JPH09216820A - Skin ointment preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a skin ointment preparation capable of adding to a water insoluble agent having a carboxyl group to solubilize the agent in a weak acidic condition without spoiling effectiveness of the agent by using an ether type nonionic surfactant together with a water soluble salt of glycyrrhizinic acid, as solubilizing ability of the nonionic surfactant is enhanced, and having transparent appearance for a long period. SOLUTION: This skin ointment preparation for external use contains (A) a water insoluble acidic agent having >1 carboxyl group in a molecule, (B) an ether-type nonionic surfactant having >14 HLB value and (C) a water soluble salt of glycyrrhizinic acid and has a pH adjusted to 3-6, and the ingredient A is solubilized in the preparation.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an external preparation for skin in which a water-insoluble acidic drug is solubilized. More specifically, the water-insoluble acidic drug is not only solubilized and blended without impairing its efficacy but also for long-term use. The present invention relates to a skin external preparation whose appearance is transparent without causing turbidity or precipitation over a long period of time.

[0002]

BACKGROUND OF THE INVENTION Dermatological diseases due to factors such as westernization of eating habits in recent years, changes in living environment, increase in stress, increase in weekend sports population, etc.
Orthopedic diseases are increasing rapidly. For these diseases, coping therapy is mainly applied.For dermatological diseases, drugs effective for improving itching, redness, inflammation of the skin, etc. Has been treated with a formulation containing a drug effective in alleviating muscle inflammation and pain.

Since these therapeutic agents are used by being directly applied to or rubbed on the skin, it is desirable to adjust the pH of the preparation to an acidity as close to the skin surface as possible. Further, dermatological diseases and orthopedic diseases often use components having an anti-inflammatory effect, and as these components, components showing effectiveness under weak acidity, particularly at least one or more in the molecule. The acidic drug having a carboxyl group is frequently used.

On the other hand, many of the active ingredients contained in these therapeutic agents have extremely low solubility in water. Therefore, when they are used as a transparent aqueous solution or an aqueous preparation such as a gel agent, they must be solubilized. Is essential. As a conventional solubilization technique, a method of using a nonionic surfactant as a solubilizing agent and appropriately adding a solubilizing agent such as an alkaline substance or a lower alcohol has been generally used. However, with these techniques, it is difficult to solubilize an acidic drug with a low concentration of a nonionic surfactant, and turbidity or precipitation occurs, which makes it difficult to form a transparent aqueous preparation. Also,
High concentrations of nonionic surfactants and lower alcohols cause skin irritation, which poses a safety issue.
Furthermore, when an alkaline substance or the like is added, the transdermal absorbability of an acidic drug is often impaired due to the increase in pH of the preparation. A method in which a plant-derived glycyrrhizate or the like is used instead of the surfactant (JP-A-52-151).
No. 736) has been proposed, but even with these means, it was necessary to adjust the pH of the preparation to a neutral to alkaline range, so that it was difficult to mix an acidic drug.

Therefore, the present invention provides a water-insoluble acidic drug even if the compounding amount of a solubilizing agent such as a surfactant, an alcal substance and a lower alcohol, which has been conventionally required in a large amount, is significantly reduced. Can be stably solubilized under mild acidity without impairing transdermal absorbability, and can maintain the transparency of its external appearance without causing turbidity or precipitation even with changes over time. The purpose is to provide an agent.

[0006]

Means for Solving the Problems and Modes for Carrying Out the Invention In order to achieve the above object and solubilize a water-insoluble acidic drug having a carboxyl group in the molecule, the present inventors As a result of extensive studies on stabilization of a water-insoluble drug solubilizing external preparation for skin using the nonionic surfactant as a solubilizing agent, an ether type nonionic surfactant having a specific HLB value for the above drug and glycyrrhizin When used in combination with a water-soluble salt of an acid, the solubilizing power of the nonionic surfactant is enhanced, the required amount of solubilizer and solubilizer is reduced, and the water-insoluble acidic drug is absorbed through the skin. It was found that an external preparation for skin which can be solubilized and blended under a weak acidity without impairing the effectiveness of the properties, etc., and has a transparent appearance for a long period of time can be made the present invention.

