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WO2022130031A1 - Composition pharmaceutique de nitazoxanide et de méfloquine et son procédé de fabrication - Google Patents

Composition pharmaceutique de nitazoxanide et de méfloquine et son procédé de fabrication Download PDF

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Publication number
WO2022130031A1
WO2022130031A1 PCT/IB2021/050775 IB2021050775W WO2022130031A1 WO 2022130031 A1 WO2022130031 A1 WO 2022130031A1 IB 2021050775 W IB2021050775 W IB 2021050775W WO 2022130031 A1 WO2022130031 A1 WO 2022130031A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
nitazoxanide
mefloquine
pharmaceutically acceptable
present
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2021/050775
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English (en)
Inventor
Chander Mohan Negi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of WO2022130031A1 publication Critical patent/WO2022130031A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Embodiments of a present disclosure relate to a technical field of pharmaceutical composition. More particularly, the present disclosure relates to pharmaceutical composition that includes a synergistic combination of Nitaoxanide and Mefloquine.
  • coronavirus disease is an infectious disease caused by a newly discovered coronavirus.
  • the disease emerged first in December 2019 in Wuhan, Hubei, China.
  • This deadly disease rapidly spread to almost 188 countries around the world, with a mortality rate of approximately 5%.
  • the outbreak was declared a Public health Emergency of International Concern by the World Health Organization (WHO) in January 2020 and was recognized as a pandemic in March 2020.
  • WHO World Health Organization
  • SARS-CoV coronavirus
  • SARS-CoV is an enveloped, positive-strand RNA virus. Its large RNA genome is approximately 30000 nucleotides in length and encodes a nonstructural replicase complex and structural proteins, including spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins.
  • Spike protein is the envelope protein responsible for invasion of host cells.
  • COVID-19 positive individual may remain asymptomatic or show symptoms that may be common, mild in nature or severe. Most common symptoms of COVID- 19 positive range from fever, dry cough, tiredness, etc., ranging to less common symptoms such as body aches and pains, sore throat, diarrhea, conjunctivitis, severe headache and loss of taste or smell and appearance of rash on skin, or discoloration of fingers or toes.
  • the disease COVID- 19 can spread from person to person through small droplets from the nose or mouth land on objects and surfaces around the person which are spread when a person with COVID- 19 coughs or exhales.
  • the disease COVID-19 present as atypical pneumonia that often leads to acute respiratory distress syndrome and respiratory failure, the main cause of death. This unusual infectious disease has become a major threat to public health and social stability since its outbreak.
  • COVID- 19 is fatal if the affected individual develops serious symptoms such as difficulty in breathing or shortness of breath, chest pain or pressure and loss of speech or movement.
  • One of the major factors contributing to the continued presence of Covid-19 is that there is no promising therapy available for the disease.
  • the prior art W01998050035A1 discloses a pharmaceutical compositions of tizoxanide and nitazoxanide, this pharmaceutical compositions is particularly useful for treatment of opportunistic infections in persons with compromised or suppressed immune systems.
  • EP2902024A1 discloses a composition of nitazoxanide and mebendazole, methods for the preparation thereof, and use of said composition is for the treatment of human parasitosis.
  • the prior art CN101919857A discloses a compound albendazole preparation comprises the following components in part by weight: 100 to 200 parts of albendazole, 400 to 600 parts of pyrantel pamoate, 30 to 60 parts of filler, 2 to 20 parts of binder, 100 to 160 parts of flavoring agent and 20 to 100 parts of lubricant, wherein the components are mixed and prepared into chewable tablets for treatment of parasitic diseases.
  • nitazoxanide and mefloquine are generally used alone not in combination. Despite their excellent intrinsic antiparasitic activity, these drugs have not shown the effective results for the treatment against SARS-CoV2 infection.
  • composition comprising a simple, easy to manufacture and therapeutically effective dosage regime.
  • a pharmaceutical composition for treating Covid- 19 virus comprising a therapeutically effective amount of a nitazoxanide or its pharmaceutically acceptable salts thereof and a mefloquine or its pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition comprises the nitazoxanide in the ratio of 0.05% to 66% w/v.
  • the pharmaceutical composition comprises the mefloquine in the ratio of 0.05% to 90% w/v.
  • the pharmaceutical composition comprises at least one of pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises at least one of pharmaceutically acceptable carrier.
