JP6016465B2 - Aqueous composition containing vitamins A - Google Patents

Description

  The present invention relates to an aqueous composition.

  Vitamin A is an essential nutrient for the human body and is known to be involved in the maintenance of biological functions such as vision, hearing, and reproduction, growth promotion, and the function of maintaining epithelial tissues such as skin and mucous membranes normally. ing. So far, vitamin A has been used in ophthalmic diseases such as night blindness, dry conjunctiva, dry cornea, and corneal softening, as well as keratinized skin diseases (such as common ichthyosis, pore lichen, simple rash) Etc.) is used as a therapeutic agent for a wide range of diseases such as dermatological diseases. Furthermore, it is also widely used as an external preparation for preventing skin aging by utilizing the antioxidant action and anti-aging action of vitamin A.

  However, vitamins A are unstable compounds that are easily denatured (for example, change in chemical structure) due to ultraviolet rays, oxygen, high temperature, and the like. Therefore, in order to blend vitamin A into an aqueous composition to produce a product, it is necessary to prevent a decrease in the content of vitamin A and improve stability.

  So far, various methods for stabilizing vitamin A have been studied. For example, in Patent Document 1, a vitamin A aqueous solution solubilized with a nonionic surfactant is added to three groups of (a) a fat-soluble antioxidant, (b) a water-soluble antioxidant, and (c) amino acids. A vitamin A-solubilized aqueous solution is disclosed in which at least one compound of at least two groups is blended.

  Patent Document 2 discloses a solubilized eye drop of vitamins A and vitamins E characterized by blending the following components (A), (B), and (C). (A) Vitamin A, (B) 100% by weight or more of vitamin E with respect to vitamin A, (C) 100-500% by weight with respect to the total weight of both vitamins of (A) and (B), Polyoxyethylene hydrogenated castor oil having an HLB value of 12-15.

JP-A-5-17350 Japanese Patent Laid-Open No. 6-247853

  By the way, the aqueous composition is also expected to have clarity and low transpiration (transpiration suppression effect). The clear aqueous composition can be easily discriminated as to whether or not impurities are mixed, and can be expected to produce an effect that precipitation hardly occurs. When the aqueous composition has an effect of suppressing transpiration, it is possible to exert an effect of maintaining moisture, and to suppress fluctuation of the component concentration due to evaporation of water at the time of manufacturing or after opening the product.

  However, even the techniques disclosed in Patent Documents 1 and 2 do not satisfy all of the stability of vitamin A in an aqueous composition, the clarity of the aqueous composition, and the transpiration suppression effect.

  In view of the above-described conventional problems, an object of the present invention is to provide an aqueous composition that is excellent in the stability of vitamins A and that is excellent in clarity and transpiration suppression effect. It is another object of the present invention to provide a stabilizer for vitamin A and a method for stabilizing vitamin A in an aqueous composition.

  That is, the present invention comprises (A) 5000 to 50000 units / 100 mL of vitamin A (hereinafter also referred to as “(A) component”), and (B) waxes, hydrocarbons, ester oil and vegetable oil. At least one oil selected from the group (hereinafter also referred to as “component (B)”), (C) a fat-soluble antioxidant (hereinafter also referred to as “component (C)”), and (D ) A nonionic surfactant (hereinafter also referred to as “component (D)”) is provided.

  Since the aqueous composition of the present invention contains the above-mentioned specific concentration of the component (A), the component (B), the component (C) and the component (D), the stability of vitamins A in the aqueous composition All of the properties, clarity of the aqueous composition and transpiration control effect can be achieved. In particular, in the aqueous composition containing the components (A) to (D), by obtaining the above-mentioned specific concentration of the component (A), surprisingly, an aqueous composition excellent in both clarity and transpiration suppression effect can be obtained. Can do.

  The aqueous composition of the present invention can be used for ophthalmology. Moreover, it can be used as eye drops, artificial tears, eyewashes, eye ointments, contact lens mounting liquids or contact lens care agents.

  Ophthalmic aqueous compositions often have very low concentrations of ingredients, and even a slight decrease in content can be a major problem. In particular, since the amount of eye drops used is extremely small, the effect of lowering the content is great. Since the aqueous composition of the present invention has high stability of vitamins A, the content can be prevented from lowering due to changes over time, and can be suitably used for applications such as ophthalmic use and eye drops.

  The inventors have found that the stability of vitamins A is improved by blending oils such as lanolin with vitamins A.

  Therefore, the present invention also provides (B) a vitamin A stabilizer containing at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils.

  Since the vitamin A stabilizer of the present invention contains the above oil, the stability of vitamin A can be improved by blending into an aqueous composition containing vitamin A.

