JPH0617316B2 - Transdermal formulation - Google Patents

Description

TECHNICAL FIELD The present invention relates to a transdermal preparation capable of effectively absorbing a drug contained therein.

(Prior Art) In order to obtain systemic or local drug efficacy, a transdermal (including transmucosal) dosage form formulation can be used to absorb a drug (physiologically active substance) through the skin (including mucous membrane). Has been done. This transdermal administration method has many advantages over conventional oral administration methods. For example, when a drug is orally administered, the drug absorbed in the intestine is circulated to the liver and metabolized, so that a considerable amount of the drug is decomposed before its drug effect is exerted. In contrast, in the transdermal administration method, the absorbed drug does not pass through the liver during the first circulation in the body. Therefore, metabolism in the liver does not significantly reduce drug efficacy. Oral administration of non-steroidal anti-inflammatory drugs tends to cause gastrointestinal disorders,
Such gastrointestinal disorders are less likely to occur by transdermal administration. By controlling the absorbability of a drug, it is possible to reduce the side effects caused by a large amount of the drug being absorbed in a short time. The frequency of drug administration can be reduced if a constant blood concentration can be maintained for a long time.

However, even when a drug is administered using a percutaneous absorption preparation, the drug hardly penetrates the skin, and the bioavailability is low in many cases. On the other hand, studies have been conducted on improving the dosage form of percutaneous absorption preparations, improving a drug-containing base, and adding a percutaneous absorption enhancer. Among these, by the means of improving the dosage form and improving the base, some effects can be obtained depending on the kind of the drug contained, but an epoch-making improvement in absorption action cannot be expected. Therefore, research on a preparation containing a percutaneous absorption enhancer to enhance the percutaneous absorption of a drug is being pursued.

In percutaneous absorption of a drug, it is considered that the main cause is that the drug is not absorbed through the skin because the stratum corneum existing on the skin surface has a barrier function of preventing foreign substances from entering the body. Therefore, a preparation containing an absorption enhancer has been produced in order to weaken the barrier function of the stratum corneum and absorb a sufficient amount of the drug. Among the transdermal absorption enhancers contained in such preparations, for example, salicylic acid,
Urea and dimethyl sulfoxide are known to dissolve keratin, but even if these are added, the transdermal absorbability of the drug is not necessarily good. Propylene glycol, glycerin, sodium pyrrolidonecarboxylate, etc. can retain water in the stratum corneum, but almost no drug absorption promoting effect is observed. In addition to the above compounds, isopropyl myristate,
Organic acid esters such as isopropyl adipate; surfactants such as sodium lauryl sulfate and polyoxyethylene-20-sorbitan monolaurate; mixtures of thioglycerol, urea derivatives or pyrrolidone type compounds with halogenated hydrocarbons (special (Kaisho 60-13720); calcium thioglycolate (Japanese Patent Laid-Open No. 60-11431);
1-Substituted azacycloalkan-2-one- (Japanese Patent Publication No. 60-3
No. 7092) is also known. However, even if these absorption enhancers are used, the amount of the drug absorbed through the skin cannot be said to be sufficient, so that a practical potting effect is often not obtained. Among the above-mentioned accelerators, there are cases where they cause an offensive odor or the compounds themselves cause skin irritation and erythema or rash. Of the liquid absorption promoters, those that act as a strong solvent may dissolve the synthetic resin. Therefore, stimulants may be eluted from contacting drug containers, clothing, jewelry, etc., which may cause skin irritation. Furthermore, the absorption enhancer itself may be absorbed and may be toxic. Particularly in the case of transmucosal absorption preparations in which a drug is absorbed through the mucous membrane, irritation is more intense than in the case of skin, and it is often difficult to use it for a long time. Many compounds are highly toxic. Absorption enhancers currently used in transmucosal absorption preparations also have the drawback that the drugs that can be used are relatively limited. in this way,
The present situation is that a transdermal preparation that effectively absorbs a drug to give a sufficient potting effect and is highly safe for the skin has not yet been obtained.

(Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional drawbacks, and an object of the present invention is to provide a preparation capable of effectively absorbing the contained drug through the skin (including mucous membranes). To provide. Another object of the present invention is to provide a percutaneous absorption preparation which enhances percutaneous absorption of a drug contained therein and contains an absorption enhancer which is not irritating to the skin and is safe to the living body. Still another object of the present invention is to provide a percutaneous absorption preparation containing an absorption enhancer which does not change the properties of the base and does not cause modification of the contained drug.

(Means for Solving Problems) The inventors of the present invention focused on the action of a surfactant which has been conventionally used as a percutaneous absorption enhancer, and aimed to reduce the side effects thereof, in the field of biochemistry. We screened various nonionic surfactants, especially membrane protein-dissolving agents used in the above. As a result, they have found that a specific type of glucose derivative is useful as a transdermal absorption enhancer. Therefore, the percutaneous absorption preparation of the present invention contains D- (thio) -glucoside represented by the following formula (I) and / or (II) and a drug, thereby achieving the above-mentioned object: Wherein X is 0 or S; R ₁ and R ₂ are each independently a C ₄ -C ₂₀ saturated or unsaturated hydrocarbon residue, or C ₄ -C ₂₀ saturated or unsaturated with a polyoxyalkylene group. It is an unsaturated hydrocarbon residue.

In the present invention, for example, "transdermal absorption enhancer" also includes "transmucosal absorption enhancer". Thus, "transdermal"
The term includes not only “through the skin” but also “through the mucous membrane (oral mucous membrane, ocular mucous membrane, nasal mucosa, cavity mucosa, rectal mucosa, etc.)”. “Skin” includes “mucous membrane” unless otherwise noted.

Examples of the compound used as the absorption promoter in the present invention include n-butyl-D-glucopyranoside, n-octyl-α-D-glucopyranoside, and n-octyl-β-D-.
Examples thereof include glucopyranoside and n-octyl-β-D-thioglucopyranoside.

The above absorption enhancer is contained in the preparation in a proportion of 0.1 to 30% by weight. This ratio shows the content with respect to the whole preparation in the case of ointments, cream preparations, liquid preparations, suppositories, etc., and shows the content with respect to the drug content in patches such as tape preparations and poultices. The same applies to the drug content described below. If the amount of the absorption enhancer is too small, the absorption enhancing effect of the drug cannot be obtained. Even if it is excessive, not only the absorbability of the drug is not further improved, but the compatibility with the base may be deteriorated.

The drug (implanted active substance) used is not particularly limited as long as it can penetrate the biological membrane by transdermal administration.
Among the skin and mucous membranes, drugs that are administered via the skin include antiphlogistic analgesics, hormones, antiseptic disinfectants, antihistamines, antifungals, vitamins, absorption agents, ultraviolet absorbers, sequestering agents, Hypnotics / sedatives, psychotropic / antiepileptic agents, antiparkinsonian agents, cardiotonic agents, antiarrhythmic agents, antianginal agents, antihypertensive agents, antipruritic agents, red cell foaming agents, emollients, antiperspirant / deodorant agents , Hair care agents and the like.

Among the above drugs, anti-inflammatory and analgesic agents include ethyl aminobenzoate, dibucaine hydrochloride, tetracaine hydrochloride, procaine hydrochloride, lidocaine, methyl salicylate, guaiazulene, sodium guaiazulene sulfonate, aluminum chlorohydroxy allantoinate, bendazac,
Indomethacin, glycyrrhetinic acid, glycyrrhizinic acid, bufexamac, dextran, sodium sulfate, crotamiton, butyl flufenamic acid, allantoin, aloe powder, ictamol, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, β-glycyrrhetinic acid, glycyrrhetinyl stearate, glycyrrhetinic acid Examples include stearyl and hinokitiol.

Hormonal agents include hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, fluocinolone acetonide, flumethasone pivalate, fluocinonide, fluorometholone, beclomethasone propionate, dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, fludroxycortide, valeric acid. Betamethasone, betamethasone dipropionate, triamcinolone acetonide, prednisolone, methylprednisolone, methylprednisolone acetate, diflucortron valerate, clobetasol propionate, amcinonide, halcinonide, prednisolone valerate propionate hydrocortisone butyrate, and adrenal cortisone butyrate , Estrone, ethinyl estradiol, diethylstilbestol, Kisesutororu, there are other hormonal agents such as prostaglandins.

