WO2021246989A1 - Combinaison de mésylate de camostat et de chlorhydrate d'umifénovir - Google Patents

Combinaison de mésylate de camostat et de chlorhydrate d'umifénovir Download PDF

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Publication number
WO2021246989A1
WO2021246989A1 PCT/TR2021/050498 TR2021050498W WO2021246989A1 WO 2021246989 A1 WO2021246989 A1 WO 2021246989A1 TR 2021050498 W TR2021050498 W TR 2021050498W WO 2021246989 A1 WO2021246989 A1 WO 2021246989A1
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Prior art keywords
umifenovir
hydrochloride
camostat mesylate
combination according
combination
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PCT/TR2021/050498
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English (en)
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Tambay Taskin
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Atabay Kimya Sanayi Ve Ticaret Anonim Sirketi
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Publication of WO2021246989A1 publication Critical patent/WO2021246989A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention relates to a combination of camostat mesylate and umifenovir hydrochloride for the non-complicated COVID-19 cases with a tentative/definitive diagnosis.
  • Said non-complicated patients are the patients who have symptoms such as fever, muscle/ joint pain, cough, sore throat and nasal congestion, have no respiratory distress, tachypnea and SP02 value of ⁇ 90%, and have a normal lung x-ray and/or pulmonary CT scan.
  • Throat swabs of 50 patients with a diagnosis of COVID-19 were taken, a chest CT scan was performed and all patiens were administered a conventional treatment, including an oxygen inhalation (2L/min for half an hour and 3 times per day) and an atomized inhalation of recombinant human interferon-a2b injection.
  • These patients were divided into two groups: lopinavir/ritonavir (34 cases) and umifenovir (arbidol) (16 cases).
  • Lopinavir/ritonavir was administered at a dose of 400mg/100 mg b.i.d. for one week, while umifenovir was administered at a dose of 3x200 mg.
  • Remdesivir is a monophosphoramidate prodrug of an adenosine analog with a broad antiviral spectrum against filoviruses, paramyxoviruses, pneumoviruses and coronaviruses. (Wang Y. et al uncomfortable 2020 Published online April 29, https://doi.org/10.1016/S0140-6736(20)31022-9). Remdesivir has inhibited all human and animal coronaviruses in vitro, which have been tested to date, including SARS (CoV-2 and SARS-CoV-1 and Middle East respiratory syndrome [MERS]). It exhibited an antiviral and clinical effects against coronavirus in animal models.
  • SARS CoV-2 and SARS-CoV-1 and Middle East respiratory syndrome [MERS]
  • Remdesivir is a potent inhibitor of SARS-CoV-2 replication in human nasal and bronchial airway epithelial cells (Wang Y. et al., 2020 Published online April 29, https://doi.org/10.1016/S0140-6736(20)31022-9).
  • a CoV-2 infected SARS-rhesus macaque model an early remdesivir administration has been shown to exert significant antiviral and clinical effects (decreased pulmonary infiltrates and virus titers in bronchoalveolar lavages).
  • Intravenous remdesivir was found to be well tolerated in Ebola virus disease, but less effective than a monoclonal antibody therapy. In some countries, it has been used in patients with COVID- 19 for the last few months on an individualized compassionate basis. It has been reported to be beneficial in severely ill patients in COVID-19 case studies. However, the clinical and antiviral efficacy of remdesivir in COVID-19 has not yet been established. The study summari ed below includes the results of the first serious placebo-controlled, randomized remdesivir trial in patients with COVID-19, published by Wang et al. in The Lancet on April 29, 2020.
  • favipiravir and umifenovir were compared for a clinical improvement.
  • 98 of 116 patients had moderate COVID-19, whereas 18 had severe COVID- 19, and 42 patients with COVID-19 were determined to have hypertension and diabetes.
  • the Arbidol group consisted of 120 patients, wherein 111 of them had moderate COVID-19 and 9 had severe COVID-19. 35 of the patients in that group were found to have a comorbidity such as hypertension and diabetes.
  • the dose of umifenovir (Arbidol) used was administered as 200 mg tid for 7-10 days. This dose is not a sufficient dose for SARS-CoV-2 inhibition.
  • a maximum plasma concentration (Cmax) of umifenovir was increased as the dose received increased and reached a peak level at 1.23 pg/ml for a dose of 200 mg 1.6-1.8 hours after the administration (Metz R).
  • Ge et al. (2020) showed that arbidol alone inhibits SARS-CoV-2 by 98% in cell cultures at a concentration of 30 mM in vitro (Ge Y et al., 2020).
  • the antiviral effect is reduced at low concentrations.
  • the dose used by Chen et al. is 600 mg per day. No effect which is superior to favipiravir was found as a monotherapy.
  • the proposed dose of umifenovir is 800 mg which is the most compatible with the IC50 values obtained in vitro cell cultures.
  • the first studies on umifenovir were based on influenza hemagglutinin. Examining the affinity of umifenovir for hemagglutinin (HI, H2, H3, H4 and H5) of influenza strains for which it has been studied as a fusion inhibitor may be a sufficient example.
