JPH0840899A - Aerosol of oxyconazone nitrate - Google Patents

Abstract

PURPOSE:To provide an aerosol of oxyconazole nitrate as an imidazole-based antifungal agent. CONSTITUTION:This antifungal aerosol is prepared by blending 10 to 60wt.% aerosol stock solution composed of 0.3 to 3.0wt.% oxyconazole nitrate, 40 to 90wt.% water and/or lower alcohol, 1 to 10wt.% crotamiton, 0.5 to 10.0wt.% surfactant and 1 to 10wt.% powder with 40 to 90wt.% propellant. In this antifungal aerosol, oxyconazole is physicochemically stable and the propelling force is kept constant with passage of time. In addition, it is excellent in long- acting cooling effect on the skin.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an aerosol preparation comprising oxyconazole nitrate, which is an imidazole antifungal drug.

More specifically, the present invention relates to an antifungal aerosol agent in which oxyconazole nitrate is physicochemically stable when used as an aerosol agent, can be expected to have a constant jetting state over time, and can maintain skin cooling ability.

[0003]

2. Description of the Related Art Chemotherapy for superficial mycoses caused by fungi is currently the mainstream of imidazole antifungal external preparations.

Conventionally, these drugs have been generally used as ointments, but in recent years, they have also been described as gel ointments in JP-B-5-25856.

However, with these dosage forms, it is necessary to apply them to the affected area by hand, etc., which is troublesome in use and is not preferable in terms of hygiene. Further, as a dosage form to be directly applied to the affected area, a liquid preparation for external use and a pump type thereof are also used, but in this case, since the liquid tends to drip when applied, it is efficient and unnecessary to the affected area. There are problems that it is difficult to apply it without affecting the parts, and it is difficult to handle.

Therefore, by using an aerosol as the dosage form, these problems are solved and handling becomes convenient.

Moreover, in the case of an aerosol agent, a propellant such as LPG or dimethyl ether is used to cool the affected area,
Since it is possible to relieve itching even temporarily, it is an effective dosage form for treating athlete's foot.

For example, as one of general aerosol prescriptions, "Latest Cosmetic Science-Revised Supplement 2-" (published on July 10, 1992, Yakuji Daily Inc.), 124-126.
The page shows an example of prescription for an aerosol hair styling agent and the like, which is applied to a spray-type hair conditioner and the like.

Further, an aerosol agent which forms a sherbet-like foam powder gel at the time of spraying is disclosed in Japanese Patent Application Laid-Open No. 4-103526, in order to have a strong and continuous cooling property of the skin, and an imidazole antifungal agent is disclosed. Has been applied to. In addition, Japanese Patent Application Laid-Open No. 2-255889 discloses an aerosol composition which forms a foam which, when jetted, crackles and cracks to enhance the psychological effect.

However, it has a moderately controlled cooling property,
Aerosols consisting of oxyconazole nitrate, which is an antifungal drug, are not yet known.

[0011]

Regarding the aerosol agent of oxyconazole nitrate, Formulation Example C-1 is applied among the formulation examples of the above-mentioned atomized jet type hair conditioner, and ethanol and Macrogol 400 are used as the solvent of the stock solution part. Select (Listed in the 12th Pharmacopoeia of Japan, abbreviated as PEG400 below),
When used as an aerosol agent, the oxyconazole nitrate aerosol agent has the drawback of poor adhesion and dripping,
This method cannot provide the target aerosol agent.

Further, the method of JP-A-4-103526 is characterized in that the water in the aerosol concentrate is frozen on the surface of the skin in a sherbet form, so that the coated surface becomes extremely cold and is continuously maintained. To be done. However, it has the drawback of causing frost and causing intense pain for a long time. When treating with drugs, it is important to apply the antifungal agent continuously to the affected area for a long period of time, and thus this method cannot be applied in winter.

In addition, when the application of the method of JP-A-2-255889 was attempted, the emulsion stability between the aerosol solution stock solution and the propellant was poor, and a constant spraying state could not always be obtained. Further, when sprayed, a foamy foam was formed, the cooling sensation showing cooling properties was lost, and at the same time contact with the affected area was hindered, and the drug effect as an antifungal agent could not be expected sufficiently.

The object of the present invention is to solve the above disadvantages of the prior art and to provide an aerosol formulation of oxyconazole nitrate, which is an antifungal agent having a proper and continuous cooling property when spray-applied. Especially.

The inventors of the present invention have conducted intensive studies in the aerosolization of oxyconazole nitrate by adding crotamiton to a stock solution of an aerosol agent and emulsifying or dissolving water and / or a lower alcohol with a surfactant. , Stabilized oxyconazole nitrate in an emulsified or dissolved state, and achieved the above object.

