WO2022238886A1 - Cyclobenzaprine for use in the treatment of coronavirus - Google Patents
Cyclobenzaprine for use in the treatment of coronavirus Download PDFInfo
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- WO2022238886A1 WO2022238886A1 PCT/IB2022/054324 IB2022054324W WO2022238886A1 WO 2022238886 A1 WO2022238886 A1 WO 2022238886A1 IB 2022054324 W IB2022054324 W IB 2022054324W WO 2022238886 A1 WO2022238886 A1 WO 2022238886A1
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- Prior art keywords
- cyclobenzaprine
- metabolites
- compounds
- pharmaceutically acceptable
- mixtures
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Classifications
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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 Cyclobenzaprine, salts thereof or metabolites thereof for use in the treatment of diseases related to Coronavirus infections.
- Cyclobenzaprine is a tricyclic compound widely used in the treatment of fibromyalgia and muscle spasms. It is the most studied muscle relaxant, but is not usable in spasticity due to neurological conditions.
- the SARS-CoV-2 coronavirus (Severe Acute Respiratory Syndrome Coronavirus 2) is a viral strain which infects humans, characterized by several variants, belonging to the subgenus Sarbecovirus, of the genus Betacoronavirus, subfamily Orthocoronavirinae, family Coronaviridae, suborder Cornidovirineae and order Nidovirales. Like the other viruses belonging to this order, it consists of a single strand of positive RNA wound by a capsid.
- Cell infection by SARS-coronavirus involves a virus internalization process initially mediated by the binding of the spike (S) surface viral protein, which recognizes and binds the human Angiotensin Converting Enzyme 2 (hACE2) receptor present on cells.
- S spike
- hACE2 human Angiotensin Converting Enzyme 2
- TMPRSS2 transmembrane serine protease 2
- the Orthocoronavirinee subfamily groups together several coronaviruses responsible for different diseases in mammals and birds, mainly in the respiratory and gastrointestinal tract. Seven coronaviruses are currently recognized, which can infect humans causing respiratory tract infections, often minor ones such as common cold, but in rare cases potentially lethal such as pneumonia and bronchitis.
- SARS-CoV Severe Acute Respiratory Syndrome
- MERS-CoV Middle East Respiratory Syndrome
- SARS-CoV-2 SARS-CoV-2 which was first identified in Wuhan, China, at the end of 2019 as the cause of coronavirus 2019 syndrome (COVID-19) and which then spread worldwide causing the current pandemic.
- SARS-CoV-2 is capable of infecting and causing damage to the central nervous system, with a possible persistence of neurological symptoms even for a few months after recovery from viral infection.
- SARS-CoV-2 infection more than 30% of patients develop neurological manifestations the severity of which is related to the severity of the infection. The most commonly reported neurological symptoms are: dizziness, headache, feeling dull, cognitive dysfunction (brain fog) , decreased levels of attention and memory, hypogeusia, ageusia, hyposmia, anosmia and myalgia.
- anosmia and ageusia have been reported frequently, especially in asymptomatic patients, so much so that they have been considered "certain" symptoms of SARS- CoV-2 positivity, and may also precede respiratory symptoms.
- severe neurological diseases such as stroke (ischemic or hemorrhagic, secondary to coagulopathy) , venous thrombosis, cerebral hemorrhage, encephalopathy, altered consciousness, meningitis, encephalitis, febrile convulsions, encephalomyelitis, myelitis, myasthenia gravis, Guillain-Barre and Miller-Fisher syndrome can also be observed in patients with COVID-19 of greater severity.
- the present invention derives from the surprising discovery that Cyclobenzaprine is effective in controlling the viral replication of Coronavirus.
- the present invention relates to Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use in the treatment of Coronavirus infections.
- the invention further relates to the use of Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for manufacturing a medicament for the treatment of Coronavirus infections.
- the present invention further relates to Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use in a combined therapy for treating a patient with SARS-related coronavirus infection, in which said Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds are administered with one or more drugs selected from the group comprising antiviral agents, immunomodulators and/or monoclonal antibodies directed against inflammatory cytokines.
