JP3496169B2 - Plaster and production method thereof - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a plaster comprising, for example, a release paper, a plaster layer spread on the release paper, and a support coated on the surface of the plaster layer. The present invention relates to a plaster and a method for producing the same, in which even an active ingredient that has been considered to be difficult to absorb through the skin can achieve a dramatic percutaneous absorption over time.

[0002]

2. Description of the Related Art In the percutaneous absorption mechanism of a patch, in order to percutaneously absorb the active ingredient over time, the active ingredient should be well retained in the patch, and the active ingredient in the patch should be retained. Continuous percutaneous absorption must be achieved by supplementing the active ingredient with diffusion of other parts of the patch accompanying skin absorption.

There are already various patches for percutaneously absorbing the active ingredient, but the active ingredient to be used has a characteristic peculiarity to the active ingredient due to its characteristics such as molecular weight, polarity and modifying group. It had a skin absorption. this is,
This is because there is a stratum corneum that inhibits invasion of water and the like into the skin.

[0004]

[Problems to be Solved by the Invention] Various measures have been taken to satisfactorily percutaneously absorb an active ingredient. In order to pass this stratum corneum well, ethanol, peppermint oil,
Although an absorption promoter such as L-menthol is added, there is a limit to this.

An object of the present invention is to obtain a plaster having a completely new composition which enables good transdermal absorption of the active ingredient into the body and a method for producing the same.

[0006]

In the plaster according to the invention described in claim 1, a release paper, a plaster layer spread on the release paper, and a coating on the surface of the plaster layer. In a plaster consisting of a coated support, the plaster layer is styrene-iso
Adhesion with a main component of prene-styrene block copolymer
After the base is dissolved in an organic solvent and spread on the release paper,
Styrene-isoprene- obtained by drying the organic solvent
On the side of the release paper of the adhesive base mainly composed of styrene block copolymer, the solubilizer liquid containing the active ingredient is added to the organic solvent.
The diameter is 2 μm to 40 μ when stirred in a melted substance dissolved in a medium.
Disperse a liquid foam composed of a solubilizer containing the active ingredient of m.
The solubilizer is propylene glycol, 1,
3-butylene glycol, polyethylene glycol 400
The adhesive group is selected from any one kind or two or more kinds of them.
It is contained in an amount of more than 10% by weight with respect to the agent .

[0007]

In the plaster according to the invention described in claim 2 , the solubilizing agent according to claim 1 contains the active ingredient exceeding the solubility in the solubilizing agent.

[0009]

In the plaster according to the invention described in claim 3 , the active ingredient described in claim 1 contains estradiol or flurbiprofen.

In the method for producing a plaster according to the present invention as set forth in claim 4 , a plaster is prepared by spreading a plaster on a release paper, drying the plaster, and then applying a support on the surface of the plaster. In the method for producing an agent, as the plaster layer, an adhesive base having a styrene-isoprene-styrene block copolymer as a main component is dissolved in an organic solvent, and a solubilizer liquid containing an active ingredient in the dissolved product. stirred diameter is dispersed in 2μm~40μm like liquid foam, and the lysate was the dispersion was spread on release paper, the organic solvent is dried, depositing a support surface Monodea
As the solubilizer liquid, propylene glycol, 1,
3-butylene glycol, polyethylene glycol 400
Use one selected from one or more of them
An adhesive base obtained by drying the solubilizer liquid with the organic solvent.
With respect to 10% by weight .

[0012]

In the present invention, in a plaster comprising a release paper, a plaster layer spread on the release paper, and a support adhered on the surface of the plaster layer, the plaster layer is , Styrene-
A pressure-sensitive adhesive base containing an isoprene-styrene block copolymer as a main component (hereinafter referred to as "SIS copolymer pressure-sensitive adhesive base" having a liquid foam containing a solubilizing agent containing an active ingredient dispersed on the release paper side. Therefore, a dramatic transdermal absorbability can be obtained even with an active ingredient that has been conventionally considered difficult to percutaneously absorb.

