Classifications

• • 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)
  • A61K36/82—Theaceae (Tea family), e.g. camellia
• • 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)
  • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
• • 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)
  • A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
• • 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
  • 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)
  • A61K36/88—Liliopsida (monocotyledons)
  • A61K36/906—Zingiberaceae (Ginger family)
  • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
• • 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
  • 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
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L9/00—Disinfection, sterilisation or deodorisation of air
  • A61L9/015—Disinfection, sterilisation or deodorisation of air using gaseous or vaporous substances, e.g. ozone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L9/00—Disinfection, sterilisation or deodorisation of air
  • A61L9/14—Disinfection, sterilisation or deodorisation of air using sprayed or atomised substances including air-liquid contact processes
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to the field of antiviral compositions, in particular antiviral compositions related to the influenza virus. Faced with the problem of the risk of pandemic avian flu, existing therapeutic solutions are solely of synthetic and expensive.
• the H5N1 subtype has a great ability to mutate over time, as well as to exchange its genes with influenza viruses belonging to other types of infecting other species.
• a subtype of virus may stop circulating for several years in the human population but remain present in an animal population. If the animal population is in direct contact with a human being, they can transmit the virus again.
• a virus subtype may also be newly created by a genetic reassortment that occurs when a host is co-infected with two different viruses.
• this new virus has H5 and Nl segments specific to the avian virus, it will completely escape the recognition of the human immune system. If he also possesses genes that allow him to multiply effectively in mammals, he will then be able to transmit himself from man to man as effectively as classical flu.
• influenza virus belonging to a viral subtype totally unknown to the human population renders the immune memory of humans totally ineffective. This makes plausible a rapid and worldwide spread of the virus.
• the idea of a vaccine is not a satisfactory solution in view of the possible evolution of the virus during the passage to humans. What is known is that the production of a vaccine will take at least six months once the circulating strain is isolated and that, given the global production capacity of vaccine manufacturers, these six months will not allow to produce more than one billion monovalent doses. With two doses needed to gain protection, fewer than 500 million people, or 14 percent of the world's population, will be vaccinated. This places a special emphasis on antiviral treatments, which will therefore be at the forefront of fighting a possible pandemic in the first place.
• the protection of populations against infection with the influenza virus has become, in the face of this pandemic, a public health problem.
• the inventors have therefore been interested in compounds that protect animal organisms, including organisms humans, against influenza infection.
• the present invention relates to a composition, preferably pharmaceutical, for the prevention and treatment of viral infections induced by viruses of the family Orthomyxoviridae characterized in that it comprises at least four different plant extracts selected from at least one olive leaf extract, at least one grapefruit seed extract, at least one rosemary extract, at least one green tea extract and / or curcumin in combination with any suitable pharmaceutical, if appropriate, excipient.
• the composition according to the invention comprises extracts of olive leaves, extracts of grapefruit seeds, rosemary extracts, green tea extracts and curcumin.
• the composition of the invention comprises 0.01 to 100 mg / kg, preferably 0.5 to 10 mg / kg of olive leaf extracts.
• composition of the invention comprises 0.01 to 100 mg / kg, preferably 0.5 to 10 mg / kg of grapefruit seed extracts.
• the composition of the invention comprises 0.01 to 100 mg / kg, preferably 0.5 to 10 mg / kg of rosemary extracts.
• the composition of the invention comprises 0.01 to 100 mg / kg, preferably 0.5 to 10 mg / kg of green tea extracts. According to one embodiment, the composition of the invention comprises 0.01 to 100 mg / kg, preferably 0.5 to 10 mg / kg of curcumin. According to a second embodiment of the invention, the composition does not comprise curcumin.
• a preferred composition of the invention comprises an olive leaf extract, a grapefruit seed extract, a rosemary extract, and a green tea extract.
• the composition according to the invention is in the form of compacted powders or not, in liquid form, in the form of a solution or dispersion, in semi-solid or gelled or emulsified or dispersed form, or in aerosol form.
