EP2717838A2

EP2717838A2 - Active ingredient combinations of e-polylysin (epsilon-polylysine) and one or more terpenes

Info

Publication number: EP2717838A2
Application number: EP12728396.8A
Authority: EP
Inventors: Bernd Traupe; Laura PRIEBE; Michael WÖHRMANN; Christian Dingler
Original assignee: Beiersdorf AG
Current assignee: Beiersdorf AG
Priority date: 2011-06-07
Filing date: 2012-06-07
Publication date: 2014-04-16
Also published as: BR112013027487A2; WO2012167936A2; WO2012167936A3

Abstract

Disclosed are active ingredient combinations comprising: a) ε-polylysine (epsilon-polylysine), b) one or more terpenes, for example esters having a terpene structure.

Description

description

Drug combinations of ε-polylysine (epsilon-polylysine) and one or more

terpenes

The present invention relates to drug combinations of ε-polylysine (epsilon-polylysine) and one or more terpenes, as well as cosmetic or dermatological preparations containing such drug combinations and their use as against

Bacteria, mycota and viruses are effective substances.

The healthy warm-blooded organism, especially the healthy human skin, is populated with a variety of non-pathogenic microorganisms. This so-called microflora of the skin is not only harmless, it represents an important protection against opportunistic or pathogenic germs.

Bacteria belong to the prokaryotic ones. They can roughly fit their shape (sphere, cylinder, curved cylinder) as well as the structure of their cell wall (gram-positive,

gram-negative). Finer subdivisions also take into account the physiology of the organisms. There are aerobic, anaerobic and facultative anaerobic bacteria. Some individuals are more medicinal in their capacity as pathogenic germs

Meaning, others are completely harmless.

Against bacteria active substances have been known for some time. The term "antibiotics", for example, which is not applicable to all antimicrobial substances, can be dated to the year 1941, although the first findings on penicillin were already found in 1929. Antibiotics in the modern sense are not for all medical, already not suitable for cosmetic applications, as often the warm-blooded

Organism, such as the diseased patient, is impaired in any way in its metabolic functions when used. An object of the present invention was therefore to enrich the state of the art in this direction, in particular therefore to provide substances which are available against

Gram-positive and / or Gram-negative bacteria are effective, without the use of the substances would be an unacceptable impairment of the health of the user would be connected.

Gram-negative bacteria are, for example, Escherichia coli, Pseudomonas species and

Enterobacteriaceae, such as Citrobacter.

Gram-positive bacteria also play a role in cosmetics and dermatology. In the case of impure skin, for example, bacterial secondary infections of etiological importance are, among other influences. One of the most important microorganisms associated with impure skin is Propionibacterium acnes.

Impure skin and / or comedones affect the well-being of those affected but even in mild cases. Since virtually every adolescent or person is affected by blemished skin of some kind, many people need to remedy this condition.

A particular object of the present invention was therefore to find a substance or combination of substances which is effective against impure skin or Propionibacterium acnes.

In a further embodiment, the present invention relates to cosmetic deodorants. Such formulations serve to eliminate body odor, which arises when the per se odorless fresh sweat is decomposed by especially gram-positive microorganisms. The usual cosmetic deodorants are based on different active principles.

Both known and customary are liquid deodorants, for example aerosol sprays, roll-ons and the like, as well as solid preparations, for example deodorant sticks ("sticks"), powders, powder sprays, intimate cleaners, etc. In so-called antiperspirants can be prevented by astringents - mainly aluminum salts such as aluminum hydroxychloride (Aluchlorhydrat) - the formation of sweat. Apart from the denaturation of the skin proteins, however, the substances used for this, depending on their dosage, drastically interfere with the heat balance of the axillary region and should at best be used in exceptional cases.

By using antimicrobial substances in cosmetic deodorants, the bacterial flora on the skin can be reduced. Ideally, only the odor causing microorganisms should be effectively reduced. In practice, however, it has been found that the entire microflora of the skin can be affected.

The sweat flow itself is not affected by this, in the ideal case, only the microbial decomposition of the sweat is temporarily stopped.

