WO2022220767A1 - A pharmaceutical product for prophylaxis and treatment of viral diseases caused by coronavirus (sars-cov-2 or covid-19) - Google Patents

A pharmaceutical product for prophylaxis and treatment of viral diseases caused by coronavirus (sars-cov-2 or covid-19) Download PDF

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Publication number
WO2022220767A1
WO2022220767A1 PCT/TR2021/051615 TR2021051615W WO2022220767A1 WO 2022220767 A1 WO2022220767 A1 WO 2022220767A1 TR 2021051615 W TR2021051615 W TR 2021051615W WO 2022220767 A1 WO2022220767 A1 WO 2022220767A1
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WIPO (PCT)
Prior art keywords
weight
pharmaceutical product
range
product according
cineole
Prior art date
Application number
PCT/TR2021/051615
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English (en)
French (fr)
Inventor
Seçkin ÖZSELANİK
Meryem ÖZSELANİK
Original Assignee
Ena Farma Sağlik Ürünleri̇ İmalat Ve Diş Ti̇caret Anoni̇m Şi̇rket
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Priority claimed from TR2021/006518 external-priority patent/TR2021006518A2/tr
Application filed by Ena Farma Sağlik Ürünleri̇ İmalat Ve Diş Ti̇caret Anoni̇m Şi̇rket filed Critical Ena Farma Sağlik Ürünleri̇ İmalat Ve Diş Ti̇caret Anoni̇m Şi̇rket
Publication of WO2022220767A1 publication Critical patent/WO2022220767A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic 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
    • A61K31/352Heterocyclic 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 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/13Coniferophyta (gymnosperms)
    • A61K36/15Pinaceae (Pine family), e.g. pine or cedar
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/61Myrtaceae (Myrtle family), e.g. teatree or eucalyptus