• composition according to the invention may be administered orally, by intravenous injection, by inhalation, or by means of a spray, a diffuser, or by prior impregnation in a tissue.
• the invention also relates to a use of the composition according to the invention for the prevention and / or treatment of diseases associated with infection with a virus, preferably an influenza virus.
• the virus is a seasonal influenza virus.
• the composition according to the invention is particularly useful for the prevention and / or the treatment of diseases associated with an influenza virus infection of the type H1N1 and / or H5N1 and / or H3N2.
• the invention also relates to a device comprising a composition of the invention.
• this device comprises a woven or non-woven fabric on which is affixed or which is impregnated with a composition according to the invention.
• the invention also for the use of the composition according to the invention for cleaning the air in public or private places, especially by diffusion of said composition in the air ducts. More generally, an object of the invention relates to any device for the diffusion of the composition according to the invention.
• the present invention relates to compositions comprising antioxidants, and more particularly comprising plant extracts having antioxidant properties having the property of protecting animal organisms against viral attacks or treating animal organisms with viral disease.
• the antioxidants used in the compositions according to the invention by virtue of their antibacterial activity, constitute a barrier helping in the prevention of new infections favored by the attack of viruses.
• the present invention resides in the combination of said substances which makes it possible to potentiate their effectiveness.
• the present invention relates to the viruses of the family Orthomyxoviridae including the influenza virus and more particularly that of the bird flu.
• the present invention also provides pharmaceutical or therapeutic compositions for the improvement, treatment and prevention of diseases associated with influenza viruses.
• H5N1 bird flu virus
• the attack of the body by H5N1, bird flu virus is characterized by the triggering of an exaggerated inflammatory reaction, which results in a secretion of mucositis, type pneumonia which causes respiratory distress in the affected subject. It is this symptom that is responsible for the exceptional severity of the disease.
• compositions according to the invention make it possible to reduce this inflammatory response. Indeed, the various components of the composition according to the invention interfere with the general mechanisms of the inflammatory response of the body to the bird flu virus.
• the compositions according to the invention make it possible to reduce the phenomenon of respiratory distress, which often has a lethal effect on the affected subject, enabling him to pass the critical stage of the disease.
• compositions according to the invention make it possible to design a prophylactic barrier for contamination between humans, in the case of a pandemic, by example by impregnating masks of protections assuring them a more sure and more durable efficiency.
• compositions according to the invention may serve as air freshener of public places by their diffusion, in particular by aerosol in the air ducts, which would reduce the financial consequences of a pandemic for society.
• the present invention is a methodical combination of different actives each of which is described in the scientific literature as acting on several pathogenic bacteria and viruses.
• the concept of the invention is based on the synergy of the different active ingredients in the compositions of the invention.
• the multiplication of the influenza virus is a complex mechanism described in the form of several stages.
• the combination of these different assets makes it possible to act on most of these stages instead of focusing on a particular stage; it is this approach that makes it possible to gain in efficiency.
• compositions of the invention comprise non-toxic natural products and can therefore be used more easily at the various factors of propagation of the virus without toxicity to the environment and its inhabitants.
• the extracts used are of the type marketed by the company Naturex, for example grapefruit seed extract marketed under the reference
• the compositions according to the invention have a concentration of extracts, all extracts combined, of 0.04 to 15 g / l, preferably 0.04 to 10 g / l.
• the compositions comprise 0.01 to 10 g / l, preferably 0.4 to 3 g / 1 of olive leaf extract of the type marketed by Naturex "extracted from 10% olive leaves”.
• the compositions comprise 0.01 to 10 g / l, preferably 0.3 to 3 g / l of grapefruit seed extract of the type marketed by Naturex "grapefruit seed pe ws”.
• the compositions comprise 0.01 to 10 g / l, preferably 0.3 to 3 g / l of green tea extract of the type marketed by Naturex with 4 to 6% caffeine.
• compositions comprise 0.01 to 10 g / 1, preferably 0.3 to 3 g / 1 of rosemary extract of the type marketed by Naturex under the name Rosemary PE 2%.
• compositions comprise 0 to 10 g / 1, preferably 0.3 to 3 g / 1 of turmeric extract type sold by Naturex.
• compositions according to the invention comprise only natural plant extracts and water.
• a preferred composition of the invention comprises 0.01 to 10 g / 1 of olive leaf extract, 0.01 to 10 g / 1 of extract extracted from grapefruit seed, 0.01 to 10 g / 1 of rosemary extract, and 0.01 to 10 g / i of green tea extract.
• the composition of the invention consists or consists essentially of water and from 0.01 to 10 g / 1 of olive leaf extract, 0.01 to 10 g / 1 of extracted extract. grapefruit seed, 0.01 to 10 g / 1 rosemary extract, and 0.01 to 10 g / 1 green tea extract.
• concentrations described in the composition of the invention are based on the implementation of the extracts mentioned above. It is within the skill of those skilled in the art implementing different concentrations of extracts, to adapt the formulations of the compositions of the invention.
• Figure 1 shows the effect of ND235 on infection of MDCK cells by Influenza A Virus. On the abscissa are given increasing concentrations of virus and on the ordinate the absorption values proportional to the number of cells. The measurements are carried out in the absence (Control) and in the presence of ND235 formulations more or less concentrated in extracts (0.04%, 0.4% and 4%).
• Example 1 Examples of compositions of the invention, efficacy, viral titre
• the ND235 composition is tested in the present example 2.
• Table 2 Dose - response effect of ND235 on the viability of cultured human lymphocytes.
• ND235 is not toxic because, on the contrary, it stimulates cell growth when its concentrations are greater than or equal to 2 ⁇ 10 -3 g / l.
• Toxicity was evaluated as soon as the product was added (acute toxicity) and 24h after the addition of the product (possible cytostatic effect).
• Table 3 Direct dose - response effect of ND235 and various combinations of its active ingredients on the viability of cultured MDCKs.
• Table 4 Effect at 24 hours in dose - response of ND235 and various combinations of its active ingredients on the viability of cultured MDCKs.
• ND235 is not toxic even at the highest concentrations of 10g / l (first line). 2) In concentrations above 3 10 "g / 1 (lines 4-1), the ND235 and different combinations of active ingredients stimulate cell growth compared to cell controls.
• ND235 is not toxic because on the contrary, it stimulates cell growth of MDCK when its concentrations are greater than or equal to 0.3 g / 1.
• ND235 acts at the level of the infected cell as follows: 4.1 ND235 action on virus attachment to the cell
• the docking of the influenza virus to the target cell is enabled by the interaction between a viral hemagglutinin and sialic acid receptors on the cell surface (Lamb, 1989).
• This operation can be compared to a key and lock system.
• Part of the subunit HA1 (the key), facing outward, has a very particular form and recognizes a specific molecule: sialic acid (the lock), which is present on the surface of some cells. Both forms are perfectly recognizable.
• This recognition between the HA and the sialic acid causes the attachment of the viral particle to the target cell (the key is inserted into the lock).
• ND235 blocks the multiplication of the virus and thus decreases the cellular interactions due to infection, this concept has a direct destructive effect of the virus on the affected cell, which reduces the excess of immune response which results in the case of bird flu respiratory distress often responsible for the death of the infected subject.
• NA proteins break this link, allowing new viruses to break off and infect new target cells.
• One of the actions of the active ingredient contained in the ND235 will prevent the action of neuraminidase (NA) which is responsible for the detachment of the virus from the host cell and the release of new infectious viruses.
• ND235 Blocking this release of infected particles in the cell will thereby decrease the number of viruses circulating. ND235 will moderate the inflammatory response of different cells affected by viral attack. 4.3 Conclusion on cellular action modes of ND235
• ND235 Several active ingredients contained in ND235 have a recognized action against the bird flu virus.
• the antiviral actions described demonstrate their effectiveness by blocking the production of the virus in the cell, particularly in steps 6 and 7 for regulating the production of viral proteins and for synthesizing effective viral proteins.
