JP2017178843A - Emulsion composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide weak acid to acidic emulsion compositions stably containing diclofenac or a salt thereof, and methods of inhibiting the decomposition of diclofenac or a salt thereof in weak acid to acidic emulsion compositions containing a nonionic surfactant.SOLUTION: In emulsion formulations containing (a) diclofenac or a salt thereof, (c) an oily component, (B) a surfactant, and (d) water, a nonionic surfactant and a cationic surfactant are used in combination as the (B) surfactant.SELECTED DRAWING: None

Description

  The present invention relates to an emulsified composition. More specifically, the present invention relates to a weakly acidic to acidic emulsion composition that stably contains diclofenac or a salt thereof.

  Conventionally, so-called non-steroidal anti-inflammatory drugs (NSAIDs) containing methyl salicylate, salicylic acid glycol, indomethacin, felbinac or a salt thereof, or diclofenac or a salt thereof as an active ingredient in order to relieve pain in the shoulders and joints. It is used. In particular, among these non-steroidal anti-inflammatory agents, diclofenac or a salt thereof has attracted attention because of its high anti-inflammatory effect.

  These non-steroidal anti-inflammatory drugs are usually transdermal preparations (external use) such as liquids (lotions), gels, emulsions such as emulsions and creams, or patches applied to or applied to the skin. Agent). Above all, emulsion formulations such as emulsions and creams can be formulated with both water-soluble active ingredients and oil-soluble active ingredients. In addition, it is an excellent formulation from the viewpoint of utility (see, for example, Patent Documents 1 and 2). In addition, the emulsified preparation has an advantage that it is easy to apply to the skin, slips on the skin and is easy to apply. In addition, nonionic surfactant is used suitably for preparation of an emulsion formulation, since it is excellent in emulsion stability.

JP 2012-77027 A Japanese Patent Laying-Open No. 2015-187085

  As mentioned above, in recent years, diclofenac or a salt thereof has attracted attention among non-steroidal anti-inflammatory agents, and the present inventors have used a nonionic surfactant as an active ingredient of diclofenac or a salt thereof. In the weakly acidic to acidic range of pH 6.5 or less, it has been found that the above-mentioned active ingredient is greatly reduced by long-term storage (for example, 1 month at 50 ° C.). . In addition, since the weight loss of diclofenac or a salt thereof does not occur when it is prepared in the form of a liquid or gel, it occurs when an emulsion preparation having a pH of 6.5 or less is prepared using a nonionic surfactant. This is a problem inherent to emulsion formulations.

  On the other hand, when the pH of the emulsion preparation is adjusted to 7 or more, the amount of other active ingredients to be added (for example, nicotinic acid benzyl ester which is a blood circulation promoter) is reduced. There is also a problem that.

  An object of the present invention is to solve the problem of an emulsified preparation containing diclofenac or a salt thereof as an active ingredient. Specifically, the present invention provides a method for improving the stability of diclofenac or a salt thereof and suppressing the weight loss of an emulsion formulation having a pH of 6.5 or less containing diclofenac or a salt thereof as an active ingredient. Objective. Another object of the present invention is to provide an emulsified preparation having a pH of 6.5 or less, in which the weight loss of diclofenac or a salt thereof is suppressed.

  As a result of intensive investigations to solve the above problems, the present inventors have shown that (a) diclofenac or a salt thereof, (c) an oil component, (B) a surfactant, And (d) In the emulsified preparation containing water, (B) the above-mentioned (a) that occurs when the pH is adjusted to 6.5 or less by using a nonionic surfactant and a cationic surfactant together as the surfactant It has been found that the weight loss of the component) can be significantly suppressed, and an emulsion preparation having a pH of 6.5 or less containing the component (a) stably can be prepared.

  The present invention has been completed based on this finding, and includes the following embodiments.

(I) Emulsified composition (I-1) Emulsified composition having a pH of 6.5 or less, comprising the following components:
(A) diclofenac or a salt thereof,
(B) nonionic surfactants and cationic surfactants,
(C) an oily component, and (d) water.
(I-2) The emulsion composition as described in (I-1) whose ratio of the cationic surfactant with respect to 100 weight part of nonionic surfactant in (b) component is 0.1-500 weight part.
(I-3) The emulsion composition described in (I-1) or (I-2), wherein the ratio of the nonionic surfactant in 100% by weight of the emulsion composition is 1 to 10% by weight.
(I-4) The emulsion composition described in any one of (I-1) to (I-3), wherein the ratio of the nonionic surfactant to 10 parts by weight with respect to 100 parts by weight of the oil phase component in the emulsion composition is 10 to 100 parts by weight. object.
(I-5) The emulsion composition according to any one of (I-1) to (I-4), wherein the proportion of component (a) in 100% by weight of the emulsion composition is 0.1 to 5% by weight. .
(I-6) The emulsion composition according to any one of (I-1) to (I-5), further comprising at least one selected from the group consisting of an antihistamine, a blood circulation promoter, and a cooling agent.
(I-7) The emulsion composition according to any one of (I-1) to (I-6), which is an oil-in-water (O / W) type or water-in-oil (W / O) type emulsion composition.
(I-8) The emulsion composition according to any one of (I-1) to (I-7), which is a pharmaceutical composition for external use.
(I-9) The emulsified composition according to any one of (I-1) to (I-8), which is an anti-inflammatory analgesic.

