WO2007082864A2 - Use of chavicol as an antiseptic - Google Patents

Use of chavicol as an antiseptic Download PDF

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Publication number
WO2007082864A2
WO2007082864A2 PCT/EP2007/050345 EP2007050345W WO2007082864A2 WO 2007082864 A2 WO2007082864 A2 WO 2007082864A2 EP 2007050345 W EP2007050345 W EP 2007050345W WO 2007082864 A2 WO2007082864 A2 WO 2007082864A2
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Prior art keywords
chavicol
use according
composition
skin
agents
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PCT/EP2007/050345
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French (fr)
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WO2007082864A3 (en
Inventor
Carlo Ghisalberti
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Polichem Sa
Carlo Ghisalberti
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Publication of WO2007082864A2 publication Critical patent/WO2007082864A2/en
Publication of WO2007082864A3 publication Critical patent/WO2007082864A3/en

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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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/08—Oxygen or sulfur directly attached to an aromatic ring system
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • 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
    • A61P17/10—Anti-acne agents
    • 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
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • A61P31/02—Local antiseptics
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/10—Antimycotics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the use of chavicol (p-allylpenol) as an antiseptic and, in particular, for the manufacture of a composition indicated for the treatment of infected skin and scalp.
  • the invention also relates to a regimen or a method for the treatment of infected skin and scalp which comprises topically applying a composition comprising chavicol.
  • chavicol p-allylpenol
  • the body normally hosts a variety of micro-organisms including bacteria and fungi. Skin and scalp are in fact a good growth medium of lipophilic, generally nonpathogenic ubiquitous anaerobic micro-organisms. Some of these are even useful to the body, some produce no harm or benefits, while others may cause harmful infections.
  • Propionibacterium acnes infects oily skin and provokes acne, a common disorder characterized by follicular papules or comedones either in inflammatory or non inflammatory conditions.
  • Acne vulgaris affects the areas of skin with the densest population of sebaceous follicles including face, the upper chest, and the back.
  • other key factors in acne are the follicular epidermal hyperproliferation and an excessive sebum production.
  • Yeasts specifically Malassezia furfur or Pityrosporum ovale are the pathogenic agents linked to several skin diseases including: dandruff, seborrheic dermatitis, folliculitis, pityriasis versicolor, and atopic dermatitis.
  • Pseudomonas folliculitis is a recognized, community-acquired skin infection resulting from the bacterial colonization of hair follicles after exposure to contained, contaminated water.
  • infection caused by strains of P. aeruginosa was acquired secondary to skin contamination.
  • P. putida is another common cause of skin and scalp infection.
  • pathogens may gain entrance to the dermis to cause high-impact disorders.
  • cellulites in skin and appendages is, in vast majority of cases, caused by Streptococcus pyogenes or Staphylococcus aureus.
  • Further aggressive pathogen such as Salmonella typhimurium is a proved skin tumor initiating and promoting bacteria.
  • An object of this invention is the use of chavicol to manufacture an antiseptic composition to kill or eradicate certain pathogenic micro-organisms in skin and scalp.
  • Another object of this invention the use of chavicol for the manufacture of a topically administrable, cosmetic/dermatologic composition for the treatment of infected skin and/or scalp.
  • Another object of this invention the use of chavicol in conjunction with other active ingredients for the manufacture of a topically administrable, cosmetic/dermatologic composition for the treatment of infected skin and/or scalp.
  • a further object of this invention is a cosmetic or regimen for the cosmetic/dermatologic treatment of infected skin and/or scalp in mammalian subjects, preferably human, in need of such a treatment.
  • chavicol is defined to include derivatives or prodrugs thereof.
  • derivative or prodrug means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivatives which capable of releasing chavicol.
  • Particularly favoured derivatives and prodrugs are those that increase the bioavailability of chavicol when administered to a subject in need thereof, e.g. enhance the delivery of chavicol into the skin layers or allow the orally administered compound to be more readily absorbed into the blood.
  • infected skin and scalp means an skin or scalp with over-growth infection of micro-organism.
  • chavicol is suitable for the treatment of infections caused by susceptible strains of the designated micro-organisms in the complicated skin and skin structure infections caused by such as, for example, yeast/fungi of genus Malassezia (or Pityrosporum) or Candida, and bacteria of genus
  • Propionibacterium Pseudomonas, Salmonella, Staphylococcus, Streptococcus, as well as Escherichia coli, Enterococcus faecalis, and Bacteroides fragilis.