  The present invention also provides an aqueous composition containing vitamin A, wherein (B) at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils is blended. It can also be called a conversion method.

  The present invention also provides the white turbidity of an aqueous composition comprising (B) at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils, and (D) a nonionic surfactant. A clarifying agent that suppresses and contains a fat-soluble vitamin.

  The present inventors have found that white turbidity may occur when the component (B) and the component (D) coexist in the aqueous composition, and the white turbidity is added by further adding a fat-soluble vitamin to the aqueous composition. It was found that it can be suppressed and clarified. Since the clarifying agent of the present invention contains the fat-soluble vitamin, at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils and a nonionic surfactant are included. The clarity of the aqueous composition can be improved by blending with the aqueous composition.

  The present invention also provides an aqueous composition comprising (B) at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils, and (D) a nonionic surfactant. It can also be called a clarification method of an aqueous composition containing a soluble vitamin.

  ADVANTAGE OF THE INVENTION According to this invention, the aqueous composition excellent in the stability of the vitamin A in an aqueous composition, and excellent in the clarity and the transpiration suppression effect of an aqueous composition is provided. The present invention also provides a stabilizer for vitamin A and a method for stabilizing vitamin A in an aqueous composition.

2 is a graph showing the residual rate of vitamin A in Test Example 1. 6 is a graph showing a residual rate of vitamin A in Test Example 2. It is a graph which shows the clarity (light transmittance of 600 nm) of the aqueous composition in Test Example 3. 6 is a photograph showing the clarity of an aqueous composition in Test Example 4. 10 is a graph showing the transpiration suppression effect of the aqueous composition in Test Example 5.

  Hereinafter, embodiments for carrying out the present invention will be described in detail.

(I) Aqueous Composition The aqueous composition of the present invention contains (A) vitamin A.

  “Vitamin A” includes retinol, retinal, retinoic acid, and pharmacologically acceptable salts or derivatives thereof. More specifically, examples include, but are not limited to, retinol, retinal, retinoic acid, retinol palmitate (retinol palmitate ester), retinol acetate (retinol acetate ester), and the like. Among these, retinol palmitate and retinol acetate are preferable. When retinol palmitate or retinol acetate is used as vitamin A, the stabilizing effect of vitamin A becomes more prominent.

  Said vitamin A class may be used individually by 1 type, and may be used in combination of 2 or more type.

  As vitamin A, a synthetic product may be used, or an extract obtained from a natural product (for example, vitamin A oil) may be used. Here, the vitamin A oil is a fatty oil obtained from a marine animal tissue or the like containing retinol, or a concentrate thereof, or a vegetable oil added thereto appropriately. Vitamin A used in the present invention is available from, for example, DSM Nutrition Japan Co., Ltd. or BASF Japan Co., Ltd.

  The content of vitamin A in the aqueous composition of the present invention is 5000 to 50000 units / 100 mL. Within this range, all of the excellent stability of vitamin A in the aqueous composition and the excellent clarity and transpiration suppression effect of the aqueous composition can be exhibited. In addition, Preferably, it is 10000-50000 units / 100mL. Within this range, in addition to the above effects, the effects of further improving the pharmacological effect and suppressing the generation of a specific odor due to denaturation over time are also obtained. From the same viewpoint, it is more preferably 25000 to 50000 units / 100 mL.

  In addition, 1 unit in the content of vitamin A means an international unit required by the method described in the 16th revision Japanese Pharmacopoeia Vitamin A Determination Method, etc. U. It is also written. For example, according to the 16th revision of the Japanese Pharmacopoeia, the content of retinol acetate is 2.5 million units or more (1 unit = 0.40 μg or less) per gram, and 1 g for retinol palmitate. The content is 1.5 million units or more per unit (1 unit = 0.667 μg or less), and when used as vitamin A oil, the content is 30,000 units or more (1 unit = 33.3 μg or less) per 1 g. Each is stipulated.

  The aqueous composition of the present invention further contains (B) at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils. Among these, it is particularly preferable to contain waxes. When waxes are contained, the stability of vitamin A in the aqueous composition is further improved.

  “Wax” refers to esters of higher fatty acids and higher alcohols. Specific examples include beeswax, whale wax, lanolin, carnauba wax, candelilla wax, and wood wax, but are not limited thereto. Among these, when lanolin is used, the stability of vitamin A is further improved. Examples of lanolin include liquid lanolin, hard lanolin, reduced lanolin, and purified lanolin, and particularly, purified lanolin is preferable from the viewpoint of excellent usability and stabilization of lamellar structure.

