JP2001278782A - Bilayer type percutaneous absorber preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a bilayer type percutaneous absorber formulation more excellent in preservation stability. SOLUTION: This bilayer type percutaneous absorber preparation is obtained by laminating an absorption promoter-substrate containing sheet on a main ingredient-containing sheet. The aforesaid main ingredient-containing sheet comprises 0.5-15 wt.% of the main ingredient based on the total weight of the formulation and the substrate selected from paper or fabrics for including the main ingredient. The aforesaid absorption promoter-substrate-containing sheet comprises 85-99.5 wt.% of the substrate and the base material selected from a group comprising paper, fabrics, polyvinylidene chlorides, polypropylenes, polyesters, acetates or copolymers thereof, chitin, chitosan, silicone thin films and cross-linked products of polyvinylpyrrolidones.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a two-layered transdermal preparation containing a drug-carrying layer and a base-absorption enhancer. More specifically, the present invention relates to a two-layered percutaneous absorption preparation in which a drug which easily undergoes modification in a base is used as an active ingredient.

[0002]

2. Description of the Related Art In general, drugs are administered by various routes such as oral, intravenous, transdermal absorption, and rectum, depending on various factors such as the target site, drug concentration at the site of action, its metabolism and biological half-life. Is selected and administered according to the prescription. However, due to problems such as destruction of the drug by digestive juices and rapid inactivation of the drug due to metabolism in the liver, and problems such as the appearance of serious side effects due to the transfer of a large amount of drug into the blood at once, It is known that there is a case where a therapeutic drug cannot be administered by such an administration route. In addition, there are cases where strict control or sustained release of the absorption amount of the drug is required, and cases where the absorption efficiency is greatly influenced by the solubility of the drug in the base.
As another administration route, a drug delivery system that continuously supplies a drug through the skin has been developed with the expectation of a systemic effect of absorbing the drug from the skin and reaching a target site.

[0003]

In this system, the applied drug penetrates into the blood through the stratum corneum of the skin and the like, but the degree of absorption of the main agent depends on the combination of the nature of the main agent and the base. , And is hardly absorbed in the case of a water-soluble base material. For this reason, conventionally, transdermal preparations containing lipophilic nitroglycerin, estradiol, and isosorbide dinitrate as main agents have been developed.
There is a demand for the development of a preparation capable of maintaining a low concentration of a water-soluble drug (active ingredient) in the body over a long period of time, and the present inventors have already developed a transdermal preparation containing L-dopa as a main agent. And Japanese Patent Application No. 207338, 1998. Although this formulation is a monolayer hydrogel formulation with good transdermal absorption efficiency of the water-soluble drug as the main agent, it has been revealed that the formulation may be discolored when marketed depending on the storage conditions in the distribution process. . That is,
There is no problem if the above formulation is prepared and used within a relatively short period of time after being protected from light and kept at a low temperature, but in consideration of storage conditions in the distribution process, etc., a transdermal absorption formulation with more excellent storage stability Development was desired.

[0004]

Means for Solving the Problems The present inventors have made intensive studies in order to prevent denaturation of the main ingredient in the base and further improve the storage stability during storage of such transdermal preparations. As a result, the storage stability of the preparation is maintained by maintaining the absorbability of the main agent from the skin by separating the main agent (hereinafter sometimes referred to as “drug” or “main agent”) from the base and the absorption enhancer. The present inventors have found that it is possible to improve the performance, and have completed the present invention. That is, the present invention is a two-layered transdermal absorption preparation comprising a base-containing sheet, and an absorption promoter-base-containing sheet containing an absorption promoter for promoting absorption of the base and a base. The main agent-containing sheet preferably comprises 0.5 to 15% by weight of the main agent, based on the total weight of the preparation, and a base material selected from paper or fabric for containing the main agent.

The main agent is a drug having a narcotic analgesic action; a drug having a nonsteroidal anti-inflammatory action;
Drug having diuretic action; drug having antipsychotic action; drug having hypnotic action; drug having antiepileptic action;
Drugs used as drugs for Kinson; drugs having an antiemetic action; hormones; drugs having an analgesic action; drugs used as drugs for angina; drugs having an antiarrhythmic action; drugs having an inotropic action; A drug having an antihistamine action; a drug having an antiallergic action; a drug having an antihypertensive action; selected from the group consisting of amino acids, amino acid derivatives, peptides having a group to be a free amino group, and proteins. Preferably, there is.

It is preferable that the absorption promoter-base containing sheet contains an absorption promoter, an oil-based base or a water-soluble base, and a supporting base material for supporting the base. The oleaginous base is preferably at least one selected from the group consisting of hydrocarbons, higher alcohols, higher fatty acids, higher fatty acid esters, glycols, vegetable oils and animal oils, and the water-soluble base is preferably , A carboxyvinyl polymer, hydroxypropylcellulose and methylcellulose.

When an oil-based base is used as the absorption enhancer, ureas, pyrrolidone derivatives, fatty acid esters, essential oils, and azone (1-dodecylazacycloheptan-2-one, Nelson, USA) And at least one member selected from the group consisting of and analogs thereof. When a water-soluble base is used, the base should be composed of at least one or more terpenes selected from the group consisting of monoterpenes, diterpenes, and sesquiterpenes, and alcohols having 2 or 3 carbon atoms. Is preferred.

[0008] The absorption accelerator-base containing sheet is 90 to 99.9% by weight based on the total amount of the absorption accelerator and the base.
Oil-based base, and 0.1 to 10% by weight of an absorption promoter,
It is preferable to contain other auxiliaries in an amount necessary to make the whole 100% by weight. Alternatively, the absorption promoter-base-containing sheet may contain 0.5 to 25% by weight of an oleaginous base based on the total amount of the absorption promoter and the base;
Preferably, it contains 55% by weight of an absorption enhancer and other auxiliaries in an amount necessary to bring the total to 100% by weight.

Preferably, the other auxiliary agent comprises at least one of a dialkylethanolamine having 4 to 8 carbon atoms and a dialkyl adipate having 2 to 8 carbon atoms, and water. Preferably further contains at least one or more polyhydric alcohols having 2 to 5 carbon atoms. Or, the supporting substrate is made of paper, fabric, polyvinyl chloride, polyvinylidene chloride, polyethylene, polypropylene, polyester, acetate or a copolymer thereof, chitin, chitosan, pigskin, a silicone thin film and a crosslinked product of polyvinylpyrrolidone. It is preferably selected from the group consisting of:

[0010] The two-layered transdermal preparation of the present invention may further comprise a covering sheet. The covering sheet is the same as the above-mentioned carrier substrate except for paper and fabric. be able to. Furthermore, Gore-Tex (registered trademark, Japan Gore-Tex Co., Ltd.), Entrant (registered trademark, Toray Industries, Inc.), Sympatex (registered trademark,
Sympatex Technologies GmbH), pig skin, and artificial skin can also be suitably used. As used herein, the “total weight of the preparation” refers to the sum of the weight of the base containing the absorption enhancer and other auxiliaries and the weight of the main ingredient. Further, the “support base material” refers to a material that supports the main agent and the absorption promoter-base. "Fabric" means woven fabric, nonwoven fabric, and knit.

