JP2967788B2 - Medical adhesive tape and tape preparation for disease treatment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a medical pressure-sensitive adhesive tape which is used by being attached to a skin surface
And a tape preparation for treating a disease for continuously administering a drug into a living body through the skin.

<Related Art> In recent years, as a preparation for treating or preventing a disease by administering a drug to a living body, drug metabolism due to the first-pass effect of the liver and various side effects can be prevented, and the drug is continuously administered for a long time. Attention has been focused on transdermal preparations that can be administered to the skin. In particular, tape preparations in which a drug is contained in an adhesive have been actively developed because the administration operation is easy and the dosage can be strictly controlled.

Since the pressure-sensitive adhesive layer constituting such a tape preparation is adhered to the skin surface, the drug content in the pressure-sensitive adhesive is prevented from lowering (drug stability), the drug is released from the pressure-sensitive adhesive, It is required to satisfy various properties such as adhesion (skin adhesion), appropriate cohesion for eliminating adhesive residue on the skin surface, and non-irritating property to the skin. In other words, when developing a tape formulation, it is necessary to study the chemical and physical properties of the adhesive used, study the chemical properties of the drug contained in the adhesive, and study the interaction of these combinations. It is important that almost no tape preparations satisfying all the above-mentioned required properties have been obtained.

In general, the stability of a drug in a tape preparation is easily affected by the amount of the functional group in the pressure-sensitive adhesive, but it is difficult for a pressure-sensitive adhesive having no functional group to exhibit good skin adhesion. Further, from the viewpoint of transdermal absorption, it is preferable to use a drug having a free structure rather than a drug having a salt structure, but such a drug is inferior in release property due to being trapped by a functional group in an adhesive or sometimes a drug. Stability may be adversely affected.

<Problems to be Solved by the Invention> Accordingly, an object of the present invention is to provide a medical adhesive tape having good skin adhesiveness and low skin irritation, and another object is to provide such an adhesive tape. An object of the present invention is to provide a tape preparation for treating a disease in which a drug is contained, whereby the stability and release of the drug are improved.

<Means for Solving the Problems> The inventors of the present invention have conducted intensive studies in order to achieve the above object, and as a result, a monomer containing a carboxyl group and / or a hydroxyl group as a functional group was converted to a conventional adhesive. By copolymerizing in an amount smaller than the amount used for the agent, and crosslinking by utilizing this functional group at the crosslinking point, it exhibits excellent skin adhesion with a balance between cohesion and skin adhesion, It has been found that a medical adhesive tape with little skin irritation can be obtained. Furthermore, they have found that a tape preparation containing a drug in the adhesive can exhibit excellent drug stability and release properties, and have completed the present invention.

That is, the present invention provides a pressure-sensitive adhesive tape having a cross-linkable pressure-sensitive adhesive layer provided on a flexible support, wherein the cross-linkable pressure-sensitive adhesive layer has an alkyl group having 4 to 12 carbon atoms (alkyl) (meth) acrylate, or 99 to 99.9% by weight of a mixture of the ester and an alkoxyalkyl (meth) acrylate having at least one group selected from methoxy, ethoxy and methoxyethylene glycol groups, and (meth)
Acrylic acid, (iso) crotonic acid, fumaric acid, (anhydride) maleic acid, itaconic acid, (meth) acrylic acid hydroxyethyl ester, (meth) acrylic acid hydroxypropyl ester, at least one carboxyl group and / or A medical pressure-sensitive adhesive tape comprising a cross-linked product of a copolymer with 0.1 to 1% by weight of a hydroxyl group-containing monomer, and a cross-linkable pressure-sensitive adhesive layer of the medical pressure-sensitive adhesive tape containing a drug. Disclosed is a tape preparation for treating a disease.

The support used for the medical pressure-sensitive adhesive tape and tape preparation of the present invention is not particularly limited as long as it has flexibility, but the drug contained in the pressure-sensitive adhesive layer passes through the support and is lost from the back surface. Which do not cause a decrease in content,
That is, a material made of a drug-impermeable material is preferable. Specifically, polyester, nylon, Saran, polyethylene, polypropylene, ethylene-vinyl acetate copolymer,
A single film such as polyvinyl chloride, ethylene-ethyl acrylate copolymer, polytetrafluoroethylene, Surlyn, metal foil, or a laminated film thereof can be appropriately used depending on the drug type.

In the present invention, the cross-linkable pressure-sensitive adhesive layer formed on the support includes an alkyl (meth) acrylate or a mixture of the ester and an alkoxyalkyl (meth) acrylate, a carboxyl group and / or a hydroxyl group. A crosslinked product of a copolymer with the contained monomer is included.