That is, the present invention provides (A) a water-insoluble acidic drug having at least one or more carboxyl groups in the molecule, (B) an ether type nonionic surfactant having an HLB value of 14 or more, and (C) ) A skin external preparation in which the component (A) is solubilized, which comprises a water-soluble salt of glycyrrhizic acid and is adjusted to have a pH of 3 to 6.

Hereinafter, the present invention will be described in more detail. The external preparation for skin of the present invention contains the above components (A), (B) and (C) as essential components and has a pH of 3
It has a weak acidity of ~ 6 and contains the above component (A) in a solubilized form. Here, the first essential component (A)
The component is a water-insoluble acidic drug having at least one or more carboxyl groups in the molecule, and such drug is
Usually, it is considered to be an effective component for the treatment and / or care of skin diseases such as anti-inflammatory analgesics, anti-inflammatory agents and keratolytic agents. Specifically, for example, tolfenamic acid, mefenamic acid, flufenamic acid, salicylic acid, aspirin, sazapyrine, alclofenac, suprofen, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenbufen, glycyrrhetinic acid, indomethacin, acemethacin, methiazinic acid, protidinic acid. , Sulindac, pranoprofen, fenthiazac, diflunisal, thiaprofenic acid, oxaprozin, etc., among which salicylic acid, suprofen, ibuprofen, flurbiprofen, ketoprofen, glycyrrhetinic acid, and indomethacin are preferably used. These drugs are used alone or in combination of two or more.

The amount of the component (A) in the external preparation for skin of the present invention is not particularly limited, but is usually 0.01 to 10% (% by weight, the same applies hereinafter) in the formulation, and more preferably. Is 0.1 to 5%. 0.01%
If the amount is less than 10%, the efficacy of the drug may not be sufficiently exerted, and if it exceeds 10%, it not only causes inconvenience such as the need for a large amount of solubilizing agent, but also increases the possibility that side effects may occur, etc. There may be a problem in terms of sex.

The second essential component (B) of the external preparation for skin of the present invention is an ether type nonionic surfactant having an HLB value of 14 or more. Examples of such a surfactant include Polyoxyethylene alkyl ether (trade name: Nikkor BL-21, BL-25, BC-15TX, BC-20 manufactured by Nikko Chemicals Co., Ltd.)
TX, BC-23, BC-25TX, BC-30TX,
BC-40TX, BS-20, BO-10TX, BO-
15TX, BO-20, BO-50, BB-20, BB
-30), polyoxyethylene alkyl phenyl ether (trade names, Nikkor NP-7.5, NP-10, NP-15, NP-18 manufactured by Nikko Chemicals Co., Ltd.)
TX, NP-20, OP-10, OP-30) and the like.

The blending amount of the above-mentioned component (B) in the external preparation for skin of the present invention is not particularly limited, but is usually 0.05 to 10%, more preferably 0.1 to 5% in the formulation. . If it is less than 0.05%, stable solubilization of the drug may be difficult. On the other hand, if it exceeds 10%, not only is it meaningless in terms of formulation, but also skin irritation may occur. In the case of the present invention, when an ester type nonionic surfactant is blended, the water-soluble salt of glycyrrhizic acid, which is the component (C), acts as an ester hydrolysis accelerating factor under acidic conditions in the formulation, and The progress of the hydrolysis of the ester causes a change over time such as turbidity or precipitation in the preparation, which deteriorates the long-term stability of the preparation, which is not preferable.

The third essential component (C) of the external preparation for skin of the present invention is a water-soluble salt of glycyrrhizic acid,
Examples of such salts include sodium salts, potassium salts, ammonium salts and the like. As such a water-soluble salt of glycyrrhizinate, specifically, Maruzen Pharmaceutical Co., Ltd. trisodium glycyrrhizinate, disodium glycyrrhizinate, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, diammonium glycyrrhizinate and the like can be mentioned. .

