JP3285617B2 - Patch - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a patch used for transdermal or transmucosal administration of a drug.

[0002]

2. Description of the Related Art In general, a transdermal patch is used to absorb a drug (a physiologically active substance) through the skin in order to obtain a systemic or local drug effect. In this case, if the viscosity of the pressure-sensitive adhesive layer of the patch is high, the drug is difficult to diffuse in the pressure-sensitive adhesive layer, and a predetermined drug release property may not be obtained.

[0003] Therefore, a compound having a plasticizing action to the pressure-sensitive adhesive layer, a plasticizer is blended to adjust the viscosity of the pressure-sensitive adhesive layer,
By controlling the release of the compounded drug, a predetermined transdermal absorption performance is obtained. However, a plasticizer added to obtain a predetermined drug release may cause excessive pressure-sensitive adhesive plasticization and excessively reduce the cohesive force of the pressure-sensitive adhesive. As a result, there are problems such as the adhesive layer protruding outside the support, sticking of the glue at the time of sticking or peeling, and contaminating the fingers, and a part of the adhesive remaining on the skin after peeling. is there.

Further, excessive plasticization of the pressure-sensitive adhesive increases the pressure-sensitive adhesive strength more than necessary, and peels off the keratin and body hair of the skin at the time of peeling, causing a problem such as causing pain and irritating the skin. There was a point.

As one solution to the above problems, for example, there is a method for improving the cohesive force of the pressure-sensitive adhesive. For this purpose, a monomer having a polar group such as a carboxyl group, a hydroxyl group or an amide group is generally copolymerized. Means such as a method of introducing as a component, a metal ion cross-linking, a urethane cross-linking, an epoxy cross-linking, a melamine cross-linking, and a cross-linking by a radical reaction with a peroxide or an electron beam are employed. However, both methods reduce the drug release performance,
There is a problem that the decomposition of the drug compounded in the adhesive is accelerated.

In order to solve the above-mentioned problems, for example, Japanese Patent Application Laid-Open No. 3-291218 discloses a method in which silicic anhydride is blended in an adhesive layer. However, this method has a problem that a high release of a drug cannot be obtained because the amount of a plasticizer that can be added is limited.

Further, for example, Japanese Patent Application Laid-Open No. Hei 4-29927 discloses that a water-absorbing filler is contained to
To improve drug release and release coating properties
However, water-absorbing fillers tend to absorb moisture,
There is a problem of being restricted by a manufacturing environment and a storage environment.

[0008]

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned drawbacks, and has as its object to increase the release of a drug from an adhesive layer and to suppress a decrease in the cohesive force of the adhesive. It is another object of the present invention to provide a patch with reduced adhesive residue on the skin and irritation to the skin.

[0009]

The patch of the present invention is a patch in which a pressure-sensitive adhesive layer is provided on one surface of a support, wherein the pressure-sensitive adhesive layer comprises a (meth) alkyl acrylate copolymer. A composition comprising 10 to 90% by weight, 2 to 70% by weight of a plasticizer, 1 to 20% by weight of an inorganic filler and 0.1 to 40% by weight of a drug (provided that they absorb water and swell, and
Do not contain water-absorbing fillers that do not qualitatively swell.
And the ball tack value of the copolymer is 2
And the weight average molecular weight is 1.2 million to 500
The above-mentioned object is achieved.

Hereinafter, the present invention will be described in detail. The support used in the present invention is not particularly limited, and examples thereof include nonwoven fabrics and fabrics; synthetic resins such as polyester, polyethylene, polyvinyl chloride, polyvinylidene chloride, polyethylene-vinyl acetate copolymer, and polyurethane. Film: a simple substance such as an aluminum foil and a laminate thereof.

As the alkyl (meth) acrylate copolymer used in the present invention, a copolymer containing an alkyl (meth) acrylate having an alkyl group of 1 to 18 carbon atoms as a copolymer component is preferable. used.

Examples of the alkyl (meth) acrylate include methyl (meth) acrylate, ethyl (meth) acrylate, n-butyl (meth) acrylate, isobutyl (meth) acrylate, and (meth) acrylic acid. Hexyl acid, octyl (meth) acrylate, isooctyl (meth) acrylate, decyl (meth) acrylate,
Isodecyl (meth) acrylate, (meth) acrylic acid 2
-Ethylhexyl, lauryl (meth) acrylate, stearyl (meth) acrylate and the like.

