JP2017190346A - Pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition comprising pharmaceutically stable ibuprofen piconol and/or a salt thereof.SOLUTION: There is provided a composition which comprises (A) at least one selected from the group consisting of ibuprofen piconol and a salt thereof and (B) at least one selected from the group consisting of isopropyl methyl phenol and a salt thereof, wherein the content of the (B) component is 0.7 to 1.5 wt.% in 100 wt.% of the composition.SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition. In more detail, this invention relates to the pharmaceutical composition excellent in the formulation stability of ibuprofen piconol and / or its salt. Furthermore, in a specific aspect, the present invention relates to a pharmaceutical composition that can exhibit an excellent melanin production inhibitory effect.

  In formulating a pharmaceutical composition, the stability of the ingredients is very important. After a compounding ingredient is formulated, when it becomes unstable over time under various environmental conditions (for example, under high temperature, low temperature, exposure, or in a humid environment), and its content greatly decreases, There is a concern that the intended effect cannot be achieved. In particular, higher pharmaceutical stability is required in pharmaceutical compositions in which the dosage of the compounding ingredients should be strictly controlled.

  And even if a drug shows a relatively stable property in a single state, when it is formulated in combination with various other components, it often destabilizes due to the influence of other components. . Therefore, when formulating various drugs together with other compounding ingredients, the formulation stability of the compounding ingredients is enhanced to a higher level, and the ingredients can be maintained for a long time in a state where they can exert the desired effects. It is required to do.

  Ibuprofen piconol is a well-known drug as a non-steroidal drug showing anti-inflammatory / analgesic action. Ibuprofen piconol is a piconol ester compound of ibuprofen that has been found in the course of developing ibuprofen derivatives that can exert more effective anti-inflammatory effects. Currently, ibuprofen piconol is a topical treatment for acute eczema, contact dermatitis, atopic dermatitis, chronic eczema, rosacea-like dermatitis, perioral dermatitis, shingles, acne vulgaris (so-called acne), etc. (Patent Document 1, Non-Patent Documents 1 and 2). And in patent document 1, in order to improve the thermal stability of ibuprofen piconol, the technique using a hydrophilic polymer, a nonionic surfactant, an oily substance, a pH adjuster, and water as a base is proposed.

  By the way, melanin production in the skin tissue is known as a cause of pigmentation such as spots, dullness, and sparrow spots, and is a phenomenon that is not desired by people (especially women) who desire whitening and transparency of the skin. Further, it is known that in the process of acne deterioration, excessive generation of active oxygen occurs, skin cells are adversely affected, melanin production is promoted, and pigmentation (so-called acne scars) is caused. Since such acne scars affect the appearance of the skin, it is a skin symptom that should be improved for people who want to have clean skin forever regardless of gender.

  And so far, it has been reported that ibuprofen piconol is used for non-invasively promoting the removal of skin pigment (Patent Document 2). The invention described in Patent Document 2 aims to positively remove skin pigments, not to prevent pigmentation by suppressing melanin production. From the results of Examples and Comparative Examples, States that ibuprofen piconol has almost no tyrosinase inhibitory action, and the pigment removal action by ibuprofen piconol is not due to inhibition of melanin production, but actively removes skin pigments (eg melanin) It is reported that

JP 62-223118 A JP 2013-82631 A

Ritsuko Hayakawa et al., West Japan Dermatology, Vol. 47, No. 5, p899-908, 1985 Taniguchi Yasuaki et al., West Japan Dermatology, Vol. 47, No. 5, p888-898, 1985

  This invention is made | formed in view of this prior art, and aims at providing the pharmaceutical composition containing ibuprofen piconol and / or its salt which are pharmaceutically stable. Furthermore, in a specific embodiment, the present invention also aims to provide a pharmaceutical composition that can exhibit an excellent melanin production inhibitory effect.

  As a result of intensive studies to solve the above-mentioned problems, the present inventor has used ibuprofen piconol and / or a salt thereof together with a specific amount of isopropylmethylphenol and / or a salt thereof. Alternatively, the present inventors have found that it is possible to provide a pharmaceutical composition excellent in formulation in which the stability of the salt is improved and the decrease in the content thereof is suppressed, and the present invention has been completed. Furthermore, the present inventor has repeatedly studied and found that melanin production can be highly suppressed by using ibuprofen piconol and / or its salt and isopropylmethylphenol and / or its salt in combination at a specific ratio. .

  That is, the gist of the present invention is as follows.

  <1> selected from the group consisting of (A) at least one selected from the group consisting of ibuprofen piconol and salts thereof (hereinafter also referred to as “component (A)”), and (B) selected from the group consisting of isopropylmethylphenol and salts thereof. Wherein the content of the component (B) is 0.7 to 1 in 100% by weight of the pharmaceutical composition. A pharmaceutical composition which is 5% by weight.

  <2> The pharmaceutical composition according to <1>, wherein the content of the component (A) is 0.1 to 10.0% by weight in 100% by weight of the pharmaceutical composition.

