JP3537947B2 - Patch - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a patch.

[0002]

2. Description of the Related Art Patches allow a drug to be absorbed into the body by the distribution, diffusion, and transfer of the drug from the adhesive base or drug reservoir to the skin. Therefore, it is known that the skin transfer rate varies depending on the state of the drug in the base. In particular, it is known that the higher the drug concentration in the adhesive base, the higher the transfer rate to the skin, and the higher the drug concentration in the adhesive base than the saturation solubility, that is, the higher the transfer rate in a supersaturated state. ing.

For example, JP-A-60-16916, JP-A-60-185713, and JP-A-63-3552
No. 1 and JP-A-63-93714 propose a patch in a supersaturated state in which a drug crystal is precipitated by increasing the drug concentration in an adhesive base, and furthermore, its saturation solubility is exceeded.

However, a patch in a supersaturated state has a problem that a drug crystal is precipitated due to a decrease in the supersaturated state during distribution, and a patch in which a drug crystal has been deposited is more than a supersaturated state on the adhesive layer. Since the drug is contained, a large amount of the drug is required, and the production cost is increased. In addition, in the method of gradually depositing in a supersaturated state first, it takes a long time to deposit, and the production efficiency is significantly reduced.

[0005] In addition to the above-mentioned publication, JP-A-62-273913 discloses a method for producing a transdermal absorption preparation in which a drug having a saturation solubility or higher is dispersed in an adhesive base. However, when the drug crystals are precipitated before distribution, there is a problem that the production efficiency is reduced as described above, and when the crystals are precipitated at the distribution stage, the crystal state at the time of reaching the user is managed. It is very difficult.

In the method of depositing drug crystals in a dispersed state, it is difficult to uniformly disperse the crystals when the viscosity of the adhesive base or the adhesive base solution is high, and a preparation of uniform quality is obtained. It becomes difficult.

On the other hand, when using a patch, there is a problem that pain is caused at the time of peeling, and there is a problem that adhesiveness is lost when reattaching. In order to solve such problems, a method of increasing the molecular weight of the pressure-sensitive adhesive, a method of crosslinking the pressure-sensitive adhesive with an electron beam or light, and the like are known. However, when the molecular weight is increased, the viscosity increases, so that the production efficiency decreases and the cost increases. In the case of cross-linking, new processes are added and special equipment is required. In addition, a method of adding a liquid component to reduce the adhesive force at the time of peeling has been attempted, but the addition of the liquid component reduces the cohesive force of the adhesive and generates adhesive residue, so the cohesive force is newly improved. It is necessary to mix additives to be added.

As described above, various attempts have been made on the skin permeability (percutaneous absorbability) and patching properties of patches, but no satisfactory preparations have been obtained.

[0009]

SUMMARY OF THE INVENTION The present invention has been made to solve the above problems, and its object is to use nitric acid as a drug.
An object of the present invention is to provide a patch which contains isosorbide stably at a high concentration, has a high transdermal absorption effect, has a reduced peeling force at the time of peeling, and has good sticking properties without adhesive residue.

[0010]

The patch of the present invention is a patch in which a pressure-sensitive adhesive layer made of an acrylic pressure-sensitive adhesive is laminated on one side of a support, and the adhesive layer has a nitric acid nitrate as a drug.
Sosorbide , and 1 to 10% by weight of an alkyl oleate as a drug supersaturation stabilizer;
One of the above drugs has a saturation solubility of 1.2 to 1.
Contains 5 times supersaturation (anhydrous silica
Excluding those containing acids) .

As the acrylic pressure-sensitive adhesive, (meth)
Alkyl acrylate (co) polymers are preferred.
Examples of the alkyl (meth) acrylate include methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl (meth) acrylate, and (meth) acrylate. )
Octyl acrylate, 2-ethylhexyl (meth) acrylate, isooctyl (meth) acrylate, decyl (meth) acrylate, isodecyl (meth) acrylate, lauryl (meth) acrylate, stearyl (meth) acrylate, etc. And one or more of these are used.