  • Chavicol alias 4-(2-propenyl)-phenol, or p-hydroxy-allylbenzene, or 4-allylphenol, with MW 134.18 (CAS 501-92-8) is a colourless liquid product with m.p. 16 0 C.
  • chavicol is used to manufacture an antiseptic topically administrable composition to kill or eradicate pathogenic micro- organisms in skin and scalp
  • chavicol is used to manufacture a cosmetic/dermatologic composition for the treatment of infected skin and/or scalp.
  • the present invention refers to the use of chavicol as active ingredient in the manufacture of a topically administrable composition suitable for the treatment of infected skin and scalp to kill superinfecting anaerobic microorganisms;
  • chavicol is used in association with other active principles which have auxiliary action in the treatment and/or the disinfection of infected skin and scalp or may provide skin benefits.
  • active principles are, for instance, other antibiotics such as erythromycin, clindamycin, tetracyclines, chlorexidine, benzoylperoxide, cedrene, caryophyllene, longifolene, and thujoene; comedolytic agents such as tretinoin, adapalene, tazarotene, salicylic acid, benzoic acid, and derivatives thereof; antinfiammatory agents such as NSAID (i.e.
  • chavicol can be incorporated into a variety of formulations suitable for topical delivery of active ingredients.
  • the topical formulations suitable for topical treatment of treat superinfected oily skin and scalp are creams, lotions, mousses, sprays, emulsions, shampoos, gels and the like, which are manufactured according to methods commonly known in the art (see, for instance: Topical Formulations: Design and Development-Bozena Michniak/Paperback/CRC Press, LLC/February 1999; Remington: The Science and Practice of Pharmacy 20 th - Alfonso L.
  • Gennaro Alfonso R. (Ed. ) Gennaro; Publisher: Lippincott Williams & Wilkins, December 2000,20th Ed.; Encyclopedia of Pharmaceutical Technology- James Swarbrick (Editor), James C. Boylan (Editor)/Hardcover/Marcel Dekker/May 1997).
  • the amount of chavicol that may be used according to the invention obviously depends on the desired effect.
  • the amount of chavicol in the topical composition for treating and/or disinfecting skin and/or scalp according to this invention may range from about 0.1% (w/w) to about 10% (w/w).
  • the topical compositions useful for delivering chavicol may contain the usual acceptable excipients, including carriers and vehicles, preservative agents, surfactants, moisturizing agents, thickeners, perfumes, chelating agents, water, alcohols, antioxidants, antiseptics, colorants and adsorbents.
  • One embodiment of the invention thus features a regimen or method to treat infected skin and scalp comprising topically applying chavicol in association with a cosmetically/dermatologically acceptable excipients.
  • the method of the present invention can be performed for a period ranging from several days to several months, e.g. between 1 week and 6 months, or even longer if necessary.
  • the dosage levels can be kept constant over the treatment period.
  • the treatment can start at relatively high dosages, e.g. between the levels indicated above and twice these levels for a first period of e.g. between 1 and 6 weeks, followed by relatively low dosages of e.g. half the levels indicated above, for a second period of e.g. between 4 weeks and 1 year or even longer.
  • the treatment can be given to any subject suffering or liable to suffering from infected skin, for example acne.
  • the treatment can also be given as a means to inhibit further expansion of acne.
  • the anti-septic treatment can also suitably be given during the menstrual period.
  • An important aspect of the present invention is that chavicol, although it kills superinfecting anaerobic micro-organisms, it possesses no significant estrogenic potential and no significant sensitizing potential.
  • Chavicol suitable for purpose of the invention can be obtained from chavicol- containing plant distillates, or by chemical synthesis with know methods, provided that the final purity of the material is not less than 95% w/w of the active ingredient.
  • Estragole l-methoxy-4-(2- propenyl)benzene
  • chavicol by demethylation (methyl-ether cleavage), e.g. with EtMgBr, MeMgI, HBr/AcOH, EtSNa/DMF, TMSI, pyridine.HCl, BBr 3 and the like.
  • chavicol suitable for the inventive purpose may be from any natural source and/or synthetic method, a convenient process for manufacturing chavicol is herein provided.
  • the process entails the demethylation of Estragole with a Lewis acid followed a 2-step extractions in alkaline and acid-neutral media.
