JPH03123727A - Percutaneous absorption preparation - Google Patents

Abstract

PURPOSE:To obtain the title preparation having excellent adhesivity to the skin and absorbing a drug controllably by laying an absorption auxiliary supporting layer between an impermeable backing substrate and a permeable film and equipping a pressure-sensitive adhesive polymer layer containing a drug on the other side of the permeable film. CONSTITUTION:An absorption auxiliary supporting layer 4 comprising a solution, dispersant (preferably one having 20-80 poise viscosity at 25 deg.C) or gel which contains a drug and a drug absorption auxiliary and has function of substantially controlling absorption of drug is laid between permeable backing substrate 2 and a permeable film 3, sealed and a pressure-sensitive adhesive polymer layer (preferably acrylic tacky agent composition of crosslinking structure) 5 which contains the same saturated or supersaturated drug as the absorption auxiliary supporting layer and is tacky at normal temperature is formed on the other side of the permeable film 3. The permeable film preferably has higher absorption auxiliary permeability than absorption auxiliary permeability rate unrelated to percutaneous absorption of the drug. Percutaneous absorption can be regulated by a composition ratio of drug and absorption auxiliary.

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention relates to transdermal absorption preparations for continuous absorption of drugs through the skin.

(b) Prior art In recent years, the following have been proposed for this type of medicinal component in order to reliably obtain pharmacological action.

■Pressure-sensitive adhesive polymer material containing supersaturated active ingredient drug.

■A drug containing an absorption aid in a pressure-sensitive adhesive polymer material to increase transdermal absorption.

■Lenovoir/IL, which contains absorption aids and drugs, allows the required amount to be effectively absorbed transdermally through a release control membrane.
, S, P 4,379,454 Publication, w4 1984-
154122).

■The absorption aid holding layer and the drug-containing adhesive layer are separated by a substrate layer,
The drug is effectively transdermally absorbed by diffusing the absorption aid from the absorption aid holding layer through the substrate layer into the drug-containing adhesive layer (Japanese Patent Publication No. 62-54283).

(c) Problems to be Solved by the Invention However, in the case of (2) above, the pressure-sensitive adhesion is severely reduced due to the drug crystals deposited on the surface of the adhesive polymeric material layer, and the adhesive properties of the adhesive polymer material layer deteriorates. The adhesion of the drug is severely reduced, and as a result, transdermal absorption of the drug is often extremely reduced.
In addition, in the case of (2) above, the safety of the absorption aid may become a problem, and there may be a limit to its amount, or the absorption aid may reduce the cohesive force of the pressure-sensitive adhesive polymer. The actual situation is that there is a limit to the amount that can be added, and as a result, sufficient effects cannot be obtained.

In addition, in the case of (2) above, controlling the amount of drug released by a control membrane is extremely effective and innovative for drugs that are relatively easily absorbed through the skin, but it is difficult to control the amount of drug released through the control membrane. Most of the drugs that are desired to be absorbed through the skin are relatively difficult to absorb through the skin, so in order to absorb the required amount through the skin,
A control membrane with extremely high permeability must be used, but highly permeable membranes limit the ability to control transdermal absorption of drugs, and are not always an effective method of administration.

In addition, as mentioned in (■) above, by incorporating all the necessary drugs into the pressure-sensitive adhesive polymer layer that comes into direct contact with the skin, and by diffusing the adjuvants from the absorption adjuvant layer, a large number of drugs can be effectively absorbed. Attempts have been made to achieve transdermal absorption. However, in this case, migration of the drug from the pressure-sensitive adhesive polymer layer to the absorption aid layer occurs, resulting in a decrease in the drug content in the pressure-sensitive adhesive polymer layer, and depending on the type of absorption aid and drug. Since the pressure-sensitive adhesive polymer layer is explicitly plasticized, it may cause cohesive failure, resulting in not only a decrease in drug release properties but also a decrease in the performance of the preparation, such as a poor feeling of use.

(d) Means for Solving the Problems The present inventors have made extensive studies to solve the above problems, and have obtained the following knowledge.

In other words, if the composition ratio of the absorption aid liquid is the same, the higher the aid permeability of the permeable membrane, the better the transdermal absorption of the drug; however, if the permeability exceeds a certain level, the transdermal absorption of the drug will decrease remains constant regardless of the permeability of the membrane, making it impossible to control percutaneous absorption using a permeable membrane.

(2) Even in formulations using a permeable membrane with high permeability that falls within the above-mentioned uncontrolled range, the transdermal absorption of the drug can be varied within an extremely high range by changing the composition ratio of the absorption aid.

■For preparations with a permeable membrane in this highly permeable uncontrolled region, even if the release rate of the absorption aid is the same, the transdermal absorption of the drug will be significantly different if the composition ratio of the drug and the absorption aid is different. different.

