Topical composition

Abstract

To provide a topical composition in which the stability of an azulene derivative is improved.SOLUTION: The topical composition comprises an azulene derivative and a heparinoid.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an external composition.

Background Art

[0002] Azulene derivatives are known to have an anti-inflammatory effect and are used as components of skin external preparations and oral and pharyngeal preparations. However, this azulene derivative has a property of being easily decomposed by heat and light, and various techniques have been developed for stabilization. For example, Patent Document 1 discloses an aqueous solution preparation containing a polyhydric alcohol, a lower alcohol, and a buffering agent.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] However, the aqueous solution preparation described in Patent Document 1 does not ensure stability at temperatures exceeding 40°C. Therefore, there has been a demand for an external composition containing an azulene derivative in which further stabilization of the azulene derivative is achieved even under conditions such as high temperatures. Therefore, an object of the present invention is to provide an external composition in which the stability of an azulene derivative is improved.

Means for Solving the Problems

[0005] An external composition according to one embodiment of the present invention contains an azulene derivative and a heparin-like substance. The concentration of the azulene derivative is preferably 0.0001 to 4.0%. Further, the azulene derivative is preferably sodium guaiazulenesulfonate. The external composition according to one embodiment of the present invention preferably further contains at least one polyhydric alcohol selected from glycerin, ethylene glycol, propylene glycol, butylene glycol, sorbitol, mannitol, or xylitol.

[0006] According to the above configuration, the stability of the azulene derivative in the external composition can be improved.

Effects of the Invention

[0007] According to the present invention, in particular, an external composition containing an azulene derivative excellent in thermal stability can be provided.

Modes for Carrying Out the Invention

[0008] The external composition of the present invention contains an azulene derivative and a heparin-like substance.

[0009] Examples of the above azulene derivative include sodium guaiazulene sulfonate (which may be a hydrate of sodium azulene sulfonate), guaiazulene, or ethyl guaiazulene sulfonate. Among these, sodium guaiazulene sulfonate is particularly preferred.

[0010] The lower limit of the concentration of the above azulene derivative is not particularly limited, but is preferably 0.0001% or more, more preferably 0.001% or more, and even more preferably 0.01% or more. When the concentration of the azulene derivative is less than 0.0001%, the anti-inflammatory action of the azulene derivative may not be exhibited. Also, the upper limit of the concentration of the azulene derivative is not particularly limited, but is desirably 4.0% or less, more preferably 2.0% or less, and even more preferably 1.0% or less. When the concentration of the azulene derivative exceeds 4.0%, the azulene derivative may not dissolve and may precipitate.

[0011] The lower limit of the concentration of the heparin-like substance is not particularly limited, but is preferably 0.01% or more, more preferably 0.05% or more, and even more preferably 0.1% or more. When the concentration of the heparin-like substance is less than 0.01%, the stability of the azulene derivative may not be ensured. Further, the upper limit of the concentration of the heparin-like substance is not particularly limited, but is preferably 3% or less, more preferably 1% or less, and even more preferably 0.5% or less. When the concentration of the heparin-like substance exceeds 3%, the heparin-like substance may not dissolve. Incidentally, the content of the heparin-like substance can be appropriately set so that the external composition has an appropriate moisturizing effect.

[0012] In addition to the azulene derivative and the heparin-like substance, the above external composition may contain other components according to the effects required for the external composition and the dosage form of the preparation.

[0013] The above external composition can contain an appropriate liquid carrier according to the properties of the composition. For example, if the external composition of the present invention is an aqueous solution (e.g., lotion or essence) or a gel, the main carrier can be water, and if it is an emulsion, an oil component (e.g., petrolatum, etc.) can be used as the main carrier together with water, and if it is an ointment or an oily cream, the main carrier can be an oil component.

[0014] The external composition may contain a polyhydric alcohol or a lower alcohol such as ethanol or propanol as the liquid carrier. However, when it is desired to reduce the irritation to the skin when the external composition of the present invention is applied to sensitive skin, it is preferable that the external composition does not contain or substantially does not contain a lower alcohol, particularly ethanol.

