JP2001026553A - Composition of external use preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition increased in percutaneous absorbability of a medicament therein through improving its solubility and having carboxyl group in its molecule to enable its pharmacological activity to be elicited to the utmost, and excellent in feeling when applied to the skin as well. SOLUTION: This composition comprises a medicament having in its molecule at least one carboxyl group, at least one kind of clay mineral comprising a phyllosilicate of the formula described below, and a polyethylene glycol; the formula: [(Si8-yAly)(M(III)aM(II)bLic)O20(OH)4-xFx]n-.Az+n/z (M(III) is a trivalent metal ion; M(II) is a bivalent metal ion; A is an exchangeable cation; 0<=x<=4.0; 0<=y<=3.0; 0<=a<=5.0; 0<=b<=7.0; 0<=c<=2.5; 3<(a+b+c)<7; 0<n<=2.0; (z) is 1, 2 or 3).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an external preparation composition containing a drug having a carboxyl group, and more particularly, to an external preparation composition in which the efficacy and the feeling of use of the above-mentioned drug are remarkably improved.

[0002]

2. Description of the Related Art In recent years, due to factors such as the westernization of eating habits, changes in living environment, increased stress, and an increase in weekend sports population, dermatological diseases,
Orthopedic diseases are increasing rapidly. For these diseases, coping therapy is mainly given, and for dermatological diseases, drugs effective in improving itching, redness, skin inflammation, etc., and for orthopedic diseases, Has been treated with a formulation containing a drug effective for alleviating muscle inflammation and damage.

[0003] Since these therapeutic agents are applied directly to the skin or rubbed, it is desirable to adjust the pH of the preparation to an acidity as close as possible to the skin surface. In addition, dermatological diseases and orthopedic diseases often use components having an anti-inflammatory effect, and as these components, components exhibiting effectiveness under weakly acidic conditions, especially at least one or more in the molecule. Acidic drugs having a carboxyl group are frequently used.

[0004] On the other hand, since many of the active ingredients incorporated in these therapeutic agents have extremely low solubility in water, when they are used as an external preparation for aqueous skin, they are required to solubilize these agents to enhance their effectiveness. For example, there has been proposed a technique of dissolving in an oily component such as crotamiton and blending it, or further, suspending the drug in glycerin to improve the stability in the preparation.

[0005] However, in these proposals, in all cases, the drug is rapidly and continuously transdermally absorbed, so that the drug is effective (quick-acting and long-lasting) and the feeling of use when the preparation is applied to the skin. There is room for further improvement, and it has been desired to develop an external preparation composition that further improves the effectiveness of a drug having a carboxyl group in the molecule and further improves the feeling in use.

The present invention has been made in view of the above circumstances,
It is an object of the present invention to provide a composition for external use in which the effectiveness of a drug having a carboxyl group in the molecule is further improved and the usability is further improved.

[0007]

Means for Solving the Problems and Embodiments of the Invention The present inventors have conducted intensive studies in order to achieve the above object, and as a result,
Clay minerals composed of layered silicates of a specific composition, such as montmorillonite, contain ions that are exchangeable with water molecules between the layers, and form other organic minerals such as forming organic complexes and swelling ability. Focusing on having different properties, as a result of further diligent studies, as a solubilizer of a drug having a carboxyl group in the molecule, especially by combining polyethylene glycol with the clay mineral, the drug quickly, and Percutaneous absorption is sustained, and not only is the efficacy of the external preparation composition as a main agent significantly improved, but also there is no problem of skin irritation, and it is possible to obtain an external preparation composition excellent in usability. This led to the present invention.

That is, the present invention provides a drug having a carboxyl group in the molecule, at least one or more clay minerals comprising a layered silicate represented by the following general formula (1) or (2), and polyethylene: The present invention provides an external preparation composition characterized by comprising glycol. _{[(Si 8-y Al y} ) (M (III) a M (II) b Li c) O 20 (OH) 4-x F x] n - · A z + n / z ··· (1) ( where Wherein M (III) is a trivalent metal ion;
(II) is a divalent metal ion, A is an exchangeable cation, x is a number satisfying the relationship 0 ≦ x ≦ 4.0, and y is 0 ≦
It is a number that satisfies the relationship y ≦ 3.0, and a, b, and c are
0 ≦ a ≦ 5.0, 0 ≦ b ≦ 7.0, 0 ≦ c ≦
2.5, a number satisfying the relationship of 3 <(a + b + c) <7,
n is a number satisfying 0 <n ≦ 2.0, and z is 1, 2 or 3. _{) [Si 8 (Mg p Li} s) O 20 F 2] B s ··· (2) ( where, the formula B is lithium or sodium,
p is a number satisfying the relationship of 3.5 ≦ p ≦ 5.5, and s is 0 ≦
This is a number that satisfies the relationship of s ≦ 3.0. )

Hereinafter, the present invention will be described in more detail. The external preparation composition of the present invention comprises a drug having a carboxyl group in the molecule, a clay mineral having the above specific composition, and polyethylene glycol as essential components.

[0010] Here, the type of the drug incorporated in the external preparation composition of the present invention is not particularly limited as long as it has a carboxyl group in the molecule, but is used as a nonsteroidal anti-inflammatory drug. The carboxyl group in the molecule may be an acid, a salt, or a derivative.

