JPH0753670B2 - Transdermal / transmucosal preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention is directed to indomethacin, salicylic acid, aspirin,
Diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, flufenamic acid, ibuhenac, fuenbufen, an anionic drug selected from the group consisting of alclofenac, bendazac and flurbiprofen; or hydrocortisone, prednisolone, furocinolone acetonide , Fludoxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone, betamethasone acetate, diflucortron valerate, clobetasol propionate, fluocinonide, pentaerythritol tetranitrate, isosorbide dinitrate, estriol, estrogen, estradiol, testosterone. Neutral drug selected from the group consisting of progesterone and prostaglandin Transdermal dosage form formulations and / or oral agents such as poultices and tape preparations containing relates transmucosal dosage form formulations such as eye drops. The present invention particularly relates to transdermal / transmucosal preparations having enhanced absorption of the drug.

(Prior Art) In order to obtain systemic or local drug efficacy, a transdermal dosage form and / or a transmucosal dosage form is used to absorb a drug (physiologically active substance) through the skin or mucous membranes. It is being appreciated. This transdermal / transmucosal 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 / transmucosal administration method, the absorbed drug does not pass through the liver during the initial 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, but transdermal and transmucosal administration methods do not 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 if the drug is administered using a transdermal / transmucosal preparation,
In many cases, the drug hardly penetrates the skin and mucous membranes, resulting in low bioavailability. In particular, there is a stratum corneum on the surface of the skin, and this stratum corneum has a barrier function that prevents foreign substances from entering the body, so there is a case where a sufficient amount of drug to exert a pharmacological effect is not absorbed through the skin. Many.

A preparation containing an absorption enhancer is manufactured to weaken the barrier function of the stratum corneum and absorb a sufficient amount of the drug. For example, JP-A-57-9714 and JP-B-58-43368.
JP-A-58-52216, JP-A-58-79918, JP-A-60-13720 and JP-A-60-11431 disclose that an absorption promoter is contained in an adhesive layer. Disclosed are patches and the like.

Among the above 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 necessarily good. Propylene glycol, glycerin, sodium pyrrolidonecarboxylate, etc. can retain water in the stratum corneum, but almost no drug absorption promoting effect is observed.
Dimethyl sulfoxide, etc., is apt to cause erythema and rash by stimulating the skin and mucous membranes. When a tape preparation is prepared by including a dicarboxylic acid ester such as diisopropyl adipate or a fatty acid ester in the pressure-sensitive adhesive layer, the compatibility between the pressure-sensitive adhesive and the drug decreases, and thus the drug easily precipitates from the pressure-sensitive adhesive.
The tackiness may decrease. Sulfur-containing compounds such as calcium thioglycolate also cause bad breath. In addition to the above compounds, myristic acid ester, adipic acid ester, lauryl sulfate ester, polyoxyethylene alkyl ether, etc. are also disclosed, but even if these absorption enhancers are used, the absorption amount of the drug through the skin or mucous membrane is not always required. It's not enough. Thus, at present, no transdermal or transmucosal preparation capable of effectively absorbing a drug has been obtained.

(Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional drawbacks, and an object thereof is to provide a preparation capable of effectively absorbing the contained drug through the skin and mucous membranes. It is in. Another object of the present invention is to improve the percutaneous / transmucosal absorbability of a drug contained therein, and to provide a transdermal / transmucosal preparation containing a complete absorption enhancer for the living body without irritation to the skin and mucous membranes. To provide. Still another object of the present invention is to provide a transdermal / transmucosal preparation containing an absorption enhancer that does not change the properties of the base and does not cause the drug to precipitate.

(Means for Solving Problems) The transdermal / transmucosal preparation of the present invention comprises indomethacin, salicylic acid, aspirin, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, flufenamic acid, ibuhenac, fuenbufen, alclofenac, bender. An anionic drug selected from the group consisting of zac and flurbiprofen; or hydrocortisone, prednisolone, furocinolone acetonide, fludoxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone, betamethasone acetate, valeric acid Diflucortron, clobetasol propionate, fluocinonide, pentaerythritol tetranitrate, isosorbide nitrate, estriol, estrogen, es A transdermal / transmucosal preparation containing a neutral drug selected from the group consisting of tradiol, testosterone, progesterone and prostaglandin, and an absorption enhancer of the drug,
The absorption promoter is N-acyl sarcosine, and the acyl group has a form in which an aliphatic hydrocarbon group having 5 to 17 carbon atoms is bonded to a carbonyl group, whereby the above object is achieved.