Further, as the acrylic pressure-sensitive adhesive, a functional monomer copolymerizable with the alkyl (meth) acrylate can be used, if necessary. Examples of the functional monomer include vinyl pyrrolidone,
Examples thereof include vinyl acetate, acrylonitrile, and styrene, and further include monomers having a carboxyl group, a hydroxyl group, an amide group, an epoxy group, an amino group, and the like.

Examples of the monomer having a carboxyl group include α-β unsaturated carboxylic acids such as (meth) acrylic acid; monoalkyl maleates such as butyl maleate; (anhydride) maleic acid; crotonic acid; Acid; fumaric acid and the like. Examples of the monomer having a hydroxyl group include (meth) acrylic acid 2-
Examples include hydroxyethyl, hydroxypropyl (meth) acrylate, mono (hydroxyethyl) maleate, ethylene glycol mono (meth) acrylate, and propylene glycol mono (meth) acrylate.

The above-mentioned monomer having an amide group includes
For example, alkyl (meth) such as (meth) acrylamide, dimethylacrylamide, diethylacrylamide, etc.
Acrylamide; N-alkoxy (methyl) acrylamide such as butoxymethylacrylamide and ethoxymethylacrylamide; and diacetoneacrylamide. As the monomer having an epoxy group,
For example, glycidyl (meth) acrylate and the like can be mentioned. Examples of the monomer having an amino group include, for example,
Examples thereof include dimethylaminoethyl (meth) acrylate and t-butylaminoethyl (meth) acrylate. The functional monomer is added to such an extent that it does not affect the tackiness and cohesiveness of the pressure-sensitive adhesive.
５０50% by weight.

As the acrylic pressure-sensitive adhesive, 25 to 50% by weight of an alkyl (meth) acrylate having 4 to 18 carbon atoms in the alkyl group and an alkyl (meth) acrylate having 3 or less carbon atoms in the alkyl group. Copolymerization of 20 to 70% by weight and 2 to 40% by weight of vinylpyrrolidone
The body is preferred.

The acrylic pressure-sensitive adhesive base is polymerized by an ordinary known method, and is prepared by, for example, blending the above-mentioned monomer in the presence of a polymerization initiator and performing solution polymerization. However, the polymerization conditions are appropriately selected mainly depending on the type of the monomer.

[0017] In the above-mentioned drug products, as described above, blood vessel expansion
Limited to isosorbide dinitrate, a tonic .

[0018]

[0019]

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0026]

[0027]

Examples of the alkyl oleate include methyl oleate, ethyl oleate, propyl oleate, butyl oleate, lauryl oleate, decyl oleate, palmityl oleate, and the like. Is preferably an alkyl oleate of 1 to 16, particularly preferably decyl oleate.

In general, when a drug having a solubility equal to or higher than the saturation solubility is contained in the pressure-sensitive adhesive layer so as to be in a supersaturated state, crystals are precipitated at the time of formulation, and even if crystals do not precipitate immediately after the formulation, the aging or the Crystals are deposited due to environmental conditions and the like. In the patch of the present invention, the supersaturated state is stably maintained by including an alkyl oleate in the pressure-sensitive adhesive layer. Therefore, the oleic acid alkyl ester acts as a drug supersaturation stabilizer when the drug is contained at a saturation solubility or higher.

When the content of the alkyl oleate in the pressure-sensitive adhesive layer is reduced, the supersaturated state cannot be stably maintained. When the content is increased, the adhesive force to the skin decreases, and the adhesive force decreases due to a decrease in cohesive force. since the remainder is or cause, Ru limited to one to 10 wt%. In this case, the drug is contained in the pressure-sensitive adhesive layer at a saturation solubility or higher, but when the content is low, the transfer rate of the drug to the skin is not sufficient, and the effect is larger than when the content is the saturation solubility or lower. Can not be expected, and if it is increased, the supersaturated state cannot be maintained stably, so it is limited to 1.2 to 1.5 times the saturated solubility.
You .

