WO2021205437A1 - Pharmaceutical compositions for treating corona virus disease - Google Patents

Pharmaceutical compositions for treating corona virus disease Download PDF

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Publication number
WO2021205437A1
WO2021205437A1 PCT/IL2021/050380 IL2021050380W WO2021205437A1 WO 2021205437 A1 WO2021205437 A1 WO 2021205437A1 IL 2021050380 W IL2021050380 W IL 2021050380W WO 2021205437 A1 WO2021205437 A1 WO 2021205437A1
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Prior art keywords
pharmaceutical composition
composition according
inhibitor
present
virus
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PCT/IL2021/050380
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French (fr)
Inventor
Susan Eve Vecht-Lifshitz
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Vecht Lifshitz Susan Eve
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Publication of WO2021205437A1 publication Critical patent/WO2021205437A1/en

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • 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 
    • 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
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • 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)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • 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
    • 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
    • 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 generally, to pharmaceutical compositions for treating a viral disease and more specifically to pharmaceutical compositions for treating a coronavims disease.
  • Corona vims Ebola vims, Marburg vims, Dengue vims are viruses with poor primate and/or human survival statistics. Many other viruses may be fatal, particularly in young children, the elderly or immunocompromised patients.
  • RNA vims families include, inter alia , Coronaviridae Arenaviridae, Filoviridae, Bunyaviridae, Flaviviridae, and Rhabdoviridae.
  • coronavims SARS- COV-2 pandemic There have previously been SARSs and MERS coronavims epidemics.
  • SARSs and MERS coronavims epidemics There have also been various endemic viral diseases in West Africa, such as Dengue, Ebola, Lassa, CCHF and others.
  • dmgs or cures which have been FDA approved, and/or tested properly in humans.
  • Corona vims SARS-COV-2
  • Corona vims pandemic in China and more than 200 other countries.
  • the limited published data on this vims suggests that it is a single- stranded positive-sense RNA vims (size ranging from 26 to 32 kB, Li el al., 2020) comprising 24 proteins (Appendix 1).
  • SARS-COV-2 (previously called 2019-NCoV, causing the disease termed COVID-19) comprises several enzymes, which could be used as targets for inhibition, including, a papain-like protease (3), a proteinase (5), an RNA- directed RNA polymerase (11), a helicase, (12), a guanine-N7 methyltransferase (13), a uridylate-specific endoribonuclease (14) and a 2-O-methyl transferase (15).
  • a papain-like protease (3) a proteinase (5)
  • an RNA- directed RNA polymerase 11
  • a helicase (12
  • a guanine-N7 methyltransferase (13)
  • a uridylate-specific endoribonuclease (14)
  • 2-O-methyl transferase 15
  • coronaviral N7-MTase is unique for its physical linkage with an exoribonuclease (ExoN) harbored in nonstmctural protein 14 (nspl4) of coronavimses.
  • the treatment was one or more small molecules, which worked at a mechanistic level, such as inhibition of one or more viral enzymes.
  • a broad- spectrum anti-corona antibiotic is developed, it is possible that it will also be effective against other pathogenic viruses, such as Ebola, HIV, Marburg, Lassa and Dengue.
  • pathogenic viruses such as Ebola, HIV, Marburg, Lassa and Dengue.
  • Some embodiments of the present invention are directed to the treatment of disorders and diseases. More particularly, the disorders and diseases may be of an unknown cause, or they may be viral disorders and diseases.
  • a pharmaceutical composition for treating COVID-19 comprising at least one of a cholesterol-lowering compound, an SAHH (s-adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor.
  • SAHH s-adenosylhomocysteine hydrolase
  • a pharmaceutical composition for treating COVID-19 comprising at least two of a cholesterol-lowering compound, an SAHH (s-adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor.
  • SAHH s-adenosylhomocysteine hydrolase
  • a synergistic pharmaceutical composition for treating a viral disease comprising at least two of a cholesterol-lowering compound, an SAHH (s- adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor, wherein the effect of the at least two compounds synergistically inhibits the virus.
  • SAHH s- adenosylhomocysteine hydrolase
  • a synergistic pharmaceutical composition for inhibiting an RNA virus comprising at least two of a cholesterol-lowering compound, an SAHH (s- adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor, wherein the effect of the at least two compounds synergistically inhibits the RNA virus.
  • SAHH s- adenosylhomocysteine hydrolase
  • a synergistic pharmaceutical composition for inhibiting a corona virus comprising at least two of a cholesterol-lowering compound, an SAHH (s- adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor, wherein the effect of the at least two compounds synergistically inhibits the corona virus.
  • SAHH s- adenosylhomocysteine hydrolase
  • a synergistic pharmaceutical composition for inhibiting a SARS COV-2 vims comprising at least two of a cholesterol-lowering compound, an SAHH (s- adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor, wherein the effect of the at least two compounds synergistically inhibits the SARS COV-2 virus.
  • SAHH s- adenosylhomocysteine hydrolase
  • a pharmaceutical composition for treating COVID-19 comprising a cholesterol-lowering compound, an SAHH (s-adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor.
  • SAHH s-adenosylhomocysteine hydrolase
  • the pharmaceutical composition is a "generally-regarded-as-safe" (GRAS) composition.
  • GRAS general-regarded-as-safe
  • the cholesterol lowering compound is eritadenine.
  • the SAHH inhibitor is selected from inosine, an inosine analog or an inosine derivative.
  • the RNA vims is SARS-COV-2 virus.
  • the DOTH inhibitor is EPZ5676.
  • a pharmaceutical composition including at least one compound as described herein.
  • the pharmaceutical composition includes two compounds.
  • the pharmaceutical composition includes an SAHH inhibitor and a DOT1L inhibitor.
  • the pharmaceutical composition includes CAC3ADO and EPZ5676.
  • the pharmaceutical composition includes DDFA and EPZ5676.
  • the pharmaceutical composition includes DDFA and SGC 0946.
  • the pharmaceutical composition includes DDFA and EPZ004777.
  • the pharmaceutical composition includes CAC3ADO and SGC 0946.
  • the vims is SARS- COV-2 virus.
  • the pathogenic disease is a pathogenic disease.
  • the pharmaceutical composition further includes at least one a-glucosidase inhibitor. Additionally, according to an embodiment of the present invention, the pharmaceutical composition further includes at least one cathepsin B inhibitor.
  • the pharmaceutical composition further includes at least one endothelial barrier enhancer.
  • the pharmaceutical composition further includes at least one TNF alpha inhibitor.
  • the pharmaceutical composition further includes at least one collagen precursor.
  • the pharmaceutical composition further includes at least one folate remover.
  • the RNA vims is SARS-COV-2 virus and the composition includes; a) At least two of a cholesterol lowering compound, an S-adenosyl homocysteine hydrolase (SAHH) inhibitor and a DOT1L inhibitor; and b) at least one TNF alpha inhibitor; and optionally at least one of; i. at least one a-glucosidase inhibitor; ii. at least one endothelial barrier enhancer; iii. at least one cathepsin B inhibitor; and iv. at least one collagen precursor.
  • SAHH S-adenosyl homocysteine hydrolase
  • the RNA vims is SARS-COV-2 vims and the composition includes; c) an S-adenosyl homocysteine hydrolase (SAHH) inhibitor and a DOT1L inhibitor; and d) at least one TNF alpha inhibitor; and optionally at least one of; i. at least one a-glucosidase inhibitor; ii. at least one endothelial barrier enhancer; iii. at least one cathepsin B inhibitor; and iv. at least one collagen precursor.
  • SAHH S-adenosyl homocysteine hydrolase
  • SAM S-adenosyl methionine
  • a method for reducing a load of an infectious RNA virus causing a pathogenic disease in a mammalian subject including administering to the subject the compound, as described herein.
  • a method for reducing a load of an infectious RNA virus causing a pathogenic disease in a mammalian subject including administering to the subject the pharmaceutical composition as described herein.
  • a method for reducing a load of a coronavirus causing a disease in a mammalian subject including administering to the subject the pharmaceutical composition as described herein..
  • the composition is further effective to enhance endothelial barrier integrity.
  • the composition is further effective to enhance collagen generation in the subject.
  • the compound is selected from compounds listed in table 1.
  • the pharmaceutical composition includes any combination of compounds in table 1 in a pharmaceutically effective amount.
  • the present invention provides compositions for reducing a load of an infectious agent causing a pathogenic disease in a mammalian subject, the composition including at least one product ( dl, d2, ...d N ) in a pharmaceutically effective amount (EDxx), wherein ED is an effective dose and XX is the percentage reduction of the load, wherein each of the at least one product is effective to inhibit at least one step (si, s2, ...sN) in a pathway associated with replication of the infectious agent to reduce the load, No of the infectious agent in the subject to a final number at time t, N t , wherein a ratio of the load No to the final number N t is sufficiently large to provide the subject with a high statistical probability to survive the disease.
  • a pharmaceutical composition for reducing a load of an infectious agent causing a pathogenic disease in a mammalian subject including; at least one product ( dl, d2, ... d N ) in a pharmaceutically effective amount (EDxx), wherein ED is an effective dose and XX is the percentage reduction of the load, wherein each of the at least one product is effective to inhibit at least one step (si, s2, ...sN) in a pathway associated with replication of the infectious agent to reduce the load, No of the infectious agent in the subject to a final number at time t, N t , wherein a ratio of the load No to the final number N t is sufficiently large to provide the subject with a high statistical probability to survive the disease.
  • the product or compound(s) act synergistically in the composition to reduce the load of the infective agent.
  • the infective agent is an RNA virus, such as a corona virus.
  • the infectious agent is selected from the group consisting of a virus, a bacterium, a fungus, a parasite and combinations thereof.
  • the infectious agent is a virus.
  • the virus is an RNA virus.
  • RNA virus is selected from families Coronaviridae, Filoviridae, Bunyaviridae, Flaviviridae, and Rhabdoviridae.
  • the virus is SARS- COV-2 virus.
  • the pathogenic disease is a respiratory disease.
  • the disease has a survival rate of less than 99%.
  • the disease has a survival rate of less than 95%.
  • the pharmaceutical composition includes at least one S-adenosyl homocysteine hydrolase (SAHH) inhibitor.
  • SAHH S-adenosyl homocysteine hydrolase
  • the pharmaceutical composition includes at least one a-glucosidase inhibitor.
  • the pharmaceutical composition includes at least one cathepsin B inhibitor.
  • the pharmaceutical composition includes at least one endothelial barrier enhancer.
  • the pharmaceutical composition includes at least one TNF alpha inhibitor.
  • the pharmaceutical composition includes at least one NF kappa B inhibitor.
  • the pharmaceutical composition includes at least one TNF alpha inhibitor.
  • the pharmaceutical composition includes at least one collagen precursor.
  • the pharmaceutical composition includes at least one DOT1L inhibitor.
  • the pharmaceutical composition includes at least one folate remover.
  • the infectious agent is an RNA virus and the composition includes; a) at least one of an S-adenosyl homocysteine hydrolase (SAHH) inhibitor or a DOT1L inhibitor; and b) at least one TNF alpha inhibitor; and optionally at least one of; i. at least one a-glucosidase inhibitor; ii. at least one endothelial barrier enhancer; iii. at least one cathepsin B inhibitor; and iv. at least one collagen precursor.
  • SAHH S-adenosyl homocysteine hydrolase
  • each of the inhibitors, enhancers and precursors has a therapeutic index of more than 30.
  • each of the inhibitors, enhancers and precursors has a therapeutic index of more than 50.
  • At least one of the inhibitors, enhancers and precursors has a therapeutic index of more than 100.
  • At least one of the inhibitors, enhancers and precursors is a generally regarded as safe (GRAS) product.
  • GRAS safe
  • GRAS safe
  • each of the inhibitors, enhancers and precursors is a generally regarded as safe (GRAS) product.
  • each at least one of the inhibitors, enhancers and precursors is an FDA approved drug for a first indication and the pathogenic disease is a second indication.
  • the composition does not require FDA approval.
  • the composition costs less than $100 for the effective dose.
  • the pharmaceutical composition includes; a) Vitamin C; b) Bioavailable curcumin; c) at least one SAHH inhibitor; and d) at least one cathepsin B inhibitor.
  • the pharmaceutical composition further includes at least one anti-retroviral drug.
  • the pharmaceutical composition further includes at least one analgesic.
  • the pharmaceutical composition further includes at least one of creatine, Coenzyme Q10, Ginseng, and N- acetyl-L cysteine; glutathione, alpha lipoic acid, ajoene, allicin, limonene, Coenzyme Q10, quercetin, N-acetyl-L cysteine, resveratrol, and lycopene; choline and carnitine.
  • the composition is liquid.
  • the composition is solid.
  • the composition is suitable for oral, parenteral, transdermal, intra-venous or intra-muscular administration.
  • the composition is a slow-release composition.
  • the slow release composition is formulated for provision by at least one of an intravenous drip, a trans dermal device and a slow-release oral formulation.
  • N t is less than or equal to N 0 x ( ⁇ ⁇ (l-xx /i oo) di x (l-xx/100) d2... x((l-xx /i oo)) dn ) ⁇ for at least one of the steps (si, s2, ...sN) si to sN.
  • N t is less than or equal to N 0 x ( ⁇ ⁇ (l-xx /i oo) di x (l-xx/100) d2... c ((1-cc / ioo)) dn ) ⁇ for at least two of the steps (si, s2, ...sN) si to sN.
  • N t is less than or equal to N 0 x ( ⁇ ⁇ (l-xx /i oo) di x (l-xx/100) d2... x((l-xx /i oo)) dn ) ⁇ for at least three of the steps (si, s2, ...sN) si to sN.
  • N t is less than or equal to N 0 x ( ⁇ ⁇ (l-xx / 100) di x (l-xx/100) d2... c ((1-cc / ioo)) dn ) ⁇ for at least three of the steps (si, s2, ... sN) si to sN.
  • N t is less than or equal to N 0 x ( ⁇ ⁇ (l-xx /i oo) di x (l-xx/100) d2... c ((1-cc / ioo)) dn ) ⁇ for at least four of the steps (si, s2, ...sN) si to sN.
  • a pharmaceutical composition as described herein, in the preparation of a medicament suitable for administration to a human in a pharmaceutically effective amount, wherein the medicament is suitable for treating a pathogenic disease or disorder in the human.
  • a method for predicting efficacy of a pharmaceutical composition in reducing a load of an infectious agent causing a pathogenic disease in a mammalian subject including determining for at least one product ( dl, d2, ...d N ) an effective dose (EDxx), wherein ED is an effective dose and XX is the percentage reduction of the load, wherein each of the at least one products is effective to inhibit at least one step (si, s2,
  • sN in a pathway associated with replication of the infectious agent to reduce the load, No of the infectious agent in the subject to a final number at time t, N t , wherein a ratio of the load No to the final number N t is sufficiently large to provide the subject with a high statistical probability to survive the disease; and wherein the pharmaceutical composition includes the at least one products in the effective dose.
  • N t is less than or equal to N 0 x ( ⁇ ⁇ (l-xx /i oo) di x (l-xx/100) d2... c ((1-cc / ioo)) dn ) ⁇ for at least one the step (si, s2, ... sN) si to S N .
  • the infectious agent is a virus and the composition includes; a) at least one cathepsin B inhibitor; and b) at least one TNFa inhibitor.
  • the infectious agent is a virus and the composition includes; a) at least one cathepsin B inhibitor; and b) at least one S-adenosyl homocysteine hydrolase (SAHH) inhibitor.
  • SAHH S-adenosyl homocysteine hydrolase
  • the infectious agent is a virus and the composition includes; a) at least one S-adenosyl homocysteine hydrolase (SAHH) inhibitor. b) at least one TNFa inhibitor.
  • SAHH S-adenosyl homocysteine hydrolase
  • the infectious agent is Ebola virus and the composition includes; a) at least one cathepsin B inhibitor; and b) at least one S-adenosyl homocysteine hydrolase (SAHH) inhibitor.
  • SAHH S-adenosyl homocysteine hydrolase
  • the infectious agent is Ebola virus and the composition includes; a) at least one cathepsin B inhibitor; and b) at least one S-adenosyl homocysteine hydrolase (SAHH) inhibitor; and c) a DOT 1L inhibitor.
  • SAHH S-adenosyl homocysteine hydrolase
  • a method for reducing a load of an RNA virus causing a pathogenic disease in a mammalian subject including administering to the subject the pharmaceutical composition as described herein.
  • a method for reducing a load of an RNA virus causing a pathogenic disease in a mammalian subject including administering to the subject the pharmaceutical composition as described herein, wherein the composition is further effective to reduce a load of inflammatory cytokines from an initial load ICYQ to a final load at time t, ICY L wherein a ratio of ICYo to ICY L is sufficiently large to provide the subject with a very high statistical probability to survive the disease.
  • the composition is further effective to enhance endothelial barrier integrity.
  • the composition is further effective to enhance collagen generation in the subject.
  • the pharmaceutical composition is liquid. In other cases, it is solid. In yet further cases, it is a suspension.
  • the composition is a slow-release composition.
  • the slow release composition is formulated for provision by at least one of an intravenous drip, a trans- dermal device and a slow-release oral formulation.
  • the pharmaceutical composition further includes at least one neuro-protective agent.
  • the disease is a viral disease.
  • a pharmaceutical composition comprising at least one of a methyltransferase inhibitor compound, a viral enzyme inhibitor compound and an SAHH (s- adenosylhomocysteine hydrolase) inhibitor compound, the composition adapted to inhibit replication of an RNA virus, said virus causing a pathogenic disease in a mammalian subject, wherein each of said compounds in said pharmaceutical composition has a molecular weight of less than 1000.
  • SAHH s- adenosylhomocysteine hydrolase
  • RNA virus is a corona virus.
  • composition according to embodiment 1, wherein said pharmaceutical composition comprises at least two compounds.
  • RNA virus is SARS-COV-2 and said composition comprises: a) at least one of an S-adenosyl homocysteine hydrolase (SAHH) inhibitor and a DOT1L inhibitor; and b) at least one TNF alpha inhibitor; and optionally at least one of: i. at least one a-glucosidase inhibitor; ii. at least one endothelial barrier enhancer; iii. at least one cathepsin B inhibitor; and iv. at least one collagen precursor.
  • SAHH S-adenosyl homocysteine hydrolase
  • composition according to embodiment 11, wherein each of said inhibitors, enhancers and precursors has a therapeutic index of more than 30.
  • a pharmaceutical composition according to embodiment 14, wherein each of said inhibitors, enhancers and precursors is a generally regarded as safe (GRAS) product.
  • SAHH S-adenosyl homocysteine hydrolase
  • a pharmaceutical composition according to embodiment 16 further comprising at least one anti-retroviral drug.
  • the present invention also provides methods of treatment of a viral disease in a mammalian subject, the method including administering at least one compound or composition as described herein to the mammalian subject to treat the viral disease.
