Butenafine-containing cream in a jar

Abstract

To provide a butenafine-containing cream suitable for use in a jar container and having a feeling of use that does not deteriorate with temperature (season).SOLUTION: The present invention relates to a cream and the like, which contains butenafine or a pharmaceutically acceptable salt thereof, water, a higher alcohol, and a surfactant, the cream being for use in a jar container, having a viscosity of 7,000 mPa s to 50,000 mPa s at 5°C to 40°C, and having a difference in viscosity between 5°C and 40°C of 38,000 mPa s or less.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a butenafine-containing cream for use in a jar. [Background technology]

[0002] Topical skin preparations containing butenafine hydrochloride, a treatment for athlete's foot, are already commercially available in various dosage forms and are widely used in clinical settings and at home. Skin topical preparations are available in various dosage forms, such as creams, ointments, gels, lotions, sprays, and patches, among which creams are known to be excellent in skin permeability and usability. As a cream containing butenafine hydrochloride, for example, Patent Document 1 describes a cream containing butenafine hydrochloride that has improved keratinocyte retention and enhanced therapeutic effects by incorporating an adjuvant. On the other hand, examples of containers for filling creams include tube containers, jar containers, etc. Jar containers have a larger opening (opening for taking out the contents) than tube containers, and therefore have the advantage that a desired amount of cream can be easily scooped with fingers and applied to a desired area. However, up until now, tube containers have usually been used for creams containing butenafine hydrochloride, and jar containers have not been used. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Laid-Open No. 2005-239679 Summary of the Invention [Problem to be solved by the invention]

[0004] The present inventors have studied butenafine-containing creams for use in jar containers and have found that changes in viscosity due to temperature can be a problem, which was not an issue with creams filled in tube containers. More specifically, they have found that the viscosity changes with temperature, and depending on the season (for example, summer or winter), the cream filled in a jar container may be difficult to scoop with fingers and apply, which may result in a reduced usability. Therefore, an object of the present invention is to provide a butenafine-containing cream preparation that is suitable for use in a jar container and whose feel during use does not deteriorate regardless of temperature (season).

[0005] While the present inventors have been conducting intensive research to solve the above-mentioned problems, they have discovered that it is possible to provide a butenafine-containing cream that is suitable for use in a jar container and that does not deteriorate in usability regardless of temperature (season). As a result of further research, they have completed the present invention.

[0006] That is, the present invention relates to the following [1] to [6]. [1] A cream comprising butenafine or a pharmaceutically acceptable salt thereof, water, a higher alcohol, and a surfactant, The cream is in a jar container, The viscosity at 5°C to 40°C is 7,000 mPa·s to 50,000 mPa·s, The difference in viscosity at 5°C and 40°C is 38,000 mPa·s or less. The cream. [2] The cream according to [1], wherein the ratio of the viscosities at 5°C and 40°C (viscosity at 40°C / viscosity at 5°C) is 0.1 to 1. [3] A cream according to [1] or [2], which contains higher alcohols with different alkyl chain lengths.

[0007] [4] A method for producing a butenafine-containing cream for a jar container, comprising: The viscosity of a cream obtained by mixing butenafine or a pharmaceutically acceptable salt thereof, water, a higher alcohol, and a surfactant is measured, and it is determined whether the following conditions are met: - Viscosity at 5°C, 25°C, and 40°C is 7,000 mPa·s to 50,000 mPa·s; and - The difference in viscosity at 5°C and 40°C is 38,000 mPa·s or less; and preparing a cream that satisfies these conditions. The method. [5] - The ratio of viscosity at 5°C and 40°C (viscosity at 40°C / viscosity at 5°C) is 0.1 to 1. We also determine whether the conditions are met. The method described in [4] prepares a cream that also satisfies these conditions. [6] The method according to [4] or [5], wherein the cream contains higher alcohols with different alkyl chain lengths. [7] A method for determining whether a butenafine-containing cream formulation is suitable for a jar container, comprising: The viscosity of a cream obtained by mixing butenafine or its pharmaceutically acceptable salt, water, a higher alcohol, and a surfactant was measured, and the viscosity was measured under the following conditions. - Viscosity at 5°C, 25°C, and 40°C is 7,000 mPa·s to 50,000 mPa·s; and - The difference in viscosity at 5°C and 40°C is 38,000 mPa·s or less; The method further comprising determining whether [8] - The ratio of viscosity at 5°C and 40°C (viscosity at 40°C / viscosity at 5°C) is 0.1 to 1. The method described in [7] also determines whether the above conditions are met. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide a butenafine-containing cream that is suitable for use in a jar container and whose feel during use does not deteriorate regardless of temperature (season). DETAILED DESCRIPTION OF THE INVENTION

