WO2023062348A1 - Compositions antivirales et leurs procédés de production et d'utilisation - Google Patents

Compositions antivirales et leurs procédés de production et d'utilisation Download PDF

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Publication number
WO2023062348A1
WO2023062348A1 PCT/GB2022/052562 GB2022052562W WO2023062348A1 WO 2023062348 A1 WO2023062348 A1 WO 2023062348A1 GB 2022052562 W GB2022052562 W GB 2022052562W WO 2023062348 A1 WO2023062348 A1 WO 2023062348A1
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WO
WIPO (PCT)
Prior art keywords
composition
viral
skin
active ingredient
virus
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PCT/GB2022/052562
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English (en)
Inventor
Sagarika BANERJEE
Maciej Witalis CHICHLOWSKI
Manas Sarkar
Deepak Sharma
Athmaram THIMMASANDRA NARAYANAPPA
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Reckitt Benckiser Health Limited
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Publication of WO2023062348A1 publication Critical patent/WO2023062348A1/fr

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Classifications

    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • 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

  • Mosquito-borne viruses such as (but not limited to) Chikungunya virus (CHIKV), Dengue virus (DENV), Zika virus (ZIKV), Yellow Fever virus (YFV), Japanese Encephalitis virus (JEV), and West Nile virus (WNV) are major global health challenges that affect hundreds of millions of people worldwide. Mosquito-borne viruses are increasingly prevalent due to the geographical expansion of mosquito vectors due to global warming.
  • inventive concept(s) Before explaining at least one embodiment of the inventive concept(s) in detail by way of exemplary language and results, it is to be understood that the inventive concept(s) is not limited in its application to the details of construction and the arrangement of the components set forth in the following description. The inventive concept(s) is capable of other embodiments or of being practiced or carried out in various ways. As such, the language used herein is intended to be given the broadest possible scope and meaning; and the embodiments are meant to be exemplary - not exhaustive. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.
  • compositions and/or methods disclosed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the inventive concept(s) have been described in terms of particular embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit, and scope of the inventive concept(s). All such similar substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the inventive concept(s) as defined by the appended claims.
  • the term "at least one” will be understood to include one as well as any quantity more than one, including but not limited to, 2, 3, 4, 5, 10, 15, 20, 30, 40, 50, 100, etc.
  • the term “at least one” may extend up to 100 or 1000 or more, depending on the term to which it is attached; in addition, the quantities of 100/1000 are not to be considered limiting, as higher limits may also produce satisfactory results.
  • the use of the term "at least one of X, Y, and Z" will be understood to include X alone, Y alone, and Z alone, as well as any combination of X, Y, and Z.
  • ordinal number terminology i.e., “first,” “second,” “third,” “fourth,” etc. is solely for the purpose of differentiating between two or more items and is not meant to imply any sequence or order or importance to one item over another or any order of addition, for example.
  • any reference to "one embodiment,” “an embodiment,” “some embodiments,” “one example,” “for example,” or “an example” means that a particular element, feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment.
  • the appearance of the phrase “in some embodiments” or “one example” in various places in the specification is not necessarily all referring to the same embodiment, for example. Further, all references to one or more embodiments or examples are to be construed as non-limiting to the claims.
  • the term "about” is used to indicate that a value includes the inherent variation of error for a composition/apparatus/ device, the method being employed to determine the value, or the variation that exists among the study subjects.
  • the designated value may vary by plus or minus twenty percent, or fifteen percent, or twelve percent, or eleven percent, or ten percent, or nine percent, or eight percent, or seven percent, or six percent, or five percent, or four percent, or three percent, or two percent, or one percent from the specified value, as such variations are appropriate to perform the disclosed methods and as understood by persons having ordinary skill in the art.
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • the term “substantially” means that the subsequently described event or circumstance completely occurs or that the subsequently described event or circumstance occurs to a great extent or degree.
  • the term “substantially” means that the subsequently described event or circumstance occurs at least 80% of the time, or at least 85% of the time, or at least 90% of the time, or at least 95% of the time.
  • the term “substantially adjacent” may mean that two items are 100% adjacent to one another, or that the two items are within close proximity to one another but not 100% adjacent to one another, or that a portion of one of the two items is not 100% adjacent to the other item but is within close proximity to the other item.
  • the term "added” is understood to refer to an element that is introduced into a composition and not to the element as it may naturally inherently exist in a composition.
  • polypeptide as used herein will be understood to refer to a polymer of amino acids.
  • the polymer may include d-, I-, or artificial variants of amino acids.
  • polypeptide will be understood to include peptides, proteins, and glycoproteins.
  • polynucleotide as used herein will be understood to refer to a polymer of two or more nucleotides. Nucleotides, as used herein, will be understood to include deoxyribose nucleotides and/or ribose nucleotides, as well as artificial variants thereof. The term polynucleotide also includes single-stranded and double-stranded molecules.
  • an analog or “variant” as used herein will be understood to refer to a variation of the normal or standard form or the wild-type form of molecules.
  • an analog may be a variant (polymorphism), a mutant, and/or a naturally or artificially chemically modified version of the wild-type polynucleotide (including combinations of the above).
