KR20200030465A - Novel serinol compounds, cosmetic compositions and pharmaceutical compositions comprising same - Google Patents

Abstract

The present invention relates to a novel serinol compound, and a cosmetic composition and a pharmaceutical composition comprising the same. Specifically, according to the present invention, the differentiation of keratinocytes in the skin is promoted, thereby reducing dead skin cells, a damaged skin barrier is normally regenerated by lipid components provided in a stable liquid crystal phase, thereby providing a normal skin protection function, and endocannabinoids are targeted and activation thereof is effectively suppressed, thereby significantly alleviating and treating skin diseases and mental diseases related thereto.

Description

A novel serinol compound, cosmetic composition and pharmaceutical composition comprising the same {NOVEL SERINOL COMPOUNDS, COSMETIC COMPOSITIONS AND PHARMACEUTICAL COMPOSITIONS COMPRISING SAME}

The present invention relates to novel serinol compounds, cosmetic compositions and pharmaceutical compositions comprising the same.

The epidermis, located on the outermost part of the skin, protects against various physical, chemical and mechanical stimuli from the outside and protects against excessive dissipation of moisture in the body through the skin. This protective function is possible by forming and maintaining the stratum corneum composed of keratinocytes normally. Keratinocytes refer to cells formed by undergoing morphological and functional changes step by step as the basal cells, which were continuously proliferating in the stratum basale, migrate to the stratum corneum. The keratinocytes thus formed are removed from the skin after a certain period of time, and new keratinocytes from the lowermost layer of the epidermis take over. This process is called epidermal differentiation, that is, keratinization, and keratinocytes repeat the keratinization process. In this keratinization process, keratinocytes produce intercellular lipids together with natural moisturizing factors, ceramides, cholesterol, and fatty acids, thereby forming a stratum corneum layer to help retain protective functions.

In terms of optimizing the protective function of the skin, many studies have been conducted to supply moisture from the outside or minimize moisture loss from the body by focusing on maintaining proper moisture in the skin. Various moisturizers including ceramide or derivatives thereof have been proposed. However, the use of such moisturizers is mostly a relief of temporary symptoms rather than a fundamental treatment, and thus does not exhibit a sufficient effect in the improvement and treatment of diseases of the skin or skin barrier, including atopic dermatitis. . Accordingly, there is a need to develop materials and agents that fundamentally regenerate the damaged skin barrier.

On the other hand, cannabinoid receptors (eg, cannabinoid type 1 receptor, CB ₁ ; cannabinoid type 2 receptor, CB ₂ ) are expressed in mast cells, and it is known that these cannabinoid receptor antagonists can regulate mast cell activity. . As described above, atopic dermatitis is a type of skin disease in which its symptoms are exacerbated by excessive activity of mast cells. Atopic dermatitis is a chronic recurrent dermatitis, and although the exact etiology is unknown, it is speculated that the genetic, environmental and immunological factors are complicatedly related. In patients with this atopic disease, mast cells are activated in both the immunoglobulin E-dependent and immunoglobulin E-independent reactions, resulting in degranulation by fusion of the plasma membrane and cytoplasmic microparticles. In addition, when various allergens are bound to specific immunoglobulin E (IgE) of mast cells, it strongly binds to the IgE receptor (FceRI) on the mast cell surface to secrete histamine. Thus, by suppressing the activity of mast cells, by reducing histamine secreted therefrom, it is possible to provide efficacy suitable for the improvement and treatment of atopic dermatitis. However, in the prior art, techniques for improving and treating atopic dermatitis have been mostly prevented and alleviated itching by taking antihistamines or using steroids. However, when these drugs are taken or applied, side effects such as central nervous system disorders, digestive system disorders, and nightmares occur, and thus, there is a need to develop new substances and preparations that can overcome these side effects and have no toxicity.

In addition, according to Non-Patent Document 1, in children with skin diseases such as atopic dermatitis, developmental disorder (autism) was found to be increased by 7.41 times. Specifically, children with skin diseases such as atopic dermatitis are often accompanied by mental disorders such as attention deficit hyperactivity disorder (ADHD), anger control disorder, depression, and behavior disorder, and have excellent skin protection. The external preparation for skin will not only be primarily effective for the management of atopic dermatitis, but also can be effectively used for the management of skin with developmental disorder, attention deficit hyperactivity disorder, anger control disorder, depression, and behavioral disorders with weakened skin barrier function. It is expected. In particular, according to recent research results, abnormalities of the endocannabinoid system have been reported even in patients with autism. Non-Patent Document 2 reported improvement of symptoms by taking palmitoyl ethanolamide (PEA), one of the cannabinoid 1 receptor agonists, in patients with autism. Under the background of this study, when developing a substance capable of acting as a cannabinoid 1 receptor agonist, it can provide an effective effect on atopic dermatitis, dry skin, itching, etc. accompanying it, and its frequency increases with atopic dermatitis. It is expected to provide an effective effect on skin care of patients with mental disorders such as autism or hyperactivity disorder.

