WO2021229514A1 - Compositions pharmaceutiques d'ivermectine - Google Patents

Compositions pharmaceutiques d'ivermectine Download PDF

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Publication number
WO2021229514A1
WO2021229514A1 PCT/IB2021/054132 IB2021054132W WO2021229514A1 WO 2021229514 A1 WO2021229514 A1 WO 2021229514A1 IB 2021054132 W IB2021054132 W IB 2021054132W WO 2021229514 A1 WO2021229514 A1 WO 2021229514A1
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Prior art keywords
ivermectin
nasal
inhalation
composition
respiratory
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PCT/IB2021/054132
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English (en)
Inventor
Hiren Patel
Bikash Kumar Sahoo
Sanjay Saha
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Orbicular Pharmaceutical Technologies Private Limited
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Publication of WO2021229514A1 publication Critical patent/WO2021229514A1/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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 nasal and inhalation compositions comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients for the treatment of respiratory disease and/ or disorders.
  • Respiratory diseases, or lung diseases are pathological conditions affecting the organs and tissues that make gas exchange difficult in air- breathing animals. They include conditions of the respiratory tract including the trachea, bronchi, bronchioles, alveoli, pleurae, pleural cavity, and the nerves and muscles of respiration. Respiratory diseases, or lung diseases, are pathological conditions affecting the organs and tissues that make gas exchange difficult in air-breathing animals. They include conditions of the respiratory tract including the trachea, bronchi, bronchioles, alveoli, pleurae, pleural cavity, and the nerves and muscles of respiration.
  • Respiratory disorders include asthma, Chronic obstructive pulmonary disease (COPD), chronic bronchitis.
  • Chronic obstructive pulmonary disease (COPD) is a severe respiratory condition that are increasing its prevalence worldwide and these disorders are preventable and treatable disease state characterized by airflow limitation that is not fully reversible.
  • the airflow obstruction is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking.
  • COPD affects the lungs it also produces significant systemic consequences. COPD is associated with mucus hyper secretion, emphysema, bronchiolitis.
  • bronchodilators are the foundation in the therapy of COPD because of their capacity to alleviate symptoms, decrease exacerbations of disease and improve quality of life. These drugs also improve airflow limitation and hyperinflation, thereby decreasing the work of breathing and improving exercise tolerance. In addition, bronchodilators may reduce respiratory muscle fatigue and improve mucociliary clearance.
  • Ivermectin a macrocyclic lactone
  • Ivermectin B1 is a macrocyclic lactone obtained from Streptomyces avermitilis culture fermentation broth and the selective hydrogenation of the existing double bonds in the position C22-C23 of avermectin B1 macrolid structures leads to the synthesis of ivermectin as described in literature.
  • Ivermectin is disclosed in US Pat. No. 4,199,569, to Chabala and Fisher. Ivermectin is a mixture, in the ratio of approximately 80:20 of 22,23-dihydro C- 076 Bla and Bib.
  • Ivermectin is used as anthelmintic used to treat parasite infestations. Ivermectin is used to treat infections in the body that are caused by certain parasites to improve quality of life. Ivermectin is approved by several regulatory agencies. Ivermectin is used for treatment of threadworm (enterobiasis), lymphatic filariasis, treatment of whipworm (Trichuris trichiura), head lice infestations. Ivermectin, is available in oral dosage form in the world-wide market for treatment of Strongyloidiasis and Onchocerciasis. The pharmacokinetic post oral dose is very well defined and available in public domain. Following oral administration of ivermectin, plasma concentrations are approximately proportional to the dose.
  • Ivermectin is approved by most of the regulatory agencies across the world. Ivermectin has an established safety profile for human use and is FDA- approved for a number of parasitic infections. Ivermectin is available as oral tablet, topical lotion and topical cream to treat various parasitic infestations.
  • US patent 4389397 discloses solubilization of Ivermectin in water wherein aqueous formulation comprising Ivermectin in a solution of a non- ionic or an anionic surface-active agent and water, characterized in that the formulation is stabilized by the inclusion of one or more water-miscible organic co-solvents suitable for parenteral or oral administration, the cosolvent(s) being glycerol formal, propylene glycol, glycerine, and/or polyethylene glycol; and/or one or more substrates also suitable for parenteral or oral administration, the substrate(s) being benzyl alcohol, lidocaine, a paraben, and/or choline.