Specific examples of the above drugs include actinomycin D, acrinol, adipiodone, piperazine adipate, aspirin, acetylkitasamycin, acetylspiramycin, acemetacin, amidotrizoic acid,
Ethyl aminobenzoate, amphotericin B, amoxicillin, alclofenac, alprostadil alphadex, 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, flufenadine enanthate, metenolone enanthate, enoxacin, acetylcholine chloride for injection, suxamethonium chloride, bethanechol chloride, aclarubicin hydrochloride, arginine hydrochloride, ethyl hydrochloride Cysteine, oxybuprocaine hydrochloride, cocaine hydrochloride, cyclopentolate hydrochloride, dilazep hydrochloride, diltiazem hydrochloride, seto hydrochloride Kisard, cefotiam hydrochloride, cefmenoxime hydrochloride, thalassopicillin hydrochloride, tetracaine hydrochloride, todralazine hydrochloride, nicardipine hydrochloride, bacampicillin hydrochloride, pivmecillin hydrochloride, flavoxate hydrochloride, procaine hydrochloride, pethidine hydrochloride, meclofenoxate hydrochloride, moxicilit hydrochloride, lysine hydrochloride, oxaprozin, Kainic acid, chlorphenesin carbamate, carbidopa, carbenicillin sodium, L-carbocysteine, potassium canrenoate, valerium betamethasone, sodium gold thiomalate, citric acid, sodium citrate, fentanyl citrate, pentoxyberinkrabran citrate Potassium acid, glycyrrhetinic acid, clinofibrate, calcium gluconate, cloxacillin sodium, clofibrate, cromoglyc , 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, Retinozol, Pitinosaline, Retinol acetate Sulfapyridine, salicylic acid, glycol salicylate, sodium salicylate, physostigmine salicylate, methyl salicylate, cyclacillin, cyclandate, dicloxacillin sodium, diclofenac,
Diclofenac sodium, dinoprost, diflunisal, betamethasone dipropionate, ipratropium bromide, distigmine bromide, scopolamine hydrobromide, homatropine hydrobromide, pyridostigmine bromide, butyl scopolamine bromide, butropium bromide, propantherin bromide, Methyl benactidium bromide, mepenzolate bromide,
Ifenprodil tartrate, protilesone tartrate, levallorphan tartrate, simfibrate, G-strophantin, suprofen, sulindac, sulbenicillin sodium, cefaclor, cefazoline sodium, cefatridine propylene glycol, cefadroxil,
Cefapirin sodium, cefamandole sodium, cephalexin, cephalotin sodium, cephaloridine, cefoxitin sodium, cefotaxime sodium, cefotetan, cefoperazone sodium, cefsulodin sodium, ceftizoxime sodium, cefpyramid sodium, cefbupera Zon sodium, cefmetazole sodium, cefradine, cefloxazine, thiaprofenic acid, ticarcillin sodium,
Dehydrocholic acid, tranexamic acid, tryptophan,
Tolfenamic acid, L-threonine, trepivton, 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, pyrenxin, piroxicam, L-phenylalanine, phenoxymethylpenicillin potassium, felbinac, fentiazac, fenbufen, clemastine fumarate, brovincamine fumarate, benzicran fumarate , Formoterol fumarate, bumetanide, pranoprofen, fluocinonide, sodium fluorescein, flufenamic acid, flurbiprofen, floctafenin, proglumide, furosemide, protidic acid, testosterone propionate, josamycin propionate, drostanolone propionate, beclomethasone propionate , Probenecid, sodium heparin, potassium benzylpenicillin Calcium folinate, mitomycin C, ergometrine maleate, chlorpheniramine maleate, prochlorperazine maleate, Purufenajin maleic acid, ergometrine maleate,
Levomepromazine maleate, Midecamycin, Gabexate mesylate, Camostat mesylate, Methiazinic acid, L-methionine, Methyldopa, Neostigmine methylsulfate, Methotrexate, Mefenamic acid, Melphalan, Folic acid, Iodamide, Hydrocortisone butyrate, Ratamoxef sodium, Lameside, Riome Thyronine sodium, rifampicin, atropine sulfate, vincristine sulfate, bleomycin sulfate, peplomycin sulfate, polymyxin B sulfate, reserpine, levothyrosine sodium,
Examples include, but are not limited to, levodopa, L-leucine, loxoprofen, loxoprofen sodium, and the like. These drugs can be used alone or in an appropriate combination of two or more.

In the case of the present invention, among the above-mentioned drugs, drugs which are usually used as active ingredients for skin diseases and / or care such as anti-inflammatory analgesics, anti-inflammatory agents, keratolytic agents, etc., for example, tolfenamic acid, mefenamic acid , Flufenamic acid, salicylic acid, aspirin, sazapyrine, alclofenac, diclofenac, suprofen, loxoprofen, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenbufen, glycyrrhetinic acid, indomethacin, acemethasin, methiazinic acid, protidinic acid, prosidic acid, sulindac, prosidine Fenchiazak,
Poorly water-soluble acidic drugs such as diflunisal, thiaprofenic acid, oxaprozin, piroxicam, cromoglycic acid, and felbinac are more preferred, and among them, indomethacin, flurbiprofen, felbinac, diclofenac, cromoglycic acid and the like are particularly preferred, and indomethacin is preferred. Is most preferably used.

In the composition of the present invention, the compounding amount of the above-mentioned drug is not particularly limited, but is an effective amount of the drug as an active ingredient of an external preparation, and is usually 0.1% based on the whole composition.
01 to 10% (% by weight, hereinafter the same), preferably 0.1%
７7%, more preferably 0.1-5%. If the amount of the above drug is too small, sufficient pharmacological effects may not be obtained, and if it is too large, the effect of further compounding may not be expected.

