JP2003321347A - Gel ointment - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a safe gel ointment which stably retains a difficultly water- soluble active constituent in spite of the water contained therein and does not irritate the skin. <P>SOLUTION: It has been found out that the safe gel ointment excellent in the stability of a difficultly water-soluble active constituent and not irritating to the skin can be made by incorporating a nonionic surfactant and at least one adjuvant selected from the group consisting of glycyrrhetinic acids, glycyrrhizic acids, vitamin Es, and monoterpenes in a gel ointment containing a difficultly water-soluble active constituent and water. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a gel ointment containing water and useful in terms of usability and safety, and relates to a gel ointment containing a specific poorly water-soluble active ingredient.

[0002]

2. Description of the Related Art A sparingly water-soluble active ingredient used in an external preparation is often selected as a sparingly water-soluble ingredient because it is necessary to exert its effect by being applied to the outer skin covered with a stratum corneum which is a lipid. Therefore, in order to stably retain the poorly water-soluble active ingredient in an external preparation containing a relatively large amount of water, it is necessary to study a formulation that sufficiently solubilizes the poorly water-soluble active ingredient. By the way, a gel ointment preparation is one of the preparation forms used for external use. Gel ointment is a semisolid ointment containing a large amount of transparent or translucent relatively large amount of liquid components, and is known to have excellent drug release properties and transdermal absorbability. Therefore, when such a gel ointment contains water and further contains a poorly water-soluble active ingredient, it is necessary to study a formulation for sufficiently solubilizing the poorly water-soluble active ingredient.

As a method for solubilizing a poorly water-soluble active ingredient in a hydrous gel ointment, a method using ethanol is typically known. Ethanol works well as a solubilizing agent for sparingly water-soluble active ingredients, and when applied with an ointment, it gives a cooling effect due to volatile evaporation and a smooth, non-sticky feeling, so it is used in large amounts in hydrous gel ointments. There is. On the other hand, when a gel ointment containing a large amount of ethanol is applied to the outer skin, degreasing from the skin occurs and skin irritation occurs. Therefore, a gel ointment containing a large amount of ethanol is not suitable for application to mucous membrane sites, dry skin, or skin with inflammation such as allergic symptoms, and the poorly water-soluble active ingredient is stably retained in the formulation. In addition, a safe gel ointment having no skin irritation has been demanded. As another method, a method using a surfactant is also known. A liquid crystal structure is formed by limiting the ratio / composition of water-poorly water-soluble active ingredient-surfactant, and a relatively large amount of the sparingly water-soluble active ingredient is solubilized by sandwiching the sparingly soluble active ingredient in the liquid crystal structure. be able to. But,
In order to solubilize stably, it is essential to form a liquid crystal structure in a limited ratio and composition, and since it is necessary to add a large amount of surfactant, it has skin irritation and gel ointment The problem is that it tends to inhibit the release of the drug. Therefore, a method of using a surfactant and ethanol in combination is also known, but it is not a method that sufficiently satisfies stability and skin irritation.

[0004]

An object of the present invention is to provide a gel ointment which stably holds a sparingly water-soluble active ingredient in a gel ointment containing water and which is not irritating to the skin and is safe.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that in a gel ointment containing a certain poorly water-soluble active ingredient and water, a nonionic surfactant is used. In addition, by containing at least one or more auxiliaries selected from the group consisting of glycyrrhetinic acid, glycyrrhizinic acid, vitamin Es and monoterpenes, a highly water-insoluble active ingredient has excellent stability and is a non-irritating safe gel. We have found that an ointment can be made.

