JP2015010060A - Pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition having excellent formulation stability of water-soluble vitamin.SOLUTION: A pharmaceutical composition comprises at least one selected from the group consisting of (A) water-soluble vitamin, and (B) ibuprofen piconol and salt thereof.

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 a water-soluble vitamin.

  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.

  It is known that water-soluble vitamins often incorporated in pharmaceutical compositions are generally unstable due to the influence of environmental factors such as heat and light and are liable to cause a decrease in the content thereof. So far, attempts to increase the stability over time of water-soluble vitamins that are prone to instability include storing them in the dark and in a light-shielded container, filling them in an expensive light-shielding container, and storing vitamin B For vitamin B derivatives, a method of preparing these as external preparations for skin comprising di-tert-butyl paracresol and an ultraviolet absorber has been proposed (Patent Document 1). In addition, it has also been proposed to prevent a decrease in the content of vitamin B6 by using vitamin B2 and vitamin B6, both water-soluble vitamins, at a certain blending ratio (Patent Document 2).

  By the way, ibuprofen piconol is a well-known drug as a non-steroidal drug having 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 3, Non-Patent Documents 1 and 2). And in patent document 3, 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. However, Patent Document 3 does not discuss what effect ibuprofen piconol has on the stability of other components.

Japanese Patent Laid-Open No. 9-249545 JP-A-6-145056 JP 62-223118 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 excellent in the formulation stability of a water-soluble vitamin.

  As a result of intensive studies to solve the above-mentioned problems, the present inventor has found that water-soluble vitamins (in particular, water-soluble vitamins belonging to the vitamin B group) can be obtained by using ibuprofen piconol and / or a salt thereof in combination with water-soluble vitamins. And the stability to heat and / or light was found to be highly improved, and the present invention was completed.

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

  <1> (A) Water-soluble vitamin (hereinafter also referred to as “component (A)”) and (B) at least one selected from the group consisting of ibuprofen piconol and salts thereof (hereinafter referred to as “component (B)” A pharmaceutical composition containing the composition.

  <2> (A) The pharmaceutical composition according to <1>, wherein the water-soluble vitamin is a water-soluble vitamin belonging to the vitamin B group.

  <3> The water-soluble vitamin belonging to the vitamin B group is at least 1 selected from the group consisting of vitamin B6, pantothenic acids, nicotinic acids, vitamin B1, vitamin B2, biotins, folic acids, and vitamin B12 The pharmaceutical composition according to <1> or <2>, which is a seed.

  <4> The water-soluble vitamin belonging to the vitamin B group is selected from the group consisting of pyridoxine, panthenol, nicotinamide, nicotinic acid, pyridoxal, pyridoxamine, pantothenic acid, thiamine, riboflavin, biotin, folic acid, cyanocobalamin, and salts thereof The pharmaceutical composition according to any one of <1> to <3>, which is at least one selected.

  <5> The pharmaceutical composition according to any one of <1> to <4>, wherein the content of the component (B) is 0.1 to 10.0% by weight in 100% by weight of the pharmaceutical composition.

  <6> (A) Pharmaceutical composition in any one of <1>-<5> whose content of water-soluble vitamin is 0.001-10.0 weight% in 100 weight% of pharmaceutical compositions. .

  <7> The pharmaceutical composition according to any one of <1> to <6>, which contains 0.05 to 1000 parts by weight of the component (B) with respect to 1 part by weight of the water-soluble vitamin (A). .

  <8> The pharmaceutical composition according to any one of <1> to <7>, which is an oil-in-water composition.

  <9> The pharmaceutical composition according to any one of <1> to <8>, which can be used for treatment and / or prevention of acne.

  <10> The pharmaceutical composition according to any one of <1> to <9>, which is a composition for external use.

  <11> Further, selected from the group consisting of (C) a refreshing agent, a bactericidal agent, an oil-soluble vitamin, an anti-inflammatory agent (excluding the component (B)) and an organic acid (excluding the component (A)) The pharmaceutical composition according to any one of <1> to <10>, which contains at least one selected from the above (hereinafter also referred to as “component (C)”).

  According to the present invention, it is possible to provide a pharmaceutical composition having excellent formulation stability of water-soluble vitamins.

