JPH03112557A - Application agent - Google Patents

Abstract

PURPOSE:To improve the properties of application on a skin by using a (meth) acrylic ester polymer as a main adhesive, crosslinking at least a part of the polymer with an irradiation of electron beam and specifying the glass transition temperature, the holding force value and the adhesion value of the adhesive layer after crosslinking. CONSTITUTION:An application agent is prepared such that an adhesive layer containing an adhesive and a drug is formed on a backing support, the adhesive consists mainly of a (meth)acrylic ester polymer, and through an irradiation of the adhesive with electron beam, at least a part of the polymer is crosslinked. A glass transition temperature (Tg) of the adhesive after crosslinking is below -71 deg.C, and a holding force value (H) and an adhesion value (F) of the adhesive layer satisfy a relation of a formula (I). In this case, by adding a softening agent having a Tg reducing effect on the (meth)acrylic alkylester polymer having the Tg of -71 deg.C or higher, the adhesive having the Tg of -71 deg.C or lower is prepared. Further, the amount of irradiation with electron beams is usually set to a range of 1-50 mega rad.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a patch in which a large amount of a drug is dissolved and is provided with an adhesive layer that has a high drug release property. The adhesive layer of this patch has excellent adhesion to the skin and a good balance between adhesiveness and cohesiveness.

(Prior Art) Many patches have been proposed for a long time, which are applied to the skin by utilizing the adhesive properties of an adhesive containing a drug to exert the medicinal effects of the drug. This type of patch generally consists of a backing support layer and an adhesive layer containing an adhesive and a drug. The drug exists in the adhesive layer in a dissolved state, a dispersed state, a dispersed state in microcapsules, a state enclosed in a septum container, or the like. Examples of such patches include Patches for the treatment of skin diseases consisting of an adhesive layer and a base material containing an anti-inflammatory cortiph steroid and a specific acrylic copolymer; (Japanese Patent Publication No. 52-31405, Eli.
Lilly Corporation), a medical bandage having a backing member and a pressure-sensitive adhesive layer, and further provided with a drug storage layer (Special Publication No. 54-1)
No. 6566, Stephen David Goldby), a pharmaceutical component comprising a carrier and a drug-containing adhesive layer mainly composed of a specific acrylic ester copolymer (
JP-A No. 56-45412, Nitto Denko Corporation), and a base containing a polymer having a glass transition temperature (Tg) of -70°C to -10''C and propyl nitrate is formed on a support. (Japanese Unexamined Patent Publication No. 57-183714, Nitto Denko Co., Ltd.).

However, the physical properties of the adhesive used in these patches are similar to those used in other conventional adhesive tapes (e.g., general stationery tape, packaging tape, plastic tape such as insulating vinyl, industrial tape). For example, the glass transition temperature (Tg) of this type of adhesive is in the range of -70°C to -15°C.

Adhesives with glass transition temperatures (Tg) outside this range are considered to be unsuitable for practical use in terms of adhesiveness, retention, and the like. However, adhesives having a Tg in this range generally have poor compatibility with drugs and cannot contain a sufficient amount of drugs. Even when attempts are made to incorporate a large amount of drug into an adhesive, the adhesive cannot sufficiently dissolve the drug. Even a small amount of dissolved drug is difficult to migrate and diffuse into the adhesive. Therefore, the drug release property of the adhesive layer is low, and the rate at which the drug reaches the skin surface and is absorbed into the skin is small. Therefore, even if a patch having such an adhesive layer is applied to the skin, sufficient medicinal efficacy cannot be obtained. Furthermore, for example, when an application side production process is employed in which a drug is applied or sprayed onto the surface of an adhesive layer formed on a backing support, this adhesive layer cannot sufficiently absorb the drug. Therefore, the drug stored on the surface of the adhesive layer reduces the surface tackiness of the adhesive. Furthermore, when the obtained patch is applied to human skin, there is a risk that it will exhibit abnormal medicinal efficacy due to the large amount of drug present on the surface. Furthermore, since this adhesive layer lacks softness, the resulting patch has poor adhesion to the skin.
Poor adhesion. Therefore, when this patch is applied to the skin of a human body, a lifting phenomenon (ie, peeling) occurs at the periphery of the patch. This phenomenon leads to a decrease in the efficacy of the patch.

(Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional problems, and its purpose is to provide a patch that dissolves a large amount of drug and has an adhesive layer with high drug release properties. Our goal is to provide the following. Another object of the present invention is to provide a patch that is well adapted to the skin and has excellent adhesion. Still another object of the present invention is to provide a patch with a good balance between adhesiveness and cohesiveness.

(Means for Solving the Problems) The present invention improves the compatibility between the adhesive and the drug by using an adhesive with a glass transition temperature (Tg) of -71°C or less, which has not been used until now. A large amount of drug can be dissolved in the adhesive layer because of the remarkable improvement; the drug dissolved in the adhesive layer has high release properties because it is easy to migrate and diffuse; It has good adhesion and adhesion (for example, the patch does not slip easily even when stretched on the skin); and at least a portion of the polymer constituting the adhesive layer is cross-linked by electron beam irradiation. This was completed based on the inventor's knowledge that by applying this, the disadvantages of using an adhesive with a low Tg can be improved and the balance between the adhesive and cohesive properties of the adhesive layer can be maintained.

The patch of the present invention is a patch in which an adhesive layer containing an adhesive and a drug is provided on a backing support, wherein the adhesive is mainly composed of a (meth)acrylic acid ester polymer. the adhesive layer is irradiated with an electron beam to crosslink at least a part of the polymer, and the glass transition temperature (Tg) of the adhesive after crosslinking is -71°C or lower,
The holding force value (H) and adhesion force value (F) of the adhesive layer satisfy the relationships of the following equations 8 and b, thereby achieving the above object.

H/F>0.3 (sec/g) ... ap>2oo(
g)...b However, the holding force value ()() and adhesive force value (F) of the adhesive layer are measured as follows.

Holding force value (H) The holding force value (H) of the adhesive layer is tested according to JIS-Z-0237, except that the following conditions are used.

Sample size: Width 25±0.5■ Sample pasting area on test plate: 25in+X 25mm
Suspension load: 1ooo g Temperature during test: 30±1°C Measured value: After applying the load, the attached part of the sample “slips”
The time it takes for the load to fall and the load to fall (seconds)
is the holding force value ()I).

Adhesive force value (F) The adhesive force value (F) of the adhesive layer is tested according to JIS-Z-0237, except that the following conditions are used.

Sample size: 2 widths: 25±0.51 Temperature during test: 23±2°C Measured value: Displayed in grams (duram) of the load at which peeling occurs.

The adhesive is mainly composed of a (meth)acrylic acid ester polymer. Acrylic compounds are generally used as adhesives for patches because they are low or non-irritating, have good adhesion to the skin, are resistant to deterioration, are compatible with many drugs, and are easy to mold. considered optimal.

In order to obtain a pressure-sensitive adhesive having a glass transition temperature (Tg) of -71'C or less, it is first considered to use the above-mentioned (meth)acrylic acid alkyl ester polymer having a Tg of -71'C or less. However, in reality, 7g
An adhesive with a Tg of -71"C or less is prepared by adding a softener (7g-lowering agent) etc. that has a softening effect. In order to maintain the physical properties of the resulting adhesive, the addition of this 7g-lowering agent In order to reduce the amount, a (meth)acrylic acid alkyl ester polymer whose Tg is close to -71°C even if it is -71'C or higher is used.The Tg defined in the present invention is JISK-7121- It was measured by the DSC method based on 1987.

(Meth)acrylic acid ester is used as a constituent component of the polymer. Acrylic acid alkyl esters include esters having a linear alkyl group having 4 to 9 carbon atoms as an ester residue, and esters having 6 to 9 carbon atoms.
Esters having non-tertiary branched alkyl groups are suitable. Further, the methacrylic acid alkyl ester is preferably an ester having a linear alkyl group having 10 to 12 carbon atoms. These acrylic acid alkyl esters and methacrylic acid alkyl esters desirably constitute 70% by weight or more of the entire polymer. Also,
The Tg of this polymer composed only of acrylic acid alkyl ester and methacrylic acid alkyl ester is:
Preferably, the temperature is at least -50°C or less.

The amount of electron beam irradiation depends on the Tg and molecular weight of the adhesive in the adhesive layer before irradiation, the required strength and flexibility of the adhesive layer, and the usage status of the resulting patch (application area, application site, number of application days). etc.), but it is usually in the range of 1 to 50 megarads. If the irradiation dose is less than 1 megarad, the polymer constituting the adhesive layer will not be sufficiently crosslinked. Therefore, the cohesive force of the adhesive layer is insufficient, and cohesive failure is likely to occur. When the irradiation dose exceeds 50 megarads, the crosslinking density of this polymer becomes too high, so that the Tg of the adhesive layer increases and its tackiness decreases. By such electron beam irradiation, the polymer, which had fluidity in a low-molecular state before irradiation, becomes cohesive and strong due to crosslinking.

If the drug used is not resistant to electron beams, the adhesive layer is irradiated with electron beams before spraying or coating the adhesive layer with the drug. If the drug is resistant to electron beams, it is pre-contained in the adhesive solution. After this solution is applied onto the backing support to form an adhesive layer, this adhesive layer is irradiated with an electron beam.

The 7g lowering agent added to adjust the Tg of the adhesive to -71"C or less includes a softener (or resin tackifier) compatible with the (meth)acrylic acid alkyl ester polymer, and a liquid plasticizer. These 7
Examples of g-lowering agents include phthalate ester plasticizers such as dibutyl phthalate and dioctyl phthalate; sepatate ester plasticizers such as dibutyl sebacate;
Adipate ester plasticizers such as dioctyl adipate; phosphate ester plasticizers such as tributyl phosphate; vegetable oils such as olive oil and cottonseed oil; ester liquid plasticizers such as isopropyl myristate and triethyl citrate. be. Liquid polymers such as (meth)acrylic acid ester oligomers can also lower the Tg of (meth)acrylic acid alkyl ester polymers.

Further, fillers, drug transfer promoters, absorption promoters, surfactants, anti-aging agents, stabilizers, dyes, pigments, etc. may be added to the adhesive layer as necessary.

Fillers are added to improve the cohesive strength of the adhesive layer. However, in the present invention, the cohesive force of the adhesive layer is mainly increased by electron beam irradiation, and the effect of adding a filler is secondary. In addition, fillers are added to increase the amount of adhesive or to add color.

The filler, in particular the reinforcing filler, may contain, for example, 10μ
There are fibrous fillers with a diameter of 1 μm or less and fine powdered silicic anhydride with a diameter of 1 μm or less.

Since the adhesive used in the present invention has a Tg of 171° C. or less, it has excellent drug transfer and absorption effects, but in order to further enhance these effects, a drug transfer and absorption enhancer is added. In addition, a surfactant is used in an appropriate amount to promote wetting of the skin by the drug.

Antiaging agents and stabilizers are used in appropriate amounts to prevent aging and stabilize adhesives, drugs, and additives.

Furthermore, although the adhesive layer is mainly composed of (meth)acrylic acid alkyl ester polymer, in order to adjust its physical properties, other polymers (for example, rubber) may be added to this polymer in an amount of about 30% or less of the total polymer components. component) may be added. Drugs added to the adhesive layer include, for example, analgesic anti-inflammatory agents, steroid hormones, anti-allergic agents, antihistamines, coronary vasodilators, calcium antagonists, anti-bacterial agents, antibiotics, antidotes, antitussives, and antipruritic agents. drugs, hypnotics,
Mental energizers, tranquilizers, blood pressure regulators, diuretics, anti-asthma drugs, anti-epileptic drugs, hormone secretagogues, anti-ulcer drugs, stone dissolvers, anticancer drugs, vitamins, blood circulation promoters, anesthetics, etc. It will be done.

The support of the backing support layer is a sheet-like material that has flexibility and extensibility in accordance with the elongation of the skin and can withstand the number of days of application (usually about 1 to 3 days). For this purpose, plastic films, sponge sheets, flexible woven fabrics, knitted fabrics, nonwoven fabrics, or laminates thereof are preferable. Support materials include polyethylene, ethylene-vinyl acetate copolymer (EVA), soft polyvinyl chloride, polybutadiene,
Nylon, polyurethane, polyester, styrene-butadiene-styrene thermoplastic/highly elastic block copolymers, etc. are used. The thickness of the support is 0 for films.
．． 03 to 0.3 mm, and 0.3 to 3 mm for sponge sheets, woven fabrics, knitted fabrics, and nonwoven fabrics.

The adhesive layer is provided on a backing support, and a removable protective paper or sheet is attached to the surface of this adhesive layer to provide the adhesive patch of the present invention. The removable protective paper or sheet is sterilized.

There are, for example, the following two methods for obtaining the patch of the present invention.

(i) An adhesive solution (or liquid adhesive) is applied onto the backing support and dried to form an adhesive layer. In this case, this adhesive layer may or may not contain a drug. After this adhesive layer is irradiated with an electron beam, a drug solution is sprayed or applied. After drying the adhesive layer again, removable protective paper is attached to the surface of the adhesive layer, and the product is cut and packaged for use. However, if the adhesive solution contains a drug in advance, the steps of spraying or applying the drug solution and redrying the adhesive layer are not necessary.

(ti) An adhesive solution (or liquid adhesive) is applied on the releasable side of the releasable protective paper and dried to form an adhesive layer. After this adhesive layer is irradiated with an electron beam, a drug solution is sprayed or applied.

After drying the adhesive layer again, a backing support is laminated and pressed onto the surface of the adhesive layer, and the product is cut and packaged for use. However, if the adhesive solution contains a drug in advance, the steps of spraying or applying the drug solution and redrying the adhesive layer are not necessary.

The holding force value ( ) ( ) and adhesive force value (F) of the adhesive layer obtained in this way are determined by the following formulas a and b, as described above.
It has the following relationship: H/F > 0.3 (sec/g) ... aF > 200
．． 9...b Here, condition a is that no cohesive failure occurs in the adhesive layer, and condition is that
This shows that the adhesive layer has sufficient adhesive strength. The holding force value (H) and adhesion force value (F) of the adhesive layer are measured as follows: (a) Holding force value (H) JIS-Z except that the following conditions were used. -0237(
The holding force value (H) of the adhesive layer was tested according to the holding force).

Sample size: 2 widths: 25±O-5i11 Area of sample attached to test plate: 25mm x 25mm Suspended load: 1000 g Temperature during test = 30±1°C (heated) Measured value: After applying the load, The part where the sample is pasted is “misaligned”
The time it takes for the load to fall and the load to fall (seconds)
is the holding force value (H). However, the measurement is limited to 18,000 seconds (5 hours).

(b) Adhesive force value (F) JIS-Z-0237 (
The adhesive force value (F) of the adhesive layer was tested according to the 180 degree peeling method (adhesion force).

Sample size: 25 ± 0.5 cm in width Temperature during test: 23 ± 2°C (room temperature) Measured value: Displayed in grams (duram) of the load at which peeling occurs.

The above-mentioned holding force value (H) and adhesive force value (F) serve as standards for the cohesive force and adhesive force of the adhesive layer, respectively. For example, if the holding force value (H) is low, the adhesive layer is likely to cause cohesive failure, and if the adhesive force value (F) is low, the adhesive layer has the necessary and sufficient adhesive force for application to the skin. I won't. However, since cohesive force and adhesive force are correlated with each other, even if the holding force value (H) and adhesive force value (F) of the adhesive layer show a value greater than or equal to -, it is not necessarily suitable for practical use. Not necessarily. For example, even if the adhesive layer has a high cohesive force value ( ) ( ), if it has an even higher adhesive force value (F), the adhesive will cause cohesive failure. On the contrary, even if the holding force value ()I) of the adhesive layer is low, the adhesive force value (F)
is similarly low, the adhesive will not undergo cohesive failure. For this reason, the above conditions are set so that the adhesive layer has a certain level of adhesive strength, and the balance between the adhesive and cohesive properties of the adhesive layer is maintained to the extent that the adhesive does not cause cohesive failure. In order to achieve this, the above condition a was set. Here, the numerical values of the above conditions a and b do not mean that the physical properties of the patch change significantly beyond these values. However, a patch that meets at least the conditions a and b above has sufficient adhesive strength and does not cause cohesive failure that would be impractical (that is, has an excellent balance between adhesiveness and cohesiveness). .

Further, whether or not a cohesive failure phenomenon occurs in the adhesive layer when the adhesive patch of the present invention is applied and then peeled off is determined as follows.

First, when measuring the adhesive strength of a patch as mentioned above,
Visually observe whether the adhesive remains on the peeled test surface in a layered or partial manner.

The degree of cohesive failure of the adhesive layer is determined based on the degree of residual adhesive. If cohesive failure of the adhesive layer cannot be determined by this method, the following chili powder test is employed.

That is, on the test surface on which the patch was applied,
Sprinkle powder (especially colored chalk powder) and observe how the powder adheres. If chalk powder adheres significantly to the test surface, it is recognized that the adhesive layer of the patch has suffered cohesive failure.

In the patch obtained in this way, the adhesive contained in the adhesive layer after electron beam irradiation has a glass transition temperature (Tg) of -71°C or less, so the adhesive layer contains a large amount of drug. Can be dissolved. Since the drug dissolved in the adhesive layer easily migrates and diffuses, it also has high release properties. This is T
This is thought to be because drug molecules can move freely and actively in adhesives with low g. An adhesive layer containing such a low-g adhesive is flexible, so it blends well with the skin and has excellent adhesion. It is presumed that this is because the polymer molecules and groups thereof that mainly constitute this adhesive become easier to move in segment units. This increases the degree of freedom of movement of polymer molecules, increases compatibility with drug molecules, and improves compatibility with the skin. Furthermore, as the cohesive force of the adhesive decreases as the Tg decreases, in order to maintain the cohesive force, electron beam irradiation is used to reduce the amount of polymer constituting this adhesive layer (and partially crosslink it). As a result, various defects that occur in the adhesive layer due to a decrease in cohesive force (for example, oozing, shearing, stringiness, and adhesive remaining on the skin) are improved. The number of crosslinking points is extremely small compared to the number of molecular chains in the entire polymer (for example, one crosslinking point per several hundred to several thousand molecular chains), so the movement of polymer molecules is not hindered. By crosslinking, the Tg of the adhesive
does not become significantly higher. As a result, an adhesive layer can be obtained that maintains a good balance between adhesiveness and cohesiveness while maintaining good drug solubility, release properties, and adhesion to the skin.

Further, by selecting the composition and content of the adhesive and drug and the amount of electron beam irradiation, the crosslinking density can be changed, and patches having various different physical properties depending on the purpose can be provided.

(Example) Examples of the present invention are shown below.

n-octyl acrylate 92 parts by weight n-decyl methacrylate 106 parts by weight ethyl acetate
100 parts by weight n-hexane
20ii parts of the above formulation was charged into a stirring/refluxing reaction vessel, and heated at 60°C for 8 hours at 70°C in a N2 stream.
Each reaction was stirred and polymerized for 8 hours at C and 8 hours at system reflux temperature (approximately 75°C). Benzoyl peroxide was added to the reaction vessel as a polymerization catalyst in an amount of 0.25 mol % based on the total amount of the monomers in 8 portions within 18 hours. Stirring and refluxing were performed during the last 6 hours of the total reaction time of 24 hours to fully decompose the catalyst and complete the reaction. After the polymerization reaction, a viscous polymer was obtained. Intrinsic viscosity of this polymer (30℃, toluene solvent system)
was 1.661. The glass transition temperature (Tg) of the obtained polymer was about -67°C as determined by DSC method.

To the resulting polymer solution, add additional ethyl acetate to
A 50% ethyl acetate solution was prepared. Per 100 parts by weight of this solution, 18 parts by weight of dioctyl sepatate was added as a 7g reducing agent to prepare an adhesive solution.

The Tg of this adhesive mass was -89°C.

The adhesive layer obtained by casting this adhesive layer on a release paper and drying it was very soft, so that according to a finger pressure re-peel test, the adhesive adhered to the fingertip in a stringy state. Therefore,
In this state, this adhesive cannot be used.

1-2 Apply the adhesive solution obtained in (1-1) to the release surface of release paper whose surface has been subjected to silicone release treatment so that the thickness after drying is approximately 60 μm. It was dried to form an adhesive layer. Next, the coated surface was irradiated with an electron beam of 8 megarads using an electron beam irradiator. The Tg of the adhesive mass obtained from the adhesive layer after electron beam irradiation was -88°C.

1-3 A 60 μm thick soft vinyl chloride film (Nismezoika V; manufactured by Sekisui Chemical Co., Ltd.) was used as the backing support for the sheet. (
This backing support was laminated in contact with the adhesive layer obtained in step 1-2), and a pressure roll was applied to the pressure-sensitive adhesive layer at a pressure of about 2 cm per 1 cm width.
A pressure-sensitive adhesive sheet was produced by applying a pressure of 1 kg or more. After peeling off the release paper of this adhesive sheet, a drug solution can be applied or sprayed onto the adhesive layer to provide a patch. The adhesive layer of the obtained adhesive sheet had high adhesiveness, did not cause cohesive failure, and had excellent cohesive properties.

! -4 - From the adhesive sheet prepared in (1-3), 1 cm +
Ten square test pieces of the size of 1 C were cut out, and each sample was pasted on a total of 10 locations on a human body, including the outside and inside of the upper arm, the left and right chest, the right and left abdomen, and the outside of both thighs. After 2 days (48 hours), the adhesion state of the adhesive sheet and the phenomenon of adhesive residue were evaluated as follows. The results are shown in Table 1.

<Application condition> A: The patch shows no peeling or any signs of peeling.
It adheres well to the human body.

B: When observed from a distance of about 40 cm, at least a portion of the patch has peeled off or lifted.

C: The patch has completely peeled off and fallen off, or has shifted position.

Glue residue phenomenon A: There is no adhesive residue phenomenon.

B: Adhesive protrusion and adhesive residue phenomena are observed only in the peripheral area (at least in part) of the patch, but not in the central area.

C: Adhesive residue phenomenon is observed not only in the peripheral part of the patch but also in the central part.

Peel off the silicone release paper of the adhesive sheet obtained in (1-3) of -5, and add a 1% tetrahydrofuran solution of fluocinolone acetonide as a drug in an amount of 1,2+*g/
A patch was prepared by coating the adhesive layer of a pressure-sensitive adhesive sheet in an area of 100 cm 2 and drying it. A circular test piece with a diameter of 30 mm was punched out from this patch, and 100 ml of water-methyl alcohol mixed solvent (weight ratio: 50: So) was cut out.
The sample was left to stand for 2 hours at 35°C to be immersed. Thereafter, the test piece was taken out from the mixed solvent, and the amount of drug extracted into the solvent was determined by liquid chromatography. The ratio (%) of the released drug amount to the drug amount calculated to be contained in the test piece was evaluated as the drug release property of the adhesive. The percentage of drug amount released was 89%. The results are shown in Table 2.

A sample with a width of 25 mm was cut out from the adhesive sheet obtained in Test 1-6 (1-3), and the test was conducted in accordance with JIS-1, except that the following conditions were used.
The holding force value (H) of the adhesive layer was tested according to Z-0237 (holding force).

Area of the sample pasted on the test plate: 25mm x 25mm Hanging load: 1G00 g Temperature during test = 30±1℃ (heated) Measured value: After applying the load, the part of the sample pasted did not shift.
The time it takes for the load to fall and the load to fall (seconds)
is the holding force value (H). Holding force value is 1180 (seconds)
Met. The results are shown in Table 3.

-(1-
A sample with a width of 25 m + m was cut out from the adhesive sheet obtained in 3), and the JIS-Z- was used except that the following conditions were used.
The adhesive force value (F) of the adhesive layer was tested in accordance with 0237 (180 degree peeling method adhesion force).

Temperature during test = 23±2°C (room temperature) Measured value: Displayed in g (duram) of the load at which peeling occurs. The adhesive strength value was 551 (g/25a+m).

The value of H/F was calculated based on the holding force [(H) and adhesive force value (F) obtained in the holding force test of (1-6) and this adhesive force test, respectively. H/F was 2.14. In addition, when the cohesive failure of the adhesive was visually observed after being peeled off in this adhesive strength test, no cohesive failure of the adhesive was observed. These results are shown in Table 3.

2-ethylhexyl acrylate too parts by weight Butyl acrylate 100 parts by weight methacrylic acid
n-dodecyl roomkH5 lauryl alcohol 50 parts by weight lauryl mercaptan
0.01 part by weight The above formulation was charged into a stirring/reflux type reaction vessel, and each reactant was stirred and polymerized in a N2 stream at 50°C for 20 hours and then at 60"C for 20 hours. A solution of 0.6 parts by weight of lauroyl peroxide dissolved in 30 parts by weight of toluene was added to the reaction vessel as a polymerization catalyst in 1/10 amounts at 3 hour intervals.After the polymerization reaction, the mixture became viscous. A liquid polymer was obtained with a viscosity of about 120,000 centipoise and a molecular weight of about 40,000 on average. Because it behaves as a liquid, it cannot be used as an adhesive as it is.

2-2-5 Apply the adhesive solution obtained in <2-1) to the release surface of release paper whose surface has been subjected to silicone release treatment so that the thickness after drying is approximately 80 μm (±10 μm). was applied and dried to form an adhesive layer. Next, the coated surface was irradiated with an electron beam of 12 megarads using an electron beam irradiator. Tg of the adhesive layer obtained from the adhesive layer after electron beam irradiation
was -78°C.

After electron beam irradiation, the adhesive layer completely lost its fluidity. After putting the adhesive layer between your thumb and index finger and applying pressure, when you peel it off, the adhesive layer will be stretched once, but it will gradually increase its elasticity, and the adhesive will be attached to either finger. All of the layers have migrated. The adhesive layer did not become filamentous and cause cohesive failure. In addition, this adhesive layer
It was sparingly soluble in organic solvents such as cyclohexane. This is considered to be because the polymer constituting the adhesive layer undergoes a crosslinking reaction due to electron beam irradiation, resulting in an increase in molecular weight.

2-3 As a backing support for the sheet, an ethylene-vinyl acetate co-in film (EVA, t[vinyl:ethylene=
30 near 0. Example 1 (1-
A pressure-sensitive adhesive sheet was produced in the same manner as in 3). After peeling off the release paper of this adhesive sheet, a drug solution can be applied or sprayed onto the adhesive layer to provide a patch.

Except for using the adhesive sheet obtained in 2-4 (2-3>),
The adhesion of the adhesive layer was tested by the same method as in Example 1 (1-4). The results are shown in Table 1.

Except for using the adhesive sheet obtained in 2-5 (2-3>),
A patch was prepared in the same manner as in Example 1 (1-5), and a drug release property test of the adhesive layer was conducted.

As a result, the percentage of released drug amount was 79%. The results are shown in Table 2.

-Other than using the adhesive sheet obtained in (2-3) of 6.
In the same manner as in Example 1, the holding force value (H) of the adhesive layer was measured. The holding force value was 1255 (seconds). The results are shown in Table 3.

2-7 Except for using the adhesive sheet obtained in Hitoshi's test (2-3),
In the same manner as in Example 1, the adhesive force value (H) of the adhesive layer was measured. The adhesive strength value was 671 (g/25am>).

The value of H/F was calculated based on the holding force value (H) and adhesive force value (F) obtained in the holding force test (2-6) and this adhesive force test, respectively. H/F was 1.87. In addition, when the cohesive failure of the adhesive was visually observed after being peeled off in this adhesive strength test, no cohesive failure of the adhesive was observed. The results are shown in Table 3.

2-ethylhexyl acrylate 152 parts by weight Butyl methacrylate 60 parts by weight Vinyl acetate
20 parts by weight methacrylic acid
8 parts by weight of the above formulation was adjusted to 40% with ethyl acetate and charged into a stirring/refluxing reaction vessel, and heated in a N2 stream at 60°C for 6 hours, at 70°C for 10 hours, and at the boiling point of the system ( Each reaction was stirred and polymerized for 14 hours at approximately 77°C. In the reaction vessel, lauroyl peroxide was used as a polymerization catalyst in an amount of 0.4 mol% based on the total amount of the monomers, and 0.04 mol% was added every 3 hours five times, and 0.05 mol% was added every 3 hours. It was added in four parts. After the polymerization reaction, a viscous (approximately 4.400 cps) polymer was obtained. The intrinsic viscosity of this polymer (30°C
, toluene solvent system) was 1.577. The glass transition temperature (Tg) of the obtained polymer was determined by the DSC method,
The temperature was -38°C.

Silicone peeling was carried out in the same manner as in (1-2) of Example 1, except that the adhesive solution obtained in (1-1) of 1°-2 agent was used and that electron beam irradiation was not performed. An adhesive layer was formed on the paper.

Except for using the adhesive layer obtained in 7 (1'-2) of the 1°-3 sheet.
A pressure-sensitive adhesive sheet was produced in the same manner as in Example 1 (1-3). After peeling off the release paper of this adhesive sheet, a drug solution can be applied or sprayed onto the adhesive layer to provide a patch.

An adhesion test of the adhesive layer was conducted in the same manner as in Example 1 (1-4), except that the adhesive sheet obtained in the 1°-4 test (1'-3) was used. . The results are shown in Table 1.

Except for using the adhesive sheet obtained in 1°-5 (1-3>),
A patch was prepared in the same manner as in Example 1 (1-5), and a drug release property test of the adhesive layer was conducted. As a result, the percentage of released drug amount was 53%. The results are shown in Table 2.

The holding power value (H) of the adhesive was measured in the same manner as in Example 1, except that the adhesive sheet obtained in the test (1'-3) of the l'-6 agent was used. The holding force value was 277 (seconds).

The results are shown in Table 3.

The adhesive force value () () was measured in the same manner as in Example 1 except that the adhesive sheet obtained in the 1'-7 trial (1'-3) was used. Adhesive force value 26 tI<g/25mm>.

The value of H/F was calculated based on the holding force value (H) and adhesive force value (F) obtained in the holding force test of (1'-6) and this adhesive force test, respectively. H/F was 1°05. In addition, macroscopic observation of the cohesive failure state of the adhesive after it was peeled off in this adhesive force test showed that
No cohesive failure of the adhesive was observed. This result is shown in Table 3.
Shown below.

(Margins below) Table 2 Table 3 As is clear from the Examples and Comparative Examples, the adhesive layer of this example has a glass transition temperature (7 g) of -71"C or less, so it is flexible and does not move easily on the skin. It is easy to follow and has excellent adhesion. Even when an adhesive sheet with this adhesive layer is attached to the human skin, the adhesive layer has excellent adaptability and adhesion to the skin, so there is no peeling of the sheet or No misalignment, stringiness, or adhesive seepage is observed at all.After the adhesive sheet is peeled off, almost no adhesive remains on the skin.

This adhesive layer can contain a large amount of drug and has high drug release properties. In addition, this adhesive layer has an excellent balance between adhesiveness and cohesiveness because polymer molecules are crosslinked by electron beam irradiation.

This means that the adhesive force value (F) of the adhesive layer containing this adhesive is 200 g or more, and the ratio of the holding force value (H) to the adhesive force value (F): H/F>0.3 Since it is,
be proven. Therefore, even if a pressure-sensitive adhesive sheet obtained from this pressure-sensitive adhesive layer is applied to the skin of a human body, the pressure-sensitive adhesive sheet will not peel off. No adhesive remains on human skin after the adhesive sheet is peeled off Glass transition temperature (Tg) is higher than -71°C (Adhesive layer with no crosslinks between polymer molecules is difficult to adhere to skin) It lacks adhesiveness and adhesiveness.When an adhesive sheet obtained from this adhesive layer is applied to the human skin, it is not compatible with the skin, so it is easy to peel off or shift the position.This adhesive is It has low solubility and poor drug release properties.Furthermore, this adhesive layer has a poor balance between adhesiveness and cohesiveness.

(Effects of the Invention) The present invention thus improves the glass transition temperature (Tg) of the adhesive.
is -71°C or lower, and the polymer molecules constituting the adhesive layer are crosslinked by electron beam irradiation.
It blends well with the skin and has excellent adhesion and stickiness. Although this adhesive layer has a low Tg, it also has an excellent balance between adhesiveness and cohesiveness due to crosslinking between polymer molecules.

Moreover, this adhesive layer can dissolve a large amount of drug and has a high drug release property. Therefore, even when a patch obtained from this adhesive layer is applied to the skin of a human body, there is little peeling or displacement of the adhesive layer. No adhesive remains on the skin after the patch is removed. Therefore, with this patch, the patient will not feel any pain or discomfort. By combining the Tg value of the adhesive layer and the amount of electron beam irradiation, the selection range of substances used as the material for the adhesive can be expanded. Furthermore, since this adhesive layer has high drug release properties, the use of a patch having this adhesive layer increases drug efficacy and drug utilization efficiency. It is also economical because a large amount of drug can be contained in one adhesive layer. By combining the Tg value of the adhesive layer and the crosslinking density of the polymer, the selection range of substances used as the material for the adhesive can be expanded.

that's all

Claims (1)

[Claims] 1. A patch in which an adhesive layer containing an adhesive and a drug is provided on a backing support, wherein the adhesive is mainly composed of a (meth)acrylic acid ester polymer. , the adhesive layer is irradiated with an electron beam so that at least a part of the polymer is crosslinked, the glass transition temperature (Tg) of the adhesive after crosslinking is -71°C or lower, and the retention strength of the adhesive layer is A patch whose value (H) and adhesive force value (F) satisfy the relationships of formulas a and b below. H/F>0.3 (sec/g)...a F>200(g)...b