The combination of astringents with antimicrobial substances in the same composition is also common. However, the disadvantages of both classes of active ingredients can not be completely eliminated in this way.

Finally, body odor can also be masked by fragrances, a method that is least in line with the consumer's aesthetic needs, as the mixture of body odor and perfume smells rather unpleasant.

However, most cosmetic deodorants, as well as most cosmetics as a whole, are perfumed even if they contain deodorizing agents. Perfuming can also serve to increase the consumer acceptance of a cosmetic product or to give a product a certain flair.

The perfuming of active ingredient-containing cosmetic agents, in particular cosmetic deodorants, however, is often problematic because active ingredients and perfume ingredients can occasionally react with each other and make each other ineffective.

Deodorants should fulfill the following conditions:

1) They should cause a reliable deodorization. 2) The natural biological processes of the skin must not be impaired by the deodorants.

3) The deodorants must be harmless in case of overdose or other improper use.

4) They should not be rich on the skin after repeated use.

5) They should be well incorporated into common cosmetic formulations.

Another object of the present invention was therefore to develop cosmetic deodorants which do not have the disadvantages of the prior art. In particular, the deodorants should protect the microflora of the skin largely, but selectively reduce the number of microorganisms that are responsible for the body odor.

Furthermore, it was an object of the invention to develop cosmetic deodorants, which are characterized by good skin compatibility. In no case should the deodorizing principles of action accumulate on the skin.

A further object was to develop cosmetic deodorants which harmonize with the widest possible variety of customary cosmetic auxiliaries and additives, in particular with the perfume ingredients which are especially important in deodorizing or antiperspirant formulations.

Yet another object of the invention was to provide cosmetic deodorants which are effective over a prolonged period, on the order of at least half a day, without noticeably reducing their effect.

Finally, it was an object of the present invention to develop deodorizing cosmetic principles which can be incorporated as universally as possible into the most diverse dosage forms of cosmetic deodorants, without being limited to one or a few special dosage forms.

Mushrooms, also called fungi, mycota or mycobionts, count as eucaryotes in contrast to the bacteria. Eucaryotes are living beings, whose cells (Eucyten), in contrast to those of the so-called Procaryonten (Procyten) over one by nuclear envelope and nuclear membrane have the nucleus delimited from the rest of the cytoplasm. The nucleus contains the genetic information stored in chromosomes.

Representatives of mycobionts include, for example, yeasts (Protoascomycetes), molds (Plectomycetes), mildew (Pyrenomycetes), downy mildew (Phycomycetes) and wild mushrooms (Basidiomycetes).

Fungi, not even the basidiomycetes, are not plant organisms, but like these they have a cell wall, cell-filled vacuoles, and a microscopically visible plasma flow. They contain no photosynthetic pigments and are C-heterotrophic. They grow under aerobic conditions and gain energy through oxidation of organic substances. However, some representatives, such as yeasts, are facultative anaerobes and capable of producing energy through fermentation processes.

Dermatomycoses are diseases in which certain types of fungi, especially dermatophytes, invade the skin and hair follicles. The symptoms of dermatomycoses include blisters, exfoliation, rhagades and erosion, usually associated with itching or allergic eczema.

Dermatomycoses can be subdivided essentially into the following four groups: dermatophytic (for example, epidermophytic, favus, microspore, trichophytic), yeast mycoses (e.g.

Pityriasis and other pityrosporum-related mycoses, candidal infections, blastomycosis, Buschke's disease, torulosis, piedra alba, torulopsidosis, trichosporosis),

Mold mycoses (e.g., aspergillosis, cephalosporidosis, phycomycosis and scopolular isopidosis), systemic mycoses (e.g., chromomycosis, coccidiomycosis, histoplasmosis).

