WO2022016202A1 - Dérivé de la pleuromutiline et/ou ivermectine, pour le traitement des infections, en particulier à coronavirus - Google Patents

Dérivé de la pleuromutiline et/ou ivermectine, pour le traitement des infections, en particulier à coronavirus Download PDF

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Publication number
WO2022016202A1
WO2022016202A1 PCT/AT2021/000012 AT2021000012W WO2022016202A1 WO 2022016202 A1 WO2022016202 A1 WO 2022016202A1 AT 2021000012 W AT2021000012 W AT 2021000012W WO 2022016202 A1 WO2022016202 A1 WO 2022016202A1
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WO
WIPO (PCT)
Prior art keywords
local
ivermectin
formulation
formulations
polysorbate
Prior art date
Application number
PCT/AT2021/000012
Other languages
German (de)
English (en)
Inventor
Gerd Ascher
Original Assignee
Gerd Ascher
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 Gerd Ascher filed Critical Gerd Ascher
Publication of WO2022016202A1 publication Critical patent/WO2022016202A1/fr

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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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • 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

  • Covid-19 is currently the greatest threat to civilization, both medically and economically. There is still no effective therapy; Vaccines have yet to be developed. Quarantine and "social distancing" are imposed worldwide. An effective prophylactic treatment to reduce or even prevent the risk of infection does not yet exist. It is known that the pili of Covidl9 are very sensitive to soaps and detergents and that a simple cleaning operation can eliminate them of viruses on skin surfaces.Therefore, a class of active ingredients that has both antibacterial and antiviral activity and also has a soap-like effect due to its chemical structure can be ideally suited for local prophylaxis.All of these requirements are met by the pleuromutilins.
  • PLEUROMUTILIN of the general formula 1 was discovered as a naturally occurring antibiotic from Pleurotus Mutilis in Austria (Brandl and Knauseder).
  • pleuromutilins of the formulas 2 and 3 also have excellent activity against mycoplasma, chlamydia and coccidia, which has led to their use in the veterinary field.
  • the glycolic acid side chain of the natural product was replaced by a ß ⁇ diethylaminomercaptoethyl group or by a corresponding thiovaline residue. (See formulas 2 and 3).
  • NABRIVA launched the first systemically and orally applicable pleuromutilin antibiotic under the trade name LEFAMULIN. Approval in Europe is still pending.
  • IVERMECTIN of formula 4 belongs to the class of avermectins, which was isolated in 1996 from Streptomyces avermectilis. It is mainly used in veterinary medicine against parasites and as an anthelmintic, but is also approved in human medicine in various countries and indications. Its long half-life is remarkable.
  • an effect is sought in the nasopharyngeal area, where 80% of all infection transmissions take place. It is advantageous to achieve an effect of 6 to 8 hours. This can be achieved, for example, by co-amination of fenoterol or salbutamol, which are known to have a long duration of action in the nasopharyngeal region.
  • an optimal pH of 5.5 to 6.5 should be achieved with suitable additives/auxiliaries
  • Self-buffering can be achieved with a pharmaceutically acceptable salt such as hydrogen fumarate.
  • the active ingredients and auxiliaries can be applied in the range from 0.1 to 1000 ppm.
  • the only limitation is the tolerability in the nasopharyngeal space and the pH values.
  • Duration of application and the intensity of the prophylactic and initial therapeutic effect can be increased by co-administration of the following local and inhalative active ingredients and excipients.
  • Astringents such as aluminum salts (dermal use), silver proteinate (nasal use) and all tannin-containing liquid or solid excipients.
  • Decongestants any antihistamines such as cetrizine, and ephedrine salts that can be made into nasal sprays.
  • Adjuvants for retaining the virus particles such as carrageenan preparations. These can form a kind of microgel in the nasopharyngeal space which, together with the antiviral antibiotics according to the invention, prevents the adhesion of Covid-19.
  • Example 1 Use of Tiamulin alone as a nasal spray:
  • tiamulin Between 0.1 and 10 mg/ml of tiamulin are dissolved in 10 ml of purified, sterile water and processed into a sterile spray solution with the addition of phosphates for pH stabilization, if necessary propylene glycol and polysorbate 80. It may also be necessary to add a non-toxic, low-boiling organic solubilizer.
  • Example 2 Using Ivermectin Alone as a Nasal Spray:
  • ivermectin is shaken with 7 ml of purified water, 2 ml of propylene glycol, and 1 ml of polysorbate 80 until a stable emulsion is obtained.
  • This spray solution is stabilized with 1 per mille sodium edteate and processed into a spray solution.
  • Example 3 Spray solution containing ivermectin and tiamulin:
  • Example 4 Drop solution containing ivermectin, tiamulin and other pharmaceutically active ingredients and excipients.
  • a dry mixture of 1-10 mg tiamulin, 50 mg xylometazoline and 20 mg gamma-carrageenan is processed with 1 ml propylene glycol, 0.5 ml polysorbate 80 and 8 ml water in an ultrasonic bath to form a stable opalescent solution. This can optionally be processed into a nasal drip solution with the addition of stabilizers.
  • Example 5 Use of the active ingredients in combination with other active ingredients:
  • valnemulin and 0.1 to 10 mg ivermectin are mixed with 10 to 50 mg silver proteinate and 10 to 50 mg/ml ephedrine levulinate, optionally with the addition of a buffer and stabilizers, 0.5 Add ml of polysorbate 80 and suspend in 10 ml of purified water and shake until a stable suspension is obtained. The preparation is made into a nasal drip solution.
  • Example 6 Use as an aqueous solution for inhalation:
  • a pharmaceutically acceptable salt of tiamulin base or valnemulin base are dissolved in 10 ml of sterile water, optionally with further addition of small amounts of aqueous buffer solution, and bottled for further dilution.
  • Example 7 Use in combination with other active ingredients as an aqueous solution for inhalation:
  • Prescription according to example 3 characterized in that the inhalation contains 1 to 10 mg/ml of a bronchodilator such as salbutamol.
  • 1 to 10 mg of a pharmaceutically tolerable salt of tiamulin base or of valnemulin base and/or ivermectin are finely micronized and, if appropriate, mixed with 1 to 10 mg of finely micronized salbutamol in a flurane-filled pressure vessel suitable for spray inhalation.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Mycology (AREA)
  • Emergency Medicine (AREA)
  • Virology (AREA)
  • Biotechnology (AREA)
  • Oncology (AREA)
  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Communicable Diseases (AREA)
  • Botany (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des associations médicamenteuses associant les dérivés de la pleuromutiline tiamuline et/ou valnémuline et l'ivermectine à d'autres principes actifs pharmaceutiques et additifs, en particulier le polysorbate 80, pour la prophylaxie non invasive et la thérapie initiale locale dans le traitement de maladies virales, en particulier de la Covid 19 causée par le SARS-2.
PCT/AT2021/000012 2020-07-21 2021-06-28 Dérivé de la pleuromutiline et/ou ivermectine, pour le traitement des infections, en particulier à coronavirus WO2022016202A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ATA60229/2020 2020-07-21
AT602292020A AT523646B1 (de) 2020-07-21 2020-07-21 Pharmazeutische Verbindungen, ihre Anwendung alleine oder in Kombination, zur Prophylaxe und lokalen Initial-Therapie bei bakteriellen und viralen Infektionen, insbesondere Coronaviren