Alkyl (meth) acrylate is a monomer that is a main component for forming a pressure-sensitive adhesive, and is a component that mainly provides skin adhesion, and is preferably an alkyl group (chain alkyl group and cyclic alkyl group). ) Has 18 carbon atoms
In the following, one or more of the compounds in the range of 4 to 12 are preferably used. In the present invention, these alkyl (meth) acrylates are copolymerized in the range of 99 to 99.9% by weight, preferably 99.2 to 99.7% by weight. Further, it is preferable to copolymerize the alkyl (meth) acrylate having 3 or less carbon atoms in the alkyl group in the range of 30% by weight or less of the alkyl ester, because the cohesive force of the pressure-sensitive adhesive layer is further improved. Things.

The (meth) acrylic acid alkoxyalkyl ester is obtained by modifying the (meth) acrylic acid alkyl ester with an alkoxy group such as a methoxy group or an ethoxy group. Specifically, (meth) acrylic acid methoxyethyl ester, (Meth) acrylic acid ethoxyethyl ester,
(Meth) acrylic acid methoxyethylene glycol ester and the like, and are mixed with the above (meth) acrylic acid alkyl ester in a range not exceeding 50% by weight, and 99 to 99.9% by weight as a mixture, preferably 99.2 to 99.7% by weight. Copolymerization within the range is preferable since it becomes an adhesive having properties such as skin adhesion, drug solubility and drug stability in a well-balanced manner.

On the other hand, the carboxyl group and / or hydroxyl group-containing monomer provides a functional group as a reaction point with a cross-linking agent described below, and includes hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate. One or more of ester, (meth) acrylic acid, (iso) crotonic acid, fumaric acid, (anhydride) maleic acid, and itaconic acid are used. The copolymerization amount is 0.1-1
% By weight, preferably in the range of 0.3 to 0.8% by weight. 0.1
When the amount is less than 10% by weight, the amount of the functional group as a crosslinking point for imparting cohesive strength is insufficient, and when the amount exceeds 1% by weight, the amount of the functional group remaining in the adhesive after the crosslinking reaction increases, It may increase skin irritation and adversely affect the stability and release of the contained drug.

Further, in copolymerizing the above monomers, copolymerizable monomers such as vinyl acetate, styrene, phenyl (meth) acrylate, N-vinylpyrrolidone, and diacetone acrylamide do not impair the effects of the present invention. It is also possible to replace these monomers with a range, for example 30% by weight of the amount of said alkyl (meth) acrylate. By copolymerizing these monomers, improvement in the solubility of the drug and the cohesive force of the pressure-sensitive adhesive layer can be expected.

The pressure-sensitive adhesive layer constituting the pressure-sensitive adhesive tape or tape preparation for medical use of the present invention is provided with a cohesive force by subjecting a copolymer obtained by copolymerizing the above monomers to a crosslinking treatment. Crosslinking treatment is physical crosslinking by irradiation such as ultraviolet irradiation or electron beam irradiation, polyisocyanate compound, organic peroxide,
Organic metal salts, metal alcoholates, metal chelate compounds,
For example, a chemical crosslinking treatment using a crosslinking agent such as a polyfunctional compound is used. When irradiation or organic peroxides are used among these crosslinking means, a decomposition reaction may occur depending on the type of drug, and highly reactive isocyanates, metal salts and organic metals used in ordinary crosslinking reactions may be used. In the case of a salt, a phenomenon of thickening of the solution occurs after blending, which may result in poor workability. A method of preliminarily blending a polyfunctional monomer such as diacrylate with a monomer for copolymerization and copolymerizing the monomer is also conceivable, but also in this case, the solution viscosity may increase. Therefore, in the present invention, trifunctional isocyanate,
A metal alcoholate or metal chelate compound of titanium or aluminum, particularly a metal chelate compound, is suitable. These crosslinking agents do not cause a thickening phenomenon of the solution until coating and drying, and are extremely excellent in workability. In this case, the amount of the crosslinking agent is 0.1 to 1 part by weight, preferably about 0.2 to 0.8 part by weight, based on 100 parts by weight of the copolymer.

In the present invention, the crosslinked pressure-sensitive adhesive layer obtained as described above is provided on a support to form a medical pressure-sensitive adhesive tape, or a drug is contained in the crosslinked pressure-sensitive adhesive layer to treat a disease. It can be a tape preparation. The drug used in the tape preparation for treating a disease can be arbitrarily selected depending on the purpose of the treatment or prevention. , Skeletal muscle relaxants, antispasmodics, antiparkinson drugs, antihistamines, cardiotonic drugs, arrhythmic drugs, antihypertensive drugs, vasoconstrictors, coronary vasodilators, peripheral vasodilators, other cardiovascular drugs, respiratory stimulants , Antitussive expectorants, various hormones, topical drugs for purulent diseases, analgesic / pruritus / astringent / anti-inflammatory drugs, drugs for parasitic skin diseases, various vitamins, hemostats, anticoagulants, antidote / habitants Addiction medicine, diabetes medicine,
Drugs that exhibit pharmacological actions such as antineoplastic drugs and narcotics, and these drugs can be used in combination of two or more as necessary. From the viewpoint of uniform dispersibility (solubility) in the crosslinked pressure-sensitive adhesive layer and percutaneous absorption, it is preferable to use a drug having a free base structure, and the content may be a pharmacologically effective amount. It can be set as appropriate according to the purpose and the like.

The medical pressure-sensitive adhesive tape or disease-treating tape preparation of the present invention includes polyethylene glycol, lanolin, olive oil, in order to improve the adhesive strength and the transdermal absorbability of a drug.
Auxiliary substances such as silicone oil, urea, dimethyl sulfoxide, dimethylformamide, diisopropyl adipate, isopropyl myristate, and terpene resin are used in a range that does not inhibit the stability and release of the drug, for example, 1 to 60% by weight in the cross-linked adhesive layer, Preferably, it can be blended in the range of 5 to 50% by weight.

<Effects of the Invention> As described above, the pressure-sensitive adhesive layer of the medical pressure-sensitive adhesive tape and the disease-treating tape preparation of the present invention has a smaller amount of a carboxyl group- and / or hydroxyl group-containing monomer than a conventional pressure-sensitive adhesive. Since it is polymerized and cross-linked, it exerts the effect of maintaining skin adhesiveness and cohesiveness and reducing skin irritation.

Further, in the tape preparation for treating a disease, the stability of the drug is good, and the drug release property is practically satisfactory.

<Example> An example of the present invention will be shown below, and will be described more specifically. In the following, parts and% mean parts by weight and% by weight, respectively.

Example 1 Isononyl acrylate under an inert gas atmosphere
99.5 parts and 0.5 part of acrylic acid were copolymerized in ethyl acetate to prepare a copolymer solution.

90 parts of the solid content of this solution was mixed with 10 parts of metoprolol, and 0.3 part of ethyl acetoacetate aluminum diisopropylate was added as a 10% acetylacetone solution.

The obtained solution was applied to one side of a 12 μm-thick polyethylene terephthalate film so that the thickness after drying was 80 μm, and dried to obtain a tape preparation for treating a disease of the present invention.

Comparative Example 1 A copolymer solution was prepared using a monomer mixture consisting of 90 parts of isononyl acrylate and 10 parts of acrylic acid.
A tape preparation was obtained in the same manner as in Example 1 except that an uncrosslinked pressure-sensitive adhesive layer was formed without adding ethyl acetoacetate aluminum diisopropylate as a crosslinking agent.

Comparative Example 2 A tape preparation was obtained in the same manner as in Example 1, except that an uncrosslinked pressure-sensitive adhesive layer was formed without adding ethylacetoacetate aluminum diisopropylate as a crosslinking agent.

Example 2 Under an inert gas atmosphere, 99 parts of acrylic acid isooctyl ester and acrylic acid 2-hydroxyethyl ester 1
Parts were copolymerized in ethyl acetate to prepare a copolymer solution.

90 parts of the solid content of this solution was mixed with 10 parts of scopolamine,
Furthermore, aluminum tris (acetylacetonate) 0.
Three parts were added as a 10% acetylacetone solution.

The obtained solution was applied on one surface of a polyethylene terephthalate film having a thickness of 9 μm so that the thickness after drying was 60 μm, and dried to obtain a tape preparation for treating a disease of the present invention.

Comparative Example 3 A tape preparation was obtained in the same manner as in Example 2, except that an uncrosslinked pressure-sensitive adhesive layer was formed without adding aluminum tris (acetylacetonate) as a crosslinking agent.

Comparative Example 4 A copolymer solution was prepared using a monomer mixture consisting of 70 parts of isooctyl acrylate and 30 parts of N-vinylpyrrolidone, and aluminum tris (acetylacetonate) as a crosslinking agent was added for crosslinking. A tape preparation was obtained in the same manner as in Example 2 except that a pressure-sensitive adhesive layer was formed.

Example 3 n-butyl acrylate under an inert gas atmosphere
89.5 parts, 10 parts of methacrylic acid methyl ester, and 0.5 part of acrylic acid were copolymerized in ethyl acetate to prepare a copolymer solution.

7.5 parts of bunitrolol was mixed with 92.5 parts of the solid content of this solution, and 0.3 part of ethyl acetoacetate titanium diisopropylate was further added as a 10% acetylacetone solution.

