JPS63218630A - Accelerator of percutaneous absorption - Google Patents

Abstract

PURPOSE:To obtain a percutaneous absorption accelerator which increases the absorption of medicament with high safety to living bodies without skin irritation, by using n-octyl-beta-D-(thio)-glucopyranoside. CONSTITUTION:The objective accelerator includes a compound of the formula (X is O, S; R is n-octyl). When the preparation containing the accelerator is closely applied to the skin surface, the active ingredients such as anti- inflammatory analgesic, hormone preparation, antiseptic or bactericidal agent is readily absorbed through the skin. One of the mechanism is presumably that the accelerator acts on the cell membrane to lower its barrier. The use of the accelerator lessens the fluctuation in the absorption according to individual bodies. Since the active ingredients are readily absorbed, the amount of the active ingredients can be reduced in the preparation. Further, the accelerator is inert to the active ingredients. As it does not deactivate protein, it can be used in manufacturing preparations including proteins and polypeptides.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a transdermal absorption enhancer that improves the absorption of a drug contained in a transdermal absorption preparation.

(Prior Art) In order to obtain systemic or local medicinal effects, transdermal absorption preparations are used to absorb drugs (physiologically active substances) through the skin. This transdermal administration method has many advantages over traditional oral administration methods. For example, when a drug is orally administered, the drug is absorbed in the intestines, circulates to the liver, and undergoes metabolism, resulting in a considerable amount of the drug being degraded before it exerts its medicinal effects. In contrast, with transdermal administration, the absorbed drug does not pass through the liver during its initial circulation in the body.

Therefore, the medicinal efficacy is not significantly reduced due to metabolism in the liver. Oral administration of nonsteroidal anti-inflammatory drugs tends to cause gastrointestinal disorders, but transdermal administration is less likely to cause such gastrointestinal disorders. By controlling the absorption of drugs, it is possible to reduce side effects caused by large amounts of drugs being absorbed in a short period of time. If a constant blood concentration can be maintained over a long period of time, the frequency of drug administration can be reduced.

However, even if a drug is administered using a transdermal absorption preparation, the drug is difficult to penetrate the skin and has a low bioavailability in many cases. In response to this, research is being conducted on improving the dosage form of transdermal absorption preparations, improving the drug-containing base, and adding transdermal absorption enhancers. Among these methods, improvements in the dosage form and base may be effective to some extent depending on the type of drug contained, but no dramatic improvement in absorption action can be expected. Therefore,
Research is currently underway on transdermal absorption enhancers that enhance the transdermal absorption of drugs.

The main reason for transdermal absorption of drugs is thought to be that the stratum corneum present on the skin surface has a barrier function that prevents foreign substances from entering the body, so the drugs are not absorbed through the skin. Therefore, absorption enhancers are used to weaken the barrier function of the stratum corneum and allow a sufficient amount of the drug to be absorbed. Among the compounds known as transdermal absorption enhancers, for example, salicylic acid, urea, and dimethyl sulfoxide are known to dissolve stratum corneum, but even if these are added, the transdermal absorption of the drug is not necessarily good. isn't it. Propylene glycol, glycerin, sodium pyrrolidone carboxylate, etc. can cause the stratum corneum to retain water, but they have little effect on promoting drug absorption. In addition to the above compounds, organic acid esters such as isopropyl myristate and isopropyl adipate; sodium lauryl sulfate.

Surfactants such as polyoxyethylene-20-sorbitan monolaurate; mixtures of thioglycerol, urea K1, or pyrrolidone-type compounds and halogenated hydrocarbons (Japanese Unexamined Patent Publication No. 13720/1982); calcium thioglycolate (Unexamined Japanese Patent Publication No. 11431/1983);l
-Substituted azacycloalkan-2-one (Special Publication No. 1986-3)
7092) and the like are also known. However, even when these absorption enhancers are used, the amount of drug absorbed through the skin is not necessarily sufficient, and therefore practical pharmacological effects are often not obtained. Some of the above accelerators may cause a bad odor, or the compounds themselves may irritate the skin, causing erythema or irritation. Furthermore, among liquid absorption enhancers, those that act as strong solvents may dissolve synthetic resins. As a result, irritating substances may be eluted from contact with pharmaceutical containers, clothing, accessories, etc., and this may cause skin irritation. As described above, at present, a transdermal absorption enhancer that effectively absorbs drugs in transdermal absorption preparations, provides sufficient pharmacological effects, and is highly safe for the skin has not yet been obtained.