(II) Method for inhibiting decomposition of diclofenac or a salt thereof (II-1) (a) Diclofenac or a salt thereof,
(B) Surfactant (c) Oil-based component, and (d) A method for inhibiting decomposition of component (a) in an emulsion composition having a pH of 6.5 or less, comprising water and a nonionic surfactant as component (B) And a cationic surfactant in combination.
(II-2) The method according to (II-1), wherein the ratio of the cationic surfactant to 100 parts by weight of the nonionic surfactant in the component (B) is 0.1 to 500 parts by weight.
(II-3) The method according to (II-1) or (II-2), wherein the ratio of the nonionic surfactant in 100% by weight of the emulsion composition is 1 to 10% by weight.
(II-4) The method according to any one of (II-1) to (II-3), wherein the ratio of the nonionic surfactant to 100 parts by weight of the oil phase component in the emulsion composition is 10 to 100 parts by weight.
(II-5) The method according to any one of (II-1) to (II-4), wherein the proportion of the component (a) in 100% by weight of the emulsion composition is 0.1 to 5% by weight.
(II-6) Any of (II-1) to (II-5), wherein the emulsified composition further contains at least one selected from the group consisting of an antihistamine, a blood circulation promoter, and a cooling agent. The method described in
(II-7) The emulsified composition is an oil-in-water (O / W) type or water-in-oil (W / O) type emulsified composition described in any one of (II-1) to (II-6). Method.

  Emulsified preparations containing diclofenac or a salt thereof as an active ingredient and having a pH of 6.5 or less usually cause a decrease in the amount of diclofenac or a salt thereof due to long-term storage. However, according to the emulsion composition and method of the present invention, diclofenac or a salt thereof is effective. About the emulsion composition used as a component, although the pH is 6.5 or less, the weight loss of the active ingredient is significantly suppressed, and the effectiveness can be stably maintained over a long period of time. In addition, according to the emulsion composition and method of the present invention, the pH can be adjusted to 6.5 or lower, so that the emulsion composition containing diclofenac or a salt thereof as an active ingredient has a high alkalinity to alkalinity. A component unstable in the pH range (for example, nicotinic acid benzyl ester which is a blood circulation promoter) can be added.

In Experimental Example 1, an emulsified composition containing only a nonionic surfactant as a surfactant (pH <6.5) (Comparative Example 1), and 1% by weight and 0% of a cationic surfactant in addition to the nonionic surfactant 1. It is the figure which showed the content (%) of the diclofenac Na before and after storage for 50 degreeC 1 month about the emulsion composition (Examples 1 and 2) contained in the ratio of 1 weight%. Regarding the emulsified compositions of Comparative Example 1 and Examples 1 and 2, image results obtained by observing with a polarizing microscope the changes in the shape and size of the emulsified particles before and after storage at 50 ° C. for one month (initial stage, after standing). Show.

(I) Emulsified Composition The emulsified composition of the present invention has an emulsified form containing (a) diclofenac or a salt thereof, (B) a surfactant, (c) an oily component, and (d) water, and has a pH of 6. It is a formulation of 5 or less, and (b) a nonionic surfactant and a cationic surfactant are used in combination as the (B) surfactant.
Hereinafter, each of these components will be described.

(A) Diclofenac or its salt diclofenac is a kind of non-steroidal anti-inflammatory drugs (NSAIDs) as described above, and is mainly used for antipyretic and analgesia. Examples of the salt include alkali metal salts such as sodium and potassium; alkaline earth salts such as magnesium and calcium; and salts such as ammonia. An alkali metal salt of diclofenac is preferable, and a sodium salt is more preferable.

  The proportion of the component (a) contained in the emulsified composition of the present invention may be an amount that exhibits an anti-inflammatory analgesic effect based on the action of the component (a), but is usually 0.1 to 5% by weight. It can be suitably selected from the range. Preferably 0.3 to 4 weight%, More preferably, 0.5 to 3 weight% can be illustrated.

(B) Surfactant (nonionic surfactant, cationic surfactant)
The surfactant used in the present invention is a nonionic surfactant and a cationic surfactant.

