JPH11199485A - Preparation for external use having durable antifungal property - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation for external use capable of attaining sufficient transferability of oxiconazol nitrate to keratin and durability of concentration in the skin by including oxiconazole nitrate, a dissolution auxiliary composed of crotamiton and a polyhydric alcohol and an oil phase composed of a hydrocarbon-based oil phase base and a higher alcohol. SOLUTION: This external preparation comprises (A) preferably 0.1-2 wt.% based on the total of the preparation of oxiconazole nitrate, (B) a dissolution auxiliary of 5-15 times as much as oxiconazole nitrate, composed of crotamiton and a polyhydric alcohol (preferably 1,3-butylene glycol, propylene glycol or the like) in the composition weight ratio of 2:3 to 4:1 and (C) an oil phase of 15-45 times as much as oxiconazole nitrate, composed of a hydrocarbon-based oil phase base (preferably white vaseline, liquid paraffin, squalane or the like) and a higher alcohol (preferably stearyl alcohol, cetanol or the like) mixed in the composition weight ratio of 4:9 to 2:1 in the external preparation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antifungal continuous external preparation comprising oxyconazole nitrate, and more particularly to a composition for maintaining an antifungal effect for a long period of time or a dissolving aid with a low irritation and good use feeling. The present invention relates to a cream that has been selectively colored.

[0002]

2. Description of the Related Art Conventionally, antifungal agents mainly comprising imidazole antifungal agents such as oxyconazole nitrate, miconazole nitrate, clotrimazole and econazole nitrate have been used for the treatment of dermatomycosis such as athlete's foot and bugs. ("Region of Chemotherapy", February 1991, p. 597-603).

Of these, oxyconazole nitrate (hereinafter referred to as "oxyconazole nitrate")
OCZ) is a 2 ', 4'-dichloro-2-imidazol-1-ylacetophenone (2) which has a strong antifungal activity and a broad antibacterial spectrum and also has an antibacterial activity against bacteria such as Gram-positive bacteria. Z)-[O-
(2,4-dichlorobenzyl) oxide] nitrate (molecular formula: C ₁₈ H ₁₃ C ₁₄ N ₃ O.HNO ₃ , molecular weight: 492.1
5). At present, liquid preparations and cream preparations have been marketed as OCZ preparations, and have shown excellent effects in treating dermatomycosis.

Further, with respect to miconazole nitrate, which is an imidazole-based antifungal drug similar to OCZ, a method of increasing the persistence by blending a substance promoting the exfoliation of the antifungal drug into the stratum corneum and a skin-adhering polymer (Japanese Patent Laid-Open No. -126164), but some components listed as substances that promote the exfoliation of the stratum corneum have a skin irritating property and are unsuitable for use as a cream due to poor use and texture of the cream. Problems.

[0005] Formulation was difficult because OCZ was insoluble in both water and oil phase bases. However, in the case of liquid preparations, ethanol and macrogol 400 (listed in the Japanese Pharmacopoeia No. 13; hereinafter abbreviated as PEG400). ) At a high rate to form a liquid formulation (Okinazole solution: manufacturing and sales, Tokyo Tanabe Seiyaku Co., Ltd.)
In the case of creams, it is a simple formulation, but fine crystals are dispersed in a base cream and formulated (Okinazole Cream: Manufacturing and Sales; Tokyo Tanabe Seiyaku Co., Ltd.) to increase drug transfer to the skin Although it has been devised, the absorption is not yet sufficient, and administration several times a day is required.

[0006] Recently, there has been a method in which a higher fatty acid ester, such as isopropyl myristate, which is in a liquid state at normal temperature, is blended to improve the storage property and absorbability in an affected part (Japanese Patent No. 2555555, Japanese Patent Application Laid-Open No. 9-555). 208464
No.). However, although this OCZ preparation is a once-a-day administration preparation, the addition of isopropyl myristate is essential, and the addition of an irritating lower alcohol is preferable. Since it is a drug that must be used for a long time in the treatment of dermatomycosis, it burdens patients in daily life. In order to reduce the burden on the patient and increase the sufficient therapeutic effect, there is no known cream in which OCZ is improved in the exfoliation of keratin, duration of drug effect, feeling in use, and texture.

[0007]

A method for reducing the irritating ethanol and the dissolution aid that impairs the feeling of use and the absorption of OCZ to the skin by blending crotamiton as a crystal precipitation inhibitor in the OCZ solution (particularly). Kaiping 8-40
No. 898) and the stability of OCZ over time and i.
Although it shows an excellent effect on the permeability of the skin substitute (silicone membrane) in n vitro, it is in vivo.
No mention is made of maintaining an effective OCZ concentration in the skin in vo over a long period of time. In addition, it is difficult to use the liquid formulation as it is in a cream which is a two-component emulsion composed of a hydrophilic component and a lipophilic component and which balances the system.

[0008] In the above-mentioned cream, OCZ is expected to be easily absorbed, and is used as fine particles. However, since it is in a crystalline state, if it is a solution and the state is stably maintained, it is expected that keratin transfer and sustainability will be further improved. You. Further, the use feeling can be improved by reducing irritating substances such as lower alcohols.

The present inventors have conducted intensive studies on OCZ-containing antifungal external preparations for the purpose of ensuring sufficient exfoliation of keratin, sustaining efficacy, and ensuring a good feeling of use and texture. A formulation prepared by dissolving OCZ in an oil base using a composition having a specific blending ratio of polyhydric alcohol as a dissolution aid, and then emulsifying the mixture by a conventional method using an appropriate emulsifier and water is used for the above purpose. Was satisfied. Further, by changing the mixing ratio of a low-polarity oil phase base represented by a hydrocarbon-based oil phase base in the oil phase base and a relatively polar oil phase base represented by a higher alcohol, By knowing that it is possible to control the exfoliation of OCZ by changing the polarity of the oil phase in which OCZ is mixed, the present invention has been completed. Also, when using a solubilizing agent consisting of crotamiton and 1,3-butylene glycol, compared to using crotamiton alone,
They also knew that it was possible to suppress the coloring of the components due to heating during production, etc., very lightly, and completed the cream according to the present invention.

[0010]

The present inventors have conducted intensive studies on an OCZ-containing topical antifungal agent for external use, and found that (a) the mixing ratio of crotamiton and polyhydric alcohol is 2: 3 to 4: 1. OCZ as a dissolution aid
Is dissolved in an oil phase base, and (b) the polarity is controlled by the blending ratio of the hydrocarbon-based oil phase base and the oil phase base containing a higher alcohol as a main component to improve the exfoliation of OCZ keratin. They found what they could do and completed the invention.

Further, since it is not affected at all by the physicochemical properties such as the kind and the mixing ratio of the added surfactant and the viscosity of the preparation or the combination of these factors, the feeling of use and stability of the preparation are not affected. In consideration of the above, it is possible to freely select an appropriate surfactant, an oil phase base and a water-soluble base in order to obtain a desired dosage form such as a cream or a suppository.

In the present invention, OCZ is used in an amount of 0.1 to 0.1% by weight of the whole preparation.
It contains 2% by weight. Preferably, the content is 0.2 to 1% by weight.

[0013] Clotamiton and a polyhydric alcohol are used as the dissolution aid, and the composition weight ratio (crotamiton: polyhydric alcohol) is a mixture of 2: 3 to 4: 1, and is based on the weight of oxyconazole nitrate. 5 to 15 times the amount used.

Preferably, the composition weight ratio of crotamiton and polyhydric alcohol (crotamiton: polyhydric alcohol) is 1: 1 to 2: 1 and is 5 to 10 times the weight of oxyconazole nitrate. It is used.

More preferably, the composition weight ratio of crotamiton and polyhydric alcohol (crotamiton: polyhydric alcohol)
Are mixed at a ratio of 1: 1 to 5: 3, and are used in an amount of 8 to 10 times the weight of oxyconazole nitrate.

As the polyhydric alcohol, 1,3-butylene glycol, propylene glycol or the like is used.

The oil phase component is a mixture of a hydrocarbon oil phase base and a higher alcohol, and the composition weight ratio of the two components (hydrocarbon oil phase base: higher alcohol) is from 4: 9 to 2: 1 and is used in an amount of 15 to 45 times the weight of oxyconazole nitrate.

Preferably, the composition weight ratio of the two components of the hydrocarbon oil phase base and the higher alcohol (hydrocarbon oil phase base: higher alcohol) is 1: 1 to 8: 5, 20 to 30 based on the weight of oxyconazole nitrate
Use twice the amount.

More preferably, the composition weight ratio of the two components of the hydrocarbon-based oil phase base and the higher alcohol (hydrocarbon-based oil phase base: higher alcohol) is 1: 1 to 3: 2. And 20 to 26 times the weight of oxyconazole nitrate.

As the hydrocarbon-based oil phase base, white petrolatum, liquid paraffin, squalene, squalane, or the like can be used, and as the higher alcohol, stearyl alcohol, cetanol, or the like can be used.

Surfactants that can be added to the present invention include polyoxyethylene (25) cetyl ether, polyoxyethylene (30) cetyl ether, and polyoxyethylene (4).
0) polyoxyethylene alkyl ethers such as cetyl ether, polyoxyethylene (30) oleyl ether, polyoxyethylene (50) oleyl ether, polyethylene glycol monostearate (25EO);
Polyethylene glycol monostearate (40EO)
Polyoxyethylene (50) castor oil, polyoxyethylene (60) hydrogenated castor oil, etc., polyoxyethylene hydrogenated castor oil, sorbitan monostearate, sorbitan monopalmitate, monolauric acid Examples include sorbitan fatty acid esters such as sorbitan and the like, and glycerin fatty acid esters such as glycerin monostearate, and are preferably polyoxyethylene alkyl ether and glycerin fatty acid ester.

Similarly, other oil phase bases that can be added include fatty acids such as stearic acid and palmitic acid, and waxes such as beeswax and lanolin.

Further, it is easy to add various compounding agents for enhancing the therapeutic effect. For example, a local anesthetic such as lidocaine or dibucaine, a bactericidal preservative such as acrynol, benzalkonium chloride or isopropylmethylphenol, glycyrrhetinic acid, or allantoin Anti-inflammatory agents such as, l-menthol, cooling agents such as d-camphor, urea, keratolytic agents such as diethyl phthalate, aluminum chlorohydroxide,
An astringent protecting agent such as zinc oxide can be added as necessary.

[0024]

[Effect] The transdermal administration of this external preparation or a preparation which is supposed to be actually administered to humans results in O in the skin.
It shows the CZ concentration and its chronological change, the feeling of use by trained panelists based on sensory tests, the properties of the cream when stored for a long period of time, and the stability of the preparation due to changes in the OCZ residual ratio.

[OCZ Concentration in Hairless Rat Skin and Changes Over Time] (Method) 180 male hairless rats (8 weeks old) were divided into 18 groups of 10 rats per group, and each of Comparative Examples 1 to 7 or Example 1 was used. , And under anesthesia with Nembutal, the applied amount of OCZ was 0.1 m / cm ^{2 on the} skin of the back of the rat.
80 mg of each preparation to 8 cm ² (2 × 4c
After the application in m), the rat was hung on the neck so as not to lick the site where the preparation was applied, and left for 8 or 24 hours.

After 8 or 24 hours, each group was euthanized with 1/2 of 10 mice at 5 times in chloroform, and the formulation remaining on the skin surface coated with the formulation was washed with a washing solution (1% phosphoric acid). And 8% sodium lauryl sulfate 7
(0% ethanol aqueous solution) was thoroughly wiped with absorbent cotton (10 times), the skin to which the preparation was applied was excised, and the amount of OCZ absorbed in the skin was measured by HPLC.

(HPLC pretreatment) 1 g of the rat back skin was weighed out, 0.5 ml of an ethyl acetate solution of o-terphenyl (3.6 μg / ml) and 10 ml of ethyl acetate were added as internal standard substances, and a glass homogenizer was added. Grind with an ultrasonic cleaner (UT-104, Sharp Corporation)
) For 2 minutes. Further, 2 ml of a 1% aqueous potassium hydroxide solution was added, and the mixture was vigorously shaken and centrifuged. After recovering the organic solvent layer and concentrating it to dryness, H
0.5 ml of methanol for PLC was added and dissolved, and insolubles were removed by filtration with a membrane filter having a pore size of 0.45 μm to prepare an HPLC test solution.

Further, after adding an OCZ solution of known concentration to 1 g of the back skin of a hairless rat to which the formulation was not applied, the same operation was performed and analyzed as a standard solution to prepare a calibration curve. The OCZ concentration in the animal skin to which was applied was calculated.

(HPLC measurement conditions) Column: Wakosil 5C18 (φ4.6 m)
Column temperature: 35 ° C. Mobile phase: 80% aqueous methanol solution containing 0.1% acetic acid and 0.2% ammonium acetate Flow rate: 0.8 ml / min Detector: UV absorption spectrophotometer (measurement wavelength: 242 nm) (Results) 1) The concentrations in the skin (after 8 hours and 24 hours) when the Examples and Comparative Examples of the present invention were transdermally administered are shown in Table 1 and FIG.

[0030]

[Table 1]

[0031]

FIG.

As shown in Table 1 and FIG.
Eleven creams showed extremely high OCZ concentrations in the skin compared to Comparative Examples 1 to 7. In particular, all creams showed a concentration of OCZ in the skin 24 hours after application that was higher than the concentration 8 hours after in the comparative example, and the examples maintained a high concentration after 24 hours. I was

This confirmed the durability of the product of the present invention.

[Feeling of use] Sensory tests on the feeling of use of the examples and comparative examples were carried out by 10 trained panelists. Table 2 shows the results.

The feeling of use was evaluated as ○ when all panelists judged good, and □ when 7 to 9 persons judged good.
場合 indicates that 7 or more persons are not good, and X indicates that 8 or more persons are not good.

[0036]

[Table 2]

As shown in Table 2, the examples had good usability.

Thus, the product of the present invention seems to be suitable as a pharmaceutical.

[Preparation stability] The prepared preparation was placed in a closed container and stored at 40 ° C and 75% RH for 3 months.
Over time, the OCZ content was adjusted to HP
It was measured by LC method, and the residual ratio was examined with the start of storage as 100%. In addition, the presence or absence of discoloration (yellow) as a change in the properties of the preparation was visually confirmed. If no discoloration is seen-
In the table, the case where slight discoloration was observed was indicated by ±, and the case where obvious discoloration was observed was indicated by +.

[0040]

[Table 3]

As shown in Table 3, the product of the present invention was at 40 ° C.
It is an extremely stable preparation without a decrease in the OCZ content or a change in properties during storage at 75% RH.

As described above, the product of the present invention was able to maintain a long-lasting efficacy concentration, and the feeling of use and stability of the preparation were good.

Further, it is not necessary to add a single special component or the like for promoting keratin transfer, and the object can be achieved only by a combination of components which are safe as an ointment base and have a sufficient use record. Furthermore, in the present invention, since OCZ is present in the oil phase base, it is hardly affected by a change in pH derived from other compounding components, and as shown in Examples 7 to 11, compounding an organic base such as lidocaine, Even when the pH of the preparation is 7 or more, no decrease in the OCZ content during storage at 40 ° C. for 3 months is observed, and an extremely stable preparation can be obtained.

That is, the product of the present invention makes it possible to provide an OCZ external preparation which achieves sufficient keratin translocation and sustained skin concentration while maintaining the feeling of use and the stability of the preparation. It became.

[0045]

The present invention will be described below with reference to production examples. However,
They do not limit the invention. A comparative example is also shown.

[0046]

[Table 4]

<Example 1> According to the formulation shown in Table 4, the oil phase component and the aqueous phase component were each heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

Example 2 According to the formulation shown in Table 4, the oil phase component and the aqueous phase component were each heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

Example 3 According to the formulation shown in Table 4, the oil phase component and the aqueous phase component were each heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C., and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

Example 4 The oil phase component and the aqueous phase component were each dissolved by heating according to the formulation shown in Table 4, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

Example 5 According to the formulation shown in Table 4, the oil phase component and the aqueous phase component were each dissolved by heating, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

Example 6 According to the formulation shown in Table 4, the oil phase component and the aqueous phase component were each dissolved by heating, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

Example 7 According to the formulation shown in Table 4, the oil phase component and the aqueous phase component were each dissolved by heating, and the aqueous phase component was added to the oil phase component at 80 ° C., and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

<Example 8> According to the formulation shown in Table 4, the oil phase component and the aqueous phase component were each heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

Example 9 According to the formulation shown in Table 4, the oil phase component and the aqueous phase component were each heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

<Example 10> The oil phase component and the aqueous phase component were each dissolved by heating according to the formulation shown in Table 4, and the aqueous phase component was added to the oil phase component at 80 ° C and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

<Example 11> According to the formulation shown in Table 4, the oil phase component and the aqueous phase component were each heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C, and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

<Comparative Example 1> In the formulation of Table 4, the oil phase component and the aqueous phase component were each heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C and emulsified according to a conventional method. The mixture was cooled to room temperature to prepare a base cream. OC below 30 ° C
While gradually adding a chemical solution in which Z was uniformly suspended, the mixture was stirred and mixed in a conventional manner to obtain a cream.

<Comparative Example 2> According to the formulation shown in Table 4, the oil phase component and the aqueous phase component were each dissolved by heating, and the aqueous phase component was added to the oil phase component at 80 ° C and emulsified according to a conventional method. The mixture was cooled to room temperature to prepare a base cream. OC below 30 ° C
While gradually adding a drug solution in which Z and lidocaine were uniformly suspended, the mixture was stirred and mixed in a conventional manner to obtain a cream.

<Comparative Example 3> The oil phase component and the aqueous phase component were each dissolved by heating according to the formulation shown in Table 4, and the aqueous phase component was added to the oil phase component at 80 ° C and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

<Comparative Example 4> According to the formulation shown in Table 4, the oil phase component and the aqueous phase component were each dissolved by heating, and the aqueous phase component was added to the oil phase component at 80 ° C and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

<Comparative Example 5> According to the formulation shown in Table 4, the oil phase component and the aqueous phase component were each dissolved by heating, and the aqueous phase component was added to the oil phase component at 80 ° C and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

<Comparative Example 6> According to the formulation shown in Table 4, the oil phase component and the aqueous phase component were each heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

<Comparative Example 7> According to the formulation shown in Table 4, the oil phase component and the aqueous phase component were each dissolved by heating, and the aqueous phase component was added to the oil phase component at 80 ° C, and emulsified according to a conventional method. The mixture was cooled to room temperature to obtain a cream.

Claims (9)

[Claims] 1. A solubilizer comprising oxyconazole nitrate and (a) crotamiton and a polyhydric alcohol, and having a composition weight ratio (crotamiton: polyhydric alcohol) of 2: 3 to 4: 1, (b) ) An oil phase component in an external preparation mixed with a hydrocarbon-based oil phase base and a higher alcohol and having a composition weight ratio (hydrocarbon-based oil phase base: higher alcohol) of 4: 9 to 2: 1. An antifungal continuous external preparation, wherein (a) contains 5 to 15 times the amount of oxyconazole nitrate and (b) 15 to 45 times the amount of oxyconazole nitrate. 2. A dissolution aid comprising oxyconazole nitrate and (a) crotamiton and a polyhydric alcohol, wherein the composition weight ratio (crotamiton: polyhydric alcohol) is mixed at 1: 1 to 2: 1; ) An oil phase component in an external preparation which is composed of a hydrocarbon-based oil phase base and a higher alcohol, and has a composition weight ratio (hydrocarbon-based oil phase base: higher alcohol) of 1: 1 to 8: 5. An antifungal persistent external preparation containing (a) 5 to 10 times the weight of oxyconazole nitrate and (b) 20 to 30 times the weight of oxyconazole nitrate 3. The antifungal continuous external preparation according to claim 1, wherein the hydrocarbon-based oil phase base is one or a mixture of two or more selected from white petrolatum, liquid paraffin, and squalane. 4. The antifungal persistent external preparation according to claim 1, wherein the higher alcohol is stearyl alcohol, cetanol or a mixture thereof. 5. The antifungal persistent external preparation according to claim 1, wherein the polyhydric alcohol is 1,3-butylene glycol, propylene glycol or a mixture thereof. 6. Oxyconazole nitrate is present in the total formulation weight,
2. The composition of claim 1, wherein the content is 0.1 to 2% by weight.
To 5 topical antifungal persistent agents 7. A composition comprising 0.2 to 1% by weight of oxyconazole nitrate, (a) crotamiton and 1,3-butylene glycol in the total weight of the preparation, and the composition weight ratio (crotamiton: 1,3-butylene glycol). Is 1: 1 to 5: 3
And (b) a hydrocarbon-based oil phase base and a higher alcohol, and the composition ratio by weight (hydrocarbon-based oil phase base: higher alcohol) is 1: 1 to 3: 2. 8 to 10 times the amount of (a) based on the weight of oxyconazole nitrate is dissolved in (b) 20 to 26 times the weight of oxyconazole nitrate. Topical antifungal persistent agent 8. The antifungal continuous external preparation according to claim 1, wherein the external preparation is a cream. 9. The preparation according to claim 8, wherein the cream comprises an O / W emulsion.