JPH0152362B2 - - Google Patents

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 applied directly to the skin surface to administer drugs transdermally for the purpose of treating local or systemic diseases. The present invention relates to a highly effective drug administration member for administration into the body. Traditionally, the main methods of administering drugs to the body for the treatment of diseases have been oral administration or direct administration by injection. Due to problems such as side effects caused by administration, in recent years various proposals have been made for transdermal administration of drugs by applying tape preparations to the skin surface. The base materials that make up these tape preparations are mainly polymeric materials such as natural rubber, synthetic rubber, and acrylic that have skin adhesive properties, but they do not have pharmacological effects, skin irritation, or drug effects. The current situation is that nothing satisfactory has been achieved in terms of suppressing the decomposition of carbon dioxide. In addition, additives such as skin penetrating agents, humectants, and antioxidants are used in combination with the aim of solving these problems, but new problems such as a decrease in skin adhesion arise, and desired results are not obtained. Furthermore, as other base materials, oil gels made of synthetic rubber and mineral oil, and aqueous gels made of water and water-soluble polymers such as sodium acrylate or polyvinyl alcohol have been proposed.
Although the former type has excellent initial adhesion, it has poor long-term skin adhesion due to its poor ability to absorb moisture such as sweat.
Due to poor adhesion to the skin, it is difficult to expect sufficient medicinal efficacy for treatment. The latter has good drug release from the base material and is fast-acting, but it has problems with shape retention, skin adhesion, and drug dissolution and dispersion when thinned, so it is used as an aid such as surgical tape. It was necessary to fix it by some means. 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 transdermal drug has excellent skin adhesion, cohesion, shape retention, and drug decomposition prevention properties (drug stability) as a pressure-sensitive adhesive. )
It also has aqueous gel-like water absorption, skin moisturizing properties, drug release properties, and immediate effect due to its water-soluble polymeric substance.
It was discovered that desirable pharmacological effects can be obtained through extremely excellent adhesion, leading to the present invention. That is, the present invention provides 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 moisture permeability. The layer is made of (a) at least one polymeric material that is sticky at room temperature and insoluble in water, selected from the group of rubber-based polymeric materials, vinyl-based polymeric materials, and poly(meth)acrylate-based polymeric materials; (b) at least one water-soluble polymeric substance selected from vinyl or acrylic polymeric substances, and/or selected from the group of cellulose ether derivatives, starch, pullulan, agar, and dextrin; 2 to 40% by weight of at least one polysaccharide; (c) water containing 5 to 500 parts by weight per 100 parts by weight of component (b); and (d) a transdermal drug. The present invention provides a drug administration member characterized in that it is configured as follows. The polymeric substance that is sticky at room temperature and water-insoluble used in the present invention can be used as a drug-containing pressure-sensitive adhesive when the drug administration member of the present invention is applied directly to the skin surface for disease treatment. It gives the agent layer sufficient skin adhesion and a sealing bandage effect (so-called ODT effect),
Furthermore, it is a base material that enables diffusion movement at a desired rate depending on the drug, such as silicone rubber, polyisoprene rubber, polybutene rubber, styrene-butadiene rubber, styrene-isoprene-styrene block copolymer rubber, acrylic rubber, natural rubber, etc. Rubber-based polymer substances such as rubber, vinyl-based polymer substances such as polyvinyl alkyl ethers and vinyl acetate polymers, and poly(meth)acrylate-based polymer substances whose main monomer is alkyl (meth)acrylate esters. , polyamide-based polymer materials, etc., 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, 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. Examples of monomers that can impart adhesiveness include ethyl acrylate, butyl (meth)acrylate, pentyl (meth)acrylate, hexyl (meth)acrylate, heptyl (meth)acrylate, and (meth)acrylate. ) acrylic acid octyl ester, (meth)acrylic acid nonyl ester, (meth)acrylic acid decyl ester, (meth)acrylic acid dodecyl ester, (meth)acrylic acid tridecyl ester, etc., and these have linear argyl groups. They may be shaped or branched, and may be used alone or in combination of two or more. In addition, it can be copolymerized with the above monomers to improve cohesion and skin adhesion, and to increase compatibility with water-soluble polymeric substances or polysaccharides.
(meth)acrylic acid, itaconic acid, maleic acid,
Functional monomers such as maleic anhydride, crotonic acid, (meth)acrylic acid 2-hydroxyethyl ester, (meth)acrylic acid 2-hydroxypropyl ester, acrylonitrile, vinyl acetate,
It is also possible to copolymerize vinyl monomers such as vinyl propionate. The above-mentioned polymeric substance is selected to be sticky at room temperature, and those having a glass transition temperature of -70 to -10°C, preferably -55 to -25°C can be used; If the glass transition temperature does not fall within the glass transition temperature range, commonly used liquid additives such as softeners may be added. In addition, it is desirable to adjust the amount of the polymeric substance added to the drug-containing pressure-sensitive adhesive layer in the range of 60 to 98% by weight. The compatibility with polysaccharides 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, if it exceeds 98% by weight, the amount of water-soluble polymeric substance or polysaccharide added will be small, so there is a possibility that effects such as water absorption, water retention, and skin wettability cannot be expected. At least one water-soluble polymer substance selected from vinyl or acrylic polymer substances used in the present invention, which is a water-soluble polymer consisting of a monomer having one ethylenically unsaturated double bond. The substance and/or polysaccharide imparts high water affinity to the drug-containing pressure-sensitive adhesive layer and has a water-retaining ability, so that when the water-containing drug administration member of the present invention is attached to the skin, the substance and/or polysaccharide imparts high water affinity to the pressure-sensitive adhesive layer containing the drug. It has the effect of increasing the amount of water retained in the skin, increasing skin moisture and skin adhesion.
For example, ethylenically unsaturated double bonds such as polyvinyl alcohol, modified polyvinyl alcohol, poly(meth)acrylic acid, sodium poly(meth)acrylate, polyvinylpyrrolidone, polyvinyl alkyl ether, vinyl methyl ether-maleic anhydride copolymer, etc. Examples include water-soluble polymer substances consisting of one monomer, polysaccharides such as carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, starch, pullulan, agar, and destrin, and at least one of these may be added. Ru. The amount of the water-soluble polymeric substance and/or polysaccharide added is preferably in the range of 2 to 40% by weight, preferably 5 to 20% by weight, in the drug-containing pressure-sensitive adhesive layer. If it is in a solid state such as a powder, it is pulverized into a powder with a particle size of 300 μm or less, and then added and mixed as it is or in the state of a solution dissolved in a solvent such as water or alcohol. The water contained in the drug administration member of the present invention provides a cooling and refreshing sensation to the skin surface, increases the moisture content of the stratum corneum, provides skin wettability, and contributes to the immediate effectiveness of the drug. In addition, since the pressure-sensitive adhesive layer is imparted with aqueous gel-like properties, the transdermal drug contained therein can diffuse and move smoothly, contributing to good release properties of the transdermal drug. The water content to achieve the above effects is
The amount ranges from 5 to 500 parts by weight, more preferably based on 100 parts by weight of the water-soluble polymeric substance and/or polysaccharide.
It is preferably in the range of 50 to 300 parts by weight. If the water content is less than 5 parts by weight, although there is a pharmacological effect, the specific effects of water content, such as skin wettability and immediate effect, may be inferior, and if the water content is more than 500 parts by weight, pressure-sensitive adhesive The content may exceed the water retention capacity of the agent layer, resulting in water separation, poor shape retention, poor compatibility between the water-insoluble polymer component and the water-soluble polymer substance, and the desired effect is not achieved. There is a risk that it will not be possible. The transdermal drug used in the present invention is
There is no particular restriction as long as the drug is absorbed transdermally into the body when the drug administration member is pasted onto the skin, such as (a) corticosteroids; for example, hydrocortisone, prednisolone, beclomethasone; Propionate, flumethasone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobetasol propionate, etc. (b) Analgesic anti-inflammatory agents; for example, acetaminophen, mefenamic acid, flufenamic acid, Indomethacin, diclofenac, diclofenac sodium, alclofenac, oxyphenbutazone, phenylbutazone, ibuprofen,
Flurbiprofen, salicylic acid, methyl salicylate, l-menthol, camphor, sulindac, tolmetin sodium, naproxen, fuenbufuen, etc. (c) Eye sedatives: e.g. phenobarbital, amobarbital, cyclobarbital, lorazepam, haloperidol, etc. (d) Tranquilizers: e.g. fluphenazine, teolitazine, diazepam, flunitrazelpam, chlorpromazine, etc. (e) Antihypertensive agents: e.g. clonidine, clonidine hydrochloride, pindolol, propranolol, propranolol hydrochloride, bufranol, indenolol, bucumolol , nifedipine, etc. (F) Antihypertensive diuretics: For example, hydrothiazide,
Bendroflunathiazide, cyclopenthiazide, etc. (g) Antibiotics: e.g. penicillin, tetracycline, oxytetracycline, fradiomycin sulfate, erythromycin, chloramphenicol, etc. (h) Anesthetics: e.g. lidocaine, benzocaine,
(i) Antibacterial substances such as benzalkonium, nitrofurazone, nystatin, acetosulfamine, clotrimazole, etc. (n) Antifungal substances such as pentamycin, amphotericin B, pyrrolnitrine, etc. Clotrimazole, etc. (l) Vitamin preparations: e.g. vitamin A, ergocalciferol, cholecalciferol, octothiacin, riboflavin butyrate, etc. (w) Antiepileptic drugs: e.g. nitrazepam, mepropamate, clonazepam, etc. (w) Coronary vasodilators: e.g. nitroglycerin,
Nitroglycol, isosorbide dinitrate, erythritol tetranitrate, pentaerythritol tetranitrate, propyl nitrate, etc. (F) Antihistamines: For example, diphenhydramine hydrochloride, chlorpheniramine, diphenylimidazole, etc. (Y) Cough medicine: e.g. dextromethorphan,
Terbutamine, efuedrine, efuedrine hydrochloride, etc. (t) Sex hormones: e.g. progesterone, estradiol, etc. (l) Antidepressants: e.g. doxepin, (g) Others: e.g. 5-fluorouracil, dihydroergotamine, fentanil, desmopressin, digoxin, metoclo Examples include placido, domperid, scopolamine, scopolamine hydrobromide, and two or more of these drugs can be used in combination if necessary. The amount of the above drug added varies depending on the desired treatment and/or administration effect, but it is sticky at room temperature,
It is contained in an amount of about 0.01 to 20 parts by weight per 100 parts by weight of the water-insoluble polymeric substance. Examples of carriers that support the drug-containing pressure-sensitive adhesive layer made of the above components directly or indirectly through an undercoat material include various plastic films, papers, nonwoven fabrics, woven fabrics, metal foils,
Alternatively, a laminated film of these and a plastic film may be mentioned, but when the drug administration member of the present invention is attached to the skin surface to treat diseases through transdermal absorption of the drug, the amount of water retained in the stratum corneum on the applied skin surface is In order to increase the permeability and improve transdermal absorption, it is necessary to select or combine carriers with substantially no moisture permeability to obtain the so-called ODT effect. Furthermore, as transdermal absorption auxiliary substances for efficiently releasing drugs from the drug administration member of the present invention, for example, glycols such as propylene glycol, diethylene glycol, polyethylene glycol, and polypropylene glycol, ethyl alcohol salicylic acid, urea, allantoin, dimethyl sulfoxide, One or more substances such as dimethylacetamide, dimethylformamide, diisopropyl adipate, diethyl sebacate, ethyl laurate, lanolin, mineral oil, and various surfactants can be added as necessary. The amount added is preferably in the range of 0.5 to 20 parts by weight based on 100 parts by weight of the water-insoluble polymer substance, taking into consideration the balance between skin adhesion and cohesive force. In the drug administration member of the present invention, first, a powder or solution of a water-soluble polymeric substance and/or a polysaccharide is uniformly dispersed in an organic solvent solution of a water-insoluble polymeric substance that is sticky at room temperature while stirring. Water is added and mixed to swell the water-soluble polymeric substance and/or polysaccharide, and then coated directly onto the carrier or indirectly coated with an undercoat, etc. The temperature is such that the water does not scatter as much as possible.
For example, it can be manufactured by scattering an organic solvent at a temperature of about 40 to 80°C. In order to strictly control the amount of water contained, it is possible to manufacture the drug administration member without adding only water in advance, and then spray water vapor or mist on the surface of the pressure-sensitive adhesive layer, or After applying water using a micro-metering pump or the like, it is preferable to cover the surface with a protective material such as a separator to swell the water-soluble polymer and/or polysaccharide. As described above, the drug administration member of the present invention can be applied directly to the skin of the body to continuously supply the transdermal drug contained therein into the body in a short period of time, thereby treating local or systemic diseases. This has the effect that it can be carried out sustainably and effectively.
In particular, water-soluble polymeric substances and/or polysaccharides made of monomers having one ethylenically unsaturated double bond, which are essential components, and water are added to the pressure-sensitive adhesive layer with aqueous gel-like characteristics, i.e., water retention and water absorption. In addition, the adhesive layer is plasticized because the water-soluble polymeric substance and/or polysaccharide is dissolved or swollen by water. Improves adhesion to the skin surface, giving it the ability to exhibit excellent pharmacological effects. In addition, with conventional acrylic skin patch members, the adhesive surface of the member becomes contaminated with oil components and grime after peeling off, making it difficult to reapply. It has improved adhesion and can be reapplied.
The contained drug can be used effectively without waste. Examples of the present invention will be shown below and will be described in more detail, but the present invention is not limited to these and can be applied in various ways without departing from the technical idea. Note that parts in the examples indicate parts by weight. Example 1 96 parts of acrylic acid 2-ethylhexyl ester,
4 parts of acrylic acid, 42.9 parts of ethyl acetate, and 0.2 parts of azobisisobutyronitrile were placed in a four-necked flask under an inert gas mist, and the temperature of the inner bath was set to 60°C.
The polymerization reaction was started by stirring at ~62°C, 190.4 parts of ethyl acetate as a reaction diluting solvent was added dropwise, and the reaction was polymerized for 8 hours while controlling the reaction, and the inner bath temperature was further raised to 75~80°C. After aging for a period of time, a polymeric substance solution was obtained with a polymerization rate of 99.3%, a solution viscosity of 230 poise at 30° C. and a solid content of 30% by weight. Next, for 89 parts of the solid content of the polymer substance solution,
After adding and mixing 0.2 parts of clobetasol propionate and thoroughly dissolving it, 4.8 parts of sodium polyacrylate crushed to a particle size of 5 to 10 μm was added.
Disperse uniformly with a homomixer, then add distilled water.
After adding 6.2 parts of sodium polyacrylate to sufficiently swell the sodium polyacrylate, it was applied onto a 60 μm thick polyethylene film to a dry thickness of 50 μm, and dried at 50°C for 15 minutes to form a drug administration material. Obtained. Example 2 Toluene solution silicone adhesive (trade name
KR101-10 (manufactured by Shin-Etsu Chemical Co., Ltd.) in acetone solution containing 3 parts of lorazepam dissolved in 85 parts of solid content 10
After adding and mixing 10 parts and thoroughly dissolving it, a particle size of 10
Add 12 parts of polyvinyl alcohol (saponification degree 98%) crushed to ~20 μm, disperse uniformly with a homo mixer, and mix into 80 μm thick polyethylene/ethylene-
Ethylene of vinyl acetate copolymer laminated film
The vinyl acetate copolymer side has a thickness of 50μm after drying.
and dried at 80°C for 7 minutes to form a drug-containing pressure-sensitive adhesive layer that is sticky at room temperature. Further, water vapor is sprayed on the surface of the layer at a concentration of 4 g/m ² . Immediately, a 80 μm thick tetrafluoroethylene polymer film was bonded and coated to obtain a drug administration member. Example 3 25 parts of styrene-isoprene-styrene block copolymer rubber (isoprene content: approximately 86% by weight), 40 parts of liquid paraffin, 3 parts of lanolin, and 20 parts of aliphatic petroleum resin (melting point 100°C) were mixed with toluene/ethyl acetate. Sufficiently dissolve in 65 parts of mixed solvent (weight ratio 1/2).
The mixture was mixed 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 thoroughly dissolved. Then, an aqueous solution of 7 parts of hydroxypropylcellulose dissolved in 15 parts of distilled water was added, and the mixture was mixed with a homomixer. Disperse it uniformly and apply it on a 50 μm thick polypropylene film so that the thickness after drying is 50 μm.
After drying at 90° C. for 7 minutes, water was further applied to the surface of the pressure-sensitive adhesive layer at a concentration of 4 g/m ² using a minute metering pump, and immediately covered with a separator to obtain a drug administration member. Comparative Examples 1-3 Comparative Examples 1-3 correspond to Examples 1-3,
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 administration member that did not contain a water-soluble polymer substance or polysaccharide and water was prepared. Obtained. Table 1 shows the characteristics of the drug administration member obtained in each Example and Comparative Example.

[Table] The measurement method for each characteristic in Table 1 is as follows. [Release rate in water]: Each sample piece (4 x 4 cm square) was
Immerse and shake in 200 ml of water at ℃, sample 1 ml of water after 1 hour and 6 hours, and measure the drug content using high performance liquid chromatography (UV detection), taking the initial drug content as 100%. The release rate was determined. [Blood concentration]: Each sample piece (3 cmφ) was pasted on the abdomen of a rat whose hair had been removed in advance, and after 8 hours, the rat's blood was drawn and the blood concentration of the drug was measured using a gas chromatography device. [Transfer rate]: Each sample piece (3 cmφ) was pasted on the abdomen of a rat whose hair had been removed in advance, and after 8 hours, each sample piece was removed and the amount of remaining drug was measured, and the initial drug content was set as 100%. The skin transfer rate was determined. [Reapplyability]: Each sample piece (4 x 4 cm square) was applied to the inside of the upper arm for 24 hours, then removed, and the same sample piece was applied again for 24 hours to visually determine the state of adhesion to the skin. , 〇 indicates that the adhesive is sufficiently adhered, △ indicates that the terminal peels off or falls off during the process.
Those that could not be reattached at all were marked as ×. As is clear from Table 1, the drug administration member of the present invention has good skin adhesion and initial drug release properties, and has a high water release rate, blood concentration, and migration rate, so it is sufficient for treatment. It has a great effect.

Claims (1)

[Scope of Claims] 1. A member comprising a drug-containing pressure-sensitive adhesive layer that is sticky at room temperature, directly or indirectly provided on a carrier having substantially no moisture permeability. The adhesive layer includes (a) at least one water-insoluble polymer that is sticky at room temperature and selected from the group of rubber-based polymeric substances, vinyl-based polymeric substances, and poly(meth)acrylate-based polymeric substances; (b) at least one water-soluble polymeric substance selected from vinyl-based or acrylic-based polymeric substances, and/or from the group of cellulose ether derivatives, starch, pullulan, agar, and dextrin; 2 to 40% by weight of at least one selected polysaccharide; (c) water containing 5 to 500 parts by weight per 100 parts by weight of component (b); and (d) 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 The water-soluble polymer substance is polyvinyl alcohol,
The drug administration according to claim 1, which is at least one selected from the group of modified polyvinyl alcohol, poly(meth)acrylic acid, sodium poly(meth)acrylate, and vinyl methyl ether-maleic anhydride copolymer. Element. 4. The drug administration member according to claim 1, wherein the water content is 5 to 500 parts by weight based on 100 parts by weight of the water-soluble polymeric substance and/or polysaccharide.