Definitions

  • the invention relates to a pharmaceutical product which is effective in inhibiting ACE2 and developed for use in the prophylaxis and treatment of the diseases such as coronavirus.
  • the angiotensin converting enzyme 2 (ACE2) is an enzyme bound to the outer surface of the cells (cell membrane) in the arteries, lungs, kidneys, heart, nasal mucosa and intestines.
  • the ACE2 enzyme is involved in the natural balance of our body, and there are pathologies which can be associated with this enzyme. Especially since December 2019, this enzyme has come to the fore in the infections caused by the Coronavirus (Covid-19) which has caused the serious health problems and deaths throughout the world, and a wide variety of the pharmaceutical products which are believed to be effective against the coronavirus through the ACE-2 enzyme inhibition have been tried, and the studies and publications have been made.
  • the ACE2 enzyme has been recognized as the specific receptor of the SARS-COV-2 virus. The strong interaction of the S protein of the SARS-COV-2 virus and the catalytic domain of the ACE2 enzyme is the first step in the development of the corona disease.
  • Alpha-Pinene the major compound of the fir essential oil (Abies sibirica), is an organic compound of the terpene class, one of two isomers of pinene.
  • 1 ,8-cineole is a terpenic aromatic main component of many plants including salvia, rosemary, myrrh, myrtle leaf, tea tree oil and eucalyptus leaves.
  • Abies sibirica and Eucalyptus (1,8-cineole) essential oil for the antiviral activity such as HN group, HIV, Herpes simplex (HSV-1)
  • HN group HN group
  • HIV Herpes simplex
  • SARS-COV-2 coronavirus
  • the effectiveness of the pharmaceutical product found as a result of the study is not included in the state of the art.
  • An object of the invention is to use the pharmaceutical product showing the antiviral activity on the coronavirus (SARS-COV-2) in the prophylaxis and treatment of the disease.
  • SARS-COV-2 coronavirus
  • Another object of the invention is to use the pharmaceutical product representing the inhibition of the ACE2 receptor in the prophylaxis and treatment of the disease.
  • Abies sibirica (alpha-pinene), preferably abies sibirica essential oil, Eucalyptus (1,8-cineole), preferably eucalyptus globulus essential oil, and pure 1,8-cineole used in the formulation of the pharmaceutical product of the invention represent the antiviral activity on the coronavirus (SARS-COV-2) and inhibit the intracellular replication of the virus by inhibiting the ACE2 receptors.
  • the formulation of the invention comprises the standardized products of plant origin and will be used in the prophylaxis and treatment of the diseases such as coronavirus in such a way that it will be effective in terms of the ACE2 inhibition.
  • the natural active ingredients in the invention are standardized according to the pharmacopoeia.
  • the standardized raw material comprises the same amount of the active ingredient in the same quality for each production batch, for each bottle in the batch, and for each drop in the bottle.
  • the fir oil comprises alpha pinene within the standard ranges in order to obtain a standardized product.
  • the natural components used in the invention are Abies sibirica (the standardized major compound there of is alpha pinene), and/or Eucalyptus (the standardized compound there of is 1,8-cineole), and 1 ,8-cineole as pure substance.
  • Abies sibirica the standardized major compound there of is alpha pinene
  • Eucalyptus the standardized compound there of is 1,8-cineole
  • 1 ,8-cineole as pure substance.
  • the activities of the compounds are measured based on the major compounds thereof or the phytochemical to which they are standardized. Therefore, the standardized product formulation of the raw materials has been emphasized in the invention, independently of the effect of alpha pinene and cineole.
  • the invention is specifically an in-vitro applied study of the inhaler drop product showing the ACE2 enzyme inhibition and showing the antiviral activity on coronavirus (COVID-19 (SARS-COV-2)).
  • the formulation in the pharmaceutical product of the invention prevents the occurrence of the corona disease by inhibiting the strong interaction of the S protein of the SARS-COV-2 virus and the catalytic domain of the ACE2 enzyme.
  • the formulation of the pharmaceutical product of the invention for the treatment and/or prevention of the coronavirus disease (COVID-19 (SARS-COV-2)) in humans and/or for the inhibition of the ACE2 receptor comprises, in the predetermined proportions, a pure active ingredient 1 ,8-Cineole which is isolated from any essential oil or synthetically obtained.
  • the formulation of the pharmaceutical product of the invention comprises, more specifically, the fir needle oil (Abies sibirica), preferably at least one component of the fir needle oil in the predetermined proportions, and/or Eucalyptus (1 ,8-Cineole), preferably at least one component of eucalyptus essential oil, and 1,8-Cineole in pure form in the predetermined proportions.
  • the fir needle oil (Abies sibirica)
  • Eucalyptus (1 ,8-Cineole) preferably at least one component of eucalyptus essential oil, and 1,8-Cineole in pure form in the predetermined proportions.
  • the fir needle oil which is used in the invention as an active ingredient comprises alpha pinene in the range of 10.0 to 25.0% by weight, camphene in the range of 5.0 to 28.0% by weight, beta pinene in the range of 1.0 to 30.0% by weight, car-3-ene in the range of 1.0 to 15.0% by weight, limonene in the range of 4.0 to 30.0% by weight, bornyl acetate in the range of 5.0 to 35.0% by weight, and borneol in the range of 1 to 5% by weight.
  • the fir needle oil comprises, in the standardized proportions of the component contained therein, 19.4% by weight of alpha pinene, 16.7% by weight of camphene, 17.7% by weight of beta pinene, 11.1% by weight of car-3-ene, 13.7% by weight of limonene, 7.7% by weight of bornyl acetate, and 2.4% by weight of Borneol.
  • the eucalyptus oil which is used in the invention as another active ingredient comprises alpha pinene in the range of 0.05 to 10.0% by weight, beta pinene in the range of 0.05 to 1.5% by weight, alpha-phellandrene in the range of 0.05 to 1.5% by weight, limonene in the range of 0.05 to 15.0% by weight, and more than 60% by weight of 1,8-Cineole.
  • Active ingredient in question eucalyptus oil comprises, in the standardized proportions of the component contained therein, 2.7% by weight of alpha pinene, 0.5% by weight of beta pinene, 0.7% by weight of alpha-phellandrene, 8% by weight of limonene, and 80.5% by weight of 1 ,8-Cineole.
  • the formulation of the pharmaceutical product of the invention comprises, in the standardized proportions of the component contained therein, 13.16% of alpha pinene and/or 10.98% of camphene and/or 10.77% of beta pinene and/or 7.06% of car-3-ene (delta-3-Carene) and/or 13.66% of limonene and/or 30.98% of 1,8-Cineole and/or 0.95% of Borneole.
  • the formulation of the pharmaceutical product of the invention is in the form of the inhaler drop or in a form administered by inhalation or transdermally, or in the form of gum or capsule or cream or pomade or tablet or rapimelt or inhalation liquid or bath water or syrup or transdermal patch or nasal spray or throat spray or lozenge or soft capsule or nasal cream, but it is not limited thereto.
  • the formulation which is preferably in the form of drop in the pharmaceutical product is dripped onto the collar, it has a mechanical effect on the patient when the vapor phase is delivered into the nose by inhalation and penetrates into the respiratory organs.
  • the pharmaceutical product of the invention provides an inhibition of more than 70% in the effective amount, i.e., in the concentration of 20 micrograms/mL, with its enzymatic activity in terms of the ACE2 enzyme inhibition.
  • the in-vitro experiments are carried out.
  • the pharmaceutical product of the invention is an antiviral (virucidal, virucide) and is an ACE2 inhibitory agent.
  • the in-vitro experiments comprising the following steps are carried out.
  • the antiviral activity and ACE2 action mechanism of the formulation of the invention works as follows: By dripping the formulation for inhalation in a close proximity so as to be inhaled in the nasal cavity, the product which passes into the vapor phase has a barrier effect on the mucosa in the nasal cavity and kills the viruses on the mucosa.
  • the virus stock culture is prepared using the Vero E6 cell line proliferated with DMEM- 10 (Dulbecco’s Minimum Essential Medium with pen/strep/fungizone containing 10% FBS (fetal bovine serum)).
  • DMEM- 10 Dulbecco’s Minimum Essential Medium with pen/strep/fungizone containing 10% FBS (fetal bovine serum)
  • FBS fetal bovine serum
  • the pharmaceutical product of the invention the effectiveness of which is tested against the COVID-19 (SARS-COV-2) virus (Clinical isolate, GenBank No: MT955161.1), is proven to kill the viruses by 79.89% in the 5 th minute and by 93.23% in the 30 th minute.
  • the virus suspension is dripped onto the area of 2 cm 2 on the stainless-steel disc specified in the standards TS EN 16777: 2019 and left to dry in the biosafety cabinet. After the discs are dried, 4 control discs are left in the biosafety cabinet in the laboratory and 6 test discs are placed in a 15 L plastic container with a lid. After 5-6 drops of inhaler drop are dropped on the fabric in the plastic container, the lid of the container is closed.
  • the exposure time of the viruses to the vapor of the drop of the invention is between 5 and 30 minutes and the ambient temperature is 30 ⁇ 1°C.
  • the medium for the virus cell incubation is 37 ⁇ 1°C, 5% CO2.
  • test results for the antiviral activity of the pharmaceutical product of the invention are shown in Table 1.
  • * 0-4 refer to % of cpe ⁇ 0: no cpe; 1 25%: 2: 50%: 3: 75%; 4: 100%)
  • the substances are dissolved in DMSO (Dimethyl sulfoxide) in order to test whether the formulation inhibits the ACE2 enzyme.
  • DMSO Dimethyl sulfoxide
  • the effect of DMSO is eliminated and the amount of DMSO in the solutions is reduced to less than 1% in order to analyze the actual enzyme inhibition of the test substances.
  • the enzyme inhibitions of the substances are calculated by the comparison in accordance with the standards included in the kit. In the presence of an ACE2-specific inhibitor, the enzyme loses its peptidase activity, resulting in a decrease in the fluorescence intensity. Based on this decrease, an inhibition value of 70% for the product of the invention and an inhibition value of more than 85% for the pure 1 ,8-Cineole used in the product of the invention are calculated.
  • Graph-1 Activity table of the pharmaceutical product with the formulation of the invention and of 1,8-Cineole as a pure substance in ACE2 enzyme inhibition
  • the pharmaceutical product of the invention is an effective and natural product against the coronavirus which is critical for the human health.
  • the pharmaceutical product of the invention is directed to the prevention and treatment of the coronavirus disease and can be applied to industry and the health sector as a self- administered prevention and treatment agent.