The pathogenic and facultative pathogens include, for example, Candida species (e.g., Candida albicans) and those of the family Pityrosporum from the group of yeasts. Pityrosporum species, in particular Pityrosporum ovale, are known for skin diseases such as pityriasis versicolor, seborrhoea in the forms Seborrhoea oleosa and Seborrhoea sicca, which manifest themselves as seborrhoea capitis (= dandruff), seborrheic eczema and

Responsible for pityrosporum folliculitis. The involvement of Pityrosporum ovale in the development of psoriasis is discussed by experts. All areas of human skin can be affected by dermatomycoses. Dermatophytes almost exclusively affect the skin, hair and nails. Yeast mycoses can also affect the mucous membranes and internal organs, systemic mycoses regularly extend to whole organ systems.

Particularly often the body areas are affected, on which through clothing, jewelry or footwear moisture and heat can accumulate. So the athlete's foot belongs to the most well-known and most widespread Dermatomycosen. Especially unpleasant are further fungal diseases of the finger and toenail areas (onychomycoses).

Furthermore, superinfections of the skin by fungi and bacteria are not uncommon.

In existing primary infection, ie, the normal germ colonization of the skin, entering new infection with high numbers of germs of one or more often physiological agents, such as staphylococci, but often also unphysiologic pathogens, such as Candida albicans, may occur in the event of unfavorable influences, a "superinfection" of the affected skin , The normal microflora of the skin (or other body organ) is literally overgrown by the secondary pathogen.

Such superinfections may, depending on the germ in question, in favorable cases in unpleasant skin manifestations (itching, unpleasant external appearance) express. In unfavorable cases, however, they can lead to extensive destruction of the skin, culminating in the worst case even in the death of the patient.

Superinfections of the kind described above are e.g. the common case of AIDS secondary diseases. In itself - at least in low germ densities - harmless, but under certain circumstances also extremely pathogenic germs overgrow in this way the healthy skin flora. In AIDS, however, other body organs are affected by superinfections.

Likewise, such superinfections in a variety of dermatological diseases, such as atopic eczema, atopic dermatitis, acne, seborrheic dermatitis or psoriasis are observed. Also many medical and therapeutic measures, eg the radio- or chemotherapy of tumor diseases, caused as a side effect, medicamentous induced immunosuppression or systemic antibiotic treatment, as well as external chemical or physical influences (eg environmental pollution, smog), promote the occurrence of superinfections of the external and internal organs, especially the skin and mucous membranes.

Although it is in some cases readily possible to combat superinfections with antibiotics, but usually such substances have the disadvantage of unpleasant side effects. For example, patients are often allergic to penicillins, and treatment would be prohibited in such a case.

Furthermore, topically administered antibiotics have the disadvantage that they free the skin flora not only from the secondary pathogen, but also the inherently physiological skin flora strong

impair the natural healing process in this way.

The object of the present invention was to eliminate the disadvantages of the prior art and to provide substances and preparations containing such substances, which in the broadest sense prevent, combat or avert microbial infestation.

It has surprisingly been found, and therein lies the solution of this problem that

Active substance combinations comprising: a) ε-polylysine (epsilon-polylysine)

b) one or more terpenes, for example esters with terpene structure have synergistic antimicrobial action and remedy the disadvantages of the prior art.

L-lysine is characterized by the following chemical structure:

ε-Polylysine represents a polymer in which the ε-terminal amino group of a lysine molecule is linked to the acid function of another lysine molecule

The index "n" (more precisely, the value n / 2) defines the degree of polymerization of the polylysine.

The INCI name is poly [imino [(2S) -2-amino-1-oxo-1,6-hexanediyl]], it has the CAS no. 28211-04-3

The homopolymer ε-polylysine is known to be described and used as an antimicrobial agent against yeasts, fungi and gram-positive and gram-negative bacteria. Currently it is used as a preservative, especially in Japan, Korea and the US. The

Production of the ε-polylysine takes place via a natural fermentative process.

References:

1. Shima, S. and Sakai H. (1977). "Polylysines produced by Streptomyces". Agricultural and Biological Chemistry 41: 1807-1809.

2. Shima, S. et al. (1984). "Antimicrobial action of ε-poly-L-lysines". Journal of Antibiotics 37 (11): 1449-1455.

3. GRAS Notice no. GRN 000135

4. Hiraki, J. et al. (2003). "Use of ADME studies to confirm the safety of ε-polylysine as a preservative in food". Regulatory Toxicology and Pharmacology 37 (2): 328-340.