  • the present invention includes methods of treatment of corona virus disease in human subjects, including SARS COV 2 (causing COVID-19 disease), the method including administering a pharmaceutical composition as described herein to the human subject in a pharmaceutically effective amount to treat the corona virus disease and/or to alleviate symptoms of the disease and/or to alleviate inflammatory cascades in the subject and/or to prevent or treat long-term COVID-19 disease in the subject.
  • SARS COV 2 causing COVID-19 disease
  • RNA virus multiplies from around a few hundred plaque forming units (PFUs) introduced into a subject at time zero to tens of thousands- many million/billion PFUs. It has been reported that the average or mean replication rate line, leading to fatalities were several orders of magnitude greater than that in surviving hosts (Sanchez et al., 2004) having a mean PFU value of a significantly lower log slope than that of the fatal cases. For example, at day 4, post-infection, the non- survivors (fatalities) have a mean PFU count/ml 256 of 10 (100 million viruses/ml) and the survivors' mean PFU/ml count 266 is only around 3 x 10 4 (30,000 viruses/ml).
  • PFUs plaque forming units
  • This ratio R FS is typically in the range of 10-100000, more typically in the range of 50-50000.
  • 1 ⁇ R FS ⁇ 10000 for Ebola for example.
  • a statistical solution for improving human survival rates, when infected with a pathogenic virus is to reduce the viral load at time t, by at least 10, at least 100 and more preferably by at least 1000 and most preferably by at least 10000 fold.
  • This graph shows the importance of early treatment.
  • non-confirmed suspected cases of infection should be treated before the lab results are received.
  • RNA vims replication In order to inhibit an RNA vims replication, several steps in its replication cycle should be inhibited. This method applies, at least in part, to all viruses, bacterial, fungal, parasitic infections, and is exemplified with respect to SARS-COV-2 vims for the sake of simplicity.
  • At least one of the replication steps 1, 2, 3, 4, 5, 6, 7 and 8 of viral replication needs to be inhibited (respectively, cathepsin B or L inhibitors, folate receptor inhibitors, SAHH inhibitors, alpha glucosidase inhibitors, RNA synthesis inhibitors, RNA reverse transcription inhibitors, protein synthesis inhibitors, viral cap formation inhibitors and translation inhibitors). More preferably, in order to inhibit viral replication, at least two of the schematic steps 1, 2, 3, 4, 5, 6, 7 and 8 of viral replication need to be inhibited. Yet more preferably, in order to inhibit viral replication, at least three of the schematic steps 1, 2, 3, 4, 5, 6, 7 and 8 of viral replication need to be inhibited.
  • At least one viral enzyme should be inhibited.
  • at least one 2, 3, 4, 5, 6, or 7 of its enzymes must be inhibited, selected from the group consisting of a papain-like protease, a proteinase , an RNA-directed RNA polymerase, a helicase, a guanine-N7 methyltransferase , a uridylate- specific endoribonuclease and a 2-O-methyl transferase (15).
  • at least two compounds are provided to inhibit the RNA virus, wherein the compounds have a synergistic effect in inhibiting the virus. By synergistic is meant greater than an additive effect that each compound has alone in inhibiting the vims.
  • At least one inhibitor of at least one of its two methyltransferases must be inhibited.
  • SAHH hydrolase inhibitors prevent viral mRNA maturation (e.g., 5'-methylated cap structure) by intracellular accumulation of AdoHcy (SAH), leading to a significant increase in the intracellular AdoHcy (SAH)/( SAM) S-adenosylmethionine ratio, and subsequent inhibition of S- adenosylmethionine- dependent methylation reactions (feedback inhibition- see Hasobe, M., McKee, J. G., Borcherding, D. R., & Borchardt, R. T. (1987).
  • a) Identify replication steps of a pathogen.
  • b) For at least one of the schematic steps 1, 2, 3, 4, 5, 6, 7 and 8 listed hereinabove, identify at least one inhibitor with a published and known effective dosage, such as ED50, the effective dose to inhibit 50% of the target pathogen (virus in this case).
  • ED50 effective dosage
  • Some non-limiting examples appear in Table 1 hereinbelow.
  • c) Calculate predicted combination therapy viral load reductions as follows:- i.
  • 2, 3, 4, 5, 6, 7 and 8 (also termed Si, S2...S N herein) calculate, for each candidate dmg/compound/effector/agent, a reduction in the viral load anticipated by that dmg/compound in a given amount. For example, if the 3-DEAZANEPLANOCIN A known ED50 is 2 mM and the EDgo is 4 pM, then the residual viral load after treatment is the initial load No multiplied by the reduction in load.
  • the initial load No of Ebola virus is 10 5 PFU/ml and an effective dose of 3-DEAZANEPLANOCIN is provided such that the in vivo concentration thereof is 2 pM
  • a combination of two drugs working on the same enzyme is combinatory (multiplied).
  • a combination of adenosine 4.2 g/day for 70 kg person provides its ED50
  • 3-DEAZANEPLANOCIN (C3-NPC-A) is used at 4 mM
  • a sum of the combination therapies to be used on that pathway using drugs or products di, d2 to d n ⁇ ⁇ (l-EDxx) dl x (l-EDxx) d2 x((l-EDxx) dn ) ⁇ s 2 ...
  • COVID-19 patients have increased loads of inflammatory cytokines, leading to reduced endothelial barrier integrity.
  • ICY t an initial load of inflammatory cytokines from an initial load ICYo to a final load at time t, ICY t, wherein a ratio of ICYo to ICY t, is sufficiently large to provide the subject with a very high statistical probability to survive the disease.
  • Collagen precursors may also be effective in "plugging the holes" in the endothelial barrier.
  • Table 1 could optionally be optimized using mathematical methods, known in the art to minimize at least one of cost, minimizing the number of drugs, possible drug combination reactions etc.
  • over-the-counter drugs or compounds which are GRAS (generally regarded as safe) should be used to treat the viral disease.
  • Lu et al., (2010) describes a method (prior art) for preventing pulmonary edema of by improving endothelial barrier function, incorporated herein by reference.
  • the methods of the present invention include methods for improving endothelial layer integrity after an SARS-COV-2 virus infection, in accordance with an embodiment of the present invention.
  • SARS-COV-2 virus infection According to published literature viruses infiltrate monocytes forming infected monocytes. Infected monocytes release massive amounts of inflammatory cytokines damaging endothelial cells on a barrier. The endothelial cells die forming dead endothelial cells and inducing vascular shock to the infected organism/host.
  • step 9 providing endothelial cell enhancers/barrier integrity enhancers (see table 1 hereinbelow) and/or providing natural TNFalpha inhibitors to reduce the cytokine load/storm made by the infected monocytes.
  • TNFalpha inhibitors known in the art are, curcumin, fisetin, genistein, resveratrol and capsaicin (see Habtemariam, 2000, incorporated herein by reference).
  • the present invention provides a method for increasing homocysteine in a patient, in accordance with an embodiment of the present invention.
  • S-adenosyl-methionine (SAM) is a cofactor for viral methyltransferase (Huggins et al., 1999).
  • SAM S-adenosyl-methionine
  • any suitable methyltransferase enzyme (EC.2.1.1) inhibitor may be used to reduce the viral load to prevent methylation of the viral RNA, protein, glycoprotein or other viral components.
  • Some non-limiting examples of these enzymes to be inhibited include 2.1.1.10 homocysteine S -methyltransferase, 2.1.1.43 histone-lysine N-methyltransferase and 2.1.1.56 mRNA (guanine-N7-)-methyltransferase.
  • Some non-limiting examples of methyl transferase inhibitors appear in Table 1 hereinbelow.
  • the methyltransferase inhibitor is operative to reduce the viral load inside a mammalian or other host.
  • the inhibitor(s) may be an s- adenosylmethionine (SAM) analog and/or competitive inhibitor of a methyl transferase enzyme, adapted to receive a methyl group from SAM.
  • SAM s- adenosylmethionine
  • One non-limiting example of such a substance is EGCG (epigallocatechin-3 gallate)- see Alemdaroglu et al., 2007 (IC 50 34.8 pmole/l).
  • Harrington et al., 2004 show that homocysteine and adenosine blunt barrier dysfunction and Rho activation.
  • Vitamin C, ornithine and arginine are all documented as being collagen precursors (see table 1 hereinbelow). According to some embodiments, vitamin C is provided in a megadose. It is possible that large doses of vitamin C would be effective in reducing viral loads, too (see Smith, Lendon H., 1988).
  • the SAHH inhibitor may be selected from any SAHH inhibitors known in the art and/or described herein, including DDFA (Huggins et al 1999).
  • the DOT1L inhibitors may include any DOT1L inhibitor, known in the art.
  • the cholesterol lowering agent may be any cholesterol lowering agent, known in the art.
  • Eritadenine is effective in lowering cholesterol (see Enman, J., Rova, U., & Berghmd, K. A. (2007). Quantification of the bioactive compound eritadenine in selected strains of shiitake mushroom (Lentinus edodes). Journal of agricultural and food chemistry, 55(4), 1177-1180.).
  • compositions of the present invention may be provided in any suitable dosage form. These dosage forms may be injectable, infusible, inhalable, edible, oral or combinations thereof, as are known in the art. According to some embodiments, the dosage form is an oral dosage form. Oral dosage forms comprise liquids (solutions, suspensions, and emulsions), semi-solids (pastes), and solids (tablets, capsules, powders, granules, premixes, and medicated blocks).
  • additional methods of administering the compositions of the invention comprise injectable dosage forms.
  • the injectable is administered intraperitoneally.
  • the injectable is administered intramuscularly.
  • the injectable is administered intradermally.
  • the injectable is administered intravenously.
  • compositions are administered by intravenous, intra arterial, or intra-muscular injection of a liquid preparation.
  • suitable liquid formulations include solutions, suspensions, dispersions, emulsions, oils and the like.
  • the compositions are administered intravenously and are thus formulated in a form suitable for intravenous administration.
  • the pharmaceutical compositions are administered intra-arterially and are thus formulated in a form suitable for intra-arterial administration.
  • the compositions are administered intra-muscularly and are thus formulated in a form suitable for intra-muscular administration.
  • the at least one neuro-protective agent is provided in a pharmaceutically effective amount and wherein the at least one neuro-protective agent is selected from the group consisting of; erythropoietin, an erythropoietin derivative, an extract of at least one of; Ginko biloba; Hydrocotyle asiatica, St.
  • the slow release formulation includes at least one of a POLYOXTM, METHOCELTM and ETHOCELTM excipient.
  • the slow release dosage form including a pharmaceutical composition as described herein covered by at least one non-allergenic, non-prolamine polymer layer.
  • the slow release dosage form the dosage form is non allergenic. According to some additional embodiments of the present invention, the slow release dosage form does not comprise animal matter (is vegetarian). According to some additional embodiments of the present invention, the slow release dosage form is kosher.
  • a use of a pharmaceutical composition for the preparation of a medicament suitable for administration to a human in a pharmaceutically effective amount, wherein the medicament is suitable for treating a disease or disorder in the human.
  • the composition is suitable for oral, parenteral, transdermal, intra-venous or intra-muscular administration.
  • the composition is a slow-release composition.
  • the slow release composition is formulated for provision by at least one of an intravenous drip, a trans-dermal device and a slow-release oral formulation.
  • oral dosage forms in the art include, W090/04391, which discloses an oral dosage form of omega-3 polyunsaturated acids to overcome the problems of vascular diseases. It is known to supply said acids in soft gelatine capsule shells.
  • EP 2 240 581 B1 discloses a gelatine capsule for pharmaceutical use with a controlled release of active ingredients and a process for the preparation of said gelatine capsules. During said process xylose is added to the liquid gelatine from which afterwards gelatine capsules are formed. Gelatine capsules manufactured according to the process provide retarded release of active ingredients.
  • US Patent No. 7,264,824 discloses and oral dosage form for food and food supplements, as well as dietetics comprising polyunsaturated acids in a xylose-hardened gelatine capsule with a retarded release time.
  • the compositions described herein may be in a suspension or emulsion.
  • a suspension is a coarse dispersion of insoluble drug particles, generally with a diameter exceeding 1 pm, in a liquid (usually aqueous) medium.
  • Suspensions are useful for administering insoluble or poorly soluble drugs/components or in situations when the presence of a finely divided form of the material in the GI tract is required.
  • the taste of most drugs is less noticeable in suspension than in solution, due to the drug being less soluble in suspension.
  • Particle size is an important determinant of the dissolution rate and bioavailability of drugs in suspension.
  • suspensions include surfactants and thickening agents. Surfactants wet the solid particles, thereby ensuring the particles disperse readily throughout the liquid. Thickening agents reduce the rate at which particles settle to the bottom of the container. Some settling is acceptable, provided the sediment can be readily dispersed when the container is shaken. Because hard masses of sediment do not satisfy this criterion, caking of suspensions is not acceptable.
  • An emulsion is a system consisting of 2 immiscible liquid phases, one of which is dispersed throughout the other in the form of fine droplets; droplet diameter generally ranges from 0.1-100 pm.
  • the 2 phases of an emulsion are known as the dispersed phase and the continuous phase.
  • Emulsions are inherently unstable and are stabilized through the use of an emulsifying agent, which prevents coalescence of the dispersed droplets. Creaming, as occurs with milk, also occurs with pharmaceutical emulsions. However, it is not a serious problem because a uniform dispersion returns upon shaking. Creaming is, nonetheless, undesirable because it is associated with an increased likelihood of the droplets coalescing and the emulsion breaking.
  • Other additives include buffers, antioxidants, and preservatives.
  • Emulsions for oral administration are usually oil (the active ingredient) in water, and facilitate the administration of oily substances such as castor oil or liquid paraffin in a more palatable form.
  • a paste is a 2-component semi-solid in which drug is dispersed as a powder in an aqueous or fatty base.
  • the particle size of the active ingredient in pastes can be as large as 100 pm.
  • the vehicle containing the drug may be water; a polyhydroxy liquid such as glycerin, propylene glycol, or polyethylene glycol; a vegetable oil; or a mineral oil.
  • Other formulation excipients include thickening agents, cosolvents, adsorbents, humectants, and preservatives.
  • the thickening agent may be a naturally occurring material such as acacia or tragacanth, or a synthetic or chemically modified derivative such as xanthum gum or hydroxypropylmethyl cellulose.
  • the degree of cohesiveness, plasticity, and syringeability of pastes is attributed to the thickening agent. It may be necessary to include a cosolvent to increase the solubility of the drug. Syneresis of pastes is a form of instability in which the solid and liquid components of the formulation separate over time; it is prevented by including an adsorbent such as microcrystalline cellulose. A humectant (eg, glycerin or propylene glycol) is used to prevent the paste that collects at the nozzle of the dispenser from forming a hard crust. Microbial growth in the formulation is inhibited using a preservative. It is critical that pastes have a pleasant taste or are tasteless.
  • a tablet consists of one or more active ingredients and numerous excipients and may be a conventional tablet that is swallowed whole, a chewable tablet, or a modified-release tablet (more commonly referred to as a modified-release bolus due to its large unit size).
  • Conventional and chewable tablets are used to administer drugs to dogs and cats, whereas modified-release boluses are administered to cattle, sheep, and goats.
  • the physical and chemical stability of tablets is generally better than that of liquid dosage forms.
  • the main disadvantages of tablets are the bioavailability of poorly water-soluble drugs or poorly absorbed drugs, and the local irritation of the GI mucosa that some drugs may cause.
  • a capsule is an oral dosage form usually made from gelatin and filled with an active ingredient and excipients.
  • Two common capsule types are available: hard gelatin capsules for solid-fill formulations, and soft gelatin capsules for liquid-fill or semi- solid-fill formulations.
  • Soft gelatin capsules are suitable for formulating poorly water-soluble drugs because they afford good drug release and absorption by the GI tract.
  • Gelatin capsules are frequently more expensive than tablets but have some advantages. For example, particle size is rarely altered during capsule manufacture, and capsules mask the taste and odor of the active ingredient and protect photolabile ingredients.
  • a powder is a formulation in which a drug powder is mixed with other powdered excipients to produce a final product for oral administration.
  • Powders have better chemical stability than liquids and dissolve faster than tablets or capsules because disintegration is not an issue. This translates into faster absorption for those drugs characterized by dissolution rate-limited absorption. Unpleasant tastes can be more pronounced with powders than with other dosage forms and can be a particular concern with in-feed powders, in which it contributes to variable ingestion of the dose. Moreover, sick animals often eat less and are therefore not amenable to treatment with in-feed powder formulations.
  • Drug powders are principally used prophylactically in feed, or formulated as a soluble powder for addition to drinking water or milk replacer. Powders have also been formulated with emulsifying agents to facilitate their administration as liquid drenches.
  • a granule is a dosage form consisting of powder particles that have been aggregated to form a larger mass, usually 2-4 mm in diameter. Granulation overcomes segregation of the different particle sizes during storage and/or dose administration, the latter being a potential source of inaccurate dosing. Granules and powders generally behave similarly; however, granules must deaggregate prior to dissolution and absorption.
  • a premix is a solid dosage form in which an active ingredient, such as a coccidiostat, production enhancer, or nutritional supplement, is formulated with excipients.
  • Premix products are mixed homogeneously with feed at rates (when expressed on an active ingredient basis) that range from a few milligrams to -200 g/ton of food/beverage
  • the density, particle size, and geometry of the premix particles should match as closely as possible those of the feed in which the premix will be incorporated to facilitate uniform mixing. Issues such as instability, electrostatic charge, and hygroscopicity must also be addressed.
  • the excipients present in premix formulations include carriers, liquid binders, diluents, anti-caking agents, and anti- dust agents.
  • Carriers such as wheat middlings, soybean mill run, and rice hulls, bind active ingredients to their surfaces and are important in attaining uniform mixing of the active ingredient.
  • a liquid binding agent such as a vegetable oil, should be included in the formulation whenever a carrier is used.
  • Diluents increase the bulk of premix formulations, but unlike carriers, do not bind the active ingredients. Examples of diluents include ground limestone, dicalcium phosphate, dextrose, and kaolin.
  • Caking in a premix formulation may be caused by hygroscopic ingredients and is addressed by adding small amounts of anti-caking agents such as calcium silicate, silicon dioxide, and hydrophobic starch.
  • the dust associated with powdered premix formulations can have serious implications for both operator safety and economic losses, and is reduced by including a vegetable oil or light mineral oil in the formulation. An alternate approach to overcoming dust is to granulate the premix formulation.
  • a medicated block is a compressed feed material that contains an active ingredient, such as a drug, anthelmintic, surfactant (for bloat prevention), or a nutritional supplement, and is commonly packaged in a cardboard box. Ruminants typically have free access to the medicated block over several days, and variable consumption may be problematic. This concern is addressed by ensuring the active ingredient is nontoxic, stable, palatable, and preferably of low solubility.
  • excipients in the formulation modulate consumption by altering the palatability and/or the hardness of the medicated block. For example, molasses increases palatability and sodium chloride decreases it.
  • a binder such as lignin sulfonate
  • the hygroscopic nature of molasses in a formulation may also impact the hardness of medicated blocks and is addressed by using appropriate packaging.
