CN116507324A - Hydroxystearic acid for inducing production of antimicrobial peptides - Google Patents
Hydroxystearic acid for inducing production of antimicrobial peptides Download PDFInfo
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- CN116507324A CN116507324A CN202180081459.7A CN202180081459A CN116507324A CN 116507324 A CN116507324 A CN 116507324A CN 202180081459 A CN202180081459 A CN 202180081459A CN 116507324 A CN116507324 A CN 116507324A
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Abstract
The present invention relates to a novel use of hydroxystearic acid for inducing secretion of antimicrobial peptides (AMPs) when applied to the external surface of the human body. Also relates to an antimicrobial composition comprising a combination of hydroxystearic acid and an antimicrobial peptide or an antimicrobial lipid or a mixture thereof. It has application in improving immunity of skin, scalp and oral cavity against microbial attack.
Description
Technical Field
The present invention relates to a novel use of hydroxystearic acid for producing AMP (antimicrobial peptide) on skin. This can be applied to improve immunity of skin, scalp and oral cavity against microbial attack. The invention also relates to the use of a combination of hydroxystearic acid and AMP or AML (antimicrobial lipids) or mixtures thereof for antimicrobial benefit, and to compositions comprising the combination.
Background
Skin is the primary defense against the intrusion of pathogens (such as viruses and bacteria). As a major defensive organ, skin tissue is always in constant contact with the environment, so it must face and address threats and challenges from invading pathogens. The exposed skin surface is not only challenged by pathogenic foreign bacteria, but also remains in contact with and interacts with resident commensal bacteria. Despite all of these challenges from such foreign microorganisms, healthy skin remains free of infection and the number of resident microflora remains generally constant. This balance of interactions between skin tissue and microorganisms is maintained because the skin has a complex defense strategy in which antimicrobial peptides (AMPs) form an important part.
AMP forms an essential part of the skin's own defense system. AMPs are ubiquitous in nature, and they generally exhibit broad spectrum activity against invading bacteria, fungi, viruses and parasites. AMPs are generally short peptides, and about 90 different AMPs are reported to exist in humans. AMPs generally have two main physical characteristics, which are: a) Cationic charge and b) a significant proportion of hydrophobic residues. The cationic charge of AMP promotes selectivity for negatively charged microbial surfaces, while hydrophobicity promotes interaction with the cell membrane of microbial species.
The inventors of the present invention have been working to provide hygienic benefits to consumers by way of increasing AMP levels in the skin. They wish to provide this benefit by using natural molecules which are perceived by the consumer as more skin friendly and thus less irritating. In addition, they also wish to provide antimicrobial benefits to the body by killing or inactivating invasive infectious microorganisms.
In particular, one of the most common and major pathogens of skin infections is staphylococcus aureus (Staphylococcus aureus), which causes various skin and soft tissue infections. Colonisation of the surface of the host skin with staphylococcus aureus is the initial stage of infection, and microorganisms establish infection by employing their complex strategy when deeper tissues are breached. In particular, staphylococcus aureus attacks the host innate system by producing a range of toxins that damage cell membranes and cause lysis, such as hemolysin, leukotoxins.
Various actives were tested for the purpose of protecting the skin against these microorganisms, and after extensive research, the inventors of the present invention have found that commonly used fatty acids (i.e., hydroxystearic acid) increase AMP levels on the skin. In addition, the AMP so produced synergistically interacts with externally applied hydroxystearic acid to provide antimicrobial activity against infectious organisms such as staphylococcus aureus, pseudomonas aeruginosa (p. It has also been found that antimicrobial benefits are achieved by compositions comprising a combination of hydroxystearic acid and AMP and/or AML.
Hydroxystearic acid, especially 12-hydroxystearic acid (12-HSA), has been used in personal care as part of a fatty acid mixture in cleansing compositions, or as an emulsifier in cosmetics. 12-HSA has a wide range of uses in industrial applications as a lubricant and for the production of greases. It is widely used as a lubricant in the petroleum drilling industry. To the best of the inventors' knowledge, its use as an active agent for AMP production on body part surfaces is unknown.
The inventors of the present invention have found that when hydroxystearic acid is applied to the skin (which may be the skin itself or the scalp or the oral cavity), the active substance induces the production of AMP, which is known to be an important step in improving the immunity of the skin against microbial attack. Thus, the consumer benefits from protecting the skin from pathogens that may be affected in the future by applying a composition comprising hydroxystearic acid.
Disclosure of Invention
In a first aspect the invention provides the use of hydroxystearic acid for inducing secretion of antimicrobial peptides (AMPs) when applied to the external surface of the human body.
Another aspect of the invention provides a method of providing an antimicrobial benefit to an external surface of a body, the method comprising the step of applying to the external surface a composition comprising hydroxystearic acid and an antimicrobial peptide or an antimicrobial lipid or a mixture thereof.
Yet another aspect of the present invention provides an antimicrobial composition comprising (i) hydroxystearic acid and (ii) an antimicrobial peptide or antimicrobial lipid or a mixture thereof.
Detailed Description
These and other aspects, features and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. For the avoidance of doubt, any feature of one aspect of the present invention may be used in any other aspect of the present invention. The word "comprising" is intended to mean "including", but not necessarily "consisting of … …" or "consisting of … …". In other words, the listed steps or options need not be exhaustive. It should be noted that the examples given in the following description are intended to clarify the invention and are not intended to limit the invention to those examples per se. Similarly, unless otherwise indicated, all percentages are weight/weight percentages and may be abbreviated as "wt%". Except in the operating and comparative examples, or where otherwise explicitly indicated, all numbers in this description and the claims indicating amounts of material or conditions of reaction, physical properties of materials and/or use are modified by the word "about". The numerical range expressed in the format of "x to y" should be understood to include x and y. Where multiple preferred ranges are described in terms of "x to y" for a particular feature, it should be understood that all ranges combining the different endpoints are also contemplated.
