WO2019151286A1 - Topical dermatological composition - Google Patents

Abstract

Provided is a topical dermatological composition having an inhibitory effect on collagen and fibronectin production. This topical dermatological composition contains pentosan polysulfate and/or a salt thereof as an active ingredient. This topical dermatological composition is useful in the prevention and/or treatment of conditions such as hypertrophic scars, scars/keloids, muscular torticollis, and nodular eruptions, and exhibits a better inhibitory effect on collagen and fibronectin production than mucopolysaccharide polysulfate (MPS).

Description

Skin external composition

The present invention relates to an external composition for skin having a collagen and fibronectin production inhibitory effect, and particularly to an external composition useful for preventing and / or treating hypertrophic scar, scar / keloid, muscular torticollis, and nodular rash.

Collagen is the main structural protein of the body. In normal skin, type I collagen fibers formed by gathering collagen molecules are found in the dermis reticular layer and occupy most of the entire collagen.
Fibronectin is a molecule involved in cell adhesion, and it has also been reported that fibronectin is increased in keloid tissues and keloid-derived fibroblasts compared to normal skin-derived fibroblasts.

A hypertrophic scar is a condition in which a fibrous tissue that can repair a wound surface is produced excessively after trauma, and a scar that is raised above the surrounding skin remains for a long period of time. is there. So far, methods for preventing and / or treating hypertrophic scars include compression and fixation methods using tapes, steroid tape methods, and methods for taking drugs that suppress scar growth. However, there remains a need for a composition that is effective in preventing and / or treating hypertrophic scars.

As a composition useful for the treatment of wounds, in particular for reducing or suppressing hypertrophic scarring or keloid formation, for example in US Pat. No. 6,057,059, gelatin having an average molecular weight of about 75,000 Da to about 250,000 Da and an average A composition comprising a high molecular weight carbohydrate having a molecular weight of about 10,000 Da to about 1,000,000 Da is disclosed, which composition is administered by injection.

Non-patent document 1 below reports the recent and future directions of keloids and hypertrophic scars. Among them, the extracellular matrix in the pathogenesis of scars, the epidermis layer of the skin, and the dermis layer The important role played is being considered. Furthermore, the following non-patent document 2 reports the molecular mechanism of hypertrophic scars, and discusses the role of various fibrous and non-fibrotic molecules (such as growth factors and cytokines).

JP-T-2014-532713

Huang C, et. Al. Keloids and Hypertrophic Scars: Update and Future Directions. Plast Reconstr Surg Glob Open. 2013 Jul; 1 (4): e25 Z. Zhu et. Al. The molecular mechanism of hypertrophic scar. J. Cell Commun. Signal. (2013) 7: 239-252

The present invention is applied to the skin to suppress the production of collagen and fibronectin to prevent and / or treat various diseases (for example, hypertrophic scar, scar / keloid, muscular torticollis, nodular rash). An object of the present invention is to provide a composition for external application to the skin.

As a result of studying substances that suppress the production of collagen and fibronectin in order to solve the above problems, the present inventors have found that pentosan polysulfate and / or a salt thereof is superior to polysulfated mucopolysaccharide (MPS). Furthermore, it has an inhibitory effect on the production of collagen and fibronectin from human skin fibroblasts, and an external composition containing pentosan polysulfate and / or a salt thereof as an active ingredient is used for hypertrophic scars, scars / keloids, nodular prurigo The present invention was completed by finding useful for the prevention and / or treatment of muscular torticollis and the like in infancy.

That is, the present invention is an external composition for skin having an inhibitory action on collagen and fibronectin production, and is characterized by containing pentosan polysulfate and / or a salt thereof as an active ingredient.

More preferably, the external composition for skin contains sodium pentosan polysulfate (hereinafter referred to as “PPS”) as an active ingredient.

Further, the present invention is characterized in that the disease ameliorated by the inhibitory action on collagen and fibronectin production is selected from the group consisting of hypertrophic scar, scar / keloid, muscular torticollis, and nodular rash. It is what.

The external composition for skin of the present invention exhibits an excellent inhibitory effect on collagen and fibronectin production, and is useful for reducing or suppressing scarring including hypertrophic scars and scars after surgery.
In addition, since pentosan polysulfuric acid and / or a salt thereof, which is an active ingredient, is a plant-derived compound and has high safety, it is possible to provide a composition for external use with few side effects.

It is the graph which compared the inhibitory effect with respect to the type I collagen production about the culture medium containing PPS and the culture medium containing MPS. It is the graph which compared the inhibitory effect with respect to the fibronectin production about the culture medium containing PPS and the culture medium containing MPS.