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  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Biotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/TR2021/051615 2021-04-13 2021-12-30 A pharmaceutical product for prophylaxis and treatment of viral diseases caused by coronavirus (sars-cov-2 or covid-19) WO2022220767A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2021/006518 TR2021006518A2 (tr) 2021-04-13 KORONAVİRÜS (SARS-COV-2 veya COVID-19) KAYNAKLI VİRAL HASTALIKLARIN PROFİLAKSİSİ VE TEDAVİSİ İÇİN BİR FARMASÖTİK ÜRÜN
TR2021/006518A TR202106518A2 (tr) 2021-04-13 2021-04-13 KORONAVİRÜS (SARS-COV-2 veya COVID-19) KAYNAKLI VİRAL HASTALIKLARIN PROFİLAKSİSİ VE TEDAVİSİ İÇİN BİR FARMASÖTİK ÜRÜN

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WO2022220767A1 true WO2022220767A1 (en) 2022-10-20

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WO (1) WO2022220767A1 (tr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023091111A1 (en) * 2021-11-18 2023-05-25 İstanbul Medi̇pol Üni̇versi̇tesi̇ Ace-2 enzyme inhibitory effects of essential oils obtained from the aerial parts of eucalyptus globulus and eucalyptus citriodora plants

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040009245A1 (en) * 2000-04-03 2004-01-15 Vail William Banning Methods and apparatus to prevent, treat and cure infections of the human respiratory system by pathogens causing severe acute respiratory syndrome (SARS)

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040009245A1 (en) * 2000-04-03 2004-01-15 Vail William Banning Methods and apparatus to prevent, treat and cure infections of the human respiratory system by pathogens causing severe acute respiratory syndrome (SARS)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ASIF M ET AL.: "COVID-19 and therapy with essential oils having antiviral, anti-inflammatory, and immunomodulatory properties", INFLAMMOPHARMACOLOGY, vol. 28, no. 5, 14 August 2020 (2020-08-14), pages 1153 - 1161, XP037257443, DOI: 10.1007/s 10787-020-00744-0 *
DA SILVA, J.K.R. ET AL.: "Essential oils as antiviral agents, potential of essential oils to treat SARS-CoV-2 infection: an in-silico investigation", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 21, no. 10, 12 May 2020 (2020-05-12), pages 3426, XP055787017, DOI: 10.3390/ijms21103426 *

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