Accordingly, the present inventors have repeatedly studied new formulations for optimizing the protective function of the skin. As a result, by effectively regenerating the damaged skin barrier as well as improved moisturizing effect, skin diseases such as atopic dermatitis and skin barrier function are weakened. The present invention has been completed to provide a novel aspect of a compound suitable for the management of mental disorders, a serinol-based compound, and uses thereof.

J ALLERGY CLIN IMMUNOL, February 2013, Volume 131, Issue 2, 428-433 pages Case Reports in Psychiatry Volume 2015, Article ID 325061, 6 pages

An object of the present invention is to provide a novel serinol-based compound.

Another object of the present invention is to provide a cosmetic composition for improving skin that can effectively regenerate a damaged skin barrier while providing excellent moisturizing effect.

Another object of the present invention is to provide a pharmaceutical composition suitable for the improvement and treatment of skin diseases such as atopic dermatitis and mental diseases accompanying skin with weakened skin barrier function.

For the purpose described above, the present invention provides a cosmetic composition comprising a serinol-based compound selected from nicotinyl serinol and biotinyl serinol as active ingredients.

The cosmetic composition according to an embodiment of the present invention may be for moisturizing the skin.

The cosmetic composition according to an embodiment of the present invention may be for strengthening the skin barrier.

The cosmetic composition according to an embodiment of the present invention may be for improving skin diseases.

The cosmetic composition according to an embodiment of the present invention may further include a sterol-based compound, a higher fatty acid and higher fatty alcohol.

The cosmetic composition according to an embodiment of the present invention, based on 1 part by weight of the serinol compound, 1 to 10 parts by weight of the sterol compound, 5 to 30 parts by weight of the higher fatty acid and 10 to 50 parts of the higher fatty alcohol It may be included in parts by weight.

The cosmetic composition according to an embodiment of the present invention may be to form a Maltese cross liquid crystal.

The cosmetic composition according to an embodiment of the present invention includes ceramide 1, ceramide 3, ceramide 3B, ceramide 4, ceramide 6, myristoyl / palmitoyl oxostearamide / aracamide a (trade name: PC-9S), and Hyd. Further comprising a ceramide selected from hydroxypropyl bispalmitamide M (trade name: PC-104), hydroxypropyl bispalmitamide M (trade name: PC-102), and dihydroxyisopropyl famyl palmamide. May be

In another aspect, the present invention provides a pharmaceutical composition comprising a serinol-based compound selected from nicotinyl serinol and biotinyl serinol.

The pharmaceutical composition according to an embodiment of the present invention may be for treating or improving skin diseases.

The pharmaceutical composition according to an embodiment of the present invention may be for treatment or improvement of mental illness.

The pharmaceutical composition according to an embodiment of the present invention may further include one or more selected from sterol-based compounds, higher fatty acids, higher fatty alcohols, and ceramides.

In the pharmaceutical composition according to an embodiment of the present invention, the skin disease is atopic dermatitis, psoriasis, contact dermatitis, eczema dermatitis, light dermatitis, seborrheic dermatitis, herpes dermatitis, squamous lichen, sclerosis, necrotizing pyoderma, It may be celestial lupus, vesicular epidermis, systemic sclerosis or leprosy.

In the pharmaceutical composition according to an embodiment of the present invention, the mental disease may be attention deficit hyperactivity disorder, anger control disorder, depression or behavior disorder.

The pharmaceutical composition according to an embodiment of the present invention may be formulated in the form of an external preparation for skin such as lotion, ointment, gel, cream, patch and spray.

The pharmaceutical composition according to an embodiment of the present invention may be formulated as a formulation for oral administration.

In another aspect, the present invention provides a novel serinol-based compound having the above-mentioned use, biotinyl serinol, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and the like.

According to the present invention, it is possible to provide a cosmetic composition comprising a liquid crystal phase stably formed. Thus, when applying the cosmetic composition according to the present invention to the skin can provide excellent skin moisturizing and skin barrier strengthening effect. Specifically, according to the present invention, by promoting the differentiation of keratinocytes in the skin, the skin keratinization is reduced, and the skin barrier damaged by lipid components provided in a stable liquid crystal phase is normally regenerated to provide a normal skin protection function. To help.

Further, according to the present invention, it is possible to effectively suppress their activation by targeting an endocannabinoid system. Specifically, the pharmaceutical composition according to the present invention is an inflammation (inflammation), irritation, itching (itching), pruritus, pain (pain), edema (oedema) and allergic reactions, etc., in which the cannabinoid receptor acts It is particularly useful for treating and preventing conditions that cause it.

In addition, according to the present invention, by acting as an effective agent for the cannabinoid 1 receptor, it can be useful for preventing, improving or treating cannabinoid 1 receptor-mediated skin diseases. Furthermore, according to the present invention, skin diseases such as atopic dermatitis and mental diseases accompanying it may be suitable for prevention, improvement or treatment of attention deficit hyperactivity disorder, anger control disorder, depression, and behavioral disorder.

1 is a liquid crystal formation photograph (polarization micrograph, magnification: 400) of the composition for external application for skin prepared in Example 2 of the present invention,
2 is a graph showing the efficacy as a cannabinoid 1 receptor agonist using ACEA, which is an agonist of the serinol compound of the present invention and a cannabinoid 1 receptor.