  <3> The pharmaceutical composition according to <1> or <2>, which contains 0.2 to 5 parts by weight of component (B) with respect to 1 part by weight of component (A).

  <4> The pharmaceutical composition according to any one of <1> to <3>, which is an oil-in-water composition.

  <5> Furthermore, it contains at least one selected from the group consisting of (C) an organic acid and a salt thereof (hereinafter also referred to as “component (C)”), and any one of <1> to <4> The pharmaceutical composition as described.

  <6> The pharmaceutical composition according to any one of <1> to <5>, which can be used to suppress melanin production.

  <7> The pharmaceutical composition according to any one of <1> to <6>, which can be used for treatment and / or prevention of acne.

  <8> The pharmaceutical composition according to any one of <1> to <7>, which is a composition for external use.

  ADVANTAGE OF THE INVENTION By this invention, the pharmaceutical composition containing the ibuprofen piconol and / or its salt excellent in the formulation stability of ibuprofen piconol and / or its salt can be provided. In a more specific embodiment, the pharmaceutical composition of the present invention can also effectively suppress melanin production.

It is a graph which shows the test result of melanin production suppression evaluation in Test Example 3. It is a graph which shows the test result of the melanin production | generation suppression evaluation in Test Example 4.

Hereinafter, the present invention will be described in detail.
[Pharmaceutical composition]
The pharmaceutical composition of this invention contains (A) component and (B) component, and content of (B) component exists in a specific range. In the said pharmaceutical composition, the formulation stability of (A) component is increasing by containing (B) component by specific content. Moreover, the said pharmaceutical composition also exhibits the inhibitory effect of melanin production by using together (A) component and (B) component by a specific ratio in a specific aspect. In particular, the pharmaceutical composition can further improve the formulation stability of the component (A) by using the component (C) as a further component. Furthermore, the said pharmaceutical composition may contain another component etc., unless the effect of this invention is impaired. Hereinafter, (A) component and (B) component which are essential components of the said pharmaceutical composition, (C) component, other components, etc. are explained in full detail.

<(A) component>
The component (A) is at least one selected from the group consisting of ibuprofen piconol and salts thereof. The component (A) is an effective component for various skin diseases such as acute eczema and acne as conventionally used.

  The ibuprofen piconol in the present invention is not particularly limited as long as it is used for ordinary pharmaceuticals, and for example, Japanese Pharmacopoeia drug standard listed products can be used. Examples of the salt of ibuprofen piconol include salts of mineral acids such as sulfuric acid, hydrochloric acid or phosphoric acid, salts of organic acids such as maleic acid or methanesulfonic acid, alkali metal salts such as sodium or potassium, and alkaline earth metal salts. Is mentioned. Ibuprofen piconol and / or a salt thereof may be obtained by synthesis or a commercially available product may be used.

  The content of the component (A) in the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of expression of the effect of the present invention, 0.1 to 10.0% by weight is preferable in 100% by weight of the pharmaceutical composition, It is more preferably 0.1 to 5.0% by weight, and further preferably 0.5 to 3.0% by weight.

<(B) component>
Component (B) is at least one selected from the group consisting of isopropylmethylphenol and salts thereof. Isopropylmethylphenol and its salt are substances that have been widely used as substances having antibacterial activity. Various positional isomers are known for isopropylmethylphenol, and any of them may be used in the present invention. Specifically, the positional isomers of isopropylmethylphenol include 3-methyl-4-isopropylphenol (also referred to as biosol), 2-isopropyl-5-methylphenol (also referred to as thymol), or 2-methyl-5-isopropyl. Phenol [also called carvacrol] and the like can be mentioned, but not limited thereto. From the viewpoint of expression of the effect of the present invention, 3-methyl-4-isopropylphenol is preferable.

  In the pharmaceutical composition of the present invention, the component (B) exhibits an antibacterial action and is contained in a specific amount to enhance the formulation stability of the component (A) in the pharmaceutical composition. Further, as will be described later, when the component (A) and the component (B) are contained in a specific ratio in the pharmaceutical composition, the pharmaceutical composition also exhibits a melanin production inhibitory action.

  In the present invention, various commercially available isopropylmethylphenols and salts thereof can be used without particular limitation, and may be obtained by synthesis. Examples of the salt of isopropylmethylphenol include salts of mineral acids such as sulfuric acid, hydrochloric acid or phosphoric acid, salts of organic acids such as maleic acid or methanesulfonic acid, alkali metal salts such as sodium or potassium, and alkaline earth metals Salt.

  The content of the component (B) in the pharmaceutical composition of the present invention needs to be 0.7 to 1.5% by weight in 100% by weight of the pharmaceutical composition from the viewpoint of the formulation stability of the component (A). 0.8 to 1.3% by weight, more preferably 0.9 to 1.1% by weight, and even more preferably 1.0% by weight.