Hereinafter, the present invention will be described in detail.
[Pharmaceutical composition]
The pharmaceutical composition of the present invention contains (A) a water-soluble vitamin and (B) a component. In the pharmaceutical composition, (A) formulation stability of water-soluble vitamins is unexpectedly improved by using the component (B), which has been known to have anti-inflammatory activity and effectiveness against various skin diseases. ing. The pharmaceutical composition contains the component (C) from the viewpoint that the formulation stability of the component (A) can be enhanced and more effective treatment and / or prevention effects can be exerted on acne and the like. Further, as long as the effects of the present invention are not impaired, other components may be contained. 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) Water-soluble vitamin>
In the present invention, (A) the water-soluble vitamin is not particularly limited, and any of natural and synthetic vitamins can be used. As water-soluble vitamins, vitamin B group vitamins and vitamin C group vitamins are typical. Some of these derivatives are not water-soluble but oil-soluble, and such vitamins are naturally not included in (A) water-soluble vitamins in the present invention. Moreover, from the viewpoint of expression of the effect of the present invention, water-soluble vitamins belonging to the vitamin B group are preferable.

As water-soluble vitamins belonging to the vitamin B group,
Vitamin B6s such as pyridoxine, pyridoxal, pyridoxamine, 5′-pyridoxal phosphate, and salts thereof (eg, pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, pyridoxamine hydrochloride);
Pantothenic acids such as pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-pantetheine, D-panthetin, coenzyme A, pantothenyl ethyl ether, and salts thereof;
Nicotinic acids such as nicotinic acid, nicotinic acid dl-α-tocopherol, benzyl nicotinate, methyl nicotinate, β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, nicotinic acid amide, and salts thereof ;
γ-oryzanol, thiamine, dibenzoyl thiamine, thiamine cetyl, thiamine monophosphate, thiamine diphosphate, thiamine triphosphate, and their salts (eg, dibenzoyl thiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, Thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate, thiamine diphosphate ester, thiamine triphosphate monophosphate ) And other vitamin B1 classes;
Vitamin B2s such as riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, sodium riboflavin 5′-phosphate, riboflavin tetranicotinate, and salts thereof;
Biotins such as biotin, biocytin, and salts thereof;
Folic acids such as folic acid, pteroylglutamic acid, and salts thereof;
Vitamin B12s such as cyanocobalamin, hydroxocobalamin, deoxyadenosylcobalamin, and salts thereof;
Is mentioned.

  Among these, from the viewpoint of expression of the effect of the present invention, pyridoxine, panthenol, nicotinamide, nicotinic acid, pyridoxal, pyridoxamine, pantothenic acid, thiamine, riboflavin, biotin, folic acid, cyanocobalamin, and salts thereof are preferable, and pyridoxine , Panthenol, nicotinamide and their salts are more preferred. Examples of these salts include salts of mineral acids such as sulfuric acid, hydrochloric acid, thiocyanic acid or phosphoric acid, salts of organic acids such as butyric acid, maleic acid or methanesulfonic acid, lysine, etc. And an alkali metal salt such as sodium or potassium, and an alkaline earth metal salt such as calcium.

  The content of the water-soluble vitamin (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, 0.001 to 10.0% by weight is 100% by weight in 100% by weight of the pharmaceutical composition. Preferably, the content is 0.005 to 7.0% by weight, and more preferably 0.01 to 5.0% by weight. In the present invention, (A) water-soluble vitamins may be used alone or in combination of two or more. According to the present invention, since (A) the water-soluble vitamin can be stabilized, a high formulation stabilizing effect can be achieved even in the case of such a low concentration as described above, which tends to cause a decrease in the content particularly with respect to light. Can be obtained.

<(B) component>
The component (B) is at least one selected from the group consisting of ibuprofen piconol and salts thereof. The component (B) is a component that is effective for various skin diseases such as acute eczema and acne as used conventionally. In the present invention, the component (B) also exhibits an effect of increasing the stability of the water-soluble vitamin (A).

  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 (B) 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.

  Moreover, about the content rate of (A) component and (B) component in the said pharmaceutical composition, (B) component is 0 with respect to 1 weight part of (A) water-soluble vitamin from a viewpoint of expression of the effect of this invention. The amount is preferably 0.05 to 1000 parts by weight, more preferably 0.1 to 700 parts by weight, and still more preferably 0.2 to 500 parts by weight.