The above copolymer has a weight average molecular weight (hereinafter referred to as Mw).
), When it gets smaller, glue remains when peeling off,
If it becomes large, it becomes difficult to coat the support.
Limited to 10,000 to 5 million.

The ball tack value of the above copolymer is as follows:
Because larger the adhesive residue and skin irritation patch of the present invention is produced, it is limited to less than 2. The ball tack value is a value measured in accordance with the tack (ball rolling method) test method of JIS Z0237 (adhesive tape / adhesive sheet test method).

The above copolymer is prepared by ordinary polymerization methods such as solution polymerization and bulk polymerization. Further, a tackifier, an antioxidant, a liquid rubber, a softener, an antioxidant, a coloring agent, a filler, and the like may be added to the copolymer as necessary.

The plasticizer used in the present invention includes, for example, compounds such as esters, hydrocarbons, alcohols, and amides. Particularly, fatty acid esters are preferably used.

Examples of the fatty acid esters include cetyl octanoate, hexyl laurate, isopropyl myristate, octyl dodecyl myristate, isopropyl palmitate, octyl palmitate, butyl stearate, octyl stearate, octyl hydroxystearate, isononane. Monohydric alcohol fatty acid esters such as isotridecyl acid, decyl oleate, ethyl mink oil fatty acid, and myristyl lactate; diisopropyl adipate, dioctyl adipate, diethyl sebacate,
Dibasic acid esters such as dioctyl succinate; polyhydric alcohol fatty acid esters such as propylene glycol dicaprate, glyceryl trioctanoate, glyceryl tri (octanoate / decanoate), glyceryl tripalmitate, sorbitan oleate and neutral fatty acid fats and oils Olive oil, safflower oil, coconut oil fatty acid triglyceride,
Animal and vegetable oils such as cottonseed oil; hydrocarbons such as squalane, α-olefin oligomer, liquid paraffin, and wax; alcohols such as cetanol, behenyl alcohol, 2-hexyldecanol, 2-octyldecanol, oleyl alcohol; polyoxyethylene lauryl ether And amide compounds such as oleamide and lauric acid monoethanolamide; and silicones such as dimethylpolysiloxane and methylphenylpolysiloxane.

In the present invention, if the amount of the plasticizer is too small, the effect of releasing the drug from the pressure-sensitive adhesive layer is not exhibited, and if the amount is too large, the cohesive force of the pressure-sensitive adhesive layer is reduced.
To 70% by weight.

In the present invention, the inorganic filler is blended to improve the cohesive strength of the patch, and for example,
Calcium carbonate, kaolin, clay, bentonite, talc, titanium oxide, zinc oxide, magnesium oxide, magnesium stearate, light anhydrous silicic acid (for example, “Aerosil” manufactured by Nippon Aerosil Co., Ltd.) and the like are preferably used.

In the present invention, the compounding amount of the inorganic filler is
It is determined by the type, composition and molecular weight of the adhesive, the type and blending amount of the drug, the type and blending amount of the plasticizer, and the like. The amount of the inorganic filler is generally limited to 1 to 20% by weight in the composition, and is preferably limited to 4 to 20% by weight, since the effect of improving the cohesive strength is not obtained when the amount is small, and the adhesiveness of the pressure-sensitive adhesive layer is insufficient when the amount is large. 18% by weight.

Drugs (bioactive substances) used in the present invention
The drug is not particularly limited as long as it is a drug that acts on a living body by transdermal administration or transmucosal administration. Examples of the above-mentioned drugs include antipyretic and anti-inflammatory analgesics, steroidal anti-inflammatory drugs, vasodilators, agents for hypertension / arrhythmia, antihypertensive agents, antitussives, antitumor agents, local anesthetics, hormonal agents, asthma -Nasal allergy treatment agents, antihistamines, anticoagulants, antispasmodics, cerebral circulation / metabolic improvers, antidepressants / anxiolytics, vitamins, hypoglycemic agents, antiulcer agents, sleeping pills, antibiotics and the like.

The pressure-sensitive adhesive layer used in the patch of the present invention comprises:
The copolymer is composed of a mixture of a plasticizer, an inorganic filler and a drug. The smaller the amount of the drug, the lower the efficacy and the larger the amount, the lower the sticking property. It is limited to 1 to 40% by weight.