  Moreover, about the content rate of (A) component in the said pharmaceutical composition, and (B) component, from a viewpoint that a favorable melanin production inhibitory effect can be anticipated, (B) with respect to 1 weight part of (A) component The component is preferably 0.2 to 5 parts by weight, more preferably 0.3 to 3 parts by weight, and considering the viewpoint of improving the formulation stability of the component (A), the content should be 0.3 to 2 parts by weight. Is more preferable, and 0.3 to 0.5 parts by weight is particularly preferable.

<(C) component>
The pharmaceutical composition of the present invention preferably contains at least one selected from the group consisting of (C) an organic acid and a salt thereof as a further component. By further blending the component (C) in the pharmaceutical composition of the present invention, the formulation stability of the component (A) can be further enhanced.

  Examples of the organic acid and / or salt thereof used in the present invention include gluconic acid, aspartic acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, citric acid, glutamic acid, succinic acid, oxalic acid, fumaric acid, propionic acid, malic acid. , Salicylic acid, glycolic acid, phytic acid, tartaric acid, acetic acid, lactic acid, and salts thereof. Examples of the salt include salts of mineral acids such as sulfuric acid, hydrochloric acid or phosphoric acid, salts of organic acids such as maleic acid or methanesulfonic acid, alkali metal salts such as sodium or potassium, alkaline earth metal salts, ammonium salts, etc. Is mentioned.

  The content of the component (C) in the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of formulation stability of the component (A), 0.001 to 5.0% by weight in 100% by weight of the pharmaceutical composition Preferably, it is 0.005 to 5.0% by weight, more preferably 0.01 to 2.0% by weight.

  Moreover, about the content rate of (A) component and (C) component in the said pharmaceutical composition, (C) component shall be 0.0001-50 weight part with respect to 1 weight part of (A) component. Preferably, the amount is 0.001 to 40 parts by weight, and more preferably 0.001 to 30 parts by weight. If it is the said content rate, it can be set as the pharmaceutical composition whose formulation stability of (A) component is more favorable.

<Other ingredients>
The pharmaceutical composition of the present invention contains the component (A) and the component (B) described above, and further contains the component (C) as necessary. Hydrated alcohol, scrub agent, UV absorbing component, UV scattering component, anti-inflammatory agent other than component (A), astringent component, vitamins, peptide or derivative thereof, amino acid or derivative thereof, cleaning component, antibacterial component other than component (B) Other components such as a component, a keratin soft component, a cell activation component, an anti-aging component, a blood circulation promoting component, and a whitening component may be included within a range not impairing the effects of the present invention. Especially, it is preferable to contain anti-inflammatory agents other than a polyhydric alcohol, vitamins, and (A) component. In addition, these other components may be used individually by 1 type, and may use 2 or more types together. Further, other components which are also listed as the component (C) also function as the component (C) in the present invention.

  Examples of the moisturizing component include diglycerin trehalose; high molecular compounds such as sodium hyaluronate, heparin-like substance, sodium chondroitin sulfate, collagen, elastin, keratin, chitin, chitosan; amino acids such as glycine, aspartic acid, arginine; Natural moisturizing factors such as sodium, urea and sodium pyrrolidone carboxylate; lipids such as ceramide, cholesterol and phospholipid; plant extract extracts such as chamomile extract, hamamelis extract, tea extract and perilla extract.

  As said polyhydric alcohol, a C2-C10 thing is preferable, for example, glycerin, diglycerin, triglycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, ethylene glycol, diethylene glycol, isoprene glycol, 1 , 3-butylene glycol, sorbitol, xylitol, erythritol, mannitol, pentanediol, hexanediol, octanediol, decanediol, neopentyl glycol and the like.

  Among these, glycerin, diglycerin, triglycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, ethylene glycol, diethylene glycol, isoprene glycol, sorbitol, xylitol, erythritol, mannitol, pentanediol, hexanediol, octanediol Glycerin, diglycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, diethylene glycol, isoprene glycol, sorbitol, xylitol, erythritol, mannitol, pentanediol, and hexanediol are more preferable.

  Examples of the scrub agent include apricot kernel powder, almond shell powder, apricot kernel powder, sodium chloride grain, olive kernel powder, dried sea water grain, candelilla wax, walnut shell powder, cherry core powder, coral powder, charcoal powder. , Hull paste powder, polyethylene powder, silicic anhydride and the like.

  Examples of the ultraviolet ray absorbing component include octyl triazone, dimethoxybenzylidene dioxoimidazolidine propionate octyl, 2-methoxyhexyl paramethoxycinnamate, phenylbenzimidazole sulfonic acid, and the like.

  Examples of the ultraviolet scattering component include inorganic compounds such as hydrous silicic acid, zinc silicate, cerium silicate, titanium silicate, zirconium oxide, cerium oxide, titanium oxide, iron oxide, and anhydrous silicic acid, and these inorganic compounds. Covered with inorganic powders such as hydrous silicic acid, aluminum hydroxide, mica and talc, compounded with resin powders such as polyamide, polyethylene, polyester, polystyrene and nylon, and with silicone oil and fatty acid aluminum salts, etc. What was processed is mentioned.