(B-1) Nonionic surfactant The nonionic surfactant is not particularly limited as long as it is usually used for pharmaceuticals, quasi drugs or cosmetics, and is an ester type, an ether type, and an ester / ether type. Nonionic surfactants can be mentioned.

  Here, as the ester type nonionic surfactant, a higher alcohol fatty acid ester in which a polyhydric alcohol such as glycerin, polyglycerin, sorbitan, sucrose, polyethylene glycol, propylene glycol and a fatty acid are ester-bonded (glycerin fatty acid ester, polyglycerin fatty acid) is used. Ester, sorbitan fatty acid ester, sucrose fatty acid ester, polyethylene glycol fatty acid ester, propylene glycol fatty acid ester).

  Although it does not restrict | limit as a fatty acid which comprises these ester type nonionic surfactant, Preferably it is C8-C24 saturated or unsaturated fatty acid. As saturated fatty acids having 8 to 24 carbon atoms, caprylic acid (8: 0), pelargonic acid (9: 0), capric acid (10: 0), lauric acid (12: 0), myristic acid (14: 0) , Pentadecylic acid (15: 0), palmitic acid (16: 0), margaric acid (17: 0), stearic acid (18: 0), arachidic acid (20: 0), behenic acid (22: 0), and And lignoceric acid (24: 0). C8-24 unsaturated fatty acids include palmitoleic acid (16: 1), oleic acid (18: 1 (9)), vaccenic acid (18: 1 (11)), and nervonic acid (24: 1) Unsaturated fatty acids with one double bond such as linoleic acid (18: 2 (9,12)), two double bonds such as 8,11-eicosadienoic acid (20: 2 (8,11)) (9,12,15) -linolenic acid (18: 3), (6,9,12) -linolenic acid (18: 3), and eleostearic acid (18: 3 (9,11 , 13)), and 5,8,11-eicosatrienoic acid (20: 3 (5,8,11)), and other unsaturated fatty acids having three double bonds. Preferably it is a C12-18 saturated fatty acid, More preferably, it is a C14-18 saturated fatty acid.

  Among the ester type nonionic surfactants, sorbitan fatty acid esters and polyethylene glycol fatty acid esters are preferable.

  Although the fatty acid which comprises sorbitan fatty acid ester is as above-mentioned, Preferably 12-18 saturated or unsaturated fatty acid can be mentioned. More preferred is a saturated fatty acid, and specific examples include palmitic acid and stearic acid. More preferably, HLB is 17 or more. Particularly suitable ester type nonionic surfactants include sorbitan monostearate having an HLB of 17 or more.

  Although the fatty acid which comprises a polyethyleneglycol fatty acid ester is as above-mentioned, Preferably 16-18 saturated or unsaturated fatty acid can be mentioned. More preferred is a saturated fatty acid, and specific examples include palmitic acid and stearic acid. More preferably, HLB is 3-5. Particularly suitable ester-type nonionic surfactants include polyethylene glycol monostearate having an HLB of 4 to 5.

  Further, the number of moles of ethylene oxide (PEG) added to the polyethylene glycol fatty acid ester is not particularly limited as long as it is described above, but can be usually selected from the range of 5 to 250 moles. Preferably it is 10-200 mol, More preferably, it is 10-150 mol.

  As ether type nonionic surfactant, for example, polyoxyethylene (POE) alkyl ether (AE) obtained by addition polymerization of ethylene oxide (EO) to higher alcohol having 10 to 18 carbon atoms; EO is added to alkylphenol. Polyoxyethylene (POE) alkylphenyl ether obtained by polymerization; and polyoxyethylene (POE) such as polyoxyethylene (POE) polyoxypropylene glycol obtained by addition polymerization of ethylene oxide (EO) to polypropylene glycol Mention may be made of additional types of surfactants.

  Here, as polyoxyethylene (POE) addition mole number, it can select from the range of 5-100 normally. Preferably it is 10-90, More preferably, it is 15-80.

  Specific examples of the ether type nonionic surfactant include POE (10-50 mol) phytosterol ether, POE (10-50 mol) dihydrocholesterol ether, POE (10-50 mol) 2-octyldodecyl ether, POE (10 ˜50 mol) Decyl tetradecyl ether, POE (10-50 mol) oleyl ether, POE (10-50 mol) cetyl ether, POE (10-50 mol) lauryl ether, POE (10-50 mol) stearyl ether, POE (10-50 mol) behenyl ether, POE (10-50 mol) alkyl (12-14) ether, POE (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl ether, POE (10 ~ 50 mol) polyoxypropylene (2- 0 mol) polyoxyethylene alkyl ethers such as cetyl ether; phosphoric acids and phosphates thereof (such as POE cetyl ether sodium phosphate); POE (20-100) castor oil; POE (20-60 mol) sorbitan mono Olate, POE (10-60 mol) sorbitan monoisostearate, POE (10-80 mol) glyceryl monoisostearate, POE (10-30 mol) glyceryl monostearate, POE (20-100) POE polyoxy Examples thereof include propylene-modified silicone and POE / alkyl-modified silicone. POE alkyl ethers such as POE behenyl ether and POE hydrogenated castor oil are preferred. More preferred are POE behenyl ether and POE hydrogenated castor oil having an HLB of 10 to 13.