5. Hiraki, J. (1995). "Basic and applied studies on ε-polylysine". Journal of Antibacterial Antifungal Agents 23: 349-354

Advantageously used according to the invention are ε-polylysines which have a degree of polymerization n / 2 of from 2 to 200, preferably from 10 to 100, particularly preferably from 23 to 35. According to the invention, ε-polylysine is preferably used in cosmetic or dermatological compositions in a content of 0.0005-50.0% by weight, in particular 0.01-20.0% by weight, based on the total weight of the composition.

The compositions advantageously contain 0.02-10.0% by weight, more preferably 0.02-5.0% by weight, of ε-polylysine, very particularly preferably 0.05-0.5% by weight, in each case based on the total weight of the composition.

ε-Polylysine is readily incorporated into common cosmetic or dermatological formulations, advantageously in pump sprays, aerosol sprays, creams, ointments, tinctures, lotions, nail care products (e.g., nail polishes, nail polish removers, nail balms) and the like.

Terpenes are a highly heterogeneous and very large group of chemical compounds that naturally occur as secondary ingredients in organisms. They are formally derived from isoprene and are characterized by a large variety of carbon skeletons and low number of functional groups. There are over 8,000 terpenes and over 30,000 closely related terpenoids known. Most terpenes are natural products, mainly of plant and rare animal origin. In nature come predominantly

Hydrocarbon, alcohol, glycoside, ether, aldehyde, ketone, carboxylic acid and ester terpenes before, but also representatives of other groups of substances are found among the terpenes. The terpenes are the main component of the essential oils produced in plants.

The original classification of terpenes is based on the observation that they can often be formally described as a series of isoprene units. A terpene formally composed of two isoprene units is a monoterpene, a sesquiterpene composed of three isoprene units (lat. "Sesqui" = "one and a half") one out of four

Isoprene units a diterpene and so on.

Advantageously according to the invention or the terpene are selected from the group of mono-, sesqui- and diterpenes.

The following terpenes are preferred according to the invention: Menthol, citronellol, geraniol, nero, linalool and terpineol, bomeol, thujol, sabinol, myrtenol, thymol, verbenol, fenchol, piperitol, (perillaaldehyde, phellandral, citronellal, citral, myrtenal, menthone, piperone, pulegone, carvone, thujone, umbellulone , Verbenone, chrysanthenone, fenchone, camphor) cineole, menthofuran, linalooloxide, rose oxide, or peroxides such as ascaridol or qinghaosu (artemisinin).

According to the invention, the or the terpenes are selected from the group of mono-, sesqui- and diterpenes which have one or more hydroxyl functions.

The following terpenes are particularly preferred according to the invention:

The following ester with terpene structure is particularly preferred according to the invention:

According to the invention or the terpenes, for example, the ester or with

Terpene structure preferably used in cosmetic or dermatological compositions a content of 0.0005 - 50.0 wt .-%, in particular 0.001 - 20.0 wt .-%, based on the total weight of the composition are preferred. The compositions advantageously contain 0.02-10.0% by weight, more preferably 0.001-5.0% by weight, of the terpenes used according to the invention, very particularly preferably 0.001-2.5% by weight, based in each case on the Total weight of the composition.

Particularly preferred according to the invention are weight ratios

a) ε-polylysine on the one hand and

b) the total of one or more terpenes, on the other hand, of 10: 1 to 1; 100, advantageously from 5: 1 to 1 to 20, in particular advantageously selected from 1: 1 to 1: 0. The active compound combinations used according to the invention are particularly suitable for use as a deodorizing active ingredient in cosmetic deodorants as well as against impure skin and mild forms of acne.

Furthermore, it has been found that the invention used

Active substance combinations can prevent spoilage of organic substances, in particular cosmetic and dermatological preparations, by infestation with Gram-positive and Gram-negative bacteria, cyanoids and viruses when added to these preparations.

