JP2001026551A - Method for improving efficacy and stability of medicament, and composition of external use preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition excellent in efficacy and stability of a medicament therein, and markedly improved in feeling when applied to the skin. SOLUTION: This composition comprises a medicament having in the molecule at least one carboxyl group, at least one kind of clay mineral comprising a phyllosilicate of the formula described below, and a water-soluble polymeric compound. When this composition is dissolved in an appropriate solvent, the resultant solution is acidic; 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]

FIELD OF THE INVENTION The present invention relates to a method for improving the efficacy and stability of a drug having at least one carboxyl group in a molecule contained in a pharmaceutical preparation and the above-mentioned drug incorporated in a composition. The present invention relates to an external preparation composition which is excellent in the efficacy and stability in a composition, and has a markedly improved feeling of use when applied to the skin.

[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, both dermatological diseases and orthopedic diseases often use components having an anti-inflammatory effect, and as such components, acidic drugs having at least one or more carboxyl groups in the molecule are frequently used. However, if these drugs are stored for a long period of time under weak alkaline conditions, the drug in the preparation may be degraded and the medicinal properties at the time of manufacture may not be obtained. It is desirable to make it acidic.

However, in the case of a drug having a carboxyl group, it tends to be in a molecular form under acidic conditions and its solubility is low. However, there is a problem that the efficacy as a drug is lowered.

[0005] Therefore, these drugs are solubilized and dissolved in an oil component such as crotamiton to mix and enhance the efficacy, or the drugs are suspended in glycerin to stabilize the drugs in the preparation. A technique for improving the performance has been proposed.

However, in the case of these proposals, there is still room for improvement in the efficacy, stability and feeling of use of a drug having a carboxyl group in the molecule, and the stability of the drug having a carboxyl group in the molecule has to be improved. There has been a demand for a technique for increasing the efficiency, improving the effectiveness, and further improving the feeling of use.

[0007] The present invention has been made in view of the above circumstances,
A method for further improving the effectiveness and stability of a drug having a carboxyl group in the molecule, and an external preparation composition which is excellent in the efficacy and stability of the drug and the stability in the composition, and further improves the usability. The purpose is to provide.

[0008]

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. We came to focus on having different properties, and after further intensive studies, combining the above clay mineral and a water-soluble polymer compound and blending them with a drug having a carboxyl group in the molecule, even under acidic conditions The drug is quickly and continuously percutaneously absorbed,
The efficacy of the external preparation composition as a main drug is remarkably improved, so that not only the pH of the preparation can be stabilized to stabilize the drug and the feeling of use can be improved, but also the clay mineral can be improved. Thus, the present invention has been found to provide a better feeling of use, and the present invention has been accomplished.

That is, the present invention relates to a method for improving the efficacy and stability of a drug having at least one carboxyl group in a molecule contained in a preparation, wherein the drug has the following general formula (1) ) Or at least one clay mineral comprising a layered silicate represented by the following general formula (2) and a water-soluble polymer compound, and at the same time, the efficacy of a drug characterized by making the liquid acidic. A method for improving stability, and a drug having at least one or more carboxyl groups in a molecule and at least one or more clays comprising a layered silicate represented by the following general formula (1) or (2) Provided is an external preparation composition comprising a mineral and a water-soluble polymer compound, and having an acidic liquidity.

[0010] _{[(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 M (III) is a trivalent metal ion, M
(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 present invention uses a drug having a carboxyl group in the molecule, a clay mineral having the above specific composition, and a water-soluble polymer compound.

The type of the drug used in the present invention is not particularly limited as long as it has a carboxyl group in the molecule, but the drug used as a nonsteroidal anti-inflammatory drug is preferred. Further, 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, acemethacin, amidetrizoic 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, Methiazic acid, L-methionine, Methyldopa, Neostigmine methylsulfate, Methotrexate, Mefenamic acid, Melphalan, Folic acid, Iodamide, Hydrocortisone butyrate, Latamoxef sodium, Rameside, Riome Examples include, but are not limited to, thyronine sodium, rifampicin, atropine sulfate, vincristine sulfate, bleomycin sulfate, peplomycin sulfate, polymyxin B sulfate, reserpine, levothyrosine sodium, levodopa, L-leucine, loxoprofen, loxoprofen sodium and the like. Not something. 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.

The present invention further uses at least one kind of clay mineral 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 a hydrogen ion, a sodium ion, a potassium ion, or a lithium ion; an alkaline earth metal ion such as calcium or magnesium;
Monovalent metal ions such as silver ions as metal ions other than these alkali metal ions and alkaline earth metal ions;
Metal ions such as divalent metal ions such as zinc ion and iron ion; and trivalent metal ions such as aluminum ion. Alkanolamine groups such as monoethanolamine, diethanolamine and triethanolamine, and trimethylammonium And organic groups such as an alkyl quaternary ammonium group such as tert.

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 present invention further uses a water-soluble polymer compound. Examples of the water-soluble polymer compound include gelatin, polyacrylic acid, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, and carboxy. Examples include sodium methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, sodium alginate, xanthan gum, arabia gum, tragacanth gum, karaya gum, maleic anhydride copolymer, polyethylene glycol and the like. These can be used alone or in an appropriate combination of two or more.
In the case of the present invention, it is more effective to use polyacrylic acid and / or polyacrylate among them.

In the case of the present invention, it is necessary that the liquidity of the preparation is acidic, and it is preferable that the pH is in the range of 2.5 to 7, more preferably in the range of 3 to 5.5. p
If the H is too low, the drug is difficult to dissolve, and it may be difficult to obtain sufficient efficacy. If the H is too high, the stability of the drug in the preparation is reduced, and sufficient efficacy cannot be obtained. In addition, the feeling of use when applied to the skin is deteriorated. The pH of the formulation
Is adjusted to the above range, a pharmaceutically acceptable acidic compound can be used in a usual amount.

A method for improving the efficacy and stability of the drug of the present invention is to use the above drug in combination with the above clay mineral and a water-soluble polymer compound and to make the liquidity of the preparation acidic, whereby the above drug is used. Improves the stability in the formulation, and improves the solubility of the drug, enhances the drug absorption by percutaneous absorption, etc., and exerts a rapid and sustained drug effect, thereby improving the efficacy of the drug. Is to improve the performance.

Here, the mixing ratio of each component is not particularly limited, and can be appropriately selected depending on the type of each component, the dosage form of the preparation, the method of application, and the like.
The mixing ratio (weight ratio) of the clay mineral and the water-soluble polymer compound is such that the drug: the clay mineral = 10: 1 to 1
1: 100, especially 5: 1 to 1:50, the drug: the water-soluble polymer compound = 100: 1 to 1: 500, particularly 10
0: 1 to 1: 300 is preferable. Outside the above range, it may be difficult to sufficiently obtain the effects aimed at by the present invention. The mixing ratio of each of the above components is
When two or more of the components are blended, the total amount is used.

The method for improving the efficacy and stability of the drug of the present invention is not particularly limited with respect to the use and kind of the preparation to be applied, and can be used for various preparations containing the above drug as a main drug. It is particularly effective when applied to an external preparation composition as described below.

The external preparation composition of the present invention is a composition containing the above-mentioned drug, the above-mentioned clay mineral and the above-mentioned water-soluble compound and having an acidic liquidity. And the amount of the water-soluble polymer compound is not particularly limited, for example, the amount of the drug,
It is a drug effective amount as a medicinal component of the external preparation, and is usually 0.01 to 10% (% by weight, the same applies hereinafter), preferably 0.1 to 5% based on the whole composition. 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 amount of the clay mineral (the total amount when two or more types are mixed) is usually 0.01 to 10%, preferably 0.01 to 7%, more preferably 0.01 to 7% based on the whole composition. Is 0.01 to 5%, more preferably 0.01 to 5%.
It is suitable to be 3%. If the amount is too small, for example, when used as a patch base, sufficient shape retention may not be obtained, and if too large, the patch base may be too hard to spread.

The compounding amount of the water-soluble polymer compound in the composition of the present invention is usually from 0.01 to 0.01 relative to the whole composition.
It is preferable to set it to 40%, especially 0.1 to 30%. If the amount is too small, it may be difficult to sufficiently obtain the effect of the compounding. If the amount is too large, the viscosity may be too high, leading to a decrease in productivity. In addition, also in the composition of the present invention, the above-mentioned mixing ratio is preferable as the mixing ratio of the three components.

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) and the like can be used. 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 if the adhesive has an adhesive force capable of fixing the patch to the skin surface at normal temperature for a long time, and is not particularly limited.For example, a water-containing adhesive, an acrylic adhesive, a rubber adhesive, and a silicone resin adhesive can be used. In the case of the present invention,
Of these, the use of a water-containing adhesive base is particularly effective.

When prepared as a water-containing adhesive base, it is preferable to use polyacrylic acid and / or polyacrylate as described above as the water-soluble polymer compound. The molecular weight and the shape such as linear or branched chain are not particularly limited, but those having a molecular weight of 10,000 to 10,000,000 are preferable, and the weight average molecular weight is particularly preferably 10,000 to less than 500,000. It is preferable to combine two or more types of polyacrylic acid having an average molecular weight of from 500,000 to less than 2,000,000 and from 2,000,000 to 7,000,000, since the feeling of 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 Carpopol (trade name: manufactured by Goodrich Corporation in the United States) is also preferably used. 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.

When polyacrylic acid and polyacrylate are used in combination, the mixing ratio (weight ratio) thereof is 1:10 to 10: 1, particularly 1: 9 to 9: 1. However, it is also possible to use one obtained by partially neutralizing polyacrylic acid or a salt so that the polyacrylate has the above-mentioned ratio. Further, the total blending amount of polyacrylic acid and polyacrylate is 0.1 to 0.1% of the whole composition.
If the amount is too small, the adhesive strength may be insufficient. If the amount is too large, the viscosity becomes high, and there is a problem in workability during production, Pain may be felt when the patch is peeled off, and particularly when the amount of polyacrylic acid is too large, the feeling of use may be poor in a low pH region.

It is also preferable to use one of the above water-soluble polymer compounds other than polyacrylic acid and salts thereof alone or in combination of two or more as appropriate. It is preferable to use them in combination.

The external preparation composition of the present invention may contain, if necessary, components usually used in the external preparation composition, if necessary, in addition to the above essential components, as long as the effects of the present invention are not impaired. If prepared as the water-based adhesive base, if necessary, further curing agent, curing regulator, inorganic powder other than the clay mineral, fragrance, plant extract, medicinal ingredients other than the drug, humectant, An emulsifier, a preservative and the like can be blended.

Here, as the curing agent, for example, magnesium aluminate silicate, magnesium aluminate hydroxide,
Magnesium aluminate metasilicate, synthetic hydrotalcite, dihydroxyaluminum amino acetate, potassium alum, ammonium alum, aluminum hydroxide, calcium hydroxide, aluminum potassium sulfate, synthetic aluminum silicate, aluminum chloride, aluminum metasilicate, calcium phosphate, silicate Examples thereof include aluminum compounds such as magnesium, magnesium compounds, and calcium compounds. One or more water-soluble or poorly water-soluble compounds such as double salts containing these metals can be used.

Examples of the curing regulator for regulating the curing by the curing agent include citric acid, malic acid, tartaric acid, disodium edetate, sodium pyrophosphate and the like. Examples of the inorganic mineral (mineral powder) other than the clay mineral include kaolin, zinc oxide, titanium oxide, and silicic anhydride.

Examples of fragrances include fennel oil, castor oil, mint oil, mint oil, daisy oil, cauliflower oil, clove oil, thymian oil, turpentine oil, henoposi oil, yamadine 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 humectant include glycerin, sorbitol, 1,3-butylene glycol, propylene glycol 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 case of acrylic pressure-sensitive adhesives, (co) polymers of alkyl (meth) acrylates obtained from aliphatic alcohols 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-mentioned components, various compounding agents such as rosin-based resin and polyterpene resin may be added to the base, if necessary.
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.

The preparation method of the external preparation of the present invention is not particularly limited, and can be prepared according to a conventional method of various dosage forms. Knead the ingredients to prepare a paste,
If necessary, the liquid property is adjusted to be acidic, and this is applied to the above-mentioned support, and if necessary, coated with a facing such as a polyethylene film. Further, for example, in the case of an acrylic, rubber, or silicone-based pressure-sensitive adhesive composition, the surface of the support contains the drug, the clay mineral, and the water-soluble polymer compound, and a liquid-based pressure-sensitive adhesive layer is formed. Thus, a patch is obtained. 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 and the like can be blended. , Ethanol, propyl alcohol, isopropyl alcohol, acetone, benzyl alcohol, etc., as oil components such as lanolin, hydrogenated oil, lecithin, plastibase, liquid paraffin, oleic acid, stearic acid, myristic acid, palmitic acid,
Beeswax, paraffin wax, microcrystalline wax, diisopropyl adipate, isopropyl myristate, isopropyl sebacate, isopropyl palmitate, squalane, squalene, cetanol, stearyl alcohol, oleyl alcohol, hexadecyl alcohol, silicone oil, etc. As surfactants such as glycerin and propylene glycol, for example, polyoxyethylene alkyl ether,
Polyoxyalkylene alkyl ethers such as polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene glycol fatty acid ester, polyoxyethylene glycol ether, Polyoxyethylene alkyl phenyl ether, polyoxyethylene phytosterol, sorbitan fatty acid ester, glycerin fatty acid ester and the like can be blended.

When prepared as an ointment or liquid, it can be manufactured by a conventional method. In the case of an ointment, for example, each of the above-mentioned components is sequentially added to the above-mentioned solvent and kneaded for an appropriate period of time. In the case of a liquid preparation, for example, it can be prepared by sequentially adding and dissolving each of the above-mentioned components in the above-mentioned solvent, and adjusting the liquid property to acidic if necessary.

In the case of a gel, a gelling agent such as carboxyvinyl polymer and glycerin monooleate can be added in addition to the optional components of the above-mentioned liquid. For example, each of the above-mentioned components other than the gelling agent is sequentially added to and dissolved in the above-mentioned solvent,
It can be prepared by adjusting the liquid property to acidic if necessary and then adding a gelling agent to cause gelation.

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

The composition for external use of the present invention has good stability in the above-mentioned drug in the composition, so that the medicinal effect at the beginning of the production is maintained, and the composition is prepared in the same manner as in the known external preparation containing the above-mentioned drug. By applying to the skin and rubbing it, the drug is quickly and continuously transdermally absorbed, and the excellent transdermal absorbability provides a drug effect with excellent fast-acting and long-lasting properties. The efficacy is remarkably improved, and there is no problem in skin irritation and the feeling of use is excellent. In addition, the external preparation composition of the present invention contains indomethacin, the above clay mineral, and polyacrylic acid and / or a salt thereof, and has a liquid pH of
It is particularly effective when prepared as a water-containing adhesive base having a value of 5.5 or less.

[0056]

According to the method for improving the efficacy and stability of a drug of the present invention, the stability of a drug having a carboxyl group in the molecule in a preparation is improved, and the effect of the drug is rapid and sustained. Therefore, the method for improving the efficacy and stability of the drug of the present invention is useful for formulations for various uses containing the drug. In addition, according to the external preparation composition of the present invention, not only is the stability of the drug having a carboxyl group in the molecule excellent in the composition, and the drug is not only highly effective, but also when applied to the skin. An external preparation composition with significantly improved feeling in use can be obtained.

[0057]

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 18 The components shown in Tables 1 and 2 were mixed and stirred with a Henschel mixer according to a conventional method, to thereby obtain Examples 1 to 21 and Comparative Examples 1 to 18.
Was prepared. 100 g /
m ² , and a 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 rapid effect of each drug, and the blood concentration 8 hours after application of the sample was used as an index of the persistence of the effect 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 subjected to 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.

The skin reaction was observed 24 hours after the specimen was removed.
Went after hours. In the judgment, a score was given according to the following criterion, 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.

[0064]

[0065]

[Table 1]

[0066]

[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 excellent efficacy similar to that of No. 1, and also showed that the drug in the patch had good stability and further excellent feeling in use.

[0068]

[Table 3]

Examples 34 to 36, Comparative Examples 19 to 21
Examples 34 to 36 using the components shown in Table 4 in a conventional manner.
And the creams of Comparative Examples 19 to 21 were prepared. Except that 0.5 g of each cream was applied to the shaved portion in a size of 5 × 8 cm, the effectiveness (rapid effect, persistence) and stability of each cream were evaluated in the same manner as in Example 1 above. . Also, 100 μl of each cream was collected and dropped on a filter paper of a fin chamber (manufactured by 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. The skin reaction was observed 24 hours after washing, and the skin irritation was evaluated in the same manner as described above. The results are also shown in Table 4.

[0070]

[Table 4]

Examples 37 to 48 Using the components shown in Table 5, the same procedures as in Examples 34 to 36 were carried out.
Forty-eight creams were prepared. When the effectiveness (quick-acting effect, persistence), stability and skin irritation of each cream were evaluated in the same manner as in Examples 34 to 36, all of the creams exhibited the same excellent effectiveness as Examples 34 to 36. Show,
It was also found that the drug stability in the preparation was excellent, and that the feeling in use was also excellent.

[0072]

[Table 5]

[Examples 49 to 51, Comparative Examples 34 to 36]
Examples 49 to 51 were prepared using the components shown in Table 6 in a conventional manner.
And the gel agent of Comparative Examples 34-36 was prepared. Effectiveness (rapid effect, long-lasting), stability and skin irritation were evaluated in the same manner as in Examples 34 to 36 except that the amount of each gel applied to the shaved portion was 0.5 g. Table 6 shows the results
It is described together.

[0074]

[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. Each gel was evaluated for effectiveness (quick-acting, long-lasting), stability and skin irritation in the same manner as in Examples 49 to 51, and all of the gels showed the same excellent effectiveness as Examples 49 to 51. In addition, it was also confirmed that the drug stability in the preparation was excellent and the feeling in use was excellent.

[0076]

[Table 7]

[Examples 64 to 66, Comparative Examples 37 to 39]
Examples 64 to 66 were carried out in the usual manner using the components shown in Table 8.
And the lotions of Comparative Examples 37 to 39 were prepared. 0.5 g of the amount of each lotion applied to the shaved part
The efficacy, stability, and skin irritation of the drug were evaluated in the same manner as described above, except for the above. The results are also shown in Table 8.

[0078]

[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 (rapid effect, long-lasting), stability and skin irritation in the same manner as in Examples 64 to 66, and all showed the same excellent effectiveness as Examples 64 to 66. Show,
It was also found that the drug stability in the preparation was excellent, and that it was also excellent in use feeling.

[0080]

[Table 9]

[Examples 79 to 81, Comparative Examples 40 to 42]
Examples 79 to 8 were prepared using the components shown in Table 10 in a conventional manner.
1 and Comparative Examples 40 to 42 were prepared. Effectiveness, stability and skin irritation were evaluated in the same manner as described above, except that the amount of each ointment applied to the shaved portion was 0.5 g. The results are shown in Table 10.

[0082]

[Table 10]

[Examples 82 to 93] Using the components shown in Table 11, the procedure of Example 82 was repeated in the same manner as in Examples 79 to 81.
~ 93 ointments were prepared. When the effectiveness (quick-acting effect, persistence), stability and skin irritation of each ointment were evaluated in the same manner as in Examples 79 to 81, all of the ointments exhibited the same excellent effectiveness as Examples 79 to 81. In addition, it was confirmed that the drug was excellent in stability in the preparation and also excellent in feeling in use.

[0084]

[Table 11]

[Examples 94 to 96, Comparative Examples 43 to 45]
Examples 94 to 9 were conducted in the usual manner using the components shown in Table 12.
6 and Comparative Examples 43 to 45 were prepared. The effectiveness, stability and skin irritation of each aerosol were evaluated in the same manner as above, except that the spray amount in the shaved portion was 0.5 g. The results are shown in Table 12.

[0086]

[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. The effectiveness (quick-acting, long-lasting), stability, and skin irritation of each aerosol were evaluated in the same manner as in Examples 94 to 96. In addition, excellent drug stability in the formulation,
Also, it was recognized that the feeling of use was excellent.

[0088]

[Table 13]

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Tomomasa Koide 1-3-7 Honjo, Sumida-ku, Tokyo Inside Lion Corporation (72) Inventor Hiroshi Yamato 1-3-7, Honjo, Sumida-ku, Tokyo No. Lion Corporation F term (reference) 4C076 AA07 AA17 AA24 AA72 CC05 DD08 DD09 DD28 DD29 DD34 DD38 DD39 DD46 DD49 DD50 DD70 EE06 EE09 EE23 EE32 EE53 EE58

Claims (2)

[Claims] 1. A method for improving the efficacy and stability of a drug having at least one carboxyl group in a molecule contained in a preparation, wherein the drug is represented by the following general formula (1) or It is used in combination with at least one or more clay minerals comprising a layered silicate represented by the formula (2) and a water-soluble polymer compound, and improves the efficacy and stability of a drug characterized by making the liquid acidic. How to let. _{[(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. ) 2. 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 a water-soluble polymer compound and having an acidic liquidity. _{[(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. )