- the present invention further relates to Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites or mixtures thereof of said compounds for use in the treatment of coronavirus as detailed below, in which said use comprises controlling or blocking the viral replication of coronavirus, in particular SARS-Cov.
- Figure 1 % inhibition of viral load measured at MOI of 0.1 (circles); % cell viability measured as number of fluorescent nuclei (squares).
- the present invention is directed to Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of such compounds for use in the treatment of Coronavirus infections.
- said virus is SARS-CoV. In a further embodiment, said virus is SARS-CoV-2. In a further embodiment, said virus is MERS-CoV.
- the present invention further relates to a composition comprising Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use in the prevention or treatment of infectious diseases from a virus belonging to the SARS-related coronavirus family (SARS-CoV, SARS-CoV-2 and MERS-CoV).
- Cyclobenzaprine has the following structural formula:
- tertiary amine nitrogen allows using compound in the form of a salt.
- Usable salts for the purposes of the present invention are all those formed by pharmaceutically acceptable acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid.
- the Cyclobenzaprine salt used for the purposes of the present invention will be Cyclobenzaprine hydrochloride.
- the present invention further includes the use of a Cyclobenzaprine metabolite.
- the term "metabolite” refers to the product (intermediate or final) of the metabolism process, i.e., the process according to which a substance assimilated by the body undergoes a transformation process which has the function of making the absorbed substance more easily absorbable or eliminable.
- the Cyclobenzaprine metabolites are selected from:
- the present invention further relates to Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use in a combined therapy for treating a patient with SARS-related coronavirus infection /SARS- CoV, SARS-CoV-2 and MERS-CoV) , in which said Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds are administered with one or more drugs selected from the group comprising antiviral agents, immunomodulators, monoclonal antibodies towards SARS- CoV-2 and/or monoclonal antibodies directed against inflammatory cytokines.
- antiviral agents are lopinavir/ritonavir, ribavirin, oseltamivir, umifenovir, remdesivir, favipiravir.
- immunomodulators are baricitinib imatinib dasat inib cyclosporine interferon b ⁇ interferon ⁇ , chloroquine, hydroxychloroquine, nitazoxanide, camostat mesylate, reparixin, corticosteroids, NSAIDs, dexamethasone.
- Preferred examples of monoclonal antibodies directed against inflammatory cytokines are bamlonivinab; etesevimab; carisivimab; imdevimab; regolanvimab; tocilizumab, sarilumab, bevacizumab, fingolimod, eculizumab .
- Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites or mixtures thereof of said compounds can be included in pharmaceutical formulations and can be formulated in dosage forms for oral, intranasal, buccal, parenteral, rectal or transdermal, topical, bronchial administration, or by any clinically acceptable method.
- the pharmaceutical compositions can be in the form of, for example, tablets, coated tablets, effervescent tablets, capsules, powders, granules, sugar-coated tablets, lozenges, pills, drops.
- the compositions can be in the form of tablets or hard or soft capsules prepared in the conventional fashion with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized cornstarch, polyvinylpyrrolidone or methylcellulose hydroxypropyl); filling agents (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or inhibiting agents (e.g.
- binding agents e.g., pregelatinized cornstarch, polyvinylpyrrolidone or methylcellulose hydroxypropyl
- filling agents e.g., lactose, microcrystalline cellulose or
- the tablets can be coated by methods well known in the art.
- the liquid preparations for oral administration can be, for example, in the form of solutions, syrups or suspensions or they can be freeze- dried or granulated products to be reconstituted, before use, with water or other suitable vehicles.
- Such liquid preparations can be prepared through conventional methods with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or edible hydrogenated fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl- or propyl-p-hydroxybenzoates or sorbic acid).
- suspending agents e.g., sorbitol syrup, cellulose derivatives, or edible hydrogenated fats
- emulsifying agents e.g., lecithin or acacia
- non-aqueous vehicles e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils
- preservatives e.g., methyl- or propyl-p-hydroxybenzoates or sorbic acid.
