipid membrane derived from the host cell, in which viral surface proteins are embedded. The proteins protruding from the viral membrane (especially the spike [S]protein) give these pathogens their characteristic halo-like appearance under the electron microscope, which has led to the name corona (Latin: garland, crown) .
  • SARS-CoV-2 coronavirus's genome is also in the form of a single-stranded ribonucleic acid (RNA) with positive polarity [S. Ludwig, A. Zarbock, International Anesthesia Research Society; July 2020, 131 (1) , 93-96. ] .
  • RNA ribonucleic acid
  • COVID-19 viral disease caused by SARS-CoV-2 can easily spread from person to person. Viruses usually get into the host via respiratory droplets through the respiratory tract, after getting into cells, they start into fast reproduction.
  • the present invention relates to a composition comprising natural ingredients in combination that makes the composition effective both in prophylaxis and in controlling viral pathogens due its natural ingredients' properties and its direct inhibition of viruses.
  • one of the main active agents is derived from a Cistus species, e.g. from Cistus creticus, containing polyphenols in concentrated form, said polyphenols show synergistic effect with the present composition's other main ingredients, like the Echinacea purpurea extract, and the optional Citrus bioflavonoid complex.
  • composition of the present invention has an antiviral activity against SARS-CoV-2 coronavirus.
  • Antiviral compositions containing herbs provide a good alternative against antiviral resistance, because synthetic drugs often have either diminished or no effectiveness against targeted viruses due to antiviral resistance.
  • the antiviral resistance is a decreased susceptibility to a drug caused by changes in viral genotypes.
  • Cistus is a genus of flowering plants in the rockrose family Cistaceae, containing about twenty species.
  • a preferrred species of the Cistus genus within the scope of the present invention is the Cistus creticus (pink rockrose, hoary rockrose) .
  • Cistus creticus has several subspecies, like e.g. Cistus creticus eriocephalus .
  • the present invention relates to all species of the Cistus genus, especially to all subspecies of Cistus creticus . Due to the significant polyphenol content of the species of the Cistus genus, the extract of them can prevent viruses from entering cells, as a result, the Cistus' extract inhibits viral replication.
  • the Cistus extract is the Cistus creticus extract.
  • the Citrus bioflavonoid complex is a molecular complex family the members of which can be extracted from citrus fruits. These biof lavonaoids show positive biological effects to the immune system, show antioxidant and anti-inflammatory properties, and provide health benefits like inhibiting the growth of microorganisms, improves blood circulation and increases mucous membrane resistance. There are more than one hundred of bioflavonoids in citrus species, including hesperidin, naringin, polymethoxyflavones, etc.
  • an extract from entire Citrus aurantium contains the following flavonoids: neoeriocitrin : 1-2%, isonarinagin : 1-2%, naringin: 25-27%, hesperidin: 1-2%, neohesperidin : 11-15%, poncirin: 1- 3%, naringenin: 0-1%, hesperetin: 0-1%; and flavones: rhoifolin: 1-3%, neodiosmin: 0-1%; and others flavonoids: 2- 4% .
  • Echinacea purpurea is a North American species of flowering plant in the sunflower family, the active agent of which can be extracted from its flowers.
  • Echinacea purpurea contains alkamides, caffeic acid derivatives, polysaccharides, and glycoproteins with purported stimulating effects on the immune system [Manayi, et al., Echinacea purpurea: Pharmacology, Phytochemistry and Analysis Methods. Pharmacognosy Reviews. January- June 2015, Vol. 9 No. 17, pages 63 and 72.] .
  • Echinacea purpurea contains a large number of other valuable substances: flavonoids, silica, polyacetylenes, alkaloids and inulin.
  • the Echinacea purpurea extract is the extract of the flower.
  • the extract of Cistus and Echinacea purpurea can be produced by extraction with water or alcohol or with the mixture thereof.
  • the alcohol is preferably ethanol.
  • the solvent used for the extraction is water.
  • the solvent used for the extraction is alcohol.
  • the solvent used for the extraction is preferably a 70% ethanol solution made with water, i.e. where the solution contains 70% ethanol and 30% water.
  • the solution used for the extraction is more preferably a 96% ethanol solution made with water, i.e. where the solution contains 96% ethanol and 4% water.
