WO2021184115A1 - Use of bucillamine in the treatment of infectious diseases - Google Patents
Use of bucillamine in the treatment of infectious diseases Download PDFInfo
- Publication number
- WO2021184115A1 WO2021184115A1 PCT/CA2021/050350 CA2021050350W WO2021184115A1 WO 2021184115 A1 WO2021184115 A1 WO 2021184115A1 CA 2021050350 W CA2021050350 W CA 2021050350W WO 2021184115 A1 WO2021184115 A1 WO 2021184115A1
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- WO
- WIPO (PCT)
- Prior art keywords
- therapeutically effective
- effective amount
- bucillamine
- per day
- infectious disease
- Prior art date
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
-
- 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
-
- 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
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
Definitions
- the present invention relates to pharmaceutical compositions comprising bucillamine and their use for the treatment of infectious diseases.
- NAC works to prevent acute lung injury caused by influenza virus infection through inhibition of these ROS-mediated mechanisms. 4 ⁇ 7 NAC has been investigated clinically and found to significantly attenuate clinical symptoms associated with influenza infection, especially in elderly at-risk patients. 5 While NAC is easily taken up by cells and has low toxicity, clinical efficacy has required long-term and high-dose administration because of modest relative potency, limiting its clinical applicability.
- Bucillamine N-(mercapto-2-methylpropionyl)-l-cysteine is a cysteine derivative with 2 thiol groups.
- the structure of bucillamine is:
- Bucillamine provides protection against oxidative stress by donating thiol groups to GSH. This reactivates GSH and increases the amount available to remove reactive oxygen species, enhancing its endogenous antioxidant activity.
- the present inventors hypthesized that Bucillamine can be used to treat infectious disease symptoms, such as influenza symptoms and coronavirus disease 2019 (COVID 19) symptoms, by reducing tissue damage from reactive oxygen species.
- the present disclosure in one aspect, relates to a method for the treatment of an infectious disease in a mammal comprising administering a therapeutically effective amount of bucillamine or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof.
- the infectious disease is influenza.
- the infectious disease is coronavirus disease 2019.
- the method of treatment is for preventing or reducing acute lung injury during an infection.
- pharmaceutically acceptable compositions of the present disclosure can be administered to humans and other animals at a unit dose within range of about 10 mg to about 50 mg, the range of 100 mg to about 200 mg, 100mg, and 200 mg and this should provide a therapeutically effective dose.
- the daily dose is 300 mg per day. In another aspect, the daily does is 600 mg per day. In certain aspects, the unit dose may be higher than 200 mg. In another aspect, the daily dose is 600 mg per day. In certain aspects, the unit dose may be 200 mg to 300 mg. In certain other aspects, the daily dose may be higher than 600 mg per day. In another aspect, the daily dose is 600 mg to 800 mg per day. In another aspect, the daily dose is up to 1000 mg per day.
- the daily dose is up to 1500 mg per day, up to 2000 mg per day, up to 2500 mg per day, up to 3000 mg per day, 300-600 mg per day, 300-1000 mg per day, 300-1500 mg per day, 300-2000 mg per day, 300-2500 mg per day, 300-3000 mg per day, 600- 1000 mg per day, 600-1500 mg per day, 600-2000 mg per day, 600-2500 mg per day, 600-3000 mg per day.
- the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.
- the present disclosure in another aspect, relates to a use of a pharmaceutical composition including bucillamine or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents and excipients for the treatment of an infectious disease.
- the infectious disease is influenza.
- the infectious disease is coronavirus disease 2019.
- the use is for preventing or reducing acute lung injury during an infection.
- pharmaceutically acceptable compositions of the present disclosure can be used at a unit dose within range of about 10 mg to about 50 mg, the range of 100 mg to about 200 mg, 100mg, and 200 mg and this should provide a therapeutically effective dose.
- the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient. DETAILED DESCRIPTION
- a therapeutically effective amount of the bucillamine or pharmaceutically acceptable salts or solvates thereof may be presented as a pharmaceutical composition.
- the invention provides a pharmaceutical composition of bucillamine or pharmaceutically acceptable salts or solvates thereof in admixture with one or more pharmaceutically acceptable carriers, diluents, or excipients.
- the carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- compositions of the present invention including bucillamine may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
- a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base as appropriate.
- the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
- Suitable addition salts are formed from acids which form non-toxic salts and examples are hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, hydrogen phosphate, dihydrogen phosphate acetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharinate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and isethionate.
- Suitable salts may also be formed from bases, forming salts including ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium.
- Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, using conventional methods.
- Those skilled in the art of organic or coordination chemistry will appreciate that many organic and coordination compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”.
- solvates For example, a complex with water is known as a “hydrate”. Solvates of bucillamine are within the scope of the present invention.
- compositions of the invention may be formulated for administration by any appropriate route, for example by the oral (including buccal or sublingual). Therefore, the pharmaceutical compositions of the invention may be formulated, for example, as tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral solutions or suspensions. Such pharmaceutical formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
- Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
- the tablets may be coated according to methods well known in normal pharmaceutical practice.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan, monooleate, or acacia; non- aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
- suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan, mono
- compositions of the present invention may be suitable for the treatment of diseases in a human or animal patient.
- the patient is a mammal including a human, horse, dog, cat, sheep, cow, or primate.
- the patient is a human.
- the patient is not a human.
- the term “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
- therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
- the term also includes within its scope amounts effective to enhance normal physiological function.
- treatment refers to defending against or inhibiting a symptom, treating a symptom, delaying the appearance of a symptom, reducing the severity of the development of a symptom, and/or reducing the number or type of symptoms suffered by an individual, as compared to not administering a pharmaceutical composition of the invention.
- treatment encompasses the use in a palliative setting
- the present invention in one embodiment, relates to a method for the treatment of an infectious disease in a mammal comprising administering a therapeutically effective amount of bucillamine or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof.
- the infectious disease is influenza.
- the infectious disease is coronavirus disease 2019.
- the primary objective is to compare the frequency of hospitalization or death in patients with mild-moderate COVID-19 receiving Bucillamine therapy with those receiving placebo.
- the primary endpoint is the proportion of patients meeting a composite endpoint of hospitalization or death from the time of the first dose through Day 28 following randomization.
- Efficacy was assessed by comparing clinical outcomes (death or hospitalization), disease severity using the 8-category NIAID COVID ordinal scale, supplemental oxygen use, and progression of COVID-19 between patients receiving standard-of-care plus Bucillamine (high dose and/or low dose) and patients receiving standard-of-care plus placebo. Preliminary indications are that none of the patients receiving Bucillamine in the trial have to date been hospitalised for COVID-19 or have died from COVID-19.
- the present invention in another embodiment, relates to a use of a pharmaceutical composition including bucillamine or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents and excipients for the treatment of an infectious disease.
- infectious disease is influenza.
- infectious disease is coronavirus disease.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/912,597 US20230172884A1 (en) | 2020-03-19 | 2021-03-16 | Use of bucillamine in the treatment of infectious diseases |
CA3172170A CA3172170A1 (en) | 2020-03-19 | 2021-03-16 | Use of bucillamine in the treatment of infectious diseases |
JP2022556099A JP2023518430A (en) | 2020-03-19 | 2021-03-16 | Use of bucillamine in the treatment of infections |
KR1020227036230A KR20230015320A (en) | 2020-03-19 | 2021-03-16 | Use of Busillamine in the Treatment of Infectious Diseases |
EP21772039.0A EP4121035A4 (en) | 2020-03-19 | 2021-03-16 | Use of bucillamine in the treatment of infectious diseases |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US202062991996P | 2020-03-19 | 2020-03-19 | |
US62/991,996 | 2020-03-19 |
Publications (1)
Publication Number | Publication Date |
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WO2021184115A1 true WO2021184115A1 (en) | 2021-09-23 |
Family
ID=77767915
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/CA2021/050350 WO2021184115A1 (en) | 2020-03-19 | 2021-03-16 | Use of bucillamine in the treatment of infectious diseases |
Country Status (6)
Country | Link |
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US (1) | US20230172884A1 (en) |
EP (1) | EP4121035A4 (en) |
JP (1) | JP2023518430A (en) |
KR (1) | KR20230015320A (en) |
CA (1) | CA3172170A1 (en) |
WO (1) | WO2021184115A1 (en) |
Citations (5)
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WO2010014953A1 (en) * | 2008-08-01 | 2010-02-04 | The Regents Of The University Of Colorado, A Body Corporate | Prolonged administration of a dithiol anti-oxidant protects against ventricular remodeling |
CA2781314A1 (en) * | 2010-01-28 | 2011-08-04 | The Johns Hopkins University | Compositions and methods for reversing corticosteroid resistance or treating respiratory infections |
WO2011147753A1 (en) * | 2010-05-26 | 2011-12-01 | Katholieke Universiteit Leuven, K.U.Leuven R&D | Antiviral activity of novel bicyclic heterocycles |
CA3017797A1 (en) * | 2016-03-17 | 2017-09-21 | Thiogenesis Therapeutics, Inc. | Compositions for controlled release of cysteamine and systemic treatment of cysteamine sensitive disorders |
US20190142792A1 (en) * | 2010-03-06 | 2019-05-16 | Cacao Bio-Technologies, Llc | Antiviral epicatechins, epicatechin oligomers, or thiolated epicatechins from theobroma cacao for treatment of genital warts |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US6025393A (en) * | 1995-09-25 | 2000-02-15 | Santen Pharmaceutical Co., Ltd. | Method for treatment of inflammatory intestinal diseases |
CA2888647A1 (en) * | 2012-11-20 | 2014-05-30 | Revive Therapeutics Inc. | The use of bucillamine in the treatment of gout |
-
2021
- 2021-03-16 WO PCT/CA2021/050350 patent/WO2021184115A1/en unknown
- 2021-03-16 KR KR1020227036230A patent/KR20230015320A/en unknown
- 2021-03-16 US US17/912,597 patent/US20230172884A1/en active Pending
- 2021-03-16 CA CA3172170A patent/CA3172170A1/en active Pending
- 2021-03-16 JP JP2022556099A patent/JP2023518430A/en active Pending
- 2021-03-16 EP EP21772039.0A patent/EP4121035A4/en active Pending
Patent Citations (5)
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WO2010014953A1 (en) * | 2008-08-01 | 2010-02-04 | The Regents Of The University Of Colorado, A Body Corporate | Prolonged administration of a dithiol anti-oxidant protects against ventricular remodeling |
CA2781314A1 (en) * | 2010-01-28 | 2011-08-04 | The Johns Hopkins University | Compositions and methods for reversing corticosteroid resistance or treating respiratory infections |
US20190142792A1 (en) * | 2010-03-06 | 2019-05-16 | Cacao Bio-Technologies, Llc | Antiviral epicatechins, epicatechin oligomers, or thiolated epicatechins from theobroma cacao for treatment of genital warts |
WO2011147753A1 (en) * | 2010-05-26 | 2011-12-01 | Katholieke Universiteit Leuven, K.U.Leuven R&D | Antiviral activity of novel bicyclic heterocycles |
CA3017797A1 (en) * | 2016-03-17 | 2017-09-21 | Thiogenesis Therapeutics, Inc. | Compositions for controlled release of cysteamine and systemic treatment of cysteamine sensitive disorders |
Non-Patent Citations (5)
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D UNGHERI, C PISANI, G SANSON, A BERTANI, G SCHIOPPACASSI, R DELGADO, M SIRONI, P GHEZZI: "Protective effect of n-acetylcysteine in a model of influenza infection in mice", INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY, vol. 13, no. 3, 2000, GB , pages 123 - 128, XP009540174, ISSN: 0394-6320 * |
FLORA DE S., GRASSI C., CARATI L.: "ATTENUATION OF INFLUENZA-LIKE SYMPTOMATOLOGY AND IMPROVEMENT OF CELL-MEDIATED IMMUNITY WITH LONG-TERM N-ACETYLCYSTEINE TREATMENT.", EUROPEAN RESPIRATORY JOURNAL, EUROPEAN RESPIRATORY SOCIETY, GB, vol. 10., 1 July 1997 (1997-07-01), GB , pages 1535 - 1541., XP002912424, ISSN: 0903-1936, DOI: 10.1183/09031936.97.10071535 * |
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See also references of EP4121035A4 * |
Also Published As
Publication number | Publication date |
---|---|
JP2023518430A (en) | 2023-05-01 |
EP4121035A4 (en) | 2024-04-24 |
CA3172170A1 (en) | 2021-09-23 |
KR20230015320A (en) | 2023-01-31 |
EP4121035A1 (en) | 2023-01-25 |
US20230172884A1 (en) | 2023-06-08 |
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