  Anti-inflammatory agents other than the component (A) are derived from allantoin and derivatives thereof, glycyrrhetinic acid and derivatives thereof, glycyrrhizic acid and derivatives thereof, salicylic acid and derivatives thereof, azulene and derivatives thereof, and plants (for example, Comfrey). Examples include components, zinc oxide, tocopherol acetate, aminocaproic acid, hydrocortisone, prednisolone, and salts thereof. Among them, allantoin and derivatives thereof, glycyrrhetinic acid and derivatives thereof, glycyrrhizic acid and derivatives thereof, salicylic acid and derivatives thereof, azulene and derivatives thereof, and aminocaproic acid are preferable, and allantoin, allantoinhydroxyhydroxyaluminum, allantoindihydroxyaluminum, glycyrrhetinic acid, glycyrrhizin Acid, stearyl glycyrrhetinate, glycol salicylate, methyl salicylate, epsilon aminocaproic acid, azulene, guaiazulene and salts thereof are more preferred, and allantoin, glycyrrhetinic acid and dipotassium glycyrrhizinate, and monoammonium glycyrrhizinate are particularly preferred. The “derivative” refers to an ester, ether, alkylated product, glycoside or the like of the described compound.

  Examples of the astringent component include zinc sulfate, zinc oxide, aluminum chloride, zinc sulfocolate, and tannic acid.

  Examples of the vitamins include vitamin E such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate; riboflavin, flavin mononucleotide, flavin Vitamin B2 such as adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate; nicotinic acid, nicotinic acid dl-α-tocopherol, benzyl nicotinate, nicotinic acid Nicotinic acids such as methyl, β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, nicotinamide; ascorbigen-A, ascorbic acid stearate, ascorb Vitamin C such as palmitate, dipalmitate L-ascorbyl; Vitamin D such as methyl hesperidin, ergocalciferol, cholecalciferol; Vitamin K such as phylloquinone, farnoquinone; γ-oryzanol, dibenzoylthiamine , Dibenzoylthiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate Vitamin B1 such as thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, thiamine triphosphate monophosphate; pyridoxine hydrochloride, acetic acid Vitamin B6 such as redoxin, pyridoxal hydrochloride, 5′-pyridoxal phosphate, pyridoxamine hydrochloride; vitamin B12 such as cyanocobalamin, hydroxocobalamin, deoxyadenosylcobalamin; folic acid such as folic acid, pteroylglutamic acid; pantothenic acid, pantothenic acid Pantothenic acids such as calcium, pantothenyl alcohol (panthenol), D-panthecin, D-panthetin, coenzyme A, pantothenyl ethyl ether; biotins such as biotin and biocytin; ascorbic acid, sodium ascorbate, dehydroascorbic acid Vitamin Cs which are ascorbic acid derivatives such as sodium ascorbate phosphate, magnesium ascorbate phosphate; carnitine, ferulic acid, α-lipoic acid, orot Vitamin-like agents such as and the like.

  Examples of the peptide or derivative thereof include keratin degrading peptide, hydrolyzed keratin, collagen, collagen derived from fish, atelocollagen, gelatin, elastin, elastin degrading peptide, collagen degrading peptide, hydrolyzed collagen, hydroxypropylammonium chloride hydrolyzed collagen, Elastin degrading peptide, conchiolin degrading peptide, hydrolyzed conchiolin, silk proteolytic peptide, hydrolyzed silk, lauroyl hydrolyzed silk sodium, soy proteolytic peptide, hydrolyzed soy protein, wheat protein, wheat proteolytic peptide, hydrolyzed wheat protein, Casein degrading peptides, acylated peptides (palmitoyl oligopeptides, palmitoyl pentapeptides, palmitoyl tetrapeptides, etc.) and the like can be mentioned.

  Examples of the amino acids or derivatives thereof include betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, β-alanine, threonine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, Examples include cystine, methionine, leucine, isoleucine, valine, histidine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnitine, carnosine, and creatine.

  Examples of the cleaning component include soaps selected from alkali metal salts such as potassium laurate, potassium myristate, potassium palmitate or potassium stearate, alkanolamide salts or amino acid salts; cocoyl glutamate Na, cocoyl methyl taurine Na Amino acid surfactants such as ether sulfate salts such as laureth sulfate Na; ether carboxylates such as lauryl ether acetate Na; sulfosuccinate salts such as alkyl sulfosuccinate Na; coconut oil fatty acid monoethanolamide, coconut oil Fatty acid alkanolamides such as fatty acid diethanolamide; monoalkyl phosphoric acid ester salts such as sodium lauryl phosphate and polyoxyethylene lauryl ether sodium phosphate; coconut oil fatty acid amidopropyl dimethy Betaine types such as aminoacetic acid betaine, lauryldimethylaminoacetic acid betaine, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, laurylhydroxysulfobetaine and lauroylamidoethylhydroxyethylcarboxymethylbetaine hydroxypropyl phosphate sodium Amphoteric surfactants; amino acid-type amphoteric surfactants such as sodium laurylaminopropionate.