The present invention was developed based on such findings. That is, the present invention is a gel ointment listed in the following (1) to (6): (1) a) Dexamethasone acetate valerate, dexamethasone, prednisolone acetate valerate, hydrocortisone butyrate, prednisolone acetate, prednisolone acetate, hydrocortisone acetate, hydrocortisone, Cortisone acetate, ibuprofen piconol, salicylic acid, methyl salicylate, bufexamac, ufenamate, crotamiton,
Diphenhydramine, ethyl aminobenzoate, lidocaine, dibucaine, undecylenic acid, homosulfamine,
At least one or more water-insoluble active ingredient selected from the group consisting of isopropylmethylphenol, methylparaben and butylparaben, b) a nonionic surfactant, and c) glycyrrhetinic acid, glycyrrhizinic acid, vitamin Es and monoterpenes A gel ointment containing at least one auxiliary selected from the group consisting of: d) water; (2) a gel ointment according to (1) containing a gelling agent; and (3) treatment for dermatitis. Agent, antipruritic agent, wound healing agent, bactericidal disinfectant, antibacterial agent, gel ointment according to (1) to (2) which is a therapeutic agent for bacterial skin disease, (4) inclusion of poorly water-soluble active ingredient in gel ointment The amount of the gel ointment according to (1) to (3) is 0.00001 to 15% by weight, and the content of the nonionic surfactant (5) in the gel ointment is 0.1 to 15% by weight. (1) (4)
The gel ointment according to (6), (6) the gel ointment according to (1) to (5) which is transparent, and the present invention is a method described in the following (7): (7) Dexamethasone valerate acetate, dexamethasone, Prednisolone acetate valerate, hydrocortisone butyrate, prednisolone acetate, prednisolone, hydrocortisone acetate, hydrocortisone, cortisone acetate, ibuprofen piconol, salicylic acid, methyl salicylate, bufexamac, ufenamate, crotamiton, diphenhydramine, aminobenzoic acid diethyl benzoate, benzoic acid dibutyric acid, ethyl benzoic acid, benzoic acid, dibenzoic acid, benzoic acid, dibenzoic acid. In a gel ointment containing water and at least one or more poorly water-soluble active ingredients selected from the group consisting of homosulfamine, isopropylmethylphenol, methylparaben and butylparaben, nonionic Method for stabilizing a poorly water-soluble active ingredient, which comprises blending at least one auxiliary selected from the group consisting of glycyrrhetinic acids, glycyrrhizinic acids, vitamin Es and monoterpenes together with a water-soluble surfactant. .

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The sparingly water-soluble active ingredient in the present invention is usually dexamethasone valerate acetate, dexamethasone acetate, dexamethasone valerate prednisolone valerate, hydrocortisone butyrate, acetic acid which is a drug used as an external skin agent in pharmaceuticals and quasi drugs. Prednisolone, prednisolone, hydrocortisone acetate, hydrocortisone, cortisone acetate, ibuprofen piconol, salicylic acid, methyl salicylate, bufexamac, ufenamate, crotamiton,
Diphenhydramine, ethyl aminobenzoate, lidocaine, dibucaine, undecylenic acid, homosulfamine,
Isopropylmethylphenol, methylparaben and butylparaben. These active ingredients may be contained in the gel ointment of the present invention in one kind or in two or more kinds.

The poorly water-soluble active ingredient of the present invention is described in the Japanese Pharmacopoeia as "slightly insoluble in water", "insoluble in water", "extremely insoluble in water", and "insoluble in water". Ingredient or 1g at 20 ℃
Alternatively, the amount of water required to dissolve 1 ml is 30 ml or more, but in the gel ointment of the present invention, 0.00001 to 1 of the poorly water-soluble active ingredient is usually added to the total weight of the gel ointment.
5% by weight, preferably 0.00001-10% by weight,
The content can be more preferably 0.001 to 10% by weight, and particularly preferably 0.00015 to 8% by weight. If it is 0.00001% by weight or less, the effect originally possessed by the active ingredient cannot be sufficiently exerted, and if it exceeds 15% by weight, the stability in the gel ointment tends to be lowered.

As the nonionic surfactant of the present invention, one or more nonionic surfactants usually used in pharmaceuticals, quasi drugs and cosmetics can be used. The nonionic surfactant of the present invention is specifically polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene glycol or Examples thereof include polyoxyethylene polyoxypropylene alkyl ether. More specifically, POE (40) hydrogenated castor oil, PO
E (60) hydrogenated castor oil, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, monococonut oil fatty acid polyoxyethylene (20) sorbitan, polyoxyethylene monopalmitate (20) Sorbitan, polyoxyethylene (20) sorbitan triisostearate, polyoxyethylene (20) sorbitan monoisostearate, polyoxyethylene (5) behenyl ether, polyoxyethylene (1
0) behenyl ether, polyoxyethylene (20) behenyl ether, polyoxyethylene oleyl ether (EO is 3,5,7,10,15,20,50), polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, Polyoxyethylene (hereinafter POE) (1) Polyoxypropylene (hereinafter POP) (4) Cetyl ether, P
OE (1) POP (1) cetyl ether, POE (10) P
OP (4) cetyl ether, POE (20) POP (4) cetyl ether, POE (20) POP (8) cetyl ether, POE (120) POP (40) glycol, POE (1
60) POP (30) glycol, POE (196) POP (6
7) Glycol, POE (20) POP (20) glycol, POE (42) POP (67) glycol, POE (5
4) POP (39) glycol and the like can be mentioned. Preferred nonionic surfactants are POE (40) hydrogenated castor oil,
POE (60) hydrogenated castor oil, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, coconut oil fatty acid polyoxyethylene (20) sorbitan, polyoxyethylene monopalmitate (20) These are sorbitan, polyoxyethylene (20) sorbitan triisostearate, and polyoxyethylene (20) sorbitan monoisostearate.