The novel serinol-based compound according to the present invention, the cosmetic composition and the pharmaceutical composition comprising the same will be described below, but there is no other definition in the technical terms and scientific terms used at this time, the general knowledge in the technical field to which this invention belongs Descriptions of well-known functions and configurations that have a meaning commonly understood by a person having an understanding and may unnecessarily obscure the subject matter of the present invention are omitted in the following description.

The term "stereoisomers" in the present specification may be in the form of enantiomers or diastereomers. In addition, these enantiomers or diastereomers, as well as mixtures thereof, including racemic mixtures, may also be one aspect of the present invention.

As used herein, the term “pharmaceutically acceptable salt” means a salt or complex that retains the desired biological activity of the serinol-based compound according to the present invention and exhibits minimal or no undesirable toxic effects. Specifically, the pharmaceutically acceptable salt is an acid addition salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc .; Or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-Toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2,2,2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert -Butyric acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxy naphthoic acid, salicylic acid, stearic acid, acid addition salt formed by an organic acid such as muconic acid; may be, but is not limited thereto.

As used herein, the term “solvate” refers to a higher order compound formed between molecules or ions of a solute and molecules or ions of a solvent. In addition, "hydrate" is an aspect of a water-bound solvate.

As used herein, the term "applying" means contacting the composition of the present invention to the skin of an individual in any suitable way, and for the purpose of absorbing the composition into the skin.

As used herein, the term "improvement" refers to any act of improving or beneficially altering skin function by application of the composition according to the present invention. In addition, "prevention" refers to all actions to suppress or delay the occurrence of skin diseases or mental diseases by application of the composition according to the present invention.

As a result of repeated studies on new formulations for optimizing the protective function of the skin, the present inventors devised a new serinol-based compound, biotinyl serinol. In addition, the present invention is proposed to provide a new useful use of a serinol-based compound selected from the biotinyl serinol and nicotinyl serinol.

Specifically, the serinol-based compound according to the present invention can effectively suppress the release of the endocannabinoid system. That is, the composition employing the serinol-based compound according to the present invention is applied to the skin to control the release of endocannabinoids such as CB ₁ and CB ₂ on keratinocytes and fibroblasts, from which Significantly modulate many of the signals involved in conditions such as inflammation caused. In addition, by acting as an agonist for the cannabinoid 1 receptor without side effects, it can exhibit an effective effect in preventing, improving or treating skin diseases mediated by the cannabinoid 1 receptor, and mental disorders accompanying skin diseases such as atopic dermatitis For example, it may exhibit an effective effect on prevention, improvement or treatment of attention deficit hyperactivity disorder, anger control disorder, depression, behavior disorder, and the like.

Specifically, the serinol-based compound according to the present invention can form a very stable liquid crystal, and the liquid crystal formed therefrom exhibits excellent long-term stability at high temperatures. Thus, the composition according to the present invention can effectively regenerate a damaged skin barrier by lipid components provided in a stable liquid crystal phase. That is, when the composition according to the present invention is applied to the skin, the skin barrier function is restored to have excellent skin moisturizing effect. In addition, the composition according to the present invention has a structure similar to a lipid-based molecule such as a lipid component, so that a liquid crystal phase can be formed, and as it has excellent affinity for skin, absorption of a serinol-based compound can be greatly improved. have. In addition, the composition may provide a long lasting effect by the lipid components in the liquid crystal phase stably supplied, thereby continuously providing an improved moisturizing effect.

Hereinafter, the composition according to the present invention will be described in detail.

An aspect of the present invention may be a composition comprising a serinol-based compound selected from nicotinyl serinol and biotinyl serinol, and the composition may be a composition for external application for skin in a form applied to the skin. At this time, the composition may use nicotinyl serinol or biotinyl serinol alone, and of course, these may be used in the form of a mixture. The specific structure of the serinol-based compound is as follows.

The biotinyl serinol is a novel compound designed by the present inventors.

In addition, the serinol-based compound includes the structure as well as its stereoisomer, its pharmaceutically acceptable salt, its hydrate or solvate in all aspects.

The composition for external application for skin according to an embodiment of the present invention may be a cosmetic composition or a pharmaceutical composition, and specific embodiments thereof will be described below. In addition, the composition for external application for skin may use 0.01 to 5% by weight of a serinol-based compound based on the total weight, specifically 0.01 to 3% by weight, and more specifically 0.1 to 2% by weight.

For example, when the serinol-based compound is used in the form of a mixture, the nicotinyl serinol may be used in an amount of 0.01 to 5 parts by weight based on 1 part by weight of the biotinyl serinol. Specifically, the mixture of biotinyl serinol and nicotinyl serinol may be mixed in a weight ratio of 1: 0.05 to 1: 3, and more specifically, mixed in a weight ratio of 1: 0.1 to 1: 1. However, it is not limited thereto.

The composition for external application for skin according to an embodiment of the present invention, as described above, may be combined with a lipid component for liquid crystal formation to provide a stable liquid crystal phase.

Specifically, the composition for external application for skin is a combination of a lipid component such as a sterol-based compound, a higher fatty acid and a higher fatty alcohol with a serinol-based compound selected from nicotinyl serinol and biotinyl serinol, to provide a very stable liquid crystal phase. have.