  Antibacterial components other than the component (B) include, for example, chlorhexidine, salicylic acid, benzalkonium chloride, acrinol, ethanol, benzethonium chloride, cresol, gluconic acid and its derivatives, popidone iodine, potassium iodide, iodine, triclocarban, triclosan , Photosensitive Element 101, Photosensitive Element 201, Paraben, Phenoxyethanol, 1,2-Pentanediol, Alkyldiaminoglycine Hydrochloride, Pyroctoolamine, Miconazole and the like.

  Examples of the keratin soft component include lactic acid, salicylic acid, glycol salicylic acid, gluconic acid, citric acid, malic acid, fruit acid, phytic acid, urea, sulfur and the like.

  Examples of the cell activation component include amino acids such as γ-aminobutyric acid and ε-aminocaproic acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride and pantothenic acids; α-hydroxy acids such as glycolic acid and lactic acid Tannins, flavonoids, saponins, photosensitizer 301 and the like.

  Examples of the anti-aging component include pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivative, silicon, silicic acid, N-methyl-L-serine, mevalonolactone, and the like.

  Examples of the above-mentioned blood circulation promoting component include plants (for example, ginseng, ashitaba, arnica, ginkgo, fennel, entomop, dutch oak, chamomile, roman chamomile, carrot, gentian, burdock, rice, hawthorn, shiitake, ginger, hawthorn, and prunus , Cucumber, assembly, thyme, clove, chimpi, capsicum, touki, tonin, spruce, carrot, garlic, butcher bloom, grapes, buttons, maronier, melissa, yuzu, yakuinin, ryokucha, rosemary, rosehip, chimpi, touki, Spruce, peach, apricot, walnut, corn, etc.): Acetylcholine, Iktamol, Cantalis tincture, Gamma oryzanol, Cephalanthin, Trazoline, Tocov nicotinate Roll, hesperidin, and the like.

  Examples of the whitening component include tocopherol and tranexamic acid.

<PH>
The pH of the pharmaceutical composition of the present invention is not particularly limited. However, from the viewpoint of applying to various diseases described below without impairing the effects of the present invention, it is usually pH 3.0 to 10.0, preferably It is in the range of pH 3.0 to 8.0.

<Method for producing pharmaceutical composition>
The method for producing the pharmaceutical composition of the present invention is not particularly limited, and other than the essential components (A) and (B), and if necessary, the usual pharmaceutical composition is produced in addition to the component (C). Various components necessary for the above (the above-mentioned other components, bases or carriers described later, additives and the like) can be appropriately selected and blended, and can be produced by a conventional method.

  The pharmaceutical composition of the present invention may be an emulsified composition or a solubilized composition. In that case, either an oil-in-water type or a water-in-oil type may be used, but from the viewpoint of manifesting the effects of the present invention and the feeling of use of the pharmaceutical composition (stickiness, spread, moist feeling, etc.) Preferably there is.

<Uses of pharmaceutical composition>
In the pharmaceutical composition of the present invention, as described above, the component (A) and the component (B) are contained, and since the component (B) is contained in a specific amount, the formulation stability of the component (A) Has improved. Component (A) is a component conventionally used for various skin diseases such as acute eczema, contact dermatitis, atopic dermatitis, chronic eczema, rosacea-like dermatitis, perioral dermatitis, shingles and acne. Therefore, the pharmaceutical composition can be used as a pharmaceutical composition for the treatment / prevention thereof, and can be suitably used as a skin external preparation. And since the formulation stability of (A) component is improving, it is anticipated that the said pharmaceutical composition can be effectively used for these for a long period of time.

  For example, acne is caused by abnormal growth of skin resident bacteria such as Staphylococcus aureus and Neisseria acne. Since the component (B) is a substance having an antibacterial action, the pharmaceutical composition of the present invention containing the component (B) together with the component (A) is expected to be particularly effective for the treatment and prevention of acne.

  And in the specific aspect of this invention as mentioned above, the said pharmaceutical composition also has a melanin production inhibitory effect by containing (A) component and (B) component by a specific ratio. In Patent Document 2, it is reported that the component (A) itself has an action of positively removing skin pigments such as melanin. However, the pharmaceutical composition of the above aspect of the present invention is not limited to this action. Inhibiting melanin production is effective for pigmentation symptoms such as spots, dullness, and sparrow spots, and is effective in preventing and improving, for example, scarring, pigmentation caused by friction, and acne scars. In particular, it is expected to be effective in preventing the occurrence of so-called acne scars and reducing or eliminating (treating) them after they occur.

  In addition, the usage, dosage, etc. of the pharmaceutical composition of the present invention are not particularly limited, and are used, for example, as an external preparation for the skin. The application amount and usage are not particularly limited, and it varies depending on the age of the subject of use and the degree of symptoms, but is usually several times a day (for example, about twice a day in the morning and evening), an appropriate amount (for example, about (Approx. 0.01 to 1 g) can be applied (for example, applied, sprayed, affixed) to an outer skin such as skin (particularly, an affected area where symptoms are anxious, for example, a site where acne occurs).