[0015] The above external composition particularly preferably contains a polyhydric alcohol. Examples of such polyhydric alcohols include glycerin, ethylene glycol, propylene glycol, butylene glycol, sorbitol, mannitol, or xylitol. By adding the polyhydric alcohol, the stability of the azulene derivative can be further improved. Among the above polyhydric alcohols, glycerin is particularly preferred.

[0016] The external composition of the present invention may further contain other active ingredients, such as anti-aging agents, anti-inflammatory agents, acne care agents, antihistamines, etc. Examples of anti-aging agents include niacinamide (also referred to as nicotinic acid amide), arbutin, tranexamic acid, vitamins (e.g., tocopherol derivatives, vitamin C derivatives, retinol palmitate, etc.), ellagic acid, linoleic acid, etc.; examples of anti-inflammatory agents include allantoin, glycyrrhizic acid or its salts (e.g., dipotassium glycyrrhizate), ε-aminocaproic acid, etc.; examples of acne care agents include isopropylmethylphenol, salicylic acid, etc.; examples of antihistamines include diphenhydramine or its salts, etc.

[0017] The external composition of the present invention may further contain a humectant. Examples of such humectants may include 1) ceramide or ceramide-like components, 2) phospholipid polymers, 3) plant extracts, 4) amino acid-based humectants, 5) squalane, 6) protein hydrolysates, 7) isomerized sugars, etc. The blending amount thereof can be set according to the moisturizing effect required for the external composition.

[0018] 1) Ceramide is a type of sphingolipid, which is a compound in which a fatty acid is amide-bonded to a sphingoid. The ceramide-like component may be a glycosphingolipid such as glucosylceramide or galactosylceramide, or a synthetic ceramide such as Sofcare (registered trademark) Ceramide SL-E (manufactured by Kao Corporation, N-(hexadecyloxyhydroxypropyl)-N-(hydroxyethylhexadecanamide)), CERACUTE (registered trademark)-L (manufactured by NOF Corporation, glyceryl-N-(2-methacryloyloxyethyl)carbamate·stearyl methacrylate copolymer). The content of ceramide and / or ceramide-like component in the external composition of the present invention may be set according to the purpose and is not particularly limited.

[0019] 2) The phospholipid polymer is a methacryloyloxyethyl phosphorylcholine polymer, which is a biocompatible polymer similar to the phospholipid that is a major constituent of the biological membrane. Examples of the phospholipid polymer include Lipidure (registered trademark) (manufactured by NOF Corporation, 2-methacryloyloxyethyl phosphorylcholine·butyl methacrylate copolymer), NIKKOL (registered trademark) Resinol S-10 (manufactured by Nikko Chemicals Co., Ltd., hydrogenated soybean phospholipid), and the like. The content of the phospholipid polymer in the external composition of the present invention may be set according to the purpose and is not particularly limited.

[0020] 3) Plant extracts include amacha extract, hollyhock root extract, arnica flower extract, aloe extract, aloe vera extract, ginkgo extract, wikstroemia extract, euonymus extract, pea extract, saffron extract, horseradish extract, orange extract, kakkon extract, chamomile extract, rye extract, carrot extract, kawarayomogi extract, strawberry extract, kidadialoe extract, cucumber extract, quince seed extract, cumin extract, clematis extract, gentiana extract, gennosyoko extract, burdock extract, wheat germ extract, condurussa crispus extract, shimotsukesou extract, peony root extract, janohige root extract, suikazura flower extract, spirulina maxima extract, common speedwell extract, common plantain root extract, common ivy extract, common nettle extract, common fleabane extract, sage extract, thyme extract, tatijakousou extract, tea leaf extract, lawnweed extract, terminalia extract, capsicum fruit extract, tokin senka extract, dokudami extract, tomato extract, tormentilla extract, garlic extract, rose extract, peony extract, buckwheat extract, parsley extract, witch hazel extract, rose extract, parietaria extract, bitter orange peel extract, hibamata extract, bilberry extract, bukuryou extract, butcher's bloom extract, grape extract, fuyubodaiju flower extract, placenta extract, prune extract, heather flower extract, red peony extract, hop extract, magnolia root bark extract, maria thistle extract, mulberry extract, melissa extract, merilot extract, mouko yomogi extract, peach extract, yagurumagiku extract, yam yomogi extract, eucalyptus extract, lily extract, european aspen extract, mugwort extract, lavender extract, laminaria digitata extract, apple extract, lettuce extract, lemon extract, rosemary extract, roman chamomile extract, etc. The external composition of the present invention can contain any plant extract, and for example, aloe extract, lawnweed extract, dokudami extract, mugwort extract, etc. are preferably exemplified.