As disinfectants and bactericides, phenol, resorcin, salicylic acid, hexachlorophene, mercurochrome, thimerosal, acrinol, iodine, benzalkonium chloride, benzethonium chloride, penicillin V, benzapenicillin G, streptomycin, chloramphenicol,
Tetracycline, tetracycline hydrochloride, erythromycin, fradiomycin, fradiomycin sulfate, bacitracin, oxytetracycline hydrochloride, kanamycin sulfate, kanamycin, chloromycetin, polymyxin B, nitrofurazone, potassium permanganate, boric acid, borax, benzoic acid, sodium benzoate, Sodium salicylate, sorbic acid, potassium sorbate, dehydroacetic acid, sodium dehydroacetate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, isopropylmethylphenol, cresol, chlorxylenol, thymol, parachlor Phenol, Photosensitive No. 101,
Photosensitizer 201, chloramine T, thiantol, lysozyme chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, trichlorocarbanilide, 3-trifluoromethyl-4,4'-dichlorocarbanilide, hexachlorophene, etc.

Antihistamines include isothipendyl hydrochloride, diphenylimidazole, clemizole sulfate, diphenhydramine, diphenhydramine lauryl sulfate, chlorpheniramine maleate and the like; antifungal agents include chrysalopine, undecylenic acid, zinc undecylenate, pentachlorophenol acetate, phenylmercuric acetate, Thimerosal, tricomycin, tolnaftate, phenyliodoundecinoate, clotrimazole, haloprozin, variotin, pyrrolenitrin, siccanin, nystatin,
Examples include exalamide, ciclopirox olamine, miconazole nitrate, econazole nitrate, and isoconazole nitrate.

As vitamin agents, retinol, retinol acetate, retinol palmitate, dehydroretinol, ergocalciferol, dl-α-tocopherol, dl-α acetate
-Tocopherol, dl-α-tocopherol calcium succinate, ubiquinone, phytonadione, menaquinone,
Menadione, Thiamine Hydrochloride, Thiamine Nitrate, Thiamine Phosphate, Riboflavin, Flavin Mononucleotide, Riboflavin Butyrate, Pyridoxine Hydrochloride,
5'-pyridoxal phosphate, pyridoxine dicaprylate, pyridoxine dipalmitate, pyridoxine tripalmitate, cyanocobalamin, hydroxycobalamin, deoxyadenosylcobalamin, methylcobalamin, nicotinic acid, nicotinamide, benzyl nicotinate, calcium pantothenate, pantothene Sodium acid, pantothenyl alcohol, dicarboethoxy pantothenic acid ethyl ester / propylene glycol solution, acetyl pantothenyl ethyl ether, pantothenyl ethyl ether, biotin, folic acid, choline, inositol, ascorbic acid, sodium ascorbate, ascorbyl stearate, palmitin Acid ascorbyl and aspalbyl dipalmitate.

Absorption agents include zinc oxide, calamine, aluminum sulfate, lead acetate, bismuth subnitrate, bismuth subgallate, tannic acid, zirconium oxide chloride, allantoin chlorohydroxyaluminum, allantoin dihydroxyaluminum, aluminum hydroxychloride, zinc chloride, chloride Examples include aluminum, ferric chloride, calamine, chlorinated aluminum bromide, aluminum phenol sulfonic acid, aluminum naphthalene sulfonic acid, potassium aluminum sulfate, and zinc paraphenol sulfonate.