  “Hydrocarbons” are compounds composed of carbon and hydrogen, specifically, liquid paraffin, light liquid paraffin, squalene, squalane, α-olefin oligomer, microcrystalline wax, ceresin, paraffin, white petrolatum, Although yellow petrolatum etc. are mentioned, it is not limited to these.

  "Ester oil" is an ester of alcohol and fatty acid, specifically, isopropyl palmitate, octyl palmitate, 2-ethylhexyl palmitate, isopropyl myristate, isononyl isononanoate, medium chain fatty acid triglyceride, tri (capryl) -Capric acid) glyceryl and the like, but are not limited thereto.

  “Vegetable oil” means oil derived from plants, specifically soybean oil, rice oil, rapeseed oil, cottonseed oil, sesame oil, safflower oil, almond oil, castor oil, olive oil, cacao oil, coconut oil, sunflower oil. Examples include, but are not limited to, oil, palm oil, flax oil, perilla oil, shea oil, coconut oil, jojoba oil, grape seed oil, and avocado oil.

  As for the compounding quantity of (B) component with respect to (A) component, it is preferable that (B) component is 0.2-200 micrograms with respect to 1 unit of vitamin A. Within this range, the effect of enhancing the stabilization of vitamins A without causing negative effects due to excessive oil becomes more prominent. For the same reason, it is more preferably 0.3 to 1.5 μg.

  The blending amount of the component (B) in the aqueous composition is preferably 0.01 to 1 w / v% in terms of the total amount of the component (B) with respect to the total amount of the aqueous composition. Within this range, the effect of reducing the sense of discomfort to the eyes while maintaining the effectiveness for stabilizing vitamin A becomes more prominent. For the same reason, it is more preferably 0.01 to 0.5 w / v%.

  The aqueous composition of the present invention further contains (C) a fat-soluble antioxidant.

  (C) Fat-soluble antioxidants include dibutylhydroxytoluene (hereinafter abbreviated as “BHT”), butylhydroxyanisole (BHA), which are commercially available as components of skin external preparations in the pharmaceutical, quasi-drug or cosmetic field. ), Tocopherol, tocopherol derivatives or pharmacologically acceptable salts thereof (tocopherol acetate, tocopherol nicotinate, tocopherol succinate, tocopherol calcium succinate, etc.), nordihydroguaiaretic acid, propyl gallate, fat-soluble vitamin C Derivatives and the like can be used. As the tocopherol and tocopherol derivative, α, β, γ, δ-tocopherol and derivatives thereof can be used. The tocopherol can be used regardless of whether it is a d-form (natural vitamin E or the like) or a dl-form.

  These fat-soluble antioxidants may be used alone or in combination of two or more.

  Among the above fat-soluble antioxidants, it is preferable to use tocopherol or a tocopherol derivative. By adding tocopherol or a tocopherol derivative, the stability of vitamins A in the aqueous composition is further improved. In addition, when the aqueous composition contains the component (B) and the component (D), the aqueous composition may become cloudy, but by adding tocopherol or a tocopherol derivative, the cloudiness is suppressed and clarified. be able to.

  Although the compounding quantity of (C) component to an aqueous composition can be suitably selected in consideration of a usability, an effect, etc., (C) component is preferably 0.005 to the total amount with respect to the total amount of the aqueous composition. Examples thereof include 0.1 w / v%, more preferably 0.01 to 0.07 w / v%, and still more preferably 0.03 to 0.06 w / v%.

  The aqueous composition of the present invention further contains (D) a nonionic surfactant. As the nonionic surfactant, a pharmacologically acceptable one can be used.

  (D) Specific examples of nonionic surfactants include monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan ( POE sorbitan fatty acid esters such as polysorbate 60), tristearic acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); POE (10) castor oil, POE (35) castor oil POE castor oils such as POE (50) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 50), POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60), etc .; Poloxamer 407 , Poloxamer 235, Polo Summer 188, poloxamer 403, poloxamer 237, POE · POP block copolymers such as Poloxamer 124, and the like. In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of moles added. These nonionic surfactants may be used individually by 1 type, and may be used in combination of 2 or more type.

  Among the nonionic surfactants described above, POE sorbitan fatty acid esters, POE castor oil, or POE hydrogenated castor oil; preferably polysorbate 80 and polyoxyethylene hydrogenated castor oil 60 are used.

  The blending amount of the component (D) in the aqueous composition can be appropriately set according to the type of the nonionic surfactant, the type and blending amount of other blending components, the use of the aqueous composition, and the like. As an example of the blending amount of the component (D), the total amount of the component (D) is preferably 0.01 to 0.5 w / v%, more preferably 0.05 to 0 based on the total amount of the aqueous composition. 0.5 w / v%, more preferably 0.1 to 0.5 w / v%.

