WO2021053651A1 - Extrait de cocculus hirsutus pour le traitement de la covid-19 - Google Patents

Extrait de cocculus hirsutus pour le traitement de la covid-19 Download PDF

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Publication number
WO2021053651A1
WO2021053651A1 PCT/IB2020/059150 IB2020059150W WO2021053651A1 WO 2021053651 A1 WO2021053651 A1 WO 2021053651A1 IB 2020059150 W IB2020059150 W IB 2020059150W WO 2021053651 A1 WO2021053651 A1 WO 2021053651A1
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Prior art keywords
extract
pharmaceutical composition
composition
sinococuline
cov
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PCT/IB2020/059150
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English (en)
Inventor
Shilpi DHAWAN
Sadhna JOGLEKAR
Arshad Hussain KHUROO
Sanjay Jagannath GURULE
Bala Krishna PANIGRAHY
Sovan MAITI
Altaf LAL
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Sun Pharmaceutical Industries Limited
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Publication of WO2021053651A1 publication Critical patent/WO2021053651A1/fr

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    • 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)
    • A61K36/59—Menispermaceae (Moonseed family), e.g. hyperbaena or coralbead
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine

Definitions

  • the present disclosure relates to a composition comprising an extract of Cocculus hirsutus and pharmaceutical compositions comprising the extract for use in the prophylactic and curative treatment of an infection caused by a Coronavirus, more particularly, the novel Coronavirus strain known as SARS-CoV-2.
  • Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Associated CoronaVirus-2 (SARS-CoV-2), a highly contagious and novel virus belonging to the Coronoviridae family which has caused a global pandemic raising worldwide health concerns.
  • SARS-CoV-2 Severe Acute Respiratory Syndrome Associated CoronaVirus-2
  • the elderly and people with underlying health conditions are more susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm.
  • ARDS acute respiratory distress syndrome
  • cytokine storm SARS-CoV-2 appears to spread easily in the human population. Many healthcare workers have been infected, and more clusters of cases are being detected with each passing day.
  • the present disclosure provides a purified extract of a plant of Menispermeaceae family and its pharmaceutical compositions for use in the prophylactic and curative treatment of an infection caused by SARS-CoV-2.
  • the present disclosure also provides for a method of reducing viral load in the treatment of an infection caused by SARS-CoV-2 virus by administering the said extract or its pharmaceutical composition to a mammal in need thereof.
  • the present disclosure provides for a stable pharmaceutical composition comprising a therapeutically effective amount of the extract for use in prophylactic and curative treatment of SARS-CoV-2 virus infection in a mammal.
  • the present disclosure further provides a process for the preparation of said extract.
  • novel and inventive composition as provided by the present disclosure have been found to highly effective for administration to human patients infected by SARS-CoV-2 virus and have not shown any toxic effects at therapeutically effective dosages required for prophylactic and curative treatment of an infection caused by SARS-CoV-2 virus.
  • the biological material disclosed in the present disclosure is plant mass of Cocculus hirsutus that was procured from Madhya Pradesh, India.
  • the present disclosure provides for an extract of a plant of Menispermeaceae family for prophylactic and curative treatment of SARS-CoV-2 virus infection.
  • the plant is from genus Cocculus. More preferably, the plant is Cocculus hirsutus. It is a perennial climber and reaches 2 to 3 m above ground.
  • the present disclosure describes a purified extract and a pharmaceutical composition of such extract from Cocculus hirsutus which was found to be effective against SARS-CoV-2 virus infection when tested in clinical studies with human patients. Applicant found that the composition was safe and showed minimal to no side effects during such treatment with the composition.
  • the present disclosure provides an extract of Cocculus hirsutus and/or a pharmaceutical composition thereof for use in the prevention and treatment of an infection caused by SARS-CoV-2.
  • the disclosed extracts and compositions reduce viral load during the treatment and provides clinical improvement in the signs and symptoms associated with SARS-CoV-2 virus infection.
  • extract refers to a product of an extraction of one or more components obtained from plant of family Menispermaceae, particularly of genus Cocculus, more particularly from Cocculus hirsutus in any concentration comprising one or more of Sinococuline, Magnoflorine, Makisterone-A or 20-Hydroxyecdysone, or a combination thereof.
  • one or more components of Cocculus hirsutus is removed during the extraction, e.g., the plant mass is removed, and other components in the extract are separated into and concentrated in the extract.
  • the present disclosure provides for an extract which is a new composition comprising compounds and components in a concentration and ratio that is not found in nature. Additionally, the present disclosure provides for an extract which is free from one or more contaminants, which may, in some embodiments, cause side effects and/or reduce efficacy.
  • the extracts as described herein exhibit properties not found or appreciated in the Cocculus hirsutus plant, e.g., increased stability, increased effectiveness against SARS-CoV-2, increased bioavailability, increased solubility, reduced side-effects, etc.
  • the extract may be a purified extract or a crude extract.
  • the purified extract is an extract that is substantially free of pesticide residues, aflatoxins or any microbial impurities.
  • the purified extract may be an extract enriched for any one of the Sinococuline, Magnoflorine, Makisterone-A or 20-Hydroxyecdysone up to 85%, preferably 90%, more preferably 95% and even more preferably up to 99% w/w of the said extract.
  • the purified extract may also be enriched in such a way that at least two of Sinococuline, Magnoflorine, Makisterone-A or 20-Hydroxyecdysone comprise up to 85%, preferably 90%, more preferably 95% and even more preferably up to 99% w/w of the said extract.
  • the extract may be enriched for any one or more of the Sinococuline, Magnoflorine, Makisterone-A or 20-Hydroxyecdysone in varying ratios of (0.5 to 85):(0.05 to 75):(0.01 to 80):(0.05 to 70).
  • the said enrichment may be carried out any time before, during or after purification by methods commonly known in the art for such enrichment, such as by way of repeated purifications and/or fractionations using a combination of solvents and other conditions.
  • the extract may be present in the form of a liquid, semisolid, solid powder, solid cake, gel, paste, dispersion, solution or a distillate. In one embodiment, the extract is a dried extract.
  • SARS-CoV-2 or “COVID-19” or “COVID” or “novel coronavirus” are used interchangeably throughout the specification, and refer to the novel coronavirus related to the Sever Acute Respiratory Syndrome (SARS) virus, and named by International Committee on Taxonomy of Viruses (ICTV) as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • SARS Sever Acute Respiratory Syndrome
  • ICTV International Committee on Taxonomy of Viruses
  • treatment is meant to include therapeutic treatment, including prophylactic or preventive and curative treatments.
  • the term treatment may include administration of an extract or composition according to present disclosure or in combination with any Standard of Care prior to or following the onset of symptoms thereby preventing or removing signs and symptoms of the disease or disorder or as caused by SARS-CoV-2.
  • administration of a substance or a pharmaceutical composition prior to or after clinical manifestation of SARS-CoV-2 virus infection to prevent or combat the signs and symptoms and/or complications and disorders associated with SARS-CoV-2 virus infection comprises “treatment” of the disease.
  • treatment of a subject comprises inducing and maintaining remission of SARS-CoV-2 virus infection in a subject.
  • treatment of SARS-CoV-2 virus infection in a subject comprises maintaining remission of SARS-CoV-2 virus in a subject.
  • clinical improvement refers to the improvement in one or more clinical signs and symptoms or one or more primary and secondary endpoints for the determination of effectiveness of the anti- SARS-CoV-2 therapy in patients enrolled for treatment of SARS-CoV-2 infection.
  • improvement parameters include one or more of: i. A patient meeting discharge criteria; or ii. At least one point improvement (from the time of enrolment) in disease severity rating on an ordinal scale, wherein the scale is as follows: 1 - not hospitalized with resumption of normal activities;
  • the clinical improvement is characterized by at least two point improvement (from the time of enrolment) in disease severity rating on the said ordinal scale.
  • the hospital discharge criteria as in i) above may be one or both of resolution of symptoms and radiological improvement with a documented virological clearance in 2 samples at least 24 hours apart.
  • One or more of secondary endpoints in addition to the above parameters may include:
  • AEs Adverse Events
  • ARs Adverse Reactions
  • SAEs Serious AEs
  • SARs Serious ARs
  • the extract according to present disclosure is an extract of a plant from Menispermeaceae family. In one aspect, the extract according to present disclosure is an extract of a plant of genus Cocculus of Menispermeaceae family. In a preferred aspect, the extract according to present disclosure is an extract of Cocculus hirsutus. In another embodiment, the extract is a purified extract comprising Sinococuline not less than 0.5 % w/w, Magnoflorine not less than 0.05% w/w, 20-Hydroxyecdysone not less than 0.01%, Makisterone-A not less than 0.01% w/w, or a combination thereof.