  • SARS- CoV-2 causative virus
  • IVM ivermectin
  • This formulation includes a pyrrolidone solvent, a bridging solvent, and a parasiticidal agent.
  • a parasiticidal agent may be included in the formulation.
  • the formulation contains both closantel and ivermectin.
  • US7064108 patent discloses topical gel composition comprising between about 0.005 and 1.0% ivermectin, between about 30 and 40% of a pharmaceutically acceptable alcohol, between about 30 and 40% of a pharmaceutically acceptable glycol, and a pharmaceutically acceptable carrier.
  • W01997026895 patent application discloses formulation for administering an avermectin consisting of from 0.1 % to 40% by weight of an avermectin dissolved in a solvent comprising at least 5% by volume N- methylpyrrolidone, or2-pyrrolidone, or a mixture thereof.
  • W003051281 patent application discloses a composition for nasal administration to animals, including humans, applicants' composition includes lysozyme in combination with zinc.
  • the composition further includes one or more anthelmentic compounds, a method to treat animals, including humans, having a pulmonary bacterial or viral infection by delivering a therapeutically effective amount of lysozyme to the animal's nasal pharynx.
  • HIV-1 human immunodeficiency virus-1
  • IMP importin
  • SARS-CoV-2 The causative agent of the current COVID-19 pandemic, SARS-CoV-2, is a single stranded positive sense RNA virus that is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV).
  • SARS-CoV proteins Studies on SARS-CoV proteins have revealed a potential role for IMRa/b-1 during infection in signal- dependent nucleocytoplasmic shutting of the SARS-CoV 51 Nucleocapsid protein, that may impact host cell division.
  • ivermectin for the prophylaxis and potential treatment of respiratory disease and/ or disorders such as, respiratory obstruction, COPD, chronic bronchitis, inflammatory or obstructive airway disease, respiratory obstruction due to Covid-19 and related respiratory disease and /or disorders.
  • Important object of the present invention is to provide an ivermectin inhalation solution, suspension, dry powder inhaler (DPI) or metered dose inhaler (MDI) for the prophylaxis and potential treatment of respiratory disease and/ or disorder.
  • DPI dry powder inhaler
  • MDI metered dose inhaler
  • Another object of the present invention is to provide a prepackaged, sterile, premixed, premeasured, therapeutic dosage ivermectin nasal and inhalation composition for the treatment of respiratory disease and/ or disorder.
  • a further object of the present invention is to provide a method of administering an ivermectin inhalation composition for treatment of respiratory disease and/ or disorder.
  • An additional object of the present invention is to provide a kit or system for prophylaxis and treatment of respiratory disease and/ or disorder.
  • the present invention relates to a nasal and inhalation composition
  • a nasal and inhalation composition comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients.
  • the present invention relates to a nasal and inhalation composition
  • a nasal and inhalation composition comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients for the treatment of respiratory disease and/ or disorders such as, respiratory obstruction, COPD, chronic bronchitis, inflammatory or obstructive airway disease, respiratory obstruction due to Covid-19, comprising administering a therapeutically effective amount of nasal and inhalation composition.
  • composition according to above embodiment wherein suitable excipients are selected from solvents and/or co-solvents, surfactants and/or co-surfactants, buffering agents, complexing agents or chelating agents, preservatives, antioxidants, viscosity modifying agents and the like or mixtures thereof.
  • suitable excipients are selected from solvents and/or co-solvents, surfactants and/or co-surfactants, buffering agents, complexing agents or chelating agents, preservatives, antioxidants, viscosity modifying agents and the like or mixtures thereof.
  • suitable excipients are selected from solvents and/or co-solvents, surfactants and/or co-surfactants, buffering agents, complexing agents or chelating agents, preservatives, antioxidants, viscosity modifying agents and the like or mixtures thereof.
  • the composition according to previous embodiment further comprises of one or more active agents.
  • composition according to previous embodiment wherein active agents are antibiotics, antiemetics, anticholinergics, bronchodilators, corticosteroids, antihistamines, antivirals and the like or combinations thereof.