  When a certain amount of (D) a nonionic surfactant is used, white turbidity occurs when at least one oil selected from the group consisting of (B) waxes, hydrocarbons, ester oils and vegetable oils is dissolved. Sometimes. However, by adding the component (A) and the component (C) to the aqueous composition containing the component (B) and the component (D), the cloudiness of the aqueous composition can be suppressed and the clarity is improved. The clarity in the present invention can be evaluated by, for example, the visible light transmittance at 600 nm.

  The aqueous composition of the present invention may further contain (E) a chelating agent. By blending the component (E), the stability of the vitamin A can be further improved, and the clarity of the aqueous composition and the transpiration inhibiting effect can be expressed in a balanced manner.

  (E) Chelating agents include ethylenediaminetetraacetic acid (EDTA), ethylenediaminehydroxyethyltriacetic acid (HEDTA), citric acid, tartaric acid, succinic acid, ascorbic acid, phytic acid, polyphosphoric acid, metaphosphoric acid, or salts thereof. It is done. The salt of EDTA is not particularly limited as long as it is pharmacologically acceptable, and examples thereof include alkali metal salts such as sodium EDTA, disodium EDTA, and tetrasodium EDTA. EDTA or a salt thereof can also be used in the form of a hydrate. Specific examples of the hydrate form include disodium EDTA (hereinafter also referred to as “sodium edetate”). The salt of HEDTA is not particularly limited as long as it is pharmacologically acceptable, and examples thereof include HEDTA trisodium. These chelating agents may be used individually by 1 type, and may be used in combination of 2 or more type.

  The blending amount of the component (E) in the aqueous composition can be appropriately selected in consideration of causing irritation if it is too high or reducing the effect if it is too low, but with respect to the total amount of the aqueous composition, The total amount of component (E) is preferably 0.0005 to 0.5 w / v%, more preferably 0.001 to 0.2 w / v%, still more preferably 0.003 to 0.1 w / v%, particularly preferably. Is exemplified by 0.004 to 0.05 w / v%.

  The reason why the stability of vitamin A in the aqueous composition is improved in the present invention is not necessarily clear, but the present inventors speculate as follows. That is, when (D) component is mix | blended with the aqueous composition containing (A) component and (B) component, the conjugate of (A) component and (B) component formed the micelle palisade by (D) component. Form a complex incorporated in the layer. At this time, the composite is oriented in the palisade layer so that the component (A) is located inside the micelle and the component (B) is located outside the micelle. Then, the substance that denatures vitamin A such as dissolved oxygen in the aqueous composition becomes difficult to react with the component (A). As a result, it is considered that the stability of vitamin A in the aqueous composition is further improved. However, the above is only a guess and does not limit the mechanism of stability of vitamins A in the aqueous composition.

  The size of micelles formed in the aqueous composition of the present invention is preferably 20 to 100 nm as an average particle size. Here, the average particle size of the micelles of the present invention is calculated from the dynamic light scattering theory based on the scattered light data measured by the batch method using a laser diffraction / scattering particle size distribution measuring device (for example, Otsuka Electronics FPAR-1000). Means the median diameter obtained by automatically calculating the particle size distribution. The median diameter is a particle diameter corresponding to a cumulative frequency distribution of 50%.

  The aqueous composition of the present invention may further contain a buffer. The buffer that can be blended in the aqueous composition of the present invention is not particularly limited as long as it is pharmacologically acceptable. Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, Tris buffer, amino acid buffer, and the like.

  Boric acid or a salt thereof (borax, etc.) as a boric acid buffer; phosphoric acid or a salt thereof (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, triphosphate) Sodium, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc .; as a carbonate buffer, carbonic acid or a salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate) Citrate buffer, citric acid or a salt thereof (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.); acetic acid buffer, acetic acid Or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); As a buffering agent, tris (hydroxymethyl) aminomethane (trometamol) and the like; as an amino acid buffer, various amino acids (epsilon - aminocaproic acid, potassium aspartate, sodium glutamate, etc.) can be exemplified. These buffering agents may be used alone or in any combination of two or more.

  As the buffer, when boric acid and borax are used in combination or tris (hydroxymethyl) aminomethane is used, an excellent antiseptic effect can be obtained, which is also suitable in terms of the stability of vitamins A.