[0016]

According to the present invention, 0.3 to 3.0% by weight of oxyconazole nitrate, 40 to 90% by weight of water and / or lower alcohol, 1 to 10% by weight of crotamiton, and 0 surfactant. 0.5-10.0% by weight, powder 1-10
The present invention relates to an aerosol agent of oxyconazole nitrate, which comprises 10 to 60% by weight of an undiluted solution of an aerosol and 40 to 90% by weight of a propellant.

More specifically, the compounding amount of oxyconazole nitrate is 0.3 to 3.0% by weight, preferably 0.5 to 3.0% by weight, in which the antifungal effect in the aerosol concentrate is sufficiently exhibited. Is about 2.0% by weight.

If the content of the antifungal aerosol is less than 0.3% by weight, a sufficient antifungal effect is not exhibited,
On the other hand, when it exceeds 3.0% by weight, oxyconazole nitrate is not stably dispersed in the container, and the spray coating cannot always be performed in a constant state.

The solvent in the aerosol concentrate is water,
Lower alcohols or a mixture of water and lower alcohols are used. Of this, the weight ratio of water to lower alcohol is 3
The range of 2: 1 to 2: 3 is preferable, and 19: 1 to
The range of 7: 3 is most preferable.

The lower alcohol is an alcohol having 1 to 4 carbon atoms, preferably ethanol or isopropanol, and denatured alcohol can also be used. As water, purified water is usually used.

The blending ratio of the solvent is 40 to 90% by weight, preferably 60 to 80% by weight in the aerosol concentrate. When the proportion of the solvent in the aerosol is less than 40% by weight, cooling does not continue, and
This is because if it exceeds 90% by weight, the emulsification with the propellant becomes unstable and liquid drops easily occur when spray coating.

As the surface active agent, a nonionic surface active agent and an anionic surface active agent are used. Of these, nonionic surfactants are suitable from the viewpoints of reaction stability with active ingredients, solvents or propellants, low irritation to the skin, and corrosiveness with metal containers for aerosols.

As the nonionic surfactant, sorbitan fatty acid ester, glycerin fatty acid ester, decaglycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene castor oil derivative and hydrogenated castor Oil, ester surfactants such as polyoxyethylene glycerin sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester or polyoxyethylene alkyl ether,
Polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkyl phenyl ether,
Examples include ether-based surfactants such as single chain length polyoxyethylene alkyl ether, polyoxyethylene secondary alcohol ether, polyoxyethylene sterol ether, and polyoxyethylene lanolin derivative.

Among the nonionic surfactants, polyoxyethylene castor oil and hydrogenated castor oil, which have the highest skin safety, are suitable.

Polyoxyethylene alkyl ether phosphates can also be used in the anionic surfactant.

These surfactants are blended in one kind or in a combination of two or more kinds according to the emulsification conditions, and the blending amount thereof is 0.5 to 10.0% by weight, preferably 1.0% in the aerosol concentrate. Is about 6.0% by weight.

When the proportion of the surfactant in the aerosol concentrate is less than 0.5% by weight, the antifungal agent, the additive, the surfactant, water and the propellant, which are essential components, are uniformly dispersed. Therefore, strong shaking or shaking for a long time is required, and if it exceeds 10.0% by weight, the surfactant remains on the skin forever and the usability is deteriorated.

Crotamiton stabilizes the emulsified dispersion of oxyconazole nitrate in the aerosol agent in the aerosol container and can always obtain a constant sprayed state without precipitating drug crystals even after long-term storage. It is an effective component for producing a transparent jetting state without forming a foamy foam.

The content of crotamiton is 1 to 10% by weight, preferably 3 to 10% by weight in the aerosol concentrate.
The mixing ratio of crotamiton in the aerosol is 1
When it is less than wt%, it forms a foamy foam and also
This is because if it exceeds 0% by weight, it will remain on the skin surface and the usability will be poor.

The addition of the powder improves the emulsion stability of the aerosol concentrate and the propellant in the aerosol container.

The powder is insoluble in water, for example, talc, zinc white, anhydrous silicic acid, magnesium silicate, nylon powder, silicon powder, magnesium oxide, titanium oxide, light (precipitated) magnesium carbonate,
Heavy magnesium carbonate, yellow iron oxide, red iron oxide, mica,
Mica titanium, bismuth oxychloride, zirconium oxide,
Chromium hydroxide, calamine, polyethylene powder, polystyrene powder, acrylic resin powder, cellulose powder, hybrid fine powder of inorganic pigment such as titanium oxide and organic polymer powder such as nylon 12, and the like can be mentioned. They may be used alone or in combination of two or more.

The blending amount of these is 1 to 1 in the stock solution of the aerosol agent.
10% by weight, preferably 3 to 8% by weight, and when the proportion of the powder in the aerosol concentrate is less than 1% by weight,
This is because the effect of stabilizing the emulsion of the aerosol solution stock solution and the propellant is small, and when it exceeds 10% by weight, caking occurs in the aerosol, which may cause clogging of the valve.

The powder has a particle diameter of 100 μm or less, preferably 20 to 50 μm.

If the particle size exceeds 100 μm, the injection port of the aerosol container may be clogged.

As the propellant, dimethyl ether having a large cooling effect, liquefied petroleum gas or a mixture thereof can be used.

A compressed gas such as carbon dioxide gas or nitrogen gas may be appropriately mixed. This is for pressure adjustment.

The compounding amount of the propellant with respect to the total amount of the aerosol agent is 40 to 90% by weight, preferably 60 to 80% by weight. 40% by weight in the aerosol formulation
This is because if the amount is less than the above range, dripping is likely to occur, and if it exceeds 90% by weight, the emulsified state of the contents is impaired and the desired injection state cannot be obtained.

Therefore, the amount of the undiluted solution of the aerosol in the aerosol is 10 to 60% by weight.

The aerosol concentrate of the present invention may contain a solubilizing agent (polyethylene glycol, propylene glycol, 1,3-butylene glycol, glycerin, isopropyl myristate, cetyl octanoate, liquid paraffin, squalane, etc.), if necessary. Emulsifying aids (cetanol, stearyl alcohol, etc.), preservatives (methylparaben, ethylparaben, propylparaben, etc.), antioxidants (dibutylhydroxytoluene, dl-α-tocopherol, etc.), pH adjusters (sodium hydroxide, citric acid) Etc.), fragrances and the like.

In the present invention, antifungal drugs other than oxyconazole nitrate, such as undecylenic acid, zinc undecylenate, phenyl-11-iodo-10-undecinoate, exalamide, constazole, decanium salicylate, diethyldithiocarbamic acid. zinc,
Ciclopirox olamine, siccanine, tricomycin, pyrrolenitrin, thiantol, 2,4,6-tribromophenylcaproic acid ester, trimethylcetylammonium pentachlorophenate, tolcyclate, torunaphthalate, paropudine, salicylic acid, sodium salicylate, phenyl salicylate, These may be used alone or in combination of two or more.

Further, as a pharmaceutically active ingredient other than the antifungal agent, for example, a bactericidal antiseptic agent, an antihistamine agent, a local anesthetic agent, an antipruritic agent, an antiphlogistic / protective agent, a cooling agent, a keratolytic agent, and an astringent agent can be used. It may be added in addition to the imidazole antifungal drug.

In the aerosol agent of the present invention, components other than the propellant are warmed, mixed and stirred to prepare an emulsified or dissolved aerosol concentrate, which is then filled in an aerosol container together with the propellant. It can be manufactured by

[0043]

EXAMPLES The present invention will be described more specifically by showing examples and test examples below.

However, the present invention is not limited to these examples.

Example 1 1 g of oxyconazole nitrate (hereinafter abbreviated as OCZ) and 20 g of PEG400 were mixed and dissolved by heating at 60 °.

Next, 3 g of polyoxyethylene (60) hydrogenated castor oil (hereinafter abbreviated as HCO60), 5 g of crotamiton, 10 g of ethanol, 58 g of water and 3 g of talc.
Was added to emulsify to give an aerosol stock solution.

After filling 10 g of this liquid into a pressure-resistant transparent container for aerosol, liquefied petroleum gas (hereinafter abbreviated as LPG) 3
0 g was injected under pressure to obtain an OCZ aerosol agent.

The LPG used was one compatible with the liquefied petroleum gas listed in the second edition of the standard for cosmetic raw materials.

Similarly, OCZ aerosols were obtained with the components and component amounts shown in Table 1 for Examples 2 to 8.

Also, isopropyl myristate was added to IPM
And the propellant dimethyl ether is abbreviated as DME.

[0051]

[Table 1]

Comparative Example 1 An aerosol agent of OCZ produced by removing crotamiton from the undiluted solution of the aerosol agent of Example 1 (Comparative Example 2) The liquid paraffin was used instead of the crotamiton used in the undiluted solution of the aerosol agent of Example 1. Produced aerosol of OCZ (Comparative Example 3) Aerosol of OCZ produced by replacing the crotamiton used in the undiluted solution of the aerosol of Example 1 with IPM. An aerosol was obtained.

[0053]

[Table 2]

Reference Example A commercially available sherbet-like aerosol for treating athlete's foot (trade name: Damarin IC (manufactured by Taisho Pharmaceutical Co., Ltd.)) was used.

(Test Example 1) Examples 1 to 8 and Comparative Examples 1 to 1
The following tests were conducted for No. 6, and the results are shown in Table-3.

(1) Presence / absence of crystal precipitation Presence / absence of crystal precipitation in each sample was visually observed immediately after production, after storage for 1 month in the refrigerator (about 4 °) and after storage for 6 months at room temperature (12-28 °). Was observed.

In order to avoid misidentifying OCZ crystals as talc used as a powder in the preparation, the presence or absence of dendritic, cubic or acicular crystals was observed after shaking well.

Criteria-: No OCZ crystal precipitation +: OCZ crystal precipitation In Comparative Example 2 and Comparative Example 3, crystal precipitation was observed immediately after production, so the following items were omitted.

(2) Dispersibility The dispersibility of the aerosol concentrate and the propellant in the transparent pressure-resistant container of each sample was observed immediately after production and after 6 months of storage at room temperature.

The method was as follows. Each sample was observed by shaking the sample with a width of about 20 cm five times by hand, and evaluated according to the following criteria.

Judgment Criteria ◯: Emulsion was formed and uniformly dispersed or became a clear liquid x: Separated into two phases and not uniformly dispersed −: Not carried out Regarding Comparative Example 6 Only the clear liquid became.

(3) Adhesiveness (presence or absence of dripping) Each sample was sprayed on about 3 cm square of a human upper arm, and the presence or absence of dripping was observed.

Judgment Criteria ○: No dripping ×: With dripping −: Not performed (4) Form of foam Each sample was sprayed in the same manner as in (3), and the form of foam was observed.

Judgment Criteria ○: A transparent liquid foam is formed Δ: A milky white liquid foam is formed ×: A white foam-like foam is formed −: Not performed

[0065]

[Table 3]

From the above results, all the items of Examples 1 to 8 were evaluated as satisfactory antifungal aerosols.

(Test Example 2) The skin surface temperature (°) when each of Example 1, Example 2, Comparative Example 1, Comparative Example 6 and Reference Example was sprayed on the skin was measured to investigate the cooling effect.

An infrared thermometer was used to measure the temperature of the skin surface.

The results are shown in Table 4.

[0070]

[Table 4]

In Comparative Example 1 in which a foamy foam was formed and Comparative Example 6 in which dripping was remarkable, the cooling effect was small and the cooling sensation disappeared almost instantly.

Further, in the reference example, the sprayed object was frozen on the skin surface immediately after spraying, and a drastic decrease in skin temperature was observed. In this case, the skin was exposed to a low temperature environment, which was accompanied by severe pain.

On the other hand, in Examples 1 and 2, the skin surface temperature was 1
There was almost no low temperature of 0 ° or less, and even if there was, it was for a very short time, so no pain due to cooling was felt, and a cool sensation was obtained for about 20 minutes after injection.

[0074]

EFFECTS OF THE INVENTION According to the present invention, it becomes possible to provide an aerosol of oxyconazole nitrate, which has a continuously comfortable cooling property without feeling pain caused by strong cooling when sprayed.

As a result, it was possible to apply it comfortably throughout the year, and it became an effective means for the complete cure of athlete's foot.

In addition, as a propellant, a chlorofluorocarbon gas, which is a substance causing environmental damage, is not used at all, and it has a refreshing sensation without dripping when sprayed, and a constant spraying state can be maintained at all times. Is also excellent.

From the above points, the oxyconazole nitrate aerosol of the present invention is a pharmaceutically useful preparation as a therapeutic agent for athlete's foot.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 47/44 H (72) Inventor Masaaki Ichikawa 1-1-20 Matsunami Furukawa, Ibaraki Prefecture

Claims (7)

[Claims] 1. Oxyconazole nitrate 0.3-3.0 wt%, water and / or lower alcohol 40-90 wt%, crotamiton 1-10 wt%, surfactant 0.5-
10.0 wt%, 10 to 60 wt% of an aerosol concentrate containing 1 to 10 wt% of powder and 40 to 90 wt% of propellant
Oxyconazole nitrate aerosol consisting of 2. The compounding amount of oxyconazole nitrate is 0.5.
% To 2.0% by weight. 3. The aerosol agent according to claim 1, wherein the surfactant is polyoxyethylene castor oil and hydrogenated castor oil. 4. The compounding amount of the surfactant is 1.0 to 6.0% by weight in the aerosol concentrate stock solution.
Or the aerosol agent according to claim 3. 5. The compounding amount of crotamiton is 2.5 to 10% by weight in the aerosol stock solution.
Alternatively, the aerosol agent according to claim 3 or claim 4. 6. The amount of powder blended is 3 to 3 in the aerosol concentrate.
It is 8% by weight. Claim 1 or Claim 2 or Claim 3
Alternatively, the aerosol agent according to claim 4 or claim 5. 7. The aerosol agent according to claim 1, 2 or 3, 4 or 5 or 6, wherein the compounding amount of the propellant is 60 to 80% by weight based on the undiluted solution of the aerosol agent.