  • the extract is a purified extract comprising Sinococuline not less than 1.0 % w/w, Magnoflorine not less than 0.1% w/w, 20-Hydroxyecdysone not less than 0.1%, Makisterone-A not less than 0.05% w/w, or a combination thereof
  • the extract is a purified extract comprising Sinococuline from about 0.5% w/w to about 85% w/w, preferably about 0.5% w/w to about 60% w/w, more preferably about 0.5% w/w to about 40% w/wand even more preferably about 0.5% w/w to about 20% w/w;
  • Sinococuline from about 0.5% w/w to about 85% w/w, preferably about 0.5% w/w to about 60% w/w, more preferably about 0.5% w/w to about 40% w/wand even more preferably about 0.5% w/w to about 20% w/w
  • Magnoflorine from about 0.05% w/w to about 75% w/w, preferably about 0.05% w/w to about 65% w/w, more preferably about 0.05% w/w to about 45% w/w and even more preferably about 0.05% w/w to about 25% w/w
  • Makisterone-A from about 0.0
  • the present provides an extract of a plant of Menispermaceae family, wherein the extract comprises therapeutically effective amount of one or more of Sinococuline from about 0.5% w/w to about 15% w/w, Magnoflorine about 0.05% w/w to about 3% w/w, Makisterone-A about 0.01% w/w to about 3% w/w, 20- Hydroxyecdysone about 0.05% w/w to about 3% w/w.
  • the extract is a purified extract comprising Sinococuline not less than 1.0 % w/w, Magnoflorine not less than 0.1% w/w, 20-Hydroxyecdysone not less than 0.1%, Makisterone-A not less than 0.05% w/w of the said extract, or a combination thereof.
  • the extract is a purified extract enriched for any one of the Sinococuline, Magnoflorine, Makisterone-A or 20-Hydroxyecdysone up to 85%, preferably 90%, more preferably 95% and even more preferably up to 99% w/w of the said extract.
  • the extract is a purified extract enriched in such a way that at least two of Sinococuline, Magnoflorine, Makisterone-A or 20-Hydroxyecdysone comprise up to 85%, preferably 90%, more preferably 95% and even more preferably up to 99% w/w of the said extract.
  • the present disclosure provides an extract of Cocculus hirsutus for use in the prophylactic and curative treatment of infection caused by SARS-CoV-2 virus.
  • the present disclosure provides a pharmaceutical composition comprising an extract of Cocculus hirsutus for use in prophylactic and curative treatment of infections caused by SARS-CoV-2 virus.
  • the pharmaceutical composition according to the present disclosure is an oral dosage form.
  • the oral dosage form is selected from powder, pellets, granules, spheroids, mini-tablets, caplets, tablets, sachet or a capsule comprising such powder, pellets, granules, spheroids, min-tablets or caplets, or a liquids selected from solutions, suspensions, emulsions, syrups, linctuses, elixirs or drops.
  • the present disclosure provides a pharmaceutical composition of the purified extract of Cocculus hirsutus for non-oral administration.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising an extract of Cocculus hirsutus administration of which to a patient suffering from SARS-CoV-2 viral infection provides clinical improvement of the signs and symptoms of the said infection.
  • the present disclosure provides a stable pharmaceutical composition comprising an extract of Cocculus hirsutus for clinical improvement of the signs and symptoms of SARS-CoV-2 virus infection.
  • the present disclosure provides a pharmaceutical composition comprising an extract of Cocculus hirsutus for reducing the SARS-CoV-2 viral load in a patient suffering from such viral infection.
  • the present disclosure provides a stable, pharmaceutical composition comprising therapeutically effective amount of Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone, or a combination thereof.
  • the stable pharmaceutical composition comprises a therapeutically effective amount of Sinococuline.
  • the pharmaceutical composition comprises a therapeutically effective amount of Sinococuline and Magnoflorine.
  • the present disclosure provides a stable, pharmaceutical composition
  • a stable, pharmaceutical composition comprising an extract of Cocculus hirsutus comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone, or a combination thereof.
  • the said extract is enriched with Sinococuline or Magnoflorine or both.
  • the present disclosure provides a stable, pharmaceutical composition
  • a stable, pharmaceutical composition comprising an extract of Cocculus hirsutus comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof for reducing viral load in a mammal in need thereof.
  • the present disclosure provides a stable, anti-COVID pharmaceutical composition
  • a stable, anti-COVID pharmaceutical composition comprising an extract of Cocculus hirsutus comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof for reducing SARS-CoV-2 viral load in a mammal in need thereof.
  • the extract or pharmaceutical composition according to present disclosure provides clinical improvement, the said clinical improvement is characterized by any one or more of the below parameters: (i) reduction in duration of supplemental oxygen requirement; (ii) reduction in duration of ECMO or mechanical ventilation; (iii) reduction in time to alleviation of cough; (iv) reduction in time to normalization of fever without use of antipyretics; (v) reduction in duration of hospitalization; or (vi) reduction in time to first negative SARS-CoV-2 RT-PCR in upper or lower respiratory tract specimen.
  • the said clinical improvement is characterized by any one or more of the below parameters: (i) reduction in duration of supplemental oxygen requirement; (ii) reduction in duration of ECMO or mechanical ventilation; (iii) reduction in time to alleviation of cough; (iv) reduction in time to normalization of fever without use of antipyretics; (v) reduction in duration of hospitalization; or (vi) reduction in time to first negative SARS-CoV-2 RT-PCR in upper or lower respiratory tract specimen.
  • administration of the extract or pharmaceutical composition according to present disclosure to a patient infected with SARS-CoV-2 virus infection provides clinical improvement in signs and symptoms, wherein the clinical improvement is characterized by a patient meeting at least one point, preferably at least two point improvement in disease severity rating on an ordinal scale after administration of the composition to the subject, the said ordinal scale defined as (i) not hospitalized with resumption of normal activities; (ii) not hospitalized, but unable to resume normal activities; (iii) hospitalized, not requiring supplemental oxygen; (iv) hospitalized, requiring supplemental oxygen; (v) hospitalized, requiring nasal high-flow oxygen therapy or noninvasive mechanical ventilation, or both; or(vi) hospitalized, requiring ECMO or invasive mechanical ventilation, or both.
  • the extract or pharmaceutical composition according to present disclosure provides clinical improvement in signs and symptoms of SARS-CoV-2 virus infection in a patient.
  • the extract or pharmaceutical composition according to present disclosure provides clinical improvement characterized by radiological improvement with a documented virological clearance in 2 samples tested at least 24 hours apart.
  • the extract or pharmaceutical composition according to present disclosure provides clinical improvement characterized by time to normalization of fever without use of one or more antipyretics in last 24 hours.
  • the extract or pharmaceutical composition according to present disclosure provides clinical improvement is further characterized by a negative SARS-CoV-2 RT-PCR of an upper or lower respiratory tract specimen.
  • the pharmaceutical composition comprises 25 mg to 1000 mg of the said extract.
  • the pharmaceutical composition according to the present disclosure for use in treatment of SARS-CoV-2 virus infection is administered to a patient in need thereof as an oral dose of 600 mg twice daily, 400 mg thrice daily, 300 mg four times daily or 200 mg six times daily.
  • the said composition is administered as an 800 mg oral dose twice daily, 400 mg oral dose four times daily or 200 mg oral dose eight times daily.
  • the said composition is administered as 500 mg oral dose once, twice, thrice or four times daily.
  • a pediatric dose may be selected from one fourth, one third, half or a two third of the adult total daily dose.
  • the said dose can be administered as a single dosage form or as multiple dosage forms equating to the required dose.
  • the present disclosure provides a pharmaceutical composition
  • Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof wherein the composition when administered to a patient in need thereof reduces viral load and improves the clinical signs and symptoms of SARS-CoV-2 infection.
  • the present disclosure provides a pharmaceutical composition
  • Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof for use in resolution of clinical signs and symptoms of SARS-CoV-2 viral infection in a patient, wherein the resolution is characterized by radiological improvement with a documented virological clearance in 2 samples at least 24 hours apart.
  • the present disclosure provides a pharmaceutical composition
  • Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof for use in resolution of clinical signs and symptoms of SARS CoV-2 infection in a patient wherein the resolution is characterized by time to normalization of fever without use of one or more antipyretics in last 24 hours.
  • the present disclosure provides a pharmaceutical composition
  • Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof for eradicating the SARS- CoV-2 viral infection from a patient infected by such virus wherein the eradication is characterized by a negative SARS-CoV-2 RT-PCR of an upper or lower respiratory tract specimen from such patient.
  • the present disclosure provides a pharmaceutical composition
  • Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof for clinical improvement of the signs and symptoms of SARS-CoV-2 viral infection in a patient by administering the extract in an oral dose of 600 mg twice daily, 400 mg thrice daily, 300 mg four times daily or 200 mg six times daily.
  • the said dose can be administered as a single dosage form or as multiple dosage forms equating to the required dose.
  • the present disclosure provides a stable, pharmaceutical composition
  • an extract of Cocculus hirsutus comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof for improving the clinical symptoms of SARS-CoV-2 infection, wherein the symptoms include cough, fever, shortness of breath, fatigue, expectoration, Myalgia, Rhinorrhea, Sore throat, diarrhea, Loss of smell (anosmia) or loss of taste (ageusia) preceding the onset of respiratory symptoms.
  • the stable, pharmaceutical composition according to present disclosure comprises a therapeutically effective amount of a Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A and 20-Hydroxyecdysone or a combination thereof, for alleviating the symptoms of SARS-CoV-2 viral infection in a human.
  • a Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A and 20-Hydroxyecdysone or a combination thereof, for alleviating the symptoms of SARS-CoV-2 viral infection in a human.
