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EP3007691A1 - Ester d'acides gras permettant le traitement d'états associés au malassezia - Google Patents

Ester d'acides gras permettant le traitement d'états associés au malassezia

Info

Publication number
EP3007691A1
EP3007691A1 EP14734023.6A EP14734023A EP3007691A1 EP 3007691 A1 EP3007691 A1 EP 3007691A1 EP 14734023 A EP14734023 A EP 14734023A EP 3007691 A1 EP3007691 A1 EP 3007691A1
Authority
EP
European Patent Office
Prior art keywords
malassezia
acid
ester
composition according
fatty acids
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Withdrawn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
EP14734023.6A
Other languages
German (de)
English (en)
Inventor
Peter Mayser
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.)
Justus Liebig Universitaet Giessen
Original Assignee
Justus Liebig Universitaet Giessen
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 Justus Liebig Universitaet Giessen filed Critical Justus Liebig Universitaet Giessen
Publication of EP3007691A1 publication Critical patent/EP3007691A1/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Withdrawn legal-status Critical Current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
    • A61K31/21—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
    • A61K31/21—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
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of esters of saturated short- and medium-chain fatty acids for the prophylaxis and therapy of diseases and cosmetic problems in humans and animals, which are caused by the involvement of Malassezia yeasts.
  • malassezia-associated diseases and cosmetic problems include pityriasis versicolor, seborrheic dermatitis, head-neck dermatitis, dandruff (increased scalp dandruff, dandruff), atopic dermatitis (atopic dermatitis), psoriasis, papillomatosis, onychomycosis, akantholytic dermatosis, follicular hyperkeratosis , Malassezia dermatitis in dogs and cats and otitis externa in dogs and cats.
  • Antifungal substance (s) for the prophylaxis and treatment of fungal infections (mycoses) in humans and animals.
  • An antifungal may be applied topically (i.e., locally at the site of the fungal infection) or systemically (i.e., it is distributed throughout the body via the blood or lymphatic circulation).
  • CFU Colony Forming Unit
  • Colony Forming Unit KbE
  • Short Chain Fatty Acid Fatty Acid containing up to seven C-atoms
  • Medium Chain Fatty Acid Fatty Acid containing 8 to 12 C-atoms
  • Malassezia-associated Disease or Cosmetic Problem Disease or cosmetic problem in humans or animals, which persists or is sustained due to Malassezia yeast infection.
  • Examples include pityriasis versicolor, seborrheic dermatitis, head-neck dermatitis, dandruff (increased scalp dandruff, dandruff), atopic dermatitis (atopic dermatitis), psoriasis, papillomatosis, onychomycosis, akantholytic Dermatosis, follicular hyperkeratosis, Malassezia dermatitis in dogs and cats, and otitis externa in dogs and cats.
  • mDixon agar modified Dixon agar, contains olive oil.
  • MIC value minimum inhibitory concentration value; that dilution stage of the antimycotic in which no growth of the yeasts (Malassezia yeasts, Candida yeasts) was detectable after the end of the incubation.
  • Mycosis fungal infection in humans and animals, for example infection with yeasts such as e.g. Malassezia or Candida yeasts.
  • Targeting Targeted or selective release or accumulation of a drug at a desired site of action to increase the efficacy of the drug and reduce the potential undesirable effects, in particular the targeted release or accumulation of an antimycotic drug for topical therapy and prophylaxis of malassezia. induced diseases or cosmetic problems in humans and animals at the site of the highest concentration of Malassezia yeasts.
  • Unwanted Suicide release of active substances that are active against this pathogen through pathogenic metabolic processes, in particular the release of free saturated short- to medium-chain fatty acids from fatty acid monoesters by malassezia's own enzymes.
  • fungi such as Malassezia or Candida yeasts can cause or sustain diseases or cosmetic problems in humans and animals, such as seborrheic dermatitis, head-neck dermatitis, Malassezia dermatitis, or many more.
  • diseases or cosmetic problems such as seborrheic dermatitis, head-neck dermatitis, Malassezia dermatitis, or many more.
  • the cell number of Malassezia yeasts at the affected skin site plays an essential role. Therefore, it is useful in all yeast-induced diseases and cosmetic problems in humans and animals, the colonization of the affected skin with Malassezia yeasts and thus their cell count on the natural Cell count of about 10 3 CFU / cm 2 to reduce the healthy skin. This applies in particular to seborrheic dermatitis in humans and Malassezia dermatitis in dogs and cats.