<Formulation>
In the pharmaceutical composition of the present invention, the essential components and the other components described above are mixed according to a conventional method together with a base or carrier usually used in pharmaceuticals and, if necessary, additives described later. If necessary, it can be emulsified or solubilized to obtain pharmaceutical compositions of various preparation forms.

  Examples of the base or carrier include hydrocarbons such as liquid paraffin, squalane, petrolatum, gelled hydrocarbon (plastibase, etc.), ozokerite, α-olefin oligomer, light liquid paraffin, etc .; methyl polysiloxane, highly polymerized methyl polysiloxane , Cyclic silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, silicone-alkyl chain co-modified polyether-modified silicone, silicone-alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, Silicone oils such as polyglycerin-modified branched silicones, acrylic silicones, phenyl-modified silicones, and silicone resins; oils and fats such as coconut oil, olive oil, rice bran oil, and shea butter; jojoba Waxes such as cetanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, octyldodecanol, isostearyl alcohol, phytosterol, cholesterol, etc .; ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. Cellulose derivatives of: polyvinyl pyrrolidone; carrageenan; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; diisopropyl adipate, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, tetranoate 2-ethylhexanoic acid pentaerythlit Esters such as dextrin, polysaccharides such as maltodextrin, vinyl polymers such as carboxyvinyl polymer and alkyl-modified carboxyvinyl polymer, lower alcohols such as ethanol and isopropanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene Glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether, etc. Glycol ether; water It is. When the pharmaceutical composition of the present invention contains a polyhydric alcohol, the polyhydric alcohol may also serve as a base or carrier. Among these, the pharmaceutical composition of the present invention preferably contains water and / or a lower alcohol, and more preferably contains water. In general, a preparation containing water is concerned that (A) ibuprofen piconol and / or a salt thereof may be destabilized to cause a decrease in the content thereof. Even if it is a formulation containing, stability of (A) component can be improved. In view of this viewpoint, the pharmaceutical composition of the present invention may contain 30% by weight or more of water in 100% by weight of the pharmaceutical composition, and may further contain 50% by weight or more.

  When the pharmaceutical composition of the present invention contains a base or carrier other than water and lower alcohol, examples of the base or carrier include higher alcohols, hydrocarbons, oils and fats, esters, silicone oils, waxes, and vinyls. Polymers are preferred, and higher alcohols, ester oils, silicone oils, and vinyl polymers are more preferred. Among these components, cetanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, glyceryl tri-2-ethylhexanoate, dimethicone, cyclomethicone, polyether-modified silicone, polyglycerin-modified silicone, and carboxyvinyl polymer are more preferable.

  The bases or carriers described above may be used alone or in combination of two or more. Further, the amount used thereof is appropriately selected from a range known to those skilled in the art.

<Formulation>
The preparation form of the pharmaceutical composition of the present invention is not particularly limited. For example, ointments, solutions, suspensions, emulsifiers (milky lotions and creams), gels, liniments, lotions, poultices, aerosols, solids Etc. Among these, liquid to semi-solid preparation forms are preferable, and it is particularly useful when applied to solutions, lotions, ointments, gels, and emulsifiers. These preparations can be produced according to conventional methods, for example, the method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.

<Additives>
In the pharmaceutical composition of the present invention, known additives that are added to the pharmaceuticals, for example, surfactants, stabilizers, antioxidants, colorants, pearly luster imparting agents, as long as the effects of the present invention are not impaired. , Dispersants, chelating agents, pH adjusters, cooling agents, preservatives, thickeners, irritation reducing agents, and the like can be added. Especially, it is preferable to add a cooling agent and a thickener. These additives may be used alone or in combination of two or more. In addition, the additive that is also listed as the component (C) also functions as the component (C) in the present invention.

  The surfactant may be any of a nonionic surfactant, a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and the like. For example, sorbitan monoisostearate, sorbitan monolaurate Sorbitan monopalmitate, sorbitan monostearate, sorbitan fatty acid esters such as diglycerol sorbitan penta-2-ethylhexylate, diglycerol sorbitan tetra-2-ethylhexylate; propylene glycol fatty acid esters such as propylene glycol monostearate; Cured castor such as polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), polyoxyethylene hydrogenated castor oil 80, etc. Derivatives: polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), polyisostearate poly Polyoxyethylene sorbitan fatty acid esters such as oxyethylene (20) sorbitan; polyoxyethylene monococonut oil fatty acid glyceryl; glycerin alkyl ether; alkyl glucoside; polyoxyalkylene alkyl ether such as polyoxyethylene cetyl ether; stearylamine, oleylamine, etc. Amines; polyoxyethylene-methylpolysiloxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, PEG-9 Silicone surfactants such as Li dimethicone and the like. Of these, nonionic surfactants are preferred, and hardened castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, and polyoxyalkylene alkyl ethers are more preferred.

  Examples of the stabilizer include sodium polyacrylate, dibutylhydroxytoluene, butylhydroxyanisole and the like.

  Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, erythorbic acid, L-cysteine hydrochloride, and the like.

  Examples of the colorant include inorganic pigments and natural dyes.

  Examples of the pearl luster imparting agent include ethylene glycol distearate, ethylene glycol monostearate, and triethylene glycol distearate.

  Examples of the dispersant include sodium pyrophosphate, sodium hexametaphosphate, polyvinyl alcohol, polyvinyl pyrrolidone, methyl vinyl ether / maleic anhydride crosslinked copolymer, and organic acid.

  Examples of the chelating agent include EDTA · disodium salt and EDTA · calcium disodium salt.

  Examples of the pH adjuster include inorganic acids (hydrochloric acid, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, sodium succinate, etc.), inorganic bases (potassium hydroxide, water, etc.). Sodium oxide), organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.). Of these, inorganic bases and / or organic bases are preferable, and potassium hydroxide and triethanolamine are more preferable.

  Examples of the refreshing agent include terpenes such as menthol, camphor, borneol, geraniol, cineol, anethole, limonene, eugenol (these may be d-form, l-form or dl-form); eucalyptus oil, bergamot Examples include essential oils such as oil, peppermint oil, cool mint oil, spearmint oil, fennel oil, mint oil, cinnamon oil, rose oil, and turpentine oil.

  Examples of the preservative include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and paraoxybenzoic acid. Examples include benzyl, methyl paraoxybenzoate, and phenoxyethanol.

  Examples of the thickener include vinyl thickeners such as polyvinyl alcohol, polyvinylpyrrolidone and carboxyvinyl polymer, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and carboxyethylcellulose. Cellulose thickener, guar gum, pectin, pullulan, gelatin, locust bean gum, carrageenan, agar, xanthan gum, alkyl methacrylate copolymer, polyethylene glycol, bentonite, alginic acid, propylene glycol alginate, macrogol, chondroitin sulfate Sodium, hyaluronic acid, sodium hyaluronate, (acrylic Hydroxyethyl / acryloyldimethyltaurinato Na) copolymer, and (ammonium acryloyldimethyltaurate / vinyl pyrrolidone) copolymers and the like. Of these, vinyl thickeners and cellulose thickeners are preferred, carboxyvinyl polymer, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxy More preferred is ethylcellulose.

  Examples of the irritation reducing agent include licorice extract, sodium alginate, gum arabic, and polyvinylpyrrolidone.

  EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

[Test Example 1: Thermal stability test (1)]
According to the formulations shown in Tables 1 to 3 below, oil-in-water compositions of Examples and Comparative Examples (each formulation shown in Table 1 is a transparent solubilized gel; The formulation was an oil-in-water emulsifier). Specifically, first, an oil-soluble component and a water-soluble component were separately mixed and dissolved at 70 to 80 ° C. to prepare an oil phase and an aqueous phase. Next, while sufficiently stirring the prepared aqueous phase with a disper (Robomix, manufactured by Primix Co., Ltd.), the oil phase prepared in advance was gradually added thereto, and the mixture was mixed thoroughly to obtain a uniform room temperature. Until cooled. The pH was adjusted by adding an appropriate amount of potassium hydroxide and / or triethanolamine to obtain compositions of Examples and Comparative Examples. In Tables 1 to 4 below, the “remaining amount” is an amount that makes the total amount of the composition 100% by weight.

  Thereafter, 5 g of the composition of each example and comparative example was filled in a screw mouth bottle having a capacity of 10 mL of each material shown in Tables 1 to 3 and stored under light shielding at 60 ° C. After completion of the test period shown in each table, each composition was cooled to room temperature at 25 ° C. for half a day, and then the content of ibuprofen piconol was quantified by HPLC under the following quantitative conditions. Tables 1 to 3 below show the residual rate (%) of ibuprofen piconol when the initial content of ibuprofen piconol before storage is 100%.

<Quantitative conditions>
・ Detector: UV absorption photometer (measurement wavelength: 254 nm)
Column: A column (Inertsil ODS2, manufactured by GL Sciences Inc.) in which a stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm was filled with 5 μm of octadecylsilylated silica gel for liquid chromatography.
-Column temperature: constant temperature around 40 ° C
-Mobile phase: Methanol / acetic acid / sodium acetate buffer mixed solution (4: 1) at pH 4.0

  The quantification results (residual rate) of the ibuprofen piconol content of the compositions of each Example and Comparative Example are shown in Tables 1 to 3 below.

<Evaluation>
In this test, thermal stability was evaluated under various test conditions. As shown in Tables 1 to 3 above, in any case, 1.0% by weight of isopropylmethylphenol was contained in the composition. In the case of not containing isopropylmethylphenol (Comparative Examples 1, 3 and 5), in the case of containing 2.0% by weight (Comparative Examples 2 and 4) and in the case of containing 0.5% by weight (Comparative Example 6) On the other hand, it was found that the decrease in the content of ibuprofen piconol was highly suppressed. In some embodiments, the residual rate was maintained at a level of almost 100%.