  • the stable, pharmaceutical composition according to present disclosure comprises a therapeutically effective amount of Cocculus hirsutus extract for improving the clinical signs and symptoms of a human patient infected with SARS-CoV-2 virus, wherein the improvement in clinical symptoms is characterized by any one or more of the measures selected from: reduction in duration of supplemental oxygen requirement; reduction in duration of mechanical ventilation; reduction in time to alleviation of cough; reduction in time to normalization of fever without use of antipyretics; reduction in duration of hospitalization; or reduction in time to first negative SARS-CoV-2 RT-PCR in upper or lower respiratory tract specimen.
  • the present disclosure provides a method of treatment of SARS-CoV-2 virus infection by administering the extract of Cocculus hirsutus in range of about 2 mg/kg to about 150 mg/kg body weight.
  • the said extract is a purified extract comprising one or more of Sinococuline, Magnoflorine, 20- Hydroxyecdysone or Makisterone-A.
  • the said extract is a crude extract of Cocculus hirsutus.
  • the present disclosure provides stable pharmaceutical composition
  • a therapeutically effective amount of an extract of Cocculus hirsutus comprising Magnoflorine not less than 0.1% w/w, Sinococuline not less than 1.0% w/w, 20-Hydroxyecdysone not less than 0.1% w/w and Makisterone-A not less than 0.05% w/w of the said extract for treating SARS-CoV-2 viral infection by administering the composition to a patient in need thereof.
  • the said composition may also be used alleviating the symptoms of SARS-CoV-2 virus infection in a patient.
  • oral administration of the pharmaceutical composition according to the present disclosure provides: a) maximum plasma concentration (Cmax) of Sinococuline at day 1 after a single oral dose administration of 100 mg of the said extract from about 1.4 ng/mL to about 110.0 ng/mL, after a single oral dose administration of 200 mg of the said extract from about 4.2 ng/mL to about 135.0 ng/mL, after a single oral dose administration of 400 mg of the said extract from about 8.0 ng/mL to about 205.0 ng/mL; or after a single oral dose administration of 600 mg of the said extract from about 14.0 ng/mL to about 240.0 ng/mL; or after a single oral dose administration of 800 mg of the said extract from about 13.0 ng/mL to about 255.0 ng/mL; or b) AUC 0-24 of Sinococuline at day 1 after a TID oral dose administration of 100 mg of the said extract from about 20.0 h*ng/mL to about 575.0 h*ng/
  • oral administration of the stable pharmaceutical composition according to the present disclosure provides: a) maximum plasma concentration (Cmax) of Sinococuline at day 10 after a single oral dose administration of 100 mg of the said extract from about 5.0 ng/mL to about 90.0 ng/mL, after a single daily oral dose administration of 200 mg of the said extract from about 13.5 ng/mL to about 300.0 ng/mL, after a single daily oral dose administration of 400 mg of the said extract from about 20.0 ng/mL to about 500.0 ng/mL; or after a single daily oral dose administration of 600 mg of the said extract from about 29.0 ng/mL to about 604.0 ng/mL; or after a single daily oral dose administration of 800 mg of the said extract from about 35.05 ng/mL to about 705.0 ng/mL; or b) AUC 0-24 of Sinococuline at day 10 of a single daily oral dose administration of 100 mg of the said extract from about 67.0 h*ng/mL to about
  • the present disclosure provides a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising an extract of Cocculus hirsutus comprising Sinococuline, wherein an area under the plasma concentration time curve to infinity (AUC ⁇ ) of Sinococuline is about 109 h*ng/ml to about 520 h*ng/ml after oral administration of a dose of 100 mg of the extract to a human subject at day 10.
  • AUC ⁇ plasma concentration time curve to infinity
  • the present disclosure provides a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising 400 mg extract of Cocculus hirsutus, wherein single oral administration of the said composition to a human subject provides maximum plasma concentration (Cmax) of Sinococuline at day 1 from about 8.0 ng/mLto about 205.0 ng/mL, or AUC 0-24 of Sinococuline at day 1 from about 135.0 h*ng/mL to about 2360.0 h*ng/mL.
  • Cmax maximum plasma concentration
  • the present disclosure provides a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising 600 mg extract of Cocculus hirsutus, wherein single oral administration of the said composition to a human subject provides maximum plasma concentration (Cmax) of Sinococuline at day 1 from about 140.0 ng/mL to about 240.0 ng/mL, or AUC 0-24 of Sinococuline at day 1 from about 263.0 h*ng/mL to about 2435.0 h* ng/mL.
  • Cmax maximum plasma concentration
  • the present disclosure provides a composition that is bioequivalent to the said composition as described in above embodiments.
  • bioequivalent as used in the present specification means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.
  • Two compositions can be considered as “bioequivalent” if the 90% Confidence Interval of the relative mean Cmax and AUC of the test to reference is within 70% to 130% or 74% to 124% or 75% to 125% or 80.00% to 125.00%.
  • AUC as used herein, means area under the plasma concentration-time curve, as calculated by the trapezoidal rule over the complete dosing interval, e.g., 24-hour interval.
  • Cmax as it is used herein is the highest plasma concentration of the drug attained within the dosing interval.
  • AUC (0-t) or “ AUC 0-24 ” as used herein means the area under the plasma concentration-time curve using linear trapezoidal summation from time zero to time t post-dose, where t is the time of the last measurable concentration Ct), for e.g., 24 hours.
  • trough levels as (Cr.ss) uscd herein refers to lowest concentration reached by a drug before administration of next dose.
  • the term “extraction” refers to the separation and removal of one or more components of Cocculus hirsutus, e.g., plant solids (e.g., fibers, cellulose, etc.) extracted from one or more fluids in the plant.
  • the extraction is a solid/liquid separation operation: e.g., a plant is placed in contact with a fluid (a solvent).
  • the plant components of interest are solubilised into solution with the solvent. The solution thus obtained is the desired extract.
  • the solvent will eventually be eliminated to arrive at the extract.
  • Separation operations can include mechanical means, e.g., homogenization, chemical means, e.g., acid, alcohol, or aqueous solubilization, and heating means.
  • the extraction includes afitration, precipitation, crystallization, concentration, or centrifugation step.
  • extraction may result into preferentially enriching the said extract with one or more of Sinococuline, Magnoflorine, 20-Hydroxyecdysone or Makisterone-A.
  • the extract of the present disclosure is an aqueous extract or an organic solvent extract, wherein the organic solvent is a polar or non-polar organic solvent.
  • the extraction is an alcoholic extraction, e.g., a C 1- C 4 alcohol extraction, a hydroalcoholic extraction, or an aqueous extraction.
  • carious parts of Cocculus hirsutus can be used, e.g., the extraction can be performed from stem or other parts of the plant, such as aerial parts or roots.
  • the extract is an aqueous extract. The solvents in the extract may be removed completely by evaporation to obtain a dried extract.
  • the dried extract may be lyophilized to form a powder, which can then be filled into a capsule of suitable size or compressed into tablets with or without pharmaceutically acceptable excipients.
  • the extract may be used as such in liquid or semisolid form without further drying along with a suitable pharmaceutically acceptable carrier for administration.
  • the extract is a purified extract.
  • the extract is a crude extract.
  • the extract is an alcoholic extract, or a hydro-alcoholic extract from stem or other parts of the plant, such as aerial parts or roots.
  • the extract will be derived from wet parts of the plant to arrive at an aqueous extract.
  • the solvents in the extract may be removed completely, e.g., by evaporation to obtain a dried extract.
  • the dried extract may be lyophilized to form a powder, which can then be filled into a vial or a capsule of suitable size or compressed into tablets with or without pharmaceutically acceptable excipients.
  • the extract may be used as such in liquid or semisolid form without further drying along with a suitable pharmaceutically acceptable carrier for administration.
  • alcoholic extract includes any alcohol-based extract, for example, methanolic, ethanolic, n-propanolic, isopropanolic, n-butanolic, iso-butanolic or t-butanolic extract of Cocculus hirsutus.
  • hydroalcoholic extract includes an extract prepared by using a mixture of alcohol and purified water. It may also include an extract prepared in denatured spirit with other organic solvents. Examples of alcohols are methanol, ethanol, n- propanol, isopropanol, n-butanol, iso-butanol, and t-butanol.
  • the ratio of alcohol to water in the hydroalcoholic extract may be in the ratio of 99: 1 to 1 :99, or 95:5 to 5:95, or 90: 10 to 10:90, or 80:20 to 20:80, or 70:30 to 30:70, or 60:40 to 40:60, or a 1: 1 mixture of alcohol and purified water.
  • aqueous extract includes a purified water extract of Cocculus hirsutus, also abbreviated as AQCH (Aqueous extract of Cocculus hirsutus).
  • the extracts of Cocculus hirsutus include (a) the extracts obtained by extraction of plant mass of Cocculus hirsutus with one or more solvents, and (b) the fractions obtained by partitioning of the extracts with one or more solvents.
  • the extracts of Cocculus hirsutus include (a) the extracts obtained by extraction of stem of Cocculus hirsutus with purified water, and (b) the fractions obtained by partitioning of the extracts with one or more solvents.
  • the solvents for extraction may be, for example, water; alcohols, for example, methanol, ethanol, propanol, isopropanol or butanol; ketones, for example, acetone or methyl isobutyl ketone; esters, for example, methyl acetate or ethyl acetate; halogenated hydrocarbons, for example, chloroform, dichloromethane or ethylene dichloride; petroleum fractions, for example, hexane, petroleum ether or heptane; or mixture(s) thereof.
