JPH0611716B2 - Transdermal absorption enhancer - Google Patents

Description

TECHNICAL FIELD The present invention relates to a transdermal absorption enhancer that improves the absorbability of a drug contained in a transdermal dosage form.

(Prior Art) In order to obtain a systemic or local drug effect, a transdermal dosage form is used to absorb a drug (physiologically active substance) through the skin. This transdermal administration method has many advantages over conventional transdermal administration methods. For example, when a drug is transdermally administered, the drug absorbed in the intestine is circulated to the liver and is 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. Although transdermal administration of nonsteroidal anti-inflammatory drugs tends to cause gastrointestinal disorders, transdermal administration does not easily cause such gastrointestinal disorders. 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 transdermal absorption enhancers that enhance the transdermal absorbability of drugs is underway.

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, an absorption enhancer is used to weaken the barrier function of the stratum corneum and absorb a sufficient amount of the drug. Of the compounds known as transdermal absorption enhancers, 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 always good. is not. 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, organic acid esters such as isopropyl myristate and isopropyl adipate; surfactants such as sodium lauryl sulfate and polyoxyethylene-20-sorbitan monolaurate; thioglycerol, urea derivatives or pyrrolidone type compounds and halogens A mixture with a modified hydrocarbon and the like (JP-A-60-13720); calcium thioglycolate (JP-A-60-11431); 1-substituted azacycloalcan-2-one (JP-B-60-37092) (Gazette) is also known. However, even if these absorption enhancers are used, the amount of drug absorbed through the skin is not always sufficient, and therefore, practical pharmacological effects are 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. Further, among the liquid absorption promoters, those having a strong solvent action may dissolve the synthetic resin. Therefore, stimulants may be eluted from contacting drug containers, clothing, jewelry, etc., which may cause skin irritation. As described above, at present, a percutaneous absorption enhancer that effectively absorbs the drug of the percutaneous absorption preparation to give a sufficient pharmacological effect and is highly safe to 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 allow a drug contained in a percutaneous absorption preparation to be effectively absorbed through the skin. And give a sufficient pharmacological effect,
Another object of the present invention is to provide a percutaneous absorption enhancer which is not irritating to the skin and is safe for living bodies. Another object of the present invention is to provide a percutaneous absorption enhancer which does not modify the base or 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. The percutaneous absorption enhancer of the present invention comprises n-octyl-β-D- (thio) -glucopyranoside represented by the following formula (I), thereby achieving the above object: Here, X represents 0 or S; R represents an n-octyl group.

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 mucosa, ocular mucosa, nasal mucosa, etc.)”.

The transdermal absorption enhancer of the present invention is represented by the above formula, wherein the compound in which X is 0 is n-octyl-β-D-glucopyranoside (OG), and the compound in which X is S is n-octyl-β. −
D-thioglucopyranoside (OTG).

In the percutaneous absorption enhancer using the above absorption enhancer, the enhancer is contained in a proportion of 0.1 to 30% by weight. This ratio shows the content in the whole preparation for ointments, cream preparations, liquid preparations, etc., and for patch preparations such as tape preparations and poultice preparations,
The content relative to the drug-containing layer is shown. 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 (physiologically active substance) used is not particularly limited as long as it can penetrate the biological membrane by transdermal administration.
For example, anti-inflammatory analgesics, hormones, antiseptic disinfectants, antihistamines, antifungals, vitamins, absorption agents, UV absorbers, sequestrants, hypnosis, sedatives, psychotropic / antiepileptic agents, antiparkinsonian There are agents, cardiotonics, antiarrhythmic agents, antianginal agents, antihypertensive agents, antipruritic agents, red foaming agents, emollients, antiperspirant / deodorant agents, and hair agents.

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. , Betamethasone valerate, Betamethasone dipropionate, Triamcinolone acetonide, Prednisolone, Methylprednisolone, Methylprednisolone acetate, Diflucortron valerate, Clobetasol propionate, Amcinonide, Halcinonide, Prednisolone valerate acetate, etc. Hormone; insulin,
Estradiol, estrone, ethinyl estradiol, diethylstilbestol, hexestrol,
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, d1-α-tocopherol acetate dl-α-
Tocopherol, dl-α-tocopherol calcium succinate, ubiquinone, phytonadione, menaquinone, menadione, thiamine hydrochloride, thiamine nitrate, thiaminephosphoric acid, 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, sodium pantothenate, Pantothenyl alcohol, dicarboethoxy pantothenic acid ethyl ester / propylene glycol liquid, acetyl opanthotenyl ether, pantothenyl ethyl ether,
Examples include biotin, folic acid, choline, inositol, ascorbic acid, sodium ascorbate, ascorbyl stearate, ascorbyl palmitate, and ascorbyl dipalmitate.

Absorption agents include zinc oxide, calamine, aluminum sulfate, lead acetate, bismuth subnitrate, bismuth subgallate, tannic acid, zirconium oxide chloride, allantoinchlorohydroxyaluminum, allantoindihydroxyaluminum, 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.