  • composition wherein composition can be administered as a metered dose inhalers (MDI), dry powder inhalers (DPI), nebuliser, nasal spray, nasal drops, inhalation spray, nasal inhalation, soft mist inhalation, nasal aerosol, propellant-containing metered-dose aerosols, inhalable solution or inhalable suspensions, propellant-free inhalable solutions, propellant-free inhalable suspensions and the like.
  • MDI metered dose inhalers
  • DPI dry powder inhalers
  • nebuliser nasal spray, nasal drops, inhalation spray, nasal inhalation, soft mist inhalation, nasal aerosol, propellant-containing metered-dose aerosols, inhalable solution or inhalable suspensions, propellant-free inhalable solutions, propellant-free inhalable suspensions and the like.
  • composition according to above embodiment wherein ivermectin is administered alone or in combination with other active agents to the upper respiratory tract and lower respiratory tracts.
  • composition according to above embodiment wherein ivermectin is administered alone or in combination with other active agents for prophylaxis of coronavirus or Covid-19 infections.
  • composition according to above embodiment wherein ivermectin is administered alone or in combination with other active agents for treatment of coronavirus or Covid-19 infections.
  • composition according to above embodiment, wherein the nasal and inhalation compositions additionally provides kits for use in prophylaxis and treatment of the respiratory diseases.
  • the present invention relates to nasal and inhalation composition
  • ivermectin and/ or its acceptable salt thereof with other suitable excipients for prophylaxis and treatment of respiratory disease and/ or disorders.
  • active agent or “active pharmaceutical ingredient” or “API” includes the compound(s), pharmaceutically acceptable salts thereof, isomers, solvates, prodrugs, complexes and hydrates, anhydrous forms thereof, and any polymorphic or amorphous forms or combinations thereof.
  • Ivermectin includes the compound, pharmaceutically acceptable salts thereof, isomers, solvates, prodrugs, complexes and hydrates, anhydrous forms thereof, and any polymorphic or amorphous forms or combinations thereof.
  • pharmaceutically acceptable salts includes pharmaceutically acceptable salts, solvates, hydrates, anhydrates, enantiomers, esters, isomers, polymorphs, tautomers, complexes and thereof.
  • nasal and inhalation refers but not limited to metered dose inhalers (MDI), dry powder inhalers (DPI), nebuliser, nasal spray, nasal drops, inhalation spray, nasal inhalation, soft mist inhalation, nasal aerosol, propellant-containing metered-dose aerosols, inhalable solution or inhalable suspensions, propellant-free inhalable solutions, propellant-free inhalable suspensions.
  • MDI metered dose inhalers
  • DPI dry powder inhalers
  • nebuliser nasal spray, nasal drops, inhalation spray, nasal inhalation, soft mist inhalation, nasal aerosol, propellant-containing metered-dose aerosols, inhalable solution or inhalable suspensions, propellant-free inhalable solutions, propellant-free inhalable suspensions.
  • composition and “formulation” refer to preparations comprising ivermectin or pharmaceutically acceptable salts thereof; in a form suitable for administration to a mammal.
  • Stability includes both physical and chemical stability. Stability parameters include but not limited to potency, stable pH value and other physico-chemical parameters.
  • compositions free from particles and that do not significantly change during storage refers to compositions free from particles and that do not significantly change during storage.
  • the term "chemical stability" relates to a limited formation of impurities, limited decrease in potency and the like.
  • the invention relates to a nasal and inhalation composition comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients for prophylaxis of respiratory disease and/ or disorders such as, respiratory obstruction, inflammatory or obstructive airway disease, respiratory obstruction due to coronavirus or Covid-19, comprising administering a therapeutically effective amount of nasal and inhalation composition.
  • the invention relates to a nasal and inhalation composition
  • a nasal and inhalation composition comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients for the treatment of respiratory disease and/ or disorders such as, respiratory obstruction, inflammatory or obstructive airway disease, respiratory obstruction due to coronavirus or Covid-19, comprising administering a therapeutically effective amount of nasal and inhalation composition.
  • the nasal and inhalation composition includes but not limited to a solution, a suspension, a dry powder inhaler, a metered dose inhaler, an aerosol and the like or combinations thereof.
  • composition comprises of suitable excipients, selected from solvents and/or co-solvents, surfactants and/or co-surfactants, buffering agents, complexing agents or chelating agents, preservatives, antioxidants, viscosity modifying agents and the like or mixtures thereof.