As used herein, "skin" is meant to include the outer surface of mammals, especially humans, and includes skin, scalp, hair, and oral cavity. The use according to the invention may be by applying hydroxystearic acid or a composition according to the invention as a leave-on or rinse-off product and includes any product applied to the human body which is primarily for hygienic benefits but may also improve appearance, cleaning, odor control or general aesthetics. The composition may be in the form of a liquid, lotion, cream, foam, scrub, gel, soap bar or lotion, or applied with a tool or through a mask, pad, wipe or patch. Non-limiting examples of such compositions include leave-on products such as skin lotions and creams, antiperspirants, deodorants, depilatories, lipsticks, foundations, mascaras, sunless tanning agents, disinfectants, gels, sprays or sunscreens, or rinse-off products such as shampoos, hair conditioners, shower gels, toilet bars, facial washes, hand washes or bath products.
Hydroxystearic acid used in the present invention preferably induces AMP secretion from keratinocytes. The AMP thus secreted is used to improve immunity of the external surface of the body. The external surface includes skin, scalp, or oral cavity.
Preferably, hydroxystearic acid is 10-hydroxystearic acid, 12-hydroxystearic acid or a trihydroxystearic acid (e.g. 9,10, 13-trihydroxystearic acid) or a trihydroxystearin or a compound which upon its decomposition yields one or more hydroxystearic acid or hydroxystearate molecules, such as a mono-, di-or triester of glycerol with hydroxystearic acid. Of these, 10-hydroxystearic acid, 12-hydroxystearic acid and 9,10, 13-trihydroxystearic acid are more preferable. 12-hydroxystearic acid (12-HSA) is most preferred. 12-HSA has the structure given below:
it has been discovered by the present invention that hydroxystearic acid activates keratinocytes, which are the primary cells in the epidermis of the skin, to provide the benefit of the present invention, namely to induce secretion of antimicrobial peptides (AMPs). This results in hydroxystearic acid enhancing the protection against bacteria, i.e. improving the immunity of the outer surface. Thus, hydroxystearic acid provides protection to the body against infection by enhancing the body's own defenses. In other words, the active substance prepares the body surface for bacterial protection. This has the advantage that it provides a durable protection, for example an antibacterial protection of up to 24 hours.
According to the invention, the use of hydroxystearic acid for inducing AMP secretion is preferably for cosmetic use, i.e. it is for non-therapeutic use.
Yet another aspect of the invention relates to hydroxystearic acid for prophylactic induction of antimicrobial peptide (AMP) secretion when applied to the external surface of the human body.
Yet another aspect of the invention relates to a method of providing protection to an external surface of a body by inducing secretion of an antimicrobial peptide (AMP), the method comprising the step of applying hydroxystearic acid to the external surface. Preferably, the method is non-therapeutic.
According to yet another aspect of the present invention there is provided the use of a composition comprising hydroxystearic acid and an antimicrobial peptide or an antimicrobial lipid or a mixture thereof for antimicrobial benefit. Preferably, the use is non-therapeutic.
According to yet another aspect of the present invention there is provided a method of providing an antimicrobial benefit to an external surface of a body, the method comprising the step of applying to said external surface a composition comprising hydroxystearic acid and an antimicrobial peptide or an antimicrobial lipid or a mixture thereof. Preferably, the method is non-therapeutic.
The composition in which hydroxystearic acid is used according to the present invention may include the following preferred features. The hydroxystearic acid is preferably present at 0.000001 to 10%, more preferably 0.00001 to 8%, even more preferably 0.0001 to 7%, still more preferably 0.0005 to 5%, still more preferably 0.001 to 4%, still more preferably 0.01 to 3% and even more preferably 0.1 to 1% by weight of the composition.
In addition to hydroxystearic acid, the composition according to the invention comprises an antimicrobial peptide (AMP) or an antimicrobial lipid (AML) or a mixture thereof to obtain the desired antimicrobial benefit. Preferably, the composition comprises AML in addition to hydroxystearic acid. Preferably, the composition is non-therapeutic.
Preferably, AMP is selected from defensins, such as human beta defensin 1, human beta defensin 2, human beta defensin 3 and human beta defensin 4; histamine (histidines), such as histamine 5, histamine 7; antimicrobial peptides (cathelicidins), such as LL-37; a dermcidin (dermcidin), such as, for example, a dermcidin 1; s100 peptides, such as psoriasis (psoriasin); and RNAse peptides, such as RNAse7, which may be used in the present invention, alone or in combination. More preferably, the AMP is selected from the group consisting of human beta defensin 1, human beta defensin 2, human beta defensin 3 and human beta defensin 4, LL-37, and mixtures thereof. Even more preferably, the selected AMPs are human beta defensin 3, LL-37 and mixtures thereof.
Recent studies have shown that various antimicrobial peptides (AMPs) mimic chemokines and have the ability to rapidly activate the host innate and adaptive immune system by acting as early warning signals. They are capable of recruiting and activating antigen presenting cells. These potent immunostimulants include defensins, antibacterial peptide (LL-37), eosinophil-derived neurotoxin (EDN) and high mobility group box protein 1 (HMGB 1). For example, defensins, LL-37, HMGB1 and EDN mimic chemokine and cytokine activity through interaction with CCR6, FPRL-1 and Toll-like receptors (TLR 2), respectively. These antimicrobial peptides are produced and released constitutively by leukocytes, keratinocytes and epithelial cells lining the gastrointestinal tract, the genitourinary system and the tracheobronchial tree. In addition, they are induced by noxious stimuli and cytokines. These peptides all have an in vivo immunoadjuvant effect. These AMPs are now classified as the new term "alarmin" because of the recognition that they play a role in the rapid motor immune system to protect against host injury.
