JP7638310B2 - Butenafine-containing cream in a jar - Google Patents

Description

The present invention relates to a butenafine-containing cream for use in a jar.

Skin preparations containing butenafine hydrochloride, a drug used to treat athlete's foot, are already available in various dosage forms and are widely used in clinical settings and at home.
Skin external preparations are available in the form of cream, ointment, gel, lotion, spray, patch, etc., among which cream is known to be a dosage form with excellent skin permeability and usability. For example, Patent Document 1 describes a cream containing butenafine hydrochloride that has improved keratin retention and enhanced therapeutic effect by incorporating an adjuvant.
On the other hand, 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, so that a desired amount of cream can be easily scooped with fingers and can be easily applied to a desired area. However, tube containers have usually been used for creams containing butenafine hydrochloride, and jar containers have not been used.

JP 2005-239679 A

The present inventors have investigated a butenafine-containing cream for use in a jar container and have found that changes in viscosity due to temperature can be problematic, whereas such changes were not a problem with creams filled in tube containers. More specifically, the inventors have found that the viscosity changes with temperature, and depending on the season (e.g., summer or winter), the cream filled in a jar container can be difficult to scoop with fingers and applied, which can reduce the usability.
Therefore, an object of the present invention is to provide a butenafine-containing cream preparation suitable for use in a jar container, the feel of which does not decrease depending on the temperature (season).

While conducting intensive research to solve the above problems, the inventors discovered that by combining a specific higher alcohol and a specific surfactant, it is possible to provide a butenafine-containing cream suitable for use in a jar container, with a texture that does not deteriorate regardless of temperature (season). As a result of further research, they have completed the present invention.

That is, the present invention relates to the following [1] to [6].
[1] A cream comprising butenafine or a pharma- ceutically acceptable salt thereof, water, a higher alcohol, and a surfactant,
The cream is in a jar container,
The higher alcohol includes at least one selected from cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and behenyl alcohol;
The surfactant comprises polyoxyethylene (POE) behenyl ether and glyceryl monostearate;
The cream.

[2] The cream according to [1], having a viscosity of 7,000 mPa·s to 50,000 mPa·s at 5°C to 40°C.
[3] The cream according to [1] or [2], which contains 4 to 15% by mass of a higher alcohol.
[4] The cream according to any one of [1] to [3], which contains higher alcohols having different alkyl chain lengths.
[5] A jar filled with the cream according to any one of [1] to [4].
[6] The cream according to any one of [1] to [4], which is filled in a jar container.

The present invention provides a butenafine-containing cream that is suitable for use in a jar container and does not lose its feel even when exposed to temperature (season).

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

The amount of water to be added can be selected as appropriate, but from the standpoint of stability and usability, it is preferably 60% by weight or more, more preferably 65% by weight or more, and even more preferably 70% by weight or more.

The cream of the present invention contains, as the higher alcohol, one or more types selected from the group consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol and behenyl alcohol.
The blending amount of the higher alcohol can be appropriately selected depending on the type of higher alcohol used, the types of other oils and their blending amounts, 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%, even more preferably 7 to 10 mass%, and in a specific embodiment, it is preferably 4 to 10 mass%, more preferably 5 to 10 mass%.

In one embodiment of the present invention, from the viewpoint of emulsion stability, the cream of the present invention preferably contains higher alcohols having 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, from the viewpoint of improving the texture and luster of the cream, the cream of the present invention contains cetostearyl alcohol and behenyl alcohol.

The cream of the present invention contains polyoxyethylene (POE) behenyl ether and glycerin monostearate as surfactants. By combining polyoxyethylene behenyl ether and glycerin monostearate, it is possible to provide a cream that does not deteriorate in feel even with temperature (season) and is suitable for use in a jar container.
The polyoxyethylene behenyl ether preferably has an average added mole number of oxyethylene units of 5 to 30, more preferably 10 to 30, even more preferably 10 to 25, and even more preferably 10 to 20.
The blending amount of polyoxyethylene behenyl ether is not particularly limited and can be appropriately selected depending on the blending amount of higher alcohol, the types and blending amounts of other oils, etc., but is preferably 1 to 5 mass %, more preferably 2 to 4 mass %.

In the present invention, glyceryl monostearate may be any of glyceryl monostearate, self-emulsifying glyceryl monostearate, and lipophilic glyceryl monostearate.
In one embodiment of the present invention, the glyceryl monostearate is preferably a self-emulsifying glyceryl monostearate.
The amount of glycerin monostearate blended is not particularly limited and can be appropriately selected depending on the amount of higher alcohol blended, the types and amounts of other oils blended, etc., but is preferably 2 to 10 mass %, more preferably 4 to 6 mass %.
The blending ratio of polyoxyethylene behenyl ether: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.

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 taking out the contents) is preferably large enough to easily scoop up a desired amount of cream with fingers, and the inside diameter is preferably 30 mm to 100 mm, more preferably 30 mm 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 is preferably polypropylene (PP) from the viewpoint of drug resistance.
Filling the cream in a jar container makes it possible to provide a product that allows the user to easily scoop up with the fingers an adequate amount to apply to relatively large areas such as the heel, sole, etc. In the case of a tube container, the area of the opening through which the cream can be pushed out is relatively narrow, so the amount of cream that can be dispensed onto the fingertips at one time is limited, but the opening of a jar container is sufficiently wide so that the desired amount can be easily dispensed at one time.

In one embodiment of the present invention, the cream of the present invention may contain, in addition to the above-mentioned components, an adjuvant, an additional oil, an additional surfactant, an aqueous component, and the like.
In one embodiment of the invention, the cream of the invention comprises an excipient, for example:
Local anesthetics such as dibucaine hydrochloride, lidocaine;
Antihistamines such as chlorpheniramine maleate, diphenhydramine;
Anti-inflammatory drugs such as glycyrrhetinic acid and allantoin;
antibacterial ingredients such as isopropyl methylphenol;
Antipruritic agents such as 1-menthol and crotamiton.
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.

The amount of these additives to be added can be appropriately selected so as to provide a desired effect. For example,
0.01 to 5.0% by weight of dibucaine hydrochloride,
It contains 0.05 to 5.0% by mass of chlorpheniramine maleate, 0.05 to 10.0% by mass of glycyrrhetinic acid, and 0.01 to 5.0% by mass of isopropyl methylphenol.

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., but examples include oils such as higher alcohols other than cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and behenyl alcohol; hydrocarbon oils; ester oils; and silicone oils, which can be used alone or in combination of two or more kinds.

Examples of higher alcohols other than cetostearyl alcohol, cetyl alcohol, stearyl alcohol and behenyl alcohol include arachidyl alcohol and ceryl alcohol.
Examples of the hydrocarbon oil include liquid paraffin, petrolatum, paraffin wax, and squalane.
The blending amount of the hydrocarbon oil can be appropriately selected within a range that does not impair the effects of the present invention, and is preferably less than the blending amount of the higher alcohol, 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.

Examples of the ester oil 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 functioning as a percutaneous absorption enhancer, preferred are cetyl 2-ethylhexanoate, isopropyl myristate, isopropyl palmitate, and the like.
The blending amount of the ester oil can be appropriately selected within a range that does not impair the effects of the present invention, and is preferably less than the blending amount of the higher alcohol, for example, 1 to 10 mass %, more preferably 3 to 5 mass %.

Examples of silicone oils include dimethylpolysiloxane and methylphenylpolysiloxane.
The amount of silicone 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, 0.1 to 5 mass %, more preferably 0.1 to 2 mass %.

In one aspect of the present invention, it is preferable that the amount of oils other than higher alcohols selected from the group consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and behenyl alcohol is less than the amount of higher alcohols selected from the group consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and behenyl alcohol in the cream of the present invention.

When an additional surfactant is used in the cream of the present invention, there are no particular limitations as long as it is an ingredient that is commonly used in pharmaceuticals, quasi-drugs, etc., and the surfactant may be any of a nonionic surfactant other than polyoxyethylene behenyl ether and glycerol monostearate; an anionic surfactant; a cationic surfactant; and an amphoteric surfactant.
Examples of the anionic surfactant include polyoxyethylene alkyl phosphate ester and sodium alkyl sulfate.
Examples of nonionic surfactants include sorbitan fatty acid esters such as 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 cationic surfactants include benzethonium chloride and benzalkonium chloride.

The amount of the additional surfactant blended can be appropriately selected within a range that does not impair the effects of the present invention, and is preferably less than the amounts of polyoxyethylene behenyl ether and glycerin monostearate blended, for example, 0 to 3 mass %, more preferably 0 to 2 mass %.
In one embodiment of the invention, the cream of the invention does not contain any additional surfactants.

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.

The cream of the present invention may further contain additives such as antioxidants, preservatives, 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, since the cream of the present invention is applied to areas such as the heels and soles of the feet that have become dry due to athlete's foot, it 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.

In one embodiment of the present invention, 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 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, a cream having a texture suitable for application with fingers to wide areas such as the heels and soles of the feet can be obtained, and the texture is particularly suitable for application with fingers to areas such as the heels and soles of the feet that have become dry due to athlete's foot.

In one aspect of the present invention, from the viewpoint of preventing dripping when the cream is scooped with fingers from the jar container, 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 even more preferably 14,000 mPa·s or more.

In one embodiment of the present invention, the cream of the present invention has a viscosity at 5°C of 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 cream of the present invention has a viscosity at 25°C of 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 cream of the present invention has a viscosity at 40°C of 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.

In one aspect of the present invention, from the viewpoint of making it easy to scoop the cream with fingers from the jar container, the cream of the present invention has a viscosity at 5°C to 40°C of 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 even more preferably 39,000 mPa·s or less.

In one embodiment of the present invention, the cream of the present invention has a viscosity at 5°C of 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 cream of the present invention has a viscosity at 25°C of 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 cream of the present invention has a viscosity at 40°C of 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.

In one embodiment of the present invention, the difference in viscosity of the cream of the present invention at 5°C and 40°C is preferably 38,000 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.

The cream of the present invention can be produced by mixing and emulsifying the respective components according to a conventional method.
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 mass % unless otherwise specified.

[Test Example 1]

^* 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.

1. Method for Producing Creams According to the compositions in Tables 1 and 2 above, the components were weighed, mixed, emulsified, and filled into a jar to produce an O/W type cream.

2. Viscosity Measurement After producing 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°C, 25°C or 40°C

3. Evaluation and judgment ◯: Viscosity at 5°C to 40°C is 7,000 mPa·s to 50,000 mPa·s ×: Viscosity at any of the temperatures 5°C, 25°C, and 40°C is outside the above range

4. Discussion It was confirmed that the creams of Comparative Examples 1 to 5 had low viscosities at any of the temperatures from 5 to 40° C., and were unsuitable as creams for use in jar containers. For example, Comparative Example 4 had good viscosities at 25° C. and 5° C., but the viscosity at 40° C. was extremely low, and when this cream is used in summer in particular, there is a high possibility of dripping, and it cannot be used as a cream for use in a jar container.

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 showed values suitable for jar containers.
The creams of Examples 2 and 3 (cetostearyl 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 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 suitable for use in jar containers.

[Test Example 2]
The effect of surfactants was examined.

In the same manner as in Test Example 1, a cream was produced, its viscosity was measured, and it was evaluated.
From the results of Comparative Examples 6 and 7, it was confirmed that when only one of polyoxyethylene behenyl ether and self-emulsifying glycerin monostearate was contained as a surfactant, the composition separated and was unsuitable as a cream, or even if separation did not occur, the viscosity at 5 to 40°C did not fall within the range of 7,000 to 50,000 mPa·s, and the composition was unsuitable as a cream for use in a jar container.
From the results of Comparative Examples 8 and 9, it was confirmed that when a surfactant other than polyoxyethylene behenyl ether was combined with self-emulsifying glycerin monostearate as a surfactant, separation occurred and the composition was unsuitable as a cream, or even if separation did not occur, the viscosity at 5 to 40°C did not fall within the range of 7,000 to 50,000 mPa·s and the composition was unsuitable as a cream for use in a jar container.

[Test Example 3]
The effect of the content of higher alcohol was examined.

In the same manner as in Test Example 1, a cream was produced, its viscosity was measured, and it was evaluated.
It was confirmed that even when the blended amount of higher alcohol was relatively small, a cream having a viscosity in the range of 7,000 to 50,000 mPa·s at 5 to 40° C. could be obtained.

[Test Example 4]
The effect of surfactant content was investigated.

In the same manner as in Test Example 1, a cream was produced, its viscosity was measured, and it was evaluated.
From the results of Examples 8 to 10, it was confirmed that a cream having a viscosity in the range of 7,000 to 50,000 mPa·s at 5 to 40° C. can be obtained by using a wide range of blending amounts of polyoxyethylene behenyl ether and self-emulsifying glycerin monostearate.

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

Claims (6)

A cream comprising butenafine or a pharma- ceutically acceptable salt thereof, water, a higher alcohol, and a surfactant,
The cream is in a jar container,
The higher alcohol includes at least one selected from cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and behenyl alcohol;
The surfactant comprises polyoxyethylene behenyl ether and glyceryl monostearate.
The cream. The cream according to claim 1, which has a viscosity of 7,000 mPa·s to 50,000 mPa·s at 5°C to 40°C. The cream according to claim 1, which contains 4 to 15% by mass of higher alcohol. The cream according to claim 1, which contains higher alcohols of different alkyl chain lengths. A jar filled with the cream according to claims 1 to 4. The cream according to claims 1 to 4, packed in a jar container.