[0011]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. The two-layered percutaneous absorption preparation of the present invention includes a main agent-containing sheet containing a main agent, and an absorption enhancer-base-containing sheet that promotes the transfer of the main agent to the skin and absorption into the skin. Normally, a main agent-containing sheet is first adhered to an application site, and an absorption enhancer-base-containing sheet is laminated thereon so that the absorption enhancer-base is in contact with the main agent-containing sheet.

First, the base material-containing sheet will be described.
Here, the base material-containing sheet is a liquid or semi-solid state of about 0.5 to 15% by weight of the base material with respect to the total weight of the preparation,
It is manufactured by impregnating or coating a substrate made of paper or cloth. The amount of the base is 0.5 to 1 of the total weight of the preparation.
The reason for setting it to 5% by weight is as follows. If the amount is less than 0.5% by weight, the number of administrations is increased due to a small dose, and administration of the drug becomes difficult. Conversely, if the amount exceeds 15% by weight, the main agent that cannot be absorbed from the skin is wasted, Also, depending on the drug, the dose may become too large and cause side effects. More preferably, the content is 2 to 10% by weight. Although it depends on the drug, when it is about 5% by weight, the number of administrations can be reduced to about once a day, and the main agent can be absorbed without waste.

As the main agent, the following drugs can be used. Specifically, for example, drugs having a narcotic analgesic effect such as morphine and a salt thereof (for example, morphine hydrochloride), fentanyl, buprenorphine, dihydroxyethorphine; indomethacin, ibuprofen, ibufenac, acrofenac, diclofenac, mefenam Non-steroidal anti-inflammatory drugs such as acid, ketoprofen, phenylbutazone, methyl salicylate, piroxicam; cortisone, hydrocortisone, prednisolone, dexamethasone, betamethasone dipropionate, betamethasone valerate, triamcinolone, fluociroacetonide, etc. Drugs with steroidal anti-inflammatory activity;

Bendroflumethiazide, polythiazide,
Methyclothiazide, trichlormethiazide, bentylhydrochlorothiazide, hydrochlorothiazide, drug with diuretic action, such as bumetanide; Emonaburido, diazepam, nitrazepam, flunitrazepam, lorazepam, prazepam, fludiazepam, clonazepam, chlorpromazine, reserpine, Torifuruperido - le, Haroperido - Le , Moperon and other antipsychotics; barbital, thiopental, phenobarbital, cyclobarbital and other hypnotics; antiepileptic and other drugs such as ethosuximide, sodium palproate, acetasolamide and meprobamate. Chlorzoxazone, talipexol hydrochloride, levodopa (hereinafter referred to as “Ld
opa ". )) And other drugs used as Parkinson's drugs;

[0015] Tokuropuramido drug having antiemetic effects, such as metoclopramide hydrochloride; azasetron, granisetron, ondansetron, ramosetron, 5-HT ₃ receptor antagonistic antiemetics such as tropisetron; insulin, testosterone, methyl testosterone, progesterone, estradiol Hormones such as aspirin, codeine, acetanilide, aminopyrine and the like having an analgesic action; sulfamine, sulfamonomethoxine,
Drugs having a sulfanilamide structure such as sulfamethizole (generally classified as drugs used as antipathogenic microbial agents, hypotensive diuretic agents, drugs for diabetes); nitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate Le;
Drugs used as drugs for angina pectoris such as provanilnitrate, dipyridamole, papaverine hydrochloride; drugs having antiarrhythmic action such as ajmaline, pindolol, propranolol, quinidine, mexiletine; caffeine, digoxin, digitoxin, Drugs with a cardiotonic effect, such as amrinone, milrinone, pimobendan;

Nicardipine hydrochloride, diltiazem hydrochloride, nivadipine, nifedipine, nitredipine, nildipine,
Drugs having calcium antagonism such as nimodipine and nildipine; diphenhydramine hydrochloride, carbinoxamine,
Diphenylpyraline, fenbenzamine, chlorpheniramine maleate, brompheniramine maleate,
Drugs having an antihistamine action such as diphenylimidazole and clemizole; ketotifen fumarate which is a drug having an antiallergic action; clonidine which is a drug having an antihypertensive action; and other substances such as taurine, glycine and lysine;
Examples include various amino acids such as cysteine, derivatives of these amino acids, peptides having a group to be a free amino group, folate derivatives such as protein, folic acid and tetrahydrofolate.

The base material-containing sheet of the present invention is prepared by dissolving the above-mentioned drug in an appropriate solvent to form a liquid or semi-solid,
The substrate is impregnated or coated, and the solvent is distilled off to produce. For this reason, when impregnating with a liquid base material, it is preferable to use one having a large liquid holding power. As described above, the woven fabric, the nonwoven fabric, and the knitted fabric are made of natural fibers, chemical fibers, and other fibers, but the fabric used in the two-layered percutaneous absorption preparation of the present invention has some extent. Any material may be used as long as it has a fiber structure having a roughness of, and is not particularly limited. Examples of the natural fibers include vegetable fibers such as cotton and hemp, and examples of the chemical fibers include regenerated fibers such as viscose rayon, semi-synthetic fibers such as acetate-rayon, and synthetic fibers such as nylon. Can be mentioned.

Specifically, such base materials include gauze and wiper sheet (Nippon Kimberly-Clark Co., Ltd.)
And non-woven fabrics made from natural fibers as a raw material, and oil-made paper (manufactured by The Daiso Co., Ltd.). Is preferable in terms of good cost and cost. Next, the absorption accelerator-base containing sheet will be described. The absorption enhancer-base containing sheet used in the two-layered transdermal absorption preparation of the present invention contains an absorption enhancer, an oily base or a water-soluble base, and a supporting base material for supporting these. It is a thing.

Generally, the base is divided into an oily base, an emulsion base and a water-soluble base as prescribed in the Japanese Pharmacopoeia. Among them, the base used for ointments and suppositories is used. The hydrophobic base is referred to as an oil base, and the base which is used as an ointment base and which is extremely soluble in water is referred to as a water-soluble base. As such an oily base, lard, beef tallow, fatty oil, hydrocarbon, higher alcohol, higher fatty acid, higher fatty acid ester, glycols, vegetable oil, animal oil and the like can be used. Specifically, examples of the hydrocarbon include hydrocarbons having 12 to 32 carbon atoms. Liquid paraffin, which is a mixture of various hydrocarbons, branched paraffin (trade name: Isopar), solid paraffin, white petrolatum And the like. Among these, it is preferable to use solid paraffin, white petrolatum, or the like.

