Classifications

• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/02—Local antiseptics
• • 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 field of the invention is antiviral compositions and methods.
• Viral diseases are often spread either directly via droplet transmission from one human to another human, or indirectly via an animal host that will then transfer the virus in a variety of manners. While numerous virucidal compositions are known in the art, most of them suffer form one or more disadvantage. Most notably, many synthetic compounds tend to be very expensive and often require uptake into a cell to inactivate a virus or stop viral propagation. Furthermore, and especially where synthetic compounds are topically applied, known compounds tend to be chemically aggressive.
• natural compounds isolated from one or more plants can be employed as antiviral agents.
• various anthraquinones and anthraquinone derivatives such as hypericin were demonstrated to be effective against certain viruses, especially in the presence of mild detergents (see e.g., Antiviral Res. 1991 Sep; 16(2): 185-96). While such compositions showed significant effect to certain viruses ⁇ e.g., vesicular stomatitis virus, herpes simplex type 1 and 2), they were substantially ineffective against other viruses ⁇ e.g., human rhinovirus).
• solid phase articles were impregnated with various plant extracts ⁇ e.g., green tea catechiiis) as described in U.S. Pat. Nos.
• SARS coronavirus SARS coronavirus
• SARSCoV SARS coronavirus
• Infected humans typically present a characteristic febrile illness with respiratory symptoms and myalgia, and many patients recover within a few days.
• SARS Severe Acute Respiratory Syndrome
• SARS SARS emerged as a disease in Southern China in November 2002 but has quickly spread to over 30 countries worldwide. The epidemic has now subsided, but a total of almost 8500 cases with over 800 deaths have been recorded. SARSCoV is transmitted mainly by exposure to respiratory secretions. SARSCoV is most probably derived from a virus that naturally infects a wild or domestic animal. Thus, eradication will be difficult and periodic "re-emergence" from the animal reservoir is possible. For detailed additional information on SARSCoV, reference is made to the "Kamps-Hoffmann SARS reference" (by Flying publisher).
• compositions and methods with antiviral activity are known in the art, all or almost all of them suffer from one or more disadvantages. Consequently, there is still a need to provide improved compositions and methods for antiviral compositions, and especially topical antiviral formulations effective against SARSCoV.
• the present invention is directed to compositions and methods of inactivation of various viruses, and especially SARSCoV using plant derived materials as virucidal component.
• the plant derived material comprises one or more catechins, and particularly green tea preparations.
• a method of reducing the number of infectious SARS viruses on a surface has a step of contacting the surface with a composition comprising a catechin preparation, wherein the catechin preparation is present at a concentration effective to reduce the number infectious SARS viruses at least by a factor of 2 logio units, and more preferably at least by a factor of 3.5 log 10 units.
• a method of reducing spread of SARS virus ex vivo may comprise a step of contacting a virus carrier with a composition that includes a near-native catechin preparation from green tea, wherein the catechin preparation is preferably present in the composition at a concentration to inactivate SARS at least by a factor of 2 log 10 units, and more preferably at least by a factor of 3.5 logio units.
• Treated surfaces particularly include those that are in contact with a non-human animal ⁇ e.g., cage or corral), and/or at least part of the animal's body surface ⁇ e.g., skin, feather, hair, etc.).
• the catechin preparation is prepared from green tea, and most preferably a green tea extract, a green tea extract powder, and/or a green tea concentrate.
• the preparation can be administered in various manners. However, it is generally preferred that the preparation is applied as a spray, as a liquid on a wipe, or as a powder.
• kits that includes a liquid or powder formulation having a catechin at a concentration effective to inactivate SARS at least by a factor of 2 log 10 units (and more preferably at least by a factor of 3.5 log 10 units) when applied to a surface.
• Contemplated kits will further include an instruction to apply the formulation to a surface to thereby reduce a number of infectious SARS viruses on the surface.
• catechins and especially green tea catechins can be effectively used as agents that reduce infectivity of a SARS (severe acute respiratory syndrome) virus ex vivo.
• SARS severe acute respiratory syndrome
• the catechins exhibit anti-viral effect on various viruses, and particularly the SARS virus where the virus is exposed to the catechin on a solid phase and/or in a liquid phase before entering a host organism.