The external preparation composition of the present invention contains at least one or more clay minerals comprising a layered silicate represented by the following general formula (1) or (2). _{[(Si 8-y Al y} ) (M (III) a M (II) b Li c) O 20 (OH) 4-x F x] n - · A z + n / z ··· (1) [Si _{8 (Mg p Li s) O} 20 F 2] B s ··· (2)

Here, in the general formula (1), M
(III) is a trivalent metal ion such as an aluminum ion, an iron ion, and a chromium ion, and M (II) is a magnesium ion, an iron ion, a nickel ion, a zinc ion, a cobalt ion, a cadmium ion, a copper ion,
It is a divalent metal ion such as manganese ion and lead ion.

In the above formula (1), A is an exchangeable cation, specifically, an alkali metal ion such as hydrogen ion, sodium ion, potassium ion or lithium ion, or an alkaline earth ion such as calcium or magnesium. Metal ions, metal ions other than these alkali metal ions and alkaline earth metal ions, such as monovalent metal ions such as silver ions, divalent metal ions such as zinc ions and iron ions, and trivalent metal ions such as aluminum ions Metal ions such as monoethanolamine,
Organic groups such as alkanolamine groups such as diethanolamine and triethanolamine, alkyl quaternary ammonium groups such as trimethylammonium and tetramethylammonium, and basic amino acid groups such as lysine and arginine are also included.

X is a number satisfying the relationship 0 ≦ x ≦ 4.0, y is a number satisfying the relationship 0 ≦ y ≦ 3.0,
a, b, and c are respectively 0 ≦ a ≦ 5.0 and 0 ≦ b ≦ 7.
A number satisfying the relationship of 0, 0 ≦ c ≦ 2.5, 3 <(a + b + c) <7, and n is a number satisfying 0 <n ≦ 2.0;
z is 1, 2 or 3.

Specific examples of the clay mineral comprising the layered silicate represented by the above formula (1) include smectite clay minerals such as bentonite, montmorillonite, beidellite, nontronite, saponite, hectorite, sauconite, and stevensite. These can be used alone or in combination of two or more.

Such smectite-based clay minerals are naturally produced, for example, as products containing montmorillonite, such as Bentonite W, Wenger, Kunimine Kogyo from Kunimine Kogyo Co., Ltd.
And hectorite such as Vegum T, Vegum HV, Vegum F and Vegum K from Vanderbild as products containing saponite, such as Kunipia F, Western Bond from American Colloid Co., and Yellowstone from Dresser Minerals. Commercially available products include Hectabrite AW, Hectabrite 200 and Benton EW from American Colloid Co., Ltd., and Macaroid, etc. from National Reed. In addition, various types of synthetic smectite clay minerals are also sold. Ionite H is available from Mizusawa Chemical Industry Co., Ltd., Lucentite SWN, SAN is available from Corp Chemical Co., Ltd., and Laponite is available from Laporte Industries.

As the smectite clay mineral, an alkali-treated acid clay can be used.
That is, the acidic clay is usually defined as a 1% aqueous dispersion having a pH of 5 to 6 or less, a swelling degree of 10 ml / 2 g or less, and a content of SiO ₂ and Al ₂ O _{3 in} a molar ratio of SiO ₂ / Al ₂ O. ₃ = 6 ~
No. 10 are named, such as acid clay from Nakajo, Koto, Kamikatani, Itoigawa, Niigata Prefecture, Mizusawa from Yamagata Prefecture, Kawasaki, Matsune, Kamikatani, Mikawa, Ome, Kamisami Fuller's earth from the United Kingdom and Fl from the United States showing similar properties to these acid clays in addition to acid clay from the United States
oride earth, Warkel e from Germany
rde and the like. Exchangeable cations present in acid clay include sodium ions, potassium ions,
There are magnesium ion, iron ion, calcium ion, aluminum ion and the like. These acidic clays can be blended in the same manner as the smectite-based clay mineral by alkali treatment.

Here, in the case of the present invention, the smectite-based clay mineral has an average particle diameter of particularly 10 to 5000 nm measured by a dynamic light scattering method and an absolute value of ζ potential measured by an electrophoretic light scattering method. It is preferable to use one having a purity of 30 mV or more and a purity of 90% or more determined by a powder X-ray diffraction method. If the average particle size of the primary particles of the clay mineral is too small, a large amount of clay mineral may be required to thicken the external preparation composition, while if the average particle size is too large, a stable dispersion state is obtained. May not be obtained. On the other hand, when the absolute value of the ζ potential is less than 30 mV, the clay mineral particles tend to be easily condensed, and agglomerates may be settled during the production of the external preparation composition, so that the dispersion stability may be reduced. further,
If the purity is too low, a sufficient thickening effect may not be obtained.

Next, another clay mineral of the present invention is a clay mineral comprising a layered silicate represented by the following general formula (2). In _{[Si 8 (Mg p Li s} ) O 20 F 2] B s ··· (2) the formula (2), B is lithium or sodium, p is the relationship of 3.5 ≦ p ≦ 5.5 A number that satisfies
Is a number that satisfies the relationship 0 ≦ s ≦ 3.0.

Specific examples of the clay mineral comprising the layered silicate represented by the above formula (2) include Somasif manufactured by Corp Chemical Co., Ltd., and DP-DM or DM Clean manufactured by Topy Industries, Ltd. Can be used alone or in an appropriate combination of two or more.

The blending amount of the above clay mineral in the external preparation composition of the present invention (the total amount when two or more kinds are blended) is not particularly limited and can be appropriately selected. On the other hand, it is suitably 0.01 to 10%, preferably 0.01 to 7%, more preferably 0.01 to 5%, and still more preferably 0.01 to 3%. If the amount is too small, sufficient shape-retaining properties may not be obtained, and if it is too large, it may be difficult to spread, for example, when used as a patch.

The external preparation composition of the present invention contains polyethylene glycol, which dissolves the above drug such as indomethacin, as one of the essential components. Polyethylene glycol is specified according to the degree of polymerization. Is not used, for example, polyethylene glycol 1
00 to 20000 (# 100 to # 20000) can be suitably used, more preferably polyethylene glycol 100 to 4000 (# 100 to # 4000), and still more preferably polyethylene glycol 100 to 3000.
(# 100 to # 3000) can be suitably used, and these can be used alone or in an appropriate combination of two or more.

The amount of polyethylene glycol in the composition of the present invention is not particularly limited, but is preferably an amount capable of completely dissolving the above-mentioned drug. 20%, especially 0.5-1
0% is preferable. If the amount is too small, it may be difficult to dissolve and mix the above drug,
If the amount is too large, not only the effect of the further compounding is not obtained but also inconvenience in the formulation design may occur. In addition, for the same reason, the compounding ratio with respect to the above drug is as follows:
Polyethylene glycol = 1: 200 to 10: 1, preferably 1:30 to 10: 1.

The composition of the present invention may further contain a solubilizer for the above-mentioned drug in addition to polyethylene glycol. In the case of the present invention, the above-mentioned drug is dissolved by adding polyethylene glycol. It is also possible to use no dissolving agent such as crotamine.

The external preparation composition of the present invention preferably has a pH in the range of 2.5 to 8, particularly 3 to 7, in consideration of application and rubbing to the skin. If the pH of the composition is too low, the feeling of use may deteriorate, and if the pH is too high, the transdermal absorbability of the drug may decrease, and sufficient efficacy may not be obtained. Here, the pH of the preparation can be adjusted using ordinary amounts of pharmaceutically acceptable acidic compounds and alkaline compounds.

The external preparation composition of the present invention is not particularly limited in its dosage form. For example, various types of skin prepared into dosage forms such as a patch base, a lotion, a gel (gel), etc. It can be prepared as an external preparation, and is particularly suitable as a patch base. When using the external preparation composition of the present invention as a patch base, a patch can be obtained by applying the patch base to a support.In this case, an adhesive used for the patch base is, It is sufficient that the adhesive has an adhesive force that can fix the patch on the skin surface at normal temperature for a long time, and is not particularly limited. For example, an aqueous adhesive, an acrylic adhesive, a rubber adhesive, a silicone resin adhesive, or the like can be used.

When prepared as an aqueous pressure-sensitive adhesive, its composition is not particularly limited, and any composition can be used.
Polyacrylic acid, polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, polyvinylpyrrolidone
Vinyl acetate copolymer, carboxyvinyl copolymer, methylcellulose, carboxymethylcellulose,
Carboxymethyl cellulose salt, hydroxypropyl cellulose, sodium alginate, gelatin, pectin, polyethylene oxide, methyl vinyl ether
One or more water-soluble polymer substances such as a maleic anhydride copolymer and carboxymethyl starch (1 to 15% of the total composition), kaolin, titanium oxide, zinc oxide, aluminum hydroxide; 1 or 2 such as silicic anhydride
Inorganic powder other than the above-mentioned clay minerals (combination amount: usually 0 to 10% of the entire composition), glycerin, sorbitol,
1,3-butylene glycol, propylene glycol,
One or more humectants such as sodium pyrrolidonecarboxylate, sodium lactate, etc.
-20%) and water in an appropriate ratio.

In this case, such an aqueous pressure-sensitive adhesive contains a metal ion-crosslinkable hydrogel base, particularly polyacrylic acid and / or polyacrylate, and further contains sodium carboxymethylcellulose and / or alkali metal alginate. A non-gelatin based base may be preferably used. That is, the hydrogel base of the above composition has a strong adhesive strength,
In addition, since the water content is high and the shape retention is excellent, by using this water-containing gel base, when a poorly soluble drug is added to the drug of the present invention, the drug is more efficiently applied to the skin. What is absorbed.

Here, any polyacrylic acid can be used, and there is no particular limitation on the molecular weight and the shape such as linear or branched chain, but those having a molecular weight of 10,000 to 10,000,000 are used. Are preferable, and particularly, the weight average molecular weight is 10,000 to less than 500,000, 500,000 to less than 2,000,000, and 2,000,000 to
It is preferable to combine two or more kinds of polyacrylic acid having an average molecular weight of 7,000,000 and a salt thereof, since the feeling in use is improved. In addition, in addition to a polymer obtained by polymerizing ordinary acrylic acid, a carboxyvinyl polymer, for example, a partially crosslinked acrylic acid polymer such as Carbopol (trade name, manufactured by Goodrich Co., USA) is also suitable. Can be used.

Examples of polyacrylates include monovalent metal salts of polyacrylic acid such as sodium polyacrylate and potassium polyacrylate, monoethanolamine polyacrylate, diethanolamine polyacrylate, triethanolamine polyacrylate and the like. One or two of amine salt of polyacrylic acid, ammonium salt of polyacrylic acid, etc.
More than one species may be suitably used.

The hydrogel base having the above composition can obtain a base having an arbitrary pH by changing the mixing ratio of polyacrylic acid and polyacrylate. In this case, The mixing ratio of polyacrylic acid and polyacrylate is preferably 1:10 to 10: 1, and the weight of polyacrylic acid is 1/1 of the weight of polyacrylate.
If it is less than 10, sufficient adhesion to the skin may not be obtained, and if the weight of polyacrylic acid is more than 10/1 of the weight of polyacrylate, sufficient thickening will not be performed, and the base will sag. Cases arise. Further, when the water-containing gel base comprising the above components is metal-crosslinked with a polyvalent metal salt, examples of the polyvalent metal salt include calcium chloride, magnesium chloride, aluminum chloride, potassium alum, ammonium alum, iron alum, aluminum sulfate, and sulfate sulfate. Ferrous iron, magnesium sulfate, EDTA (ethylenediaminetetraacetic acid)
Soluble salts such as calcium, EDTA-aluminum, EDTA-magnesium, stannous chloride, calcium hydroxide, ferric hydroxide, aluminum hydroxide, calcium carbonate, magnesium carbonate, calcium phosphate, magnesium stearate, aluminum stearate, Calcium citrate, barium sulfate, barium hydroxide, aluminum allantoinate, aluminum acetate, aluminum glycinate, synthetic hydrotalcite, magnesium metasilicate aluminate, magnesium aluminate silicate, stannous hydroxide, α-stannic acid One or more selected from sparingly soluble or poorly soluble salts, and the like, and a chelating or dispersing agent for metal ions such as sodium EDTA-2, citric acid, tartaric acid, urea, and ammonia as a crosslinking speed regulator. Competent Organic acids, organic acid salts, may be formulated and organic bases.

Further, if necessary, a fragrance, a plant extract, a medicinal ingredient other than the above-mentioned drugs, an emulsifier, a preservative and the like can be further blended.

Examples of the fragrance include fennel oil, castor oil, mentha oil, mint oil, fennel oil, cauliflower oil, clove oil, thymian oil, turpentine oil, henoposi oil, yamajin oil, eucalyptus oil, lavender oil, lemon oil, Orange oil, toca oil, bergamot oil, rose oil, citronella oil, lemongrass oil, camphor oil, geranium oil and the like can be mentioned. Further, as the plant extract, for example, aloe, anise, angelica, benzoin, immortelle, chamomile, chamomile, garlic, cardamom,
Galvanum, caraway, carrot seed, guaiac wood, grapefruit, cypress, sandalwood, cedarwood, juniper, star anise, sage, geranium, celery, thyme, tarragon, turpentine, frankincense, violet, pine, parsley, birch, patchouli, rose , Hyssop, fennel, black pepper. Bodily flower, myrrh, myrrh, lemon, lemongrass, rosemary, laurel, sycamore, sycamore, cornflower, almond, thistle, arnica, cypress, fennel, enishida, erika, giant mulberry, mustard, kankoi, kansui, kikunigana, gypsophila , Celandine, Watercress, Genka, Gentian, Sarilambo, Shikazenshi, Birch,
Ferns, stalks, camphors, gingerbreads, jingos, plums, pears, pears, peduncles, squirrels, takshas, dandelions, plums, cherries, chervils, chorei, tenmondou, capsicum, noibara, nolan carrots, balsam pears, lycopodiums, lycopodiums Extracts from bukuro, borage, magwirt, majorana, melissa, mokutsu, peach, mistletoe, eucalyptus, yokuinin, lavender, forsythia, horseradish and the like can be mentioned, and among these, chamomile, sage, parsley, rose in particular Extracts from marie, sycamore, sycamore, cornflower, anise, laurel, angelica, fennel, peppermint, peppermint, lemon balm, lavender, thyme, etc. are preferred. Specific components of such extracts include, for example, monoterpene hydrocarbons, cineole, borneol, camphor (camphor), linanol, berbenol, flavonoids, choline, amino acids, tannins, vegetable acids, fatty acids, hydrocyanic acids Glycosides, salicylic acid derivatives, salvin, condensed tannins, phenolic acids, carnosic acid, triterpene acid, thiyon, salben, pinene, apiol, apiolin, myristicin, coumarin, kama azulene, farnesene, bisabolol, geraniol, eugenol, terpenes, ferrandrin,
Anethole, menthol, menthol, limonene, citral, citronellal, eugenol acetate and the like can be mentioned.

When used as a patch, it is possible to add a warming component and a cooling agent. Examples of the heat-imparting substance that can be blended include, for example, capsicoside, capsaicin, capsaicinoid, dihydroxycapsaicin,
Capsaicin analogs such as capsanthin, capsicum extract, capsicum tincture, capsicum-derived warming-imparting substances such as capsicum powder, benzyl nicotinate, nicotinic acid β-butoxyethyl, N-acylvanillylamide, nonylanilinylamide, and the like. . In addition, camphor, thymol, menthol, and N
-Ethyl-p-menthane-carboxamide, p-menthane-3,8-diol, l-isopulegol, menthol derivatives such as l-menthyl glyceryl ether and the like.

Examples of the emulsifier include fatty acid soap, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, alkyl sulfate, N-acylmethyltaurine salt, alkylammonium salt, betaine acetate, Examples include polyoxyalkylene alkyl ethers such as polyoxyethylene alkyl ether and polyoxyethylene polyoxypropylene alkyl ether, propylene glycol fatty acid esters, vitamin derivatives, glycyrrhizic acid, glycyrrhetinic acid, and derivatives thereof. Oleate, glyceryl monooleate, decaglyceryl monooleate, diglyceryldiolate, hexaglyceryl monolaurate, propylene glycol Stearate, POE (20) sorbitan monooleate, POE (60) sorbit tetraoleate, POE (40) monostearate, POE
(10) Oleyl ether, POE (10) nonylphenyl ether, POE (50) hydrogenated castor oil, POE
(5) Oleic acid amide, sodium lauryl sulfate, P
OE alkyl ether sodium sulfate, POE alkyl ether sodium acetate, tri-POE (10) alkyl ether phosphoric acid, stearyl trimethyl ammonium chloride, benzalkonium chloride, betaine lauryl dimethylamino acetate, egg yolk, lecithin, imidazolinium betaine, diethyl sebacate And the like. Examples of the preservative include benzoic acid, sodium benzoate, benzalkonium chloride, salicylic acid, methyl parahydroxybenzoate, propyl paraoxybenzoate, oxyquinoline sulfate, cresol, sodium citrate and the like.

Each of the above-mentioned optional components can be used in a usual amount as long as the effects of the present invention are not impaired.

In the acrylic pressure-sensitive adhesive, the (co) polymer of an alkyl (meth) acrylate obtained from an aliphatic alcohol having 4 to 18 carbon atoms and (meth) acrylic acid, A copolymer of the above-mentioned alkyl (meth) acrylate and other functional monomers is preferably used.

Examples of the (meth) acrylate include butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate. , Stearyl acrylate, methyl methacrylate, butyl methacrylate, isobutyl methacrylate, 2-methacrylic acid
Examples include ethylhexyl, isooctyl methacrylate, isodecyl methacrylate, lauryl methacrylate, and stearyl methacrylate. Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group, and a monomer having an amino group. Examples of the monomer having a hydroxyl group include hydroxyalkyl (meth) acrylates such as 2-hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate. Examples of the monomer having a carboxyl group include α, β unsaturated carboxylic acids such as acrylic acid and methacrylic acid, monoalkyl maleates such as butyl maleate, maleic acid, fumaric acid, crotonic acid and the like. Maleic anhydride also provides the same (co) polymerization component as maleic acid. Examples of the monomer having an amide group include alkyl (meth) acrylamides such as acrylamide, dimethylacrylamide, and diethylacrylamide; butoxymethylacrylamide,
Examples include alkyl ether methylol (meth) acrylamide such as ethoxymethylacrylamide, diacetone acrylamide, and vinylpyrrolidone. Examples of the monomer having an amino group include dimethylaminoacrylate. Other copolymerizable monomers and vinyl acetate,
Examples thereof include styrene, α-methylstyrene, vinyl chloride, acrylotrile, ethylene, propylene, and butadiene, and these may be copolymerized. The pressure-sensitive adhesive preferably contains 30% or more of (meth) acrylic acid alkyl ester as a (co) polymerization component.

As the rubber-based pressure-sensitive adhesive, natural rubber, synthetic isoprene rubber, polyisobutylene, polyvinyl ether, polyurethane, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer and the like are used. As the silicone resin-based pressure-sensitive adhesive, silicone rubber such as polyorganosiloxane is used.

Further, when the external preparation composition of the present invention is used as an adhesive base, in addition to the above components, various compounding agents such as a rosin-based resin and a polyterpene resin may be used as needed.
Coumarone-indene resin, petroleum resin, tackifier such as terpene phenol resin, liquid polybutene, mineral oil, lanolin, liquid polyisoprene, liquid polyacrylate,
Plasticizers such as latex, various polyvalent metal salts as cross-linking gelling agents, organic cross-linking agents such as dialdehyde starch, liquid paraffin, vegetable oil,
Appropriate components such as lard, beef tallow, higher alcohols, higher fatty acids, and activators can be blended.

As a support of the above-mentioned patch base, a support usually used for a patch is used. Materials for such a support include cellulose acetate, ethyl cellulose, polyethylene terephthalate, vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride. , Aluminum and the like. These are used, for example, as a single-layer sheet (film) or a laminate of two or more sheets (laminate). Materials other than aluminum may be used as a woven or nonwoven fabric.

As long as the effects of the present invention are not impaired, the external preparation composition of the present invention may contain, in addition to the above essential components, water-soluble components, preservatives, pH adjusters, thickeners, Agents, antioxidants, fragrances, dyes, and the like can be appropriately added as necessary.

The preparation method is not particularly limited, and it can be prepared according to a conventional method of various dosage forms. For example, when used as a patch, the above components are kneaded to prepare a paste. Then, this is obtained by applying the above-mentioned support to the above-mentioned support, and, if necessary, coating facing such as a polyethylene film. Further, for example, in the case of an acrylic, rubber, or silicone-based pressure-sensitive adhesive composition, a pressure-sensitive adhesive layer containing a drug, a clay mineral, and polyethylene glycol is formed on the surface of the support to obtain a patch. In order to form the pressure-sensitive adhesive layer, various coating methods such as a solvent coating method, a hot melt coating method, and an electron beam emulsion coating method can be used.

Further, in the case of a liquid preparation such as an ointment and a lotion, a solvent as a base, an oil component, glycols, a surfactant, a water-soluble polymer compound and the like can be blended. , As a solvent, for example, water, ethanol, propyl alcohol, isopropyl alcohol,
As oil components such as acetone and benzyl alcohol, for example, lanolin, hydrogenated oil, lecithin, plastibase, liquid paraffin, oleic acid, stearic acid, myristic acid, palmitic acid, beeswax, paraffin wax, microcrystalline wax, diisopropyl adipate, myristic acid Isopropyl, isopropyl sebacate, isopropyl palmitate, squalane, squalene, cetanol, stearyl alcohol, oleyl alcohol, hexadecyl alcohol, silicone oil, etc., as glycols, such as glycerin, propylene glycol, polypropylene glycol, etc., as a surfactant, Polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid Steal, polyoxyethylene glycol fatty acid ester, polyoxyethylene glycol ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene alkyl ether, polyoxyalkylene alkyl ether such as polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene phytosterol, sorbitan Fatty acid esters,
As a water-soluble polymer compound such as glycerin fatty acid ester, carboxyvinyl polymer, sodium carboxymethylcellulose, polyvinyl alcohol, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, polyacrylic acid, etc. .

When prepared as an ointment or liquid, it can be produced by a conventional method. In the case of an ointment, for example, it can be prepared by sequentially adding the above-mentioned components to the above solvent and kneading for an appropriate time. If so, for example, it can be prepared by sequentially adding and dissolving each of the above components to the above solvent.

In the case of a gel, a gelling agent such as a carboxyvinyl polymer or glycerin monooleate can be added in addition to the optional components of the above-mentioned liquid. For example, it can be prepared by sequentially adding and dissolving each of the above components other than the gelling agent to the above solvent, and then adding the gelling agent to cause gelation.

Further, other external preparation compositions can be produced by a usual method using components according to the kind.

The external preparation composition of the present invention is applied and rubbed on the skin in the same manner as the known external preparation containing the above-mentioned drug, whereby the above-mentioned drug is rapidly and continuously transdermally absorbed. Due to such excellent transdermal absorption, the efficacy of the drug is remarkably improved, and the feeling upon use is also excellent.

[0052]

According to the present invention, not only the solubility of a drug having a carboxyl group in the molecule can be improved to enhance the transdermal absorbability, and its pharmacological action can be maximized, but also the feeling of use can be improved. Is obtained.

[0053]

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 21 and Comparative Examples 1 to 13 Each of the components shown in Tables 1 and 2 was mixed and stirred by a Henschel mixer according to a conventional method to obtain Examples 1 to 21 and Comparative Examples 1 to 13.
Was prepared. 100 g /
m ² , and the mixture was uniformly applied, and the polyethylene film was faced to produce a patch. For each patch, the blood concentration was measured according to the following method to determine the efficacy of the drug (quick-acting, long-lasting), the stability of the drug in the formulation,
Skin irritation was evaluated. The results are shown in Tables 1 and 2. In the following table, POE means polyoxyethylene, and POP means polyoxypropylene.
Hydrocortisone is a drug having no carboxyl group in the molecule.

<Measurement of Blood Concentration> Ten Wistar male rats (5 to 6 weeks of age) were subjected to the experiment as a group. Rats had their backs shaved the day before the experiment. On the day of the experiment, a patch having a size of 5 × 8 cm was applied to the shaved portion, and the animals were kept in individual cages. Rat blood was collected 2 hours and 8 hours after application of the sample. The collected blood was subjected to high performance liquid chromatography analysis according to a conventional method, and the blood concentration of each drug was calculated from a predetermined calibration curve. The blood concentration 2 hours after application of the sample was used as an index of the immediate effect of each drug, and the blood concentration 8 hours after application of the sample was used as an index of sustainability of each drug.

<Evaluation of stability>
It was stored for 6 months under the condition of 75% humidity, and the drug content was analyzed by high performance liquid chromatography according to a conventional method.
The content of each drug was calculated from a calibration curve determined in advance, and the residual ratio (% by weight) of the drug after storage relative to the drug amount before storage, which was similarly measured immediately before the start of the storage test, was calculated by the following formula. Calculated. Persistence of drug = amount of drug after storage / amount of drug before storage x
100

<Skin irritation test> Male rabbits were used for the test. Prior to the administration of the sample, a rabbit having a good health condition was selected, and the back was shaved with a hair clipper, and 10 were selected as animals to be used.

The sample was cut into a size of 2.5 × 2.5 cm, attached to the depilated back of a rabbit, and the specimen was removed 24 hours later.

Observation of the skin reaction was performed 24 hours after removing the specimen.
Went after hours. In the judgment, a score was given according to the judgment criteria as shown below, and an average value was calculated. When the average point of skin irritation was 4.0 or more, the feeling of use was judged to be good.

[0060]

[0061]

[Table 1]

[0062]

[Table 2]

Examples 22 to 33 Examples 22 to 33 were carried out in the same manner as in Examples 1 to 21 using the components shown in Table 3.
3 patches were prepared. Example 1 for each patch
The efficacy (quick-acting effect, persistence), stability, and skin irritation were evaluated in the same manner as in Examples 21 to 21.
It showed the same excellent efficacy as that of No. 1, and also showed that the medicinal component in the patch had good stability and good feeling in use.

[Table 3]

Examples 34 to 36, Comparative Examples 14 and 15
Examples 34 to 36 using the components shown in Table 4 in a conventional manner.
And the creams of Comparative Examples 14 and 15 were prepared. 0.5 x 8 g of each cream (sample) was placed on the back of a shaved rat.
cm, and blood was collected after 2 hours and 8 hours, and the drug concentration was measured in the same manner as in Example 1 to determine the effectiveness (rapid effect, sustainability) of each cream. The evaluation was performed in the same manner as in Example 1. In addition, 100% of each cream
Collect μl and fin chamber (Taisho Pharmaceutical Co., Ltd.)
And attached to the depilated back of a rabbit. After 24 hours, it was removed and the application site was gently washed with water soaked cotton. 24 hours after washing, skin reaction was observed,
Skin irritation was evaluated in the same manner as described above. The results are also shown in Table 4.

[0065]

[Table 4]

[Examples 37-48] Using the components shown in Table 5, the same procedures as in Examples 34-36 were carried out.
Forty-eight creams were prepared. Effectiveness (quick-acting, long-lasting) for each cream as in Examples 34-36 above
When the skin irritation was evaluated, it was found that all of them exhibited the same excellent efficacy as those of Examples 34 to 36, and also had excellent feeling upon use.

[0067]

[Table 5]

[Examples 49 to 51, Comparative Examples 16 and 17]
Examples 49 to 51 were prepared using the components shown in Table 6 in a conventional manner.
And the gel agent of Comparative Examples 16 and 17 was prepared. For each gel, the effectiveness (rapid effect, sustainability) and skin irritation were evaluated in the same manner as in Examples 34 to 36 above. The results are also shown in Table 7.

[0069]

[Table 6]

Examples 52 to 63 In the same manner as in Examples 49 to 51, but using the components shown in Table 7,
63 gels were prepared. The effectiveness (quick-acting effect, long-lasting) and skin irritation of each gel were evaluated in the same manner as in Examples 49 to 51.
The same excellent efficacy as that of No. 1 was exhibited, and it was also recognized that the feeling of use was excellent.

[0071]

[Table 7]

[Examples 64 to 66, Comparative Examples 18 and 19]
Examples 64 to 66 were carried out in the usual manner using the components shown in Table 8.
And the lotions of Comparative Examples 18 and 19 were prepared. Each lotion was evaluated for drug efficacy and skin irritation in the same manner as described above. The results are also shown in Table 8.

[0073]

[Table 8]

[Examples 67 to 78] The components of Examples 67 to 78 were prepared in the same manner as in Examples 64 to 66 using the components shown in Table 9.
78 lotions were prepared. Each lotion was evaluated for effectiveness (quick action, long-lasting) and skin irritation in the same manner as in Examples 64 to 66, and all showed the same excellent efficacy as Examples 64 to 66. It was also found that it had excellent usability.

[0075]

[Table 9]

[Examples 79 to 81, Comparative Examples 20 and 21]
Examples 79 to 8 were prepared using the components shown in Table 10 in a conventional manner.
1 and Comparative Examples 20 and 21 were prepared. The efficacy and skin irritation of each ointment were evaluated in the same manner as described above.
The results are shown in Table 10.

[0077]

[Table 10]

[Examples 82 to 93] The same procedures as in Examples 79 to 81 were carried out except that the components shown in Table 11 were used.
~ 93 ointments were prepared. Each ointment was evaluated for effectiveness (rapid action, long-lasting) and skin irritation in the same manner as in Examples 79 to 81.
It showed the same excellent efficacy as 81 and was also excellent in usability.

[0079]

[Table 11]

[Examples 94 to 96, Comparative Examples 22 and 23]
Examples 94 to 9 were conducted in the usual manner using the components shown in Table 12.
6 and Comparative Examples 22 and 23 were prepared. The effectiveness and skin irritation of each aerosol were evaluated as described above. The results are shown in Table 12.

[0081]

[Table 12]

Examples 97 to 108 Example 9 was carried out in the same manner as in Examples 94 to 96 using the components shown in Table 13.
7-108 aerosols were prepared. When each of the aerosols was evaluated for effectiveness (rapid effect, long-lasting) and skin irritation in the same manner as in Examples 94 to 96, all of the aerosols exhibited excellent efficacy similar to those in Examples 94 to 96,
Also, it was recognized that the feeling of use was excellent.

[0083]

[Table 13]

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Kiyoshi Kudo 1-3-7, Honjo, Sumida-ku, Tokyo Inside Lion Corporation (72) Inventor Shinichi Nagashima 1-3-7, Honjo, Sumida-ku, Tokyo F term in Lion Corporation (reference) 4C076 AA07 AA09 AA16 AA24 AA72 BB31 CC05 DD08 DD09 DD28 DD29 DD34 DD38 DD39 DD46 DD49 DD50 DD70 EE06 EE09 EE23 EE32 EE53 EE58 FF31 FF34 FF56

Claims (1)

[Claims] 1. A drug having at least one carboxyl group in a molecule, at least one or more clay minerals comprising a layered silicate represented by the following general formula (1) or (2): An external preparation composition comprising polyethylene glycol. _{[(Si 8-y Al y} ) (M (III) a M (II) b Li c) O 20 (OH) 4-x F x] n - · A z + n / z ··· (1) ( where Wherein M (III) is a trivalent metal ion;
(II) is a divalent metal ion, A is an exchangeable cation, x is a number satisfying the relationship 0 ≦ x ≦ 4.0, and y is 0 ≦
It is a number that satisfies the relationship y ≦ 3.0, and a, b, and c are
0 ≦ a ≦ 5.0, 0 ≦ b ≦ 7.0, 0 ≦ c ≦
2.5, a number satisfying the relationship of 3 <(a + b + c) <7,
n is a number satisfying 0 <n ≦ 2.0, and z is 1, 2 or 3. _{) [Si 8 (Mg p Li} s) O 20 F 2] B s ··· (2) ( where, the formula B is lithium or sodium,
p is a number satisfying the relationship of 3.5 ≦ p ≦ 5.5, and s is 0 ≦
This is a number that satisfies the relationship of s ≦ 3.0. )