  • alcohols for example, methanol, ethanol, propanol, isopropanol or butanol
  • ketones for example, acetone or methyl isobutyl ketone
  • esters for example, methyl acetate or ethyl acetate
  • halogenated hydrocarbons for example, chloroform, dichloromethane or ethylene dichloride
  • petroleum fractions for example, hexane
  • the solvents for partitioning may be, for example, water; petroleum fractions, for example, hexane, petroleum ether or heptane; halogenated hydrocarbons, for example, chloroform, dichloromethane or ethylene dichloride; esters, for example, ethyl acetate or methyl acetate; ketones, for example, acetone or methyl isobutyl ketone; alcohols, for example, butanol; ethers, for example, diethyl ether; or mixture(s) thereof.
  • plant mass of Cocculus hirsutus refers to the whole plant, which includes aerial parts, for example, fruits, flowers, leaves, branches, stem bark, stems, seeds or heartwood, and roots.
  • plant mass of Cocculus hirsutus refers to stem of Cocculus hirsutus.
  • the present disclosure provides enriched fraction of the extract for use in treatment of SARS-CoV-2 infection in mammals.
  • the extract may be enriched with respect to any of the flavonoid, alkaloids, steroids for e.g., Alkaloids like Sinococuline and Magnoflorine, steroids like Makisterone-A and 20-hydroxyecdysne or a combination thereof.
  • the extract may be enriched and standardized with respect to marker compounds, for e.g., Sinococuline, Magnoflorine, Makisterone-A, 20- Hydroxyecdysone or combination thereof.
  • the enriched extract may be prepared by using the respective solvent for the marker compound(s).
  • the solvent may be any of the solvent as disclosed above.
  • the present disclosure provides a composite extract of Cocculus hirsutus to reduce the viral load at an early stage in the treatment of COVID-19 infection in mammals.
  • the present disclosure provides extract of Cocculus hirsutus or pharmaceutical composition thereof for treatment of mild to moderate COVID- 19 infection. In yet another embodiment the present disclosure provides extract of Cocculus hirsutus or pharmaceutical composition thereof for treatment of moderate to severe COVID-19 infection or SARS-CoV-2 infection. In another embodiment, the present disclosure provides a pharmaceutical composition comprising an extract of Cocculus hirsutus for clinical improvement of the signs and symptoms of SARS-CoV-2 virus infection in a patient.
  • the patient with clinical severity of SARS-CoV-2 infection is categorized as mild, moderate or severe, wherein:
  • Mild infection is said to be with clinical presentation as patients with uncomplicated upper respiratory tract infection, may have mild symptoms such as fever, cough, sore throat, nasal congestion, malaise, headache and clinical parameters like no evidence of breathlessness or hypoxia;
  • Moderate infection is said to be with pneumonia with no signs of sever disease and clinical parameters in adults with presence of clinical features of dyspnea and or hypoxia, fever, cough, including SpO 2 £93% on room air, Respiratory Rate more or equal to 24 per minute and in case of child with presence of clinical features of dyspnea and or hypoxia, fever, cough, including SpO 2 ⁇ 94% (range 90-94%) on room air, Respiratory Rate more or equal to 24 per minute; Fast breathing (in breaths/min): ⁇ 2 months: 3 60; 2-11 months: 3 50; 1-5 years: 3 40.
  • Sever Pneumonia clinical parameters with clinical signs of Pneumonia plus one of the following; respiratory rate >30 breaths/min, severe respiratory distress, SpO 2 ⁇ 90% on room air and in case of child with cough or difficulty in breathing, plus at least one of the following: central cyanosis or SpO 2 ⁇ 90%; severe respiratory distress (e.g. grunting, chest in- drawing); signs of pneumonia with any of the following danger signs: inability to breastfeed or drink, lethargy or unconsciousness, or convulsions. Other signs of pneumonia may be present: chest in drawing, fast breathing (in breaths/min): ⁇ 2 months 360; 2- 11 months 350; 1-5 years 340; The diagnosis is clinical; chest imaging can exclude complications;
  • Acute respiratory distress syndrome clinical parameters at onset: new or worsening respiratory symptoms within 1 week of known clinical consult; chest imaging (Chest X ray and portable) bed side lung ultrasound): bilateral opacities, not fully explained by effusions, lobar or lung collapse, or nodules; Origin of Pulmonary infdtrates: respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g.
  • Oxygenation impairment in adults Mild ARDS: 200 mmHg ⁇ PaO 2 /FiO 2 £300 mmHg (with PEEP or CPAP 35 cm H 2 O) Moderate ARDS: 100 mmHg ⁇ PaO 2 /FiO 2 £200 mmHg with PEEP 35 cm H 2 O), Severe ARDS: PaO 2 /FiO 2 £ 100 mmHg with PEEP 35 cm H 2 O), When PaO 2 is not available, SpO 2 /FiO 2 £15 suggests ARDS (including in non- ventilated patients); Oxygenation impairment in Children Note Oxygenation Index (OI) and OSI (Oxygen Saturation Index); Use OI when available.
  • OI Oxygenation Index
  • OSI Oxygen Saturation Index
  • the extract of Cocculus hirsutus according to the present disclosure was surprisingly found to be useful both to be directly administrated to a mammal and to be used in the preparation of a pharmaceutical composition, with the dose in the range of approximately 0.05 mg/kg to approximately 1500 mg/kg body weight, particularly in the range of approximately 0.1 mg/kg to approximately 1200 mg/kg body weight, more particularly in the range of approximately 1 mg/kg to approximately 500 mg/kg body weight, more particularly in the range of approximately 2mg/kg to approximately 150 mg/kg body weight.
  • the composite extract or its composition may be administered once, twice, thrice or four times a day in patients with mild to severe COVID-19 infection, preferably mild to moderate COVID-19 infection with Standard of Care therapy.
  • SOC Standard of Care
  • SARS-CoV-2 standard or routine care administered to patient by a health care professional for the treatment of viral infections, in particular SARS-CoV-2, including, but not limited to, medication for fever, inflammation, antitussives, adequate nutrition, hypoxia including antipyretics, methyl prednisolone, dexamethasone, hydroxychloroquine, ventilation, oxygen support therapy or any other medication or treatment as instructed in an institutional protocol of various Clinical setup depending upon patients conditions and need of the therapy.
  • SARS-CoV-2 standard or routine care administered to patient by a health care professional for the treatment of viral infections, in particular SARS-CoV-2, including, but not limited to, medication for fever, inflammation, antitussives, adequate nutrition, hypoxia including antipyretics, methyl prednisolone, dexamethasone, hydroxychloroquine, ventilation, oxygen support therapy or any other medication or treatment as instructed in an institutional protocol of various Clinical setup depending upon patients conditions and need of the therapy.
  • the pharmaceutical the composition according to the present disclosure comprises a therapeutically effective amount of the extract of Cocculus hirsutus.
  • the composition according to the present disclosure is administered to a patient or mammal in need thereof in a dosage range of about 25 mg to about 1000 mg for once, twice or thrice or four times daily.
  • the composition may be administered in a dosage range of about 25 mg to about 1000 mg per day, such as for example 25mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg 950 mg or 1000 mg for once, twice or thrice a day.
  • composition according to present disclosure is administered at a dose of 400 mg, 600 mg or 800 mg for once, twice or thrice daily or four times daily.
  • the extract or the a composition according to present disclosure is administered to a patient in need thereof as 600 mg twice daily, 400 mg thrice daily, 300 mg four times daily or 200 mg six times daily.
  • the extract or the composition is administered to a patient in need thereof as 600 mg twice daily, 400 mg thrice daily, 300 mg four times daily or 200 mg six times daily, wherein the said dose can be administered as single dosage form or as multiple dosage forms equating to the required dose i.e., two 100 mg strengths can be combined to form a single 200 mg dosage or a 300 mg and a 100 mg strengths can be combined to give a single administration of 400 mg or one or more 100 mg strengths can be combined to form a higher dose.
  • the present disclosure provides pharmaceutical composition of Cocculus hirsutus extract, wherein the composition comprises about 10-80% of the extract by weight of the tablet. In another embodiment the present disclosure provides pharmaceutical composition of Cocculus hirsutus extract, wherein the composition comprises about 15-70% of the extract by weight of the tablet.
  • mammal herein refers to all mammals, by way of example only, humans, non-human primates, cows, dogs, cats, goats, sheep pigs, rats, mice and rabbits.
  • the present disclosure provides a pharmaceutical composition for use in the prevention and treatment of SARS-CoV-2 virus infection in mammals comprising a composite extract of Cocculus hirsutus and one or more pharmaceutically acceptable excipients.
  • the present disclosure provides a stable pharmaceutical composition comprising a therapeutically effective amount of a composite extract of Cocculus hirsutus for use in the prevention and treatment of SARS-CoV-2 in a mammal, wherein the composition when administered to a mammal in need thereof reduces the viral load.
  • the stable pharmaceutical composition of the present disclosure further comprises one or more pharmaceutically acceptable excipient.
  • pharmaceutical composition includes any composition that can effectively deliver the extracts of Cocculus hirsutus to the desired site of action to treat or prevent SARS-CoV-2 infection.
  • the extract and pharmaceutical compositions described herein can be administered via various modes of delivery, e.g., oral delivery, enteral/gastrointestinal delivery, parenteral delivery, intravenous delivery, topical delivery, rectal delivery, vaginal delivery, ophthalmic delivery, transmucosal delivery, nasal, pulmonary, or transdermal.