The gel ointment of the present invention contains a non-ionic surfactant and a certain kind of auxiliaries, so that a sparingly water-soluble active ingredient is stably retained and a gel ointment excellent in safety is obtained. be able to. In such a gel ointment, the content of the nonionic surfactant can be used without particular limitation, but it is 0.1 to 15% by weight, preferably 0.1 to 10% by weight, more preferably 1% by weight.
It is good to use in the range of ˜8% by weight, particularly preferably 2 to 8% by weight. If the amount of the nonionic surfactant exceeds 15% by weight, the irritation becomes strong and the skin cannot be adapted.
When applied to the skin, a sticky feeling is liable to be generated, and a feeling of use is easily felt. When the amount is less than 0.1% by weight, stable solubilization tends to be difficult. Further, these nonionic surfactants used in the present invention are not particularly limited,
From the viewpoint of stability, HLB is preferably 6-18.

The gel ointment of the present invention uses one or more auxiliaries selected from the group consisting of glycyrrhetinic acids, glycyrrhizic acids, vitamin Es and monoterpenes.

In the present invention, glycyrrhizinic acid is glycyrrhizinic acid, a derivative of glycyrrhizinic acid or a pharmacologically acceptable salt thereof, and specifically, methyl glycyrrhizinate, stearyl glycyrrhizinate, nitric acid or acetic acid of glycyrrhizinate. Examples thereof include esters, disodium glycyrrhizinate, trisodium glycyrrhizinate, dipotassium glycyrrhizinate, and alkali metal salts such as tripotassium glycyrrhizinate, and ammonium salts such as monoammonium glycyrrhizinate.
These glycyrrhizic acids can be used alone or in combination of two or more kinds. Among them, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, glycyrrhizinate, and stearyl glycyrrhizinate are preferred. Examples of the pharmacologically acceptable salt that can be used in the present invention include, for example, organic acid salts (eg, acetate, trifluoroacetate, fumarate, maleate, tartrate, citrate, methanesulfone). Acid salt, toluene sulfonate, lactate, gluconate, aspartate, oxalate, etc.), inorganic acid salt (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.), organic Salts with bases (eg trimethylamine salts,
Triethylamine salts, monoethanolamine salts, triethanolamine salts, salts with tertiary amines such as pyridine salts, etc., salts with inorganic bases (eg ammonium salts,
Alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt,
Aluminum salt). The content of glycyrrhizic acids can be appropriately selected without any particular limitation, but is usually 0.01 to 100 parts by weight based on the total weight of the gel ointment.
It can be used in an amount of 10% by weight, preferably 0.1 to 5% by weight, particularly preferably 0.2 to 3% by weight.
If it is less than 0.01% by weight, sufficient stability cannot be obtained, and if it is more than 10% by weight, problems such as irritation are likely to occur.

Glycyrrhetinic acid is glycyrrhetinic acid, a derivative of glycyrrhetinic acid, or a pharmacologically acceptable salt thereof. Specifically, stearyl glycyrrhetinate, pyridoxine glycyrrhetinate, glyceryl glycyrrhetinate, nitric acid or acetic acid ester of glycyrrhetinic acid, disodium glycyrrhetinate, trisodium glycyrrhetinate, dipotassium glycyrrhetinate, tripotassium glycyrrhetinate, monoammonium glycyrrhetinate, etc. It can be illustrated. These glycyrrhetinic acids can be used alone or in appropriate combination of two or more. Of these, stearyl glycyrrhetinate and dipotassium glycyrrhetinate are preferred. The content of glycyrrhetinic acid can be appropriately selected without any particular limitation, but is usually 0.01 to 10% by weight, preferably 0.1% to the total weight of the gel ointment.
It can be used in the range of 1 to 5% by weight, particularly preferably 0.2 to 3% by weight. If it is less than 0.01% by weight, sufficient stability cannot be obtained, and if it is more than 10% by weight, problems such as irritation are likely to occur.

Examples of the vitamin Es include tocopherol, tocopherol derivatives and pharmacologically acceptable salts thereof. As the vitamin Es, both natural products and synthetic products can be used, and specifically, d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, vitamin E. Acetate (tocopherol acetate), vitamin E
Examples thereof include nicotinic acid ester, vitamin E succinic acid ester, vitamin E linolenic acid ester, and tocopherol calcium succinate. These vitamin Es can be used alone or in combination of two or more kinds. Among them, tocopherol acetate (acetic acid d-α-
Tocopherol, dl-α-tocopherol acetate, etc.) or a salt thereof is preferable. The content of vitamin Es can be appropriately selected without particular limitation, but is usually 0.01 to 10% by weight, preferably 0.1 to 10% by weight, particularly preferably, to the total weight of the gel ointment. Can be used in the range of 0.1 to 5% by weight. If it is less than 0.01% by weight, sufficient stability cannot be obtained.
With the above, problems such as irritation are likely to occur.

