JPH0238569B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a pharmaceutical component for continuously absorbing a drug through the skin or mucous membrane. One method of administering drugs to the human body is
A so-called transdermal absorption method in which drugs are absorbed through the skin or mucous membranes is known. Drug-containing ointments are widely used in this method, but absorption is temporary, resulting in side effects and the majority of the absorbed drug being excreted. Recently, the concept of controlled release, which releases drugs over a long period of time with a constant drug supply amount, has been introduced, and several proposals have been made. For example, there is a type in which a drug and a polymeric substance such as a pressure-sensitive adhesive are mixed and molded, brought into contact with the skin or mucous membrane, and absorbed by a concentration gradient. There are problems in that drugs are degraded or denatured or polymeric substances become plasticized during storage. There are also systems in which ionic bonds are dissociated and supplied by moisture supplied from the skin or mucous membranes, but there is a problem that the dissociation of ionic bonds is insufficient and the desired medicinal effect cannot be obtained. As a result of various studies in view of the state of the prior art, the inventors encapsulated a drug absorption aid in microcapsules made of a specific substrate, and incorporated it in a dispersed state into a drug-containing polymer layer. By forming the microcapsules into a shape that fits closely to the application surface and applying it to the skin or mucous membrane surface, the substrate that makes up the microcapsules swells with the supplied moisture, making it permeable to the aid agent, and the aid released outside the capsule. The present invention was based on the discovery that the drug in the polymer material layer diffuses and moves together with the drug, thereby making it possible to reliably and accurately supply the drug to the skin or mucous membranes. That is, this invention is composed of a drug-containing polymer material layer containing dispersed microcapsules encapsulating a drug absorption aid, and a flexible carrier formed on the surface of one of the layers. , the microcapsules provide a medicinal component composed of a matrix that swells with the supply of water and becomes permeable to an auxiliary agent. In one embodiment of this invention, a drug absorption aid is encapsulated in microcapsules made of a substrate that becomes permeable when swollen with water, and this is combined with a viscous adhesive made of a moisture-permeable pressure-sensitive adhesive composition. This is a pharmaceutical component that is held in a dispersed state by a drug layer and is combined with a carrier formed on one of the layers. When the drug absorption aid in the microcapsule is applied to the skin or mucous membrane through a viscous material layer, the drug absorption aid is swollen by water supplied from the skin or mucous membrane to the capsule, making it permeable to the aid. The auxiliary agent released thereby diffuses and moves in the viscous material layer, increasing the solubility of the drug in the viscous material layer and continuously and quantitatively supplying the drug to the skin or mucous membranes. At the same time, it swells the stratum corneum, lowers its barrier function, and improves the permeability of drugs into the skin. Another embodiment of the present invention is a pharmaceutical member in which a polymer which is normally non-adhesive as a polymer substance, and which is flexible and moisture permeable is used as a holding matrix for microcapsules. The embodiments of this invention are not limited to the above examples. In this invention, the amount of drug supplied is substantially different depending on the amount of water supplied from the skin or mucous membrane. By selecting the drug absorption aid to be used, the speed of movement of the drug in the polymer substance, the concentration, etc., it is possible to supply the drug continuously and quantitatively for a predetermined period of time. To provide a possible medical device. The microcapsules used in this invention are highly swollen by supplied moisture and have adjuvant permeability that facilitates the elution of the drug absorption aid encapsulated in the microcapsules. Examples include single hydrophilic polymers such as gelatin, polysodium acrylate, polyacrylamide, carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether-maleic anhydride copolymer, carbopol, hydroxyethyl cellulose, methyl cellulose, etc. A mixture of these or a partially crosslinked product thereof may be used. The drug absorption aid encapsulated in the microcapsules has the function of increasing the dissolution ability of the drug in the polymeric substance;
It has the function of promoting the movement of drugs through substances, or the function of promoting the absorption of drugs through the skin or mucous membranes (e.g. keratin softening function), such as methyloctyl sulfoxide and dimethyl laurylamide. , dimethyl sulfoxide,
dimethylacetamide, dimethylformamide,
Sulfoxide-based, phosphooxide-based, dimethylamide-based, alkylpyrrolidone-based, and isosorbitol-based solvents such as dodecylpyrrolidone; alcohols such as ethyl alcohol, ethylene glycol, polyethylene glycol, and glycerin;