  • suitable excipients selected from solvents and/or co-solvents, surfactants and/or co-surfactants, buffering agents, complexing agents or chelating agents, preservatives, antioxidants, viscosity modifying agents and the like or mixtures thereof.
  • the composition includes a solution which comprises of ivermectin with solvents and/ or co-solvents and other suitable excipients.
  • the solvents include but not limited to glycols, alcohols, and the like or mixture thereof; glycols include ethylene glycol, butylene glycol, propylene glycol, polypropylene glycol, and the like or mixtures thereof; alcohols include ethanol, isopropanol and the like or mixtures thereof.
  • Co -solvents for use herein include, but are not limited to, hydroxylated solvents or other polar solvents, such as alcohols such as isopropyl alcohol, glycols such as propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and the like or mixtures thereof.
  • hydroxylated solvents or other polar solvents such as alcohols such as isopropyl alcohol, glycols such as propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and the like or mixtures thereof.
  • Surfactants and/or co-surfactants include but not limited to cationic surfactant, and non-ionic surfactants.
  • Surfactants include, but not limited to Polysorbates such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 65, polysorbate 85, sorbitan fatty acid esters such as Span 20, Span 40, Span 60, Span 80, Span 85, Span 120; sodium lauryl sulfate; polyethoxylated castor oil; polyethoxylated hydrogenated castor oil, sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl amine oxide, Docusate sodium, Cetyl trimethyl ammonium bromide (CTAB) Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N,N-dimethyldodecylamine-N-oxide, Hexadecyltrimethylammonium bromide,
  • Carboxylates Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates, Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated natural oils & fats, Sulphated esters, Sulphated alkanolamides, Alkylphenols, ethoxylated & sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters Polyethylene glycol esters, Anhydrosorbitol ester & it’s ethoxylated derivatives, Glycol esters of fatty acids, Carboxylic amides, Monoalkanolamine condensates, Polyoxyethylene fatty acid amides, Quaternary ammonium salts, Amines with amide linkages, Polyoxyethylene alkyl & alicyclic amines, N,N,N,N tetrakis substituted ethylenediamines 2-alky
  • the present invention includes buffers in its composition and buffering agents comprise of one or more of organic or inorganic acids and its salt thereof, such as but not limited to citric acid/sodium hydrogensulphate borate buffer, phosphates (sodium hydrogen orthophosphate, disodium hydrogen phosphate), trometamol, tartrate buffer, acetate buffer, citrate buffer, sodium citrate dehydrate, citric acid monohydrate, sodium dihydrogen phosphate dehydrate, sodium chloride, anhydrous disodium hydrogen phosphate or equivalent conventional buffers.
  • citric acid/sodium hydrogensulphate borate buffer phosphates (sodium hydrogen orthophosphate, disodium hydrogen phosphate), trometamol, tartrate buffer, acetate buffer, citrate buffer, sodium citrate dehydrate, citric acid monohydrate, sodium dihydrogen phosphate dehydrate, sodium chloride, anhydrous disodium hydrogen phosphate or equivalent conventional buffers.
  • phosphates sodium hydrogen orthophosphate, disodium hydrogen phosphate
  • the buffer is selected from the group but not limited to acetic acid, citric acid, phosphoric acid, maleic acid, tartaric acid, citric acid/phosphate buffer, acetate buffer, citrate buffer, phosphate buffer, maleate buffer, tartrate buffer and the like or mixtures thereof. Buffers may also be used as pH adjusting agents.
  • Complexing agents or chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) or its salt thereof, such as the disodium salt, citric acid, nitrilotriacetic acid and the salts thereof.
  • EDTA ethylenediaminetetraacetic acid
  • the complexing agent is EDTA.
  • Preservatives include, but are not limited to, those that protect the solution from contamination with pathogenic particles, including benzalkonium chloride or benzoic acid, or benzoates such as sodium benzoate.
  • Antioxidants include, but are not limited to, vitamins, provitamins, ascorbic acid, vitamin E or salts or esters thereof.
  • Viscosity modifiers include but not limited to hydroxy propyl methyl cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, microcrystalline cellulose/sodium carboxymethylcellulose, pectin, and the like or mixtures thereof.
  • examples of other acceptable excipients include carriers which may be used to prepare the inhalable dry powders according to the invention include, for example, monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixture of these excipients with one another.
  • Other carriers include, maltodextrins, inositol, sodium starch glycolate, leucine, and the like or mixtures thereof.
  • carriers for use in the invention include, without limitation, lactose, glucose, or sodium starch glycolate particulates.
  • the carrier is lactose.
  • the particulate lactose is in some instance alpha lactose monohydrate.
  • the particle size of the lactose should be such that it can be entrained in an air stream but not deposited in the key target sites of the lung. Accordingly, in some embodiments, lactose with a mean particle size of less than 40 pm is excluded. Particle size is determined using laser light scattering.
  • the carrier particles have a VMD of from about 50 to about 250 pm. Within that range, the carrier particles of a given composition according to the invention may have a VMD of from about 50 to about 60 pm or from about 60 to about 90 pm or from about 90 to about 150 pm.
  • the powder for inhalation according to the invention are prepared by mixing the coarser carrier fractions with the finer excipient fractions and subsequently mixing the resulting carrier mixtures with the ivermectin or its acceptable salt thereof.
  • the powder for inhalation according to the invention are prepared by mixing the coarser carrier fractions with the finer carrier fractions and subsequently mixing the resulting carrier mixtures with the ivermectin and/or other active agent.
  • the nasal compositions comprise of propellants such as hydrofluoroalkane (HFA) propellants and the like; the nasal aerosol compositions comprise of propellants such as hydrofluoroalkane (HFA) propellants and the like; MDI compositions comprise of propellants such as hydrofluoroalkane (HFA) propellants and the like.
  • propellants such as hydrofluoroalkane (HFA) propellants and the like
  • the nasal aerosol compositions comprise of propellants such as hydrofluoroalkane (HFA) propellants and the like
  • MDI compositions comprise of propellants such as hydrofluoroalkane (HFA) propellants and the like.
  • the composition includes a solution which comprises of ivermectin with suitable excipients.
  • the composition includes a suspension which comprises of ivermectin with suitable excipients.
  • the composition includes a dry powder inhaler which comprises of ivermectin with other suitable excipients.
  • the composition includes a metered dose inhaler which comprises of ivermectin with other suitable excipients.
  • composition includes a nasal aerosol which comprises of ivermectin with other suitable excipients.
  • the composition further comprises of one or more active agents, wherein the active agents include but not limited to antibiotics, antiemetics, anticholinergics, bronchodilators, corticosteroids, antihistamines, antiviral agents, anthelmintic and/or one or more anthelmintic and the like or combinations thereof.
  • active agents include but not limited to antibiotics, antiemetics, anticholinergics, bronchodilators, corticosteroids, antihistamines, antiviral agents, anthelmintic and/or one or more anthelmintic and the like or combinations thereof.
  • Antibiotics include, but not limited to azithromycin, tobramycin, enoxacin, doxycycline, minocycline and the like or combinations thereof.
  • Antiemetics include, but not limited to emetine, prochlorperazine, aprepitant, rolapitant, ondansetron granisetron, and the like or combinations thereof.
  • Anticholinergics include, but not limited to aclidinium, glycopyrronium or glycopyrrolate, ipratropium, tiotropium, umeclidinium and the like or combinations thereof.
  • Bronchodilators include, but not limited to formoterol, arformoterol, salmeterol, olodaterol, vilanterol, carmoterol and the like or combinations thereof.
  • Corticosteroids include, but not limited to fluticasone, mometasone, beclomethasone, ciclesonide, budesonide, flunisolide and the like or combinations thereof.
  • Antihistamines include, but not limited to azelastine, phenylephrine, oxymetazoline, olopatadine, alcaftadine, and the like or combinations thereof.
  • Antiviral agents include, but not limited to ribavirin, lopinavir, nelfinavir, ritonavir, ganciclovir, favipravir, remdesivir, brincidofovir, and the like or combinations thereof.
  • the composition includes a solution which comprises of ivermectin and other active agent with suitable excipients.
  • the composition includes a suspension which comprises of ivermectin and other active agent with suitable excipients.
  • the composition includes a dry powder inhaler which comprises of ivermectin and other active agent with other suitable excipients.
  • the composition includes a metered dose inhaler which comprises of ivermectin and other active agent with other suitable excipients.
  • composition includes a nasal aerosol which comprises of ivermectin and other active agent with other suitable excipients.
  • composition in another embodiment can be administered but not limited to metered dose inhalers (MDI), dry powder inhalers (DPI), nebuliser, nasal spray, nasal drops, inhalation spray, nasal inhalation, soft mist inhalation, nasal aerosol, propellant-containing metered-dose aerosols, inhalable solution or inhalable suspensions, propellant- free inhalable solutions and the like.
  • MDI metered dose inhalers
  • DPI dry powder inhalers
  • nebuliser nasal spray, nasal drops, inhalation spray, nasal inhalation, soft mist inhalation, nasal aerosol, propellant-containing metered-dose aerosols, inhalable solution or inhalable suspensions, propellant- free inhalable solutions and the like.
  • present composition is administered alone or in combination with other active agents to the upper respiratory tract and lower respiratory tracts.
  • composition according to above embodiment wherein ivermectin is administered alone or in combination with other active agents for prophylaxis of coronavirus or Covid-19 infections.
  • composition according to above embodiment wherein ivermectin is administered alone or in combination with other active agents for treatment of coronavirus or Covid-19 infections.
  • SARS-CoV-2 is a novel strain of coronaviruses or Covid-19 which is associated with a cluster of cases of pneumonia in China.
  • Coronaviruses are a broad family of viruses that includes SARS-CoV, MERS-CoV, HCoV-229E, HCoV-OC43, HCoVNL63 and HCoV-HKlM strains.
  • HCoV-229E, HCoV-OC43, HCoVNL63 and HCoV-HKlM strains are usually associated with mild, self-limiting upper respiratory tract infections, such as the common cold.
  • people infected with MERS-CoV, SASRS-CoV or SARS-CoV-2 could develop severe respiratory illness.
  • a US government interagency group developed a variant Classification scheme that defines three classes of SARS-CoV-2 variants:
  • the invention discloses ivermectin nasal and inhalation composition for targeted delivery to nasal cavity and nasopharyngeal area for prophylaxis and treatment of Corona virus(es) or Covid-19 infections.
  • the invention discloses, ivermectin with other active agents as nasal and inhalation composition for targeted delivery to nasal cavity and nasopharyngeal area for prophylaxis and treatment of Corona virus(es) or Covid-19 infections.
  • the ivermectin nasal spray composition for targeted delivery to nasal cavity and nasopharyngeal area via nasal spray would allow drug distribution across nasal cavity to allow maximal reduction of viral load in such an area which is responsible to maximal bioaerosol and cross infection.
  • Saliva contains a high viral load in COVID-19 with up to T2 c 10 8 infective copies/mL when the saliva of patients was analysed at the time of admission to hospital. It has recently been found, through PCR assay techniques, that the nasopharynx appears to have a higher viral load than that found in the oropharynx.
  • the ivermectin nasal spray composition is postulated to be effective in: 1. reduction of Bioaerosols from Covid-19 patients in hospital settings. 2. reduction in viral load in patients with Covid-19 as a treatment measure. 3. preventive measure for frontline workers, physicians, paramedics, police staff handling Covid-19 patients. 4. presymptomatic patients who are known to be highly infectious can use/ can be prescribed with nasal and inhalation composition of Ivermectin for reduction in viral transmission.
  • nasal and inhalation ivermectin composition to lower respiratory tract holds great potential in reducing viral load at alevolar level.
  • Inhalation composition could play a pivotal role in: i. eradicating viral sancturies, ii. reducing viral replication linked inflammatory reactions, iii. reducing possibility of Cytokine storm.
  • ivermectin dose is selected ranging from about 0.1 pg to about 3 mg; from about 0.15 pg to about 2.5 mg; for example, 0.2 pg to about 2 mg.
  • the dose may vary for each of the nasal and inhalation compositions.
  • ivermectin has an average particle size of from about 0.5 pm to about 10 pm; for example, from about 1 pm to about 6 pm, for example, from about 2 pm to about 5 pm.
  • active agent has an average particle size of from about 0.5 p to about 10 pm; for example, from about 1 pm to about 6 pm, for example, from about 2 pm to about 5 pm.
  • composition according to the present invention may be provided in suitable containers with suitable means enabling the application of the contained formulation to the respiratory tract.