The monoterpenes are not particularly limited as long as they are monoterpenes usually used in medicines, quasi-drugs and cosmetics. For example, camphor, menthol, borneol, eugenol, cineol, thymol, bisabolol, α-pinene, Alternatively, limonene can be exemplified. It is preferably camphor or menthol, more preferably menthol. These monoterpenes can be natural products or synthetic products,
Any of d-form, l-form and dl-form may be used. Of these, menthol and camphor are preferred. These monoterpenes can also be used in gel ointments as essential oils containing monoterpenes, such as eucalyptus oil, mint oil,
Examples include clove oil, cinnamon oil, peppermint oil, mint oil, tea tree oil, chamomile oil, rosemary oil, lemon oil, orange oil, thyme oil, sage oil, clove oil and the like. Eucalyptus oil, peppermint oil or tea tree oil is preferred, and more preferably eucalyptus oil or peppermint oil may be used in the gel ointment. These monoterpenes may be used alone or in combination of two or more. The content of monoterpenes is
It can be appropriately selected without particular limitation,
0.001 to 10% by weight based on the total weight of the gel ointment,
It is preferably 0.001 to 8% by weight, particularly preferably 0.1.
It can be used in the range of 01 to 8% by weight, particularly preferably 0.01 to 5% by weight. If it is less than 0.001% by weight, sufficient stability cannot be obtained, and if it is more than 20% by weight, problems such as irritation are likely to occur.

In the present invention, the above-mentioned auxiliaries can be used alone or in any combination, and when they are used in combination, the solubilization or stability is further enhanced, which is preferable. The aspect of such a combination is not particularly limited, but glycyrrhetins and monoterpenes, glycyrrhetins and vitamin Es, glycyrrhizins and monoterpenes, glycyrrhitins and vitamin Es, glycyrrhetins and monoterpenes and vitamins Es. , Glycyrrhizins, monoterpenes and vitamin E
A combination of classes is preferred.

The gelling agent used in the present invention is a drug,
There is no particular limitation as long as it is a gelling agent such as a natural polymer, a semi-synthetic polymer, or a synthetic polymer used in the field of quasi drugs or cosmetics. Specifically, carboxyvinyl polymer, polyacrylic acid, polyethylene glycol, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, silicic acid, acrylic acid / methacrylic acid (C10 to C3).
0) Alkyl copolymers or salts thereof, soluble starch, propylene glycol alginate, guar gum, carrageenan, gelatin, galactan tragacanth, pectin, mannan, starch, xanthan gum, dextrin, gum arabic, casein, albumin, collagen and the like. These gelling agents may be used alone or in any combination of two or more. Among them, preferably, carboxyvinyl polymer,
Carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, polyacrylic acid, acrylic acid / methacrylic acid (C10 to C30)
Alkyl copolymers or salts thereof, particularly preferably carboxyvinyl polymers, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose or salts thereof. Here, the salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, ammonium salts, organic amine salts such as triethanolamine, and basic amino acids such as arginine. is there.

The amount of the gelling agent to be added to the gel ointment of the present invention is not particularly limited and can be appropriately selected.
Usually 0.01 to 15% by weight, based on the total weight of the gel ointment,
The range is preferably 0.01 to 10% by weight, more preferably 0.05 to 7.5% by weight, and particularly preferably 0.1 to 4% by weight. If it is 0.01% by weight or less, the gel strength tends to be too weak, and if it exceeds 10% by weight, the gel strength tends to be too strong. In addition, it tends to be inferior in the feeling of use and easily affects the solubilization.

In the present invention, the addition of a polyhydric alcohol is preferable in that it can assist the solubilization of the poorly water-soluble active ingredient and can hold it more stably. Examples of such polyhydric alcohols include glycerin, 1,3-butylene glycol, propylene glycol, diglycerin, 1,2-pentanediol, and 1,2-hexylene glycol. 1 of these polyhydric alcohols
One kind or two or more kinds can be used.

The amount of polyhydric alcohol to be incorporated into the gel ointment is not particularly limited and may be appropriately selected, but is usually 0.01 to 50% by weight, preferably 0 based on the total weight of the gel ointment. The range of 0.01 to 20% by weight, more preferably 0.1 to 15% by weight, particularly preferably 0.1 to 10% by weight can be mentioned. If the amount is less than 0.01% by weight, the effect on use feeling cannot be sufficiently exerted, and if the amount exceeds 50% by weight, the use feeling such as irritation and stickiness is likely to be impaired.