  The blending amount of the buffering agent in the aqueous composition can be appropriately set according to the type of buffering agent used, the type and blending amount of other blending components, the use of the aqueous composition, and the like. As an example of the amount of the buffering agent, the total amount of the buffering agent is preferably 0.01 to 5 w / v%, more preferably 0.05 to 3 w / v%, still more preferably 0, based on the total amount of the aqueous composition. .1 to 2 w / v% is exemplified.

  The aqueous composition of the present invention can take various preparation forms depending on the purpose. For example, the form of the aqueous composition of the present invention includes liquid, semi-solid (such as ointment). Here, the aqueous composition means a composition containing water, and usually 50% by mass or more of water in the composition, preferably 75% by mass or more, more preferably 80% by mass or more, and still more preferably. It means what contains 90% by mass or more. The water contained in the aqueous composition may be pharmacologically acceptable. For example, distilled water, ordinary water, purified water, sterilized purified water, water for injection, and distilled water for injection can be used. These definitions are based on the 16th revised Japanese Pharmacopoeia.

  In addition, the aqueous composition of the present invention can be used as a pharmaceutical preparation, a quasi-drug, and the like. For example, an ophthalmic composition, a nasal composition, an oral composition, an ear composition, a composition for subcutaneous administration. It can be used in various applications such as products and compositions for external use on the skin.

  Here, ophthalmic compositions include eye drops, artificial tears, eyewashes, eye ointments, contact lens mounting liquids, contact lens care agents (contact lens disinfectants, contact lens preservatives, contact lens cleaners). , Contact lens cleaning preservatives, etc.). In addition, nasal compositions include nasal drops, nasal washings, and the like. Oral compositions include internal medicines (eg, liquids, syrups, extracts), oropharyngeal drugs, mouthwashes, and the like. The eardrop composition includes eardrops. The composition for subcutaneous administration includes injections and the like.

  Among the above uses, ophthalmic compositions are often much lower in concentration of compounding components than compositions for other uses such as oral compositions, and even a slight decrease in compounding amount is a major problem. It can be. In addition, the ophthalmic composition needs to consider the interaction with the filter member for filter sterilization and the permeability for the foreign substance test in the manufacturing process, and safety for application to highly sensitive ocular tissue. It is necessary to consider the guarantee of sensory characteristics, taste characteristics felt through the nasolacrimal duct, adhesion to wrinkles and clothes, and there are very high restrictions on prescription design. In particular, eye drops in ophthalmic compositions have a large effect on the amount of compounding because they are used in a very small amount, and the contents dripped from a small nozzle (inner plug). There is also a need for a device that does not cause the eye drop component to precipitate or change color. In view of the effects of the present invention, a preferred example of the aqueous composition of the present invention is an ophthalmic composition, and a particularly preferred example is an eye drop.

  The pH of the aqueous composition of the present invention is not particularly limited as long as it is within a pharmacologically acceptable range. Examples of the pH of the aqueous composition of the present invention include a range of 5 to 9, preferably 5.5 to 8.5, more preferably 6 to 8, and more preferably 6.5 to 7.5. it can. Moreover, if it is in the said pH range, it is safe even if it applies to an eye or a lens, and it is useful as an aqueous composition for ophthalmology.

  If necessary, the aqueous composition of the present invention can be adjusted to an osmotic pressure ratio within a range acceptable for a living body. The appropriate osmotic pressure ratio varies depending on the use and form of the composition, but is usually 0.4 to 2.5, preferably 0.5 to 1.8, more preferably 0.6 to 1.7, more preferably It is about 0.85 to 1.55, particularly preferably about 0.95 to 1.30.

  In the aqueous composition of the present invention, the osmotic pressure ratio is determined as the osmotic pressure ratio with respect to physiological saline based on the osmotic pressure measuring method (osmolarity measuring method) of the 16th revision Japanese Pharmacopoeia.

  The pH and osmotic pressure ratio can be adjusted by a method known in the art using inorganic salts and polyhydric alcohols, sugar alcohols, saccharides, and the like.

  In the aqueous composition of the present invention, various pharmacologically active ingredients and physiologically active ingredients are appropriately added in addition to the above-mentioned components according to the usual method depending on the use and the form of the preparation as long as the effects of the present invention are not impaired. It may be selected, and one or more may be used in combination to contain an appropriate amount. Examples of these pharmacologically active components and physiologically active components include active ingredients in various pharmaceuticals described in the generic drug manufacture (import) approval standard 2000 edition (supervised by the Pharmaceutical Affairs Research Committee).

Specific examples of the pharmacologically active component or physiologically active component include the following components.
Antihistamine or antiallergic agent: for example, ketotifen fumarate, iproheptin, chlorpheniramine maleate, diphenhydramine hydrochloride, sodium cromoglycate, tranilast, pemirolast potassium and the like.
Decongestant: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, and the like.
Bactericides: for example, acrinol, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride, polyhexamethylene biguanide hydrochloride, etc.
Vitamins: For example, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, cyanocobalamin, panthenol, calcium pantothenate and the like.
Amino acids: For example, potassium aspartate, magnesium aspartate, aminoethylsulfonic acid and the like.
Anti-inflammatory agent: for example, dipotassium glycyrrhizinate, azulene sulfonic acid, allantoin, tranexamic acid, epsilon-aminocaproic acid, berberine, lysozyme and the like.
Astringent: For example, zinc white, zinc lactate, zinc sulfate and the like.
Other: For example, sodium hyaluronate, sulfamethoxazole, sulfamethoxazole sodium, pranoprofen and the like.

Further, in the eye drop of the present invention, various additives are appropriately selected according to conventional methods and used in combination with one or more, as long as the effects of the invention are not impaired. Thus, an appropriate amount may be contained. Examples of these additives include various additives described in Pharmaceutical Additives Encyclopedia 2007 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.
Thickener: For example, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, alginic acid, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol, sodium chondroitin sulfate, sodium hyaluronate, etc. .
Sugars: for example, glucose, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.
Preservatives, bactericides or antibacterial agents: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glowyl (manufactured by Rhodia) Name) etc.
pH adjuster: for example, hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, boro Sand, triethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, gluconolactone, ammonium acetate and the like.
Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol and the like.
Stabilizers: for example, trometamol, sodium formaldehyde sulfoxylate (Longalite), sodium pyrosulfite, aluminum monostearate, glyceryl monostearate, etc.
Perfume or refreshing agent: for example, menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, ryuno and the like. These may be either d-form, l-form or dl-form, and are formulated as essential oils (mint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, rose oil, etc.) May be.

(II) Vitamin A class stabilizer and stabilization method As described above, the aqueous composition containing vitamin A class is at least selected from the group consisting of (B) waxes, hydrocarbons, ester oils and vegetable oils. By blending one oil, vitamin A can be stabilized. Accordingly, the present invention further comprises (B) a vitamin A stabilizer containing at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils, and vitamin As. There is also provided a method for stabilizing vitamin A, wherein (B) at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils is blended with the aqueous composition. In the vitamin A stabilizer and stabilization method, vitamin A and (B) at least one kind and blending ratio selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils The other compounding components and the like are as described in the column of the aqueous composition (I).

(III) Clarification agent and clarification method At least one oil component selected from the group consisting of (B) waxes, hydrocarbons, ester oils and vegetable oils using a certain amount of (D) a nonionic surfactant. When dissolved, white turbidity may occur. The present inventors include (B) at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils, and (D) a nonionic surfactant containing an oil composition. It has been found that by adding soluble vitamins, white turbidity of the aqueous composition can be suppressed, and clarity is improved. Accordingly, the present invention further provides a clear aqueous composition comprising (B) at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils, and (D) a nonionic surfactant. A clarifying agent containing a fat-soluble vitamin, and (B) at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils; Provided is a method for clarifying an aqueous composition, which comprises incorporating a fat-soluble vitamin into an aqueous composition containing an ionic surfactant. In addition, the clarity in this invention can be evaluated by the visible light transmittance in 600 nm, for example.

  Examples of fat-soluble vitamins include vitamins A and vitamins E. Vitamin A refers to vitamin A (that is, retinol) and derivatives thereof (for example, various isomers and esters of retinol). Specifically, as vitamin A, retinol, retinol palmitate, retinol acetate, retinol butyrate, retinol propionate, retinol octylate, retinol laurate, retinol oleate, retinol linolenate, retinal, retinoic acid, methyl retinoate , Retinoic acid ethyl, retinoic acid retinol, vitamin A fatty acid ester, δ-tocopheryl retinoate, α-tocopheryl retinoate, β-tocopheryl retinoate, and the like. Vitamin E refers to α, β, γ, δ-tocopherol and derivatives thereof (for example, tocopherol acetate, tocopherol nicotinate, tocopherol succinate), α, β, γ, δ-tocotrienol and derivatives thereof, vitamin E Examples include linoleate. The tocopherol and tocotrienol can be used regardless of whether they are d-form (natural vitamin E or the like) or dl-form.

  The said fat-soluble vitamin may be used individually by 1 type, and may be used in combination of 2 or more type. In particular, when vitamin A and vitamin E are used in combination, the clarification effect becomes remarkable. As a specific example of the combination of vitamin A and vitamin E, a combination of retinol palmitate and tocopherol acetate is preferable.

  For example, when vitamin A is used, the amount of the fat-soluble vitamin is preferably 5000 to 50000 units, more preferably 10,000 to 50000 units, and further preferably 25000 to 50000 per 100 mL of the aqueous composition. Unit. When vitamin E is used, the total amount of vitamin E is preferably 0.005 to 0.05 w / v, more preferably 0.01 to 0.05 w / v, based on the total amount of the aqueous composition. %, And more preferably 0.02 to 0.05 w / v%.

  Further, when the vitamin A and vitamin E are used in combination, the ratio of the two is preferably 0.1 to 10 μg of vitamin E, more preferably 0.6 to 1 unit of vitamin A. It is -1.6 microgram, More preferably, it is 0.8-1.2 microgram.

  In the clarification agent and clarification method, (B) component and (D) component, and other compounding components other than fat-soluble vitamins are as described in the column of the aqueous composition of (I) above. is there.

  Hereinafter, the present invention will be described in more detail based on test examples, but the present invention is not limited thereto.

[Test Example 1 Stability Evaluation of Vitamin A-1]
A test solution was prepared according to the formulation in Table 1. Specifically, components other than boric acid and borax (wet retinol palmitate, acetic acid-d-α-tocopherol, l-menthol, purified lanolin, dibutylhydroxytoluene and polyoxyethylene hydrogenated castor oil 60) are weighed. Under stirring in a warm bath at 70 ° C., a 5-fold pre-preparation solution (fat-soluble component preparation solution) was prepared. Separately, an aqueous solution in which boric acid and borax were dissolved was prepared, and the test solution was prepared by adding the 5 times pre-prepared solution prepared earlier and then measuring up with purified water. These test solutions were filled in a transparent glass vial so that the porosity was 10% or less, sealed, and stored at 4 ° C. and 50 ° C. for 2 weeks under light shielding conditions. Two weeks later, the content of retinol palmitate contained in the taken-out test solution was quantified by the HPLC method and calculated as the residual rate of vitamin A according to the following formula. The result is shown in FIG.
Vitamin A residual rate (%) = (Retinol palmitate content of 50 ° C. product / 4 retinol palmitate content of 4 ° C. product) × 100

  The prescription of Example 1 containing (A) component retinol palmitate and (B) purified lanolin is higher than the prescription of Comparative Example 1 which does not contain (B) component. It is high and it turns out that stability of vitamin A is improving. That is, the stability of vitamin A is improved by blending purified lanolin as the component (B). Moreover, according to the prescription of Examples 1-4, it turns out that stability of vitamin A is improving with the compounding quantity of refined lanolin increasing (FIG. 1).

[Test Example 2 Stability Evaluation of Vitamin A-2]
According to the formulation of Table 2, a test solution was prepared in the same manner as in Test Example 1. These test solutions were filled in a transparent glass vial so that the porosity was 10% or less, sealed, and stored at 4 ° C. and 60 ° C. for 4 days under light shielding conditions. After storage, the content of retinol palmitate contained in the taken out test solution was quantified by HPLC method, and calculated as the residual rate of vitamin A according to the following formula. The result is shown in FIG.
Vitamin A residual rate (%) = (Retinol palmitate content of 60 ° C. product / 4 retinol palmitate content of 4 ° C. product) × 100

  Tocopherol acetate as component (C) in the formulation of Reference Example 1 containing retinol palmitate as component (A), purified lanolin as component (B), and polyoxyethylene hydrogenated castor oil 60 as component (D) (Example 5) shows that the residual ratio of vitamin A is further increased, and the stability of vitamin A is further improved. In addition, when sodium edetate, which is the component (E), is further added to the formulation of Example 5 (Example 6), the residual ratio of vitamin A is further increased and the stability of vitamin A is further improved. I understand. Further, when dibutylhydroxytoluene as component (C) is further added to the formulation of Example 6 (Example 7), the residual ratio of vitamin A is further increased, and the stability of vitamin A is further improved. I understand. (FIG. 2).

[Test Example 3 Clarity Evaluation-1]
According to the formulation of Table 3, a test solution was prepared in the same manner as in Test Example 1. Immediately after preparation, the degree of cloudiness of the test solution was evaluated by measuring the light transmittance. The light transmittance (%) at 600 nm was measured with UV spectrophotometer UV-2450 (manufactured by Shimadzu). The obtained results are shown in FIG.

Compared to the formulation of Comparative Example 2 in which the purified lanolin (B) component and the polyoxyethylene hydrogenated castor oil 60 (D) component were blended, the formulation of Reference Example 1 further blended with retinol palmitate was 600 nm. It can be seen that the light transmittance is high and the clarity is improved. That is, the cloudiness produced by the component (B) and the component (D) can be clarified by blending retinol palmitate which is a fat-soluble vitamin.
Further, the formulation of Example 5 in which tocopherol acetate as component (C) was added to the formulation in Reference Example 1, the formulation in Example 6 in which sodium edetate as component (E) was added to the formulation in Example 5, and It can be seen that the formulation of Example 7 obtained by adding dibutylhydroxytoluene as component (C) to the formulation of Example 6 has high clarity equivalent to that of Reference Example 1.

[Test Example 4 Clarity Evaluation-2]
According to the prescription in Table 4, a pre-prepared solution having a normal use amount of 5 times was prepared in the same manner as in Test Example 1, and the visible light transmittance was measured. Here, the reason why the visible light transmittance in the 5-fold preparatory liquid was measured is to emphasize the difference in clarity between samples. As the visible light transmittance, a light transmittance of 600 nm was measured. Each appearance photograph is shown in FIG.

  As shown in Table 4, retinol palmitate, a fat-soluble vitamin, was added to an aqueous composition (Reference Example 2) containing purified lanolin as component (B) and polyoxyethylene hydrogenated castor oil 60 as component (D). By blending (Reference Example 3), it can be seen that the light transmittance at 600 nm is increased and the clarity is improved. It can also be seen that by further adding tocopherol acetate, which is a fat-soluble vitamin (Example 8), the light transmittance at 600 nm is further increased and the clarity is further improved. The above results are also apparent by comparing the appearance photograph of FIG.

[Test Example 5: Evaluation of clarity and transpiration suppression]
According to the prescription in Table 5, a test solution was prepared in the same manner as in Test Example 1, and the visible light transmittance and the transpiration suppression effect were evaluated.
The transpiration suppression effect was evaluated as follows. That is, about 20 mg of the test solution prepared on the slide glass was dropped and allowed to stand at room temperature for 1 hour. The preparation weight before and after standing was measured, and the transpiration rate (%) by dry transpiration was calculated from the change in weight. The obtained results are shown in FIG.
The particle diameter was determined as the median diameter obtained by automatically calculating the particle size distribution using Otsuka Electronics FPAR-1000.
As the visible light transmittance, a light transmittance of 600 nm was measured.
Visual evaluation of cloudiness was performed as follows. That is, a sample having no white turbidity and being clear was evaluated as ◯, a sample having slight turbidity was evaluated as Δ, and a sample having severe white turbidity was evaluated as ×.

  As shown in Table 5 and FIG. 5, when the concentration of retinol palmitate, which is component (A), is in the range of 5000 to 50000 units / 100 mL, the transpiration rate is low, indicating that the transpiration suppression effect is high. In this range, the light transmittance at 600 nm is high and the visual evaluation of cloudiness is good. That is, in the range of 5000 to 50000 units / 100 mL, the clarity of the aqueous composition and the transpiration suppression effect are compatible. On the other hand, if the concentration of retinol palmitate is less than 5000 units / 100 mL, the transpiration rate increases although the clarity is good. When the concentration of retinol palmitate exceeds 50000 units / 100 mL, clarity is lowered. When the concentration of retinol palmitate exceeds 100,000 units / 100 mL, the transpiration rate increases.

Claims (8)

(A) 5000 to 50000 units / 100 mL of vitamin A,
(B) at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils;
(C) a fat-soluble antioxidant,
(D) a nonionic surfactant;
It contains, and
An aqueous composition containing 75% by mass or more of water (excluding a mouthwash) .   (E) The aqueous composition of Claim 1 containing a chelating agent. The aqueous composition according to claim 1 or 2, which is an ophthalmic or nasal composition. The aqueous composition according to any one of claims 1 to 3, comprising a buffer. The aqueous composition according to any one of claims 1 to 4, wherein the pH is 5 to 9. (A) 5000 to 50000 units / 100 mL of vitamin A, (B) at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils, (C) a fat-soluble antioxidant, And (D) an evaporation inhibitor comprising a nonionic surfactant. (A) 5000 to 50000 units / 100 mL of vitamin A, (B) at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils, (C) a fat-soluble antioxidant, And (D) a moisturizing retainer comprising an aqueous composition containing a nonionic surfactant.   (B) A fat-soluble vitamin is blended with an aqueous composition containing at least one oil selected from the group consisting of waxes, hydrocarbons, ester oils and vegetable oils and (D) a nonionic surfactant. A method for clarifying the aqueous composition.