JP2000351738A - Drug for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a drug for external use having improved solubility of active component, effectivity, stability and skin stimulation by including a specific cyclodextrin and a water-soluble polymer in combination with an active component and adjusting the pH of the product. SOLUTION: The objective drug is produced by including (A) an active drug component (e.g. actinomycin D and acrinol) together with (B) a cyclodextrin free from the modification of hydroxy group in the molecule (e.g. α-cyclodextrin) and (C) a water-soluble polymer (e.g. sweet potato starch and polyvinyl alcohol) and adjusting the pH to <=7. The amounts of the components A, B and C are 0.05-10 wt.%, 0.01-10 wt.% and 0.05-20 wt.% based on the total preparation, respectively. The preparation exhibits remarkable effect as a water-based preparation and the amount of water is usually 10-90 wt.%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention improves the solubility and stability of an active ingredient by blending, together with the active ingredient, a cyclodextrin and a water-soluble polymer whose hydroxyl group in the molecule is not modified. In addition, the present invention relates to an external preparation in which skin irritation is significantly reduced, and the transdermal absorption of the active ingredient and its sustainability are excellent.

[0002]

2. Description of the Related Art Conventionally, active ingredients, especially non-steroidal anti-inflammatory drugs having a carboxyl group in a molecule, have been difficult to dissolve under acidic conditions due to the presence of carboxylic acid as a molecular form in an aqueous preparation. Was not enough. Therefore, when the pH of the preparation is increased, the efficacy is improved, but the skin may be irritated, and thus it is not suitable as an external preparation. On the other hand, as a method for increasing the solubility of such an active ingredient under acidic conditions, solubilization using a surfactant or the like is generally used, but if the surfactant is added in a large amount, skin irritation may occur. In addition, there is a problem in stability. In addition, solubilization with alcohol is also widely used as a general means, but there is a problem that there are various restrictions on formulation.

[0003] On the other hand, even if the active ingredient is relatively easily soluble in water, it is still difficult to use it as an external preparation because, for example, when the active ingredient is dissolved and stored in an aqueous solution, the stability of the active ingredient decreases over time. Had a problem. At present, the technology for improving the transdermal absorbability and sustainability of any of the active ingredients has not been sufficient.

[0004] The present invention has been made in view of the above circumstances,
By blending the active ingredient with cyclodextrins in which the hydroxyl group in the molecule is not modified and a water-soluble polymer, the solubility of the active ingredient is improved and the efficacy (percutaneous absorption of the active ingredient and its sustainability) is improved. The purpose of the present invention is to provide an external preparation which has improved stability and safety (skin irritation) as a preparation while improving the preparation. In particular, the present invention is useful for aqueous external preparations.

[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
By blending the active ingredient with cyclodextrins in which the hydroxyl group in the molecule is not modified and a water-soluble polymer, the solubility and effectiveness of the active ingredient, especially in aqueous external preparations (percutaneous absorption of the active ingredient and The present inventors have found that their durability, stability and safety (skin irritation) are improved, and have accomplished the present invention. Especially active ingredients,
The present inventors have further found that when a non-steroidal anti-inflammatory agent having a carboxyl group in the molecule, the effect is remarkable.

Hereinafter, the present invention will be described in more detail. As described above, the external preparation of the present invention has a
It improves efficacy, stability and safety. Here, the active ingredient is not particularly limited as long as it is a drug that acts directly or indirectly on any part of the body, and the effect of the present invention is particularly effective for non-steroidal anti-inflammatory drugs having a carboxyl group in the molecule. Are remarkably seen. Further, the carboxyl group in the molecule may be an acid, a metal salt, or a derivative.

Specific examples of the drug include actinomycin D, acrinol, adipiodone, piperazine adipate, aspirin, acetylkitasamycin, acetylspiramycin, amidetrizoic acid, ethyl aminobenzoate, amphotericin B, amoxicillin, and alprostadil alfa. Dex, benzoic acid, estradiol benzoate, sodium benzoate, ampicillin, iotaramic acid, iotroxic acid, iopanoic acid, sodium ipodate, L-isoleucine, ibuprofen, indomethacin, ursodesoxycholic acid, ethacrynic acid, quinine ethyl carbonate, Testosterone enacinate, fluphenazine enanthate, metenolone enanthate, enoxacin, acetylcholine chloride for injection, suxamethonium chloride, bethanechol chloride Aclarubicin hydrochloride, arginine hydrochloride, ethyl cysteine hydrochloride, oxybuprocaine hydrochloride, cocaine hydrochloride, cyclopentolate hydrochloride, dilazep hydrochloride, diltiazem hydrochloride, cetraxate hydrochloride, cefotiam hydrochloride, cefmenoxime hydrochloride, thalassopicillin hydrochloride, tetracaine hydrochloride, todralazine hydrochloride, nicardipine hydrochloride , Bacampicillin hydrochloride, pivmecillinam hydrochloride, flavoxate hydrochloride, procaine hydrochloride, pethidine hydrochloride, meclofenoxate hydrochloride, ensamoxysilite, lysine hydrochloride, oxaprozin, kainate, chlorphenesin carbamate, carbidopa, carbenicillin sodium, L-carbocysteine , Potassium canrenoate, licorice betamethasone, sodium gold thiomalate, citric acid,
Sodium citrate, fentanyl citrate, pentoxyberin citrate potassium potassium, clinofibrate, calcium gluconate, cloxacillin sodium, clofibrate, sodium cromoglycate,
Ketoprofen, tocopherol calcium succinate,
Hydrocortisone succinate, prednisolone succinate,
Guanabenth acetate, Chlormadinone acetate, Cortisone acetate, Tocopherol acetate, Hydrocortisone acetate, Prednisolone acetate, Sidecamycin acetate, Methenolone acetate, Retinol acetate, Salazosulfapyridine, Salicylic acid, Sodium salicylate, Physostigmine salicylate, Methyl salicylate, Cyclacilin, Cyclaciline Sodium, diclofenac sodium, dinoprost, betamethasone dipropionate, ipratropium bromide, distigmine bromide, scopolamine hydrobromide, fomatropine hydrobromide, pyridostigmine bromide, butyl scopolamine bromide, butropium bromide, propantheline bromide, Methylbenactidium bromide, mepenzolate bromide, ifenprodil tartrate, protileson tartrate, tartar Levallorphan, simfibrate, G-strophantin, sulindac, sulbenicillin sodium, cefaclor, cefazolin sodium, cephatrizine propylene glycol, cefadroxil, cephapirin sodium, cephamandole sodium, cephalexin, cephalotin sodium, cephaloridine, cefoline Xitin sodium, cefotaxime sodium, cefotetan, cefoperazone sodium, cefsulodin sodium ceftizoxime sodium, cefpyramid sodium, cefbuperazone sodium, cefmetazole sodium, cefradine,
Cefloxazine, ticarcillin sodium, dehydrocholic acid, tranexamic acid, tryptophan, L-threonine, trepibutone, naproxen, nalidixic acid, nicotinic acid, nicomol, niceritrol, nifedipine, baclofen, pyrantel pamoate, calcium paraaminosalicylate, L-valine, Sodium valproate, retinol palmitate, calcium pantothenate, bisacodyl, pipemidic acid trihydrate, piperacillin sodium, tipepidine hibenzate, pyrenxine, L-
Phenylalanine, phenoxymethylpenicillin potassium, felbinac, fenbufen, clemastine fumarate, brovincamine fumarate, bencyclane fumarate, formoterol fumarate, bumetanide, pranoprofen, fluocinonide, sodium fluorescein, flurbiprofen, floctafenin, proglumide, furosemide , Testosterone propionate, josamycin propionate, drostanolone propionate, beclomethasone propionate, probenecid, sodium heparin, benzylpenicillin calcium, folinate calcium, mitomycin C, ergometrine maleate, chlorpheniramine maleate, prochlorperazine maleate, Purphenazine maleate, ergometrine maleate, Rain acid Levomepromazine,
Midecamycin, gabexate mesylate, camostat mesylate, L-methionine, methyldopa, neostigmine methyl sulfate, methotrexate, mefenamic acid, melphalan, folic acid, iodamide, hydrocortisone butyrate,
Latamoxef sodium, lameside, liothyronine sodium, rifampicin, atropine sulfate, vincristine sulfate, bleomycin sulfate, pepromycin sulfate, polymyxin B sulfate, reserpine, levothyrosine sodium, levodopa, L-leucine, loxoprofen sodium, etc. However, the present invention is not limited to these. These drugs may be used alone or in combination of two or more.

[0008] The amount of the active ingredient in the external preparation of the present invention is not particularly limited. However, in consideration of the object of the present invention, the amount is an amount sufficient to effectively exhibit the effect of the external preparation. 0.05% by weight of the whole formulation
It is desirable that the content be 10 to 10% by weight (hereinafter simply abbreviated as%), preferably 0.1% to 5%. 0.0%
If it is less than 5%, the effect of the active ingredient is not sufficiently exhibited, while if it is more than 10%, no further effect can be expected.

The cyclodextrin of the present invention in which the hydroxyl group in the molecule is not modified includes α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and the like. Specifically, the hydroxyl group in the molecule is methyl. −,
Alkyl derivatives such as ethyl-, propyl-, allyl-, benzyl-, trityl- and hydroxyalkyl-, acyls such as acetyl-, benzoyl-, tosyl-, mesyl-, cinnamoyl-, succinyl-, glutaryl- and lauryl- Derivatives, amino-, alkylamino-,
Nitrogen-containing derivatives such as azido-, imidazoyl-, piperidyl-, adenyl-, histaminel- and pyridyl-, halogens such as 6-deoxy-6-chloro, bromo- and iodo-, mono (d3-deoxy-3-iodo) , A sulfur-containing derivative such as a 6-deoxy derivative, a sulfopropyl ether-, a deoxymercapto-, a deoxythioglycolamide-, and a disulfide-linked duplex; a silyl such as dimethylsilyl-, trimethylsilyl-, and t-butyldimethylsilyl- Derivative,
Carboxyl group-containing derivatives such as C5-carboxyl- and carboxymethyl-, saccharide-containing derivatives such as glucosyl- and D-glucose-, and unmodified ones such as macrocyclic derivatives. These may be used alone or in combination of two or more.

The amount of the cyclodextrin in the external preparation of the present invention is not particularly limited. However, in consideration of the object of the present invention, the amount of the cyclodextrin may be sufficient if the above-mentioned effects can be effectively exhibited. Well, 0.01% of the whole formulation
It is desirably 10%, preferably 0.05% to 5.0%. If the amount is less than 0.01%, a sufficient effect cannot be obtained. On the other hand, if the amount is more than 10%, no more effect can be obtained, and the productivity is deteriorated. In order to more effectively obtain the effects of the present invention, the mixing ratio of the cyclodextrin to the active ingredient (cyclodextrin /
The weight ratio of the active ingredient) is more preferably 0.006 to 200, preferably 0.03 to 100.

The water-soluble polymer of the present invention includes natural, synthetic,
It may be any of semi-synthetic, and is not particularly limited, but as a natural water-soluble polymer, potato starch,
Starch such as potato starch, tapioca starch, wheat starch, corn starch, mannan such as konjac, seaweed such as seaweed, agar, sodium alginate, etc., plant viscous substances such as trolley mallow, tragacanth gum, gum arabic etc., and microorganisms such as dextran and leban Mucus, glue, gelatin, casein, proteins such as collagen, hyaluronic acid, heparin-like substances, sugars such as maltitol, etc. are exemplified.Semi-synthetic water-soluble polymers include viscose, methylcellulose, ethylcellulose, hydroxy Cellulose based such as ethylcellulose and carboxymethylcellulose, starch based such as soluble starch, carboxymethyl starch and dialdehyde starch are exemplified.Furthermore, as a water-soluble polymer of a synthetic product, polyvinyl alcohol is used. Sodium Lumpur, polyacrylic acid, polyethylene oxide, but polyhydric alcohols such as polyethylene glycol (molecular weight = 100 to 5000) is exemplified, but not limited thereto. These water-soluble polymers may be used alone or in combination of two or more.

The amount of the water-soluble polymer in the preparation for external use of the present invention is not particularly limited, but may be an amount sufficient to effectively exhibit the above effects in consideration of the object of the present invention. It is sufficient that it is 0.05% to 20%, preferably 0.1% to 10% of the whole preparation. If the amount is less than 0.05%, a sufficient effect cannot be obtained.
Even if it is more than 0%, the solubility and stability of the active ingredient,
No further improvement in safety can be expected. In order to more effectively obtain the effects of the present invention, the mixing ratio of the water-soluble polymer to the active ingredient (weight ratio of water-soluble polymer / active ingredient) is 0.03 to 400, preferably 0.06 to 200. It is desirable.

The external preparation of the present invention is particularly remarkable in an aqueous preparation, and the amount of water in this case is not particularly limited, but is usually 10% to 90%.
%, Preferably 50% to 80%. 10% blended amount
If the amount is less than the above, the solubility, effectiveness and stability of the active ingredient are not sufficient, and if it is more than 90%, problems occur in the safety and the productivity.

The preparation for external use of the present invention further has a pH of 7 or less, preferably 3.5 to 3.5, from the viewpoint of the stability of the active ingredient.
A range of 7.0 is desirable. Examples of the pH adjusting agent for adjusting the pH range include organic acids such as citric acid, acetic acid, malic acid, lactic acid, and tartaric acid and / or metal salts thereof, amine salts such as monoethanolamine, diethanolamine, and triethanolamine; Salt (hereinafter, simply referred to as salts),
Examples thereof include 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 external preparation of the present invention contains essential oil components, moisturizing components, absorption enhancers, warming components, refreshing agents, and the like, which are added to ordinary external preparations as required, as long as the effects of the present invention are not impaired. Other aqueous and oily components, activators, preservatives, thickeners, antioxidants, organic and inorganic powders and the like are used.

The essential oil components include essential oils for reducing headache 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,
Appetizing essential oils such as oregano oil, myrrh oil, nutmeg oil, tarragon oil, cinnamon oil, chamomile 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 Oils, thyme oils, hyssop oils, bergamot oils, eucalyptus oils, benzoic oils, balm oils, rosewood oils, peppermint oils, terpetine oils, pine oils, sandalwood oils, sage oils, neroli oils, etc. However, the present invention is not limited to these. These essential oil components may be used alone or in combination of two or more.

Examples of the moisturizing component include amino acids such as glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol and pyrrolidone carboxylic acid, and natural moisturizing factors of various amino acids (hereinafter simply referred to as NM).
Abbreviated as F. ), Natural oils extracted from natural oils such as animal and vegetable oils such as esters, and alginates, but are not limited thereto. These moisturizing components may be used alone or as a mixture of two or more.

Examples of the absorption promoter include pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,
1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-
Pyrrolidone, pyrrolidone derivatives such as 2-pyrrolidone-5-carboxylic acid, thioglycolic acid and / or salts thereof,
Higher alcohols such as oleyl alcohol, lauryl alcohol, 2-octyldodecanol and 2-hexyldodecanol, fatty acids such as capric acid, linoleic acid, and oleic acid and / or salts thereof, ethyl myristate, octyldodecyl myristate, myristic acid Isopropyl,
Fatty acid esters such as diisopropyl sebacate, diethyl sebacate, isopropyl palmitate, decyl oleate, ethyl laurate, ethyl caprate, monoglyceride caprate, etc .; polybasic acid esters such as diethyl adipate, isopropyl adipate, diisopropyl adipate , Diethyl succinate, triacetin,
Examples include tributyrin, enamine and / or its derivatives, salicylic acid derivatives such as salicylic acid, 5-methoxysalicylic acid, glycol salicylate, etc., sodium edetate, crotamiton, terpenes, nicotinic acid ester, benzyl alcohol, squalane, and Λzone. However, the present invention is not limited to these. These absorption promoters may be used alone or as a mixture of two or more.

Examples of the warming sensation component include 8-methyl-N-vanillyl-6E-nonenamide, N-vanillylnonanamide, N-vanillyl-9-octadecenenamide, N-vanillyl-alkanedienamide, and N-vanillyl-amide. Alkandienyl, N-vanillyl-cis-monounsaturated alkenamide, benzyl nicotinate, β-butoxyethyl nicotinate, saltylate, capsicum powder, capsicum extract, N-acylwanilamide, nonylate vanilamide, capsaicin, capsaicin, and similar Although a body etc. are illustrated, it is not limited to these. These warming sensation components may be used alone or in combination 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 cooling agents may be used alone or in combination of two or more.

Other aqueous components include ethanol,
Propyl alcohol, lower alcohols such as isopropyl alcohol, glycerin, ethylene glycol, propylene glycol, butylene glycol, sucrose, lactose,
Examples include sugars and sugar alcohols such as maltose, mannitol, erythritol and xylitol, and natural moisturizing factors (NMF) components such as sodium lactate and various amino acids.

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.

The activator is not particularly limited, but is preferably a nonionic surfactant, specifically, ethylene glycol monostearate, propylene glycol monostearate, glyceryl monostearate, glyceryl trioctanoate. Sorbitan monostearate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquioleate, sorbitan tristearate, sorbitan trioleate, polyoxyethylene monostearate (hereinafter abbreviated as “POE”). (5) glyceryl, POE monostearate (15) glyceryl, POE monostearate (4) sorbitan, POE monostearate (6) sorbitan, POE monostearate
(20) sorbitan, POE monooleate (20) sorbitan, POE monolaurate (6) sorbit, POE monopalmitate (20) sorbitan, POE trioleate (20) sorbitan, PO tetraoleate
E (6) sorbit, POE tetraoleate (30)
Sorbit, POE (40) sorbite tetraoleate, POE (60) sorbite tetraoleate, polyethylene glycol monostearate (2EO), polyethylene glycol monostearate (4EO), polyethylene glycol monostearate (10EO), monostearic acid Polyethylene glycol (25EO),
Polyethylene glycol monostearate (40E
O), polyethylene glycol monostearate (45
EO), polyethylene glycol monostearate (5
5EO), polyethylene glycol monooleate (2
EO), polyethylene glycol monooleate (6E
O), polyethylene glycol monolaurate (10E
O), polyethylene glycol distearate, POE
(3) Castor oil, POE (10) Castor oil, POE (2
0) Castor oil, POE (30) Castor oil, POE (4
0) Castor oil, POE (5) Hardened castor oil, POE (1
0) Hardened castor oil, POE (20) Hardened castor oil, PO
E (30) hardened castor oil, POE (40) hardened castor oil, POE (50) hardened castor oil, POE (60) hardened castor oil, POE (100) hardened castor oil, ester activators such as cetyl octanoate, POE (2) stearyl ether, POE (4) stearyl ether, POE
(6) Stearyl ether, POE (20) Stearyl ether, POE (2) Oleyl ether, POE
(7) oleyl ether, POE (10) oleyl ether, POE (15) oleyl ether, POE (2
0) oleyl ether, POE (50) oleyl ether, POE (2) lauryl ether, POE (3) lauryl ether, POE (4,2) lauryl ether, P
OE (5) lauryl ether, POE (7) lauryl ether, POE (9) lauryl ether, POE (1
0) lauryl ether, POE (12) lauryl ether, POE (15) lauryl ether, POE (20)
Lauryl ether, POE (25) lauryl ether,
POE (30) lauryl ether, POE (40) lauryl ether, POE (50) lauryl ether, PO
E (2) cetyl 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 (5) behenyl ether, POE (10) behenyl ether, POE (20)
Behenyl ether, POE (30) behenyl ether,
POE (2) nonyl phenyl ether, POE (5) nonyl phenyl ether, POE (7.5) nonyl phenyl ether, POE (10) nonyl phenyl ether,
POE (15) nonylphenyl ether, POE (1
8) Nonyl phenyl ether, POE (20) nonyl phenyl ether, POE (10) octyl phenyl ether, POE (30) octyl phenyl ether, POE
E (10) POP (4) cetyl ether, POE (2
0) POP (4) cetyl ether, POE (20) PO
Examples include ether-based activators such as P (8) cetyl ether. POE (8) is an anionic surfactant.
Alkyl ether phosphate-based activators such as sodium oleyl ether phosphate, POE (4) sodium lauryl ether phosphate, POE (10) sodium lauryl ether phosphate, POE (5) sodium cetyl ether phosphate, sodium lauryl sulfate, An alkyl sulfate-based activator such as sodium cetyl sulfate can be suitably used.
These activators may be used alone or as a mixture of two or more.

As preservatives, parabens such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, benzoic acids, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, alkyltrimethylammonium chloride ( The alkyl group has 10 to 22 carbon atoms, preferably 12 to 12 carbon atoms.
18 means any of linear, side chain and cyclic. Less than,
Same. ), Alkyldiaminoethylglycine hydrochloride, chlorhexidine hydrochloride, chlorobutanol, domiphen bromide, phenoxyethanol and the like.

Examples of the antioxidant include tocopherol, erythorbic acid, propyl gallate, BHT (dibutylhydroxytoluene), BHA (butylhydroxyanisole), and NDGA (nordihydroguaiaretinic acid).

Examples of the organic powder include spherical powders such as nylon, silica and polymethyl methacrylate, and polyethylene beads.

Examples of the inorganic powder include clay minerals such as smectite, talc, bentonite, kaolin and mica, aluminum silicate, aluminum magnesium silicate, titanium oxide, zinc oxide and the like. As described above, the inorganic powder in the present invention is not particularly limited, but for the purpose of the present invention, a water-swellable clay mineral is preferably used. Specific examples include layered silicate minerals belonging to the genus smectite such as montmorillonite, paterite, nontronite, saponite, hectorite and the like, and these may be natural or synthetic products. These may be used alone or in combination of two or more.

The above-mentioned additives vary depending on their chemical properties and applications, etc., and cannot be said unconditionally. However, generally, the additives should be 0.01 to 50%, preferably 0.1 to 30% of the whole preparation. desirable.

The dosage form of the external preparation of the present invention is not particularly limited as long as the active ingredient can be stably compounded, but is not limited to lotions, emulsions, gels, gel lotions, ointments, creams, sprays, etc. Agents, aerosols, poultices, packs, sheets and the like are exemplified as suitable dosage forms, and are particularly suitable for lotions, sprays, and aerosols.

The amount and usage of the external preparation of the present invention are not particularly limited, and can be appropriately selected depending on the above-mentioned dosage form and the like.

[0031]

As described above, the external preparation of the present invention can be prepared by blending a cyclodextrin having an unmodified hydroxyl group in the molecule and a water-soluble polymer with the active ingredient. It provides an external preparation with improved solubility and improved efficacy (percutaneous absorption of the active ingredient and its persistence), as well as significantly improved stability and safety (skin irritation). is there.

[0032]

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 5 and Comparative Examples 1 to 3 The components shown in Table 1 were mixed and dissolved according to a conventional method to prepare the external preparations of Examples 1 to 5 and Comparative Examples 1 to 3.

The effectiveness of the active ingredient was evaluated by measuring the transdermal absorbability of the active ingredient and the rate of inhibition of carrageenan paw edema. [Percutaneous Absorption Test] As an index for evaluating the percutaneous absorption of the active ingredient, the blood concentration in rats was measured. Specifically, male Wistar rats (weight 14
(0 g to 160 g) 10 animals were used as a group for the experiment. Rats had their backs shaved the day before the experiment. On the day of the experiment, they were stuck or applied to a shaved area of 5 cm × 8 cm and raised in individual cages. After pasting (application), 1, 2, 3, 4,
After 6 and 8 hours, a total of 6 blood samples were collected from the rats 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. In addition, the persistence of the active ingredient was evaluated by blood concentration (ug / ml) after 4 hours, and is also shown in Table 1. [Carrageenin foot edema inhibition rate measurement test] Next, the edema inhibition rate by various external preparations was determined by the following carrageenan foot edema test method and used as an index of the efficacy of the nonsteroidal anti-inflammatory drug. Specifically, male Wistar rats (weight 140
g-160 g) Each group consisted of 10 rats. The right hind paw volume of each rat was measured with a volume differential meter, and then 0.1 ml of a 1% carrageenin suspension was injected subcutaneously into the same footpad. The external preparation was applied to the right hind limb 4 hours before the injection of the pro-inflammatory agent, and the control group was injected without applying the agent 4 hours before the injection of the pro-inflammatory agent, and the paw volume of the right hind limb after the injection was measured. Measured with the above meter, the edema rate of each rat was determined from the difference in paw volume before and after the injection by the following formula, and the edema inhibition rate by various external preparations was determined from the average edema rate of the control group and the average edema rate of the applied group. . In addition, the site applied during the test was covered with a black cloth bag from the rat's head to the forelimbs so that the rat would not bite or lick. Edema rate (%) = [(Vt−Vn) / Vn] × 100 Vn: Paw volume before carrageenin injection Vt: Paw volume 4 hours after carrageenin injection Edema inhibition rate (%) = [(Ec−Et) / Ec ] X 100 Ec: average edema rate of control group Et: average edema rate of applied group

[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. . 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.

[Skin irritation test] As an index for evaluating the skin irritation of the prepared external preparation, 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

[0037]

[Table 1]

From the results shown in Table 1, in the case of an external preparation having a pH of more than 7, the stability of the active ingredient was poor and skin irritation was also observed (comparison between Example 1 and Comparative Example 1). In addition, when the cyclodextrins in which the hydroxyl group in the molecule is modified are blended, the effectiveness of the active ingredient (percutaneous absorption of the active ingredient and its sustainability is higher than in the case where cyclodextrins without modification are blended). Sex, and carrageenan foot edema suppression rate)
And the stability and safety (skin irritation) of the preparation were poor (Example 1 and Comparative Examples 2 and 3)
And contrast). Furthermore, it was found that when no water-soluble polymer was blended, the stability and safety as a preparation were further reduced (comparison between Example 1 and Comparative Example 3).

Example 2 An external preparation was prepared by blending 0.5% of felbinac instead of indomethacin and 2.5% of γ-cyclodextrin instead of α-cyclodextrin in Example 1 above. As a result of the test, the same effect as in Example 1 was observed.

Example 3 In place of indomethacin in Example 1, flurbiprofen was replaced with 0.285
%, An external preparation containing 3.0% of β-cyclodextrin instead of α-cyclodextrin was prepared and subjected to the same test. As a result, the same effects as in Example 1 were recognized.

Example 4 Diclofenac sodium was used instead of indomethacin in Example 1
%, Α-cyclodextrin and 5.0% were prepared, and the same test was carried out. As a result, the same effect as in Example 1 was recognized.

Claims (3)

[Claims] An external preparation characterized by blending an active ingredient with a cyclodextrin and a water-soluble polymer whose hydroxyl group in the molecule is not modified, and adjusting the pH to 7 or less. 2. The external preparation according to claim 1, wherein the active ingredient is a nonsteroidal anti-inflammatory drug having a carboxyl group in the molecule. 3. The external preparation according to claim 1, wherein the external preparation contains 50% by weight or more of water.