EP3349741A1 - Composition à effet antiviral - Google Patents

Composition à effet antiviral

Info

Publication number
EP3349741A1
EP3349741A1 EP16767247.6A EP16767247A EP3349741A1 EP 3349741 A1 EP3349741 A1 EP 3349741A1 EP 16767247 A EP16767247 A EP 16767247A EP 3349741 A1 EP3349741 A1 EP 3349741A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
viral infection
benzocaine
benzalkonium chloride
tyrothricin
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.)
Withdrawn
Application number
EP16767247.6A
Other languages
German (de)
English (en)
Inventor
Richard Ammer
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.)
Medice Arzneimittel Puetter & Co KG GmbH
Original Assignee
Medice Arzneimittel Puetter & Co KG GmbH
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 Medice Arzneimittel Puetter & Co KG GmbH filed Critical Medice Arzneimittel Puetter & Co KG GmbH
Publication of EP3349741A1 publication Critical patent/EP3349741A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising rothricin, benzalkonium chloride, and / or benzocaine for use in anti-viral therapy or in the treatment of a viral infection.
  • Viruses and bacteria are the causative agents of very common acute pharyngitis.
  • Dorithricin ® throat tablets Classic These are usually used with the antiseptic and antibacterial agents contained therein for clinically effective relief of the typical pharyngitis symptoms swallowing pain and pharyngeal redness.
  • Tyrothricin is a mixture of various antibacterial linear and cyclic polypeptides from the groups of gramicidines and tyrocidines. They are endotoxin-like formed by the anaerobic spore-forming Bacillus aneurinolyticus (Syn. Bacillus brevis). The range of action includes predominantly Gram-positive bacteria, but also some Gram-negative bacteria and various types of fungi, such as Candida albicans. Tyrothricin contains 50 to 70% tyrocidines and 25 to 50% gramicidines, which together make up at least 85% of the active substance. In addition, other structurally related polypeptides are present in small quantities.
  • Benzalkonium chloride is a mixture of alkylbenzyldimethylammonium chlorides whose alkyl moiety consists of C8 to C18 chains. It generally has disinfecting and preserving effect and is effective against bacteria, fungi, yeasts and algae (to a lesser extent also antiviral).
  • Benzocaine (4-Aminobenzoeklathylester) is a local anesthetic and is mainly for local pain therapy of the skin and mucous membranes, such as in the mouth and throat area, as well as medicines for colds, antitussive preparations, painkillers such as solutions or lozenges in cervical, gastric and Teething problems, astringents, application.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising rothricin, benzalkonium chloride, and / or benzocaine for use in anti-viral therapy or in the treatment of a viral infection.
  • the composition comprises all three active ingredients in combination.
  • Figure 1. - 4 Percent inhibition of the viral activity of viruses HR14, H1N1 and RSV by variously diluted solutions of Dorithricin®.
  • Fig.l synergistic, antiviral effect of all 3 active ingredients tyrothricin, benzalkonium chloride and benzocaine in combination in increasing dilution. Synergistic effect is demonstrated in comparison to Fig. 2-4.
  • Fig.2 weak antiviral effect of tyrothricin alone in increasing dilution.
  • Fig.3 very weak antiviral effect of benzalkonium chloride alone in increasing dilution.
  • Tyrothricin as an antibiotic is classified as active against bacteria, benzalkonium chloride and benzocaine are classified as analgesics for pain acting (1-4).
  • the present invention thus relates to a pharmaceutical composition
  • a pharmaceutical composition comprising
  • composition of the present invention may comprise, consist of, or consist essentially of the above-mentioned active ingredients.
  • the phrase "consists essentially of” means that the pharmaceutical composition contains these ingredients as effective ingredients. However, it may further contain one or more solvents, adjuvants, etc., which, while necessary for the preparation of a pharmaceutical composition, do not or do not significantly contribute to the pharmacological activity.
  • pharmaceutical composition as used herein includes in particular peroral dosage forms, for example solid, semi-liquid or liquid compositions for oral administration In a preferred embodiment, the composition is in the form of a tablet, in particular a lozenge.
  • solid oral dosage forms such as powder or capsules.
  • limited additions of magnesium stearate or calcium behenate can be used as lubricant and of starch as disintegrant.
  • aqueous lactose solution, ethanol and suitable concentrations of starch pastes may be used.
  • Common excipients for preparing a throat tablet include, for example, sorbitol (E 420), talc, sucrose fatty acid esters, saccharin sodium dihydrate, mint oil, povidone 25, and carmellose sodium.
  • the pharmaceutical composition of the present invention may contain parenteralia, i. liquid dilutions for injection, as well as liquid liniments and ointments, suppositories, eye drops, nose drops.
  • the composition is used to treat an infection caused by rhinoviruses, influenza viruses, and / or pneumoviruses.
  • the pharmaceutical composition finds use in a method of treating a viral infection, wherein the viral infection is by HRV14 (human rhinovirus type 14), RSV (human respiratory syncytial virus), and / or H1N1 (influenza A virus H1N1) is caused.