  • Such analogs may have higher, full, intermediate, or lower activity than the normal form of the molecule, or no activity at all.
  • an analog may be any structure that has the desired functionalities (including alterations or substitutions in the core moiety), even if comprised of different atoms or isomeric arrangements.
  • association with and “coupled to” include both direct association/binding of two moieties to one another as well as indirect association/binding of two moieties to one another.
  • associations/couplings include covalent binding of one moiety to another moiety either by a direct bond or through a spacer group, non-covalent binding of one moiety to another moiety either directly or by means of specific binding pair members bound to the moieties, incorporation of one moiety into another moiety such as by dissolving one moiety in another moiety or by synthesis, and coating one moiety on another moiety, for example.
  • substantially pure means an object species is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition), and preferably a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all macromolecular species present. Generally, a substantially pure composition will comprise more than about 80 percent of all macromolecular species present in the composition, more preferably more than about 85%, 90%, 95%, and 99%. Most preferably, the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species.
  • pharmaceutically acceptable refers to compounds and compositions which are suitable for administration to humans and/or animals without undue adverse side effects such as (but not limited to) toxicity, irritation, and/or allergic response commensurate with a reasonable benefit/risk ratio.
  • patient includes human and veterinary subjects.
  • mammal for purposes of treatment refers to any animal classified as a mammal, including (but not limited to) humans, domestic and farm animals, nonhuman primates, and any other animal that has mammary tissue.
  • treatment refers to both therapeutic treatment and prophylactic or preventative measures.
  • Those in need of treatment include, but are not limited to, individuals already having a particular condition/disease/infection as well as individuals who are at risk of acquiring a particular condition/disease/infection (e.g., those needing prophylactic/preventative measures).
  • treating refers to administering an agent to a subject/patient for therapeutic and/or prophylactic/preventative purposes.
  • a “therapeutic composition” or “pharmaceutical composition” refers to an agent that may be administered in vivo to bring about a therapeutic and/or prophylactic/preventative effect.
  • Administering a therapeutically effective amount or prophylactica lly effective amount is intended to provide a therapeutic benefit in the treatment, prevention, and/or management of a disease, condition, and/or infection.
  • the specific amount that is therapeutically effective can be readily determined by the ordinary medical practitioner, and can vary depending on factors known in the art, such as (but not limited to) the type of condition/disease/infection, the patient's history and age, the stage of the condition/disease/infection, and the co-administration of other agents.
  • the term "effective amount” refers to an amount of a biologically active molecule or sufficient to exhibit a detectable therapeutic effect without undue adverse side effects (such as (but not limited to) toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of the inventive concept(s).
  • the therapeutic effect may include, for example but not by way of limitation, preventing, inhibiting, or reducing the occurrence of infection by or growth of microbes and/or opportunistic infections.
  • the effective amount for a subject will depend upon the type of subject, the subject's size and health, the nature and severity of the condition/disease/infection to be treated, the method of administration, the duration of treatment, the nature of concurrent therapy (if any), the specific formulations employed, and the like. Thus, it is not possible to specify an exact effective amount in advance. However, the effective amount for a given situation can be determined by one of ordinary skill in the art using routine experimentation based on the information provided herein.
  • the term “concurrent therapy” is used interchangeably with the terms “combination therapy” and "adjunct therapy,” and will be understood to mean that the patient in need of treatment is treated or given another drug for the disease/infection in conjunction with the compositions of the present disclosure.
  • This concurrent therapy can be sequential therapy, where the patient is treated first with one composition and then the other composition, or the two compositions are given simultaneously.
  • compositions of the present disclosure may be designed to provide delayed, controlled, or sustained release using formulation techniques which are well known in the art.
  • compositions having at least one anti-viral activity are directed to a composition having at least one anti-viral activity.
  • the composition includes at least one anti-viral active ingredient in combination with at least one skin penetrant.
  • the composition is further defined as a topical or transdermal composition.
  • the at least one anti-viral active ingredient may be any anti-viral agent known in the art or otherwise contemplated herein.
  • the at least one anti-viral active ingredient comprises a natural ingredient (such as, but not limited to, a plant-based anti-viral ingredient) and/or a pharmaceutical agent.
  • the at least one anti-viral active ingredient is a substance that has received a Generally Regarded as Safe (GRAS) designation.
  • GRAS Generally Regarded as Safe
  • any natural ingredients known in the art or otherwise contemplated herein that possess anti-viral activity may be utilized as the anti-viral active ingredient(s) in accordance with the present disclosure.
  • Non-limiting examples of natural ingredients that possess anti-viral activity that can be utilized include essential oils, cyclodextrin, plant-based anti-viral ingredients, Human Milk Oligosaccharides (HMOs), Natural or chemical surfactants, and the like, as well as any combination thereof.
  • any plant-based anti-viral ingredients known in the art or otherwise contemplated herein may be utilized in accordance with the present disclosure.
