JP3260370B2 - Tolnaftate-containing liquid - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a tolnaftate-containing liquid preparation which is excellent in skin retention, persistence and stability of tolnaftate.

BACKGROUND ART Tolnaftate has the following structural formula [Chemical name: N-methyl-N- (3-tolyl) thiocarbamic acid-2-naphthyl ester], which has a bactericidal activity against Trichophyton, Epidermophytes and Microspores at a low dose. And Trichophytia pompholyciformi
s), vulgaris (t.eczematosa), vesicular tinea pedis (t.mac)
ulovesiculosa) or versicolor (pytyriasis vericolor)
It is a topical drug widely used as a remedy for skin diseases such as skin disorders (see the 12th revised edition of the Japanese Pharmacopoeia C-1579 tolnaftate).

Tolnaphthate-containing liquids are relatively soluble in organic solvents such as ketones, but are difficult to dissolve in organic solvents commonly used for external preparations such as ethanol, are hardly soluble in water, and use solvents with a low boiling point. However, there is a limitation on the formulation that the solvent evaporates over time or upon application to the skin and crystals of tolnaftate precipitate. Therefore, a tolunaphate liquid formulation having a basic composition of a solubilizer having a relatively high boiling point, such as a solubilizing agent such as triacetin, which has an effect of preventing crystal precipitation, methyl ethyl ketone, and ethanol as a liquid regulator is commercially available.

In percutaneous administration therapy for tinea, most of the tinea bacilli use the lower part of the stratum corneum in the epidermal tissue of the animal as the breeding site. It is well known that the effective bactericidal action of is important in preventing recurrence and curing completely.

A method for improving the solubility of tolnaftate, preventing crystal precipitation, and consequently increasing the amount of absorbed skin, with the aim of developing an effective formulation of tolnaftate, which has an excellent anti-tineaphytic effect. Various attempts have been made such as a method of selecting a shape.

As a new attempt, the concentration of the absorbed drug in the skin, that is, the skin retentivity, has been increased, and a stable preparation has been supplied while maintaining the enhanced skin retentivity. This method has attracted attention as the most effective method for the treatment of tinea.

To enhance the skin retention of tolnaftate, liquid preparations that are considered to have poorer skin absorption than other conventional dosage forms have been studied.
No. 150509 reports an aqueous solution containing tolnaphthalate.

DISCLOSURE OF THE INVENTION The present inventors have intensively studied non-aqueous tolnaftate-containing liquid preparations and liquid preparations that enhance the skin retention of tolnaftate because tolnaftate is hardly soluble in water. The present inventors have found a completely different non-aqueous solution containing tolnaftate and completed the present invention.

Hereinafter, the tonaphate-containing liquid preparation of the present invention will be described in detail.

The tonaphate-containing liquid preparation of the present invention comprises tolnaphthate, octyldodecyl myristate (ODM), isopropyl palmitate (IPP) and octyldodecanol (ODM).
CD) or one or more selected from the group consisting of
And a solvent.

As the solvent, ketones such as methyl ethyl ketone and acetone, low boiling alcohols such as ethanol and isopropanol, and a mixed solvent thereof are used. Preferably, ethanol and isopropyl alcohol are used.

Further, a solvent other than the above may be added as long as the object of the present invention is not impaired.

For example, lower alkyl diesters of dibasic acids such as benzyl alcohol and phenethyl alcohol which are local anesthetics, crotamiton which is an antipruritic agent, diisopropyl adipate and diethyl sebacate are exemplified.

In addition to the tolnaphthate-containing liquid preparation of the present invention, tolnaphtate may be used alone or as a mixture of tolnaphthate and one or more other antifungal agents or in combination with an antifungal agent within a range not to impair the object of the present invention. However, advantageous adjuvants may be used.

Other antifungal agents include imidazole antifungal agents (clotrimazole, bifonazole, miconazole nitrate,
Econazole nitrate, isoconazole nitrate, sulconazole nitrate, oxyconazole nitrate, croconazole hydrochloride,
Ketoconazole, thioconazole, etc.), pyridone antifungals (ciclopirox olamine, etc.), triazole antifungals (exalamisod, etc.), antibiotic antifungals (pyrronitrin, etc.) or undecylenic acid and salts thereof. Can be

When a combination of tolnaftate and one other antifungal agent,
The mixing ratio is preferably 1: 1.

Adjuvants include antihistamines (diphenhydrazine or its salt, chlorpheniramine or its salt, etc.), local anesthetics (benzyl alcohol, phenethyl alcohol, lidocaine hydrochloride, dibucaine hydrochloride, etc.), antipruritics (crotamiton, glycyrrhizin, glycyrrhizin) Salts, glycyrrhetinic acid, etc.), keratin softeners (salicylic acid, etc.) or antibacterial agents (chlorhexidine or its salts, decalinium chloride, benzalkonium chloride, benzethonium chloride, isopropylmethylphenol, etc.)
And the like.