[0009] The cream of the present invention contains butenafine or a pharmaceutically acceptable salt thereof, water, a higher alcohol, and a surfactant. Butenafine or a pharmaceutically acceptable salt thereof is an antifungal agent and is the active ingredient in the cream of the present invention. Pharmaceutically acceptable salts of butenafine include butenafine hydrochloride. In this specification, creams containing butenafine or a pharmaceutically acceptable salt thereof are also collectively referred to as "butenafine-containing creams." The amount of butenafine or a pharmaceutically acceptable salt thereof can be selected as appropriate, but from the viewpoint of efficacy as an antifungal agent, it is preferably 0.1 to 10 mass% and more preferably 0.5 to 5 mass% in terms of butenafine hydrochloride based on the entire formulation (unless otherwise specified, in this specification, "mass%" means mass% based on the entire formulation).

[0010] The amount of water to be added can be selected appropriately, but from the viewpoints of stability and usability, it is preferably 60% by mass or more, more preferably 65% ​​by mass or more, and even more preferably 70% by mass or more.

[0011] The cream of the present invention can contain, as the higher alcohol, any higher alcohol commonly used in pharmaceuticals, quasi-drugs, etc. In one embodiment of the present invention, from the viewpoint of easily obtaining a cream with an appropriate viscosity, it preferably contains one or more alcohols selected from the group consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and behenyl alcohol, but it can also contain other higher alcohols, such as arachidyl alcohol, ceryl alcohol, lauryl alcohol, octyldodecanol, decyltetradecanol, myristyl alcohol, and oleyl alcohol, either alone or in combination. The amount of higher alcohol to be blended can be selected as appropriate depending on the type of higher alcohol used, the type of additional oil and its blending amount, etc., but from the viewpoint of preventing deterioration in the feeling of use depending on the temperature (season), it is preferably 4 to 15 mass%, more preferably 6 to 12 mass%, and even more preferably 7 to 10 mass%.

[0012] In one embodiment of the present invention, from the viewpoint of emulsion stability, the cream of the present invention preferably contains higher alcohols with different alkyl chain lengths. Therefore, in a preferred embodiment of the present invention, the cream of the present invention contains cetostearyl alcohol, which is a mixture containing cetyl alcohol and stearyl alcohol. In a further preferred embodiment, the cream of the present invention contains cetostearyl alcohol and behenyl alcohol, from the viewpoint of improving the texture and gloss of the cream.

[0013] The cream of the present invention can use, as a surfactant, any surfactant that is commonly used in pharmaceuticals, quasi-drugs, etc., and may be any of a nonionic surfactant, an anionic surfactant, a cationic surfactant, or an amphoteric surfactant. Examples of nonionic surfactants include sorbitan fatty acid esters such as polyoxyethylene behenyl ether, glycerin monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate, sorbitan monolaurate, and polyoxyethylene sorbitan stearate; polyoxyethylene ethers such as polyoxyethylene nonyl ether, monooxyethylene cetyl ether, and monooxyethylene lauryl ether; and other polyoxyethylene alkyl ethers. Examples of anionic surfactants include polyoxyethylene alkyl phosphate esters and sodium alkyl sulfates. Examples of cationic surfactants include benzethonium chloride and benzalkonium chloride. The amount of surfactant to be added is not particularly limited and can be appropriately selected depending on the type of surfactant used, the amount of higher alcohol added, the type and amount of additional oil added, etc., but is preferably 3 to 15 mass %, more preferably 6 to 10 mass %.

[0014] In a preferred embodiment of the present invention, the cream contains polyoxyethylene behenyl ether, and the amount of polyoxyethylene behenyl ether is not particularly limited and can be appropriately selected depending on the amount of higher alcohol, the type and amount of additional oil, etc., but is preferably 1 to 5 mass %, more preferably 2 to 4 mass %.

[0015] In a preferred embodiment of the present invention, the cream preferably contains glycerin monostearate, and in the present invention, the glycerin monostearate may be any of glycerin monostearate, self-emulsifying glycerin monostearate, and lipophilic glycerin monostearate. In one embodiment of the present invention, the glyceryl monostearate is preferably a self-emulsifying glyceryl monostearate. The amount of glycerin monostearate to be blended is not particularly limited and can be selected appropriately depending on the amount of higher alcohol blended, the type and amount of additional oil, etc., but is preferably 2 to 10 mass %, more preferably 4 to 6 mass %.

[0016] From the viewpoint of easily obtaining a cream with an appropriate viscosity, it is preferable to contain polyoxyethylene behenyl ether and glycerin monostearate. In a preferred embodiment of the present invention, the cream contains polyoxyethylene behenyl ether and glycerin monostearate, and the blending ratio of polyoxyethylene behenyl ether to glycerin monostearate is not particularly limited, but is preferably 2:1 to 1:3, more preferably 1:1 to 1:2.5, and even more preferably 1:1.5 to 1:2. In one embodiment of the present invention, it is preferable to use polyoxyethylene behenyl ether and glycerin monostearate, and these can be combined with an additional surfactant. The amount of the additional surfactant can be selected appropriately, and is preferably less than the amount of polyoxyethylene behenyl ether and glycerin monostearate, for example, 0 to 3% by mass, more preferably 0 to 2% by mass. In one embodiment of the present invention, the cream of the present invention contains only polyoxyethylene behenyl ether and glyceryl monostearate as surfactants, and does not contain any additional surfactants.

[0017] The cream of the present invention is filled in a jar container. The shape and size of the jar are not particularly limited, but the opening of the container (the opening for dispensing the contents) is preferably large enough to allow the desired amount of cream to be easily scooped with the fingers, and the inner diameter is preferably 30 to 100 mm, more preferably 30 to 60 mm. The depth of the jar is preferably 20 to 80 mm, more preferably 25 to 40 mm. The material of the jar is not particularly limited, but polypropylene is preferred from the viewpoint of drug resistance. Filling the product in a jar makes it possible to provide a product that allows the user to easily scoop up with the fingers an amount sufficient to apply to a relatively large area such as the heel, sole, etc. In the case of a tube container, the area of ​​the opening through which the cream can be squeezed out is relatively small, so the amount of cream that can be dispensed onto the fingertips at one time is limited, but the opening of a jar is sufficiently wide so that the desired amount can be dispensed at one time easily and at will.

[0018] In one embodiment of the present invention, the cream of the present invention may contain, in addition to the above-mentioned ingredients, an adjuvant, an additional oil other than higher alcohols, an aqueous ingredient, and the like. In one embodiment of the invention, the cream of the invention comprises an excipient, such as local anesthetics such as dibucaine hydrochloride, lidocaine; antihistamines such as chlorpheniramine maleate and diphenhydramine; anti-inflammatory drugs such as glycyrrhetinic acid and allantoin; antibacterial ingredients such as isopropyl methylphenol; Antipruritic agents such as l-menthol and crotamiton Examples include: In one embodiment of the present invention, from the viewpoint of suppressing various symptoms by combining synergistic drugs having different actions, the cream of the present invention contains dibucaine hydrochloride, chlorpheniramine maleate, glycyrrhetinic acid, and isopropylmethylphenol. In one embodiment of the invention, the cream of the invention does not contain l-menthol and / or crotamiton.

[0019] The amount of these adjuvants to be added can be appropriately selected as an amount sufficient to achieve the desired effect, for example, 0.01 to 5.0% by mass of dibucaine hydrochloride, 0.05 to 5.0% by mass of chlorpheniramine maleate 0.05 to 10.0% by mass of glycyrrhetinic acid 0.01 to 5.0 mass% isopropylmethylphenol Includes.

[0020] The additional oil used in the cream of the present invention is not particularly limited as long as it is a component commonly used in pharmaceuticals, quasi-drugs, etc., and examples thereof include oils such as hydrocarbon oils, ester oils, and silicone oils, which can be used alone or in combination of two or more.

[0021] Examples of hydrocarbon oils include liquid paraffin, petrolatum, paraffin wax, and squalane. The amount of hydrocarbon oil to be blended can be selected appropriately within a range that does not impair the effects of the present invention, and is preferably less than the amount of higher alcohol to be blended, for example, 0.01 to 5.0 mass%, more preferably 0.05 to 1.0 mass%. In one embodiment of the present invention, squalane is preferred from the viewpoint of moisturizing effect.

[0022] Examples of ester oils include esters of higher fatty acids such as 2-ethylhexanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid, caprylic acid, and capric acid with alcohols having 1 to 18 carbon atoms. From the viewpoint of also functioning as a transdermal absorption enhancer, cetyl 2-ethylhexanoate, isopropyl myristate, isopropyl palmitate, and the like are preferred. The amount of ester oil to be blended can be appropriately selected within a range that does not impair the effects of the present invention, and is preferably less than the amount of higher alcohol to be blended, for example, 1 to 10% by mass, more preferably 3 to 5% by mass.

[0023] Examples of silicone oils include dimethylpolysiloxane and methylphenylpolysiloxane. The amount of silicone oil to be blended can be selected appropriately as long as it does not impair the effects of the present invention, and is preferably less than the amount of higher alcohol to be blended, for example, 0.1 to 5 mass %, more preferably 0.1 to 2 mass %.

[0024] In one aspect of the present invention, it is preferable that the amount of higher alcohol blended in the cream of the present invention is greater than the amount of additional oily agent blended, and in a more particular aspect, it is preferable that the amount of oily agent blended other than the higher alcohol selected from the group consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and behenyl alcohol is less than the amount of these higher alcohols blended in.

[0025] The cream of the present invention may also contain an aqueous component such as a polyhydric alcohol. Examples of polyhydric alcohols include glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, dipropylene glycol, polyethylene glycol, and polypropylene glycol.

[0026] The cream of the present invention may further contain additives such as antioxidants, antiseptics, preservatives, moisturizers, chelating agents, gelling agents, fragrances, and other additives that are usually incorporated into creams for external use on the skin. In one embodiment of the present invention, the cream of the present invention is applied to areas such as the heels and soles that have become dry due to athlete's foot, and therefore preferably contains a moisturizing agent such as sodium hyaluronate. In one embodiment of the present invention, the cream of the present invention does not contain a gelling agent from the viewpoint of usability.

[0027] The cream of the present invention has a viscosity of 7,000 mPa·s to 50,000 mPa·s at 5°C to 40°C. If the viscosity is 7,000 mPa·s or less, the cream is likely to drip when scooped with fingers. On the other hand, if the viscosity is 50,000 mPa·s or more, the cream is too hard to scoop with fingers and is therefore difficult to use as a cream for a jar container. Furthermore, by setting the viscosity to 7,000 mPa·s to 50,000 mPa·s, it is possible to produce a cream that is suitable for application with the fingers to a wide area such as the heels and soles of the feet, and is particularly suitable for application with the fingers to areas such as the heels and soles that have become dry due to athlete's foot.

[0028] In one embodiment of the present invention, from the viewpoint of preventing dripping of the cream when scooped with fingers from the jar, the viscosity of the cream of the present invention at 5°C to 40°C is 7,000 mPa·s or more, preferably 9,000 mPa·s or more, more preferably 11,000 mPa·s or more, even more preferably 12,000 mPa·s or more, and still more preferably 14,000 mPa·s or more.

[0029] In one embodiment of the present invention, the viscosity of the cream of the present invention at 5°C is 7,000 mPa·s or more, preferably 15,000 mPa·s or more, more preferably 25,000 mPa·s or more, even more preferably 30,000 mPa·s or more, and still more preferably 32,000 mPa·s or more. In one embodiment of the present invention, the viscosity of the cream of the present invention at 25°C is 7,000 mPa·s or more, preferably 10,000 mPa·s or more, more preferably 15,000 mPa·s or more, even more preferably 20,000 mPa·s or more, and still more preferably 21,000 mPa·s or more. In one embodiment of the present invention, the viscosity of the cream of the present invention at 40°C is 7,000 mPa·s or more, preferably 8,000 mPa·s or more, more preferably 9,000 mPa·s or more, even more preferably 10,000 mPa·s or more, and still more preferably 14,000 mPa·s or more.

[0030] In one embodiment of the present invention, from the viewpoint of making it easy to scoop the cream from the jar with fingers, the viscosity of the cream of the present invention at 5°C to 40°C is 50,000 mPa·s or less, preferably 47,000 mPa·s or less, more preferably 44,000 mPa·s or less, even more preferably 41,000 mPa·s or less, and still more preferably 39,000 mPa·s or less.

[0031] In one embodiment of the present invention, the viscosity of the cream of the present invention at 5°C is 50,000 mPa·s or less, preferably 48,000 mPa·s or less, more preferably 46,000 mPa·s or less, even more preferably 44,000 mPa·s or less, and still more preferably 39,000 mPa·s or less. In one embodiment of the present invention, the viscosity of the cream of the present invention at 25°C is 50,000 mPa·s or less, preferably 44,000 mPa·s or less, more preferably 38,000 mPa·s or less, even more preferably 32,000 mPa·s or less, and still more preferably 26,000 mPa·s or less. In one embodiment of the present invention, the viscosity of the cream of the present invention at 40°C is 50,000 mPa·s or less, preferably 30,000 mPa·s or less, more preferably 25,000 mPa·s or less, even more preferably 20,000 mPa·s or less, and still more preferably 17,000 mPa·s or less.

[0032] The viscosity of the cream of the present invention at 5°C to 40°C is preferably 9,000 to 47,000 mPa·s, more preferably 11,000 to 44,000 mPa·s, even more preferably 12,000 to 41,000 mPa·s, and particularly preferably 14,000 to 39,000 mPa·s. The difference in viscosity of the cream of the present invention at 5°C and 40°C is 38,000 mPa·s or less, preferably 35,000 mPa·s or less, more preferably 33,000 mPa·s or less, even more preferably 29,000 mPa·s or less, and still more preferably 23,000 mPa·s or less. In one embodiment of the present invention, the cream of the present invention has a viscosity ratio at 5°C and 40°C (viscosity at 40°C / viscosity at 5°C) of preferably 0.1 to 1, more preferably 0.15 to 1, even more preferably 0.2 to 1, and still more preferably 0.4 to 1.

[0033] The cream of the present invention can be produced by mixing and emulsifying the components according to a conventional method. The viscosity of the obtained cream is measured and it is determined whether it satisfies the following conditions, thereby providing a butenafine-containing cream suitable for jar containers. - The difference in viscosity at 5°C and 40°C is not more than 38,000 mPa·s; and - Viscosity at 5°C, 25°C and 40°C is 7,000mPa·s to 50,000mPa·s. The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples and various modifications are possible within the scope of the technical concept of the present invention. In this specification, % means % by mass unless otherwise specified. [Example]

[0034] [Test Example 1] [Table 1]

[0035] [Table 2]

[0036] * Other ingredients include oils (dimethylpolysiloxane, squalane, isopropyl myristate, cetyl 2-ethylhexanoate), propylene glycol, sodium hyaluronate, diethanolamine, dibutylhydroxytoluene (BHT), and methylparaben, each of which is blended in equal amounts in each comparative example and example.