  • Non- limiting examples thereof include tea tree oil (or at least one component thereof), eucalyptus oil (or at least one component thereof), a cyclodextrin, oleuropein, Pau d'arco extract (or a component thereof), a quinoid, Ampelocissus tomentosa root extract (or at least one component thereof), a flavonoid, baicalein, Justicia gendarussa extract (or a component thereof), 6-deoxyglucose-diphyllin (DGP, i.e., Patentiflorin A), Clove Bud oil, Peppermint oil, Diallyl thiosulfinate (allicin), Allyl methyl thiosulfinate, Ajoene, Deoxyalliin, Alliin, Diallyl trisulfide, Diallyl disulfide, Lippi
  • any pharmaceutical agents known in the art or otherwise contemplated herein that possess anti-viral activity may be utilized as the anti-viral active ingredient(s) in accordance with the present disclosure.
  • pharmaceutical agents that possess anti-viral activity include acyclovir, valacyclovir, famciclovir, ganciclovir, penciclovir, docosanol, edoxudine, ibacitabine, idoxuridine, imiquimod, inosine, muramidase, podophyllotoxin, sinecatechins, tromantadine, an analogue or derivative of any of the above, and the like, as well as any combinations of two or more of any of the above.
  • the composition contains two or more anti-viral active ingredients, such as (but not limited to), three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 35 or more, 40 or more, 45 or more, or 50 or more anti-viral active ingredients, wherein each anti-viral active ingredient is a natural ingredient, a plant-based anti-viral ingredient, or a pharmaceutical agent as described or otherwise contemplated herein.
  • the composition includes at least one natural anti-viral active ingredient and at least one pharmaceutical agent.
  • the anti-viral active ingredient(s) may be present in the composition at any percentage of concentration that allows the anti-viral active ingredient(s) to function as described or as otherwise contemplated herein.
  • each anti-viral active ingredient may be present in the composition at a percent concentration of about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 99%.
  • each anti-viral active ingredient in the composition at any percent concentration that falls within any range formed from the combination of two values listed above (for example, a range of from about 0.001% to about 90%, a range of from about 1% to about 99%, a range of from about 2% to about 80%, a range of from about 3% to about 60%, a range of from about 10% to about 95%, a range of from about 40% to about 75%, etc.).
  • any skin penetrants known in the art or otherwise contemplated herein may be utilized as the skin penetrant(s) of the compositions of the present disclosure.
  • skin penetrants that may be utilized in accordance with the present disclosure include an emulsion system, a microemulsion system, a nanoemulsion system, an emulsifier (such as, but not limited to, phosphatidylcholine, propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, oleic acid and laurocapram, a ceramide, a phospholipid, an essential fatty acid (EFA), and the like, as well as any combinations thereof), a surfactant (such as, but not limited to, sodium lauryl sulfate (SLS), an oleic acid, a lauryl ether, a polysorbate, a cetyl alcohol, sorbitan stearate, a stearyl alcohol, a cetosteary
  • SLS sodium
  • the composition contains two or more skin penetrants, such as (but not limited to), three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 35 or more, 40 or more, 45 or more, or 50 or more skin penetrants.
  • skin penetrants such as (but not limited to), three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more 24
  • the skin penetrant(s) may be present in the composition at any percentage of concentration that allows the skin penetrant(s) to function as described or as otherwise contemplated herein.
  • each skin penetrant is present in the composition at a percent concentration of about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 99%.
  • each skin penetrant in the composition at any percent concentration that falls within any range formed from the combination of two values listed above (for example, a range of from about 0.001% to about 90%, a range of from about 1% to about 99%, a range of from about 2% to about 80%, a range of from about 3% to about 60%, a range of from about 10% to about 95%, a range of from about 40% to about 75%, etc.).
  • the composition may further include at least one milk oligosaccharide.
  • the milk oligosaccharide(s) may be human milk oligosaccharide(s) or milk oligosaccharides from another source (such as, but not limited to, another mammalian source).
  • milk oligosaccharides known in the art or otherwise contemplated herein may be utilized as the milk oligosaccharide(s) of the composition.
  • Non-limiting examples of milk oligosaccharides that may be utilized in accordance with the present disclosure include sialyl(a2,3)lactose, lacto-N-fucopentaose III, Lactoferrin, milk-derived peptides or other components, and the like, as well as any combinations thereof.
  • the milk oligosaccharide(s) may be present in the composition at any percentage of concentration that allows the milk oligosaccharide(s) to function as described or as otherwise contemplated herein.
  • each milk oligosaccharide is present in the composition at a percent concentration of about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 99%.
  • each milk oligosaccharide in the composition at any percent concentration that falls within any range formed from the combination of two values listed above (for example, a range of from about 0.001% to about 90%, a range of from about 1% to about 99%, a range of from about 2% to about 80%, a range of from about 3% to about 60%, a range of from about 10% to about 95%, a range of from about 40% to about 75%, etc.).
  • compositions of the present disclosure may be defined, in certain nonlimiting embodiments, as anti-viral compositions.
  • compositions may be defined as compositions effective against at least one Arbovirus (i.e., "Arthropod-Borne Virus").
  • Arboviruses include all viruses that are transmitted by arthropod vectors, such as (but not limited to) mosquitos, ticks, fleas, flies, midges, mites, and the like.