Further, these liquids may optionally contain additives.

Additives include preservatives or antioxidants (parabens such as methylparaben and ethylparabe, sorbin or its salts, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), nordihydroguaiaretic acid, guaiacol esters, etc.) , pH adjusters (organic acids such as citric acid), humectants (glycerin, 1,3-
Polyhydric alcohols such as butylene glycol), flavors (such as 1-menthol), and other skin absorption enhancers (such as terpenes used within a range not to impair the purpose of the present invention).

As a preferable example of the liquid agent containing tolnaftate of the present invention,
The following are mentioned.

1. Liquid agent consisting of tolnaftate, methyl ethyl ketone, octyldodecyl myristate and anhydrous ethanol 2. Liquid agent consisting of tolnaftate, methyl ethyl ketone, isopropyl palmitate and anhydrous ethanol 3. Liquid agent consisting of tolnaftate, methyl ethyl ketone, 2-octyldodecanol and anhydrous ethanol 4. Liquid preparation comprising tolnaftate, clotrimazole, methyl ethyl ketone, octyldodecyl myristate and anhydrous ethanol The compounding amounts of each component of the liquid preparation containing tolnaftate of the present invention are as follows.

Tolnaphthate: 0.1 to 4 (W / V)% when used alone, preferably 1 to 3 (W / V)%, 0.1 to 2 (W / V)% when used in combination
(W / V)%, preferably 0.5 to 1.5 (W / V)%, one or more selected from the group consisting of octyldodecyl myristate (ODM), isopropyl palmitate (IPP) and octyldodecanol (OCD) or 2 or more: 4 to 30 (W / V)%, preferably 5 to 20 (W / V)%, depending on the type.

For octyldodecyl myristate, 5 to 20 (W /
V)%.

5 to 20 (W / V) for isopropyl palmitate
%.

For octyldodecanol (OCD), 10 to 25 (W /
V)%.

Solvent: Used as a balance for preparing the tonaphate-containing liquid preparation of the present invention, and the amount is appropriately set.

Additives: 0 to 20 (W / V), depending on the type
%.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the therapeutic effect on Trichophyton infection in the case of Example 1, Comparative Example 1 and the control group (untreated).

FIG. 2 shows the therapeutic effect on Trichophyton infection in the cases of Example 4, Example 1 and the control group (untreated).

BEST MODE FOR CARRYING OUT THE INVENTION The tonaphthate-containing liquid preparation of the present invention has been described above, but will be described in more detail with reference to the following examples.

Example 1 To 2 g of tolnaftate, 25 ml of methyl ethyl ketone and 10 ml of octyldodecyl myristate were added and mixed, and anhydrous ethanol was added thereto to make a total volume of 100 ml, followed by thorough mixing to obtain a liquid preparation.

Example 2 To 2 g of tolnaftate, 25 ml of methyl ethyl ketone and 10 ml of isopropyl palmitate were added and mixed, and anhydrous ethanol was added thereto to make a total volume of 100 ml, followed by thorough mixing to obtain a liquid preparation.

Example 3 To 2 g of tolnaftate, 25 ml of methyl ethyl ketone and 20 ml of 2-octyldodecanol were added and mixed, and anhydrous ethanol was added thereto to make a total amount of 100 ml, followed by thorough mixing to obtain a liquid preparation.

Example 4 To 1 g of tolnaftate, 1 g of clotrimazole, 15 ml of methyl ethyl ketone and 10 ml of octyldodecyl myristate
Was added and mixed, and anhydrous ethanol was added thereto to make a total volume of 100 ml, and mixed well to obtain a liquid preparation.

Example 5 To 1 g of tolnaftate, 1 g of clotrimazole, 25 ml of methyl ethyl ketone and 10 ml of octyldodecyl myristate
Was added and mixed, and anhydrous ethanol was added thereto to make a total volume of 100 ml, and mixed well to obtain a liquid preparation.

Example 6 To 1 g of tolnaftate, 1 g of bifonazole, 15 ml of methyl ethyl ketone and 10 ml of octyldodecyl myristate were added and mixed, and anhydrous ethanol was added to make a total volume of 100 ml, and the mixture was mixed well to obtain a liquid preparation.

Example 7 To 1 g of tolnaftate, 25 ml of methyl ethyl ketone and 10 ml of octyldodecyl myristate were added and mixed, and anhydrous ethanol was added thereto to make a total volume of 100 ml, followed by thorough mixing to obtain a liquid preparation.