  • the pharmaceutical composition includes one or more pharmaceutically acceptable excipients.
  • the oral pharmaceutical composition can be in the form of powder, pellets, granules, spheroids, mini -tablets, caplets, tablets, or capsules.
  • the powder can be in the form of a lyophilized powder fdled, with pharmaceutically acceptable excipients, into a capsule of suitable size.
  • the pharmaceutical composition is in the form of a tablet.
  • the oral pharmaceutical composition can be present in the form of liquid, including but not limited to solutions, suspensions, emulsions or syrups.
  • the pharmaceutical composition comprising extract according to present disclosure is an oral dosage form selected from powder, pellets, granules, spheroids, mini -tablets, caplets, tablets, or capsules.
  • the pharmaceutical composition comprising extract according to present disclosure is storage stable at accelerated condition of 40 ⁇ 2°C/75 ⁇ 5% RH, long term storage condition of 30 ⁇ 2°C/75 ⁇ 5% RH or at 25 ⁇ 2°C/75 ⁇ 5% RH for at least 3 months.
  • the pharmaceutical composition comprising extract according to present disclosure comprises one or more of the pharmaceutically acceptable excipients selected from diluents, binders, disintegrants, lubricants, glidants, polymers, flavoring agents, surfactants, solvents, suspending agents, stabilizers, preservatives, antioxidants, buffers, and tonicity modifying agents.
  • the pharmaceutically acceptable excipients selected from diluents, binders, disintegrants, lubricants, glidants, polymers, flavoring agents, surfactants, solvents, suspending agents, stabilizers, preservatives, antioxidants, buffers, and tonicity modifying agents.
  • a “stable pharmaceutical composition” as used herein refers to a composition which is stable over extended period of time on storage as assessed from the content of one or more impurities in the composition as described in standard textbooks.
  • the stable pharmaceutical composition of the present disclosure were found to be stable for at least 3 months at accelerated condition of 40 ⁇ 2°C/75 ⁇ 5% RH; and for at least 3 months at long term storage condition of 30 ⁇ 2°C/75 ⁇ 5% RH and at 25 ⁇ 2°C/75 ⁇ 5% RH.
  • the product can be stored at room temperature for a shelf life of 6 months to 2 years.
  • a “therapeutically effective amount” as used herein refers to an amount of the extract of the disclosure sufficient to provide a benefit in the treatment or prevention of COVID-19, to delay or minimize symptoms associated with the infection or to cure or ameliorate the infection or cause thereof.
  • a therapeutically effective amount means an amount sufficient to provide a therapeutic benefit in-vivo.
  • pharmaceutically acceptable excipients includes diluents, binders, disintegrants, lubricants, glidants, polymers, flavoring agents, surfactants, preservatives, antioxidants, buffers, and tonicity modifying agents.
  • the pharmaceutical composition comprising extract according to present disclosure comprises intragranular excipients in a concentration range of about 8% to about 45% by weight of the composition and extragranular excipients in a concentration range of about 6% to about 38% by weight of the composition.
  • the pharmaceutical composition comprising extract according to present disclosure comprises diluent in a concentration range of about 5% to about 50% by weight of the composition and disintegrant in a concentration range of about 2% to about 33% by weight of the composition.
  • Non-limiting examples of diluents include microcrystalline cellulose, powdered cellulose, starch, pregelatinised starch, dextrates, lactitol, fructose, sugar compressible, sugar confectioners, dextrose, anhydrous lactose, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, and mixtures thereof.
  • Non-limiting examples of binders include a water-soluble starch, for example, pregelatinized starch; a polysaccharide, for example, agar, gum acacia, dextrin, sodium alginate, tragacanth gum, xanthan gum, hyaluronic acid, pectin, or sodium chondroitin sulfate; a synthetic polymer, for example, polyvinylpyrrolidone, polyvinyl alcohol, carboxy vinyl polymer, polyacrylic acid-series polymer, polylactic acid, or polyethylene glycol; a cellulose ether, for example, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, or hydroxypropyl methyl cellulose; and mixtures thereof.
  • Non-limiting examples of disintegrants include calcium carbonate, carboxymethyl cellulose or a salt thereof, for example, croscarmellose sodium, crosslinked povidone, low-
  • Non-limiting examples of lubricants/glidants include talc, magnesium stearate, hydrogenated vegetable oils, sodium stearyl fumarate, calcium stearate, colloidal silicon dioxide, Aerosil®, stearic acid, sodium lauryl sulphate, sodium benzoate, polyethylene glycol, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof.
  • Non-limiting examples of flavoring agents include synthetic flavor oils and flavoring aromatics; natural oils or extracts from plants, leaves, flowers, and fruits; and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, bay oil, anise oil, eucalyptus, thyme oil, vanilla, citrus oil, including lemon, orange, lime, and grapefruit, and fruit essences including apple, banana, grape, pear, peach, strawberry, raspberry, cherry, plum, pineapple, and apricot.
  • Non-limiting examples of surfactants include anionic surfactants, for example, a sulfonic acid or a salt thereof such as benzenesulfonic acid, dodecylbenzenesulfonic acid, or dodecanesulfonic acid; an alkyl sulfate, for example, sodium dodecyl sulfate or sodium lauryl sulfate; cationic surfactants, for example, a tetraalkylammonium salt such as a tetraalkylammonium halide, benzethonium chloride, benzalkonium chloride, or cetylpyridinium chloride; a nonionic surfactant, for example, a (poly) oxyethylene sorbitan long-chain fatty acid ester such as a polyoxyethylene sorbitan monolaurate, for example, a polysorbate; amphoteric surfactants, for example, a glycine compound such as dodecy
  • Non-limiting examples of buffers include phosphate buffers such as dihydrogen sodium phosphate, citrate buffers such as sodium citrate, meglumine, tri(hydroxymethyl) aminomethane, and mixtures thereof.
  • Non-limiting examples of tonicity modifying agents include sodium chloride, mannitol, dextrose, glucose, lactose, sucrose, and mixtures thereof.
  • Non-limiting examples of solvents for the preparation of the pharmaceutical composition include water; water miscible organic solvents, for example, isopropyl alcohol or ethanol; protic solvent or dipolar aprotic solvents; methylene chloride; acetone; polyethylene glycol; polyethylene glycol ether; polyethylene glycol derivatives of a mono- or di-glyceride; buffers; organic solvents; and combinations thereof.
  • the pharmaceutical excipient as used in the present disclosure can be used interchangeably for various roles in the pharmaceutical composition, and are not limited by their application as widely known.
  • a diluent may be used as binder in particular concentration.
  • the pharmaceutically acceptable excipient in the composition of the disclosure includes microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.
  • the present disclosure provides a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a therapeutically effective amount of a composite extract of Cocculus hirsutus for use in the treatment of SARS-CoV-2 infection in a mammal, wherein the composition when administered to a mammal in need thereof reduces the viral load.
  • the present disclosure provides a pharmaceutical composition comprising a composite extract of Cocculus hirsutus and one or more pharmaceutically acceptable excipients to reduce the viral load at an early stage in the treatment of SARS-CoV-2 infection in mammals.
  • the composition is a stable pharmaceutical composition. More preferably, the composition is a stable oral pharmaceutical composition.
  • the present disclosure provides a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a therapeutically effective amount of a composite extract of Cocculus hirsutus for use in the treatment of SARS-CoV-2 infection in a mammal, wherein the composition when administered to a mammal in need thereof is effective in a delayed treatment onset.
  • the present disclosure provides a stable pharmaceutical composition comprising a therapeutically effective amount of an extract of Cocculus hirsutus for use in the prevention of SARS-CoV-2 virus infection in a mammal.
  • the extract of Cocculus hirsutus comprises one or more constituents selected from the group consisting of flavonoids, lignans and alkaloids or combinations thereof.
  • the extract of Cocculus hirsutus comprises Magnoflorine as one of the alkaloids. More preferably, the composite extract of Cocculus hirsutus comprises Magnoflorine in an amount of 0.1% to 1% of the total weight of extract in the composition. In a preferred embodiment, the composite extract of Cocculus hirsutus comprises Magnoflorine in an amount of 0.45% of the total weight of extract in the composition.
  • the extract of Cocculus hirsutus comprises quercetin as one of the flavonoids. In another aspect of the embodiment, the extract of Cocculus hirsutus comprises Sinococuline as one of the alkaloid.
  • the present disclosure provides an extract of a plant of Menispermeaceae family, wherein the extract comprises Sinococuline from about 0.5% w/w to about 15% w/w, Magnoflorine from about 0.05% w/w to about 3% w/w, Makisterone-A from about 0.01% w/w to about 3% w/w, 20-Hydroxyecdysone from about 0.05% w/w to about 3% w/w., or a combination thereof.
  • the extract comprises Sinococuline not less than 1.0 % w/w, Magnoflorine not less than 0.1% w/w, 20- Hydroxyecdysone not less than 0.05%, Makisterone not less than 0.05% w/w, or a combination thereof.