(Problem to be solved by the invention) The present invention solves the above-mentioned conventional drawbacks.

The purpose is to provide a transdermal absorption enhancer that allows the drug contained in transdermal preparations to be effectively absorbed through the skin to provide sufficient pharmacological effects, and that is non-irritating to the skin and safe for living organisms. Our goal is to provide the following. Another object of the present invention is to provide a transdermal absorption enhancer that does not denature the base or drug.

(Means for Solving the Problems) The inventors focused on the effects of surfactants, which have conventionally been used as transdermal absorption enhancers, and applied research in the field of biochemistry with the aim of reducing their side effects. We screened various nonionic surfactants, especially membrane protein solubilizers, used in the result.

We have found that certain types of glucose derivatives are useful as transdermal absorption enhancers. The transdermal absorption enhancer of the present invention is n-octyl-β-0-(thio)-glucopyranoside represented by the linear formula (I), thereby achieving the above object: H, where X is 0 or S; R represents an n-octyl group.

In the present invention, for example, "transdermal absorption enhancer" includes "transmucosal absorption enhancer". In this way, "transdermal"
This includes not only "through the skin" but also "through the mucous membranes (oral mucosa, ocular mucosa, nasal mucosa, etc.)".

The transdermal absorption enhancer of the present invention is represented by the above formula.

The compound where X is O is n-octyl-β-D-glucopyranoside (OG), and the compound where X is S is n-octyl-β-D-glucopyranoside (OG).

n-octyl-β-D-thioglucopyranoside (OTG
).

In a transdermal absorption enhancer using the above absorption enhancer.

The accelerator is contained in a proportion of 0.1 to 30% by weight.

For ointments, cream preparations, liquid preparations, etc., this ratio indicates the content relative to the entire preparation, and for tape preparations and patches such as plasters, it indicates the content relative to the drug-containing layer. The same applies to the drug content described below. If the amount of absorption enhancer is too small, the effect of promoting absorption of the drug cannot be obtained. Even if it is in excess, the absorption of the drug will not improve any further, and
The compatibility with the base may deteriorate in some cases.

The drug (physiologically active substance) used is not particularly limited as long as it can permeate biological membranes by transdermal administration.

For example, anti-inflammatory analgesics, hormonal drugs.

Disinfectants, antihistamines, antifungals, vitamins,
Absorbent, ultraviolet absorber, metal ion sequestrant.

Hypnotic/Sedative, Psychotropic/Anti-Epileptic, Anti-Parkinson's Disease Agent 9 Cardiotropes, Anti-Arrhythmic Agents, Anti-anginal Agents.

Antihypertensive agent, antipruritic agent, red foaming agent, emollient.

There is one anti-perspirant/deodorizer for hair.

Among the above drugs, anti-inflammatory analgesics include ethyl aminobenzoate, dibucaine hydrochloride, tetracaine hydrochloride, procaine hydrochloride, lidocaine, methyl salicylate, guaiazulene, sodium guaiazulene sulfonate, aluminum chlorohydroxyallantoinate, pendazac, and indomethacin.

Glycyrrhetinic acid, glycyrrhizic acid, Bufexamac, dextran, sodium sulfate, crotamiton, butyl flufenamate, allantoin.

Examples include aloe powder, ictamol, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, β-glycyrrhetinic acid, glycyrrhetinyl stearate, stearyl glycyrrhetinate, and hinokitiol.

Hormonal agents include hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, fluocinolone acetonide, and flumethacin pivalate.

Fluocinonide, fluoromesolone, beclomethasone propionate, dexamethacin, dexamethacin sodium phosphate, dexamethacin acetate, fludroxycortide, betamethacin valerate, betamethacin dipropionate,
Doriamcinolone acetonide, prednisolone, methylprednisolone.

