JP2014172857A - External composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an external composition containing diclofenac, felbinac, loxoprofen or a salt of these and water, the composition having no precipitate/suspended matter and reduction in the active ingredient content and coloration of the composition with time being suppressed.SOLUTION: An external composition contains (A) one or more selected from among diclofenac, felbinac, loxoprofen and salts of these, (B) one or more selected from among malic acid and salts thereof and (C) water, and has a pH of 6 to 8.

Description

  The present invention relates to a composition for external use containing (A) one or more selected from diclofenac, felbinac, loxoprofen and salts thereof.

  Diclofenac, felbinac, loxoprofen and their salts are blended as active ingredients for external analgesics and anti-inflammatory agents. When these active ingredients are blended into an aqueous composition containing water, precipitates and floating substances are generated in the composition, and the content of the active ingredient in the composition decreases with time, and the composition becomes yellow. There was a problem of discoloration from brown to brown. On the other hand, there is a method of making the discoloration over time inconspicuous by coloring the composition in advance, but the composition for external use is likely to contaminate clothes after application. There has been a demand for a technique for suppressing a decrease in content and discoloration of the composition.

JP 2010-6790 A

  The present invention has been made in view of the above circumstances, and is a composition for external use containing diclofenac, felbinac, loxoprofen and their salts and water, wherein precipitation / floating matter in the composition is suppressed, and over time, It aims at providing the composition for external use in which the content fall of the active ingredient and the discoloration of the composition were suppressed.

  As a result of diligent studies to achieve the above object, the present inventors have adjusted the pH of a composition containing at least one selected from diclofenac, felbinac, loxoprofen and salts thereof and water to 6 to 8, and malic acid. And by adding at least one selected from the salts thereof, precipitation / floating matter in the composition is suppressed, content in the composition of the above components is decreased with time, and yellowish browning is suppressed. It has been found and the present invention has been made.

Accordingly, the present invention provides the following inventions.
[1]. (A) at least one selected from diclofenac, felbinac, loxoprofen and salts thereof, (B) at least one selected from malic acid and salts thereof, and (C) water, and has a pH of 6-8. Composition for external use.
[2]. The composition for external use according to [1], which is a liquid composition.
[3]. (B) The composition for external use as described in [1] or [2] whose component is DL-malic acid or its salt.
[4]. (B) The composition for external use in any one of [1]-[3] whose content of a component is 0.1-5 mass% in a composition as malic acid.
[5]. Furthermore, (D) The composition for external use in any one of [1]-[4] containing 30-80 mass% of ethanol.

  According to the present invention, a composition for external use containing at least one selected from diclofenac, felbinac, loxoprofen sodium and salts thereof and water, the precipitation / floating matter in the composition is suppressed, The composition for external use in which the content fall of the said active ingredient and the discoloration of the composition were suppressed can be provided.

Hereinafter, the present invention will be described in detail.
The composition for external use of the present invention contains (A) one or more selected from diclofenac, felbinac, loxoprofen and salts thereof, (B) one or more selected from malic acid and salts thereof, and (C) water. The composition for external use whose pH is 6-8.

(A) One or more types selected from diclofenac, felbinac, loxoprofen, and salts thereof The component (A) of the present invention is one or more types selected from diclofenac, felbinac, loxoprofen, and salts thereof. Two or more kinds can be used in appropriate combination. Examples of the salt include the pharmaceutically acceptable salts described above, such as diclofenac sodium and loxoprofen sodium. As the component (A), diclofenac sodium, felbinac, and loxoprofen sodium are preferable, and felbinac is more preferable because the effect of the present invention is more exhibited.

  The content of the component (A) in the composition is an effective amount thereof and is appropriately selected depending on the drug, but is preferably 0.5 to 10% by mass, and more preferably 1 to 6% by mass. Usually, when 0.5% by mass or more is blended in the composition, the effect of the drug can be further obtained. On the other hand, even if it exceeds 10% by mass, the effect is not so high, and it may be difficult to maintain the uniformity of the composition.

(B) One or more types selected from malic acid and salts thereof In the present invention, by blending one or more types selected from (B) malic acid and salts thereof, the effect of suppressing the decrease in the content of component (A) over time And the discoloration inhibitory effect of a composition is acquired, and (B) component acts as a time-dependent stabilization component of (A) component and a composition discoloration suppression component. Malic acid includes D-form, L-form and DL-form, and DL-malic acid, which has high versatility and high solubility in water, is preferable. Malic acid may be blended as a salt, and examples of malate include sodium malate and potassium malate.

  The content of the component (B) is preferably 0.1 to 5% by mass in the composition as malic acid, more preferably 0.1 to 3% by mass, and still more preferably 0.2 to 1.5% by mass. By making 0.1-5 mass% in a composition as malic acid, the effect which suppresses the content fall of (A) component and the effect which suppresses discoloration of a composition are exhibited more.

  The content mass ratio represented by (A) / (B) is preferably 0.2 to 50, more preferably 0.5 to 20, and still more preferably 0.8 to 20. By setting it as this range, the effect which suppresses the content fall of (A) component and the effect which suppresses discoloration of a composition are exhibited more.

(C) Water Since the composition of the present invention is an aqueous composition containing water and is an aqueous composition, problems such as a decrease in the content of the active ingredient (A) over time and discoloration of the composition are particularly caused. is there. The content of the component (C) in the composition is usually 5 to 60% by mass, more preferably 10 to 45% by mass, and particularly preferably 15 to 45% by mass.

(D) Alcohol The composition of the present invention preferably contains a lower (carbon number 1 to 4) alcohol in addition to water. Examples of lower (1 to 4 carbon) alcohols include ethyl alcohol, methyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, 2-methyl-1-propanol, 2-butanol, and 2-methyl-2. -Propanol etc. are mentioned. Among these, ethyl alcohol (ethanol) is preferable in terms of odor and irritation.

  The content of the component (D) in the composition is preferably 30 to 80% by mass, more preferably 40 to 80% by mass, and still more preferably 50 to 80% by mass. If the content of component (D) exceeds 80% by mass, irritation may occur.

  Moreover, 0.1-2 are preferable and, as for the content mass ratio represented by (C) / (D), 0.2-0.8 are more preferable. By setting it to the above ratio or more, the effect of suppressing the decrease in the content of component (A) over time and the effect of suppressing discoloration of the composition are more exhibited. By setting the ratio to the ratio or less, there is no precipitation / floating matter in the composition. A more uniform composition can be obtained.

  6-8 are preferable and, as for pH (25 degreeC) of a composition, 6.4-8.0 are more preferable. By setting it as this range, the effect which suppresses the content fall of (A) component and the effect which suppresses discoloration of a composition are exhibited more. When the pH is less than 6, the orientation of the component (A) starts to occur. On the other hand, when it is higher than 8, the effect of suppressing discoloration of the composition is insufficient.

  pH adjusters include organic acids such as citric acid and lactic acid, inorganic acids such as hydrochloric acid, phosphoric acid and boric acid, sodium citrate, sodium hydroxide, triethanolamine, diethanolamine, monoethanolamine, diisopropanolamine, trometamol Etc. From the viewpoint of suppressing the decrease in the content of the component (A) over time, the content is preferably 5% by mass or less, more preferably 3% by mass or less, and the content of inorganic acid such as hydrochloric acid is preferably smaller, and desirably not contained.

  In the composition for external use of the present invention, the drugs and additives used for external preparations such as skin are within the range not impairing the effects of the present invention, for example, the following components are used alone or in appropriate combination of two or more. It can mix | blend in combination. However, if there are too many components other than the components (A) to (D), it may be difficult to uniformly prepare the composition. Therefore, components other than the components (A) to (D) are included in the composition. It is desirable that the content is not more than mass%, more preferably not more than 15 mass%. Although a minimum is not specifically limited, 0 mass% may be sufficient and it is good also as 0-10 mass%.

  Examples of the refreshing agent include essential oils such as l-menthol, dl-menthol, camphor, dl-camphor, peppermint oil, spearmint oil, peppermint oil and the like.

  The surfactant is not particularly limited as long as it is a surfactant used in general external preparations such as cosmetics, pharmaceuticals, and quasi drugs. Examples of the lipophilic nonionic surfactant include glycerin fatty acid ester, alkyl glyceryl ether, polyoxyethylene glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene hydrogenated castor Oil, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil fatty acid ester, polyglycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene Polyoxypropylene copolymer, polyoxyethylene alkylphenyl ether, polyoxyethylene Le bit beeswax, and sucrose fatty acid esters.

  Examples of the hydrophilic nonionic surfactant include self-emulsifying glycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene lanolin, polyoxyethylene lanolin. Alcohol, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene cholestanol ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyglycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, propylene Glycol fatty acid ester, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene Lioxypropylene copolymer, polyoxyethylene alkylphenyl ether, sucrose fatty acid ester (sucrose stearate ester, sucrose palmitate ester, sucrose myristic acid ester, succinic acid oleic acid ester, sucrose lauric acid ester), etc. Is mentioned. In addition to the aforementioned nonionic surfactants, fatty acid soaps such as sodium laurate and sodium palmitate, sulfates such as sodium lauryl sulfate and sodium POE lauryl sulfate, sodium lauroyl sarcosine, sodium cocoyl-N-methyltaurate, Examples include acylated amino acid salts such as sodium lauryl glutamate, anionic surfactants such as phosphate ester salts such as sodium monolauryl phosphate, and cationic surfactants such as quaternary ammonium salts.

  The higher alcohol is not particularly limited, and examples thereof include myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, oleyl alcohol, cetostearyl alcohol, octyldodecanol and the like.

  The higher fatty acid is not particularly limited, and examples thereof include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, and behenic acid.

  The sterols are not particularly limited. For example, animal sterols such as cholesterol, cholestanol, lanosterol, and dehydrocholesterol, plant sterols such as β-sitosterol, stigmasterol, campesterol, and ergosterol, myco Examples include sterols derived from microorganisms such as sterol and timosterol. These may be used as they are or may be subjected to chemical treatment such as hydrogenation for stabilization.

  Oily components include hydrocarbons such as squalane and liquid paraffin, olive oil, macadamia nut oil, vegetable oil such as jojoba oil, animal oil such as beef tallow, cetyl palmitate, myristyl myristate, isopropyl myristate, isopropyl palmitate, sebacin Diethyl adipate, diisopropyl adipate, hydroxystearate phytosteryl, polyglycerol fatty acid ester, (hydroxystearic acid / stearic acid / eicosanedioic acid) polyglyceryl and other esters, dimethyl silicone, phenylmethyl silicone, cyclomethicone, etc. And silicones.

  Examples of the moisturizing component include polyethylene glycol, propylene glycol, 1,3-butylene glycol, dipropylene glycol, glycerin, sorbitol, xylitol, maltitol, chondroitin sulfate, hyaluronic acid, sodium pyrrolidone carboxylate and the like.

  Examples of the fragrances include essential oils such as eucalyptus oil, lavender oil, rosemary oil, lemon oil, orange oil, and grapefruit oil, lavender fragrance, herb fragrance, rosemary fragrance, citrus fragrance, and grapefruit fragrance.

  Examples of the preservative include parabens, sodium benzoate, dibutylhydroxytoluene and the like.

  Examples of the viscosity modifier include water-soluble polymers such as hydroxypropylmethylcellulose, hyaluronic acid, polyvinyl alcohol, carboxyvinyl polymer, carrageenan, xanthan gum, and pullulan.

  Other active ingredients include local stimulants such as nonylic acid vanillylamide, menthyl lactate, cantharis tincture, blood circulation promoters such as benzyl nicotinate, benzyl nicotinate, capsaicin, pepper tincture, carpronium chloride, assembly extract, arnica tincture Herbal medicine components such as eucalyptus oil and salamander extract, glycyrrhetinic acid and salts thereof, glycyrrhizic acid and salts thereof, anti-inflammatory agents such as glycyrrhizin and guaiazulene, NMF components such as amino acids, water-soluble collagen, elastin, salicylic acid and ceramide Anti-roughing agent, pantothenic acid, tocopherol, tocopherol acetate, retinol, vitamin A acid and other anti-aging agents and various vitamins and their derivatives, ascorbic acid, ascorbyl palmitate, ascorbyl stearate , Ascorbyl tetraisopalmitate, ascorbic acid glucoside, arbutin, can be mentioned ellagic acid, rucinol, glycine zinc complex, whitening agents such as tranexamic acid and its derivatives, sodium edetate hydrate such as a chelating agent.

  As the dosage form of the external composition of the present invention, a liquid composition is preferable. It does not specifically limit as a liquid composition, It fills and uses a container suitably, and may have application parts, such as sponge shape and a ball shape.

  The color difference of the composition for external use of the present invention is preferably 5 or less, and more preferably 2 or less, from the viewpoint of suppressing contamination of clothing with a spectral color difference meter (b * value). The lower limit is not particularly limited, and may be 0. The method for measuring the color difference of the composition for external use is measured using a spectral color difference meter. The water is corrected to 0 with purified water, and the yellowness (b * value) of the composition is determined. More specifically, the measurement is performed at a room temperature of 15 to 25 ° C., the optical path length of the cell is 10 mm, and a glass cell is used.

  Although it is preferable not to mix | blend a pigment | dye from the said point, you may mix | blend a legal pigment | dye (dye, pigment, lake), etc. so that it may become b * value 2 or less depending on the case.

  Although it does not restrict | limit especially as a preparation method of the composition for external use of this invention, It can carry out easily with the following well-known method. For example, usual stirring and emulsifying devices such as a three-one motor, paddle mixer, and homomixer can be used. Using these, prepare a uniform solution.

  In addition, the present invention includes (A) one or more selected from diclofenac, felbinac, loxoprofen and salts thereof and (C) a composition for blending into an external composition having a pH of 6-8. Disclosed is a discoloration inhibitor, (B) a composition discoloration inhibitor comprising at least one selected from malic acid and salts thereof. The preferred range is the same as above.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, “%” in the composition represents mass%, and the ratio represents mass ratio.

[Examples 1-18, Comparative Examples 1-5]
Liquid compositions having the compositions shown in Tables 1 to 6 were stirred with a three-one motor to prepare a uniform solution. About the obtained liquid composition, the external appearance was evaluated by the following method, and 50 mL of the obtained liquid composition was filled in a glass screw tube made of plastic having an inner diameter of 35 mm and having a lid, and stored at 60 ° C. for 2 weeks. The following (2) and (3) were evaluated after storage.

(1) Appearance The liquid composition filled in a glass screw tube made of plastic having an inner diameter of 35 mm and having a lid was visually determined using a white background. A result is shown on the following reference | standard.
<Standard>
A: Clear with no turbidity.
○: Although there is some turbidity, no sediment or suspended matter is observed in a uniform 3 minute centrifugation process *.
Δ: Slight turbidity, uniform and sedimentation / floating matter is observed by centrifugation for 3 minutes *.
X: Nonuniformity, orientation, and turbidity are observed.
* 2000rpm, 3 minutes, room temperature

(2) Suppression of content reduction of component (A) The content of component (A) after storage at 60 ° C. for 2 weeks was quantitatively confirmed by internal standard method using high performance liquid chromatography. Compared with the content of component (A) immediately after production, the content reduction rate (%) is obtained by the following formula, and the results are shown by the following criteria.

Content reduction rate (%) = ((A) component content immediately after production− (A) component content after storage at 60 ° C. for 2 weeks) / (A) component content immediately after production * 100
<Standard>
◎: Less than 0.3% ○: 0.3% or more and less than 0.5% Δ: 0.5% or more and less than 1.0% ×: 1.0% or more

(3) Discoloration suppression of the composition The yellowness (b * value) of the liquid composition after storage at 60 ° C. for 2 weeks was measured with a spectral color difference meter (manufactured by Nippon Denshoku Industries Co., Ltd., Spectro color meter SE2000 type). It was measured. The standard was zeroed with purified water. Compared with the b * value immediately after production, it is shown by the following criteria.
<Standard>
A: Increase in b * value is less than 0.5 as compared with b * value immediately after manufacture. B: Increase in b * value is 0.5 or more and less than 1 compared with b * value immediately after manufacture. Increase in b * value is 1 or more and less than 2 compared to b * value immediately after production x: Increase in b * value is 2 or more compared with b * value immediately after production

Claims (5)

  (A) at least one selected from diclofenac, felbinac, loxoprofen and salts thereof, (B) at least one selected from malic acid and salts thereof, and (C) water, and has a pH of 6-8. Composition for external use.   The composition for external use according to claim 1, which is a liquid composition.   The external composition according to claim 1 or 2, wherein the component (B) is DL-malic acid or a salt thereof.   (B) Content of a component is 0.1-5 mass% in a composition as malic acid, The composition for external use of any one of Claims 1-3.   Furthermore, (D) composition for external use of any one of Claims 1-4 containing 30-80 mass% of ethanol.