JPH111433A - Tolnaftate-containing liquid agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an aqueous alcoholic liquid agent with low skin irritancy while attaining high percutaneous absorbability affording antifungal effect exceeding those experienced so far, thus useful as a medicine for dematophytosis, by incorporating sparingly solbule tolnaftate at leavels comparable to its maximum solubility in a water-contg. base. SOLUTION: This liquid agent is obtained by incorporating (A) about 0.1-0.5 wt.% of tolnaftate (at levels comparable to its maximum solubility to the base, pref. 80 to <100% of its saturated solubility to the base) and (B) about 1-15 wt.% of a film-forming agent such as of ethyl acrylate-methyl methacrylate copolymer in a medium comopsed of 50-95 wt.% of water plus an alcohol (wherein about 1-30 wt.% water and about 50-90 wt.% of an alcohol such as isopropanol). This liquid agent is substantially free from any solubilizing agent such as a ketone or glycol essentially irritant to the skin, being hopeful of sufficient therapeutic effect in a single daily application to affected parts for the purpose of dematophytosis therapy.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a solution containing tolnaftate, which is excellent in percutaneous absorption and has little skin irritation. More specifically, the present invention is a tolnaftate-containing solution characterized by containing water and not containing a skin irritating solubilizer.

[0002]

2. Description of the Related Art Tolnaftate is used in various antifungal compositions for external use, but is a poorly soluble drug. For example, Japanese Patent Publication No. 7-116035 discloses a substantially water-free film-forming agent. As disclosed in antifungal compositions,
It is common to formulate a formulation without containing water. As a commercial product, a formulation in which methyl ethyl ketone, triacetin and the like are blended in a well-balanced manner is also known (Japanese Patent Publication No. 5-77).
648). In JP-A-4-316517, diethyl sebacate, ethylene glycol salicylate and propylene glycol, which are special bases, are exclusively added to prevent crystal precipitation. However, there was no change in that methyl ethyl ketone, triacetin and the like had to be added in order to achieve a prescription of 2% of a commercial preparation, and skin irritation could not be reduced.

[0003] In order to solve this problem, various approaches have been devised for aqueous solutions of tolnaftate. For example,
In 49126, tolnaftate and urea are dissolved in a solvent in which three components of methyl ethyl ketone, water and alcohol are mixed at a specific ratio, so that storage stability and penetration of the drug into the stratum corneum are excellent. Liquid preparations are being prepared. In Japanese Patent Application Laid-Open No. 62-61515, an aqueous liquid preparation is prepared by adding a phospholipid and propylene glycol. As described above, even when an aqueous solution of tolnaftate is used, it is usual to formulate a formulation by adding an organic solvent (solubilizing agent). Examples of the formulation of tolnaftate as an aqueous composition without using any organic solvent include JP-A-1-275527 and JP-A-2-2314.
22. However, these are prepared by dispersing a fine powder composition obtained by co-grinding magnesium, a water-soluble polymer compound and the like and tolnaftate in an aqueous medium and formulating them. Therefore, it is necessary to perform a special treatment such as co-grinding and the like, and the tolnaftate is dispersed. Therefore, an aqueous alcohol solution in which the tolnaftate is dissolved as in the present invention is developed. Technology to do so. Further, Japanese Patent Application Laid-Open No. 7-277975 discloses, as a general technique, an external preparation for skin containing an antifungal agent, water, an alcohol, and two or more kinds of film-forming agents (and plasticizers). Tolnaftate is also mentioned as an example of the agent. However, there is no description or suggestion of a specific technique for tolunafate which is hardly soluble.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a solution containing tolnaftate which is useful as a remedy for athlete's foot. It is another object of the present invention to provide an aqueous alcohol solution in spite of formulating tolunaphate which is a poorly soluble drug. Another object of the present invention is to provide a liquid preparation which does not add a solubilizer which causes a problem of skin irritation while adding a solubilizer which causes a problem with skin irritation while achieving an antifungal effect equivalent to or higher than that of the conventional method. It is in. Still another object of the present invention is to provide a formulation having a formulation amount of 2
It is an object of the present invention to provide a pharmaceutical formulation capable of achieving a higher transdermal absorption amount than conventional formulations, while reducing the formulation amount of tolnaftate relative to%.

