JP6155863B2 - Mucosal composition and method for producing the same - Google Patents

Description

  The present invention relates to a composition for mucosa containing a nanoemulsion containing a fat-soluble active ingredient 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.

  In addition, when a refreshing agent is appropriately blended, a refreshing feeling and a refreshing feeling can be imparted. In particular, in the case of an ophthalmic composition, it is useful for alleviating eye discomfort and fatigue.

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

  A composition comprising a fat-soluble active ingredient and a refreshing agent can be expected to have a synergistic effect. In particular, in the case of an ophthalmic composition containing vitamin A and a refreshing agent, the eye feels dry and tired. It is effective. On the other hand, people with dry eyes or tired eyes may have a more sensitive corneal conjunctival surface than normal, and depending on the condition of the eyes, a refreshing agent may be felt as an unpleasant stimulus. In some cases, the irritation may be increased by the surfactant. However, if the surfactant is reduced to suppress irritation, the eye irritation is alleviated by the concentration, but the appearance stability (transparency) cannot be maintained. The concentration had to be increased.

  Therefore, the present invention provides a mucosal composition in which the appearance of the composition is transparent, a refreshing sensation is obtained, and the irritation caused by the combined use of a surfactant and a cooling agent is suppressed, and a method for producing the same. The purpose is to provide.

  As a result of intensive investigations to achieve the above object, the present inventors set the amount of the nonionic surfactant with respect to the fat-soluble active ingredient in a specific range, the aqueous phase temperature in the specific range in production, and the oil phase. By adding to the water phase and stirring, the appearance stability can be achieved even if the amount of surfactant is reduced, and the surfactant can be reduced, thus simultaneously reducing irritation due to the coexistence of menthol and surfactant. In addition, the present inventors have found that a refreshing feeling can be maintained while at the same time achieving the present invention. Further, the present invention has been found that the adsorption of the fat-soluble active ingredient to the mucous membrane can be enhanced and the stability of the fat-soluble active ingredient can be maintained.

Accordingly, the present invention provides the following inventions.
[1]. (A) Fat-soluble active ingredient 0.005-0.2 W / V%, (B) Nonionic surfactant containing polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component, nonionic The total amount of the surfactant is 0.01 to 0.5 W / V%, and the mass ratio represented by (A) :( B) is 1: 0.4 to 7.0, and (C) the cooling agent. The oil phase containing the components (A) and (B) is added to the water phase at 80 to 90 ° C. and stirred, and the components (A) and (B) are contained as constituent components. A composition for mucosa comprising nanoemulsion particles.
[2]. (A) Fat-soluble active ingredient 0.005-0.2 W / V%, (B) Nonionic surfactant containing polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component, nonionic The total amount of the surfactant is 0.01 to 0.5 W / V%, and the mass ratio represented by (A) :( B) is 1: 0.4 to 7.0, and (C) the cooling agent. The oil phase containing the components (A) and (B) is added to the water phase at 80 to 90 ° C. and stirred, and the components (A) and (B) are contained as components. A composition for mucosa comprising nanoemulsion particles, wherein the ratio of (A) component-free nonionic surfactant is less than 44% by mass of the total amount of component (B).
[3]. The composition for mucous membrane according to [1] or [2], wherein the component (A) is an antioxidant selected from (A-1) vitamin A and (A-2) tocopherol acetate, dibutylhydroxytoluene and butylhydroxyanisole. object.
[4]. (C) component is 1-menthol, dl-camphor, d-camphor, d-borneol, eucalyptus oil, bergamot oil, geraniol, linalool, cineol, fennel oil, spearmint oil, peppermint oil, rose oil, cool mint oil and The composition for mucosa according to any one of [1] to [3] selected from mint oil.
[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) A fat-soluble active ingredient 0.005 to 0.2 W / V%, and (B) a nonionic surfactant containing polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component, nonionic An oil phase that is 0.01 to 0.5 W / V% as a total amount of the surfactant and includes 1: 0.4 to 7.0 in a mass ratio represented by (A) :( B), The method for producing a composition for mucosa according to [1] or [2], comprising a step of adding 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, the sustainability of a refreshing feeling can be obtained, and the composition for mucosa with which irritation | stimulation was suppressed and its manufacturing method can be provided. Moreover, adsorption | suction of the fat-soluble active ingredient to a mucous membrane can be improved, and the stability of a fat-soluble active ingredient can be maintained.