  • Non-limiting examples of mosquito-borne viruses include Chikungunya virus (CHIKV), Dengue virus (DENV), Zika virus (ZIKV), Yellow Fever virus (YFV), Japanese Encephalitis virus (JEV), West Nile virus (WNV), California Encephalitis virus (CEV), Rift Valley Fever virus (RVFV), Ross River virus, African Swine Fever virus (ASFV), Eastern Equine Encephalitis virus (EEEV), Huaiyangshan banyangvirus, Bunyamwera virus, Jamestown Canyon virus, La Crosse encephalitis virus, Toscana virus, Murray Valley Encephalitis virus, St.
  • tick-borne viruses include Deer Tick virus (DTV), Colorado Tick Fever virus (CTFV), Heartland virus (HRTV), Tick-borne Encephalitis virus (TBEV), Tick-borne Meningoencephalitis virus (TBMV), Crimean-Congo Hemorrhagic Fever virus (CCHFV), Severe Fever With Thrombocytopenia Syndrome virus (SFTSV), Powassan virus (POWV), Bourbon virus, Tofla virus, Kyasunar Forest Disease virus (KFDV), Alkhurma Haemorrhagic Fever virus (AHFV), African Swine Fever virus (ASFV), Kenya Sheep Disease virus, and the like.
  • fly-borne viruses include Sandfly fever virus, Ebola virus, Avian Influenza virus, Seneca virus, Newcastle Disease virus, Porcine Reproductive and Respiratory Syndrome virus (PRRSV), Musca domestica Salivary Gland Hypertrophy virus (MdSGHV), and the like.
  • the anti-viral compositions may be effective against at least one sexually transmitted virus.
  • sexually transmitted viruses include Human Immunodeficiency virus (HIV), Human Papillomavirus (HPV), Hepatitis virus (such as, but not limited to, Hepatitis B virus), Herpes Simplex virus (HSV), Cytomegalovirus (CMV), and the like.
  • compositions of the present disclosure may be defined as being at least one of an anti-fungal, an antibacterial, or an anti-protozoan composition.
  • compositions of the present disclosure are defined as being substantially non-toxic and substantially hypoallergenic.
  • compositions of the present disclosure have a delayed, controlled, or sustained release formation.
  • the anti-viral active ingredient(s) of the compositions of the present disclosure has a high minimum inhibitory concentration (MIC) for components of the beneficial skin microbiome, and a low MIC for at least one secondary bacterial/fungal infectious agent (i.e., pathogenic strains).
  • MIC minimum inhibitory concentration
  • the compositions are safe on the skin microbiome but substantially prevent or reduce the occurrence of secondary bacterial or fungal infections, such as (but not limited to) due to scratching.
  • Non-limiting examples of secondary bacterial/fungal infectious agents for which the compositions of the present disclosure substantially inactivate or reduce the activity thereof include E. coll, P. aeruginosa, S. aureus, L. innocua, S. sonnei, C. albicans, S. enterica, S. aureus, and P. aeruginosa, and the like, as well as combinations thereof.
  • the anti-viral active ingredient(s) is present in the compositions of the present disclosure in a therapeutically effective amount capable of preventing, reducing the occurrence or severity of, or otherwise treating a viral infection in a mammal.
  • the therapeutically effective amount of the one or more anti-viral active ingredients is further defined as an amount sufficient to induce a response protective against at least one viral infection.
  • the compositions may also include a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically acceptable carrier or excipient Any carriers or excipients known in the art may be utilized in accordance with the present disclosure.
  • a physiological compatible carrier e.g., saline
  • saline a physiological compatible carrier that is compatible with maintaining the structure/activity of the anti-viral active ingredient(s) (as well as skin penetrant(s) and/or milk oligosaccharide(s), when present) when administered, and compatible with the desired mode of administration, may be utilized as the pharmaceutically acceptable carrier in accordance with the present disclosure.
  • the anti-viral active ingredient(s) may be mixed with excipients which are pharmaceutically acceptable and compatible with the anti-viral active ingredient(s).
  • excipients include, for example but not by way of limitation, water, saline, dextrose, glycerol, ethanol, and the like, or any combination thereof.
  • excipients include, for example but not by way of limitation, water, saline, dextrose, glycerol, ethanol, and the like, or any combination thereof.
  • excipients include, for example but not by way of limitation, water, saline, dextrose, glycerol, ethanol, and the like, or any combination thereof.
  • compositions disclosed or otherwise contemplated herein may contain minor amounts of auxiliary substances, such as (but not limited to) wetting or agents, pH buffering agents, thickeners, diluents, dispersing aids, binders, scents/odorants, or the like, as well as any combination thereof.
  • auxiliary substances such as (but not limited to) wetting or agents, pH buffering agents, thickeners, diluents, dispersing aids, binders, scents/odorants, or the like, as well as any combination thereof.
  • the compositions of the present disclosure may contain any such additional ingredients so as to provide the composition in a form suitable for administration.
  • compositions of the present disclosure may be administered by any of the many suitable means described herein and/or which are well known to those of skill in the art, including but not limited to: topical, transdermal, or intradermal administration; as eye drops, sprays, etc.; and the like.