The liquid crystal formed by the above-described combination has excellent affinity for the skin, and can be absorbed by the skin to increase the uniformity and firmness of the intercellular lipid. Accordingly, a more improved moisturizing effect can be realized, and the skin barrier damaged by lipid components provided in a stable liquid crystal phase can be effectively regenerated.

For example, the sterol-based compound is cholesterol (cholesterol), phytosterol (phytosterol), 3b- [N- (N ', N'-dimethylaminoethane) -carbamyl} cholesterol (3b- [N- (N', N '-dimethylaminoethane) -cabamyl] cholesterol, DC-Chol), stigmasterol, campesterol, sitosteol, ergosterol, lanosterol, dinosterol, gorgo Gorgosterol, avenasterol, saringosterol, fucosterol, cholesteryl hemisuccinate, cholesteryl benzoate, cholesteryl benzoate Cholesteryl oleate, cholesteryl oleyl carbonate, cholesteryl isostearate, cholesteryl linoleate, cholesteryl acetate, Cholesteryl Palmitate (cholesteryl palmitate), cholesteryl stearate, cholesteryl chloride (Cholesteryl chloride), cholesteryl nonanoate (Cholesteryl nonanoate) and cholesteryl arachidonate (Cholesteryl arachidonate) or It can be two or more.

For example, the higher fatty acid may be a higher fatty acid having 10 to 25 carbon atoms, and specifically, oleic acid, linoleic acid, behenic acid, arachidonic acid ( Arachidonic A cid ), stearic acid ( Stearic A cid ), palmitic acid (Palmitic Acid), myristic acid (Myristic Acid) and lauric acid (Lauric Acid) and the like may be selected from one or two or more.

For example, the higher fatty alcohol may be a higher fatty alcohol having 10 to 25 carbon atoms, that is, higher aliphatic alcohol, specifically, cetearyl alcohol, stearyl alcohol, cetostaaryl alcohol ( cetostearyl alcohol) and behenyl alcohol (Behenyl Alcohol).

The composition for external application for skin according to an embodiment of the present invention may use the above-described serinol compound and lipid component in an amount used to form a liquid crystal, and specifically, based on 1 part by weight of the serinol compound, the sterol compound It may be from 0.1 to 10 parts by weight, the higher fatty acid 1 to 30 parts by weight and the higher fatty alcohol 1 to 50 parts by weight.

For example, the composition for external application for skin includes 0.5 to 10 parts by weight of the sterol compound, 1 to 20 parts by weight of the higher fatty acid, and 3 to 45 parts by weight of the higher fatty alcohol based on 1 part by weight of the serinol compound. It may be.

For example, the composition for external application for skin includes 0.8 to 8 parts by weight of the sterol compound, 2.5 to 20 parts by weight of the higher fatty acid, and 5 to 40 parts by weight of the higher fatty alcohol based on 1 part by weight of the serinol compound. It may be.

The liquid crystal formed in the composition for external application for skin according to an embodiment of the present invention may be a malteser cross liquid crystal. At this time, the Maltese cross liquid crystal may be a single layer or multiple layers.

By implementing its shape, it is possible to prevent the precipitation of lipid components by forming a more stable liquid crystal, and it is possible to further improve the uniformity and firmness of the intercellular lipids due to easy skin penetration.

The composition for external application for skin according to an embodiment of the present invention may form a liquid crystal with a composition similar to the components of intercellular lipids, and form a maltese cross liquid crystal film on the skin as it is applied to the skin. That is, the composition for external application for skin may provide an immediate moisturizing effect when applied to the skin, as well as a continuous moisturizing effect through realization of a long-lasting effect, thereby improving and treating skin diseases such as dry skin and atopic dermatitis. It seems to work.

For example, the maltese cross liquid crystal in the composition for external application for skin may have a size in the range of 10 μm or less, specifically 8 μm or less, and more specifically, a size in the range of 0.5 to 4 μm. .

In addition, the composition for external application for skin according to an embodiment of the present invention may further include ceramide, thereby further enhancing stability of the liquid crystal.

For example, the ceramide may be selected from natural ceramides, synthetic ceramides, and similar ceramides, and specifically, ceramide 1, ceramide 3, ceramide 3B, ceramide 4, ceramide 6, myristoyl / palmitoyloxosteamide / Arachamide M (Myristoyl / palmitoyl oxostearamide / arachamide MEA, brand name: PC-9S), hydroxypropyl bispalmitamide M (brand name: PC-104), hydroxypropyl bispalmitamide M (brand name: PC-102) and dihydroxyisopropylpamoyl palmamide, and the like.

In the composition for external application for skin according to an embodiment of the present invention, the ceramide may include 0.001 to 10 parts by weight based on 1 part by weight of the serinol-based compound. Specifically, 0.01 to 8 parts by weight, more specifically 0.1 to 6 parts by weight may further include ceramide.

For example, when the composition for external application for skin is based on the total weight of the composition, the serinol-based compound is contained in an amount of 0.01 to 5% by weight, and the serinol-based compound and ceramide are mixed in a weight ratio of 1: 0.1 to 1: 6, It is good to be able to form a more stable liquid crystal.