UV absorbers include urocanic acid, 2-ethoxyethyl 4-methoxycinnamate, ethyl paraamine benzoate, 2- (2-hydroxy-5-methylphenyl) benzotriazole, 2-hydroxy-4-methoxybenzophenone, etc. However, examples of the sequestering agent include disodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, and gluconic acid.
Hypnotics / sedatives include barbital, thiopental, chloral hydrate, potassium bromide, etc .; psychotropic / antiepileptic agents include chlorpromazine, reserpine,
Chlordiazepoxide, etc .; anti-Parkinson's disease agents, chlorzoxazone, levodopa, etc .; cardiotonics, digitoxin, digoxin, etc .; antiarrhythmic agents, procainamide hydrochloride, propranolol hydrochloride,
Lidocaine hydrochloride, indenolol hydrochloride, etc .; anti-anginal agents such as dipyridamole, amyl nitrite, nitroglycerin, isosorbide nitrate; anti-hypertensive agents such as reserpine, guanethidine sulfate; antipruritic agents ictamol, moctal , Camphor, thymol, diphenhydramine, chlorpheniramine, promethazine hydrochloride, N-ethyl-o-crotonotoluidine, etc .; as red-blowing foaming agents, cantharis, capsicum tincture, ictamol, turpentine oil, bismuth subgallate, etc .; Emollients include purified sulfur, precipitated sulfur, salicylic acid, urea, etc .; perspiration and deodorants include aluminum chloride, aluminum sulfate, aluminum acetate,
Aluminum phenolsulfonate, sodium perborate, etc .; For hair agents, selenium disulfide, alkylisoquinolinium bromide, zinc pyrithione, biphenamine, thiantol, canthari tincture, tincture of tincture, tincture of tincture, potassium bromate , Sodium bromate, carpronium chloride, acetylcholine chloride, pilocarpine chloride, vitamin A oil, etc.

Drugs administered via the mucous membrane include anti-inflammatory agents, hypnotic sedatives, nerve agents, antibiotics, antineoplastic agents, antihistamines, sulfa agents, cardiotonics, antiarrhythmic agents, antianginal agents, antihypertensive agents. , Polysaccharide bioactive substances, peptide type antitumor substances, enzyme agents, peptide hormones, peptide hormone releasing / suppressing factors, polynucleotides and the like.

Among the above drugs, anti-inflammatory agents include acetylsalicylic acid, acetaminophen, aminopyrine, indomethacin, meptatinol, ibuprofen, pentazocine,
Naproxen, sodium salicylate, oxyphenbutazone, tinoridine hydrochloride, feprazone, flufenamic acid, mefenamic acid, prednisolone, dexamethasone,
Examples include hydrocortisone acetate and acetanilide. Phenobarbital, chloral hydrate, diazepam, etc., as hypnotic sedatives; L-DOP as nerve agents
A, mepivacaine, chlorpromazine, reserpine, chlordiazepoxide, chlorzoxazone and the like.

Antibiotics include penicillin, cephalosporins, erythromycin, tetracycline, chloramphenicol, streptomycin, cefatrizine, Philippines, amphotericin B, gramindin A, bacitrazine A; anticancer agents such as 5-fluorouracil, cyclophosphine. Famid, busulfan, actinomycin, sulfizoxazole, sulfanilamide,
Examples include nitrofurantoin and para-aminosalicylic acid. Antihistamines include triperenamine, incypendyl, chlorpheniramine, diphenhydramine, and promethazine; sulfa drugs include sulfamonomethoxy and sulfamethazole; cardiotonics include digitoxin and digoxin; antiarrhythmic drugs. Are procainamide hydrochloride, propranolol hydrochloride, etc .; anti-anginal agents include dipyridamole, amyl nitrite, etc .; antihypertensive agents include reserpine, guanethidine sulfate, etc.

Polysaccharide bioactive substances include heparin, dextran sulfate, pentosan sulfate (heparinoid), chondroitin sulfate and salts thereof; peptide-type antitumor substances include glucoamylase inhibitor, bleomycin, neocartinostane, L-asparaginase Enzyme agents include trypsin, chymotrypsin, bromelain, papain, proteinase, peroxidase, nagase, proctase, serathiopeptidase,
Seaprose, lysozyme, streptokinase, streptodonase, plasmin, urokinase, cytochrome C, hyaluronidase, fibrinolysin, thrombin, kallidin, kallikrein, plasmin, glucose oxidase, β-galactosidase, phytin,
Examples include deoxyribonuclease, cholinesterase, pronase, and pancreatin. Peptide hormones include calcitonin, paratormon, relaxin,
Insulin, glucagon, prolactin, adrenocorticotropin (ACTE), gonadotropin, thyrotropin
(TSH), growth hormone (HGH), luteinizing hormone (LH), follicle stimulating hormone (FSH), oxytocin, vasopressin,
Antidiuretic hormone, coherin, melanocyte stimulating hormone
(MSH), gastrin, tetragastrin, pentagastrin, secretin, pancreosymine, cholecystokiyun, substance P, gonadotron (HCG), vasopressin, etc. Peptide hormone releasing / suppressing factors include adrenocorticotropic hormone releasing factor (ACTH-RH), egg cell stimulating hormone releasing factor (FSH-RH), growth hormone releasing factor (GH-RH), luteinizing hormone releasing factor (LH- RH), prolactin releasing factor (PR-RH), prolactin inhibitor (PR-I)
H) and thyroid-stimulating hormone releasing factor (TSH-RH).
Examples of the polynucleotide include polyribonucleotide, a complex of polyinosinic acid and polycytidylic acid, a complex of polyadenylic acid and polyuridylic acid, and polydeoxyribonucleotide. In addition, insulin secretion activating protein (I
AP), splenic basic trypsin inhibitor, antipain hydrochloride, chymostatin A, elastatinal, pepstatin A, polylysine, polyornithine, polyethyleneimine, polyvinylamine and the like. The blending amount of these drugs varies depending on the kind of the drug, the purpose of use of the preparation, etc., but the drug is usually contained in the preparation in an amount of 0.01 to 30% by weight.

In the form of the preparation of the present invention, as a transdermal preparation, a patch (a tape preparation or a patch having a drug-containing layer having an adhesive property on the surface of a support, a drug having a relatively low adhesive property on the surface of a support) is used. (Eg, a poultice having a layer formed therein), an ointment, a cream preparation, a liquid preparation (including a suspension preparation), and the like; transmucosal preparations include nasal drops, eye drops, suppositories, and liquid preparations.

Of the above-mentioned preparations, acrylic acid ester is used as the base for the drug-containing layer of tape preparations and patches.
(Co) polymer as a polymerization component, natural rubber, synthetic isoprene rubber, styrene-butadiene rubber, polyisobutylene, styrene-isoprene copolymer, polyvinyl ether, silicone rubber and the like are used. . A tackifying resin is used as necessary to impart tackiness. These include rosin, rosin derivatives, polyterpene resins, coumarone-indene resins, petroleum-based resins, terpene phenolic resins and the like. Furthermore, if necessary, liquid polybutene, mineral oil, lanolin, liquid polyisoprene,
It contains a plasticizer such as liquid polyacrylate; a filler; an antiaging agent and the like.

Examples of bases that form the drug-containing layer of poultices include natural polymers such as sodium alginate, gelatin, corn starch, and tragacanth gum; cellulose derivatives (eg, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose), starch derivatives (including starch degradation products; , Polymers derived from natural polymers such as dextrin and carboxymethyl starch); synthetic polymers such as polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether and polyvinylpyrrolidone. In addition to the above-mentioned base, the drug-containing layer contains polyhydric alcohol such as glycerin and propylene glycol and purified water as a moisturizing agent. In addition, inorganic fillers (kaolin, bentonite, zinc white, titanium dioxide, etc.); viscosity modifiers; cross-linking agents;

As a support for patches (tape preparations, poultices, patches, etc.), supports usually used for patches are 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 woven or non-woven fabrics.

To obtain a patch, for example, a drug and an absorption promoter, and if necessary, a tackifier, a plasticizer, a moisturizer, a filler, etc. are added to the above base, mixed, and coated on a release paper. A drug-containing layer is formed, and this is laminated and adhered to the surface of the support. The release paper is peeled off when the patch is used. A mixed solution containing the drug and the absorption enhancer may be directly applied to the surface of the support.

Of the obtained patches, those containing a water-insoluble polymer as a base polymer, such as an acrylic polymer, usually have the drug-containing layer itself adhesive. On the contrary,
When a water-soluble polymer is used, the drug-containing layer usually has no adhesiveness, and the patch is in the form of a poultice.

The main components of the bases of ointments and creams are beeswax, oils and fats, lanolin, white petrolatum, paraffin, plastibase, Zelen 50W (trade name), higher fatty acids, higher alcohols, macrogol, carboxyvinyl polymer, etc. In addition, fat-soluble solubilizers, purified water, water-soluble solubilizers, stabilizers, pH adjusters, etc. are used as necessary. Liquid paraffin, isopropyl myristate, diethyl sebacate or the like is used as the fat-soluble solubilizer, and alcohol (for example, ethanol) or polyhydric alcohol (for example, glycerin) is used as the water-soluble solubilizer. To obtain an ointment or cream preparation, for example, the above-mentioned base, drug, percutaneous absorption enhancer, and if necessary, purified water, water-soluble dissolving agent, pH adjusting agent, etc. are added and uniformly mixed.

For liquids, purified water, ethanol, glycols,
A mixed solution of tragacanth, gum arabic, sodium alginate, gelatin, methyl cellulose, carboxymethyl cellulose, etc. is used. Drugs in these mixed solutions,
Liquid formulations (including suspensions) are prepared by adding a transdermal absorption enhancer and, if necessary, a stabilizer and the like.

As a base for oral preparations, nose drops and eye drops, various water-soluble or water-insoluble polymers are used. Natural polymers among water-soluble polymers include gum arabic, tragacanth gum, locust bean gum, guar gum, xanthan gum, echo gum, karaya gum, agar, starch, carrageenan, alginic acid and its salts (sodium alginate, etc.), propylene glycol alginate, dextran. , Dextrin, amylose, gelatin, collagen, pullulan, pectin, amylopectin starch,
Amylopectin sodium semiglycolate, chitin,
Examples include albumin, casein, polyglutamic acid, polyaspartic acid, and gluten. Semi-synthetic polymers include methyl cellulose, ethyl cellulose, propyl cellulose, ethyl methyl cellulose, carboxymethyl cellulose, hydroxy cellulose, hydroxyalkyl cellulose, hydroxypropyl methyl cellulose,
Hydroxypropyl starch, carboxymethyl starch, alkali metal carboxymethyl cellulose, alkali metal cellulose sulfate, cellulose acetate phthalate, starch acrylic acid graft polymer, crosslinked gelatin, phthalic anhydride modified gelatin, succinic acid modified gelatin, etc. Synthetic polymers include polyvinyl alcohol; polyacrylic acid; polyacrylic acid ester; polyvinylpyrrolidone; polyvinyl methyl ether; methyl vinyl ester; polyacrylic acid and its salts (sodium polyacrylate, etc.); polyacrylic acid copolymer ( Carboxyvinyl polymer; carbopol); water-soluble copolymer of vinylpyrrolidone with ethyl acrylate, styrene, vinyl acetate or other copolymerizable monomer; polyvinyl acetate or vinyl acetate with acrylic acid, methacrylic acid or Copolymers with crotonic acid; polyvinyl sulfonic acid; polyitaconic acid; polyhydroxyethyl acrylate; polyacrylamide; copolymers of styrene or ethylene with maleic anhydride; copolymers of acrylamide with acrylic acid, etc. . Water-insoluble polymers include vinyl acetate and natural chicle.

In addition to the above-mentioned base, various solvents such as water and various additives are contained if necessary. As additives, lactose, glucose, sucrose, crystalline cellulose, cyclodextrin,
Examples include silicic acid anhydride, aluminum silicate, talc, calcium stearate, magnesium stearate, beeswax, polyethylene glycol, polyphosphoric acid, sterotex, and waxes. Buccal, nasal drops and eye drops can be obtained by mixing the above-mentioned base, drug, absorption promoter and, if necessary, various solvents and additives.

Examples of the suppository base include cocoa butter, palm oil, coconut oil, fractionated coconut oil and other oils and fats; vaseline and the like. A suppository is prepared by adding a drug, an absorption enhancer and, if necessary, an additive to these bases, mixing them, and then molding.

(Function) When the preparation of the present invention is brought into close contact with the skin surface, the contained drug is easily absorbed through the skin. Although the detailed mechanism thereof is unknown, it is considered that one of the causes is that the absorption enhancer acts on the cell membrane of skin cells to lower the barrier property. Therefore, it is considered that the contained drug is easily absorbed through the skin because it normally penetrates the stratum corneum of the skin surface, which is difficult to penetrate the drug. When the conventional preparation was used, there was a large variation in the absorbability of the contained drug due to the individual difference in the skin condition, but such individual difference is reduced by using the preparation of the present invention. The range of applicable drugs is extremely wide.

With the use of the preparation of the present invention, a sufficient amount of the drug to obtain the required drug effect is easily absorbed, so that it is not necessary to include a large amount of the drug in the preparation as in the conventional case. That is, the bioavailability of the drug is high and a sufficient therapeutic effect can be obtained. Such absorption enhancing effect is much higher than that of conventional absorption enhancers. Furthermore, the absorption enhancer used in the present invention has no irritation to the skin and is highly safe to the human body. It does not modify the contained drug. In particular, this absorption enhancer hardly deactivates the protein, as can be understood from the fact that it has been conventionally used as a solubilizer for membrane proteins. Therefore, for example, it is preferably used for a preparation containing a drug composed of a protein or a polypeptide.

(Example) Hereinafter, the present invention will be described with reference to Examples.

Example 1 (A) Preparation of tape formulation: 2-ethylhexyl acrylate 4
An ethyl acetate solution containing a copolymer consisting of 0 mol%, butyl acrylate 50 mol% and vinylpyrrolidone 10 mol% in a proportion of 25% by weight was prepared. Into this solution, 100 parts by weight of copolymer (solid content), 8 parts by weight of indomethacin as a drug, and lauryl-β-D as a transdermal absorption enhancer
5 parts by weight of glucopyranoside (transdermal absorption enhancer) were added and mixed well. Apply this to a polyethylene terephthalate (PET) film (release paper) with one side treated with silicone so that the thickness after drying will be 60 μm.
It was dried in a gear oven at ℃ for 20 minutes. A polyethylene film was laminated as a support on the surface of the obtained adhesive layer to obtain a tape preparation. The release paper is peeled and removed at the time of use.

(B) Performance evaluation of tape preparation: Using the tape preparation obtained in (A), an in vitro drug permeability test and an in vivo drug absorption test were conducted. The results are shown in Tables 1 and 2.
The results of Examples 2 to 4 and Comparative Example 1 described later are also shown in Table 1 and Table 2. The test method is as follows.

In vitro drug permeability test: Prepare a Franz diffusion cell with an opening diameter of 25 mm. Hot water of 37 ° C is circulated on the outer wall of the receptor of the Franz diffusion cell to keep the temperature of the receptor constant. The excised skin of a nude mouse is attached to the cell. Fill the receptor solution (physiological saline) with care so that no bubbles enter between the skin and the receptor solution.
The patch test piece (circle with a diameter of 20 ml) obtained in section (A) was applied, and the receptor solution was sampled 24 hours after application, and the drug concentration was measured by high performance liquid chromatography using a reversed phase column. , Calculate the drug permeability.

In vivo drug absorption test: The patch was cut into a size of 60 cm ² and applied to the skin surface of the dehaired back of a Japanese white rabbit (male). Blood is collected from the rabbit auricular vein over time and centrifuged to obtain plasma. This is subjected to high performance liquid chromatography using a reversed phase column to measure the drug concentration.

Example 2 The same as Example 1 except that a mixture of lauryl-α-D-glucopyranoside and lauryl-β-D-glucopyranoside was used as the transdermal absorption enhancer.

Example 3 The same as Example 1 except that 3 parts by weight of n-octyl-β-D-glucopyranoside was used as the transdermal absorption enhancer.

Example 4 The same as Example 1 except that 3 parts by weight of n-heptyl-β-D-thioglucopyranoside was used as a percutaneous absorption enhancer.

Comparative Example 1 The same as Example 1 except that the percutaneous absorption enhancer was not added.

Example 5 (A) Preparation of ointment: A mixture of 60 parts by weight of Macrogol 4000 and 40 parts by weight of Macrogol 1500 was added to 10 parts by weight of nifedipine (drug), n-butyl-α-D-glucopyranoside and n-butyl-β-. Mixture of D-glucopyranoside
Ointment was obtained by adding 10 parts by weight and mixing well at 80 ° C.

(B) Ointment performance evaluation: ointment 40 obtained in this Example (A)
mg was uniformly applied to a polyethylene film (20 mmφ). This ointment-coated film was attached to the extracted epidermis of a nude mouse, and an in vitro drug permeability test was conducted according to the item of Example 1 (B).

Next, 500 mg of the ointment obtained in this Example (A) was used as a rabbit (male).
Was applied to the skin surface (40 cm ² ) of the depiled back of the hair, and blood was collected over time to measure the drug concentration in the blood by gas chromatography (E
CD). In each of the above tests, the operation was carried out under light shielding to prevent the decomposition of nifedipine.
The test results are shown in Tables 3 and 4. The results of Examples 6 to 7 and Comparative Example 2 described later are also shown in Table 3 and Table 4.

Example 6 The same as Example 5 except that 6 parts by weight of n-octyl-β-D thioglucopyranoside was used as a percutaneous absorption enhancer.

Example 7 The same as Example 5 except that 10 parts by weight of a mixture of stearyl-α-D-glucopyranoside and stearyl-β-D-glucopyranoside was used as a percutaneous absorption enhancer.

Comparative Example 2 The same as Example 2 except that the percutaneous absorption enhancer was not added.

Example 8 (A) Preparation of solution: insulin at a rate of 20 U / ml and lauryl-β-D-thioglucopyranoside (transdermal absorption enhancer) at a rate of 0.5 w / v% in 0.01 M phosphate buffer. To prepare a liquid preparation.

(B) Performance evaluation of liquid agent: the liquid agent obtained in the section (A) of this Example.
2 ml was added to the method of HIRAI et al. (International Journal of Pharma
ceutics, 7 317-325 (1981) according to
0 g; fasted for 20 hours before the test) was administered to the nasal mucosa.
Table 5 shows changes in the glucose concentration in rat blood (the glucose concentration at the time of liquid drug administration is 100%). The results of Examples 9 to 10 and Comparative Example 3 described later are also shown in Table 5.

Example 9 Example 8 except that n-octyl-β-D-glucopyranoside was used at a ratio of 0.4 w / v% as a percutaneous absorption enhancer.
Is the same as.

Example 10 The same as Example 8 except that 0.4-w / v% of n-heptyl-β-D-glucopyranoside was used as a transdermal absorption enhancer.

Comparative Example 3 The same as Example 8 except that the absorption enhancer was not included.

From Table 5, a decrease in blood glucose level was observed in Examples 8 to 10, which is considered to be a result of effective transmucosal absorption of insulin.

(Effects of the Invention) As described above, the percutaneous absorption preparation of the present invention containing a specific type of glucoside as a percutaneous absorption enhancer is extremely excellent in percutaneous absorption of a drug. Therefore, it is not necessary to include a large amount of drug in the preparation as in the conventional case in order to obtain the necessary pharmacological effect. Since the absorption enhancer used is not irritating to the skin and mucous membranes, it does not cause rash even after long-term application. It is also non-toxic to living organisms. It does not alter the drug. Furthermore, the absorption promoter does not cause the deposition of the drug and the adhesive property of the tape preparation does not deteriorate. In such a preparation, various drugs can be percutaneously absorbed. Therefore, it can be used for various medical purposes depending on the type of drug contained.

Claims (1)

[Claims] 1. D represented by the following formula (I) and / or (II)
Percutaneous absorption preparation containing-(thio) -glucoside and drug: Wherein X is 0 or S; R ₁ and R ₂ are each independently a C ₄ -C ₂₀ saturated or unsaturated hydrocarbon residue, or C ₄ -C ₂₀ saturated or unsaturated with a polyoxyalkylene group. It is an unsaturated hydrocarbon residue.