  • the composition of the present invention is in a chewable oral dosage form.
  • the chewable oral dosage form is a chewable tablet.
  • the chewable tablet of the invention is taken slowly by chewing or sucking in the mouth.
  • the chewable tablet of the invention enables the vitamins contained therein to be orally administered without drinking.
  • the composition further comprises fructose, sorbitol, microcrystalline cellulose, magnesium stearate, or any combination thereof.
  • the composition further comprises chamomile.
  • the composition further comprises ginger.
  • the composition further comprises peppermint.
  • the composition further comprises anise.
  • the composition of the present invention is in the form of a chewing gum product.
  • chewing gum compositions contemplated by the present invention comprise all types of sugar and sugarless chewing gums and chewing gum formulations known to those skilled in the art, including regular and bubble gum types.
  • chewing gum compositions of the invention comprise a chewing gum base, a modifier, a bulking agent or sweetener, and one or more other additives such as, flavoring agents, colorants and antioxidants.
  • the modifying agents are used to soften, plasticize and/or compatibilize one or more of the components of the gum base and/or of the formulation as a whole.
  • the present invention provides a soft, chewable dosage form which is pliable and chewy, yet dissolves quickly in the mouth, has a long shelf life, contains little moisture which improves stability and decreases the tendency for the dosage form to dry out, does not require cooking or heating as part of the manufacturing process.
  • the dosage form is used as a matrix for vitamins.
  • the chewable tablet of the invention comprises a metal salt such as calcium, magnesium, aluminum salt, or any mixture thereof.
  • the chewable tablet of the invention comprises hydroxyalkyl cellulose.
  • the chewable tablet of the invention comprises low viscosity hydroxyalkyl cellulose.
  • the chewable tablet of the invention comprises high viscosity hydroxyalkyl cellulose.
  • the chewable tablet of the invention comprises various additives. In another embodiment, the chewable tablet of the invention comprises sweeteners. In another embodiment, the chewable tablet of the invention comprises acidic ingredients. In another embodiment, the chewable tablet of the invention comprises taste correctives. In another embodiment, the chewable tablet of the invention comprises polymeric compounds. In another embodiment, the chewable tablet of the invention comprises essential oils.
  • the chewable tablet of the invention is a soft tablet. In another embodiment, the chewable tablet of the invention is made in a state of soft candy. In another embodiment, the chewable tablet of the invention is made in a state of jelly.
  • the chewable tablet of the invention comprises a core comprising the vitamins of the invention.
  • the chewable tablet of the invention comprises an outer layer wrapping the core which is made up of chewable base such as a gum, a soft candy or a caramel.
  • sugar used in the present invention may be selected from the group consisting of white sugar, liquid glucose, sorbitol, dextrose, isomalt, liquid maltitol, aspartame and lactose, and this sugar may comprise 30-90 weight % by total weight of the ingredients.
  • the chewable tablet of the invention comprises a sweetener such as but not limited to: glucose (com syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as suralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like.
  • a sweetener such as but not limited to: glucose (com syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside
  • glycerin, lecithin, hydrogenated palm oil or glyceryl monostearate are used as a protecting agent of crystallization of the sugars in 0.02-3.0 weight % by total weight of the ingredients, to prevent adhesion to oral cavity and improve the soft property of the products.
  • isomalt or liquid maltitol are used as an enhancing agent of chewing property.
  • gelatin or arabic gum are used as a keeping agent of hardness and extension property in 0.1-3.0 weight % by total weight of the ingredients.
  • food flavor or a fruits extract; a souring agent such as citric acid are added in adequate amount.
  • a coloring agent such as a food color is optionally added in a small amount.
  • Yet a further embodiment of the present invention includes the use of an effervescent disintegration agent.
  • its action aids in the masking of objectionable taste of the vitamins.
  • the effervescent disintegration agent is an acid. In another embodiment, of the present invention the effervescent disintegration agent is citric acid. In another embodiment, of the present invention the effervescent disintegration agent is tartaric acid.
  • the chewable tablet of the invention comprises a crystallization modifier such but not limited to, surfactants (Spans. TM. and Tweens. TM.), dextrose, polyethylene glycol (PEG), polypropylene glycol (PPG), etc. These modifiers generally provide controlled acceleration of crystallization while the matrix is bound. In another embodiment, these crystallization modifiers enhance the formation of a crystalline frame and the conversion of the remaining mass.
  • a crystallization modifier such but not limited to, surfactants (Spans. TM. and Tweens. TM.), dextrose, polyethylene glycol (PEG), polypropylene glycol (PPG), etc.
  • these modifiers generally provide controlled acceleration of crystallization while the matrix is bound.
  • these crystallization modifiers enhance the formation of a crystalline frame and the conversion of the remaining mass.
  • crystallization modifiers are surfactants having a hydrophilic to lipid balance (HLB) of six or greater, i.e., they have the same degree of hydrophilicity as surfactants characterized by degree of HLB .
  • such materials include, but are not limited to anionic, cationic and zwitterionic surfactants as well as neutral materials which have an HLB of six or greater.
  • crystallization modifiers are hydrophilic materials having polyethylene oxide linkages.
  • crystallization modifiers have a molecular weight of at least 100.
  • the chewable tablet of the invention comprises a filler. In another embodiment, filler increases the bulk of the tablet.
  • the filler is calcium sulfate, both di- and tri basic, starch, calcium carbonate, microcrystalline cellulose, modified starches, lactose, sucrose, mannitol, sorbitol, or any combination thereof.
  • the chewable tablet of the invention comprises a binder such as but not limited to: starches, pregelatinize starches, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols.
  • the chewable tablet of the invention comprises a lubricant such as but not limited to: magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene, monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate and light mineral oil.
  • a lubricant such as but not limited to: magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene, monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate and light mineral oil.
  • the chewable tablet of the invention comprises a dispersion enhancer such as but not limited to: starch, alginic acid, polyvinylpyrrolidones, guar gum, partially hydrolyzed guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.
  • a dispersion enhancer such as but not limited to: starch, alginic acid, polyvinylpyrrolidones, guar gum, partially hydrolyzed guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.
  • the chewable tablet of the invention comprises an absorbent such as but not limited to: maltodextrin.
  • the chewable tablet of the invention comprises an emulsifier such as but not limited to: Mono- and diglycerides, Oleaginous substances such as food oils like Medium, Chain Triglycerides (MCT), and Stearine D 17.
  • the chewable tablet of the invention comprises a water soluble bulking agent such as but not limited to: hydrocolloid thickeners and binders, such as gum arabic, pectins, modified starches, alginates, carrageenans, xanthan gums, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, propylene glycol alginate, polyvinylpyrrolidone (PVP), carboxyvinyl polymers (such as Carbopol.RTM.), polyethylene oxide polymers (such as Polyox. RTM.), sorbitol, xylitol, sucrose, fructose, dextrose, mannitol, starch maltodextrin, com syrup solids, or combinations thereof.
  • hydrocolloid thickeners and binders such as gum arabic, pectins, modified starches, alginates, carrageenans, xanthan gums, carboxymethylcellulose
  • the chewable tablet of the invention comprises a water insoluble bulking agent such as but not limited to: talc, dicalcium phosphate, powdered celluloses, microcrystalline celluloses and antacid compounds.
  • the chewable tablet of the invention comprises vitamins in compressed particles.
  • individual particles are coated with a blend of cellulose acetate or cellulose acetate butyrate and polyvinyl pyrrolidone (USP Povidone or "PVP").
  • the coating provides excellent taste masking while still permitting acceptable bioavailability of the vitamins.
  • the chew able tablet of the invention comprises a water insoluble bulking agent such as but not limited to: talc, dicalcium phosphate, powdered celluloses, microcrystalline celluloses and antacid compounds.
  • the chewable tablet of the invention comprises vitamins in compressed particles.
  • individual particles are coated with a blend of cellulose acetate or cellulose acetate butyrate and polyvinyl pyrrolidone (USP Povidone or "PVP
  • the invention relates to a composition of the invention comprised within chewable and edible soft gelatin capsules, the shells of which comprise gelatin, water, plasticizer and a hydrogenated starch hydrolysate.
  • soft gelatin shell comprises about 10-45% gelatin; about 5-30% water; about 12-35% plasticizer; and about 2-25% of a hydrogenated starch hydrolysate.
  • the shell encloses a soft gelatin capsule fill material.
  • the gelatin may be of Type A, Type B, or a mixture thereof.
  • the present capsule shell further comprises a hydrogenated starch hydrolysate.
  • compositions and dosage forms of the present invention are useful in promoting health and preventing or treating a large number of disorders in human patients and other mammalian subjects.
  • compositions and methods are provided for treating and/or preventing heart disease, such as, but not limited to, atherosclerotic and hypertensive diseases, congenital heart disease, rheumatic heart disease, and other conditions.
  • compositions and methods are provided for treating and/or preventing peripheral blood vessel disorders.
  • Peripheral blood vessel disorders affect the blood vessels of the arms, legs, and trunk (except those supplying the heart). These disorders include disorders of the blood vessels supplying the brain, namely cerebrovascular disorders.
  • compositions and methods are provided for treating and/or preventing blood disorders, disorders of nutrition or metabolism, hormonal disorders, bone, joint or muscle disorders, spinal cord or nervous disorders, immunological disorders, infectious disorders, urinary tract and kidney disorders, or skin disorders, vitamin deficiencies and other nutritional disorders, lung or airway disorders, digestive disorders, or reproductive disorders.
  • compositions may be provided to the subject in an oral dosage form.
  • the oral dosage form includes a capsule.
  • the oral dosage form may be chewable.
  • the oral dosage form may further comprise at least one of fructose, sorbitol, microcrystalline cellulose, magnesium stearate, or a combination thereof.
  • the oral dosage form includes at least one additional antioxidant.
  • the oral dosage form may also include additional agents and components.
  • compositions of the present invention may comprise an additional active agent.
  • the additional active agent is selected from the group consisting of active herbal extracts, acaricides, age spot and keratose removing agents, allergen, analgesics, local anesthetics, antiacne agents, antiallergic agents, antiaging agents, antibacterials, antibiotic agents, antibum agents, anticancer agents, antidandmff agents, antidepressants, antidermatitis agents, antiedemics, antihistamines, antihelminths, antihyperkeratolyte agents, antiinflammatory agents, antiirritants, antilipemics, antimicrobials, antimycotics, antiproliferative agents, antioxidants, anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosacea agents antiseborrheic agents, antiseptic, antiswelling agents, antiviral agents, anti-yeast agents, astringents, topical cardiovascular agents, chemotherapeutic
  • the antibiotic agent is selected from the group consisting of beta-lactam antibiotics, aminoglycosides, ansa-type antibiotics, anthraquinones, antibiotic azoles, antibiotic glycopeptides, macrolides, antibiotic nucleosides, antibiotic peptides, antibiotic polyenes, antibiotic polyethers, quinolones, antibiotic steroids, sulfonamides, tetracycline, dicarboxylic acids, antibiotic metals including antibiotic metal ions, oxidizing agents, substances that release free radicals and/or active oxygen, cationic antimicrobial agents, quaternary ammonium compounds, biguanides, triguanides, bisbiguanides and analogs and polymers thereof, naturally occurring antibiotic compounds, including antibiotic plant oils and antibiotic plant extracts and any one of the following antibiotic compounds: chlorhexidine acetate, chlorhexidine gluconate and chlorhexidine hydrochloride, picloxydine, alexidine, polihexanide, chlorproguanil hydroch
  • the additional active agent is selected from the group consisting of alclometasone dipropionate, amcinafel, amcinafide, amcinonide, beclomethasone, beclomethasone dipropionate, betamethsone, betamethasone benzoate, betamethasone dexamethasone -phosphate, dipropionate, betamethasone valerate, budesonide, chloroprednisone, chlorprednisone acetate, clescinolone, clobetasol, clobetasol propionate, clobetasol valerate, clobetasone, clobetasone butyrate, clocortelone, cortisone, cortodoxone, craposone butyrate, desonide, desoxymethasone, dexamethasone, desoxycorticosterone acetate, dichlorisone, diflorasone diacetate, diflucortolone valerate,
  • compositions of the present invention comprise a metal salt such as calcium, magnesium, zinc, selenium, copper, vanadium, chromium, iron, aluminum salt, or any mixture thereof.
  • the compositions of the present invention further comprise a buffering agent.
  • the buffering agent can be any of the known buffering systems used in pharmaceutical or cosmetic formulations as would be appreciated by a man of the art. It can also be an organic acid, a carboxylic acid, a fatty acid an amino acid, an aromatic acid, an alpha or beta hydroxyl acid an organic base or a nitrogen containing compound.
  • compositions of the present invention further comprise a pH modulating agent.
  • pH modulating agent is used to describe an agent which can effect pH in an aqueous solution the term modulating agent more particularly means an acid or base or buffer system or combinations thereof, which is introduced into or is present in and acts to modulate the ionic or polar characteristics and any acidity or basicity balance of a composition,.
  • compositions of the present invention further comprise an antiviral agent
  • Suitable antiviral agents include but are not limited to, acyclovir, gancyclovir, ribavirin, amantadine, rimantadine nucleoside-analog reverse transcriptase inhibitors, such as zidovudine, didanosine, zalcitabine, tavudine, lamivudine and vidarabine, non-nucleoside reverse transcriptase inhibitors, such as nevirapine and delavirdine, protease inhibitors, such as saquinavir, ritonavir, indinavir and nelfinavir, and interferons and derivatives, esters, salts and mixtures thereof.
  • compositions of the present invention further comprise a chemotherapeutic agent.
  • chemotherapeutic agents include but are not limited to daunorubicin, doxorubicin, idambicin, ammbicin, pirambicin, epirubicin, mitoxantrone, etoposide, teniposide, vinblastine, vincristine, mitomycin C, 5-FU, paclitaxel, docetaxel, actinomycin D, colchicine, topotecan, irinotecan, gemcitabine cyclosporin, verapamil, valspodor, probenecid, MK571, GF120918, LY335979, biricodar, terfenadine, quinidine, pervilleine A, XR9576 and derivatives, esters, salts and mixtures thereof.
  • compositions of the present invention further comprise a corticosteroid.
  • Suitable corticosteroids include but are not limited to alclometasone dipropionate, amcinafel, amcinafide, amcinonide, beclomethasone, beclomethasone dipropionate, betamethsone, betamethasone benzoate, betamethasone dexamethasone-phosphate, dipropionate, betamethasone valerate, budesonide, chloroprednisone, chlorprednisone acetate, clescinolone, clobetasol, clobetasol propionate, clobetasol valerate, clobetasone, clobetasone butyrate, clocortelone, cortisone, cortodoxone, craposone butyrate, desonide, desoxymethasone, dexamethasone, desoxycorticosterone acetate, dichlorisone, diflor
  • -methyl dexamethasone methylprednisolone, methylprednisolone acetate, mometasone furoate, paramethasone, prednisolone, prednisone, pregnenolone, progesterone, spironolactone, triamcinolone, triamcinolone acetonide and derivatives, esters, salts and mixtures thereof.
  • compositions of the present invention further comprise an analgesic.
  • analgesics include but are not limited to benzocaine, butamben picrate, dibucaine, dimethisoquin, dyclonine, lidocaine, pramoxine, tetracaine, salicylates and derivatives, esters, salts and mixtures thereof.
  • compositions of the present invention further comprise a non-steroidal anti-inflammatory agent.
  • Suitable non-steroidal anti-inflammatory agent include but are not limited to azelaic acid, oxicams, piroxicam, isoxicam, tenoxicam, sudoxicam, CP- 14,304, salicylates, aspirin, disalcid, benorylate, trilisate, safapryn, solprin, difhmisal, fendosal, acetic acid derivatives, diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, ketorolac, fenamates, mefenamic, meclofenamic, flu
  • compositions of the present invention further comprise a vasodilator.
  • Suitable vasodilators include but are not limited to agents that modulate the activity of the enzyme nitric oxide synthase, nicotinic acid, ethyl nicotinate, amyl nitrite, amyl nitrate, ethyl nitrite, butyl nitrite, isobutyl nitrite, glyceryl trinitrate, octyl nitrite, sodium nitrite, sodium nitroprusside, clonitrate, erythrityl tetranitrate, isosorbide mononitrate, isosorbide dinitrate, mannitol hexanitrate, pentaerythritol tetranitrate, penetrinitol, triethanolamine trinitrate, trolnitrate phosphate (triethanolamine trinitrate diphosphate),
  • compositions of the present invention further comprise a vasoconstrictor.
  • Suitable vasodilators include but are not limited to ephedrine, epinephrine, phenylephrine, angiotensin, vasopressin; an extract ephedra sinica (ma huang), polygonum bistorta (bistort root), hamamelis virginiana (witch hazel), hydrastis canadensis (goldenseal), lycopus virginicus (bugleweed), aspidosperma quebracho (quebracho bianco), cytisus scoparius (scotch broom) and cypressand and derivatives, esters, salts and mixtures thereof.
  • Vitamin C may be produced according to any method known in the art today or by any future method.
  • the vitamin C may be from a natural source, semi- synthetic source, synthetic source or combinations thereof. It may be extracted from one or more animal or vegetable sources, produced by fermentation, chemically synthesized or modified, or any combination of the aforesaid.
  • vitamin C comprises the L-enantiomer of ascorbate.
  • vitamin C is provided as calcium ascorbate, which is non-acidic (pH neutral), making it gentle on the digestive system.
  • curcumin and EGCG are known to act synergistically in other models (Khafif et ah, 1998) and these compounds are active in several metabolic pathways. Thus, this kind of therapy could move this person from the fatality risk group into the survivors' group.
  • curcumin and EGCG are known to act synergistically in other models (Khafif et ah, 1998) and these compounds are active in several metabolic pathways. Thus, this kind of therapy could move this person from the fatality risk group into the survivors' group.
  • curcumin and EGCG are known to act synergistically in other models (Khafif et ah, 1998) and these compounds are active in several metabolic pathways.
  • this kind of therapy could move this person from the fatality risk group into the survivors' group.
  • a 30 year old male (70 kg) suffering from COVID-19 has had a fever for seven days and has profuse internal bleeding and skin lesions.
  • a blood test is positive for Ebola and he has a virus count of 10 10 PFU/ml (putting him into a fatality risk group).
  • a 30 year old male (70 kg) suffering from COVID-19 has had a fever for seven days and has profuse internal bleeding and skin lesions. He has a virus count of 10 10 PFU/ml (putting him into a fatality risk group).
  • Example 8 might be appropriate for use in pregnant women, too (but adjusted to the weight of the subject).
  • a six-month old male baby (7 kg) suffering from EVD (Ebola virus disease) has had a fever for four days and is listless.
  • a blood test is positive for Ebola and he has a virus count of 10 PFU/ml (putting him into a fatality risk group).
  • a six-month old male baby (7 kg) suffering from EVD (Ebola virus disease) has had a fever for four days and is listless.