Hereinafter, a specific aspect of the composition for external application for skin according to the present invention will be described.

The composition for external application for skin according to an embodiment of the present invention may be a cosmetic composition, which may have a non-therapeutic use.

For example, the cosmetic composition may be for moisturizing the skin or strengthening the skin barrier.

For example, the cosmetic composition may be for improving skin diseases.

For example, the cosmetic composition may be used for skin improvement of mental diseases accompanying skin diseases such as atopic dermatitis.

The cosmetic composition effectively inhibits the activation of the endocannabinoid system, and inflammation, irritation, itching, pruritus, pain, edema, and allergic reactions acting on the cannabinoid receptors (eg, CB ₁ and CB _2, etc.) It is particularly useful for treating and preventing conditions that cause back.

In addition, the cosmetic composition does not cause skin side effects such as epidermal hyperproliferation, but also has an improved skin moisturizing effect and an effective regeneration of damaged skin barrier.

In addition, the cosmetic composition has an improved skin moisturizing effect. In addition, the cosmetic composition for improving skin diseases effectively improves the damaged skin barrier, thereby maximizing the skin moisturizing effect, thereby exhibiting an excellent effect on skin diseases.

In addition, the cosmetic composition exerts an improvement effect on mental diseases accompanying skin with weakened skin barrier function, keratinized or hyperkeratized skin.

The cosmetic composition may be formulated into a general emulsifying formulation, a solubilizing formulation, or the like, using a commonly known manufacturing method.

For example, the cosmetic composition is formulated into a formulation selected from the group consisting of softening makeup, converging makeup, nutritional makeup, eye cream, nutrition cream, massage cream, cleansing cream, cleansing foam, cleansing water, powder, essence, pack, etc. It can be.

The cosmetic composition, if desired, may further include additional additives as appropriate. For example, the additive is a stabilizer, emulsifier, thickener, moisturizer, liquid crystal film strengthening agent, pH adjusting agent, antibacterial agent, water-soluble polymer, coating agent, metal ion blocker, amino acid, organic amine, polymer emulsion, pH adjusting agent, skin nutritional agent, oxidation One or more aqueous additives selected from antioxidants, antioxidants, preservatives, fragrances, and the like; And one or more oil additives selected from oils, waxes, hydrocarbon oils, higher fatty acid oils, higher alcohols, synthetic ester oils, and silicone oils; And the like.

In this case, each of the additives may be included in an amount of 0.001 to 20% by weight based on the total weight of the composition, and specifically, it may be included in an amount of 0.01 to 10% by weight and 0.05 to 10% by weight, but is not limited thereto.

The composition for external application for skin according to an embodiment of the present invention may be a pharmaceutical composition, which may have a therapeutic use.

For example, the pharmaceutical composition may be for the treatment, prevention or improvement of skin diseases.

For example, the pharmaceutical composition may be for treatment, prevention or improvement of the skin of a mental illness accompanying due to skin diseases such as atopic dermatitis.

For example, the pharmaceutical composition may be for the treatment, prevention or improvement of mental disorders accompanying skin diseases such as atopic dermatitis.

The pharmaceutical composition effectively regenerates the damaged skin barrier and optimizes the protective function of the skin, thereby exhibiting an excellent effect on skin diseases.

In addition, the pharmaceutical composition effectively inhibits the activation of the endocannabinoid system. As the release of endocannabinoids such as CB ₁ and CB ₂ is appropriately controlled, it exerts strong anti-inflammatory and anti-allergic effects on keratinocytes and fibroblasts. Moreover, it was confirmed that the pharmaceutical composition exerts an effect on the treatment or improvement of the skin of a mental illness accompanied by skin with weakened skin barrier function as well as showing a beneficial effect on the mental disorder. That is, the serinol-based compound included in the pharmaceutical composition according to the present invention acts as an endocannabinoid-based agonist or modulator, and the above-described diseases responding to CB ₁ and CB ₂ , such as skin diseases and mental diseases It has a significant effect on treatment, improvement and prevention. Moreover, the inventors noted that despite this effect, it does not cause side effects.

The pharmaceutical composition may be formulated into a formulation containing a pharmaceutically acceptable carrier, using a conventionally known manufacturing method.

For example, the pharmaceutical composition may be formulated as a formulation selected from the group consisting of lotions, ointments, gels, creams, patches, sprays, and the like.

For example, the pharmaceutical composition may include a solid preparation such as tablets, pills, powders, granules, capsules for oral administration; And suspensions, emulsions, emulsions, syrup agents, etc .; may be formulated as.

The pharmaceutical composition may, if desired, include additional pharmaceutically acceptable carriers as appropriate. Examples include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose , Methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil, but is not limited thereto. In addition, a carrier such as a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent or a preservative may be further included in addition to the carrier.

At this time, each of the carriers may be included in 0.001 to 20% by weight relative to the total weight of the composition, specifically 0.01 to 10% by weight, but may be included in 0.05 to 10% by weight, but is not limited thereto.

In addition, when the pharmaceutical composition is formulated as a solid preparation for oral administration, excipients such as starch, calcium carbonate, sucrose or lactose, gelatin; And lubricants such as magnesium stearate and talc.