[0021] 4) An amino acid-based humectant is a humectant derived from amino acids such as glutamic acid. Examples of amino acid-based humectants include pyrrolidone carboxylic acid or its salts (e.g., sodium salt), pyrrolidine carboxylic acid or its salts, acylpyrrolidine carboxylic acid or its salts, acyl basic amino acid alkyl esters or their salts, etc. The amino acids of the amino acid-based humectants may be racemates or optically active substances. Amino acid-based humectants are available on the market under names such as AJIDEW (registered trademark) (Ajinomoto Co., Inc.), PRODEW (registered trademark) (Ajinomoto Co., Inc.), Aquadew (registered trademark) (Ajinomoto Co., Inc.), CAE (registered trademark) (Ajinomoto Health Supply Co., Ltd.). The content of the amino acid-based humectant in the external composition of the present invention may be set according to the purpose and is not particularly limited.

[0022] 5) Squalane is a saturated hydrocarbon obtained by reducing (hydrogenating) squalene, which is a hydrocarbon obtained from the liver oil of sharks such as dogfish living in the deep sea, and is a colorless liquid. The content of the amino acid-based humectant in the external composition of the present invention may be set according to the purpose and is not particularly limited.

[0023] 7) Protein hydrolyzates are not particularly limited, and include hydrolyzed elastin, hydrolyzed casein, hydrolyzed keratin, hydrolyzed wheat, hydrolyzed collagen, hydrolyzed conchiolin, hydrolyzed silk, hydrolyzed gelatin, hydrolyzed soybean protein, hydrolyzed corn protein, hydrolyzed tosaka, hydrolyzed potato protein, hydrolyzed fibronectin, etc.

[0024] The external composition of the present invention may contain a thickening agent. The thickening agent is not particularly limited as long as it is pharmaceutically acceptable. Examples thereof include water-soluble polymers such as carboxyvinyl polymer, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; celluloses such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose. These thickening agents may be used alone or in combination of two or more.

[0025] The external composition of the present invention may contain a pH adjuster for adjusting the pH of the composition to a desired value. Examples of the pH adjuster include inorganic acids (such as phosphoric acid, pyrophosphoric acid, metaphosphoric acid, polyphosphoric acid, sulfuric acid, nitric acid, hydrochloric acid, etc.) and their salts; organic acids {monocarboxylic acids (such as acetic acid, sorbic acid), polycarboxylic acids (such as oxalic acid, succinic acid, maleic acid, fumaric acid), oxycarboxylic acids [such as hydroxymonocarboxylic acids (such as glycolic acid, lactic acid, gluconic acid), hydroxy polycarboxylic acids (such as tartaric acid, malic acid, citric acid, etc.)]} and their salts; inorganic bases (such as metal hydroxides (such as sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.)); organic bases (amines [such as alkanolamines (such as monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, N-methylethanolamine, N-aminoethylethanolamine, N-methyldiethanolamine, etc.)], amino acids (such as glycine, etc.)). The external composition of the present invention may contain a combination of multiple types of pH adjusters.

[0026] The external composition of the present invention may contain a preservative. Examples of preservatives include paraoxybenzoic acid esters so-called "parabens". Specifically, methyl paraben (methyl paraoxybenzoate), ethyl paraben (ethyl paraoxybenzoate), propyl paraben, isopropyl paraben, butyl paraben, isobutyl paraben, etc., and their salts are exemplified as preservatives. The external composition of the present invention may contain a combination of multiple types of parabens. For example, methyl paraben may be combined with ethyl paraben or propyl paraben. When the external composition of the present invention contains parabens, the content of parabens in the composition may be 1% or less, preferably 0.5% or less, and more preferably 0.25% or less.

[0027] When the dosage form of the external composition of the present invention is an emulsion, it contains an emulsifier. The emulsifier can be any of anionic, cationic, amphoteric, and nonionic surfactants. Examples of emulsifiers include glycerin monostearate, polyoxyl stearate, glycol distearate, lecithin, sorbitan sesquioleate, sorbitan trioleate, stearess-2, glyceryl PEG-7 coconut oil fatty acid, etc., but are not particularly limited.

[0028] The external composition of the present invention may contain a softening agent, a coloring agent, a fragrance, etc.

[0029] The external composition of the present invention is preferably a liquid preparation, but the dosage form is not particularly limited, such as an aqueous preparation, an oily preparation, an emulsion preparation (either oil-in-water emulsion or water-in-oil emulsion), a suspension preparation, an aerosol preparation, a gel preparation, etc. Also, the external composition of the present invention can be solid, pressed, oil, liquid, gel, balm, mud, cream, emulsion, lotion, foam, film, powder, water, pencil, spray, stick, sheet, etc.

[0030] The pH of the external composition of the present invention is preferably adjusted to the range of 5 to 7. This is because it is easy to enhance the skin permeability of the external composition for skin.

[0031] The viscosity of the external composition of the present invention can be appropriately adjusted according to the dosage form of the preparation and the feeling in use required when applying the composition to the skin. For example, when the viscosity of the composition is lower, it is more likely to have a spreading property when applied to the skin; when the viscosity of the composition is higher, it is more likely to have an affinity when applied to the skin. For example, as a guideline, if the external composition of the present invention is an aqueous solution, the viscosity may be in the range of 400 to 1300 mPa·s, and if it is an emulsion, the viscosity may be in the range of 2000 to 12000 mPa·s. The viscosity is measured as the viscosity after 90 seconds at 25°C and 0.33 rpm under rheometer conditions.

[0032] The external composition of the present invention is filled in a container, for example, filled in a light-shielding container. Further, by filling the external composition of the present invention in a pump or spray-type container, the application to the skin can be made convenient.

[0033] The external composition of the present invention is used by applying it to the skin, for example, by applying it to the skin. For example, the external composition can be directly rubbed on the skin, or a gauze impregnated with the external composition can be applied to the skin. The affected area to which the external composition of the present invention is applied is not particularly limited as long as it is the skin. For example, affected areas that particularly require moisturization, such as the face, knees and ankles with powder application, the back, etc. are exemplified, but not particularly limited. The frequency of application to the skin is not particularly limited, but can be about 1 to several times a day.

[0034] It is expected that the external composition of the present invention will exhibit a moisturizing effect, an anti-inflammatory effect, a blood circulation promoting effect, etc. when applied to the skin; thereby, it can prevent rough skin and allergic reactions, prevent sweat rash, sunburn, cracks, acne, etc., improve the skin texture, keep the skin healthy, give moisture to the skin, protect the skin, prevent skin dryness, etc.

[0035] The manufacturing method of the external composition of the present invention is not particularly limited and can be produced according to conventional methods depending on the dosage form. For example, it can be obtained by sequentially adding and mixing predetermined amounts of each compounding component to a liquid carrier. The manufacturing method of the composition of each dosage form is described, for example, in "Collection of Technical Cases for the Preparation of Emulsions (Publisher: Technical Information Association, Authors: Asako Mizuno, Chiharu Terada, Planning and Editing)", and can be referred to.

Examples

[0036] The present invention will be specifically described below with reference to the following examples, but these examples do not limit the scope of the present invention.

[0037] Each component was mixed in the blending amounts shown in Table 1, and finally an external composition was prepared so that the total amount became 100 g with water.

[0038]

Table 1

[0039] Regarding the external compositions prepared in the examples and comparative examples, after storing at 60 °C for 1 week and 2 weeks, the measurement of the sodium guaiacolsulfonate content (stability over time) was carried out as follows. The results are shown in Table 1.

[0040] (Measurement of sodium guaiacolsulfonate content) 5 mL of the prepared external composition was accurately weighed, water was added to make it exactly 10 mL, and it was used as a sample solution. Separately, 0.1 g of dried sodium guaiacolsulfonate was accurately weighed, purified water was added to make it exactly 100 mL, and then 5 mL of that solution was accurately weighed, purified water was added to make it exactly 20 mL, and it was used as a standard solution. For the sample solution and the standard solution, using water as a control, a test was carried out by the ultraviolet-visible absorbance measurement method, and the absorbances A T and A S were measured. Content of sodium guaiacolsulfonate (%) = A T / A S × W S / 2 W S : Amount of sodium guaiacolsulfonate collected for quantification (g) 2: Coefficient due to dilution For the topical compositions of each example and comparative example, the residual rates immediately after preparation and after 1 week and 2 weeks at 60°C were calculated.

[0041] As shown in the results after 2 weeks at 60°C in Table 1, in the sample of Comparative Example 1 containing 0.1% sodium guaiacolsulfonate, the remaining amount of sodium guaiacolsulfonate immediately after preparation was 16.57%, while in the sample of Example 1 it was 63.57% and in the sample of Example 2 it was 63.86%. This result indicates that the stability of sodium guaiacolsulfonate is improved by adding a heparin-like substance to sodium guaiacolsulfonate. Similarly, in the sample of Comparative Example 2 containing 0.1% sodium guaiacolsulfonate and 40% glycerin, the remaining amount of sodium guaiacolsulfonate immediately after preparation was 30.40%, while in the sample of Example 3 it was 79.05%. This result indicates that the stability of sodium guaiacolsulfonate is further improved by adding a heparin-like substance and glycerin to sodium guaiacolsulfonate.

Example

[0042] The topical composition of Example 4 was prepared in the composition shown in the following table in the same manner as the above examples.

[0043] For Example 4, after storage at 60°C for 1 week and 2 weeks, the measurement of the sodium guaiacolsulfonate content (stability over time) was carried out. The results are shown in Table 2.

[0044]

Table 2

[0045] In addition, for the external compositions prepared in the examples and comparative examples, after storage for 1 week and 2 weeks at room temperature under light-shielded conditions, the sodium guaiacolsulfonate content was measured (stability over time). The results are shown in Table 3.

[0046]

Table 3

[0047] As shown in Table 3 above, in the examples, the reduction rates of sodium guaiacolsulfonate were all lower than those in Comparative Example 1, indicating that sodium guaiacolsulfonate was stabilized by the heparin-like substance. In particular, it can be seen that the stabilization of sodium guaiacolsulfonate is remarkable by combining the heparin-like substance with a polyhydric alcohol such as glycerin.

Industrial Applicability

[0048] According to the external composition of the present invention, an external composition with improved stability of the azulene derivative can be provided.

Claims

1. An azulene derivative and, a heparin-like substance, An external composition containing the same.

2. The external composition according to Claim 1, wherein the azulene derivative is at least one selected from sodium guaiazulenesulfonate, guaiazulene or ethyl guaiazulenesulfonate.

3. The external composition according to Claim 1 or 2, wherein the concentration of the azulene derivative is 0.0001 to 4.0%.

4. The external composition according to Claim 1 or 2, further containing a polyhydric alcohol.

5. The external composition according to Claim 4, wherein the polyhydric alcohol contains at least one selected from glycerin, ethylene glycol, propylene glycol, butylene glycol, sorbitol, mannitol or xylitol.

5. The external composition according to Claim 1, further containing glycyrrhizic acid or a salt thereof.

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