- the preparation can also
- the preparations for oral administration can be formulated appropriately to allow the controlled release of the active constituent.
- compositions can be in the form of tablets or pills formulated in the conventional fashion, adapted to be absorbed at the level of the buccal mucosa.
- Typical buccal formulations are tablets for sub-lingual administration.
- composition of the invention can be formulated for parenteral administration by injection.
- the injection formulations can be presented as a single dose, for example in vials, with an added preservative.
- the compositions can appear in this form as suspensions, solutions, or emulsions in oily or aqueous vehicles and can contain form agents such as suspension, stabilizing and/or dispersing agents.
- the active constituent can be found in the form of a powder to be reconstituted, before use, with a suitable vehicle, for example with sterile water.
- composition of the invention can also be formulated according to rectal formulations such as suppositories or retention enemas, for example containing the basic components of the common suppositories such as cocoa butter or other glycerides.
- composition of the invention can also be formulated as a deposit preparation.
- Such long-acting formulations can be administered by implantation (e.g., subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection. Therefore, for example, the composition can be formulated with appropriate polymer or hydrophobic materials (for example in the form of an emulsion in a suitable oil) or ion exchange resins or as minimally soluble derivatives.
- the dose of the active compounds suggested for administration to a man is from 1 mg to 100 mg per dose unit, preferably from 10 mg to 50 mg per dose unit.
- the dose unit can be administered, for example, 1 to 4 times a day.
- the dose will depend on the form in which the active compounds are administered.
- the dose will also depend on the route chosen for administration. It should be considered that it may be necessary to continuously vary the dosage depending on the age and weight of the patient and also on the severity of the clinical condition to be treated. The exact dose and route of administration will ultimately be at the discretion of the attending physician.
- formulations according to the invention can be prepared according to conventional methods, such as those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., N.Y.,
- Huh 7 cells (cell line originating from a human hepatocarcinoma) were used in the experimental test, which were engineered using a lentivirus to overexpress the human ACE2 receptor (Huh7-hACE2). Such cells were cultured in Dulbecco's modified Eagle's medium DMEM (Gibco) supplemented with 10% fetal bovine serum FBS (Gibco).
- the viral strain used is the isolate SARS-CoV ICGEB_FVG_S5 (Licastro D et al. Journal of Virology, 2020) which was cultured and quantified on Vero E6 cells.
- Dose preparation the compound was prepared in double serial dilutions (8-point dilutions) in DMSO (starting at a concentration of 5 mM) and then diluted 16 times in IX PBS in an intermediate plate. Finally, the compounds were transferred to the 96-well analysis plate for infection assay (6x in cultured medium, final dilution lOOx).
- Huh7-hACE2 cells were seeded in a 96-well plate, at a density of 8x10 3 cells/well and incubated at 37°C overnight. The next day, cells were treated with cyclobenzaprine hydrochloride at different concentrations (0.39- 50 ⁇ M) and simultaneously infected with SARS-CoV-2 at an MOI of 0.1. Two types of controls were prepared, one positive, represented by infected cells in the presence of 50 mM hydroxychloroquine, and by uninfected cells treated with vehicle (1% DMSO), and a negative control represented by infected cells in the presence of vehicle (1% DMSO).
- the plates were then incubated for 24 hours at 37°C, then fixed with 4% paraformaldehyde (PFA) for 15 minutes at room temperature and washed twice with lx PBS.
- PFA paraformaldehyde
- the cells were treated with 0.1% Triton-X for 15 min, followed by a 30 minute incubation in blocking buffer (PBS containing 1% bovine serum albumin - BSA).
- the cells were then incubated for 2 hours at 37°C with the primary antibody represented by a murine recombinant monoclonal antibody against the viral protein Spike (CR3022) diluted in blocking buffer (Milani M et al Antiviral Res., 2021).
