JP5467722B2 - External emulsion formulation - Google Patents

Description

  The present invention relates to an emulsion preparation for external use with improved formulation stability. Furthermore, the present invention also relates to an emulsified preparation for external use with an active ingredient having excellent intradermal retention.

There are various types of external preparations applied to the skin and mucous membranes, such as patches, ointments, emulsified preparations, lotions, and solid preparations. Emulsified preparations are effective in expecting a base and pharmacological effects. It is often used because of its good blendability with ingredients and good usability because of its good affinity with the skin. However, emulsified preparations have a problem that the skin adhesion is reduced due to perspiration and the like, and it is easy to remove. For improvement, the viscosity of the emulsion preparation is increased according to the base component of the emulsion preparation, or a W / O type preparation is used. , Lecithin, carboxyvinyl polymer and petroleum jelly emulsified formulation, when it is made to be highly viscous or W / O type formulation, stickiness and glare will appear at the time of application even after adhesion, and after use and after application There is a problem that the appearance of becomes worse.
In addition, active ingredients such as antifungals, steroids, and non-steroidal anti-inflammatory analgesics include those with low solubility in water and those that are salt compounds. There may be problems. In addition, some active ingredients are effective only in a specific pH range or exist stably, but adjusting the emulsion formulation to the specific pH range may cause problems with the stability of the formulation. May come out.
For example, when an active ingredient with low solubility in water (poorly water-soluble active ingredient) is blended, the ingredient may be dispersed in the emulsion preparation, or a solubilizing agent such as a polyhydric alcohol or surfactant may be used in combination. However, it is considered that a satisfactory feeling of use cannot be obtained, and that the percutaneous absorbability may be lowered only by dispersing the active ingredient, and therefore examination is required.
Furthermore, when a large amount of a salt compound such as terbinafine hydrochloride, butenafine hydrochloride, dipotassium glycyrrhizinate, or benzalkonium chloride is added to the emulsion preparation, aggregation or precipitation of the emulsion particles in the preparation occurs, resulting in changes in appearance such as separation. The formulation may become unstable, such as easier. For this reason, a preparation emulsified with soap using a solid oil and water is generally used, but a satisfactory feeling of use such as easy whitening cannot be obtained and sufficient transdermal absorbability cannot be obtained.
On the other hand, ethanol, isopropanol, and diethylene glycol monoethyl ether are widely used in topical medicines, quasi drugs, and cosmetics, and their uses are diverse, such as bases, preservatives, and solubilizers, and are known to promote transdermal absorption. However, since ethanol, isopropanol, and diethylene glycol monoethyl ether also have the effect of destabilizing the emulsion preparation, it is difficult to mix in a large amount in the emulsion preparation and to stabilize the preparation containing a large amount of them over a long period of time. I couldn't.
In addition, water-soluble polymers may be used to stabilize emulsion formulations, but sufficient and stable thickening effects cannot be obtained if salt compounds are added or the pH of the formulation is adjusted to be low or high. It is difficult to stabilize an emulsified preparation. Examples of improving the storage stability of external preparations using water-soluble polymers include gels containing oleyl alcohol and / or oleic acid added to poorly water-soluble acidic drugs such as ketoprofen and acrylic acid / alkyl methacrylate polymers. An agent (Patent Document 1) has been reported.
As described above, there are various restrictions in the design of an emulsified preparation, and there is a demand for an emulsified preparation for external use having excellent versatility, preparation stability, transdermal absorbability, skin adhesion, and feeling of use.
Japanese Patent Laid-Open No. 2003-95983

An object of the present invention is to provide an emulsified preparation for external skin with improved formulation stability, and to provide an emulsified preparation for external skin excellent in intradermal retention of an active ingredient. In particular, it contains an active ingredient (especially a poorly water-soluble active ingredient or a salt compound that destabilizes the emulsifying system), has excellent formulation stability, and has an excellent active ingredient retention in the skin. It is an issue to provide.
Furthermore, an object of the present invention is to provide an external preparation for skin that has excellent usability.

As a result of intensive studies to achieve the above object, the present inventors have found that phospholipids; one or more selected from the group consisting of petrolatum, polyethylene glycol, lanolin and gelled hydrocarbons; One or more selected from the group consisting of vinyl polymers and alkyl-modified carboxyvinyl polymers; and selected from the group consisting of 5 to 15 wt% ethanol, isopropanol and diethylene glycol monoethyl ether It was found that even when one or more of these were added, the preparation was stable and the feeling of use was excellent, and the present invention was completed. Moreover, when an active ingredient was further mix | blended with the said formulation, it discovered that it was excellent in the intradermal retention of an active ingredient.
That is, the present invention is an emulsified preparation for external skin as described in the following (1) to (13).
(1) (A) 5 to 15% by weight of one or more selected from the group consisting of ethanol, isopropanol and diethylene glycol monoethyl ether;
(B) one or more selected from the group consisting of petrolatum, polyethylene glycol, lanolin and gelled hydrocarbon;
(C) one or more selected from the group consisting of a carboxyvinyl polymer and an alkyl-modified carboxyvinyl polymer;
(D) An external preparation for skin containing phospholipids.
(2) The total amount of one or more selected from the group consisting of (C) a carboxyvinyl polymer and an alkyl-modified carboxyvinyl polymer is 0.5 to 2% by weight with respect to the entire skin external emulsion formulation. 1) An emulsified preparation for external application to the skin.
(3) (B) The total amount of one or more selected from the group consisting of petrolatum, polyethylene glycol, lanolin and gelled hydrocarbon is 3 to 10% by weight with respect to the whole external emulsion formulation (1) or (2) external skin emulsification preparation.
(4) The skin external emulsion formulation according to any one of (1) to (3), wherein the total amount of (D) phospholipid is 0.6 to 4% by weight based on the whole skin external emulsion formulation.
(5) The emulsified preparation for external skin according to any one of (1) to (4), further comprising (E) an active ingredient.
(6) The external preparation for skin according to (5), wherein the active ingredient (E) is a poorly water-soluble active ingredient or a salt compound.
(7) The emulsified preparation for external application to the skin according to (5), wherein the active ingredient (E) is a poorly water-soluble active ingredient.
(8) The external preparation for skin according to (5), wherein the active ingredient (E) is a poorly water-soluble salt compound.
(9) (E) The skin external emulsion formulation as described in (5) whose active ingredient is 1 type (s) or 2 or more types selected from the group which consists of an anti-inflammatory analgesic component, an antifungal component, and a steroid component.
(10) (E) The active ingredient is one or more selected from the group consisting of indomethacin, felbinac, terbinafine hydrochloride, butenafine hydrochloride, prednisolone valerate acetate and hydrocortisone acetate, (5) to (7) An emulsified preparation for external use according to any one of the above.
(11) Any of (5) to (7), wherein (E) the active ingredient is one or more selected from the group consisting of indomethacin, terbinafine hydrochloride, butenafine hydrochloride, prednisolone valerate acetate and hydrocortisone acetate An emulsified preparation for external application to the skin.
(12) The emulsified preparation for external skin according to any one of (1) to (11), wherein the emulsified preparation for external skin is a cream.
(13) The emulsified preparation for external skin according to any one of (1) to (12), wherein the pH is 4 to 6.

The present invention includes (A) 5 to 15% by weight of one or more selected from the group consisting of ethanol, isopropanol and diethylene glycol monoethyl ether, and (B) petrolatum, polyethylene glycol, lanolin and gelled hydrocarbon. 1 type, or 2 or more types selected from the group consisting of: (C) 1 type or 2 or more types selected from the group consisting of carboxyvinyl polymer and alkyl-modified carboxyvinyl polymer, and (D) phospholipid By doing so, an emulsified preparation for external skin can be obtained which has high adhesion to the skin and excellent usability and is stable for a long period of time.
Further, (A) 5 to 15% by weight of one or more selected from the group consisting of ethanol, isopropanol and diethylene glycol monoethyl ether, and (B) petrolatum, polyethylene glycol, lanolin and gelled hydrocarbon One or more selected from the group, (C) one or more selected from the group consisting of a carboxyvinyl polymer and an alkyl-modified carboxyvinyl polymer, and (D) a topical skin containing a phospholipid By adding (E) an active ingredient (especially poorly water-soluble active ingredient or salt compound that makes the emulsion system unstable) to the emulsified preparation, the skin has excellent skin retention of the active ingredient and is stable for a long time. Since it becomes an emulsified preparation for external use, it is particularly useful. In addition, since the emulsion preparation for external use of the present invention is excellent in the retention of the active ingredient in the skin, the active ingredient is expected to exert its pharmacological effect sufficiently by staying at the site where the preparation is applied. It can be particularly suitably used as a product (especially a pharmaceutical product).

  In the emulsion preparation for external use of the present invention, (A) one or more selected from the group consisting of ethanol, isopropanol and diethylene glycol monoethyl ether (hereinafter sometimes simply referred to as “component A”) is 5 to 5 15% by weight, and (B) one or more selected from the group consisting of petrolatum, polyethylene glycol, lanolin and gelled hydrocarbon (hereinafter may be simply referred to as “component B”), (C ) One or more selected from the group consisting of a carboxyvinyl polymer and an alkyl-modified carboxyvinyl polymer (hereinafter sometimes simply referred to as “C component”), and (D) a phospholipid (hereinafter simply referred to as “D”). It may be referred to as “component”).

Ethanol, isopropanol and diethylene glycol monoethyl ether used in the present invention are not particularly limited as long as they are usually used in pharmaceuticals, quasi drugs and cosmetics, and can be used alone or in combination of two or more.
Of the components A used in the present invention, ethanol and isopropanol are preferable, and ethanol is particularly preferable from the viewpoint of versatility as a pharmaceutical and a quasi-drug (particularly a pharmaceutical).
The total amount of the component A in the present invention may be usually 5 to 15% by weight, preferably 5 to 12% by weight, particularly preferably 6 to 10% by weight, based on the whole external preparation for skin application. When the total amount of the component A in the present invention is less than 5% by weight, the active ingredient has low intradermal retention and the feeling of use is not preferred, and when it exceeds 15% by weight, sufficient formulation stability cannot be obtained.

Vaseline, polyethylene glycol, lanolin and gelled hydrocarbon used in the present invention are not particularly limited as long as they are usually used in pharmaceuticals, quasi drugs, and cosmetics, and are used alone or in combination of two or more. it can. As for the gelled hydrocarbon, for example, liquid paraffin is gelled with a polyethylene powder and semi-solidified, for example, plastibase (trade name) may be blended, or liquid paraffin and polyethylene powder may be blended. Polyethylene glycol is also called macrogol.
Among the B components used in the present invention, petrolatum is preferable from the viewpoint of safety.
The total amount of component B in the present invention may be usually 0.1 to 20% by weight, preferably 1 to 15% by weight, particularly preferably 3 to 10% by weight, based on the whole emulsion preparation for external use. If it is less than 0.1%, sufficient formulation stability cannot be obtained, and if it is 1% by weight or more, the shape retention is good, and if it exceeds 20% by weight, the feeling in use is not preferred.

The carboxyvinyl polymer and alkyl-modified carboxyvinyl polymer used in the present invention are not particularly limited as long as they are usually used in pharmaceuticals, quasi drugs, and cosmetics, and can be used alone or in combination of two or more. Various water-soluble polymers are used for the purpose of stabilizing the emulsion preparation and improving the feeling of use. With the water-soluble polymer other than the C component of the present invention, the preparation containing the A component, the B component and the D component is used. Sufficient stability and usability were not obtained.
Specific examples of the C component used in the present invention include carboxyvinyl polymers such as BF Goodrich's CARBOPOL940 and CARBOPOL941 (both trade names), BFGoodrich's CARBOPOL1342, CARBOPOL2050, PEMULEN TR-1, and PEMULEN TR-2 (all Alkyl-modified carboxyvinyl polymers such as trade names), and the alkyl-modified carboxyvinyl polymers are also referred to as acrylic acid / alkyl methacrylate copolymers.
Of the component C used in the present invention, a carboxyvinyl polymer is preferred from the viewpoint of versatility as a pharmaceutical product or a quasi-drug (particularly a pharmaceutical product).

  The total amount of component C in the present invention may be usually 0.001 to 5% by weight, preferably 0.01 to 3% by weight, particularly preferably 0.5 to 2% by weight, based on the whole external preparation for skin application. If it is less than 0.001% by weight, sufficient formulation stability cannot be obtained, and if it is 0.5% by weight or more, the shape retention is good, and if it exceeds 5% by weight, the feeling in use is not preferred.

  In the emulsion preparation for external use of the present invention, the ratio of the total amount of the A component to the total amount of the C component is not particularly limited as long as the effect of the present invention is achieved. -200 parts by weight, preferably 2-100 parts by weight, particularly preferably 3-50 parts by weight.