The pentosan polysulfate and / or salt thereof contained as an active ingredient in the composition of the present invention is a semi-synthetic polysulfated polysaccharide containing a mixture of polyanionic polysaccharides. Pentosan polysulfate is produced by chemical sulfation of polysaccharides (eg, xylan) obtained from woody, eg, beech. In general, it is considered to be a polysulfated product in which O-methylglucuronic acid is bonded as a side chain to a xylan chain. At this time, the pentosan polysulfate may be present in the form of a salt. Preferred salts include alkali metal salts such as sodium pentosan polysulfate and potassium potassium pentosan polysulfate, and alkaline earth metals such as pentosan polycalcium sulfate. Examples thereof include salts and pentosan polymagnesium sulfate. A particularly preferred salt is sodium pentosan polysulfate.
The PPS is not particularly limited, but those having a weight average molecular weight of 1000 to 30000 are preferable, and those having 4000 to 6500 are more preferable.

The composition of the present invention is not particularly limited as long as it is a preparation form applicable to the skin. For example, the ointment, plaster, patch, cream, liniment or lotion described in the Japanese Pharmacopoeia And the like, and can be used as a pharmaceutical composition together with pharmaceutically acceptable additives.

Since the composition of the present invention has an inhibitory action on the production of collagen and fibronectin, it is useful for the prevention and / or treatment of fibrotic diseases, such as scars (such as hypertrophic scars), keloids, nodular rashes, and It is useful for preventing and / or treating muscular torticollis in infancy. The present invention therefore also relates to methods for preventing and / or treating these diseases.

The content of pentosan polysulfuric acid and / or a salt thereof as an active ingredient in the composition of the present invention is preferably 0.0001 to 30% by weight, more preferably 0.001 to 10% by weight, and 0.01 to 1% by weight is particularly preferred.
In addition, the amount and frequency of application of the composition according to the present invention to the skin are appropriately determined according to the target disease and the degree of its symptoms, the concentration of pentosan polysulfate and / or its salt in the composition, age, weight, etc. For example, as pentosan polysulfate and / or a salt thereof, 0.015 μg to 5 mg, preferably 0.15 μg to 2 mg per 10 cm ² may be applied once or several times a day.

When the external composition for skin of the present invention is in the form of an ointment, examples of the additive blended in the ointment include a base, a humectant, a thickener, and an emulsifier. As the base, higher hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, esters and the like can be used. Examples of higher hydrocarbons include squalane, synthetic paraffin, liquid paraffin, white petrolatum, microcrystalline wax, etc., waxes include beeswax, white beeswax, lanolin, ceresin wax and the like, and fatty acids include stearin. Examples include acids and oleic acid, higher alcohols include lanolin alcohol and cetostearyl alcohol, and esters include isopropyl myristate and stearyl myristate.

Examples of the humectant include glycerin and 1,3-butylene glycol. Examples of the thickener include carboxyvinyl polymer and carboxymethyl cellulose. Examples of the emulsifier include a cationic surfactant and an anionic interface. An activator, an amphoteric surfactant, a nonionic surfactant, etc. are mentioned.

Additives blended in plasters or patches include thickeners, moisturizers, fillers, crosslinking agents, solubilizers, emulsifiers and the like. Specifically, examples of the thickener include sodium alginate, gelatin, methylcellulose, carboxyvinyl polymer, sodium polyacrylate and the like, examples of the humectant include glycerin and the like, examples of the filler include kaolin, titanium dioxide, Examples of the cross-linking agent include acetaldehyde, dimethyl ketone, and aluminum sulfate. Examples of the solubilizer include alcohols such as ethanol and isopropanol. Examples of the emulsifier include an anionic surfactant. Examples thereof include agents and nonionic surfactants.

Moreover, as an additive mix | blended with a cream, an oil-soluble substance, a water-soluble substance, an emulsifier, etc. are mentioned. As the oil-soluble substance, higher hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, esters and the like can be used. Examples of higher hydrocarbons include squalane, synthetic paraffin, liquid paraffin, white petrolatum, microcrystalline wax, etc., waxes include beeswax, white beeswax, lanolin, ceresin wax and the like, and fatty acids include stearin. Acid, oleic acid, etc., higher alcohols include lanolin alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, cholesterol, etc., and esters include isopropyl myristate, stearyl myristate, etc. Can be mentioned.

As water-soluble substances, water (purified water), thickeners, humectants, and the like can be used. Examples of the thickener include carboxyvinyl polymer and carboxymethyl cellulose, and examples of the humectant include glycerin, propylene glycol, and 1,3-butylene glycol.

Examples of the emulsifier include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant.