Other examples include vegetable and animal oils, fats and oils, higher fatty acids, and paraffins. In addition, drugs that are preferably dissolved in a polymeric substance and/or dispersed in a crystalline state are transdermally absorbable;
It does not dissolve very well or at all in moisture supplied from the skin or mucous membranes, and has the property of being able to be released together with the drug absorption aid mentioned above. Examples of such drugs include the following. (b) Corticosteroids: For example, hydrocortisone, prednisolone, paramethasone, beclomethasone propionate, flumethasone, betamethasone, beclomethasone propionate,
Dexamethasone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobetasol propionate, etc. (b) Analgesic and anti-inflammatory agents: for example, acetaminophen, mefenamic acid, flufenamic acid, indomethacin, diclofenac, Oxyphenbutazone, phenylbutazone, salicylic acid, methyl salicylate, l-menthol, camphor and combinations thereof, etc. (c) Eye sedatives: e.g. phenobarbital, amobarbital, cyclobarbital, etc. (d) Tranquilizers: For example, fluphenazine, thioridazine, diazebam, chlorpromazine, etc. (E) Antihypertensive agents: For example, clonidine, etc. (F) Antihypertensive diuretics: For example, hydrothiazide,
Bendrofluna thiadide, etc. (g) Antibiotics: e.g. erythromycin, chloramphenicol, etc. (h) Local anesthetics: e.g. lidocaine, (li) Antibacterial substances: e.g. acetosulfamine, clotrimazole, etc. (n) Antifungal substances: e.g. pentamycin, amphotericin B, pyrrolnitrin, clotrimazole, etc. (l) Vitamin preparations: e.g. vitamin A, ergocalciferol, cholecalciferol, octothiacin, riboflavin butyrate, etc. (e) Antiepileptic drugs: e.g. nitrazebam, meprobamate, etc. (w) Coronary vasodilators: e.g. nitroglycerin,
Two or more of these drugs, such as isosorbite dinitrate, can be used in combination if necessary. The blending ratio of the polymeric substance and drug varies depending on the substance and drug used, the amount of drug to be delivered to the skin or mucous membranes, etc., but the mixture of the two contains 0.01 to 30% by weight of the drug. is preferable. Microcapsules encapsulating the drug absorption aid described above are blended into the drug-containing polymer material thus constituted in a proportion of about 1 to 50% by weight to form a mixture. The resulting mixture is made into a medicinal component that maintains a predetermined shape with the help of a flexible carrier in the form of a film. One group of the polymeric substances is a group consisting of substances that hold microcapsules in a dispersed state and do not have pressure-sensitive adhesive properties under normal conditions, and this group includes soft polyvinyl chloride, soft polyamide, polyolefin,
It is composed of polyvinyl alcohol, polyacrylic resin, thermosetting or room temperature vulcanizable silicone rubber, ethylene-vinyl acetate copolymer, etc.
Pharmaceutical components using these substances can be made by molding a mixture of a capsule and the substance, and forming a water-impermeable carrier on one surface of the mixture, which allows the drug to be contained. There is little remaining in the polymer material layer. Another group of polymeric substances are viscous substances that hold capsules in a dispersed state and have moderate moisture permeability and pressure-sensitive adhesive properties in normal state, and one such group includes n-butyl (meth)acrylate. , hexyl (meth)acrylate, 2-ethylbutyl (meth)acrylate, isooctyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, decyl (meth)acrylate, dodecyl (meth)acrylate (meth)acrylate (meth)acrylic acid esters such as tridecyl acid, and (meth)acrylic acid, itaconic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide that can be copolymerized with the esters. Examples include acrylic compositions which are copolymers with functional monomers such as , methylaminoethyl methacrylate, and methoxyethyl (meth)acrylate, and/or vinyl monomers such as acrylonitrile, vinyl acetate, and vinyl propionate. Other examples include rubbers such as silicone rubber,
Rubber-based viscous materials containing polyisoprene rubber, polyisobutylene rubber, styrene-butadiene (or isoprene)-styrene block copolymer rubber, acrylic rubber, natural rubber, etc., vinyl-based polymers such as polyvinyl ether, polyvinyl alcohol, polyester, etc. Examples include vinyl-based viscous materials whose main component is vinyl acetate. The carrier supporting the drug-containing polymeric substance that holds the microcapsules in a dispersed state must be substantially impermeable to moisture, or have a moisture permeability level that does not cause side effects such as irritation or whitening of the skin or mucous membranes. It consists of designed films, sheets, foils, non-woven fabrics, etc. The drug content in the polymer material formed on the surface of the carrier varies depending on the type and amount of the drug absorption aid in the polymer material or microcapsules, but the drug amount is 0.05 to 50 mg/24 hours. It is preferable to carry it so that it is supplied to the skin or mucous membranes. The pharmaceutical component of the present invention essentially consists of a flexible carrier and a drug-containing polymer material layer formed thereon containing microcapsules encapsulating an absorption aid.