  • topical, transdermal, or intradermal administration as eye drops, sprays, etc.; and the like.
  • one or more than one route of administration can be employed, either simultaneously or partially or wholly sequentially.
  • compositions may be administered in conjunction with other compositions constructed in accordance with the present disclosure and/or other treatment modalities.
  • additional treatment modalities may include (but are not limited to) various substances that have anti-inflammatory, antiitching, and/or wound healing properties.
  • the compositions may be combined in a single composition or administered simultaneously or separately.
  • compositions of the present disclosure possess multiple characteristics. These characteristics include one or more of: (i) broad spectrum anti-viral activity mediated by the anti-viral active ingredient(s) described herein, as well as a combination of two or more anti-viral active ingredients (whether natural or synthetic) for synergistic effects; (ii) milk oligosaccharide/HMO-mediated stimulation of skin macrophages that enhances quick virus clearance in the skin; (iii) additional anti- bacterial and/or anti-fungal activities that substantially prevent or reduce the occurrence or severity of post-bite secondary infections; (iv) rapid skin penetrability to act on a broader panel of mosquito-borne virus inactivation in short window of time; and (v) a combination of herbal actives that promote the wound healing repair mechanism post arthropod bite.
  • non-limiting embodiments of the present disclosure are directed to a method of producing one or more of any of the compositions described or otherwise contemplated herein.
  • one or more anti-viral active ingredients is mixed with one or more skin penetrants (and one or more milk oligosaccharides, if present) to produce the compositions described or otherwise contemplated herein.
  • at least one natural anti-viral active ingredient is mixed with at least one pharmaceutical agent and one or more skin penetrants (and one or more milk oligosaccharides, if present) to produce the compositions described or otherwise contemplated herein.
  • Particular (but non-limiting) examples of production methods are provided herein below in the Examples.
  • compositions described or otherwise contemplated herein are directed to a method of using one or more of any of the compositions described or otherwise contemplated herein.
  • one or more of any of the compositions disclosed or otherwise contemplated herein is applied to at least a portion of a skin of a subject or patient.
  • the two or more compositions may be administered simultaneously or wholly or partially sequentially.
  • compositions disclosed or otherwise contemplated herein are applied to at least a portion of a skin of the subject/patient.
  • the composition is applied to and/or in a vicinity of at least one insect bite.
  • the composition is applied in a vicinity of a break in the skin.
  • application in this manner may be effective at substantially preventing or reducing the occurrence of sexually transmitted diseases (as discussed in detail elsewhere herein) or other types of skin infections caused by viruses.
  • the application of the composition reduces the occurrence of post-bite (or post-break) secondary infections.
  • compositions that are administered to a subject in need thereof varies according to many factors, e.g., the age, weight, overall health, gender, genetic history, history of allergies, prior infection, stage of current infection, etc. of the subject.
  • the compositions can be administered in a manner compatible with the dosage formulation and in such amounts as will be therapeutically effective. Precise amounts of active ingredient(s) required to be administered depend on the judgment of the practitioner and may be monitored on a patient-by-patient basis.
  • the dosage may also depend, without limitation, on the route of administration, the patient's state of health and weight, and the nature of the formulation.
  • compositions disclosed or otherwise contemplated herein are usually mammals and are frequently humans. However, this need not always be the case.
  • Veterinary uses of the compositions and methods disclosed or otherwise contemplated herein are also contemplated, e.g., for companion pets, ruminants, or other animals that are of commercial value e.g., as a food source, or for any other animal, etc.
  • dogs, cats, and horses are particularly susceptible to Arthropod-borne illnesses, and thus can particularly benefit from the compositions and methods of the present disclosure.
  • compositions comprising at least one anti-viral active ingredient and at least one skin penetrant
  • compositions that include one or more broad spectrum anti-viral actives, wherein the compositions have multiple targeted applications to health, hygiene, and nutrition.
  • the composition is a post-mosquito bite, fast penetrating skin cream, gel, ointment, lotion, serum, foam, paste, balm, spray, etc., that delivers active anti-viral ingredient(s) to the dermal layers of a subject's skin, where the anti-viral ingredient(s) inhibits viral activity (such as, but not limited to, entry of virus into host cell and/or viral replication, etc.) without affecting wound healing.
  • compositions of the present disclosure are developed to provide broadly applicable, cost-effective interventions for mosquito- and tick-borne infections, in contrast to the existing non-effective repellents and post-bite creams that simply possess anti-itching and/or wound healing properties, but have no effect on preventing transmission of the infection to the blood stream.
  • the anti-viral active ingredient(s) are GRAS and substantially non-toxic, and as such, will be safe to use on the wound/bite area.
  • the anti-viral active ingredient(s) can effectively protect from mosquito-borne viruses based on: (i) broad spectrum anti-viral activity; (ii) high and quick skin penetrability to act on inactivating the virus within a short window of time (and potentially in the skin layers before the virus reaches the blood stream and spreads through the body); (iii) stimulation of skin macrophages for enhancing viral clearance; and/or (iv) broad range anti-microbial effects to prevent post-bite secondary infections.