Examples of ester / ether type nonionic surfactants include compounds obtained by adding EO to fatty acid esters of polyhydric alcohols. Here, the fatty acid constituting the ester / ether type nonionic surfactant is as described above. Although not limited, Saturated or unsaturated fatty acids having 8 to 24 carbon atoms are preferable. Specific examples of the ester / ether type nonionic surfactant include polyoxyethylene sorbitan fatty acid ester.

These nonionic surfactants can be used singly or in combination of two or more.
HLB is an abbreviation for hydrophile-lipophile balance of nonionic surfactants and is one of the indices representing the hydrophilicity / hydrophobicity of nonionic surfactants. A larger HLB value indicates higher hydrophilicity. In the present invention, HLB refers to a value calculated by the Davies formula, HLB = 7 + Σ (the number of hydrophilic groups) −Σ (the number of lipophilic groups). Moreover, the HLB value in the case of containing two or more kinds of nonionic surfactants is indicated by a weighted average value. In the present invention, the nonionic surfactant is preferably used alone or in combination of two or more thereof, with the blending ratio adjusted so that the HLB value is 8 to 15, preferably 10 to 14.

  In the emulsified composition of the present invention, the blending amount of the nonionic surfactant can be appropriately selected from the range of 1 to 10% by weight per 100% by weight of the emulsified composition from the viewpoint of thermal stability. Preferably it is 2-9 weight%, More preferably, it is 3-8 weight%. Moreover, it is preferable to mix | blend a nonionic surfactant in the ratio of 10-100 weight part with respect to 100 weight part of oily components contained in an emulsion composition, More preferably, it is 20-90 weight part, Most preferably, it is 30-80. Parts by weight.

(B-2) Cationic surfactant The cationic surfactant is not particularly limited as long as it is usually used in pharmaceuticals, quasi drugs, cosmetics, and the like, and is an amine salt type and a quaternary ammonium salt type. Can be mentioned. Preferably, it is a quaternary ammonium salt type cationic surfactant which is not easily affected by pH, metal ions and the like.

  Specifically, examples of amine salt type cationic surfactants include coconut amine acetate and stearylamine acetate. Quaternary ammonium salt type cationic surfactants include stearyl trimethyl ammonium chloride, cetyl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, distearyl dimethyl ammonium chloride, alkyl benzyl dimethyl ammonium chloride, alkyl benzyl dimethyl ammonium chloride, and benzil chloride. Mention may be made of ruthenium, benzethonium chloride, cetylpyridinium chloride, hexadecyltrimethylammonium bromide, and decalinium chloride. Preferred are benzalkonium chloride having a bactericidal action, benzethonium chloride, cetylpyridinium chloride, hexadecyltrimethylammonium bromide, and decalinium chloride, and benzalkonium chloride is particularly preferable.

  In the emulsified composition of the present invention, the amount of the cationic surfactant is appropriately selected from the range of 0.01 to 5% by weight per 100% by weight of the emulsified composition from the stabilizing action (decomposition inhibiting action) of the component (a). You can choose. Preferably it is 0.02 to 4 weight%, More preferably, it is 0.05 to 3 weight%. The cationic surfactant is preferably blended at a ratio of 0.1 to 500 parts by weight, more preferably 1 to 400 parts by weight, particularly preferably 100 parts by weight of the nonionic surfactant contained in the emulsion composition. Is 5 to 300 parts by weight.

(C) Oily component In this invention, an oily component (oil phase) is a component which comprises the oil droplet (oil phase) of the emulsion composition of this invention. For example, olive oil, wheat germ oil, rice bran oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, peanut oil are commonly used in pharmaceuticals, quasi drugs, cosmetics, etc. Vegetable oil such as lard, fish oil, squalane, beeswax, etc .; liquid paraffin, light liquid paraffin, hydrogenated polyisobutene, α-olefin oligomer, CD squalane, vegetable squalane, squalane, paraffin, pristane, polyethylene powder, polyethylene wax, Microcrystalline wax, liquid paraffin, light liquid paraffin, mineral oil, sesilene, petrolatum, etc .; lecithin derivatives such as soybean lecithin; isopropyl myristate, isopropyl palmitate, cetyl palmitate, diethyl sebacate, o Fatty acid esters such as ethyl inoate; Silicones such as dimethyl silicone and cyclic silicone; Fatty acids such as oleic acid and linoleic acid; Hormones such as ethinyl estradiol; Fennel oil, clove oil, mint oil, eucalyptus oil, lemon oil And essential oils. Silicon oil, waxes and the like are also included.