  • antimicrobial substances there are a variety of antimicrobial substances, some of which are used as antimycotics for use against fungal infections, for example Malassezia or Candida infections.
  • a known group of substances used as antimycotic is the group of azoles or pyrroles.
  • Known antifungal agents from the group of azoles or pyrroles are, for example, clotrimazole, ketoconazole, bifonazole, econazole, isoconazole, sertaconazole, miconazole, itraconazole, fluconazole, voriconazole, posaconazole and fosfluconazole.
  • Antifungals from the group of the azoles or pyrroles are preferably used in pityriasis versicolor, seborrheic dermatitis and head-neck dermatitis.
  • the known antifungal agents from the group of azoles or pyrroles can cause as a side effect liver damage and fruit damage to the embryo or fetus, especially if they are used systemically.
  • antimycotics are, for example, amphotericin B, nystatin, natamycin, griseofulvin, caspofungin, cilofungin, flucytosine and ciclopirox. These antimycotics have some serious side effects, some are not effective against Malassezia yeasts and some are not suitable for topical use.
  • antimycotic substances are, for example, zinc pyrithione or selenium disulphide.
  • antimycotics other substances are used for the prophylaxis and treatment of diseases and cosmetic problems caused or sustained by Malassezia yeasts. These include, for example, anti-inflammatory agents (e.g., glucocorticoids, corticosteroids), disinfectants, or calcineurin inhibitors. These substances may also have undesirable and sometimes serious side effects.
  • the object of the present invention is to provide agents which can be used for topical therapy and prophylaxis of diseases and cosmetic problems caused or sustained by the involvement of Malassezia yeasts. These substances should have a selective antifungal activity against Malassezia yeasts, be inexpensive, non-allergenic and non-toxic, and be suitable for topical use in humans and animals. Furthermore, a targeted topical therapy and prophylaxis should be made possible at the site of the highest concentration of Malassezia yeasts in order to reduce the concentration of Malassezia yeasts as specifically as possible.
  • fatty acid esters of monohydric alcohols e.g. Fatty acid monoesters of saturated short- or medium-chain fatty acids have an antifungal effect against Malassezia yeasts, but not against Candida yeasts.
  • This antifungal effect arises because malassezia's own enzymes, namely hydrolases and lipases, split the fatty acid esters and thus release the free saturated short- and medium-chain fatty acids, which then exert the antifungal effect against the Malassezia yeasts.
  • the concentration of malassezia's own enzymes directly correlates with the concentration of Malassezia yeasts, most of the free saturated short- and medium-chain fatty acids are released at the sites of highest Malassezia yeast concentration, thus achieving the highest antifungal effect.
  • the present invention enables targeting, that is, targeted activation of the desired antifungal effect at the site of a high density of Malassezia yeasts. Since the Malassezia yeast release the free saturated short- and medium-chain fatty acids by their own enzymes, the active principle according to the invention is an unwanted suicide.
  • the solution of the invention is to utilize the topical antifungal effect of free short- and medium-chain saturated fatty acids by administering fatty acid esters of saturated short and medium chain fatty acids topically in humans and animals, with malassezia's own Enzymes the actually effective means, namely the free short- and medium-chain saturated fatty acids from the fatty acid esters of saturated short and medium chain fatty acids are released.
  • malassezia's own Enzymes the actually effective means, namely the free short- and medium-chain saturated fatty acids from the fatty acid esters of saturated short and medium chain fatty acids are released.
  • Suitable fatty acid esters are methyl, ethyl, propyl, isopropyl or butyl esters, that is to say that preferably the alcohol portion of the ester is methyl, ethyl, propyl, isopropyl or butyl.
  • Particularly suitable are ethyl esters, which means that preferably the alcohol content of the ester is ethyl.
  • Ethyl esters are preferably hydrolyzed by Malassezia yeasts and are established as natural or natural flavorings in the food industry. They are non-toxic and without allergic potential. Therefore, ethyl esters are particularly suitable for topical use for the therapy and prophylaxis of diseases and cosmetic problems in humans and animals caused or sustained by Malassezia yeasts.