  • Fusion peptides are not able to bind to the host membrane in the endosomal membrane, and a fusion cannot occur. This applies to new CoV-19 spike protein. Umifenovir has been shown to act on spike protein through a similar mechanism. Today, many S proteins have been shown to be cleavaged at the interface of SI and S2, and this is called the S1/S2 site. This site is close to the N-terminus of the fusion peptide. The cleavage of this site is important in that it creates a mature N-terminus of the fusion peptide. This peptide allows the entry to the target cell membrane. If this cannot be achieved, there will be no successful membrane fusion reaction (Hoffmann M., Hofmann-Winkler H., Pohlmann S., 2018) (Belouzard S, 2009) (Xia S, 2018).
  • Umifenovir and the mesylate salt thereof have been shown to have a direct antiviral effect on early viral replication in the cells cultured with SARS virus.
  • the mesylate salt has been shown to be about 5 times effective than arbidol for reducing the replication of the SARS virus in the cultured cells.
  • the interferon-inducing effect of umifenovir has been studied in the trypsinized fibroblasts of chicken embryo.
  • umifenovir was mixed in 2% diethylaminoethyl dextran at a ratio of 1:4, and 0.2 ml of each fibroblast was added to the cell culture tube. After the drug-treated cells were kept at 37°C for 1 hour, the cells were washed. The fibroblast cells of chicken embryo were titrated for interferon by re-incubation for 8, 24 and 48 hours (Xiao LiuQ.- G. ZhouH. Li et al.) ⁇
  • the interferon titer was 64 — 1280 U/ml at a concentration of 20 mg/ml after 8 hours and reached a maximum level of 2560 U/ml after 24 hours.
  • Spike protein is a structurally trimeric protrusion.
  • the way of processing thereof by the host proteases for the entry is a complex matter.
  • the proteolytic separation of the SI and S2 units of the viral spike protein may be called “priming”, that is, “pre-treatment”, which provides the S protein of COVID-19 with a structural flexibility which may be used during the membrane fusion (Hoffmann M., Hofmann-Winkler H., Pohlmann S., 2018).
  • pre-treatment which provides the S protein of COVID-19 with a structural flexibility which may be used during the membrane fusion
  • FLUAV highly pathogenic avian influenza A viruses
  • SARS-CoV may not occur without trypsin activity.
  • S1/S2 site This site is close to the N-terminal of the fusion peptide. The cleavage of this site is important in that it creates a mature N-terminus of the fusion peptide. This peptide allows the entry to the target cell membrane. If this cannot be achieved, there will be no successful membrane fusion reaction (Hoffmann M., Hofmann -Winkler H., Pohlmann S., 2018) (Belouzard S, 2009) (Xia S, 2018).
  • TMPRSS2 Transmembrane Serine Protease 2
  • Camostat Mesylate a serine protease inhibitor
  • TMPRSS2 a serine protease inhibitor
  • E64d an inhibitor of cathepsin B/L which is an endosomal protease, has been shown to have an opposite effect (Hoffmann M, 2020.)
  • the object of the invention is a combination of Camostat Mesylate and Umifenovir Hydrochloride and the combined use thereof, for the treatment of Covid-19.
  • the term “combination” refers to, but not limited to, the presence of Camostat mesylate and Umifenovir hydrochloride compounds in the same pharmaceutical composition (fixed dose combination), separate pharmaceutical composition (combined use) and different pharmaceutical compositions in the same kit package.
  • Umifenovir is licensed in Russia and China (Arbidol®) and has been used for more than 20 years as a prophylaxis and treatment for influenza A and B infections. Unfortunately, it is not well known in western countries. It has become a current issue with the COVID-19 outbreak and has been included in many study protocols. Recent studies have shown that the fusion inhibition applies to a large family of viruses, including rhinoviruses and coronaviruses (Brooks MJ).
  • Umifenovir exhibits its effect through the inhibition of viral fusion and has also the capacity to induce serum interferon (Teissier El) (Leneva IA).
  • Umifenovir hydrochloride inhibits the viral replication by inhibiting the fusion of the lipid membrane of the virus to the host cells.
  • Umifenovir has been shown to effectively inhibit coronavirus up to 60-fold at a concentration of 10-30 pmol/L and to significantly reduce the pathological effects of the virus on the cells, as compared to the control group.
  • the results of a docking study for umifenovir in the context of possible drug targets of the new coronavirus were linked to the non-structural proteins (Nsp7_Nsp8 complex, Nspl4, Nspl5), E-channel protein and Spike, respectively, with the following scores: -136.087, -118.253, -118.253, -117.879 and 145.125 (Wu C, 2020).
  • Low score values indicate low binding energies and are inversely proportional to the affinity.
  • the spike protein is divided into SI and S2 by a protease of the host cell such as TMPRSS2, etc.
  • TMPRSS2 transmembrane serine protease 2
  • transmembrane serine protease 2 is a multi-domain type II transmembrane serine protease responsible for priming the surface glycoproteins of the virus like hemagglutinin and spike. No entry and fusion to the cell may occur wihout this process.
  • the main function of SI is to bind the surface receptors of the host cell, and the S2 subunit mediates virus-cell and cell-cell membrane fusion.
  • the structural integrity and activation of the spike protein plays a key role in the invasion and virulence of the virus.