The gel ointment of the present invention can be used for any application utilizing the inherent pharmacological action of the poorly water-soluble active ingredient used in the present invention as a drug or quasi drug,
It is not particularly limited. The poorly water-soluble active ingredients of the present invention are each a component that exerts a useful pharmacological action in an external preparation, dexamethasone acetate valerate, dexamethasone, prednisolone acetate valerate, hydrocortisone butyrate, prednisolone acetate, prednisolone acetate, hydrocortisone acetate, hydrocortisone, acetic acid. Cortisone, ibuprofen piconol, salicylic acid, methyl salicylate, bufexamac, and ufenamate are typically used as anti-inflammatory drugs, and crotamiton and diphenhydramine are typically antipruritic agents, and aminoaminobenzoate, lidocaine, and dibucaine are typically. As a local anesthetic, undecylenic acid, homosulfamine, isopropylmethylphenol, methylparaben, and butylparaben are typically used as antibacterial or bactericidal agents, respectively. It has been. Examples of the use of the gel ointment of the present invention include those that can suitably exhibit the typical pharmacological action of these poorly water-soluble active ingredients. For example, eczema, rash, pruritus dryness, xeroderma, urticaria,
Dermatitis therapeutic agent or antipruritic agent for treating pruritus and inflammation such as insect bites, burns, rashes, etc., to prevent treatment and deterioration of scratches, scratches, scissors, burns, purulent wounds, etc. Examples of suitable uses include use as a bactericidal / disinfectant, a wound healing agent, a bacterial skin disease therapeutic agent for treating athlete's foot, acne and the like, or an antibacterial agent.

Since the gel ointment of the present invention is safe without irritation, it is particularly sensitive to irritation in the outer skin, including mucosal parts (rectal mucosa, anal mucosa, vulva or internal genital mucosa, oral mucosa) and It is preferable to use a gel ointment that is applied to skin with inflammation that becomes hypersensitive to irritation.

The gel ointment of the present invention may generally have a liquidity of pH 2 to 9, but preferably has a pH of 3 to 8 and more preferably a pH of 3 to 8 from the viewpoints of low irritation to the skin and mucous membranes and good feeling on use on the skin. The pH is preferably 4 to 8, particularly preferably 5 to 8. Also, the viscosity is BH
Type viscometer, No. It should have a viscosity of 10,000 to 200,000 mPa when measured with a 7 rotor at 20 rpm, but from the viewpoint of finger picking property and ease of application, it is preferably 30,000 to 150,000 mPa, more preferably 3000 to 10
0000 mPa is preferable.

The method of preparing the gel ointment of the present invention is not particularly limited, and various components necessary for preparing a usual gel ointment may be appropriately selected and blended and prepared by a conventional method. Further, the amount and usage of the gel ointment of the present invention applied to the outer skin are not particularly limited, and usually, it can be used by applying an appropriate amount to the outer skin such as the skin several times a day. In addition, gel ointment containing a poorly water-soluble active ingredient is often an opaque gel ointment, but the gel ointment of the present invention can be sufficiently solubilized and stability is maintained, so that a transparent gel ointment is used. Easy to do. A transparent gel ointment is preferable in that it does not cause white residue or the like and does not impair the color of the skin, and that it is not noticeable even when it adheres to clothing.

The gel ointment of the present invention may contain, in addition to the above-mentioned essential poorly water-soluble components, one or a combination of two or more active ingredients used in pharmaceuticals and quasi drugs. Each of these components is not particularly limited as long as it is a medicinal component used in an external preparation, and for example, an antipruritic agent other than the above essential poorly water-soluble component, a wound healing drug, an anti-inflammatory analgesic, a bactericidal disinfectant, a moisturizer, Keratin softeners, acne remedies, armpit odor preventives, athlete's foot remedies and the like can be optionally used.

The gel ointment of the present invention is, if necessary, within the quantitative and qualitative range that does not impair the storage stability and quality such as viscosity, and does not impair the effects of the present invention. Various components generally used in the field of cosmetics, such as surfactants, stabilizers, irritation reducing agents, thickeners, preservatives, colorants, dispersants, pH adjusters, and fragrances can be added. . In addition, these components can be blended individually by 1 type or in arbitrary combination of 2 or more types.

The present invention relates to a gel ointment containing a certain poorly water-soluble active ingredient used as an external preparation and water,
Glycyrrhetinic acid, glycyrrhizinic acid, vitamin E without using a nonionic surfactant alone
It also includes a method of stabilizing a poorly water-soluble active ingredient, which comprises blending at least one or more auxiliaries selected from the group consisting of compounds and monoterpenes. The types and contents of poorly water-soluble active ingredients, nonionic surfactants, and auxiliaries in these methods can be used in the same manner as in the gel ointment described above.