  • the antifungal activity of the fatty acid esters is dependent on the fatty acid portion.
  • a particularly suitable fatty acid moiety is caprylic acid (octanoic acid, CAS 124-07-2), as it most effectively reduces the concentration of Malassezia yeast in the form of its ethyl ester (ethyl caproate, hexanoic acid ethyl ester, CAS 123-66-0).
  • Other suitable fatty acid moieties are caproic acid (hexanoic acid, CAS 142-62-1) or capric acid (decanoic acid, CAS 334-48-5).
  • ethyl caproate is not effective against Malassezia pachydermatis. Since multiple Malassezia species often co-occur on the skin, it is advantageous to combine the ethyl esters of various short- and medium-chain, unbranched saturated fatty acids with a chain length of up to 10 carbon atoms in order to obtain a broader antifungal effect.
  • fatty acids caproic acid hexanoic acid, CAS 142-62-1
  • caprylic acid Octanoic acid, CAS 124-07-2
  • capric acid decanoic acid, CAS 334-48-5) or the corresponding esters hexanoic acid ethyl ester (ethyl caproate, CAS 123-66-0), ethyl octanoate (ethyl caprylate, CAS 106-32-1) or decanoic acid ethyl ester (ethyl caprate, CAS 1 10-38-3).
  • the agents according to the invention additionally contain pharmaceutically innocuous excipients and / or additives in order to improve the pharmaceutical or cosmetic application of the agents according to the invention.
  • the agents of the invention are used to prepare a medicament or cosmetic used for the prophylaxis or therapy of diseases or cosmetic problems in humans and animals caused or sustained by the involvement of Malassezia yeasts.
  • agents according to the invention are combined with other antifungals known from the prior art, antipruritic substances, antiphlogistics such as, for example, corticosteroids or disinfectants, in order to enhance their action.
  • ethyl caproate hexanoic acid ethyl ester, CAS 123-66-0
  • Malassezia globosa reference strain CBS 7966
  • Malassezia pachydermatis reference strain CBS 1892
  • Malassezia sympodialis reference strain CBS 7222
  • Malassezia furfur reference strains CBS 1878 and 7019
  • Candida albicans and Candida krusei These Malassezia species were incubated on mDixon agar, the Candida species on Sabouraud-4% glucose agar. The test substances were incorporated in various concentrations in the respective agar.
  • the test was carried out on 24-well plates with an area of 1.75 cm 2 per well.
  • the incubation temperature was 32 ° Celsius, the incubation period 7 Days.
  • the cell count per well was 5 million CFU.
  • the MIC value was the first dilution stage in which no growth was detectable after incubation for 7 days.
  • Table 1 shows the MIC values of caproic acid and ethyl caproate in mol / l in the individual yeast species.
  • Ethylcaproat shows no antifungal effect, even at higher concentrations.
  • Candida species can not hydrolyze ethyl esters due to their enzyme endowment, so they do not release free-fungal antifungal acids.
  • the MIC values are between 5 and 10 mmol regardless of the agar used (Dixon agar, Leeming-Nitman agar) for Malassezia globosa, Malassezia pachydermatis and Malassezia sympodialis and are thus comparable to those of the free fatty acid, for Malassezia furfur because of over 20 mmol.
  • the amount added was extrapolated to the surface of a well, ie to 1.75 cm 2 . Subsequently, the 24-well plates were inoculated. The inoculated 24-well plates were incubated at 32 ° C for 14 days. Under the chosen conditions 1 1 day proved to be the optimal reading time.
  • Tables 2 show the MIC values of the various ethyl esters after 1 1 day incubation at different cell counts of the inoculum (in CFU / cm 2 ).
  • Table 2.1 shows the MIC values of ethyl esters of ethyl hexanoate, ethyl octanoate and ethyl decanoate on the Malassezia species Malassezia globosa, Malassezia pachydermatis and Malassezia sympodialis at a concentration of inoculates of 10 4 / cm 2 .
  • Table 2.1 shows the MIC values of the ethyl esters of ethyl hexanoate, ethyl octanoate and ethyl decanoate on the Malassezia species Malassezia globosa, Malassezia pachydermatis and Malassezia sympodialis at a concentration of the inoculate of 10 5 / cm 2 .
  • Table 2.3 shows the MIC values of ethyl esters of ethyl hexanoate, ethyl octanoate and ethyl decanoate on the Malassezia species Malassezia globosa, Malassezia pachydermatis and Malassezia sympodialis at a concentration of inoculates of 10 6 / cm 2 .
  • Table 2.3 shows the MIC values of the ethyl ester of hexanoic acid ethyl ester