  • the compositions may have soothing, anti-itching, anti-inflammatory, and/or wound healing properties.
  • compositions may be utilized prior to or after exposure to the Arthropods. As such, the compositions provide mechanisms to manage both infection and disease manifestation.
  • the compositions provide a treatment for post-vector bites to stop the spread of virus into the blood stream.
  • the composition uses, in one non-limiting embodiment, at least one anti-viral active ingredient that is GRAS and substantially safe on the skin beneficial microbiome, while substantially preventing or reducing the occurrence or severity of secondary bacterial/fungal infections (due to, for example (but not by way of limitation) scratching).
  • ICso virucidal efficacy
  • cytotoxicity of the anti-viral actives of this Example are studied in vitro and in a 3D skin model.
  • Screening of the anti-viral actives involves the following protocol. At least six Arboviruses are procured (Dengue, Chikungunya, Zika, West Nile, Japanese encephalitis, and Yellow Fever viruses) and grown under Institutional Biosafety Committee (IBC) and BSL-3 protocols. Required cell lines are obtained from ATCC. Virus titration techniques are standardized. The cytotoxicities of at least twelve (12) compounds/substances are then tested on cell lines used to grow and test antiviral effects, as well as on primary cells isolated from blood.
  • IBC Institutional Biosafety Committee
  • the antiviral effects of the twelve organic compounds are evaluated at different non-toxic concentrations on four Arboviruses in a BSL-2 laboratory (Dengue, Chikungunya, Zika, and Yellow Fever viruses), and on two Arboviruses in a BSL-3 laboratory (West Nile and Japanese Encephalitis viruses).
  • the results are then analyzed to identify anti-viral active ingredients that are safe/GRAS and that exhibit anti-viral activity against at least one of the six viruses tested.
  • the top performing anti-viral active ingredient(s) formulations are then tested on a 3D skin culture model to determine skin permeability and stimulation of skin macrophages for virus clearance.
  • the formulations being tested include anti-viral active ingredients singularly and in combination with one or more other anti-viral active ingredients, and these ingredient(s) are also tested in combination with skin penetrant(s) and HMO(s), so as to identify formulations that have a synergistic effect and that can work against a broad panel of viruses.
  • Formulations of active(s) at differing concentrations are also tested, both alone and in combination with skin penetrant(s), so as to determine optimal concentrations thereof along with rapid release thereof to allow for clearance of the virus before it enters the blood stream.
  • the formulations tested are also analyzed to determine that they are safe on the skin microbiome (i.e., high MIC for beneficial microbiome).
  • the microbiota is able to influence host health and individual fitness through multiple pathways, such as nutrient synthesis, immune system development, and even behavioral processes.
  • changes in the microbiome's composition can lead to physiological changes that can increase the risk of opportunistic pathogen infection or impair the immune response.
  • the formulations tested are also analyzed to determine if they are capable of preventing secondary bacterial/fungal skin infections (such as, but not limited to, due to scratching; i.e., low MIC on pathogenic strains).
  • the Minimum Inhibitory Concentration (MIC) is determined by culturing the microorganism in liquid media or on plates of solid growth medium. A lower MIC value indicates that less drug is required for inhibiting growth of the organism; therefore, drugs with lower MIC scores are more effective antimicrobial agents.
  • Oleuropein contained in olive leaves is a powerful inhibitor to a wide range of viruses that blocks the production of enzymes for virus replication.
  • Methanol extract of roots of Ampelocissus tomentosa have a low ICso (7.79 pg/ml) for CHIKV and higher CCso or cytotoxic 50% effector dose of 36.6 pg/ml.
  • these extracts have high other antimicrobial inhibitory ability, showing 100% relative inhibition for E. coll, P. aeruginosa, S. aureus, and L. innocua; 93% relative inhibition for 5. sonnei; 62% relative inhibition for C. albicans; and 14% relative inhibition for 5. enterica.
  • the MIC for 5. aureus and P. aeruginosa is below the CCso level.
  • flavone baicalein exerts potent activity against DENV, JEV, and CHIKV adsorption to the host and post-entry viral replication.
  • the complexity of chemical structures that flavonoids offer presents potential broad-spectrum antiviral activities that can target various enzymes to disrupt the viral replication cycle.
  • DGP 6-deoxyglucose-diphyllin
  • Patentiflorin A is a naphthalene-derived bioactive phytoconstituent molecule from a medicinal plant Justicia gendarussa. It can be chemically synthesized and exhibits broadspectrum antiviral activity that potently blocks infection by Zika, Dengue, Yellow Fever, Tickborne Encephalitis, Japanese Encephalitis, West Nile, and Ebola viruses. DGP has been shown to be highly effective against Zika virus infection in vivo at very low concentrations (nM range) with undetected toxicity, and has reached into clinics as Diphyllin.
  • plant products utilized as the anti-viral active ingredient(s) in accordance with the present disclosure are natural, substantially non-toxic, and mild to human skin, with no allergy or health risks aroused by skin contact.
  • plant products are typically readily available and have very few or no side effects.