  • a blood test is positive for Ebola and he has a vims count of 10 PFU/ml (putting him into a fatality risk group).
  • Example 11 Analysis of in vitro and in vivo neutralizing activity of different compounds against a virus such as Ebola virus:
  • plaque reduction neutralization assays PRNT80
  • a concentrated compound or cocktail of compounds
  • Ebolavirus Sudan Gulu 100 plaque-forming units of Ebolavirus Sudan Gulu at 37°C for 1 hour in the presence and absence of 5% guinea pig complement (Cedarlane) and used to infect Vero cell monolayers.
  • Cells are overlaid with agarose and a second overlay containing 5% neutral red is added 8 days later. Plaques are counted the next day.
  • Neutralization titers are determined to be the last dilution of serum that reduced the number of plaques by 80% compared with control wells. The experiments were repeated six times.
  • Example 12 Analysis of in vitro and neutralizing activity of different compounds against a corona virus:
  • compositions comprising eritadenine were prepared in a solvent, such as water, ethanol and DMSO.
  • a solvent such as water, ethanol and DMSO.
  • the range of the eritadenine concentration was from 1 nanomolar to 100 millimolar. It was found that non-pathogenic coronavims was inhibited at a concentration of 10 nanomolar up to 100 inhibition atlOO micromolar.
  • the IC50 was around 30-60 nM.
  • these cocktails may be provided in one or two mixed compositions, or some compounds may be provided separately. Additionally, according to some embodiments, the dosage regimes may be spread over 12 or over 24 hours, as is known in the art.
  • Cell Titer Glo Assay (luminescence assay) a. Thaw the CellTiter-Glo® Buffer, and equilibrate to room temperature prior to use. b. The CellTiter-Glo® Buffer may be stored at 4°C for up to 48 hours prior to use. c. Equilibrate the lyophilized CellTiter-Glo® Substrate to room temperature prior to use d. Transfer 10ml of CellTiter-Glo® Buffer into the amber bottle containing CellTiter-Glo® Substrate to reconstitute the lyophilized enzyme/substrate mixture. e. This forms the CellTiter-Glo® Reagent. f.
  • HSPA5 is an essential host factor for Ebola virus infection.

Abstract

The present invention provides compounds and a pharmaceutical composition for inhibiting an RNA virus causing a viral disease in a mammalian subject, the c pharmaceutical composition comprising at least two of a cholesterol-lowering compound, a methyltransferase inhibitor, a viral enzyme inhibitor, an SAHH (s-adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor, wherein the effect of the at least two compounds synergistically inhibits the RNA virus.

Description

PHARMACEUTICAL COMPOSITIONS FOR TREATING CORONA VIRUS
DISEASE
FIELD OF THE INVENTION
The present invention relates generally, to pharmaceutical compositions for treating a viral disease and more specifically to pharmaceutical compositions for treating a coronavims disease.
BACKGROUND OF THE INVENTION
There are several viral disease which have no or limited treatment options. Corona vims, Ebola vims, Marburg vims, Dengue vims are viruses with poor primate and/or human survival statistics. Many other viruses may be fatal, particularly in young children, the elderly or immunocompromised patients.
To date, most research groups are looking for a "one dmg treatment" or "perfect fit immunological solution" such as a vaccine or monoclonal antibody.
RNA vims families include, inter alia , Coronaviridae Arenaviridae, Filoviridae, Bunyaviridae, Flaviviridae, and Rhabdoviridae. There is currently a coronavims SARS- COV-2 pandemic. There have previously been SARSs and MERS coronavims epidemics. There have also been various endemic viral diseases in West Africa, such as Dengue, Ebola, Lassa, CCHF and others. There are no known dmgs or cures, which have been FDA approved, and/or tested properly in humans.
There is currently a Corona vims (SARS-COV-2) pandemic in China and more than 200 other countries. The limited published data on this vims suggests that it is a single- stranded positive-sense RNA vims (size ranging from 26 to 32 kB, Li el al., 2020) comprising 24 proteins (Appendix 1). SARS-COV-2 (previously called 2019-NCoV, causing the disease termed COVID-19) comprises several enzymes, which could be used as targets for inhibition, including, a papain-like protease (3), a proteinase (5), an RNA- directed RNA polymerase (11), a helicase, (12), a guanine-N7 methyltransferase (13), a uridylate- specific endoribonuclease (14) and a 2-O-methyl transferase (15). Thus, it would appear that there are only 7 enzyme targets, of which two are methyltransferases and two are proteases/proteinases.
The Corona virus spreads easily and has human-human transmission, with an apparently low (2-3%) death rate (Chan et al, 2020). Chan et al. (2020) demonstrated that older patients have increased inflammatory markers (CRP), increased anaerobic respiration (high LDH), reduced platelet count (Table 1). The older patients exhibited multifocal patchy ground-glass opacities in their lungs. Chan et al. (2020) further analyzed the phylogenic trees of genetic sequences of 2019-nCoV from the patients and found very high nucleotide identity between the patients, as well as being close to SARS-related coronavims (Fig. 3).
Chen et al., 2009, described a cap N7 methyltransferase in the SARS coronavims. Bouvet et al., 2010, demonstrated an additional methyltransferase in the SARS coronavims, namely a 2-O-methyl transferase. Thus, it is understood that both the SARS coronavims and SARS-COV-2= 2019-NCoV possess these two methyltransferases.
Chen et al., 2013, and his group at Wuhan University School of Medicine, went on to demonstrate that Coronavimses possess a cap structure at the 5= ends of viral genomic RNA and subgenomic RNAs, which is generated through consecutive methylations by virally encoded guanine-N7-methyltransferase (N7-MTase) and 2=-0- methyltransferase (2=-OMTase). The coronaviral N7-MTase is unique for its physical linkage with an exoribonuclease (ExoN) harbored in nonstmctural protein 14 (nspl4) of coronavimses. In this study, they showed the structure-function relationships of the N7- MTase were analyzed by deletion and site-directed mutagenesis of severe acute respiratory syndrome coronavims (SARS-CoV) nspl4. The results showed that the ExoN domain is closely involved in the activity of the N7-MTase, suggesting that coronavims N7-MTase is different from all other viral N7-MTases, which are separable from other structural domains located in the same polypeptide.
Two of the 12 critical residues identified to be essential for the N7-MTase were located at the N terminus of the core ExoN domain, reinforcing a role of the ExoN domain in the N7-MTase activity of nspl4. The other 10 critical residues were distributed throughout the N7-MTase domain but localized mainly in the S-adenosyl-L-methionine (SAM)-binding pocket and key structural elements of the MTase fold of nspl4. The sequence motif DxGxPxA (amino acids [aa] 331 to 338) was identified as the key part of the SAM binding site. These results provide insights into the structure and functional mechanisms of coronaviral nspl4 N7-MTase.
Currently, there is no vaccine for SARS-COV-2, nor any known effective and safe drug therapy. Moreover, it is not certain that there is only one strain of 2019-NCoV, or if SARs- like or MERs- like strains are active within the current pandemic.
There is thus an unmet need for broad- spectrum antiviral therapies, which are active specifically against the current Corona virus (SARS-COV-2) pandemic. It would be "nice- to-have" a treatment that was effective against all corona viruses, even if they mutate.
It would be further advantageous if the treatment was one or more small molecules, which worked at a mechanistic level, such as inhibition of one or more viral enzymes. Thus, if a broad- spectrum anti-corona antibiotic is developed, it is possible that it will also be effective against other pathogenic viruses, such as Ebola, HIV, Marburg, Lassa and Dengue. There therefore remains an urgent need to find reliable methods for predicting, diagnosing and effective products for treating viral diseases. These products should be adapted to treating a number of strains of the same virus. Additionally, they should be "broad spectrum" and be useful in treating viruses, whose identity is not known, genetic variants of known viral strains and mutated viral strains. There is an unmet need to provide pharmaceutical compositions, suitable for treating
RNA virus-induced human diseases.
SUMMARY OF THE INVENTION
Some embodiments of the present invention are directed to the treatment of disorders and diseases. More particularly, the disorders and diseases may be of an unknown cause, or they may be viral disorders and diseases.
There is thus provided according to an embodiment of the present invention, a pharmaceutical composition for treating COVID-19, the composition comprising at least one of a cholesterol-lowering compound, an SAHH (s-adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor.
There is thus provided according to another embodiment of the present invention, a pharmaceutical composition for treating COVID-19, the composition comprising at least two of a cholesterol-lowering compound, an SAHH (s-adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor.
There is thus provided according to another embodiment of the present invention, a synergistic pharmaceutical composition for treating a viral disease, the composition comprising at least two of a cholesterol-lowering compound, an SAHH (s- adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor, wherein the effect of the at least two compounds synergistically inhibits the virus.
There is thus provided according to another embodiment of the present invention, a synergistic pharmaceutical composition for inhibiting an RNA virus, the composition comprising at least two of a cholesterol-lowering compound, an SAHH (s- adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor, wherein the effect of the at least two compounds synergistically inhibits the RNA virus.
There is thus provided according to another embodiment of the present invention, a synergistic pharmaceutical composition for inhibiting a corona virus, the composition comprising at least two of a cholesterol-lowering compound, an SAHH (s- adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor, wherein the effect of the at least two compounds synergistically inhibits the corona virus.
There is thus provided according to another embodiment of the present invention, a synergistic pharmaceutical composition for inhibiting a SARS COV-2 vims, the composition comprising at least two of a cholesterol-lowering compound, an SAHH (s- adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor, wherein the effect of the at least two compounds synergistically inhibits the SARS COV-2 virus.
There is thus provided according to another embodiment of the present invention, a pharmaceutical composition for treating COVID-19, the composition comprising a cholesterol-lowering compound, an SAHH (s-adenosylhomocysteine hydrolase) inhibitor and a DOTH inhibitor.
Additionally, according to an embodiment of the present invention, the pharmaceutical composition is a "generally-regarded-as-safe" (GRAS) composition.
Furthermore, according to an embodiment of the present invention, the cholesterol lowering compound is eritadenine.
Further, according to an embodiment of the present invention, the SAHH inhibitor is selected from inosine, an inosine analog or an inosine derivative.
Additionally, according to an embodiment of the present invention, the RNA vims is SARS-COV-2 virus.
Furthermore, according to an embodiment of the present invention, the DOTH inhibitor is EPZ5676.
Moreover, according to an embodiment of the present invention, there is provided a pharmaceutical composition including at least one compound as described herein.
Additionally, according to an embodiment of the present invention, the pharmaceutical composition includes two compounds.
Importantly, according to an embodiment of the present invention, the pharmaceutical composition includes an SAHH inhibitor and a DOT1L inhibitor.
Further importantly, according to an embodiment of the present invention, the pharmaceutical composition includes CAC3ADO and EPZ5676.
Yet further importantly, according to an embodiment of the present invention, the pharmaceutical composition includes DDFA and EPZ5676.
Yet further, according to an embodiment of the present invention, the pharmaceutical composition includes DDFA and SGC 0946.
Additionally, further, according to an embodiment of the present invention, the pharmaceutical composition includes DDFA and EPZ004777.
Additionally, further, according to an embodiment of the present invention, the pharmaceutical composition includes CAC3ADO and SGC 0946.
Moreover, according to an embodiment of the present invention, the vims is SARS- COV-2 virus.
Notably, according to an embodiment of the present invention, the pathogenic disease is a pathogenic disease.
Additionally, according to an embodiment of the present invention, the pharmaceutical composition further includes at least one a-glucosidase inhibitor. Additionally, according to an embodiment of the present invention, the pharmaceutical composition further includes at least one cathepsin B inhibitor.
Yet further, according to an embodiment of the present invention, the pharmaceutical composition further includes at least one endothelial barrier enhancer.
Additionally, according to an embodiment of the present invention, the pharmaceutical composition further includes at least one TNF alpha inhibitor.
Moreover, according to an embodiment of the present invention, the pharmaceutical composition further includes at least one collagen precursor.
Furthermore, according to an embodiment of the present invention, the pharmaceutical composition further includes at least one folate remover.
Additionally, according to an embodiment of the present invention, the RNA vims is SARS-COV-2 virus and the composition includes; a) At least two of a cholesterol lowering compound, an S-adenosyl homocysteine hydrolase (SAHH) inhibitor and a DOT1L inhibitor; and b) at least one TNF alpha inhibitor; and optionally at least one of; i. at least one a-glucosidase inhibitor; ii. at least one endothelial barrier enhancer; iii. at least one cathepsin B inhibitor; and iv. at least one collagen precursor.
Additionally, according to an embodiment of the present invention, the RNA vims is SARS-COV-2 vims and the composition includes; c) an S-adenosyl homocysteine hydrolase (SAHH) inhibitor and a DOT1L inhibitor; and d) at least one TNF alpha inhibitor; and optionally at least one of; i. at least one a-glucosidase inhibitor; ii. at least one endothelial barrier enhancer; iii. at least one cathepsin B inhibitor; and iv. at least one collagen precursor.
There is thus provided according to an embodiment of the present invention, a compound adapted to reduce a load of an RNA vims by at least 50%, the vims causing a pathogenic disease in a mammalian subject, the compound adapted to inhibit the formation of S-adenosyl methionine (SAM) in the vims, wherein the compound has a molecular weight of less than 1000, and a therapeutic index greater than 30 in the mammalian subject.
There is thus provided according to another embodiment of the present invention, use of a compound as described herein, in the preparation of a medicament suitable for administration to a human in a pharmaceutically effective amount, wherein the medicament is suitable for treating a pathogenic disease or disorder in the human.
There is thus provided according to another embodiment of the present invention, a method for reducing a load of an infectious RNA virus causing a pathogenic disease in a mammalian subject, the method including administering to the subject the compound, as described herein.
There is thus provided according to another embodiment of the present invention, a method for reducing a load of an infectious RNA virus causing a pathogenic disease in a mammalian subject, the method including administering to the subject the pharmaceutical composition as described herein.
There is thus provided according to another embodiment of the present invention, a method for reducing a load of a coronavirus causing a disease in a mammalian subject, the method including administering to the subject the pharmaceutical composition as described herein..
Additionally, according to an embodiment of the present invention, the composition is further effective to enhance endothelial barrier integrity.
Furthermore, according to an embodiment of the present invention, the composition is further effective to enhance collagen generation in the subject.
Yet further, according to an embodiment of the present invention, the compound is selected from compounds listed in table 1.
Additionally, according to an embodiment of the present invention, the pharmaceutical composition includes any combination of compounds in table 1 in a pharmaceutically effective amount.
The present invention provides compositions for reducing a load of an infectious agent causing a pathogenic disease in a mammalian subject, the composition including at least one product ( dl, d2, ...dN) in a pharmaceutically effective amount (EDxx), wherein ED is an effective dose and XX is the percentage reduction of the load, wherein each of the at least one product is effective to inhibit at least one step (si, s2, ...sN) in a pathway associated with replication of the infectious agent to reduce the load, No of the infectious agent in the subject to a final number at time t, Nt , wherein a ratio of the load No to the final number Nt is sufficiently large to provide the subject with a high statistical probability to survive the disease.
There is thus provided according to an embodiment of the present invention, a pharmaceutical composition for reducing a load of an infectious agent causing a pathogenic disease in a mammalian subject, the composition including; at least one product ( dl, d2, ... dN) in a pharmaceutically effective amount (EDxx), wherein ED is an effective dose and XX is the percentage reduction of the load, wherein each of the at least one product is effective to inhibit at least one step (si, s2, ...sN) in a pathway associated with replication of the infectious agent to reduce the load, No of the infectious agent in the subject to a final number at time t, Nt, wherein a ratio of the load No to the final number Nt is sufficiently large to provide the subject with a high statistical probability to survive the disease.
According to some embodiments, the product or compound(s) act synergistically in the composition to reduce the load of the infective agent. According to some embodiments the infective agent is an RNA virus, such as a corona virus.
Additionally, according to an embodiment of the present invention, the infectious agent is selected from the group consisting of a virus, a bacterium, a fungus, a parasite and combinations thereof.
Furthermore, according to an embodiment of the present invention, the infectious agent is a virus.
Further, according to an embodiment of the present invention, the virus is an RNA virus.
Yet further, according to an embodiment of the present invention the RNA virus is selected from families Coronaviridae, Filoviridae, Bunyaviridae, Flaviviridae, and Rhabdoviridae.
Moreover, according to an embodiment of the present invention, the virus is SARS- COV-2 virus.
Additionally, according to an embodiment of the present invention, the pathogenic disease is a respiratory disease.
It should be noted that, according to an embodiment of the present invention, the disease has a survival rate of less than 99%.
It should be noted that, according to an embodiment of the present invention, the disease has a survival rate of less than 95%.
Notably, according to an embodiment of the present invention, the pharmaceutical composition includes at least one S-adenosyl homocysteine hydrolase (SAHH) inhibitor.
Furthermore, according to an embodiment of the present invention, the pharmaceutical composition includes at least one a-glucosidase inhibitor.
Further, according to an embodiment of the present invention, the pharmaceutical composition includes at least one cathepsin B inhibitor.
Importantly, according to an embodiment of the present invention, the pharmaceutical composition includes at least one endothelial barrier enhancer.
Additionally, according to an embodiment of the present invention, the pharmaceutical composition includes at least one TNF alpha inhibitor.
Moreover, according to an embodiment of the present invention, the pharmaceutical composition includes at least one NF kappa B inhibitor.
Additionally, according to an embodiment of the present invention, the pharmaceutical composition includes at least one TNF alpha inhibitor.
Furthermore, according to an embodiment of the present invention, the pharmaceutical composition includes at least one collagen precursor.
Additionally, according to an embodiment of the present invention, the pharmaceutical composition includes at least one DOT1L inhibitor.
Further, according to an embodiment of the present invention, the pharmaceutical composition includes at least one folate remover.
Notably, according to an embodiment of the present invention, the infectious agent is an RNA virus and the composition includes; a) at least one of an S-adenosyl homocysteine hydrolase (SAHH) inhibitor or a DOT1L inhibitor; and b) at least one TNF alpha inhibitor; and optionally at least one of; i. at least one a-glucosidase inhibitor; ii. at least one endothelial barrier enhancer; iii. at least one cathepsin B inhibitor; and iv. at least one collagen precursor.
Additionally, according to an embodiment of the present invention, each of the inhibitors, enhancers and precursors has a therapeutic index of more than 30.
Importantly, according to an embodiment of the present invention, each of the inhibitors, enhancers and precursors has a therapeutic index of more than 50.
Further, according to an embodiment of the present invention, at least one of the inhibitors, enhancers and precursors has a therapeutic index of more than 100.
Additionally, according to an embodiment of the present invention, at least one of the inhibitors, enhancers and precursors is a generally regarded as safe (GRAS) product.
Furthermore, according to an embodiment of the present invention, some of the inhibitors, enhancers and precursors is a generally regarded as safe (GRAS) product. Further, according to an embodiment of the present invention, each of the inhibitors, enhancers and precursors is a generally regarded as safe (GRAS) product.