Example 8 To 2 g of tolnaftate, 5 g of crotamiton, 0.05 g of dibucaine hydrochloride, 2 g of salicylic acid, and 0.05 g of BHT were added and mixed with 25 ml of methyl ethyl ketone and 10 ml of octyldodecyl myristate.
and mixed well to obtain a liquid preparation. This was aseptically filtered, filled into a 30 ml container and sealed.

Example 9 To 1 g of tolnaftate, 1 g of clotrimazole, 5 g of crotamiton, 0.1 g of dibucaine hydrochloride, 1 g of l-menthol and BH
To 0.05 g of T., 25 ml of methyl ethyl ketone and 10 ml of octyldodecyl myristate were added and mixed, and anhydrous ethanol was added thereto to make a total volume of 100 ml. The mixture was mixed well to obtain a liquid preparation. This was aseptically filtered, filled into a 30 ml container and sealed.

INDUSTRIAL APPLICABILITY The tolnaftate-containing liquid preparation of the present invention has a remarkable effect of absorbing and storing tolnaftate inside the skin keratin, which is a site where fungi such as Trichophyton breeds, and is particularly useful as an anti-ringworm-containing liquid preparation. It is. In addition, a liquid preparation using a mixture of tolnaftate and an antifungal agent other than tolnaftate has a high rate of relieving symptoms and has an excellent therapeutic effect.

Furthermore, the liquid preparation containing tolnaphthalate of the present invention is also excellent in the effect of preventing the precipitation of tolnaftate crystals.

The effect of the skin retention of the present invention has been confirmed by the following experimental methods.

Tonaphthate skin retention in vivo test Experimental method The abdominal skin of a 5- to 7-week-old male Hartley guinea pig (body weight: 300 to 450 g), which had been shaved the previous day and depilated with Eva Claims, was wiped with warm water, and the administration area was 4.28 cm ² . The chamber is adhered, and 1 ml of a sample (Examples 1 to 4, 6, and 8 and Comparative Examples 1 to 3) is administered. The upper part of the chamber was sealed. After collecting the administered sample over time, remove the chamber, wipe the skin at the site of administration with ethanol and methyl ethyl ketone for disinfection, and collect 1.3 cm ² . Tolnaftate, clotrimazole and / or bifonazole in the collected skin were extracted with ether, and the amount of tolnaftate in the skin was measured by high performance liquid chromatography (HPLC method).

Table 1 shows the amount of tolnaftate stored in the skin and the amount of clotrimazole or bifonazole stored in the skin after 2 hours and 4 hours obtained in the experimental results, and Table 2 shows the time course of the amount of tolnaftate stored in the skin. .

 Comparative examples were prepared as follows.

Comparative Example 1 To 2 g of tolnaftate, 25 ml of methyl ethyl ketone and 25 ml of triacetin were added and mixed, and anhydrous ethanol was added thereto to make a total amount of 100 ml. The mixture was thoroughly mixed to obtain a liquid preparation.

Comparative Example 2 To 2 g of tolnaftate, 25 ml of methyl ethyl ketone and 25 ml of isopropyl myristate were added and mixed, and anhydrous ethanol was added thereto to make a total volume of 100 ml, followed by thorough mixing to obtain a liquid preparation.

Comparative Example 3 To 1 g of tolnaftate, 15 ml of methyl ethyl ketone was added to 1 g of clotrimazole and mixed, and anhydrous ethanol was added thereto to make a total volume of 100 ml, followed by thorough mixing to obtain a liquid preparation.

As is clear from the experimental results, the ODM, IPP
And / or tolunaphthate solution containing OCD is at least 8 times greater than that containing triacetin, and myristic acid which has been used as an oily component in gels, gel emulsions and microemulsion formulations of tolnaftate It was confirmed that the skin retention property was at least twice as high as that of isopropyl. In particular, O
When using DM, it is about 34 times less than triacetin solution.
It was a completely unexpected result that the skin storage amount was about 9 times that of the isopropyl myristate solution. Further, it has been clarified that even when the composition of the present invention is combined with clotrimazole or bifonazole, the skin retention of tolnaftate is enhanced.

It has been confirmed that diisopropyl adipate, diethyl sebacate, propylene glycol, and the like, which are widely used in gels and emulsions of tolnaftate, are inferior in skin retention.

Experiment 2 Therapeutic effect test for Trichophyton infection The method of Sakai et al. (J. Scient. Res. Inst., 46,
113, (1952)).