Methylprednisolone acetate, diflucortolone valerate,
Clobetasol propionate, amcinonide, haldinonide, prednisolone acetate valerate.

Corticosteroids such as hydrocortisone acetate propionate: insulin, estradiol.

Other hormones include estrone, ethinylestradiol, diethylstilbestol, hexestrol, and prostaglandins.

Phenol and resorcinol are used as disinfectants.

Salicylic acid, hexachlorophene, merculochrome, 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 baraoxybenzoate, butyl baraoxybenzoate, propyl baraoxybenzoate, methyl baraoxybenzoate, isopropylmethylphenol, cresol, chlorxylenol, thymol, balachlorphenol, i element No. 101 , Photosensor No. 201, Chloramine T, Thianthol, Lysozyme chloride, Chlorhexidine hydrochloride.

Examples include chlorhexidine gluconate, trichlorocarbanilide, 3-trifluoromethyl-4,4°-dichlorocarbanilide, and hexachlorophene.

Isothibenzyl hydrochloride is an antihistamine.

Diphenylimidazole, clemizole sulfate, diphenhydramine, diphenhydramine lauryl sulfate, chlorpheniramine maleate, etc.; anti-seedling agents include chrysalopine and undecylenic acid.

Zinc undecylenate, pentachlorophenol.

These include phenylmercuric acetate, thimerosal, trichomycin, tolnaftate phenyl iodo undesinoate, clotrimazole, haloprozin, variotin, virolnidoline, cinkanin, nyscutin, exalamide, ciclopirox olamine, miconazole nitrate, econazole nitrate, and isoconazole nitrate.

Vitamins include retinol, retinol acetate, retinol palmitate, dehydroretinol, ergocalciferol, and d! -α-tocopher O-l, acetic acid J
-α-tocopherol, succinic acid -α-tocopherol calcium, ubiquinone, phytonadione, menaquinone, menadione.

Thiamine hydrochloride, thiamine nitrate, thiamine phosphate,
Riboflavin, flavin mononucleotide.

Riboflavin butyrate, pyridoxine hydrochloride.

5-Pyridoxal phosphate, pyridoxine caprilate, pyridoxine cybalmitate, pyridoxine tripalmitate, dianocobalamin, hydroxycobalamin, deoxyadenosylcobalamin, methylcobalamin,
Nicotinic acid, nicotinamide, benzyl nicotinate,
Calcium pantothenate, sodium pantothenate, bantothenyl alcohol, dicarboethoxybantothenic acid ethyl ester/propylene glycol solution, acetyl bantothenyl ethyl ether, bantothenyl ethyl ether, biotin, folic acid, choline, inositol, ascorbic acid, sodium ascorbate , ascorbyl stearate, ascorbyl palmitate, and ascorbyl civalmitate.

As absorbents, zinc oxide, calamine, aluminum sulfate, lead acetate secondary bismuth nitrate, hismuth subgallate, tannic acid, zirconium oxide chloride.

Allantoin chlorhydroxyaluminum, allantoin dihydroxyaluminum, aluminum hydroxychloride, zinc chloride, aluminum chloride, ferric chloride, calamine, chlorinated aluminum bromide, aluminum phenolsulfonic acid.

These include aluminum naphthalene sulfonic acid, aluminum potassium sulfate, and zinc paraphenolsulfonate.

Examples of ultraviolet absorbers include urocanic acid, 2-ethoxyethyl 4-methoxycinnamate, ethyl para-aminobenzoate, 2-(2-hydroxy-5-methylphenyl)benzotriazole, 2-hydroxy-4-methoxybenzophenone, etc. However, the metal ion sequestering agent is edetate disodium.

Examples include sodium citrate, sodium polyphosphate, sodium metaphosphate, and gluconic acid. Hypnotic and sedative drugs include barbital, thiopencour, chloral hydrate, and potassium bromide; psychotropic and antiepileptic drugs include chlorpromazine.

Reserpine, chlordiazepoxide, etc.; anti-Parkinson's agents include chlorzoxazone, levodopa, etc.; cardiac inotropic agents include digitoxin.