  • the powder for inhalation intended for administration through DPI may either be encapsulated in capsules of gelatin or HPMC or in blisters or alternatively, the dry powder may be contained as a reservoir either in a single dose or multi-dose dry powder inhalation device.
  • the powder for inhalation intended to be used for MDI may be suspended or solubilized in a suitable liquid vehicle and packed in an aerosol container along with suitable propellants or mixtures thereof.
  • the powder for inhalation intended to be used for DPI may also be dispersed in a suitable gas stream to form an aerosol composition.
  • the MDI composition according to the present invention may be packed in plain aluminum cans or SS (stainless steel) cans.
  • Some aerosol drugs tend to adhere to the inner surfaces, i.e., walls of the cans and valves, of the MDI. This can lead to the patient getting significantly less than the prescribed amount of the active agent upon each activation of the MDI.
  • Coating the inner surface of the container with a suitable polymer can reduce this adhesion problem.
  • Suitable coatings include fluorocarbon copolymers such as FEPPES (fluorinated ethylene propylene and polywethersulphone) and PFA-PES (perfluoroalkoxyalkane and polyethersulphone), epoxy and ethylene.
  • the inner surfaces of the cans may be anodized, plasma treated or plasma coated.
  • compositions comprising nebulization are hereby provided.
  • the nebulization compositions are sterilized and filled in ampoules or vials, including unit dose vials, providing sterile unit dose formulations for use in a nebulizer.
  • sterile it is meant that the resultant pharmaceutical composition meets the requirements of sterility enforced by medicine regulatory authorities, such as the FDA in the US or the MCA in the UK. Tests are included in current versions of the compendia, such as the US Pharmacopoeia and the British Pharmacopoeia.
  • the present invention provides a container comprising a vial, an ampule, comprising a single unit dose in a sterile solution, or a plurality of such vials, for use in a nebulizer.
  • the nebulizer compositions are supplied as LDPE vials in aluminum pouch or other suitable equivalent materials.
  • nasal spray compositions are supplied as LDPE/HDPE bottle and/ or glass/HDPE bottle with actuator and pump.
  • the MDI compositions are supplied in Aluminum cans and/ or bottles with actuator and pump.
  • the DPI compositions are supplied as capsule based dry powder device and/ or reservoir based dry powder device.
  • the kits comprise:
  • a container containing a required dose of a therapeutically effective amount of ivermectin; and/ or combination with other active agents,
  • the present invention also provides a process to manufacture the compositions according to the present invention.
  • the present invention provides a process of preparing a metered dose inhalation composition which process comprises admixing of a pharmaceutically acceptable carrier or excipient with the actives and the propellant and providing the composition in precrimped cans.
  • the present invention provides a process of preparing a dry powder inhalation composition which process comprises admixing of a pharmaceutically acceptable carrier or excipient with the actives and providing the composition to be administered through dry powder inhaler.
  • the present invention also provides a process of preparing an inhalation solution/suspension respule which process comprises dissolving/dispersing the drugs, with solvent, optionally surfactant, optionally chelating agents, buffering agents and any other suitable ingredients and adjusting the pH using a suitable pH adjusting agent.
  • the present invention provides a prophylactic treatment in a mammal, such as a human, for treating chronic obstructive pulmonary disease and asthma, for the treatment of respiratory disease and/ or disorders such as, respiratory obstruction, inflammatory or obstructive airway disease, respiratory obstruction due to Covid-19, which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention.
  • the prophylactic treatment may be characterized in that the pharmaceutical compositions according to the present invention are administered once or twice daily in therapeutically effective amounts.
  • the present invention also provides a method for the treatment in a mammal, such as a human, for treating chronic obstructive pulmonary disease and asthma, for the treatment of respiratory disease and/ or disorders such as, respiratory obstruction, inflammatory or obstructive airway disease, respiratory obstruction due to corona virus or Covid-19 infection, which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention.
  • the method of treatment may be characterized in that the pharmaceutical compositions according to the present invention are administered once or twice daily in therapeutically effective amounts.
  • compositions were found to be stable at both accelerated and real time conditions.