  • composition of the present disclosure improves the clinical symptoms of human patient infected with SARS-CoV-2 virus, wherein the improvement in clinical symptoms is characterized by any one or more of the measures selected from: reduction in duration of supplemental oxygen requirement; reduction in duration of mechanical ventilation; reduction in time to alleviation of cough; reduction in time to normalization of fever without use of antipyretics; reduction in duration of hospitalization; or reduction in time to first negative SARS-CoV-2 RT-PCR in upper or lower respiratory tract specimen.
  • the extract and composition of the present disclosure were surprisingly found to be safe and didn’t show any toxic effect when administered in a therapeutically effective dose to the mammal in need thereof.
  • composition according to present disclosure comprising the Cocculus hirsutus extract were found to be safe and with minimal adverse events in the dosage range of about 25 mg to about 1000 mg once, twice or thrice or four times daily, more preferably in the range of about 200 to about 600 mg once, twice or thrice or four times daily.
  • the present disclosure provides a method of treating SARS- CoV-2 virus infection in a mammal comprising administering a pharmaceutical composition comprising a therapeutic effective amount of an extract of Cocculus hirsutus to a mammal in need thereof, wherein the extract reduces the viral load and improves the clinical signs and symptoms of infection.
  • the present disclosure provides a method for reducing the viral load at an early stage in the treatment of SARS-CoV-2 virus infection in mammals comprising administering an extract of Cocculus hirsutus to the mammals in need thereof.
  • the present disclosure provides a method of treating SARS- CoV-2 virus infection in mammals comprising administering an extract of Cocculus hirsutus to the mammals in need thereof. In one embodiment, the present disclosure provides a method for reducing the SARS-CoV-2 viral load in a patient suffering from such viral infection.
  • the present disclosure provides a method for improving clinical signs and symptoms of SARS-CoV-2 viral infection by administering a pharmaceutical composition comprising Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof wherein the composition when administered to a patient in need thereof reduces the SARS-CoV-2 viral load.
  • a pharmaceutical composition comprising Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof wherein the composition when administered to a patient in need thereof reduces the SARS-CoV-2 viral load.
  • the present disclosure provides a method for resolution of clinical signs and symptoms of SARS-CoV-2 viral infection in a patient, by administering a pharmaceutical composition comprising Cocculus hirsutus extract comprising
  • the present disclosure provides a method for resolution of clinical signs and symptoms of SARS-CoV-2 viral infection in a patient, by administering a pharmaceutical composition comprising Cocculus hirsutus extract comprising
  • the present disclosure provides a method for eradicating the SARS-CoV-2 viral infection in a patient, by administering a pharmaceutical composition comprising Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone, 20-Hydroxyecdysone or a combination thereof, wherein the eradication is determined by a negative SARS-CoV-2 RT-PCR of an upper or lower respiratory tract specimen from such patient.
  • the present disclosure provides a method for clinical improvement of the signs and symptoms of SARS-CoV-2 viral infection in a patient, by administering a pharmaceutical composition comprising Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof, in a dosage range of 100-800 mg once, twice, thrice or four times daily.
  • the clinical signs and symptoms as used herein include one or more symptoms comprising cough, fever, shortness of breath, fatigue, expectoration, Myalgia, Rhinorrhea, Sore throat, diarrhea, Loss of smell (anosmia) or loss of taste (ageusia) preceding the onset of respiratory symptoms, duration of supplemental oxygen requirement, duration of mechanical ventilation, duration of hospitalization, time to first negative SARS-CoV-2 RT- PCR in upper or lower respiratory tract specimen.
  • the present disclosure provides a method for treating SARS-CoV- 2 viral infection by administering to a patient in need thereof a stable, anti-COVID composition
  • a stable, anti-COVID composition comprising a therapeutically effective amount of an extract of Cocculus hirsutus comprising Magnoflorine not less than 0.1% w/w, Sinococuline not less than 1.0% w/w, 20-Hydroxyecdysone not less than 0.1% w/w and Makisterone-A not less than 0.05% w/w for alleviating the symptoms of SARS-CoV-2 virus infection in a human patient.
  • the present disclosure provides a method of inhibiting the secretion of cytokines in SARS-CoV-2 infection in mammals comprising administering an extract of Cocculus hirsutus to the mammals in need thereof.
  • the present disclosure provides a method of treatment of SARS-CoV-2 virus infection in mammals comprising administering a composite extract of Cocculus hirsutus to the mammals in need thereof, wherein the extract is effective in a delayed treatment onset.
  • the present disclosure provides a method of prevention of SARS-CoV-2 virus infection in mammals comprising administering an extract of Cocculus hirsutus to the mammals in need thereof.
  • the present disclosure provides use of a pharmaceutical composition comprising a therapeutic effective amount of an extract of Cocculus hirsutus for reducing the viral load in a method of treating SARS-CoV-2 virus infection in a mammal.
  • the present disclosure provides use of an extract of Cocculus hirsutus for a method of reducing the viral load at an early stage in the treatment of SARS-CoV-2 virus infection in mammals by administering the said composition.
  • the present disclosure provides use of an extract of Cocculus hirsutus for administering to a mammal for treatment of SARS-CoV-2 virus infection, wherein the composition reduces the SARS-CoV-2 viral load in the patient suffering from such viral infection.
  • the method of treatment according to present disclosure comprise administration of the extract or the pharmaceutical composition according to present disclosure in an oral dosage form and is administered once, twice, thrice or four times a day to a mammal in need thereof.
  • the treatment period is of 7-28 days, optionally extendible up to 60 days or up to 90 days or up to 180 days.
  • the present disclosure provides use of a pharmaceutical composition
  • a pharmaceutical composition comprising Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof in method for improving clinical signs and symptoms of SARS-CoV-2 viral infection by administering the composition to a patient in need thereof, wherein the composition reduces the SARS-CoV- 2 viral load.
  • the present disclosure provides use of a pharmaceutical composition
  • a pharmaceutical composition comprising Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof in a method for resolution of clinical signs and symptoms of SARS-CoV-2 viral infection in a patient, wherein the resolution is characterized by radiological improvement with a documented virological clearance in 2 samples at least 24 hours apart.
  • the present disclosure provides use of a pharmaceutical composition
  • a pharmaceutical composition comprising Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof in a method for resolution of clinical signs and symptoms of SARS-CoV-2 viral infection in a patient, wherein the resolution is characterized by time to normalization of fever without use of one or more antipyretics in last 24 hours.
  • the present disclosure provides use of a pharmaceutical composition comprising Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof in a method for eradication the SARS-CoV-2 viral infection in a patient, by administering, wherein the eradication is determined by a negative SARS-CoV-2 RT-PCR of an upper or lower respiratory tract specimen from such patient.
  • the present disclosure provides use of a pharmaceutical composition
  • a pharmaceutical composition comprising Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof in a method for clinical improvement of the signs and symptoms of SARS-CoV-2 viral infection in a patient, by administering, in a dosage range of 100-800 mg once, twice or thrice daily.
  • the dosage range for the composition is in the range of 200-600 mg once, twice or thrice daily.
  • the dosage range for the composition is in the range of 400-600 mg once, twice or thrice daily.
  • composition alleviates the symptoms of SARS-CoV-2 infection within a period of 7-28 days, optionally extendible up to 60 days, up to 90 days or up to 180 days.
  • the clinical signs and symptoms as used herein include one or more symptoms comprising cough, fever, shortness of breath, duration of supplemental oxygen requirement, duration of mechanical ventilation, duration of hospitalization, time to first negative SARS- CoV-2 RT-PCR in upper or lower respiratory tract specimen.
  • the present disclosure provides use of a pharmaceutical composition comprising Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof in a method of inhibiting the secretion of cytokines in SARS-CoV-2 infection in mammals comprising administering a composite extract of Cocculus hirsutus to the mammals in need thereof.
  • the present disclosure provides use of a pharmaceutical composition comprising Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof for a method of treatment of SARS-CoV-2 virus infection in mammals comprising administering a composite extract of Cocculus hirsutus to the mammals in need thereof, wherein the extract is effective in a delayed treatment onset.
  • the present disclosure provides use of a pharmaceutical composition comprising Cocculus hirsutus extract comprising Sinococuline, Magnoflorine, Makisterone-A, 20-Hydroxyecdysone or a combination thereof in a method of prevention of SARS-CoV-2 virus infection in mammals comprising administering a composite extract of Cocculus hirsutus to the mammals in need thereof.
  • the present disclosure provides use of the extract according to present disclosure for manufacture of a medicament useful for clinical improvement of the signs and symptoms of SARS-Cov-2 virus infection in a patient
  • the extract is prepared by a process comprises of extracting the plant mass of Cocculus hirsutus with one or more solvents, concentrating the extract, and drying the extract, or extracting the plant mass of Cocculus hirsutus with one or more solvents, concentrating the extract, adding water and partitioning the extract with one or more solvents, and drying the extract, or extracting the plant mass of Cocculus hirsutus with one or more solvents, concentrating the extract, extracting the extract with one or more solvents, and drying the extract.
  • the extraction of the plant mass of Cocculus hirsutus is done at a temperature in the range of about 50° to about 100°C.
  • the extraction of the plant mass of Cocculus hirsutus is done at a temperature of about 80° to about 85°C. In another aspect of the above embodiment, the extraction of the plant mass of Cocculus hirsutus is done at a temperature of about 60° to 65°C. In another aspect of the above embodiment, the drying of extract of Cocculus hirsutus is done at a temperature in the range of about 40° to about 95°C. In another aspect of the above embodiment, the drying of extract of Cocculus hirsutus is done at a temperature in the range of about 40° to about 45°C.