Furthermore, examples of the additive added to the external liquid or spray include oil-soluble substances, water-soluble substances, and emulsifiers. As the oil-soluble substance, hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, esters and the like can be used. Examples of hydrocarbons include squalane, α-olefin oligomers, synthetic paraffin, liquid paraffin, white petrolatum, microcrystalline wax, and waxes include beeswax, white beeswax, lanolin, ceresin wax, and the like. Examples of fatty acids include stearic acid and oleic acid, examples of higher alcohols include lanolin alcohol, cetyl alcohol, and cetostearyl alcohol. Examples of esters include isopropyl myristate, stearyl myristate, and octyldodecyl myristate. Etc.

As water-soluble substances, water (purified water), thickeners, humectants, and the like can be used. Examples of the thickener include carboxyvinyl polymer and carboxymethylcellulose, and examples of the humectant include glycerin and 1,3-butylene glycol.

Examples of the emulsifier include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant.

Examples of the additive blended in the gel include bases, and isopropanol, propylene glycol and the like are used as the base.

Specific examples of the cationic surfactant that can be used in each of the above preparations in the present invention include cetyltrimethylammonium chloride, lauryldimethylbenzylammonium chloride, tetrabutylammonium chloride, dioctadecyldimethylammonium chloride, and the like.
Examples of the anionic surfactant include sodium alkylbenzene sulfonate, sodium dodecyl sulfate, coconut alcohol sodium ethoxy sulfate, sodium α-olefin sulfonate, emulsified cetostearyl alcohol and the like.
Nonionic surfactants include polyoxyethylene alkyl ethers such as polyoxyethylene oleyl ether and polyoxyethylene octyldodecyl ether, polyoxyethylene alkylphenol ether, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, and glyceryl monostearate. Glycerin fatty acid esters such as glyceryl monostearate, glyceryl monostearate, glyceryl palmitate, glyceryl myristate, glyceryl oleate, glyceryl triisooctanoate, diglycerin laurate, diglyceryl stearate, diglycerin oleate Diglycerin fatty acid esters such as sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, Oil fatty acid sorbitan, sorbitan tristearate, sorbitan fatty acid esters such as sorbitan trioleate, polyethylene glycol monolaurate, polyethylene glycol monostearate, polyethylene glycol fatty acid esters such as polyethylene glycol monooleate and the like.
Examples of the amphoteric surfactant include N-alkyl-N, N-dimethylammonium betaine and imidazoline type amphoteric surfactant.
Any of the above surfactants can be used alone or in combination.

In the above-mentioned ointments, plasters, patches, creams, liquids for external use, sprays, gels, etc., pH adjusters, preservatives, macrogols, etc. are used as necessary.

Examples of the pH regulator include diisopropanolamine, triisopropanolamine, triethanolamine, potassium hydroxide, sodium hydroxide, sodium citrate, phosphoric acid, tartaric acid, dl-malic acid, glacial acetic acid and the like. Examples of the agent include thymol, dibutylhydroxytoluene, sodium edetate hydrate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and the like.
EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples of the present invention, but the present invention is not limited to the following examples.

In the following experiments, as PPS, sodium pentosan polysulfate (weight average molecular weight: 4000-6500, sulfur content: 13.0-20.0% w / w, glucuronic acid content: 2.5-4.0%, manufactured by Molcone Labs) w / w) was used.
Further, as MPS, a heparin-like substance (organic sulfate group: 25.8 to 37.3% w / w, glucuronic acid content 19.0 to 24.0% w / w) was used.
[Inhibitory effect of PPS on type I collagen and fibronectin production from human skin fibroblasts]
Normal human skin dermal fibroblasts (Lifeline Cell Technology) (1 × 10 ⁴ cells) were seeded in a medium (Growth Medium (FibroLife® BM + FibroLife® S2 LifeFactors) at 37 ° C., 5% CO ₂ . After culturing at 95% air for 24 hours, the medium was changed to a medium containing PPS or MPS (Growth Medium with FBS), and cultured at 37 ° C., 5% CO ₂ , 95% air for 48 hours. The concentration of type I collagen and fibronectin was measured using an ELISA kit (Human Collagen Type I ELISA kit (ACEL), Fibronectin Human ELISA kit (abcam)).
The results for type I collagen are shown in FIG. 1, and the results for fibronectin are shown in FIG. In the figure, ** P <0.01 indicates a significant difference with respect to the result in the absence of PPS or MPS.

The experimental results shown in FIGS. 1 and 2 confirm that PPS has an inhibitory action on both type I collagen and fibronectin production, whereas MPS shows an inhibitory action only on type I collagen production. It was done.

Claims (3)

An external composition for skin having an inhibitory action on collagen and fibronectin production, comprising pentosan polysulfate and / or a salt thereof as an active ingredient. The composition according to claim 1, wherein the active ingredient is sodium pentosan polysulfate. The composition according to claim 1 or 2, which is used for preventing and / or treating a disease selected from the group consisting of hypertrophic scar, scar / keloid, muscular torticollis, and nodular rash.

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