<(C) component>
The component (C) is selected from the group consisting of a refreshing agent, a disinfectant, an oil-soluble vitamin, an anti-inflammatory agent (excluding the component (B)) and an organic acid (excluding the component (A)). At least one. When a refreshing agent is blended in the pharmaceutical composition of the present invention, it is expected that the feeling of use and the bactericidal power are improved due to the skin tightening effect. When a fungicide is blended, it is expected that abnormal growth of bacteria that worsen acne and the like can be suppressed. When oil-soluble vitamins are added, an action of suppressing the sebaceous gland hyperfunction is expected. When an anti-inflammatory agent is added, it is expected that inflammation accompanying acne and the like can be suppressed. And when an organic acid is mix | blended, it is anticipated that a turnover will be accelerated | stimulated by the peeling effect to skin, and keratin thickening will be improved, and it will lead to the discharge | emission promotion of sebum. Therefore, by blending such a component (C), not only the formulation stability of the water-soluble vitamin (A) is improved, but also the therapeutic and / or preventive effects on acne and the like are improved in addition to the improvement in the feeling of use. Or a pharmaceutical composition.

  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 bactericides include isopropylmethylphenol, chlorhexidine, salicylic acid, benzalkonium chloride, acrinol, ethanol, benzethonium chloride, cresol, gluconic acid and derivatives thereof, 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 oil-soluble vitamin include vitamin E such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, and dl-α-tocopherol calcium succinate; ascorbigen-A, ascorbic acid Oil-soluble vitamin C such as stearic acid ester, ascorbic acid palmitic acid ester, L-ascorbyl dipalmitate, ascorbyl tetra-2-hexyldecanoate; Vitamin D such as ergocalciferol, cholecalciferol; phylloquinone, farnoquinone, etc. Vitamin Ks; and vitamin-like factors such as ferulic acid.

  Anti-inflammatory agents other than the component (B) 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). Ingredients, zinc oxide, tocopherol acetate, aminocaproic acid, hydrocortisone, prednisolone and salts thereof can be mentioned. Specifically, for example, allantoin, allantoinchlorohydroxyaluminum, allantoindihydroxyaluminum, glycyrrhetinic acid, glycyrrhizic acid, stearyl glycyrrhetinate, glycol salicylate, methyl salicylate, epsilon aminocaproic acid, azulene, guaiazulene and salts thereof (e.g. Dipotassium, monoammonium glycyrrhizinate) and the like. The “derivative” refers to an ester, ether, alkylated product, glycoside or the like of the described compound.

  Examples of (A) organic acids other than water-soluble vitamins include gluconic acid, aspartic acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, citric acid, glutamic acid, succinic acid, oxalic acid, fumaric acid, propionic acid, apple Examples include acids, 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 preferably 0.01 to 5% by weight in 100% by weight of the pharmaceutical composition from the viewpoint of expression of the effect of the component, More preferably, it is 5% by weight.

<Other ingredients>
The pharmaceutical composition of the present invention contains the above-described (A) water-soluble vitamin and (B) component, and optionally contains (C) component, and, in addition, according to various purposes, a moisturizing component. , Polyhydric alcohol, scrub agent, UV absorbing component, UV scattering component, astringent component, peptide or derivative thereof, amino acid or derivative thereof, washing component, keratin softening component, cell activation component, anti-aging component, blood circulation promoting component, Other components such as a whitening component may be included within a range not impairing the effects of the present invention. Especially, it is preferable that the pharmaceutical composition of this invention contains a polyhydric alcohol. 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.

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

  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 dimethyl 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.

  Examples of the keratin soft component include salicylic acid, salicylic acid glycol, gluconic 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; oil-soluble vitamins such as retinol; α-hydroxy acids such as glycolic acid and lactic acid; tannins, flavonoids, saponins, and photosensitivity. Element 301 etc. are mentioned.

  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, but the effect of the present invention is not impaired, and when applied to various diseases described later, higher therapeutic and / or prophylactic effects can be expected. From the viewpoint, it is usually in the range of pH 3.0 to 10.0, preferably 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 in addition to the essential components (A) water-soluble vitamin and (B) component, and (C) component blended as necessary, the usual pharmaceutical composition Various components (other components, bases or carriers described later, additives, etc.) necessary for producing the product 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>
As described above, the pharmaceutical composition of the present invention contains (A) a water-soluble vitamin and (B) component. Component (B) is conventionally used as an anti-inflammatory agent, and various skins such as acute eczema, contact dermatitis, atopic dermatitis, chronic eczema, rosacea dermatitis, perioral dermatitis, shingles, acne Although it is used as a component effective for diseases, in the present invention, (A) an unexpected effect of enhancing the formulation stability of the water-soluble vitamin is exhibited. (A) Water-soluble vitamins, particularly water-soluble vitamins belonging to the vitamin B group, are components widely used for various skin inflammations due to their sebum-suppressing effect, anti-inflammatory effect, activation effect, blood circulation promoting effect, and the like.