Digoxin, etc.; antiarrhythmic agents include brocainamide hydrochloride, propranol hydrochloride, lidocaine hydrochloride, indenolol hydrochloride, etc.; antianginal agents include dipyridamole, amyl nitrite, nitroglycerin, isosorbide nitrate, etc.; antihypertensive agents Agents include reserpine and guanethidine sulfate; antipruritic agents include ictamol and moctal.

Camphor, thymol, diphenhydramine, chlorpheniramine, promethacin hydrochloride, N-ethyl-〇-crotonotoluidine, etc.; as red foaming agents, cantharis, capsicum tincture, ictamol, turpentine oil primary bismuth gallate, etc.; Softeners include purified sulfur, precipitated sulfur, salicylic acid, urea, etc.; as antiperspirants and deodorants.

Aluminum chloride, aluminum sulfate, aluminum acetate, aluminum phenolsulfonate.

Sodium perborate, etc.; as a hair preparation.

Selenium disulfide, alkylisoquinolinium bromide.

Zinc pyrithione, biphenamine, thianthol.

Cantharis tincture, ginger tincture, capsicum tincture, potassium bromate, sodium bromate.

These include carpronium chloride, acetylcholine chloride, pirocarbin chloride, and vitamin A oil. The amount of these drugs to be mixed varies depending on the type of drug, the purpose of use of the preparation, etc.
Usually, the drug is contained in the formulation in a proportion of 0.01 to 30% by weight.

Various transdermal absorption preparations are prepared using the transdermal absorption enhancer of the present invention. For example, tape preparations and batch preparations in which a drug-containing layer with adhesiveness is formed on the surface of the support; patches such as poultices in which a drug-containing layer with relatively poor adhesion is formed on the surface of the support; ointments, Cream preparations; liquid preparations (including suspensions), etc. Among the above formulations, the bases used for the drug-containing layer of tape formulations and patch formulations include (co)polymers containing acrylic ester as a (co)polymerization component;
Natural rubber, synthetic isoprene rubber, styrene-butadiene rubber, polyisobutylene, styrene-isoprene copolymer, polyvinyl ether, silicone rubber, etc. are used. A tackifying resin is used as necessary to impart tackiness. These include rosin, rosin derivatives, and polyterpene resins.

Coumarone-indene resin 1 Petroleum-based resin, terpene phenol resin, etc. Furthermore, if necessary, the drug-containing layer may contain plasticizers such as liquid polybutene, mineral oil, lanolin, liquid polyisoprene, liquid polyacrylate, fillers, anti-aging agents, and the like.

As a base for forming the drug-containing layer of poultices.

Natural polymers such as sodium alginate, gelatin, cornstarch, gum tragacanth; cellulose derivatives (
Polymers derived from natural polymers such as methylcellulose, hydroxyethylcellulose, carboxymethylcellulose), starch derivatives (including starch decomposition products; e.g. dextrin, carboxymethylstarch); polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride Acid copolymer.

Synthetic polymers include polyvinyl ether and polyvinylpyrrolidone. In addition to the above-mentioned base, the drug-containing layer contains polyhydric alcohols such as glycerin and propylene glycol and purified water as humectants. In addition, inorganic fillers (kaolin) are added as necessary.

Bentonite, zinc white, titanium dioxide, etc.); viscosity modifier; crosslinking agent; anti-aging agent, etc.

As a support for a patch (tape preparation, poultice, patch, etc.), a support commonly used for a patch is used. Materials for such supports include cellulose acetate, ethyl cellulose, polyethylene terephthalate, vinyl acetate-vinyl chloride copolymer, nylon, and ethylene-vinyl chloride copolymer.
Examples include vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride, and aluminum. These materials are used, for example, as a single-layer sheet (film) or a laminate of two or more sheets. Materials other than aluminum may be used as woven or non-woven fabrics.

To obtain a patch 2 For example, add a drug and an absorption enhancer to the above base, and further add a tackifier if necessary.

Plasticizers, humectants, fillers, etc. are added and mixed, coated on release paper to form a drug-containing layer, and this is laminated and adhered to the surface of the support. The release paper is peeled off when the patch is used. A liquid mixture containing the above-mentioned drug and absorption enhancer may be applied directly to the surface of the support.

Among the resulting patches, those in which a water-insoluble polymer such as an acrylic polymer is used as the base polymer usually have a drug-containing layer itself that is adhesive. On the contrary,
When a water-soluble polymer is used, the drug-containing layer usually does not have adhesive properties, resulting in a patch in the form of a poultice.

The main ingredients of the base of ointments and creams are beeswax, oil, lanolin, white petrolatum, and paraffin.

These include Plastibase, Zelen 50W (trade name), higher fatty acids, higher alcohols, macrogol, carboxyvinyl polymer, etc. In addition, a fat-soluble solubilizer, purified water, a water-soluble solubilizer, a stabilizer, a pH adjuster, etc. may be used as necessary. Examples of the fat-soluble dissolving agent include liquid paraffin, isopropyl myristate, diethyl sebacate, etc., and examples of the water-soluble dissolving agent include alcohol (for example, ethanol).

Polyhydric alcohols (eg, glycerin) are used. To obtain an ointment or cream formulation, 1. For example, the above base,
Add the drug, transdermal absorption enhancer, and if necessary, purified water, a water-soluble solubilizer, pHtP adjuster, etc., and mix uniformly.

In the case of liquid formulations, purified water, ethanol, glycols,
A mixed solution of tragacanth, gum arabic, sodium alginate, gelatin, methylcellulose, carboxymethylcellulose, etc. is used. Drugs in these mixed solutions,
A solution (including a suspension) is prepared by adding a transdermal absorption enhancer and, if necessary, a stabilizer.

(Function) When a preparation containing the transdermal absorption enhancer of the present invention is brought into close contact with the skin surface, the drug contained therein is easily absorbed through the skin. The detailed mechanism is unknown, but the cause is
This is thought to be because absorption enhancers act on the cell membranes of skin cells and lower their barrier properties. Therefore, it is believed that the drug contained therein is easily absorbed through the skin because it penetrates the stratum corneum on the skin surface, which is normally difficult for drugs to pass through. When conventional formulations containing transdermal absorption enhancers were used, there were large variations in the absorption of the drug contained therein due to individual differences in skin conditions; however, the transdermal absorption enhancer of the present invention is used. This also reduces these individual differences.

When using a preparation containing the transdermal absorption enhancer of the present invention, a sufficient amount of the drug to obtain the necessary medicinal efficacy is easily absorbed.
There is no need to include a large amount of drug in the formulation as in the past. In other words, the bioavailability of the drug is high. Such an absorption promoting effect is much higher than when using conventional absorption enhancers. Furthermore, the absorption enhancer used in the present invention has no irritation to the skin and is highly safe for the human body.

It does not denature the drug contained. especially.

As understood from the fact that the absorption enhancer of the present invention has been conventionally used as a dissolving agent for membrane proteins, it hardly deactivates proteins. Therefore, it is suitably used, for example, in preparations containing drugs made of proteins or polypeptides.

(Example) The invention will be explained below with reference to examples.

EXAMPLE 1 Using 6-carboxyfluorescein (CF) as a model of a poorly absorbed drug, the effect of the transdermal absorption enhancer of the present invention on the skin permeability and absorption of this compound was investigated.

As a transdermal absorption enhancer, n-octyl-β-D
- Glucopyranoside (OG) was used. First, CF
(manufactured by Eastman Kodak) in phosphate buffer (pH 7).
, 4) so that O,Q was 2w/v%. OG (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in this to a predetermined concentration to prepare a test solution. Using this test solution, in vitro drug permeability test and in
An in vivo (rat) drug absorption study was conducted. The OG concentration was Ow/v% (control) 0.3w/ν% and 1.5w/v%, and the appropriate OGf' was adjusted according to each test item.
A test solution of 1,000 ml was selected. The results of each test are shown in FIGS. 1(a) and (b).

In vitro drug permeability test method: A Franz-shaped diffusion cell with an aperture diameter of 25 mm is prepared. Warm water at 37° C. is circulated through the outer wall of a portion of the receptor of the Franz-type diffusion cell to keep the temperature of the portion of the receptor constant. The abdominal epidermis of male Wistar rats (weight 180 to 200 g) was removed after hair removal treatment.

Attach this to the cell. A portion of the receptor is filled with receptor fluid (physiological saline with a pH of 7.2), being careful not to introduce air bubbles between the skin and the receptor fluid surface. Drop 0.3 ml of the test solution onto the donor side of the device, and
The F concentration is measured by fluorophotometry over time.

1nvivo (rat) drug absorption test: Wista
The abdomens of r-strain rats (body weight 200-250 g) are dehaired 24 hours before the start of the test. 10Tnl of the test solution, J, Pharn+, Dyn, 7648~
655 (I984), the glass chamber (i,
d, 3 cm).

This chamber is attached to the depilated skin of the rat, and the test solution in the chamber is brought into contact with the rat's skin. Blood is collected over time, and the CP concentration and protein concentration in the blood are measured.

From Figure 1, in vitro drug permeability test (1st
In Figure (a), it can be seen that when the ot4 degree is 0.3 w/v% or more, a remarkable effect is observed on the absorbability of CF.

In an in vivo (rat) drug absorption test.

The blood CF concentration when oc > 74 degrees is 1.5 w/v% is determined by the concentration of CF in the blood using known absorption enhancers (I-dodecyl azacyclohebutan-2-one (Azone) and poly Oxyethylene hydrogenated castor oil derivative () ICO
-60)) in combination (2.Ow/v% and 3.Ow/v%, respectively).
Almost the same effect as that obtained when using 0w/v%) was obtained. In this way, the effect can be obtained with a smaller amount than known transdermal absorption enhancers. Furthermore, the amount of protein eluted into the test solution in the glass chamber was almost the same as in Comparative Example 1 (I5 μg
(below), safety for the skin is also confirmed.

A test was conducted 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 (b). In an in vivo (rat) drug absorption test, the blood CF concentration when OTG: a degree was 1.5 w/ν% was compared with the known absorption enhancers (Azone and HCO) shown in Comparative Example 1 below. -60) was used in combination (2.O-/shi% and 3.Ow/v%, respectively), almost the same effect was obtained. In this way, the effect can be obtained with a smaller amount than known transdermal absorption enhancers.

1-dodecyl azacyclohebutane-2- instead of comparative flame OG
Example 1 except that Azone (abbreviated as Az) and polyoxyethylene hydrogenated castor oil derivative (HCO-60) (both are types of surfactants) were used.
The test was conducted according to. The results are shown in Figures 3(a) and 3).

Implementation ■ Preparation of tape formulation (A) Preparation of an ethyl acetate solution containing 25% by weight of a copolymer consisting of 40% by mole of di-tylhexyl diacrylate, 50% by mole of butyl acrylate, and 10% by mole of vinylpyrrolidone. did. In this solution, 8 parts by weight of indomethacin as a drug was added to 100 parts by weight of the copolymer (solid content).

3 parts by weight of OG was added as a transdermal absorption enhancer and thoroughly mixed. This was applied onto a polyethylene terephthalate (PET) film (release paper), one side of which had been treated with silicone, to a dry thickness of 60 μm, and dried in a gear oven at 70° C. for 20 minutes.

A tape formulation was obtained in which a polyethylene film was laminated as a support on the surface of the resulting adhesive layer.

The release paper is peeled off and removed during use.

(B) Performance evaluation of tape preparation: The tape preparation 2011 mφ obtained in section (A) was applied to the epidermis of a nude mouse.

An in vitro drug permeability test was conducted according to Example 1. After 24 hours, the receptor fluid was sampled, the drug concentration was measured by high performance liquid chromatography using a reverse phase column, and the drug permeability was calculated. Drug permeability was 25%.

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

1nvivo (rabbit) drug absorption evaluation: 60c of patch
n! This was cut into pieces of size and applied to the depilated skin surface of the back of a Japanese white rabbit (a). Blood is collected from the auricular vein of a rabbit over time and centrifuged to obtain plasma. This is subjected to high performance liquid chromatography using a reverse phase column to measure the drug concentration.