  • the pharmaceutical composition is a granule, tablet, capsule, liquid, or mixture pellets.
  • the pharmaceutical composition can be administered as oral, parental, topical or any combination thereof.
  • the combined preparation comprises of one or more dosage units of a nitazoxanide or its pharmaceutically acceptable salts thereof, and a mefloquine or its pharmaceutically acceptable salts thereof.
  • the COVID-19(SARS-CoV-2) is an ongoing pandemic of Corona virus disease 2019(COVID-19). It is an infectious disease caused by newly discovered Severe acute respiratory syndrome Corona virus 2 (SARS-CoV-2).
  • the disease (SARS- CoV-2) can spread from person to person through small droplets from the nose or mouth land on objects and surfaces around the person which are spread when a person with COVID- 19 coughs or exhales.
  • the SARS presents as atypical pneumonia that often leads to acute respiratory distress syndrome and respiratory failure, the main cause of death. This unusual infectious disease has become a major threat to public health and social stability since its outbreak.
  • Embodiments of the present invention relates to a pharmaceutical composition for treating Covid- 19 virus comprising a therapeutically effective amount of a nitazoxanide or its pharmaceutically acceptable salts thereof, and a mefloquine or its pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition comprises of the nitazoxanide in the ratio of 0.05% to 66% w/v.
  • the pharmaceutical composition comprises of the mefloquine in the ratio of 0.05% to 90% w/v.
  • nitazoxanide is the prototype member of thiazolides, a class of drugs which are synthetic nitrothiazolyl- salicylamide derivates with broad- spectrum anti-parasitic and broad-spectrum antiviral activity suggests that it possesses efficacy in treating a number of viral infections as well.
  • nitazoxanide and mefloquine are used alone not in combination, despite, their excellent intrinsic antimalarial activity, they have not shown any effective results for the treatment against SARS-CoV2 infection.
  • the nitazoxanide combines synergistically with mefloquine.
  • This combination of nitazoxanide and mefloquine exhibited promising In-Vitro antiviral activity against SARS-CoV2. Therefore, this promising In-Vitro results renders the nitazoxanide and mefloquine combination a good candidate for its use in drug combination therapy for SARS-CoV2 infections.
  • the combination of therapeutic effective amount of nitazoxanide and mefloquine are shown to be rapidly effective and produce faster resolution of SARS-CoV2 and fever than all other identified compounds.
  • the pharmaceutical composition comprising nitazoxanide along with mefloquine were found to limit virus entry, reduces virus particles, inhibit both viral release and cell-to-cell transmission, and possess broad anti-viral activities which makes the purposing of existing drugs a timely and attractive alternative.
  • the pharmaceutical composition comprises at least one of pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises at least one of pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is selected from one or more of the group consisting of mannitol, sorbitol, a sorbic acid or potassium salt, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin A, vitamin C, vitamin E, vitamin D, azone, disodium ethylenediaminetetraacetate, calcium sodium ethylenediaminetetraacetate, monovalent alkali metal carbonate, acetate, phosphate or an aqueous solution thereof, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol,
  • the pharmaceutically acceptable carrier is
  • the pharmaceutical composition is a granule, tablet, capsule, oral, liquid, or mixture pellets.
  • the pharmaceutical composition can be administered as oral, parental, topical or any other mode of administration.
  • the combined preparation comprises of one or more dosage units of a nitazoxanide or its pharmaceutically acceptable salts thereof and a mefloquine or its pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable excipients are selected from the group comprising diluents/fillers, binders, disintegrants, glidants, lubricants, solubilizers/surfactants/wetting agents, plasticizers, solvents and the like.
  • the pharmaceutical compositions of the present invention can be in the form of modified release dosage form which include, but not limited to, controlled release, sustained release, extended release, prolonged release dosage form.
  • modified release dosage form which include, but not limited to, controlled release, sustained release, extended release, prolonged release dosage form.
  • rate controlling agents/techniques known in the art may be used to control the release of the drug from the dosage form.
  • the pharmaceutical composition may be in the form of tablets, capsules, tablets filled in capsule, minitablets filled in capsule, sachets containing powder or granules, pellets, and the like.
  • the pharmaceutical composition is meant for once daily or twice daily administration.