The absorption enhancer used in the present invention is N represented by the following formula.
Is an acyl sarcosine: Here, R is an aliphatic hydrocarbon group having 5 to 17 carbon atoms. Examples of such compounds include sarcosine, a fatty acid such as caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, margaric acid, stearic acid, hexadecenoic acid, oleic acid, and linoleic acid. There are (N-methylglycine) derivatives. These salts are also used. Particularly, lauroyl sarcosine and its salts, which are derivatives of lauric acid, show excellent effects. Such N-acyl sarcosine is contained in the preparation in an amount of 0.01 to 30% by weight. This ratio indicates the content with respect to the whole preparation in the case of ointments, cream preparations, suppositories, eye drops, etc. For example, in the case of patch preparations such as tape preparations and poultice preparations, the content shows the content excluding the support. The same applies to the drug content described below. If the amount of N-acyl sarcosine is too small, a drug absorption promoting effect cannot be obtained. If the amount is excessive, for example, the adhesive properties of the tape preparation will deteriorate and the compatibility with the adhesive will also deteriorate.

The drugs (bioactive substances) used are indomethacin,
Anionic drug selected from the group consisting of salicylic acid, aspirin, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, flufenamic acid, ibuhenac, fuenbufen, alclofenac, bendazac and flurbiprofen; or hydrocortisone, prednisolone, furo Osinolone acetonide, fludoxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone, betamethasone acetate, diflucortron valerate, clobetasol propionate, fluocinonide, pentaerythritol tetranitrate, isosorbide nitrate, estriol, estrogen, Consists of estradiol, testosterone, progesterone and prostaglandins It is limited to the neutral drug selected from the group. The compounding amount of these drugs varies depending on the type of drug, purpose of use of the drug product, etc.
It is contained in a proportion of 0% by weight.

Among the transdermal / transmucosal preparations of the present invention containing these drugs and the above-mentioned N-acyl sarcosine, transdermal dosage forms include tape preparations, patches, poultices, ointments and cream preparations. Transmucosal dosage forms include suppositories,
There are oral, nasal, and eye drops.

Of the above-mentioned preparations, the tape preparation and the patch preparation have an adhesive layer containing a drug and an absorption enhancer formed on one side of a support. The base (adhesive) of the tape preparation or patch is sufficient as long as it has an adhesive force capable of fixing the preparation on the skin surface at room temperature for a long time, and is not particularly limited. For example, an acrylic, rubber-based, silicone resin-based adhesive or the like may be used, and an acrylic-based and rubber-based adhesive is usually used.

In the case of acrylic adhesives, because of their adhesive properties,
(Co) polymer of (meth) acrylic acid alkyl ester obtained from aliphatic alcohol having 4 to 18 carbon atoms and (meth) acrylic acid and / or the above (meth) acrylic acid alkyl ester and other functional monomer The copolymer of is preferably used.

Examples of the (meth) acrylic acid ester include butyl acrylate, isobutyl acrylate, hexyl acrylate,
Octyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate, stearyl acrylate, methyl methacrylate, ethyl methacrylate, butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate, Examples include isooctyl methacrylate, decyl methacrylate, isodecyl methacrylate, lauryl methacrylate, and stearyl methacrylate.

Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group, a monomer having an amino group, and the like. Examples of monomers having a hydroxyl group include hydroxyalkyl (meth) acrylates such as 2-hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate. Examples of monomers having a carboxyl group include α-β unsaturated carboxylic acids such as acrylic acid and methacrylic acid; maleic acid monoalkyl esters such as butyl maleate; maleic acid; coumaric acid; crotonic acid. Maleic anhydride also gives the same (co) polymerization components as maleic acid. Examples of the amide group-containing monomer include acrylamide, dimethylacrylamide, and diethylacrylamide, and other alkyl (meth) acrylamides; butoxymethylacrylamide, ethoxymethylacrylamide, and other alkyl ether methylol (meth) acrylamides; diacetone acrylamide; and vinylpyrrolidone. Examples of the monomer having an amino group include dimethylamino acrylate.

Examples of copolymerizable monomers other than the above include vinyl acetate, styrene, α-methylstyrene, vinyl chloride, acrylotolyl, ethylene, propylene, butadiene and the like, and these may be copolymerized. It is preferable that the pressure-sensitive adhesive contains 50% by weight or more of (meth) acrylic acid alkyl ester as a (co) polymerization component.