The phospholipid used in the present invention is not particularly limited as long as it is usually used in pharmaceuticals, quasi drugs, and cosmetics, and can be used alone or in combination of two or more.
Specific examples of the D component used in the present invention include glycerophospholipid and sphingophospholipid.
Glycerophospholipid is a substance having a glycerophosphoric acid skeleton, and has a fatty acid ester, a long-chain alkyl ether, a vinyl ether or the like as a lipophilic part. Specifically, phosphatidylcholine (PC), phosphatidylethanolamine, phosphatidylserine, phosphadiylinositol, phosphatidylinositol polyphosphate, phosphatidylglycerol, diphosphatidylglycerol (cardiolipin), phosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidyl Examples include serine, lysophosphatidylinositol, lysophosphatidylglycerol, and lysophosphatidic acid.
Sphingophospholipids have long-chain bases or long-chain fatty acids such as sphingosine and phytosphingosine, and phosphoric acid or phosphonic acid. Ceramide 1-phosphate derivatives (such as sphingomyelin), ceramide 1-phosphonic acid derivatives ( Ceramide aminoethylphosphonic acid and the like).
Among D components used in the present invention, glycerophospholipid is preferable from the viewpoint of versatility, and phosphatidylcholine, phosphatidylethanolamine, and phosphatidylglycerol are particularly preferable.

  The D component used in the present invention may be a natural product extracted and purified from animals and plants, or may be chemically synthesized. Commercial products may also be used. Examples of natural products include extracted and purified products from soybeans or egg yolks, and soybean lecithin is preferable. Further, hydrogenated phospholipids, hydroxylated phospholipids and the like may be used, but phospholipids with a low degree of hydrogenation are preferred, and the iodine value of phospholipids is usually 35 to 110, preferably 50 to 110, more preferably 70 to 110, particularly preferably 80 to 110.

  The total amount of component D used in the present invention is not particularly limited as long as the effects of the present invention are exhibited, but is usually 0.001 to 10% by weight, preferably 0.01 to 6% by weight, particularly preferably, based on the whole emulsion preparation for external use. It may be 0.6 to 4% by weight. If it is less than 0.001% by weight, sufficient formulation stability and intradermal retention cannot be obtained, and if it exceeds 10% by weight, the feeling of use is not preferred.

In the emulsion preparation for external use of the present invention, as a suitable combination of the A component, the B component, the C component and the D component,
One or more selected from the group consisting of ethanol and isopropanol;
B component is petrolatum;
One or more selected from the group consisting of a carboxyvinyl polymer and an alkyl-modified carboxyvinyl polymer; and a D component is a phospholipid;
The combination of these is mentioned.

Among these, particularly suitable combinations include
A component is ethanol;
B component is petrolatum;
C component is carboxyvinyl polymer; and D component is phospholipid;
The combination of these is mentioned.

  The emulsified preparation for external use of the present invention has high preparation stability, and (E) an active ingredient (particularly, a poorly water-soluble active ingredient or a salt compound that destabilizes the emulsifying system) can be suitably added.

  (E) The active ingredient is a component having a useful effect on the skin, such as a pharmacologically active component or a physiologically active component, and is not particularly limited. For example, anti-inflammatory analgesic component, antifungal component, steroid component, hair growth component, vitamins , Local anesthetic component, antipruritic component, antibacterial component, keratin softening component, moisturizing component and the like, preferably antiphlogistic analgesic component, antifungal component, steroid component, hair growth component, vitamins, particularly preferably antiphlogistic analgesic component, Antifungal component, steroid component. These components can be used alone or in combination of two or more.

  Anti-inflammatory analgesic ingredients include indomethacin, ferbinac, methyl salicylate, glycol salicylate, ibuprofen, ibuprofen piconol, bufexamac, butyl fenfenate, bendazac, piroxicam, ketoprofen, glycyrrhetinic acid, suprofen, ufenamate, diclofenac sodium, etc. Is mentioned.

  The compounding amount of the anti-inflammatory analgesic component used in the present invention is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. As a whole, the emulsion preparation for external use is usually 0.1 to 30% by weight, preferably 0.5 to 25% by weight, particularly preferably 1 to 20% by weight.

  Antifungal ingredients include terbinafine hydrochloride, sulconazole nitrate, clotrimazole, isoconazole nitrate, miconazole nitrate, econazole nitrate, oxyconazole nitrate, bifonazole, thioconazole, ketoconazole, tolnaphthalate, tolcyclate, pyrrolnitrin, butenafine hydrochloride, amorolfine hydrochloride, Examples include neticonazole hydrochloride, ranoconazole, rylanaphthalate, and avafazine.

  The amount of the antifungal component used in the present invention is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. The total amount of the emulsified preparation for external use is usually 0.01 to 5% by weight, preferably 0.05 to 3% by weight, particularly preferably 0.1 to 2% by weight.

  Steroids include dexamethasone acetate dexamethasone acetate, dexamethasone dexamethasone propionate, dexamethasone acetate, dexamethasone valerate, prednisolone valerate acetate, prednisolone acetate acetate, hydrocortisone valerate, hydrocortisone butyrate, hydrocortisone acetate, hydrocortisone acetate, hydrocortisone butyrate propionate, Cortisone, prednisolone acetate, prednisolone acetate, betamethasone, betamethasone valerate, betamethasone dipropionate, clobetasone butyrate, clobetasol propionate, diflorazone acetate, diflucortron valerate, beclomethasone propionate, flumethasone pivalate, triamcinolone acetonolone acetonide Nido, fluocinonide, amsinonide, harsinonide, diflupre Inert, budesonide, mometasone furoate, betamethasone butyrate propionate, Deporodon propionate, fludroxycortide, methylprednisolone acetate, and the like Akurometazon propionate.

  Although the compounding quantity of the steroid component used by this invention is not restrict | limited in particular, In consideration of the usability and effect on skin, it can select suitably and can be used. The total amount of the emulsion preparation for external use is usually 0.0005 to 15% by weight, preferably 0.001 to 10% by weight, particularly preferably 0.01 to 5% by weight.

  Hair growth ingredients include procyanidins, dipotassium glycyrrhizinate, carpronium chloride, cephalanthin, menthol, hinokitiol, L-hydroxyproline, acetylhydroxyproline, fucoidan, capsicum tincture, sultianine, symphonginidine, flavonosteroid, minoxidil, FGF-10, capsaicin , Yellow extract (extract), assembly extract (extract), beetle extract (extract), amachazuru extract (extract), hypericum extract (extract), gentian extract (extract), sage extract (extract), Peppermint extract (extract), hop extract (extract), Yokuinin extract (extract), persimmon leaf extract (extract), ginger extract (extract), carrot extract (extract), bodaiju extract Extract), it is like moutan bark extract (extract), preferably procyanidins, assembly extract (extract), Mitsuishikonbu extract (extract).

  The blending amount of the hair-growth component used in the present invention is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. As a whole, the emulsion preparation for external use is usually 0.1 to 30% by weight, preferably 0.5 to 25% by weight, particularly preferably 1 to 20% by weight.

  Examples of vitamins include retinol derivatives such as retinol and retinol acetate, retinal, retinoic acid, methyl retinoic acid, ethyl retinoic acid, retinoic acid retinol, vitamin A oil, vitamin A fatty acid ester, and the like; β-carotene, α -Provitamin A such as carotene, γ-carotene, δ-carotene, lycopene, zeaxanthin, cryptoxanthine, echinone; dl-α-tocopherol, dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-acetate Vitamin Es such as tocopherol, retinoic acid tocopherol, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, δ-tocopherol; riboflavin, flavin mononucleotide, flavin adenine dinucleotide, Vitamin B2 such as riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5′-phosphate sodium, riboflavin tetranicotinate; ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, phosphorus ascorbate Vitamin C such as acid ester magnesium, ascorbic acid stearate, ascorbyl dipalmitate, ascorbyl tetraisopalmitate; Vitamin D such as methyl hesperidin, ergocalciferol, cholecalciferol; Vitamin K such as phylloquinone, farnoquinone Γ-oryzanol, dibenzoyl thiamine, dibenzoyl thiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine Thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride Vitamin B1 such as thiamine triphosphate, thiamine triphosphate monophosphate; vitamin B6 such as pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5'-pyridoxal phosphate, pyridoxamine hydrochloride; cyanocobalamin, hydroxocobalamin, deoxyadeno Vitamin B12 such as silcobalamin; Folic acid such as folic acid, pteroylglutamic acid; Nicotinic acid such as nicotinic acid, nicotinic acid amide, methyl nicotinate; Pantothenic acid, Pantothe Pantothenic acids such as calcium phosphate, pantothenyl alcohol (panthenol), D-panthethine, D-panthetin, coenzyme A, pantothenyl ethyl ether; biotins such as biotin and bioticin; others, carnitine, ferulic acid, α -Vitamin-like agents such as lipoic acid and orotic acid.

  The amount of vitamins used in the present invention is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. As a whole, the emulsion preparation for external use is usually 0.1 to 30% by weight, preferably 0.5 to 25% by weight, particularly preferably 1 to 20% by weight.

  In addition, examples of the local anesthetic component, antipruritic component, antibacterial component, keratin softening component, and moisturizing component include the following.

Local anesthetic components: lidocaine, lidocaine hydrochloride, dibucaine, dibucaine hydrochloride, ethyl aminobenzoate, eucalyptus oil, eugenol, camphor, menthol, mint oil, chlorobutanol and the like.
Antipruritic ingredients: crotamiton, chlorpheniramine, chlorpheniramine maleate, diphenhydramine, diphenhydramine hydrochloride, diphenhydramine salicylate, salicylic acid, nonylic acid vanillylamide, mequitazine, camphor, thymol, eugenol, polyoxyethylene lauryl ether, comfrey extract, perilla extract, etc.

  Antibacterial components: isopropylmethylphenol, chlorhexidine gluconate, chlorhexidine hydrochloride, benzalkonium chloride, benzethonium chloride, cetyltrimethylammonium bromide, decalinium chloride, triclosan, trichlorocarbanilide and the like.

  Keratin softening ingredients: benzyl alcohol, phenylethyl alcohol, propylene carbonate, hexyl decanol, allantoin, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, triethanolamine, diisopropyl adipate, ethyl laurate, fatty acid dialkyrolamide, urea, sulfur, Resorcin, phytic acid, lactic acid, lactate, sodium hydroxide, potassium hydroxide, etc.

  Moisturizing ingredients: Propylene glycol, 1,3-butylene glycol, 1,2-pentanediol, 1,2-hexanediol, glycerin, dipropylene glycol, diglycerin, diglycerin trehalose and other polyhydric alcohols, diethylene glycol monobutyl ether, etc. Glycol ether, sodium hyaluronate, heparin analogue, sodium chondroitin sulfate, collagen, elastin, keratin, chitin, chitosan and other high molecular compounds, glycine, aspartic acid, arginine and other amino acids, sodium lactate, urea, sodium pyrrolidone carboxylate, etc. Natural moisturizing factor, chamomile extract, aloe extract, aloe vera extract, hamamelis extract, rosemary extract, thyme extract, tea extract, perilla extract, etc.

  As the active ingredient (E) used in the present invention, anti-inflammatory and analgesic ingredients, antifungal ingredients, steroid ingredients, hair growth ingredients, vitamins, local anesthetic ingredients, antipruritic ingredients, antibacterial ingredients, keratin softening ingredients, moisturizing ingredients exemplified above Of these, a poorly water-soluble active ingredient or a salt compound is preferred, a poorly water-soluble active ingredient is more preferred, and a poorly water-soluble salt compound is particularly preferred.

“Slightly water-soluble” means that when water is used as a solvent, it has a solubility of “not easily soluble” or less according to the solubility standard of the Japanese Pharmacopoeia. As a poorly water-soluble active ingredient,
Anti-inflammatory analgesics such as indomethacin, felbinac, methyl salicylate, glycol salicylate, ibuprofen, ibuprofen piconol, bufexamac, flufenamic acid, bendazac, piroxicam, ketoprofen, glycyrrhetinic acid, suprofen, ufenamate, flurbiprofen, diclofenac sodium;
Terbinafine hydrochloride, sulconazole nitrate, clotrimazole, isoconazole nitrate, miconazole nitrate, econazole nitrate, oxyconazole nitrate, bifonazole, thioconazole, ketoconazole, tolnaphthalate, tolcyclate, pyrrolnitrin, butenafine hydrochloride, amorolfine hydrochloride, neticoconazole hydrochloride, lanoconazole , Antifungal ingredients such as avafazine;
Dexamethasone acetate dexamethasone acetate, dexamethasone dexamethasone propionate, dexamethasone acetate, dexamethasone valerate, prednisolone valerate acetate, prednisolone acetate, hydrocortisone valerate acetate, hydrocortisone butyrate, hydrocortisone acetate, hydrocortisone propionate, cortisone propionate, cortisone acetate propionate Prednisolone, betamethasone, betamethasone valerate, betamethasone dipropionate, clobetasone butyrate, clobetasol propionate, diflorazone acetate, diflucortron valerate, beclomethasone propionate, flumethasone pivalate, triamcinolone acetonide, fluocinolone acetonide, fluocinolone acetonide , Halsinonide, Difluprednate, Butesonide, Fu Nkarubon furoate, betamethasone butyrate propionate, Deporodon propionate, fludroxycortide, methylprednisolone acetate, steroid components such Akurometazon propionic acid;
Hair growth ingredients such as capsaicin;
Etc.

The poorly water-soluble active ingredient is preferably indomethacin, ferbinac, ibuprofen, ketoprofen, terbinafine hydrochloride, butenafine hydrochloride, hydrocortisone valerate acetate, prednisolone valerate acetate, clobetasone butyrate, prednisolone acetate and hydrocortisone acetate,
More preferably are indomethacin, ferbinac, ketoprofen, terbinafine hydrochloride, butenafine hydrochloride, hydrocortisone valerate acetate, prednisolone valerate acetate, clobetasone butyrate, prednisolone acetate and hydrocortisone acetate,
More preferably, indomethacin, felbinac, terbinafine hydrochloride, butenafine hydrochloride, prednisolone valerate acetate and hydrocortisone acetate,
Particularly preferred are indomethacin, felbinac, terbinafine hydrochloride and prednisolone valerate acetate.

The amount of the poorly water-soluble anti-inflammatory analgesic component used in the present invention is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. As a whole, the emulsion preparation for external use is usually 0.1 to 30% by weight, preferably 0.5 to 25% by weight, particularly preferably 1 to 20% by weight.
The blending amount of the poorly water-soluble antifungal component used in the present invention is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. The total amount of the emulsified preparation for external use is usually 0.01 to 5% by weight, preferably 0.05 to 3% by weight, particularly preferably 0.1 to 2% by weight.
The blending amount of the poorly water-soluble steroid component used in the present invention is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. The total amount of the emulsion preparation for external use is usually 0.0005 to 15% by weight, preferably 0.001 to 10% by weight, particularly preferably 0.01 to 5% by weight.

  The salt compound is a salt among anti-inflammatory analgesic component, antifungal component, hair-restoring component, vitamins, local anesthetic component, antipruritic component, antibacterial component, keratin softening component, moisturizing component exemplified as the active ingredient (E) above. For example, salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, thiocyanic acid; salts with organic acids such as acetic acid, maleic acid, gluconic acid, salicylic acid; alkali metal salts such as sodium and potassium, magnesium Various metal salts such as alkaline earth metal salts such as calcium and barium, polyvalent metal salts such as aluminum; ammonium salts such as ammonium, tricyclohexylammonium and trimethylammonium; monoethanolamine, diethanolamine, triethanolamine, mono Isopropanolamine, diisopropanolamine, triisopropanol Salts with amino acids such as lysine; salts with alkanolamines such as an amine and the like, also contain more sparingly water-soluble and water-soluble.

  Specific examples of such salt compounds include anti-inflammatory analgesic components such as diclofenac sodium; terbinafine hydrochloride, sulconazole nitrate, isoconazole nitrate, miconazole nitrate, econazole nitrate, oxyconazole nitrate, butenafine hydrochloride, amorolfine hydrochloride, neticonazole hydrochloride, and the like. Fungal ingredients; hair growth ingredients such as dipotassium glycyrrhizinate and carpronium chloride; vitamins such as riboflavin 5'-sodium phosphate ester, sodium ascorbate, sodium ascorbate phosphate magnesium, ascorbate phosphate magnesium, pyridoxine hydrochloride; chlorhexidine hydrochloride , Antibacterial components such as benzalkonium chloride, benzethonium chloride, cetyltrimethylammonium bromide, decalinium chloride; lidocaine hydrochloride, Acid dibucaine, local anesthetic components, such as aminoethyl benzoate; and the like; diphenhydramine hydrochloride, antipruritic ingredients such as chlorpheniramine maleate.

  As a salt compound, preferably a poorly water-soluble salt compound such as terbinafine hydrochloride, sulconazole nitrate, isoconazole nitrate, miconazole nitrate, econazole nitrate, oxyconazole nitrate, butenafine hydrochloride, amorolfine hydrochloride, neticoconazole hydrochloride, etc .; More preferred are terbinafine hydrochloride and butenafine hydrochloride, and particularly preferred is terbinafine hydrochloride.

The amount of the anti-inflammatory analgesic component, which is a salt compound used in the present invention, is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. As a whole, the emulsion preparation for external use is usually 0.1 to 30% by weight, preferably 0.5 to 25% by weight, particularly preferably 1 to 20% by weight.
The amount of the antifungal component, which is a salt compound used in the present invention, is not particularly limited, but can be appropriately selected and used in consideration of the feeling of use and effects on the skin. The total amount of the emulsified preparation for external use is usually 0.01 to 5% by weight, preferably 0.05 to 3% by weight, particularly preferably 0.1 to 2% by weight.

  The method for preparing the emulsion preparation for external use of the present invention is not particularly limited, and various components necessary for preparing an ordinary emulsion preparation for external skin can be appropriately selected and blended, and can be prepared by a conventional method. Moreover, the application amount and usage of the emulsion preparation for external application of the present invention to the outer skin are not particularly limited, and it can be used usually by applying an appropriate amount to the outer skin such as skin several times a day.

  The emulsion preparation for external use of the present invention may be usually provided with a liquidity of pH 3 to 9, preferably from the viewpoints of the stability of the active ingredient, low irritation to the skin and mucous membranes, and good skin feeling. It is desirable to be in the acidic region of pH 3-7, more preferably pH 3-6. In particular, when a poorly water-soluble active ingredient or a salt compound is blended, pH 4 to 6 is preferable from the viewpoint of formulation stability.

The external preparation for skin of the present invention can be prepared in various forms. For example, dosage forms such as cream, milky lotion, gel milky lotion are mentioned. Especially, from the stabilization effect of the external preparation for skin containing A component, as embodiment of this invention, cream or emulsion is preferable and cream is especially preferable. In the present invention, the cream is a semi-solid externally applied emulsion preparation having a viscosity of 5000 mPas · s or more and uniform throughout. In addition, if the measurement cannot be performed due to slipping of the preparation or exceeding the upper limit of measurement in the viscosity measurement, the cream is made into a semisolid emulsified preparation for skin external application with a hardness of 1000 g or less.
Viscosity refers to the value when the preparation is placed in a glass 50 ml screw cap bottle and measured with a BL type viscometer, M4 rotor at 25 ° C., rotation speed 60 rpm, after 1 minute. Hardness refers to the maximum value until entering 1 cm when the preparation is placed in a plastic 50 g jar and measured with a rheometer under the conditions of T.Speed (UP) 2 cm / min and φ20 (compression elasticity) adapter.

  Since the emulsion preparation for external use of the present invention may belong to any category of pharmaceuticals, quasi-drugs, and cosmetics, it can be used for various applications. The use of the emulsion preparation for external application of the present invention depends on the active ingredient to be blended. For example, a pharmaceutical agent [for example, a therapeutic agent for infectious skin diseases or an antibacterial agent (antifungal agent, Anti-acne agents); eczema, rash, dry pruritus, psoriasis, moist, dermatitis, dermatitis treatment or antipruritic agent for treating itching and inflammation; cuts, scratches, shoe rubs Bactericidal disinfectant and wound healing agent for promoting and preventing exacerbation of scratches, scratches, scuffs, burns, purulent wounds, wrinkles, cracks, bruises, etc .; cheilitis, keratitis, lip cracks, sores Treatment for lips for treatment; keratosis such as fingertips, elbows, knees, heels and ankles, keratin softeners for treating shark skin, anti-inflammatory analgesics, etc., quasi drugs (hair growth, Scalp preparation for hair growth promotion and hair growth (hair growth agent); rough hands, Prevention of rough skin, rough lips, hot flashes after sunburn, wrinkles, sagging, dryness, frostiness, cracks, red spots, rashes, etc. on skin; prepares skin, smoothes lips, keeps skin and lips smooth, Examples of suitable uses include, but are not limited to, moisturizing the lips, protecting the skin and lips, and controlling odor and the like, and cosmetics (used for moisturizing, keratin softening, whitening, etc.). Preferred are antifungal agents, anti-inflammatory analgesics, anti-inflammatory agents, hair restorers, and whitening agents, and particularly preferred are antifungal agents, anti-inflammatory analgesics, and anti-inflammatory agents.

  The emulsified preparation for external use of the skin of the present invention is a pharmaceutical, quasi-drug or cosmetic as needed within a quantitative and qualitative range that does not impair quality such as storage stability and viscosity, and does not impair the effects of the present invention. Various components commonly used in the field, such as bases, surfactants, thickeners, preservatives, pH adjusters, stabilizers, irritation reducers, preservatives, colorants, dispersants, fragrances, etc. Can be blended. In addition, these components can be mix | blended individually by 1 type or in combination of 2 or more types.

  Base: paraffin, ozokerite, ceresin, hard fat, microcrystalline wax, squalane (synthetic / vegetable), α-olefin oligomer, hydrocarbons such as liquid paraffin, light isoparaffin, liquid isoparaffin, polyethylene powder; lauric acid, myristic acid Fatty acids such as palmitic acid, stearic acid, behenic acid, isostearic acid, oleic acid, linoleic acid; trifatty acid glycerides such as glyceryl tri-2-ethylhexanoate (trioctanoin); highly polymerized methylpolysiloxane, dimethylsiloxane methyl (Polyoxyethylene) siloxane methyl (polyoxypropylene) siloxane copolymer, dimethylsiloxane methyl (polyoxyethylene) siloxane copolymer, dimethylsiloxane methyl (polyoxypropylene) Pyrene) siloxane copolymer, polyoxyethylene / methylpolysiloxane copolymer, poly (oxyethylene / oxypropylene) / methylpolysiloxane copolymer, dimethylsiloxane / methylcetyloxysiloxane copolymer, dimethylsiloxane / methylstea Roxysiloxane copolymer, alkyl acrylate copolymer methylpolysiloxane ester, crosslinked methylpolysiloxane, crosslinked methylphenylpolysiloxane, crosslinked polyether-modified silicone, crosslinked alkylpolyether-modified silicone, crosslinked alkyl-modified silicone Polymerized silicones such as ethylene glycol monoacetate, ethylene glycol diacetate, triethylene glycol diacetate, hexylene glycol diacetate, and 2-methyl-2-pro 1,1-diol diacetate glycol acetate; triethylene glycol divalerate, 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate, 2,2,4-trimethyl- Glycol esters such as 1,3-pentanediol diisobutyrate; ethylene glycol diacrylate, diethylene glycol diacrylate, propylene glycol monoacrylate, 2,2-dimethyl-trimethylene glycol diacrylate, and 1,3-butylene Glycol acrylates such as glycol diacrylate; glycol dinitrates such as ethylene glycol dinitrate, diethylene glycol dinitrate, triethylene glycol dinitrate, and propylene glycol dinitrate; cetanol, stearyl alcohol, behenyl alcohol, cetos Higher alcohols such as allyl alcohol, hexyl decanol, isostearyl alcohol, octyldodecanol, oleyl alcohol, decyltetradecanol; isopropyl myristate, cetyl octanoate, cetyl isooctanoate, octyldodecyl myristate, octyldodecyl oleate, myristyl myristate Decyl oleate, isodecyl oleate, isopropyl palmitate, butyl myristate, butyl stearate, hexyl laurate, isopropyl isostearate, isostearyl palmitate, cetyl palmitate, isooctyl palmitate, 2-ethylhexyl stearate, linoleic acid Ethyl, isopropyl linoleate, cholesteryl stearate, cholesteryl isostearate, hydroxy Cholesteryl stearate, phytosteryl hydroxystearate, 2-ethylhexyl hydroxystearate, phytosteryl isostearate, cetyl 2-ethylhexylate, cetostearyl 2-ethylhexylate, stearyl 2-ethylhexylate, diisopropyl adipate, diethyl sebacate, diacid malate Isostearyl, ethyl oleate, hexyl isostearate, 2-hexyldecyl isostearate, 2-hexyldecyl myristate, 2-hexyldecyl stearate, 2-hexyldecyl palmitate, cetyl lactate, 2-octyl dodecyl lactate, citric acid Tri-2-ethylhexyl, tri-2-octyldodecyl citrate, 2-ethylhexyl succinate, pentaerythritol tetra-2-ethylhexanoate, trii Diglyceryl stearate, propylene glycol dicaprate, propylene glycol di (capryl / caprin), propylene glycol dioleate, neopentyl glycol dicaprate, neopentyl glycol di2-ethylhexylate, glyceryl tricaprate, glyceryl tri-2-ethylhexylate , Esters such as glyceryl tri (capryl / caprin), glyceryl triisostearate, glyceryl triisopalmitate; avocado oil, camellia oil, jojoba oil, macadamia nut oil, coconut oil, cottonseed oil, corn oil, olive oil, rapeseed oil, Safflower oil, sesame oil, soybean oil, peanut oil, wheat germ oil, rice bran oil, castor oil, persic oil, kukui nut oil, grape seed oil, almond oil, kyounin oil, carrot , Spearmint oil, sage oil, thyme oil, evening primrose oil, tea seed oil, turpentine oil, wild rose oil, mint oil, pearl barley oil, sunflower oil, hazelnut oil, meadowweed oil, eucalyptus oil, roman chamomile oil, rosehip oil, maltierra Vegetable oils such as oil and shea butter; egg yolk oil, 2,2 '-[1,4-phenylenedioxy] diethanol, dioxane, butylene glycol adipic acid polyester, etc.

  Surfactants: Sorbitan fatty acid esters such as sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexylate, diglycerol sorbitan tetra-2-ethylhexylate Glyceryl fatty acids such as glyceryl monostearate and glyceryl monostearate malate, polyglyceryl fatty acids such as polyglyceryl monoisostearate and polyglyceryl diisostearate, propylene glycol fatty acid esters such as propylene glycol monostearate, polyoxyethylene cured Castor oil derivatives such as castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 80, polylauric acid poly Polyoxyethylene sorbitan fatty acid esters such as xylene (20) sorbitan (polysorbate 20), polyoxyethylene monostearate (20) sorbitan (polysorbate 60), polyoxyethylene (20) sorbitan (polysorbate 80) monooleate, poly Oxyethylene monococonut oil fatty acid glyceryl, glycerin alkyl ether, alkyl glucoside, polyoxyethylene cetyl ether (cetomacrogol), stearylamine, oleylamine and the like.

  Thickener: Guar gum, locust bean gum, carrageenan, xanthan gum, dextran, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium alginate, propylene glycol ester of alginate, polyvinyl alcohol, polyvinylpyrrolidone, polyvinylmethyl Ether, sodium polyacrylate, bentonite, dextrin fatty acid ester, pectin, etc.

  Preservatives: Benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, benzyl paraoxybenzoate, paraoxybenzoic acid Methyl, phenoxyethanol, BHT, etc.

  pH adjusters: inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acids (lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, sodium succinate, oxalic acid, gluconic acid, Fumaric acid, propionic acid, acetic acid, aspartic acid, epsilon-aminocaproic acid, glutamic acid, aminoethylsulfonic acid, etc.), gluconolactone, ammonium acetate, inorganic base (sodium bicarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, Calcium hydroxide, magnesium hydroxide, etc.), organic bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.).

  Stabilizer: sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, etc.

  These components can be used alone or in combination of two or more. In addition, the blending amounts thereof are not particularly limited as long as the effects of the present invention are achieved. Desirably, these blending amounts can be appropriately selected and used up to the pharmaceutically acceptable upper limit blending amount. Specifically, it can be prepared according to the purpose from the range of usually 0.001 to 20 parts by weight, preferably 0.001 to 10 parts by weight, and more preferably 0.001 to 5 parts by weight per 100 parts by weight of the external preparation for skin.

  EXAMPLES The present invention will be specifically described below with reference to examples, but these examples do not limit the scope of the present invention. In addition, especially a compounding quantity does not have a unit description, all represent weight%.

Test Example 1 Formulation Stabilization Test
According to the formulation shown in Table 1, after emulsifying the water phase and the oil phase, an ethanol solution of terbinafine hydrochloride and sodium hydroxide were added to adjust pH to prepare an external skin emulsion.
Regarding the separation of the preparation immediately after the preparation, it was evaluated that ○: none, Δ: slight separation was observed, and x: clear separation was observed. In addition, the stability (appearance, discoloration, separation) after 3 months of standing in a constant temperature room with a humidity of 75% and 40 ° C. is as follows: ○: Appearance is smooth, Δ: Slightly non-uniform or Slightly cracked, x: uneven or cracked surface, discoloration, separation: ○: no, Δ: slight discoloration / separation, x: obvious discoloration / separation did.
The results are shown in Table 1.

From Comparative Examples 1 to 3, if any of phospholipid, petrolatum, or carboxyvinyl polymer is missing, there is a problem because separation occurs immediately after preparation. In Comparative Example 4, there was no problem immediately after preparation, but the stability after 3 months was not very good. On the other hand, Examples 1 to 3 were excellent up to the long-term stability 3 months after the preparation, and even when 1% terbinafine hydrochloride (poorly water-soluble and salt compound) was added, the preparation was kept stable. .
Moreover, when the usability (smell, spread, stickiness) was evaluated for the creams of Examples 1 to 3, it was confirmed that all the items were satisfactory without problems.
As described above, the emulsion preparation for external use in Examples has a stable and good feeling even when it contains a specific amount of ethanol, and isopropanol and diethylene glycol monoethyl ether show the same tendency, and thus have usefulness. high.

Test Example 2 Skin retention test
Preparation of Comparative Example 5: Purified water 55.4 g, terbinafine hydrochloride 1.0 g, isopropyl myristate 5.0 g, isopropyl palmitate 3.0 g, propylene glycol 20 g, stearyl alcohol 8.0 g, cetanol 3.0 g, benzyl alcohol 1.0 g, polysorbate 60 2.0 g, 1.3 g of sorbitan monostearate was added, heated to 60 ° C. and mixed until evenly dissolved, and potassium hydroxide (appropriate amount) was added to prepare a formulation (pH 5).
For Example 2 in Table 1 and Comparative Example 5 above, hairless rats (strain: HWY: Slc, 6 weeks old, female) were fixed by ether and urethane anesthesia, and 100 μl of each preparation was patched (effective area: 201 mm ² ). Wet and attach to the back. After removing the preparation 24 hours later, the application site was removed, homogenized in 5 ml of ethanol, and terbinafine hydrochloride was quantified by HPLC.
The results are shown in Table 2.

  Since Example 2 showed a storage amount nearly three times that of Comparative Example 5, it was found that skin retention was significantly improved. Thus, Example 2 is an emulsified preparation for external application with excellent transdermal absorbability, and the preparations shown in Table 1 show the same tendency. Therefore, the active ingredient stays at the site where the preparation is applied, so that the pharmacological effect is sufficient. It is particularly useful because it can be expected.

Test example 3 Usability test
Preparation of Comparative Examples 6 and 7: Comparative Example 6 in which the amount of ethanol in Table 1 Example 1 was 0%, the amount of terbinafine hydrochloride was 0.01%, and Comparative Example 6 and Table 1 Example 1 in which the amount of ethanol was 3% were compared. Example 7 was prepared in the same manner as in Table 1.
For Examples 1, 2, and 3 in Table 1 and Comparative Examples 6 and 7, skin adhesion, stickiness, and glare were evaluated.
≪Evaluation of skin adhesion≫
Apply 10 mg of 2 mg x 2 cm of the inner side of the forearm to a test product colored with 1 mg of blue No. 1 to 1 g of the preparation, and use the spectrophotometer CM-3500d (manufactured by MINOLTA). Measured using * a * b color system. A cup was placed on the test site, 10 ml of water was placed therein, shaken for 3 minutes (200 times / min), water was removed, the test site was dried, and the measurement was performed in the same manner. ΔE was calculated on the basis of the preparation immediately after application, and ΔE was evaluated as ◎: 0 to less than 4, ○: less than 4 to 8, Δ: less than 8 to 12, and x: 12 or more.
≪Sticky≫
For 5 subjects, we performed a three-level evaluation of stickiness when applying each preparation immediately after preparation to the hand. The number of respondents with no was ◎: 5 people, ○: 3 ～ 4 people, x: evaluated as 2 or less.
≪Glitter≫
In 5 subjects, the glaring of the preparation immediately after preparation was placed in a 50 g jar (diameter 5 cm), the surface of the preparation was observed, and a three-stage evaluation was performed. ◎: 5 people, ○: 3-4 people, ×: 2 people or less.
The results are shown in Table 3.

In Comparative Examples 6 and 7, there was a problem because both the adhesion was poor and stickiness and glare were recognized and the usability was poor. On the other hand, in Examples 1 to 3, it was found that adhesion, stickiness, and glare were improved by adding 5 to 15% of ethanol.
As described above, the emulsion preparation for external use in Examples has good usability even when it contains a specific amount of ethanol, and isopropanol and diethylene glycol monoethyl ether show the same tendency, and thus have usefulness. high.

Test Example 4 Formulation Stabilization Test
According to the formulation shown in Table 4, after emulsifying the aqueous phase and the oil phase, potassium hydroxide was added to adjust the pH to prepare an external preparation for skin.
Regarding the separation of the preparation immediately after the preparation, it was evaluated that ○: none, Δ: slight separation was observed, and x: clear separation was observed. In addition, regarding stability (appearance, discoloration, separation) after 2 months in a constant temperature room with a humidity of 75% and 40 ° C., the appearance is: ○: Appearance is smooth, Δ: Slightly uneven surface Slightly cracked, x: uneven or cracked surface, discoloration, separation: ○: no, Δ: slight discoloration / separation, x: obvious discoloration / separation did.
The results are shown in Table 4.

  Examples 4 to 10 are excellent from long-term stability immediately after preparation to 2 months later, and further contain terbinafine hydrochloride (poorly water-soluble and salt compound), indomethacin, felbinac, prednisolone valerate acetate (all sparingly water-soluble). Even so, the formulation was kept stable.

Test Example 5 Skin retention test
According to the formulation shown in Table 5, after emulsifying the water phase and the oil phase, potassium hydroxide was added to adjust the pH to prepare an external preparation for skin.
PBS 10mL was added to the reservoir side of a vertical Franz cell (radius 0.75cm), and after fixing the full thickness skin excluding fat of hairless mice (strain: HR-1, 6 weeks old, male) between the cells, donor 2 g of Example 12 or Comparative Example 8 was added to the side. 24 hours after addition of the test preparation, the entire skin was removed from the cell, and the surface of the stratum corneum was washed with ethanol and purified water. The entire skin was homogenized and extracted with ethanol, and indomethacin and felbinac were quantified by HPLC.
The results are shown in Table 5.

  It was found that the skin retention of Example 12 was significantly improved as compared with Comparative Example 8 in both felbinac and indomethacin. Thus, Example 12 is an emulsified preparation for external use with excellent transdermal absorbability, and is particularly useful because a poorly water-soluble active ingredient can be sufficiently expected to remain at the site where the preparation is applied. .

  The formulation examples are given below. In addition, the compounding quantity in the following Examples represents weight% about all the things which have no description of a unit especially.

Example 4: Antifungal agent (cream)
Ethanol 12.0
White petrolatum 10.0
Carboxyvinyl polymer 1.5
Phospholipid 4.0
Butenafine hydrochloride 1.0
Squalane 5.0
Polysorbate 60 1.8
Triethanolamine 1.3
Stearyl alcohol 0.8
Purified water remaining
Total 100%

Example 5: Anti-inflammatory analgesic (cream)
Isopropanol 8.0
Gelled hydrocarbon 12.0
Carboxyvinyl polymer 1.0
Phospholipid 0.5
Felbinac 1.0
Isopropyl myristate 3.0
Squalane 3.0
Polysorbate 60 2.0
Cetanol 1.0
Triethanolamine 0.7
Purified water remaining
Total 100%

Example 6: Anti-inflammatory analgesic (cream)
Diethylene glycol monoethyl ether 15.0
Lanolin 5.0
Acrylic acid / alkyl methacrylate copolymer 1.0
Phospholipid 2.0
Felbinac 1.0
Isopropyl myristate 4.0
Squalane 2.0
Polyoxyethylene hydrogenated castor oil 40 2.0
Cetanol 1.0
Triethanolamine 0.7
Purified water remaining
Total 100%

Example 7: Steroid agent (cream)
Diethylene glycol monoethyl ether 10.0
Macrogol 400 8.0
Macrogol 4000 3.0
Acrylic acid / alkyl methacrylate copolymer 0.7
Phospholipid 1.5
Hydrocortisone acetate 0.2
Squalane 7.0
Polyoxyethylene hydrogenated castor oil 50 2.0
Cetanol 1.0
Triethanolamine 0.6
Purified water remaining
Total 100%

Example 8: Steroid agent (cream)
Ethanol 10.0
Polyethylene glycol 1500 8.0
Carboxyvinyl polymer 0.5
Phospholipid 2.0
Prednisolone valerate acetate 0.3
Crotamiton 3.0
Isopropyl palmitate 2.0
Cetanol 1.0
Stearyl alcohol 1.0
Seto Macrogol 1000 1.0
Glycerol monostearate0.8
Triethanolamine 0.3
Purified water remaining
Total 100%

Example 9: Antifungal agent (milky lotion)
Ethanol 12.0
White petrolatum 10.0
Carboxyvinyl polymer 0.2
Phospholipid 1.0
Terbinafine hydrochloride 1.0
Squalane 5.0
Polysorbate 60 1.8
Triethanolamine 0.21
Stearyl alcohol 0.8
Purified water remaining
Total 100%

Claims (2)

(A) 5 to 15% by weight of one or two selected from the group consisting of ethanol and isopropanol;
(B) 0.1-20% by weight of one or more selected from the group consisting of petrolatum, lanolin and gelled hydrocarbon;
(C) 0.001 to 5% by weight of one or more selected from the group consisting of carboxyvinyl polymer and alkyl-modified carboxyvinyl polymer;
(D) 0.001 to 10% by weight of phospholipid,
(E) Contains one or more selected from the group consisting of 0.1 to 30% by weight of ferbinac, 0.01 to 5 % by weight of terbinafine hydrochloride, 0.1 to 30% by weight of indomethacin and prednisolone valerate acetate 0.0005 to 15 % by weight O / W type skin external emulsion formulation. The emulsified preparation for external use according to claim 1 , wherein the total amount of the component (A) is 1 to 200 parts by weight with respect to 1 part by weight of the total amount of the component (C).