JPS60123417A - Drug delivery member - Google Patents

Abstract

PURPOSE:To provide a drug delivery member having the water absorptivity, the skin-moisturizing property, the drug releasability and the adhesivity to the skin, etc. as a pressure-sensitive adhesive, by compounding a water-insoluble polymer having stickiness at normal temperature with a specific water-soluble polymer and a drug for transcutaneous absorption. CONSTITUTION:A water-insoluble polymer having stickiness at normal temperature, preferably an uncrosslinked substance having a glass transition temperature of -70--10 deg.C is compounded with a water-soluble polymer composed of a monomer having one ethylenic unsaturated double bond [e.g. PVA, poly(meth) acrylic acid, etc.] and/or a polysaccharide (e.g. starch, pullullan, etc.) and a drug for transcutaneous absorption (e.g. corticosteroid, analgesic anti-inflammatory agent, etc.), and the mixture is applied as a pressure-sensitive adhesive layer to a carrier to obtain a drug delivery member. The obtained product is essentially free from water, and exhibits unique characteristics by absorbing the moisture of the skin. It has water-absorptivity, drug-releasability, adhesivity, etc., and exhibits excellent drug action.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a drug administration member for administering transdermally absorbable drugs into the body, and more specifically, it is attached directly to the skin surface for the purpose of treating local or systemic diseases. The present invention relates to a drug administration member for transdermally administering drugs into the body.

Conventionally, the main methods of administering drugs to the body for the purpose of disease treatment have been oral administration and direct administration by injection. Due to problems such as side effects caused by administering large kites,
In recent years, various proposals have been made for transdermal administration of drugs by applying tape preparations to the skin surface. As the base material constituting these tape preparations, polymeric substances such as natural rubber, 9 synthetic rubber, and acrylic, which have skin-in-adhesion properties, are mainly used, but they do not have pharmacological effects or skin irritation. .

The current situation is that a satisfactory product has not yet been obtained with drugs such as 1li (1).In addition, in order to solve these problems, skin penetration agents, humectants, antioxidants, etc. Although additives are used in combination, new problems such as a decrease in skin adhesion have arisen, and the desired results have not been obtained.

Furthermore, as base materials for ponds, oil-based gels made of synthetic rubber and mineral oil, and water-based gels made of water and water-soluble polymers such as sodium acrylate or polyvinyl alcohol have been proposed. Although the initial adhesion is excellent, G! 8! Due to poor moisture properties, long-term skin adhesion is poor, and due to poor adhesion to the skin, it is difficult to maintain sufficient medicinal efficacy for treatment. In addition, the latter has good drug release from the base material, but has poor shape retention when made into a thin film.
Skin adhesion and drug solubility/dispersion were difficult, requiring fixation with auxiliary means such as surgical tape.

As a result of intensive studies to eliminate these drawbacks, the present inventors have identified polymeric substances that are sticky at room temperature and water-insoluble, such as natural rubber, synthetic rubber, and acrylic polymers. A drug administration member containing a water-soluble polymeric substance and a transdermal drug has excellent adhesion, cohesion, shape retention, and drug decomposition inhibiting properties (drug stability) as a pressure-sensitive adhesive.
and water-based gel-like water absorbency due to water-soluble polymeric substances, skin I
#We discovered that it has both wettability and drug release properties, and that desirable pharmacological effects can be obtained due to its excellent adhesion.
This led to the present invention.

That is, in the present invention, on a carrier having substantially no moisture permeability,
A member directly or indirectly provided with a drug-containing pressure-sensitive adhesive layer that is sticky at room temperature, the pressure-sensitive adhesive layer comprising a water-insoluble polymer substance that is sticky at room temperature; A drug administration member comprising a water-soluble polymer substance and/or polysaccharide made of a monomer having one ethylenically unsaturated double bond and a transdermal absorbable drug as essential components. This is what we provide.

The polymer substance used in the present invention, which is adhesive at room temperature and water-insoluble, is a pressure-sensitive adhesive containing a drug when the drug administration member of the present invention is applied directly to the skin surface for disease treatment. A base that provides the drug layer with sufficient skin adhesion and an occlusive bandage effect (the so-called ODT effect) and, depending on the drug, allows its diffusion at a desired rate, such as silicone rubber.

Rubber-based polymers such as polyisoprene rubber, polybutene rubber, styrene-butadiene rubber, styrene-isobrene-styrene block copolymer rubber, acrylic rubber, natural rubber, polyvinyl alkyl ether, vinyl acetate polymers, etc. Vinyl polymer material, poly(meth) whose main monomer is (meth)acrylic acid alkyl ester
Examples include acrylate polymer substances, polyamide polymer substances, and the like, and these may be poorly soluble in water. Furthermore, it is desirable to use non-crosslinked polymeric substances from the viewpoint of eliminating decomposition of the drug by the crosslinking agent. Among the above-mentioned polymeric substances, considering the stability of the contained drug against decomposition and the skin adhesion of the drug administration member,
Particularly preferred are poly(meth)acrylate-based polymers, and examples of monomers that can be polymerized and impart tackiness at room temperature include ethyl acrylate, butyl (meth)acrylate, and (meth)acrylate. Acrylic acid pentyl ester, (meth)acrylic acid hexyl ester, (meth)acrylic acid heptyl ester, (meth)acrylic acid octyl ester, (meth)acrylic acid/nyl ester, (meth)acrylic acid decyl ester, (meth)acrylic acid decyl ester
Acrylic acid dodecyl ester and (meth)acrylic acid tridecyl ester may also be used. In addition, for the purpose of copolymerizing with the above monomers and improving cohesion and skin adhesion, and increasing compatibility with water-soluble polymeric substances or polysaccharides, (meth)acrylic acid, itaconic acid, maleic acid, Maleic anhydride, crotonic acid, (meth)acrylic acid 2-hydroxyethyl ester, (meth)acrylic acid 2-hydroxypropyl ester.

Functional monomers such as acrylonitrile, vinyl acetate,
It is also possible to copolymerize vinyl monomers such as vinyl propionate.

The polymer material is selected to have adhesiveness at room temperature, and those having a glass transition temperature of -70 to -10°C, preferably -55 to -25°C can be used.1. +
;6 Molecules/substances vt alone that are not included in these glass transition ranges may be mixed with commonly used liquid additives such as softeners. The amount of the polymeric substance added is 6() to 98% in the drug-containing pressure-sensitive adhesive layer.
It is desirable to adjust the pressure-sensitive adhesive layer to 61% so that it is in the range of Historically, individual skin tends to have poor adhesion to curved surfaces. Also, in 9 8 jR, i・(% or more), water 1
Since the amount of added polymeric substances or polysaccharides is reduced, there is a possibility that the effects such as water absorption and skin wettability cannot be expected.

One ethylenically unsaturated double bond used in the present invention, fj? 1 (a water-soluble polymeric substance consisting of
Alternatively, the polysaccharide imparts water affinity to the pressure-sensitive adhesive layer containing the drug, and when the drug administration member of the present invention is applied to the skin, it absorbs moisture and moisturizes the skin. Increases sex and skin 1f/1
] For example, polyvinyl alcohol, modified polyvinyl alcohol, poly(meth)acrylic, sodium poly(meth)acrylic,
Carboxymethyl cellulose is a water-soluble polymeric substance consisting of a monomer having one ethylenically unsaturated double bond, such as a vinyl methyl nitride-maleic anhydride copolymer.

Saccharides such as hydroxyethyl cellulose, hydroxyprovirceno[loose, methyl cellulose, starch, pullulan, agar, dextrin, etc.] can be added, and at least one of these may be added. The amount of water-based polymeric substances and/or polysaccharides added depends on the drug level.
2 to 40%, preferably 5% in the lU pressure bonding adhesive layer
It is best to add it in a range of ~20% by weight. If these are in a powdered form or other hard-formed form, grind them to a powder with a particle size of 300 μm or less, and then add them as they are or by soaking them in a solvent such as water or alcohol. Add and mix in the IM bath liquid state.

The transdermal absorbable drug used in the present invention is not particularly limited as long as the drug is absorbed transdermally into the body when the drug administration member is pasted on the skin IP1 surface. ) Corticosteroids: e.g. hydrocortisone, prednisolone, beclomethasone proionate,
flumethacin, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, propion
? Clobetasol, etc., mouth),! 1. Anti-inflammatory drugs: eg acetaminophen, mefenamic acid, flufenamic acid, indomethacin.

Diclofenac, Diclofenac Sodium.

Alclofenac, oxyphenbutacin, phenylbutacin, ibupro7e/.

Phen, salicylic acid, salicylic acid/I/m-methyl, l-menthol, camphor, sulindac, tolmetin sodium, naproxen, fenbufen, etc. c) WtJ sleep gVfrM: For example, 7e/barbital, amoparbital, cyclobarbital, lorazenogum, haloperidol etc., 2) 'A tranquilizers: e.g. fluphenazine, theoridazine, dirzepam, flunitrazepam, chlorpromazine, etc. e) antihypertensive agents: e.g. clonidine 9-hydrochloride,
Pintorol, propranolol, fLuM propranolol, pufranol, indenolol.

Bucumolol, nifedipine, etc. f) Antihypertensive diuretics: e.g. hydrothiazide.

Bendrofluna thiazide, cyclopenthiazide, etc. g) Antibiotics: e.g. penicillin, tetracycline,
Oxytetracycline, fradiomain sulfate, erythromycin, chloramphenifur, etc.; 1) Anesthetics: e.g. lidocaine, benzicaine.

Ethyl aminobenzoate, etc. li) An example of an antibacterial substance is benzalkonium chloride.

Nitrofurazone, nystatin, acetosulfamine,
clotrimazole, etc. n) Antifungal substances: e.g. pentamycin, amphotericin B, pyrrolnidoline, clotrimazole, etc. l) Vitamin preparations: e.g. vitamin A, ergocalciferol, cholecalcif, roll, octothiazine, riboflavin butyrate, etc. , w) Anti-epileptic drugs: e.g. nitraze/gum, meprobamate, clonazepam, etc. w) Crown plate 4/'1lJ = e.g. nitroglycerin, nitrocricol, isosorbide dinitrate.

Erythritol tetranitrate, pentaerythritol tetranitrate, propyl nitrate, etc.) Antihistamines: For example, diphenhydramine hydrochloride, Chlorf, Niramine, diphenylimidazole, etc. (L1 cough medicines: For example, dextromethorphan, tilbutamine, ephedrine, hydrochloric acid) ephedrine, etc. ii) Sex hormones: e.g. progesterone, estradiol, etc. ii) Anti-Confucian agents: e.g. doxepin, etc. N) Others: e.g. 5-fluorouracil, dihydroergotamine, 7-entanyl, tesmofrecin, digoxin, metoclobraside, dope-1-nod, sufboramine , scopolamine hydrobromide, and two or more of these drugs can be used in combination as necessary.

The additive solution for the above drug varies depending on the intended treatment and/or administration effect, but is in the range of approximately 0.01 to 20 parts by weight per 100 parts by weight of a water-insoluble polymer substance that is sticky at room temperature. Contained in

Examples of carriers that support the drug-containing pressure-sensitive adhesive layer made of the above components directly or indirectly through an undercoating material include various plastic films, papers, nonwoven fabrics, woven fabrics, metal foils, and the like. When applying the drug administration member of the present invention to the skin surface to treat diseases through transdermal absorption of drugs, the amount of spring water in the stratum corneum on the skin surface to which it is applied can be reduced. In order to enhance transdermal absorption, it is necessary to select or combine carriers that do not have substantially moisture permeability, so that the so-called ODT effect can be obtained.

Furthermore, transdermal absorption auxiliary substances for efficient drug release from the drug administration member of the present invention include, for example, glycols such as pyrene glycol, diethylene glycol, polyethylene glycol, and polypropylene glycol, ethyl alcohol, and salidil. , urea, allantoin, dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, diisopropyl adipate, diethyl sebacate, ethyl laurate, lanolin, mineral oil,
Substances such as various surfactants may be added as necessary.
It is possible to add more than txi. In consideration of the balance between skin adhesion and cohesive force, the additive amount is desirably in the range of 0.5 to 20 parts by weight per 100 parts by weight of the water-insoluble polymer.

The drug-containing pressure-sensitive adhesive layer composed of the above-mentioned essential components is formulated in a form that does not contain substantially water, and after the drug administration member is applied to the skin surface, it absorbs moisture secreted from the skin surface. Since the dispensing member has an epoch-making l$f characteristic, it is preferable to store the dispensing member in sealed packaging such as aluminum packaging.

As described above, the drug administration member of the present invention can be applied directly to the skin surface of the body to continuously supply the transdermal absorbable drug contained therein into the body, thereby providing continuous treatment for local or systemic diseases. , and can be carried out effectively. A water-soluble polymeric substance consisting of a single substance having one ethylenically unsaturated double bond, which is an essential component of Koma, and/
Alternatively, the polysaccharide imparts aqueous gel characteristics to the pressure-sensitive adhesive layer, that is, water absorption, skin wettability, and drug release properties, and furthermore, it swells and swells due to the water absorption effect of moisture secreted from the skin. The adhesive layer is plasticized to improve its adhesion to the skin I# surface, giving it the ability to exhibit excellent pharmacological effects. In addition, with the conventional acrylic thread skin patch ladle, the adhesive surface of the member is stained with oil components and dirt after peeling off, making it difficult to apply multiple patches, but with the drug administration member of the present invention, For example, after the drug administration member is pasted, it has water-absorbing properties and has aqueous gel-like properties, which improves its tackiness, making it possible to apply the drug once (a), making it possible to use the drug effectively without wasting it.

Hereinafter, examples of the present invention will be shown and explained in more detail, but the present invention is not limited to these examples, and various types of glazes can be used without departing from the technical idea. In addition, in the examples, parts are heavy IK ffl! shows.

Example 1 -r 96 parts of 2-ethylhexyl acrylate, 4 parts of acrylic acid, 42.9 parts of ethyl acetate, and 0.2 parts of azobisisobutyronitrile were charged into a fourth flask under an inert gas atmosphere. , the internal temperature was stirred at 60 to 62°C to start the IR combination reaction, 190.4 parts of ethyl acetate as a reaction diluting bath agent was added dropwise, and the molds were combined for 8 hours while controlling the reaction, and the mixture was further heated to 75 to 80°C. The internal temperature was kept at η' and aged for 3 hours.
A polymer substance solution having a solution viscosity of 230 voids at 0% by weight was obtained.

Next, 0.2 parts of clobetasol propionate was added and mixed to 95 parts of the solid content of the polymer substance solution, and after sufficiently dissolving, 4.81 parts of sodium polyacrylate was ground to a particle size of 5 to 10 μB. %, dispersed uniformly with a homomixer, applied on a polyethylene film with a door thickness of 60 μm so that the thickness after drying was 50 μm, and heated at 80°C.
The mixture was dried for 7 minutes to obtain a drug administration member.

Example 2 Silicone adhesive in toluene solution (trade name: KRIOI)
10 parts of an acetone solution in which 3 parts of lorazepam was dissolved were added and mixed to 85 parts of solid content of 101 (manufactured by Shin-Etsu Chemical Co., Ltd.), and after sufficiently dissolving, polyvinyl alcohol ( Add 12 parts of saponification degree 98%), disperse uniformly with a homomixer, apply on a thin 80μ thick Teflon film so that the thickness after drying is 50μ, and dry at 80°C for 7 minutes. to form a pressure adhesive layer of drug 3 which is sticky at room temperature.
A drug administration member was obtained by rolling a laminated film of vinyl copolymer.