  • this reaction is carried out under mild conditions with a Lewis acid such as boron alogenide (BX 3 ) associated with a quaternarium ammonium-iodine salt, preferably the former is BCl 3 and the latter 77-Bu 4 NI, preferably in 1 : 1 ratio at around 1.5 eq., wherein the reaction is followed by at least two solvent-water extractions to afford pure chavicol.
  • a Lewis acid such as boron alogenide (BX 3 ) associated with a quaternarium ammonium-iodine salt
  • Samples are taken from the patients' scalp are isolated, purified on agar and stored in peptone/dextrose slant agar tubes. The strains were applied, undiluted or diluted 1:100, to an RPMI 1640 agar (Gibco/BRL, Life Technologies GmbH, Eggenstein, D) containing about 1.0 [mu]g/ml Pityrosporum ovale strains. The activity of chavicol was determined by the microtiter dilution technique in RPMI 1640 medium. The growth medium RPMI 1640 buffered with 0.165 M morpholinopropanesulfonic acid pH 7.0 is introduced into 96-well microtiter plates.
  • a single colony of C. albicans has been incubated at 30 0 C for 48 hours in a 5 ml growth medium Yeast Peptone-Dextrose ("YPD") containing lOg/1 yeast extract, 20 g/1 peptone and 20 g/1 dextrose.
  • YPD Yeast Peptone-Dextrose
  • At day 3.5 ⁇ l of saturated culture in 2 ml in YPD was incubated at 30 0 C for 65 hours in the presence of different concentration of chavicol prepared in serial dilutions by a factor of 10 in ethanol.
  • plates have been visually analyzed, wherein the absence of turbidity indicates no growth. Chavicol MIC50 on C. albicans results ⁇ 2 mmol.
  • Example 3 Antiseptic activity on Pseudomonas yutida
  • KT2440 Pseudomonas putida
  • LB rich medium LePoivre
  • 20 ⁇ l of the saturated colony has been inoculated in 2 ml of LP medium in the presence of different concentration of chavicol, prepared in serial dilutions by a factor of 10 in ethanol.
  • plates have been analyzed for optical density at 600nm (OD 600) by triplicate samples. Chavicol MIC50 on Pseudomonas putida results ⁇ 2 mmol.
  • a single colony of E. coli 71/18 has been inoculated in 2 ml a poor medium named "M9" prepared with Na 2 HPO 4 (7.526 g/1), KH 2 PO 4 (3.0 g/1), NH 4 Cl (l.Og/1), NaCl (0.5 g/1), MgSO 4 (1 mM), CaCl 2 (0.1 mM), vitamin Bl (5 ⁇ g/ml), and glucose (0.2%), then incubated at 37°C under slow stirring.
  • M9 prepared with Na 2 HPO 4 (7.526 g/1), KH 2 PO 4 (3.0 g/1), NH 4 Cl (l.Og/1), NaCl (0.5 g/1), MgSO 4 (1 mM), CaCl 2 (0.1 mM), vitamin Bl (5 ⁇ g/ml), and glucose (0.2%), then incubated at 37°C under slow stirring.
  • Example 5-6 Antiseptic activity on Salmonella Typhimurium and Propionibacterium acnes
  • Example 4 The method of Example 4 has been applied with Salmonella Typhimurium (ATCC 14028) and Propionibacterium acnes, wherein Chavicol MIC50 results 2 and 2.5 mmol, respectively.
  • Chavicol Determination of the efficacy of Chavicol on strains of Propionibacterium acnes and Pityrosporum ovale.
  • samples are taken from the patients' skin or scalp are isolated, purified on agar and stored in peptone/dextrose slant agar tubes.
  • the strains were applied, undiluted or diluted 1:100, to an RPMI 1640 agar (Gibco/BRL, Life Technologies GmbH, Eggenstein, Germany) containing about 1.0 [mu]g/ml Propionibacterium acnes and Pityrosporum ovale strains.
  • the activity of Chavicol is determined by the microtiter dilution technique in RPMI 1640 medium.
  • the growth medium RPMI 1640 buffered with 0.165 M morpholinopropanesulfonic acid pH 7.0 is introduced into 96-well microtiter plates. Serial dilutions by a factor of 2 are prepared to result in final concentrations of 256 to 0.002 [mu]g/ml of Chavicol.
  • the microtiter plates prepared in this way are incubated with the test strains. The initial cell count is 1-5x10 3 colony- forming units per ml of growth medium.