The antimicrobial lipid (AML) that in combination with hydroxystearic acid provides synergistic antimicrobial activity preferably comprises hexadecenoic acid (Sapienic acid), sphingosine, sphinganine, palmitoleic acid, lauric acid, phytosphingosine, or a combination of one or more AMLs. More preferably, AML is selected from sphingosine, phytosphingosine, lauric acid and mixtures thereof.
The structures of the various antimicrobial lipids used in the present invention are as follows:
hexadecenoic acid
Sphingosine
Sphinganine
Phytosphingosine
Palmitoleic acid
Hexadecenoic acid and palmitoleic acid are typically added to antimicrobial agents in purified form.
Preferably, the composition comprises AML or AMP or a mixture thereof in an amount of from 0.000001 to 2%, more preferably from 0.00005 to 1%, even more preferably from 0.00001 to 0.1%, still more preferably from 0.0001 to 0.05% and still more preferably from 0.001 to 0.01% by weight of the composition.
Preferred combinations of AML and hydroxystearic acid include:
12-HSA+lauric acid,
-12-hsa+ phytosphingosine; and
-12-hsa+sphingosine.
Preferred combinations of AMP and hydroxystearic acid include:
-12-HSA+LL-37，
-12-hsa+human beta defensin 3.
Preferably, such a combination is selected from:
12-HSA+Ll37+lauric acid,
12-HSA+L37+ phytosphingosine,
12-HSA+L37+sphingosine,
12=hsa+human beta defensin 3+lauric acid,
12-HSA+human beta defensin 3+ phytosphingosine,
-12-hsa+human beta defensin 3+ sphingosine.
The composition preferably comprises a cosmetically acceptable base. The cosmetically acceptable base is preferably a cream, lotion, gel or emulsion. It is particularly preferred that the cosmetically acceptable base comprises a surfactant.
The compositions of the present invention may be prepared such that they are suitable for use as skin cleansing products or oral care, skin care, scalp or hair care products. The product may be delivered in solid, soft solid, liquid, emulsion, microemulsion, emulsion, cream, gel, or aerosol form.
Skin cleansing
As used herein, "cleansing composition" refers to compositions comprising a surfactant for topical application to the skin, hair and/or scalp of a mammal, especially a human, for cleansing benefits, and such compositions generally comprise a surfactant. Such compositions are typically applied to the desired body part surface for a period of time ranging from a few seconds up to a few minutes after dilution with water. After this application time, the composition is typically rinsed off or wiped off with water.
The cleaning composition may be in any form, either solid or liquid. In solid form, it is preferably a soap bar.
Soap bar:
the soap used to prepare the cleaning compositions of the present invention is preferably C 8 -C 24 Soap, more preferably C 10 -C 20 Soap, and most preferably C 12 -C 18 Soap. The cation of the soap may be an alkali metal, alkaline earth metal or ammonium. Preferably, the cation of the soap is selected from sodium, potassium or ammonium. More preferably, the cation of the soap is sodium or potassium. Fatty acids derived from other suitable oils/fats (e.g., peanut, soybean, tallow, palm kernel, etc.) may also be used in other desired proportions.
The cosmetically acceptable base comprising the anionic surfactant forms the remainder of the composition except for the water-in-oil emulsion present in the cleansing composition. Thus, the cosmetically acceptable base typically forms 80 to 99% by weight of the cleaning composition.
When present, the anionic surfactant (e.g., soap) is preferably present in an amount of from 1 to 90% by weight, preferably from 10 to 85% by weight, more preferably from 25 to 75% by weight of the cleaning composition. The cleaning composition is preferably in a solid or semi-solid form, most preferably in a solid form. The preferred solid composition is in the shape of a bar.
The other anionic surfactant is preferably selected from alkyl ether sulphates, primary alkyl sulphates, secondary alkyl sulphonates, alkylbenzenesulphonates or ethoxylated alkyl sulphates. Preferred anionic surfactants other than soaps in the cleaning composition are alkyl ether sulphates, preferably those having 1 to 3 ethylene oxide groups, from natural or synthetic sources and/or sulphonic acids. Sodium lauryl ether sulfate is particularly preferred. Alkyl polyglucosides may also be present in the composition, preferably having a carbon chain length C 6 To C 16 Those of alkyl polyglucosides.
Preferred cleansing compositions may include other known ingredients such as perfumes, pigments, preservatives, emollients, sunscreens, gelling agents and thickeners. The choice of these ingredients will depend largely on the form of the composition. Water is a preferred carrier. When water is present, it is preferably present at least 1%, more preferably at least 2%, even more preferably at least 5% by weight of the composition. Where water is the carrier, preferred cleaning compositions comprise from 10 to 50%, more preferably from 12 to 40% by weight of water.
The compositions of the present invention may also be delivered by a moisturizing bar or liquid composition. Moisturizing bar compositions comprising fatty acyl isethionates (e.g., cocoyl isethionate) are particularly preferred.