From the above three important facts, the present inventors have reached the following conclusion. In other words, when a drug that is poorly absorbed or a drug that is relatively easily absorbed requires transdermal absorption, there is a limit to membrane-controlled preparations, and therefore the above-mentioned high permeability It is extremely advantageous to control the transdermal absorption of the drug by controlling the composition ratio of the drug and the absorption aid using a permeable membrane with an uncontrolled region.

In addition, in addition to containing saturated or supersaturated drugs in the pressure-sensitive adhesive polymer layer that is directly attached to the skin,
An absorption aid-retaining layer is interposed and encapsulated between a permeable membrane laminated on one side of the polymer layer and an impermeable backing support, and the drug and absorption aid are retained in the polymer layer. By making the drug in the layer the same as that of the drug in the polymer layer, it is possible to prevent the drug in the polymer layer from migrating to the side opposite to the skin surface, that is, to the drug (and absorption aid) holding layer side, and also to prevent the drug from moving from the drug holding layer. The length of the drug can maintain a balance between the migration of the drug (and drug absorption aid) into the above-mentioned polymer layer and the release of the drug (and drug absorption aid) from this polymer layer into the body. It was found that good transdermal administration over a period of time is possible.

In addition, for drugs with poor transdermal absorption, it is necessary to add a considerable amount of drug absorption aid, but with this structure, the drug absorption aid can be stored in the drug holding layer, which makes it possible to use pressure-sensitive adhesives. It is not necessary to increase the concentration of the drug absorption aid in the polymer layer to a certain extent (thereby, cohesive failure of the polymer layer can be prevented as much as possible, and when this medical component is applied to the human body, the drug and drug absorption aid It was also found that both agents migrated into the polymer layer, resulting in good transdermal administration.

The present invention has been completed based on the above-mentioned findings.

The present invention will be explained in detail below.

The transdermal absorption preparation of the present invention contains a drug and a drug absorption aid between an impermeable backing support and a permeable membrane, and has a solution or dispersion that has the function of substantially controlling absorption of the drug. Alternatively, an absorption aid-holding layer made of gel is interposed and enclosed, and the other side of the permeable membrane is a pressure-sensitive adhesive that is sticky at room temperature and contains the same drug as the absorption aid-holding layer in a saturated or supersaturated amount. It is characterized by being provided with a polymer layer.

The backing support used in the present invention is not particularly limited as long as it is essentially impermeable in order to prevent loss of the drug or drug absorption aid, but for example,
A single film of polyester, nylon, saran, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, ethylene-ethyl acrylate copolymer, Surlyn, etc., or a thermoplastic inert film for polyester, nylon, saran, etc. Examples include films laminated with polyethylene, polypropylene, ethylene-vinyl acetate copolymer, Surlyn, etc.Furthermore, films made of polyester, nylon, and Saran are coated with aluminum vapor deposition or printing to improve appearance and light-shielding properties. Preferably, a polyester film with a thickness of 6 to 25 μm is printed, and the opposite side to the printed side is coated with a polyethylene film, a polypropylene film, or a Surlyn film with a thickness of 5 to 100 μm, more preferably 20 to 80 μm. The total laminated thickness is 30 to 140μ
It is a film of m.

The permeable membrane used in the present invention allows the absorption aid (and drug) to migrate from the absorption aid holding layer into the pressure-sensitive adhesive polymer layer.

Examples of this permeable membrane include acetylcellulose, polyurethane, polyacrylonitrile, polyvinyl chloride, polyethylene, ethylene-vinyl alcohol copolymer, ethylene-vinyl acetate copolymer, ethylene-methacrylic acid copolymer, and ethylene-acrylic acid. Ethyl copolymer, polypropylene, silicone rubber, hydrophilic acrylic polymer
Examples include films made of grooves of polyvinyl alcohol, gelatin, polyvinyl acetate, sulfonated polystyrene, etc., porous membranes, nonwoven fabrics, meshes, etc., but preferably ethylene-vinyl acetate copolymer films or porous membranes made of polyethylene or polypropylene. It is. Furthermore, in ethylene-vinyl acetate copolymers, the vinyl acetate content is generally 14%, although it varies depending on the type of absorption aid.
If the content is 19% by weight or more and the thickness is 30 to 40 μl, the absorption aid permeability required for the present invention can be obtained.

However, if the vinyl acetate content exceeds 55% by weight, the mechanical strength will drop significantly, which is not preferable. In addition, in the case of porous membranes, they do not necessarily have to be homogeneous; they may be partially porous or homogeneous with perforations, but the air permeability is important. It is desirable that the measured value is 4000 seconds/100cc or less.

The value of 4000 sec/100 cc or less in the gas method measurement means that, for example, the accelerator liquid composition is ethanol/alcohol/water =
A formulation laminated with a 100 μm acrylic adhesive layer at a ratio of 80/20 (weight ratio), which exhibits ethanol permeability of 6 wag/am2/81+ or more in the transdermal ethanol release test described below.

In this case, the permeable membrane can control the transdermal absorption of the drug by having an absorption aid permeability higher than the absorption aid permeation rate which is substantially irrelevant to the transdermal absorption of the drug. Since the liquid composition in the absorption aid can be changed, it is possible to achieve good and controlled transdermal absorption of a wide range of drugs, from poorly absorbed drugs to relatively easily absorbed drugs. Therefore, safe and effective therapeutic effects can be achieved.

The feature of the present invention is that an absorption aid holding layer is interposed and enclosed between the above-mentioned lining support and the permeable membrane, and the other side of the drug release control layer is the same as the absorption aid holding layer. The present invention is characterized by providing a pressure-sensitive adhesive polymer layer that is sticky at room temperature and contains a saturated or supersaturated drug.

In other words, it is characterized in that the drug-containing pressure-sensitive adhesive polymer layer and the absorption aid holding layer each contain a drug, and the same drug is used in both, thereby producing the desired effect.

This absorption aid-holding layer may be made of a solution, dispersion, or gel containing the drug and the drug absorption aid.

In addition, in the above-mentioned absorption aid-holding layer, the gel agent for forming the gel containing the drug and absorption aid is not particularly limited as long as it stably retains the drug and absorption aid used. For example, gels such as cellulose acetate, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, acrylic acid, polyethylene glycol, polypeptide gels made of gelatin, collagen, alginic acid polymers, etc., or silicone-based or rubber-based gels. and oily gels made of fatty acid esters.

In addition, the viscosity of the solution or dispersion containing the absorption aid encapsulated in the absorption aid holding layer is preferably 10 to 120 voids at a temperature of 25° C. from the viewpoint of handling, retention, etc.
More preferably, the number is 20 to 80 voices. Moreover, the filling amount is preferably 5 to 60 mg/am2.

If the amount of charged jtA is less than 5+ng/clI2, there is no absorption promoting effect, while if it exceeds 60mg/cm2,
If it exceeds 111 g/Cm2, there will be a limit to the effect, which will be economically disadvantageous, and the handling properties of the preparation will be extremely poor, which is not desirable.

The pressure-sensitive adhesive polymer layer used in the present invention is not particularly limited as long as it is a layer formed of a pressure-sensitive adhesive polymer that is sticky at room temperature.

Also, this pressure sensitive 4! The adhesive polymer layer contains the same drug as the absorption aid holding layer described below, but the proportion of the drug varies depending on the pressure-sensitive adhesive polymer, the type of drug, or the drug to be delivered to the skin. Although it varies depending on the amount, it is preferable that the mixture contains 0.1 to 40% by weight of the drug.If the content of the drug is less than 0.1% by weight, the therapeutic effect will be poor; Exceeding this limits the therapeutic effect and is economically disadvantageous.

In this case, it is possible to include a drug absorption aid in advance, and the blending ratio in this case is preferably 0.5 to 30% by weight of the entire drug-containing adhesive polymer layer. If the content of the agent is less than 0.5% by weight, the effect will be poor and there is no point in adding it (on the other hand, if it exceeds 30% by weight, it will plasticize the pressure-sensitive adhesive polymer layer, causing cohesive failure and causing damage to the drug. I/O is not preferred because it may lead to not only a decrease in release properties but also a decrease in the performance of the preparation, such as poor feeling of use.
1゜Examples of this pressure-sensitive adhesive polymer include n-butyl (meth)acrylate, hexyl (meth)acrylate, and (meth)acrylate.
2-ethylbutyl acrylate, inoctyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, (
(meth)acrylic acid esters such as decyl (meth)acrylate, dodecyl (meth)acrylate, and tridecyl (meth)acrylate; itaconic acid, maleic acid, maleic anhydride, droxyethyl (meth)acrylate, and (meth)acrylate;
Functional monomers such as hydroxypropyl acrylate, (meth)acrylamide, trimethylacrylamide, methylaminoethyl methacrylate, methoxyethyl (meth)acrylate and/or vinyl such as acrylonitrile, vinyl acetate, vinyl propionate, vinylpyrrolidone, etc. An example is an acrylic pressure-sensitive adhesive composition that is a monomer and its copolymer.