  • the microtiter plates are incubated at 35 0 C for 48 hours. As determined by photometry at 510 nm, Chavicol MIC50 is ⁇ 2.5 mmol on Propionibacterium acnes, and ⁇ 0.5 mmol on Pityrosporum ovale.
  • a 2% cream is made by melting 2 g of Chavicol at 75 0 C in 10 g EmulvamaTM AGC (premix of: glyceril stearate, cetearyl alcohol, stearic acid, sodium cocoyl glutamate) from VaMa Farmacosmetica (Zibido (MI), Italy) in water at 75 0 C under high stirring.
  • EmulvamaTM AGC premix of: glyceril stearate, cetearyl alcohol, stearic acid, sodium cocoyl glutamate
  • Influence of Chavicol 2% on sebum excretion rate is expressed as % area occupied by sebum spots.
  • Each line represents an individual study volunteer (Skin Oiliness Reference: Low: 4%>; Normal: 4-6.5%; Oily: 6.5-9%; Very Oily: >9%).
  • Safety evaluations are based on detection of potential skin irritation or other signs of adverse reaction to the treatment.
  • Example 9 Emulsion 100 g of emulsion contains
  • Azelaic acid 1.5 g perfume, additives, preservatives q.b.
  • Example 10 - Shampoo 100 g of detergent contains:
  • Triethanolamine laurylsulfate 5.O g
  • Example 11 - Gel 100 g of gel contains:
  • Example 12 Cream-Gel 100 g of cream-gel contains:

Abstract

Topical compositions comprising chavicol (p-allylpenol) are an efficient approach to the treatment of skin and scalp infected by pathogenic microorganisms such as yeast, fungi or bacteria. Chavicol, may be present in an amount which ranges from 0.1 to 10 % by weight of the composition which, on its turn, may be in the form of cream, lotion, mousse, spray, emulsion, shampoo or gel. The composition may further contain an additional active principle, together with the usual topically acceptable excipients.

Description

Title USE OF CHAVICOL AS AN ANTISEPTIC
Description
The invention relates to the use of chavicol (p-allylpenol) as an antiseptic and, in particular, for the manufacture of a composition indicated for the treatment of infected skin and scalp. The invention also relates to a regimen or a method for the treatment of infected skin and scalp which comprises topically applying a composition comprising chavicol. BACKGROUND OF THE INVENTION The body normally hosts a variety of micro-organisms including bacteria and fungi. Skin and scalp are in fact a good growth medium of lipophilic, generally nonpathogenic ubiquitous anaerobic micro-organisms. Some of these are even useful to the body, some produce no harm or benefits, while others may cause harmful infections. For example, Propionibacterium acnes infects oily skin and provokes acne, a common disorder characterized by follicular papules or comedones either in inflammatory or non inflammatory conditions. Acne vulgaris affects the areas of skin with the densest population of sebaceous follicles including face, the upper chest, and the back. Besides presence and activity of Propionibacterium acnes, other key factors in acne are the follicular epidermal hyperproliferation and an excessive sebum production.
Yeasts, specifically Malassezia furfur or Pityrosporum ovale are the pathogenic agents linked to several skin diseases including: dandruff, seborrheic dermatitis, folliculitis, pityriasis versicolor, and atopic dermatitis. Another yeast-like fungi, Candida spp., most commonly due to Candida albicans, are other infective pathogens. Cutaneous candidiasis can involve almost any skin surface on the body, but usually occurs in warm, moist, creased areas such as armpits and groins.
Pseudomonas folliculitis is a recognized, community-acquired skin infection resulting from the bacterial colonization of hair follicles after exposure to contained, contaminated water. First reported in the 70s in association with whirlpool contamination, infection caused by strains of P. aeruginosa was acquired secondary to skin contamination. P. putida is another common cause of skin and scalp infection.
Other pathogens may gain entrance to the dermis to cause high-impact disorders. For example, cellulites in skin and appendages is, in vast majority of cases, caused by Streptococcus pyogenes or Staphylococcus aureus. Further aggressive pathogen such as Salmonella typhimurium is a proved skin tumor initiating and promoting bacteria.
The International patent application WO03/082233 discloses the use of allylphenols for the treatment of androgenic disorders by the inhibition of 5-alpha-testosterone reductase ("5α-TR") enzymes.