In order to produce the patch of the present invention, an ordinary method for producing an adhesive tape is employed, for example, a solution coating method or a hot melt coating method. As the above solution coating method, for example, after uniformly mixing the copolymer and other components, coating and drying on a support to form an adhesive layer, or the copolymer and other components Is transferred to a support by transferring the mixture onto a release paper and drying the pressure-sensitive adhesive layer. Examples of the hot melt coating method include, for example, a method in which a copolymer and other compounds are heated, melted, uniformly mixed, and then melt-coated on a support to form an adhesive layer. Can be

The thickness of the pressure-sensitive adhesive layer is 10 to 2000 μm
Is preferred. A release paper for protecting the pressure-sensitive adhesive layer may be laminated on the pressure-sensitive adhesive layer, if necessary.

The ball tack value of the pressure-sensitive adhesive layer used in the patch of the present invention is preferably in the range of 4 to 13. The ball tack value is JIS Z0237 (adhesive tape /
This is a value measured in accordance with the tack (ball rolling method) test method of (Adhesive sheet test method).

[0026]

Embodiments of the present invention will be described below. (Example 1) (1) Preparation of (meth) acrylic acid alkyl ester copolymer 9322 g of 2-ethylhexyl methacrylate, 1642 g of dodecyl methacrylate, and 3600 g of ethyl acetate
Is uniformly mixed in a 40-liter polymerization machine, heated to 80 ° C., and a polymerization reaction is carried out while adding a solution of 60 g of lauroyl peroxide dissolved in 3 liter of cyclohexane over 10 hours to prepare a copolymer. did. The Mw of the obtained copolymer was 1,630,000.

(2) Preparation of patch The above copolymer, isopropyl myristate, hydrophilic light anhydrous silicic acid (trade name “AEROSI” manufactured by Nippon Aerosil Co., Ltd.)
LA-200 ”) and isosorbide dinitrate (coronary vasodilator) were blended so that the composition after drying was as shown in Table 1, dissolved in ethyl acetate, and then uniformly mixed with a dissolver to obtain a nonvolatile component. A 30% by weight dispersion was prepared. The dispersion was coated on a polyethylene terephthalate film so that the thickness after drying was 100 μm, and dried at 60 ° C. for 30 minutes to form an adhesive layer. Next, polyethylene terephthalate and EVA are placed on the pressure-sensitive adhesive layer.
A patch was prepared by laminating a laminated film of (ethylene-vinyl acetate copolymer).

(3) Measurement of ball tack value The ball tack value of the copolymer and the pressure-sensitive adhesive layer was measured according to JIS.
It was measured in accordance with the tack (ball rolling method) test method of Z0237 (adhesive tape / adhesive sheet test method), and the results are shown in Table 1.

(4) Adhesive Remaining Test The patch was cut into a size of 15 × 15 mm to prepare a sample. The sample was peeled off 24 hours after the sample was applied to the chest of the subject, and the state of the adhesive residue was visually observed. Observation was made and evaluated according to the following criteria. The results are shown in Table 1. ◎: No adhesive residue at all, ○: Almost no adhesive residue, Δ: Slight adhesive residue around, ×: Adhesive residue throughout.

(5) Drug Release Test The drug release was evaluated by a nude mouse skin permeability test. The skin from the back of a nude mouse was fixed to a Franz diffusion cell, and a circular patch having a diameter of 1 cm was attached to the upper part of the skin. The diffusion cell was kept at a constant temperature of 37 ° C., and a physiological saline containing 20% polyethylene glycol was used as a receptor solution. High-performance liquid chromatography (HPLC) measures the amount of drug transferred to the receptor liquid under the skin 24 hours after application.
The drug release from the patch was evaluated by measuring the amount of the transferred drug with respect to the drug in the patch, and the results are shown in Table 1.

Example 2 9351 g of 2-ethylhexyl methacrylate, 1645 g of dodecyl methacrylate and 3600 g of ethyl acetate were placed in a 40-liter polymerization machine, mixed uniformly, heated to 80 ° C., and heated to lauroyl peroxide 6.
A solution of 2 g dissolved in 3 liters of cyclohexane is added to 10
The polymerization reaction was carried out while adding over time to prepare a copolymer (Mw of the copolymer: 2.04 million).
In the same manner as in Example 1, an adhesive layer was formed to obtain a patch. Using the obtained copolymer and patch, evaluation was performed in the same manner as in Example 1, and the results are shown in Table 1.

Example 3 5575 g of 2-ethylhexyl methacrylate, 5584 g of dodecyl methacrylate and 3600 g of ethyl acetate were placed in a 40-liter polymerization machine, mixed uniformly, heated to 80 ° C., and then heated to lauroyl peroxide 6.
A solution of 2 g dissolved in 3 liters of cyclohexane is added to 10
A polymerization reaction was carried out while adding over time to prepare a copolymer (Mw of the copolymer: 2.13 million).
In the same manner as in Example 1, an adhesive layer was formed to obtain a patch. Using the obtained copolymer and patch, evaluation was performed in the same manner as in Example 1, and the results are shown in Table 1.

(Example 4) 3085 butyl acrylate
g, butyl methacrylate 12428 g and ethyl acetate 3
600 g was placed in a 40 liter polymerization machine and mixed uniformly.
After heating to 0 ° C., a polymerization reaction was carried out while adding a solution of 62 g of lauroyl peroxide in 3 liters of cyclohexane over 24 hours, and the copolymer (M of the copolymer) was added.
w: 2.05 million). Compositions of the above copolymer, isopropyl myristate, hydrophilic light anhydrous silicic acid (manufactured by Nippon Aerosil Co., Ltd., trade name "AEROSIL A-200") and isosorbide dinitrate (coronary vasodilator) are as shown in Table 1 after drying. And dissolved in ethyl acetate, and then uniformly mixed with a dissolver to obtain about 30 non-volatile components.
After preparing a dispersion by weight of 1% by weight, in the same manner as in Example 1,
An adhesive layer was formed to obtain a patch. Using the obtained copolymer and patch, evaluation was performed in the same manner as in Example 1,
The results are shown in Table 1.

Comparative Example 1 9332 g of 2-ethylhexyl methacrylate, 1661 g of dodecyl methacrylate and 3600 g of ethyl acetate were uniformly mixed in a 40-liter polymerization machine, heated to 80 ° C., and 63 g of lauroyl peroxide was added to cyclohexane 3 The polymerization reaction was carried out while adding the solution dissolved in 1 liter over 10 hours, and the copolymer (Mw of copolymer: 110
10,000) was prepared. 74.6 parts by weight of the above copolymer, 4.7 parts by weight of isopropyl myristate, hydrophilic light anhydrous silicic acid (trade name “AEROSIL A- manufactured by Nippon Aerosil Co., Ltd.”)
200 ”) 10.4 parts by weight of isosorbide dinitrate and 10.3 parts by weight of isosorbide dinitrate (coronary vasodilator) were mixed, dissolved in ethyl acetate, and uniformly mixed with a dissolver to obtain about 3 nonvolatile components.
After preparing a 0% by weight dispersion, an adhesive layer was formed in the same manner as in Example 1 to obtain a patch. Evaluation was performed in the same manner as in Example 1 using the obtained copolymer and patch.
went.

Comparative Example 2 The copolymer prepared in Comparative Example 1, isopropyl myristate, hydrophilic light anhydrous silicic acid (trade name “AEROSIL A- manufactured by Nippon Aerosil Co., Ltd.”)
200 ") and isosorbide dinitrate (a coronary vasodilator)
Formulated so that the composition after drying becomes the ratio shown in Table 1, dissolved in ethyl acetate, and then uniformly mixed with a dissolver,
After preparing a dispersion having a nonvolatile component content of about 30% by weight, an adhesive layer was formed in the same manner as in Example 1 to obtain a patch. Using the obtained copolymer and patch, evaluation was performed in the same manner as in Example 1, and the results are shown in Table 1.

[0036]

[Table 1]

[0037]

The patch of the present invention has the above-mentioned pressure-sensitive adhesive layer composition, which can realize a high drug release property and can prevent an excessive decrease in cohesive force. It does not protrude and does not cause adhesive residue or skin irritation when peeled off.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. ⁷ , DB name) A61K 47/32 A61K 9/70 401

Claims (1)

(57) [Claims] 1. A patch having a pressure-sensitive adhesive layer provided on one surface of a support, wherein the pressure-sensitive adhesive layer comprises 10 to 90% by weight of a (meth) acrylic acid alkyl ester copolymer, and 2 to 7 plasticizers.
0% by weight, inorganic filler 1-20% by weight and drug 0.1-
Composition consisting of 40% by weight (however, it absorbs water and swells
And water absorbing properties that do not substantially swell with the drug
And a ballistic value of less than 2 and a weight average molecular weight of 1.2 to 5,000,000.