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WO2022014813A1 - Composition pharmaceutique pour la prévention ou le traitement d'une infection par le sars-cov-2 - Google Patents

Composition pharmaceutique pour la prévention ou le traitement d'une infection par le sars-cov-2 Download PDF

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Publication number
WO2022014813A1
WO2022014813A1 PCT/KR2021/002355 KR2021002355W WO2022014813A1 WO 2022014813 A1 WO2022014813 A1 WO 2022014813A1 KR 2021002355 W KR2021002355 W KR 2021002355W WO 2022014813 A1 WO2022014813 A1 WO 2022014813A1
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Prior art keywords
nelfinavir
infection
cov
day
sars
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Inventor
Min-Hyo Ki
Moon-Jung BACK
Jang-Hyun Lee
Jong-Hwan Lee
Hyeong-Woo MOON
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Samjin Pharmaceutical Co Ltd
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Samjin Pharmaceutical Co Ltd
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Priority claimed from KR1020210015797A external-priority patent/KR20220009314A/ko
Application filed by Samjin Pharmaceutical Co Ltd filed Critical Samjin Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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 disclosure relates to a pharmaceutical composition for preventing SARS-CoV-2 infectious diseases or treating diseases caused by SARS-CoV-2 infection.
  • Coronavirus is an RNA virus belonging to the subfamily Coronavirinae in family Coronaviridae, which is enveloped virus with a positive ssRNA and a nucleocapsid of helical symmetry. Coronaviruses are named after the Latin word corona, referring to crown, and have crown-like spike proteins, club-shaped projections, protruding from the surfaces thereof, resembling the sun's corona.
  • coronaviruses found in various animals such as bats, birds, cats, dogs, cows, pigs, mice, and the like, are classified into four groups (alpha-, beta-, gamma-, and delta coronaviruses).
  • the alpha-coronaviruses and beta-coronaviruses mainly infect mammals, and the gamma-coronaviruses and delta-coronaviruses can be identified in birds.
  • Coronaviruses are reported to cause various diseases such as stomach disorder and respiratory diseases in animals.
  • HCoV-229E and HCoV-OC43 discovered in the 1960s, HCoV-NL63 (2004) and HCoV-HKU1 (2005) discovered after the severe acute respiratory syndrome (SARS, discovered in 2003) coronavirus (SARS-CoV) pandemic, and middle east respiratory syndrome (MERS) coronavirus (MERS-CoV) having severe respiratory symptoms such as high fever, cough, and respiratory distress, similar to those of SARS, identified first in Saudi Arabia in September 2012.
  • SARS-coronavirus SARS-coronavirus
  • SARS-CoV-2 which originated in Wuhan in December 2019 and has spread worldwide, was reported to be the seventh strain of human infectious coronavirus, different from the existing six strains of coronavirus.
  • Coronavirus disease 2019 (hereinafter, interchangeable referred to as "COVID-19”) is a respiratory infection disease caused by SARS-CoV-2, the new type of coronavirus (hereinafter, interchangeably referred to as "the novel coronavirus”).
  • COVID-19 may be spread through droplets from coughing or sneezing of an infected person which permeate into mucous members of eyes, nose, mouth, and the like, or may be spread by touching eyes, nose, and mouth after contact with a contaminated object or hand.
  • the possibility of airborne transmission of COVID-19 is under discussion, and infectibility of COVID-19 is significantly high.
  • Nelfinavir is a drug developed as an anti-AIDS drug, and is developed to be used to treat AIDS infections by being taken in a dose of 2,500 mg or 2,250 mg per day for an adult human.
  • the document regarding side effects of nelfinavir states that when nelfinavir is taken at a dose of 2,500 mg or 2,250 mg per day for an adult human as a treatment of AIDS, about 49% of people showed a symptom of diarrhea as a side effect of nelfinavir and about 33% of people should be medically treated for a symptom of diarrhea.
  • cytotoxicity of nelfinavir (Autophagy, 2008, 4(1), 107-109) states that nelfinavir amplifies endoplasmic reticulum stress and increases autophagy to increase cellular death caused by apoptosis and non-apoptosis.
  • Nelfinavir has been developed as an anticancer drug based on a multifactorial cytotoxicity effect using such autophagy or the like, and clinical trials for anticancer drugs have been made within the range of a dose of anti-AIDS drug. This means that when nelfinavir is taken within the range of a dose of an anti-AIDS drug, blood concentration may already reach a value at which cytotoxicity required for anticancer treatment is induced.
  • SARS-CoV SARS-Coronavirus
  • SARS-CoV and SARS-CoV-2 are genetically different from each other and, even in an asymptomatic state, SARS-CoV-2 has a higher viral load than SARS-CoV to show infectivity, and thus, has a significantly high transmission rate, which is different in epidemiological aspect.
  • One clinic example report discloses a case report in which nelfinavir was applied to six COVID-19 patients in the situation in which many drugs have been tested in humans due to the COVID-19 pandemic. According to the case report, two patients with predominant gastrointestinal symptoms such as diarrhea stopped taking the drug due to dehydration or showed only little improvement in the symptoms. Therefore, there was an obvious limitation in applying the same dose as a dose of nelfinavir used as an anti-AIDS drug for treatment of COVID-19 because of the concern about side effects of nelfinavir such as diarrhea.
