JPS6242919A - Pharmaceutical member for external use - Google Patents

Abstract

PURPOSE:To obtain a pharmaceutical member for external use capable of suppressing the photooxidation of a drug without deteriorating the drug effect, by incorporating a photooxidizable drug and an oxidizing agent in a pressure- sensitive adhesive to form a drug-containing base layer and laminating the above-mentioned base layer to a carrier body and release body to nip the base layer therewith. CONSTITUTION:A pharmaceutical member for external use obtained by incorporating a photooxidizable drug. e.g. steroid, diazepam or nifedipine and an antioxidant, e.g. ascorbic acid or beta-carotene, in a pressure-sensitive adhesive having tackiness at ordinary temperature, e.g. polymer of alkyl (meth)acrylate or silicone rubber, to form a drug-containing base layer, coating the above-mentioned base layer so that the base layer may be preferably nipped with a light-shielding carrier body and a release body. The photooxidation of the drug can be remarkably suppressed by the antioxidant and the deterioration in drug effect during the production, use and handling can be prevented.

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention relates to a medicinal component for external use that has improved stability against photo-oxidation.

(b) Prior art In recent years, a drug-containing base layer is formed by incorporating a drug into a pressure-sensitive adhesive layer, and the base layer is attached to the skin to allow the drug to be continuously absorbed from the skin. Research on disease treatment components (external medicinal components) has been actively conducted, and many proposals have been made to improve their transdermal absorption (for example,
JP-A-58-79918, etc.).

However, in general, some of the above-mentioned drugs are unstable to light; for example, dihydropyridine calcium antagonists such as Nianidivine can be 80% of their original state after being irradiated with indoor scattered light for an extremely short period of about 10 minutes. The degree of photooxidative decomposition.

Therefore, if the product is left for a short period of time during the manufacturing process, or if the drug is exposed to light when handled by the user, there is a risk that the drug will undergo photo-oxidative decomposition, resulting in product defects or a decrease in drug efficacy. Therefore, with regard to this type of external medicinal components, there is an urgent need to promote stabilization of the product against photooxidation, as well as to improve transdermal absorption.

For this reason, it has been proposed to place the above-mentioned external medical components in aluminum packaging materials to prevent the effects of light.
In this case, the product cost becomes extremely high, and as a result of being directly exposed to the effects of photooxidation 9 after opening, problems similar to those described above occur.

Therefore, in order to suppress photooxidation (including photodegradation or photodegradation) of drugs and/or pressure-sensitive adhesives, it has recently been proposed to form carriers in pharmaceutical parts for dispensing with light-shielding materials. ing.

(c) Problems to be Solved by the Invention However, in the topical medicinal member described in Section 1, the carrier is only formed of a light-shielding material.In other words, the carrier is formed in the drug-containing base layer described in Section 2. Since the drug-containing base layer is covered with a light-shielding carrier only when it is laminated, the carrier was peeled off from this base layer before laminating the light-shielding carrier on the base J. In this case, as a result of light entering from the exposed surface side of the base layer, it was not possible to reliably prevent the adverse effects of light on the base layer.

(d) Means for Solving the Problems Therefore, the inventors of the present invention have made extensive studies to solve the above-mentioned problem. In order to complete the present invention, we discovered that 1) Inactivation occurs in a short period of time, and 2α, which reduces drug efficacy, and photooxidation can be suppressed by incorporating a special antioxidant into the drug-containing base layer. This is what we have come to.

That is, the present invention involves forming a drug-containing base layer by incorporating a photo-oxidizing drug and an antioxidant IL agent that suppresses photo-oxidation into a pressure-sensitive adhesive that is sticky at room temperature, and forming a drug-containing base layer. It is characterized by being laminated so as to be sandwiched between a carrier and a peeling body.

Hereinafter, the present invention will be explained in detail.