  • HRV14 human rhinovirus type 14
  • RSV human respiratory syncytial virus
  • H1N1 influenza A virus H1N1
  • a single dose of the pharmaceutical composition contains about 0.5 mg of tyrothricin, about 1.0 mg of benzalkonium chloride and / or about 1.5 mg of benzocaine, and one or more pharmaceutically acceptable excipients.
  • the term "approximately” in this context means a range of ⁇ 50%, preferably ⁇ 20%, most preferably ⁇ 10%, based on the active substance indicated above.
  • the pharmaceutical composition of the present invention is administered in a daily dose of about 2-4 mg of tyrothricin, 4-8 mg of benzalkonium chloride and 6-12 mg of benzocaine.
  • Viruses and bacteria are the causative agents of very common acute pharyngitis.
  • This disease also known as pharyngeal catarrh, is an inflammation of the pharyngeal mucosa and underlying pharyngeal structures, accompanied by the typical symptoms of sore throat, scratching, burning, dryness in the throat and redness of the pharyngeal mucosa (1).
  • acute pharyngitis requires symptomatic treatment to alleviate the pain.
  • Antibiotic therapy is less frequently indicated and should only be used in 10-15% of patients with streptococcal pharyngitis (1-3), or in cases where long-term effects such as haemorrhagic fever are to be prevented.
  • Throat painkillers such as Dorithricin ® have repeatedly proven clinically useful in symptomatic treatment (4).
  • the combination of the antibacterial and analgesic active ingredients tyrothricin, benzalkonium chloride and benzocaine effectively reduces typical pharyngitis symptoms (4).
  • Soluble Dorithricin ® tablets were tested in various dilution stages for viruses that cause respiratory infections in humans.
  • One tablet contains tyrothricin 0.5 mg, benzalkonium chloride 1.0 mg, and benzocaine 1.5 mg.
  • a tablet of Dorithricin ® was first pulverized, then mixed with 1 ml of dimethyl sulfoxide (DMSO) dissolved with distilled water, diluted to 1: 100, and sterile filtered (0.45 ⁇ filter). From the filtrate adjusted to pH 7.4 dilution series were prepared by means of complete nutrient medium in log2 or log10 stages.
  • the solvent (DMSO) prepared according to the procedure described was used as the solvent control.
  • test solutions were subjected to a vitality test in the cell culture in a first step.
  • test solutions were added in all dilution stages and the solvent control to growing virus-sensitive HeLa, MDCK and HEp-2 cells and for a total of
  • MTT 4,5-dimethylthiazol-2-y
  • the optical density of the cell culture supernatants was determined photometrically at a wavelength of 570 nm. A higher optical density indicates a higher number of vital cells.
  • a possible change in cell morphology was assessed microscopically on day 3 (HeLa, MDCK) and day 6 (HEp-2) after substance addition.
  • OD values of the test sample batches were normalized to the OD values of the untreated controls defined as 100% vitality and reported as percentages.
  • IC 50 mean inhibitory concentration across several parallel samples in dose response curves of the test samples could be determined, up to the concentration, which had no test substance-related impairment of cell vitality and thus suitable for use in the antiviral tests.
  • the antiviral activity was tested against HRV14, FluA and RSV.
  • the virus-sensitive cells were infected with the corresponding viruses in a mean infection dose (MOI) between 0.0004 and 0.0008 (HeLa with HRV14, MDCK with FluA, HEp-2 with RSV).
  • MOI mean infection dose
  • the virus-infected cells were treated 1 h after infection with the test solutions in physiological substance concentrations in the semipermeable agarose supernatant.
  • test solutions were used with drug concentrations corresponding to the dilution of 1: 400 and higher of a Dorithricin ® tablet (Table 1). At these concentrations of active substance, no vitality-reducing effects on the HeLa, MDCK and HEp2 cells used could be detected in the vitality test.
  • the 1: 100 and 1: 400 diluted Dorithricin ® drug combination exhibited significant antiviral activity and markedly reduced the plaques of RNA viruses HRV14, HlNl and RSV by 97% and 68%, 53% and 74, respectively %.
  • This effect on PIa formation decreased with increasing dilution. Only at high dilutions was an effect no longer detectable: with HRV14 from 1: 3200, with RSV from 1: 6400 and with HlNl from 1: 64000.
  • the relative inhibitory effect depending on the Dorithricin ® -Verkowsgrad is shown in Figure 1.
  • the ribavirin (RIBA) used for the control produced a 5.3% viruspiaque reduction for HRV14 (RIBA 10 ⁇ g / ml), 96% for FluA (RIBA 3 ⁇ g / ml) and 97% for RSV (RIBA 1 ⁇ g) / ml).
  • the pharmaceutical composition of the present invention additionally exhibits pronounced, dose-dependent and synergistic antiviral properties against the viruses RSV, HRV14 and H1N1.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant de la tyrothricine, du chlorure de benzalkonium, et/ou de la benzocaïne, à utiliser dans la thérapie antivirale ou dans le traitement d'une infection à virus.
EP16767247.6A 2015-09-17 2016-09-16 Composition à effet antiviral Withdrawn EP3349741A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15185764 2015-09-17
PCT/EP2016/071944 WO2017046312A1 (fr) 2015-09-17 2016-09-16 Composition à effet antiviral