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Abstract

La présente invention concerne une composition nasale et d'inhalation comprenant de l'ivermectine et/ou son sel acceptable avec d'autres excipients appropriés pour le traitement prophylactique et/ou pour le traitement de maladies et/ou de troubles respiratoires tels qu'une obstruction respiratoire, une maladie des voies respiratoires inflammatoire ou obstructive, une obstruction respiratoire due à des infections à coronavirus ou à la Covid-19, comprenant l'administration d'une quantité thérapeutiquement efficace d'une composition nasale et d'inhalation.
PCT/IB2021/054132 2020-05-14 2021-05-14 Compositions pharmaceutiques d'ivermectine WO2021229514A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022170027A1 (fr) * 2021-02-04 2022-08-11 Edenbridge Pharmaceuticals, LLC Ivermectine inhalée
WO2023003003A1 (fr) * 2021-07-20 2023-01-26 興和株式会社 Nouveau produit à inhaler
EP4209212A1 (fr) * 2022-01-05 2023-07-12 HWI pharma services GmbH Composition aqueuse comprenant des avermectines
WO2023180802A1 (fr) * 2022-03-25 2023-09-28 Sava Healthcare Ltd Formulation d'inhalation de poudre sèche (dpi)
WO2023180955A1 (fr) * 2022-03-22 2023-09-28 Equilibre Biopharmaceuticals Bv Méthodes d'utilisation de compositions d'avermectine pour traitement de troubles neurologiques et schémas posologiques
WO2023180954A1 (fr) * 2022-03-22 2023-09-28 Equilibre Biopharmaceuticals Bv Méthodes d'utilisation de compositions d'avermectine pour le traitement de troubles inflammatoires et de schémas posologiques
WO2023180956A1 (fr) * 2022-03-22 2023-09-28 Equilibre Biopharmaceuticals Bv Méthodes d'utilisation de compositions d'avermectine pour traitement de spasticité et schémas posologiques
WO2023180957A1 (fr) * 2022-03-22 2023-09-28 Equilibre Biopharmaceuticals Bv Méthodes d'utilisation de compositions d'avermectine pour le traitement de la douleur et posologies

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WO2018053029A1 (fr) * 2016-09-13 2018-03-22 Prothera Biologics, Inc. Procédés de traitement d'une maladie pulmonaire à l'aide de protéines inhibitrices d'inter-alpha

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LEON CALY, DRUCE JULIAN D., CATTON MIKE G., JANS DAVID A., WAGSTAFF KYLIE M.: "The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro", ANTIVIRAL RESEARCH, ELSEVIER BV, NL, vol. 178, 1 June 2020 (2020-06-01), NL , pages 104787, XP055731793, ISSN: 0166-3542, DOI: 10.1016/j.antiviral.2020.104787 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022170027A1 (fr) * 2021-02-04 2022-08-11 Edenbridge Pharmaceuticals, LLC Ivermectine inhalée
WO2023003003A1 (fr) * 2021-07-20 2023-01-26 興和株式会社 Nouveau produit à inhaler
EP4209212A1 (fr) * 2022-01-05 2023-07-12 HWI pharma services GmbH Composition aqueuse comprenant des avermectines
WO2023131584A1 (fr) * 2022-01-05 2023-07-13 Hwi Pharma Services Gmbh Composition aqueuse composée d'avermectines
WO2023180955A1 (fr) * 2022-03-22 2023-09-28 Equilibre Biopharmaceuticals Bv Méthodes d'utilisation de compositions d'avermectine pour traitement de troubles neurologiques et schémas posologiques
WO2023180954A1 (fr) * 2022-03-22 2023-09-28 Equilibre Biopharmaceuticals Bv Méthodes d'utilisation de compositions d'avermectine pour le traitement de troubles inflammatoires et de schémas posologiques
WO2023180956A1 (fr) * 2022-03-22 2023-09-28 Equilibre Biopharmaceuticals Bv Méthodes d'utilisation de compositions d'avermectine pour traitement de spasticité et schémas posologiques
WO2023180957A1 (fr) * 2022-03-22 2023-09-28 Equilibre Biopharmaceuticals Bv Méthodes d'utilisation de compositions d'avermectine pour le traitement de la douleur et posologies
WO2023180802A1 (fr) * 2022-03-25 2023-09-28 Sava Healthcare Ltd Formulation d'inhalation de poudre sèche (dpi)

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