  • the extracts of Cistus and Echinacea purpurea are independent from each other.
  • the composition of the invention can have a Cistus extract made with water and an Echinacea purpurea extract made with 70% ethanol.
  • the extracts of Cistus and Echinacea purpurea, and the Citrus bioflavonoid complex can be in the form of dry extracts, e.g. in the form of a powder.
  • the Cistus extract The Citrus bioflavonoid complex and the
  • Echinacea purpurea extract can be present in different mass percentages in the composition of the present invention.
  • the composition of the present invention further comprises other antiviral agents known according to the state of the art.
  • Known antiviral agents include for example favipiravir and remdesivir .
  • antiviral agents can be taken into account .
  • the composition of the present invention further comprises flavouring agents , colouring agents , pH adj usting agents .
  • these excipients include among other acerola, sage ( Sal via offi cinali s) , peppermint oil ( Oleum menthae piperitae ) , sweetener, or potassium sorbate . These types of excipients are well known in the state of the art and are described in Remington' s Pharmaceutical Sciences ( Gennaro ed, 1995 , Mack Publishing) .
  • the present invention further relates to a medical device that is suitable for the administration of the composition of the present invention for a patient who is in the need of treatment or prophylaxis of the COVID- 19 viral disease .
  • the preferred embodiment of the medical device of the present invention is the nasal spray .
  • This type of medical device is suitable for delivering of the composition of the present invention into the nasal tract of said patient .
  • Another preferred embodiment of the medical device of the present invention is the oral spray .
  • This type of medical device is suitable for delivering of the composition of the present invention into the oral cavity of said patient .
  • the nasal spray or oral spray according to the present invention is preferably is in the form of a spray without a propellant .
  • the composition can be administered with the help of a mechanical pump built in the spray device .
  • the medical device of the present invention is a solution suitable for oral administration . By the use of this medical device , the composition of the present invention can be administered into the oral cavity of said patient in the form of drops .
  • the composition forms a protective coating on the respective mucosa, thereby the pathogens are inhibited to enter into the body in a direct , physical way .
  • the spray forms allow easy application and even distribution of the product on the mucous membranes of the nasal tract , mouth and throat .
  • the composition of the present invention has furthermore antimicrobial ef fect , thereby eliminating bacteria, thus reducing the risk of additional infections .
  • the composition has furthermore antioxidative ef fect due to its high polyphenol content .
  • Nasal spray or oral spray contains the composition of the present invention in the form of a suspension which is administered directly to the nasal or oral mucosa .
  • the medical device in these cases is equipped with a noz zle , operating on the principle of the mechanical pump, used without any propellant .
  • the medical device is preferably coated in such a way that it protects the composition from light and moisture from the outside .
  • the medical device is preferably kept dry and at room temperature .
  • the medical device of the present invention is a tablet suitable for oral administration .
  • the medical device of the present invention is a capsule suitable for oral administration .
  • the preparation of the medical device according to the present invention is well known by a person skilled in the art .
  • Medical devices such as nasal sprays , oral sprays , solutions , tablets and capsules are described in Remington' s Pharmaceutical Sciences ( Gennaro ed, 1995 , Mack Publishing) .
  • the starting materials can be in the form of an extract , which can be an alcoholic extract ( see above ) or a dry extract . According to a preferred embodiment , all starting materials are in powder form . Granulation is usually not needed .
  • the ingredients are mixed together and are pressed into tablets or filled into capsules .
  • I f filler is needed, it can be for example microcrystalline cellulose .
  • Magnesium stearate can be used as lubricant .
  • the total amount of the ingredients is between 300 mg and 600 mg .
  • the capsule is preferably in the form a hard gelatine capsule .
  • Example 1 Used cell cultures , medium and methods
  • Vero E 6 cells in the present speci fication is understood to mean the African green monkey kidney cell line , belong to epithelial cell , from African green monkey kidney cell , are female Cell Vero 76 clone strain, Anchorage Dependent Growth, can continuous passage culture , no oncogenicity, the cell line by hanging for several times .
  • EMEM Eagle ' s minimal essential medium
  • RPMI 1640 Complete Medium is a sterile- f iltered liquid containing L-alanyl-glutamine and rhodium bicarbonate , which is suitable for cell culture . This medium was developed by Moore et . al . at Roswell Park Memorial Institute , hence the acronym RPMI .
  • TCID50% or TCID50 in the present speci fication is understood to mean the determination of 50% Tissue Culture Infectious Doses , it is calculated by the Reed-Muench method . Setting the constant number of viruses is inevitable in serology methods , that is why TCID50% assay is used to quanti fy viral titres by determining the concentration at which 50% of the infected cells display cytopathic ef fect ( CPE ) . For simplicity during evaluation of CPE studies , meticulous+" symbol means 100% of the cells are dead, symbol means 0% of the cells are dead, noir ⁇ " symbol means 50% of the cells are dead .
  • Serology methods may be applied to establish the diagnosis of a recent infection even when attempts to detect the virus are negative due to the detected signi ficant increase in antibody titers .
  • serologic techniques such as the hemagglutinin inhibition test (HI) , the immunof luorescent (IF) assay, the virus neutralization test, and enzyme-linked immunosorbent assay (ELISA) are the fundamental tools in epidemiologic and immunologic studies as well as in the evaluation of vaccine immunogenicity.
  • the virus neutralization test is a highly sensitive and specific assay applicable to the identification of virusspecific antibody in animals and humans.
  • the neutralization test is performed in two stages:
  • virus-antibody reaction step in which the virus is mixed and inoculated with the appropriate antibody reagents
  • an inoculation step in which the mixture is inoculated into the appropriate host system (e.g. cell cultures, embryonated eggs, or animals) .
  • the appropriate host system e.g. cell cultures, embryonated eggs, or animals.
  • the absence of infectivity constitutes a positive neutralization reaction and indicates the presence of virus-specific antibodies in human or animal sera .
  • the virus neutralization test gives the most precise answer to the questions whether an individual has antibodies that can neutralize infectivity of given virus strain.
  • Conventional neutralization tests for viruses based on the inhibition of cytopathogenic effect (CPE)- formation in cell cultures are laborious and rather slow, but in combination with rapid culture assay principles, the neutralization test can yield results within two days.
  • CPE cytopathogenic effect
  • our virus microneutralization assay it is expected that serum neutralizing antibodies to virus specific proteins will inhibit the infections of cells with virus.
  • Serially diluted sera should be pre-incubated with a standardized amount of virus prior to the addition of cells. After an overnight incubation, the cells are fixed and the presence of virus specific proteins in infected cells is detected by enzyme linked immunosorbent assay (ELISA) .
  • ELISA enzyme linked immunosorbent assay
  • chromogenic substrate is added to the system, which results coloured product due to the enzyme activity.
  • the colour intensity is proportional to the enzyme bound in the complex.
  • the applied protocol is divided into three parts: Virus Titration, Virus neutralization Assay and ELISA.
  • Example 2 VERO E6 cells infected by SARS-CoV-2
  • Cistus extract and/or a composition according to Example 5 were homogenised with the pathogenic SARS-CoV-2 coronavirus. These mixtures were added to VERO E6 cell cultures.
  • the VERO E6 cell culture is quite sensitive to SARS-CoV-2, the reproduction of SARS-CoV-2 coronavirus in VERO E6 cell culture is excellent.
  • the tests' results around a thousand-fold dilution of the Cistus extract and the present invention are able to inhibit the reproduction of the SARS-CoV-2 coronavirus in an in vitro tissue culture system.
  • Example 4 Composition Example The following Table II lists the ingredients of a composition example of the present invention.
  • Example 5 Composition in a medical device
  • Table III lists the ingredients of a composition example of the present invention.
  • the composition according to this example is the most preferred embodiment of the present invention .
  • composition according to this example can be applied in an oral spray.
  • the composition is a brown liquid, with a pH between 5.0 and 7.0.
  • the content of the oral liquid dispenser can be about 30 ml .
  • the ingredients are first solved in water, mixed at ambient temperature. Once prepared, the resulting composition is than filled into the dispenser.
  • the composition can be used within 36 months, it shall be kept between about 10 to 25 °C.
  • Table IV lists the ingredients of an example composition suitable for use in a capsule.
  • the above listed ingredients in powder form are mixed together and homogenized.
  • the resulting powder has a beige colour.