- the cells were then washed 2 times in IX PBS and incubated with Alexa 488-conjugated anti-mouse secondary antibody with the addition of DAPI fluorescent dye (for cell nuclei staining) for 2 hours at 37°C. After such a time, the plates were washed twice with lx PBS and then each well was filled with 150 m ⁇ of PBS. Digital images of all plates were acquired using a high-resolution image analysis system (Operetta, Perkin Elmer). Nine different fields were acquired from each well at 20x magnification. The total number of cells and the number of infected cells were analyzed using the Columbus Image Data Storage and Analysis System (Perkin Elmer).
- the vitality test was conducted with Alamar Blue (Invitrogen) as recommended by the manufacturer's protocol.
- the Huh7-hACE2 cells were seeded at 8x103 cells per well in a 96-well plate and incubated at 37°C overnight. Then 50 ⁇ L of compound at the concentrations used for the replication inhibition test were added to 150 ⁇ L of medium (200 ⁇ L final). The final concentration range tested was 7- 1000 mM of compound.
- the plates were incubated at 37°C for 24 hours and then the colorimetric reagent alamar blue was added (20 pL for 4 hours). The colorimetric readings were normalized for the untreated control cells and the percentage was plotted with respect to the dilutions expressed as antilog.
- the antiviral activity was calculated with the formula:
- this compound primarily acts at the central neuronal level, whereby it is capable of counteracting viral action at the level of the central nervous system. ***
- One tablet contains:
- One hard gelatin capsule contains:
- One coated tablet contains:
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Abstract
The present invention relates to Cyclobenzaprine, salts thereof or metabolites thereof for use in the treatment of diseases related to Coronavirus infections. In particular, the present invention is directed to Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use in the treatment of Coronavirus infections.
Description
CYCLOBENZAPRINE FOR USE IN THE TREATMENT OF CORONAVIRUS
Description
Technical field of the invention
The present invention relates to Cyclobenzaprine, salts thereof or metabolites thereof for use in the treatment of diseases related to Coronavirus infections.
Background art
Cyclobenzaprine is a tricyclic compound widely used in the treatment of fibromyalgia and muscle spasms. It is the most studied muscle relaxant, but is not usable in spasticity due to neurological conditions.
The SARS-CoV-2 coronavirus (Severe Acute Respiratory Syndrome Coronavirus 2) is a viral strain which infects humans, characterized by several variants, belonging to the subgenus Sarbecovirus, of the genus Betacoronavirus, subfamily Orthocoronavirinae, family Coronaviridae, suborder Cornidovirineae and order Nidovirales. Like the other viruses belonging to this order, it consists of a single strand of positive RNA wound by a capsid. Cell infection by SARS-coronavirus involves a virus internalization process initially mediated by the binding of the spike (S) surface viral protein, which recognizes and binds the human Angiotensin Converting
Enzyme 2 (hACE2) receptor present on cells. The spike protein then undergoes proteolytic processing at the expense of the cellular proteases which promotes fusion between virus and cell. One of the cellular proteases involved in the entry of the virus into host cells is transmembrane serine protease 2 (TMPRSS2).
The Orthocoronavirinee subfamily groups together several coronaviruses responsible for different diseases in mammals and birds, mainly in the respiratory and gastrointestinal tract. Seven coronaviruses are currently recognized, which can infect humans causing respiratory tract infections, often minor ones such as common cold, but in rare cases potentially lethal such as pneumonia and bronchitis. The latter include the three viruses which have recently caused major outbreaks of lethal pneumonia: SARS-CoV, which was identified in 2003 as responsible for the epidemic of Severe Acute Respiratory Syndrome (SARS) which began in China towards the end of 2002; MERS-CoV, which was identified in 2012 as the cause of Middle East Respiratory Syndrome (MERS); SARS-CoV-2 which was first identified in Wuhan, China, at the end of 2019 as the cause of coronavirus 2019 syndrome (COVID-19) and which then spread worldwide causing the current pandemic.