[0028]

EXAMPLES The present invention will be described below based on Examples and Test Examples.
The present invention will be described in more detail, but the present invention is not limited to these examples.
It is not fixed. In each prescription below,%
Means weight (W / W)% unless otherwise stated
I shall. Example 1 Gel ointment (pruritic agent for mucosa) Isopropylmethylphenol 0.1 (%) Diphenhydramine 1.0 Lidocaine 0.3 Dipotassium glycyrrhizinate 0.3 Tocopherol acetate 0.1 dl-menthol 0.1 Methylparaben 0.15 Butylparaben 0.05 Polysorbate 60 6.0 Carboxy vinyl polymer 0.8 Hydroxyethyl cellulose 0.4 1,3-butylene glycol 10.0 Concentrated glycerin 5.0 Triethanolamine 0.2Purified water Suitable amount 100.0g in total

[0029] Example 2 Gel ointment (pruritic agent for mucous membrane) Isopropylmethylphenol 0.1 (%) Diphenhydramine 1.0 Lidocaine 2.0 Tocopherol acetate 0.5 Dipotassium glycyrrhizinate 1.0 dl-menthol 0.1 POE (40) hydrogenated castor oil 4.0 Carboxy vinyl polymer 0.8 Sodium hyaluronate 0.01 1,3-butylene glycol 5.0Purified water Suitable amount   100.0g in total

[0030] Example 3 Gel ointment (acne remedy) Salicylic acid 5.0 (%) Isopropyl methylphenol 0.3 Dipotassium glycyrrhizinate 0.5 Polyoxyethylene (10) lauryl ether 3.0 1,3-butylene glycol 5.0 Carboxy vinyl polymer 1.0 Triethanolamine 0.5 Ethanol 2.0Purified water Suitable amount 100.0g in total

[0031] Example 4 Gel ointment (scalp gel ointment which is a remedy for dandruff and kayumi) Salicylic acid 2.0 (%) Estradiol benzoate 0.001 Hydrocortisone 0.0016 Diphenhydramine 0.2 l-menthol 0.3 Retinol palmitate 20 million U / 100g Polysorbate 60 3.0 Hinokitiol 0.01 Hydroxyethyl cellulose 0.5 Carboxy vinyl polymer 0.5 Triethanolamine 0.2Purified water Suitable amount 100.0g in total

[0032] Example 5 Gel ointment (sterilizing / disinfecting agent) Salicylic acid 4.0 (%) Isopropyl methylphenol 1.5 Trimethyl cetyl ammonium pentachlorophenate 3.0 Methylparaben 0.2 Butylparaben 0.2 Lecithin 0.1 l-menthol 0.2 Carboxy vinyl polymer 0.6 Sodium hydroxide 0.3 Polyoxyethylene (10) behenyl ether 3.0Purified water Suitable amount 100.0g in total

[0033] Example 6 Gel ointment (dermatitis therapeutic agent) Crotamiton 5.0 (%) Diphenhydramine 1.0 Glycyrrhetinic acid 0.2 Tocopherol acetate 5.0 Lecithin 0.1 l-menthol 0.1 Camphor 0.1 Polyoxyethylene (20) sorbitan monopalmitate 4.0 Triethanolamine 0.3 Carboxy vinyl polymer 0.6Purified water Suitable amount 100.0g in total

[0034] Example 7 Gel ointment (drug for dry skin eczema with itching) Lidocaine 2.0 (%) Salicylic acid 1.5 Menthol 1.0 Glycyrrhetinic acid 0.5 Allantoin 0.2 Polysorbate 80 2.5 Carboxy vinyl polymer 1.2 Sodium hydroxide 0.3 Glycerin 10.0Purified water Suitable amount 100.0g in total

[0035] Example 8 Gel ointment (skin eczema drug) Diphenhydramine 2.0 (%) Glycyrrhetinic acid 1.5 Dexamethasone 0.025 l-menthol 0.3 Salicylic acid 2.0 Polyoxyethylene (30) lauryl ether 5.0 Ethoxydiglycol 5.0 Ethanol 2.0 Carboxy vinyl polymer 0.8 Triethanolamine 0.4Purified water Suitable amount 100.0g in total

Test Example 1 Storage Stability Test Gel ointments of Comparative Examples and Examples having formulations shown in Tables 1 to 7 containing poorly water-soluble active ingredients were prepared and stored at 40 ° C. for 3 months. The appearance change was visually observed. The results are shown in Tables 1 to 7. As a result of the test, in the comparative example using the nonionic surfactant alone, the poorly water-soluble active ingredient could not be sufficiently solubilized in the gel ointment, and the gel ointment in the gel ointment stored at 40 ° C. for 3 months was used. The appearance changes such as the separation of the particles, the separation of the particles, and the precipitation of the components were observed. On the other hand, in the gel ointment of the present invention, tocopherol acetate together with a nonionic surfactant, or dipotassium glycyrrhizinate, glycyrrhetinic acid, a poorly water-soluble active ingredient is sufficiently solubilized in the gel ointment by blending, 40 No change in appearance was observed in the gel ointment stored at 3 ° C for 3 months. Therefore, it was confirmed that the gel ointment of the present invention stably holds the poorly water-soluble active ingredient.