The solubilizer used in the present invention is one selected from propylene glycol, 1,3-butylene glycol and polyethylene glycol 400, or two or more thereof. For example, propylene glycol (CH ₃ CH
(OH) CH ₂ OH) is used as a moisturizer and solubilizer.
Mix with methanol, ethanol, ethyl acetate or pyridine. Utilizing its hygroscopicity, it is used as a substance that prevents evaporation of water in the preparation and retains water in the skin. In addition, 1,3-butylene glycol (CH ₃ CH
(OH) CH ₂ CH ₂ OH) is also used as a moisturizer and a solubilizer, and is soluble in water and ethanol. Finally, polyethylene glycol 400 is also a conventional solubilizer.

The action mechanism model of the present invention is shown in FIG.
As shown in Figure c, the plaster of the present plaster has a liquid foam structure of a solubilizer in which the active ingredient is dissolved or crystals thereof are dispersed in the SIS copolymer adhesive base dissolved in an organic solvent. Dispersed and present, the active ingredient is in the liquid foam, not in the SIS copolymer adhesive base.

When the organic solvent that had dissolved the SIS copolymer adhesive base is evaporated and the SIS copolymer adhesive base is cured, the individual liquid bubble structures dispersed inside this base are SIS.
Retained in the copolymer adhesive base. Further, when the release paper is peeled off, a part of the outer wall of the liquid bubble structure on the boundary surface is torn along with the peeling and the active ingredient is exposed on the sticking surface together with the solubilizer.

When a part of the liquid foam structure exposed on the sticking surface is adhered to the skin, the solubilizing agent inside the liquid foam structure penetrates the skin to moisturize the skin and at the same time, the active ingredient dissolved therein. Is easily penetrated into the skin structure, and the SIS adhesive base layer prevents evaporation of water from the skin and hydrates the stratum corneum to help the skin to satisfactorily penetrate into the skin from the adhered surface. Dramatically increase skin absorption.

As described above, the active ingredient and the solubilizing agent are not uniformly dispersed in the plaster layer as in the conventional plaster, but are dispersed in a liquid foam structure. Therefore, it reaches and penetrates the skin irrespective of the diffusion rate in the plaster layer. Therefore, it is possible to obtain a plaster that gives good percutaneous absorption, not only with an active ingredient having good transdermal absorption, but also with an active ingredient having a small transdermal absorption such as estradiol.

Since the SIS copolymer adhesive base is also exposed on the sticking surface, the plaster of the present invention can be easily stuck to the skin or the like immediately after the release paper is peeled off. When left alone for a while, or once peeled and then re-adhered, the solubilizer wraps around the exposed part of the adhesive and covers it, resulting in extremely weak adhesion. have.

In plasters, which require the active ingredient to be transdermally absorbed over a long period of time, it is also an important requirement to replenish the active ingredient with time, which decreases with transdermal absorption.
In the present invention, since the solubilizing agent contains the above-mentioned active ingredient exceeding the solubility in the solubilizing agent, crystals of the active ingredient are also retained in the liquid foam structure. This crystal dissolves and replenishes the active ingredient, which decreases with permeation from the sticking surface. Therefore, continuous transdermal absorption can be performed.

The liquid bubbles of the active ingredient and the solubilizer related to the percutaneous absorption of the present plaster are only those dispersed on the release paper side of the plaster layer and the liquid bubbles in contact therewith. Therefore, it is possible to effectively use the active ingredient to which the liquid foam structure is dispersed only on the release paper side of the plaster layer. Therefore, preferably, the plaster layer in which the liquid foam structure is dispersed is formed as thin as possible. As a preferred example, the diameter of the liquid bubble is 2
Since it was from 40 μm to 40 μm, the thickness of the plaster layer in which the preferable liquid bubble structure is dispersed will be from 50 to 80 μm. still,
If the strength of the plaster layer is a problem, a plaster layer in which the liquid foam structure is not dispersed may be formed on the plaster layer in which the liquid foam structure is dispersed.

Since the specific gravity of the liquid bubbles is usually larger than that of the SIS adhesive base solution, when spread on a release paper, the liquid bubbles settle on the surface of the release paper and are aligned. Therefore, in the present invention,
When the solubilizing agent is contained in an amount of more than 10%, preferably 20% with respect to the adhesive base, the solubilizer is added to the organic solvent solution of the SIS copolymer adhesive base and stirred. In the case of forming a plaster layer that does not further disperse the liquid foam structure on the plaster layer in which the liquid foam structure is dispersed as described above, a good liquid foam structure of the solubilizer can be formed. It is also possible to form a total amount of less than 10%.

Further, as the active ingredient used in the present invention,
Any material may be used as long as it is well retained together with the solubilizing agent in the liquid bubble structure and increases the percutaneous absorption amount by the solubilizing agent. The present invention particularly discloses that the active ingredient contains estradiol or that the active ingredient contains flurbiprofen. In particular, the increase in the transdermal absorption amount of estradiol, which is remarkably increased by the liquid foam structure with the solubilizing agent of the present invention, is remarkable.

This estradiol has a very small transdermal absorption amount, and there is a formulation containing a large amount of ethanol.
There was a problem with high skin irritation. With the plaster of the present invention, a drastic increase in percutaneous absorption was obtained without adding a large amount of ethanol. For example, as shown in detail in Examples described later, when propylene glycol was used as a solubilizing agent, with estradiol, a cumulative permeation amount of 20 μg / cm ² or more was measured after application for 24 hours.
Even with flurbiprofen, which has been considered to have a relatively good transdermal absorption, a dramatic cumulative permeation amount of 67 μg / cm ² or more was measured after application for 8 hours.

As described above, the plaster of the present invention can achieve a dramatic percutaneous absorption with time even if the active ingredient is said to be particularly difficult to percutaneously absorb.

In the method for producing a plaster as described above, what is important is the formation of a plaster layer in which liquid bubbles are dispersed on the release paper side. In the production method of the present invention, in the method for producing a plaster in which a plaster is spread on a release paper, the plaster is dried, and then a support is applied to the surface of the plaster; The polymer adhesive base is dissolved in an organic solvent, and the solubilizer solution containing the active ingredient in this solution is stirred to disperse it in the form of a liquid foam; the dispersed solution is spread on a release paper, The organic solvent is dried and a support is attached to the surface.

As a result, a plaster in which the liquid foam structure of the active ingredient and the solubilizer is dispersed in the SIS copolymer adhesive base is obtained. Further, by spreading this plaster on the release paper, the specific gravity of the liquid bubbles is larger than that of the SIS adhesive base solution, so when spread on the release paper, the liquid bubbles settle and line up on the release paper surface side. . Therefore, this liquid bubble structure is arranged on the boundary surface with the release paper, and when the release paper is peeled off, a part of the outer wall of the liquid foam structure on the boundary surface is torn along with the peeling and is effective together with the solubilizer. The component is exposed on the sticking surface.

It should be noted that since the SIS copolymer adhesive base is also exposed on the sticking surface, the plaster of the present invention should be properly stuck to the skin immediately after the release paper is peeled off. There is a point that can. However, if the release paper is peeled off and left for a while, or if it is once attached and then reattached, the solubilizing agent wraps around the exposed portion of the adhesive and covers it. Becomes extremely weak.

Therefore, as a support for supporting the plaster layer, it is a conventional practice that a flexible material is selected in order to fit the sticking surface. However, in the plaster of the present invention, When peeling the release paper and attaching it,
In order to satisfactorily break the structure existing in the boundary surface with at least the release paper of the liquid foam structure dispersed in the plaster layer, more preferably, the path to the sticking surface in the liquid foam structure subsequent to this boundary surface is provided. A flexible material will be chosen to form it.

The SIS copolymer adhesive base used in the present invention is usually used as a hot melt adhesive base, and the SIS copolymer rubber is used as a tackifier such as polyisoprene rubber and terpene resin. And a softening agent such as ester gum, dibutylhydroxytoluene, etc., and an antioxidant are kneaded by heating when necessary. Any of these may be a commercially available SIS copolymer and tackifier. In addition, polyisoprene rubber, SBR, polyisobutylene, silicone rubber and the like can also be used. The adhesive base containing the SIS copolymer as a main component is dissolved in an organic solvent such as ethyl acetate or n-hexane, and the solution is stirred with a solubilizer containing an active ingredient.

When the solution of the SIS copolymer adhesive base in an organic solvent and the solubilizing agent containing the active ingredient are stirred to form a liquid foam structure, what is important is the state of stirring and the viscosity of the solution. is there. If the degree of stirring is not vigorous, good dispersion of the liquid foam structure cannot be obtained. Therefore, it is necessary to vigorously stir the solution of the solubilizer so that it is torn off.