  • teachings of the present invention relates to the combination of nitazoxanide and mefloquine administrations that improves the dosage regimen and combinational therapy that is not only effective and safe but also simple in administration resulting in a maximum of patients' compliance.
  • Compliance of the patient is, therefore, a crucial consideration and a key determinant in the successful treatment of COVID regarding both efficacy of the therapy and prevention of recurrence.
  • Long duration regimens, complex dosing schemes, poor understanding of the patient of how or why to adhere to the recommended regimen as well as rapid perception of wellness induce the patient to discontinue the therapy prematurely.
  • nitazoxanide and mefloquine has been found that it provides a simple fixed-dose treatment administered one to two times a day for 3-10 days. This combination is unexpectedly well tolerated with a low rate of side-effects, and equally high cure- rates than in comparable treatments. Due to the simple dosing regimen the patients' compliance is excellent.
  • fixed-dose means daily dosage of both antiviral that are same every day for a given treatment course, wherein the amount of the effective dose can be individually determined by the medical practitioner.
  • a method for the treatment of SARS-CoV2 in a 3-10 day course is also provided administering a therapeutically effective amount of the combination of nitazoxanide and mefloquine is provided, wherein the dosage of nitazoxanide and mefloquine for each day remains the same.
  • the amount of the combination of nitazoxanide and mefloquine required to be effective as an antiviral will, of course, vary and is ultimately at the discretion of the medical practitioner.
  • the factors to be considered include the nature and severity of the SARS-CoV2 infection to be treated, route of administration, high or low transmission area, the immune status of the patient as well as age and weight of the patient.
  • the present invention provides a pharmaceutical composition for treatment of SARS-CoV2 with existing pharmaceutical APIs and salts in novel composition
  • the respective raw materials, pharmaceutically acceptable carrier and an extract can be prepared as granules, tablets, capsules, oral liquid, or mixture pellets.
  • the pharmaceutical composition can be a tablet, carrier as lactose or corn starch, magnesium stearate lubricants are added when required, mixed well, and then tableted.
  • the powder when the present invention is made in capsules, the powder is filled in required doses in the capsule shells to form capsules.
  • the dosage of the pharmaceutical composition in the present invention can carry out suitable variation according to the dosage form difference of administration object, route of administration or medicine, but take, guarantees that this pharmaceutical composition can reach effective blood drug level as prerequisite in mammalian body.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une composition pharmaceutique pour traiter le virus de la COVID-19 comprenant une quantité thérapeutiquement efficace de nitazoxanide ou de ses sels pharmaceutiquement acceptables et de méfloquine ou de ses sels pharmaceutiquement acceptables. La composition pharmaceutique comprend du nitazoxanide dans un rapport de 0,05 % à 66 % en p/v et de la méfloquine dans un rapport de 0,05 % à 90 % en p/v. La composition s'avère efficace pour le traitement de la COVID-19 (SARS-CoV2). La composition pharmaceutique de nitazoxanide et de méfloquine s'est avérée efficace et est étonnamment bien tolérée avec un faible taux d'effets secondaires, et des taux de guérison aussi élevés que dans les traitements comparables.
PCT/IB2021/050775 2020-12-17 2021-02-01 Composition pharmaceutique de nitazoxanide et de méfloquine et son procédé de fabrication Ceased WO2022130031A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202021054967 2020-12-17
IN202021054967 2020-12-17

Publications (1)

Publication Number Publication Date
WO2022130031A1 true WO2022130031A1 (fr) 2022-06-23

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020202111A1 (fr) * 2019-04-04 2020-10-08 Tarsus Pharmaceuticals, Inc. Parasiticides systémiques à base d'isoxazoline pour le traitement ou la prophylaxie d'une maladie virale et à vecteur
CN111743899A (zh) * 2020-01-21 2020-10-09 中国人民解放军军事科学院军事医学研究院 硝唑尼特及其活性形式替唑尼特在治疗SARS-CoV-2感染中的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020202111A1 (fr) * 2019-04-04 2020-10-08 Tarsus Pharmaceuticals, Inc. Parasiticides systémiques à base d'isoxazoline pour le traitement ou la prophylaxie d'une maladie virale et à vecteur
CN111743899A (zh) * 2020-01-21 2020-10-09 中国人民解放军军事科学院军事医学研究院 硝唑尼特及其活性形式替唑尼特在治疗SARS-CoV-2感染中的应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JEAN-FRANCOIS ROSSIGNOL: "Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus", JOURNAL OF INFECTION AND PUBLIC HEALTH, vol. 9, 2016, pages 227 - 230, XP029547996, DOI: 10.1016/j.jiph.2016.04.001 *

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