Test Example 2 Stinging Test Eight in-house monitors applied a small amount of the gel ointment of the examples shown in Tables 1 to 7 to the cheeks under the eyes to confirm the presence or absence of irritation. As an evaluation standard, 2 points: No stimulus is felt, 1
Points: A little irritation was felt, 0 points: Irritation was felt, and the average score of 8 subjects was calculated for each gel ointment. When the average score was 0.5 or less, the score was ○, and the average score was 0. .5
A case of ~ 1 point was evaluated as Δ, and a case where the average point was 1 point or more was evaluated as x. The results are shown in the bottom of Tables 1 to 7. As a result of the stinging test, it was confirmed that the gel ointment of the present invention solubilized by the combination of the nonionic surfactant and the auxiliary agent was safe without irritation in any of the examples. It was confirmed that the gel ointment of the present invention is not irritating even when applied to a site that strongly acts on the ocular mucosa under the eyes, and therefore the gel ointment of the present invention is suitable as an ointment applied to the mucous membrane part of the outer skin or the inflammatory site. It has been shown.

[0038]

[Table 1]

[0039]

[Table 2]

[0040]

[Table 3]

[0041]

[Table 4]

[0042]

[Table 5]

[0043]

[Table 6]

[0044]

[Table 7]

Test Example 3 Releasability Test The releasability of the poorly water-soluble active ingredient from the gel ointment of the present invention was tested with diphenhydramine, lidocaine and isopropylmethylphenol. First, a Franz-type membrane permeation cell (capacity: 8 ml, effective area: 1.17 cm, VIDREX
Co., Ltd., is filled with phosphate buffer solution (pH7.4, 0.01M), and cellulose mixed ester membrane filter (pore size 0.2c)
m ² (ADVANTEC) was attached so as to cover the upper part of the Franz-type membrane permeation cell. After refluxing water from the water jacket of the Franz-type membrane permeation cell to keep the inside of the cell constant at 37 ° C., the formulation of Examples or Comparative Examples shown in Table 1.
2 g was taken and applied to the upper part of the cellulose mixed ester filter. Next, after applying the gel ointment of the Example or Comparative Example, the phosphate buffer solution in the Franz-type membrane permeation cell was sampled 4 hours later, and the drug concentration in the phosphate buffer solution in the cell was measured by HPLC. The amount of diphenhydramine released from the gel ointment and released into the phosphate buffer through the cellulose mixed ester membrane filter was calculated.
HPLC used Inertsil ODS-2 for the column, and the mobile phase was added with 1000 ml of water to 2.02 g of sodium 1-heptanesulfonate, and added with acetic acid (100) to adjust the pH to 650 ml. 220n of measurement wavelength
It was measured in m. The release rate (%) was calculated from the amount of drug released from the gel ointment (the amount of drug in the phosphate buffer solution after 4 hours / the amount of drug in the initial gel ointment x 100), and the results are shown in Table 8. It was

[0046]

[Table 8]

As a result of the test, POE (40) was compared with Comparative Example in which diphenhydramine, lidocaine, and isopropylmethylphenol were solubilized with POE (40) hydrogenated castor oil alone.
It was confirmed that the release of diphenhydramine from the gel ointment was improved in the examples of the present invention which contained an auxiliary agent together with hydrogenated castor oil and were sufficiently solubilized. Therefore,
In the gel ointment in which the sparingly water-soluble component is solubilized by the combination of the nonionic surfactant and the auxiliary agent of the present invention, the release property of the sparingly water-soluble active ingredient from the gel ointment is not inhibited, and is rapidly released. It was confirmed.

Test Example 5 Drug Efficacy Test The transdermal absorbability of the gel ointment Example 2 of the present invention containing diphenhydramine was confirmed by the diphenhydramine drug efficacy test. First, Example 2 or Comparative Example 10 was placed in the vagina of a female rat SD system 6 weeks old (6 animals in one group).
(Comparative example prepared in the same manner as in Example 2 except that tocopherol acetate, potassium glycyrrhizinate, and dl-menthol were not mixed) was administered in an amount of 0.1 g. Administration 3
After 0 minutes, 0.1 ml of a 3% histamine aqueous solution was intravaginally administered to induce inflammation in the vagina. Immediately after the induction of inflammation, 0.5 ml of a 1% aqueous solution of Evans blue was administered through the tail vein. After 30 minutes, the rat was killed, and about 1 cm of the vagina was excised from the vaginal opening, Evans blue was extracted from the excised tissue, and Evans blue was quantified from the absorbance at 620 nm.