Example 3 25 parts of styrene-[styrene-styrene brosoxylic composite rubber (isoprene content: about 86% by weight), 40 parts of Ml paraffin, 3 parts of lanolin, aliphatic petroleum oil (melting point 100°C) 20 parts were sufficiently dissolved and mixed in 65 parts of toluene/ethyl acetate mixed solvent (weight ratio 1/2) to obtain a polymer substance solution.

Next, 5 parts of clonidine was added and mixed to 88 parts of the solid content of the polymer substance solution, and after sufficiently dissolving, 7 parts of human IF gicipropyl cellulose was added to 15 g of mt7 water [a water bath solution dissolved in , evenly in a homomixer in minutes R'(d
The mixture was coated onto a polypropylene film with a thin thickness of 50 μm to a thickness of 50 μm, and dried at 90”C for 7 minutes to obtain a drug administration member.

Comparative Examples 1 to 3 Comparative Examples 1 to 3 correspond to '88 Parts 1 to 3, and were carried out in the same manner as in each Example except that sodium polyacrylate, polyvinyl alcohol, and hydroxypropyl cellulose were removed from each Example. A drug administration member containing no water-soluble polymeric substance or polysaccharide was obtained.

Table 1 shows the characteristics of drug administration area H obtained in each Example and Comparative Example.

Table 1 The measurement method for each characteristic in Table 1 is as follows.

[Water absorption rate]: Each sample piece (4 x 4 α angle) was immersed in water at 25°C, and calculated by dividing the increase in weight hL after 30 minutes by the overlapping value before immersion.

[Water release rate]: Each sample piece (4X4Crn angle) was held at 30°
It was immersed in 200 ml of water and shaken, and after 1 and 6 hours, it was mixed with water and the drug content was measured by high performance liquid chromatography (UV detection).
The release rate was calculated when the initial drug content m was set as 100%.

[Blood concentration]: Each sample piece (3CInφ) was pasted on the abdomen of a rat whose hair had been removed in advance, and after 8 hours, blood was drawn from the rat and the blood concentration of the drug was measured using a gas chromatograph.

[Transfer rate]: Each sample piece (3CIRφ) was pasted on the abdomen of a rat whose hair had been removed in advance, and the latter sample piece was removed for 8 hours to measure the amount of remaining mulberry, and the initial drug content was 100%.
The skin j-transfer rate was calculated.

[Paperability]: Each sample piece (4x4aR square) was attached to the inside of the upper arm for 24 hours, then removed, and the same sample piece was attached again for 24 hours.
Visually judge the state of adhesion to the leather 1 hat when pasting (= J'), and if it is fully adhered, ○, if the end peels off or falls off during the process, △, or completely reapplied. Items that cannot be done are marked as ×.

As is clear from Table 1, the drug administration member of the present invention has good skin contact, relatively crystalline water absorption, and high water release rate, blood concentration, and migration rate, so it is suitable for treatment. It is fully effective against.

Permit applicant Nitto Electric Industry Co., Ltd. Representative: 3rd Department

Claims (4)

[Claims] (1) A member in which a drug-containing pressure-sensitive adhesive layer that is sticky at room temperature is provided directly or indirectly on a carrier having substantially no moisture permeability, wherein the pressure-sensitive adhesive layer is A water-insoluble polymer substance that is sticky at room temperature, a water-soluble polymer substance and/or polysaccharide made of a monomer having one ethylenically unsaturated double bond, and a transdermal drug. A drug administration member comprising an essential component. (2) The drug administration member according to claim 1, wherein the water-insoluble polymeric substance that is sticky at room temperature is an uncrosslinked substance having a glass transition temperature of -70 to -10°C. (3) Water bathable polymeric substances consisting of monomers having one ethylenically unsaturated double bond, polyvinyl alcohol, modified polyvinyl alcohol, poly(meth)acrylic acid, sodium poly(meth)acrylic acid, vinyl methyl ether - At least one member selected from the group of maleic anhydride copolymers. The drug administration member according to claim 1. (4) The polysaccharide is a cellulose ether derivative, starch,
The drug administration member according to claim 1, which is at least one member selected from the group of pullulan, agar, and dextrin.