Other examples include rubber-based adhesives mainly composed of rubber, such as silicone rubber, polyisoprene rubber, polyisobutylene rubber, styrene-butanoene (also (superisoprene)-styrene block copolymer rubber, acrylic rubber, natural rubber, etc.) Examples include vinyl adhesive compositions containing vinyl polymers such as polyvinyl ether, polyvinyl alcohol, polyvinyl acetate, and ethylene-vinyl acetate copolymers as main components.

By the way, by using a pressure-sensitive adhesive polymer layer with a crosslinked structure, even if the drug absorption aid or drug causes the pressure-sensitive adhesive polymer layer to become severely plasticized, this can be prevented. This is possible and is advantageous because cohesive failure can be prevented.

In this case, for this crosslinking, a vulcanizing agent (if the main ingredient is rubber), a polyisocyanate compound, an organic peroxide,
For example, a method may be used in which a crosslinking component such as a metal salt, a metal chelate compound, or a polyfunctional compound is blended, and the mixture is reacted by heating to chemically crosslink. The rubber-based polymer contains 0.01 to 2.0 parts by weight of a vulcanizing agent represented by sulfur and sulfur-containing compounds per 100 parts by weight of the rubber component, and the acrylic polymer contains a polyisocyanate-based compound, A crosslinking component such as an organic peroxide, an organic metal salt, a metal chelate compound, or a polyfunctional compound is blended in an amount of 0,601 to 2.0 parts by weight per 100 parts by weight of the pressure-sensitive adhesive polymer.

In addition, the drug absorption aids include water, lower alcohols such as ethanol, glycols (mainly drug solubilizers) such as glycerin, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, polyethylene glycol, and polypropylene glycol. , oils and fats such as olive oil, castor oil, squalene, and lanolin (mainly to improve drug diffusion), urea, urea derivatives such as 7lantoin (mainly to improve water retention in the stratum corneum), oleic acid, ethyl oleate, dimethyldecyl Polar solvents such as sulfoxide, methyloctyl sulfoxide, dimethyl sulfoxide, dimethylformamide, trimethylacetamide, trimethyllaurylamide, dodecylpyrrolidone, isosorbitol (mainly improves keratin softening properties), amino acids (mainly improves keratin permeability), lauryl Various surfactants such as sodium sulfate, sorbitan moacaprylate, sorbitan moaoleate, glyceryl monooleate, glyceryl monostearate, polyethylene glycol fatty acid ester (mainly change the surface condition of the skin), Salocol (good transdermal absorption) (concomitant use of drugs), etc.

Other neuisopropyl anopate, 7-talic acid ester,
Examples include plasticizers such as diethyl sebacate, hydrocarbons such as liquid paraffin, ethoxylated stearyl alfur, glycerin esters, isopropyl mystylate, ethyl laurate, N-methylpyrrolidone, and the like. In addition to using these materials alone or in combination, they can also be mixed with components such as cellulose acetate, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and acrylic acid to improve handling and operability. is desirable.

The M-class absorption aid to be used varies depending on the type of drug, so it cannot be generalized, but for example, in the case of an ethanol-water mixture, by changing the ethanol composition between 20% and 80% by weight, for example, It is possible to significantly change the transdermal absorption of insorbidoniitrate.

The drug used in the present invention is not particularly limited as long as it is a physiologically active substance and has percutaneous absorption.

Examples of such drugs include those shown below.

b) Corticosteroids: for example, hydrocortiscin, prednisolone, beclomethasone probionate,
flumethacin, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluoci/ron acetonide acetate, clobetasol propionate, etc.) Analgesic and anti-inflammatory agents: e.g. acetamino 7ene, mefenamic acid, flufenamic acid, indomethacin, Nocro 7 Enac, Nocro 7enac sodium, flucro7enac, oxyphenbutacin, phenylftasone, isofuro7ene, flurbipro7ene, salicylic acid, methyl salicylate, β-menthol, can77-sulindac, tolmetin sodium, naproxen, 7enac 7
C) Hypnotic sedatives: For example, phenoparbital, amobarbital, cyfrobarbicur, tri7zolam, nitrazepam, '7zepam, haloberidol, etc. 2) Tranquilizers: For example, full7 enanone theoritazine, diazepam, fludiazepam, fludiazepam, haloperidol, chlorpromanone, etc. e) Antihypertensive agents: e.g. clonidine, clonidine hydrochloride,
Pindolol, metoprolol, propranolol, propranolol hydrochloride, butol, indenolol,
Nianidipine, Nivanobin, Nimodipine, Roanidixin, Nitrendipine, Nipranolol, Bukumolol, etc.; f) Antihypertensive diuretics: For example, hydrothiazide, pendroalunathiazide, cyclobenziazide, etc.; G) Antibiotics: For example, penicillin, tetracycline,
Oxytetracycline, furanomycin sulfate, erythromycin, chloramphenicol, etc.; 1) Anesthetic agents, such as docaine, gypcaine hydrochloride, pensicaine, ethyl amyl-7benzoate, etc.; 2) Antibacterial substances, such as benzalcohydrochloride. n) Antifungal substances: e.g. pentamycin, amphotericin B, pyrrolnidoline, clotrimazole, etc. l) Vitamins: e.g. vitamin A1 ergocalciferol , cholecalciferol, octothiazine, riboflavin butyrate, etc., 2) Antiepileptic drugs: e.g., nitrazebam, meprobamate, clonazepam, etc., 4) Coronary vasodilators: e.g., nitroglycerin, nitroglycol, insorbido nonitrate, erythritol tetrana hydrate, pentaerythritol tetranitrate, propyl nitrate, nianizibin, etc.) Antihistamines: e.g. noaenhydramine hydrochloride,
Chlorpheniramine, diphenylimidazole, etc. ii) Antitussives: For example, dextromethorphan, dextromethorphan hydrobromide, terptasone sulfate, 7-edrine, ephedrine hydrochloride, salbutamol, salbutamol sulfate, Inprotere 70-ol, Inprotere hydrochloride/ 1) Sex hormones: e.g. propsterone, estradiol, etc. 2) Antibiotics: e.g. doxebin, etc.) Cerebral circulation improving agents: e.g. Nilgott alkaloids, iaenprodil, etc. Anti-emetics, anti-ulcer agents: e.g. metoclopramide,
Crevopride, tonbelitone, scopolamine, scopolamine hydrobromide, 5-fluorouracil, mercaptopurine, etc.) Biopharmaceuticals: For example, polypeptides (T, RH, LH
(derivatives of RH), prostaglandins, etc.; n) Others: For example, 7-entanyl, nogoquine, desmopressin, nohydroergotamine methanesulfonic acid, nohydroergotamine tartrate, etc., and these drugs may be administered as needed. Two or more types can be used together.

Furthermore, in the transdermal absorption preparation of the present invention, it is preferable that the drug be hydrophobic, because hydrophilic drugs generally form salts and have a higher melting point, making them more difficult to administer than hydrophobic drugs. This is because, in addition to poor skin absorption, it has poor solubility in the pressure-sensitive adhesive polymer layer, so that supersaturation is reached in a very small amount in the pressure-sensitive adhesive polymer layer.

In the present invention, a hydrophobic drug refers to water 1 of the above-mentioned drugs.
The dissolution amount for 00mf is 0.48 or less at room temperature.

In addition, by using insorbitononitrate as the above drug, the blood concentration is higher than that of conventional tape-type preparations.
This makes it possible to achieve high durability and more effective treatment.

In the transdermal absorption preparation of the present invention, if the absorption aid-retaining layer has a saturated solubility of the drug, it is possible to not only retain the drug to the maximum extent (but also to effectively transfer the drug to the drug-containing pressure-sensitive adhesive). In addition to being able to transfer the drug to the polymer layer, it is also possible to prevent the drug from transferring from the pressure-sensitive adhesive polymer layer to the drug-retaining layer, making effective use of the drug possible and extremely economical.

(e) Effect The transdermal absorption preparation of the present invention has the above-mentioned structure, and not only contains a saturated or supersaturated drug in the pressure-sensitive adhesive polymer layer that is directly attached to the skin (but also contains a saturated or supersaturated drug). An absorption aid-retaining layer having PIi ability that substantially controls transdermal absorption of the drug is interposed and encapsulated between the permeable membrane laminated on one side of the layer and the impermeable backing support, In addition, by making the drug in the polymer layer and the drug in the absorption aid retention layer the same, the drug in the polymer layer is retained on the side opposite to the skin surface, that is, the drug (and absorption aid). In addition to preventing the drug (and drug absorption aid) from migrating from the drug-retaining layer into the polymer layer, the drug (and drug absorption aid) from this polymer layer into the living body can be prevented. It has the effect of maintaining the balance of release of drugs (adjuvants), which enables good transdermal administration of drugs over a long period of time.It also has the effect of maintaining the balance of release of drugs and drug absorption aids in the pressure-sensitive adhesive polymer layer. Even if the concentration of the drug is lowered, the drug and drug absorption aid are replenished from the absorption aid holding layer, and therefore the concentration of the drug and drug absorption aid can be reduced. It has the effect of preventing cohesive failure of the layer and increasing the safety of transdermal absorption preparations.

In addition, the permeable membrane is set to have an absorption aid permeability that is higher than the absorption aid permeation rate that is substantially unrelated to the transdermal absorption of the drug, and furthermore, the transdermal absorption of the drug is controlled. By adjusting the liquid composition in the absorption aid layer, it is extremely advantageous when a large amount of transdermal absorption is desired even for poorly absorbed drugs or relatively well-absorbed drugs.