As a result of the test, assuming that the amount of Evans blue leakage in the untreated control group in which inflammation was induced by histamine without administration of Example 2 or Comparative Example 10 was 100, the amount of Evans blue leakage in Example 2 administration was 32. The leakage amount of Evans blue after administration of Comparative Example 10 was 51, and Example 2 of the present invention was different from Comparative Example 10 containing no auxiliary agent in that the dye derived from histamine (Evans Blue).
It was confirmed that the elution of E. coli was suppressed and the antihistamine action of diphenhydramine was sufficiently exerted. Therefore, in the gel ointment in which the poorly water-soluble component is solubilized by the combination of the nonionic surfactant and the auxiliary agent of the present invention, the poorly water-soluble active ingredient has a high pharmacological action at the application site without impairing the transdermal absorbability. Was confirmed to be expressed.

[0050]

INDUSTRIAL APPLICABILITY The present invention can provide a highly safe gel ointment in which a poorly water-soluble active ingredient is sufficiently solubilized and stably retained in the gel ointment. Further, the gel ointment of the present invention in which a poorly water-soluble active ingredient is solubilized by a nonionic surfactant and an auxiliary agent has excellent release properties when applied to the skin, and is poorly water-soluble without impairing transdermal absorbability. It is possible to exert the high pharmacological action that the component originally has.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/18 A61K 31/18 31/201 31/201 31/235 31/235 31/245 31/245 31 / 4402 31/4402 31/4704 31/4704 31/573 31/573 31/60 31/60 31/618 31/618 47/06 47/06 47/12 47/12 47/22 47/22 47/26 47/26 A61P 17/00 101 A61P 17/00 101 17/02 17/02 17/04 17/04 F Term (reference) 4C076 AA09 BB31 CC01 CC04 CC05 CC18 CC19 DD07Q DD34Q DD37Q DD38 DD43Q DD50 DD59Q DD69Q EE09P EE32 EE33 EE47P FF36 FF63 4C086 AA01 AA02 BC17 BC29 DA10 DA17 MA03 MA05 MA09 MA10 MA28 NA03 ZA89 ZA90 4C206 AA01 AA02 CA17 DA04 DB17 FA05 FA33 FA36 GA01 GA18 GA31 HA13 HA16 MA03 MA05 MA12 MA21 MA48 NA03 ZA89 ZA90

Claims (7)

[Claims] 1. A) Dexamethasone valerate acetate, dexamethasone valerate, prednisolone valerate acetate, hydrocortisone butyrate, prednisolone acetate, prednisolone, hydrocortisone acetate, hydrocortisone, cortisone acetate, ibuprofen piconol, salicylic acid, methyl salicylate, bufexamac, ufenamate,
Diphenhydramine, ethyl aminobenzoate, lidocaine, dibucaine, undecylenic acid, homosulfamine,
At least one or more water-insoluble active ingredient selected from the group consisting of isopropylmethylphenol, methylparaben and butylparaben, B) a nonionic surfactant, and C) glycyrrhetinic acid, glycyrrhizinic acid, vitamin Es and monoterpenes A gel ointment containing at least one auxiliary agent selected from the group consisting of: and D) water. 2. The gel ointment according to claim 1, which further contains a gelling agent. 3. A dermatitis therapeutic agent, an antipruritic agent, a wound healing agent, a bactericidal disinfectant, an antibacterial agent, and a bacterial skin disease therapeutic agent.
The gel ointment according to 2). 4. The gel ointment according to claim 1, wherein the content of the sparingly water-soluble active ingredient in the gel ointment is 0.00001 to 15% by weight. 5. The gel ointment according to claim 1, wherein the content of the nonionic surfactant in the gel ointment is 0.1 to 15% by weight. 6. The gel ointment according to claim 1, which is transparent. 7. Dexamethasone valerate acetate, dexamethasone valerate, prednisolone valerate acetate, hydrocortisone butyrate, prednisolone acetate, prednisolone, hydrocortisone acetate, hydrocortisone, cortisone acetate, ibuprofen piconol, salicylic acid, methyl salicylate, bufexamac, ufenamate, crotaminate, crothamate.
Diphenhydramine, ethyl aminobenzoate, lidocaine, dibucaine, undecylenic acid, homosulfamine,
At least one selected from the group consisting of isopropylmethylphenol, methylparaben and butylparaben
In a gel ointment containing at least one poorly water-soluble active ingredient and water, at least one or more auxiliaries selected from the group consisting of glycyrrhetinic acids, glycyrrhizinic acids, vitamin Es and monoterpenes together with a nonionic surfactant. A method for stabilizing a poorly water-soluble active ingredient, characterized by comprising: