JPS60123416A - Drug delivery member - Google Patents

Abstract

PURPOSE:To provide a drug delivery member having the adhesivity to the skin, the drug releasability, the rapid action, etc. as a pressure-sensitive adhesive, by compounding a water-insoluble polymer having stickiness at normal temperature with a specific water-soluble polymer, water, and a drug for transcutaneous absorption. CONSTITUTION:A water-insoluble polymer having stickiness at normal temperature (e.g. natural rubber, synthetic rubber, acrylic polymer, etc.) 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.), water, and a drug for transcutaneous absorption (e.g. corticosteroid, analgesic antiinflammatory agent, etc.). The obtained pressure-sensitive adhesive layer is applied to a carrier to obtain the objective drug delivery member. An excellent drug action can be exhibited by the action of the water-soluble polymer, the polysaccharide and water to impart the adhesive layer with the characteristics of an aqueous gel, i.e. skin moisturizing effect, drug-releasing property, adhesivity, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a drug administration member for administering transdermal drugs into the body. The present invention relates to a highly effective drug administration member for transdermally administering a drug into the body for the purpose of treatment.

Conventionally, the main methods of administering drugs to the body for the purpose of disease treatment have been oral administration or direct administration by injection, but primary metabolism by the liver and maintenance of effective blood concentrations over a long period of time are important. , due to problems such as side effects due to large doses,
In recent years, various proposals have been made for transdermal administration of drugs by applying tape preparations to the skin surface. The base material constituting these tape preparations and 1. In this field, polymeric materials such as natural rubber, synthetic rubber, and acrylic materials that have skin adhesive properties are mainly used, but these materials are not satisfactory in terms of pharmacological effects, skin irritation, and inhibition of drug decomposition. The current situation is that we are not getting anything. In addition, in order to eliminate these problems, additives such as skin penetrating agents, humectants, and antioxidants are used in conjunction with -C.
However, new problems such as decreased skin adhesion occur, and the desired results are not achieved.

Furthermore, there are products using other base materials such as synthetic rubber, oily gels made of mineral oil, and aqueous gels made of water and water-soluble polymers such as sodium acrylate and polyvinyl alcohol. However, although the former has excellent initial adhesion, it has poor long-term skin adhesion due to its poor ability to absorb moisture such as sweat, and is expected to have sufficient medicinal efficacy for treatment due to its poor adhesion to the skin. It's difficult. In addition, the latter has good drug release from the base material and is fast-acting, but it also has problems with shape retention, skin adhesion, and drug dissolution/dispersibility when forming a thin film, so it is used as surgical tape, etc. Fixation with auxiliary means was required.

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 polymer substance, water, and a medicinally absorbable drug has excellent skin adhesion, cohesion, shape retention, and drug decomposition inhibiting properties (drug stability) as a pressure-sensitive adhesive. and water-based gel-like water absorption due to water-soluble polymeric substances.
Combines skin dregs wettability, drug release properties, and immediate effect 1. It was discovered that desirable pharmacological effects can be obtained through extremely excellent adhesion, leading 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; The essential ingredients are a water-soluble polymer fvA substance and/or polysaccharide made of a monomer having one ethylenically unsaturated divalent bond, water, and a transdermal drug. The present invention provides a drug administration member characterized in that it is configured as follows.

The water-insoluble polymer substance that is sticky at room temperature and used in the present invention is applied by directly pasting the drug administration member of the present invention to the skin surface for the purpose of curing disease.1. At the time of application, the drug-containing one-pressure adhesive layer has sufficient skin adhesion and occlusive bandage effect (so-called ODT effect), and furthermore, depending on the drug, it can be spread and transferred11.
A base material that allows flJ to stop at a desired speed, such as rubber-based rubbers such as silicone rubber, polyisoprene rubber, polybutene rubber, styrene-butadiene rubber, styrene-isoprene-styrene block copolymer rubber, acrylic rubber, and natural rubber. Polymeric substances, vinyl-based polymeric substances such as polyvinyl alkyl ethers, vinegar-based vinyl polymers, poly(meth)acrylate-based polymeric substances whose main monomer is (meth)acrylic alkyl esters, polyamide-based Examples include polymeric substances, and these may be water-releasable. 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, poly(meth)acrylate-based polymeric substances are particularly preferable in consideration of the stability against decomposition of the drug they contain and the skin adhesion of the drug administration member, as they can be polymerized and are stable at room temperature. Monomers capable of imparting tackiness and monomers, such as acrylic acid ethyl ester, (meth)acrylic acid butyl ester, (meth)acrylic acid pentyl ester, (meth)acrylic acid hexyl ester,
(meth)acrylic acid hebutyl ester, (meth)acrylic acid octyl ester, (meth)acrylic acid J+, /acid nonyl ester, (meth)acrylic acid ethyl ester, (meth)acrylic acid dodecyl ester, (meth)well, They may be used alone or in combination of two or more. In addition, (meth)acrylic IL/acid, itaconic acid, which can be copolymerized with the above monomers, improves cohesiveness and surface adhesion, and improves compatibility with water bathing polymeric substances or polysaccharides. , maleic acid, maleic anhydride, crotonic acid, (meth)acrylic acid 2-hydroxyethyl ester, (meth)acrylic acid 2-hydroxyproyl ester, acrylonitrile, vinyl acetate, propionic acid, etc. It is also possible to copolymerize vinyl monomers such as vinyl.

The polymer substance is selected to be sticky at room temperature, and preferably has a glass transition temperature of -70 to -10°C f-j
-55 to -25℃ can be used, and if the polymer substance alone does not fall within these glass transition temperature ranges, a liquid Id≦additive such as a commonly used softener can be added. 1. But that's fine.

In addition, the amount of the compound C added in the drug-containing pressure-sensitive adhesive layer should be adjusted to be in the range of 6% to 98% by weight, and below 60% by weight. The compatibility with the water-soluble polymeric substance or polysaccharide described in 2.1 becomes poor, making it difficult to obtain a uniform pressure-sensitive adhesive layer, and furthermore, the initial adhesion to the skin surface to which it is applied tends to be poor.

Moreover, at 98 weight #C% or more, water-soluble qr+: Yoko Masayoshi C'
1 water absorption due to less amount of 〆q or polysaccharide added,
There is a possibility that effects such as water retention and skin/IIl wettability cannot be expected.

In the present invention, the water-soluble polymer consisting of a monomer having one ethylenically unsaturated phase double bond and/or polyester is highly effective in the drug-containing pressure-sensitive adhesive layer. 1. Contains water because it imparts water affinity and has water retention ability. The drug administration member of the present invention is applied to the skin 1111 to increase the water retention capacity of the stratum corneum, thereby increasing anti-Jril wettability and anti-1 mW resistance. For example, polyvinyl alcohol, polyvinyl alcohol-I and ethylenically unsaturated compounds such as poly(methacrylic acid, sodium poly(meth)acrylate, polyvinylpyrrolidone, polyvinyl alkyl ether, vinyl methyl ether-maleic anhydride copolymer) Examples include water-soluble polymer substances consisting of a single unit having one bond, polysaccharides such as carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, starch, pullulan, agar, and destrin;
At least one of these is added. The amount of the water-soluble polymeric substance and/or polysaccharide added is preferably 2N40% by weight, preferably 5 to 20% by weight, into the drug-containing pressure-sensitive adhesive layer. If it is in a solid state such as a powder, it can be crushed into a powder with a particle size of 300 μm or less, and then either as it is or dissolved in a bath medium such as water or alcohol.1. Add and mix in a solution state.

The water contained in the drug administration member of the present invention provides a cooling sensation on the skin surface.
It not only gives a refreshing feeling, but also increases the moisture content of the stratum corneum, providing moisture to skin debris and contributing to the immediate effectiveness of the drug. In addition, the sexual feelings of aquatic sex I will be transferred to pressure-sensitive lovemaking II'4 ("
Therefore, the percutaneously absorbable drug contained therein spreads smoothly and contributes to good release properties of the percutaneously absorbable adjuvant hj.

The content of water &+1 in order to achieve the above-mentioned effect is preferably in the range of 5 to 500 parts by weight per 1 part by weight of the water-soluble polymeric substance and/or polysaccharide (1).

It is preferably in the range of 50 to 3 (10 parts by weight).

If the water content is 5 parts by weight or less, although there is a pharmacological effect, the specific effects of water content, such as skin placement and immediate effect, may be inferior, and if the water content is 50 parts by weight or more, The water retention f of the pressure sensitive adhesive layer may be exceeded, resulting in separation of water, poor shape retention, poor compatibility between the water-insoluble polymer component and the water-soluble polymer material, and other problems. There is a risk that the desired effect may not be obtained.