  • the drying of extract of Cocculus hirsutus is done at a temperature in the range of about 45° to about 50°C. In another aspect of the above embodiment, the drying of extract of Cocculus hirsutus is done at a temperature in the range of about 55° to about 65°C. In another aspect of the above embodiment, the drying of extract of Cocculus hirsutus is done at a temperature in the range of about 90° to about 95°C. In yet another aspect, the plant mass can be extracted from a dry part or a wet part of the plant.
  • the present disclosure provides a dried extract from Cocculus hirsutus, wherein the dried extract is obtained by: a) performing an C1-C4 alcohol extraction or an aqueous extraction, whereby the alcohol extraction or an aqueous extraction uses heat, thereby forming a liquid phase and a solid phase; b) separating the liquid phase from the solid phase, c) drying the liquid phase to obtain dried extract from Cocculus hirsutus, whereby the extract comprises less than 1% of the solid mass of the Cocculus hirsutus plant, whereby the dried extract is stable at 25°C for at least one week.
  • the dried extract according to present disclosure has a water concentration of not more than 5% w/w.
  • the dried extract according to present disclosure has a C1-C4 alcohol concentration of not more than 10,000 ppm.
  • the present disclosure provides a process for preparation of an extract of Cocculus hirsutus comprising: a) collecting dry or wet part of plant mass of Cocculus hirsutus; b) charging the plant mass into an extractor and adding solvent for extraction; c) heating the reaction mixture to obtain an extract; d) filtering the extract and collecting the filtrate; e) optionally filtering the residue at least once with solvent to obtain filtrate; f) concentrating the filtrate from any one of the above steps, and optionally drying to obtain said extract; g) optionally enriching the said extract with one or more of Sinococuline, Magnoflorine, 20-Hydroxyecdysone or Makisterone-A
  • the present disclosure provides a process of preparation of tablet composition of Cocculus hirsutus extract for use in the treatment of SARS-CoV-2 infection, the process comprising the steps of: i. sifting the extract and blending with pharmaceutically acceptable excipients; ii. lubricating the blend and compressing into tablets and iii. film coating the tablets.
  • the present disclosure provides a process of preparation of tablet composition of Cocculus hirsutus extract for use in the treatment of SARS-CoV-2 infection, the process comprising the steps of: i. blending the extract with pharmaceutically acceptable excipients; ii. granulating the blend with a solvent; iii. lubricating and compressing the blend into tablets and iv. film coating the tablets.
  • the present disclosure provides a process of preparation of tablet composition of Cocculus hirsutus extract for use in the treatment of SARS-CoV-2 infection, the process comprising the steps of: i. blending the extract with pharmaceutically acceptable excipients and compacting the mixture; ii. milling the compacts and blending with extragranular excipients; iii. lubricating the blend and compressing into tablets and iv. film coating the tablets.
  • the composite extract of Cocculus hirsutus may also be formulated into any other suitable oral dosage forms like powder, pellets, granules, spheroids, mini-tablets, caplets, tablets, sachet or a capsule comprising such powder, pellets, granules, spheroids, min-tablets or caplets or liquids selected from solution, suspensions, emulsions, linctuses, elixirs, drops or syrups.
  • the extract may be co-administered simultaneously or sequentially with one or more additional therapeutic agents.
  • the composition of the disclosure may further comprise one or more additional therapeutic agents.
  • the one or more additional therapeutic agents may be selected from related antiviral therapies or compounds such as which may provide symptomatic relief from the conditions, for examples antipyretic and analgesic drugs.
  • co-administration herein refers to administration of one or more additional therapeutic agents with the extract to a mammal.
  • the extract and additional therapeutic agents may be in a single pharmaceutical composition, or may be in separate pharmaceutical compositions or may include a Standard of Care therapy as defined in various Global COVID guidelines. Each of the extract or additional therapeutic agents may be administered through the same or different routes of administration simultaneously of sequentially.
  • Example 1 Preparation of 95:5 Ethanol: purified water extract of Cocculus hirsutus
  • the plant mass of Cocculus hirsutus (1kg) was charged into an extractor at ambient temperature*.
  • a mixture of ethanol and purified water (95:5; 6L) was added and the reaction mixture was heated at a temperature of 60-65°C for about 3 hours.
  • the extracted mass was filtered, collected and stored in a container.
  • the extraction and filtration steps were repeated twice with a mixture of ethanol and purified water (95:5; 3L).
  • the three filtered extracts were combined and concentrated to the maximum possible extent under reduced pressure at a low temperature.
  • the resulting extract was decanted into stainless steel trays, and then dried under vacuum at 45-50°C until ethanol content was not more than 10000 ppm and the moisture content was not more than 5%.
  • the dried extract was cooled to about 20-25°C and unloaded at controlled humidity (RH NMT 40%).
  • Example 2 Preparation of 1:1 Ethanol: purified water extract of Cocculus hirsutus The plant mass of Cocculus hirsutus (1kg) was charged into an extractor at ambient temperature* . A mixture of ethanol and purified water (1: 1; 6L) was added and the reaction mixture was heated at a temperature of 60-65°C for about 3 hours. The extracted mass was filtered, collected and stored in a container. The extraction and filtration steps were repeated twice with ethanol and purified water (1: 1, 3L). The three filtered extracts were combined and concentrated to the maximum possible extent under reduced pressure at a low temperature.
  • the resulting extract was decanted into stainless steel trays, and then dried under vacuum at 45-50°C until the ethanol content was not more than 10000 ppm and the moisture content was not more than 5%.
  • the dried extract was cooled to about 20-25°C and unloaded at controlled humidity (RH NMT 40%).
  • ambient temperature includes a temperature ranging from about 18°C to about 25°C.
  • Example 4 Preparation of Tablets from the extract of Cocculus hirsutus using direct compression
  • Step 1 material along with Magnesium aluminium trisilicate was sifted through # 14 mesh (1.4 mm);
  • Microcrystalline cellulose, Colloidal silicon dioxide and Croscarmellose were passed through # 25 mesh(600 m); 5. The material from steps 3 and 4 were mixed in a blender with the step 2 material;
  • step 6 The blend obtained from step 5 was lubricated with magnesium stearate and compressed into tablets;
  • Opadry green was dispersed in purified water to prepare a dispersion
  • step 4 The dried material from step 3 was passed through 16 mesh (1 mm);
  • Microcrystalline cellulose, Colloidal silicon dioxide and Croscarmellose were passed through # 25 mesh (600 m);
  • step 7 The blend obtained from step 7 was lubricated with magnesium stearate and compressed into tablets;
  • Example 6 Preparation of Tablets from the extract of Cocculus hirsutus using dry granulation technique
  • step 1 material was sifted along with Magnesium aluminium trisilicate through # 14 mesh (1.4 mm);
  • Magnesium stearate was sifted through #36 mesh (420 m) and mixed with step 2 material in a blender;
  • step 4 The compacts obtained from step 4 were milled; 6. The extra granular excipients were sifted and blended with magnesium stearate to obtain a lubricated blend;
  • Opadry green was dispersed in purified water to prepare a dispersion
  • Example 7 Various strengths of the extract based composition were prepared following the below manufacturing method:
  • step 3 Compacted material of step 3 and passed the compacts through upper granulation screen followed by lower granulation screen followed by sifting over suitable sieve until the desired percentage of granules were obtained;
  • step 6 Sifted a second set of excipients (extragranular part) as in step 1 through suitable sieve, and then blended them with step 5 material; 7. Sifted lubricant through suitable sieve and blended with step 6 material followed by compression of the blend to get sufficient strength;
  • the Extract used in below examples is an aqueous extract of Cocculus hirsutus.
  • Example-7.1 Preparation of tablets of strength 25 mg, 50 mg, 100 mg and 300 mg:
  • Example-7.2 Preparation of tablets of strength 400 mg and 500 mg:
  • Example-7.3 Preparation of tablets of strength 600 mg and 800 mg:
  • Example 7.4 Stability data of AQCH and AQCH tablets with respect to content of
  • Example 8 Biological activity Evaluation of the efficacy of the pharmaceutical composition comprising aqueous extract of Cocculus hirsutus in treatment of SARS-CoV-2 infected patients:
  • Day of discharge can be day 14 or later as per patient’s clinical condition and includes the following evaluation:
  • ECG on rest of the days was done as per given schedule); Body Temperature (Body temperature was measured every 4- 6 hourly till fever subsides, every 24 hours ( ⁇ 10 minutes) until day of discharge, and as clinically indicated); RT-PCR for SARS-CoV-2 viral load (was repeated on Day 14 if patient was discharged based on 2 negative RT-PCR test results before day 14); Arterial Blood Gas; Hematology; Biochemistry (ALT/AST, S. creatinine, BUN, ALP); Exploratory markers* (D-dimer, CRP, LDH and Serum ferritin); Chest X-RAY/ CT Scan; Adverse events; and Concomitant Medications.
  • the selected patients as per the inclusion and exclusion criteria below were administered tablets of aqueous extract of Cocculus hirsutus 400 mg thrice daily (every 8 ⁇ 1 hours) before meal, preferably at same time, for 10 days.