  • the resources of most natural viral inhibitors identified above have been well documented with easy extraction processes.
  • each of the compositions of the present disclosure also contain at least one skin penetrant in the formulations thereof.
  • These ingredients have good skin penetrability and include (for example, but not by way of limitation) emulsifiers that form micelles which can surround and encapsulate the "active" ingredients of the compositions.
  • emulsion penetration can be enhanced by reducing the particle size of the emulsion.
  • emulsion system a microemulsion system, a nanoemulsion system
  • an emulsifier such as, but not limited to, phosphatidylcholine, propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, oleic acid and laurocapram, a ceramide, a phospholipid, an essential fatty acid (EFA), and the like, as well as any combinations thereof
  • a surfactant such as, but not limited to, sodium lauryl sulfate (SLS), an oleic acid, a lauryl ether, a polysorbate, a cetyl alcohol, sorbitan stearate, a stearyl alcohol, a cetostearyl ether, a cetostearyl alcohol
  • Phytosome propylene glycol, allantoin, panthenol,
  • micro-emulsions and nanoemulsions of phosphatidylcholine and propylene glycol are excellent penetration enhancers and are used to help shuttle soluble active ingredients through the lipid top layers of the skin into the lower layers.
  • Phytosome a complex of a natural active ingredient and a phospholipid (mostly lecithin), is claimed to increase absorption of "conventional herbal extracts" or isolated active principles both topically as well as orally.
  • Sodium lauryl sulfate an anionic surfactant, possesses skin penetration enhancer properties and enhances penetration into the skin by increasing the fluidity of epidermal lipids.
  • the increase in lipid fluidity below the applied site may allow SLS to diffuse in all directions including the radial path. SLS thus increases intraepidermal drug delivery when utilized in the formulations of the present disclosure.
  • Example 2 anti-viral compositions of Example 1 and similar to those described in Example 2 are provided, except that where Example 2 utilizes natural and/or plant-based anti-viral active ingredient(s), this Example utilizes one or more pharmaceutical agents, either alone or in combination with one or more plant-based anti-viral active ingredients (or other natural anti-viral ingredient(s)).
  • ALDARA® (Imiquimod, Graceway Pharmaceuticals, LLC, Bristol, TN), which was originally approved for treating genital warts, has been repurposed to stimulate skin resident macrophages. This was demonstrated to effectively clear viruses from skin for up to five hours in experimental animals with post mosquito bite situation (Bryden et al., Sc/. Transl. Med. (2020) 12, eeax2421).
  • WO 2017/029298 discloses a topical antiviral composition for treating cold sores.
  • the topical antiviral composition comprises antiviral active ingredient or analogues or derivatives thereof in combination with antiherpes oils and an acid active ingredient.
  • Non-limiting examples of pharmaceutical agents utilized in formulations of the compositions of the present disclosure include acyclovir, valacyclovir, famciclovir, ganciclovir, penciclovir, docosanol, edoxudine, ibacitabine, idoxuridine, imiquimod, inosine, muramidase, podophyllotoxin, sinecatechins, tromantadine, an analogue or derivative of any of the above, and any combinations of two or more of any of the above.
  • compositions are prepared that include at least one anti-viral active ingredient, at least one skin penetrant, and at least one milk oligosaccharide.
  • the milk oligosaccharide(s) serves to enhance viral clearance by (for example, but not by way of limitation) recruiting skin macrophages, as described in greater detail herein below.
  • TLRs Toll like receptors
  • a wound healing repair mechanism begins; however, the skin does not prepare itself to respond to viral attack, and so the mosquito-borne viruses entering the skin through a bite are able to reach the bloodstream and lymphatic system to spread throughout the body.
  • a broad-spectrum antiviral agent combined with suitable milk components/HMOs can quickly act on the virus released by the mosquito in the dermis/deep layers of the skin. This is achieved through combined activities of skin macrophages recruited by HMOs and direct virucidal action of anti-viral actives.
  • the combination of the anti-viral active ingredient(s), skin penetrants, and milk oligosaccharides/HMOs can effectively protect from mosquito-borne viruses based on: (i) broad spectrum anti-viral activity; (ii) H MO-mediated stimulation of skin macrophages that enhances virus clearance; (iii) additional anti-bacterial/anti-fungal activities that prevents post-bite secondary infections; and (iv) rapid skin penetrability to act on virus inactivation in a short window of time.
  • compositions of this Example include the presence of milk oligosaccharides/HMOS that further enhance the efficacy and direct virucidal action of one or more GRAS anti-viral actives, wherein the compositions also provide additional benefits such as (but not limited to) skin repair/wound healing, anti-bacterial activity, and anti-fungal activity.
  • A-Q interaction studies of different potential actives (A-Q, wherein each of A-Q is (in a particular but non-limiting embodiment) selected from 1-37 above) are studied through a DOE study using Placket Burman design as shown in Table 1 below, either in the presence or absence of a test compound.
  • the scope of the present disclosure explicitly includes all variations of formulations 1-20 above wherein each of A-Q is selected from anti-viral active ingredients 1-37 above.