Fatty acyl isethionate (e.g., cocoyl isethionate) surfactant "product" is defined as a mixture of anionic acyl isethionate surfactant and fatty acid/fatty acid soap. They are highly desirable in personal care skin or hair cleansing products, particularly in personal care products, because they lather well, are mild to the skin and have good emollient properties. Typically, fatty acid isethionate surfactant products are prepared by esterification of fatty acids or by reaction of fatty acid chlorides having carbon chain lengths of from C8 to C20 with isethionic acid. Typical surfactant products containing fatty acyl isethionates contain, in addition to isethionates (typically less than 5%) and trace amounts (less than 2% by weight) of other additives, from about 40 to 95% by weight of acid isethionates and from 5 to 50% by weight, typically from 10 to 40% by weight of free fatty acids. Fatty acid soaps may be included in the range of 5 to 15% by weight. Other surfactants (e.g., betaines) may be included at 1 to 5% by weight. Water is typically included at 2 to 8% by weight of the composition.
Liquid cleaning composition:
the liquid cleaning compositions of the present invention are typically used for personal cleaning. Preferred are compositions for cleaning topical surfaces of the body, hands or face, which contain low concentrations of surfactants and are mild on the skin. The surfactant is typically included at 1 to 30%, preferably 4 to 18%, more preferably 6 to 12% by weight of the liquid cleaning composition.
The surfactant for inclusion in the liquid cleaning compositions of the present invention may preferably be of the anionic, nonionic, cationic or amphoteric type. A useful surfactant for inclusion in the liquid cleaning compositions of the present invention is Sodium Lauryl Ether Sulfate (SLES). SLES for use in the present invention generally preferably have 1 to 3 Ethoxylate (EO) groups. SLES is preferably included at 3 to 15% by weight of the composition. Other surfactants that may be included in the present invention are Cocoamide Monoethanolamine (CMEA). CMEA is preferably included at 1 to 5% by weight of the composition. A preferred aspect of the liquid cleaning composition of the present invention relates to aspects wherein the surfactant comprises a mixture of Sodium Lauryl Ether Sulfate (SLES) and Cocamide Monoethanolamine (CMEA).
Another useful surfactant for inclusion in the liquid cleaning compositions of the present invention is an amphoteric surfactant, preferably a betaine surfactant, more preferably an alkylamidopropyl betaine surfactant, such as cocamidopropyl betaine. In a preferred embodiment, the composition comprises from 0.1 to 5% by weight, preferably from 0.5 to 4% by weight, more preferably from 1 to 3% by weight of betaine surfactant.
The nonionic surfactants included in the liquid cleaning compositions of the present invention are preferably polyoxyethylene sorbitan alkyl esters (sold as Tween surfactants), fatty alcohol ethoxylates (sold as Brij surfactants), alkylphenol ethoxylates (sold as Triton surfactants), fatty acid ethoxylates (sold as Myrj surfactants) and alkyl polyglucosides (sold as plant surfactants).
Water is a preferred carrier in the liquid cleaning compositions of the present invention. In such compositions, water is typically present at 70 to 95% by weight. Preferred liquid cleansing compositions may contain other known ingredients such as electrolytes, fragrances, pigments, preservatives, emollients, sunscreens, emulsifiers, gelling agents and thickeners.
The invention can also be used in private hygiene products, especially for female use. Such products are generally available as liquids having an amount of surfactant and emollient formulated to a pH that is gentle to women when used to achieve personal hygiene. Such products are also known as feminine hygiene products or menstrual hygiene products. Such liquid products generally comprise a large amount of water in the range of 40 to 80wt%, preferably 50 to 70 wt%. They also contain surfactants, such as anionic and/or amphoteric surfactants. Such surfactants are preferably included at 10 to 50wt%, preferably 20 to 40wt% of the composition. Particularly preferred surfactants for use in such products are triethanolamine lauryl sulfate, ammonium lauryl sulfate, cocamidopropyl betaine, or mixtures thereof. In addition, the product may contain oils, emollients, thickeners and other additives to help impart a mild feel to the skin. Carboxylic acids, such as lactic acid, are often included in such compositions to provide additional hygienic benefits. The pH of such products is generally in the range of 2.5 to 6.0, preferably in the range of 2.5 to 4.5.
Oral care
When the personal care composition is delivered for oral care, it includes a cosmetically acceptable base, which may be an abrasive, thickener, humectant, or orally acceptable surfactant. The product may be provided in the form of an ointment, gel, dentifrice or mouthwash. The oral care composition preferably comprises an abrasive. Gels typically contain silica, while opaque creams typically contain calcium-based abrasives, especially chalk.
Preferred toothpaste compositions have 5 to 60wt% calcium based abrasive.
In a preferred embodiment, the composition comprises a thickener. In general, thickened silica, sodium carboxymethyl cellulose and/or carbomers are preferred thickeners for the compositions of the present invention. The thickener, when present, preferably comprises from 0.01 to about 10%, more preferably from 0.1 to 9%, and most preferably from 1.5 to 8% by weight of the composition.
Suitable humectants are preferably employed in the oral care compositions of the present invention. Glycerin, polyethylene glycol, sorbitol, or mixtures thereof are preferred humectants.
The humectant may be present in the range of 10 to 90% by weight of the oral care composition. Preferably, the oral care composition comprises a surfactant. Preferably, the composition comprises at least 0.01%, more preferably at least 0.1% and most preferably from 0.5 to 7% by weight of the composition of surfactant. Preferred anionic surfactants are sodium dodecyl sulfate and/or sodium dodecyl benzene sulfonate. Most preferably, the surfactant is sodium dodecyl sulfate.
The water may preferably be included in 5% to 95%, in particular 10% to 75%, in particular 10% to 60%, even more preferably 10% to 45% of the total weight of the composition.