Bacterial strain: Trichophyton mentagrophytes (TIMM1189) Bacterial solution: Suspended moss cultivated for 1 to 2 weeks at room temperature (27 ° C) on Sabouraud agar slope, suspended in 0.1% Tween 80 (trade name) -added physiological saline (medium filtration by gauze filtration) ), And adjust the concentration to 10 ⁶ cells / 50μl. Inoculum: 10 ^{6 /} 2.8cm ² epidermis (1.9cm in diameter) Animal: Hartley male guinea pig 5 weeks old (350g), 25
Inoculation site: Back epidermis (sheared with hair clipper on the day before the experiment, dehaired with evaclaim, and inoculated in 4 places) Reagents: Comparative Example 1, Example 1 or Example 4 Drug administration: 5 days after bacterial inoculation Administer once a day for 9 days.

Application amount: 100 μl × 1 time Application method: Drop drying method Symptom observation: Observation is performed for 20 days after inoculation, and a clinical symptom evaluation value (Note 1) is attached by Weilstein's method.

Reverse culture test: At the end of the experiment (day 21), the epidermis of the infected site is peeled off, cut into small pieces, placed on a Sabouraud agar plate supplemented with chloramphenicol 50 ppm and cycloheximide 500 ppm, and cultured to check for the presence of bacteria.

Experimental results From FIG. 1, comparing the maximum values of the clinical symptom determination values of the respective reagents, Example 1 (solution using ODM) was significantly more significant than the control group (untreated) or Comparative Example 1 (solution using triacetin). Are better.

In addition, even when comparing the time to the symptom relief, Example 1
Is significantly better than the control or Comparative Example 1.

From FIG. 2, comparing the maximum values of the clinical symptom determination values of the respective reagents, Example 4 (solution using tolnaftate and clotrimazole) is significantly superior to the control group as in Example 1.

In addition, the speed at which the symptoms relieved was high, and the combination of tolnaftate and clotrimazole was more effective than Example 1.

After 15 days, the spontaneous healing including control was headed. In this experimental system, it was important to determine whether the maximum value of the clinical symptom judgment value showed a significant difference. Shows data up to 14 days.

As a result of examining the presence of bacteria on the 21st day, the positive rate was lower in the example prescription than in the control group.

Experiment 3 Persistence test of tolnaftate-containing liquid preparation of the present invention (Experimental method) Bacterial strain: Trichophyton mentagrophytes (TIMM1189) Bacterial solution: 0.1% Tween 80 (0.1% Tween 80) cultured for 1 to 2 weeks on a subrow agar slope at room temperature (27 ° C.) Suspended in a physiological saline solution (trade name) (excluding coarse foreign substances such as culture medium by filtration with gauze), and the concentration of bacteria (spores) is measured and adjusted to 10 ⁶ cells / 50 μl.

Inoculation amount: 10 ^{6 /} 2.8cm ² epidermis (1.9cm in diameter) Animal: Hartley male guinea pig 5 weeks old (350g), 10 animals Inoculation site: back epidermis (inoculation of the bacterial solution to the site where the drug was applied in advance To create the drug application site, partially shaving with a clipper and removing the hair with Eva cream.) Inoculation method: Eppendorf at one place (2.8 cm ^{2 in} area)
Apply 50 μl uniformly.

Reagent: Example 4 Drug administration: The drug was applied to independent sites on the back of the same animal three days before, two days before, and one day before the inoculation of the bacterium. It is clear from Experiment 2 that no lesion was observed in the case of no treatment (no drug application).

 Application amount: 50 μl × 1 time Application method: Drop drying method Symptom observation: Observed 11 days after inoculation.

(Experimental results) The results are shown in Table 3 below.

The tolnaftate solution of the present invention did not show any local lesions even when applied three days before inoculation of the bacterium, and showed remarkable persistence, suggesting that skin retention is excellent.

Experiment 4 The results of examining the precipitation properties of tolnaftate crystals and the presence or absence of discoloration of the tolnaftate-containing liquid preparation of the present invention when stored at 5 ° C., room temperature, and 40 ° C. and 75% relative humidity are shown in the table below. As shown in FIG.

As is evident from Table 4, the solution of the present invention did not precipitate tonaphthalate crystals even after storage at 5 ° C. for 6 months under conditions in which tolnaphthalate crystals were likely to precipitate, and the relative humidity at 40 ° C.
Even in a severe test for 6 months under 75% severe conditions, no discoloration of the solution was observed and the solution was stable.

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int. Cl. ⁷ , DB name) A61K 31/27 A61K 47/14 A61K 9/08

Claims (2)

(57) [Claims] 1. One or two members selected from the group consisting of octyldodecyl myristate and isopropyl palmitate.
An agent for improving skin retention of tolnaftate, comprising a seed and a solvent. 2. One or two members selected from the group consisting of octyldodecyl myristate and isopropyl palmitate.
An agent for improving the durability of a non-aqueous solution containing tolnaftate, comprising a seed and a solvent.