In the patch of the present invention, by containing an alkyl oleate in the pressure-sensitive adhesive layer,
The peeling force at the time of peeling is reduced, and pain can be prevented. Therefore, the oleic acid alkyl ester acts as a peeling force reducing agent. When the content of the oleic acid alkyl ester in the pressure-sensitive adhesive layer is reduced, the peeling force is not sufficiently reduced, so that pain occurs at the time of peeling. since or cause, Ru limited to one to 10 wt%. In this case, since the content of the drug is less becomes the transfer rate of drugs to the skin is not sufficient, the or precipitated crystal in the adhesive layer often can not be maintained stably supersaturated state, saturated <br / > Limited to 1.2 to 1.5 times the total solubility.

When isosorbide dinitrate is used as the above-mentioned drug, 25 to 50% by weight of alkyl (meth) acrylate having 4 to 18 carbon atoms in the alkyl group, and (meth) alkyl having 3 or less carbon atoms in the alkyl group are used as the adhesive. A copolymer comprising 20 to 70% by weight of an alkyl acrylate and 2 to 40% by weight of vinylpyrrolidone has a saturated solubility of
1.2 to 1.5 times isosorbide dinitrate, 1 to 10 % by weight
Of decyl oleate.

The support is not particularly limited as long as it has flexibility, imparts self-supporting properties to the patch, and prevents volatilization and migration of the drug in the adhesive layer. Examples include cellulose acetate, ethyl cellulose, polyethylene, polyurethane, polyethylene terephthalate (PET), plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer (E
VA), ethylene-methyl acrylate copolymer (E
MA), plasticized polyvinyl chloride, polyvinylidene chloride,
Aluminum and the like can be mentioned. The support is used as a film or a woven or non-woven fabric. For example, the support may be used as a single-layer film or sheet, or a film or sheet obtained by laminating two or more kinds, and the thickness is usually 500 μm or less. To 150 μm is preferred. The support is preferably made of a material having the ability to follow the skin. For example, a laminate of polyethylene terephthalate and a polyester nonwoven fabric (PET / polyester nonwoven fabric), a laminate film of polyethylene terephthalate and an ethylene-vinyl acetate copolymer ( PET / EV
A), polyethylene terephthalate film and the like.

The patch of the present invention usually has a release paper to protect the adhesive layer until use. As the release paper, generally used is a polyethylene terephthalate film, a polyethylene-coated high-quality paper, a polypropylene film, or the like, which is subjected to a silicon treatment. The thickness of the release paper is 1000 μm or less, preferably 30 to 200 μm
It is.

The patch of the present invention can be prepared according to a conventional method for producing an adhesive tape, and for example, a solvent coating method, a hot melt coating method, an electron beam curing emulsion coating method and the like can be used. A coating method is preferred. To prepare a patch by a solvent coating method, for example, a drug, an oleic acid alkyl ester and, if necessary, an absorption enhancer, a plasticizer or other additives are dissolved or dispersed in an adhesive solution,
The resulting solution is applied to one side of the support and dried to form a pressure-sensitive adhesive layer having a predetermined thickness. Apply the above solution on release paper
After drying, the support may be adhered to the obtained pressure-sensitive adhesive layer. The thickness of the pressure-sensitive adhesive layer varies depending on the purpose of use, but when it is small, it cannot contain the required amount of drug, and when it is large, the drug near the support does not sufficiently diffuse into the pressure-sensitive adhesive layer and the drug release rate decreases. So usually 10-20
0 μm.

The patch obtained as described above is directly applied to the skin or mucous membrane in order to administer the drug transdermally or transmucosally to the circulatory system.

[0037]

The present invention will be described in more detail with reference to the following examples. [Preparation of adhesive solution] Octyl acrylate 40% by weight
(200 g), 50% by weight of ethyl acrylate (250
g) and 10% by weight (50 g) of vinylpyrrolidone were charged into a separable flask, and the initial monomer concentration of polymerization was 5%.
500 g of ethyl acetate was added so as to be 0% by weight. This solution was heated to a temperature of 80 ° C. under a nitrogen atmosphere, and lauroyl peroxide as a polymerization initiator was gradually added little by little to obtain a solution.
Polymerization was performed for a time to obtain an acrylic pressure-sensitive adhesive solution.