(f) Examples Hereinafter, the present invention will be explained in detail based on Examples, but the present invention is not limited thereto.

In addition, in the following, parts or % mean parts by weight or weight %.

(2) Structure example of the transdermal absorption preparation of the present invention Next, the structure of the transdermal absorption preparation of the present invention will be specifically explained based on the drawings.

In FIG. 1, the transdermal absorption preparation (1) of the present invention includes an absorption aid holding N (4) interposed between an impermeable backing support (2) and a permeable membrane (3). On the other side of the permeable membrane (3), that is, on the side opposite to the side on which the absorption aid holding layer (4) is formed, there is formed a pressure-sensitive adhesive polymer layer (5) that is adhesive at room temperature. It will be done.

And the above absorption aid retention/! ! ! (4) consists of a solution, dispersion, or gel containing a drug and a drug absorption aid;
It has the function of substantially controlling transdermal absorption, and the pressure-sensitive adhesive polymer layer (5) contains the same drug as the absorption aid holding layer (4) in a saturated or supersaturated state. It is made to contain.

In this case, the permeable membrane (3) has an absorption aid permeability that is higher than the absorption aid permeation rate which is substantially irrelevant to the transdermal absorption of the drug, thereby reducing the drug production. They can improve the administration of drugs into the body over a long period of time, and they can also change the absorption of drugs.

Note that (6) is a peeled body.

Example 1 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid were placed in a 7 flask under an inert gas atmosphere, 0.3 parts of azobisisobutyronitrile was added as a polymerization initiator, and acetic acid was added. Acrylic pressure-sensitive adhesive polymer solution (solid content 34.9%) polymerized in ethyl while maintaining the temperature at 60℃
I got it.

To 80 parts of the solid content of this solution, 19.9 parts of insorbitononitrate and 1 part of Coronate HL were added, and ethyl acetate was added to obtain a solution with a total solid content of 22%.

This solution was applied onto a polyester release body with a thickness of 75 μm so that the thickness after drying would be 100 μm, and this was dried at a temperature of 100°C for 3 minutes.
4% ethylene-vinyl acetate copolymer film (thickness 3
The drug-containing pressure-sensitive adhesive polymer layer (5 μl) was laminated and dried for 48 hours at room temperature.
) and the permeable membrane (3) were obtained.

Next, a flesh-colored polyester film with a thickness of 12 μm is printed; this is an impermeable backing support (2) made of polyethylene laminated with a thickness of 30 μm, and the above laminated film is made into a 11711 mm + 1 width 71 mm (or a circular shape with an inner diameter of 25 mm + m). Heat sealing was performed so that the size and seal width were 4 Inm (or 5 ma+). This is composed of 2.0 parts of insorbitononitrate, 2 parts of hydroxypropyl cellulose, 3.0 parts of PEG-400, 74.4 parts of ethanol, and 18.6 parts of water, and has a viscosity of approximately 50 boids (temperature: °C). drug-containing (retention) solution of 2
Inject g (or 0.2. is the lined support (2) and the permeable membrane (3)
The transdermal absorption preparation of the present invention (
1) was obtained.

Twenty days after the preparation of this transdermal absorption preparation (1), the test described below was conducted.

Example 2 Example 1 except that the permeable membrane (3) in Example 1 was replaced with one with a vinyl acetate content of 28% and a thickness of 30μ.
In the same manner as above, a transdermal absorption preparation (1) of the present invention was obtained.

Twenty days after the preparation of this transdermal absorption preparation (1), the test described below was conducted.

Example 3 In Example 1, the permeable membrane (3) was prepared using a perforated roll with a vinyl acetate content of 9% and a thickness of 30 μm.
A transdermal absorption preparation (1) of the present invention was obtained in the same manner as in Example 1, except that the film was replaced with a film having through holes of 0.2 mm in diameter at intervals of m.

This transdermal absorption preparation (1) was subjected to the test described below 20 days after its preparation.

Example 4 In Example 1, the permeable membrane (3) was replaced with a polyethylene porous membrane having a thickness of 50 μm and which had a rate of 3000 seconds/100 cc as measured by the Leh method, and a crosslinking agent for the pressure-sensitive adhesive polymer layer was added. 0.1 part of aluminum triisopropylate
A transdermal absorption preparation (1) of the present invention was obtained in the same manner as in Example 1, except that a % acetyl acetate solution was used instead.

Twenty days after the preparation of this transdermal absorption preparation (1), the test described below was conducted.

Example 5 In Example 4, the permeable membrane (3) was
A transdermal absorption preparation (1) of the present invention was obtained in the same manner as in Example 4, except that a polyethylene porous membrane having a volume of 100 cc and a thickness of 50/jm was used instead.