Examples of the rubber adhesive include natural rubber, synthetic isoprene rubber, polyisobutylene, polyvinyl ether, polyurethane, polyisoprene, polyisobutylene, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-isoprene-butylene block. A copolymer or the like is used. Silicone rubber such as polyorganosiloxane is used as the silicone resin adhesive.

If necessary, various additives such as rosin-based resins, polyterpene resins, coumarone-indene resins, petroleum-based resins, terpene-phenol resins, etc. may be included in the above-mentioned adhesives; liquid polybutene, mineral oil, lanolin, liquid poly Plasticizers such as isoprene and liquid polyacrylate; fillers; antioxidants are added.

As the support for the tape preparation, patch, and poultice, which will be described later, a support usually used for patches is used. Materials for such a support include cellulose acetate, ethyl cellulose, polyethylene terephthalate,
Plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride,
Examples include polyurethane, polyethylene, polyvinylidene chloride, and aluminum. 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.

An adhesive layer containing a drug and an absorption enhancer is formed on the surface of the support to obtain a tape preparation or a patch. To form the pressure-sensitive adhesive layer, various coating methods such as a solvent coating method, a hot melt coating method, and an electron beam curing emulsion coating method can be used. Among them, the solvent coating method is preferably used. To form an adhesive layer by a solvent coating method, for example, the adhesive is diluted with an appropriate solvent, and then a drug, an absorption enhancer,
Further, if necessary, a compounding agent is added and uniformly mixed, and the resulting solution is applied to the surface of the support and dried. Instead of directly applying the solution to the surface of the support, the solution may be applied onto a release paper coated with a silicone resin or the like, dried and then brought into close contact with the support. Such release paper is used to protect the surface of the adhesive layer of the patch until use. Even in coating methods other than the solvent coating method, it is recommended that a release paper be placed to protect the surface of the adhesive layer after forming the adhesive layer. The thickness of the pressure-sensitive adhesive layer varies depending on the purpose of use, but is usually 30 to 200 μm. If it is less than 30 μm, the required amount of drug cannot be contained and the adhesiveness is insufficient. When it exceeds 200 μm, the drug contained in the pressure-sensitive adhesive layer near the support does not sufficiently diffuse, and the drug release property decreases.

The poultice also has a drug-containing layer containing a drug and an absorption enhancer formed on one surface of the support. It is usually less adhesive than tape preparations and patches, so it is fixed to the skin surface with a bandage. Examples of bases for poultices include natural polymers such as sodium alginate, gelatin, corn starch, and tragacanth gum; cellulosic polymers such as methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose; starch polymers such as dextrin and carboxymethyl starch; polyvinyl alcohol, Synthetic polymers such as sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether and polyvinylpyrrolidone are used.

The above-mentioned base, drug and absorption promoter are uniformly mixed and a drug-containing layer is formed on the surface of the support to obtain the desired poultice. Purified water is added to the drug-containing layer; polyhydric alcohol (eg, glycerin, propylene glycol).
Moisturizers such as; inorganic fillers such as kaolin, bentonite, zinc white, and titanium dioxide; viscosity modifiers; crosslinking agents; antiaging agents;

Beeswax, fats and oils as the base of ointments and creams
Lanolin, white petrolatum, paraffin, plastibase, Zelen 50W (trade name), higher fatty acid, higher alcohol, emulsifier, acrogol, carboxyvinyl polymer, etc. are used. A drug and an absorption enhancer are mixed with these bases to obtain an ointment or a cream preparation. At the time of mixing, if necessary, fat-soluble solubilizers such as crotamiton, liquid paraffin, isopropyl myristate, and diethyl sebacate; purified water; water-soluble solubilizers such as ethanol and polyhydric alcohols (eg, glycerin); pH adjusters; etc. Is added.

When the oral agent, nasal drops, and eye drops are in the form of ointment or cream, the base of the above-mentioned ointment or cream formulation is used.
It is prepared in the same manner as an ointment or cream. When it is in the form of a solution (suspension) or jelly, for example, a desired preparation can be obtained by dissolving or suspending a drug or an absorption enhancer in ethanol, purified water, or glycols. Tragacanth, gum arabic, sodium alginate, gelatin,
Methyl cellulose, carboxymethyl cellulose (CM
The drug or absorption enhancer may be dissolved or suspended in a solution containing C) or the like.

As the base of suppositories, oils and fats such as cacao butter, palm oil, coconut oil, and fractionated coconut oil; petrolatum and the like are used.
A drug and an absorption enhancer are uniformly mixed with the above base, and a desired suppository is prepared using a suppository molding machine.

