JP2512565B2 - Patch - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a patch in which a large amount of a drug is dissolved and a pressure-sensitive adhesive layer having a high drug release property is provided. The pressure-sensitive adhesive layer of this patch has excellent sticking properties to the skin, and has a good balance between tackiness and cohesiveness.

(Prior Art) Patches that are applied to the skin by utilizing the adhesiveness of an adhesive containing a drug and exhibit the medicinal properties of the drug have been proposed in many cases. This type of patch is generally composed of a backing support layer and a pressure-sensitive adhesive layer containing a pressure-sensitive adhesive and a drug. The drug exists in the adhesive layer in a dissolved state, a dispersed state, a microencapsulated dispersed state, a state sealed in a partition container, and the like. Examples of such patches include:
Patch for skin disease treatment comprising an adhesive layer containing an anti-inflammatory corticosteroid and a specific acrylic copolymer and a substrate (Japanese Patent Publication No. 52-18813, Teijin Ltd.), anti-inflammatory steroid and acrylic With a pressure-sensitive adhesive material containing a copolymer formed on an impermeable support film (Japanese Examined Patent Publication No. Sho 52-31405, Eli Lilly), a backing member and a pressure-sensitive adhesive layer. In addition, a medicine bandage further provided with a drug storage layer (Japanese Patent Publication No. 54-16566, Stephen David Goldby), a drug-containing patch layer mainly composed of a specific acrylate copolymer and a carrier And a pharmaceutical member comprising
No. 412, Nitto Denko Co., Ltd.), and a pharmaceutical preparation formed by forming a base material containing a polymer having a glass transition temperature (Tg) of −70 ° C. to −10 ° C. and propatil nitrate on a support (Japanese Patent Application Laid-Open No. S60-187242) 57
No. 183714, Nitto Denko Corporation).

However, the physical properties of the pressure-sensitive adhesive used in these adhesives can be measured using other normal pressure-sensitive adhesive tapes (eg, general stationery tapes, packaging tapes, plastic tapes such as insulating vinyl, and industrial tapes). It is no different from the adhesive that is used. For example, the glass transition temperature (Tg) of this type of adhesive is in the range of approximately -70 ° C to -15 ° C. It is considered that a pressure-sensitive adhesive having a glass transition temperature (Tg) outside this range cannot be put to practical use in terms of tackiness and retention. However, pressure-sensitive adhesives having a Tg in this range cannot generally contain a sufficient amount of drug because of poor compatibility with the drug. Even if an attempt is made to include a large amount of the drug in the adhesive, the adhesive cannot sufficiently dissolve the drug. Even a small amount of dissolved drug is less likely to migrate and diffuse into the adhesive.
Therefore, the drug release of the pressure-sensitive adhesive layer is low, and the rate at which the drug reaches the skin surface and is absorbed by the skin is small. Therefore, even when a patch having such an adhesive layer is applied to the skin,
Sufficient efficacy cannot be obtained.

(Problems to be Solved by the Invention) The present invention is to solve the above-mentioned conventional problems, and an object of the present invention is to provide a patch having a pressure-sensitive adhesive layer in which a large amount of drug is dissolved and the drug is highly released. Is to provide.
Another object of the present invention is to provide a patch which has good adhesion to the skin and has excellent adhesion. Still another object of the present invention is to provide a patch having a good balance between tackiness and cohesiveness.

(Means for Solving the Problems) The present invention uses an adhesive having a glass transition temperature (Tg) of -71 ° C. or lower, which has not been used before.
Since the compatibility between the adhesive and the drug is remarkably improved, a large amount of the drug can be dissolved in the adhesive layer; the drug dissolved in the adhesive layer has high release property because it easily migrates and diffuses; The adhesive layer has good compatibility with the skin and is excellent in adhesiveness and adhesiveness (for example, even if the skin is stretched, the patch does not easily slip); and a reinforcing filler is added to this adhesive. By doing so, the drawbacks of using a pressure-sensitive adhesive having a low Tg are improved, and the balance between the tackiness and cohesiveness of the pressure-sensitive adhesive layer is maintained;

The patch of the present invention is a patch having a backing support layer and an adhesive layer, wherein the adhesive layer has a glass transition temperature (T
g) contains a pressure-sensitive adhesive having a temperature of −71 ° C. or less, a reinforcing filler, and a drug, and the pressure-sensitive adhesive is mainly composed of a non-acrylic compound, and has a retention value (H) and a pressure-sensitive adhesive force of the pressure-sensitive adhesive layer. The value (F) satisfies the relationship between the following expressions a and b, whereby the above object is achieved.

H / F> 0.3 (sec / g) ... a F> 200 (g) ... b In the patch of the present invention, a pressure-sensitive adhesive having a glass transition temperature (Tg) of −71 ° C. or lower is used. By this, a large amount of drug can be dissolved in the adhesive. The drug dissolved in the adhesive has a high release property because it easily migrates and diffuses.
This is considered to be because drug molecules can move freely and actively in an adhesive having a low Tg. Such low
The adhesive layer containing the Tg adhesive has excellent adhesion to the skin. It is presumed that this is because the polymer molecules that mainly constitute this pressure-sensitive adhesive become easy to move in segment units. Further, since the cohesive force of the pressure-sensitive adhesive decreases as Tg decreases, a reinforcing filler is contained in this pressure-sensitive adhesive layer in order to maintain the cohesive force. As a result, various defects (for example, exudation, slippage, stringing, and sticking of the adhesive on the skin) that occur in the adhesive layer due to the decrease in cohesive force are improved. As a result, a patch having an adhesive layer in which the balance between adhesiveness and cohesiveness is maintained can be obtained. This adhesive is
Good compatibility with the skin and excellent adhesion. Furthermore, by selecting the composition and content of the pressure-sensitive adhesive, the reinforcing filler and the drug, a patch having various different physical properties depending on the purpose is provided.