6 is a chart showing EGPC measurement results of Reference Example 1. 14 is a chart showing EGPC measurement results of Example 17;

  The present invention provides a nonionic surfactant comprising (A) a fat-soluble active ingredient 0.005 to 0.2 W / V% and (B) a polyoxyethylene hydrogenated castor oil or a polyoxyethylene sorbitan fatty acid ester as an essential component. The total amount of the nonionic surfactant is 0.01 to 0.5 W / V%, and the mass ratio represented by (A) :( B) is 1: 0.4 to 7.0, and (C ) It is obtained by adding an oil phase containing a cooling agent and containing the above components (A) and (B) to an aqueous phase at 75 to 90 ° C., and stirring the components (A) and (B). It is the composition for mucous membranes containing the nanoemulsion particle | grains contained as a structural component.

(A) Fat-soluble active ingredient Although it does not specifically limit as a fat-soluble active ingredient, The following are included and it can be used individually by 1 type or in combination of 2 or more types. Hereinafter, the components (A-1) to (A-4) are collectively referred to as the component (A).

(A-1)
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.

(A-2)
Antioxidants such as tocopherol acetate (dl-α-tocopherol acetate, d-α-tocopherol acetate (vitamin E)), dibutylhydroxytoluene, butylhydroxyanisole, nordihydroguaiaretic acid.

(A-3)
Vitamins such as vitamin D and vitamin K, steroidal anti-inflammatory agents such as dexamethasone, betamethasone and prednisolone, immunosuppressants such as cyclosporine, tacrolimus and paclitaxel, antibacterial agents such as clarithromycin and ofloxacin, chloramphenicol and acyclovir Antiviral agents such as diphenhydramine, ketoprofen, glycol salicylate, indomethacin, amlexanox, beclomethasone propionate, mometasone furan carboxylate, fluticasone furan carboxylate, vasoconstrictor such as epinephrine, lidocaine, etc. Local anesthetic.

(A-4)
Glycerides such as castor oil and sesame oil, liquid paraffin, gelled hydrocarbon, lanolin and the like.

  (A) The compounding quantity of a component is 0.005-0.2 W / V% (g / 100 mL) as a total amount of (A) component with respect to the composition whole quantity, and 0.05-0.15 W / V%. Is preferred. Moreover, it can select suitably according to the effectiveness and application of a compounding component.

  For example, when (A-1) a composition for mucosa using vitamin A or an ophthalmic composition is used, 0.0005 to 0.15 W / V% (g / 100 mL) is more than the total amount of the composition. Preferably, when the ophthalmic 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, 0.005-0.2 W / V% (g / 100 mL) is more preferable, and 0.01-0.15 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.

  For example, when the composition for mucosa using the component (A-2) or an ophthalmic composition is used, the blending amount of tocopherol acetate is preferably 0.01 to 0.5 W / V% with respect to the total amount of the composition. 0.02-0.2 W / V% is more preferable, and 0.03-0.05 W / V% is more preferable. The amount of dibutylhydroxytoluene is preferably 0.001 to 0.1 W / V%, more preferably 0.002 to 0.05 W / V%, and more preferably 0.003 to 0.005 W / V based on the total amount of the composition. % Is more preferable.