Publications (1)

Publication Number Publication Date
WO2022016202A1 true WO2022016202A1 (fr) 2022-01-27

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AT2021/000012 WO2022016202A1 (fr) 2020-07-21 2021-06-28 Dérivé de la pleuromutiline et/ou ivermectine, pour le traitement des infections, en particulier à coronavirus

Country Status (2)

Country Link
AT (1) AT523646B1 (fr)
WO (1) WO2022016202A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1028961B1 (fr) 1997-10-29 2004-09-29 SmithKline Beecham plc Derives de pleuromutiline utilises comme agents antimicrobiens
WO2009106839A1 (fr) * 2008-02-28 2009-09-03 Cambridge Enterprise Limited Utilisation de la tiamuline en tant qu’agent antiviral

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9807503D0 (en) * 1998-04-07 1998-06-10 Smithkline Beecham Plc Use
WO2003007938A1 (fr) * 2001-07-17 2003-01-30 Aidan, Inc. Procede de traitement de la dermatite atopique
CA2945692A1 (fr) * 2014-01-29 2015-08-06 Vyome Biosciences Pvt. Ltd. Traitements pour l'acne resistante
FR3052360B1 (fr) * 2016-06-10 2019-11-01 Friulchem Compositions lipidiques auto-emulsionnables

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1028961B1 (fr) 1997-10-29 2004-09-29 SmithKline Beecham plc Derives de pleuromutiline utilises comme agents antimicrobiens
WO2009106839A1 (fr) * 2008-02-28 2009-09-03 Cambridge Enterprise Limited Utilisation de la tiamuline en tant qu’agent antiviral

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
EGGERREINSHAGEN, J. ANTIBIOTICS, vol. 29, 1976, pages 923
LI VINCENT CY ET AL: "Dermatological pharmacology: topical agents", MEDICINE - U K EDITION, THE MEDICINE PUBLISHING COMPANY, GB, vol. 45, no. 6, 3 May 2017 (2017-05-03), pages 359 - 362, XP085026747, ISSN: 1357-3039, DOI: 10.1016/J.MPMED.2017.03.002 *
ROBERT T. JACOBS ET AL: "Boron-Pleuromutilins as Anti- Wolbachia Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis", JOURNAL OF MEDICINAL CHEMISTRY, vol. 62, no. 5, 7 February 2019 (2019-02-07), pages 2521 - 2540, XP055626382, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.8b01854 *

Also Published As

Publication number Publication date
AT523646B1 (de) 2021-10-15
AT523646A4 (de) 2021-10-15

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