  • This powder is filled into hard gelatine capsules.
  • the capsules are packaged into a blister packaging. They can be used within 36 months; it shall be kept between about 10 to 25 °C.
  • Table V lists the ingredients of an example composition suitable for use in a solution in the form of drops .
  • the Citrus bioflavonoid complex in this example is the Citrus
  • the composition is a brown liquid, with a pH between 4.0 and 5.0.
  • the ingredients are first solved in water, optionally preservative is added, mixed at ambient temperature.
  • the composition can be used within 36 months, it shall be kept at between 10 to 25 °C.
  • Example 8 SARS CoV-2 TCID501 analysis
  • VERO E6 African green monkey kidney cell line- American Type Culture Collection (ATCC) #CCL-81) ;
  • SARS-CoV-2 (ATCC strain VR-1493 and clinical strain from National Institute of Virology, Pune, India) ;
  • RPMI 1640 Complete Medium (RPMI, Gibco, USA, Cat no: 12430) ;
  • VERO E6 cell line was propagated in complete growth medium i.e. RPMI.
  • the 25 mL VERO E6 cell culture (total cell content: 3xl0 7 ) was diluted in 10 mL medium, from this 100-100 pL was measured in each well (1-12 columns, A-H rows, 96-well plate) at a density of ⁇ 3xl0 5 cells by pipetting.
  • + symbol means CPE is +
  • -symbol means CPE is -
  • Cl and C2 mean control 1 and control 2.
  • VERO E6 African green monkey kidney cell line
  • Virus SARS-CoV-2 (ATCC strain VR-1493 and clinical strain from National Institute of Virology, Pune, India) Medium: EMEM Medium (Gibco, USA, Cat no: 12430)
  • Method a) 100-100 pL of EMEM medium were added to 96-well plate (this was the dilution plate) ; b) 50-50 pL/well RPMI medium were added to the virus back titration wells; c) 100 pL sterile-f iltered Example 5 were added to the first column of the plate; d) a serial dilution was carried out from the first column per 100 pL with the same pipette tips from column 1 to column 9; e) 50-50 pL were carried forward to the second, parallel plate; f) 50-50 pL of the SARS-CoV-2 coronavirus stock were added to the designated wells (dilution between 10 ⁇ 4 - 10 ⁇ 7 , see Table VII) ; g) 50-50 pL of the SARS-CoV-2 coronavirus stock were added to the rows A to D (the dilution is 10 ⁇ 4 , that equal to TCID5%; h) to the other rows (from E to
  • Example 5 is significant at the dilution 1/512, even after 96 hours incubation. This composition significantly inhibits the 100xTCID50% solution of the SARS CoV-2 virus.
  • Example 9 inhibition of SARS CoV-2 coronavirus using the composition according to of Example 5 and Cistus extract:
  • VERO E6 African green monkey kidney cell line- American Type Culture Collection (ATCC) #CCL-81)
  • SARS-CoV-2 (ATCC strain VR-1493 and clinical strain from National Institute of Virology, Pune, India)
  • Cistus extract 4.9 g Cistus creticus powder diluted in 47 mL of RPMI 1640 Complete Medium, its concentration is equal to the Cistus creticus content of Example 5.
  • Method a) 50-50 pL of RPMI medium were added to columns 2 to 9; b) 50-50 pL/well RPMI medium were added to the virus back titration wells; c) 100 pL sterile-f iltered composition according to Example 5 were added to 1A and IB wells of the plate; d) 100-100 pL sterile-f iltered Cistus extract were added to 1C and ID wells of the plate; e) 100-100 pL sterile-f iltered calf whey (diluted 1/5, required for cell growth) were added to IE and IF wells of the plate; f) a serial dilution was carried out from the first column per 50 pL with switched pipette tips from column 1 to column 9; g) 50-50 pL were carried forward to the second, parallel plate; h) 50-50 pL of the SARS-CoV-2 coronavirus stock were added to the designated wells (dilution between 10
  • Example 5 and the Cistus extract have positive CP effect on the VERO E6 cell culture until dilution 1/5.
  • the antiviral effect of the composition according to Example 5 is significant even at the dilution of 1/640, even after 48 hours incubation.