In addition, when the pharmaceutical composition is formulated as an oily agent for oral administration, it may include water, liquid paraffin, wetting agent, sweetener, fragrance, preservative, and the like.

The pharmaceutical composition according to an embodiment of the present invention is atopic dermatitis, psoriasis, contact dermatitis, eczema dermatitis, photodermatitis, seborrheic dermatitis, herpes dermatitis, squamous lichen, scleroderma, which are skin diseases due to weakening of the skin barrier function, It can also exert effects on gangrene pyoderma, pemphigus, vesicular epidermis, systemic sclerosis or leprosy. Specifically, the pharmaceutical composition may be a pharmaceutical composition for the treatment or prevention of atopic dermatitis, which exerts an excellent effect on atopic dermatitis.

In addition, the pharmaceutical composition according to an embodiment of the present invention may be a pharmaceutical composition for the treatment or improvement of the skin of mental disorders accompanying the skin disease.

In addition, the pharmaceutical composition according to an embodiment of the present invention may be a pharmaceutical composition for the treatment or improvement of mental illness.

For example, the mental disease may be a developmental disorder, attention deficit hyperactivity disorder, anger control disorder, depression, behavioral disorder, and the like.

For example, the mental disease may be a mental disease accompanied by the skin disease described above.

In addition, the pharmaceutical composition according to an embodiment of the present invention may be a pharmaceutical composition for treating or improving degenerative brain neurological diseases such as Alzheimer's disease, which may be a cannabinoid 1 receptor-associated disease.

As described above, the pharmaceutical composition according to an embodiment of the present invention exerts excellent effects on all skin diseases and mental diseases corresponding to improvement or treatment by implementing the effects according to the present invention described above, as well as accompanying them It is expected to be able to provide synergy to treatment, prevention and improvement of cannabinoid 1 receptor-mediated diseases.

In addition, the pharmaceutical composition according to an embodiment of the present invention is expected to exert excellent effects on all skin diseases corresponding to improvement or treatment by implementing the effects according to the present invention described above.

(Assessment Methods)

1.Skin moisturizing effect

To evaluate the moisturizing power of each sample (Examples and Comparative Examples), a short-term moisturizing test was performed. Specifically, after washing the left and right sides of each subject with soap, the skin was adapted at a temperature of about 20 ° C and a humidity of about 40%. The skin softening effect was evaluated together by a moisturizing power experiment. The test site was defined as a rectangle of 4 x 3 cm2 on the left and right sides of the lower extremity, and the skin surface capacitance was measured three times using a Corneometer (CM825). 24 µl (2 mg / cm 2) of each sample was applied to the test site.

After 2 and 20 minutes after application, the skin surface electrical capacity was measured three times in the same manner as before application. After obtaining the average value of the capacitance measured repeatedly three times, this value is shown in Table 2 below. Before application, the skin surface capacitance measured after 20 minutes after washing.

2. Skin barrier strengthening effect

In order to evaluate the effect of strengthening the skin barrier function of each sample (Example and Comparative Example), transdermal moisture loss was measured. Specifically, the measurement of trans-epidermal water loss (TEWL) was measured using Tewameter TM210 (Courage & Khazaka Electronic GmbH, Germany). The method of applying each sample to the test site follows the evaluation of the moisturizing power.

Table 2 shows the values measured by the above-described method.

In addition, to evaluate the stability of the skin barrier at the application site, D-Squame tape (CuDerm Corporation, Dallas, TX, USA) was used to measure percutaneous moisture loss while repeatedly removing the stratum corneum from each application site.

3. Confirmation of liquid crystal formation

The liquid crystal formation confirmation of each sample (Example and Comparative Example) was measured using a polarization microscope (NIKON ECLIPSE 80i (Nikon, Japan)).

The polarization micrograph of Example 1 confirmed by the above-described method is shown in FIG. 1 below.

Further, after storage for 30 days in a constant temperature bath at 25 ° C (room temperature), 30 ° C, and 50 ° C, changes in the liquid crystal structures of Examples and Comparative Examples were confirmed.

4. Confirmation of occurrence toxicity through zebrafish

For each of nicotinyl serinol and biotinyl serinol, the presence or absence of developmental toxicity through zebrafish was confirmed. At this time, a control material was used as a stock solution (1% DMSO aqueous solution).

Specifically, each sample was prepared at a concentration of 1, 10, 100 μg / ml using a storage solution. Their concentration was exposed to the zebrafish fertilized egg 4 hours after fertilization, and the presence or absence of overall toxicity occurred 24 hours after fertilization (20 hours after each sample exposure) and 48 hours after fertilization (44 hours after each sample exposure). Judged. At this time, evaluation of toxicity was evaluated through indicators divided into 8 stages (Normal development: normal occurrence; Death: death; Coagulated Egg: coagulation; Necrotic Tissue: cell necrosis; Eye development alteration: eye development change; Edema: edema ( Heart edema); Tail formation: General retardation).

As a result, it was confirmed to be normal in both concentration samples of nicotinyl serinol and biotinyl serinol. That is, it was confirmed that the serinol-based compound according to the present invention has no developmental toxicity.