The oral care compositions of the present invention may contain a variety of other ingredients commonly used in the art to enhance physical properties and performance. These ingredients include antimicrobial agents, anticaries agents, plaque buffers, fluoride sources, vitamins, plant extracts, desensitizing agents, anticalculus agents, biomolecules, flavoring agents, proteinaceous materials, preservatives, opacifiers, colorants, pH adjusting agents, sweeteners, particulate abrasive materials, polymeric compounds, pH and ionic strength buffers and salts of buffer compositions, and mixtures thereof. These ingredients generally and collectively constitute less than 20%, preferably from 0.0 to 15%, most preferably from 0.01 to 12% by weight of the composition, including all ranges subsumed therein.
Hair care
According to a preferred aspect of the invention, the composition may be used for hair care or cleaning. One medium by which this may be achieved is that of a shampoo. The compositions of the present invention, especially shampoos, are formulated with anionic surfactants (e.g., alkyl sulfate and/or ethoxylated alkyl sulfate surfactants). These anionic surfactants are preferably present in a content of 1 to 20%. Preferred alkyl sulphates are C8-18 alkyl sulphates, more preferably C12-18 alkyl sulphates, preferably in the form of salts with solubilising cations such as sodium, potassium, ammonium or substituted ammonium. An example is Sodium Lauryl Ether Sulfate (SLES). A preferred ethoxylated alkyl sulfate anionic surfactant is Sodium Lauryl Ether Sulfate (SLES). SLES having an average degree of ethoxylation of from 0.5 to 3, preferably from 1 to 3, are particularly preferred. The shampoo preferably additionally comprises an amphoteric surfactant, preferably a betaine surfactant, preferably an alkylamidopropyl betaine surfactant, such as cocamidopropyl betaine. In a preferred embodiment, the composition comprises 0.1 to 10wt.%, preferably 0.5 to 8wt.%, more preferably 1 to 5wt.% betaine surfactant.
In order to enhance deposition of active materials from the compositions of the present invention, especially shampoos, cationic polymers are typically included therein. Also in the present invention, it is preferable that the composition further comprises 0.01 to 2.0% of a cationic polymer. The cationic polymer is preferably guar hydroxypropyl trimethylammonium chloride.
When a conditioning benefit is delivered by the composition of the present invention, the composition is referred to as a hair conditioner. Typically, the most commonly used conditioning agents for use in hair care compositions are water insoluble oily materials such as mineral oils, naturally occurring oils such as triglycerides and silicone polymers.
Conditioning benefits are achieved by depositing oily material onto the hair resulting in the formation of a film which makes the hair easier to comb when wet and easier to manage when dry. Particularly useful conditioning agents are silicone compounds, preferably nonvolatile silicone compounds. The pH of the composition is preferably equal to or higher than 4.0, more preferably in the range of 5.0 to 7.0.
Hair conditioning compositions typically comprise a conditioning surfactant selected from cationic surfactants, alone or in combination. Particularly useful cationic surfactants for use in the conditioning agents according to the present invention are cetyltrimethylammonium chloride, behenyl trimethylammonium chloride or stearamidopropyl dimethylamine. The hair conditioning compositions of the present invention preferably may additionally comprise fatty alcohols.
Skin care
The compositions of the present invention are useful for skin care. Skin care refers to the application of a composition to the skin and left thereon until a person typically takes a shower or bath after a few hours or after about one day. The cosmetically acceptable base is typically present in an amount of from 10 to 99.9%, more preferably 40 to 85% by weight of the total composition. It is particularly preferred that the cosmetically acceptable base includes water. The water is preferably present in an amount of from 30 to 90%, more preferably from 30 to 85%, most preferably from 30 to 80% of the total weight of the composition. In addition to water, suitable carrier classes include silicones, polyols, hydrocarbons, triglycerides and thickened powders.
The skin care compositions of the present invention may be in any form suitable for topical application to the skin, including lotions, emulsions, creams, mousses, scrubs, essential oils or gels. Preferably the composition is a skin lotion or cream.
The composition may comprise emollient oils that act as co-solvents. Suitable emollient oils include, for example, esters of alkoxylated aromatic alcohols with fatty carboxylic acids, polyglycols or esters of glycols with fatty carboxylic acids such as caprylic/capric triglyceride, esters of fatty alcohols and fatty acids, alkoxylated derivatives of benzyl alcohol, and mixtures thereof. Preferably, the emollient oil is caprylic/capric triglyceride.
Typically, such compositions comprise a co-solvent in an amount of from 0.01 to 10%, more preferably from 0.1 to 8%, most preferably from 1 to 6%, based on the total weight of the sunscreen composition, and include all ranges subsumed therein.
The composition may additionally comprise a sunscreen agent, such as an inorganic sunscreen agent or an organic sunscreen agent. Examples of organic sunscreens are zinc oxide, titanium dioxide, iron oxide, silica, such as fumed silica. The composition of the present invention may comprise Sup>A UV-Sup>A sunscreen selected from the group consisting of dibenzoylmethane derivatives, triazine derivatives, benzophenone derivatives, and mixtures thereof. The compositions of the present invention may also contain a UV-B sunscreen. Suitable UV-B sunscreens according to the invention are selected from the group consisting of benzophenones, anthranilates, salicylates, cinnamates, camphora, benzylidene malonates, triazinones and derivatives thereof.
Skin lightening agents may also be incorporated into the compositions of the present invention.
Skin care products also include disinfectants that ensure the almost immediate killing of microorganisms present on the skin. The disinfectant preferably comprises 20 to 90% by weight, preferably 30 to 80% by weight, of C 2 To C 4 A monohydric alcohol, wherein the monohydric alcohol is selected from ethanol, isopropanol, or a combination. The disinfectant composition may comprise a combination of ethanol and isopropanol. Most preferably, the alcohol is preferably 40 to 75wt.%, and optimally the composition comprises 55 to 70wt.% C 2 To C 4 Monohydric alcohols.
Preferably, the disinfectant composition may contain 30 to 80wt.%, more preferably 40 to 70wt.%, and most preferably 50 to 68wt.% ethanol. The disinfectant may include certain polyols. The polyols in the composition according to the invention are preferably sorbitol, glycerol, polyethylene glycol, propylene glycol and combinations thereof.
The disinfectant preferably comprises 0.01 to 1wt.% of a thickener. More preferably, the composition comprises from 0.05 to 0.8wt.% thickener, most preferably from 0.08 to 0.2wt.% thickener. Water is typically present in the disinfectant composition at 10 to 40 wt.%. More preferably, the composition comprises 12 to 35wt. water, most preferably 25 to 30wt. water.
Deodorant product
One particular class of skin care compositions is the so-called deodorant compositions. These compositions are typically applied to areas of skin that develop body malodor, such as the underarm area. These products function by masking odors or by ensuring that odor-causing molecules are not produced or by killing or inactivating odor-causing microorganisms. One class of such products is also known as antiperspirant products because they reduce or minimize the amount of perspiration that is produced by a person.
These products can be applied cosmetically and topically to the skin, generally by one of two methods. In one method (sometimes referred to as the contact method), the composition is rubbed onto the skin surface and a portion of the composition is deposited as it passes. In the second method (sometimes referred to as the non-contact method), the composition is sprayed from a dispenser that is held close to the skin. The spray may be formed by mechanical means (e.g. a pump or squeezable side wall) that creates pressure on the contents of the dispenser or by internally created pressure caused by the volatilization of a portion of the liquefied propellant, the dispenser being commonly referred to as a nebulizer.
Broadly, there are two types of contact compositions, one of which is liquid and is typically applied or likely absorbed into or onto a wipe using a roll-on dispenser, while in the second composition the desired active is distributed in a carrier liquid within the continuous phase that forms the gel. In one variant, the carrier fluid comprises a solvent for the desired active substance, and in a second variant, the active substance is maintained as a particulate solid suspended in an oil (typically a blend of oils).
Stick or soft solid compositions:
many different materials have been proposed as gellants for continuous oil phases, including waxes, small molecule gellants, and polymers. They each have their advantages, and one of the most commonly used classes of gellants includes waxes, at least in part because of their ready availability and ease of processing, particularly linear fatty alcohol wax gellants. The gelled deodorant composition is topically applied to the skin by wiping over and contacting the skin, thereby depositing a thin film on the skin.
And (3) roll coating:
liquid compositions that can be used in roll-on applications can be broadly divided into two categories, those in which the active is suspended in a hydrophobic carrier (e.g., volatile silicone) and those in which the active is dissolved in a carrier liquid. The latter has proven to be more popular. There are mainly two types of dissolved carrier liquids, namely a carrier that is mainly an alcohol, that is to say a majority of the dissolved carrier liquid contains ethanol, and a second type in which the medium carrier liquid is mainly water. The former is very popular because ethanol itself is a mild germicide, but its popularity is reduced because it can cause stinging, especially if the surface to which the composition is applied has been damaged or cut, as may be the case during shaving or other epilation operations.
The second class of formulations as alternatives to alcoholic formulations comprises dispersions of water-insoluble or poorly water-soluble ingredients in aqueous solutions of the active substances. Such compositions will be referred to herein as emulsions. A roller coating emulsion typically contains one or more emulsifiers to maintain the distribution of water-soluble ingredients.
Aerosol composition:
the deodorant composition may be delivered by aerosol, which contains a propellant in addition to the other ingredients described above.
The propellants herein generally fall into one of three categories: i) By compressing liquefied low boiling point gas, ii) volatile ether and iii) compressed non-oxidizing gas.
The species i) are conveniently low boiling materials, typically boiling below-5 ℃, and typically below-15 ℃, and in particular alkanes and/or halogenated hydrocarbons. Such propellants are typically liquefied and vaporized under pressure in aerosol cans to create a pressure that forces the composition out of the can. Examples of suitable alkanes include in particular propane, butane or isobutene. The second class of propellants comprises very highly volatile ethers, of which the ether most widely used to date is dimethyl ether. The propellant may advantageously be used in a relatively low weight ratio of propellant to base formulation, for example as low as 5:95. It can also be used in combination with, for example, a compressible/liquefiable alkane gas. A third class of propellants comprises compressed non-oxidizing gases, and in particular carbon dioxide or nitrogen. Inert gases such as neon are theoretical alternatives.
The skin care composition may also contain other ingredients commonly used in the art to enhance physical properties and performance. Suitable ingredients include, but are not limited to, humectants, thickeners, opacifiers, binders, colorants and pigments, pH adjusting agents, preservatives, optical agents (optics), perfumes, viscosity adjusting agents, biological additives, buffers, conditioning agents, essential oils and skin benefit agents including anti-inflammatory agents, cooling agents, antiperspirant agents, anti-aging agents, anti-acne agents, antimicrobial agents and antioxidants.
The invention will now be further described by the following non-limiting examples.
Examples
Examples 1 to 5: effect of 12-HSA (1. Mu.M concentration) on AMP Gene expression
The following protocol was used to evaluate the active substance (12-HSA) against AMP gene expression on keratinocytes
Materials:
normal Human Epidermal Keratinocytes (NHEK), epiLife Keratinocyte Growth Medium (KGM) (containing antibiotic Pen-Strep), dulbecco Phosphate Buffered Saline (DPBS), trypsin-EDTA, trypsin neutralizer solution, ethanol, RNA extraction kit (RNeasy kit), RLT buffer, RT-PCR kit.
The procedure is as follows:
1. NHEK cells were thawed and expanded in KGM to 80% confluence in 2-25cc and then 75cc flasks, every other dayMedium was changed and at 37℃at 5% CO 2 Incubation in incubator.
2. The spent medium was discarded and adherent cells in the flask were rinsed with DPBS. trypsin-EDTA was added and tapped to detach adherent cells. Trypsin neutralizer was added and mixed gently.
3. The contents were transferred to a 15-ml tube and the cells were spun down. The supernatant was discarded and the cells resuspended in KGM. Count and incubate to 80-85% confluence (2-3 days) in 24 well TC plates at 30,000-50,000 cells per well. The medium was changed every other day. Differentiation Medium (containing 2mM CaCl) was added 2 KGM) and incubated for 2-3 days.
4. The desired concentration of active material (if used, the final concentration of ethanol solvent should be less than 0.1%) is prepared in KGM.
5. The differentiation medium was replaced with medium containing the active substance and incubated for 24h.
6. The supernatant was discarded and the cells were washed once with DPBS. To each well 250 μ LRLT buffer was added to lyse the cells and the entire contents were transferred to a 1.5mL tube. Storing at-80deg.C until extraction.
7. RNA extraction, quantification of RNA, cDNA synthesis and real-time qPCR of cDNA samples were performed according to the kit. The relative expression levels relative to the control normalized to the housekeeping gene were calculated.
Using the protocol described above, the expression of AMP genes was measured and the data is summarized in table-1 below.
Table-1: AMP gene expression using 12HSA at a concentration of 1 μm (=0.00003 wt%)
| Examples | AMP genes | Fold change relative to control |
| 1 | Control | 1.00 |
| 2 | S100A7 | 1.66 |
| 3 | RNase7 | 2.56 |
| 4 | LL-37 | 2.09 |
| 5 | HBD-3 | 2.16 |
Fold change is an indication of the amount of gene expressed compared to a control without active agent (12-HSA). Thus, for example, a sample with 12-HSA causes 1.66-fold higher expression of gene S100A7 than a sample without 12-HSA. Thus, the data in the above table indicate that when 12-HSA is used on keratinocytes, the expression of many AMP genes is many times higher than that of the control.
Examples 6 to 10: antimicrobial peptide expression from different concentrations of 12-HSA treatment
Psoriasis (S100A 7) AMP from the above list was selected to investigate the effect of 12-HSA concentration on AMP secretion. The procedure used was as follows:
protocols for assessing active substances (12-HSA) on keratinocytes against AMP secretion
Materials:
normal Human Epidermal Keratinocytes (NHEK), epiLife Keratinocyte Growth Medium (KGM) (containing antibiotic Pen-Strep), dulbecco Phosphate Buffered Saline (DPBS), trypsin-EDTA, trypsin neutralizer solution, ethanol, psoriasis ELISA kit.
The procedure is as follows:
1. NHEK cells were thawed and expanded to 80% confluence in KGM in 2-25cc and then 75cc flasks, medium was changed every other day and at 37℃at 5% CO 2 Incubation in incubator.
2. The spent medium was discarded and adherent cells in the flask were rinsed with DPBS. trypsin-EDTA was added and tapped to detach adherent cells. Trypsin neutralizer was added and mixed gently.
3. The contents were transferred to a 15-ml tube and the cells were spun down. The supernatant was discarded and the cells resuspended in KGM. Count and incubate to 80-85% confluence (2-3 days) in 24 well TC plates at 30,000-50,000 cells per well. The medium was changed every other day. Differentiation Medium (containing 2mM CaCl) was added 2 KGM) and incubated for 2-3 days.
4. The desired concentration of active material (if used, the final concentration of ethanol solvent should be less than 0.1%) is prepared in KGM.
5. The differentiation medium was replaced with medium containing the active substance and incubated for 72h.
6. The supernatant was collected and stored at-80 ℃. Complete thawing was performed before ELISA to measure AMP (psoriasis).
7. For ELISA, the required standards and samples (undiluted and diluted) were run and the amount of AMP in the samples was calculated using a standard curve.
Using the protocol described above, peptide expression was measured and the data is summarized in table-2 below.
TABLE 2
| Examples | Concentration of 12-HSA | Fold change relative to control (psoriasis increased) |
| 6 | Control | 1.00 |
| 7 | 0.25μM | 8.12 |
| 8 | 0.50μM | 15.07 |
| 9 | 1.0μM | 9.79 |
| 10 | 2.0μM | 15.70 |
The data in the above table indicate that 12-HSA causes keratinocytes to express AMP in large amounts, and this is observed over a large concentration range.
It will be appreciated that the experiments described herein were performed in vitro assays to evaluate synergistic antimicrobial effects. It is expected that the concentration actually used to prepare the composition for topical use may be several orders of magnitude higher due to the following reasons affecting the concentration difference in bulk compared to the concentration at the cellular level. The composition may be formulated as an emulsion or gel with a very large number of additional ingredients. The desired concentration of active material in the oil and water phases is expected to be very different. They may also have very different physical and hydrodynamic properties such as partition coefficient, diffusion rate, convection transport rate, rheological properties, etc. Thus, it is expected that the concentration used when formulated into a composition will be very different from the concentration at the cellular level.