Publications (1)

Publication Number Publication Date
EP3349741A1 true EP3349741A1 (fr) 2018-07-25

Family

ID=54151132

Family Applications (1)

Application Number Title Priority Date Filing Date
EP16767247.6A Withdrawn EP3349741A1 (fr) 2015-09-17 2016-09-16 Composition à effet antiviral

Country Status (6)

Country Link
EP (1) EP3349741A1 (fr)
AR (1) AR106057A1 (fr)
DE (1) DE202016008745U1 (fr)
EA (1) EA039000B1 (fr)
UA (1) UA123054C2 (fr)
WO (1) WO2017046312A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2021245379A1 (en) * 2020-04-02 2022-11-10 Inflamed Pharma Gmbh Active substances for medical use
LU101724B1 (de) * 2020-04-02 2021-10-04 Inflamed Pharma Gmbh Wirkstoffe zur medizinischen Verwendung
EP4091608B1 (fr) * 2021-05-21 2024-04-17 Medice Arzneimittel Pütter GmbH & Co. KG Composition avec effet antiviral
EP4275681A1 (fr) * 2022-05-10 2023-11-15 inflamed pharma GmbH Principes actifs à usage médical

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19823319A1 (de) * 1998-05-26 1999-12-02 Karl Engelhard, Fabrik Pharm.- Praeparate Gmbh & Co. Kg Topisch anwendbares Arzneimittel zur Behandlung von Virusinfektionen
DE19823318A1 (de) * 1998-05-26 1999-12-02 Karl Engelhard, Fabrik Pharm.- Praeparate Gmbh & Co. Kg Verwendung eines Arzneimittels mit einem Gehalt an Tyrothricin zur Behandlung von Virusinfektionen

Also Published As

Publication number Publication date
UA123054C2 (uk) 2021-02-10
AR106057A1 (es) 2017-12-06
EA039000B1 (ru) 2021-11-19
WO2017046312A1 (fr) 2017-03-23
EA201890653A1 (ru) 2018-08-31
DE202016008745U1 (de) 2019-06-21

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