Additionally, according to an embodiment of the present invention, each at least one of the inhibitors, enhancers and precursors is an FDA approved drug for a first indication and the pathogenic disease is a second indication.
Most importantly, according to an embodiment of the present invention, the composition does not require FDA approval.
Usefully for Africa, according to an embodiment of the present invention, the composition costs less than $100 for the effective dose.
Additionally, according to an embodiment of the present invention, the pharmaceutical composition includes; a) Vitamin C; b) Bioavailable curcumin; c) at least one SAHH inhibitor; and d) at least one cathepsin B inhibitor.
Additionally, according to an embodiment of the present invention, the pharmaceutical composition further includes at least one anti-retroviral drug.
Further, according to an embodiment of the present invention, the pharmaceutical composition further includes at least one analgesic.
Moreover, according to an embodiment of the present invention, the pharmaceutical composition further includes at least one of creatine, Coenzyme Q10, Ginseng, and N- acetyl-L cysteine; glutathione, alpha lipoic acid, ajoene, allicin, limonene, Coenzyme Q10, quercetin, N-acetyl-L cysteine, resveratrol, and lycopene; choline and carnitine.
Furthermore, according to an embodiment of the present invention, the composition is liquid.
Additionally, according to an embodiment of the present invention, the composition is solid.
Notably, according to an embodiment of the present invention, the composition is suitable for oral, parenteral, transdermal, intra-venous or intra-muscular administration.
Additionally, according to an embodiment of the present invention, the composition is a slow-release composition.
Moreover, according to an embodiment of the present invention, the slow release composition is formulated for provision by at least one of an intravenous drip, a trans dermal device and a slow-release oral formulation. Importantly, according to an embodiment of the present invention, Nt is less than or equal to N0 x (å {(l-xx/ioo)di x (l-xx/100)d2... x((l-xx/ioo)) dn)} for at least one of the steps (si, s2, ...sN) si to sN.
Additionally, according to an embodiment of the present invention, Nt is less than or equal to N0 x (å {(l-xx/ioo)di x (l-xx/100)d2... c((1-cc/ioo)) dn)} for at least two of the steps (si, s2, ...sN) si to sN.
Moreover, according to an embodiment of the present invention, Nt is less than or equal to N0 x (å {(l-xx/ioo)di x (l-xx/100)d2... x((l-xx/ioo)) dn)} for at least three of the steps (si, s2, ...sN) si to sN.
Furthermore, according to an embodiment of the present invention, Nt is less than or equal to N0 x (å {(l-xx/100)di x (l-xx/100)d2... c((1-cc/ioo)) dn)} for at least three of the steps (si, s2, ... sN) si to sN.
Additionally, according to an embodiment of the present invention, Nt is less than or equal to N0 x (å {(l-xx/ioo)di x (l-xx/100)d2... c((1-cc/ioo)) dn)} for at least four of the steps (si, s2, ...sN) si to sN.
There is thus provided according to another embodiment of the present invention, use of a pharmaceutical composition, as described herein, in the preparation of a medicament suitable for administration to a human in a pharmaceutically effective amount, wherein the medicament is suitable for treating a pathogenic disease or disorder in the human.
There is thus provided according to an additional embodiment of the present invention, a method for predicting efficacy of a pharmaceutical composition in reducing a load of an infectious agent causing a pathogenic disease in a mammalian subject, the method including determining for at least one product ( dl, d2, ...dN) an effective dose (EDxx), wherein ED is an effective dose and XX is the percentage reduction of the load, wherein each of the at least one products is effective to inhibit at least one step (si, s2,
... sN) in a pathway associated with replication of the infectious agent to reduce the load, No of the infectious agent in the subject to a final number at time t, Nt , wherein a ratio of the load No to the final number Nt is sufficiently large to provide the subject with a high statistical probability to survive the disease; and wherein the pharmaceutical composition includes the at least one products in the effective dose.
Additionally, according to another embodiment of the present invention, in the method, Nt is less than or equal to N0 x (å {(l-xx/ioo)di x (l-xx/100)d2... c((1-cc/ioo)) dn)} for at least one the step (si, s2, ... sN) si to SN. There is thus provided according to another embodiment of the present invention, a method for reducing a load of an infectious agent causing a pathogenic disease in a mammalian subject, the method including administering to the subject the pharmaceutical composition as described herein.
Additionally, according to an embodiment of the present invention, the infectious agent is a virus and the composition includes; a) at least one cathepsin B inhibitor; and b) at least one TNFa inhibitor.
Further, according to an embodiment of the present invention, the infectious agent is a virus and the composition includes; a) at least one cathepsin B inhibitor; and b) at least one S-adenosyl homocysteine hydrolase (SAHH) inhibitor.
Yet further, according to an embodiment of the present invention, the infectious agent is a virus and the composition includes; a) at least one S-adenosyl homocysteine hydrolase (SAHH) inhibitor. b) at least one TNFa inhibitor.
Additionally, according to an embodiment of the present invention, the infectious agent is Ebola virus and the composition includes; a) at least one cathepsin B inhibitor; and b) at least one S-adenosyl homocysteine hydrolase (SAHH) inhibitor.
Importantly, according to an embodiment of the present invention, the infectious agent is Ebola virus and the composition includes; a) at least one cathepsin B inhibitor; and b) at least one S-adenosyl homocysteine hydrolase (SAHH) inhibitor; and c) a DOT 1L inhibitor.
There is thus provided according to another embodiment of the present invention, a method for reducing a load of an RNA virus causing a pathogenic disease in a mammalian subject, the method including administering to the subject the pharmaceutical composition as described herein.
There is thus provided according to another embodiment of the present invention, a method for reducing a load of an RNA virus causing a pathogenic disease in a mammalian subject, the method including administering to the subject the pharmaceutical composition as described herein, wherein the composition is further effective to reduce a load of inflammatory cytokines from an initial load ICYQ to a final load at time t, ICYL wherein a ratio of ICYo to ICYL is sufficiently large to provide the subject with a very high statistical probability to survive the disease.
Additionally, according to an embodiment of the present invention, the composition is further effective to enhance endothelial barrier integrity.
Furthermore, according to an embodiment of the present invention, the composition is further effective to enhance collagen generation in the subject.
According to some additional embodiments of the present invention, the pharmaceutical composition is liquid. In other cases, it is solid. In yet further cases, it is a suspension.
According to some additional embodiments of the present invention, the composition is a slow-release composition.
According to some further embodiments of the present invention, the slow release composition is formulated for provision by at least one of an intravenous drip, a trans- dermal device and a slow-release oral formulation.
According to some yet further embodiments of the present invention, the pharmaceutical composition further includes at least one neuro-protective agent.
There is thus provided according to some additional embodiments of the present invention, a use of a pharmaceutical composition as described herein in the preparation of a medicament suitable for administration to a human in a pharmaceutically effective amount, wherein the medicament is suitable for treating a disease or disorder in the human.
According to further embodiments, the disease is a viral disease.
EMBODIMENTS
1. A pharmaceutical composition comprising at least one of a methyltransferase inhibitor compound, a viral enzyme inhibitor compound and an SAHH (s- adenosylhomocysteine hydrolase) inhibitor compound, the composition adapted to inhibit replication of an RNA virus, said virus causing a pathogenic disease in a mammalian subject, wherein each of said compounds in said pharmaceutical composition has a molecular weight of less than 1000.
2. A pharmaceutical composition according to embodiment 1, wherein said RNA virus is a corona virus.
3. A compound according to embodiment 2, wherein said corona virus is SARS-COV-
2.
4. A pharmaceutical composition according to embodiment 1, wherein said pharmaceutical composition is effective in treating COVID-19 disease in a mammalian patient.
5. A pharmaceutical composition according to embodiment 1, wherein said pharmaceutical composition comprises at least two compounds.
6. A pharmaceutical composition according to embodiment 5, wherein said at least two compounds are adapted to inhibit said RNA virus synergistically.
7. A pharmaceutical composition according to embodiment 6, wherein said methyl transferase inhibitor comprises at least one DOTH inhibitor.
8. A pharmaceutical composition according to embodiment 7, wherein said DOTH inhibitor is EPZ5676.
9. A pharmaceutical composition according to embodiment 6, further comprising at least one TNF alpha inhibitor.
10. A pharmaceutical composition according to embodiment 6, further comprising at least one collagen precursor.
11. A pharmaceutical composition according to embodiment 6, wherein said RNA virus is SARS-COV-2 and said composition comprises: a) at least one of an S-adenosyl homocysteine hydrolase (SAHH) inhibitor and a DOT1L inhibitor; and b) at least one TNF alpha inhibitor; and optionally at least one of: i. at least one a-glucosidase inhibitor; ii. at least one endothelial barrier enhancer; iii. at least one cathepsin B inhibitor; and iv. at least one collagen precursor.
12. A pharmaceutical composition according to embodiment 11, wherein each of said inhibitors, enhancers and precursors has a therapeutic index of more than 30.
13. A pharmaceutical composition according to embodiment 12, wherein each of said inhibitors, enhancers and precursors has a therapeutic index of more than 50.
14. A pharmaceutical composition according to embodiment 13, wherein each of said inhibitors, enhancers and precursors has a therapeutic index of more than 100.
15. A pharmaceutical composition according to embodiment 14, wherein each of said inhibitors, enhancers and precursors is a generally regarded as safe (GRAS) product.
16. A pharmaceutical composition according to embodiment 6, wherein said composition further comprises: a) zinc; and b) at least one of an S-adenosyl homocysteine hydrolase (SAHH) inhibitor and a DOT1L inhibitor.
17. A pharmaceutical composition according to embodiment 16, further comprising at least one anti-retroviral drug.
18. A pharmaceutical composition according to embodiment 16, further comprising at least one of creatine, Coenzyme Q10, Ginseng, and N-acetyl-L cysteine; glutathione, alpha lipoic acid, ajoene, allicin, limonene, Coenzyme Q10, quercetin, N-acetyl-L cysteine, reservatrol, and lycopene; choline and carnitine.
19. A pharmaceutical composition according to embodiment 6, wherein the pharmaceutical composition is liquid.
20. A pharmaceutical composition according to embodiment 6, wherein the pharmaceutical composition is solid.
21. A pharmaceutical composition according to embodiment 6, wherein the pharmaceutical composition is suitable for oral, inhalable, parenteral, transdermal, intra-venous or intra-muscular administration.
22. A pharmaceutical composition according to embodiment 6, wherein the pharmaceutical composition is a slow-release composition.
23. A pharmaceutical composition according to embodiment 22, wherein the slow release composition is formulated for provision by at least one of an intravenous drip, a trans-dermal device and a slow-release oral formulation.
24. Use of a composition according to any one of embodiments 1 to 6, in the preparation of a medicament suitable for administration to a human in a pharmaceutically effective amount, wherein said medicament is suitable for treating a pathogenic disease or disorder in said human.
25. Use of a pharmaceutical composition according to any one of embodiments 7 to 24, in the preparation of a medicament suitable for administration to a human in a pharmaceutically effective amount, wherein said medicament is suitable for treating a pathogenic disease or disorder in said human.
26. A pharmaceutical composition according to embodiment 6, wherein said pharmaceutical composition further comprises any combination of compounds listed in table 1 in a pharmaceutically effective amount.
27. A pharmaceutical composition according to embodiment 6, further comprising copper and selenium.
28. A pharmaceutical composition according to embodiment 6, further comprising at least one of choloroquine, hydroxychloroquine an antimalarial drug, azithromycin, ivermectin, a quinine derivative, a choloroquine derivative, colchicine and combinations thereof.
29. A pharmaceutical composition according to embodiment 6, further comprising an adenine analog, an adenine derivative, an inosine analog, an inosine derivative, and combinations thereof.
The present invention also provides methods of treatment of a viral disease in a mammalian subject, the method including administering at least one compound or composition as described herein to the mammalian subject to treat the viral disease.
Additionally, the present invention includes methods of treatment of corona virus disease in human subjects, including SARS COV 2 (causing COVID-19 disease), the method including administering a pharmaceutical composition as described herein to the human subject in a pharmaceutically effective amount to treat the corona virus disease and/or to alleviate symptoms of the disease and/or to alleviate inflammatory cascades in the subject and/or to prevent or treat long-term COVID-19 disease in the subject.
DETAILED DESCRIPTION OF THE EMBODIMENTS
In the detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that these are specific embodiments and that the present invention may be practiced also in different ways that embody the characterizing features of the invention as described and claimed herein.
Over the first few days post infection, an RNA virus multiplies from around a few hundred plaque forming units (PFUs) introduced into a subject at time zero to tens of thousands- many million/billion PFUs. It has been reported that the average or mean replication rate line, leading to fatalities were several orders of magnitude greater than that in surviving hosts (Sanchez et al., 2004) having a mean PFU value of a significantly lower log slope than that of the fatal cases. For example, at day 4, post-infection, the non- survivors (fatalities) have a mean PFU count/ml 256 of 10 (100 million viruses/ml) and the survivors' mean PFU/ml count 266 is only around 3 x 104 (30,000 viruses/ml). Thus a ratio Ri s of the mean number of PFUs/ml in fatalities at time t= N- . to the mean number of PFUs/ml in fatalities at time t= NTS is around 3333. This ratio RFS is typically in the range of 10-100000, more typically in the range of 50-50000. Generally, one can state that 1 < RFS <10000 for Ebola, for example.
A statistical solution for improving human survival rates, when infected with a pathogenic virus is to reduce the viral load at time t, by at least 10, at least 100 and more preferably by at least 1000 and most preferably by at least 10000 fold. After three days, for example, the ratio RFS is around (2 x 10 )/(7x 10 )= 28.6. After two days, the ratio is less than ten.
This graph shows the importance of early treatment. In other words, to provide a potential "fatality" with a given treatment three days post infection may be 3333/28.7 =116.5, at least one hundred times more effective than at day four. Providing a treatment at day two may be 3333/10= 333 times as effective in saving the person's life, than at day four. Thus, non-confirmed suspected cases of infection should be treated before the lab results are received.
In order to inhibit an RNA vims replication, several steps in its replication cycle should be inhibited. This method applies, at least in part, to all viruses, bacterial, fungal, parasitic infections, and is exemplified with respect to SARS-COV-2 vims for the sake of simplicity.
In order to inhibit viral replication, at least one of the replication steps 1, 2, 3, 4, 5, 6, 7 and 8 of viral replication needs to be inhibited (respectively, cathepsin B or L inhibitors, folate receptor inhibitors, SAHH inhibitors, alpha glucosidase inhibitors, RNA synthesis inhibitors, RNA reverse transcription inhibitors, protein synthesis inhibitors, viral cap formation inhibitors and translation inhibitors). More preferably, in order to inhibit viral replication, at least two of the schematic steps 1, 2, 3, 4, 5, 6, 7 and 8 of viral replication need to be inhibited. Yet more preferably, in order to inhibit viral replication, at least three of the schematic steps 1, 2, 3, 4, 5, 6, 7 and 8 of viral replication need to be inhibited. Even more preferably, in order to inhibit viral replication, at least four of the schematic steps 1, 2, 3, 4, 5, 6, 7 and 8 of viral replication need to be inhibited. Yet even more preferably, in order to inhibit viral replication, at least five of the schematic steps 1, 2, 3, 4, 5, 6, 7 and 8 of viral replication need to be inhibited.
Without being bound to any particular theory, it is thought that in order to inhibit replication of an RNA virus, at least one viral enzyme should be inhibited. In order to inhibit replication of SARS-COV-2, at least one 2, 3, 4, 5, 6, or 7 of its enzymes must be inhibited, selected from the group consisting of a papain-like protease, a proteinase , an RNA-directed RNA polymerase, a helicase, a guanine-N7 methyltransferase , a uridylate- specific endoribonuclease and a 2-O-methyl transferase (15). According to some embodiments, at least two compounds are provided to inhibit the RNA virus, wherein the compounds have a synergistic effect in inhibiting the virus. By synergistic is meant greater than an additive effect that each compound has alone in inhibiting the vims.
According to one embodiment, in order to inhibit replication of SARS-COV-2, at least one inhibitor of at least one of its two methyltransferases must be inhibited.
Without being bound to any particular theory, it is thought that SAHH hydrolase inhibitors prevent viral mRNA maturation (e.g., 5'-methylated cap structure) by intracellular accumulation of AdoHcy (SAH), leading to a significant increase in the intracellular AdoHcy (SAH)/( SAM) S-adenosylmethionine ratio, and subsequent inhibition of S- adenosylmethionine- dependent methylation reactions (feedback inhibition- see Hasobe, M., McKee, J. G., Borcherding, D. R., & Borchardt, R. T. (1987). 9-(trans-2', trans-3'- Dihydroxycyclopent-4'-enyl)-adenine and-3-deazaadenine: analogs of neplanocin A which retain potent antiviral activity but exhibit reduced cytotoxicity. Antimicrobial agents and chemotherapy, 31(11), 1849-1851.).
In order to quantify a predicted inhibition of viral replication and reduction in the viral load, the following steps are performed in the method of the present invention. a) Identify replication steps of a pathogen. b) For at least one of the schematic steps 1, 2, 3, 4, 5, 6, 7 and 8 listed hereinabove, identify at least one inhibitor with a published and known effective dosage, such as ED50, the effective dose to inhibit 50% of the target pathogen (virus in this case). Some non-limiting examples appear in Table 1 hereinbelow. c) Calculate predicted combination therapy viral load reductions as follows:- i. For each step 1, 2, 3, 4, 5, 6, 7 and 8 (also termed Si, S2...SN herein) calculate, for each candidate dmg/compound/effector/agent, a reduction in the viral load anticipated by that dmg/compound in a given amount. For example, if the 3-DEAZANEPLANOCIN A known ED50 is 2 mM and the EDgo is 4 pM, then the residual viral load after treatment is the initial load No multiplied by the reduction in load. For example, if the initial load No of Ebola virus is 105 PFU/ml and an effective dose of 3-DEAZANEPLANOCIN is provided such that the in vivo concentration thereof is 2 pM, then the final load Nt at a time after administration of the 3-DEAZANEPLANOCIN Nt = N0 x(l-(ED50/100)= (1-0.5)= 0.5 x 105 PFU/ml at 4 pM and (1-0.8)= 2 x 104at 4 pM. ii. If the dmgs/compounds combined are on different steps (or pathways) 1, 2, 3, 4, 5, 6, 7 and 8, then assume (this is a preliminary assumption until practical kinetic values can be obtained-see Chou and Talalay, 1984, for a full mathematical analysis) that combining them produces a combination effect. Thus, at least as a first estimate, the values of Nt are assumed to be a multiple of each Nt calculated alone.
For example 4 pM 3-DEAZANEPLANOCIN + 0.004 g BETA-OLEANOLIC ACID (B.O.A) (ED50) for Cathepsin B, provides an EDgo and Nt 3-deaz xB.O.A= No x (1- 0.8)(l-0.5)= 10000- reducing the viral load 10 fold.