• MDCK cells are the reference cells for the study of influenza A virus multiplication.
• H1N1 the strain A / PR / 8/34. This viral strain was obtained from a Puerto Rican patient and this reference virus is accessible at the American Tissue and Collection Bank (American Type Culture Collection).
• CPE cytopathic effect
• TCID50 is the viral concentration that will give a CPE effect on 50% of cells in culture.
• MDCK cells are derived from cells isolated by S.H. Madin and N.B. Darby in 1958 from a kidney of an adult cocker spaniel puppy. These cells are accessible at the American bank of ATCC tissues and viruses.
• the MDCK cells are cultured at 37 ° C. in a humid atmosphere containing
• influenza A virus strain used is the A / PR / 8/34 type strain
• H1N1 (ATCC VR-1249).
• the MDCK cells are cultured at 33 ° C. in a humid atmosphere containing 5% CO 2 and in MEM medium with 0.125% BSA and in the presence of 1 ⁇ g / ml trypsin treated with TPCK ( Perbio SA, Be).
• 96-well culture plates are seeded at 5 MDCK cells per well. These cells are cultured at 37 ° C. in a humid atmosphere containing 5% CO 2 in DMEM medium with 10% fetal calf serum in the presence of Penicillin Streptomycin antibiotics. When they form a confluent monolayer, they are infected with decreasing amounts of virus resulting from one-third dilutions of a stock solution of virus. The title of the starting virus stock solution established in 96-well culture plates is 81 TCID50. These infections are carried out in the absence or presence of ND235 at different concentrations. The cells are then kept in culture at 33 ° C. in a humid atmosphere containing 5% CO 2 for four days and then stained with Crystal Violet. The cytopathogenic effects are then recorded in order to establish the percentage inhibition of viral infection obtained by different concentrations of ND235.
• the remaining cell quantities are estimated by measuring the monolayer uptake at 595 nm performed in a microplate reader.
• the absorption values at 595 nm are corrected by those of the non-specific absorptions measured at 405 nm.
• Table 5 Raw data of absorbances as a function of ND235 concentration and viral quantities.
• Viral Input amounts of virus in TCID50 used for infection at time 0.
• Table 6 Inhibition of infection with Influenza A virus by different concentrations of ND235 viral titre: in TCID50. Effect: +: destruction> 60% of the cells; + -: destruction of 30% to 60% of the cells; -: presence of 70% to 100% of the cells.
• Percent viral inhibition can be calculated by comparing wells infected with the lowest effective viral dilutions in the presence and absence of the product.
• Table 7 Mean values and standard deviation of absorbances as a function of ND235 concentration and viral input.
• the absorption values in the control wells without virus are of the order of 0.75 and 0.45 in the presence respectively of 4% ND235 and 0% (control) of ND235.
• the ND235 at the highest concentrations (ND235 4%) will promote the development of cells compared to the control cells not having ND235 (Control).
• concentrations 10 and 100 times lower in ND235 this cell growth stimulating effect is less pronounced but seems nevertheless present.
• ND235 is an effective antiviral against in vitro infection with influenza A virus. We have demonstrated that its efficacy is dose - dependent.
• the concentrations of curcumin (Cu) products, extracts of grapefruit seed (PP), rosemary (Ro), olive leaf (01) and green tea (Tv) are the same as those contained in ND235.
• the last column (ND235 - Cu) corresponds to the formulation containing ND235 components at concentrations of ND 235 without Curcumin.
• the control (control) corresponds to the same viral load as the other columns without product. Viral Title: in TCID50.
• ND235 The different products contained in ND235 are effective against the virus. Percent viral inhibition can be calculated by comparing wells infected with the lowest effective viral dilutions in the presence and absence of the product. Thus it follows that: - ND235 0.4%: 86% viral inhibition Curcumin: 7% viral inhibition
• ND 235 is a blend of active flu-based products that work synergistically, resulting in increased efficacy.
• ND235 is an effective antiviral against in vitro infection with mfluenza type A virus. We have shown that its efficacy is dose-dependent.

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