A tape formulation was prepared in the same manner as in Example 3, except that no transdermal absorption enhancer (OG) was added. Using this, evaluation was performed in the same manner as in Example 3.

The drug permeation rate after 24 hours was 2.8%. in v
iv.

(Rabbit) The results of the drug absorption test are shown in Table 1.

Table 1 (^) Preparation of ointment: Add 10 parts by weight of nifedibine (drug) and 6 parts by weight of OTG to a mixture of 60 parts by weight of Macrogol 4000 and 40 parts by weight of Macrogol 1500, and mix thoroughly at 80°C. Got the ointment.

(B) Performance evaluation of ointment 2. Example 40 squares of the ointment obtained in section (A) were uniformly applied to a polyethylene film (20 uφ). This ointment application film was applied to the epidermis of a nude mouse, and in vitro according to Example 3 (B) was applied.
A drug permeability test was conducted. Drug permeability after 24 hours is 5
．． It was 4%.

Next, 500 μl of the ointment obtained in Example 2 (8) was applied to the skin surface (40811) of the depilated back of a domestic rabbit (male), and blood was collected over time to determine the drug concentration in the blood. Measured by chromatography (ECD). 1n like this
The results of the vivo (rabbit) drug absorption test are shown in Table 2.
In each of the above tests, the operations were performed under light shielding in order to prevent the decomposition of nifedipine.

Comparison ±1 An ointment was prepared in the same manner as in Example 4, except that no transdermal absorption enhancer (OTG) was added. Using this, evaluation was performed in the same manner as in Example 4. The drug permeation rate after 24 hours was 0.15%. The results of the in vivo (rabbit) drug absorption test are shown in Table 2.

(Margin below) Jitsushin 11 pairs (8) Preparation of liquid preparation: Insulin at a ratio of 200/ml and OG at a ratio of 0.5 w/v%. OIM
A solution was prepared by dissolving it in a phosphate buffer.

(B) Performance evaluation of liquid agent 2 The liquid agent 0.2- obtained in Example (A) was evaluated using the method of HIRAI et al.
onalJournal of Pharmaceut
ics, 7 (I981) 317-325) to the nasal mucosa of rats (body weight 250 g; fasted for 20 hours before testing). Changes in the concentration of glucose in rat blood (glucose concentration at the time of liquid drug administration is 100%)
) are shown in Table 3.

Comparative Charcoal ↓ A liquid agent similar to that of Example 5 was prepared except that it did not contain OG, and its performance was evaluated in the same manner.

The results are shown in Table 3.

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

(Effects of the Invention) As described above, it has been found that n-octyl-β-0-(thio)glucopyranoside is useful as a transdermal absorption enhancer. Transdermal absorption preparations containing such absorption enhancers have extremely excellent transdermal absorption of drugs. Therefore,
In order to obtain the necessary pharmacological effect, it is not necessary to include a large amount of drug in the formulation as in the past. The absorption enhancer used is not irritating to the skin or mucous membranes, so it does not cause a rash even when applied for a long time. It does not alter the quality of the drug.

Furthermore, absorption enhancers may cause drug precipitation,
The adhesive properties of the tape formulation do not deteriorate. With such formulations, nine different drugs can be absorbed transdermally. Therefore, it can be used for various medical purposes depending on the type of drug contained.

4. Figures 1 and 2 show the in vitro drug permeability test and in vitro drug permeability test using the transdermal absorption enhancer of the present invention.
A graph showing the results of the in vivo drug absorption test, and Figure 3 shows the results of in vitro drug absorption when using a conventional transdermal absorption enhancer.
1 is a graph showing the results of a tro drug permeability test and an in vivo drug absorption test.

that's all

Claims (1)

[Claims] 1. n-octyl-β-D-(
Transdermal absorption enhancer comprising thio)-glucopyranoside: ▲Mathical formula, chemical formula, table, etc.▼(I) Here, X is O or S; R represents an n-octino group.