The individual active ingredients used according to the invention can be incorporated without difficulty into customary cosmetic or dermatological formulations, advantageously in pump sprays, aerosol sprays, creams, ointments, tinctures, lotions, nail care products (e.g.

Nail polishes, nail polish removers, nail balms) and the like.

The individual active ingredients used according to the invention are advantageously in the form of antidandruff shampoos.

It is also possible and optionally advantageous to use the invention

To combine individual active ingredients with other active substances, for example, with other antimicrobial, antimycotic, antiparasitic or antiviral effective substances.

It may also be advantageous to buffer the compositions according to the invention. A pH range of 3.5 to 7.5 is advantageous. It is particularly favorable to choose the pH in a range of 4.0-6.5.

The cosmetic and / or dermatological formulations according to the invention may be composed as usual and used for the treatment of the skin and / or the hair in the sense of a dermatological treatment or a treatment in the sense of nourishing cosmetics. But they can also be used in make-up products in decorative cosmetics. For use, the cosmetic and / or dermatological formulations according to the invention are applied to the skin and / or the hair in a sufficient amount in the manner customary for cosmetics and dermatological agents.

Advantageous are those cosmetic and dermatological preparations that are in the form of a sunscreen. Advantageously, these additionally contain at least one UVA filter and / or at least one UVB filter and / or at least one inorganic pigment.

Cosmetic preparations according to the invention for protecting the skin from UV rays may be in various forms, such as e.g. Usually used for this type of preparations. So they can e.g. a solution, a water-in-oil (W / O) or oil-in-water (O / W) type emulsion, or a multiple emulsions, such as water-in-oil-in-water (W / O / W), a gel, a hydrodispersion, a solid stick or even an aerosol.

The cosmetic preparations according to the invention may contain cosmetic adjuvants such as are commonly used in such preparations, e.g. Antioxidants, perfumes, antifoaming agents, colorants, pigments which have a coloring effect, thickeners, surface-active substances, emulsifiers,

softening substances, moisturizing and / or moisturizing substances, fats, oils, waxes or other customary constituents of a cosmetic formulation, such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives.

Emulsions are advantageous according to the invention and contain e.g. the said fats, oils, waxes and other fatty substances, as well as water and an emulsifier, as commonly used for such a type of formulation.

Gels according to the invention usually contain low C number alcohols, e.g. Ethanol, isopropanol, 1, 2-propanediol, glycerol and water or an above-mentioned oil in

Presence of a thickening agent which in oily-alcoholic gels preferably silica or an aluminum silicate, in aqueous-alcoholic or alcoholic gels

preferably a polyacrylate. Solid sticks according to the invention contain, for example, natural or synthetic waxes, fatty alcohols or fatty acid esters. Preference is given to lip balms and deodorant sticks ("deodorant sticks").

Suitable propellants for cosmetic or dermatological preparations which can be sprayed from aerosol containers according to the invention are the customary known highly volatile, liquefied propellants, e.g. Hydrocarbons (propane, butane, isobutane) suitable, which can be used alone or in combination with each other. Also, compressed air is advantageous to use.

Advantageously, the preparations according to the invention may also contain substances which absorb UV radiation in the UVB range, the total amount of the filter substances being e.g. 0.1 wt .-% to 30 wt .-%, preferably 0.5 to 10 wt .-%, in particular 1 to 6 wt .-%, based on the total weight of the preparation to provide cosmetic preparations, which protect the skin from the entire range of ultraviolet radiation.

Cosmetic preparations for the care of the hair are, for example, shampooing agents, preparations which rinse the hair before or after the hair

Shampooing, before or after the permanent wave treatment, before or after the coloring or discoloration of the hair are applied to preparations for blowing or inserting the hair, preparations for dyeing or decolorizing, a hairdressing and treatment lotion, a hair dye or perming agent.

The cosmetic preparations contain active ingredients and adjuvants such as are commonly used for this type of preparations for hair care and hair treatment.