While the sebum regulation is one of the factors contributing to some skin infection, there is a continuous effort to find agent that will target most pathogenic microorganism without producing adverse effects.
SUMMARY OF THE INVENTION
An object of this invention is the use of chavicol to manufacture an antiseptic composition to kill or eradicate certain pathogenic micro-organisms in skin and scalp.
Another object of this invention the use of chavicol for the manufacture of a topically administrable, cosmetic/dermatologic composition for the treatment of infected skin and/or scalp.
Another object of this invention the use of chavicol in conjunction with other active ingredients for the manufacture of a topically administrable, cosmetic/dermatologic composition for the treatment of infected skin and/or scalp.
A further object of this invention is a cosmetic or regimen for the cosmetic/dermatologic treatment of infected skin and/or scalp in mammalian subjects, preferably human, in need of such a treatment.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, chavicol is defined to include derivatives or prodrugs thereof. A
"derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivatives which capable of releasing chavicol. Particularly favoured derivatives and prodrugs are those that increase the bioavailability of chavicol when administered to a subject in need thereof, e.g. enhance the delivery of chavicol into the skin layers or allow the orally administered compound to be more readily absorbed into the blood.
As used herein "infected skin and scalp" means an skin or scalp with over-growth infection of micro-organism. Hence, chavicol is suitable for the treatment of infections caused by susceptible strains of the designated micro-organisms in the complicated skin and skin structure infections caused by such as, for example, yeast/fungi of genus Malassezia (or Pityrosporum) or Candida, and bacteria of genus
Propionibacterium, Pseudomonas, Salmonella, Staphylococcus, Streptococcus, as well as Escherichia coli, Enterococcus faecalis, and Bacteroides fragilis.
Chavicol, alias 4-(2-propenyl)-phenol, or p-hydroxy-allylbenzene, or 4-allylphenol, with MW 134.18 (CAS 501-92-8) is a colourless liquid product with m.p. 16 0C.
In an embodiment of the present invention, chavicol is used to manufacture an antiseptic topically administrable composition to kill or eradicate pathogenic micro- organisms in skin and scalp
In a preferred embodiment of the present invention, chavicol is used to manufacture a cosmetic/dermatologic composition for the treatment of infected skin and/or scalp.
According to another aspect, the present invention refers to the use of chavicol as active ingredient in the manufacture of a topically administrable composition suitable for the treatment of infected skin and scalp to kill superinfecting anaerobic microorganisms;
In a preferred embodiment of the present invention, chavicol is used in association with other active principles which have auxiliary action in the treatment and/or the disinfection of infected skin and scalp or may provide skin benefits. Examples of said active principles are, for instance, other antibiotics such as erythromycin, clindamycin, tetracyclines, chlorexidine, benzoylperoxide, cedrene, caryophyllene, longifolene, and thujoene; comedolytic agents such as tretinoin, adapalene, tazarotene, salicylic acid, benzoic acid, and derivatives thereof; antinfiammatory agents such as NSAID (i.e. acetylsalicylic acid, ibuprofen, naproxen, sulfacetamide); steroidal antinfiammatory agents. According to the invention, chavicol can be incorporated into a variety of formulations suitable for topical delivery of active ingredients. The topical formulations suitable for topical treatment of treat superinfected oily skin and scalp are creams, lotions, mousses, sprays, emulsions, shampoos, gels and the like, which are manufactured according to methods commonly known in the art (see, for instance: Topical Formulations: Design and Development-Bozena Michniak/Paperback/CRC Press, LLC/February 1999; Remington: The Science and Practice of Pharmacy 20th - Alfonso L. Gennaro, Alfonso R. (Ed. ) Gennaro; Publisher: Lippincott Williams & Wilkins, December 2000,20th Ed.; Encyclopedia of Pharmaceutical Technology- James Swarbrick (Editor), James C. Boylan (Editor)/Hardcover/Marcel Dekker/May 1997).
The amount of chavicol that may be used according to the invention obviously depends on the desired effect. In general the amount of chavicol in the topical composition for treating and/or disinfecting skin and/or scalp according to this invention may range from about 0.1% (w/w) to about 10% (w/w).
The topical compositions useful for delivering chavicol may contain the usual acceptable excipients, including carriers and vehicles, preservative agents, surfactants, moisturizing agents, thickeners, perfumes, chelating agents, water, alcohols, antioxidants, antiseptics, colorants and adsorbents. One embodiment of the invention thus features a regimen or method to treat infected skin and scalp comprising topically applying chavicol in association with a cosmetically/dermatologically acceptable excipients.