Twenty days after the preparation of this transdermal absorption preparation (1), the test described below was conducted.

Example 6 In Example 4, the permeable membrane (3) had a thickness of 25 μm, a maximum pore diameter of 0.4×O, an elliptical shape of 0.4 μm, and a porosity of 4.
5% polypropylene porous membrane and an impermeable backing support on a 12 μm polyester film with a thickness of 3
A transdermal absorption preparation (1) of the present invention was obtained in the same manner as in Example 4, except that a film laminated with 0 μm of polypropylene was used.

Twenty days after the preparation of this transdermal absorption preparation (1), the test described below was conducted.

Example 7 In Example 5, the composition of the absorption aid holding layer (4) was 1.0 part of isosorbitonitrate and 3 parts of PEG-400.
, 0 parts of hydroxypropyl cellulose, 37.6 parts of ethanol, and 56°4 parts of water, the transdermal absorption preparation (1) of the present invention was obtained in the same manner as in Example 5. .

Twenty days after the preparation of this transdermal absorption preparation (1), the test described below was conducted.

Example 8 In Example 5, the composition of the absorption aid holding layer (4) was 1.5 parts of insorbitinitrate and 3 parts of PEG-400.
．． A transdermal absorption preparation (1) of the present invention was obtained in the same manner as in Example 5, except that 0 parts of hydroxypropylcellulose, 2.0 parts of hydroxypropylcellulose, 56.1 parts of ethanol, and 37.4 parts of water were used.

Twenty days after the preparation of this transdermal absorption preparation (1), the test described below was conducted.

Example 9 In Example 5, the composition of the absorption aid retaining agent N (4) was 1.7 parts of isosorbitodinitrate and 3 parts of PEG-400.
, 0 parts of hydroxypropyl cellulose, 65.3 parts of ethanol, and 28.0 parts of water, the transdermal absorption preparation (1) of the present invention was obtained in the same manner as in Example 5. .

Twenty days after the preparation of this transdermal absorption preparation (1), the test described below was conducted.

Comparative Example 1 To 80 parts of the solid content of the pressure-sensitive adhesive polymer solution obtained in Example 1, Insorbitononitrate 20 (\Is) and ethyl acetate were added to obtain a solution with a total solid content of 22%. .

'This solution was applied onto a polyester release body with a thickness of 25 μm so that the thickness after drying was 100 μm.
After drying at ℃ for 3 minutes, a 9 μm thick polyester film was laminated thereon. This laminate [71m111. horizontal 7
1111 was punched out into other sizes to obtain tape-like preparations.

Comparative Example 2 A transdermal absorption preparation (1) of the present invention was obtained in the same manner as in Example 1, except that the permeable membrane (3) in Example 1 was replaced with a 40 μm-thick polyethylene film.

Twenty days after the preparation of this transdermal absorption preparation (1), the test described below was conducted.

Comparative Example 3 The permeable membrane (3) in Example 1 was replaced with vinyl acetate-containing f
The transdermal absorption preparation (1) of the present invention was prepared in the same manner as in Example 1, except that the EVA film with i9% and a thickness of 30 μm was used.
I got it.

Twenty days after the preparation of this transdermal absorption preparation (1), the test described below was conducted.

Comparative Example 4 The transdermal absorption preparation (1) of the present invention was prepared in the same manner as in Example 4, except that the permeable membrane (3) in Example 4 was replaced with a polyethylene porous membrane with an air permeability of 6000 seconds/100 cc. Obtained.

Twenty days after the preparation of this transdermal absorption preparation (1), the test described below was conducted.

Comparative Example 5 In Example 5, the composition of the drug-containing pressure-sensitive adhesive polymer solution was changed to 97.9 parts of solid content of the adhesive, 0.1 g of aluminum triisopropylate, and 2.0 parts of insorbitinitrate. Same as Example 5 except that
A transdermal absorption preparation (1) of the present invention was obtained.

Twenty days after the preparation of this transdermal absorption preparation (1), the test described below was conducted.

Rabbit pasting test The samples of each Example and each Comparative Example (m 71 m 111. horizontal 71 LI 11 samples) were pasted on the back of a rabbit whose hair had been removed in advance, and the ear vein was pasted at each time point in 1.2.5.5.8. 4ta1 blood samples were collected from each patient, and the drug concentration in the blood was measured using a chromatography device.

The results are shown in Tables 1 to 3 and FIG.

5 Fix it in a special circular holder of eie+ (5am2).

This holder is immersed in 300 L111 degassed distilled water at 37° C. in a sealed container and slowly stirred with a magnetic stirrer. From this sealed container, 3-1 samples were taken every hour until the 8th hour, and the concentration of ethanol was measured using a chromatography device.