[0005]

As a result of various studies, the inventors of the present invention have found that (a) tolnaphthate is contained in the same amount as the upper limit that can be dissolved in the base, and (b) film forming agent And (c) an aqueous alcohol solution characterized by substantially not containing a solubilizing agent having a skin irritation, thereby providing a high transdermal absorbability and an external use without skin irritation. It has been found that a liquid preparation is obtained. In addition, a specific compounding ratio capable of solving the above-mentioned problem has been found.
That is, about 0.1 to 0.5% by weight of tolnaftate and 1 to 1 of water.
Formulating an aqueous alcohol solution of tolnaftate containing 30% by weight, 50 to 90% by weight of alcohol and 1 to 15% by weight of a film-forming agent, and substantially containing no organic solvent other than alcohol. As a result, the present inventors have found that an external preparation for skin with excellent percutaneous absorption and little skin irritation can be provided.

First, the present invention relates to (1) (a) that tonaphate is contained in the same amount as the upper limit that can be dissolved in a base;
It is intended to provide an aqueous alcohol solution characterized by comprising (b) a film-forming agent and (c) substantially not containing a solubilizer having skin irritation. here,
A description will be given of "contains about the same amount of tolnaftate as the upper limit that can be dissolved in a base" as used herein. Since tolnaftate is a poorly soluble drug, it is difficult to dissolve in a base containing water and alcohol as main components, and has not been developed from the viewpoint of a prescribed amount. However, surprisingly, the percutaneous absorption can be surprisingly improved by containing tolnaftate at the same upper limit as that which can be dissolved in the base material, and as a result, the tolnaftate can be reduced in the whole preparation. Was also able to be planned. In addition, this eliminates the need to add a solubilizing agent, and provides an external solution that does not cause skin irritation. If the amount is the same as the saturation solubility, there are disadvantages such as precipitation of tolnaphthate crystals. Therefore, it is not preferable to include 100% of the saturation solubility in the base. Therefore, it is set to "about the same as the upper limit that can be dissolved in the base material". In order to achieve the effects of the present invention, it is preferable that tolnaphthate be contained in an amount of about 60% or more of the saturated solubility in the base. More preferably, it is about 80% or more. The aqueous alcohol solution means a solution containing water and alcohol, and the solution is transparently dissolved and is distinguished from a gel. The present invention limits the content of tolnaphate to a base mainly composed of water and alcohol to a specific ratio (preferably about 0.1 to 0.5%).

According to another aspect of the present invention, the present invention is useful as a remedy for athlete's foot because it is a solution containing tolnaftate. According to another aspect, by containing tolnaphate as much as the upper limit that can be dissolved in this base while being a water-containing base, the tolnaphate content can be reduced as a result and the conventional method can be used. The antifungal effect by tolnaftate which is equal to or more than that of the above is obtained. This means that the solution has achieved high transdermal absorption. According to another aspect, there is no need to add a solubilizing agent having a problem with skin irritation to the present liquid preparation which requires a small content of tolnaftate, and it is possible to provide an external preparation having no skin irritation. it can. From another aspect, the liquid preparation of the present invention contains a film-forming agent, which dries quickly after application and forms a soft and tough film on the skin, so that it has excellent usability without adhesion to clothes and the like. ing. In addition, the medicinal effect can be maintained for a long time by forming a film. Therefore, the liquid preparation of the present invention is an aqueous alcohol preparation capable of continuously achieving high transdermal absorption, and a sufficient therapeutic effect can be expected by applying once a day to athlete's foot. The fact that the high intradermal concentration lasts for a long time means that the availability is high.

Next, the present invention relates to (2) (a) that tonaphate is contained in the same amount as the upper limit that can be dissolved in the base material;
(B) an aqueous alcoholic solution characterized by containing a film-forming agent, and (c) containing substantially no organic solvent other than alcohol, and (3) an aqueous alcoholic solution based on (a) tolnaphthate. (B) containing the same amount as the upper limit that can be dissolved in the agent.
An aqueous alcohol solution characterized by containing a film-forming agent, and (c) containing substantially no skin-irritating ketones or glycols; (4) tolnafte
(1) to (3) containing about 0.1 to 0.5% by weight of
And (5) a film-forming agent in an amount of about 1 to 1
The liquid preparation according to any one of (1) to (3), which contains 5% by weight; (6) The liquid preparation according to any one of (1) to (3), wherein the total amount of water and alcohol is about 50 to 95% by weight. The liquid preparation described in Crab,
(7) (1) to (3) containing about 1 to 30% by weight of water.
(8) The alcohol according to any one of (1) to (5),
The liquid preparation according to any one of (1) to (3), which contains 90% by weight, (9) the liquid preparation according to any one of (1) to (3), which further contains an antifungal agent other than tolnaftate. Liquid, (1
0) Antifungal agents other than tolnaphthate are croconazole hydrochloride, isoconazole nitrate, miconazole nitrate, thioconazole, itraconazole, oxyconazole, ketoconazole, fluconazole, clotrimazole. , Terconazole, sulconazole, bifonazole, naftifine, terbinafine, tolcicrete, pyro-lunitrin, bifucine, tricomycin, ciclopirox okramin, exalamide and haloprazine The above antifungal agent,
(9) The liquid preparation according to any one of (1) to (3), further comprising (11) a liquid preparation according to any one of (1) to (3), further comprising a pharmaceutically active ingredient other than the antifungal agent, The liquid preparation according to (11), which is an anti-inflammatory agent, (13) the liquid preparation according to any of (1) to (3), further comprising a medium-chain fatty acid ester, Glycerin caprylate (GMC), tetraglycerin monocaprylate (TGMC), propylene glycol dicaprylate (P
GDC) and tetraglycerin hexacaprylate (T
(13) The liquid preparation according to (13), which is one or more medium-chain fatty acid esters selected from the group consisting of GHC).
(5) Aqueous alcohol solution characterized in that high availability of tolnaftate was achieved by making the content of tolnaphate about the same as the upper limit that can be dissolved in the base, (16) tolnaphtate Aqueous alcohol solution characterized by achieving high availability of tolnaftate by making the content of the same as the upper limit that can be dissolved in the base and by containing a film forming agent,
(17) The liquid preparation according to (15) or (16), further comprising not adding a solubilizing agent having a skin irritation, and (18) about 0.1 to 0.5% by weight of tolnaftate, about water. An aqueous alcohol solution containing 1 to 30% by weight, about 50 to 90% by weight of an alcohol and about 1 to 15% by weight of a film-forming agent, and substantially containing no organic solvent other than the alcohol. .

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The addition ratio used in the present specification is shown by weight ratio (W / W%) to the total weight of the preparation. In practicing the present invention, it is preferable that the total components of the preparation include tolnaphate about 0.1 to 0.5% by weight, water about 1 to 30% by weight, alcohol about 50 to 90% by weight, About 1 to 15% by weight of a forming agent is contained.

In the test example, the solution containing tolnaftate in the amount closest to the saturation solubility in the base achieves the highest intradermal concentration, so that "tolunaphate can be dissolved in the base. About the same as the upper limit. " If the content ratio of tolnaftate is objectively specified,
The upper limit of the weight percentage of the total weight of the solution is preferably about 0.5 weight%. The lower limit is preferably about 0.1% by weight, more preferably about 0.3% by weight.

The total amount of water and alcohol in the whole liquid preparation is preferably about 50 to 95% by weight. More preferably, about 7
0 to 95% by weight. Even if the content of tolnaftate and the total amount of water and alcohol are the same, as the proportion of water increases, the content of tolnaphate approaches the "upper limit of dissolution in the base". It will be. The weight percentage of water in the total liquid is preferably about 1 to 30% by weight. More preferably, it is about 5 to 25% by weight. Examples of the alcohol include isopropanol, ethanol and propanol. The weight percent of the alcohol in the total solution is preferably about 50 to 90% by weight. More preferably, it is about 60 to 85% by weight.

Examples of the film-forming agent used in the present invention include ethyl cellulose, polyvinyl butyrate, hydroxypropyl cellulose-phthalate, methyl methacrylate copolymer, and diethylaminoethyl methacrylate methyl methacrylate. Copolymer, Ethyl methacrylate Methacrylate trimethylammonium ethyl copolymer, Methyl methacrylate Methacrylate butyl methacrylate Diethylaminoethyl methacrylate copolymer, Ethyl methacrylate acrylate copolymer, Ethyl methacrylate Methyl methacrylate trimethylammonium ethyl copolymer, methyl methacrylate ethyl acrylate copolymer
But are not particularly limited to these.
The weight% of the film forming agent in the total liquid is preferably about 1 to 15% by weight.

According to a preferred embodiment of the present invention, one or more other antifungal agents may be compounded in addition to tolnaftate to form a mixture. This is because a synergistic effect is expected from the combined use of two drugs having different action points. For example, croconazole hydrochloride, isoconazole nitrate, miconazole nitrate, thioconazole, itraconazole, oxyconazole, ketoconazole, fluconazole, naftifine, terbinafine, clotrimazole, terconazole.
, Torsiculate, sulconazole, bifonazo
, Pyrro-Lunitrin, bifumacin, tricomycin,
Ciclopirox ochlamin, exalamide and haloprazine. The amount of these antifungal agents varies greatly depending on the type of the antifungal agent.

Further, other medicinal ingredients may be added. Examples include anti-inflammatory agents (glycyrrhetinic acid and the like) and lidocaine. In addition, the drug is not particularly limited as long as it is a drug suitable for administration by transdermal absorption.

[0015] The remedy for athlete's foot of the present invention may contain a stabilizer or the like. Examples include antioxidants, fragrances, preservatives, pH adjusters, surfactants, thickeners, and the like. A coloring agent and a transdermal absorption enhancer may be added.
Examples of the preservative or disinfectant include chlorhexidine, chlorhexidine gluconate, and examples of the preservative include parahydroxybenzoates, dehydroacetic acid, and orthophenylphenol. Examples of antioxidants include alkyl gallate, butylhydroxyanisole, butylhydroxytoluene, tocopherol, sodipropionic acid, nordihydroguaiaretic acid, and the like. Examples of the thickener used in the present invention include cellulose derivatives such as ethylcellulose, hydroxycellulose, and hydroxypropylcellulose.

According to a preferred embodiment, the liquid preparation comprises:
Medium-chain fatty acid esters can also be included. Thereby, the effect as a surfactant is obtained. Examples of the “medium chain fatty acid ester” used in the present invention include glycerin monocaprylate (GMC), tetraglycerin monocaprylate (TGMC), and propylene glycol dicaprylate.
(PGDC), tetraglycerin hexacaprylate (TGHC) and the like. Of these, propylene glycol dicaprylate (PGDC) is preferred. The weight% of the medium-chain fatty acid ester in the total solution is about 0.5 to 1%.
0% by weight is preferred.

Examples of the solubilizer having skin irritation that is not substantially contained in the liquid preparation of the present invention include ketones such as methyl ethyl ketone and crotamiton, and glycols. In addition, the medium-chain fatty acid ester is not included because it has almost no skin irritation. Examples of organic solvents other than alcohols which are not substantially contained in the liquid preparation of the present invention include benzene, hexane, ether and the like in addition to the above-mentioned ketones and glycols. Next, examples of the liquid preparation of the present invention and results of a test showing transdermal absorbability are shown. The present invention is not limited to the following.

[0018]

The present invention will be described in more detail with reference to the following examples. (Example 1) 73.17 g of isopropanol (IPA) and 5 g of propylene glycol dicaprylate (Sefsol-228 (trademark)) were placed in a closed vessel equipped with a suitable stirring device.
Under stirring, 0.3 g of tolnaftate (TOL) is added and dissolved. 4.68 g of purified water was added to this solution, and while stirring,
0.85 g of croconazole hydrochloride (CCZ), 0.5 g of glycyrrhetinic acid and triisopropanolamine (T
(IPA) 0.5 g is added and dissolved. Furthermore, an ethyl acrylate / methyl methacrylate copolymer (EA / MM
A) 30% aqueous dispersion (Eudragit NE30D (trademark) 15 g)
Is added little by little under stirring and dissolved.
0.0 g is obtained.

Examples 2 to 6 Basically, liquid preparations having the compositions shown in the table were obtained according to the preparation method of Example 1. The numbers in the table indicate the addition ratio (% by weight).

[Table 1]

(Test Example 1) In vivo transdermal absorption tests were performed on Examples 3 to 5 and a commercially available product, and the intradermal concentration after 16 hours was examined. (Test method 1 ) The in vivo transdermal absorption test shown in the following test examples was basically performed by the following method. 1. The abdomen of an SD male rat (9 weeks old, n = 4 to 5) is shaved using an electric clipper and an electric razor under urethane anesthesia. 2. The rat is fixed below the back, and a glass absorption cell (administration area: 10 cm ² ) is attached to the hair removal part with an instant adhesive. 3. About 0.3 g of the sample is administered to the skin surface in the cell. 4. After a certain time, the coating formed on the skin surface in the cell is dissolved in ethanol and collected. 5. Remove the cell and excise the dosing surface. After recovery of 6.4, the amount of drug contained in each of the 5 skins is quantified using HPLC. In addition, a commercially available product (Pasca (trademark) gel: Shionogi & Co., Ltd.) has a TOL of 20 mg (2%), methyl salicylate 2
0 mg, triisopropanolamine, macrogol 4
00, a gel containing 5% water.

(Test result 1) Table 2 shows the TOL after 16 hours.
Shows intradermal concentration.

[Table 2] Compared to gels (commercial products) which are generally considered as a base for enhancing percutaneous absorption, the composition of the present invention has a significantly higher percutaneous absorption despite its low TOL content of 0.3%. Achieved sex. Example 3 containing the amount of TOL closest to the saturation solubility of TOL in the base was the highest T
The OL skin concentration was shown (the TOL content is considered to be about 96% of the saturated solubility in Example 3, about 91% in Example 4, and about 75% in Example 5).

Test Example 2 The TOL skin concentration of the composition of Example 4 and the above-mentioned commercially available product was measured with time, and the TOL was measured.
Was tested for its duration of action. (Test Method 2) The test method is the same as Test Method 1. (Test Result 2) The results are shown in FIG. Compared with the commercially available product, the composition of the present invention has significantly improved transdermal absorption of TOL, and a high intradermal concentration was maintained for a long time. The composition of the present invention is a preparation having a lower TOL content than a commercially available product.
Although such high transdermal absorbability was exhibited despite the small dose of L, it can be said that the preparation has a high bioavailability of TOL. From these results,
The liquid preparation of the present invention can be expected to have a sufficient therapeutic effect when applied once a day. It should be noted that the above-mentioned commercial products have also been found to have a sufficient therapeutic effect, and that their TOL intradermal concentration is sufficient for treatment.

(Test Example 3) The therapeutic effect on guinea pig experimental tinea was compared between Example 2 and a commercially available product. (Test method 3) Hartley male guinea pig (body weight 500 g, n =
4) Under Nembutal anesthesia, the entire back surface is depilated using an electric clipper. 2. Trichophyton is applied to the depilated area for infection. 3. From day 5 of infection, when the onset of the disease has progressed sufficiently,
About 0.3 g of a sample is applied to 0 cm ² once a day for 10 days. 4.3 Excise the treatment site and cut into 5 mm square sections. 5.5 sections are cultured on a Sabouraud-agar medium for 1 week to determine the presence of infectious bacteria. In addition, only the individual in which the bacteria in all five sections disappeared was a negative individual,
An individual in which the bacterium was observed in one section was regarded as a positive individual. In addition, a case where no treatment was performed at the site of infection was used as a control.

(Test Results 3) Table 3 shows the therapeutic effect on guinea pig experimental tinea.

[Table 3] The liquid preparation of the present invention exerts a remarkable therapeutic effect as compared with the control and commercial products, and has been proved to be a useful liquid preparation for ringworm.

[0025]

According to the present invention, the antifungal effect of tolnaftate which is equal to or higher than that of the conventional one can be obtained by containing tolnaftate in the same amount as the upper limit that can be dissolved in this base, even though it is a water-containing base. Percutaneous absorption could be achieved. Further, it was not necessary to add a solubilizing agent having a problem with skin irritation to the present liquid preparation which requires a small content of tolnaftate, and an external preparation having no skin irritation could be provided. Further, the liquid preparation of the present invention contains a film-forming agent, which dries quickly after application and forms a soft and tough film on the skin, so that it has an excellent feeling in use without being attached to clothes or the like. In addition, the medicinal effect can be maintained for a long time by forming a film. Therefore, the liquid preparation of the present invention is an aqueous alcohol liquid preparation capable of continuously achieving high transdermal absorbability, and a sufficient effect can be expected by applying once a day for treating athlete's foot.

[Brief description of the drawings]

FIG. 1 A composition of Example 4 and a commercially available product (Pasca (trademark))
It is the graph which measured the TOL skin concentration of the rat with time about the gel (Shinogi Pharmaceutical Co., Ltd .: TOL content 2%).

Claims (18)

[Claims] 1. A method comprising: (a) containing tonaphthate as much as the upper limit of solubility in a base; (b) containing a film-forming agent; and (c) solubilization with substantial skin irritation. An aqueous alcoholic solution, characterized in that it does not contain an agent. 2. An organic solvent other than an alcohol containing (a) tolnaphthate as much as the upper limit of solubility in a base, (b) containing a film-forming agent, and (c) substantially containing an alcohol. An aqueous alcohol solution containing no solvent. 3. Ketones which contain (a) tolnaphthate as much as the upper limit soluble in the base, (b) a film-forming agent, and (c) substantially skin irritants Or an aqueous alcoholic solution containing no glycols. 4. The liquid preparation according to claim 1, which contains about 0.1 to 0.5% by weight of tolnaftate. 5. The liquid preparation according to claim 1, wherein the liquid preparation contains about 1 to 15% by weight of a film forming agent. 6. The liquid preparation according to claim 1, wherein the total amount of water and alcohol is about 50 to 95% by weight. 7. The liquid preparation according to claim 1, comprising about 1 to 30% by weight of water. 8. The liquid preparation according to claim 1, which contains about 50 to 90% by weight of an alcohol. 9. The liquid preparation according to claim 1, further comprising an antifungal agent other than tolnaftate. 10. Antifungal agents other than tolnaftate include croconazole hydrochloride, isoconazole nitrate, miconazole nitrate, thioconazole, itraconazole, oxyconazole, ketoconazole, fluconazole, Clotrimazole, terconazole, sulconazole, bifonazole, naftifine, terbinafine, tolcicre
G, pyro-Lunitrin, bifumacin, tricomycin,
The liquid preparation according to claim 9, which is one or more antifungal agents selected from the group consisting of ciclopirox oclamin, exalamide, and haloprosin. 11. The liquid preparation according to claim 1, further comprising a pharmaceutically active ingredient other than the antifungal agent. 12. The liquid preparation according to claim 11, wherein the active ingredient other than the antifungal agent is an anti-inflammatory agent. 13. The composition further comprising a medium-chain fatty acid ester.
The liquid preparation according to claim 1. 14. The medium-chain fatty acid ester is selected from the group consisting of glyceryl monocaprylate (GMC), tetraglyceryl monocaprylate (TGMC), propylene glycol dicaprylate (PGDC) and tetraglycerin hexacaprylate (TGHC). 14. The liquid preparation according to claim 13, which is one or more selected medium chain fatty acid esters. 15. An aqueous alcoholic solution characterized in that high availability of tolnaftate is achieved by making the content of tolnaftate approximately equal to the upper limit that can be dissolved in the base material. 16. An aqueous solution characterized by achieving high availability of tolnaftate by making the content of tolnaftate approximately equal to the upper limit of dissolvability in a base and by including a film-forming agent. Alcohol solution. 17. The liquid preparation according to claim 15, wherein a solubilizer having skin irritation is not added. 18. The composition contains about 0.1 to 0.5% by weight of tolnaftate, about 1 to 30% by weight of water, about 50 to 90% by weight of alcohol and about 1 to 15% by weight of a film-forming agent, and Aqueous alcohol containing substantially no organic solvent other than alcohol
Solution.