  As the component (A), (A-1) vitamin A is preferable. In particular, when (A-1) vitamin A is used, the stability of vitamin A can be maintained and the adsorption of vitamin A to the cornea at the time of instillation (diluted state with tears) can be enhanced. Moreover, it is preferable to use together (A-1) vitamin A and (A-2) an antioxidant selected from tocopherol acetate, dibutylhydroxytoluene and butylhydroxyanisole, and in particular, (A-2) an antioxidant. It is good to use 2 or more types together. Thereby, the storage stability (residual rate) of (A-1) vitamin A is further improved. In the case of this combined use, the blending amount when the component (A-2) is tocopherol acetate is preferably 0.01 to 0.5 W / V%, preferably 0.02 to 0.1 W / V% with respect to the total amount of the composition. Is more preferable, and 0.03-0.05 W / V% is further more preferable. When the component (A-2) is dibutylhydroxytoluene, the blending amount is preferably 0.001 to 0.1 W / V%, more preferably 0.002 to 0.05 W / V%, based on the total amount of the composition. 0.003-0.005 W / V% is more preferable. By setting it as this range, (A) storage stability of vitamin A and appearance transparency are further improved.

(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 contains other nonionic surfactants. Also good. 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 nonionic surfactants other than the above include polyoxyethylene polyoxypropylene copolymers and polyoxyethylene alkyl ethers. 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 0.01-0.5 W / V% in a composition as a nonionic surfactant whole quantity, Comprising: 0.02-0.3 W / V% is preferable. By setting it as this range, when the appearance is transparent and the component (A) contains (A-1) vitamin A, the stability of vitamin A is excellent, and the adsorption of vitamin A to the cornea can be 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.

  The mass ratio represented by (A) :( B) is 1: 0.4 to 7.0, preferably 1: 0.7 to 5.0, and 1: 0.9 to 4.0. More preferred. (A) If the amount of (B) nonionic surfactant per fat-soluble active ingredient 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 the amount of (B) nonionic surfactant per (A) fat-soluble active ingredient is too large, the particle size of the emulsion is small, the appearance is more uniform and transparent, and the mucous membrane has excellent appearance stability of the preparation. However, the effect of improving the adsorption of the (A) fat-soluble active ingredient to the cornea or the like is insufficient, and as a result, the effect of improving the action of the target fat-soluble active ingredient is not satisfactory. It will be enough. In the present invention, at 7.0 or less, the fat-soluble active ingredient is improved in adsorbability to mucous membranes such as cornea, and the effect of the component (A) is exhibited in a small amount, not only reducing irritation, A moderate refreshing effect can be obtained.

Further, when the component (A) contains (A-1) vitamin A, 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-1) Vitamin A 0.003 W / V% or more and less than 0.015 W / V% (BI) Polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester The nonionic surfactant selected is from 1: 3.0 to 10.0 in a mass ratio represented by (A-1) :( BI).
I- (2): HCO-VA concentration (A-1) Vitamin A 0.015-0.05 W / V%,
(BI) A nonionic surfactant selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester is used at a mass ratio represented by (A-1) :( BI) of 1: 1. 6 to 10.0, preferably 1: 1.6 to less than 8.0.
I- (3): HCO-VA high concentration (A-1) Vitamin A 0.05 W / V% and 0.2 W / V% or less (BI) Polyoxyethylene hydrogenated castor oil 60 and / or monooleic acid POE (20) sorbitan is used at a mass ratio represented by (A-1) :( BI): 1: 1.6 to 5.0

(C) Coolant As the refresher, 1-menthol, dl-camphor, d-camphor, d-borneol, eucalyptus oil, bergamot oil, geraniol, linalool, cineol, fennel oil, spearmint oil, peppermint oil, rose Examples thereof include oil, cool mint oil, and peppermint oil. These may be used alone or in combination of two or more. Of these, l-menthol, dl-camphor, d-camphor, d-borneol, eucalyptus oil, bergamot oil, and geraniol are preferred.

  (C) The compounding quantity of a component is 0.001-0.05 W / V% in a composition as a refreshing agent whole quantity, Comprising: 0.003-0.03 W / V% is preferable. By setting it as this range, there is no irritation and a comfortable feeling that a moderate refreshing feeling is sustained is obtained.

  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, buffers, thickeners, sugars, pH adjusters, preservatives, tonicity agents, stabilizers, humectants, 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 glycerin, propylene glycol, 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 glucose, cyclodextrin, xylitol, sorbitol, mannitol 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%. is there.

  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 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 azulenesulfonate, etc.), antihistamine agent (e.g., hydrochloric iproheptine, diphenhydramine hydrochloride, isothipendyl hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (activated vitamin B _2, vitamin B ₆ Vitamin B _12, etc.), amino acids (e.g., potassium L- aspartic acid, L- magnesium aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate, etc.), sulfa drugs, fungicides (e.g., sulfur, isopropyl methyl phenol, hinokitiol, etc.), Antiallergic agents (cromoglycic acid, ketotifen fumarate, tranilast, etc.), local anesthetics (eg, lidocaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, etc.), mydriatics (cyclopentato hydrochloride, tropicamide, etc.), cataract treatments (pyrenoxine) , 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 the water, purified water, sterilized water, or the like can be used, and it is appropriately selected according to the aqueous phase. However, the content of the total amount of the composition only needs to be 100 (remainder), 90 to 99.985 W / V% is preferable, and 95 to 99.6 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. The following is mentioned as a manufacturing method of the composition for mucous membranes.
(A) Fat-soluble active ingredient 0.005-0.2 W / V%, (B) Nonionic surfactant containing polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component, nonionic The total amount of the surfactant is 0.01 to 0.5 W / V%, and the oil phase containing 1: 0.4 to 7.0 in a mass ratio represented by (A) :( B) is 75 to A production method comprising a step of adding to a 90 ° C. aqueous phase and stirring.

  In the “oil phase”, (A) “lipid soluble active ingredient”, “oil phase blending component” such as a nonionic surfactant such as component (B) is blended, and “water phase” includes water, In addition, “water phase blending components” such as water-soluble components (water-soluble drugs, inorganic salts, water-soluble polymers, preservatives, etc.) that dissolve in water are blended. (C) The cooling agent may be added to the oil phase, or a part of the (C) cooling agent may be blended in the water phase as long as it is soluble in water. A pre-dissolved material (small item) in which the agent is pre-dissolved in a polyhydric alcohol such as propylene glycol may be added separately after, for example, the stirring.

  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) the fat-soluble active ingredient 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 aqueous phase 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. is there. The allowable deflection width with respect to the average temperature of the aqueous phase is ± 4 ° C. 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 or more, 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 components, and is nanoemulsion particles containing a fat-soluble active ingredient. . According to the present invention, it has been found that a composition for mucosa having a uniform appearance can be obtained, the stability of the fat-soluble active ingredient is unexpectedly improved, and the adsorption of the active ingredient to the mucosa is 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) a fat-soluble active ingredient in the emulsion particles, and the above components (A) and (B) are essential constituents. 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 (particularly when the component (A) is vitamin A). When the particle diameter exceeds 40 nm, the active ingredient release properties from the active ingredient-containing nanoemulsion particles, for example, the adsorptivity of the active ingredient to the cornea at the time of instillation and the like are 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 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.

“Fat-soluble active ingredient-free nonionic surfactant” refers to a nonionic surfactant that does not contain a fat-soluble active ingredient, and includes “free micelles” and “free surfactant molecules”.
“Free micelle” refers to a surfactant aggregate that does not contain (A) a fat-soluble active ingredient.
“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 the (A) fat-soluble active ingredient, makes the appearance of the mucosal composition transparent, and enhances the adsorption of the (A) fat-soluble active ingredient to the mucosa. The reason why is more exhibited is unknown. In the composition for mucosa of the present invention, the ratio of “fat-soluble active ingredient-free nonionic surfactant” (“free micelle” and “free surfactant molecule”) containing no fat-soluble active ingredient was small. From this, one of the reasons why the composition for mucosa of the present invention has increased the adsorption of the fat-soluble active ingredient to the mucosa is that "the fat-soluble active ingredient-free nonionic surfactant" adheres to the mucosal surface. In order to inhibit adhesion of the “nanoemulsion 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 “fat-soluble active ingredient-free nonionic surfactant”, that is, the ratio of (B) component constituting “free micelle” and “free surfactant molecule” to the total amount of component (B) is 44% by mass. Less than, 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, samples were detected by RI (detecting nonionic surfactant and fat-soluble component) and UV (detecting only oily component), respectively, and “nanoemulsion particles (RI + UV detection)” according to their elution time and peak area, The ratio can be calculated by separating into “free micelle (RI detection)” and “free surfactant molecule (RI detection)”. 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 the fat-soluble active ingredient 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 an active ingredient 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 easily becomes dry eye, it is suitable for contact lenses such as eye drops for contact lenses, eye wash used after removing the contact lenses, contact lens mounting liquid, contact lens removing 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 of a type that can be used any number of times by opening and closing the cap until the filled composition runs out, or may be a type that can be used up once 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 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 24, Comparative Examples 1 to 5]
The composition for mucous membrane (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 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 IU), acetic acid d-α-tocopherol (tocopherol acetate: vitamin E), dibutylhydroxytoluene, polyoxyethylene hydrogenated castor oil (60) (85 ° C), uniformly mixed, added to 400 mL of water phase (purified water) heated at the set temperature with stirring using a magnetic stirrer, and stirred for 10 minutes after completion of dropping using a magnetic stirrer. The water phase temperature after addition of the oil phase from the start of stirring to the end of stirring is the same as the water phase temperature before the addition of the oil phase. The component (C) preliminarily dissolved in propylene glycol is gradually added and dissolved by stirring, and other aqueous phase ingredients are added as necessary, resulting in a total volume of 500 mL. In the table, the part of (B) with respect to (A) 1 in the mass ratio represented by (A) :( B) is shown as (B) / (A). In the table, the part of (B) with respect to (A-1) 1 in the mass ratio represented by (A-1) :( B) is shown as (B) / (A-1).

[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.

[Eye irritation (no irritation)]
Four subjects (sensitive panelists) with symptoms of dryness and itching of the eyes instilled 1 to 2 drops of the ophthalmic composition and evaluated eye irritation according to the following evaluation criteria.
<Evaluation criteria>
Stimulation is strong 1 point stimulation is slightly strong 2 point stimulation is weak 3 point stimulation is hardly felt 4 point stimulation is not felt at all 5 points Based on the average value of the obtained evaluation points, it indicates eye irritation (no stimulation) .
Average score of 4 or more ◎
3 points or more and less than 4 points ○
2 points or more and less than 3 points △
Less than 2 points ×

[Continuation of cool feeling]
Four subjects (sensitive panelists) with symptoms of dry eyes and itching were instilled with 1 to 2 drops of ophthalmic composition, and the time of refreshing feeling felt comfortable was measured. A result is shown below from the average value of four persons.
4 minutes or more ◎
3 minutes or more and less than 4 minutes ○
Less than 3 minutes △

The following evaluation was performed about the following Example and the comparative example.
[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)

  Since the stability of vitamin A was good and the absorption rate of vitamin A was high, the effect of vitamin A was exerted more effectively, and an ophthalmic composition effective for dry eyes and fatigue was obtained.

About the following reference example 1, the ratio of the fat-soluble active ingredient free nonionic surfactant was measured by the following method.
[Ratio of fat-soluble active ingredient-free nonionic surfactant (% by mass)]
The ratio of “fat-soluble active ingredient-free nonionic surfactant” was measured using an elemental 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 ionic surfactant aqueous 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 using non-ionic surfactant and oily component (fat-soluble active ingredient), RI (detecting non-ionic 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) “Liquid-soluble active ingredient-containing nanoemulsion particles” (2) “Free micelles” and (3) “Free surfactant molecules”. The peak of 1) appears. The peak (RI) other than (1) was defined as “fat-soluble active ingredient-free nonionic surfactant”, and the concentration of the active agent was calculated from the RI peak area value from the calibration curve obtained in (i). In the table, “Ratio (%) of fat-soluble active ingredient-free nonionic surfactant” is shown.