The amount of the component (C) in the external preparation for skin of the present invention is not particularly limited, but is usually 0.02 to 2% in the preparation, preferably 0.1 to 1%. is there. If the blending amount is less than 0.02%, not only does the stable blending of the drug become difficult and its efficacy is not fully exerted,
Inconveniences such as requiring a large amount of the above-mentioned component (B) which is a solubilizing agent may occur. On the other hand, if the blending amount exceeds 2%, the usability as an external preparation for the skin may be deteriorated, such as foaming when the preparation is rubbed.

The blending ratio (weight) of the components (A), (B) and (C) in the external preparation for skin of the present invention is such that the components (B) and (C) are relative to the component (A). Are 1 to 50 times, 1 to 30 times, especially 1 to 20 times, 1 to 1
It is preferably 0 times, and in this case, the component (B) /
Component (C) = 1/1 to 10/1, particularly 2/1 to 3/1. Outside the above range, the effects of the present invention may not be sufficiently obtained.

The external preparation for skin of the present invention has a pH value of
Is required to be 3 to 6, more preferably pH.
It is 3.5 to 5.5. When the pH of the preparation is less than 3, stable solubilization of the drug becomes difficult, and the appearance stability of the preparation also deteriorates. On the other hand, when the pH of the preparation exceeds 6, the transdermal absorbability of the solubilized drug is remarkably reduced, which causes inconvenience such as insufficient effectiveness.

The external preparation for skin of the present invention contains, in addition to the above-mentioned essential components, a water-soluble component, a preservative, a pH adjusting agent, a thickening agent, which are used in ordinary external preparations for skin, unless the effects of the present invention are impaired. Antioxidants and the like can be appropriately blended as necessary. As the water-soluble component, for example, glycerin, propylene glycol, sorbitol, polyethylene glycol, 1,3-butylene glycol, ethanol, isopropyl alcohol and the like can be blended. As the preservative, for example, parabens, benzoic acids, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, alkyltrimethylammonium chloride, alkyldiaminoethylglycine hydrochloride, chlorhexidine hydrochloride, chlorobutanol, domiphen bromide, phenoxyethanol and the like are mixed. be able to. As the pH adjuster, for example, acids such as citric acid, tartaric acid and lactic acid, and alkalis such as sodium hydroxide, potassium hydroxide and triethanolamine can be added. As the thickener, for example, sodium carboxymethyl cellulose, sodium alginate, carboxy vinyl polymer, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol and the like can be blended. As the antioxidant, for example, tocopherol,
Erythorbic acid, propyl gallate, BHT, BHA,
NDGA etc. can be blended. In addition, these compounding amounts are appropriately selected.

The external preparation for skin of the present invention may have any dosage form as long as it can solubilize and incorporate the above-mentioned component (A), and examples thereof include gels, lotions and patches. However,
It is not limited to the above dosage forms.

The amount of the external preparation for skin of the present invention to be used is not particularly limited as it varies depending on the type, dosage form, usage and the like of the water-insoluble acidic drug, but is not limited to the above (A) and (B). ), (C) component is appropriately blended in the above blending amount and blending ratio, and the skin external preparation is applied in the usual amount and usage of the various skin external preparations containing the above water-insoluble acidic drug. Sufficient effectiveness such as transdermal absorbability can be obtained.

[0019]

EXAMPLES The present invention will be described below in detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples.

[Examples 1 and 2 and Comparative Examples 1 to 5] Compositions for external use for skin (external preparations for skin) of Examples and Comparative Examples were prepared by the conventional method according to the formulations shown in Table 1, and salicylic acid was prepared according to the following experimental method. A transdermal absorption experiment was conducted. Further, the external composition for skin was stored at 50 ° C. for 3 months, and then the appearance stability was visually observed. These results are also shown in Table 1. In the table, "Nikkor NP-10" is polyoxyethylene (10) nonyl phenyl ether (HLB).
= 16.5), "Nikkor BC-7" is polyoxyethylene (7) cetyl ether (HLB = 11.5),
"Nikkor MYS-25" is polyoxyethylene (2
5) Polyethylene glycol monostearate (HLB
= 15.0), all of which are manufactured by Nikko Chemicals Co., Ltd. In addition, the appearance was evaluated according to the following criteria. Appearance evaluation: ◯; after storage at 50 ° C for 3 months, colorless and transparent ×: after storage at 50 ° C for 3 months, white turbidity / precipitation

Experimental method Wistar rats weighing 140 to 160 g (male, 5
After slaughtering, the back skin was removed and excised and attached to a diffusion cell (vertical type) device. Subsequently, 0.5 mg of the sample was applied to the skin surface (donor side), the receiver side was filled with physiological saline, and stirring was continued under a constant temperature of 37 ° C. After 24 hours, the solution was collected from the receiver side, and the amount of salicylic acid in the solution was quantified by liquid chromatography.