• the inventor contemplates a method of reducing a number of infectious SARS viruses on a surface.
• the surface is contacted with a composition that includes a catechin preparation, wherein the catechin preparation is present at a concentration effective to reduce the number infectious SARS viruses at least by a factor of 2 1Og 10 units, and more preferably at least by a factor of 3.5 1Og 1O units.
• inventive subject matter is not limited to one or another surface, and that all surfaces are deemed suitable so long as such surfaces are exposed to potential contact with the SARS virus or even contain the SARS virus.
• especially preferred surfaces include those that are in contact with a non-human animal, and most typically a pet or animal used as a source of food.
• all structures suitable to at least temporarily guide and/or retain an animal e.g., cage, corral, leash, fences, etc. are particularly contemplated.
• the catechin preparation may also be applied to the surface of an animal.
• the catechin preparation may be sprayed onto the animal, or the animal may be at least partially immersed in a solution containing the catechin preparation.
• the catechin preparation comprises at least one of an esterified catechin and a galloyl-containing catechin, and even more preferably a mixture of such catechins (optionally also comprising free catechins).
• suitable catechin preparations may comprise one or more of (-)-Catechin Gallate, (-)-Epicatechin Gallate, (-)-Epigallocatechin Gallate, (-)- Gallocatechin Gallate, free Theaflavin, and Theaflavindigallate.
• complex extracts e.g., Polyphenon-70A, Polyphenon-E, Polyphenon-60, Polyphenon-70, from Mitsui Norm are especially contemplated.
• the catechin preparation may also include a green tea extract (typically solvent-extract or CO 2 extract), green tea extract powder (e.g., freeze-dried extract or spray-dried green tea), and/or green tea concentrate which will typically (but not necessarily) include a solvent, and most typically water.
• the catechin or catechin mixture will include an optionally additional carbohydrate portion that promotes hygroscopic properties of a surface that is coated or otherwise comprises catechins. Therefore, direct antiviral action may also be due to a tackifying effect in which the catechin retains the virus on the treated surface.
• the catechin preparation will be sprayed or dusted onto the surface that is in need of treatment.
• concentration of the catechin is sufficient to inactivate SARS at least by a factor of 2 1Og 10 units, more preferably at least by a factor of 3.0 logio units, and most preferably at least by a factor of 3.5 logio units. Consequently, the catechins will be present in the formulations at a concentration of between about 0.01 ⁇ M (or lower, e.g., where the formulation is repeatedly applied to the surface) to about 1.0 niM (or higher, e.g., where the formulation is a concentrate).
• the catechin concentration will preferably be between about 0.1 ⁇ M to about 100 ⁇ M.
• the catechin preparation may include one or more solvents (e.g., water, organic solvents [e.g., ethanol, DMSO, etc], and all reasonable combinations thereof), which may be miscible or form emulsions, multiple phases, liposomes, etc.
• solvents e.g., water, organic solvents [e.g., ethanol, DMSO, etc]
• ingredients especially include anionic, cationic, and neutral detergents. Therefore, suitable preparations may be formulated as a powder, spray, soap, or shampoo, and may be directly applied to the surface and/or together with water.
• the inventor also contemplates a method of reducing spread of SARS virus ex vivo, wherein a virus carrier is contacted with a composition comprising a near-native catechin preparation from green tea.
• a composition comprising a near-native catechin preparation from green tea.
• the near-native catechin preparation is present at a concentration to inactivate SARS at least by a factor of 2 log 10 units units, more preferably at least by a factor of 3.0 log 10 units, and most preferably at least by a factor of 3.5 log 10 units.
• near-native catechin preparation from green tea refers to a preparation in which brewed green tea and/or green tea leaves are minimally processed (i.e., at least partially dehydrated, and/or pressed or otherwise macerated, which may be followed by solvent extraction that enriches the preparation in catechins) to form the preparation.
• Particularly preferred near-native catechin preparations include green tea extracts, green tea extract powders, green tea concentrates, each of which may or may not include one or more solvents.