[0037] 1. Cream manufacturing method Each component was weighed out, mixed and emulsified according to the compositions in Tables 1 and 2 above, and the mixture was filled into a jar to produce a cream.

[0038] 2. Viscosity measurement After preparing the creams, the viscosity of each cream was measured under the following conditions. <Measurement conditions> Device name: BROOKFIELD VISCOMETER (manufactured by Brookfield, USA) Model: RVDV2T Spindle / chamber: SC4-14 / SC4-6R(P) Spindle speed: 10 rpm Measurement time: 330 seconds Measurement temperature: 5℃, 25℃ or 40℃

[0039] 3. Evaluation and Judgment Good: Viscosity at 5°C to 40°C is 7,000 mPa·s to 50,000 mPa·s, and the difference in viscosity between 5°C and 40°C is 38,000 mPa·s or less. ×: If the viscosity is outside the above range at any of the temperatures of 5°C, 25°C, and 40°C, and / or if the difference in viscosity between 5°C and 40°C is 38,000 mPa s or more.

[0040] 4. Discussion The creams of Comparative Examples 1 to 5 had low viscosities at any of the temperatures from 5 to 40°C, and were therefore unsuitable as creams for jar containers. For example, Comparative Example 4 had good viscosity at 25°C and 5°C, but its viscosity dropped drastically at 40°C, making it highly likely that dripping would occur when the cream is used, particularly in summer, and therefore it cannot be used as a cream for jar containers.

[0041] The cream of Example 1 (cetyl alcohol) had a viscosity of 7,000 mPa·s to 50,000 mPa·s at 5°C to 40°C, and it was confirmed that the viscosity change due to temperature was small, and the values ​​were suitable for jar containers. The creams of Examples 2 and 3 (cetostearyl alcohol) had viscosities of 7,000 mPa·s to 50,000 mPa·s at temperatures between 5°C and 40°C, and it was confirmed that the viscosity change due to temperature was particularly small, showing values ​​suitable for jar containers. The creams of Examples 4 and 5 (behenyl alcohol) had a viscosity of 7,000 mPa·s to 50,000 mPa·s at 5°C to 40°C, which was confirmed to be a value suitable for jar containers. [Industrial Applicability]

[0042] The cream of the present invention does not lose its feel when used regardless of the temperature (season), can be used in a jar container, and can provide a butenafine-containing cream product filled in a jar container.

Claims

1. A cream comprising butenafine or a pharmaceutically acceptable salt thereof, water, a higher alcohol, and a surfactant, The cream is in a jar container, The viscosity at 5°C to 40°C is 7,000 mPa s to 50,000 mPa s, The difference in viscosity at 5°C and 40°C is 38,000 mPa s or less. The cream.

2. 2. The cream according to claim 1, wherein the ratio of viscosities at 5°C and 40°C (viscosity at 40°C / viscosity at 5°C) is 0.1 to 1.

3. 3. A cream according to claim 1 or 2, comprising higher alcohols of different alkyl chain lengths.

4. 1. A method for producing a butenafine-containing cream for a jar, comprising: The viscosity of a cream obtained by mixing butenafine or a pharmaceutically acceptable salt thereof, water, a higher alcohol, and a surfactant is measured, and it is determined whether the following conditions are met: - a viscosity at 5°C, 25°C and 40°C of 7,000 mPa·s to 50,000 mPa·s; and - the difference in viscosity at 5 ° C and 40 ° C is less than or equal to 38,000 mPa s; and preparing a cream that satisfies these conditions. The method.

5. - The ratio of viscosity at 5°C and 40°C (viscosity at 40°C / viscosity at 5°C) is 0.1 to 1. We also determine whether the conditions are met. The method according to claim 4, wherein a cream is prepared that also satisfies these conditions.

6. 6. The method of claim 4 or 5, wherein the cream comprises higher alcohols of different alkyl chain lengths.

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