5. Confirmation of efficacy as a cannabinoid 1 receptor agonist

For each of nicotinyl serinol and biotinyl serinol, the effect of inhibiting cAMP production by antagonism was confirmed using CHO cells overexpressing the cannabinoid 1 receptor. At this time, ACEA (arachidonyl-2-chloroethylamide) known as a cannabinoid 1 receptor agonist was used as a control material.

Specifically, CHO cells overexpressing the cannabinoid 1 receptor were purchased from Chantest and cultured in F-12 medium (Gibco) containing 10% fetal bovine serum (FBS, Gibco). Cells were dispensed in a 96 well dish and cultured for 24 hours, and then treated with 0, 0.781, 1.562, 3.125, 6.25, 12.5, 25, 50 μM (0.1% DMSO in PBS) concentration. The cells were treated with 10 μM forskolin (Sigma) to induce cAMP production by adenylyl cyclase in the cells. Intracellular cAMP concentration was measured using an HTRF cAMP assay kit purchased from Cisbio. Cells were lysed with lysis buffer in the kit according to the manufacturer's manual, and then the anti-cAMP cryptate conjugate and cAMP-d2 in the kit were treated at room temperature for 2 hours. Thereafter, 665nm and 620nm fluorescence was measured and corrected at a ratio of 665nm / 620nm. Thereafter, the intracellular cAMP concentration was confirmed using a standard curve.

The results are shown in Figure 2 below.

(Production Example 1)

Step 1.

Nicotine (Nicotin, 1g, 1 eq) was added to the excess thionyl chloride (SOCl ₂ , 84 eq) and stirred at room temperature (25 ° C) for 2 hours. Then, toluene (3x 30ml) was added and distilled under vacuum. The product was dried under high vacuum for 12 hours to give Product A quantitatively. The product A-1 was used directly in the next reaction without further purification.

Step 2.

Serinol (Serinol, 1g, 1 eq) was dissolved in dichloromethane (DCM, 30ml), and triethylamine (Et ₃ N, 3eq) was further added. Subsequently, dichloromethane (DCM, 10 ml) in which the product A-1 (1 eq) obtained in Step 1 was dissolved in the prepared solution was slowly added under 0 ° C., and stirred for 3 hours under the same temperature. After completion of the reaction, the solvent was distilled in vacuo and purified by chromatography to obtain a final product (yield = 82%, purity 95%).

¹ H NMR (500 MHz, D ₂ O) δ 8.96-8.93 (1H), 8.73-8.63 (1H), 8.28-8.24 (1H), 7.63-7.53 (1H), 4.32-4.29 (1H), 3.88-3.84 (2H), 3.81-3.78 (2H), 3.68-3.65 (1H), 3.58-3.56 (1H), 3.02-2.95 (1H)

HRMS (EI, double focusing) m / z: [M] ⁺ Calcd for C ₉ H ₁₂ N ₂ O ₃ 197.1; Found 196.08.

(Example 1)

Step 1.

Biotin (Biotin, 1g, 1 eq) was added to the excess thionyl chloride (SOCl ₂ , 84 eq), and stirred at room temperature (25 ° C) for 2 hours. Then, toluene (3x 30ml) was added and distilled under vacuum. The product was dried under high vacuum for 12 hours to give Product A quantitatively. The product A-2 was used directly in the next reaction without further purification.

Step 2.

Serinol (Serinol, 1g, 1 eq) was dissolved in dimethylformamide (DMF, 30ml), and triethylamine (Et ₃ N, 3eq) was further added. Thereafter, dimethylformamide (DMF, 10 ml) in which the product A-2 (1 eq) obtained in step 1 was dissolved in the prepared solution was slowly added under 0 ° C., and stirred for 3 hours under the same temperature. After completion of the reaction, the solvent was distilled in vacuo and purified by chromatography to obtain a final product (yield = 90%, purity 95%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.44-7.42 (1H), 6.40-6.34 (2H), 4.57-4.55 (2H), 4.32-4.29 (1H), 4.14-4.11 (1H), 3.71-3.68 ( 1H), 3.39-3.37 (2H), 3.32 (2H), 3.12-3.08 (1H), 3.84-3.80 (1H), 2.59-2.56 (1H), 2.09-2.06 (2H), 1.62-1.59 (2H), 1.51-1.44 (2H), 1.34-1.28 (2H)

HRMS (EI, double focusing) m / z: [M] ⁺ Calcd for C ₉ H ₁₂ N ₂ O ₃ 316.1; Found 317.4.

(Examples 2 to 8)

Using the components in Table 1, a composition for external application for skin (cream composition, 100 g) was prepared through the following method.

(1) All the water phase components were mixed.

(2) All of the oil components were mixed, dissolved and warmed to 70 ° C, and then added to the water phase components and emulsified with a homomixer for 3 minutes to prepare a composition for external application for skin.

(Comparative Example 1 to Comparative Example 2)

Using the components shown in Table 1, a composition for external application for skin (cream composition, 100 g) was prepared through the method of Example 2.