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 applied on the skin IM surface. ) Corticosteroids; e.g. no-hydronautisone, prednisolone, beclomethasone brobionate,
flumethacin, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolocyanacetonide acetate, clobetasol propionate, etc. o) anti-inflammatory agents; for example acetaminophen, mefenamic acid, flufenamic acid, indomethacin, diclofenac , Diclof 1 Nac Sodium, Alclofenac, Oxyphengetacin, Phenylbutacin,
Impro7ene, flurbiprofen, salicylic acid, methyl salicylate,! - Menthol, camphor, sulindac, tolmetin sodium, naproxen, fenbufen, etc. c) Eye stimulants "FII agents such as phenobarbital, amohalchtal, cycloparbital, lorazepam, haloperidol, etc., 2) Mental stabilizing drugs" : Examples include fluphenazine, teoritazine, diazepam, flunitrazebam, chlorpromazine, etc. e) Antihypertensive agents such as clonidine, clonidine hydrochloride,
pindolol, propranolol, propranolol hydrochloride, bufranol, indenolol, bucumolol, nifedipine nato, antihypertensive diuretics: e.g. hydrothiazide, pen F
Roflunacyadide, cyclopenthiaside, etc. g) Antibiotics For example, penicillin, tetracycline,
Oxytetracycline, fradiomycin sulfate, erythromycin, chloramphenicol, etc. 1) Anesthetics; for example, lidocaine, pensicaine, ethyl aminobenzoate, etc.; n) Antifungal substances: such as pentamycin, amphotericin B1 pyrrolnidoline, clotrimazole, etc. l) Vitamins: such as vitamin A, ergocalciferol, cholecalciferol, octothiazine, riboglavin butyrate, etc. ) Antiepileptic drugs: e.g. nitrazepam, meprobamate, clonazebam, etc.; c) Coronary vasodilators: e.g. nitroglycerin, nitroglycol, insorbidodinitrate, erythritol tetranitrate, pentaerythritol tetranitrate, propyl nitrate, etc. A) Antihistamines: e.g. t=tm diphenhydramine, chlorpheniramine, cyphenylimitazole, etc. e) Antitussive III: e.g./kistromethorphan,
tilbutamine, ephedrine, ephedrine hydrochloride, etc. 1) Sex hormones (e.g. progesterone, estradiol, etc.) 2) Antibiotics: e.g. doxepin, etc. 3) Others: e.g. 5-fluorocracil, dihydroergotamine, fentanil, desmobrecin, digoxin, metoclograside , domperid, scopolamine,
Examples include scopolamine hydrobromide, and two or more of these drugs can be used in combination if necessary. The amount of the above-mentioned drug added varies depending on the desired treatment and/or administration effect, but it is added at a rate of about (1,01-2
(l 7', f Contained in the range of fair and evil.

Examples of carriers that support the drug-containing pressure-sensitive adhesive layer consisting of component 11a directly or indirectly through an undercoating material include various plastic films, papers,
Nonwoven fabrics, woven fabrics, metal foils, or mR films made of these and plastic films may be used, but the drug administration part assembly of the present invention can be attached to the skin surface to treat diseases through the absorption of drugs. In order to increase the water retention capacity of the stratum corneum on the applied skin surface and improve transdermal absorption, the above-mentioned carrier is selected to have substantially no moisture permeability, or by combining them, the so-called ODT effect can be obtained. It is necessary to do so.

Furthermore, transdermal absorption auxiliary substances for efficient drug release from the drug administration member of the present invention, such as glycols such as propylene glycol, diethylene glycol, polyethylene glycol, and polypropylene glycol, ethyl alcohol salicylic acid, urea, and allantoin. , dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, diisopropyl adipate, diethyl sepacate, ethyl laflate, lanolin, mineral oil, and various surfactants can be added as needed. The amount added is desirably in the range of 5 to 20 parts by weight based on 100 parts by weight of the water-insoluble polymer substance, taking into account the balance between adhesive strength and cohesive force.
stomach.