  Therefore, the pharmaceutical composition of the present invention containing these (A) water-soluble vitamin and (B) component can be used as a pharmaceutical composition for the treatment and prevention of the above-mentioned various skin diseases. It can be suitably used as an external preparation. And (A) Since the formulation stability of water-soluble vitamins is improved, it is expected that the pharmaceutical composition can be effectively used for these for a long period of time. Further, among the above skin diseases, in addition to the sebaceous gland hyperfunction inhibitory action and the metabolism promoting action of the component (A), the anti-inflammatory action and the lipase activity inhibitory action of the component (B) can also be expected. The thing is effective for acne.

  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>
The pharmaceutical composition of the present invention usually contains the essential component, the component (C) described above and other components, together with a base or carrier usually used in pharmaceuticals, and, if necessary, additives described later. It can be mixed according to the method and emulsified or solubilized as necessary 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 them, the pharmaceutical composition of the present invention preferably contains water and / or a lower alcohol, and more preferably contains water. In general, preparations containing water are concerned that (A) water-soluble vitamins may be unstable and cause a decrease in the content thereof. According to the present invention, however, Also, the stability of the component (A) 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, preservatives, thickeners, irritation reducing agents and the like can be added. Among these, it is preferable to add a surfactant 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, erythorbic acid, and L-cysteine hydrochloride.

  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 the like.

  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 acid salts (sodium lactate, sodium citrate, sodium succinate, etc.), inorganic bases (potassium hydroxide, sodium hydroxide, etc.), organic Examples include bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.). Of these, organic bases are preferable, and triethanolamine is more preferable.

  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.

[(A) Stability improving action of water-soluble vitamins]
As shown in the results of the test examples described later, the formulation stability of the component (A) can be improved by using the component (A) and the component (B) in combination. Therefore, the present invention is characterized in that at least one selected from the group consisting of (B) ibuprofenpiconol and a salt thereof is added to (A) the water-soluble vitamin from another viewpoint. ) A method for improving the stability of the component. The types and amounts of component (A) and component (B) that can be used in this method, and other components that can be used in combination, are the same as those described above for [Pharmaceutical composition].

  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]
According to the formulations shown in Tables 1 to 5 below, compositions of Examples and Comparative Examples were prepared by a conventional method. 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 triethanolamine to obtain compositions of Examples and Comparative Examples. In addition, in the following Tables 1 to 5 (and Tables 6 and 7 in Test Example 2 described later, and Table 8 in Reference Test Example 1), the “remaining amount” is an amount that makes the total amount of the composition 100% by weight. is there.

  Thereafter, 5 g of each of the compositions of Examples and Comparative Examples was filled into a 10 mL glass screw cap bottle and stored at a predetermined temperature (50 ° C. or 60 ° C.) under light shielding. After completion of the test periods shown in Tables 1 to 5, each composition was cooled to room temperature at 25 ° C. for half a day, and then the content of water-soluble vitamins (pyridoxine hydrochloride, panthenol and nicotinamide) was determined as follows. Quantified by HPLC under conditions. Tables 1 to 5 below show the residual ratio (%) of each water-soluble vitamin when the initial content of each water-soluble vitamin before storage is 100%.

<Quantification conditions for water-soluble vitamins>
・ Detector: UV absorption photometer (measurement wavelength: 220 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: 0.01M 1-heptanesulfonic acid Na solution (pH 3) / acetonitrile = 9/1

<Evaluation>
As is apparent from the results (water-soluble vitamin residual rate) shown in the bottom column of Tables 1 to 5 above, water-soluble vitamins belonging to the vitamin B group represented by pyridoxine hydrochloride, panthenol and nicotinamide are represented. By blending ibuprofen piconol and / or a salt thereof with a vitamin, the heat stability of the water-soluble vitamin is highly improved, and a stable pharmaceutical composition can be provided.

[Test Example 2: Light stability test]
According to the formulations shown in Tables 6 and 7 below, compositions of Examples and Comparative Examples were prepared by a conventional method. Specifically, it was prepared by the same method as the method for preparing the composition of Test Example 1.