The method of the present invention can be performed for a period ranging from several days to several months, e.g. between 1 week and 6 months, or even longer if necessary. The dosage levels can be kept constant over the treatment period. Alternatively, and advantageously, the treatment can start at relatively high dosages, e.g. between the levels indicated above and twice these levels for a first period of e.g. between 1 and 6 weeks, followed by relatively low dosages of e.g. half the levels indicated above, for a second period of e.g. between 4 weeks and 1 year or even longer. The treatment can be given to any subject suffering or liable to suffering from infected skin, for example acne. In cases of severe acne which, without treatment, tends to increase even further in time, the treatment can also be given as a means to inhibit further expansion of acne. The anti-septic treatment can also suitably be given during the menstrual period. An important aspect of the present invention is that chavicol, although it kills superinfecting anaerobic micro-organisms, it possesses no significant estrogenic potential and no significant sensitizing potential.
Chavicol suitable for purpose of the invention can be obtained from chavicol- containing plant distillates, or by chemical synthesis with know methods, provided that the final purity of the material is not less than 95% w/w of the active ingredient.
A convenient method is the conversion of Estragole (l-methoxy-4-(2- propenyl)benzene), which is readily available starting material obtained in large quantity as aroma chemicals from estragon oil, into chavicol by demethylation (methyl-ether cleavage), e.g. with EtMgBr, MeMgI, HBr/AcOH, EtSNa/DMF, TMSI, pyridine.HCl, BBr3 and the like.
Although the chavicol suitable for the inventive purpose may be from any natural source and/or synthetic method, a convenient process for manufacturing chavicol is herein provided. The process entails the demethylation of Estragole with a Lewis acid followed a 2-step extractions in alkaline and acid-neutral media. In a preferred embodiment, this reaction is carried out under mild conditions with a Lewis acid such as boron alogenide (BX3) associated with a quaternarium ammonium-iodine salt, preferably the former is BCl3 and the latter 77-Bu4NI, preferably in 1 : 1 ratio at around 1.5 eq., wherein the reaction is followed by at least two solvent-water extractions to afford pure chavicol. The present invention is more specifically described and explained by means of the following examples. It is to be understood that the present invention is not limited to those examples, and may be made various changes and modifications without departing from the scope or spirit of the present invention. The following examples are intended to illustrate the scope of the present invention but not to limit it. Example 1 - Antiseptic activity on Pityrosporum ovale
Samples are taken from the patients' scalp are isolated, purified on agar and stored in peptone/dextrose slant agar tubes. The strains were applied, undiluted or diluted 1:100, to an RPMI 1640 agar (Gibco/BRL, Life Technologies GmbH, Eggenstein, D) containing about 1.0 [mu]g/ml Pityrosporum ovale strains. The activity of chavicol was determined by the microtiter dilution technique in RPMI 1640 medium. The growth medium RPMI 1640 buffered with 0.165 M morpholinopropanesulfonic acid pH 7.0 is introduced into 96-well microtiter plates. Serial dilutions by a factor of 2 are prepared to result in final concentrations of 256 to 0.002 [mu]g/ml of chavicol. The microtiter plates prepared in this way are incubated with the test strains. The initial cell count is 1-5x103 colony- forming units per ml of growth medium. The microtiter plates are incubated at 35 0C for 48 hours. As determined by photometry at 510 nm, chavicol MIC50 on Pityrosporum ovale results ~ 0.5 mmol.
Example 2 - Antiseptic activity on Candida albicans
A single colony of C. albicans has been incubated at 300C for 48 hours in a 5 ml growth medium Yeast Peptone-Dextrose ("YPD") containing lOg/1 yeast extract, 20 g/1 peptone and 20 g/1 dextrose. At day 3.5 μl of saturated culture in 2 ml in YPD was incubated at 30 0C for 65 hours in the presence of different concentration of chavicol prepared in serial dilutions by a factor of 10 in ethanol. At day 6th, plates have been visually analyzed, wherein the absence of turbidity indicates no growth. Chavicol MIC50 on C. albicans results ~ 2 mmol.
Example 3 - Antiseptic activity on Pseudomonas yutida A single colony of Pseudomonas putida (KT2440) has been inoculated in 2 ml of rich medium LePoivre ("LB") and incubated at 37°C under slow stirring. After one day, 20 μl of the saturated colony has been inoculated in 2 ml of LP medium in the presence of different concentration of chavicol, prepared in serial dilutions by a factor of 10 in ethanol. After 24 hours, plates have been analyzed for optical density at 600nm (OD 600) by triplicate samples. Chavicol MIC50 on Pseudomonas putida results ~ 2 mmol.
Example 4 - Antiseptic activity on Escherichia coli
A single colony of E. coli 71/18 has been inoculated in 2 ml a poor medium named "M9" prepared with Na2HPO4 (7.526 g/1), KH2PO4 (3.0 g/1), NH4Cl (l.Og/1), NaCl (0.5 g/1), MgSO4 (1 mM), CaCl2 (0.1 mM), vitamin Bl (5 μg/ml), and glucose (0.2%), then incubated at 37°C under slow stirring.
After one day, 30μl of the saturated colony has been inoculated in 3ml of M9 medium in the presence of different concentration of chavicol. After 48 hours growth the optical density at 600nm (OD600) of the cultures have been analyzed by triplicate sample, wherein OD600 = 1.00 correspond to around 109 bacteria/ml. Chavicol
MIC50 on E. coli results ~ 2 mmol.
Example 5-6 - Antiseptic activity on Salmonella Typhimurium and Propionibacterium acnes
The method of Example 4 has been applied with Salmonella Typhimurium (ATCC 14028) and Propionibacterium acnes, wherein Chavicol MIC50 results 2 and 2.5 mmol, respectively.
Example 7 - Test on anaerobic bacteria
Determination of the efficacy of Chavicol on strains of Propionibacterium acnes and Pityrosporum ovale. For this purpose, samples are taken from the patients' skin or scalp are isolated, purified on agar and stored in peptone/dextrose slant agar tubes. The strains were applied, undiluted or diluted 1:100, to an RPMI 1640 agar (Gibco/BRL, Life Technologies GmbH, Eggenstein, Germany) containing about 1.0 [mu]g/ml Propionibacterium acnes and Pityrosporum ovale strains. The activity of Chavicol is determined by the microtiter dilution technique in RPMI 1640 medium. The growth medium RPMI 1640 buffered with 0.165 M morpholinopropanesulfonic acid pH 7.0 is introduced into 96-well microtiter plates. Serial dilutions by a factor of 2 are prepared to result in final concentrations of 256 to 0.002 [mu]g/ml of Chavicol. The microtiter plates prepared in this way are incubated with the test strains. The initial cell count is 1-5x103 colony- forming units per ml of growth medium. The microtiter plates are incubated at 35 0C for 48 hours. As determined by photometry at 510 nm, Chavicol MIC50 is ~ 2.5 mmol on Propionibacterium acnes, and ~ 0.5 mmol on Pityrosporum ovale.
Example 8 - Assessment of efficacy and safety
A 2% cream is made by melting 2 g of Chavicol at 75 0C in 10 g Emulvama™ AGC (premix of: glyceril stearate, cetearyl alcohol, stearic acid, sodium cocoyl glutamate) from VaMa Farmacosmetica (Zibido (MI), Italy) in water at 75 0C under high stirring.
Ten adult female volunteers, mean age of 43 years (range 25-56) with oily facial skin enrolled in the study are free of dermatosis and not assuming any drug. Patients are instructed to apply the lotion twice daily to forehead and cheeks, by applying - 1.5 mg/cm2 but in the 24 hr-period preceding the clinic visits after 4 and 8 weeks. Sebum excretion levels are assessed on the central forehead and nasolabial region of the cheek (sebum-test sites) at baseline and after 4 and 8 weeks of treatment by Sebutape® (Pagnoni et all, J Soc Cosmet. Chem. 1994; 45: 221-225). Influence of Chavicol 2% on sebum excretion rate is expressed as % area occupied by sebum spots. Each line represents an individual study volunteer (Skin Oiliness Reference: Low: 4%>; Normal: 4-6.5%; Oily: 6.5-9%; Very Oily: >9%). Safety evaluations are based on detection of potential skin irritation or other signs of adverse reaction to the treatment.
No skin irritation are observed after 8 weeks of treatment. Neither changes in skin infrastructure, nor skin dryness, redness or peeling are noted during the 8-weeks period.