Examples 11 to 26: synergistic combination of 12-HSA and AML or AMP or mixtures thereof for providing antimicrobial efficacy
By using
The antimicrobial efficacy of a combination of 10 μm (=0.0003 wt%) 12-HSA with 1 μg/ml (=0.0001 wt%) AML (phytosphingosine) and 0.5 μg/ml (=0.00005 wt%) AMP (LL-37) against the two organisms staphylococcus aureus (s.aureus) and pseudomonas aeruginosa (p.aeromonas) was studied. The experiments were performed using the following assays.
Microdilution assay
Materials: trypsin Soybean Agar (TSA) medium, AMP stock (LL 37), AML stock (phytosphingosine), test microorganisms (Staphylococcus aureus, pseudomonas aeruginosa), phosphate buffer (pH 5.8), D/E medium.
The method comprises the following steps:
1. the test cultures were inoculated in TSA plates and incubated in an incubator at 37℃for 18-24h.
2. The cultures were scraped off and resuspended in 10mM phosphate buffer to adjust the cell number to 1X 10 8 cfu/mL。
3. The culture was serially diluted in 10mM phosphate buffer to obtain 1X 10 6 cfu/mL。
4. Stock solutions of 10-100 times the concentration of active substance (in water, ethanol or DMSO), LL37 (in MilliQ water) and phytosphingosine (in ethanol) were prepared.
5. In a 96-well microtiter plate, buffer, active LL37& phytosphingosine were added and the total volume was made up to 165 μl with water. Appropriate controls were maintained.
6. 135. Mu.L of diluted culture was added, mixed and incubated at 37℃for 4h.
7. After incubation, aliquots were removed from each reaction and neutralized by 1:10 dilution in D/E medium.
8. The dilutions were further diluted in D/E medium and plated on TSA plates. Incubate at 37℃for 24h.
9. The colonies were counted the next day and recovery and log reduction compared to the control were calculated.
Log (recovery) data for each of the different samples are given in tables 3 and 4 below.
Hydroxystearic acid, AMP and AML used in the following examples were commercially available from suppliers and the catalog numbers are shown below.
12-HSA (TCI; H0308), LL-37 (Tocris; 5213/1), phytosphingosine (TCI; P1765), hexadecenoic acid (Chemscene; CS-0105451), sphingosine (Sigma; S9666), palmitoleic acid (Sigma; P9417). Bacteria mentioned in the following table and their American Type Culture Collection (ATCC) accession numbers were found in Chromachemie.
Table-3: antimicrobial killing of staphylococcus aureus ATCC 6538
Table-4: antimicrobial killing of pseudomonas aeruginosa ATCC15442
The data in tables 3 and 4 show that the combination of 12-HSA along with AML and AMP provides synergistic antimicrobial activity compared to the antimicrobial activity achieved with each active alone.
Table 5: antimicrobial killing of staphylococcus aureus ATCC 6538
| Examples | Sample of | Recovery rate (logarithm) |
| 19 | Control | 6.59 |
| 20 | 0.005％12-HSA | 6.26 |
| 21 | 1.0μg/ml LL-37 | 5.48 |
| 22 | 0.005％12-HSA+1.0μg/ml LL-37 | 4.62 |
Table-6: antimicrobial killing of pseudomonas aeruginosa ATCC15442
| Examples | Sample of | Recovery rate (logarithm) |
| 23 | Control | 6.3 |
| 24 | 0.0003％12-HSA | 6.1 |
| 25 | 1.0. Mu.g/ml phytosphingosine | 5.9 |
| 26 | 0.0003% 12-HSA+1.0. Mu.g/ml phytosphingosine | 5.4 |
Claims (14)
1. Use of hydroxystearic acid for inducing secretion of antimicrobial peptides (AMPs) when applied to the external surface of the human body.
2. The use according to claim 1, wherein hydroxystearic acid induces AMP secretion by keratinocytes.
3. Use according to claim 1 or 2 for improving the immunity of the outer surface.
4. The use of any preceding claim, wherein the external surface comprises skin, scalp or oral cavity.
5. Use according to any one of the preceding claims, wherein the hydroxystearic acid is 12-hydroxystearic acid.
6. The use according to any one of the preceding claims, wherein the use is a non-therapeutic use.
7. A method of providing protection to an external surface of a body by inducing secretion of an antimicrobial peptide (AMP), the method comprising the step of applying hydroxystearic acid to the external surface.
8. Use of a composition comprising hydroxystearic acid and an antimicrobial peptide or an antimicrobial lipid or a mixture thereof for antimicrobial benefit.
9. A method of providing an antimicrobial benefit to an external surface of a body, the method comprising the step of applying to the external surface a composition comprising hydroxystearic acid and an antimicrobial peptide or antimicrobial lipid or a mixture thereof.
10. An antimicrobial composition comprising (i) 0.000001 to 10% by weight of hydroxystearic acid and (ii) 0.000001 to 2% by weight of antimicrobial peptide or antimicrobial lipid or mixture thereof.
11. The composition of claim 10, wherein the composition comprises (i) 0.000001 to 10% by weight hydroxystearic acid and (ii) 0.000001 to 1% by weight antimicrobial lipid.
12. The composition according to any of the preceding claims 10 or 11, comprising a cosmetically acceptable base.
13. The composition according to any one of the preceding claims 10 to 12, wherein the cosmetically acceptable base is a cream, lotion, gel or emulsion.
14. The composition according to any one of the preceding claims 10 to 13, wherein the cosmetically acceptable base comprises a surfactant.
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| Application Number | Priority Date | Filing Date | Title |
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| IN202021052758 | 2020-12-03 | ||
| EP21152775.9 | 2021-01-21 | ||
| PCT/EP2021/082733 WO2022117404A1 (en) | 2020-12-03 | 2021-11-24 | Hydroxystearic acid for inducing generation of antimicrobial peptides |
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