  Moreover, higher alcohol is mentioned as another oil-based component. Examples of the higher alcohol include aliphatic alcohols having 6 or more carbon atoms. Specific examples include behenyl alcohol, myristyl alcohol, cetyl alcohol, oleyl alcohol, stearyl alcohol, hexadecyl alcohol, lanolin alcohol and the like.

  The oil component is preferably liquid at room temperature (25 ° C.) from the viewpoint of ensuring the fluidity of the emulsion composition. Among the oil components, vegetable oils, animal oils, mineral oils, and fatty acid esters are preferable, and animal oils, mineral oils, and fatty acid esters are more preferable because an emulsion composition having excellent heat stability and fluidity can be prepared. preferable. In particular, liquid paraffin (light liquid paraffin) is preferably used alone or in combination as mineral oil. Furthermore, it is preferable to mix | blend the said higher alcohol with these components. As the oil component, one type of component may be used alone, or two or more types may be used in combination.

  The proportion of the component (c) contained in the emulsified composition of the present invention is not particularly limited as long as it is an amount that does not impair the effects of the present invention. Usually, it can select suitably from the range of 5 to 50 weight%. Preferably 7.5-40 weight%, More preferably, 10-30 weight% can be illustrated. Moreover, it is preferable to mix | blend (c) component in the ratio of 10-50 weight part with respect to 100 weight part of water contained in an emulsion composition from a stability viewpoint of the emulsion composition of this invention. The ratio is preferably 15 to 45 parts by weight, more preferably 20 to 40 parts by weight.

(D) Water Water is not to question, especially the type, for example, purified water, distilled water, ion water, sterile water, and deep sea water, etc., it can be used without limitation. Preferably it is purified water. The mixing ratio of the water in the emulsified composition of the present invention can be appropriately set from the range of usually 20 to 90% by weight. Preferably it is 30 to 80 weight%, More preferably, it is 40 to 80 weight%.

(E) Other components The emulsion composition of this invention can mix | blend active ingredients other than the said (a) component in the range which does not impair the effect of this invention. Examples of active ingredients here include antihistamines (diphenhydramine, diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), local anesthetics (lidocaine, dibucaine, procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilucaine, or these Salts, alkyl benzoates (for example, ethyl aminobenzoate, diethylaminoethyl parabutylaminohydrochloride), orthocaine, oxesasein, oxypolyentoxydecane, funnel extract, percamine ase, tesitdecitine, etc., anti-inflammatory agents (glycyrrhetinic acid, glycyrrhizic acid) Dipotassium, monoammonium glycyrrhetinate, allantoin, salicylic acid, glycol salicylate, methyl salicylate, indometha , Felbinac, diclofenac sodium, loxoprofen sodium, etc.), bactericides (isopropylmethylphenol, chlorhexidine hydrochloride, chlorhexidine gluconate, aqueous ammonia, sulfadiazine, lactic acid, phenol, etc.), antipruritic agents (crotamiton, thianthol, etc.), skin protectants (colodione) , Castor oil, etc.), blood circulation promoting components (nonyl acid vanillylamide, nicotinic acid benzyl ester, capsaicin, pepper extract, etc., vitamin E), vitamins (vitamin A, B, C, D etc.), mucopolysaccharide (sodium chondroitin sulfate) , Glucosamine, hyaluronic acid, etc.), refreshing agents (menthol, l-menthol, mint oil, peppermint oil, camphor (camphor), thymol, spiranthol, methyl salicylate), etc. These active ingredients can be used individually by 1 type or in combination of 2 or more types according to the objective of the emulsion composition of this invention.

  Moreover, if it is a range which does not impair the effect of this invention, if it is a range which does not impair the effect of this invention, according to the form etc., another component can be selected suitably and it can mix | blend 1 type (s) or 2 or more types together. For example, various additives such as stabilizers, thickeners, preservatives, buffers, pH adjusters and the like generally used for the preparation of emulsified preparations (solutions and semisolid agents) can be mentioned. Include the following:

Stabilizer: Dibutylhydroxytoluene, sodium edetate, sodium sulfite, dry sodium sulfite and the like.

Thickener: xanthan gum, hypromellose (hydroxypropylmethylcellulose), hydroxypropylcellulose, macrogol 400, macrogol 1500, macrogol 4000, carboxyvinyl polymer and the like.

Preservatives: butyl paraben, methyl paraben, propyl paraben, ethyl paraben, sodium benzoate, paraoxybenzoate (methyl paraoxybenzoate, propyl paraoxybenzoate), benzyl alcohol and the like.