In order to obtain a pressure-sensitive adhesive having a glass transition temperature (Tg) of -71 ° C or lower, it is first considered to use a non-acrylic compound having Tg of -71 ° C or lower. However, in reality, by adding a softening agent having a Tg lowering effect (Tg lowering agent) to a non-acrylic compound having a Tg higher than -71 ° C, an adhesive having Tg of -71 ° C or lower is prepared. It In order to maintain the physical properties of the obtained pressure-sensitive adhesive, in order to reduce the addition amount of this Tg lowering agent,
Even if Tg is -71 ° C or higher, a non-acrylic compound close to -71 ° C is used.

The pressure-sensitive adhesive used in the patch of the present invention is mainly composed of a non-acrylic compound. Examples of the non-acrylic compound include a rubber compound having a repeating unit of butadiene or isoprene in the main chain, a polyisobutylene compound, a polyvinyl ether compound, a polyurethane compound, or a mixture thereof. As an adhesive for patches, generally, an acrylic compound is used because it is excellent in hypoallergenicity or non-irritancy, adhesion to skin, deterioration resistance, compatibility with many drugs, and ease of molding. Is considered optimal. However, these non-acrylic compounds also have excellent hypoallergenic or non-irritative properties comparable to acrylic compounds, adhesion to the skin, and the like, and solventless coating and high-concentration coating are possible. Moreover, the non-acrylic compound is less expensive than the acrylic compound.

Examples of the rubber compound having a repeating unit of butadiene or isoprene in the main chain include natural or synthetic polyisoprene rubber, styrene-isoprene random copolymer rubber, styrene-butadiene block copolymer rubber, styrene-isoprene block copolymer rubber. , Polybutadiene rubber, and the like, and mixtures thereof. Of these compounds, a diene rubber (in the above example, a rubber having butadiene as a constituent unit) is preferable because it has the lowest Tg. A mixture of such a diene rubber and another rubber has a Tg of −71 ° C. or lower, or a Tg close to −71 ° C. even at −71 ° C. or higher, and therefore the amount of the Tg lowering agent added is small. Good and preferred. This rubber compound is usually blended with the following resin components and used as a rubber-resin compound. The resin component includes, for example, a rubber tackifier. The softening temperature of this rubber tackifier is in the range of 25 ° C to 150 ° C. Examples of rubber tackifiers include rosin-based resins such as ester gums, terpene-based resins obtained by polymerization of terpenes such as α-pinene and β-pinene, and polymerized resins obtained from various fractions by petroleum refining (this is , Aliphatic hydrocarbon resins, alicyclic hydrocarbon resins, and aromatic hydrocarbon resins). Other additives added to this rubber compound include a liquid Tg lowering agent, a rubber anti-aging agent, and a crosslinking agent.

The polyisobutylene compound is a compound mainly composed of an isobutylene polymer. This compound is
For example, it is prepared by mixing a rubber-like polymer having a molecular weight of about 50,000 or more with a semi-liquid or liquid polymer having a molecular weight of about 10,000 or less. This compound includes
Further, an isobutylene-isoprene co-heavy rubber may be added if necessary. If necessary, a tackifier for rubber, a liquid Tg lowering agent, an antioxidant, a cross-linking agent and the like may be added to this compound.

The polyvinyl ether compound includes a polyvinyl ethyl ether compound or a polyvinyl isobutyl ether compound. Both compounds are prepared by mixing a rubbery elastic polymer with a viscous liquid polymer.
If necessary, a tackifier for rubber, a liquid Tg lowering agent, an antioxidant, a cross-linking agent and the like may be added to this compound.

Although various compounds are used as the polyurethane-based compound, for example, a liquid prepolymer having a main chain of 1,4-butadiene and hydroxyl groups at both ends and a main chain of 1,4
-A liquid prepolymer having an isocyanate group at both ends with butadiene, in an appropriate ratio (-OH group: -NCO group = 1:
It is obtained by reacting 0.3 to 1: 1.2). A liquid Tg lowering agent, a cross-linking accelerator and the like may be added to this compound as well. This polyurethane compound is a solvent-free system,
It is preferable in that it can be coated on a backing support.

It is added to adjust the Tg of the adhesive below -71 ° C
A compound compatible with the non-acrylic compound is used as the Tg lowering agent. Examples of the Tg lowering agent include phthalate ester plasticizers such as dibutyl phthalate and dioctyl phthalate; sebacate ester plasticizers such as dibutyl sebacate; adipate ester plasticizers such as dioctyl adipate; tributyl. Phosphate,
Phosphate ester plasticizers such as trioctyl phosphate; glycerine triester plasticizers derived from nature such as castor oil; vegetable oils such as olive oil; citrate ester plasticizers such as triethyl citrate; liquid poly Liquid plasticizers such as ethers; ester compounds such as isopropyl myristate, triethyl citrate, glycerin triacetate, polypropylene (generally polyalkylene) glycol dialkyl esters;
Polyalkylene glycol dialkyl ethers; aliphatic or alicyclic hydrocarbon oils; liquid polybutadiene; liquid polyisoprene and the like. These Tg lowering agents are usually included up to 70%, depending on the composition of the non-acrylic compound. If the addition amount of this Tg lowering agent is too large, the obtained pressure-sensitive adhesive layer becomes too soft and sufficient cohesiveness cannot be obtained.

Reinforcing fillers are organic or inorganic. The reinforcing filler is fibrous or non-fibrous. Examples of the inorganic and fibrous fillers include glass fiber and asbestos fiber. Further, examples of the inorganic and non-fibrous fillers include fine powder silicic anhydride (usually called fine powder silica or white carbon), fine powder diatomaceous earth, fine powder calcium carbonate, zinc white, carbon black, and the like. is there. Organic fillers, including fibrous and non-fibrous fillers, include cellulose, cellulose derivatives (cellulose acetate, ethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, etc.),
Polyvinyl chloride, poly (meth) acrylate, poly (meth) acrylonitrile, poly (meth) acrylamide, polystyrene, polyvinyl acetate, polypropylene,
Examples thereof include polyethylene, polyvinylidene chloride, polyester and polyamide. Natural organic non-fibrous fillers such as the following micronized polysaccharide compounds can also be used: chitin, chitosan, pectin, starches, gum arabic, konjac mannan and the like. The fibrous reinforcing filler should be 20 μm or less (preferably 10 μm).
m) and an average fiber length of 1 mm to 25 mm. The non-fibrous reinforcing filler has an average diameter of 30 μm or less, preferably 10 μm or less.