(Action) When the transdermal / transmucosal preparation of the present invention is brought into close contact with the skin or the mucous membrane surface, the contained drug is easily absorbed through the skin or the mucous membrane. Although the detailed mechanism is unknown, it is considered that the absorption enhancer acts on the skin or mucous membrane to denature the protein, increase the water content and soften the protein. Therefore, it is generally considered that the stratum corneum on the skin surface, which is difficult to penetrate the drug, is softened and the contained drug is easily absorbed through the skin.

Since it is easy to absorb a sufficient amount of the drug to obtain the required drug effect, it is not necessary to include a large amount of drug in the formulation as in the conventional case. That is, the bioavailability of the drug is high. Such percutaneous / transmucosal absorption promoting effect is much higher than that when using conventional absorption promoters. Furthermore, the absorption enhancer used in the present invention is not irritating to the skin and is highly safe. It does not change the drug contained.
Excellent compatibility with the base. Since the compatibility between the drug and the base does not change, the drug does not precipitate from the preparation after preparation. When used as a tape preparation or patch, the absorption enhancer itself does not adversely affect the physical properties of the adhesive, such as decreasing the adhesive function of the adhesive.

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

Example 1 (A) Preparation of patch (tape preparation): 25% by weight of a copolymer consisting of 40% by mole of 2-ethylhexyl acrylate, 50% by mole of butyl acrylate and 10% by mole of vinylpyrrolidone
A solution of ethyl acetate was prepared, containing the following components. To this solution, 8 parts by weight of indomethacin as a drug and 5 parts by weight of lauroyl sarcosine as an absorption promoter were added to 100 parts by weight of a copolymer (solid content). Further, ethyl acetate was added to adjust the solid content to 15% by weight, and the mixture was thoroughly stirred in a closed system stirrer. This is dried on a polyethylene terephthalate (PET) film with one side treated with silicone to give a thickness of 6
It was applied so as to have a thickness of 0 μm and dried in a gear oven at 70 ° C. for 20 minutes. A polyethylene film was laminated on the surface of the obtained pressure-sensitive adhesive layer as release paper. This release paper is removed by peeling when used.

(B) Performance evaluation of patch The drug permeability test: using the patch obtained in (A), i
A drug permeability test was performed using an in vitro diffusion cell. twenty four
Table 1 shows the drug permeability (%) after the elapse of time. The test method is as follows.

In Vitro Diffusion Cell Method for Drug Permeability: Opening Diameter is 25
Prepare a Franz diffusion cell of cm. A physiological saline adjusted to pH 7.2 is put into the receptor part of the Franz diffusion cell, and hot water of 37 ° C is circulated on the outer wall part to keep the temperature of the receptor part constant. Attach the test piece (circle with a diameter of 20 cm) of the patch obtained in (A) to the epidermis (4 cm x 4 cm) of the abdomen of the normal rabbit (male) that has undergone hair removal, and attach the epidermis to the cell. . Fill the receptor liquid, being careful not to let air bubbles enter between the skin and the surface of the receptor liquid. After 24 hours, the receptor solution is sampled, the drug concentration is measured by high performance liquid chromatography using a reversed phase column, and the drug permeability is calculated from the following formula.

Drug blood concentration: Using the patch obtained in (A),
The in vivo blood concentration was measured by the following method. The results are shown in the figure.

In vivo blood concentration measurement method: using the patch obtained in section (A)
Cut it to a size of 0 cm ² and apply it to the skin surface of the debacked back of a normal rabbit (male). Blood samples were collected from the ear vein of rabbits at 1 hour, 3 hours, 6 hours, 9 hours, and 24 hours later, and the drug concentration in the serum was measured by high-performance liquid chromatography using a reversed-phase column. To do.

From the figure, it can be seen that when the patch obtained in this Example is used, the blood concentration of the drug is high and the drug has excellent skin permeability. The area under the blood concentration curve (AUC) up to the 24th hour is (447
4 ± 939) ng · hr / ml, which is about 2.4 as compared with (1919 ± 369) ng · hr / ml in Comparative Example 5 in which an absorption enhancer described later is not added.
The value was 5 times higher.

Drug release test: using the patch obtained in (A),
The drug release test was conducted by the following method. The result is the second
Shown in the table.

Drug release test: The patch obtained in (A) has a diameter of 52 mm.
A test piece is obtained by cutting into a circle.

The test piece is immersed in 250 ml of a 10 mM phosphate buffer solution having a pH of 7.0 and kept at 37 ° C. in a constant temperature water bath and stirred. 10 minutes later, 20 minutes later, 4
After 0 minutes, 60 minutes, 120 minutes, and 180 minutes, the phosphate buffer solution is collected little by little, and the amount of drug eluted is measured by high-performance liquid chromatography using a reversed-phase column. The drug dissolution rate is calculated from the following formula.

Comparative Example 1 (A) Preparation of patch (tape formulation): The same as in Example 1 (A) except that oleic acid polyoxyethylamide was used as the absorption promoter.

(B) Performance evaluation of patch The drug permeability test: The patch obtained in the item (A) of this comparative example was used, and the test was carried out according to the item (B) of Example. The results are shown in Table 1.

Comparative Example 2 (A) Preparation of patch (tape formulation): Same as in Example 1 (A) except that urea was used as an absorption promoter.

(B) Performance evaluation of patch The drug permeability test: The patch obtained in the item (A) of this comparative example was used, and the test was carried out according to the item (B) of Example. The results are shown in Table 1.

Drug release test: The patch obtained in this Comparative Example (A) was used, and the drug release test was carried out in accordance with Example 1 (B). The results are shown in Table 2.

Comparative Example 3 (A) Preparation of patch (tape formulation): Example 1 except that diisopropyl adipate was used as an absorption promoter.
It is the same as the item (A).

(B) Performance evaluation of patch The drug permeability test: The patch obtained in the item (A) of this comparative example was used, and the test was carried out according to the item (B) of Example. The results are shown in Table 1.

Drug release test: The patch obtained in this Comparative Example (A) was used, and the drug release test was carried out in accordance with Example 1 (B). The results are shown in Table 2.

Comparative Example 4 (A) Preparation of patch (tape formulation): Example 1 except that propylene glycol was used as an absorption promoter.
It is the same as the item (A).

(B) Performance evaluation of patch The drug permeability test: The patch obtained in the item (A) of this comparative example was used, and the test was carried out according to the item (B) of Example. The results are shown in Table 1.

Drug release test: The patch obtained in this Comparative Example (A) was used, and the drug release test was carried out in accordance with Example 1 (B). The results are shown in Table 2.

Comparative Example 5 (A) Preparation of patch (tape preparation): Same as Example 1 (A) except that the absorption promoter was not added.

(B) Performance evaluation of patch The drug permeability test: The patch obtained in the item (A) of this comparative example was used, and the test was carried out according to the item (B) of Example. The results are shown in Table 1.

Drug concentration in blood: The patch obtained in this Comparative Example (A) was used, and the drug concentration was measured according to Example 1 (B). The results are shown in the figure.

Drug release test: The patch obtained in this Comparative Example (A) was used, and the drug release test was carried out in accordance with Example 1 (B). The results are shown in Table 2.

From Table 1, it can be seen that the patch of Example 1 exhibits a drug permeability of about 5 times that of the patch of Comparative Example 5 containing no absorption enhancer. Even when compared with conventional patches containing an absorption enhancer (Comparative Examples 1 to 4), extremely high drug permeability is exhibited. For example, lauroyl sarcosine is an excellent absorption enhancer, showing a drug penetration rate of about 2.8 times that of diisopropyl adipate and about 3.3 times that of oleic acid polyoxyethylamide. Is clear.

It can be seen from Table 2 that the patch of Example 1 exhibits almost the same drug release properties as the patch of Comparative Example 5 containing no absorption enhancer. This is considered to be because the compatibility of the drug and the adhesive hardly changed even when the absorption enhancer was added.

Example 2 (A) Preparation of patch (tape preparation): 30 parts by weight of styrene-isoprene block copolymer, 70 parts by weight of terpene resin, 70 parts by weight of liquid polyisoprene, 6.8 parts by weight of isosorbide dinitrate (drug) and N- 8.5 parts by weight of caproylsarcosine (absorption enhancer) was dissolved in 863 parts by weight of toluene. This was applied on a polyester film and dried to obtain a patch having an adhesive layer thickness of 50 μm.

(B) Performance evaluation of patch: Using the patch obtained in this Example (A), a drug permeability test was conducted according to Example 1 (B). However, instead of the rabbit epidermis, the back epidermis of a nude mouse that had been subjected to hair removal was used. The results are shown in Table 3.

Comparative Example 6 (A) Preparation of patch (tape preparation): Same as Example 2 (A) except that N-caproylsarcosine was not added.

(B) Performance evaluation of patch: Using the patch obtained in this Comparative Example (A), the same procedure as in Example 2 (B) was performed. The results are shown in Table 3.