Buffer: borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, aspartic acid, aspartate and the like.

pH adjusters: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid; lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid, propionic acid, acetic acid, Organic acids such as aspartic acid, epsilon-aminocaproic acid, glutamic acid, aminoethylsulfonic acid; inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide; monoethanolamine, Organic salts such as triethanolamine, diisopropanolamine, triisopropanolamine and lysine.

Other: Sodium carboxymethyl starch, magnesium stearate, cellulose, lactose, hard fat, self-emulsifying glyceryl monostearate, glyceryl stearate, D-sorbitol, medium chain fatty acid triglyceride, corn starch, propylene glycol, propylene glycol fatty acid ester, 1,3-butylene glycol, glycerin, polyethylene glycol, glyceryl monostearate and the like.

(F) Manufacturing method and usage method As a method of manufacturing the emulsion composition of this invention, the conventionally well-known manufacturing method regarding an O / W type emulsion composition and a W / O type emulsion composition can be mentioned.

Although not limited, for example, any of these emulsion compositions can be prepared by the following method.
(A) A water-soluble component is mixed and dissolved to prepare a uniform aqueous phase, and an oil-soluble component and a surfactant (nonionic surfactant, cationic surfactant) are dissolved or dispersed in the oil component. Heat to about 85 ° C and mix and dissolve to prepare a uniform oil phase.
(B) Next, the water phase and the oil phase are mixed and emulsified while being heated to about 75 to 85 ° C., so that the intended emulsion composition (O / W type emulsion composition, W / O type emulsion composition) is obtained. Thing).

  In addition, as an emulsification method, it can finely emulsify and commercialize using a stirring emulsifier, a high-pressure homogenizer, an ultrasonic emulsifier, an ultra mixer, a colloid mill, etc.

  In the present invention, the blending ratio of the water phase (aqueous component) and the oil phase (oil component) constituting the emulsion composition varies depending on the type of the emulsion composition (oil-in-water type, water-in-oil type). For example, when producing a W / O type emulsion composition, the ratio of a water phase and an oil phase can mention water phase: oil phase = 1: 99-40: 60 by weight ratio. Preferably it is 1: 99-30: 70, More preferably, it is 2: 98-20: 80. Moreover, when manufacturing an O / W type emulsion composition, the ratio of an oil phase and a water phase can mention oil phase: water phase = 1: 99-40: 60 by weight ratio. Preferably it is 1: 99-30: 70, More preferably, it is 2: 98-20: 80.

  The average emulsified particle diameter of the emulsified composition of the present invention is not particularly limited, but is usually 100 μm or less, particularly about 0.01 to 50 μm. The average emulsified particle diameter can be obtained from a polarizing microscope image obtained with a polarizing microscope.

  Although the viscosity of the emulsified composition of the present invention is not particularly limited, it is preferably 4000 to 150,000 cP, and more preferably 2000 to 130,000 cP, from the viewpoint of the feeling of use at the time of application to the skin. The viscosity is a value measured by the following method using a viscometer “model: LVDV-II + (manufactured by BROOK FIELD, Inc., spindle E type)”.

(Method)
35 g of the sample (emulsified composition) is put in a sample container of a marem screw tube (No. 7) and measured at 4.0 RPM while moving up and down at room temperature (around 25 ° C.). Is adopted as the measured value.

  The form of the emulsion composition of the present invention is a liquid to semi-solid oil-in-water emulsion composition or a water-in-oil emulsion composition. By blending medicinal ingredients and the like according to the affected area to be applied, application method, and the like, and setting them appropriately, it can be suitably used as a skin external preparation (external medicine or external medicine use), and a therapeutic effect is obtained. In addition, the emulsified composition has fluidity in a liquid to semi-solid state, so it is easy to take in use, has good spreadability, has little stickiness, is easy to adjust to the skin, and has little irritation. Therefore, it can be suitably applied to a layer such as women who place importance on sensory elements such as tactile sensation and vision.

  Specific examples of the form of the external preparation for skin include liquid to semi-solid O / W creams and emulsions. Among these, a preferable example is an emulsion. In particular, as an analgesic, specifically as an anti-inflammatory analgesic, it is possible to loosen or heal muscles by applying to the affected area of stiff shoulders or muscle fatigue.

  When the emulsified composition of the present invention is used as an analgesic for reducing or relieving physical pain, such physical pain is not particularly limited, but is caused by external stimuli such as trauma or aging It may be caused by things such as bad posture, long working hours, long-term maintenance of stationary posture, excessive exercise, mental stress. Examples of the pain that can be treated include neuralgia, joint pain, low back pain, muscle pain, stiff shoulder pain, fracture pain, bruise pain, sprain pain, trauma pain, headache, post-operative pain and the like. Preferred are neuralgia, low back pain, muscle pain, stiff shoulder pain, and joint pain caused by aging, poor posture, long working hours, etc., and more preferred are low back pain, muscle pain, stiff shoulder pain, and joint pain. Moreover, in addition to analgesia, it can be used for the purpose of anti-inflammation (anti-inflammatory) and / or fatigue and fatigue.