The higher alcohols include, for example, monovalent aliphatic alcohols having 12 to 30 carbon atoms. Specifically, lauryl alcohol, dodecyl alcohol,
Myristyl alcohol, pentadecyl alcohol, cetyl alcohol, hexadecyl alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, nonadecyl alcohol, eicosyl alcohol, ceryl alcohol, mesyl alcohol, and the like. Among these, it is preferable to use cetyl alcohol, hexadecyl alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, and the like, and it is preferable to use cetyl alcohol, stearyl alcohol, or oleyl alcohol.

The higher fatty acids include, for example, straight-chain or branched saturated or unsaturated fatty acids having 6 to 32 carbon atoms. Specifically, for example, caproic acid,
Enanthic acid, caprylic acid, pelargonic acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, oleic acid, nonadecanoic acid, arachinic acid, linoleic acid, linolenic acid, behenic acid Lignoceric acid, cerotic acid, heptacosanoic acid, montanic acid, melicic acid, lacceric acid, elaidic acid, brassic acid, and the like, and it is preferable to use myristic acid, oleic acid, and the like.

Examples of the higher fatty acid ester include an ester of a fatty acid having 10 to 32 carbon atoms and a monohydric aliphatic alcohol having 14 to 32 carbon atoms, and a saturated or unsaturated fatty acid having 10 to 22 carbon atoms and glycerin. And hydrogenated products of these esters. Specifically, fatty acid esters such as myristyl palmitate, stearyl stearate, myristyl myristate, ceryl lignoserate, lanolin, various waxes described below, glyceryl laurate, glyceryl monomyristylate, glyceryl monooleate, glyceryl monoester Stearates, glyceryl dilaurate, glyceryl dimyristylate, glyceryl distearate, glyceryl trilaurate, glyceryl trimyristylate,
Glyceryl tristearate and the like can be mentioned. Preference is given to using glyceryl monooleate, glyceryl monostearate, glyceryl tristearate.

The fatty oils include soybean oil obtained from soybean seeds, camellia oil obtained from the seeds of a camellia or a closely related plant obtained by removing the seed coat, rapeseed oil obtained from rapeseed seeds, and peanut oil obtained from peanut seeds. Peanut oil, sesame oil obtained from sesame seeds, vegetable oils such as safflower oil obtained from safflower, mink oil, egg yolk oil, squalane, lanolin obtained by purifying fat-like substances obtained from sheep hair,
Animal oils such as fish oil, whale oil, and liver oil can be mentioned. In some cases, hydrogenated hydrogenated oils and the like may be included in the above fatty oils. Examples of the wax include carnauba wax obtained from carnauba palm leaves, beeswax obtained by purifying wax obtained from a beehive such as bee honey bees or European bees, and beeswax bleached from beeswax. When beeswax and the above vegetable oils (vegetable oils listed in the Japanese Pharmacopoeia, usually used for food) are blended according to the Japanese Pharmacopoeia,
It becomes a single ointment.

Vaseline can be divided into three types: yellow petrolatum, white petrolatum and hydrophilic petrolatum. Of these, yellow petrolatum is a refined mixture of hydrocarbons obtained from petroleum, and is less soluble in ethanol,
Poorly soluble in water, soluble in ether, petroleum benzene or turpentine with a clear or slightly insoluble content. White petrolatum is obtained by refining a mixture of hydrocarbons obtained from petroleum and can be blended with almost all drugs without change. Therefore, white petrolatum is widely used as a base for various ointments and cosmetics. In addition, hydrophilic petrolatum can be prepared by blending salami beeswax, stearyl alcohol, cholesterol, and white petrolatum according to the description in the Japanese Pharmacopoeia. When white beeswax, sorbitan sesquioleate and white petrolatum are blended according to the description of the Japanese Pharmacopoeia, a white ointment is obtained.

In order to increase the hardness of an ointment using an oleaginous base, paraffin, which is a mixture of solid hydrocarbons obtained from petroleum, and liquid paraffin, which is a mixture of liquid hydrocarbons obtained from petroleum, are used. What is necessary is just to add. Examples of the water-soluble base include carboxyvinyl polymer, hydroxypropylcellulose (hereinafter, also referred to as “HPC”), macrogol, methylcellulose, and the like. The carboxyvinyl polymer, HPC, Macrogol can be suitably used. These base compounds may be used alone,
Two or more types may be appropriately selected and used in combination. These bases also determine the preservability of the ointment and other properties of the preparation.

Carboxy vinyl polymer is a water-soluble vinyl polymer having a carboxyl group, and is a copolymer mainly composed of acrylic acid and a small amount of sucrose or the like. Goodrich Co. (Cleveland, Ohio, USA)
Developed as a thickening, dispersing and emulsifying agent by 9
34, 940, and 941 grades are commercially available. The molecular weight of 934 and 940 is 2,
000 to 3,000,000, 941 is 1,000,000
00 to 1,500,000. It is also commercially available under the trade name of Hibiswako (manufactured by Wako Pure Chemical Industries, Ltd.).

The carboxyvinyl polymer is required to have high purity and uniform quality to give good reproducibility in the production of cosmetics and pharmaceuticals, to exhibit a high degree of thickening (thickening) without losing fluidity, In the temperature range of 70 ° C., the viscosity hardly changed due to the temperature change, the affinity was good for ethanol and glycerin, it was hard to undergo biological decomposition by bacteria, etc., and a suitable neutralizing agent was used. In some cases, it has properties such as exhibiting gel stability over a wide pH range and having high affinity with raw materials used in many cosmetics and pharmaceuticals. Macrogol is a polymer of ethylene oxide and water.

[0028]

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Is a general term for polyethylene glycol. Polyethylene glycol 400, 150
0, 4000, 6000 and 20,000 are listed in the Japanese Pharmacopoeia. All of them are easily soluble in water, ethanol and organic solvents, 400 is used as a base and emulsifier for ointments and tablets, 1500 is also used as a base for pharmaceuticals and cosmetics, and 4000 is a plasticizer for solidified cosmetics or a pharmaceutical. It is used as an ointment base. What was produced by adding Macrogol 4000 and 400 in half each is called Macrogol ointment and is used as a water-soluble ointment base.

HPC is obtained by obtaining alkali cellulose from wood pulp or linter pulp, reacting with propylene oxide to form a crude HPC, neutralizing with weak residue, gelling and purifying with hot water, drying and pulverizing. . Since HPC has a hydrophilic group and a lipophilic group in its structure and is nonionic, it is also stable to salts, acids and alkalis. When you add water, methanol, ethanol, or isopropanol,
It becomes a viscous liquid. Since it has an appropriate surface activity and has excellent compatibility with propylene glycol and the like, it is used for lotions, creams and the like. When a carboxyvinyl polymer is used among the above-mentioned bases, a compound having a certain range of molecular weight can be selected, and therefore, there is an advantage that characteristics of the composition serving as an ointment base can be easily made constant.

When a large amount of the carboxyvinyl polymer is used as a base, the ointment becomes acidic and causes skin irritation. Therefore, the amount used is about 0.1 to the total weight of the preparation.
Preferably, it is 5 to about 2% by weight. When an acidic base-soluble water-soluble polymer is used, a neutralizing agent described later is added as an auxiliary agent. When a neutral substance such as HPC is used, a neutralizing agent is not required. The neutral base water-soluble polymer is preferably used in an amount of 5 to 15% by weight based on the total weight of the preparation. If the amount is less than 5% by weight, the hardness of the base is too low to be too soft, and if it is more than 15% by weight, the base is too hard to apply. About 10% by weight
Then, the best feeling of use is obtained.

The polyhydric alcohol having 2 to 5 carbon atoms includes
Examples thereof include dihydric alcohols such as ethylene glycol and propylene glycol, and trihydric alcohols such as glycerin. These polyhydric alcohols
They may be used alone or in an appropriate combination of two or more, but it is preferable to use propylene glycol. Propylene glycol is a colorless and transparent syrup-like liquid that dissolves organic drugs, water-soluble vitamins, pigments, fragrances, and the like often used in pharmaceuticals, is wettable, and has bactericidal properties. In addition, when formulated in pharmaceuticals and the like, it softens the skin without leaving stickiness and improves spreadability and adhesiveness, so that it can be suitably used as an ointment base.

[0033] Absorption enhancers are those that increase the absorption of the main ingredient from the skin. In the present invention, the absorption enhancer, when using a combination of a fat-soluble base and an oil-based base as described above, it is sufficient if it is usually used in a transdermal absorption preparation, for example, , Ureas such as urea and thiourea, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5
-Methyl-2-pyrrolidone, pyrrolidone derivatives such as 1,5-dimethylpyrrolidone, fatty acid esters such as methyl myristate, butyl myristate, isopropyl myristate, isopropyl palmitate, isopropyl caprate and isopropyl caproate, 1-menthol, Essential oils such as rosemary oil, cardamom oil, basil oil, eucalyptus oil, spearmint oil, lavender oil, ylang-ylang oil, sandalwood oil, Aison and its analogs, cyclodextrin, calcium thioglycolate and the like. It may be appropriately selected in consideration of the skin permeability of the main agent and the oil-based base and the compatibility with them. Further, when using a combination of a water-soluble base and a water-soluble base, a monoterpene,
It is preferable to use an alcohol having 2 or 3 carbon atoms in order to appropriately increase the transdermal absorption of the main ingredient.

When the lipophilic base material and the oleaginous base are combined, if necessary, for example, ethanol and
-Menthol, 1,3-butylene glycol and l-menthol, ethanol and l-menthol and rosemary oil, ethanol and l-menthol and lavender oil, ethanol, l-menthol and sandalwood oil, and the like are preferably used. it can. When the oil-based base has sufficiently high skin permeability, it is not necessary to add an absorption enhancer. Examples of the alcohol having 2 or 3 carbon atoms used in the combination of the water-soluble main agent and the water-soluble base include ethanol, n-propanol, and isopropanol, and ethanol is preferred from the viewpoint of absorption promoting action. 5 to 59% by weight based on the total weight of the composition
Is preferably used. If the ethanol concentration is less than 5% by weight, the absorption of the main agent will be insufficient, and if it exceeds 59% by weight, significant damage to the skin will appear.

The monoterpene refers to a group of terpene compounds having 10 carbon atoms. Specifically, hydrocarbons such as myrcene, limonene, and camphene; alcohols such as citronellol, geraniol, and menthol; and aldehydes such as citral and peraldehyde. And ketones such as mentone and yonone, and cineole. Sesquiterpene refers to a group of terpene compounds having 15 carbon atoms, and includes hydrocarbons such as bisabolene and gingiberene, alcohols such as farnesol, eudesmol, and cedrole, ketones such as cyberone, and hinokinic acid.

Diterpene refers to a group of terpene compounds having 20 carbon atoms, and includes alcohols such as retinol and phytol, and other substances such as abietic acid, pimaric acid, and manoyl oxide. As a member selected from the group consisting of these terpenes, d-limonene or 1-menthol is preferable. When these are used, there are advantages that the absorption enhancing effect of the main agent is enhanced, and that the patient has a refreshing feeling and is easily accepted when used by patients. d
-The content of limonene and l-menthol is preferably about 1 to about 5% by weight, based on the total weight of the preparation. If the amount is less than about 1% by weight, both the absorption enhancing effect of the main ingredient and the refreshing feeling are insufficient, and if it exceeds about 5% by weight, the skin becomes irritating. About 1 to about 3% by weight
And more preferably about 2% by weight from the viewpoint that the effect of enhancing absorption of the main ingredient and a sufficient refreshing feeling can be obtained.

The combination of the ethanol concentration and the terpene concentration to be used is determined as follows. Here, a combination of ethanol and l-menthol will be described as an example. Specifically, using a combination of a certain concentration of ethanol and l-menthol, an increase in the K ′ value, which is a distribution parameter, is observed. First, a combination of a certain concentration of ethanol and l-menthol is selected, and its K 'value is measured. Then, as the concentration of ethanol increases, the K 'value increases, but when the concentration exceeds a certain concentration, the K' value does not increase. Based on this, a combination of an ethanol concentration and a terpene concentration is selected from among combinations in which the K ′ value is increased, in consideration of the distribution ratio of levodopa from the donor solution to the skin.

For example, a mixture of 20% by weight of ethanol and 1 to 5% by weight of 1-menthol, 40% by weight of ethanol and 1 to 5% by weight of 1-menthol, 50% by weight of ethanol and 1 to 5% by weight When comparing the combination of 1-menthol and l-menthol, 20% by weight of ethanol and 1%
The K 'value obtained with the combination of ５5% by weight of l-menthol is greater than that of 40% by weight of ethanol and 1 to 5% by weight of l-menthol.
It is assumed that the K ′ value obtained with the combination of menthol was high, but the K ′ value was not increased with the combination with 50% by weight of ethanol. In this case, a combination of up to about 40% by weight of ethanol and 1 to 5% by weight of l-menthol is preferred.

As described above, the auxiliary agent used in the present invention comprises a neutralizing agent used for neutralization when an acidic water-soluble base is used. For example, when the above carboxyvinyl polymer is used, the auxiliary agent is at least one compound selected from the group consisting of dialkylethanolamine having 4 to 8 carbon atoms and dialkyl adipate having 2 to 8 carbon atoms. And water. Examples of the dialkylethanolamine having 4 to 8 carbon atoms include diethylethanolamine, dipropylethanolamine, diisopropylethanolamine, dibutylethanolamine, diisobutylethanolamine, and the like.

Examples of the dialkyl adipate having 2 to 8 carbon atoms include diisopropyl adipate and dibutyl adipate. When an acidic polymer such as a carboxyvinyl polymer is used as a base, diisopropylethanolamine, diisopropyl adipate, and water are used as assistants. These compounds contain diisopropylethanolamine at about 0.1%.
The use of 5 to about 2% by weight and diisopropyl adipate as about 1 to about 4% by weight can neutralize the acidity of the carboxyvinyl polymer, and provide a smooth hydrogel with good feeling on use and skin. Is preferred. More preferably, about 1% by weight of diisopropylethanolamine and about 2% by weight of diisopropyl adipate are used.

The preparation of the present invention contains about 0.5 to 15% by weight of the base in the base-containing sheet, based on the total weight of the preparation,
Absorption enhancer-0.5 to 25% by weight of a water-soluble base, 10 to 55% by weight of an absorption enhancer, and other auxiliaries in the base-containing sheet in an amount sufficient to bring the total to 100% by weight. Do it. Here, the water-soluble base, absorption promoter, main agent, and other auxiliaries are as described above. The production of the hydrogel-containing sheet will be described by taking as an example a case where a carboxyvinyl polymer is used as a water-soluble polymer for a base and l-menthol and ethanol are used as absorption enhancers.

A predetermined amount of a carboxyvinyl polymer is mixed with a predetermined amount of purified water, and left overnight. When a gel is formed by absorbing water, an appropriate amount of propylene glycol, diisopropylethanolamine and diisopropyl adipate are mixed. As an absorption enhancer, ethanol containing a predetermined amount of l-menthol is added thereto and mixed, and then water is added and mixed again to obtain the indicated amount. The obtained base is applied on the above-mentioned base to obtain a hydrogel-containing sheet. In addition, it is preferable that the base material of the hydrogel-containing sheet is slightly larger than the main material-containing sheet in order to efficiently absorb the main agent.

The case where the sheet containing the main agent is prepared by using the sheet as the L-dopa main agent will be described as an example. A predetermined amount of L-dopa is dissolved in hydrochloric acid, a fixed amount of this solution is transferred to another container, and impregnated into the base material-containing sheet base. After freezing the main agent in a freezer at -25 ° C, the substrate is dried under reduced pressure for 1 to 2 hours to obtain a levodopa-containing sheet. The above-mentioned hydrogel-containing sheet and levodopa-containing sheet are stored separately from light until use. In addition, when using an oleaginous base, the absorption from the skin can be kept high by using a main agent having high fat solubility.
Further, the hardness of the base can be adjusted by adding stearyl alcohol or the like.

When the knitted fabric is used as the base material of the sheet containing the absorption promoter and the base, there is an advantage that the application area of the preparation is widened because of high follow-up properties. Further, the composition containing the above-described absorption promoter and the base may be spread on a covering sheet described later. When a two-layered percutaneous absorption preparation using a water-soluble base is used, the above-mentioned coating sheet is used as a base material for the absorption enhancer-base containing sheet, or these films are used as coating layers. It is preferable to use as a base for preventing drying of the base containing the absorption promoter. Since the covering sheet is to be directly adhered to the skin around the sheet, it is preferable that an adhesive having little irritation to the skin is applied to the contact surface with the skin. Further, it is more preferable that it is made of a material that allows air to pass but does not allow moisture to pass.

The coating sheet is not particularly limited as long as it is formed of a material having such properties. Specifically, polyvinylidene chloride, polyethylene, polypropylene, polyester, acetate, or a copolymer thereof is used. Film, silicone thin film, chitin, chitosan, urethane, Gore-Tex (registered trademark, Japan Gore-Tex Inc.), entrant (registered trademark,
Toray Industries, Inc.), Sympatex (registered trademark, Sympatex T)
echnologies GmbH) or the like.

Therefore, when such a film or fabric is used as a coating layer, the size should be such that the sheet containing the main agent and the sheet containing the absorption promoter-base are completely covered. When a film or fabric as described above is used as the covering sheet, a material having a small skin irritating property on the contact surface with the skin and having a stable adhesive applied to light and oxygen is preferably used. can do. An acrylic adhesive can be used as such an adhesive. The thickness of the covering sheet is not particularly limited, but when used clinically, it is thin and has good elasticity, has good followability to the movement of the application site, and
This is preferable in that the application site is widened.

The sheet containing the absorption promoter-base is, for example,
A predetermined amount of HPC was added with an appropriate amount of water and left for a while. When the mixture became a gel, limonene and ethanol whose proportions were determined as described above were added as absorption promoters, and if necessary, water was further added to form a hydrogel. Is prepared. The composition thus obtained is produced by spreading a fixed amount on the above-mentioned paper or fabric, or a substrate such as film or fabric.

[0048] Among the two-layered transdermal preparations of the present invention prepared as described above, first, the main agent-containing sheet is applied to the application site of the patient as shown in FIG. The hydrogel-containing sheet is overlaid thereon such that the hydrogel is in direct contact with the base material of the base material-containing sheet. In this case, when the base material of the coating sheet is used as the base material of the hydrogel-containing sheet, the above two layers may be stacked. When paper or cloth is used as the base material of the hydrogel-containing sheet, the transdermal absorption effect of the main agent is further enhanced by further using a cover sheet having a size capable of completely covering the hydrogel-containing sheet. be able to. The application site of the two-layered transdermal preparation of the present invention is not particularly limited because the size of the base material can be appropriately changed and the content of the main agent can be appropriately adjusted. For example,
It can be attached to any site such as arm, palm, leg, foot, back, neck and mucous membrane.

[0049]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. (Example 1) Experimental animals and reagents (1) Experimental animals Wistar male rats (Saitama Experimental Animal Co., Ltd.) weighing 300 ± 10 g were acclimated to ordinary cages, and before the test,
Water and standard solid feed (CE-2, CLEA Japan)
Was given freely. Each of the drug administration group and the control group was used in 7 animals per group.

(2) Reagents HPC-H (hydroxypropylcellulose), Hibiswako 105, reduced glutathione (hereinafter abbreviated as GSH), propylene glycol, ether, diisopropylethanolamine, diisopropyl adipate,
d-limonene and 1-menthol, ethanol, acetonitrile, ethyl acetate, hydrochloric acid, perchloric acid, octanesulfonic acid, sodium chloride, ammonium hydroxide, disodium ethylenediaminetetraacetate (EDTA-2N
a), EGTA, sodium dihydrogen phosphate, and trishydroxyammonium aminomethane (hereinafter abbreviated as "Tris") were all purchased from Wako Pure Chemical Industries, Ltd.

Levodopa (L-3,4-dihydroxyphenylalanine), dopamine, norepinephrine, epinephrine and propylene glycol were all Sigm
Purchased from a company. Also, carboxyvinyl polymer (934, BF Goodrich Chemical Co., Cleveland,
Ohio, USA) and the wiper sheet (type CR-4, manufactured by Nippon Kimberly-Clark Co., Ltd.) used above. Α-chloralose, urethane, and DHB
A (dihydroxybenzylamine) was purchased from Sigma. Deuterated methanol and deuterated chloroform were purchased from Kanto Chemical Co., Ltd. Purified water is Otsuka Pharmaceutical Co., Ltd.
The alumina particles were purchased from Wako Pure Chemical Industries, Ltd.