(Examples 1 to 5 and Comparative Examples 1 to 13)
And the composition shown in Table 2 was added to the adhesive solution, drug (isosorbide dinitrate), alkyl oleate (decyl oleate), and other additives.
Ethyl acetate was added so as to be 0% by weight, and the mixture was stirred overnight using a ball mill so that the whole was uniform to obtain a coating liquid. (The numerical values in the table indicate weight% as solid content)

This coating solution was applied on release paper obtained by subjecting a polyethylene terephthalate film having a thickness of 75 μm to silicon treatment so that the thickness after drying became 40 μm.
It dried in a gear oven at 30 degreeC for 30 minutes, and formed the adhesive layer. This was adhered to a support to obtain a patch.
As a support, a polyethylene terephthalate film having a thickness of 38 μm was used for Examples 1 and 2 and Comparative Examples 1 to 3, and a polyethylene terephthalate-polyester nonwoven fabric (manufactured by Toyobo Co., Ltd., polyethylene terephthalate) was used for Examples 3 to 5 and Comparative Examples 4 to 12. : 7 μm, polyester nonwoven fabric: 40 g / m ² ).

The following test was carried out on the patch obtained above. Test Example 1 The patches obtained in Examples 1 and 2 and Comparative Examples 1 to 3 were punched into 37 cm ² and stored in a thermostat set at 1 ° C., and after 36 days, the presence or absence of crystal precipitation was observed. . Table 1 shows the results. [Test Example 2] The patches obtained in Examples 3 to 5 and Comparative Examples 4 to 12 were punched into a piece of 4 cm x 4 cm, and the adhesive surface was lightly touched with a finger and released (finger tack test), followed by peeling. The force and cohesion were sensory evaluated. Comparative Example 4 containing no additive was used as a control, and the change in peeling force or cohesive force was evaluated based on the patch of Comparative Example 4. Table 2 shows the results.

[0041]

[Table 1]

[0042]

[Table 2]

From the above results, when decyl oleate was added, no precipitation of crystals was observed, even though the drug was mixed in an amount of about 1.5 times the saturation solubility. Also, by adding decyl oleate, the peeling force could be reduced without decreasing the cohesive force.

[0044]

The patch of the present invention is as described above and contains an alkyl oleate, so that the drug can be contained at a saturation solubility or higher and can be stably maintained in a supersaturated state. Moreover, since the alkyl oleate is contained, the peeling force is reduced without lowering the cohesive force, and it is possible to prevent pain at the time of peeling,
Physical irritation due to peeling can be prevented. Therefore, a patch having a high transdermal absorption effect and an excellent sticking property can be easily obtained at low cost.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. ⁷ , DB name) A61K 9/70 A61K 31/70 A61K 47/14 A61P 9/10

Claims (3)

(57) [Claims] 1. A patch comprising a support and a pressure-sensitive adhesive layer comprising an acrylic pressure-sensitive adhesive laminated on one side thereof, wherein said pressure-sensitive adhesive layer comprises isosorbide dinitrate as a drug and a drug supersaturation stabilizer.
Alkyl oleates 1-10 wt% are contained as, and the drug saturation solubility in the pressure-sensitive adhesive layer
A patch characterized by being contained in a supersaturated state of 1.2 to 1.5 times the degree of adhesion (silicic acid anhydride contained in the pressure-sensitive adhesive layer)
) . 2. The method of claim 1, wherein the alkyl oleate is oleic acid.
The patch according to claim 1, which is decyl. 3. The acrylic pressure-sensitive adhesive according to claim 1, wherein the number of carbon atoms in the alkyl group is
Having 4 to 18 alkyl (meth) acrylates 25
(Meta) having an alkyl group carbon number of 3 or less by weight
20-70% by weight of alkyl acrylate and vinyl
A copolymer comprising 2 to 40% by weight of lupyrrolidone
The patch according to claim 1 or 2, characterized in that: