JP2000351726A - Aerosol preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a sherbet-like aerosol preparation having improved dustability, solubility, stability and percutaneous absorption of an active ingredient, extremely reduced skin irritation and excellent durability of refreshing feeling by adding a specific component to the active ingredient. SOLUTION: This aerosol preparation comprising at least (A) a stock solution composed of (i) 0.05-10 wt.% of an active ingredient, (ii) <=30 wt.% of water, (iii) <=30wt.% of a lower alcohol, (iv) 0.05-2.5 wt.% of a sorbitan fatty acid ester and (v) 0.05-3.0 wt.% of an ether-based surfactant nonliquid at a room temperature and (B) 60-99 wt.% of a propellant. The total of the component iv and the component v formulated is 0.1-5.5 wt.% and the weight ratio of the component iv: the component v is adjusted to 2.0:0.05 to 0.05:2.0.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to a surfactant comprising at least (a) an active ingredient, (b) water, (c) a lower alcohol, (d) a sorbitan fatty acid ester, and (e) a non-liquid ether surfactant at room temperature. By mixing the stock solution consisting of the agent and the propellant, the dispersibility, solubility, stability, and transdermal absorbability of the active ingredient are improved, skin irritation is significantly reduced, and a refreshing feeling is obtained. The present invention relates to a sherbet-like aerosol preparation having good persistence.

[0002]

2. Description of the Related Art Conventionally, lotions and sprays (fog aerosols, etc.) have been formulated as active ingredients.
However, in these preparations, scattering of the active ingredient at the time of application to the skin, and furthermore, inhalation toxicity of the active ingredient due to the scattering are problems. In addition, the cooling effect after coating is insufficient, and the usability and effect are hardly sufficient. Therefore, a foamed aerosol formulation has been developed to improve the scattering property of the active ingredient (Japanese Patent Application Laid-Open No. 63-119420). It was difficult to apply. Further, the cooling effect was not sufficient.

On the other hand, gel preparations and sherbet preparations have been developed (JP-A-4-103526 and the like).
Since the amount of water must be increased, the solubility of the active ingredient is inhibited, and the stability over time, such as the precipitation of surfactants and active ingredients in the formulation, is reduced, and the formulation is satisfactory. It didn't work. Therefore, in order to enhance the solubility of the active ingredient, a large amount of surfactants and alcohols must be used, and there is a problem that skin irritation is caused.

[0004] The present invention has been made in view of the above circumstances,
At least (a) the active ingredient, (b) water, (c) a lower alcohol, (d) a sorbitan fatty acid ester, and (e)
By mixing a stock solution composed of a non-liquid ether surfactant at room temperature and a propellant, the dispersibility, solubility, stability, and percutaneous absorption of the active ingredient are improved, and skin irritation is caused. It is also an object of the present invention to provide a sherbet-like aerosol preparation having a significantly reduced refreshing effect and a good refreshing feeling.

[0005]

Means for Solving the Problems and Embodiments of the Invention As a result of intensive studies to achieve the above object, the present inventor has found that
In an aerosol formulation comprising at least (a) an active ingredient, (b) water, (c) a lower alcohol, and a propellant,
The combined use of (d) a sorbitan fatty acid ester and (e) a non-liquid ether surfactant at room temperature improves the dispersibility, solubility, stability, and transdermal absorption of the active ingredient, and The present inventors have found that a sherbet-like aerosol preparation having a significantly reduced skin irritation and a good refreshing sensation is obtained, and the present invention has been accomplished. In particular,
(A) 0.05 to 10% by weight of the active ingredient (hereinafter, referred to as
Abbreviated simply to%. ), (B) 30% or less of water, (c) 30% or less of lower alcohol, (d) 0.05% to 2.5% of sorbitan fatty acid ester, and (e) 0.05% of ether surfactant. % To 3.0%, and 60% to 9 propellants
It is effective at 9%.

Hereinafter, the present invention will be described in more detail. The aerosol preparation of the present invention comprises a stock solution and a propellant, and improves the solubility and stability of the active ingredient when prepared as an aerosol preparation as described above. It is to let. Here, the active ingredient may be any substance that acts directly or indirectly on any part of the body. Examples of such an active ingredient include hydrocortisone, hydrocortisone acetate, prednisolone, methylprednisolone, prednisolone acetate, and prednisolone acetate. Hydrocortisone propionate,
Steroid hormones such as prednisolone valerate, dexamethasone, betamethasone, triamcinolone, clobetasone acetate, clobetasol propionate, fluocinonide, dexamethasone acetate, betamethasone valerate, triamcinolone acetonide, aspirin, salicylic acid,
Acetaminophen, methyl salicylate, glycol salicylate, mefenamic acid, flufenamic acid, indomethacin, felbinac, diclofenac sodium, ketoprofen, ibuprofen, flurbiprofen,
Fenbrofen, bufexamac, piroxicam,
Oxyfenbutazone, mepilizole, ibuprofen piconol, clidanac, phenylbutazone, naproxen, glycyrrhizin, glycyrrhetinic acid, azulene,
Anti-inflammatory analgesics such as camphor, thymol, 1-menthol,
Dibucaine hydrochloride, ethyl aminobenzoate, brocaine hydrochloride, lidocaine, tetracaine hydrochloride, lidocaine hydrochloride,
Thecaine, benzyl alcohol, bramoxine hydrochloride,
Local anesthetics such as catacaine hydrochloride, butanicaine hydrochloride, piberocaine hydrochloride, chlorobutanol, barbital,
Amobarbital, Amobarbital Sodium, Phenobarbital, Phenobarbital Sodium, Secobarbital Sodium, Pentobarbital Calcium, Hexobarbital, Triclofos, Bromvalerylurea, Glutethimide, Metacaron, Berlabine, Nitrazebam, Estazolam, Ensanflurazazem, Flunitrazebam Sedatives such as estazolam, cyclophosphamide, busulfan, paraaminosalicylic acid, 5-fluorouracil, mailcaptopurine, tegaflu, methotrexate, azathioprine, vinplastin sulfate, doxorubicin hydrochloride, pleomycin hydrochloride,
Antineoplastic agents such as mitomycin C, cyclosporine, L-asparakinase, cisbratin, chloramphenicol, cefmetazole, bacitracin, penicillin,
Antibiotics such as cephalexin, tetracycline, streptomycin, nystatin, erythromycin, fradiomycin sulfate, tocopherol acetate, benzyl nicotinate, trazoline, parabamil, caffeine, cyclandate, acetylcholine, a blood circulation promoter such as tocopherol nicotinate, nifedipine, Drugs for coronary vasodilation such as dipyridamole, prenylamine lactate, efloxate, phenytoin, phenasemide,
Antiepileptic drugs such as ethylphenasemide, etotoin, primidone, fensuximide, nitrazeban, clonazeban, and carbamazepine; antibiotics such as griseofulvin and tolnaftate; drugs for relaxing skeletal muscles such as clozobazone and fenoprobamate; and antihistamines such as diphenhydramine and metachidin. , Digoxin digotoxin,
Cardiotonic agents such as copidecarenone, arrhythmic agents such as phenytoin, disopyramide, diuretic agents such as polythiazide, spironolactone, chlorthalidone, blood pressure lowering agents such as deservidin, meptame, reserpine, meptamate, vitamins, diet, brostagladin F2
Examples thereof include those that hardly dissolve in water, such as danazol and mepithiostane, and salts thereof, but are not limited thereto. Among them, an active ingredient containing a carboxyl group in the structural formula is preferable. These various active ingredients may be used alone or in combination of two or more.

[0007] The amount of the active ingredient in the aerosol preparation of the present invention is not particularly limited, but in consideration of the object of the present invention, the amount is an amount sufficient to effectively exhibit the effect of the aerosol preparation. It is sufficient if it is present, and it is desirably 0.05% to 10%, preferably 0.05% to 5% of the whole preparation. If the amount is less than 0.05%, the effect of the active ingredient is not sufficiently exhibited, while if it is more than 10%, no further effect can be expected.

[0008] The amount of water in the aerosol preparation of the present invention is not particularly limited, but may be 30% of the whole preparation.
%, Preferably 0% to 25%. If the amount is outside the above range, the solubility of the active ingredient will be poor, making the preparation difficult, and the efficacy is low.

In the aerosol preparation of the present invention, the pH of the stock solution is desirably 2.0 to 8.0, preferably 2.5 to 6.5, from the viewpoint of the stability of the active ingredient. As the pH adjuster for adjusting the pH range, citric acid, acetic acid, malic acid,
Organic acids such as lactic acid and tartaric acid and / or metal salts thereof, amine salts such as monoethanolamine, diethanolamine and triethanolamine, amide salts (hereinafter simply referred to as salts), and inorganic acids such as phosphoric acid, boric acid and hydrochloric acid. And / or metal salts thereof, hydroxide salts such as sodium hydroxide and potassium hydroxide, and carbonate salts such as sodium carbonate. These may be used alone or in combination of two or more.

The lower alcohol in the present invention includes:
Examples thereof include methanol, ethanol, isopropanol, propanol, butanol, and denatured alcohols thereof. These lower alcohols can be used alone or
You may mix and use more than seeds.

The amount of the lower alcohol is not particularly limited, but is preferably 30% or less, preferably 0% to 25% of the whole preparation in view of the object of the present invention. If the amount is more than 30%, the skin may be irritated.

The sorbitan fatty acid ester in the present invention is not particularly limited, but may be sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquistearate, sorbitan tristearate. Sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, sorbitan isostearate, sorbitan sesquiisostearate, sorbitan monotol oil fatty acid ester, sorbitan sesquitol oil fatty acid ester, sorbitan tritol oil fatty acid ester, polyoxyethylene Examples thereof include sorbitan fatty acid esters. These sorbitan fatty acid esters may be used alone or in combination of two or more.

The amount of the sorbitan fatty acid ester is not particularly limited. However, in view of the object of the present invention, 0.05% to 2.5%, preferably 0.1% of the whole preparation.
It is desirable to set it to be from 05% to 2.0%. The blending amount is 2.
If it is more than 5%, skin irritation may occur, and the stability of the preparation may be reduced. On the other hand, if it is less than 0.05%, the solubility of the active ingredient is reduced, and the effectiveness is not sufficiently exhibited.

The non-liquid ether surfactant at room temperature in the present invention is not particularly limited, but may be polyoxyethylene (hereinafter simply abbreviated as POE) (2).
0) Polyoxypropylene (hereinafter simply referred to as POP) (4) Cetyl ether, POE (20) POP
(8) Cetyl ether, POE (12) POP (6) Decyl tetradecyl ether, POE (20) POP
(6) decyltetradecyl ether, POE (30) P
OP (6) decyl tetradecyl ether, POE (2
1) Lauryl ether, POE (25) lauryl ether, POE (2) cetyl ether, POE (5.5) cetyl ether, POE (7) cetyl ether, POE
(10) Cetyl ether, POE (15) Cetyl ether, POE (20) Cetyl ether, POE (23) Cetyl ether, POE (25) Cetyl ether, POE
(30) cetyl ether, POE (40) cetyl ether, POE (2) stearyl ether, POE (4) stearyl ether, POE (20) stearyl ether, POE (20) oleyl ether, POE (50)
Oleyl ether, POE (30) octylphenyl ether and the like are exemplified. In the present invention, the term "non-liquid at room temperature" refers to a state which is in a solid state and a vaseline-like state when observed at 25 ° C. Among the above-mentioned ether-based surfactants, in particular, POE (20) POP
(4) Cetyl ether, POE (20) POP (8) cetyl ether, POE (12) POP (6) decyl tetradecyl ether, POE (20) POP (6) decyl tetradecyl ether, POE (30) POP (6) ) Decyltetradecyl ether and the like are preferably used. These ether-based surfactants may be used alone or in combination of two or more.

The amount of the ether-based surfactant is not particularly limited, but considering the object of the present invention, 0.05% to 3.0%, preferably 0.1% of the whole preparation.
It is desirable to set it to 05% to 2.5%. The blending amount is 3.
If it is more than 0%, skin irritation may occur, and the stability of the preparation may be reduced. On the other hand, if it is less than 0.05%, the solubility of the active ingredient is reduced, and the effectiveness is not sufficiently exhibited.

It is preferable that the total amount of the sorbitan fatty acid ester and the ether surfactant is 0.1% to 5.5%, preferably 0.1% to 4.5% of the whole preparation. . If it is less than 0.1%, the solubility of the active ingredient is reduced and the effectiveness is not sufficiently exerted, and the preparation becomes difficult. On the other hand, if the content is more than 5.5%, skin irritation may occur, and the stability of the preparation is undesirably reduced. Further, as a preferable compounding ratio, sorbitan fatty acid ester: the above-mentioned ether-based surfactant (weight ratio) = 2.0: 0.05 to 0.05: 2.
0, preferably in the range of 1.8: 0.05 to 0.05: 1.8.

Examples of the propellant in the present invention include, but are not limited to, dimethyl ether, liquefied petroleum gas, carbon dioxide gas, nitrogen gas, argon gas, air, and chlorofluorocarbon gas. These propellants may be used alone or in combination of two or more.

The amount of the propellant is not particularly limited.
% To 99%, preferably 60% to 85%. If the amount is more than 99%, the efficacy as a preparation is not sufficiently exhibited, while if it is less than 60%, an appropriate sherbet is not formed.

The aerosol preparation of the present invention contains an emulsifying aid, a solubilizing aid, a solubilizing agent, an essential oil component, a moisturizing component, and the like, which are added to an ordinary aerosol preparation, if necessary, as long as the effects of the present invention are not hindered. Absorption promoters, warming ingredients, fresheners, other aqueous and oily ingredients, water-soluble polymers, preservatives, bactericides, chelating agents, thickeners, antioxidants, organic and inorganic powders, fragrances, Dyes and the like are used.

Examples of the emulsifying aid include, but are not limited to, cetanol, stearyl alcohol, behenyl alcohol, lanolin alcohol and the like. These may be used alone or in combination of two or more.

Examples of solubilizers include crotamiton, benzyl alcohol, diisopropyl adipate, diethyl sebacate, diisopropyl sebacate, propylene glycol fatty acid (C6-22) ester, glycerin fatty acid ester (C6-22), myristin Fatty acid esters such as isopropyl acid, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, octyl dodecyl myristate, higher alcohols such as 2-hexyldecanol and 2-octyldodecanol, natural animal and vegetable oils, butylene glycol , Polyethylene glycol, propylene glycol, polyhydric alcohols such as glycerin, liquid paraffin,
Examples include hydrocarbons such as squalane, silicone oils such as methylpolysiloxane, methylphenylpolysiloxane, and cyclomethicone, but are not limited thereto. These may be used alone or in combination of two or more.

As the solubilizer, L-aspartic acid,
Acetone, L-arginine, calcium alkyl allyl sulfonate / polyoxyethylene lauryl ether mixture, sodium alkylnaphthalene sulfonate, sodium benzoate, benzyl benzoate, sodium chloride, hydrochloric acid, dilute hydrochloric acid, sodium citrate, L-glutamic acid L
-Lysine, potassium hydroxide, sodium hydroxide, diethyl sebacate, soybean oil, sodium bicarbonate, propylene carbonate, low-substituted hydroxypropylcellulose, lactic acid, hydroxypropylcellulose, fenprobamate, polyvinyl alcohol, polyvinylpyrrolidone, maleic acid , Maleic anhydride, D-mannitol, meglumine, potassium iodide, sodium iodide, liquid paraffin and the like, but are not limited thereto. These may be used alone or in combination of two or more.

Essential oil components include headache-relieving essential oils such as rosemary, menthol, lemon oil, peppermint oil, cardamom oil, veneroy oil, basil oil, sandalwood oil, neroli oil, melissa oil, ylang ylang oil, cloves Oil, savory oil, borneol oil, coriander oil, jasmine oil, orange oil, lavender oil and other sleep-promoting essential oils, fennel oil, constipation-relieving essential oils such as black pepper oil, appetite-reducing essential oils such as patchouli oil,
Appetite-enhancing essential oils such as oregano oil, myrrh oil, nutmeg oil, tarragon oil, cinnamon oil, camille oil, ginger oil, etc.
Fatigue-recovering essential oils such as marjoram oil, geranium oil, seporie oil, clary sage oil, rose oil and lemongrass oil, essential oils for moisturizing living surfaces such as olive oil and jojoba oil, anise oil, cypress oil, cedarwood oil, camphor oil, juniper Oil, thyme oil, hyssop oil, bergamot oil, yuri oil, benzoic oil, frank oil, rosewood oil,
Examples include, but are not limited to, activity-enhancing essential oils such as peppermint oil, turpentine oil, pine oil, sandalwood oil, sage oil, neroli oil and the like. These may be used alone or as a mixture of two or more.

Glycerin, propylene glycol, dipropylene glycol, 13-butylene glycol, polyethylene glycol (molecular weight = 10)
05000), saccharides such as hyaluronic acid and maltitol, amino acids such as pyrrolidone carboxylic acid, and natural moisturizing factors (hereinafter simply referred to as N) of various amino acids.
Abbreviated as MF. ), Natural oils such as synthetic oils such as esters, and animal and vegetable oils, as well as alginates, cellulose derivatives, quince seed gum, pectin, pullulan, xanthan gum, bur gum, carboxyvinyl polymers, acrylic polymers, laponite, etc. Although illustrated, it is not limited to these. These may be used alone or as a mixture of two or more.

As the absorption promoter, pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,
Pyrrolidone derivatives such as 5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, thioglycolic acid and / or salts thereof, oleyl alcohol, lauryl alcohol, 2-octyldodecanol; Higher alcohols such as 2-hexyldecanol, fatty acids such as capric acid, linoleic acid and oleic acid and / or salts thereof, ethyl myristate, octyldodecyl myristate, isopropyl myristate, diisopropyl sebacate, diethyl sebacate, palmitic acid Fatty acid esters such as isopropyl, decyl oleate, ethyl laurate, ethyl caprate, and monoglyceride capric acid; polybasic acid esters such as diethyl adipate, isopropyl adipate and diisopropyl adipate; diethylsa Shineto, triacetin, tributyrin, enamine and / or derivatives thereof, salicylic acid, 5
-Salicylic acid derivatives such as methoxysalicylic acid, glycol salicylate, etc., sodium edetate, crotamiton, terpenes, nicotinic acid ester, α-cyclodextrin, β-cyclodextrin, polyols, smectites such as bentonite, benzyl alcohol, squalane , Azone and the like, but are not limited thereto. These may be used alone or as a mixture of two or more.

As the warming sensation component, 8-methyl-N-vanillyl-6E-nonenamide, N-vanillylnonanamide, N-vanillyl-9-octadecenenamide, N-vanillyl-alkane (1 to 40 carbon atoms) Dienamide, N-
Vaniryl alkane (C1-40) dienyl, N
-Vanillyl-cis-monounsaturated alkene (having 1 to 1 carbon atoms)
40) Examples include, but are not limited to, amides, capsaicin, capsaicin derivatives, benzyl nicotinate, β-butoxyethyl nicotinate, saltylate, pepper powder, pepper extract, N-acylvanilamide, nonylate vanilamide, and the like. Not something. These may be used alone or as a mixture of two or more.

Examples of the cooling agent include limonene, terpinolene, menthane, terpinene, 1-menthol, isopulegol, ethyl-p-menthane-3-carboxamide,
1- (2-hydroxyphenyl) -4- (3-nitrophenyl) -1,2,3,6-tetrahydroxypyrimidin-2-oneethyl-p-menthan-3-carboxamide, p-menthan-3,8- Diols, 3,8-dihydroxy-p-menthane-3,9-diol, other p
-Menthane and monocyclic monoterpene hydrocarbons derived therefrom, 3,1-menthoxypropane-1,2-diol, and other menthol-related compounds. These may be used alone or as a mixture of two or more.

Other aqueous components include glycerin,
Polyhydric alcohols such as sorbitol, ethylene glycol, propylene glycol, butylene glycol, glycols such as polyethylene glycol, sucrose, lactose,
Maltose, mannitol, erythritol, sugars such as xylitol and sugar alcohols, further hyaluronic acid,
Heparin analogues, mucopolysaccharides such as chondroitin sulfate,
Examples include natural moisturizing factor (NMF) components such as sodium pyrrolidonecarboxylate, sodium lactate, and various amino acids. These may be used alone or in combination of two or more.

Other oily components include liquid paraffin, paraffin wax, petrolatum, squalane, beeswax, carnauba wax, olive oil, jojoba oil, lanolin, higher alcohols, higher fatty acids and / or their derivatives, silicone oil, crotamiton and the like. Is exemplified.
These may be used alone or in combination of two or more.

Examples of the water-soluble polymer include hydroxypropylcellulose, carboxymethylcellulose, carboxyethylcellulose, and salts thereof, sodium hyaluronate, polyvinyl alcohol, and carboxyvinyl polymer. These may be used alone or in combination of two or more.

Examples of the preservative include parabens such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate and butyl parahydroxybenzoate, benzoic acids, chlorobutanol, domiphen bromide and phenoxyethanol. Is done. These may be used alone or in combination of two or more.

The fungicides include benzalkonium chloride,
Benzethonium chloride, cetylpyridinium chloride, alkyltrimethylammonium chloride (the alkyl group has 1 carbon atom)
0 to 22, preferably a straight chain having 12 to 18 carbon atoms, a side chain,
Refers to any one of the rings. The same applies hereinafter. ), Alkyldiaminoethylglycine hydrochloride, chlorhexidine hydrochloride and the like. These may be used alone or in combination of two or more.

Examples of the chelating agent include, but are not limited to, disodium ethylenediaminetetraacetate, citric acid, and salicylic acid. These may be used alone or in combination of two or more.

Examples of the thickener include sodium carboxymethylcellulose, sodium alginate, carboxyvinyl polymer, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol and the like and / or cross-linked products thereof. These may be used alone or in combination of two or more.

Examples of the antioxidant include tocopherol, erythorbic acid, propyl gallate, BHT (dibutylhydroxytoluene), BHA (butylhydroxyanisole), and NDGA (nordihydroguaiaretinic acid). These may be used alone or in combination of two or more.

Examples of the organic powder include spherical powders such as nylon, silica, and polymethyl methacrylate, polyethylene beads, cellulose powder, starch and the like. These may be used alone or in combination of two or more.

Examples of the inorganic powder include clay minerals such as smectite, talc, mica, mica titanium, bentonite and kaolin, silicic anhydride, aluminum silicate, aluminum magnesium silicate, titanium oxide and zinc oxide. However, the present invention is not limited to these. Among them, a water-swellable clay mineral is preferably used for the purpose of the present invention. Specific examples include layered silicate minerals belonging to the genus smectite such as montmorillonite, paterite, nontronite, saponite, and hectorite, and these may be either natural or synthetic products, and commercially available products include kunipia and smecton. (Kunimine Industries), Become (Vanderbilt), Laponite (Laporte), tetrasilicic mica (Topy Industries), Benclay SL, Mizuka Ace (Mizusawa Chemical Industries) and the like are used. These may be used alone or in combination of two or more.

The total amount of additives was 0.0
1% to 39.85%, preferably 0.01% to 30.0
% Is preferable.

The amount, usage, etc., of the aerosol preparation of the present invention are not particularly limited, and can be appropriately selected.

[0040]

As described above, the aerosol preparation of the present invention comprises at least (a) an active ingredient, (b) water,
By mixing a propellant with a stock solution comprising (c) a lower alcohol, (d) a sorbitan fatty acid ester, and (e) a non-liquid ether-based surfactant at room temperature, the dispersibility and solubility of the active ingredient It is intended to provide a sherbet-like aerosol preparation having improved skin stability and percutaneous absorbability, significantly reduced skin irritation, and good refreshing sensation.

[0041]

EXAMPLES The present invention will be described below in detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples.

Examples 1 to 7 and Comparative Examples 1 to 3 The components shown in Table 1 were mixed and dissolved according to a conventional method to prepare aerosol preparations of Examples 1 to 7 and Comparative Examples 1 to 3.

[Solubility test] As an index for evaluating the solubility of the active ingredient, the presence or absence of the precipitation of the active ingredient in the stock solution excluding the propellant was evaluated by visual observation. When it was found very slightly, it was marked with △, and when it wasn't found, it was marked with ○. The results are also shown in Table 1.

[Percutaneous Absorption Test] As an index for evaluating the percutaneous absorption of the active ingredient, the blood concentration of the rat was measured. Specifically, 10 Wistar male rats (body weight 140 g to 160 g) were subjected to the experiment as one group. Rats had their backs shaved the day before the experiment. On the day of the experiment, 1 ml of the undiluted solution excluding the propellant was applied to the shaved portion at 5 cm x
It was spread over a range of 8 cm and raised in individual cages. After application, 1, 2, 3, 4, 6, and 8 hours later, a total of 6 times of blood was collected from the rat under ether anesthesia. The collected blood was immediately centrifuged, and the serum components were separated and subjected to high performance liquid chromatography analysis according to a conventional method. The blood concentration of each active ingredient was calculated from a predetermined calibration curve, and the area under blood concentration (AUC) from application to 8 hours later was calculated using blood concentration analysis software. The results are also shown in Table 1.

[Test for sustainability of refreshing sensation] As an index for evaluating the persistence of refreshing sensation, each aerosol formulation was applied to the upper arm of 20 normal panelists (panelers), and the cooling sensation after 2 hours was evaluated as follows. The sensory evaluation was performed based on the criteria, and the evaluation points of each panel were averaged to obtain an index of sustainability of the refreshing feeling. Table 1 also shows the average value of the evaluation points. <Evaluation criteria> 5: Very refreshing feeling 4: Strong cooling feeling 3: Refreshing feeling 2: Low cooling feeling 1: Slight cooling feeling 0: No cooling feeling at all

[Skin Irritation Test] As an index for evaluating the skin irritation of the prepared aerosol preparations, each preparation was applied to the upper arm of 20 healthy persons (panelers) and the skin 24 hours after the closed patch for 24 hours The irritation was sensory evaluated based on the following evaluation criteria, and the evaluation points of each panel were averaged to obtain an index of skin irritation. Table 1 also shows the average value of the evaluation points. <Evaluation criteria> 5: No skin irritation at all 4: Little skin irritation 3: Very little skin irritation 2: Some skin irritation 1: Some skin irritation

[Storage Stability Test] As an index for evaluating the storage stability of the active ingredient, the content of the active ingredient after storage for 6 months at 40 ° C. and 75% humidity was subjected to high performance liquid chromatography analysis according to a conventional method. did. The content of each active ingredient was calculated from a predetermined calibration curve, and the amount of the active ingredient after storage relative to the amount of the initial active ingredient (% by weight = the amount of the active ingredient after storage / the content of the initial active ingredient × 100) was calculated. . The results are also shown in Table 1.

[0048]

[Table 1]

From the results shown in Table 1, it is found that a non-liquid ether surfactant at room temperature was not used and a liquid ether surfactant was used instead (comparison between Example 1 and Comparative Example 1). In the case where neither the sorbitan fatty acid ester nor the ether surfactant is contained (comparison between Example 1 and Comparative Example 2), the solubility and stability of the active ingredient are reduced,
As a result, it was confirmed that the transdermal absorbability was also reduced.
Similar results were also observed when sorbitan fatty acid esters were contained but no ether-based surfactant was contained (comparison between Example 2 and Comparative Example 3).

On the other hand, when the content of water or lower alcohol is 30
%, The solubility of the active ingredient and the skin irritation were found to be better (Examples 2 and 3 and 4).
And contrast). Further, the contents of the sorbitan fatty acid ester and the ether surfactant are 2.5% and 3.0%, respectively.
% Or less was observed in terms of skin irritation and storage stability of the active ingredient (Comparative Example 5 with Examples 6 and 7).

The aerosol preparation of the present invention (Examples 1 to 5)
7) No scattering of the drug was observed during use.

Claims (2)

[Claims] 1. At least (a) an active ingredient, (b) water,
An aerosol preparation comprising a stock solution comprising (c) a lower alcohol, (d) a sorbitan fatty acid ester, and (e) a non-liquid ether surfactant at room temperature, and a propellant. 2. The method according to claim 1, wherein (a) the active ingredient is 0.05% by weight to 10% by weight.
% By weight, (b) 30% by weight or less of water, (c) 30% by weight or less of lower alcohol, (d) 0.05 to 2.5% by weight of sorbitan fatty acid ester, (e) Ether-based surfactant The aerosol formulation according to claim 1, wherein the composition comprises 0.05% to 3.0% by weight of the propellant and 60% to 99% by weight of the propellant.