As auxiliaries are preservatives, surface-active substances, substances for preventing foaming, emulsifiers, thickeners, fats, oils, waxes, organic solvents, bactericides, perfumes, dyes or pigments, whose job is to dye the hair or the preparation itself, electrolytes , Preparations against the greasing of the hair.

Cosmetic preparations which are a shampoo or a washing, shower or bath preparation preferably comprise at least one anionic, nonionic or amphoteric surfactant or mixtures thereof, at least one dialkyl substituted carboxylic acid in the aqueous medium and adjuvants conventionally used therefor.

The following examples are intended to illustrate the embodiments of the present inventions. The information always refers to weight%, unless otherwise stated.

25

efficacy

Bacterial suspension test

Preparation of the bacterial suspension:

Corynebacterium. jeikeium (DSM 7171) was streaked from a cryovial (EN 12353) on an agar plate (C + T agar) and incubated at 30 ° C for 48 h. Then a second passage was created.

With the second passage, 10 mL of AC medium and 5 g of glass beads (4 mm

Diameter) and shaken for 3 min. Thereafter, this approach was adjusted to an OD ₆ oo of 0.08 and then diluted 1:50 with AC medium (bacterial count 2 * 0 ⁵ ). This bacterial suspension was then used for the suspension test.

Preparation of the drug solution:

The raw materials were heated at 80 ° C in a water bath and then proportionally mixed with PE water to produce the raw material / water solutions. For the combinations with ε-polylysine, solid ε-polylysine was dissolved in the emulsifier / water mixture. As a control, a sample was prepared solely with ε-polylysine in water.

Test:

To 500 pL of the presented drug solution was added 500 μl of bacterial suspension

added and incubated on a thermo shaker (30 ° C, 1200 rpm). After 20, 60 and 180 minutes, 100 μl each were taken from the batch and diluted with 900 μl of AC medium. This suspension was used for plating on agar plates. The control was also sampled at time T = 0 min. Finally, the plates were incubated for 48 h at 30 ° C and then evaluated using the CounterMat.

1st result

See Figure 1 - 4

The combination of an aliphatic alcohol (linalool, tetrahydrolidinalool, ethyllinalool, tetrahydromuguol) with ε-polylysine resulted in a stronger bacterial cutaneous kinetics than with the sole antimicrobial agent ε-polylysine. 2nd result

See Figure 5

The combination of a typical ester with terpene structure (linalyl acetate) with ε-polylysine resulted in a stronger bacteria-killing kinetics than with the sole antimicrobial agent ε-polylysine.

Claims

claims:

1. active substance combinations comprising:

a) ε-polylysine (epsilon-polylysine)

b) one or more terpenes, for example esters with terpene structure

2. active compound combinations according to claim 1, in which ε-polylysines are used which have a degree of polymerization of 2 to 200, preferably 10 to 100, particularly preferably from 23 to 35.

3. W rkstoffkombinationen according to claim 1 or 2, in which the terpene or selected from the group of mono-, sesqui- and diterpenes.

4. active compound combinations according to claim 1, 2 or 3, in which the terpene or be selected from the group of mono-, sesqui- and diterpenes, which have one or more hydroxyl functions.

5. Active substance combinations according to one of the preceding claims, in which the one or more terpenes are selected from the group linalool, tetrahydrolinalool,

Tetrahydromyrcenol Tetrahydromuguol, ethyllinalool, linalyl acetate.

6. active substance combinations according to claim 1, in which weight ratios

a) ε-polylysine on the one hand and

b) the entirety of one or more terpenes on the other

from 10: 1 to 1: 100, advantageously from 5: 1 to 1 to 20, especially advantageously from 1: 1 to 1:10.

7. Cosmetic preparations containing active ingredient combinations according to one of

preceding claims.

8. Preparations according to claim 5, in which ε-polylysine in concentrations of 0.0005 - 50.0 wt .-%, in particular 0.01 - 20.0 wt .-%, based on the total weight of the composition are used.

9. Preparations according to claim 5, 6 or 7, in which the or terpene in concentrations of 0.0005 - 50.0 wt .-%, in particular 0.01 - 20.0 wt .-%, based on the total weight of the composition be used.