• surface is a virus carrier, which may be an animal or a surface in contact with the animal (e.g., cage, rail, corral, etc.), and/or which may be a surface that was previously exposed to a human infected with the SARS virus (e.g., bedding surface, garment surface, medical device, etc.)
• a virus carrier which may be an animal or a surface in contact with the animal (e.g., cage, rail, corral, etc.), and/or which may be a surface that was previously exposed to a human infected with the SARS virus (e.g., bedding surface, garment surface, medical device, etc.)
• kits that includes a liquid (e.g. , spray or aerosol) or powder formulation comprising a catechin at a concentration effective to inactivate SARS at least by a factor of 2 logio units, more preferably at least by a factor of 3.0 log 10 units, and most preferably at least by a factor of 3.5 logio units when the formulation is applied to a surface.
• a liquid e.g. , spray or aerosol
• an instruction is associated with the formulation to apply the formulation to a surface to thereby reduce a number of infectious SARS viruses on the surface.
• the instruction is provided as a printed matter on the container that encloses the formulation, but may also be provided as an independent printed (e.g., flyer, newspaper ad, etc.) or displayed (e.g., TV or Internet ad) information.
• an independent printed e.g., flyer, newspaper ad, etc.
• displayed e.g., TV or Internet ad
• contemplated compositions are thought to reduce infectivity of a virus, wherein the reduction in infectivity need not necessarily be due to the reduction of the virus count.
• catechins may interact with the virus (and especially the virus coat) to render the virus less infective.
• reduction in infectivity may be due to conformational changes in the virus coat, steric interaction with a viral docking protein, unspecific coating of the virus with the catechin, etc.
• the catechin may be disposed on a surface and the catechin- virus interaction will therefore be on or near a solid phase.
• Such solid phase interaction is especially desirable in numerous application where a solid phase is contaminated with the virus.
• all fomites are contemplated herein.
• particularly contemplated solid phases will be (part of) materials that directly contact a viral source.
• patient and/or care-giver garments, protective wear, or medical devices are deemed materials that directly contact a viral source.
• contemplated solid phases include materials that indirectly get exposed to the viral source.
• Such solid phases include those that receive the virus in an aerosolized form from a patient (e.g., via cough or sneeze) or other virus source (e.g., waste material, air-borne dust, etc.), liquid form (e.g., from biological fluid), or other manner of indirect transmission. Therefore, especially contemplated solid phases include garments, bedding, disposable covers, medical equipment, air filters and air ducts, respirators, masks, etc., and even walls, floors, ceilings, shades, and other components of a room or even building in which a patient and/or virus carrier was housed.
• virus source e.g., waste material, air-borne dust, etc.
• liquid form e.g., from biological fluid
• the catechin may be disposed in a solvent and the catechin- virus interaction will therefore be in a liquid phase.
• suitable solvents include aqueous solvents, which may further include a stabilizer, bacteriostatic, and/or antiviral agent.
• a catechin or catechin mixture is dissolved or dispersed in a solvent that is then aerosolized (or otherwise applied in liquid phase) to a surface that was, is, or will be exposed to a virus.
• Such liquid phase application is particularly desirable where a virus contaminated surface is to be disinfected, or where a locale is preemptively exposed to the catechins to reduce spread of the virus when the virus is introduced to the locale.
• the catechin solution may be employed in a handwash, a spray, a detergent, or other wash- or rinse fluid for decontamination of a surface (e.g., the catechin solution may be added during the final cycle of a laundering process to coat the fabric, thus reducing the infectivity of any remaining virus and also coating the fabric with remaining catechin).
• catechins may also be used in a vaporizer, mister, humidifier, or other device (local or building- wide via air conditioner) to reduce infectivity of a virus in the air (e.g., may be introduced into a building as an aerosol and then circulated by moving air to coat the surfaces of the building including internal duct work and crevices not normally accessible to disinfection).
• contemplated compositions and methods need not be limited to treatment of a room or patient, but may also be especially useful in animal housing.
• the virus has an intermittent host (e.g., bird, pig, or other domestic animal)
• the catechins may be used to reduce, if not even eradicate spread of the virus before the virus moves from the intermittent host to a human. Consequently, while reduction of infectivity of the SARS virus is particularly contemplated, other pathogens are also included.
• contemplated pathogens include air-borne viruses, bacteria, and spores, as well as aerosols and other transmissible forms of such pathogens. Examples
• % inhibition of viral infection was measured as known in the art and substantially as described below.
• Vero 76 cells were plated at 10,000 cells/well in 50 ⁇ l DMEM (5% FBS, L-glutamate, medium must NOT contain phenol red) in barcoded plates. The cells were allowed to adhere overnight at 37 0 C at 5% CO 2 . 25 ⁇ l of the catechin solutions (see below) were added to the cells, and DMEM (5% FBS L-glut P/S (no phenol red)) was further added to the wells. Subsequently, 25 ⁇ l diluted virus (about 1:500 dilution of Toronto-2 virus in DMEM 5 % FBS L-glut P/S) was added to wells. Cells with virus and catechins were incubated at 37 0 C for 72 hours.
• DMEM 5% FBS, L-glutamate, medium must NOT contain phenol red
• catechins had cytoprotective effect against the SARS virus. Furthermore, almost all of the tested catechins failed to exhibit any apparent cytotoxicity when contacted with the catechins. Remarkably, only the esterified and/or galloyl- containing catechins [e.g., (-)- epicatechin gallate, (-)- epigallocatechin gallate, (-)- gallocatechin gallate], but not the free catechins [e.g., (+)- catechin, (+)- gallocatechin, (-)-epicatechin, (-)- epigallocatchin] had cytoprotective effect in the assay.
• catechins e.g., (+)- catechin, (+)- gallocatechin, (-)-epicatechin, (-)- epigallocatchin
• antiviral concentrations may be significantly lower ⁇ e.g. , between 0.1 and 1 uM, between 0.01 and 0.1 uM, or even lower) and still provide at least some antiviral effect.
• IFN-beta Interferon-beta
• IFN-beta control incubations provided substantially no cytoprotective effect at a concentration of 50 International Units (IU), and showed at least some cytoprotective effect at a concentration of 50 IU.
• IFN-beta also stimulated cell growth in the assay, the exact degree of cytoprotective effect is difficult to ascertain.
• the results for exemplary esterified or galloyl-containing catechins are listed in Table 1, while the results for free catechins are listed in Table 2.
• %CPE values of less than 30 were labeled inactive.
• the SARS virus was pre-incubated with various catechin-containing preparations. The so pre-treated virus was then added to cells substantially as described below.
• SARSCoV strain Urbani
• Vero 76 cells American Type Culture Collection, Manassas, VA.
• MEM fetal bovine serum
• gentamicin was added to 50 ⁇ g/ml, and serum was reduced to 2%.
• a variety catechin-containing preparations was obtained from Dr. Yukihiko Hara of Mitsui Norm Co., Ltd. of Tokyo, Japan, and added to the cell-virus mixture as follows.
• the virus was also incubated without test substance in compound solvent or MEM, under the conditions described above and assayed in parallel by CPE assay. The latter treatments served as virus controls. Results were expressed in Table 3 as logio units relative to the controls (*sign denotes the catechin-containing preparation reduced the virus titer to below detectable limits).
• Table 4 lists the individual catechin content for selected catechins of the compounds of Table 3. All numbers are expressed as mg catechins per 100 mg or 100 ml as appropriate of the tested compound.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Natural Medicines & Medicinal Plants (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
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• Medical Informatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Microbiology (AREA)
• Botany (AREA)
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• Alternative & Traditional Medicine (AREA)
• Engineering & Computer Science (AREA)
• Organic Chemistry (AREA)
• Virology (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Mycology (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Molecular Biology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)
• Medicines Containing Plant Substances (AREA)
• Apparatus For Disinfection Or Sterilisation (AREA)
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• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2005
  • 2005-07-05 US US11/571,626 patent/US8652533B2/en not_active Expired - Fee Related
  • 2005-07-05 CA CA2567766A patent/CA2567766C/en not_active Expired - Fee Related
  • 2005-07-05 WO PCT/US2005/023351 patent/WO2006083318A2/en not_active Ceased
  • 2005-07-05 JP JP2007520384A patent/JP2008505901A/ja not_active Withdrawn

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