The obtained solution was applied on one side of a polyethylene terephthalate film having a thickness of 9 μm so that the thickness after drying became 100 μm, and dried to obtain a tape preparation for treating a disease of the present invention.

Comparative Example 5 A copolymer solution was prepared using a monomer mixture composed of 87 parts of n-butyl acrylate, 10 parts of methacrylic acid methyl ester, and 3 parts of acrylic acid, and ethyl acetoacetate titanium diisopropylate was used as a crosslinking agent. Example 3 except that an uncrosslinked pressure-sensitive adhesive layer was formed without adding a rate.
A tape preparation was obtained in the same manner as described above.

Comparative Example 6 A tape preparation was obtained in the same manner as in Example 3, except that an uncrosslinked pressure-sensitive adhesive layer was formed without adding ethylacetoacetate titanium diisopropylate as a crosslinking agent.

Each property of the tape preparation obtained in each of the above Examples and Comparative Examples was measured by the following methods.

Example 4 Under an inert gas atmosphere, 64.25 parts of 2-ethylhexyl acrylate, 25 parts of 2-methoxyethyl acrylate, 10 parts of methyl methacrylate, and 0.75 part of acrylic acid were copolymerized in ethyl acetate. Thus, a copolymer solution was prepared.

90 parts of the solid content of this solution was mixed with 10 parts of l-methoprolol, and 0.4 part of ethyl acetoacetate aluminum diisopropylate was added as a 5% acetylacetone solution.

The obtained solution was applied to one side of a 12 μm-thick polyethylene terephthalate film so that the thickness after drying was 80 μm, and dried to obtain a tape preparation for treating a disease of the present invention.

(Drug stability over time)

The samples obtained in each of the Examples and Comparative Examples were 5 cm × 4 cm
, And stored under a temperature condition of 40 ° C, the drug content before and after storage was measured, and the residual drug amount was measured. The quantification was performed by high performance liquid chromatography.

 The results are shown in Table 1.

(Skin adhesion)

The samples obtained in each of the examples and comparative examples were cut into a size of 30 mmφ, adhered to the inner side of a human upper arm, and 24 hours later, the state of adhesion to the skin and the phenomenon of adhesive residue at the time of peeling were visually determined.

Judgment was made based on the following criteria, and the average value of five persons was determined.
The results are shown in Table 1.

 ：: 90% or more of the affixed area is adhered, and no glue remains.

 △: 〃 50-90% adhered, 〃.

×: 未 満 Less than 50% adhered or much adhesive residue.

(Drug release)

The samples obtained in the respective Examples, Comparative Examples 1 and 5 were cut into a size of 5 cm × 5 cm, and subjected to a water release test according to the Japan Petr method.

 The results are shown in FIG.

As is clear from Table 1 and FIG. 1, the tape preparation for treating a disease of the present invention satisfies drug stability, skin adhesion and drug release. Further, when the skin irritation of each of the products of Examples was observed after the skin adhesion test, the skin irritation was extremely low.

In each of the above Examples, although a drug was contained, when a medical adhesive tape was prepared by removing the drug from each Example, skin adhesion and skin irritation showed the same results as those of the Example product. .

[Brief description of the drawings]

FIG. 1 is a graph showing the results of an in-water release test of a drug from the tape preparation obtained in each of Examples, Comparative Examples 1 and 5.

 ──────────────────────────────────────────────────続 き Continuing on the front page Jury President Yasuo Yoshimura Judge Hiroshi Fukatsu Judge Shinichi Naito

Claims (3)

(57) [Claims] 1. A pressure-sensitive adhesive tape having a cross-linkable pressure-sensitive adhesive layer provided on a flexible support, wherein the cross-linkable pressure-sensitive adhesive layer is an alkyl (meth) acrylate having an alkyl group having 4 to 12 carbon atoms, or The ester and a methoxy group, an ethoxy group,
99 to 99.9% by weight of a mixture with a (meth) acrylic acid alkoxyalkyl ester having at least one group selected from methoxyethylene glycol groups, and (meth) acrylic acid, (iso) crotonic acid, fumaric acid, and (maleic anhydride) Acid, itaconic acid, (meth) acrylic acid hydroxyethyl ester, (meth) acrylic acid hydroxypropyl ester
A pressure-sensitive adhesive tape for medical use, comprising a crosslinked product of 1% by weight to 1% by weight of a copolymer. 2. The medical pressure-sensitive adhesive tape according to claim 1, wherein the crosslinked product is a crosslinked product of a metal chelate compound. 3. A tape preparation for treating a disease, wherein the cross-linkable pressure-sensitive adhesive layer of the medical pressure-sensitive adhesive tape according to claim 1 or 2 contains a drug.