Examples of UV absorbers include urocanic acid, 2-ethoxyethyl 4-methoxycinnamate, ethyl paraaminobenzoate, 2- (2-hydroxy-5-methylphenyl) benzotriazole, and 2-hydroxy-4-methoxybenzophenone. 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. 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.

Various percutaneous absorption preparations are prepared using the percutaneous absorption enhancer of the present invention. For example, a tape preparation or a patch having a drug-containing layer having adhesiveness formed on the surface of a support, a patch such as a patch having a drug-containing layer having relatively poor adhesiveness formed on the surface of a support; an ointment or Cream formulations; solutions (including suspensions) and the like. Among the above-mentioned preparations, the base used in the drug-containing layer of the tape preparation or patch preparation is a (co) polymer containing an acrylic ester as a (co) 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. Further, if necessary, the drug-containing layer contains a plasticizer such as liquid polybutene, mineral oil, lanolin, liquid polyisoprene, liquid polyacrylate; a filler; and an antiaging agent.

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.

(Action) When the preparation containing the transdermal absorption enhancer of the present invention is brought into close contact with the skin surface, the contained drug is easily absorbed through the skin. The detailed mechanism is unknown, but one of the causes is
It is considered that the absorption enhancer acts on the cell membrane of skin cells to reduce the barrier property thereof. 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 a conventional preparation containing a percutaneous absorption enhancer was used, there was a large variation in the absorbability of the contained drug due to individual differences in the skin condition, but the percutaneous absorption enhancer of the present invention is used. This also reduces such individual differences.

When a formulation containing the transdermal absorption enhancer of the present invention is used, a sufficient amount of the drug to obtain the required drug effect is easily absorbed,
It is not necessary to include a large amount of drug in the formulation as in the past. That is, the bioavailability of the drug is high. Such absorption-promoting effect is much higher than that when using conventional absorption promoters. 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, as understood from the fact that the absorption enhancer of the present invention has been conventionally used as a solubilizer for membrane proteins, it hardly deactivates proteins. Therefore, it is preferably used for a preparation containing a drug composed of a protein or a polypeptide, for example.

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

Example 1 Using 6-carboxyfluorescein (CF) as a model of a poorly absorbable drug, the effect of the percutaneous absorption enhancer of the present invention on the skin permeability and absorbability of this compound was investigated. As a transdermal absorption enhancer, n-octyl-β-D-glucopyranoside (OG) was used. First, CF (manufactured by Eastman Kodak Company) was dissolved in a phosphate buffer (pH 7.4) at 0.02 w / v%. OG (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in the solution at a predetermined concentration to give a test solution. Using this test solution, the in vitro drug permeability test and in
An in vivo (rat) drug absorption test was performed. OG concentration is 0w / v
% (Control) was set to 0.3 w / v% and 1.5 w / v%, and a test solution having an appropriate OG concentration was selected according to each test item. The respective test results are shown in FIGS. 1 (a) and 1 (b).

In vitro drug permeability test method: 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. Wistar male rats (body weight 180-200
The epidermis of the abdomen that was subjected to the hair removal treatment of g) is extracted and attached to a cell. Fill the receptor with receptor liquid (physiological saline of pH 7.2), being careful not to let air bubbles enter between the skin and the surface of the receptor liquid. 0.3m test solution on the donor side of the device
Drop 1 and measure the CF concentration in the receptor phase over time by the fluorescence method.

In vivo (rat) drug absorption test: The abdomen of Wistar rats (body weight: 200 to 250 g) is shaved 24 hours before the start of the test. 10 ml of the test solution was added to J. Pharm. Dyn., 7 648 to 655 (19
Put in the glass chamber (id 3 cm) described in 84), attach this chamber to the dehaired skin of the rat, and bring the test solution in the chamber into contact with the skin of the rat. Blood samples are taken over time and the CF and protein concentrations in the blood are measured.

From Fig. 1, it can be seen that in the in vitro drug permeability test (Fig. 1 (a)), when the OG concentration is 0.3 w / v% or more (a remarkable effect on the absorbability of CF is observed. vivo (rat)
In the drug absorption test, the blood CF concentration at an OG concentration of 1.5 w / v% was determined by using the known absorption enhancer (1-dodecylazacycloheptan-2-one (Azo) shown in Comparative Example 1 below.
ne) and polyoxyethylene hydrogenated castor oil derivative (HCO-
60)) was used together (2.0 w / v% and 3.0 w / v%, respectively), and almost the same effect was obtained. Thus, the effect can be obtained with a smaller amount than the known percutaneous absorption enhancer. further,
Since the amount of the protein eluted in the test solution in the glass chamber is almost the same as that of Comparative Example 1 described later (15 μg or less), the safety to the skin is also confirmed.

Example 2 A test was performed according to Example 1 except that n-octyl-β-D-thioglucopyranoside (OTG) was used instead of OG. The results are shown in FIGS. 2 (a) and 2 (b). in viv
o (Rat) In the drug absorption test, OTG concentration was 1.5w
The CF concentration in the blood in the case of / v% is obtained when the known absorption enhancers (Azone and HCO-60) shown in Comparative Example 1 below are used together (2.0w / v% and 3.0w / v%, respectively). The effect is almost equal to. Thus, the effect can be obtained with a smaller amount than the known percutaneous absorption enhancer.

Comparative Example 1 Instead of OG, 1-dodecylazacycloheptan-2-one (abbreviated as Azone; Az) and polyoxyethylene hydrogenated castor oil derivative (HCO-60) (both are types of surfactants) were used. Other than that, the test was performed according to Example 1. The results are shown in FIGS. 3 (a) and 3 (b).

Example 3 (A) Preparation of tape formulation: 2-ethylhexyl acrylate 40
An ethyl acetate solution was prepared containing 25% by weight of a copolymer consisting of mol%, butyl acrylate 50 mol% and vinylprolidone 10 mol%. To this solution, to 100 parts by weight of the copolymer (solid content), 8 parts by weight of indomethacin as a drug and 3 parts by weight of OG as a transdermal absorption enhancer were added and mixed sufficiently. 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 70 ° C for 20 minutes. A tape preparation was obtained by laminating a polyethylene film as a support on the surface of the obtained adhesive layer. The release paper is peeled and removed at the time of use.

(B) Performance evaluation of tape preparation: Tape preparation obtained in (A)
20 mm was attached to the epidermis of a nude mouse, and an in vitro drug permeability test was performed according to Example 1. After 24 hours, the receptor fluid was sampled, the drug concentration was measured by high performance liquid chromatography using a reversed phase column, and the drug permeability was calculated. The drug penetration rate was 25%.

Next, the drug absorption by rabbits was evaluated in vivo using the tape preparation obtained in (A). The results are shown in Table 1. The test method is as follows.

Evaluation of drug absorption in vivo (rabbit): 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.

Comparative Example 2 A tape preparation was prepared in the same manner as in Example 3 except that the transdermal absorption enhancer (OG) was not added. Using this, evaluation was carried out in the same manner as in Example 3. The drug permeability after 24 hours was 2.8%. The results of in vivo (rabbit) drug absorption test are shown in Table 1.

Example 4 (A) Preparation of ointment: To a mixture of 60 parts by weight of Macrogol 4000 and 40 parts by weight of Macrogol 1500, 10 parts by weight of nifedipine (drug) and 6 parts by weight of OTG were added and mixed well at 80 ° C. An ointment was obtained.

(B) Performance evaluation of ointment: 40 mg of ointment obtained in this Example (A)
Was evenly applied to a polyethylene film (20 mm).
Stick this ointment coating film on the epidermis of nude mice,
An in vitro drug permeability test was carried out according to Example 3 (B). The drug permeability after 24 hours was 5.4%.

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). Table 2 shows the results of such an in vivo (rabbit) drug absorption test. In each of the above tests, the operation was carried out under light shielding to prevent the decomposition of nifedipine.

Comparative Example 3 Example 4 except that no transdermal absorption enhancer (OTG) was added.
An ointment was prepared in the same manner as in. Using this, evaluation was performed in the same manner as in Example 4. The drug permeability after 24 hours is 0.
It was 15%. The results of in vivo (rabbit) drug absorption test are shown in Table 2.

Example 5 (A) Preparation of solution: A solution was prepared by dissolving insulin at a rate of 20 U / ml and OG at a rate of 0.5 w / v% in 0.01 M phosphate buffer.

(B) Performance evaluation of the liquid agent: 0.2m of the liquid agent obtained in this Example (A)
l HIRAI et al. (International Journal of Pharmace
utics, 7 (1981) 317-325).
g; fasted for 20 hours before the test)).
Table 3 shows changes in the glucose concentration in rat blood (the glucose concentration at the time of liquid drug administration is 100%).

Comparative Example 4 A liquid agent similar to that of Example 5 was prepared except that it did not contain OG, and its performance was evaluated by the same method. The results are shown in Table 3.

From Table 3, a decrease in blood glucose level was observed in Example 5, which is considered to be a result of effective transmucosal absorption of insulin.

(Effect of the invention) As described above, it was found that n-octyl-β-D- (thio) glycopyranoside is useful as a transdermal absorption enhancer. A percutaneous absorption preparation containing such an 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 or mucous membranes, it does not cause irritation even when applied for a long time. 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.

[Brief description of drawings]

1 and 2 are graphs showing the results of in vitro drug permeability test and in vivo drug absorption test using the percutaneous absorption enhancer of the present invention, and FIG. It is a graph which shows the result of an in vitro drug permeability test and an in vivo drug absorption test when an absorption promoter is used.

Claims (1)

[Claims] 1. An n-octyl-β-D represented by the following formula (I):
Transdermal absorption enhancer consisting of-(thio) -glucopyranoside: Here, X represents 0 or S; R represents an n-octyl group.