(Example 2) Examination of absorption enhancer (1) Examination of composition of absorption enhancer In order to select an optimal alcohol concentration as a skin absorption enhancer, a single layer transdermal preparation using L-dopa as the main ingredient was used. Absorbable hydrogels were prepared as described below and spread on the substrate in 1 g increments. L-dopa, carboxyvinyl polymer, propylene glycol, diisopropylethanolamine, diisopropyl adipate, d-limonene and l
-Menthol, ethanol and purified water were as described above. About 30 mL of 1 g of carboxyvinyl polymer
And purified water, and allowed to stand for 24 hours a day. After absorbing water and forming a gel, 10 g of propylene glycol, 1 g of diisopropylethanolamine, and 2 g of diisopropyl adipate were mixed therein.

An absorption enhancer having any one of the following compositions was added thereto and mixed. Note that the concentrations shown in the above are all final concentrations. 10% by weight ethanol solution containing 2% by weight l-menthol 20% by weight ethanol solution containing 2% by weight l-menthol 30% by weight ethanol solution containing 2% by weight l-menthol 2% by weight l 40% by weight ethanol solution with menthol 10% by weight ethanol solution with 2% by weight d-limonene 20% by weight ethanol solution with 2% by weight d-limonene 30% by weight with d-limonene 30 40% by weight ethanol solution containing 2% by weight d-limonene

(2) Investigation of the effect of the absorption enhancer in vitro The effect of the use of the absorption enhancer prepared in Example 2 (1) above was determined using the amount of L-dopa permeated in vitro as an index. Was measured as follows. The abdominal hair of the rat was cut with an electric hair clipper, and the whole skin at the cut portion was extracted and used as a permeable membrane. 2-chamber diffusion cell with water jacket (effective diffusion area 0.785
cm ² , each half-cell volume 3.0 mL) was used. water,
, Suspend L-dopa in an excessive amount, put the above three kinds of liquids in a donor cell, and add phosphate buffered saline (pH
The receiver cell was filled in 7.4). Each cell was warmed to 40 ° C., and the suspension in the cell was stirred with a magnetic stirrer.

After placing the L-dopa suspension in the donor cell, at 0, 30, 60 and 180 minutes, 0.5 mL of the sample for analysis was withdrawn from the receiver cell, and an equal volume was taken out each time. Phosphate buffered saline was added to the receiver cell. Each extracted sample was used as a detector for ECD
Analyzed by HPLC using L-
dopa concentration was quantified. Further, this data was processed according to the following equations (1) to (3), and parameter analysis was performed.

<HPLC conditions> Column: Mightysil RP-18 (particle size 5 μm)
m, inner diameter 4 mm × 250 mm, manufactured by Kanto Chemical Co., Ltd.) Mobile phase: 12% acetonitrile-10 mM sodium dihydrogen phosphate / 0.01 mM EDTA (pH 3.1) Flow rate: 1.0 mL / min Column temperature: 40 ° C. Detector: ECD, + 0.7V

[0057]

(Equation 1)

[0058]

(Equation 2)

[0059] In the formula (1) ~ (3), D is the diffusion constant, L is the effective diffusion length of the film, receiver solution in the partition coefficient of the permeate, Q _t is the time t between the K membrane and the donor phase A represents the accumulated amount of permeate present therein, A represents an appropriate amount range, and C ₀ represents the solubility of L-dopa in the donor phase. Ld obtained
Table 1 shows the effect of the donor liquid on the effective diffusion coefficient D 'and the effective distribution coefficient K' of opa.

[0060]

[Table 1]

When the change with time was examined, as shown in FIG. 2, when containing 40% of ethanol, L-dop was determined.
It became clear that the skin permeation amount of a was significantly increased. It was also found that the concentration of L-dopa accumulated in the receiver cell increased as the ethanol concentration increased. On the other hand, comparing the K 'values shown in Table 1, when the 20% ethanol and l-menthol were combined (), the latter K' value was greatly improved. On the other hand, when 40% ethanol and + 2% l-menthol were combined (), the value of K ′ increased only slightly as compared with the case of 20% ethanol. From the above, it was considered that the upper limit of the ethanol concentration in the absorption promoter was preferably set to 40%.
Therefore, the ethanol concentration used in the following experiments was 40
% By weight.

Example 3 Preparation of Two-Layer-Type Preparation (1) Preparation of L-dopa-Containing Sheet An L-dopa-containing sheet was prepared as follows. Levodopa was dissolved at a concentration of 100 mg / mL in 5 mol / L hydrochloric acid in a weighing dish. This hydrochloric acid solution is
mL, wiper sheet (type CR-4, Nippon Kimberly Clark Co., Ltd.) cut into a rectangle of about 1 × 3 cm
Was impregnated in this, frozen in a freezer at −25 ° C., transferred to a desiccator, and the air in the desiccator was sucked with an aspirator and freeze-dried for about 2 hours to produce an L-dopa-containing sheet. . L-do
The pa content was 185.1 ± 3.4 mg / sheet.

(3) Preparation of Hydrogel-Containing Sheet The carboxyvinyl polymer, propylene glycol, diisopropylethanolamine, diisopropyl adipate, d-limonene and l-menthol, ethanol and purified water were used as described above. Was prepared. First, 1 g of a carboxyvinyl polymer is mixed with about 30 mL of purified water, and left for a day and night to absorb water and form a gel. Then, 10 g of propylene glycol and 1 g of diisopropylethanolamine and 2 mL of diisopropyl adipate are mixed. I mixed it here.

Then, water was added and mixed again, 2 g of 1-menthol or 2 g of d-limonene was added, and ethanol was added so that the concentration became the above-mentioned final concentration (40% by weight) to form a hydrogel. Obtained. 1g on clear tape
Was spread to prepare a hydrogel-containing sheet. (4) Preparation of Comparative Sample A single-layered percutaneous absorption preparation having the same hydrogel composition as in (3) above and also containing levodopa as the main agent was prepared.

(Example 4) Stability test of L-dopa-containing sheet (1) Examination of L-dopa content in L-dopa-containing sheet At each of the above sampling times, L-dopa prepared in Example 3 was examined.
The dopa-containing sheets were taken out of the light-shielding box 10 sheets at a time and subjected to analysis. One sheet was placed in 100 mL of perchloric acid having a concentration of 0.2 mol / L to obtain 10 samples for analysis.
These solutions were stirred for 1 hour using a magnetic stirrer to cause L-dopa to leach out of the sheet. 10,
Centrifuged at 000 × g for 10 minutes at 4 ° C. The sample thus obtained was quantified under the following HPLC conditions using ECD as a detector.

<HPLC conditions for L-dopa analysis> Column: Wakosil II 5C18HG (particle size 5)
μm, 4.6 mm × 25 cm, manufactured by Wako Pure Chemical Industries, Ltd. Mobile phase: 100 mmol / L sodium dihydrogen phosphate (NaH ₂ PO ₄ ) /0.01 mmol / L EDTA
-2Na / 100 mg / L 1-octanesulfonic acid (pH 3.5) Flow rate: 1.0 mL / min Column temperature: 40 ° C. ECD voltage: +0.7 V Sample injection volume: 100 μL

As shown in FIG. 3, L-
The content of L-dopa in the dopa-containing sheet was 1 on average.
85.1 ± 3.4 mg / sheet, and the L-dopa content in the sheet 12 weeks after the preparation of the L-dopa-containing sheet was 95.3% on the day of preparation (week 0). This indicated that the L-dopa content in the L-dopa-containing sheet was substantially constant up to 12 weeks after preparation.

(2) Change in sheet color tone 24 sheets each of the L-dopa-containing sheet and the comparative sheet produced in Example 3 were placed in a light-shielding box, and kept at room temperature. Discoloration of the sheet after one week and 12 weeks was visually observed. Simultaneously with the naked eye observation, 10 sheets of the L-dopa-containing sheet prepared as described above were taken at each sampling time, and the L-dopa in the sheet was taken.
The change in the content of was investigated. The color of the sheet also remained white throughout the entire observation period (Table 2). This indicates that L-dopa or L-dopa butyl ester in the sheet is stable for at least 12 weeks when stored at room temperature in the absence of light.

[0069]

[Table 2]

With respect to the single-layer preparation prepared in Example 4, normal changes on the first day, the second day, the fifth day, the seventh day, and the fourteenth day on the day of preparation were visually observed. The results are shown in Table 3 and FIG. The one-layer L-dopa-containing hydrogel preparation was placed in a light-shielding box similarly to the two-layer preparation, and the color change was observed. As shown in Table 3, when stored at room temperature, the hydrogel containing L-dopa turned dark brown on day 7 and almost black on day 14. As described above, it was shown that the storage stability of the two-layer transdermal preparation is higher than that of the single-layer transdermal preparation.

[0071]

[Table 3]

(Example 6) Investigation of blood profile after intravenous administration of L-dopa (1) Intravenous administration of L-dopa Eight rats were anesthetized with ether in two groups of four rats each. A polyethylene tube (PE-5) filled with physiological saline in which 0.2 mol / L EGTA is dissolved in the left jugular vein
0) was cannulated. Via this route, saline was infused at 0.1 mg / kg body weight / min, urethane (500 mg / kg body weight) and α for deep anesthesia and fixation.
-Chloralose (70 mg / kg body weight).
2.5 mg / mL L-dopa physiological saline solution
Dosing was via this cannula. Thereafter, intubation was performed to ensure free breathing.

Thirty minutes before the blood collection, a polyethylene tube (PE-50) filled with phosphate buffered saline containing 0.2 mol / L EGTA was placed in the left femoral artery of the rat.
Was cannulated. L-dopa was administered once intravenously, and 0 minute (before administration), 5 minutes, 15 minutes, 25 minutes after administration.
0.2 mol / L of E in 37.5 minutes, 52.5 minutes
A tube containing 40 μL of a solution containing GTA and 0.2 mol / L reduced glutathione was placed on ice, and the collected blood was collected (Eriksson and Persson, 198).
2). The blood collection volume was within 2 mL to avoid physiological changes in amine concentration induced by blood loss.

(2) Measurement of L-dopa blood concentration The sample collected as described above was centrifuged at 1,700 × g for 10 minutes at 4 ° C., and the plasma of a rat to which L-dopa was intravenously administered was obtained. I got Ericsson and his method (Eriksson and
Pretreatment was performed using purified alumina according to Persson, J. Chromatogr., 228: 143-154 (1982). Alumina was purified as follows. 100 g of alumina 2
The mixture was added to a beaker containing 500 mL of mol / L perchloric acid, and vigorously stirred with a bladed stirrer for 45 minutes while heating at 95 ° C., and the supernatant containing fine components was discarded. The precipitate was again treated with 500 mL of 2 mol / L perchloric acid at 95 ° C. for 15 minutes, the supernatant containing fine substances was discarded, and 500 × 2
The precipitate was transferred to a 50 mm glass column. The column was washed with water until the pH of the eluate became 3.5, the alumina was transferred to a beaker, heated at 120 ° C. for 1 hour, then at 200 ° C. for 2 hours, and stored in a desiccator in a dry state.

Next, based on the method of Ericsson et al.
Blood samples were processed as follows. 20 μL EG
Blood was collected in cooled test tubes containing TA (anticoagulant) and 0.2 mol / L GSH (antioxidant). The tubes were centrifuged at 1,000 xg for 5 minutes at 4 ° C, and the plasma was separated and stored at -70 ° C until analysis. 4mL capacity
Transfer 2 mL of plasma sample into a centrifuge tube of
μL of GSH (0.05 mol / L), 50 μL of ED
TA (0.3 mol / L, pH 7) and 20 mg of the above-treated alumina were added. While the centrifuge tube was vortexed, 0.2 mL of Tris buffer (1 mol / L, pH 8.6) was added, and the mixture was stirred for 10 to 30 minutes using a rotary mixer. 0.1 mol /
L of catecholamine in perchloric acid as a stock solution, which was diluted to 2 pmol / L and 20 pm
ol / L catecholamine was used as a control. DHBA was added to each sample as an internal standard.

The alumina particles adhering to the inner wall of the centrifuge tube were dropped to the bottom of the tube by shaking, and the supernatant was discarded. EDT
The solution was mixed with the solution A (3 mol / L, pH 7) for several seconds to wash the alumina. This operation was repeated three times.
Then, centrifuged at 1,700 × g for 10 minutes at 4 ° C.
Excess liquid was discarded. 150 μL of perchloric acid (0.2mo
levodopa was eluted from the alumina by vortexing at 1 / L) for 1 minute. The compound released from alumina as described above was prepared by the method of Sudo et al. (Biol. Pharm. Bull. 1
8 (4) 610-614 (1995)), reverse phase HPLC was carried out under the conditions described in Example 5, and the amount was determined electrochemically.

(3) Measurement Results FIG. 4 shows the time-dependent change (unit: minute) of L-dopa plasma concentration (unit: ng / mL). L-dopa is
The first measurement point, 5 minutes after administration, was the highest concentration (664.0).
± 59.7 ng / mL), and gradually decreased over time.

(Example 7) Examination of blood profile after L-dopa transdermal absorption (1) Transdermal absorption of L-dopa Rats were anesthetized as described in Example 2 above, Urethane and the like were injected for fixation, and the trachea was intubated to ensure free breathing. Thereafter, the hair of the abdomen of the rat was cut with an electric clipper, and a glass cell (1.
13 cm, contact area of the above hydrogel 1 cm ² , height 1
cm) on the shaved abdominal skin and an adhesive (cyanoacryl type, Aron Alpha A; Sankyo Co., Ltd.)
), Saline (control group) or L-dopa described above.
And filled with parafilm. After this, 0 minutes, 30 minutes, 60 minutes, and 1 minute
At 4/80, blood was collected in the same manner as in Example 2 to quantify each compound, and the blood profiles of L-dopa and its metabolites were examined.

(2) Measurement Results The measurement results are shown in FIG. The plasma L-dopa concentration of the control group did not change during the experiment. On the other hand, Ld
After administration of the opa-containing hydrogel administration group, plasma L-do was
The pa concentration became a plateau in 30 minutes (50 ng / m
L), lasting up to 180 minutes (see FIG. 5). From the above,
It was shown that when L-dopa was transdermally absorbed, L-dopa remained at a certain level of blood level without a sharp increase in blood concentration.

[0080]

According to the present invention, there is provided a two-layer transdermal preparation having excellent storage stability. In the two-layered percutaneous absorption preparation of the present invention, since the base agent and the hydrogel do not come into contact during storage, it is possible to prevent the occurrence of an undesired state of discoloration of the preparation even after a long period of time after preparation of the preparation. it can. In addition, the two-layered transdermal preparation of the present invention can be applied to a desired site on the patient's body surface, and the applicable site can be further expanded by using a base material having good followability. .

[0081]

[Brief description of the drawings]

FIG. 1 is a diagram showing a state where a two-layered transdermal absorption preparation of the present invention is applied to the skin surface.

FIG. 2: Alcohol concentration and Ld in skin absorption enhancer
It is a figure which shows the relationship with the skin penetration amount of opa in vitro.

FIG. 3 is a view showing the stability of L-dopa in an L-dopa-containing sheet.

FIG. 4 is a graph showing the time-dependent change in L-dopa concentration in plasma when L-dopa is intravenously administered.

FIG. 5 is a graph showing the time-dependent change in L-dopa concentration in plasma when L-dopa is transdermally absorbed.

FIG. 6 is a view showing discoloration of a single-layered transdermal preparation.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) A61K 47/16 A61K 47/16 47/18 47/18 47/32 47/32 47/34 47/34 47 / 36 47/36 47/38 47/38 47/44 47/44 A61P 1/08 A61P 1/08 3/14 3/14 5/00 5/00 7/00 7/00 9/06 9/06 9 / 10 9/10 9/12 9/12 25/04 25/04 25/08 25/08 25/16 25/16 25/18 25/18 25/20 25/20 29/00 29/00 37/08 37/08 43/00 113 43/00 113 (72) Inventor Katsuhiko Tsuno 5-7-4 Nakamachidai, Tsuzuki-ku, Yokohama-shi, Kanagawa Prefecture Promenade 410 (72) Inventor Hiroaki Iwase 6-4-6- Ohnodai, Sagamihara-shi, Kanagawa 617 F term (reference) 4C076 AA74 AA77 BB31 CC01 CC13 CC18 CC30 DD34A DD37A DD41A DD43A DD45A DD45N DD47 DD50 DD54N DD60N EE02A EE07A EE24A EE27A EE30A EE31A EE32A EE53A EE53N EE54A

Claims (15)

[Claims] 1. A two-layered transdermal preparation comprising a base-containing sheet containing a base, and an absorption-base-containing sheet containing at least an absorption promoter for promoting absorption of the base and a base. 2. The base material-containing sheet comprises 0.5 to 15% by weight of a base material based on the total weight of the preparation, and a base material selected from paper or fabric for containing the base material. Item 2. The two-layered transdermal absorption preparation according to Item 1. 3. A drug having a narcotic analgesic action; a drug having a nonsteroidal anti-inflammatory action; a drug having a diuretic action; a drug having an antipsychotic action; a drug having a hypnotic action; Drugs having an action; drugs used as Parkinson's drugs; drugs having an antiemetic action; hormones; drugs having an analgesic action; drugs used as a drug for angina pectoris; drugs having an antiarrhythmic action; A drug that modulates calcium sensitivity;
2. A drug selected from the group consisting of: a drug having an antihistamine action; a drug having an antiallergic action; a drug having an antihypertensive action; an amino acid, an amino acid derivative, a peptide having a group to be a free amino group, and a protein. Or the two-layered percutaneous absorption preparation according to 2. 4. The absorption promoter-base containing sheet comprises an absorption promoter, an oil-based base or a water-soluble base, and a supporting base material for supporting them. A two-layered transdermal absorption preparation according to the present invention. 5. The oil-based base according to claim 4, wherein the base is at least one selected from the group consisting of hydrocarbons, higher alcohols, higher fatty acids, higher fatty acid esters, glycols, vegetable oils and animal oils. A two-layer transdermal preparation. 6. The two-layer transdermal preparation according to claim 4, wherein the water-soluble base is at least one selected from the group consisting of a carboxyvinyl polymer, hydroxypropylcellulose, and methylcellulose. 7. The method according to claim 5, wherein the absorption enhancer is at least one selected from the group consisting of ureas, pyrrolidone derivatives, fatty acid esters, essential oils, azacycloalkylenes and analogs thereof. Two-layer transdermal preparation. 8. The two-layer transdermal preparation according to claim 6, wherein the absorption enhancer is at least one selected from the group consisting of monoterpenes, diterpenes, and sesquiterpenes. 9. The absorption enhancer-base containing sheet contains 90 to 99.9% by weight of an oleaginous base and 0.1 to 10% by weight based on the total amount of the absorption enhancer and the base. 5. The two-layered transdermal preparation according to claim 4, comprising an absorption enhancer of the formula (I) and other auxiliaries necessary to make the total amount 100% by weight. 10. The absorption enhancer-base containing sheet,
0.5 to 25% by weight of a water-soluble base relative to the total amount of the absorption promoter and the base, 10 to 55% by weight of the absorption promoter,
The two-layered percutaneous absorption preparation according to claim 5, which contains other auxiliaries in an amount necessary to make the whole 100% by weight. 11. The two-layer composition according to claim 10, wherein the other auxiliary comprises at least one of a dialkylethanolamine having 4 to 8 carbon atoms and a dialkyl adipate having 2 to 8 carbon atoms, and water. Skin absorption preparation. 12. The other auxiliary agent further comprises at least one or more polyhydric alcohol having 2 to 5 carbon atoms.
2. The two-layered transdermal absorption preparation according to 1. 13. The supporting substrate is made of paper, cloth, polyvinyl chloride, polyvinylidene chloride, polyethylene, polypropylene, polyester, acetate or a copolymer thereof, chitin, chitosan, pigskin, silicone thin film and polyvinylpyrrolidone. The two-layered transdermal preparation according to claim 4, which is selected from the group consisting of crosslinked products. 14. The method according to claim 1, further comprising a covering sheet.
13. The two-layered transdermal absorption preparation according to any one of the above items 13. 15. The coating sheet comprises polyvinyl chloride, polyvinylidene chloride, polyethylene, polypropylene, polyester, acetate or a copolymer thereof, chitin, chitosan, pigskin, a silicone thin film, and a crosslinked polyvinylpyrrolidone. The two-layered transdermal absorption preparation according to claim 14, which is selected from the group.