The results are shown in Tables 1 to 53 and FIG.

(Left below) Transdermal ethanol permeability test Samples for each example and comparative example (outer diameter 35I, seal width 5
The circular shape (circle I) is pasted on the same area of dehaired rat abdominal skin, and the diameter of the transparent part is 2 (g). be effective.

The transdermal absorption preparation according to claim 1 is a solution containing a drug and Vryi synergist q, which has an impermeable lining and a function of substantially controlling transdermal absorption between the support and the permeable membrane. , an absorption aid-holding layer made of a dispersion or gel is interposed and enclosed, and the other side of the permeable membrane contains a saturated or supersaturated drug containing the same drug as the absorption aid-holding layer, which is sticky at room temperature. A pressure-sensitive adhesive polymer layer is provided, and this structure provides good adhesion to the skin and maintains a balance in the release of the drug from the polymer layer. Therefore, drugs can be administered efficiently (transdermally) over a long period of time. Therefore, the transdermal absorption preparation of the present invention exhibits significantly higher transdermal absorption than conventional tape preparations.

The transdermal absorption preparation according to claim 2 is capable of controlling the transdermal absorption of the drug by having the permeable membrane having an absorption aid permeability higher than the absorption aid permeation rate which is substantially unrelated to the transdermal absorption of the drug. This can be done by changing the liquid composition of the absorption aid to be filled, allowing for good and controlled transdermal absorption of a wide range of drugs, from those that are poorly absorbed to those that are relatively easily absorbed. This makes it possible to achieve safe and effective therapeutic effects.

In the transdermal absorption preparation according to claim 3, the drug in the absorption aid-retaining layer has a saturated solubility, and by configuring it in this way, it is possible to not only retain the drug to the maximum extent, but also to effectively retain the drug. In addition to being able to transfer the drug to the pressure-sensitive adhesive polymer layer containing the drug, it is also possible to prevent the transfer of the drug from the pressure-sensitive adhesive polymer layer to the absorption aid holding layer, making it possible to use the drug effectively. It is possible to achieve effects such as being economical.

The transdermal absorption preparation of myR item 4 uses a pressure-sensitive adhesive polymer layer with a cross-linked structure, so that the drug absorption aid and drug can properly plasticize the pressure-sensitive adhesive molecular layer. Even in such cases, this can be prevented and cohesive failure can be prevented, which is advantageous.

By using isosorbitononitrate as a drug, the transdermal absorption preparation of claim 5 makes it possible to obtain high blood concentration and high persistence of this drug, thereby enabling more effective treatment. Therefore, it is beneficial.

[Brief explanation of drawings]

FIG. 1 is a sectional view showing an embodiment of the present invention, FIG. 2 is an explanatory view showing changes over time in a transdermal ethanol permeability test,
FIG. 3 is an absorption characteristic diagram showing changes in blood concentration of a drug over time. (1) Transdermal absorption preparation 1, (2) Impermeable backing support, (3) Permeable membrane, (4) Absorption aid holding layer, (5) ...pressure-sensitive adhesive polymer layer, (6)
...Releasable body Figure 1 1...Transdermal absorption preparation 2...Impermeable backing support 3...Permeable membrane 4...Absorption aid retaining layer 5...Pressure sensitive adhesiveness Polymer layer 6... Stripped body Figure 2 O Time (hr) 1-o--: Comparative example 2 11: LOL Example 1 1--Moo--: Example 5 3rd time 10-: Comparative example 1 11←--: Comparative example 4 1--6-----lol Example 1 -11-m: Example 4 1-1)--1: Lol Example 5

Claims (5)

[Claims] (1) An absorption aid consisting of a solution, dispersion, or gel that contains a drug and a drug absorption aid between an impermeable backing support and a permeable membrane, and has the function of substantially controlling the absorption of the drug. A drug-retaining layer is interposed and encapsulated, and a pressure-sensitive adhesive polymer layer that is sticky at room temperature and contains the same drug as the absorption aid-retaining layer in a saturated or supersaturated state is provided on the other side of the permeable membrane. A transdermal absorption preparation characterized by: (2) The transdermal absorption preparation according to claim 1, wherein the permeable membrane has an absorption aid permeability higher than an absorption aid permeation rate that is substantially irrelevant to transdermal absorption of the drug. (3) The transdermal absorption preparation according to claim 1, wherein the drug in the absorption aid holding layer is at a saturation concentration. (4) Claim 1, wherein the pressure-sensitive adhesive polymer layer that is sticky at room temperature is a layer formed of an acrylic adhesive composition with a crosslinked structure.
The transdermal absorption preparation described. (5) The transdermal absorption preparation according to claim 1, wherein the drug is isosorbide dinitrate.