[Reference Example 1] (oil phase (retinol palmitate ester: vitamin A, 1.74 million I.U.)) 0.026 W / V%, d-α-tocopherol acetate 0.05 W / V%, dibutylhydroxytoluene 005 W / V%, polyoxyethylene hydrogenated castor oil (60) 0.1 W / V% was heated and uniformly mixed at 85 ° C., and stirred with a magnetic stirrer in 400 mL of 85 ° C. aqueous phase (purified water). The mixture was added while stirring, and stirred for 10 minutes from the end of dropping using a magnetic 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, lipid-soluble active ingredient-containing 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. A chart showing the EGPC measurement results of Example 17 is shown in FIG. The peak observed at about 42 minutes in RI is that in which an additive component such as a refreshing agent is detected. Since Example 17 has a smaller particle diameter than Reference Example 1, the elution time of the peak of (1) is 14 minutes. In Reference Example 1 and Examples, the ratio of the fat-soluble active ingredient-free nonionic surfactant was 43% by mass or less of the total amount of the component (B). Specifically, Reference Example 1 was 41% by mass, Example 17 was 18.6% by mass, and Comparative Example 5 was 44.0% by mass.

  Formulation examples of the present invention (Table 8: Eye drops or eye wash, Table 9: Eye drops, Table 10: Eye drops) are shown below. In addition, the composition of the formulation example was formed with nanoemulsion particles as in the examples, had a uniform appearance, no eye irritation, and a pleasant refreshing feeling.

Claims (7)

(A) Fat-soluble active ingredient 0.005-0.2 W / V%, (B) Nonionic surfactant containing polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component, nonionic The total amount of the surfactant is 0.01 to 0.5 W / V%, and the mass ratio represented by (A) :( B) is 1: 0.4 to 7.0, and (C) the cooling agent. The oil phase containing the components (A) and (B) is added to the water phase at 80 to 90 ° C. and stirred, and the components (A) and (B) are contained as constituent components. A composition for mucosa comprising nanoemulsion particles. (A) Fat-soluble active ingredient 0.005-0.2 W / V%, (B) Nonionic surfactant containing polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component, nonionic The total amount of the surfactant is 0.01 to 0.5 W / V%, and the mass ratio represented by (A) :( B) is 1: 0.4 to 7.0, and (C) the cooling agent. The oil phase containing the components (A) and (B) is added to the water phase at 80 to 90 ° C. and stirred, and the components (A) and (B) are contained as components. A composition for mucosa comprising nanoemulsion particles, wherein the ratio of (A) component-free nonionic surfactant is less than 44% by mass of the total amount of component (B).   The mucosa composition according to claim 1 or 2, wherein the component (A) is an antioxidant selected from (A-1) vitamin A and (A-2) tocopherol acetate, dibutylhydroxytoluene and butylhydroxyanisole.   (C) component is 1-menthol, dl-camphor, d-camphor, d-borneol, eucalyptus oil, bergamot oil, geraniol, linalool, cineol, fennel oil, spearmint oil, peppermint oil, rose oil, cool mint oil and The composition for mucosa according to any one of claims 1 to 3, which is selected from mint oil.   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) A fat-soluble active ingredient 0.005 to 0.2 W / V%, and (B) a nonionic surfactant containing polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester as an essential component, nonionic An oil phase that is 0.01 to 0.5 W / V% as a total amount of the surfactant and includes 1: 0.4 to 7.0 in a mass ratio represented by (A) :( B), The method for producing a composition for mucosa according to claim 1 or 2, comprising a step of adding to and stirring the aqueous phase at 80 to 90 ° C.

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