In all volunteers, baseline sebum excretion levels on the forehead are higher than those detected on the nasolabial area of the cheek. Baseline SER measurements indicate oily to very-oily forehead skin and oily skin at the nasolabial region of the cheek (%areas covered by spots = 8.9 ± 1.0 and 6.5 ± 0.6, respectively). Mean sebum excretion rates after 4 weeks of Chavicol 2% application, declined 35% (forehead) and 29% (cheek) and approached normal values in all participants. At 8 weeks of treatment, SER is 55% and 62% of the baseline at the forehead and cheek, respectively. It may be concluded that Chavicol is a sebum regulator, being safe and useful in the application to skin and scalp.
Example 9 - Emulsion 100 g of emulsion contains
Laurylmethicone copolyol 2.O g
Liquid paraffme 1.0 g Chavicol 2.O g
Lanolin 1.5 g
Soybean oil 10.0 g
Cyclomethycone 6.O g
Azelaic acid 1.5 g Parfum, additives, preservatives q.b.
Demineralized water q.b. to 100 g
Sodium biphosphate q.b. to pH 3.8
Example 10 - Shampoo 100 g of detergent contains:
S o dium laurylsulfate 5.O g
Triethanolamine laurylsulfate 5.O g
Betaine lauryldimethylaminoacetate 6.O g
Ethylene glycol distearate 2.O g Octopirox 2.0 g
Chavicol 4.O g
Ethanol 2.O g
Parfum, additives, preservatives q.b.
Deionized water q.b. to 100 g Example 11 - Gel 100 g of gel contains:
Aluminum oxychloride 1-2 g
Alantoin o.i g alfa-Bisabolol o.i g
Chavicol 2.O g
Acrylic gel of Carbopol™ q.b. to 100 g
Example 12 - Cream-Gel 100 g of cream-gel contains:
Isododecane 8.1
Cyclopentasiloxane 6.3
Hydrogenated polydecene 2.1
Glyceryl stearate 2.0 Undecylenic acid 3.0
Ricinoleic acid 3.0
Salicylic acid 0.6
Chavicol 1.0
Isocide P4M 0.6 Pemulen 0.5
Nicotinamide 1.0
Disodium EDTA 0.5
Aqua 70
Carbopol 0.3 NaOH ION 0.9

Claims

(1) Use of chavicol for the manufacture of a topically applicable antiseptic composition.
(2) Use according to claim 1 characterized in that said composition is for the treatment or prevention of skin and/or scalp infection.
(3) Use according to claim 2 characterized in that said infection is caused by yeast/fungi and/or bacteria.
(4) Use according to claim 3 characterized in that said yeast or fungi belongs to one or more of the genus Malassezia, Pityrosporum and/or Candida.
(5) Use according to claim 3 characterized in that said bacteria belongs to one or more of the genus/species Propionibacterium, Pseudomonas, Salmonella, Staphylococcus, Streptococcus, Escherichia coli, Enterococcus faecalis and/or Bacteroides fragilis
(6) Use according to claim 1 wherein chavicol is present in an amount which ranges from 0.1 to 10 % by weight of the composition.
(7) Use according to claim 1 , characterized in that said composition is in the form of cream, lotion, foam, spray, emulsion, shampoo or gel.
(8) Use according to claim 1, characterized in that said composition contains topically acceptable excipients, carriers, vehicles, preservative agents, surfactants, moisturizing agents, thickeners, perfumes, chelating agents, water, alcohols, antioxidants, antiseptics, colorants and/or adsorbents.
(9) Use according to claim 1, characterized in that said composition contains one or more additional active principles.
(10) Use according to claim 9, characterized in that said active principle is selected from antibiotics, such as erythromycin, clindamycin, tetracyclines, chlorexidine, benzoylperoxide, cedrene, caryophyllene, longifolene, and thujoene; comedolytic agents such as tretinoin, adapalene, tazarotene, salicylic acid, benzoic acid, and derivatives thereof; antinfiammatory agents such as NSAID (i.e. acetylsalicylic acid, ibuprofen, naproxen, sulfacetamide); steroidal antinfiammatory agents.
PCT/EP2007/050345 2006-01-20 2007-01-15 Use of chavicol as an antiseptic WO2007082864A2 (en)

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US9486394B2 (en) 2003-01-24 2016-11-08 Stiefel West Coast, Llc Pharmaceutical foam
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