Example 3 (A) Preparation of patch (tape preparation): 100 parts by weight of a copolymer consisting of 55 parts by weight of butyl acrylate, 35 parts by weight of butyl methacrylate, 10 parts by weight of 2-ethylhexyl acrylate, 1.6 parts by weight of estriol and pal 5 parts by weight of mityl sarcosine was added to 500 parts by weight of ethyl acetate and mixed uniformly. This was applied on a polyester film and dried to obtain a patch having an adhesive thickness of 50 μm.

(B) Performance evaluation of patch: Using the patch obtained in this Example (A), the same procedure as in Example 2 (B) was carried out. The results are shown in Table 3.

Comparative Example 7 (A) Preparation of patch (tape formulation): Same as Example 3 (A) except that palmityl sarcosine was not added.

(B) Performance evaluation of patch: Using the patch obtained in this Example (A), the same procedure as in Example 2 (B) was carried out. The results are shown in Table 3.

Example 4 (A) Preparation of suppository: 5 parts by weight of diclofenac sodium (drug), 2 parts by weight of lauroyl sarcosine sodium (absorption enhancer), and 93 parts by weight of cocoa butter were uniformly mixed,
Molded into a cylinder, 0.25 g of suppository was obtained.

(B) Performance evaluation of suppository: The suppository obtained in this Example (A) was administered from the anus of a rabbit, and blood was collected from the ear vein over time. The plasma is extracted with benzene and the extract is ECD
The amount of diclofenac sodium in plasma was measured by gas chromatography. The results are shown in Table 4.

Comparative Example 8 (A) Preparation of suppository: Same as Example 4 (A) except that sodium lauroyl sarcosine was not added.

(B) Performance evaluation of suppositories: Using the suppositories obtained in this Example (A), the same procedure as in Example 4 (B) was performed. The results are shown in Table 4.

(Effects of the Invention) According to the present invention, as described above, N- having a specific structure is
By including acyl sarcosine in the preparation as an absorption enhancer, a preparation having extremely excellent transdermal or transmucosal absorbability of the drug can be obtained. Since the drug absorbability is excellent, it is not necessary to include a large amount of drug in the formulation as in the past 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 or transmucosally absorbed. Therefore, it can be effectively used for various medical purposes depending on the type of drug contained.

[Brief description of drawings]

The figure is a graph showing changes in the blood concentration of the drug when the preparation of the present invention (tape preparation) and the preparation containing no absorption enhancer were applied to the skin surface of rabbits, respectively.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A 61-210024 (JP, A) JP-A 61-254532 (JP, A) JP-A 60-11431 (JP, A) JP-A 58- 52216 (JP, A)

Claims (5)

[Claims] 1. An anionic drug selected from the group consisting of indomethacin, salicylic acid, aspirin, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, flufenamic acid, ibuhenac, fuenbufen, alclofenac, bendazac and flurbiprofen. Or hydrocortisone, prednisolone, furocinolone acetonide, fludoxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone, betamethasone acetate, diflucortron valerate, clobetasol propionate, fluocinonide, pentaerythritol tetranitrate, Isosorbide, estriol, estrogen, estradiol, testosterone, progesterone A transdermal / transmucosal preparation containing a neutral drug selected from the group consisting of: and a prostaglandin, and an absorption enhancer for the drug, wherein the absorption enhancer is N-acyl sarcosine, and the acyl group is A transdermal / transmucosal preparation in which an aliphatic hydrocarbon group having 5 to 17 carbon atoms is bonded to a carbonyl group. 2. The transdermal / transmucosal preparation according to claim 1, which contains the absorption enhancer in a proportion of 0.01 to 30% by weight. 3. The transdermal / transmucosal preparation according to claim 1, wherein an adhesive layer containing the drug and the absorption enhancer is provided on one surface of a support. 4. The transdermal / transmucosal preparation according to claim 3, wherein the adhesive is an acrylic adhesive or a rubber adhesive. 5. The acrylic pressure-sensitive adhesive has a (co) polymer of a (meth) acrylic acid alkyl ester having an alkyl group having 4 to 18 carbon atoms and / or an alkyl group having 4 to 18 carbon atoms (meta). ) A copolymer of an acrylic acid alkyl ester and another functional monomer, wherein the (meth) acrylic acid alkyl ester is contained as a (co) polymerization component in a proportion of 50% by weight or more in the adhesive. The transdermal / transmucosal preparation according to item 4 above.