If the melt has a high viscosity, no liquid foam structure can be obtained no matter how vigorous the stirring is. Further, if the viscosity is low, the small liquid bubble structures obtained by stirring stick to each other and become large liquid bubbles before the organic solvent evaporates and the adhesive base is dried, and a good dispersion state cannot be obtained. Therefore, when the viscosity of the solubilizing agent liquid becomes such that it mixes with the adhesive base, while stirring, gradually add the organic solvent to gradually reduce the viscosity, and when the desired liquid bubbles are dispersed, Immediately spread it on release paper and let it dry.

In the present invention, additives other than the active ingredient and the solubilizer may be appropriately added within the range where they can be added normally. For example, as an absorption promoter, isopropyl myristate, lemon oil, limonene, crotamiton, ethanol, benzyl alcohol, peppermint oil, L-menthol and the like can be added in an amount of about 1 to 5%.

[0033]

【Example】

Example 1. Production of flurbiprofen plaster In organic solvent, SIS copolymer adhesive base (SIS copolymer 3
0.0 parts, polyisoprene rubber 9.1 parts, terpene resin 32.0 parts, ester gum 28.0 parts, dibutylhydroxytoluene 0.9 parts) were dissolved in a dissolved product and the active ingredient and PG were stirred. Then, the dispersed solution was spread on a release paper, the organic solvent was dried with a dryer, and a support was attached to the surface to obtain a prototype.

Example 2. Rat skin permeability test Propylene glycol (hereinafter referred to as "PG"), peppermint oil as an absorption enhancer for the purpose of improving the rat skin permeability of flurbiprofen by adding an absorption enhancer to the plaster. , Crotamiton, etc. were added and a rat skin permeability test was conducted.

A: Prototype 1 As the absorption promoter, the prototypes shown in Table 1 below were prepared by the procedure of Example 1. That is, add 1% of peppermint oil (FH
-B00 to FH-B03) with 0% and 5% PG, respectively.
%, 10%, and 20% were added, and those without mint oil were prepared.

[0036]

[Table 1]

By attaching these prototypes to the skin of the rat,
A permeation experiment was carried out using a Franz cell to calculate the cumulative permeation amount. The results are shown in Table 2 below. The flurbiprofen content in each prototype was 285.7 μg / c.
It becomes m ² . In addition, [8 hr transmittance (%)] in Table 2
Was determined as the cumulative permeation amount after 8 hours per the flurbiprofen content ([8 hr transmissivity (%)] = cumulative permeation amount after 8 hours / flurbiprofen content).

[0038]

[Table 2]

As shown in Table 2, it was shown that the cumulative amount of permeation increased depending on the concentration of PG. However, the addition of 20% showed a high accumulation which was incomparable to those of other addition rates. It was shown to be the permeation amount. The numerical values in the table indicate the cumulative amount of permeation of flurbiprofen (μg / cm ² ), and each value is the average ± S. D. Indicates.

B: Prototype 2 By the same procedure as in Prototype 1, prototypes shown in Table 3 were prepared as absorption promoters. That is, 1% addition of crotamiton (FH-B
04 to FH-B07), PG is 0%, 5 respectively
%, 10% and 20% were added.

[0041]

[Table 3]

By attaching these prototypes to the skin of a rat,
A permeation experiment was carried out using a Franz cell to calculate the cumulative permeation amount. The results are shown in Table 4 below. The flurbiprofen content in each prototype was 285.7 μg / c.
It becomes m ² . In addition, [8 hr transmittance (%)] in Table 4
Was determined as the cumulative permeation amount after 8 hours per the flurbiprofen content ([8 hr transmissivity (%)] = cumulative permeation amount after 8 hours / flurbiprofen content).

[0043]

[Table 4]

As shown in Table 4, it was shown that the cumulative amount of permeation increased depending on the concentration of PG, but the addition of 20% showed a high accumulation which was incomparable to those of other addition rates. It was shown to be the permeation amount. The numerical values in the table represent the cumulative amount of permeation of flurbiprofen (μg / cm ² ), and each value is the average ± S. D. Indicates.