  • the case report discloses that among four patients who administered a dose of nelfinavir used as an anti-AIDS drug, three patients responded to treatment, but discloses only results obtained when the three patients took a combination of nelfinavir and baloxavir, or had already been taking hydroxychloroquine and baloxavir. Therefore, the case report is inappropriate as base data of a clinical treatment effect of nelfinavir alone, and it is unpredictable as to whether nelfinavir has a treatment effect for SARS-CoV-2, or the like, without occurrence of side effects and as to a dosage of nelfinavir for obtaining effective treatment effect.
  • the present disclosure provides a low dose of a nelfinavir composition, capable of obtaining a treatment effect for COVID-19 while reducing side effects, and uses thereof.
  • An aspect of the present disclosure is to provide a pharmaceutical composition for preventing or treating SARS-CoV-2 infection using nelfinavir or a pharmaceutically acceptable salt thereof at a low dose.
  • Another aspect of the present disclosure is to provide a novel use of a low dose of nelfinavir or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present disclosure is to provide a method for preventing or treating SARS-CoV-2 infection using a low dose of nelfinavir or a pharmaceutically acceptable salt thereof.
  • Example embodiments of the present disclosure provide a pharmaceutical composition for preventing or treating SARS-CoV-2 infection, containing nelfinavir expressed by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient at a low dose of 100 mg/day to 1,500 mg/day for an adult human.
  • Example embodiments of the present disclosure provide a use of nelfinavir or a pharmaceutically acceptable salt thereof for preventing or treating SARS-CoV-2 infection using the nelfinavir or the pharmaceutically acceptable salt thereof as an active ingredient at a low dose of 100 mg/day to 1,500 mg/day for an adult human.
  • Example embodiments of the present disclosure provide a use of nelfinavir or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing or treating SARS-CoV-2 infection using the nelfinavir or the pharmaceutically acceptable salt thereof as an active ingredient at a low dose of 100 mg/day to 1,500 mg/day for an adult human.
  • Example embodiments of the present disclosure provide a method for preventing or treating SARS-CoV-2 infection, including administering nelfinavir or a pharmaceutically acceptable salt thereof to a subject in need of treatment, as an active ingredient at a low dose of 100 mg/day to 1,500 mg/day for an adult human.
  • a composition containing nelfinavir for preventing or treating SARS-CoV-2 or a pharmaceutically acceptable salt thereof at a low dose, and uses of the composition are provided.
  • a low dose of nelfinavir or a pharmaceutically acceptable salt thereof may significantly reduce side effects while being administered at a lower dose than a common dose of an existing anti-AIDS drug or anticancer drug and, and thus, are expected to be useful in treating SARS-CoV-2 infection, in detail, COVID-19 because side effects unfavorable to treatment, such as gastrointestinal side effects, are reduced or are not accompanied and even gastrointestinal symptoms of COVID-19 are not exacerbated.
  • FIG. 1 illustrates a dose-response curve of a compound against the expression level of SARS-CoV-2.
  • the present disclosure is based on expression of a significant treatment effect and discovery the possibility of reducing side effects when nelfinavir, known as a conventional anti-AIDS drug, or a pharmaceutically acceptable salt thereof are used. Accordingly, the present disclosure provides a pharmaceutical composition, containing nelfinavir for preventing or treating SARS-CoV-2 infection accompanying COVID-19 at a low dose or a pharmaceutically acceptable salt thereof, novel uses of the nelfinavir and the pharmaceutically acceptable salt thereof, and a method of preventing or treating SARS-CoV-2 infection using the nelfinavir and the pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical composition for preventing or treating SARS-CoV-2 infection, containing and using nelfinavir expressed by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient at a low dose of 100 mg to 1,500 mg per day for an adult human.
  • the pharmaceutical composition of the present disclosure contains the nelfinavir or a pharmaceutically acceptable salt thereof with low dose, gastrointestinal side effects may be reduced or may not be accompanied, and gastrointestinal symptoms may not be exacerbated.
  • the pharmaceutical composition of the present disclosure may use low dose of nelfinavir to reduce or prevent side effects in patients who have no gastrointestinal symptoms; and/or to prevent exacerbation of gastrointestinal symptoms and to express even effects of treating and relieving gastrointestinal symptoms of patients who have the gastrointestinal symptoms.
  • the present disclosure provides uses of nelfinavir or a pharmaceutically acceptable salt thereof for preventing or treating SARS-CoV-2 infection using nelfinavir expressed by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient at a low dose of 100 mg to 1,500 mg per day for an adult human.
  • nelfinavir or a pharmaceutically acceptable salt thereof for preparing a medicine for preventing or treating SARS-CoV-2 infection using nelfinavir expressed by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient at a low dose of 100 mg to 1,500 mg per day for an adult human.
  • gastrointestinal side effects may be reduced or may not be accompanied, and gastrointestinal symptoms may not be exacerbated.
  • active ingredient refers to target activation alone, or an ingredient effective in recovering a disease defined as "SARS-CoV-2 infection” (relieving a symptom of the disease), treating the disease, and preventing the disease (inhibiting or delaying occurrence of the disease) and may be chemically, in detail, a free base not containing salt or hydrate.
  • prevention refers to all actions for inhibiting infection by the novel coronavirus or delaying occurrence thereof, may include reduction in a hazard ratio of infection.
  • treatment refers to all actions for recovering, fully covering, or beneficially changing at least a portion or entire symptom of COVID-19, caused by novel coronavirus infection, by the present disclosure.
  • coronavirus refers to single-stranded RNA coronavirus belonging to Coronaviridae family and Coronavirinae subfamily, and may be alpha coronavirus or beta coronavirus, in detail, beta coronavirus.
  • coronavirus may include human coronavirus, infecting human, and variants thereof.
  • the coronavirus, to which the present disclosure may be applied may be, in detail, SARS-CoV-2.
  • a pharmaceutical composition of the present disclosure may be used to prevent or treat COVID-19 caused by SARS-CoV-2.
  • COVID-19 may accompany symptoms which may be accompanied by malaise and/or fever (37.5 degrees) and/or redness after an incubation period of 1 to 14 days.
  • the symptoms may include at least one selected from the group consisting of loss of at least one of taste and smell, respiratory symptom such as phlegm, nasal stuffiness, coughing, dyspnea, sore throat, headache, gastrointestinal symptoms including diarrhea and/or abdominal pain and abdominal discomfort, hemoptysis, nausea, body aches, muscular pain, joint pain, chest pain, chest tightness, chill, vertigo, lymphopenia, hemocoagulation, hematologic symptoms such as an increase in inflammatory index, dysphrasia, dyscinesia, mental aberration, anxiety, depression, somnipathy, stroke, delirium, brain injury, nerve injury, liver injury, kidney injury, skin rash, skin discoloration, acute myocardial infarction, myocarditis, cardiac insufficiency, conjunctivitis, upper respiratory tract infection, lower respiratory tract infection
  • the corona virus disease-19 may be at least one selected from the group consisting of upper respiratory tract infection of SARS-CoV-2, lower respiratory tract infection of SARS-CoV-2, respiratory organ infection of SARS-CoV-2, gastrointestinal tract infection of SARS-CoV-2, pneumonia caused by SARS-CoV-2, ophthalmic infection of SARS-CoV-2, skin infection of SARS-CoV-2, nervous system infection of SARS-CoV-2, cardiovascular system infection of SARS-CoV-2, kidney infection of SARS-CoV-2, liver infection of SARS-CoV-2, and a blood corpuscle infection of SARS-CoV-2.
  • respiratory organ refers to an organ involved in inh thereto.
  • the above-described symptoms includes all symptoms caused by SARS-CoV-2 infection.
  • COVID-19 caused by SARS-CoV-2 is intended to include not only a case in which at least one of the symptoms is expressed but also an asymptomatic case in which no symptom is expressed.
  • the "subject” or “patient”, to which a pharmaceutical composition for preventing or treating SARS-CoV-22 infection of the present disclosure is applied may be a subject who exhibits the symptom, not limited to the above-mentioned symptoms, caused by SARS-CoV-2 infection and/or at least one of the other symptoms, a subject who has an asymptomatic virus, or a subject which is concerned about coronavirus infection.
  • "subject” may include any subject which participated in a clinical study trial showing no clinical finding for any disease, any subject which participated in an epidemiological study, or any subject used as a control group.
  • the "subject” or “patent” may be, for example, mammals and may be, in detail, any subject selected from the group consisting of humans, cow, dog, cat, pig, goat, guinea pig, rabbit, chicken, and the like and required to be treated.
  • COVID-19 may accompany at least one of the symptoms such as fever, redness, loss of at least one of taste and smell, phlegm, coughing, sore throat, headache, diarrhea, abdominal pain, abdominal discomfort, hemoptysis, nausea, dyspnea, nasal stuffiness, body aches, muscular pain, joint pain, chest pain, chest tightness, fatigue, chill, vertigo, lymphopenia, hemocoagulation, dysphrasia, dyscinesia, mental aberration, anxiety, depression, somnipathy, stroke, delirium, brain injury, nerve injury, liver injury, kidney injury, skin rash, skialing and exhaling, and may include an upper respiratory tract and a lower respiratory tract.
  • the symptoms such as fever, redness, loss of at least one of taste and smell, phlegm, coughing, sore throat, headache, diarrhea, abdominal pain, abdominal discomfort, hemoptysis, nausea, dyspnea, nasal stuffiness, body aches, muscular pain, joint pain, chest pain, chest tightness, fatigue
  • the "upper respiratory tract” includes mouth, nose, sinuses, middle ear, throat, larynx, and trachea
  • the “lower respiratory tract” includes bronchial tube and lungs (bronchi, bronchioles, and alveoli) as well as interstitial tissue of the lungs.
  • gastrointestinal tract refers to a canal from the mouth to the anus, including mouth, esophagus, stomach and intestines.
  • the term “nervous system” refers to a system responding to, transmitting, integrating, and determining stimuli and transmitting commands.
  • the "nervous system” includes brains including cerebrum, cerebellum, diencephalon, mesencephalon, and medulla oblongata, a central nervous system including spinal cord, a peripheral nervous system, and an autonomic nervous system.
  • cardiac system may be used interchangeably with the term “circulatory system”, and may include heart and blood vessels.
  • the term "pharmaceutically acceptable salt” refers to a formulation of a compound which does not cause serious stimulus in an organism, to which the compound is administered, and does not damage biological activity and physical properties of the compound.
  • the pharmaceutical acceptable salt includes acid addition salt prepared by acid preparing non-toxic acid addition salt containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid (bromic acid), hydroiodic acid (iodic acid), perchloric acid, or tartaric acid, organic carboxylic acid such as succinic acid, oxalic acid, tartaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicy
  • the pharmaceutically acceptable salt thereof may be selected from, in detail, mesilate salt, methanesulfonic acid, and benzenesulfonic acid.
  • the compound according to the present disclosure may be converted into salt thereof using a conventional method.
  • IC 50 of nelfinavir was confirmed to be 0.01 ⁇ M using Calu-3 cell line, a human lung cell line in which proteins such as ACE2 and TMPRSS2 important for human cell infection of SARS-CoV-2 were expressed well, and a low effective dose of the present disclosure was derived based on the confirmation.
  • low dose refers to a dose below a usual dose (a common dose), for example, a dose lower than or equal to a usual dose when nelfinavir is used as an anti-AIDS medicine which may be calculated as a dose per day (a daily dose). For example, even when divided into two or three parts to be taken twice or three times a day, a daily total dose of nelfinavir is calculated to be lower than a daily dose of nelfinavir used as an anti-AIDS medicine. In this case, the dose is referred to as "low dose.”
  • nelfinavir is used as an anti-AIDS medicine
  • 1,250 mg of nelfinavir is taken twice a day for an adult human or 750 mg of nelfinavir is taken three times a day for an adult human. That is, a total daily dose of nelfinavir is 2,500 mg or 2,250 mg.
  • a dose of nelfinavir or a pharmaceutically acceptable salt thereof, based on a usual dose for an adult human is 100 mg/day or more to 1,500 mg/day or less, for example, 100 mg/day or more to less than 1,500 mg/day, in detail, for example, 100 mg/day, or 250 mg/day, 300 mg/day, 500 mg/day, 600 mg/day, 750 mg/day, 900 mg/day, 1,000 mg/day, 1,200 mg/day, 1,250 mg/day, 1,400 mg/day, and 1,500 mg/day, and is intended to include numerical ranges of all combinations which may be derived within the above range.
  • the present disclosure is aimed at administering nelfinavir or a pharmaceutically acceptable salt thereof at a dose of 100 mg/day to 1,500 mg/day, and the nelfinavir, or the pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same can be administered once a day or can be divided into two or four parts to be administered twice or four times a day.
  • each numerical range is intended to include the numerical range of all combinations which may be derived within the range, and is not limited as examples of the above-mentioned numerical range.
  • nelfinavir when nelfinavir is divided into two parts to be administered twice a day, 50 mg to 750 mg of the nelfinavir may be administered at a single dose.
  • nelfinavir When nelfinavir is divided into three parts to be administered three times a day, 33.3 mg to 500 mg of the nelfinavir may be administered at a single dose.
  • such a low dose may be effectively used to relieve COVID-19 symptoms because nelfinavir may exhibit efficacy for preventing or treating SARS-CoV-2 infection at a low dose while reducing cytotoxicity or side effects which may occur in a usual dose as an existing anti-AIDS medicine.
  • the term "effective dose” may be used interchangeably with the "therapeutic dose”, and is 100 mg/day or more to 1,500 mg/day or less for an adult human.
  • the term “effective dose” refers to a dose of an active ingredient which may exhibit intended medical and pharmacological effects, such as an effect of relieving SARS-CoV-2 infection during an administration period based on suggestions of medical experts, for mammals, in detail, people, an application target of the present disclosure. Such an effective dose is based on an adult having a weight of about 60 kg.
  • nelfinavir has various side effects, 1,250 mg of nelfinavir has been inevitably administered twice a day, or 750 mg of nelfinavir has been inevitably administered three times a day (i.e., a daily dose of 2,500 mg or 2,250 mg has been administered) as an anti-AIDS medicine or an anticancer medicine to express efficacy of nelfinavir.
  • nelfinavir is known to cause typical side effects such as diarrhea, fatigue, headache, and the like. In particular, it was reported that diarrhea symptoms were shown in about 49.4% of total patients, and 33% of total patients needed treatment for diarrhea symptoms (Pharmacotherapy 24(6), 727-35, 2004).
  • gastrointestinal symptoms such as abdominal pain, abdominal discomfort, and diarrhea caused by COVID-19 were shown in about 61% of total COVID-19 patients (Gut 69(6), 997-1001, 2020).
  • gastrointestinal symptoms such as abdominal pain, abdominal discomfort, and diarrhea caused by COVID-19 were shown in about 61% of total COVID-19 patients (Gut 69(6), 997-1001, 2020).
  • patients having gastrointestinal symptoms had 50% higher probability of being severely ill than patients having no gastrointestinal symptoms (Gut gutjnl-2020-321751, 2020).
  • side effects of nelfinavir itself may cause symptoms of COVID-19 patents, in particular, gastrointestinal symptoms, to be exacerbated or become more severe.
  • nelfinavir is able to achieve sufficient medicinal effects at a low dose. Therefore, limiting the dose of nelfinavir to a maximum of 1,500 mg or less a day could be applied to the treatment of COVID-19 so that the side effects of nelfinavir, known to comprise the above-described gastrointestinal side effects, are not accompanied or are significantly reduced and gastrointestinal symptoms of COVID-19 are not exacerbated.
  • nelfinavir having IC 50 with a level of 0.01 ⁇ M in Calu-3 cells, the human lung cells. Accordingly, in order to exhibit treatment effectiveness most appropriate to COVID-19 patients who show various symptoms including gastrointestinal inflammation which occur simultaneously, a daily dose of nelfinavir should be a low dose of 1,500 mg or less to significantly reduce side effects of a drug and to optimize an effect of the drug.
  • nelfinavir had excellent IC 50 of 0.01 ⁇ M (5.7 ng/mL) in Calu-3 cells, the human lung cells, to exhibit a significantly excellent inhibition effect against SARS-CoV-2.
  • a dose of nelfinavir to be maintained at 0.1 ⁇ M (57 ng/mL), 10 times the IC 50 of the nelfinavir, or more during administration of the nelfinavir may be calculated.
  • the calculated dose of nelfinavir corresponds to a dose when about 40 mg is taken twice a day and a dose when about 20 mg is taken three times a day.
  • nelfinavir when 40 mg of nelfinavir is administered twice a day or 20 mg of nelfinavir is administered three times a day, even lowest blood concentration immediately before next administration of nelfinavir after administration of nelfinavir may be maintained at blood concentration corresponding to 10 times or higher than the IC 50 of nelfinavir against SARS-CoV-2. Since the above doses are respectively converted into daily doses of 80 mg and 60 mg, about 100 mg or more should be administered at a daily dose to secure a minimum effect of nelfinavir against SARS-CoV-2. For the reference, the calculation of 10 times the IC 50 takes a margin of safety into account, considering a clinical individual difference.
  • nelfinavir has been concomitantly administered with other antiviral agents for the purpose of AIDS treatment or anti-cancer drug.
  • nelfinavir is concomitantly administered with other antiviral agents, other than drugs proved to have superior antiviral effects for SARS-CoV-2, for the purpose of COVID-19 treatment because side effects caused by nelfinavir and/or other antiviral agents may occur or may be exacerbated.
  • antiviral agents which is not preferable to be concomitantly administered with nelfinavir, may be saquinavir, lopinavir, ritonavir, amprenavir, indinavir, atazanavir, fosamprenavir, darunavir, and the like, as HIV protease inhibitors, and tenofovir, lamivudine, zidovudine), dianosine, emtricitabine, zalcitabine, stavudine, abacavir, and the like, as reverse transcriptase inhibitors.
  • various side effects such as diarrhea, fatigue, and headache may be accompanied.
  • HIV protease inhibitors may cause gastrointestinal side effects such as severe diarrhea, and the like.
  • nelfinavir should not be concomitantly administered with these medicaments in the case of treatment of COVID-19 patients.
  • antiviral drugs having superior inhibitory effects on SARS-CoV-2 may be concomitantly administered as long as they do not cause side effects.
  • nelfinavir needs to be administered at a daily dose from 100 mg or more to 1,500 mg or less for an adult human to clinically apply the nelfinavir to treatment of COVID-19, in overall consideration of typical side effects and high cytotoxicity of nelfinavir and a wide range of mucosal side inflammatory symptoms such as gastrointestinal tract of COVID-19. Accordingly, the present disclosure is aimed at administering nelfinavir at a low dose of 100 mg/day to 1,500 mg/day for an adult human, rather than an existing high dose of 2,250 mg/day to 2,500 mg/day.
  • the present disclosure is aimed at frictionally administering nelfinavir once to four times a day at the low dose to provide an optimal pharmaceutical use and pharmaceutical composition for relieving symptoms of COVID-19 while reducing gastrointestinal side effects, or not accompanying the gastrointestinal side effects, and not exacerbating gastrointestinal symptoms.
  • the pharmaceutical composition of the present disclosure may further include a carrier, an excipient, a diluent, and the like, commonly used in preparation of pharmaceutical compositions.
  • the “carrier” may be defined as a substance facilitating administration of a compound into a cell or tissue.
  • the “excipient” refers to a substance added to provide an appropriate form to a drug or to increase an amount of the drug to be conveniently used.
  • the “diluent” may be defined as a substance not only stabilizing biologically active form of the compound but also dissolving and diluting the compound.
  • Such a carrier, excipient, or diluent may be, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, hydroxycellulose, hydroxypropylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, crospovidone, croscarmellose sodium, water, physiological saline, buffered saline, dimethylsulfoxide (DMSO), methylhydroxybenzoate, talc, magnesium stearate, mineral oil, or the like, but is not limited thereto.
  • DMSO dimethylsulfoxide
  • a pharmaceutical composition according to the present disclosure may be formulated as a formulation appropriate for oral administration such as a powder, a granule, a tablet, a capsule, a solution, a suspension, an emulsion, a syrup, an aerosol, or the like, and may be used as a formulation for injection administration such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection, or a formulation for external composition, but is not limited thereto.
  • nelfinavir, an active ingredient, or a pharmaceutically acceptable salt thereof may be formulated as a unit dosage form containing the content (potency) of 25 mg to 1,500 mg to prevent or treat SARS-CoV-2 infection, COVID-19, for example.
  • nelfinavir or a pharmaceutically acceptable salt thereof may be formulated as a unit dosage form containing 33 mg to 750 mg for an adult human (each having a weight of 60 kg).
  • a formulation of the formulated unit dosage may be administered once to four times a day such that a daily dosage may be 100 mg to 1,500 mg.
  • nelfinavir, an active ingredient, or a pharmaceutically acceptable salt thereof may be administered as a unit dosage formulation of 25 mg to 1,500 mg a day to prevent or treat SARS-CoV-2 infection, COVID-19, for example.
  • nelfinavir or a pharmaceutically acceptable salt thereof may be administered as a unit dosage formulation of 33 mg to 750 mg per day for an adult human.
  • a formulation of the formulated unit dosage may be administered once to four times a day such that a daily dosage may be 100 mg to 1,500 mg.
  • the dosage of the composition according to the present disclosure may be adjusted, based on a usual dose for adjusts, depending on various factors such as type of disease, severity of the disease, type and content of another ingredient contained in a pharmaceutical composition, type of formulation, a patient's age, weight, general health status, gender, and diet, administration time and route, duration of treatment, and concurrently used drugs.
  • Nelfinavir or a pharmaceutically acceptable salt thereof according the present disclosure may be commercially available or may be synthesized by an organic synthesis method known in the art, and a method of the preparing nelfinavir or the pharmaceutically acceptable salt thereof is not necessarily limited.
  • the present disclosure provides a method for preventing or treating SARS-CoV-2 infection, which includes administering nelfinavir or a pharmaceutically acceptable salt thereof as an active ingredient to a subject, requiring the same, at a low dose of 100 mg or more to 1,500 mg or less per day for an adult human.
  • nelfinavir and the pharmaceutically acceptable salt thereof are applied to the present method.
  • subjects, to which the method for preventing or treating SARS-coronavirus-2 (SARS-CoV-2) infection according to the present disclosure may include patients who have gastrointestinal symptoms, such as abdominal pain, abdominal discomfort, diarrhea, and the like, caused by an inflammatory response intensified in gastrointestinal mucosal tissues, but the present disclosure is not limited thereto.
  • SARS-coronavirus-2 SARS-CoV-2
  • the operation of administering may be conventionally performed by, in detail, systemically administering a compound, containing the compound expressed by the chemical formula 1 as an active ingredient, but the present disclosure is not limited thereto.
  • the systemic administration may be performed by oral or non-oral administration.
  • the non-oral administration may be performed by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the systemic administration may be performed by, in detail, oral administration.
  • Example 1 Evaluation of anti-coronavirus activity of nelfinavir against SARS-CoV-2 in human lung cells
  • Calu-3 cell line a human lung cell line, was obtained from Korea Cell Line Bank (KCLB), and then cultured in Dulbecco's Modified Eagle's Medium (DMEM) under conditions of 37°C and CO 2 of 5%. Calu-3 cells were treated with various concentrations of nelfinavir mesylate (Sigma Aldrich) corresponding to 25, 12.5, 6.25, 3.125, 1.563, 0.781, 0.391, 0.195, 0.098, 0.049, 0.024, and 0.012 ⁇ M. After two hours from the treatment, the Calu-3 cells were infected with SARS-CoV-2 (NCCP43326) at multiplicity of infection (MOI) of 0.1.
  • SARS-CoV-2 NCCP43326
  • MOI multiplicity of infection
  • FIG. 1 illustrates dose-response curves based on the amount of SARS-CoV-2 RNA depending on nelfinavir mesylate concentration.
  • X-axis represents the treated drug concentration ( ⁇ M) in log scale
  • Y-axis represents the amount of virus expressed in the drug-treated group by percentage (%) when a virus-infected group without the drug treatment (a control group) is set to 100%.
  • IC 50 of nelfinavir mesylate a concentration at which the amount of corresponding virus is decreased by 50%
  • Comparative Example 1 Evaluation of anti-coronavirus activity of remdesivir against SARS-CoV-2 in human lung cells
  • Calu-3 cell line a human lung cell line, was obtained from Korea Cell Line Bank (KCLB) and cultured in Dulbecco's Modified Eagle's Medium (DMEM) under conditions of 37°C and CO 2 of 5%. Calu-3 cells were treated with various concentrations of remdesivir (BLD Pharm) corresponding to 25, 12.5, 6.25, 3.125, 1.563, 0.781, 0.391, 0.195, 0.098, 0.049, 0.024, and 0.012 ⁇ M. After two hours from the treatment, the Calu-3 cells were infected with SARS-CoV-2 (NCCP43326) at multiplicity of infection (MOI) of 0.1.
  • SARS-CoV-2 NCCP43326
  • MOI multiplicity of infection
  • FIG. 1 illustrates dose-response curves based on the amount of SARS-CoV-2 RNA depending on remdesivir concentration.
  • X-axis represents the treated drug concentration ( ⁇ M) in log scale
  • Y-axis represents the amount of virus expressed in the drug-treated group by percentage (%) when a virus-infected group without the drug treatment (a control group) is 100%.
  • IC 50 of remdesivir a concentration at which the amount of corresponding virus is decreased by 50%
  • Comparative Example 2 Evaluation of anti-coronavirus activity of hydroxychloroquine against SARS-CoV-2 in human lung cells
  • Calu-3 cell line a human lung cell line, was obtained from Korea Cell Line Bank (KCLB) and cultured in Dulbecco's Modified Eagle's Medium (DMEM) under conditions of 37°C and CO 2 of 5%. Calu-3 cells were treated with various concentrations of hydroxychloroquine (Sigma Aldrich) corresponding to 100, 50, 25, 12.5, 6.25, 3.125, 1.563, 0.781 and 0.391 ⁇ M. After two hours from the treatment, the Calu-3 cells were infected with SARS-CoV-2 (NCCP43326) at multiplicity of infection (MOI) of 0.1.
  • SARS-CoV-2 NCCP43326
  • MOI multiplicity of infection
  • FIG. 1 illustrates dose-response curves based on the amount of SARS-CoV-2 RNA depending on hydroxychloroquine concentration.
  • X-axis represents the treated drug concentration ( ⁇ M) in log scale
  • Y-axis represents the amount of virus expressed in the drug-treated group by percentage (%) when a virus-infected group without the drug treatment (a control group) is 100%.
  • IC 50 of hydroxychloroquine a concentration at which the amount of corresponding virus is decreased by 50%
  • Remdesivir and hydroxychloroquine used in the comparative examples, are drugs which have been most extensively in the worldwide clinical trials to discover SARS-CoV-2-related therapeutic agents. Remdesivir has been reported to be effective in reducing a period of treatment for patients who were hospitalized with COVID-19 by about four days, while the effectiveness of hydroxychloroquine has been reported to be insignificant in the clinical trials.
  • nelfinavir used in Example 1 of the present disclosure exhibited IC 50 of 0.01 ⁇ M significantly effective against SARS-CoV-2
  • remdesivir used in Comparative Example 1 exhibited IC 50 of 0.03 ⁇ M
  • hydroxychloroquine used in Comparative Example 2 exhibited IC 50 of 50 ⁇ M or more and, accordingly, nelfinavir of the present disclosure had the most excellent antiviral effects against SARS-CoV-2.
  • nelfinavir cells started to be gradually detached at concentration of 10 ⁇ M or more in a virus-infected experimental system. As compared with other common drugs which are not substantially problematic even at higher concentration than that of 10 ⁇ M, nelfinavir may be considered to be a relatively cytotoxic drug.
  • maximum plasma concentration Cmax is predicted to be 160 ng/mL and AUC is predicted to be 2,112 ng ⁇ hr/mL when 50 mg of nelfinavir is administered twice a day (100 mg/day), and maximum plasma concentration Cmax is predicted to be 2,400 ng/mL and AUC is predicted to be 31,680 ng ⁇ hr/mL when 750 mg of nelfinavir is administered twice a day (1,500 mg/day).
  • the drug concentration in blood plasma immediately before the next taking of nelfinavir after taking the nelfinavir that is, the minimum plasma concentration Ctrough is quite high.
  • Ctrough was observed to be 1,980 ng/mL when 1,250 mg of nelfinavir was taken twice daily and was observed to be 2,380 ng/mL when 750 mg of nelfinavir was taken three times daily.
  • maximum plasma concentration Cmax was 5,440 ng/mL and AUC was 2,920 ng ⁇ hr/mL when 200mg of remdesivir was administered by intravenous infusion.
  • remdesivir can be administered only by intravenous infusion.
  • nelfinavir When the maximum plasma concentration Cmax of each of the above drugs is divided by IC 50 of each of the drugs, a low dose of nelfinavir is calculated to be 28 to 421, remdesivir is calculated to be 301, and hydroxychloroquine is calculated to be 0.004, as illustrated in Table 2.
  • an AUC value of each of the drugs referring to a total amount of drugs present in blood plasma, is divided by IC 50 of each of the drugs, a low dose of nelfinavir is calculated to be 371 to 5,558, remdesivir is calculated to be 161, and hydroxychloroquine is calculated to be 0.07, as illustrated in Table 2.
  • nelfinavir is an oral formulation and maintained at high AUC because it is exhibits excellent in-vivo duration, whereas remdesivir requires drip injection through a vein for 30 minutes to 2 hours and has low AUC because fast drug elimination occurs after the injection is finished. Therefore, considering AUC, the most relevant pharmacokinetic factor with expected treatment effectiveness, the low dose of nelfinavir according to the present disclosure has a remarkably higher value, obtained by dividing the AUC by IC 50 , than remdesivir. As a result, excellent clinical efficacy of the low dose of nelfinavir is expected.
  • remdesivir is limited to inpatients and patients with severe symptoms because intravenous infusion should be continuously performed through a vein, whereas nelfinavir may be advantageously applied to a treatment for mild to moderate COVID-19 patients including outpatients as well as severe COVID-19 patients.
  • Example 2 Evaluation of anti-coronavirus activity of nelfinavir against SARS-CoV-2 in Golden Syrian hamsters
  • Nelfinavir mesylate (TCI Co., Ltd) was orally administered twice daily at doses of 100 mg/kg/day and 200 mg/kg/day (corresponding to 85.5 mg/kg/day or 171 mg/kg/day of nelfinavir as an active ingredient) for a week to the SARS-CoV-2 infected hamsters.
  • a vehicle 1% of Tween80 solution was administered without nelfinavir under the same conditions.
  • a hamsters was sacrificed to obtain a lung tissue.
  • the amounts of SARS-CoV-2 remaining in the lung tissue were confirmed as the amounts of expression of an envelope gene (E gene), a nucleocapsid protein gene (N gene), and an RNA-dependent RNA polymerase gene (RdRP gene) of a virus using quantitative RT-PCR (qRT-PCR, Allplex TM 2019-nCoV assay kit, Seegene Inc.).
  • Nelfinavir 85.5 mg/kg/day Inhibition Rate (%) E gene N gene RdRp gene 3 dpi 99.789 % 99.999 % 99.874 % 5 dpi 99.926 % 99.998 % 99.955 % 7 dpi 99.984 % 99.997 % 99.868 %
  • Nelfinavir 171 mg/kg/day Inhibition Rate (%) E gene N gene RdRp gene 3 dpi 99.966 % 99.996 % 99.999 % 5 dpi 99.995 % 99.998 % 99.974 % 7 dpi 99.994 % 99.997 % 99.335 %
  • nelfinavir had an inhibition rate of at up to 99.99% against SARS-CoV-2, and exhibited excellent antiviral activity.
  • HED human equivalent dose
  • nelfinavir Since the values correspond to 693 mg/day and 1,387 mg/day of nelfinavir for a 60kg adult human respectively, it was confirmed well, in an actual in-vivo test, that nelfinavir exhibited excellent anti-SARS-CoV-2 activity even at a significantly lower dose than an usual dose (2,500 mg or 2,250 mg/day) when nelfinavir is used as an anti-AIDS drug. In addition, it was confirmed that a low dose of nelfinavir which was orally administered efficiently inhibited the viral expression in the lung tissue ( ⁇ 99.99% inhibition rate), so that nelfinavir may be orally well absorbed and then effectively delivered to the infected tissues to have excellent efficacy.
  • nelfinavir will exhibit excellent anti-SARS-CoV-2 effects while significantly reducing a risk of side effects of nelfinavir, and thus, will be advantageously used in treatment of COVID-19.

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Abstract

La présente invention concerne une composition pharmaceutique destinée à prévenir ou à traiter une infection par le SARS-CoV-2, et plus particulièrement, une composition pharmaceutique pour prévenir ou traiter une infection par le SARS-CoV-2, contenant nelfinavir exprimé par la formule chimique 1 suivante ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif à une faible dose de 100 mg/jour à 1500 mg/jour pour un être humain adulte ; une utilisation de nelfinavir, exprimé par la formule chimique 1 suivante, ou un sel pharmaceutiquement acceptable de celui-ci pour prévenir ou traiter et pour préparer un médicament pour prévenir ou traiter une infection par le SARS-CoV-2 à l'aide du nelfinavir ou du sel pharmaceutiquement acceptable de celui-ci en tant que principe actif à une faible dose de 100 mg/jour à 1500 mg/jour pour un être humain adulte ; et une méthode de prévention ou de traitement d'une infection par le SARS-CoV-2, incluant l'administration de nelfinavir, exprimé par la formule chimique 1 suivante, ou un sel pharmaceutiquement acceptable de celui-ci à un sujet, nécessitant le nelfinavir ou son sel pharmaceutiquement acceptable, en tant que principe actif à une faible dose de 100 mg/jour à 1500 mg/jour pour un être humain adulte.
PCT/KR2021/002355 2020-07-15 2021-02-25 Composition pharmaceutique pour la prévention ou le traitement d'une infection par le sars-cov-2 Ceased WO2022014813A1 (fr)

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WO2016176396A1 (fr) * 2015-04-29 2016-11-03 Foresight Biotherapeutics, Inc. Combinaisons thérapeutiques pour traitements antiviraux et anti-inflammatoires

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ARSHAD USMAN, PERTINEZ HENRY, BOX HELEN, TATHAM LEE, RAJOLI RAJITH KR, CURLEY PAUL, NEARY MEGAN, SHARP JOANNE, LIPTROTT NEILL J, V: "Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics", MEDRXIV, 22 April 2020 (2020-04-22), pages 1 - 37, XP055875256, Retrieved from the Internet <URL:https://www.medrxiv.org/content/10.1101/2020.04.16.20068379v1.full.pdf> DOI: 10.1101/2020.04.16.20068379 *
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