  • G6PD glucose-6-phosphate dehydrogenase
  • Patient had any concurrent medical condition or uncontrolled, clinically significant systemic disease e.g., heart failure, COPD, hypertension, liver disease, chronic respiratory failure, chronic kidney disease, diabetes, anaemia etc.
  • systemic disease e.g., heart failure, COPD, hypertension, liver disease, chronic respiratory failure, chronic kidney disease, diabetes, anaemia etc.
  • Vital signs (pulse rate, respiratory rate, systolic and diastolic pressure, oxygen saturation by SaO 2 or SpO 2 ) at screening, within 10 minutes before first dosing on day 1 and then every 24 hours ( ⁇ 10 minutes) until discharged (on day 11 or later), at the FU visit on Day 17 and as clinically indicated;
  • Body temperature (oral) was measured at screening, within 30 minutes before first dosing on day 1 and then every 24 hours ( ⁇ 10 minutes) until day of discharge (on day 11 or later), at the FU visit on day 17 (or later) and as clinically indicated;
  • RT-PCR for Corona virus titer At screening, within 30 minutes before first dosing on day 1 and then every 24 hours ( ⁇ 10 minutes) till day 10 and on Discharge.
  • Adverse events were classified according to their severity based on CTCAE v 5.0 criteria. Any clinically significant abnormal changes from baseline in the concurrent medical condition(s), physical examination and/or laboratory data were recorded as an AE. 12 lead ECG was conducted at screening, 1-hour post-dose on day 1 and repeated after 24 hours ( ⁇ 10 minutes) until day 10, on day of discharge and as clinically indicated. Any subject who was judged by the treating physician/ PI to be at risk for developing severe disease was managed as per standard of care.
  • the Primary end points were:
  • Hospital Discharge Criteria was defined as resolution of symptoms, radiological improvement with a documented virological clearance in 2 samples at least 24 hours apart: reduction in viral load in nasopharyngeal swab and percentage of subject achieving Clinical Cure (clinical Cure was defined as negative viral load of the respiratory specimen for two consecutive times when measured on frequency of greater than or equal to one day, improvement in lung image, normal body temperature for more than 3 days, and improvement in clinical manifestation).
  • Clinical improvement was defined as patient meeting discharge criteria OR a 2 point improvement (from time of enrolment) in disease severity rating on the 7-point ordinal scale
  • the ordinal scale was an assessment of the clinical status at the first assessment of a given study day. The scale was as follows:
  • Table I Proportion of patients showing clinical improvement [Time Frame: Day 141 - PP population:
  • Table III Proportion of patients showing clinical improvement [Time Frame: Day 28]
  • Table V Analysis of Time (Day) to first negative SARS-CoV-2 RT-PCR in upper or lower respiratory tract specimen [Time Frame: up to 28 days] - PP population: Table VI: Analysis of Time (Day) to normalization of fever without use of antipyretics in last 24 hours [Time Frame: up to 28 days] - PP population:
  • Table VIII Summary of duration (Days) of supplemental oxygen therapy [Time
  • Table X Summary of duration (Days) of Hospitalization [Time Frame: up to 28 days]
  • Table XI Number (%) of patients with TEAE(s) by SOC and PT - Safety Population
  • Time to clinical improvement 8 vs. 11 days
  • Time to first RT-PCR negative 7 vs. 10 days
  • Time to normalization of fever 6 vs. 7 days
  • the pharmaceutical compositions of the extract according to present disclosure are superior and effective in the treatment of patients with COVID-19 with no significant side-effects.
  • the therapy was found to be promising: in relieving the clinical symptoms or improving the condition of the patient as defined in the primary and secondary endpoints as: a. time to clinical improvement of the condition; b. time to normalization of fever without antipyretics; c. time to first RT-PCR negative results; d. duration of hospitalisation; e. duration of oxygen therapy or mechanical ventilation.
  • Example 9 Safety and Pharmacokinetic Study data for the tested samples:
  • Sinococuline is identified as biomarker and analyzed. There is linear increase in Cmax and AUC with ascending dose up to 400 mg. The Tmax observed at day 1 and day 10 and across doses is consistent. The Tmax ranged between 1.0 to 1.5 hours across doses.
  • Trough levels at steady state observed based on various patient data at dose 100 mg. 200 mg and 400 mg at day 10 is shown below:
  • the trough levels at steady state (Cr,ss ) of Sinococubne from day 3-10 is ranging from about 2.8 to about 31.0 ng/mL at a thrice daily oral dose administration of 100 to 400 mg of the said extract, wherein the steady state is achieved at around day 3.
  • an area under the plasma concentration time curve to infinity (AUC ⁇ ) of Sinococubne is found to be in a range of about 109.0 h*ng/ml to about 520.0 h*ng/ml after oral administration of a dose of 100 mg of the extract to a human subject at day 10.
  • HPLC fingerprinting 100 mg of AQCH was transferred in 20 ml volumetric flask and added ⁇ 10 ml of diluent with sonication/shaking/stirring for 5-10 minutes to dissolve. The volume was made up with diluent, mixed and filtered through 0.45 mm filter for HPLC fingerprinting. It was performed on RP18e Purospher-STAR (Hibar) (250 x 4.6 mm; 5 pm) column. The mobile phase containing a buffer (0.1% formic acid in water) and acetonitrile was used at the flow rate of 0.65 ml/ min at a column temperature of 30 °C at 254 nm wavelength.
  • volume of injection was 5 pi and a total run time of the assay was 75 min.
  • a gradient program was used as follows: 0-15 min, 00-05% B; 15-40 min, 05-20% B; 40- 55 min, 20-30% B; 55-65 min, 30-60% B; 65-68 min, 60-00% B and 68-75 min, 00% B.
  • SI Fig For the isolation (SI Fig), 500 g of AQCH was suspended in distilled water and partitioned between ethyl acetate (A) and H20 (B). The aqueous layer (B) was basified with NH40H solution (pH 9) and then extracted with chloroform, CHC13.
  • the CHC13 layer (C) was further purified through repeated column chromatography in neutral alumina and eluted with a gradient of CHC13-MeOH (100:0 to 0: 100) to obtain Compound 1 as major constituent along with Compound 2.
  • the Aqueous layer (D) was lyophilized (480.5 g) and suspended in methanol.
  • the methanol soluble portion (400.0 g) was purified by column chromatography (silica gel, 100-200 mesh), eluted with a gradient of CHC13-MeOH (100:0 to 0: 100, 500 ml, collected volumes of each fraction), and concentrated, giving fifty fractions (Fr.l-Fr.50) and their composition was monitored by TLC. Those showing similar TLC profiles were grouped into six major fractions (Fr- la to Fr-5a). Fraction Fr-2a afforded two UV active compounds as crystals.
  • the ethyl acetate soluble fraction (A) was subjected to column chromatography (silica gel, 100-200 mesh), eluted with a gradient of CHC13-MeOH (100:0 to 0:100, 250 ml, collected volumes of each fraction), and concentrated, giving thirty fractions (Fr.51-Fr.80).
  • Compound 5 was obtained from fractions Fr. 66-Fr. 70 in pure. All the isolated compounds 1-5 were identified by detailed spectral analysis 1D and 2D NMR, and HRESI-MS data and comparisons with the reported spectral data.

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Abstract

La présente invention concerne un extrait de Cocculus hirsutus pour le traitement prophylactique et/ou curatif d'une infection provoquée par le virus du SARS-CoV-2. L'invention concerne également une composition pharmaceutique stable comprenant ledit extrait. La présente invention concerne en outre un procédé pour réduire la charge virale et/ou atténuer les signes et les symptômes d'une infection par le virus du SARS-CoV-2 chez un mammifère infecté par le virus du SARS-CoV-2 par administration de l'extrait ou de la composition comprenant celui-ci au mammifère en ayant besoin.
PCT/IB2020/059150 2020-04-27 2020-09-30 Extrait de cocculus hirsutus pour le traitement de la covid-19 WO2021053651A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022084908A1 (fr) * 2020-10-21 2022-04-28 Sun Pharmaceutical Industries Limited Compositions d'inhibition du virus sras-cov-2
WO2023204775A1 (fr) 2022-04-21 2023-10-26 Ipmc Group Ilac San. Ve Tic. Ltd. Sti. Produit à base d'herbes destiné à être utilisé dans la prévention et/ou le traitement de la covid-19

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"CSIR Seeks Approval for Human Trials to Test Efficacy of Botanical Medicine Against Covid-19", NEWS18 INDIA, 25 April 2020 (2020-04-25), XP055808728 *
BALKRISHNA A. ET AL.: "Tinospora cordifolia (Giloy) may curb COVID-19 contagion: Tinocordiside disrupts the electrostatic interactions between ACE2 and RBD", AUTHOREA, 16 April 2020 (2020-04-16), DOI: 10.22541/au.158707095.53639175 *
GEORGE, M. ET AL.: "Tinospora cordifolia; A Pharmacological Update", THE PHARMA INNOVATION, vol. 5, no. 7, 2016, pages 108 - 111, XP055808731 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022084908A1 (fr) * 2020-10-21 2022-04-28 Sun Pharmaceutical Industries Limited Compositions d'inhibition du virus sras-cov-2
WO2023204775A1 (fr) 2022-04-21 2023-10-26 Ipmc Group Ilac San. Ve Tic. Ltd. Sti. Produit à base d'herbes destiné à être utilisé dans la prévention et/ou le traitement de la covid-19

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