Thus, for example a combination of 4 pM 3-DEAZANEPLANOCIN + 0.004 g BETA-OLEANOLIC ACID (ED50) for Cathepsin B+ MIGLUSTAT 2g/day (ED50) would provide a theoretical 20 fold reduction in the viral load.
The combinations of similar drugs working at the same step on the same active site in an enzyme cannot be fully predicted without experimentation (Chou et ah, 1984) but may be additive. This may also depend on if they are provided at the same time or at different times.
According to some embodiments, for the sake of simplicity, it is assumed that a combination of two drugs working on the same enzyme is combinatory (multiplied). For example a combination of adenosine 4.2 g/day for 70 kg person provides its ED50, then the residual viral load for adenosine alone is (1-0.5)= 0.5 and if 3-DEAZANEPLANOCIN (C3-NPC-A) is used at 4 mM and adenosine at 4.2 g/day, the statistical combined residual viral load is ((1-0.8)x (1-0.5)) = 0.2 x0.5= 0.1 x original viral load. Thus, this combination of only two compounds working on only one of the steps (step 2 in this case) of steps si, s2, s3, s4, s5, s6, s7 and s8 in Fig 2B, would be sufficient to "move the patient from the fatalities curve 252 to the survivors' curve 262, if treated before or on day two. It would not be sufficient on day three or four.
For each pathway, such as inhibiting 2 by s-adenosyl homocysteine hydrolase (SAHH) E.C. 3.3.1.1. inhibitors, a sum of the combination therapies to be used on that pathway, using drugs or products di, d2 to dn å {(l-EDxx)dl x (l-EDxx)d2x((l-EDxx) dn)}s2...
Thus, in the example above this would lead to a ten-fold reduction in viral load.
However, if these two drugs were provided with 32.85 mg (this value needs to be verified) of MIGLUSTAT, which is an ED50 for viral integration pathways, and 0.185 mg of berberine and 0.03g of quercetin, both inhibitors of step IB, then the reduction in the viral load would be 0.1x0.5x0.5x 0.5=0.0125 of the initial viral load, or roughly a hundred fold reduction in the viral load. This could be applied on day three successfully.
All these calculations assume that the literature provided and published is reliable and accurate.
A partially effective combination on day four would be the five drugs/compounds, as above with a combination of 0.004g beta-oleanolic acid and 0.2 g beta-ursolic acid + viral load reduction =0.0125 xO.5x0.5=0.003125. This would mean that the treated person would have 10 times more PFUs/ml than the mean survivor and this may/may not be sufficient to save him/her.
Additionally or alternatively, it has been found that COVID-19 patients have increased loads of inflammatory cytokines, leading to reduced endothelial barrier integrity. Thus there is a further/alternative requirement to reduce a load of inflammatory cytokines from an initial load ICYo to a final load at time t, ICYt, wherein a ratio of ICYo to ICYt, is sufficiently large to provide the subject with a very high statistical probability to survive the disease. Collagen precursors may also be effective in "plugging the holes" in the endothelial barrier.
The data provided in Table 1 could optionally be optimized using mathematical methods, known in the art to minimize at least one of cost, minimizing the number of drugs, possible drug combination reactions etc.
In bacterial and other pathogenic models other pathogenic replication steps would be required, as are known in the art.
In order to avert the requirement for lengthy FDA approval, over-the-counter drugs or compounds, which are GRAS (generally regarded as safe) should be used to treat the viral disease.
Lu et al., (2010) describes a method (prior art) for preventing pulmonary edema of by improving endothelial barrier function, incorporated herein by reference.
The methods of the present invention include methods for improving endothelial layer integrity after an SARS-COV-2 virus infection, in accordance with an embodiment of the present invention. According to published literature viruses infiltrate monocytes forming infected monocytes. Infected monocytes release massive amounts of inflammatory cytokines damaging endothelial cells on a barrier. The endothelial cells die forming dead endothelial cells and inducing vascular shock to the infected organism/host. This vascular shock and perturbation of endothelial cell barriers can be reduced by step 9- providing endothelial cell enhancers/barrier integrity enhancers (see table 1 hereinbelow) and/or providing natural TNFalpha inhibitors to reduce the cytokine load/storm made by the infected monocytes. Some non-limiting examples of TNFalpha inhibitors known in the art are, curcumin, fisetin, genistein, resveratrol and capsaicin (see Habtemariam, 2000, incorporated herein by reference).
The present invention provides a method for increasing homocysteine in a patient, in accordance with an embodiment of the present invention. S-adenosyl-methionine (SAM) is a cofactor for viral methyltransferase (Huggins et al., 1999). Thus, for COVID-19 patients, every effort should be made to reduce the level of SAM (for at least the first week after infection) and reduce the SAM:SAH ratio to reduce SAM, while increasing SAH. This should reduce the viral replication rate.
Additionally or alternatively, any suitable methyltransferase enzyme (EC.2.1.1) inhibitor may be used to reduce the viral load to prevent methylation of the viral RNA, protein, glycoprotein or other viral components. Some non-limiting examples of these enzymes to be inhibited include 2.1.1.10 homocysteine S -methyltransferase, 2.1.1.43 histone-lysine N-methyltransferase and 2.1.1.56 mRNA (guanine-N7-)-methyltransferase. Some non-limiting examples of methyl transferase inhibitors appear in Table 1 hereinbelow.
Preferably, the methyltransferase inhibitor is operative to reduce the viral load inside a mammalian or other host. According to some embodiments, the inhibitor(s) may be an s- adenosylmethionine (SAM) analog and/or competitive inhibitor of a methyl transferase enzyme, adapted to receive a methyl group from SAM. One non-limiting example of such a substance is EGCG (epigallocatechin-3 gallate)- see Alemdaroglu et al., 2007 (IC 50 34.8 pmole/l). Harrington et al., 2004 show that homocysteine and adenosine blunt barrier dysfunction and Rho activation. Vitamin C, ornithine and arginine are all documented as being collagen precursors (see table 1 hereinbelow). According to some embodiments, vitamin C is provided in a megadose. It is possible that large doses of vitamin C would be effective in reducing viral loads, too (see Smith, Lendon H., 1988).
TABLE 1. EXEMPLARY CANDIDATE COMPOUNDS USEFUL IN THE TREATMENT OF VIRAL DISEASES
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
The SAHH inhibitor may be selected from any SAHH inhibitors known in the art and/or described herein, including DDFA (Huggins et al 1999). The DOT1L inhibitors may include any DOT1L inhibitor, known in the art. The cholesterol lowering agent may be any cholesterol lowering agent, known in the art.
Eritadenine is effective in lowering cholesterol (see Enman, J., Rova, U., & Berghmd, K. A. (2007). Quantification of the bioactive compound eritadenine in selected strains of shiitake mushroom (Lentinus edodes). Journal of agricultural and food chemistry, 55(4), 1177-1180.).
The compositions of the present invention may be provided in any suitable dosage form. These dosage forms may be injectable, infusible, inhalable, edible, oral or combinations thereof, as are known in the art. According to some embodiments, the dosage form is an oral dosage form. Oral dosage forms comprise liquids (solutions, suspensions, and emulsions), semi-solids (pastes), and solids (tablets, capsules, powders, granules, premixes, and medicated blocks).
In another embodiment, additional methods of administering the compositions of the invention comprise injectable dosage forms. In another embodiment, the injectable is administered intraperitoneally. In another embodiment, the injectable is administered intramuscularly. In another embodiment, the injectable is administered intradermally. In another embodiment, the injectable is administered intravenously. Each possibility represents a separate embodiment of the present invention.
In another embodiment, the compositions are administered by intravenous, intra arterial, or intra-muscular injection of a liquid preparation. Suitable liquid formulations include solutions, suspensions, dispersions, emulsions, oils and the like. In another embodiment, the compositions are administered intravenously and are thus formulated in a form suitable for intravenous administration. In another embodiment, the pharmaceutical compositions are administered intra-arterially and are thus formulated in a form suitable for intra-arterial administration. In another embodiment, the compositions are administered intra-muscularly and are thus formulated in a form suitable for intra-muscular administration.
Additionally, according to some embodiments of the present invention, the at least one neuro-protective agent is provided in a pharmaceutically effective amount and wherein the at least one neuro-protective agent is selected from the group consisting of; erythropoietin, an erythropoietin derivative, an extract of at least one of; Ginko biloba; Hydrocotyle asiatica, St. Johns Wort, Kava Kava, Passion Flower, Skull Cap, valerian, vervain, passionflower and catnip; Omega 3, a myelin precursor, bilobide, ginsenoside, ginseng radix, Cantella asiatica, Peoniae alba, Radix paeonifloria, watermelon extract and a cantaloupe extract.
According to some additional embodiments of the present invention, the slow release formulation includes at least one of a POLYOX™, METHOCEL™ and ETHOCEL™ excipient. According to some additional embodiments of the present invention, the slow release dosage form including a pharmaceutical composition as described herein covered by at least one non-allergenic, non-prolamine polymer layer.
According to some additional embodiments of the present invention, the slow release dosage form the dosage form is non allergenic. According to some additional embodiments of the present invention, the slow release dosage form does not comprise animal matter (is vegetarian). According to some additional embodiments of the present invention, the slow release dosage form is kosher.
According to some additional embodiments of the present invention, a use of a pharmaceutical composition is provided for the preparation of a medicament suitable for administration to a human in a pharmaceutically effective amount, wherein the medicament is suitable for treating a disease or disorder in the human.
According to some additional embodiments of the present invention, the composition is suitable for oral, parenteral, transdermal, intra-venous or intra-muscular administration.
According to some embodiments, the composition is a slow-release composition. In some cases, the slow release composition is formulated for provision by at least one of an intravenous drip, a trans-dermal device and a slow-release oral formulation.
Some examples of oral dosage forms in the art include, W090/04391, which discloses an oral dosage form of omega-3 polyunsaturated acids to overcome the problems of vascular diseases. It is known to supply said acids in soft gelatine capsule shells.
EP 2 240 581 B1 discloses a gelatine capsule for pharmaceutical use with a controlled release of active ingredients and a process for the preparation of said gelatine capsules. During said process xylose is added to the liquid gelatine from which afterwards gelatine capsules are formed. Gelatine capsules manufactured according to the process provide retarded release of active ingredients.
US Patent No. 7,264,824 discloses and oral dosage form for food and food supplements, as well as dietetics comprising polyunsaturated acids in a xylose-hardened gelatine capsule with a retarded release time. According to some embodiments of the present invention, the compositions described herein may be in a suspension or emulsion.
A suspension is a coarse dispersion of insoluble drug particles, generally with a diameter exceeding 1 pm, in a liquid (usually aqueous) medium. Suspensions are useful for administering insoluble or poorly soluble drugs/components or in situations when the presence of a finely divided form of the material in the GI tract is required. The taste of most drugs is less noticeable in suspension than in solution, due to the drug being less soluble in suspension. Particle size is an important determinant of the dissolution rate and bioavailability of drugs in suspension. In addition to the excipients described above for solutions, suspensions include surfactants and thickening agents. Surfactants wet the solid particles, thereby ensuring the particles disperse readily throughout the liquid. Thickening agents reduce the rate at which particles settle to the bottom of the container. Some settling is acceptable, provided the sediment can be readily dispersed when the container is shaken. Because hard masses of sediment do not satisfy this criterion, caking of suspensions is not acceptable.
An emulsion is a system consisting of 2 immiscible liquid phases, one of which is dispersed throughout the other in the form of fine droplets; droplet diameter generally ranges from 0.1-100 pm. The 2 phases of an emulsion are known as the dispersed phase and the continuous phase. Emulsions are inherently unstable and are stabilized through the use of an emulsifying agent, which prevents coalescence of the dispersed droplets. Creaming, as occurs with milk, also occurs with pharmaceutical emulsions. However, it is not a serious problem because a uniform dispersion returns upon shaking. Creaming is, nonetheless, undesirable because it is associated with an increased likelihood of the droplets coalescing and the emulsion breaking. Other additives include buffers, antioxidants, and preservatives. Emulsions for oral administration are usually oil (the active ingredient) in water, and facilitate the administration of oily substances such as castor oil or liquid paraffin in a more palatable form.
A paste is a 2-component semi-solid in which drug is dispersed as a powder in an aqueous or fatty base. The particle size of the active ingredient in pastes can be as large as 100 pm. The vehicle containing the drug may be water; a polyhydroxy liquid such as glycerin, propylene glycol, or polyethylene glycol; a vegetable oil; or a mineral oil. Other formulation excipients include thickening agents, cosolvents, adsorbents, humectants, and preservatives. The thickening agent may be a naturally occurring material such as acacia or tragacanth, or a synthetic or chemically modified derivative such as xanthum gum or hydroxypropylmethyl cellulose. The degree of cohesiveness, plasticity, and syringeability of pastes is attributed to the thickening agent. It may be necessary to include a cosolvent to increase the solubility of the drug. Syneresis of pastes is a form of instability in which the solid and liquid components of the formulation separate over time; it is prevented by including an adsorbent such as microcrystalline cellulose. A humectant (eg, glycerin or propylene glycol) is used to prevent the paste that collects at the nozzle of the dispenser from forming a hard crust. Microbial growth in the formulation is inhibited using a preservative. It is critical that pastes have a pleasant taste or are tasteless.
A tablet consists of one or more active ingredients and numerous excipients and may be a conventional tablet that is swallowed whole, a chewable tablet, or a modified-release tablet (more commonly referred to as a modified-release bolus due to its large unit size). Conventional and chewable tablets are used to administer drugs to dogs and cats, whereas modified-release boluses are administered to cattle, sheep, and goats. The physical and chemical stability of tablets is generally better than that of liquid dosage forms. The main disadvantages of tablets are the bioavailability of poorly water-soluble drugs or poorly absorbed drugs, and the local irritation of the GI mucosa that some drugs may cause.
A capsule is an oral dosage form usually made from gelatin and filled with an active ingredient and excipients. Two common capsule types are available: hard gelatin capsules for solid-fill formulations, and soft gelatin capsules for liquid-fill or semi- solid-fill formulations. Soft gelatin capsules are suitable for formulating poorly water-soluble drugs because they afford good drug release and absorption by the GI tract. Gelatin capsules are frequently more expensive than tablets but have some advantages. For example, particle size is rarely altered during capsule manufacture, and capsules mask the taste and odor of the active ingredient and protect photolabile ingredients.
A powder is a formulation in which a drug powder is mixed with other powdered excipients to produce a final product for oral administration. Powders have better chemical stability than liquids and dissolve faster than tablets or capsules because disintegration is not an issue. This translates into faster absorption for those drugs characterized by dissolution rate-limited absorption. Unpleasant tastes can be more pronounced with powders than with other dosage forms and can be a particular concern with in-feed powders, in which it contributes to variable ingestion of the dose. Moreover, sick animals often eat less and are therefore not amenable to treatment with in-feed powder formulations. Drug powders are principally used prophylactically in feed, or formulated as a soluble powder for addition to drinking water or milk replacer. Powders have also been formulated with emulsifying agents to facilitate their administration as liquid drenches.
A granule is a dosage form consisting of powder particles that have been aggregated to form a larger mass, usually 2-4 mm in diameter. Granulation overcomes segregation of the different particle sizes during storage and/or dose administration, the latter being a potential source of inaccurate dosing. Granules and powders generally behave similarly; however, granules must deaggregate prior to dissolution and absorption.
A premix is a solid dosage form in which an active ingredient, such as a coccidiostat, production enhancer, or nutritional supplement, is formulated with excipients. Premix products are mixed homogeneously with feed at rates (when expressed on an active ingredient basis) that range from a few milligrams to -200 g/ton of food/beverage The density, particle size, and geometry of the premix particles should match as closely as possible those of the feed in which the premix will be incorporated to facilitate uniform mixing. Issues such as instability, electrostatic charge, and hygroscopicity must also be addressed. The excipients present in premix formulations include carriers, liquid binders, diluents, anti-caking agents, and anti- dust agents. Carriers, such as wheat middlings, soybean mill run, and rice hulls, bind active ingredients to their surfaces and are important in attaining uniform mixing of the active ingredient. A liquid binding agent, such as a vegetable oil, should be included in the formulation whenever a carrier is used. Diluents increase the bulk of premix formulations, but unlike carriers, do not bind the active ingredients. Examples of diluents include ground limestone, dicalcium phosphate, dextrose, and kaolin. Caking in a premix formulation may be caused by hygroscopic ingredients and is addressed by adding small amounts of anti-caking agents such as calcium silicate, silicon dioxide, and hydrophobic starch. The dust associated with powdered premix formulations can have serious implications for both operator safety and economic losses, and is reduced by including a vegetable oil or light mineral oil in the formulation. An alternate approach to overcoming dust is to granulate the premix formulation.
A medicated block is a compressed feed material that contains an active ingredient, such as a drug, anthelmintic, surfactant (for bloat prevention), or a nutritional supplement, and is commonly packaged in a cardboard box. Ruminants typically have free access to the medicated block over several days, and variable consumption may be problematic. This concern is addressed by ensuring the active ingredient is nontoxic, stable, palatable, and preferably of low solubility. In addition, excipients in the formulation modulate consumption by altering the palatability and/or the hardness of the medicated block. For example, molasses increases palatability and sodium chloride decreases it. Additionally, the incorporation of a binder such as lignin sulfonate in blocks manufactured by compression or magnesium oxide in blocks manufactured by chemical reaction, increases hardness. The hygroscopic nature of molasses in a formulation may also impact the hardness of medicated blocks and is addressed by using appropriate packaging.
In another embodiment, the composition of the present invention is in a chewable oral dosage form. In another embodiment, the chewable oral dosage form is a chewable tablet. In another embodiment, the chewable tablet of the invention is taken slowly by chewing or sucking in the mouth. In another embodiment, the chewable tablet of the invention enables the vitamins contained therein to be orally administered without drinking.
In another embodiment of the present invention, the composition further comprises fructose, sorbitol, microcrystalline cellulose, magnesium stearate, or any combination thereof. In another embodiment, the composition further comprises chamomile. In another embodiment, the composition further comprises ginger. In another embodiment, the composition further comprises peppermint. In another embodiment, the composition further comprises anise. In another embodiment, the composition of the present invention is in the form of a chewing gum product. In another embodiment, chewing gum compositions contemplated by the present invention comprise all types of sugar and sugarless chewing gums and chewing gum formulations known to those skilled in the art, including regular and bubble gum types. In another embodiment, chewing gum compositions of the invention comprise a chewing gum base, a modifier, a bulking agent or sweetener, and one or more other additives such as, flavoring agents, colorants and antioxidants. In another embodiment, the modifying agents are used to soften, plasticize and/or compatibilize one or more of the components of the gum base and/or of the formulation as a whole.
In another embodiment, the present invention provides a soft, chewable dosage form which is pliable and chewy, yet dissolves quickly in the mouth, has a long shelf life, contains little moisture which improves stability and decreases the tendency for the dosage form to dry out, does not require cooking or heating as part of the manufacturing process. In another embodiment, the dosage form is used as a matrix for vitamins.
In another embodiment, the chewable tablet of the invention comprises a metal salt such as calcium, magnesium, aluminum salt, or any mixture thereof. In another embodiment, the chewable tablet of the invention comprises hydroxyalkyl cellulose. In another embodiment, the chewable tablet of the invention comprises low viscosity hydroxyalkyl cellulose. In another embodiment, the chewable tablet of the invention comprises high viscosity hydroxyalkyl cellulose.
In another embodiment, the chewable tablet of the invention comprises various additives. In another embodiment, the chewable tablet of the invention comprises sweeteners. In another embodiment, the chewable tablet of the invention comprises acidic ingredients. In another embodiment, the chewable tablet of the invention comprises taste correctives. In another embodiment, the chewable tablet of the invention comprises polymeric compounds. In another embodiment, the chewable tablet of the invention comprises essential oils.
In another embodiment, the chewable tablet of the invention is a soft tablet. In another embodiment, the chewable tablet of the invention is made in a state of soft candy. In another embodiment, the chewable tablet of the invention is made in a state of jelly.
In another embodiment, the chewable tablet of the invention comprises a core comprising the vitamins of the invention. In another embodiment, the chewable tablet of the invention comprises an outer layer wrapping the core which is made up of chewable base such as a gum, a soft candy or a caramel.
In another embodiment, sugar used in the present invention may be selected from the group consisting of white sugar, liquid glucose, sorbitol, dextrose, isomalt, liquid maltitol, aspartame and lactose, and this sugar may comprise 30-90 weight % by total weight of the ingredients.
In another embodiment, the chewable tablet of the invention comprises a sweetener such as but not limited to: glucose (com syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as suralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like. In another embodiment, glycerin, lecithin, hydrogenated palm oil or glyceryl monostearate are used as a protecting agent of crystallization of the sugars in 0.02-3.0 weight % by total weight of the ingredients, to prevent adhesion to oral cavity and improve the soft property of the products.
In another embodiment, isomalt or liquid maltitol are used as an enhancing agent of chewing property. In another embodiment, gelatin or arabic gum are used as a keeping agent of hardness and extension property in 0.1-3.0 weight % by total weight of the ingredients. In another embodiment, food flavor or a fruits extract; a souring agent such as citric acid are added in adequate amount. In another embodiment, a coloring agent such as a food color is optionally added in a small amount.
Yet a further embodiment of the present invention includes the use of an effervescent disintegration agent. In another embodiment, its action aids in the masking of objectionable taste of the vitamins.
In another embodiment, of the present invention the effervescent disintegration agent is an acid. In another embodiment, of the present invention the effervescent disintegration agent is citric acid. In another embodiment, of the present invention the effervescent disintegration agent is tartaric acid.
In another embodiment, the chewable tablet of the invention comprises a crystallization modifier such but not limited to, surfactants (Spans. TM. and Tweens. TM.), dextrose, polyethylene glycol (PEG), polypropylene glycol (PPG), etc. These modifiers generally provide controlled acceleration of crystallization while the matrix is bound. In another embodiment, these crystallization modifiers enhance the formation of a crystalline frame and the conversion of the remaining mass.
In another embodiment, crystallization modifiers are surfactants having a hydrophilic to lipid balance (HLB) of six or greater, i.e., they have the same degree of hydrophilicity as surfactants characterized by degree of HLB . In another embodiment, such materials include, but are not limited to anionic, cationic and zwitterionic surfactants as well as neutral materials which have an HLB of six or greater. In another embodiment, crystallization modifiers are hydrophilic materials having polyethylene oxide linkages. In another embodiment, crystallization modifiers have a molecular weight of at least 100. In another embodiment, the chewable tablet of the invention comprises a filler. In another embodiment, filler increases the bulk of the tablet. In another embodiment, the filler is calcium sulfate, both di- and tri basic, starch, calcium carbonate, microcrystalline cellulose, modified starches, lactose, sucrose, mannitol, sorbitol, or any combination thereof. In another embodiment, the chewable tablet of the invention comprises a binder such as but not limited to: starches, pregelatinize starches, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols.
In another embodiment, the chewable tablet of the invention comprises a lubricant such as but not limited to: magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene, monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate and light mineral oil.
In another embodiment, the chewable tablet of the invention comprises a dispersion enhancer such as but not limited to: starch, alginic acid, polyvinylpyrrolidones, guar gum, partially hydrolyzed guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.
In another embodiment, the chewable tablet of the invention comprises an absorbent such as but not limited to: maltodextrin. In another embodiment, the chewable tablet of the invention comprises an emulsifier such as but not limited to: Mono- and diglycerides, Oleaginous substances such as food oils like Medium, Chain Triglycerides (MCT), and Stearine D 17.
In another embodiment, the chewable tablet of the invention comprises a water soluble bulking agent such as but not limited to: hydrocolloid thickeners and binders, such as gum arabic, pectins, modified starches, alginates, carrageenans, xanthan gums, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, propylene glycol alginate, polyvinylpyrrolidone (PVP), carboxyvinyl polymers (such as Carbopol.RTM.), polyethylene oxide polymers (such as Polyox. RTM.), sorbitol, xylitol, sucrose, fructose, dextrose, mannitol, starch maltodextrin, com syrup solids, or combinations thereof.
In another embodiment, the chewable tablet of the invention comprises a water insoluble bulking agent such as but not limited to: talc, dicalcium phosphate, powdered celluloses, microcrystalline celluloses and antacid compounds. In another embodiment, the chewable tablet of the invention comprises vitamins in compressed particles. In another embodiment, individual particles are coated with a blend of cellulose acetate or cellulose acetate butyrate and polyvinyl pyrrolidone (USP Povidone or "PVP"). In another embodiment, the coating provides excellent taste masking while still permitting acceptable bioavailability of the vitamins. In another embodiment, the chew able tablet
In another embodiment, the invention relates to a composition of the invention comprised within chewable and edible soft gelatin capsules, the shells of which comprise gelatin, water, plasticizer and a hydrogenated starch hydrolysate. In another embodiment, soft gelatin shell comprises about 10-45% gelatin; about 5-30% water; about 12-35% plasticizer; and about 2-25% of a hydrogenated starch hydrolysate. In another embodiment, the shell encloses a soft gelatin capsule fill material. In another embodiment, the gelatin may be of Type A, Type B, or a mixture thereof. In another embodiment, in order to augment the taste and chewability of the capsule shell, as well as to assist in the rapid dissolution of the shell upon chewing, the present capsule shell further comprises a hydrogenated starch hydrolysate.
The compositions and dosage forms of the present invention are useful in promoting health and preventing or treating a large number of disorders in human patients and other mammalian subjects.
In additional embodiments of the present invention, compositions and methods are provided for treating and/or preventing heart disease, such as, but not limited to, atherosclerotic and hypertensive diseases, congenital heart disease, rheumatic heart disease, and other conditions.
In further embodiments of the present invention, compositions and methods are provided for treating and/or preventing peripheral blood vessel disorders. Peripheral blood vessel disorders affect the blood vessels of the arms, legs, and trunk (except those supplying the heart). These disorders include disorders of the blood vessels supplying the brain, namely cerebrovascular disorders.
In additional embodiments of the present invention, compositions and methods are provided for treating and/or preventing blood disorders, disorders of nutrition or metabolism, hormonal disorders, bone, joint or muscle disorders, spinal cord or nervous disorders, immunological disorders, infectious disorders, urinary tract and kidney disorders, or skin disorders, vitamin deficiencies and other nutritional disorders, lung or airway disorders, digestive disorders, or reproductive disorders.
The compositions may be provided to the subject in an oral dosage form. In some cases, the oral dosage form includes a capsule. In other embodiments, the oral dosage form may be chewable. The oral dosage form may further comprise at least one of fructose, sorbitol, microcrystalline cellulose, magnesium stearate, or a combination thereof.
In some cases, the oral dosage form includes at least one additional antioxidant. The oral dosage form may also include additional agents and components.
The compositions of the present invention may comprise an additional active agent. The additional active agent is selected from the group consisting of active herbal extracts, acaricides, age spot and keratose removing agents, allergen, analgesics, local anesthetics, antiacne agents, antiallergic agents, antiaging agents, antibacterials, antibiotic agents, antibum agents, anticancer agents, antidandmff agents, antidepressants, antidermatitis agents, antiedemics, antihistamines, antihelminths, antihyperkeratolyte agents, antiinflammatory agents, antiirritants, antilipemics, antimicrobials, antimycotics, antiproliferative agents, antioxidants, anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosacea agents antiseborrheic agents, antiseptic, antiswelling agents, antiviral agents, anti-yeast agents, astringents, topical cardiovascular agents, chemotherapeutic agents, corticosteroids, dicarboxylic acids, disinfectants, fungicides, hair growth regulators, hormones, hydroxy acids, immunosuppressants, immunoregulating agents, insecticides, insect repellents, keratolytic agents, lactams, metals, metal oxides, mitocides, neuropeptides, non-steroidal anti-inflammatory agents, oxidizing agents, pediculicides, photodynamic therapy agents, retinoids, sanatives, scabicides, self tanning agents, skin whitening agents, asoconstrictors, vasodilators, vitamins, vitamin D derivatives, wound healing agents and wart removers.
According to some embodiments the antibiotic agent is selected from the group consisting of beta-lactam antibiotics, aminoglycosides, ansa-type antibiotics, anthraquinones, antibiotic azoles, antibiotic glycopeptides, macrolides, antibiotic nucleosides, antibiotic peptides, antibiotic polyenes, antibiotic polyethers, quinolones, antibiotic steroids, sulfonamides, tetracycline, dicarboxylic acids, antibiotic metals including antibiotic metal ions, oxidizing agents, substances that release free radicals and/or active oxygen, cationic antimicrobial agents, quaternary ammonium compounds, biguanides, triguanides, bisbiguanides and analogs and polymers thereof, naturally occurring antibiotic compounds, including antibiotic plant oils and antibiotic plant extracts and any one of the following antibiotic compounds: chlorhexidine acetate, chlorhexidine gluconate and chlorhexidine hydrochloride, picloxydine, alexidine, polihexanide, chlorproguanil hydrochloride, proguanil hydrochloride, metformin hydrochloride, phenformin, buformin hydrochloride, abomycin, acetomycin, acetoxycycloheximide, acetylnanaomycin, an actinoplanes sp. compound, actinopyrone, aflastatin, albacarcin, albacarcin, albofungin, albofungin, alisamycin, alpha-R,S-methoxycarbonylbenzylmonate, altromycin, amicetin, amycin, amycin demanoyl compound, amycine, amycomycin, anandimycin, anisomycin, anthramycin, anti-syphilis imune substance, anti-tuberculosis imune substance, antibiotic from Eschericia coli, antibiotics from Streptomyces refuineus, anticapsin, antimycin, aplasmomycin, aranorosin, aranorosinol, amgomycin, ascofuranone, ascomycin, ascosin, Aspergillus flavus antibiotic, asukamycin, aurantinin, an Aureolic acid antibiotic substance, aurodox, avilamycin, azidamfenicol, azidimycin, bacillaene, a Bacillus larvae antibiotic, bactobolin, benanomycin, benzanthrin, benzylmonate, bicozamycin, bravomicin, brodimoprim, butalactin, calcimycin, calvatic acid, candiplanecin, carumonam, carzinophilin, celesticetin, cepacin, cemlenin, cervinomycin, chartreusin, chloramphenicol, chloramphenicol palmitate, chloramphenicol succinate sodium, chlorflavonin, chlorobiocin, chlorocarcin, chromomycin, ciclopirox, ciclopirox olamine, citreamicin, cladosporin, clazamycin, clecarmycin, clindamycin, coliformin, collinomycin, copiamycin, corallopyronin, corynecandin, coumermycin, culpin, cuprimyxin, cyclamidomycin, cycloheximide, dactylomycin, danomycin, danubomycin, delaminomycin, demethoxyrapamycin, demethylscytophycin, dermadin, desdamethine, dexylosyl- benanomycin, pseudoaglycone, dihydromocimycin, dihydronancimycin, diumycin, dnacin, dorrigocin, dynemycin, dynemycin triacetate, ecteinascidin, efrotomycin, endomycin, ensanchomycin, equisetin, ericamycin, esperamicin, ethylmonate, everninomicin, feldamycin, flambamycin, flavensomycin, florfenicol, fluvomycin, fosfomycin, fosfonochlorin, fredericamycin, frenolicin, fumagillin, fumifungin, funginon, fusacandin, fusafungin, gelbecidine, glidobactin, grahamimycin, granaticin, griseofulvin, griseoviridin, grisonomycin, hayumicin, hayumicin, hazymicin, hedamycin, heneicomycin, heptelicid acid, holomycin, humidin, isohematinic acid, karnatakin, kazusamycin, kristenin, L- dihydrophenylalanine, a L-isoleucyl-L-2-amino-4-(4'-amino-2', 5'-cyclohexadienyl) derivative, lanomycin, leinamycin, leptomycin, libanomycin, lincomycin, lomofungin, lysolipin, magnesidin, manumycin, melanomycin, methoxycarbonylmethylmonate, methoxycarbonylethylmonate, methoxycarbonylphenylmonate, methyl pseudomonate, methylmonate, microcin, mitomalcin, mocimycin, moenomycin, monoacetyl cladosporin, monomethyl cladosporin, mupirocin, mupirocin calcium, mycobacidin, myriocin, myxopyronin, pseudoaglycone, nanaomycin, nancimycin, nargenicin, neocarcinostatin, neoenactin, neothramycin, nifurtoinol, nocardicin, nogalamycin, novobiocin, octylmonate, olivomycin, orthosomycin, oudemansin, oxirapentyn, oxoglaucine methiodide, pactacin, pactamycin, papulacandin, paulomycin, phaeoramularia fungicide, phenelfamycin, phenyl, cerulenin, phenylmonate, pholipomycin, pirlimycin, pleuromutilin, a polylactone derivative, polynitroxin, polyoxin, porfiromycin, pradimicin, prenomycin, Prop-2-enylmonate, protomycin, Pseudomonas antibiotic, pseudomonic acid, purpuromycin, pyrinodemin, pyrrolnitrin, pyrrolomycin, amino, chloro pentenedioic acid, rapamycin,rebeccamycin, resistomycin, reuterin, reveromycin, rhizocticin, roridin, rubiflavin, naphthyridinomycin, saframycin, saphenamycin, sarkomycin, sarkomycin, sclopularin, selenomycin, siccanin, spartanamicin, spectinomycin, spongistatin, stravidin, streptolydigin, streptomyces arenae antibiotic complex, streptonigrin, streptothricins, streptovitacin, streptozotocine, a strobilurin derivative, stubomycin, sulfamethoxazol-trimethoprim, sakamycin, tejeramycin, terpentecin, tetrocarcin, thermorubin, thermozymocidin, thiamphenicol, thioaurin, thiolutin, thiomarinol, thiomarinol, tirandamycin, tolytoxin, trichodermin, trienomycin, trimethoprim, trioxacarcin, tyrissamycin, umbrinomycin, unphenelfamycin, urauchimycin, usnic acid, uredolysin, variotin, vermisporin, verrucarin, metronidazole, erythromycin and analogs, salts and derivatives thereof.
According to some embodiments, the additional active agent is selected from the group consisting of alclometasone dipropionate, amcinafel, amcinafide, amcinonide, beclomethasone, beclomethasone dipropionate, betamethsone, betamethasone benzoate, betamethasone dexamethasone -phosphate, dipropionate, betamethasone valerate, budesonide, chloroprednisone, chlorprednisone acetate, clescinolone, clobetasol, clobetasol propionate, clobetasol valerate, clobetasone, clobetasone butyrate, clocortelone, cortisone, cortodoxone, craposone butyrate, desonide, desoxymethasone, dexamethasone, desoxycorticosterone acetate, dichlorisone, diflorasone diacetate, diflucortolone valerate, diflurosone diacetate, diflurprednate, fluadrenolone, flucetonide, flucloronide, fluclorolone acetonide, flucortine butylesters, fludroxycortide, fludrocortisone, flumethasone, flumethasone pivalate, flumethasone pivalate, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluosinolone acetonide, fluperolone, fluprednidene acetate, fluprednisolone hydrocortamate, fluradrenolone, fluradrenolone acetonide, flurandrenolone, fluticasone, halcinonide, halobetasol, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone cyclopentylpropionate, hydrocortisone valerate, hydroxyltriamcinolone, medrysone, meprednisone, .alpha.-methyl dexamethasone, methylprednisolone, methylprednisolone acetate, mometasone furoate, paramethasone, prednisolone, prednisone, pregnenolone, progesterone, spironolactone, triamcinolone, triamcinolone acetonide and derivatives, esters and salts thereof.
According to some embodiments, the compositions of the present invention comprise a metal salt such as calcium, magnesium, zinc, selenium, copper, vanadium, chromium, iron, aluminum salt, or any mixture thereof.
According to some embodiments, the compositions of the present invention further comprise a buffering agent. The buffering agent can be any of the known buffering systems used in pharmaceutical or cosmetic formulations as would be appreciated by a man of the art. It can also be an organic acid, a carboxylic acid, a fatty acid an amino acid, an aromatic acid, an alpha or beta hydroxyl acid an organic base or a nitrogen containing compound.
According to some embodiments, the compositions of the present invention further comprise a pH modulating agent. The term pH modulating agent is used to describe an agent which can effect pH in an aqueous solution the term modulating agent more particularly means an acid or base or buffer system or combinations thereof, which is introduced into or is present in and acts to modulate the ionic or polar characteristics and any acidity or basicity balance of a composition,.
According to some embodiments, the compositions of the present invention further comprise an antiviral agent Suitable antiviral agents include but are not limited to, acyclovir, gancyclovir, ribavirin, amantadine, rimantadine nucleoside-analog reverse transcriptase inhibitors, such as zidovudine, didanosine, zalcitabine, tavudine, lamivudine and vidarabine, non-nucleoside reverse transcriptase inhibitors, such as nevirapine and delavirdine, protease inhibitors, such as saquinavir, ritonavir, indinavir and nelfinavir, and interferons and derivatives, esters, salts and mixtures thereof.
According to some embodiments, the compositions of the present invention further comprise a chemotherapeutic agent. Suitable chemotherapeutic agents include but are not limited to daunorubicin, doxorubicin, idambicin, ammbicin, pirambicin, epirubicin, mitoxantrone, etoposide, teniposide, vinblastine, vincristine, mitomycin C, 5-FU, paclitaxel, docetaxel, actinomycin D, colchicine, topotecan, irinotecan, gemcitabine cyclosporin, verapamil, valspodor, probenecid, MK571, GF120918, LY335979, biricodar, terfenadine, quinidine, pervilleine A, XR9576 and derivatives, esters, salts and mixtures thereof.
According to some embodiments, the compositions of the present invention further comprise a corticosteroid. Suitable corticosteroids include but are not limited to alclometasone dipropionate, amcinafel, amcinafide, amcinonide, beclomethasone, beclomethasone dipropionate, betamethsone, betamethasone benzoate, betamethasone dexamethasone-phosphate, dipropionate, betamethasone valerate, budesonide, chloroprednisone, chlorprednisone acetate, clescinolone, clobetasol, clobetasol propionate, clobetasol valerate, clobetasone, clobetasone butyrate, clocortelone, cortisone, cortodoxone, craposone butyrate, desonide, desoxymethasone, dexamethasone, desoxycorticosterone acetate, dichlorisone, diflorasone diacetate, diflucortolone valerate, diflurosone diacetate, diflurprednate, fluadrenolone, flucetonide, flucloronide, fluclorolone acetonide, flucortine butylesters, fludroxycortide, fludrocortisone, flumethasone, flumethasone pivalate, flumethasone pivalate, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluosinolone acetonide, fluperolone, fluprednidene acetate, fluprednisolone hydrocortamate, fluradrenolone, fluradrenolone acetonide, flurandrenolone, fluticasone, halcinonide, halobetasol, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone cyclopentylpropionate, hydrocortisone valerate, hydroxyltriamcinolone, medrysone, meprednisone, .alpha. -methyl dexamethasone, methylprednisolone, methylprednisolone acetate, mometasone furoate, paramethasone, prednisolone, prednisone, pregnenolone, progesterone, spironolactone, triamcinolone, triamcinolone acetonide and derivatives, esters, salts and mixtures thereof.
According to some embodiments, the compositions of the present invention further comprise an analgesic. Suitable analgesics include but are not limited to benzocaine, butamben picrate, dibucaine, dimethisoquin, dyclonine, lidocaine, pramoxine, tetracaine, salicylates and derivatives, esters, salts and mixtures thereof.
According to some embodiments, the compositions of the present invention further comprise a non-steroidal anti-inflammatory agent. Suitable non-steroidal anti-inflammatory agent include but are not limited to azelaic acid, oxicams, piroxicam, isoxicam, tenoxicam, sudoxicam, CP- 14,304, salicylates, aspirin, disalcid, benorylate, trilisate, safapryn, solprin, difhmisal, fendosal, acetic acid derivatives, diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, ketorolac, fenamates, mefenamic, meclofenamic, flufenamic, niflumic, tolfenamic acids, propionic acid derivatives, ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofen, pyrazoles, phenylbutazone, oxyphenbutazone, feprazone, azapropazone, trimethazone and derivatives, esters, salts and mixtures thereof.
According to some embodiments, the compositions of the present invention further comprise a vasodilator. Suitable vasodilators include but are not limited to agents that modulate the activity of the enzyme nitric oxide synthase, nicotinic acid, ethyl nicotinate, amyl nitrite, amyl nitrate, ethyl nitrite, butyl nitrite, isobutyl nitrite, glyceryl trinitrate, octyl nitrite, sodium nitrite, sodium nitroprusside, clonitrate, erythrityl tetranitrate, isosorbide mononitrate, isosorbide dinitrate, mannitol hexanitrate, pentaerythritol tetranitrate, penetrinitol, triethanolamine trinitrate, trolnitrate phosphate (triethanolamine trinitrate diphosphate), propatylnitrate, nitrite esters of sugars, nitrite esters of polyols, nitrate esters of sugars, nitrate esters of polyols, nicorandil, apresoline, diazoxide, hydralazine, hydrochlorothiazide, minoxidil, pentaerythritol, tolazoline, scoparone, a beta-adrenergic blocker, an alpha- adrenoceptor blocker, a prostaglandin, sildenafil, dipyridamole, catecholamine, isoproternol, furosemide, prostaglandin, prostacyclin, enalaprilat, morphine, acepromazine, prazosin (a-blocker), enalapril, Captopril, amlodipine, minoxidil, tadalafil, vardenafil, phenylephrin, etilefein, caffeine, capsaicin, an extract capsicum, achillea millefolium (Yarrow), allium sativum (garlic), amoracia rusticana (horseradish), berberis vulgaris (barberry), cimicifuga racemosa (black cohosh), coleus forskholii (coleus), coptis (goldenthread), crataegus (hawthorn), eleutherococcus senticosus (Siberian ginseng), ginkgo biloba(ginkgo), melissa offiicnalis (lemon balm), olea europaea (olive leaf), panax ginseng (Chinese ginseng), petroselinum crispum (parsley), Scutellaria baicalensis (baical skullcap), tilia europaea (linden flower), trigonella foenum-graecum (fenugreek), urtica dioica (nettles), valeriana officinalis (valerian), viburnum (cramp, bark, black haw), veratrum viride (American hellebore), verbena officinalis (vervain), xanthoxylum americanum (prickly ash), zingiber officinale (ginger), rauwolfia serpentina (Indian snakeroot), viscum album, wild yam, sasparilla, licorice, damiana, yucca, saw palmetto, gotu kola (centella asiatica), yohimbine and salts, hazel nut, brazil nut and walnut, and derivatives, esters, salts and mixtures thereof.
According to some embodiments, the compositions of the present invention further comprise a vasoconstrictor. Suitable vasodilators include but are not limited to ephedrine, epinephrine, phenylephrine, angiotensin, vasopressin; an extract ephedra sinica (ma huang), polygonum bistorta (bistort root), hamamelis virginiana (witch hazel), hydrastis canadensis (goldenseal), lycopus virginicus (bugleweed), aspidosperma quebracho (quebracho bianco), cytisus scoparius (scotch broom) and cypressand and derivatives, esters, salts and mixtures thereof.
VITAMIN C
Vitamin C may be produced according to any method known in the art today or by any future method. The vitamin C may be from a natural source, semi- synthetic source, synthetic source or combinations thereof. It may be extracted from one or more animal or vegetable sources, produced by fermentation, chemically synthesized or modified, or any combination of the aforesaid. In another embodiment, vitamin C comprises the L-enantiomer of ascorbate.
According to some embodiments, vitamin C is provided as calcium ascorbate, which is non-acidic (pH neutral), making it gentle on the digestive system.
Examples Example 1.
A 30 year old male (70 kg) suffering from COVD-19 has had a fever for three days. He has a vims count of 105 PFU/ml (putting him into a fatality risk group).
He is provided with the following non-drug cocktail:
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0002
In fact, such a combination may prove even better, since, for example curcumin and EGCG are known to act synergistically in other models (Khafif et ah, 1998) and these compounds are active in several metabolic pathways. Thus, this kind of therapy could move this person from the fatality risk group into the survivors' group.
In some cases, it would be good, where possible, to provide this combination together with sodium, potassium, magnesium ions by drip infusion. Additionally, vitamin B 1 (thiamine), calcium, copper, zinc, selenium and iron ions to the infusion should improve the patient’s metabolism. Example 2.
A three-month old female baby (5 kg) suffering from COVID-19 has had a fever for
-j four days and is listless. She has a virus count of 10 PFU/ml (putting her into a fatality risk group).
She is provided with the following cocktail:
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
In fact, such a combination may prove even better, since, for example curcumin and EGCG are known to act synergistically in other models (Khafif et ah, 1998) and these compounds are active in several metabolic pathways. Thus, this kind of therapy could move this person from the fatality risk group into the survivors' group.
Example 3.
A 30 year old male (70 kg) suffering from COVID-19 has had a fever for five days. A blood test is positive for Ebola and he has a virus count of 109 PFU/ml (putting him into a fatality risk group). He is provided with the following cocktail:
Figure imgf000054_0002
Figure imgf000055_0001
Figure imgf000056_0001
Example 4.
A 30 year old male (70 kg) suffering from EVD (Ebola virus disease) has had a fever for seven days and has profuse internal bleeding and skin lesions. A blood test is positive for Ebola and he has a virus count of 1010 PFU/ml (putting him into a fatality risk group).
He is provided with the following cocktail:
Figure imgf000056_0002
Figure imgf000057_0001
Figure imgf000058_0001
In fact, such a combination may prove even better, since, for example curcumin and EGCG are known to act synergistically in other models (Khafif et ah, 1998) and these compounds are active in several metabolic pathways. Thus, this kind of therapy could move this person from the fatality risk group into the survivors' group. However, one cannot predict survival at a late stage of this disease.
Example 5.
A 30 year old male (70 kg) suffering from COVID-19 has had a fever for seven days and has profuse internal bleeding and skin lesions. A blood test is positive for Ebola and he has a virus count of 1010 PFU/ml (putting him into a fatality risk group).
He is provided with the following cocktail:
Figure imgf000059_0001
Figure imgf000060_0001
Example 6.
A 30 year old male (70 kg) suffering from EVD (Ebola virus disease) has had a fever for seven days and has profuse internal bleeding and skin lesions. A blood test is positive for Ebola and he has a virus count of 1010 PFU/ml (putting him into a fatality risk group).
He is provided with the following cocktail:
Figure imgf000061_0001
Figure imgf000062_0001
Example 7.
A 30 year old male (70 kg) suffering from COVID-19 has had a fever for seven days and has profuse internal bleeding and skin lesions. He has a virus count of 1010 PFU/ml (putting him into a fatality risk group).
He is provided with the following cocktail:
Figure imgf000063_0001
Figure imgf000064_0001
Example 8.
A three-month old female baby (5 kg) suffering from EVD (Ebola virus disease) has had a fever for four days and is listless. A blood test is positive for Ebola and she has a vims
-j count of 10 PFU/ml (putting her into a fatality risk group).
She is provided with the following cocktail:
Figure imgf000064_0002
Figure imgf000065_0001
Figure imgf000066_0001
Example 8 might be appropriate for use in pregnant women, too (but adjusted to the weight of the subject).
Example 9.
A six-month old male baby (7 kg) suffering from EVD (Ebola virus disease) has had a fever for four days and is listless. A blood test is positive for Ebola and he has a virus count of 10 PFU/ml (putting him into a fatality risk group).
He is provided with the following:
Figure imgf000066_0002
Figure imgf000067_0001
Example 10
A six-month old male baby (7 kg) suffering from EVD (Ebola virus disease) has had a fever for four days and is listless. A blood test is positive for Ebola and he has a vims count of 10 PFU/ml (putting him into a fatality risk group).
He is provided with the following:
Figure imgf000067_0002
Figure imgf000068_0001
It should be understood that these tables provide "sequential reduction in the viral load". However, when all products are provided together in one composition (cocktail), then this reduction should be in parallel. Moreover, if these doses of the composition are provided repeatedly, then the fold reduction should be repeated or near to repeated.
Example 11. Analysis of in vitro and in vivo neutralizing activity of different compounds against a virus such as Ebola virus:
For in vitro neutralization studies, plaque reduction neutralization assays (PRNT80) will be performed. To this end, six ten-fold serial dilutions of a concentrated compound (or cocktail of compounds) are mixed with 100 plaque-forming units of Ebolavirus Sudan Gulu at 37°C for 1 hour in the presence and absence of 5% guinea pig complement (Cedarlane) and used to infect Vero cell monolayers. Cells are overlaid with agarose and a second overlay containing 5% neutral red is added 8 days later. Plaques are counted the next day. Neutralization titers are determined to be the last dilution of serum that reduced the number of plaques by 80% compared with control wells. The experiments were repeated six times.
Exemplary Results
Figure imgf000068_0002
Figure imgf000069_0001
Example 12. Analysis of in vitro and neutralizing activity of different compounds against a corona virus:
Several compositions comprising eritadenine were prepared in a solvent, such as water, ethanol and DMSO. The range of the eritadenine concentration was from 1 nanomolar to 100 millimolar. It was found that non-pathogenic coronavims was inhibited at a concentration of 10 nanomolar up to 100 inhibition atlOO micromolar. The IC50 was around 30-60 nM.
It should be further noted that these cocktails may be provided in one or two mixed compositions, or some compounds may be provided separately. Additionally, according to some embodiments, the dosage regimes may be spread over 12 or over 24 hours, as is known in the art.
In cases where no concentration is provided, standard commercially available concentration/daily dosage of dosage forms of the same vitamin/antioxidant/dmg are assumed. Disorders deemed to be within the scope of the present invention include endogenous viral infections, responses to vaccinations and/or immunizations, allergic responses.
EXPERIMENTAL PROTOCOL
Obtain/purchase X different candidate compounds and store appropriately 1. Prepare solutions and dilutions of all candidate compounds a. Prepare compound A 1000X stocks as follows: b. In a U96 well sterile plate, add DMSO c. Prepare 100-200 mM stock solutions for each compound d. Make 5 serial dilutions X10 for each compound. e. Add sterile medium
2. Prepare virus a. Thaw vims b. Dilute viruses
3. Add compounds and viruses to the cells a. Take the plates from the incubator. b. Discard medium c. Add medium with virus d. Prepare control.
4. Incubate plates for 6 days at 35 °C
5. Cell Titer Glo Assay (luminescence assay) a. Thaw the CellTiter-Glo® Buffer, and equilibrate to room temperature prior to use. b. The CellTiter-Glo® Buffer may be stored at 4°C for up to 48 hours prior to use. c. Equilibrate the lyophilized CellTiter-Glo® Substrate to room temperature prior to use d. Transfer 10ml of CellTiter-Glo® Buffer into the amber bottle containing CellTiter-Glo® Substrate to reconstitute the lyophilized enzyme/substrate mixture. e. This forms the CellTiter-Glo® Reagent. f. Store unused reconstituted CellTiter-Glo® Reagent at -20°C. g. At end of incubation, equilibrate the plate and its contents at room temperature for approximately 30 minutes. h. Add IOOmI/well of CellTiter-Glo® Reagent (1 volume of cell titer glo to 1 volume of medium). i. Mix contents for 2 minutes on an orbital shaker to induce cell lysis j. Allow the plate to incubate at room temperature for 10 minutes to stabilize luminescent signal. k. Transfer lysates into a white 96 well plate.
6. Record luminescence using Clariostar BMG plate reader.
7. Analyze results.
The synergistic results of the experiment are displayed in Table 2.
Figure imgf000070_0001
Figure imgf000071_0001
Table 2- results of experiment- proof of concept that a methyltransferase inhibitor (DOT1L inhibitor EPZ 5676) and an SAHH inhibitor eritadenine act synergistically to inhibit replication of a corona virus. The references cited herein teach many principles that are applicable to the present invention. Therefore the full contents of these publications are incorporated by reference herein where appropriate for teachings of additional or alternative details, features and/or technical background.
The invention is capable of other embodiments and of being practiced and carried out in various ways. Those skilled in the art will readily appreciate that various modifications and changes can be applied to the embodiments of the invention as hereinbefore described without departing from its scope, defined in and by the appended claims.
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Claims

1. A pharmaceutical composition comprising at least one of a methyltransferase inhibitor compound, a viral enzyme inhibitor compound and an an SAHH (s- adenosylhomocysteine hydrolase) inhibitor compound, the composition adapted to inhibit replication of an RNA virus, said virus causing a pathogenic disease in a mammalian subject, wherein each of said compounds in said pharmaceutical composition has a molecular weight of less than 1000.
2. A pharmaceutical composition according to claim 1, wherein said RNA virus is a corona virus.
3. A compound according to claim 2, wherein said corona virus is SARS-COV-2.
4. A pharmaceutical composition according to claim 1, wherein said pharmaceutical composition is effective in treating COVID-19 disease in a mammalian patient.
5. A pharmaceutical composition according to claim 1, wherein said pharmaceutical composition comprises at least two compounds.
6. A pharmaceutical composition according to claim 5, wherein said at least two compounds are adapted to inhibit said RNA virus synergistically.
7. A pharmaceutical composition according to claim 6, wherein said methyl transferase inhibitor comprises at least one DOTH inhibitor.
8. A pharmaceutical composition according to claim 7, wherein said DOTH inhibitor is EPZ5676.
9. A pharmaceutical composition according to claim 6, further comprising at least one TNF alpha inhibitor.
10. A pharmaceutical composition according to claim 6, further comprising at least one collagen precursor.
11. A pharmaceutical composition according to claim 6, wherein said RNA virus is SARS-COV-2 and said composition comprises: c) at least one of an S-adenosyl homocysteine hydrolase (SAHH) inhibitor and a DOT1L inhibitor; and d) at least one TNF alpha inhibitor; and optionally at least one of: i. at least one a-glucosidase inhibitor; ii. at least one endothelial barrier enhancer; iii. at least one cathepsin B inhibitor; and iv. at least one collagen precursor.
12. A pharmaceutical composition according to claim 11, wherein each of said inhibitors, enhancers and precursors has a therapeutic index of more than 30.
13. A pharmaceutical composition according to claim 12, wherein each of said inhibitors, enhancers and precursors has a therapeutic index of more than 50.
14. A pharmaceutical composition according to claim 13, wherein each of said inhibitors, enhancers and precursors has a therapeutic index of more than 100.
15. A pharmaceutical composition according to claim 14, wherein each of said inhibitors, enhancers and precursors is a generally regarded as safe (GRAS) product.
16. A pharmaceutical composition according to claim 6, wherein said composition further comprises: c) zinc; and d) at least one of an S-adenosyl homocysteine hydrolase (SAHH) inhibitor and a DOT1L inhibitor.
17. A pharmaceutical composition according to claim 16, further comprising at least one anti-retroviral drug.
18. A pharmaceutical composition according to claim 16, further comprising at least one of creatine, Coenzyme Q10, Ginseng, and N-acetyl-L cysteine; glutathione, alpha lipoic acid, ajoene, allicin, limonene, Coenzyme Q10, quercetin, N-acetyl-L cysteine, resveratrol, and lycopene; choline and carnitine.
19. A pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is liquid.
20. A pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is solid.
21. A pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is suitable for oral, inhalable, parenteral, transdermal, intra-venous or intra-muscular administration.
22. A pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is a slow-release composition.
23. A pharmaceutical composition according to claim 22, wherein the slow release composition is formulated for provision by at least one of an intravenous drip, a trans dermal device and a slow-release oral formulation.
24. Use of a composition according to any one of claims 1 to 6, in the preparation of a medicament suitable for administration to a human in a pharmaceutically effective amount, wherein said medicament is suitable for treating a pathogenic disease or disorder in said human.
25. Use of a pharmaceutical composition according to any one of claims 7 to 24, in the preparation of a medicament suitable for administration to a human in a pharmaceutically effective amount, wherein said medicament is suitable for treating a pathogenic disease or disorder in said human.
26. A pharmaceutical composition according to claim 6, wherein said pharmaceutical composition further comprises any combination of compounds listed in table 1 in a pharmaceutically effective amount.
27. A pharmaceutical composition according to claim 6, further comprising copper and selenium.
28. A pharmaceutical composition according to claim 6, further comprising at least one of choloroquine, hydroxychloroquine an antimalarial drug, azithromycin, ivermectin, a quinine derivative, a choloroquine derivative, colchicine and combinations thereof.
29. A pharmaceutical composition according to claim 6, further comprising an adenine analog, an adenine derivative, an inosine analog, an inosine derivative, and combinations thereof.
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WO2023108905A1 (en) * 2021-12-16 2023-06-22 中国人民解放军军事科学院军事医学研究院 Use of inosine in preparation of drug for treating coronavirus disease 2019

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