  Then, 5 g of each of the compositions of Examples and Comparative Examples was filled in a transparent glass 10 mL screw mouth bottle, stored in a light irradiator, and the cumulative irradiation amount was 300,000 using a D65 fluorescent lamp as a light source. Each composition was irradiated with light under the condition of lux. After completion of light irradiation, each composition was cooled to room temperature at 25 ° C. for half a day, and then the content of water-soluble vitamins (pyridoxine hydrochloride and panthenol) was quantified by HPLC under the following quantitative conditions. Tables 6 and 7 below show the residual ratio (%) of each water-soluble vitamin when the initial content of each water-soluble vitamin before storage is 100%.

<Quantification conditions for water-soluble vitamins>
・ Detector: UV absorption photometer (measurement wavelength: 220 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: 0.01M 1-heptanesulfonic acid Na solution (pH 3) / acetonitrile = 9/1

<Evaluation>
As is clear from the results shown in the bottom column of Tables 6 and 7 (water-soluble vitamin residual rate), by adding ibuprofen piconol and / or its salt together with water-soluble vitamins, In addition, it was revealed that the light stability is also highly improved.

[Reference Test Example 1: Thermal stability evaluation for oil-soluble vitamins]
In order to confirm whether the vitamin stabilization effect by ibuprofen piconol is specific to water-soluble vitamins, the stabilization effect for oil-soluble vitamins was also evaluated by the same procedure as in Test Example 1.

  Specifically, the following tests were conducted using tocopherol acetate, which is a kind of oil-soluble vitamin belonging to the vitamin E group, as a representative of oil-soluble vitamins. First, according to the formulation described in Table 8 below, compositions of Reference Examples 1 and 2 were prepared by a conventional method.

  Next, 5 g of each of the compositions of the reference examples was filled in a glass-capacity screw-cap bottle with a capacity of 10 mL, and stored for 1 week under 60 ° C. shading. One week later, each composition was cooled to room temperature at 25 ° C. for half a day, and then tocopherol acetate was quantified by HPLC under the following quantification conditions. Table 8 below shows the residual ratio (%) of tocopherol acetate when the initial content of tocopherol acetate before storage is 100%.

<Quantitative conditions for oil-soluble vitamins>
・ Detector: UV absorption photometer (measurement wavelength: 270 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

<Evaluation>
As is apparent from the results shown in the bottom column of Table 8 above, tocopherol acetate, which is an oil-soluble vitamin E, is very stable in this test, and thus the stability improvement effect by ibuprofen piconol is also recognized. There wasn't. Therefore, it was revealed that the vitamin stabilization effect by ibuprofen piconol and / or its salt is an effect specific to water-soluble vitamins.

  Below, the formulation example of the pharmaceutical composition of this invention is shown.

Claims (10)

A pharmaceutical composition comprising (A) a water-soluble vitamin, and (B) at least one selected from the group consisting of ibuprofen piconol and a salt thereof.   The pharmaceutical composition according to claim 1, wherein the water-soluble vitamin (A) is a water-soluble vitamin belonging to the vitamin B group.   The water-soluble vitamin belonging to the vitamin B group is at least one selected from the group consisting of vitamin B6, pantothenic acid, nicotinic acid, vitamin B1, vitamin B2, biotin, folic acid, and vitamin B12 The pharmaceutical composition according to claim 1 or 2.   The water-soluble vitamin belonging to the vitamin B group is selected from the group consisting of pyridoxine, panthenol, nicotinamide, nicotinic acid, pyridoxal, pyridoxamine, pantothenic acid, thiamine, riboflavin, biotin, folic acid, cyanocobalamin, and salts thereof The pharmaceutical composition according to any one of claims 1 to 3, which is at least one kind.   (B) Pharmaceutical composition in any one of Claims 1-4 whose content of component is 0.1-10.0 weight% in 100 weight% of pharmaceutical compositions.   (A) Pharmaceutical composition in any one of Claims 1-5 whose content of water-soluble vitamin is 0.001-10.0 weight% in 100 weight% of pharmaceutical compositions.   (A) Pharmaceutical composition in any one of Claims 1-6 which contains (B) component in the ratio of 0.05-1000 weight part with respect to 1 weight part of water-soluble vitamins.   The pharmaceutical composition according to any one of claims 1 to 7, which is an oil-in-water composition.   The pharmaceutical composition according to any of claims 1 to 8, which can be used for the treatment and / or prevention of acne.   The pharmaceutical composition according to any one of claims 1 to 9, which is an external composition.