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation d'esters d'acides gras saturés à chaînes courtes et moyennes pour la prophylaxie et le traitement de maladies et de problèmes cosmétiques chez des hommes et des animaux, lesquels sont provoqués ou entretenus par les levures Malassezia.
EP14734023.6A 2013-06-10 2014-06-10 Ester d'acides gras permettant le traitement d'états associés au malassezia Withdrawn EP3007691A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102013009616.2A DE102013009616A1 (de) 2013-06-10 2013-06-10 Verwendung von Estern von gesättigten kurz- und mittelkettigen Fettsäuren zur Prophylaxe und Therapie von malassezia-assoziierten Erkrankungen und kosmetischen Problemen
PCT/EP2014/062052 WO2014198736A1 (fr) 2013-06-10 2014-06-10 Ester d'acides gras permettant le traitement d'états associés au malassezia

Publications (1)

Publication Number Publication Date
EP3007691A1 true EP3007691A1 (fr) 2016-04-20

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP14734023.6A Withdrawn EP3007691A1 (fr) 2013-06-10 2014-06-10 Ester d'acides gras permettant le traitement d'états associés au malassezia

Country Status (3)

Country Link
EP (1) EP3007691A1 (fr)
DE (1) DE102013009616A1 (fr)
WO (1) WO2014198736A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112021015252A2 (pt) * 2019-02-04 2021-10-05 Symrise Ag Ésteres de ácido graxo como agentes anti-malassezia
US20250000766A1 (en) 2021-08-27 2025-01-02 Symrise Ag Antimicrobial esters for skin and scalp care
WO2024133645A1 (fr) * 2022-12-21 2024-06-27 Firmenich Sa Compositions antipelliculaires

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2447627A1 (de) * 1974-10-05 1976-04-08 Rudolf Kuerner Chem Spezialpro Antimikrobielles praeparat
US5231087A (en) * 1988-03-16 1993-07-27 Cellegy Pharmaceuticals, Inc. Treatment of skin diseases and tumors with esters and amides of monocarboxylic acids
WO2007092633A2 (fr) * 2006-02-09 2007-08-16 Elevance Renewable Sciences, Inc. Compositions antimicrobiennes, procédés et systèmes correspondants
WO2008140469A2 (fr) * 2006-10-13 2008-11-20 Elevance Renewable Sciences, Inc. Compositions antimicrobiennes, procédés et systèmes

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4234188C2 (de) * 1992-10-10 1996-01-11 Beiersdorf Ag Antimycotische kosmetische und dermatologische Verwendungen
DE4237367C2 (de) * 1992-11-05 1995-10-12 Beiersdorf Ag Verwendung von Fettsäureestern in kosmetischen oder dermatologischen Zubereitungen
DE19742275A1 (de) * 1997-09-25 1999-04-01 Beiersdorf Ag Estern verzweigtkettiger Carbonsäuren und verzweigtkettiger Alkohole als antibakterielle, antimycotische, antiparasitäre oder antivirale Wirkstoffe
WO2004069219A1 (fr) * 2003-01-08 2004-08-19 L'oreal Composition cosmetique pour le soin des peaux grasses, contenant un acide gras carboxylique ou l'un de ses derives
DE102004046603A1 (de) * 2004-09-25 2006-03-30 Goldschmidt Gmbh Mittel mit Depotwirkung zur Bekämpfung von Mikroorganismen

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2447627A1 (de) * 1974-10-05 1976-04-08 Rudolf Kuerner Chem Spezialpro Antimikrobielles praeparat
US5231087A (en) * 1988-03-16 1993-07-27 Cellegy Pharmaceuticals, Inc. Treatment of skin diseases and tumors with esters and amides of monocarboxylic acids
WO2007092633A2 (fr) * 2006-02-09 2007-08-16 Elevance Renewable Sciences, Inc. Compositions antimicrobiennes, procédés et systèmes correspondants
WO2008140469A2 (fr) * 2006-10-13 2008-11-20 Elevance Renewable Sciences, Inc. Compositions antimicrobiennes, procédés et systèmes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2014198736A1 *

Also Published As

Publication number Publication date
WO2014198736A1 (fr) 2014-12-18
DE102013009616A1 (de) 2014-12-11

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