The surface of the layer is preferably coated with a flexible, moisture- and drug-impermeable release film such as a release-treated polyethylene terephthalate film. Then, the medical components are packaged individually or in bulk in a packaging material having excellent moisture impermeability, such as a composite of aluminum foil and plastic film, for transportation or storage. The pharmaceutical component of the present invention maintains the initial drug amount over a long period of time without being decomposed or modified during storage, and the microcapsules swell due to the supply of water and the drug An absorption aid is released, and the drug is delivered to the skin or mucous membrane without waste by the transfer of the aid. Examples of this invention will be shown below. The words "part of the text" indicate parts by weight. Example 1 95 parts of 2-ethylhexyl acrylate, 5 parts of acrylic acid, 0.3 parts of benzoyl peroxide, and 300 parts of ethyl acetate were copolymerized using a conventional method to prepare a copolymer, and an appropriate amount of dexamethasone was added to this to prepare a drug. Obtain a liquid containing a polymer substance. Per 100 parts of the solid content of the liquid, gelatin microcapsules of methyl octyl sulfoxide (average particle size 1 to 5 μ, solvent:substrate = 3:1 (weight ratio))
Blend 20 parts of this product, apply it on the release liner so that the coating thickness after drying is 50μ, and dry at 60℃ for 10 minutes.
The drug component of the present invention (drug content: 20 mg/cm ² ) is obtained by laminating it on a polyester film having a thickness of 12 μm. Example 2 Styrene-isoprene-styrene block copolymer rubber 100 parts, rosin resin (softening point 80°C) 80 parts
An appropriate amount of isosorbite dinitrate is added to a hot melt pressure-sensitive adhesive composition consisting of 40 parts of olive oil and 10 parts of polybutene. :substrate=3:1)
The pharmaceutical component of this invention (drug content 30mg/
cm ² ). Table 1 shows the test results of Examples 1 and 2.

[Table] In Table 1, Comparative Example 1a is the same as Example 1 without microcapsules, Comparative Example 2a is the same as Example 1 in which 20 parts of methyl octyl sulfoxide is blended alone into the drug-containing polymeric substance, and Comparative Example 1b is the same as Example 1 in which no microcapsules are mixed. In Example 2, no microcapsules are added,
2b is a mixture of dimethyl laurylamide alone in a drug-containing polymeric substance. Test method in Table 1 Adhesive strength: In a constant temperature room at 20°C x 65% RH, cut the sample into 12mm wide and 15cm long pieces, press them to a Bakelite board once with a 2kg load roll, and then age for 30 minutes. Peel adhesion strength was measured using a 180 degree peeling method using a constant speed shotter peel test (peeling speed: 300 mm/min). Holding power: Cut the sample into a piece 10 mm wide and 10 cm long, paste it on a Bakelite board with a pasting area of 2 cm long, apply a load of 300 g in the shearing direction, cause cohesive failure, and measure the time it takes for it to fall off at 40℃. Measured in a thermostatic chamber. Adhesive residue after application: Each sample was applied to the side of the lower arm, and when removed 24 hours later, it was visually observed whether adhesive remained on the skin. Remaining drug amount: Paste multiple 2 x 2 cm square samples on the rabbit hair removal site, peel them off 3 hours, 24 hours and 48 hours after the pasting time, and measure the amount of drug remaining in the samples using gas chromatography. It was quantified using tography and used as a measure of transdermal absorption. Pallor test: As a method to check the pharmacological effects of dexamethasone, there is a skin pallor test using capillary constriction.A sample is applied to the side of the upper arm, and after 3 hours, 24 hours, and 48 hours, the tape is removed, and 30 minutes later, the sample is applied to the side of the upper arm. The degree of pallor was determined by comparing it with a placebo. (Tests were conducted on 10 in-house volunteers) Pharmacological effects: The pharmacological testing method for isosorbite dinitrate was myocardial electrocardiography using an angina pectoris model from a coronary artery stenosis experiment in cynomolgus monkeys. Coronary blood flow is reduced to 1/2 of normal due to stenosis, and pacing in the stenotic state → pasting a sample with ST changes on the electrocardiogram (chest hair removal area) → the above ST changes disappear due to pharmacological effects ST changes disappear in the myocardial electrocardiogram Each sample was tested 5 times using the pharmacological testing method of 1999, and the number of times that clearly disappeared ST changes was shown.

Claims (1)

[Claims] 1 It is composed of a drug-containing polymer material layer containing dispersed microcapsules encapsulating a drug absorption aid, and a flexible carrier formed on the surface of one of the layers, and the microcapsules are is a medical component composed of a matrix that swells with the supply of moisture and becomes permeable to an auxiliary agent.