JP6179204B2 - Mucosal composition and method for producing the same - Google Patents

Description

  The present invention relates to a composition for mucosa containing a nanoemulsion containing vitamin A, and a method for producing the same.

  Active ingredients such as vitamin A, which is fat-soluble, are attracting attention as effective ingredients for treating the cornea / conjunctiva, nasal mucosa and pharynx. However, these active ingredients are very sensitive to air, light, heat, acid, metal ions, etc., and are particularly unstable in an aqueous solution, so eye drops, rhinitis drugs, external liquids, and mouthwashes. It has been a subject to be stably blended into a composition for mucous membranes.

  In order to stabilize these active ingredients such as vitamin A in a solution, various measures have been taken (setting of optimum pH, nitrogen filling in pillow, combination with antioxidant, container color, etc.). . A surfactant is necessary for emulsifying fat-soluble active ingredients such as vitamin A, but if the amount is too large, the stability of vitamin A and the like is poor, and if it is small, appearance uniformity cannot be maintained (vitamin A). Etc.).

  Furthermore, in the case of eye drops containing these active ingredients, for example, vitamin A, as measures to increase the effectiveness of vitamin A, increasing the amount of vitamin A, adding an absorption promoter to the cornea, adding a thickener Although it has been carried out, there are problems that the stability of vitamin A is lowered, the appearance of the composition becomes non-uniform, irritation to the eyes, and a sticky feeling remains.

JP-A-11-302195 Japanese Patent Laid-Open No. 2003-113078

  This invention is made | formed in view of the said situation, and it aims at providing the composition for mucous membranes which made the external appearance of the composition transparent, and was excellent by stability of vitamin A, and its manufacturing method.

  As a result of intensive studies to achieve the above object, the present inventors have determined that the amount of the nonionic surfactant with respect to vitamin A is in a specific range, the aqueous phase temperature is in a specific range in production, and the oil phase is By adding to the phase and stirring, appearance stability can be achieved even if the amount of surfactant is reduced, and furthermore, by adding the component (C), the stability of vitamin A can be further improved. It has been found and the present invention has been made. The inventors have also found that the adsorption of vitamin A to the mucous membrane can be enhanced.

Accordingly, the present invention provides the following inventions.
[1]. (A) Vitamin A 0.0005 to 0.12 W / V%, (B) Nonionic surfactant containing polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component, nonionic surfactant The total amount is 0.007 to 0.5 W / V%, and the mass ratio represented by (A) :( B) is 1: 0.4 to 14, and (C) lower alcohol, sugar alcohol, sugar, An oil phase containing at least one selected from chlorpheniramine maleate, diphenhydramine hydrochloride and flavin adenine dinucleotide sodium and containing the above components (A) and (B) is added to the water phase at 80 to 90 ° C. A composition for mucous membranes comprising nanoemulsion particles obtained by stirring and containing the components (A) and (B) as constituents.
[2]. (A) Vitamin A 0.0005 to 0.12 W / V%, (B) Nonionic surfactant containing polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component, nonionic surfactant The total amount is 0.007 to 0.5 W / V%, and the mass ratio represented by (A) :( B) is 1: 0.4 to 14, and (C) lower alcohol, sugar alcohol, sugar, An oil phase containing at least one selected from chlorpheniramine maleate, diphenhydramine hydrochloride and flavin adenine dinucleotide sodium and containing the above components (A) and (B) is added to the water phase at 80 to 90 ° C. obtained by stirring and includes a nanoemulsion particles containing the (a) and (B) component as a constituent component, the proportion of the component (a) free nonionic surfactant, ( ) Mucosal composition and less than 44% by weight of the component total.
[3]. (C) The composition for mucosa according to [1] or [2], wherein the lower alcohol is ethanol, propylene glycol or glycerin, the sugar alcohol is mannitol, and the sugar is glucose.
[4]. The composition for mucosa according to any one of [1] to [3], further comprising (D) an antioxidant selected from tocopherol acetate, dibutylhydroxytoluene and butylhydroxyanisole.
[5]. The composition for mucosa according to any one of [1] to [4], wherein the temperature of the oil phase is 65 to 90 ° C.
[6]. The composition for mucosa according to any one of [1] to [5], which is an ophthalmic composition.
[7]. (A) and vitamin A, (B) a non-ionic surfactant polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid esters as essential components, the mass ratio represented by (A) :( B) The method for producing a composition for mucosa according to [1] or [2], comprising a step of adding an oil phase containing 1: 0.4 to 14 to an aqueous phase at 80 to 90 ° C. and stirring.

  ADVANTAGE OF THE INVENTION According to this invention, the external appearance of a composition can be made transparent and the composition for mucosa excellent in stability of vitamin A and its manufacturing method can be provided.

6 is a chart showing EGPC measurement results of Reference Example 1.

  The present invention provides (A) vitamin A 0.0005 to 0.12 W / V% and (B) a nonionic surfactant containing polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component. The total amount of ionic surfactant is 0.007 to 0.5 W / V%, and the mass ratio represented by (A) :( B) is 1: 0.4 to 14, (C) lower alcohol, sugar An oil phase containing at least one selected from alcohol, sugar, chlorpheniramine maleate, diphenhydramine hydrochloride and flavin adenine dinucleotide sodium and containing the above components (A) and (B) It is a composition for mucous membranes comprising nanoemulsion particles obtained by adding to the aqueous phase and stirring and containing the above components (A) and (B) as constituent components.

(A) Vitamin A
Examples of vitamin A include, in addition to vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, vitamin A derivatives such as vitamin A fatty acid esters, and the like. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoid. Of these, retinol palmitate, retinol acetate, and retinoic acid are preferred. Retinol palmitate is usually commercially available from 1 million to 1.8 million international units (hereinafter abbreviated as IU). Specifically, retinol palmitate (manufactured by DSM Nutrition Japan Co., Ltd.) 174,000 I.U.) and the like.

  The blending amount of the component (A) is 0.0005 to 0.12 W / V% (g / 100 mL) as the total amount of the component (A) with respect to the total amount of the composition, and 0.001 to 0.1 W / V%. Is preferred. Moreover, it can select suitably according to the effectiveness and application of a compounding component. Vitamin A has the effect of treating corneal / conjunctival damage, dry eye, and fatigue / hazy eyes. In this range, the desired effect can be obtained. There is a risk of separation.

  For example, in the case of a mucosal composition or an ophthalmic composition using retinol palmitate, 0.0005 to 0.12 W / V% (g / 100 mL) is preferable with respect to the total amount of the composition. When the composition is an eye wash, 0.0005 to 0.02 W / V% (g / 100 mL) is more preferable, and 0.001 to 0.01 W / V% is more preferable. When the ophthalmic composition is an eye drop, 0.005 to 0.12 W / V% (g / 100 mL) is more preferable, and 0.01 to 0.1 W / V% is more preferable. Vitamin A has the effect of treating corneal / conjunctival damage, dry eye, and fatigue / hazy eyes. In this range, the desired effect can be obtained. There is a risk of separation.

(B) Nonionic surfactant The nonionic surfactant used in the present invention contains polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component, and includes other nonionic surfactants. You may go out. These can be used individually by 1 type or in combination of 2 or more types.

  The present invention comprises polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component, but polyoxyethylene hydrogenated castor oil, or polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester. It is preferable to use together. Examples of the polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 60 (polyoxyethylene (60) hydrogenated castor oil), polyoxyethylene hydrogenated castor oil 40 (polyoxyethylene (40) hydrogenated castor oil), Polyoxyethylene hydrogenated castor oil 60 (polyoxyethylene (60) hydrogenated castor oil) is preferred. Examples of polyoxyethylene sorbitan fatty acid esters include monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60), and tristearic acid. POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80), and monooleic acid POE (20) sorbitan (polysorbate 80) are preferred.

  Examples of the nonionic surfactant other than the above include polyoxyethylene polyoxypropylene copolymer, polyoxyethylene alkyl ether and the like. More specifically, polyoxyethylene polyoxypropylene copolymers include polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160). Polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol Can be mentioned. Examples of the polyoxyethylene alkyl ether include polyoxyethylene (9) lauryl ether, and the like can be used singly or in appropriate combination of two or more. Among these, polyoxyethylene (200) polyoxypropylene (70) glycol is preferable. You may combine 2 or more types suitably.

  (B) The compounding quantity of a component is 0.007-0.5 W / V% in a composition as a nonionic surfactant whole quantity, Comprising: 0.01-0.4 W / V% is preferable. By setting it as this range, the appearance is transparent, the stability of vitamin A is excellent, and the adsorption of vitamin A to the cornea can be further improved. From the viewpoint of eye irritation, 0.3 W / V% or less is preferable, and 0.2 W / V% or less is more preferable.

  Moreover, it is 1: 0.4-14 by mass ratio represented by (A) :( B), 1: 1.0-10 are preferable, and 1: 1.5-7.0 are more preferable. If the amount of (B) nonionic surfactant per (A) vitamin A is too small, the oily component cannot be sufficiently emulsified, and the appearance transparency is lowered or separated without becoming a stable emulsion. On the other hand, if (A) the amount of (B) nonionic surfactant per vitamin A is too large, the particle size of the emulsion is small, the appearance is more uniform and transparent, and the formulation has excellent appearance stability. Although the composition can be obtained, for example, the effect of improving the adsorption of (A) vitamin A to the cornea or the like is insufficient, and as a result, the effect of improving the intended action of vitamin A is insufficient. In the present invention, corneal / conjunctival damage, which is 14 or less, improves the adsorption property of vitamin A to the mucous membrane such as cornea, and exhibits the effect of the component (A) in a small amount. Healing effect, dry eye improvement, fatigue eyes and blurred eyes can be improved.

Furthermore, the following amounts and ratios are preferable from the viewpoint of the stability and adsorbability of vitamin A and the appearance of the composition.
I- (1): HCO-VA low concentration (A) Vitamin A 0.003 W / V% or more and less than 0.015 W / V% (B) Non-ion selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester 1: 3.0-10, 1: 3.0-10.0 are more preferable by the mass ratio represented by (A) :( B).
I- (2) -1: Concentration in HCO-VA (A) Vitamin A 0.015-0.05 W / V%,
(B) A nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester is used at a mass ratio represented by (A) :( B) of 1: 1.6 to 7.0. 1.6 to 4 or less is more preferable, and 1.6 to less than 4.0 is more preferable.
I- (3): HCO-VA high concentration (A) Vitamin A exceeding 0.05 W / V% and 0.12 W / V% or less (B) Polyoxyethylene hydrogenated castor oil 60 and / or monooleic acid POE (20) Sorbitan is used at a mass ratio of (A) :( B) of 1: 1.6 to 5.0.

Component (C) Examples of the component (C) include lower alcohols, sugar alcohols, sugars, chlorpheniramine maleate, diphenhydramine hydrochloride, flavin adenine dinucleotide sodium and the like. They can be used in combination. Examples of lower alcohols include ethanol, propylene glycol, and glycerin. Examples of the sugar alcohol include mannitol. Examples of the sugar include glucose. Of these, chlorpheniramine maleate, ethanol, diphenhydramine hydrochloride, and glycerin are preferable. In the present invention, the stability of (A) vitamin A can be unexpectedly increased by blending the component (C).

  (C) The compounding quantity of a component is 0.01-10 W / V% in a composition as a total amount, and 0.02-8 W / V% is more preferable. By setting it as this range, the effect which raises the stability of vitamin A more is acquired.

(D) Antioxidant An antioxidant can be further mix | blended with the composition of this invention. Antioxidants include tocopherol acetate (dl-α-tocopherol acetate, d-α-tocopherol acetate (vitamin E)), dibutylhydroxytoluene, butylhydroxyanisole, etc., one of these alone or two A combination of the above can be used.

  The total amount of the antioxidant is 0.001 to 0.5 W / V% in the composition, and preferably 0.005 to 0.1 W / V%. By setting it as this range, the storage stability of vitamin A is improved.

  Further, glycerides such as castor oil and sesame oil, liquid paraffin, gelled hydrocarbon, lanolin and the like can also be blended.

  In the present invention, (A) vitamin A and (D) an antioxidant selected from tocopherol acetate, dibutylhydroxytoluene and butylhydroxyanisole are preferably used in combination, and in particular, (D) two antioxidants are used. It is good to use together. Thereby, the storage stability (residual rate) of (A) vitamin A is further improved. In the case of this combination, the blending amount when the component (D) is tocopherol acetate is preferably 0.01 to 0.5 W / V%, more preferably 0.02 to 0.1 W / V% with respect to the total amount of the composition. Preferably, 0.03 to 0.05 W / V% is more preferable. (D) As for the compounding quantity in case a component is dibutylhydroxytoluene, 0.001-0.1 W / V% is preferable with respect to the composition whole quantity, 0.002-0.05 W / V% is more preferable, 0.00. 003 to 0.005 W / V% is more preferable. By setting it as this range, (A) storage stability of vitamin A and appearance transparency are further improved.

  In the composition of the present invention, in addition to the above components, various components to be blended in the composition for mucosa can be blended within a range not impairing the effects of the present invention. Examples of these components include various drugs and various additives shown below, and these can be used alone or in appropriate combination of two or more. These components include polyhydric alcohols other than the component (C), buffers, thickeners, sugars other than the component (C), pH adjusters, preservatives, isotonic agents, stabilizers, and cooling agents. , Moisturizers, drugs and the like. These can be used individually by 1 type or in combination of 2 or more types, respectively, and can mix | blend suitable amount.

  Examples of the polyhydric alcohol include butylene glycol and polyethylene glycol. The content of the polyhydric alcohol is preferably 0.01 to 5 W / V%, more preferably 0.05 to 3 W / V% in the composition for mucosa.

  Examples of the buffer include boric acid or a salt thereof (such as borax), citric acid or a salt thereof (such as sodium citrate), phosphoric acid or a salt thereof (such as sodium monohydrogen phosphate), tartaric acid or a salt thereof (tartaric acid) Sodium), gluconic acid or a salt thereof (sodium gluconate, etc.), acetic acid or a salt thereof (sodium acetate, etc.), carbonic acid or a salt thereof (sodium bicarbonate, etc.), trometamol, various amino acids (epsilon-aminocaproic acid, aspartic acid) Potassium, aminoethylsulfonic acid, glutamic acid, sodium glutamate, etc.). Of these, trometamol is preferable from the viewpoint of mildness and the antiseptic effect of the composition. Furthermore, when boric acid and borax are used in combination, a particularly high antiseptic effect is obtained. The content of the buffer is preferably 0.001 to 10 W / V%, more preferably 0.01 to 5 W / V%, based on the total amount of the mucosa composition.

  Examples of the thickener include polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, polyethylene glycol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, alginic acid, carrageenan, gelatin and the like. It is done. The content of the viscous agent relative to the total amount of the composition for mucosa is, for example, 0.001 to 10 W / V%, preferably 0.001 to 5 W / V%, more preferably 0.01 to 3 W / V%. .

  Examples of the saccharide include cyclodextrin, xylitol, sorbitol and the like. These may be any of D-form, L-form and DL-form. The content of saccharides with respect to the total amount of the composition for mucosa is, for example, 0.001 to 10 W / V%, preferably 0.005 to 5 W / V%, more preferably 0.01 to 3 W / V%.

  As the pH adjuster, it is preferable to use an inorganic acid or an inorganic alkali agent. For example, (diluted) hydrochloric acid is mentioned as an inorganic acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like. Of these, hydrochloric acid and sodium hydroxide are preferable. The pH (20 ° C) of the composition for mucosa of the present invention is preferably 4.0 to 9.0, more preferably 5.0 to 8.0, and still more preferably 6.0 to 8.0. . In the present invention, pH is measured at 20 ° C. using a pH osmometer (HOSM-1, Toa DKK Co.). The content of the pH adjuster with respect to the total amount of the composition for mucosa is, for example, 0.00001 to 10 W / V%, preferably 0.0001 to 5 W / V%, more preferably 0.001 to 3 W / V%. .

  The preservative can be blended within a range that does not impair the effects of the present invention, but the mucosa composition of the present invention can also be free from preservatives containing no preservative from the viewpoint of irritation. As preservatives, benzalkonium chloride, benzethonium chloride, sorbic acid or a salt thereof, paraoxybenzoic acid ester (methylparaben, ethylparaben, propylparaben, etc.), chlorhexidine gluconate, tiromesal, phenylethyl alcohol, alkyldiaminoethylglycine hydrochloride, Examples include polydronium chloride and polyhexanide hydrochloride. The content of the preservative with respect to the total amount of the composition for mucosa is, for example, 0.00001 to 5 W / V%, preferably 0.0001 to 3 W / V%, more preferably 0.001 to 2 W / V%. When the preservative is not added, the preservative power may be one or more, preferably two or more, in combination of sodium edetate, boric acid and trometamol. Moreover, when it is set as a unit dose container and a container with a filter, it can be set as preservative-free.

  Examples of the isotonic agent include sodium chloride, potassium chloride, glycerin and the like. The content of the tonicity agent relative to the total amount of the mucosa composition is, for example, 0.001 to 5 W / V%, preferably 0.01 to 3 W / V%, more preferably 0.1 to 2 W / V%.

  Examples of the stabilizer include sodium edetate, cyclodextrin, sulfite, ascorbic acid and the like. The content of the stabilizer relative to the total amount of the mucosa composition is, for example, 0.001 to 5 W / V%, preferably 0.01 to 3 W / V%, more preferably 0.1 to 2 W / V%. .

  Examples of the refreshing agent include menthol, camphor, borneol, geraniol, linalool, cineol and the like. The content of the refreshing agent with respect to the total amount of the mucosa composition is preferably 0.0001 to 2 W / V%, more preferably 0.001 to 1 W / V%, and more preferably 0.005 to 0.5 W / V as the total amount of the compound. V% is more preferable, and 0.007 to 0.3 W / V% is particularly preferable.

Examples of drugs (pharmaceutical active ingredients) include decongestants (eg, naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, naphazoline nitrate), anti-inflammatory / astringent agents (eg, , Methyl sulfate neostigmine, ε-aminocaproic acid, allantoin, berberine chloride, zinc sulfate, zinc lactate, lysozyme chloride, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, methyl salicylate, tranexamic acid, sodium azulene sulfonate, etc.), antihistamine agent (e.g., hydrochloric iproheptine, isothipendyl hydrochloride, water-soluble vitamins (activated vitamin B _2, vitamin B _6, vitamin B _12, etc.), amino acids (e.g., L- aspartic acid number , Magnesium L-aspartate, aminoethyl sulfonic acid, sodium chondroitin sulfate, etc.), sulfa drugs, fungicides (eg, sulfur, isopropylmethylphenol, hinokitiol, etc.), antiallergic agents (cromoglycic acid, ketotifen fumarate, tranilast, etc.) Local anesthetics (for example, lidocaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, etc.), mydriatics (cyclopentolate hydrochloride, tropicamide, etc.), and cataract treatment agents (pirenoxine, glutathione, etc.) can be appropriately blended.

  The content of these components is appropriately selected according to the type of preparation, the type of drug, and the like, and the content of various components is known in the art. For example, when it is set as an ophthalmic composition, it can select suitably from the range of 0.0001-30 W / V% with respect to the ophthalmic composition whole quantity, Preferably it is 0.001-10 W / V%. More specifically, the content of each component with respect to the total amount of the ophthalmic composition is as follows.

If it is a decongestant, for example, it is 0.0001 to 0.5 W / V%, preferably 0.0005 to 0.3 W / V%, more preferably 0.001 to 0.1 W / V%.
If it is a flame retardant / astringent, it is 0.0001-10 W / V%, for example, Preferably it is 0.0001-5 W / V%.
If it is an antihistamine, it is 0.0001-10W / V%, for example, Preferably it is 0.001-5W / V%.
If it is a water-soluble vitamin, it is 0.0001-1 W / V%, Preferably, it is 0.0001-0.5 W / V%.
If it is an amino acid, it is 0.0001-10W / V%, Preferably it is 0.001-3W / V%.
If it is a sulfa agent and a disinfectant, it is 0.00001-10W / V%, for example, Preferably, it is 0.0001-10W / V%.
If it is an antiallergic agent, it is 0.0001-10 W / V%, for example, Preferably it is 0.001-5 W / V%.
In the case of a local anesthetic, mydriatic, or cataract therapeutic agent, for example, it is 0.001 to 1 W / V%, preferably 0.005 to 1 W / V%.

  Water is used as the aqueous phase solvent. As water, purified water, sterilized water, or the like can be used, and it is appropriately selected according to the aqueous phase. The content of the total amount of the composition should be 100 (remainder), 90 to 99.999 W / V is preferable, and 95 to 99.995 W / V% is more preferable.

The composition for mucosa of the present invention comprises the components (A) and (B) obtained by adding the oil phase containing the components (A) and (B) to the aqueous phase at 75 to 90 ° C. and stirring. It is the composition for mucous membranes containing the nanoemulsion particle contained as a structural component. As a production method, (A) Vitamin A 0.0005 to 0.12 W / V% (in composition) , (B) Nonionic interface containing polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component The active agent is 0.007 to 0.5 W / V% (in the composition) as the total amount of the nonionic surfactant, and the mass ratio represented by (A) :( B) is 1: 0.4. Adding the oil phase containing -14 to the 75-90 degreeC aqueous phase and stirring. The “oil phase” contains (A) “vitamin A”, “oil phase blending component” such as a nonionic surfactant such as component (B), (D) an antioxidant, and “water phase” "Includes water and water-soluble components (water-soluble drugs, inorganic salts, water-soluble polymers, preservatives, etc.) that are soluble in water. Component (C) may be added after stirring the oil phase and the aqueous phase.

  The oil phase compounding component concentration with respect to the mucosa composition is preferably 3.0 W / V% or less, more preferably 1.0 W / V% or less. By setting this range, the appearance uniformity is further improved.

  The oil phase temperature is preferably 50 to 90 ° C, more preferably 65 to 90 ° C, and further preferably 70 to 85 ° C. By setting it within this temperature range, a uniform mixed state of the oil phase can be obtained, and a composition for mucosa having a more uniform appearance can be obtained.

  What is important in the present invention is the aqueous phase temperature, which is 75 to 90 ° C, preferably 80 to 90 ° C, more preferably 82 to 90 ° C, and still more preferably 83 to 90 ° C. If the temperature is too low, a nanoemulsion cannot be obtained with the amount of the (B) nonionic surfactant of the present invention, and a mucosal composition having a uniform appearance cannot be obtained. On the other hand, if the temperature is too high, (A) vitamin A may be decomposed.

  The amount of the aqueous phase at the time of adding and stirring the oil phase is not particularly limited, but it is preferably 50 W / V% or more of the whole composition as per the method for producing a composition containing an ordinary emulsion, and preferably 75 W / V. % Or more is more preferable.

  Add the oil phase to the water phase as soon as possible. The average temperature of the water tank from the start of stirring to the end of stirring after addition of the oil phase is preferably 75 to 90 ° C, more preferably 80 to 90 ° C, further preferably 82 to 90 ° C, and particularly preferably 83 to 90 ° C. . The allowable deflection width with respect to the average temperature of the aqueous phase is ± 4 ° C. In the present invention, the aqueous phase temperature after addition of the oil phase from the start of stirring to the end of stirring is preferably between 75 and 90 ° C, more preferably 80 to 90 ° C, still more preferably 82 to 90 ° C, 83 ˜90 ° C. is particularly preferred. In addition, although cooling is performed after completion | finish of stirring, the cooling temperature after completion | finish of stirring is not included in the said temperature.

  The stirring time is preferably 5 to 60 minutes, more preferably 5 to 30 minutes from the end of dropping of the oil phase. By setting it as this time, the input oil phase can be more uniformly dispersed in the aqueous phase.

  The stirring method when adding the oil phase to the aqueous phase may be a general stirring method used when producing a composition such as eye drops, and is appropriately performed using a pulsator, propeller blade, paddle blade, turbine blade, or the like. Although it is carried out, the number of rotations is not particularly limited, and it is preferable to set it to such an extent that it does not foam vigorously.

  The composition for mucosa obtained by the above method includes “nanoemulsion particles” containing the components (A) and (B) as constituents, and a composition for mucosa having a uniform appearance can be obtained. It was also found that the stability of vitamin A was unexpectedly improved and the adsorption of vitamin A to the mucous membrane was improved. As a result of further research, the present inventors have obtained the following knowledge.

The meaning of the terms of the present invention is defined as follows.
“Nanoemulsion particles” are nanoemulsion particles containing (A) vitamin A in the emulsion particles, and contain the above components (A) and (B) as essential components. The particle diameter of the nanoemulsion particles is 1 nm or more and less than 500 nm, preferably 10 to 500 nm, and more preferably 10 to 300 nm. For example, a particularly preferable range is more than 40 nm and 140 nm or less. When the particle diameter exceeds 40 nm, the release property of vitamin A from the nanoemulsion particles, for example, the adsorption property of vitamin A to the cornea at the time of instillation and the like is further improved. In this respect, the lower limit is particularly preferably 45 nm or more, 50 nm or more, or 55 nm or more. On the other hand, when the particle diameter of the nanoemulsion particles is 140 nm or less, a mucosal composition having a transparent appearance can be obtained. From this point, 115 nm or less is preferable, and 110 nm or less is more preferable. In the present invention, the particle diameter refers to the average diameter (median diameter nm) of the particle size distribution calculated from the scattered light intensity. The particle diameter is measured under a constant temperature condition of 25 ° C. using a thermostatic chamber by various measuring devices applying the principle of light scattering and the like.

“Vitamin A-free nonionic surfactant” refers to a nonionic surfactant that does not contain vitamin A, and includes “free micelles” and “free surfactant molecules”.
“Free micelle” refers to (A) a surfactant aggregate that does not contain vitamin A.
“Free surfactant molecule” refers to a surfactant that does not form micelles (aggregates).

  The composition for mucosa of the present invention maintains the stability of (A) vitamin A, makes the appearance of the composition for mucosa transparent, enhances the adsorption of (A) vitamin A to the mucosa, and exhibits its effect more The reason for this is unknown. In the composition for mucosa of the present invention, the ratio of “vitamin A-free nonionic surfactant” (“free micelle” and “free surfactant molecule”) not containing vitamin A was small. From this, one of the reasons why the composition for mucosa of the present invention increased the adsorption of vitamin A to the mucosa was that “vitamin A-free nonionic surfactant” adhered to the mucosal surface, and “nano In order to inhibit adhesion of “emulsion particles” to the mucosal surface, it is presumed that the adsorption of vitamin A to the cornea was improved by reducing these.

  The ratio of “vitamin A-free nonionic surfactant”, that is, the ratio of (B) component constituting “free micelle” and “free surfactant molecule” to the total amount of (B) component is less than 44% by mass Is preferable, and 43 mass% or less is more preferable. The lower limit is preferably 0% by mass, that is, not included, but may be 1% by mass or 0.01% by mass. Further, the ratio of the component (B) constituting the “nanoemulsion particles” with respect to the total amount of the component (B) is preferably more than 56% by mass, preferably 100% by mass, more preferably 57% by mass or more, and the upper limit is not limited. It is good also as mass%.

The composition such as “nanoemulsion particles”, “free micelles”, and “free surfactant molecules” in the composition for mucous membrane can be measured by using an eluting gel permeation chromatography (hereinafter referred to as EGPC).
In other words, each sample is detected by RI (detects nonionic surfactant and fat-soluble components ((A) vitamin A, (D) antioxidant, etc.)) and UV (detects only oily components), and elution Depending on the time and peak area, it can be separated into “nanoemulsion particles (RI + UV detection)”, “free micelles (RI detection)” and “free surfactant molecules (RI detection)”, and the ratio can be calculated. Assuming that all of these are contained in the sample, in RI, peaks appear in the order of (1) “nanoemulsion particles”, (2) “free micelles”, and (3) “free surfactant molecules”. In UV, the peak (1) appears. Detailed conditions will be described in Examples.

  The adsorption rate of vitamin A to the mucous membrane is preferably 10% or more, more preferably 20% or more, and further preferably more than 30%. For example, in the case of the ophthalmic composition of the present invention blended with vitamin A, the vitamin A adsorption rate at the time of 3-fold dilution is preferably 45% or more, more preferably 60% or more. The closer the upper limit is to 100%, the better. In addition, the measuring method of a vitamin A adsorption rate is a method as described in the Example mentioned later.

  The composition for mucosa of the present invention may be used as it is, or may be prepared as a gel or the like. Specific examples of usage forms include ophthalmic compositions, nasal drops, nasal sprays, oral sprays such as oral cavity and throat diseases, and throat sprays.

  Specific examples of ophthalmic compositions include eye drops (eg, general eye drops, contact lens eye drops, etc.), eye wash (general eye wash, eye wash used after removing contact lenses, etc.). , Contact lens mounting liquid, contact lens removing liquid, and the like, and eye drops are preferable. Among them, since the contact lens user tends to have dry eyes, it is suitable for contact lenses such as eye drops for contact lenses, eye wash used after removing the contact lenses, contact lens attachment liquid, contact lens removal liquid and the like. The contact lens is not particularly limited, and examples thereof include hard contact lenses (oxygen-impermeable hard contact lenses, oxygen-permeable hard contact lenses), soft contact lenses (disposable contact lenses, silicon hydrogel lenses, etc.) and the like.

  The viscosity of the composition for mucosa of the present invention is preferably 1 to 100 mPa · s, more preferably 1 to 50 mPa · s, and further preferably 1 to 30 mPa · s. The viscosity is measured at 20 ° C. using an E-type viscometer (VISCONIC ELD-R, Tokyo Keiki Co., Ltd.).

  As a material of the container filled with the composition for mucosa of the present invention, polyethylene terephthalate, polypropylene and polyethylene are preferable, and polyethylene terephthalate is particularly preferable. The polyethylene terephthalate is not particularly limited as long as it can be molded as a container. The container is preferably a container capable of blocking ultraviolet rays.

  When filling the container with the composition for mucosa of the present invention, it is preferable to fill the container aseptically using a sterilizing filter or the like. The container to be filled may be a type that can be used any number of times by opening and closing the cap until the filled mucosal composition is exhausted, or may be a type that can be used once it is opened (unit dose type). In the case of a type that can be used any number of times, there may be a micropore filter at the outlet of the contents so that bacteria and foreign substances do not enter the container. When filling these containers, it is preferable that they are sterile.

  The container filled with the composition for mucosa of the present invention is preferably sealed with a package and filled with an inert gas between the container and the package (inner space). Examples of the inert gas include gases such as nitrogen, helium, neon, and argon. Further, the oxygen scavenger may be put in a package and sealed, or may be put in a package using a film having an oxygen absorbing function.

  The composition for mucosa of the present invention is not limited to a specific form, and can be used as a liquid or a spray depending on the purpose. These preparations are obtained by a conventional method, and in this case, in addition to the above-mentioned components, conventional additives corresponding to the preparation can be used.

  EXAMPLES Hereinafter, although an Example, a reference example, and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

[Examples 1 to 16, Comparative Examples 1 and 2]
The composition for mucous membranes (ophthalmic composition) having the composition (W / V% (g / 100 mL)) described in the table was obtained by the following production method at the aqueous phase temperature and oil phase temperature described in the table. The following evaluation was performed about the obtained composition. The results are also shown in the table.
Oil phase (retinol palmitate ester (vitamin A, 1.74 million I.U.), acetic acid d-α-tocopherol (vitamin E), (D) dibutylhydroxytoluene, (B) component is heated at a set temperature to be uniform. The mixture was added to 400 mL of an aqueous phase (purified water) heated at a set temperature with stirring using a magnetic stirrer, and stirred for 10 minutes using the magnetic stirrer. The water phase temperature after the oil phase addition is the same as the water phase temperature before the oil phase addition.After stirring, cool at room temperature, add component (C), stir dissolve or mix, As necessary, purified water was added so that the total amount was 500 mL, with (B) in the table indicating the mass ratio represented by (A) :( B) (B) ) Part Shown as (B) / (A).

[Particle size]
The measurement was performed using various measuring devices applying a principle such as light scattering and a dynamic light scattering particle size distribution analyzer (LB-500, Horiba, Ltd.). The measurement was performed using a thermostatic chamber under a constant temperature condition of 25 ° C. In addition, the particle diameter of the Example was 1 nm or more and less than 500 nm, and was a composition containing nanoemulsion particles.

[Appearance (Transmittance (%))]
About the ophthalmic composition immediately after manufacture, the transmittance | permeability (%) in wavelength 600nm was measured at room temperature using Hitachi spectrophotometer U-3310.

[Appearance (transparency)]
When the oily component was separated, it was judged as “X”, the appearance transmittance (%) was judged as “Δ” when less than 80%, “◯” when 80% or more and less than 90%, and “◎” when 90% or more.

[Stability of vitamin A]
<Remaining Vitamin A>
The content of vitamin A (retinol palmitate) was measured immediately after production and after storage for 1 week at 70 ° C. in a sealed ampoule (severe test). The measurement was performed using a high performance liquid chromatography method. From the obtained retinol palmitate content, the retinol palmitate residual rate (%) was calculated based on the following formula.

[Adsorption rate of vitamin A at 3 times dilution (%) (assuming dilution with tears when instilled)]
Since the hydrophobicity of C8 was close to the corneal surface, the vitamin A adsorption rate to C8 silica gel was measured as a vitamin A adsorption model for the cornea.
(I) C8 silica gel was washed with water to remove surface stains and dried.
(Ii) 10 mL of purified water was added to and mixed with 5 mL of the sample, and 0.2 g of C8 silica gel was dispersed in the solution obtained by separating 10 mL therefrom, and the mixture was stirred for 10 minutes.
(Iii) The silica gel and the sample were separated by filtration, and the amount of vitamin A in the filtrate and the amount of vitamin A in the sample before adsorption were measured by high performance liquid chromatography.
(Iv) The amount of vitamin A obtained was compared, and the adsorption rate of vitamin A was calculated.
* C8 silica gel: SEPTRA ™ bulk filler C8 (Phenomenex) (particle size 50 μm, pore size 65 mm)

  From the results of Table 1, it can be seen that the effect of adding the component (C) is enhanced when the concentration of the (B) nonionic surfactant is low.

With respect to the following Reference Example 1, the ratio of vitamin A-free nonionic surfactant was measured by the following method.
[Ratio of vitamin A-free nonionic surfactant (% by mass)]
The ratio of “Vitamin A-free nonionic surfactant” was measured using an Elient gel permeation chromatography (hereinafter referred to as EGPC).
(I) Non-concentration of various concentrations (0.0027 mass%, 0.08 mass%, 0.16 mass%, 0.3 mass%, 0.5 mass%, 1.0 mass%, 3.0 mass%) An aqueous ionic surfactant solution (polyoxyethylene hydrogenated castor oil 60 (HCO)) was measured by EGPC, and a calibration curve for the concentration of the active agent and the RI peak area value was prepared.
(Ii) EGPC measurement condition column: Superose 6 10/300 GL (10 × 300 mm)
Injection: 100 μL
Eluent: HCO aqueous solution (500 ppm)
Flow rate: 0.5mL / min
Temperature: 35 ° C
Detection: RI, UV (280 nm)
(Iii) Analyzing the sample by EGPC and detecting nonionic surfactant and oily component (vitamin A) by RI (detecting nonionic surfactant and oily component) and UV (detecting only oily component), respectively Detected at the same time. In RI, peaks appear in the order of (1) “Vitamin A-containing nanoemulsion particles” (2) “Free micelles”, (3) “Free surfactant molecules”, and in UV, (1) The peak appears. The peak (RI) other than (1) was regarded as “vitamin A-free nonionic surfactant”, and the active agent concentration was calculated from the RI peak area value from the calibration curve obtained in (i).

[Reference Example 1]
Oil phase (retinol palmitate (vitamin A, 1.74 million I.U.) 0.026 W / V%, d-α-tocopherol acetate 0.05 W / V%, dibutylhydroxytoluene 0.005 W / V%, polyoxy Ethylene hydrogenated castor oil (60) 0.1 W / V%) is heated and uniformly mixed at 85 ° C., and is added to 400 mL of an aqueous phase (purified water) at 85 ° C. with stirring using a magnetic stirrer. It was obtained by stirring for 10 minutes from the end of dropping using a stirrer. The aqueous phase temperature after addition of the oil phase from the start of stirring to the end of stirring is the same as the aqueous phase temperature before addition of the oil phase. After completion of the stirring, the mixture was cooled at room temperature, and other water phase ingredients were added as necessary, and purified water was added so that the total amount became 500 mL. The chart which shows the measurement result of EGPC of the obtained reference example 1 is shown in FIG. The composition for mucosa of Reference Example 1 has a peak (UV) in which the elution time of the peak top appears in less than 12 minutes, and the peak in which the peak top appears in 12 minutes or more (with a relatively small particle size) (UV)) was not seen. Specifically, from FIG. 1, peaks were observed at 9 and 36 minutes for RI and only 9 minutes for UV. That is, Reference Example 1 has a peak of RI and UV at an elution time of 9 minutes. (1) Because the presence of “vitamin A-containing nanoemulsion particles” is a peak of only RI at an elution time of 36 minutes ( 3) Presence of “free surfactant molecule” was confirmed.

  From the above results, nanoemulsion particles containing the components (A) and (B) as constituents were confirmed in the mucosa compositions (ophthalmic compositions) of Reference Example 1 and Examples. When EGPC was performed on the examples, the peak of (1) appeared at the same elution time in RI and UV, and “vitamin A-containing nanoemulsion particles” were confirmed. And the ratio of the vitamin A free nonionic surfactant of the reference example 1 and an Example was 43 mass% or less of (B) component total amount.

[Prescription Examples 1 to 20]
Formulation examples of the present invention are shown below. In addition, the composition of the formulation example was a thing with the nanoemulsion particle | grains formed similarly to an Example, the external appearance is uniform, and the stability of vitamin A is high.

Claims (7)

(A) Vitamin A 0.0005 to 0.12 W / V%, (B) Nonionic surfactant containing polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component, nonionic surfactant The total amount is 0.007 to 0.5 W / V%, and the mass ratio represented by (A) :( B) is 1: 0.4 to 14, and (C) lower alcohol, sugar alcohol, sugar, An oil phase containing at least one selected from chlorpheniramine maleate, diphenhydramine hydrochloride and flavin adenine dinucleotide sodium and containing the above components (A) and (B) is added to the water phase at 80 to 90 ° C. A composition for mucous membranes comprising nanoemulsion particles obtained by stirring and containing the components (A) and (B) as constituents. (A) Vitamin A 0.0005 to 0.12 W / V%, (B) Nonionic surfactant containing polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component, nonionic surfactant The total amount is 0.007 to 0.5 W / V%, and the mass ratio represented by (A) :( B) is 1: 0.4 to 14, and (C) lower alcohol, sugar alcohol, sugar, An oil phase containing at least one selected from chlorpheniramine maleate, diphenhydramine hydrochloride and flavin adenine dinucleotide sodium and containing the above components (A) and (B) is added to the water phase at 80 to 90 ° C. obtained by stirring and includes a nanoemulsion particles containing the (a) and (B) component as a constituent component, the proportion of the component (a) free nonionic surfactant, ( ) Mucosal composition and less than 44% by weight of the component total.   (C) The composition for mucosa according to claim 1 or 2, wherein the lower alcohol is ethanol, propylene glycol or glycerin, the sugar alcohol is mannitol, and the sugar is glucose.   The composition for mucosa according to any one of claims 1 to 3, further comprising (D) an antioxidant selected from tocopherol acetate, dibutylhydroxytoluene and butylhydroxyanisole.   The composition for mucous membrane according to any one of claims 1 to 4, wherein the temperature of the oil phase is 65 to 90 ° C.   The composition for mucous membrane according to any one of claims 1 to 5, which is an ophthalmic composition. (A) and vitamin A, (B) a non-ionic surfactant polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid esters as essential components, the mass ratio represented by (A) :( B) The manufacturing method of the composition for mucosa of Claim 1 or 2 including the process of adding and stirring the oil phase containing 1: 0.4-14 in 80 to 90 degreeC aqueous phase.

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