The pressure-sensitive adhesive used in the present invention is not particularly limited as long as it is commonly used and exhibits tackiness at room temperature, such as (meth)acrylic acid ethyl ester, (meth)acrylic acid Butyl ester, (meth)acrylic acid hexyl ester, (meth)acrylic acid-2-
Ethyl butyl ester, (meth)acrylic acid-2-ethylhexyl ester, (meth)acrylic acid isooctyl ester, (meth)acrylic acid nonyl ester, (meth)acrylic acid undecyl ester, (meth)acrylic acid dodecyl ester, (meth)acrylic acid dodecyl ester, ) Homopolymers of (meth)acrylic acid alkyl esters such as acrylic stearyl ester and/or (meth)acrylic acid, itaconic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, and acrylic acid which can be copolymerized with the ester. Hydroxypropyl acid, methoxyethyl (meth)acrylate, ethoxyethyl (meth)acrylate, butoxyethyl acrylate,
(meth)acrylamide, dimethylacrylamide,
In addition to copolymers such as 1-butylacrylamide, trimethylaminoethyl (meth)acrylate, t-butylaminoethyl (meth)acrylate, ac-17Cl2), vinylpyrrolidone, and vinylimiguzole, Examples of the vinylistermo/mer include copolymers with vinyl acetate, vinyl propionate, and the like.

Other examples of the pressure-sensitive adhesives include silicone rubber, polyisoprene rubber, polyisobutylene rubber, styrene-isoprene (or butadiene)-styrene block copolymer rubber, styrene-butadiene copolymer rubber, and acrylic rubber. Rubber-based pressure-sensitive adhesives whose main ingredients include , natural gono, etc.; vinyl-based pressure-sensitive adhesives whose main ingredients include polyvinyl alkyl ether (alkyl group has 1 to 12 carbon atoms), polyvinyl alcohol, polyvinyl acetate, etc. Examples include adhesives.

The above-mentioned photo-oxidative drugs are drugs that are absorbed transdermally into the body when the preparation is applied to the skin, are oxidized and decomposed by light, and are inactivated in a short time. In other words, it is not particularly limited as long as its medicinal efficacy decreases in a short period of time.

Specifically, these include steroids, benzodiazepines such as diazepam, nohydrobiridine calcium antagonists such as nianizibine and nivazibine, and dibucaine hydrochloride which is an anesthetic. It is directly affected by photo-oxidation and becomes inactivated in a short period of time.

The blending ratio of drug (B) to the pressure-sensitive adhesive (A) is 0 to the total weight of (A) and (B).
．． It is best to adjust it within the range of 1 to 30% by weight, preferably 20% by weight to O02.If it is less than 0.1% by weight, there is almost no therapeutic effect, while if it exceeds 30% by weight, there is a limit to the therapeutic effect. This is economically disadvantageous because crystals are precipitated and difficult to absorb through the skin.

The most significant feature of the present invention is that an antioxidant is added to (A) and (B) in -J2.

The antioxidant 1 agent used in the present invention is one that prevents a decomposition reaction from occurring even when the photooxidizing drug is irradiated with light, such as ascorbic acid, sodium ascorbate, and β. - In addition to carotene, examples include carotenoids such as xanthophylls. The higher the content of these antioxidant TFZ agents, the more pronounced the effect will be. 30% by weight, preferably in the range of 0.2 to 20% by weight, and 0.
．． If it is less than 1% by weight, a sufficient antioxidant effect will not be obtained, while if it is less than 30% by weight, the adhesive strength of the drug-containing base layer will decrease, and the shape retention and cohesive force of the base layer will deteriorate. Moreover, it is economically disadvantageous.

The carrier and release body used in the present invention may be light-transmissive, but in order to exhibit a remarkable antioxidant effect for a long time, both sides of the drug-containing base layer should be used. It is most desirable to sandwich and coat the two layers between a light-shielding carrier and a release material.

Examples of carriers to be subjected to light-shielding treatment include polyvinyl chloride, polyethylene, polypropylene, polyethylene terephthalate, polyethylene-polyvinyl acetate laminate, polyethylene tere-7-thalerate-polyvinyl acetate laminate, polycarbonate, polyacetate, polyacrylic ester, polysulfone, and cellulose. Examples include a film or sheet made of ester or the like, cloth, nonwoven fabric, paper, and the like.

Then, the above-mentioned carrier is made with holes, cuts, etc. by physical or chemical methods to prevent itching, inflammation, etc.
Even if J:<, the carrier has at least 1
0%, preferably 50% or more, practically 100-8
It is preferable to select a material with 00% elasticity or use a material that has been subjected to an elastic process so that the -I base does not peel off in conjunction with the expansion and contraction of the skin.

As the release body, a material similar to that of the carrier mentioned in "2" can be used, and this material can be subjected to a release treatment by a conventionally known method.

Examples of the peeling treatment include treatment with silicone, Teflon, Poval, and the like. Furthermore, a film or sheet made of polyethylene or the like described in 1. may be subjected to an uneven treatment in order to promote light scattering and reduce light transmittance.

The method described below is preferably employed as a method for applying light-shielding treatment to the above-mentioned carrier and peeling body.

(2) The first method is a method in which a metal thin film layer is formed on one or both sides of the above-mentioned carrier and release body.

Examples of the metal include aluminum, silver, gold, copper, etc., and aluminum is preferred because it is inexpensive and chemically stable.

Supporting standard (r'4i11,!'
, j1. ', ''''''The method for forming the film layer is to attach it to a holder, etc., or to apply I-Formulation 1/IS to a battering method. The metal thin film may be formed by ion blating, vacuum evaporation, or other known vacuum metal evaporation methods, and/or other methods such as electroless plating may be employed.

The thickness of the metal thin film layer may be as long as it can sufficiently exhibit the light-shielding function.In other words, in order to suppress the photo-oxidation reaction of the drug, 80 or more people are required, and preferably The thickness is preferably 100 Å or more.

(2) Method t52 involves adding a filler that imparts light-shielding properties to the materials forming the carrier and the release body.

In this method, firstly, fine carbon powder or fine metal powder is added and mixed into the distributing material, and the conventionally known Karen Goo method is used.
The light-shielding film may be manufactured by employing a method most suitable for the material used, such as an extrusion method, an inflation method, a T-Guy method, a solution method, or a rolling method.

Another method is to add a dye to the above-mentioned material, and make the dye absorb light with a wavelength that decomposes the drug.

The blending ratio of the above-mentioned material and the dye is appropriately determined depending on the stability of the drug used.

(2) The third method is to print an ink that absorbs and reflects light at a wavelength that decomposes the drug on the film or sheet that forms the carrier and the release body.

When the light-shielding carrier and peeling body are irradiated with light of a wavelength that decomposes each drug, the transmittance thereof is 40%.
The following are preferred, particularly 20% or less.

In the present invention, in order to improve the transdermal absorption of the drug in the drug-containing base layer, drug solubility and drug absorption promoting aids such as keratin softeners are added to the base layer. It may be added.

Examples of this type of auxiliary agent include lower alcohols such as ethanol, glyfurs such as ethylene glycol, triethylene glycol, polyethylene glycol, and propylene glycol, polyhydric alcohols such as glycerin and sorbitol, urea, dimethyl sulfoxide, trimethylacetamide, and Examples include methylformamide, diethyl sebacate, propylene carbonate, imigzolidin derivatives, N-methyl-2-pyrrolidone, and various surfactants, and at least one of these is added.

"2 drug-containing base (8) and the drug absorption promoting agent (B)
The mixing ratio of (B) is preferably in the range of 0.5 to 20% by weight based on the total weight of (A) and (B), and less than 0.5% by weight. If it exceeds 20% by weight, problems will arise in skin adhesion, cohesive force, etc., which is not preferable.

Next, to briefly explain the manufacturing method of the external medical component of the present invention, the external medical component is prepared by adding a photo-oxidizing drug and an oxidizing agent that suppresses photo-oxidation to the above-mentioned pressure-sensitive adhesive that is sticky at room temperature. Adding an inhibitor and, if desired, the above-mentioned transdermal absorption promoting aid,
After mixing to form a drug-containing base, the base is laminated to one side of the carrier, or a pressure-sensitive adhesive layer is laminated to the carrier, and then the drug, antioxidant, and optionally A drug-containing base layer is formed by dissolving each of the above-mentioned auxiliary substances such as the transdermal absorption promoting aid in an appropriate solvent, applying the solution to the surface of the pressure-sensitive adhesive layer, and drying it. In the layer, the release body is laminated on the side opposite to the blade side on which the carrier is laminated, or in other words, the drug-containing base layer is laminated so as to be sandwiched between the carrier and the release body.

(e) The photooxidation reaction between active drugs and oxygen (air) takes place through an extremely complex mechanism that is not yet completely understood, but both the drug and oxygen are excited in a short period of time due to the absorption of light. The interaction between these two generates free radicals, and the drug is oxidized in a short time due to the action of these free radicals, or the drug absorbs light and is excited in a short time, and this excited drug It is presumed that the oxygen in the drug-containing base is immediately activated, and the activated oxygen oxidizes the drug in a short period of time.

However, the antioxidant used in the present invention prevents the excitation of drugs and oxygen, or immediately annihilates the 7-reelanocal generated by photochemical reactions, and as a result, the stability against light is essentially improved. It is understood that it has an effect.

(f) Examples The present invention will be explained in more detail by Examples below, but the present invention is not limited to these Examples, and various modifications may be made without departing from the technical idea of the present invention. Application is possible.

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

Example 1 To a monomer mixture consisting of 80 parts of isononyl acrylate and 20 parts of acrylic acid, 0.2 part of azobisin butyronitrile was added as a polymerization initiator, and the mixture was diluted with 65 parts of azobisin butyronitrile in ethyl acetate.
The temperature was raised to 80°C to polymerize and react for about 8 hours, and then the temperature was further raised to 80°C and aged for 2 hours to obtain a temperature-sensitive adhesive solution that was sticky at room temperature.

Next, 10% diazepam, a tranquilizer, was added to the total solid concentration of the pressure-sensitive adhesive solution obtained in this way.
, and ascorbic acid, which is an antioxidant, were added and mixed at a concentration of 15% to prepare a drug-containing base solution.

This drug-containing base solution was coated on a polyethylene film support to a dry thickness of 40 μm and dried to form a drug-containing base layer.

Next, a peelable body was laminated on the exposed surface of the drug-containing base layer to obtain a medicinal member for external use having a structure in which the drug-containing base layer was sandwiched between a carrier and a peelable body.

Example 2 A monomer mixture consisting of 60 parts of 2-ethylhexyl acrylate, 20 parts of 2-ethoxyethyl acrylate, and 20 parts of vinyl acetate was mixed with 0.2 parts of azobisisobutyronitrile in ethyl acetate. Under the same conditions as in Example 1, a pressure-sensitive adhesive solution having tackiness at room temperature was obtained.

Next, nivazibin, an antihypertensive agent, and β-carotene, an antioxidant, were added to the pressure-sensitive adhesive solution at 5% and 10%, respectively, based on the total solid concentration. A drug-containing base solution was prepared.

As a light-shielding carrier, a red polyethylene film with a thickness of 50 μm and a transmittance of light (wavelength: 40 mm) of 0.05% was used, and on one side of the carrier, a drug-containing base solution was added. was coated and dried to a thickness of 50 μm after drying to form a drug-containing base layer, and then the same procedure as in Example 1 was carried out using aluminum vapor-deposited paper with a thickness of 200 mm as a light-shielding release body. A medical component for external use was obtained.

Comparative Examples 1 and 2 In Comparative Examples 1 and 2, the samples of Examples 1 and 2 above were prepared without adding an antioxidant.

Test method Each sample of the above Examples and Comparative Examples was cut into 10c+n squares, the release paper was peeled off from this test piece to expose the drug-containing base layer, and the test piece with one side exposed was directly placed on the exposed surface indoors. It was installed so as to be exposed to scattered light, the drug content before irradiation was set as 100%, and the drug content after the irradiation time shown in Table 1 was quantified by gas chromatography.

The results are shown in Table 1.

From Table 1 and Table 11, it can be seen that even when the drug-containing base layer of the externally used pharmaceutical member of the present invention is exposed, the photo-oxidation of the drug is significantly suppressed by the antioxidant in the base layer compared to the comparative example. It is recognized that there are

(g> Effects of the Invention The external medicinal member of the present invention has a drug-containing base layer formed by adding a photo-oxidizing drug and an antioxidant that suppresses photo-oxidation to a pressure-sensitive adhesive that is sticky at room temperature. are laminated so as to be sandwiched between a carrier and a release body to cover the drug-containing base layer. Drugs are inactivated by exposure to light during production, use, or handling.
In other words, it is possible to prevent the decline in drug efficacy as much as possible, and as a result, there are fewer defective products during the manufacturing process.
In addition, users can use it with peace of mind and the handling is easy.
Ail becomes easier.

In particular, if the carrier and release body of external medicinal components are formed of a light-shielding film or sheet, the stability of the drug against photooxidation is further improved, so that the external medicinal components will remain stable against light for a long period of time. It has medicinal effects.

Claims (3)

[Claims] (1) Form a drug-containing base layer by incorporating a photo-oxidizing drug and an antioxidant that suppresses photo-oxidation into a pressure-sensitive adhesive that is sticky at room temperature, and apply the drug-containing base layer to a carrier. 1. A medicinal component for external use, characterized in that it is laminated in such a way as to be sandwiched between a peelable body and a peelable body. (2) A pharmaceutical component for external use, characterized in that the antioxidant is at least one selected from ascorbic acid, sodium ascorbate, carotenoids, and derivatives thereof. (3) A medicinal component for external use, characterized in that the carrier and/or the release body are light-shielding.