  • Table XI CPE results of SARS CoV-inhibition after 96 hours As can be seen in Table XI, the composition according to Example 5 and Cistus extract have positive CP effect on the VERO E6 cell culture until dilution 1/10.
  • Antiviral effect against the SARS CoV-2 virus of the composition according to Example 5 is significant at the dilution 1/640, even after 48 hours incubation.
  • This composition inhibits the 100xTCID50% solution of the SARS CoV- 2 virus
  • the antiviral effect of the Cistus extract is smaller at the significance level than the multi-component composition according to Example 5.
  • the Cistus extract was applied in the same concentration as in the composition according to Example 5. Consequently, a synergy can be observed in case of the composition according to Example 5 compared to the Cistus extract, as shown in Table XII.
  • Table XII Comparison of the effect of the Cistus extract with the composition of Example 5 having the same concentration of Cistus extract.
  • Example 10 Comparison of the antiviral effect of the main ingredients of the composition Materials :
  • Composition according to Example 5 (sterile filtered, 0.22 pm filter) ;
  • Cistus (9.33%) : 4.67 g of the extract of Cistus creticus ericephalus was dissolved in 40 mL RPMI and completed to 50 mL by the addition of further RPMI, the solution was filtered via a 0.22 pm filter (Millipore) ;
  • Citrus bioflavonoid complex (CBC) , 1.66 m/v% dissolved in RPMI medium, the solution was filtered via a 0.22 pm filter (Millipore) ;
  • Echinacea purpureae extract 23.33 m/v% dissolved in RPMI medium, the solution was filtered via a 0.22 pm filter (Millipore) ;
  • the concentrations of Cistus (9.33%) , Citrus bioflavonoid complex (CBC, 1.66 m/v%) , Echinacea purpureae extract (23.33 m/v%) , and Acerola dried extract 11.66 m/v% are identical with the concentrations of the same ingredient in the composition according to Example 5.
  • Method a) 50-50 pL of EMEM medium were added to columns 1 to 6 (Table XIII) ; b) 50 pL/well RPMI medium was added to the virus back titration wells ; c) 50 pL sterile-f iltered composition according to Example 5 in a 1/20 dilution was added to wells in the H line (columns 1 to 6) of the plate (final dilution: 1/40) ; before the sterile- filtration the composition according to Example 5 was incubated at 37 °C for 30 minutes in water bath and filtered thereafter via a 0.22 pm Millipore filter; d) 50 pL amounts were transferred into the respective wells of the parallel plate; e) 50-50 pL SARS-CoV-2 in dilutions ICh 4 to ICh 7 were added to the respective wells .
  • the composition according to Example 5 has a much higher inhibitory potential than its active components in the same concentrations separately . Consequently, these active components show a synergistic ef fect .
  • Antiviral compositions of the present invention contain herbs and provide a good alternative against antiviral drugs .
  • the cost of the natural herbal medicines is much lower compared to pharmaceutical drugs . They can be sel f-administered which is convenient , moreover these compositions have health benefits , and they can hardly be overdosed .

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Abstract

L'invention concerne une composition antivirale, ladite composition comprend de l'extrait de ciste, l'extrait de Echinacea purpurea, et éventuellement le complexe bioflavonoïde de Citrus, et la composition inhibe le coronavirus du SARS-CoV -2. L'invention concerne également un dispositif médical comprenant ladite composition.
PCT/EP2020/085858 2020-12-11 2020-12-11 Composition antivirale comprenant du ciste et dispositif médical pour son administration Ceased WO2022122175A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
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WO2024046653A1 (fr) * 2022-08-29 2024-03-07 Mycotech Pharma As Extraits fongiques antiviraux
WO2024225922A3 (fr) * 2023-04-27 2024-11-28 Aronpharma Sp. Z O. O. Composition pharmaceutique pour soutenir le système immunitaire avant et pendant des infections des voies respiratoires supérieures

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024046653A1 (fr) * 2022-08-29 2024-03-07 Mycotech Pharma As Extraits fongiques antiviraux
WO2024225922A3 (fr) * 2023-04-27 2024-11-28 Aronpharma Sp. Z O. O. Composition pharmaceutique pour soutenir le système immunitaire avant et pendant des infections des voies respiratoires supérieures

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