[0022]

[Table 1]

According to the results shown in Table 1, when a water-insoluble acidic drug is mixed in an aqueous preparation, a specific ether type nonionic surfactant and a water-soluble salt of glycyrrhizic acid are used in combination to produce a nonionic It was found that the solubilizing power of the surfactant was enhanced, and that the use of a small amount of the solubilizing agent could stably solubilize the water-insoluble acidic drug even under weak acidic conditions.
On the other hand, a specific ether type nonionic surfactant and a water-soluble salt of glycyrrhizic acid are not used in combination (Comparative Examples 1 and 2), or an ester type nonionic surfactant is used instead of the specific ether type nonionic surfactant. Ionic surfactant (Comparative Example 4),
Alternatively, when an ether type nonionic surfactant having an HLB value of less than 14 (Comparative Example 3) was used, a turbidity or a precipitate was observed as a result of a storage test at 50 ° C. for 3 months. Furthermore, when the pH of the aqueous preparation prepared by solubilizing the water-insoluble acidic drug was high (Comparative Example 5), the transdermal absorbability of the drug was remarkably lowered, but the preparation of the present invention showed that the transdermal absorbability of the drug was low. It has been confirmed that there is almost no damage to.

Hereinafter, the present invention will be described more specifically by showing examples. [Example 3] Gel composition (g / 100g) Salicylic acid 0.5 10% Benzalkonium chloride solution 0.3 Dipotassium glycyrrhizinate 0.5 Polyoxyethylene (21) lauryl ether [Nikkor BL-21 (HLB = 19) .0)] 0.6 Concentrated glycerin 1.0 Ethanol 7.0 Methylparaben 0.1 Propylparaben 0.02 Carboxyl vinyl polymer (Carbopol 940) 1.0 Sodium hydroxide Suitable amount Purified water Remaining amount Of the above components, 10 % Benzalkonium chloride solution, dipotassium glycyrrhizinate, polyoxyethylene (21)
After dissolving lauryl ether in purified water, salicylic acid, concentrated glycerin, and parabens dissolved in ethanol were added and mixed, and the pH of the preparation was adjusted to 4.0 with sodium hydroxide. A carboxyvinyl polymer was dissolved in this to obtain a transparent gel agent as an external preparation for the skin of Example 3. As a result of a storage test of this preparation at 40 ° C. for 1 month, it was confirmed that there was no problem in its stability. The formulation is used as a therapeutic drug for acne.

[Example 4] Lotion composition (g / 100g) Indomethacin 0.1 Polyoxyethylene (10) nonyl phenyl ether [Nikkor NP-10 (HLB = 16.5)] 1.0 Monoammonium glycyrrhizinate 0 .5 ethanol 9.0 10% benzalkonium chloride solution 0.5 l-menthol 0.1 sodium hydroxide appropriate amount purified water remaining amount Of the above components, polyoxyethylene (10) nonylphenyl ether, monoammonium glycyrrhizinate,
After dissolving the 10% benzalkonium chloride solution in purified water,
A mixture of indomethacin and 1-menthol dissolved in ethanol was mixed and dissolved, and sodium hydroxide was added to the p
H was adjusted to 5.0 to obtain a transparent lotion as an external preparation for the skin of Example 4. As a result of a storage test of this preparation at 40 ° C. for 1 month, it was confirmed that there was no problem in its stability. The preparation is used as an external anti-inflammatory analgesic.