  The emulsified composition of the present invention is usually used by applying it to the target skin once to several times a day in a timely manner. In this case, the amount of diclofenac or a salt thereof contained in a single application amount of the emulsified composition is not limited, but 15 to 150 mg / day can be exemplified.

(II) Method for inhibiting decomposition of diclofenac or a salt thereof The present invention is an emulsion composition having a pH of 6.5 or less, comprising (a) diclofenac or a salt thereof, (B) a surfactant, (c) an oil component, and (d) water. Provided is a method for inhibiting decomposition of component (a) in a product. This method can be achieved by using a combination of a nonionic surfactant and a cationic surfactant as the component (B).

  (A) diclofenac or a salt thereof used in the method of the present invention, (b) nonionic surfactant and cationic surfactant, (c) oily component, and (d) the kind of water, and its blending ratio, and the present invention The method for producing the emulsified composition is as described in (I) above. Therefore, in the said invention, the description of (a), (B), (c), (d), (e) and (f) in said (I) can be used.

  In the method for inhibiting decomposition (stabilization method) of diclofenac or a salt thereof of the present invention, the method for producing the target emulsion composition is also as described in the above (I) and (f). Therefore, in the invention, the description in (I) above can be incorporated.

  As shown in the experimental examples to be described later, according to the method of the present invention, an emulsification prepared using only a nonionic surfactant as a surfactant with respect to an emulsion composition having a pH of 6.5 or less containing diclofenac or a salt thereof. The decomposition of diclofenac or a salt thereof generated in the composition can be suppressed. Therefore, according to the present invention, an emulsion composition that suppresses the decomposition of the active ingredient diclofenac or a salt thereof and stably maintains the quality, particularly a liquid or semi-solid external emulsification that has analgesic / anti-inflammatory effects. Compositions (emulsions, creams) can be provided.

  Hereinafter, the present invention will be specifically described based on experimental examples and examples. However, the present invention is not limited by these.

Experimental Example 1 Preparation and Evaluation of Emulsified Composition
(1) Preparation of test emulsion composition O / W type emulsion compositions (Examples 1 and 2 and Comparative Example 1) having the composition described in Table 1 were prepared. Specifically, an aqueous phase (aqueous component and thickener excluding absolute ethanol) and an oil phase (L-menthol, tocopherol acetate, oil component, nonionic surfactant, cationic surfactant, preservative, and dimethylpolysiloxane ) Were prepared, heated to 80 ° C. or higher, mixed, and emulsified by stirring at 9000 rpm for 3 minutes with a homogenizer (ROBOMICS [manufactured by TOKUSUKIKA Co., Ltd.]). Then, after adjusting with a pH adjuster so that pH might be 6.5 or less, and cooling to room temperature, the diclofenac sodium and absolute ethanol were added and the emulsion composition was prepared.

In addition, HLB etc. of each nonionic surfactant are as follows.
Polyethylene glycol monostearate (Nippon Surfactant Kogyo Co., Ltd.): HLB = 20
Polyoxyethylene behenyl ether (BB-20) (manufactured by Nippon Surfactant Kogyo Co., Ltd.): HLB = 16.5, POE = 20 mol polyoxyethylene hydrogenated castor oil (HCO-40) (manufactured by Nippon Surfactant Kogyo Co., Ltd.): HLB = 12 .5, POE = 40 mol sorbitan monostearate (SS-10MV) (manufactured by Nikko Chemicals): HLB = 4.7

(2) Test method About the test emulsion composition prepared above (Examples 1 and 2, Comparative Example 1), the composition immediately after the preparation, and the composition stored in a thermostatic chamber at 50 ° C. for one month. For each of the above, the amount of diclofenac sodium contained therein was measured using high performance liquid chromatography under the following conditions to evaluate the stability of diclofenac sodium against high temperature storage.

(A) HPLC condition detector: ultraviolet absorptiometer (measurement wavelength: 275 nm)
Column: 4.6 mm inner diameter, 15 cm long stainless tube filled with 5 μm octadecylsilylated silica gel for liquid chromatography (Wakosil-II 5C18 RS 4.6 mm × 150 mm, 5 μm) Column temperature: constant temperature around 40 ° C. Mobile phase: Methanol / diluted acetic acid (100) (1 → 100) mixture (67:33)
Flow rate: Adjusted so that the retention time of diclofenac is about 10 minutes (about 1.0 mL / min)
Injection volume: 10 μL
Analysis time: 13 minutes

(B) Preparation of samples for HPLC measurement (internal standard solution, test solution and standard solution) (1) Preparation of internal standard solution Butyl paraoxybenzoate was used as an internal standard substance. Specifically, 0.1 g of butyl paraoxybenzoate was weighed and ethanol (95) was added to make 100 mL. This is used as an internal standard solution.