Increasing experimental and clinical evidence is
showing that SARS-CoV-2 is capable of infecting and causing damage to the central nervous system, with a possible persistence of neurological symptoms even for a few months after recovery from viral infection. Several studies have reported that during SARS-CoV-2 infection, more than 30% of patients develop neurological manifestations the severity of which is related to the severity of the infection. The most commonly reported neurological symptoms are: dizziness, headache, feeling dull, cognitive dysfunction (brain fog) , decreased levels of attention and memory, hypogeusia, ageusia, hyposmia, anosmia and myalgia. Some of these, such as anosmia and ageusia, have been reported frequently, especially in asymptomatic patients, so much so that they have been considered "certain" symptoms of SARS- CoV-2 positivity, and may also precede respiratory symptoms. In addition to these neurological symptoms, severe neurological diseases such as stroke (ischemic or hemorrhagic, secondary to coagulopathy) , venous thrombosis, cerebral hemorrhage, encephalopathy, altered consciousness, meningitis, encephalitis, febrile convulsions, encephalomyelitis, myelitis, myasthenia gravis, Guillain-Barre and Miller-Fisher syndrome can also be observed in patients with COVID-19 of greater severity.
Currently, the treatment of neurological disorders
during SARS-CoV-2 infection does not include a specific therapy, therefore it is extremely important to have drugs available capable of crossing the blood-brain barrier and capable of interfering with viral replication or the spread thereof both in the early stages of viral infection with mild neurological symptoms and in patients of greater severity who have established neurological diseases.
Therefore, the need to have a drug capable of crossing the blood-brain barrier and interfering with the viral infection or the spread thereof even in the early stages of Coronavirus infection is strongly felt.
Summary of the invention
The present invention derives from the surprising discovery that Cyclobenzaprine is effective in controlling the viral replication of Coronavirus.
Therefore, the present invention relates to Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use in the treatment of Coronavirus infections.
The invention further relates to the use of Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said
compounds for manufacturing a medicament for the treatment of Coronavirus infections.
The present invention further relates to Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use in a combined therapy for treating a patient with SARS-related coronavirus infection, in which said Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds are administered with one or more drugs selected from the group comprising antiviral agents, immunomodulators and/or monoclonal antibodies directed against inflammatory cytokines.
The present invention further relates to Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites or mixtures thereof of said compounds for use in the treatment of coronavirus as detailed below, in which said use comprises controlling or blocking the viral replication of coronavirus, in particular SARS-Cov.
These and further objects, as outlined in the appended claims, will be described in the following description. The text of the claims should be considered included in the description for the purpose of assessing the sufficiency of the description.
Further features and advantages of the invention will become apparent from the following description of preferred embodiments, given by way of non-limiting example.
Brief description of the drawings
Figure 1: % inhibition of viral load measured at MOI of 0.1 (circles); % cell viability measured as number of fluorescent nuclei (squares).
Data are expressed as mean ± standard deviation StdErr.
Detailed description of the invention
In a first aspect, the present invention is directed to Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of such compounds for use in the treatment of Coronavirus infections.
In an embodiment, said virus is SARS-CoV. In a further embodiment, said virus is SARS-CoV-2. In a further embodiment, said virus is MERS-CoV.
The present invention further relates to a composition comprising Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use in the prevention or treatment of infectious diseases from a virus belonging to the SARS-related coronavirus family (SARS-CoV, SARS-CoV-2 and MERS-CoV).
Cyclobenzaprine has the following structural formula:
The presence of the tertiary amine nitrogen allows using compound in the form of a salt. Usable salts for the purposes of the present invention are all those formed by pharmaceutically acceptable acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid. Preferably, the Cyclobenzaprine salt used for the purposes of the present invention will be Cyclobenzaprine hydrochloride.
The present invention further includes the use of a Cyclobenzaprine metabolite. The term "metabolite" refers to the product (intermediate or final) of the metabolism process, i.e., the process according to which a substance assimilated by the body undergoes a transformation process which has the function of making the absorbed substance more easily absorbable or eliminable.
For the purposes of the present invention, the Cyclobenzaprine metabolites are selected from:
The present invention further relates to Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use in a combined therapy for treating a patient with SARS-related coronavirus infection /SARS- CoV, SARS-CoV-2 and MERS-CoV) , in which said Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds are administered with one or more drugs selected from the group comprising antiviral agents, immunomodulators, monoclonal antibodies towards SARS- CoV-2 and/or monoclonal antibodies directed against inflammatory cytokines.
Preferred examples of antiviral agents are lopinavir/ritonavir, ribavirin, oseltamivir, umifenovir, remdesivir, favipiravir.
Preferred examples of immunomodulators are baricitinib imatinib dasat inib cyclosporine
interferon bβ interferon α, chloroquine, hydroxychloroquine, nitazoxanide, camostat mesylate, reparixin, corticosteroids, NSAIDs, dexamethasone.
Preferred examples of monoclonal antibodies directed against inflammatory cytokines are bamlonivinab; etesevimab; carisivimab; imdevimab; regolanvimab; tocilizumab, sarilumab, bevacizumab, fingolimod, eculizumab .
For the purposes of the invention, Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites or mixtures thereof of said compounds can be included in pharmaceutical formulations and can be formulated in dosage forms for oral, intranasal, buccal, parenteral, rectal or transdermal, topical, bronchial administration, or by any clinically acceptable method.
For oral administration, the pharmaceutical compositions can be in the form of, for example, tablets, coated tablets, effervescent tablets, capsules, powders, granules, sugar-coated tablets, lozenges, pills, drops. For example, the compositions can be in the form of tablets or hard or soft capsules prepared in the conventional fashion with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized cornstarch, polyvinylpyrrolidone or
methylcellulose hydroxypropyl); filling agents (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or inhibiting agents (e.g. sodium lauryl sulfate). The tablets can be coated by methods well known in the art. The liquid preparations for oral administration can be, for example, in the form of solutions, syrups or suspensions or they can be freeze- dried or granulated products to be reconstituted, before use, with water or other suitable vehicles. Such liquid preparations can be prepared through conventional methods with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or edible hydrogenated fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl- or propyl-p-hydroxybenzoates or sorbic acid). The preparation can also conveniently contain flavorings, dyes, and sweetening agents.
The preparations for oral administration can be formulated appropriately to allow the controlled release of the active constituent.
For buccal administration, the compositions can be in the form of tablets or pills formulated in the
conventional fashion, adapted to be absorbed at the level of the buccal mucosa. Typical buccal formulations are tablets for sub-lingual administration.
The composition of the invention can be formulated for parenteral administration by injection. The injection formulations can be presented as a single dose, for example in vials, with an added preservative. The compositions can appear in this form as suspensions, solutions, or emulsions in oily or aqueous vehicles and can contain form agents such as suspension, stabilizing and/or dispersing agents. Alternatively, the active constituent can be found in the form of a powder to be reconstituted, before use, with a suitable vehicle, for example with sterile water.
The composition of the invention can also be formulated according to rectal formulations such as suppositories or retention enemas, for example containing the basic components of the common suppositories such as cocoa butter or other glycerides.
In addition to the compositions described above, the composition of the invention can also be formulated as a deposit preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection. Therefore, for example, the composition can
be formulated with appropriate polymer or hydrophobic materials (for example in the form of an emulsion in a suitable oil) or ion exchange resins or as minimally soluble derivatives.
According to the present invention the dose of the active compounds suggested for administration to a man (with a body weight of about 70 Kg) is from 1 mg to 100 mg per dose unit, preferably from 10 mg to 50 mg per dose unit. The dose unit can be administered, for example, 1 to 4 times a day. The dose will depend on the form in which the active compounds are administered. The dose will also depend on the route chosen for administration. It should be considered that it may be necessary to continuously vary the dosage depending on the age and weight of the patient and also on the severity of the clinical condition to be treated. The exact dose and route of administration will ultimately be at the discretion of the attending physician.
The formulations according to the invention can be prepared according to conventional methods, such as those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., N.Y.,
USA, 17th edition, 1985.
EXPERIMENTAL SECTION
Biological experimentation
Materials and methods
Cell cultures , viral infections and drug treatment
Huh 7 cells (cell line originating from a human hepatocarcinoma) were used in the experimental test, which were engineered using a lentivirus to overexpress the human ACE2 receptor (Huh7-hACE2). Such cells were cultured in Dulbecco's modified Eagle's medium DMEM (Gibco) supplemented with 10% fetal bovine serum FBS (Gibco). The viral strain used is the isolate SARS-CoV ICGEB_FVG_S5 (Licastro D et al. Journal of Virology, 2020) which was cultured and quantified on Vero E6 cells.
Compound preparation: cyclobenzaprine hydrochloride was solubilized in DMSO at a stock concentration of 20 mM and was maintained at -20°C until use.
Screening for viral inhibition and toxicity
Dose preparation: the compound was prepared in double serial dilutions (8-point dilutions) in DMSO (starting at a concentration of 5 mM) and then diluted 16 times in IX PBS in an intermediate plate. Finally, the compounds were transferred to the 96-well analysis plate for infection assay (6x in cultured medium, final dilution lOOx).
Antiviral analysis: the Huh7-hACE2 cells were seeded in a 96-well plate, at a density of 8x103 cells/well and
incubated at 37°C overnight. The next day, cells were treated with cyclobenzaprine hydrochloride at different concentrations (0.39- 50 μM) and simultaneously infected with SARS-CoV-2 at an MOI of 0.1. Two types of controls were prepared, one positive, represented by infected cells in the presence of 50 mM hydroxychloroquine, and by uninfected cells treated with vehicle (1% DMSO), and a negative control represented by infected cells in the presence of vehicle (1% DMSO). The plates were then incubated for 24 hours at 37°C, then fixed with 4% paraformaldehyde (PFA) for 15 minutes at room temperature and washed twice with lx PBS. Next, the cells were treated with 0.1% Triton-X for 15 min, followed by a 30 minute incubation in blocking buffer (PBS containing 1% bovine serum albumin - BSA). The cells were then incubated for 2 hours at 37°C with the primary antibody represented by a murine recombinant monoclonal antibody against the viral protein Spike (CR3022) diluted in blocking buffer (Milani M et al Antiviral Res., 2021).
The cells were then washed 2 times in IX PBS and incubated with Alexa 488-conjugated anti-mouse secondary antibody with the addition of DAPI fluorescent dye (for cell nuclei staining) for 2 hours at 37°C. After such a time, the plates were washed twice with lx PBS and then each well was filled with 150 mΐ of PBS. Digital images
of all plates were acquired using a high-resolution image analysis system (Operetta, Perkin Elmer). Nine different fields were acquired from each well at 20x magnification. The total number of cells and the number of infected cells were analyzed using the Columbus Image Data Storage and Analysis System (Perkin Elmer).
Vitality test
The vitality test was conducted with Alamar Blue (Invitrogen) as recommended by the manufacturer's protocol. The Huh7-hACE2 cells were seeded at 8x103 cells per well in a 96-well plate and incubated at 37°C overnight. Then 50 μL of compound at the concentrations used for the replication inhibition test were added to 150 μL of medium (200 μL final). The final concentration range tested was 7- 1000 mM of compound. The plates were incubated at 37°C for 24 hours and then the colorimetric reagent alamar blue was added (20 pL for 4 hours). The colorimetric readings were normalized for the untreated control cells and the percentage was plotted with respect to the dilutions expressed as antilog.
The antiviral activity was calculated with the formula:
[1- (average number of infection plaquestreated with compound/average number of infection plaquesUntreated)] x100 and plotted with respect to the dilutions expressed as antilog.
Half of the maximum cytotoxic concentration (CC50) was calculated using GraphPad Prism Version 7.
RESULTS
The results of the experiments are shown in figure 1 and in the following table:
a Half concentration for half of the maximum effect obtained by high-content screening b Half concentration of the cytotoxic effect c Values obtained from the cores counted in the high content procedure d Values obtained from Alamar Blue assay.
The above data are indicative of high antiviral activity with Cyclobenzaprine and low cytotoxicity resulting in a significant selective index (CC50/EC50).
As reported in the NCI Thesaurus (code C28947), this compound primarily acts at the central neuronal level, whereby it is capable of counteracting viral action at the level of the central nervous system. ***
The invention will now be further described by means of the following examples of formulations.
EXAMPLE 1 - Tablet for oral administration
One tablet contains:
- Cyclobenzaprine hydrochloride 30.00 mg
- Microcrystalline cellulose 78.47 mg
- Croscarmellose sodium 45.00 mg
- Polyvinylpyrrolidone 10.00 mg
- Magnesium stearate 4.0 mg
- Polysorbate 80 2.00 mg
EXAMPLE 2 - Hard gelatin capsule
One hard gelatin capsule contains:
- Cyclobenzaprine hydrochloride 40 mg
- Soy lecithin 100 mg
- Lactose 80 mg
EXAMPLE 3 - Coated tablet
One coated tablet contains:
- Cyclobenzaprine hydrochloride 20 mg
- Polyvinylpyrrolidone 30 mg
Croscarmellose sodium 80 mg
Magnesium stearate 7 mg .
Claims
1. Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use in the treatment of Coronavirus infections.
2. Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use in the prevention or treatment of infectious diseases from a virus belonging to the SARS- related coronavirus family.
3. Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use according to claim 2, wherein said coronavirus is SARS-CoV.
4. Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use according to claim 2, wherein said coronavirus is SARS-CoV-2.
5. Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use according to claim 1, wherein said coronavirus is MERS-CoV.
6. Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use according to any one of claims 1 to 5, wherein said Cyclobenzaprine salts are selected
from hydrochloride, hydrobromide, hydroiodide and sulfate, preferably hydrochloride.
7. Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use according to any one of claims 1 to 6, wherein the metabolites are selected from norcyclobenzaprine, cis-10,11-Dihydroxy Nortriptyline and Cyclobenzaprine N-b-D-Glucuronide.
8. Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use according to any one of claims 1 to 7, in a combined therapy for treating a patient with a SARS-related coronavirus infection, wherein said Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds are administered with one or more drugs selected from the group comprising antiviral agents, immunomodulators, monoclonal antibodies against SARS- CoV-2 and/or monoclonal antibodies directed against inflammatory cytokines.
9. Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use according to claim 8, wherein said antiviral agents are selected from lopinavir/ritonavir, ribavirin, oseltamivir, umifenovir, remdesivir, favipiravir; said immunomodulators are
selected from baricitinib, imatinib, dasatinib, cyclosporine, interferon b, interferon a, chloroquine, hydroxychloroquine, nitazoxanide, camostat mesilate, reparixin, corticosteroids; said monoclonal antibodies directed against inflammatory cytokines are selected from bamlonivinab; etesevimab; carisivimab; imdevimab; regolanvimab; tocilizumab, sarilumab, bevacizumab, fingolimod, eculizumab.
10. Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use according to any one of claims 1 to 9, wherein said Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds are included in pharmaceutical formulations and are formulated in dosing forms for oral, intranasal, buccal, parenteral, rectal or transdermal, topical or bronchial administration.
11. Cyclobenzaprine or pharmaceutically acceptable salts thereof and/or metabolites thereof or mixtures of said compounds for use according to any one of claims 1 to 10, wherein said use comprises controlling or blocking the viral replication of coronavirus, in particular SARS-Cov.
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EP3964206A1 (en) * | 2020-09-04 | 2022-03-09 | Dompe' Farmaceutici S.P.A. | Compounds for the treatment of covid-19 |
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US20190175525A1 (en) * | 2017-12-11 | 2019-06-13 | Tonix Pharma Holdings Limited | Cyclobenzaprine treatment for agitation, psychosis and cognitive decline in dementia and neurodegenerative conditions |
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