[Example 5] Lotion composition (g / 100g) Ketoprofen 0.1 Polyoxyethylene (20) oleyl ether [Nikkor BO-20 (HLB = 18.0)] 2.0 Dipotassium glycyrrhizinate 1.0 Isopropyl alcohol 9.0 1,3-Butylene glycol 8.0 l-Menthol 0.1 Methylparaben 0.2 Sodium hydroxide Suitable amount Purified water Remaining amount Of the above components, polyoxyethylene (20) oleyl ether and dipotassium glycyrrhizinate were added. After dissolving in purified water, ketoprofen in isopropyl alcohol,
A mixture of 1,3-butylene glycol, 1-menthol, and methylparaben dissolved and dissolved, and the pH of the preparation was adjusted to 5.0 with sodium hydroxide to obtain a transparent lotion as an external preparation for the skin of Example 5. It was About this formulation,
As a result of a storage test at 40 ° C. for 1 month, it was confirmed that there was no problem in its stability. The preparation is used as an external anti-inflammatory analgesic.

[Example 6] Gel composition (g / 100g) Suprofen 0.2 Polyoxyethylene (20) oleyl ether [Nikkor BO-20 (HLB = 18.0)] 2.0 Dipotassium glycyrrhizinate 1.0 Ethanol 9.0 1,3-butylene glycol 5.0 Concentrated glycerin 5.0 Methylparaben 0.2 Carboxyl vinyl polymer (Carbopol 940) 0.8 Triethanolamine Appropriate amount Purified water Remaining amount Of the above components, polyoxyethylene ( 20) After dissolving oleyl ether and dipotassium glycyrrhizinate in purified water, a mixture of suprofen, 1,3-butylene glycol, concentrated glycerin and methylparaben in ethanol was mixed and dissolved, and the pH of the preparation was adjusted with triethanolamine. Adjusted to 5.0. A carboxyl vinyl polymer was dissolved in this to obtain a transparent gel agent as an external preparation for the skin of Example 6. As a result of a storage test of this preparation at 40 ° C. for 1 month, it was confirmed that there was no problem in its stability. In addition, this preparation is used as an eczema drug.

[Example 7] Patch composition (g / 100g) Ketoprofen 0.1 Polyoxyethylene (20) oleyl ether [Nikkor BO-20 (HLB = 18.0)] 2.0 Dipotassium glycyrrhizinate 1.0 Ethanol 5.0 Propylene glycol 5.0 Concentrated glycerin 20.0 Sodium polyacrylate 1.5 Polyacrylic acid 5.0 Sodium carboxymethyl cellulose 5.0 Dihydroxyaluminum aminoacetate 0.2 Purified water Remaining amount Of the above components, ketoprofen After dissolving polyoxyethylene (20) oleyl ether, dipotassium glycyrrhizinate, ethanol and propylene glycol in purified water, the remaining components were dissolved and kneaded to obtain a patch plaster of pH 4.5. 100 g of this plaster was spread on 1 m ² of polyester non-woven fabric to obtain a patch as a skin external preparation of Example 7. As a result of a storage test of this preparation at 40 ° C. for 1 month, it was confirmed that there was no problem in its stability. In addition, this preparation is used as an anti-inflammatory analgesic patch.

[0029]

INDUSTRIAL APPLICABILITY The present invention relates to a water-insoluble acidic drug having at least one or more carboxyl groups in the molecule, and an ether type nonionic surfactant having an HLB value of 14 or more as a solubilizer and glycyrrhizic acid. The combined use of water-soluble salts enhances the solubilizing power of nonionic surfactants, so the amount of solubilizing agent is small and it is solubilized by weak acidification so that the effectiveness of the drug is not impaired. Can be mixed,
Moreover, it is possible to provide an external preparation for skin which has a transparent appearance for a long period of time.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/60 AAG A61K 31/60 AAG (72) Inventor Masayuki Toda 1-chome, Sumida-ku, Tokyo No. 3-7 Lion Corporation

Claims (1)

[Claims] 1. (A) Water-insoluble acidic drug having at least one carboxyl group in the molecule, (B) HLB
An ether type nonionic surfactant having a value of 14 or more, and (C) a water-soluble salt of glycyrrhizic acid,
The external preparation for skin in which the above-mentioned component (A) is solubilized, wherein H is adjusted to 3 to 6.