(2) Preparation of standard solution Diclofenac sodium for quantitative determination (manufactured by Nippon Bulk Chemical Co., Ltd.) was dried at 105 ° C for 3 hours, approximately 0.1g was precisely weighed, and ethanol (95) was added to make exactly 100mL. Use standard stock solution (n = 3). Pipet 5 mL of the standard stock solution, add exactly 5 mL of the internal standard solution prepared above, and add 50 mL of ethanol (95) to make the standard solution.

(3) Preparation of test solution Weigh accurately 0.5 g of the test emulsion composition prepared above (Examples 1 and 2, Comparative Example 1), accurately add 5 mL of internal standard solution, and add 30 mL of ethanol (95) ( 3 lots, each n = 3). This is dispersed by vortexing, ethanol (95) is added to make 50 mL, and ultrasonic waves are irradiated for 15 minutes. What filtered this with the membrane filter is made into a test solution.

(3) The test result is shown in FIG. In addition, the result showed the amount of diclofenac sodium immediately after preparation of each test solution as 100% (initial), and the amount of diclofenac sodium after storage at 50 ° C. for one month as a residual ratio (%) with respect to the initial amount (after storage). The average value of each experimental result (n = 3) is shown.

  As can be seen from this result, in the emulsion composition containing only nonionic surfactant as the surfactant (pH <6.5) (Comparative Example 1), significant degradation of diclofenac Na was observed after storage at 50 ° C. for one month. However, it was confirmed that the decomposition of diclofenac Na was suppressed in a dose-dependent manner by adding a cationic surfactant thereto (Examples 1 and 2). Therefore, when preparing an emulsion composition having a pH of 6.5 or less containing diclofenac Na as an active ingredient, it is important to use a cationic surfactant in combination with a nonionic surfactant in order to suppress the decomposition of diclofenac Na. I know that there is.

  The image which shows the state of the emulsified particle contained in each emulsified composition in FIG. 2 is shown. From this result, it was confirmed that the decomposition of diclofenac Na was significantly suppressed by increasing the amount of the cationic surfactant. In particular, from the results of Comparative Example 1 and Example 1, by adding 0.1% by weight of the cationic surfactant, the decomposition of diclofenac Na in the emulsion composition is significantly suppressed. From the results of Example 2, it was confirmed that the decomposition inhibitory effect (stable effect) was further improved by increasing the amount of the cationic surfactant from 0.1% by weight to 1% by weight. From this, it is considered that by further increasing the blending amount of the cationic surfactant to 2% by weight, decomposition of diclofenac Na in the emulsion composition can be further suppressed and stabilized.

Examples 3-8
According to the method described in Examples 1 and 2, O / W type emulsion compositions (Examples 3 to 8) having the compositions described in Table 2 were prepared.
These emulsion compositions (pH <6.5) are those in which the decomposition of diclofenac Na in the emulsion compositions is significantly suppressed as in the emulsion compositions of Examples 1 and 2.

Claims (8)

An emulsified composition having a pH of 6.5 or less, comprising the following components:
(A) diclofenac or a salt thereof,
(B) nonionic surfactants and cationic surfactants,
(C) an oily component, and (d) water. The emulsion composition of Claim 1 whose ratio of the cationic surfactant with respect to 100 weight part of nonionic surfactant in (b) component is 0.1-500 weight part. The emulsion composition according to claim 1 or 2, wherein the proportion of the nonionic surfactant in 100% by weight of the emulsion composition is 1 to 10% by weight. The emulsion composition in any one of Claims 1-3 whose ratio of the (a) component in 100 weight% of emulsion compositions is 0.1-5 weight%. (A) diclofenac or a salt thereof,
(B) Surfactant (c) Oil-based component, and (d) A method for inhibiting decomposition of component (a) in an emulsion composition having a pH of 6.5 or less, comprising water and a nonionic surfactant as component (B) And a cationic surfactant in combination. The method of Claim 5 that the ratio of the cationic surfactant with respect to 100 weight part of nonionic surfactant in (B) component is 0.1-500 weight part. The method according to claim 5 or 6, wherein the proportion of the nonionic surfactant in 100% by weight of the emulsified composition is 1 to 10% by weight. The method in any one of Claims 5-7 whose ratio of the (a) component in 100 weight% of emulsion compositions is 0.1-5 weight%.