  From the above results, it can be seen that it is important to combine isopropylmethylphenol and / or a salt thereof in a specific blending amount in order to improve the formulation stability of ibuprofen piconol and / or a salt thereof.

[Test Example 2: Thermal stability test (2)]
Each oil-in-water emulsion composition shown in Table 4 below was prepared in the same procedure as in Test Example 1. 5 g of each prepared composition was filled in a glass screw cap bottle with a capacity of 10 mL, and stored for 2 weeks in the dark at 50 ° C. Thereafter, ibuprofen piconol was quantified under the same quantitative conditions as in Test Example 1, and the residual ratio (%) of ibuprofen piconol was calculated in each composition, assuming the initial content before storage as 100%. did.

<Evaluation>
The test results are also shown in Table 4 above. As is apparent from the results in Table 4, it was revealed that the effect of suppressing the decrease in the content of ibuprofen piconol was particularly excellent when 1.0% by weight of isopropylmethylphenol was blended with the organic acid (gluconic acid).

[Test Example 3: Melanin production inhibition evaluation (1)]
Mouse-derived melanoma cells are seeded in a 6-well plate at a density of 1.0 × 10 ⁴ cells / mL using DMEM medium containing 10% FBS, and in an environment of 37 ° C., 5% carbon dioxide gas and 95% air. After culturing for 1 day, the medium was replaced with the same medium, and each test drug shown in Table 5 below (the components shown in Table 5 dissolved in ethanol) was diluted to 5 / 10,000,000. The culture medium was added to the culture medium and cultured in an environment of 37 ° C., 5% carbon dioxide gas and 95% air for 3 days.

  After culturing for 3 days, the supernatant was removed, washed once with PBS (−), added with 600 μL of 1N NaOH, allowed to stand at room temperature for 24 hours, lysed cells, and measured for absorbance at 475 nm. The amount of melanin was determined. Next, as the melanin production rate (%), the relative value of the amount of melanin when the test drug of each Example or Comparative Example is added when the test drug is not added (control) is 100%. Calculated.

  Further, the protein was quantified using a BCA protein quantification kit, and the number of viable cells was calculated. As a result, it was confirmed that there was no significant difference in the number of viable cells when treated with the control and the test drug of each Example / Comparative Example.

  The evaluation results are shown in FIG. As is clear from the results shown in FIG. 1, it can be seen that ibuprofen piconol and isopropylmethylphenol may both have the same or higher melanin production rate than the control alone (Comparative Examples 10 to 12). . Even when isopropylmethylphenol is combined at a blending ratio of 0.5% by weight with respect to 3.0% by weight of ibuprofen piconol, the melanin production rate is almost the same as that of the control, and the melanin production inhibitory effect is little. (Comparative Example 13).

  On the other hand, unexpectedly, when isopropylmethylphenol was combined at a specific mixing ratio of 1.0% by weight with respect to 3.0% by weight of ibuprofenpiconol (Example 5), The amount of melanin has decreased, and as shown in FIG. 1, the melanin production rate is about 90%, which is lower than the control, and it has been clarified that melanin production can be suppressed synergistically in the case of such a specific blending ratio. .

[Test Example 4: Melanin production inhibition evaluation (2)]
Mouse-derived melanoma cells are seeded in a 6-well plate at a density of 1.0 × 10 ⁴ cells / mL using DMEM medium containing 10% FBS, and in an environment of 37 ° C., 5% carbon dioxide gas and 95% air. After culturing for 1 day, the medium was changed with the same medium, and each test drug shown in Table 6 below (the components shown in Table 6 dissolved in ethanol) was diluted to 5 / 1,000,000 to a final concentration. The culture medium was added to the medium, and further cultured for 4 days in an environment of 37 ° C., 5% carbon dioxide gas and 95% air. After culturing for 4 days, the amount of melanin and the number of viable cells were measured in the same procedure as in Test Example 3 above, and when treated with the control and the test drug of each Example / Comparative Example, It was confirmed that there was no melanin and the melanin production rate (%) relative to the control was calculated.

  The evaluation results are shown in FIG. From this test result, as in Test Example 3 above, the amount of melanin in melanoma cells when combined at a specific blending ratio of 1.0% by weight of isopropylmethylphenol to 3.0% by weight of ibuprofenpiconol Was found to be synergistically reduced. Furthermore, from the result of Comparative Example 18, when ibuprofen piconol and isopropylmethylphenol are combined at a preferable blending ratio in the present invention, when the weight range of isopropylmethylphenol and / or a salt thereof is not satisfied, melanin formation occurs. It turns out that the inhibitory effect is not exhibited.

  Hereinafter, pharmaceutical formulation examples of the pharmaceutical composition of the present invention will be shown.

Claims (1)

(A) a composition comprising at least one selected from the group consisting of ibuprofen piconol and a salt thereof, and (B) at least one selected from the group consisting of isopropylmethylphenol and a salt thereof, (B) The composition whose content of a component is 0.7 to 1.5 weight% in 100 weight% of compositions.

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