The surface of these reinforcing fillers may be optionally subjected to various treatments in order to improve its surface activity (eg, adhesiveness). These processes include, for example, surface electron beam irradiation, surface ion plating, surface chemical treatment or surface coating.

Drugs added to the adhesive include, for example, analgesic and anti-inflammatory agents,
Steroid hormones, antiallergic agents, antihistamines, coronary vasodilators, calcium antagonists, antibacterial agents, antibiotics, antidotes, antitussives, antipruritics, hypnotics, psychoactive agents, tranquilizers, blood pressure regulators , Diuretics, asthma agents, antiepileptic agents, hormone secretagogues, antiulcer agents, stone dissolving agents, carcinostatic agents, vitamin agents, blood circulation promoting agents, anesthetics, and the like.

The adhesive layer of the patch of the present invention, if necessary, an antioxidant, an antioxidant, an adhesion improver, a drug absorption promoter, a stabilizer, a surfactant, a dye or a pigment is added. Good. Anti-aging agents and stabilizers are used in appropriate amounts for the purpose of preventing and stabilizing the adhesives, drugs and additives. Since the pressure-sensitive adhesive used in the present invention has an excellent drug transfer effect and absorption effect because the Tg is -71 ° C or less, a drug transfer and absorption promoter is added to further enhance these effects. In order to promote the wetting of the skin by the drug, a surfactant is used in an appropriate amount. Further, although the pressure-sensitive adhesive layer is mainly composed of a non- (meth) acrylic acid alkyl ester polymer, in order to adjust the physical properties thereof, the amount of the polymer is about 30% or less based on the total amount of the polymer component, and this polymer is mixed with other polymer (for example, A poly (meth) acrylic acid ester component may be added.

The support of the backing support layer includes any material conventionally known and used. In particular, a plastic film or a sponge sheet having flexibility and extensibility, a flexible woven fabric, a knitted fabric, a non-woven fabric, or a laminated body thereof is preferable. For example, the material of the support is polyethylene terephthalate (PET), ethylene-vinyl acetate copolymer (EV
A), polyethylene (especially low density polyethylene), polybutadiene, styrene-butadiene or styrene-
Of isoprene-based block copolymer resin, butadiene-styrene-methyl methacrylate (MMA) copolymer resin, nylon, polyurethane, alkoxyalkyl (meth) acrylate copolymer, polyvinyl acetal, plasticized cellulose acetate and ethyl cellulose Such fibrin derivatives, polyamino acids, water-insolubilized water-soluble polymers (eg pullulan, polyvinylpyrrolidone) and the like are used. The thickness of the support is 30 to 30 for film.
0 μm, 0.3 for sponge sheets, woven fabrics, knitted fabrics, and non-woven fabrics
~ 3mm.

The patch of the present invention is mainly provided with a backing support layer and a pressure-sensitive adhesive layer, and is provided with a peelable protective paper or sheet attached to the surface of the pressure-sensitive adhesive layer. The releasable protective paper or sheet is sterilized.

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

(I) A pressure-sensitive adhesive solution (or liquid pressure-sensitive adhesive) is applied onto the backing support and dried to form a pressure-sensitive adhesive layer. In this case, the pressure-sensitive adhesive layer may or may not contain a drug. The drug solution is sprayed or applied to this adhesive layer. After drying the pressure-sensitive adhesive layer again, a peelable protective paper is attached to the surface of the pressure-sensitive adhesive layer, cut and packaged, and then used.
However, when the drug is contained in the pressure-sensitive adhesive solution in advance, the steps of spraying or applying the drug solution and drying the pressure-sensitive adhesive layer are not necessary.

(Ii) Releasability A pressure-sensitive adhesive solution (or liquid pressure-sensitive adhesive) is applied on the releasable surface of the protective paper and dried to form a pressure-sensitive adhesive layer. The drug solution is sprayed or applied to this adhesive layer. After drying the pressure-sensitive adhesive layer again, a backing support is laminated on the surface of the pressure-sensitive adhesive layer and pressure-bonded, and cut and packaged for use. However, when the drug is contained in the pressure-sensitive adhesive solution in advance, the steps of spraying or applying the drug solution and drying the pressure-sensitive adhesive layer are not necessary.

In the patch of the present invention thus obtained, the cohesive force value (H) and the cohesive force value (F) of the pressure-sensitive adhesive layer containing the pressure-sensitive adhesive, the reinforcing filler and the drug are, as described above, It has the relationship of the a formula and the b formula.

H / F> 0.3 (sec / g) ... a F> 200g ... b Here, the formula a indicates that cohesive failure does not occur in the adhesive layer, and the formula b indicates that the adhesive layer has sufficient adhesive force. Indicates having. The holding force value (H) and the adhesive force value (F) of the adhesive layer are measured as follows.

(A) Holding force value (H) The holding force value (H) of the pressure-sensitive adhesive layer was tested according to JIS-Z-0237 (holding force) except that the following conditions were used.

Sample size: width 25 ± 0.5mm Attached area of sample to test plate: 25mm × 25mm Hanging load: 1000g Temperature during test: 30 ± 1 ℃ (heating) Measured value: sample after applying load "Slip" is attached part of
Time until the load comes off (in seconds)
Is the holding force value (H). However, the measurement is 18000 seconds (5
Hours).

(B) Adhesive force value (F) The adhesive force value (F) of the adhesive layer was tested according to JIS-Z-0237 (180 degree peeling method adhesive force) except that the following conditions were used.

Sample size: width 25 ± 0.5 mm Temperature during test: 23 ± 2 ° C (room temperature) Measured value: Expressed in g (gram) of the load to be peeled off.

The holding force value (H) and the adhesive force value (F) serve as a reference for the cohesive force and the adhesive force of the adhesive layer, respectively. For example, if the holding power value (H) is low, the pressure-sensitive adhesive layer is liable to cause cohesive failure, and if the adhesive force value (F) is low, the pressure-sensitive adhesive has a necessary and sufficient adhesive force for application to the skin. No longer. However, since the cohesive force and the adhesive force are correlated with each other, the cohesive force value (H) and the adhesive force value (F) of the adhesive layer are
Is not always suitable for practical use. For example, even if the holding power value (H) of the pressure-sensitive adhesive layer shows a high value, if it has a higher pressure value (F), the pressure-sensitive adhesive causes cohesive failure. Conversely, even if the holding force value (H) of the pressure-sensitive adhesive layer is low, if the pressure-sensitive adhesive value (F) is similarly low, the pressure-sensitive adhesive does not cause cohesive failure. Because of this, in order for the pressure-sensitive adhesive layer to have a certain adhesive strength,
The above condition b was set, and the above condition a was set so as to maintain the balance between the adhesiveness and the cohesiveness of the adhesive layer to the extent that the adhesive does not cause cohesive failure. Here, the numerical values of the above-mentioned conditions a and b do not mean that the physical properties of the patch significantly change from the values. However, a patch that meets at least the above conditions a and b has sufficient adhesive strength and does not cause cohesive failure that cannot be put to practical use (that is, it has an excellent balance between adhesiveness and cohesiveness). ).

In addition, whether or not the cohesive failure phenomenon occurs in the pressure-sensitive adhesive layer when the patch of the present invention is applied and then peeled off is determined as follows.

First, when the adhesive strength of the patch is measured as described above, it is visually observed whether or not the adhesive is partially or partially left on the peeled test surface. The degree of cohesive failure of the pressure-sensitive adhesive layer is determined by the degree of residual pressure-sensitive adhesive. When the cohesive failure of the pressure-sensitive adhesive layer cannot be determined by this method, the following chalk powder test is employed. That is, chalk powder (particularly, colored chalk powder) is sprinkled on the test surface from which the patch has been peeled, and the state of powder adhesion is observed. When chalk powder adheres significantly to the test surface, it is recognized that the adhesive layer of the patch has undergone cohesive failure.

(Examples) Examples of the present invention will be described below.

Example 1 (1-1) Preparation of adhesive solution cis-1,4-polybutadiene (97% purity: JSR-BR-0
1) 70 parts by weight Natural rubber (Grade: Pale crepe) 30 parts by weight Poly-β-pinene resin (Piccolite S-100: Softening point
100 ° C) 60 parts by weight Squalane (liquid plasticizer) 20 parts by weight 2,5-di-t-amylhydroquinone (antiaging agent)
1.5 parts by weight The above formulation was added to cyclohexane, stirred and mixed to prepare a 30% cyclohexane solution. Here, the rubber component and the resin component were cut or pulverized to have an appropriate size or less, and then used. The Tg (after drying) of the obtained pressure-sensitive adhesive solution was -112 ° C.

(1-2) Preparation of adhesive plaster In the adhesive solution obtained in (1-1), per 100 parts by weight of the adhesive component in the solution, finely powdered silicic acid anhydride (average particle size) as a reinforcing filler is used. (2 μm or less) and 24 parts by weight of acetylsalicylic acid (analgesic) as a drug, and the mixture was stirred and mixed to prepare a viscous adhesive plaster.

(1-3) Preparation of adhesive patch A corona treatment was applied to one surface of a soft polyethylene film having a thickness of 70 μm, and then the adhesive plaster obtained in (1-2) was applied to the treated surface and dried, An adhesive layer having a thickness of about 50 μm was formed. Silicone release paper was attached to the surface of this adhesive layer.

(1-4) Adhesiveness test of patch The test patch of 20 mm x 20 mm square was cut out from the patch obtained in (1-3), and this was stuck on the outer side of the upper arm of the human body. After 24 hours, the state of the attached test piece was observed. As a result, the exfoliation of the adhesive plaster of about 1 mm was observed in the peripheral portion of the test piece, but no natural peeling was observed. When this test piece was peeled from one end,
The human body had only a moderate peeling feeling (adhesiveness), and no pain was felt. Further, when the test piece was peeled off, there was no stringing phenomenon, and it was not observed that the adhesive plaster remained on the skin of the human body after the test piece was peeled off.

(1-5) Drug release test of patch A circular test piece having a diameter of 60 mm was cut out from the patch obtained in (1-3). Peel off the peelable sheet from this test piece, ethyl alcohol-water mixed solvent (weight ratio; 50: 5
0) It was left to stand in 100 ml at 35 ° C. for 6 hours for immersion (in this case, the surface of the pressure-sensitive adhesive layer faced up). After that, the test piece is taken out from the mixed solvent, and by the liquid chromatography method,
The amount of drug extracted in the solvent was quantified. The ratio (%) of the amount of the released drug to the amount of the drug calculated to be contained in the test piece was used as an evaluation of the drug release property of the adhesive.
The percentage of drug released was 45%. Table 1 shows the results.

(1-6) Adhesive holding power test JIS-Z except that a sample with a width of 25 ± 0.5 mm was cut out from the patch obtained in (1-3) and the following conditions were used.
-0237 (holding power) according to the holding force value (H) of the adhesive layer
Was tested. However, when the sample was liable to stretch, a PET tape was attached to the backing support side of the sample to prevent easiness of stretching (rear surface reinforcement), and the test was performed.

Attached area of sample to test plate: 25mm x 25mm Hanging load: 1000g Temperature during test: 30 ± 1 ° C (heating) Measured value: After applying the load, the affixed part of the sample was “deviation”
Time until the load comes off (in seconds)
Is the holding force value (H). The holding power value was 662 (seconds).

(1-7) Adhesive strength test of pressure sensitive adhesive JIS-Z except that a sample having a width of 25 ± 0.5 mm was cut out from the patch obtained in (1-3) and the following conditions were used.
The adhesive strength value (F) of the adhesive layer was tested according to −0237 (180 degree peeling adhesive strength). However, if necessary,
The back surface of the sample was reinforced in the same manner as in (1-6).

Temperature during the test: 23 ° C ± 2 ° C (room temperature) Measured value: The load to be peeled off is expressed in g (gram). The adhesive strength value was 276 (g / 25 mm).

The value of H / F was calculated based on the holding force value (H) and the adhesive force value (F) obtained in the holding force test of (1-6) and this adhesive force test, respectively. H / F was 2.40 seconds / g.
In this adhesive strength test, the cohesive failure of the pressure-sensitive adhesive after peeling was visually observed, and no cohesive failure of the pressure-sensitive adhesive was observed. Table 2 shows the results.

Comparative Example 1-1 An adhesive solution was prepared in the same manner as in (1-1) of Example 1. An adhesive plaster was prepared and a patch was prepared in the same manner as in (1-2) and (1-3) of Example 1 except that no reinforcing filler was added to this adhesive solution. . A patch test was conducted on this patch by the same method as in (1-4) of Example 1. As a result, the exudation of the adhesive plaster around the sample piece at the part where the human body was attached was
It was 3 mm on average. Moreover, after the test piece was peeled off, the adhesive plaster remained on the skin of the human body and became dirty.

In addition, a drug release test was performed on this patch by the same method as in (1-5) of Example 1. The percentage of drug released was 48%. Table 1 shows the results.

Further, regarding this patch, (1-6) of Example 1
By the same method as described in (1-7) and (1-7), the holding force value (H) and the adhesive force value (F) of the pressure-sensitive adhesive layer were measured, and the H / F value was calculated. The retention value was 59 (sec), the adhesion value was 390-780 (g / 25mm), and the H / F was 0.15 sec / g. The variation in the adhesive strength value is recognized because of the tendency of the adhesive layer to undergo cohesive failure. Further, when the cohesive failure condition of the adhesive after being peeled off in this adhesive strength test was visually observed, a slight tendency of the cohesive failure of the adhesive was observed. Table 2 shows the results.

Comparative Example 1-2 A 30% cyclohexane solution was prepared by adding the following compounds to cyclohexane and stirring and mixing them as a pressure-sensitive adhesive composition having a Tg exceeding -71 ° C.

Natural rubber (Pale crepe) 100 parts by weight Poly-β-pinene resin (softening point 100 ° C) 80 parts by weight Squalane 10 parts by weight 2,6-di-t-amylhydroquinone 1.5 parts by weight Using this adhesive solution, and this Except that the amount of acetylsalicylic acid as a drug added to the solution was 12 parts by weight per 100 parts by weight of the adhesive component in the solution,
An adhesive plaster was prepared and a patch was prepared in the same manner as in Example 1. For this patch, (1- of Example 1
An adhesive property test was conducted by the same method as in 4). As a result, the area around the test piece floated up with a width of about 1 mm at the site where the human body was attached, indicating that the adhesive was not sufficiently adapted to the skin. When the test piece was peeled off, a sufficient adhesive force was not felt by the human body.

In addition, a drug release test was performed on this patch by the same method as in (1-5) of Example 1. The percentage of drug released was 32%. Table 1 shows the results.

Further, regarding this patch, (1-6) of Example 1
By the same method as described in (1-7) and (1-7), the holding force value (H) and the adhesive force value (F) of the pressure-sensitive adhesive layer were measured, and the H / F value was calculated. The retention value was 641 (sec), the adhesion value was 433 (g / 25mm), and the H / F was 1.48 sec / g. In this adhesive strength test, the cohesive failure of the pressure-sensitive adhesive after peeling was visually observed, and no cohesive failure of the pressure-sensitive adhesive was observed. Table 2 shows the results.

Example 2 (2-1) Preparation of adhesive solution elastomeric shaped polyisobutylene (molecular weight: ¹⁰⁶ or higher, Vistanex MML-100; manufactured by Exxon Corp.) 35 parts by weight of styrene - isoprene - styrene block copolymer (EX- 2359; Sumitomo Chemical Co., Ltd.) 5 parts by weight liquid polybutene (molecular weight: 1000 or less, Opanol B-
1; manufactured by BASF) 60 parts by weight Liquid paraffin 10 parts by weight 2,6-di-t-butyl-p-cresol (anti-aging agent) 1.5 parts by weight By adding the above formulation to cyclohexane and stirring the mixture, A 50% cyclohexane solution was prepared. The Tg (after drying) of the obtained pressure-sensitive adhesive solution was -81 ° C.

(2-2) Preparation of adhesive plaster In the adhesive solution obtained in (2-1), polypropylene short fibers (average fiber diameter; 11 μm) as a reinforcing filler per 100 parts by weight of the adhesive component in the solution. , Average fiber length; 15 ~ 20m
m) and 25 parts by weight of prednisolone (anti-inflammatory agent) as a drug were added, and the mixture was stirred and mixed to prepare an adhesive plaster.

(2-3) Preparation of patch On the EVA side surface of a laminate film of a PET (polyethylene terephthalate) film having a thickness of 15 μm and an EVA (ethylene-vinyl acetate copolymer) film having a thickness of 35 μm,
The adhesive plaster obtained in (2-2) has a thickness after drying of 40
It was applied and transferred by a transfer method using a silicone release paper so that the thickness becomes μm. Thereby, a patch having an adhesive layer on the laminate film was produced.

(2-4) Adhesiveness test of patch A patchy test of the patch was performed in the same manner as in Example 1 except that the patch obtained in (2-3) was used. As a result, a maximum of about 2 mm of exudation of the adhesive plaster was observed in the peripheral portion of the test piece, but no spontaneous peeling was observed. When this test piece was peeled from one end, the human body had only an appropriate peeling feeling (feeling of adhesive force), and no pain was felt. In addition, it was not observed that the adhesive plaster remained on the skin of the human body after the test piece was peeled off.

(2-5) Drug release test of patch The circular patch having a diameter of 60 mm was punched out from the patch obtained in (2-3). Peel off the peelable sheet from this test piece, ethyl alcohol-water mixed solvent (weight ratio; 70: 3
0) Immersed in 100 ml by allowing it to stand at 35 ° C. for 6 hours. Then, the test piece was taken out from the mixed solvent, and the amount of the drug extracted in the solvent was quantified by the liquid chromatography method. The ratio (%) of the amount of the released drug to the amount of the drug calculated to be contained in the test piece was used as an evaluation of the drug release property of the adhesive. The percentage of drug released was 88%. Table 1 shows the results.

(2-6) Adhesive Cohesive Strength Test The adhesive strength value (H) of the adhesive layer was measured in the same manner as in Example 1 except that the patch obtained in (2-3) was used. . The holding power value was 226 (seconds).

(2-7) Adhesive force test of adhesive The adhesive value (H) of the adhesive layer was measured in the same manner as in Example 1 except that the patch obtained in (2-3) was used. . The adhesive strength value was 462 (g / 25 mm).

The value of H / F was calculated based on the holding force value (H) and the adhesive force value (F) obtained in the holding force test (2-7) and the adhesive force test, respectively. H / F was 0.49 sec / g.
In this adhesive strength test, the cohesive failure of the pressure-sensitive adhesive after peeling was visually observed, and no cohesive failure of the pressure-sensitive adhesive was observed. Table 2 shows the results.

Comparative Example 2-1 A pressure-sensitive adhesive solution was prepared in the same manner as in Example 2 (2-1). An adhesive plaster was prepared and a patch was prepared in the same manner as in (2-2) and (2-3) of Example 2 except that no reinforcing filler was added to this adhesive solution. . A patch test was conducted on this patch by the same method as in (1-4) of Example 1. As a result, displacement of the test piece over approximately 8 mm occurred at the location of attachment on the human body,
The adhesive plaster remained on the gap. In addition, when the test piece was peeled off, a stringing phenomenon occurred, and after the test piece was peeled off, a thin adhesive plaster remained on the skin of the human body and became dirty.

In addition, the patch was subjected to a drug release test by the same method as in (1-5) of Example 1. The percentage of drug released was 92%. Table 1 shows the results.

Further, regarding this patch, (1-6) of Example 1
By the same method as described in (1-7) and (1-7), the holding force value (H) and the adhesive force value (F) of the pressure-sensitive adhesive layer were measured, and the H / F value was calculated. The holding value was 91 (sec), the tack value was 507 (g / 25 mm), and the H / F was 0.18 sec / g. Further, when the cohesive failure condition of the adhesive after being peeled off in this adhesive strength test was visually observed, the cohesive failure of the adhesive was barely noticeable.
Table 2 shows the results.

Comparative Example 2-2 An acrylic polymer-based pressure-sensitive adhesive prepared by polymerization of the following compounds was used as a pressure-sensitive adhesive having a Tg exceeding -71 ° C.

2-Ethylhexyl acrylate 70 parts by weight Vinyl acetate 25 parts by weight Methacrylic acid 5 parts by weight Charge a 30% ethyl acetate solution of the above formulation into a reaction vessel,
Each reaction was polymerized at 60 ° C. for 10 hours and at the system reflux temperature (74-75 ° C.) for 14 hours. As a polymerization catalyst, 0.5% by weight of the total amount of the above monomers, lauroyl peroxide, was added to the reaction vessel in 8 batches within 18 hours.

An adhesive plaster was prepared and a patch was prepared in the same manner as in Example 2 except that this adhesive was used. A patch test was conducted on this patch by the same method as in (1-4) of Example 1. As a result, the part where the test piece floated from the skin (that is, the part where it peeled off) reached about 25% of the total area of the test piece at the attachment site on the human body. Further, when the test piece was peeled off, sufficient adhesive force was not felt by the human body, and it was recognized that the test piece was familiar to the skin and had low adhesiveness. However, the adhesive plaster did not remain on the skin of the human body after peeling the test piece.

In addition, a drug release test was performed on this patch by the same method as in (1-5) of Example 1. The percentage of drug released was 14%. Table 1 shows the results.

Further, regarding this patch, (1-6) of Example 1
By the same method as described in (1-7) and (1-7), the holding force value (H) and the adhesive force value (F) of the pressure-sensitive adhesive layer were measured, and the H / F value was calculated. The holding power value was 247 (sec), the adhesive strength value was 412 (g / 25 mm), and the H / F was 0.6 sec / g. In this adhesive strength test, the cohesive failure of the pressure-sensitive adhesive after peeling was visually observed, and no cohesive failure of the pressure-sensitive adhesive was observed. Table 2 shows the results.

Example 3 (3-1) Preparation of pressure-sensitive adhesive solution Rubber elastic polyvinyl isobutyl ether (Rutnal IC; manufactured by BASF) 40 parts by weight Liquid polyvinyl isobutyl ether (Rutnar I-
30; manufactured by BASF Co., Ltd.) 60 parts by weight BPBG (plasticizer) 20 parts by weight The above formulation was added to ethyl acetate and stirred to prepare a 45% ethyl acetate solution. Here, the rubber component and the resin component were cut or pulverized to have an appropriate size or less, and then used. Tg of the obtained adhesive solution
(After drying) was -78 ° C.

(3-2) Preparation of adhesive plaster In the adhesive solution obtained in (3-1), 100 parts by weight of the adhesive component in the solution was used as a reinforcing filler, and glass short fibers (average diameter: 8 to 10 μm, average fiber length; 12 to 15 mm) 20
An adhesive plaster was prepared by adding 1 part by weight and 14 parts by weight of isosorbite 2-nitrate (a coronary vasodilator) as a drug, stirring and mixing.

(3-3) Preparation of patch On the EVA surface of the laminate film similar to that in Example 2, (3
-2) by the same method as in Example 2, so that the adhesive plaster obtained in 2) has an average thickness after drying of 60 μm.
Coated and transferred. Thereby, a patch having an adhesive layer on the laminate film was produced.

(3-4) Adhesiveness test of patch A patchy test of the patch was performed in the same manner as in Example 1 except that the patch obtained in (3-3) was used. As a result, a maximum of about 2 mm of exudation of the adhesive plaster was observed in the peripheral portion of the test piece, but no spontaneous peeling was observed. When this test piece was peeled from one end, the human body had only an appropriate peeling feeling (feeling of adhesive force), and no pain was felt. In addition, it was not observed that the adhesive plaster remained on the skin of the human body after the test piece was peeled off.

(3-5) Drug release test of patch The drug release of the patch was tested in the same manner as in Example 1 using the patch obtained in (2-3). As a result, the ratio of the released drug amount was 79%. Table 1 shows the results.

(3-6) Retention force test of pressure-sensitive adhesive The retention force value (H) of the pressure-sensitive adhesive layer was measured in the same manner as in Example 1 except that the patch obtained in (3-3) was used. . The holding power value was 651 (seconds).

(3-7) Adhesive force test of adhesive agent The adhesive force value (H) of the adhesive layer was measured in the same manner as in Example 1 except that the patch obtained in (3-3) was used. . The adhesive strength value was 529 (g / 25 mm).

The value of H / F was calculated based on the holding force value (H) and the adhesive force value (F) obtained in the holding force test (3-7) and the adhesive force test, respectively. H / F was 1.23. In this adhesive strength test, the cohesive failure of the pressure-sensitive adhesive after peeling was visually observed, and no cohesive failure of the pressure-sensitive adhesive was observed. Table 2 shows the results.

Comparative Example 3-1 A pressure-sensitive adhesive solution was prepared in the same manner as in (3-1) of Example 3. An adhesive plaster was prepared and a patch was prepared in the same manner as in (3-2) and (3-3) of Example 3, except that no reinforcing filler was added to this adhesive solution. . A patch test was conducted on this patch by the same method as in (1-4) of Example 1. As a result, the exudation of the adhesive plaster around the test piece at the location where the human body was attached,
It was 3 mm on average and 5 mm in one direction. The position of the test piece was moved due to the shift. After peeling off the test piece, the adhesive plaster remained on the skin of the human body and became dirty.

In addition, a drug release test was performed on this patch by the same method as in (1-5) of Example 1. The percentage of drug released was 81%. Table 1 shows the results.

Further, regarding this patch, (1-6) of Example 1
By the same method as described in (1-7) and (1-7), the holding force value (H) and the adhesive force value (F) of the pressure-sensitive adhesive layer were measured, and the H / F value was calculated. Although the holding power value was 21 (seconds), the adhesive power value could not be measured due to cohesive failure of the adhesive. As a result, H / F is estimated to be 0.1 or less. Further, when the cohesive failure condition of the pressure-sensitive adhesive after being peeled off in this adhesive strength test was visually observed, the cohesive failure of the pressure-sensitive adhesive was remarkable. Table 2 shows the results.

Comparative Example 3-2 A pressure-sensitive adhesive plaster was prepared and a patch was prepared in the same manner as in Example 1 except that the pressure-sensitive adhesive having the following composition was used as the pressure-sensitive adhesive having a Tg of more than -71 ° C. It was made.

Lutonal IC 60 parts by weight Lutonal I-30 40 parts by weight The pressure-sensitive adhesive composition having the above composition was a 30% ethyl acetate solution. (Tg of the solid content: −33 ° C.) A patching test was performed on this patch by the same method as in (1-4) of Example 1. As a result, exudation of the adhesive plaster to the periphery of the test piece was about 1 mm on average at the site where the test piece was attached to the human body, but the area where the test piece was lifted from the skin over about 4 places (that is, The peeled part) was seen. Further, after peeling off the test piece, the adhesive plaster remained on the skin surface of the human body while causing a stringing phenomenon, resulting in stain.

In addition, a drug release test was performed on this patch by the same method as in (1-5) of Example 1. The percentage of drug released was 53%. Table 1 shows the results.

Further, regarding this patch, (1-6) of Example 1
By the same method as described in (1-7) and (1-7), the holding force value (H) and the adhesive force value (F) of the pressure-sensitive adhesive layer were measured, and the H / F value was calculated. The retention value was 109 (sec), the adhesion value was 390 to 1560 (g / 25 mm), and the H / F was 0.28. The variation in the adhesive strength value is due to the tendency of the adhesive layer to undergo cohesive failure. Further, when the cohesive failure condition of the pressure-sensitive adhesive after being peeled off in this pressure-sensitive adhesive strength test was visually observed, a tendency for cohesive failure of the pressure-sensitive adhesive was slightly recognized. Table 2 shows the results.

Example 4 (4-1) Preparation of adhesive solution Liquid polybutadiene containing hydroxyl groups at both ends (polybd R-45D; manufactured by Idemitsu Petrochemical Co., Ltd.) (Component A)
94 parts by weight Polyfunctional (2-2.5 functional) NCO at positions including both ends
Group-containing liquid polybutadiene (polybd HTP-9; manufactured by Idemitsu Petrochemical Co., Ltd.) (Component B) 6 parts by weight dibutyltin acetate (crosslinking catalyst) (Component C) 0.00
5 parts by weight Reinforcing filler mixture of the following composition (Component D) 25 parts by weight Finely ground alumina having an average particle size of 5 μm or less 10 parts by weight, polyvinyl chloride having an average particle size of 5 μm or less 10 parts by weight, average particle size 5 μm Finely ground zinc oxide 10% by weight In the above formulation, Component A and Component D, and Component B and Component C are mixed in advance. Both mixtures are mixed through the mixing head up to about 30 minutes before coating on the silicone treated release paper in the adhesive sheet making step below. The Tg after the crosslinking reaction (curing) of this adhesive is about −
78 ° C.

(4-2) Preparation of pressure-sensitive adhesive sheet A mixture of the formulation of (4-1) and a thickness of about 100 was applied to the surface of the silicone release paper, the surface of which was smoothed by polyamid.
The pressure-sensitive adhesive layer was formed by coating so as to have a thickness of μm. After the coated release paper is cooled at 100 ° C for about 1 minute through the cure zone, the pressure-sensitive adhesive layer is laminated on the surface of the soft vinyl chloride film and pressure-bonded to form a three-layer sandwich structure. A sheet was prepared. This pressure-sensitive adhesive sheet is used for sticking by peeling off the silicone release paper. This pressure-sensitive adhesive sheet is made into a patch by first peeling off the silicone release paper, applying or spraying the drug itself or a solution thereof onto the surface of the pressure-sensitive adhesive layer, and then attaching the silicone release paper again.

(4-3) Stickiness test of pressure-sensitive adhesive sheet A stickiness test of a pressure-sensitive adhesive sheet was performed in the same manner as in Example 1 except that the pressure-sensitive adhesive sheet obtained in (4-2) was used. As a result, although exudation of the pressure-sensitive adhesive within 3 mm was observed in the peripheral portion of the test piece, no spontaneous peeling was observed. When this test piece was peeled off from one end, the adhesive was slightly pulled, but since it was elastically restored, no adhesive remained on the skin of the human body.

(4-4) Retention force test of pressure-sensitive adhesive Retention force value (H) of pressure-sensitive adhesive layer was obtained in the same manner as in Example 1 except that the pressure-sensitive adhesive sheet obtained in (4-2) was used.
Was measured. The holding power value was 370 (seconds).

(4-5) Adhesive Strength Test of Adhesive Adhesive strength value (H) of adhesive layer in the same manner as in Example 1 except that the adhesive sheet obtained in (4-2) was used.
Was measured. The adhesive strength value was 421 (g / 25 mm).

The value of H / F was calculated based on the holding force value (H) and the adhesive force value (F) obtained in the holding force test (4-4) and the adhesive force test, respectively. H / F was 0.88. In this adhesive strength test, the cohesive failure of the pressure-sensitive adhesive after peeling was visually observed, and no cohesive failure of the pressure-sensitive adhesive was observed. Table 2 shows the results.

Comparative Example 4 A pressure-sensitive adhesive solution was prepared and a pressure-sensitive adhesive sheet was prepared in the same manner as in (4-1) and (4-2) of Example 4 except that the reinforcing filler was not added. An adhesiveness test was conducted on this pressure-sensitive adhesive sheet by the same method as in (1-4) of Example 1. As a result, bleeding of the pressure-sensitive adhesive within about 4 mm on average was observed in the peripheral portion of the test piece. Further, when the test piece was peeled off, a stringing phenomenon of pulling a long foot occurred, and after peeling the test piece, about 1/3 of the whole amount of the adhesive remained on the skin of the human body.

Furthermore, regarding this pressure-sensitive adhesive sheet, (1-
6) and (1-7), the coercive force value (H) and the cohesive force value (F) of the adhesive layer were measured and the H / F value was calculated. The retention value was 123 (sec), the adhesion value was 559 (g / 25 mm), and the H / F was 0.22. In this adhesive strength test, the cohesive failure of the pressure-sensitive adhesive after peeling was visually observed, and no cohesive failure of the pressure-sensitive adhesive was observed. Table 2 shows the results.

As is clear from the examples and comparative examples, the patch of the present invention contains a reinforcing fibrous filler in the pressure-sensitive adhesive layer, and therefore has an excellent balance between tackiness and cohesiveness. This means that the adhesive strength value (F) of the patch is 200 g or more,
It is proved from the ratio of holding force value (H) to adhesive force value (F): H / F> 0.3 sec / g. Therefore, the stringing phenomenon and the residue of the adhesive on the skin are not recognized even in the finger touch compression / removal test of the adhesive. Moreover, even if this patch is applied to a human body, the exudation of the adhesive is small. Moreover, the adhesive does not remain on the skin of the human body after the patch is peeled off. In the patch of the present invention, since the pressure-sensitive adhesive layer is composed of a pressure-sensitive adhesive having a glass transition temperature (Tg) of −71 ° C. or less, a large amount of drug can be contained in the pressure-sensitive adhesive layer and release of the drug can be achieved. It has excellent properties.

An adhesive patch containing no reinforcing filler in the adhesive layer has a poor balance between adhesiveness and cohesiveness, and its adhesive force is 200 g or more, but the ratio of holding force value (H) to adhesive force value (F) : H / F
≦ 0.3 seconds / g. Therefore, when this patch is applied to a human body, the adhesive oozes out to the peripheral portion, and the patch remarkably shifts. Moreover, after peeling off the patch, the adhesive remains on the skin of the human body and becomes dirty. Glass transition temperature (Tg) is -71
A patch whose pressure-sensitive adhesive layer comprises a pressure-sensitive adhesive having a temperature higher than 0 ° C cannot contain a large amount of a drug in the pressure-sensitive adhesive layer. Moreover, the release of the drug from the adhesive layer is also poor. In addition, this patch is poor in adhesion to the skin because it is less familiar to the skin. Therefore, when this patch is applied, a floating phenomenon (that is, peeling) occurs in the peripheral portion of the patch.

(Effect of the invention) In the patch of the present invention, since the novel acrylic acid ester-based polymer having a glass transition temperature (Tg) of −71 ° C. or less is used as the pressure-sensitive adhesive, the pressure-sensitive adhesive layer is A large amount of the drug is dissolved, and the drug is highly released. Moreover, since this patch contains a reinforcing filler in the pressure-sensitive adhesive layer, it has an excellent balance between tackiness and cohesiveness. Therefore, if this patch is used, the drug efficacy is increased and the drug utilization efficiency is increased. It is economical because a large amount of drug can be contained in one patch. Furthermore, even when the patch is applied to the skin of the human body, the exudation of the adhesive and the displacement of the patch are small. Even when the skin is stretched, the patch will not shift. The human body does not feel any pain when peeling the patch from the skin. The adhesive does not remain on the skin after peeling the patch. Therefore, according to this patch, the patient does not feel pain or discomfort. By combining the Tg value of the adhesive in the patch and the reinforcing filler, the selection range of the substance used as the material of the adhesive can be expanded.

Claims (1)

(57) [Claims] 1. A patch having a backing support layer and a pressure-sensitive adhesive layer, wherein the pressure-sensitive adhesive layer comprises a pressure-sensitive adhesive having a glass transition temperature (Tg) of −71 ° C. or lower, a reinforcing filler, and a drug. Contained, the pressure-sensitive adhesive is mainly composed of a non-acrylic compound, and the coercive force value (H) and the cohesive force value (F) of the pressure-sensitive adhesive layer are as follows:
A patch that satisfies the relationship between the formula and the formula b. H / F> 0.3 (sec / g)… a F> 200 (g)… b