  • Therapeutic strategies to prevent coronavirus from entering the host cells by targeting the spike proteins or specific receptors on the host surface are valuable targets for the development of anti-viral drugs.
  • Camostat mesylate has been licensed in Japan since 1986. The main indication thereof is that it is a narrow spectrum TMPRSS2 inhibitor. In this way, unlike aprotinin and famostat, it does not act like other protease inhibitors effective on hemodynamic balances and thrombosis process. Camostat at a treatment dose of 3x200 mg will be an effective antiviral in combination with umifenovir hydrochloride at a dose of 4x200 mg for 8-10 days.
  • TMPRSS2 The host cell serine proteases, TMPRSS2, provide the cleavage of the S1/S2 coupling of the viral spike protein, also called “priming", and allow the viral entry by binding the SI receptor binding part (RBD) of the virus to the ACE 2 receptor.
  • RBD SI receptor binding part
  • Camostat mesylate is a potent TMPRSS2 inhibitor and prevents the virus from entering inside the cell from the outside.
  • the fusion of the virus, which has overcome this effect and managed to enter the cell, through the endosomal membrane is provided by the S2 fusion peptides of the spike protein. Umifenovir interferes with that process by binding to the fusion peptides during this step.
  • a secondary object will be to reveal how strong the correlation is between the individual mechanistic construct of the drugs used in this study and clinical outcome. For example, it is important to prove that targeting serine proteases such as TMRPSS2, which helps the virus entry and has no risk of mutation is a rational approach, instead of targeting constantly mutating viral proteases.
  • the importance of the host proteases for priming the spike protein of the virus is well known. Therefore, it is a correct approach that one of the targets against the virus is these critical enzymes. Without priming, the SI part of the spike protein is not able to be cleavaged from S2, is not able to bind to the angiotensin converting enzyme 2 (ACE 2) and cannot enter the cell.
  • ACE 2 angiotensin converting enzyme 2
  • camostat is a TMRPPS2 protease inhibitor
  • umifenovir is a fusion peptide inhibitor
  • the dose of umifenovir in the present invention is preferably 800 mg per day, which is most consistent with the IC50 values obtained in in vitro cell cultures.
  • the present invention is a combination of Camostat Mesylate and Umifenovir Hydrochloride for use in the prevention, delay of progression or treatment of Covid-19 disease.
  • Camostat Mesylate and Umifenovir Hydrochloride may present in different pharmaceutical compositions.
  • the combination of Camostat Mesylate and Umifenovir Hydrochloride is preferably administered simultaneously, separately or sequentially.
  • the unit dose of Camostat Mesylate is preferably 200 mg and the unit dose of Umifenovir Hydrochloride is preferably 200 mg.
  • Camostat Mesylate may be preferably applied 3 to 4 times a day and Umifenovir Hydrochloride may be preferably applied 4 times a day.
  • said combination of Camostat Mesylate and Umifenovir Hydrochloride may be applied as 200 mg of Camostat Mesylate 3 times a day and 200 mg Umifenovir Hydrochloride 4 times a day for use in the prevention, delay of progression or treatment of Covid-19 disease.
  • said combination of Camostat Mesylate and Umifenovir Hydrochloride may be applied as 200 mg of Camostat Mesylate 4 times a day and 200 mg Umifenovir Hydrochloride 4 times a day for use in the prevention, delay of progression or treatment of Covid-19 disease.
  • Camostat Mesylate and Umifenovir Hydrochloride are present in the same pharmaceutical composition.
  • Said pharmaceutical composition may preferably comprise from 120 to 200 mg of Camostat Mesylate and 200 mg of Umifenovir Hydrochloride. More specifically, the pharmaceutical composition may comprise 150 mg of Camostat Mesylate and 200 mg of Umifenovir Hydrochloride, or 200 mg of Camostat Mesylate and 200 mg of Umifenovir Hydrochloride.
  • Said pharmaceutical composition in which Camostat Mesylate and Umifenovir Hydrochloride are present in the same pharmaceutical composition may preferably comprises at least one pharmaceutically acceptable excipient.
  • Said pharmaceutical composition preferably comprises from 120 to 200 mg of Camostat Mesylate, 200 mg of Umifenovir Hydrochloride and at least one pharmaceutically acceptable excipient.
  • Said pharmaceutical composition comprises 150 mg of Camostat Mesylate, 200 mg of Umifenovir Hydrochloride and at least one pharmaceutically acceptable excipient.
  • Said pharmaceutical composition comprises 200 mg of Camostat Mesylate, 200 mg of Umifenovir Hydrochloride and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition may be one of a tablet, a capsule or the other oral solid dosage forms and may be prepared using the methods known in the art.
  • Camostat Mesylate and Umifenovir Hydrochloride are present in different pharmaceutical composition in the same kit package.
  • the combination may be administered to a patient for 8-10 days.
  • Covid-19 patients to whom the combination will be applied preferably are the non-complicated COVID-19 patients with a tentative or definitive diagnosis, wherein the non-complicated patients are the patients who: a) have symptoms such as fever, muscle and joint pain, cough, sore throat and nasal congestion, b) have no respiratory distress, tachypnea and SP02 value of ⁇ 90%, c) have a normal lung x-ray and/or pulmonary CT scan.

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Abstract

La présente invention concerne une combinaison de mésylate de camostat et de chlorhydrate d'umifénovir, destinée à être utilisée dans la prévention, le retardement de la progression ou le traitement de la maladie de COVID-19. Dans la combinaison selon l'invention, le mésylate de camostat et le chlorhydrate d'umifénovir sont présents dans des compositions pharmaceutiques séparées ou dans la même composition pharmaceutique. Les patients COVID-19 auxquels la combinaison de l'invention est administrée peuvent être des patients COVID-19 non compliqués avec un diagnostic provisoire ou définitif.
PCT/TR2021/050498 2020-06-01 2021-05-27 Combinaison de mésylate de camostat et de chlorhydrate d'umifénovir WO2021246989A1 (fr)

Applications Claiming Priority (2)

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TRTR2020/08399 2020-06-01
TR2020/08399A TR202008399A2 (tr) 2020-06-01 2020-06-01 Kamostat mesi̇lat ve umi̇fenovi̇r hi̇droklorür kombi̇nasyonu

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023121629A1 (fr) * 2021-12-22 2023-06-29 Tambay Taskin Combinaison de camostat mésilate et de chlorhydrate d'umifénovir avec des inhibiteurs de pompe à protons

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
COSTANZO MICHELE, DE GIGLIO MARIA ANNA RACHELE, ROVIELLO GIOVANNI NICOLA: "SARS-CoV-2: Recent Reports on Antiviral Therapies Based on Lopinavir/Ritonavir, Darunavir/Umifenovir, Hydroxychloroquine, Remdesivir, Favipiravir and other Drugs for the Treatment of the New Coronavirus", CURRENT MEDICINAL CHEMISTRY, BENTHAM, NL, vol. 27, no. 27, 5 August 2020 (2020-08-05), NL , pages 4536 - 4541, XP055788748, ISSN: 0929-8673, DOI: 10.2174/0929867327666200416131117 *
DWIGHT L. MCKEE, STERNBERG ARIANE, STANGE ULRIKE, LAUFER STEFAN, NAUJOKAT CORD: "Candidate drugs against SARS-CoV-2 and COVID-19", PHARMACOLOGICAL RESEARCH, ELSEVIER, AMSTERDAM, NL, vol. 157, 1 January 2020 (2020-01-01), AMSTERDAM, NL, pages 104859, XP055693376, ISSN: 1043-6618, DOI: 10.1016/j.phrs.2020.104859 *
JAMES M. SANDERS, MARGUERITE L. MONOGUE, TOMASZ Z. JODLOWSKI, JAMES B. CUTRELL: "Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19) : A Review", JAMA THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, AMERICAN MEDICAL ASSOCIATION, US, US , XP055695738, ISSN: 0098-7484, DOI: 10.1001/jama.2020.6019 *
ZHU ZHEN; LU ZHAOHUI; XU TIANMIN; CHEN CONG; YANG GANG; ZHA TAO; LU JIANCHUN; XUE YUAN: "Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19", JOURNAL OF INFECTION., ACADEMIC PRESS, LONDON., GB, vol. 81, no. 1, 10 April 2020 (2020-04-10), GB , XP086182185, ISSN: 0163-4453, DOI: 10.1016/j.jinf.2020.03.060 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023121629A1 (fr) * 2021-12-22 2023-06-29 Tambay Taskin Combinaison de camostat mésilate et de chlorhydrate d'umifénovir avec des inhibiteurs de pompe à protons

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