The drug administration member of the present invention is first prepared by adding water-soluble polymer I! to an organic solvent solution of a water-insoluble polymer substance that is sticky at room temperature. For the powder component of $A quality and/or polysaccharide, stir the solution to disperse it uniformly (11), then add water and mix (17) to add the water-soluble polymeric substance and/or polysaccharide (11).
1. Let it moisten, then apply it directly onto the carrier or indirectly through F coating agent, etc., at a temperature that prevents the contained water from scattering as much as possible, for example, at a temperature of about 4 () to 80 degrees Celsius. It can be manufactured by scattering an organic solvent. In order to strictly control the amount of water contained, the drug administration member is manufactured without adding only water in advance, and then water vapor or water mist is sprayed onto the surface of the pressure-sensitive adhesive layer. After applying water using a dispersion metering pump or the like, it is preferable to cover the surface with a protective material such as a separator to moisten the water-soluble polymer and/or polysaccharide.

As shown above, the drug administration member of the present invention can be applied directly to the opposite side of the body to continuously supply the transdermal drug contained therein into the body in a short period of time, and can be applied locally or systemically. The effect is that disease treatment can be carried out continuously and effectively.

In particular, water-soluble polymer substances and/or polysaccharides made of monomers having one ethylenically unsaturated double bond, which are essential components, and water give the pressure-sensitive adhesive layer an aqueous gel-like characteristic, that is, water retention.
Provides water absorption, skin moisture, drug release, and immediate effect 1-
1. Furthermore, water-soluble polymer substances and/or polysaccharides are dissolved or swelled by water.1. Because of this, the adhesive layer is plasticized and its adhesion to ffA is improved.1-2 It provides a full range of functions that exhibit excellent pharmacological effects. In addition, after peeling off a normal acrylic skin patch, the adhesive surface of the member becomes contaminated with oil components and grime, making it difficult to reapply.
Since the drug administration member has aqueous gel-like properties, it has improved adhesion and can be attached with a nail, allowing the drug contained therein to be used effectively without wasting it.

Examples of the present fi IU+ are shown below and will be described in more detail in 1-1. However, the present invention is not limited to these examples, and various applications are possible within the scope of not departing from the technical idea. be. In addition, in the examples, parts are heavy ktL.
Shows glni.

Example 1 96 parts of acrylic acid 2-ethylhexyl ester, 4 parts of acrylic acid, 42.9 parts of ethyl acetate, and 2 parts of azobisisobutyronitrile (2) were charged into a fourth flask under an inert gas atmosphere. The combination reaction was started by stirring at an internal temperature of 60 to 62'C, and 1.4 parts of ethyl acetate, a reaction diluting solvent, was added dropwise to control the reaction and the combination was continued for 8 hours. Raising the internal bath temperature to 80℃ and aging for 3 hours 1-2 Polymerization rate 99.3 Solid content at 30℃ 3
A polymeric substance solution having a solution viscosity of 230 voids at 0 weight was obtained.

Next, 1.0 parts per 89 parts of solid content of the polymer substance solution. Te 0.2
After adding and mixing 1.0 parts of clopetazole propionate and fully dissolving it, 4.8 parts of sodium polyacrylate ground to a particle size of 5 to 10 μm was added, uniformly dispersed with a homomixer, and further added with 6.0 parts of distilled water. Add 2 parts 1. After sufficiently swelling sodium polyacrylate by 1, (i
Coating 1 to 1 on a polyethylene film with a thickness of 1 μm so that the thickness after drying becomes 50 μm. A drug administration site was obtained by drying at 50°C for 15 minutes.

Example 2 Silicone adhesive in toluene solution (trade name: KRIOI)
-1 (1, manufactured by Shin-Etsu Chemical Co., Ltd.) 10 parts of acetone # solution in which 3 parts of lorazepam is dissolved are added to 85 parts of the solid content and mixed, and after being sufficiently dissolved, it is pulverized to a particle size of 10 to 20 μm. Add 12 parts of polyvinyl alcohol (saponification degree 98%) and disperse uniformly with a homomixer to 80μηl.
Coat the ethylene-vinyl acetate copolymer side of a thick polyethylene/ethylene-vinyl acetate copolymer laminate film so that the thickness after drying is 5 μm, and dry the surface at 80°C for 7 minutes. 2, a drug-containing pressure-sensitive adhesive IBM that is sticky at room temperature is formed, and 49/η is further applied on the surface of the layer.
Sprinkle water vapor so that i 1-. , immediately 80μtn
If, the tetrafluoroethylene polymer film was attached and removed to obtain a drug administration member with coating 1-.

Example 3 Styrene-isoprene-styrene block copolymer rubber (isoprene combination: approximately 86% vg.) > 25 parts, flow tdJ
40 parts paraffin, 3 parts lanolin, aliphatic petroleum resin (
Melting point l l) (l tE ) 2 (1 part was thoroughly dissolved and mixed in 65 parts of l-trenine/ethyl acetate mixed solvent (air volume ratio 1/2)! A 77-part substance solution was obtained.

Next, 5 parts of clonidine was added to 88 parts of the solid solution of the molecular substance solution.
After adding MQ and thoroughly dissolving it, add an aqueous solution of 7 parts of hydroxypropylcellulose dissolved in 15M AM water (11), homogeneously disperse with a homomixer, and (5)
It was coated on 0 μm thick polypropylene 47 L/μm so that the thickness after drying was 50 μm, and dried at 90° C. for 7 minutes. Then, water was further applied to the surface of the pressure-sensitive adhesive layer using a minute metering pump to give a ratio of 49/1, and immediately the coating was applied using a Yabarator. A drug administration member was obtained.

Comparative Examples 1 to 3 Comparative Examples 1 to 3 correspond to Examples 1 to 3.1. The same operations as in each example were performed except that sodium polyacrylate, polyvinyl alcohol, hydroxypropyl cellulose, and water were removed from each example, and a drug containing no water-soluble polymeric substance or polysaccharide and water was obtained. A dosing member was obtained.

Table 1 shows the characteristics of the drug administration member obtained in each Example and Comparative Example.1. Ta.

Each 47i4'1. in Table 1, No. 1k. The measurement method is as follows.

[Water release rate]: Each sample piece (4 x 4 Sonoko angle) was
After 11.1 hours of shaking, 1st of water was sampled without 1filtration of the drug, and the drug-containing 4 solution was subjected to 1f-i 1-speed chromatography-( The release rate was measured by UV, p+, and initial release when the drug was 10% and l- containing the drug.

[Blood 1 ILi, J: 8 sample pieces (3 pieces φ) were prepared 1. After 8 hours, the blood of the rat was removed and the blood concentration of drug 1 was measured using a gas chromatograph device.

[Transfer rate]: Each sample piece (3mmφ) was pasted on the abdomen of a rat whose hair had been removed in advance, and after 8 o'clock li+, each sample piece was removed 1
- Measure the amount of remaining drug and set the initial drug content to 100
% and the skin transfer rate at 1-.

[Rebinding property]: Place each sample piece (4 x 4 squares) on top! 19
After pasting on the inside for 24 hours, it was removed (12), and the same sample piece was pasted on the inside for 24 hours (1). Visually check the adhesion to the skin when applying.
1. Those that cause the terminal to peel off or fall off during the process are △, and those that cannot be reattached at all are marked 1. Ta.

As is clear from Table 1, paulownia is suitable for treatment because it has good skin adhesion and initial drug release, and has high water release rate, blood concentration, and migration rate. [
, it is fully effective.

patent applicant Nitto Electric Industry Co., Ltd. Representative Sanbe Hijikata

Claims (5)

[Claims] (1) A member in which a drug-containing pressure-sensitive adhesive layer that is sticky at room temperature is directly or indirectly provided on a carrier having substantially no ifi wettability, wherein the pressure-sensitive adhesive layer is a water-insoluble polymer substance that is sticky at room temperature;
It is characterized by being composed of a water-soluble polymer substance and/or polysaccharide made of a monomer having one ethylenically unsaturated double bond, water, and a transdermally absorbable drug as essential components. drug administration member. (2) The drug administration member according to claim 1, wherein the molecular substance that is sticky and water-insoluble at room temperature is an uncrosslinked substance having a glass transition of -70 to -1 ()°C. (3) Polyvinyl alcohol, modified polyvinyl alcohol, poly(meth)acrylic
, sodium poly(meth)acrylate, polyvinylpyrrolidone, polyvinyl alkyl ether, and vinyl methyl ether-maleic anhydride copolymer. (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. (5) The drug administration member according to claim 1, wherein the water-containing ring is 5 to 500 parts by weight per 10,111 parts by weight of the water-soluble polymeric substance and/or polysaccharide.