As shown in Figure 1 below, the composition for external application for skin according to the present invention was confirmed to be a stable Maltese cross liquid crystal (Example 2). In particular, in the case of the embodiment further comprising ceramide, it was confirmed that the liquid crystal is stably preserved even during long-term storage. On the other hand, in the case of the comparative example, it was not possible to confirm the Maltes cross liquid crystal.

In addition, as shown in Table 2, it was confirmed that the composition for external application for skin according to the present invention imparts an immediate skin moisturizing effect after being applied to the skin. However, in Comparative Example 1 and Comparative Example 2 in which the Maltese cross liquid crystal structure did not appear, although the instant moisturizing effect was shown, it was confirmed that the moisturizing effect was significantly lowered over time.

In addition, it was confirmed that the composition for external application for skin according to the present invention was significantly lower than Comparative Example 1 and Comparative Example 2 used as a control substance in increasing the transdermal moisture loss (see Table 2). At this time, the transdermal moisture loss (TEWL) shown in Table 2 means that the smaller the displayed value, the better the skin barrier strengthening effect.

In addition, the composition for external application for skin according to the present invention acts as a cannabinoid 1 receptor agonist to inhibit the activity of adenylate cyclase and effectively inhibit the production of intracellular cAMP. According to FIG. 2, when each serinol-based compound was treated, it was confirmed that the cAMP concentration decreased depending on the concentration of each serinol-based compound. This means that the composition for external application for skin according to the present invention is effective as a cannabinoid 1 receptor agonist. In addition, it was confirmed that this inhibitory effect corresponds to an effect equal to or greater than that of ACEA, a well-known cannabinoid 1 receptor agonist. Particularly, it was confirmed that the biotinyl serinol according to the present invention exhibits a more remarkable effect in this inhibitory effect.

As confirmed above, the composition for external application for skin according to the present invention is expected to be able to exert an excellent effect in improving and strengthening the natural function of the skin. In addition, the composition for external application for skin according to the present invention provides excellent skin moisturizing and skin barrier strengthening effects and acts as an effective agent for cannabinoid 1 receptors, preventing, improving or treating cannabinoid 1 receptor-mediated skin diseases. It is expected to be useful.

As described above, the present invention has been described by specific matters and limited embodiments, but it is provided only to help a more comprehensive understanding of the present invention, and the present invention is not limited to the above embodiments, and the field to which the present invention pertains Those skilled in the art can make various modifications and variations from these descriptions.

Accordingly, the spirit of the present invention should not be limited to the described embodiments, and should not be determined, and all claims that are equivalent or equivalent to the scope of the claims as well as the claims to be described later belong to the scope of the spirit of the invention. .

Claims (14)

A skin moisturizing or skin barrier strengthening, cosmetic composition comprising a serinol-based compound selected from nicotinyl serinol and biotinyl serinol. A cosmetic composition for improving skin diseases comprising a serinol-based compound selected from nicotinyl serinol and biotinyl serinol as active ingredients. The method according to claim 1 or 2,
The cosmetic composition,
A cosmetic composition further comprising a sterol-based compound, a higher fatty acid, and a higher fatty alcohol. According to claim 3,
The cosmetic composition,
Based on 1 part by weight of the serinol-based compound,
A cosmetic composition comprising 1 to 10 parts by weight of the sterol-based compound, 5 to 30 parts by weight of the higher fatty acid, and 10 to 50 parts by weight of the higher fatty alcohol. The method of claim 4,
The cosmetic composition,
The cosmetic composition which forms a Maltese cross liquid crystal. According to claim 3,
The cosmetic composition,
Ceramide 1, Ceramide 3, Ceramide 3B, Ceramide 4, Ceramide 6, Myristoyl / palmitoyl oxostearamid / aracamide M, hydroxypropyl bispalmitamide M, hydroxypropyl bispalmitamide M And a ceramide selected from dihydroxyisopropylpamoyl palmamide. A pharmaceutical composition for the treatment or improvement of skin diseases comprising a serinol-based compound selected from nicotinyl serinol and biotinyl serinol as an active ingredient. Nicotinyl serinol and biotinyl serinol for the treatment or amelioration of mental disorders comprising a serinol-based compound selected as an active ingredient, pharmaceutical composition. The method of claim 7 or 8,
The pharmaceutical composition,
A pharmaceutical composition further comprising one or more selected from sterol compounds, higher fatty acids, higher fatty alcohols, and ceramides. The method of claim 7,
The skin disease,
Atopic dermatitis, psoriasis, contact dermatitis, eczema dermatitis, photodermatitis, seborrheic dermatitis, herpes dermatitis, lichen planus, scleroderma, necrotizing pyoderma, pemphigus, vesicular epidermolysis, systemic sclerosis or leprosy, pharmaceutical composition. The method of claim 8,
The mental illness,
Attention deficit hyperactivity disorder, anger control disorder, depression or behavioral disorder, pharmaceutical composition. The method of claim 7 or 8,
The pharmaceutical composition,
The pharmaceutical composition, which is formulated as a lotion, ointment, gel, cream, patch and spray. The method of claim 7 or 8,
The pharmaceutical composition,
It is formulated as a formulation for oral administration, pharmaceutical composition. A serinol-based compound represented by Formula 1 below, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof.
[Formula 1]

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