  • fractional factorial designs are also utilized (in certain non-limiting embodiments) for testing the various compositions formulations of the present disclosure. For example (but not by way of limitation), three or four factor designs are used to see the main anti-viral effects that they are completely confounded with those factors.
  • Example 6 [0149] Various compositional formulations where the anti-viral active ingredient(s) includes at least one natural ingredient
  • Tables 2-37 below contain various formulations that list at least a portion of the ingredients present in compositions prepared in accordance with the present disclosure and that include at least one natural anti-viral active ingredient.
  • compositions of the present disclosure also include formulations of Tables 2-37 that further include one or more additional natural anti-viral active ingredients, one or more skin penetrants, and/or one or more milk oligosaccharides in addition to the ingredients listed in the above formulations.
  • Formulation 20 could further include A. tomentosa root extract and Patentiflorin A active ingredients, a nanoemulsion system of phosphatidyl choline and propylene glycol, and sialyl(a2,3)lactose. Therefore, this modified Formulation 20 contains tea tree oil, eucalyptus oil, A. tomentosa root extract, and Patentiflorin A active ingredients; skin penetrants of sodium lauryl sulfate and a nanoemulsion system of phosphatidyl choline and propylene glycol; and the HMOs Lacto-N-fucopentaose-lll and sialyl(a2,3)lactose.
  • an additional anti-viral active ingredient selected from tea tree oil (or at least one component thereof), eucalyptus oil (or at least one component thereof), a cyclodextrin, oleuropein, Pau d'arco extract (or a component thereof), a quinoid, Ampelocissus tomentosa root extract (or at least one component thereof), a flavonoid, baicalein, Justicia gendarussa extract (or a component thereof), 6-deoxyglucose-diphyllin (DGP, i.e., Patentiflorin A), Clove Bud oil, Peppermint oil, Diallyl thiosulfinate (allicin), Allyl methyl thiosulfinate, Ajoene, Deoxyalliin, Alliin, Diallyl trisulfide, Diallyl disulfide, Lipp
  • Table 42 below contains various formulations that list at least a portion of the ingredients present in compositions prepared in accordance with the present disclosure and that include at least one additional ingredient as listed above.
  • Example 7 Various formulations of compositions where the anti-viral active ingredient(s) includes at least one pharmaceutical agent [0156] Table 43 below contains various formulations that list at least a portion of the ingredients present in compositions prepared in accordance with the present disclosure and that include at least one pharmaceutical anti-viral active ingredient in combination with at least one natural anti-viral active ingredient.
  • Formulation 42J when Formulation 42J includes Formulation 28B, the resulting Formulation 42J contains: imiquimod, Eucalyptus oil, Oleuropein, Pau d'arco extract, and sialyl(a2,3)lactose in a phosphatidyl choline and propylene glycol micro- or nano-emulsion.
  • Formulation 42P could contain acyclovir and imiquimod as the two pharmaceutical agents and Formulation 24H as the other components. Therefore, the resulting Formulation 42P contains acyclovir, imiquimod, cyclodextrin, Pau d'arco extract, propylene glycol, and sialyl(a2,3)lactose.

Abstract

L'invention concerne des compositions comprenant au moins un principe actif antiviral et au moins un agent pénétrant dans la peau. L'invention concerne également des procédés de production et d'utilisation de ces compositions pour traiter ou réduire l'apparition ou la gravité d'une infection virale, et en particulier (mais non à titre limitatif), l'invention concerne également une infection à arbovirus.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000004884A1 (fr) * 1998-07-20 2000-02-03 Hartmut Osswald Preparations medicamenteuses pour traitement topique d'infections herpetiques cutaneo-muqueuses et de l'herpes de la keratite de l'oeil
WO2017029298A1 (fr) 2015-08-17 2017-02-23 Sanovel Ilac Sanayi Ve Ticaret A.S. Composition antivirale topique
US20200101087A1 (en) * 2015-08-03 2020-04-02 Pop Test Oncology Llc Pharmaceutical compositions and methods

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000004884A1 (fr) * 1998-07-20 2000-02-03 Hartmut Osswald Preparations medicamenteuses pour traitement topique d'infections herpetiques cutaneo-muqueuses et de l'herpes de la keratite de l'oeil
US20200101087A1 (en) * 2015-08-03 2020-04-02 Pop Test Oncology Llc Pharmaceutical compositions and methods
WO2017029298A1 (fr) 2015-08-17 2017-02-23 Sanovel Ilac Sanayi Ve Ticaret A.S. Composition antivirale topique

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Title
BRYDEN ET AL., SCI. TRANSL. MED., vol. 12, 2020, pages eeax2421
FONSECA-SANTOS BRUNO ET AL: "An effective mosquito-repellent topical product from liquid crystal-based tea tree oil", INDUSTRIAL CROPS AND PRODUCTS, vol. 128, 27 November 2018 (2018-11-27), pages 488 - 495, XP085568034, ISSN: 0926-6690, DOI: 10.1016/J.INDCROP.2018.11.020 *
YINGYING HE ET AL., ADV NUTR, vol. 7, no. 1, 15 January 2016 (2016-01-15), pages 102 - 11

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