C: Trial Production 3 Prototypes shown in Table 5 were prepared as absorption promoters by the same procedure as in trial production 1 and 2. That is, isopropyl myristate (IPM) 1% addition (FH-B08 to FH-B11), P
Prepared were G added with 0%, 5%, 10% and 20%, respectively.

[0046]

[Table 5]

By attaching these prototypes to the skin of the rat,
A permeation experiment was carried out using a Franz cell to calculate the cumulative permeation amount. The results are shown in Table 6 below. The flurbiprofen content in each prototype was 285.7 μg / c.
It becomes m ² . In addition, [8 hr transmittance (%)] in Table 6
Was determined as the cumulative permeation amount after 8 hours per the flurbiprofen content ([8 hr transmissivity (%)] = cumulative permeation amount after 8 hours / flurbiprofen content).

[0048]

[Table 6]

As shown in Table 6, it was shown that the cumulative amount of permeation increased depending on the concentration of PG, but the one with 20% addition had such a high accumulation that it could not be compared with other addition ratios. It was shown to be the permeation amount. The numerical values in the table represent the cumulative amount of permeation of flurbiprofen (μg / cm ² ), and each value is the average ± S. D. Indicates.

Example 4. Structure of plaster As described above, it was shown that, in all of the trial manufactures 1 to 3, when PG was added in an excess of 20%, the cumulative permeation amount was remarkably high. Also, with the three prototypes (FH-B03, FH-B07, FH-B11) in which the obtained PG was added in an excess of 20%, immediately after the release paper was peeled off, this plaster was well applied to the skin etc. It can be adhered, but it has been shown that the adhesive strength becomes extremely weak when peeled and left for a while or after once adhered and then reattached.

Therefore, when the pastes of the three prototypes were observed with a microscope, it was found that the three pastes had a common structure. Figure 1
FIG. 3 is an explanatory view of a plaster showing the constitution of one example of the plaster of the present invention. FIG. A is a schematic diagram showing a cross section of the present plaster, and FIG. B is a schematic diagram in which the inside of the circle in FIG. As shown in Fig. A, the plaster (1) consists of the release paper (2) and the release paper
(2) Consists of a plaster layer (3) spread on the top and a support (4) deposited on the surface of the plaster layer (3).

As shown in FIG. B, the plaster layer (3) was prepared by dispersing PG containing an active ingredient therein in a SIS copolymer adhesive base (5) once dissolved in an organic solvent. Since PG is spread and hardened, the liquid foam structure (6) of PG that holds the active ingredient inside is dispersed, and the active ingredient is SI
It is considered that it is mainly dissolved in PG, not in the S copolymer adhesive base. Further, the active ingredient may be added to PG in excess of the solubility, and in this case, the crystal of the active ingredient is added.
It is considered that (7) exists in the liquid bubble as if it was surrounded by PG.

The prototypes other than those in which PG was added in an excessive amount of 20% were small in size, and a similar liquid bubble structure (6) was observed although the number was small. This is probably because the amount of PG penetrating into the skin was small and the transdermal absorption effect was not improved except for the case where PG was added in excess of 20%. Therefore, the plaster layer (3) on the side to be attached to the skin preferably contains 20% PG.

If the release paper (2) is removed, release paper
Part of the outer wall of the liquid bubble structure (61) that was on the interface with (2)
It breaks with peeling and the active ingredient is exposed on the sticking surface together with PG. Since the SIS copolymer adhesive base (5) is also exposed on the sticking surface, immediately after peeling the release paper (2), the plaster
Although (1) can be successfully applied to the skin, etc., when peeled and left for a while, or once peeled and then re-adhered, the PG is exposed to the adhesive (5). Since it wraps around the covered part and covers it, the adhesive force is extremely weak.

Example 5. Estradiol-containing plaster 1 For the purpose of developing estradiol which is a therapeutic agent for menopausal disorders and menstrual disorders, or a plaster capable of continuously releasing estradiol and progesterone, estradiol is used for various solubilizing agents. An in vitro skin permeability test was performed.

Although PG was used as the solubilizing agent for forming the liquid bubble structure in the above-mentioned Examples, various solubilizing agents were examined. As a solubilizing agent, PG, isopropyl myristate (hereinafter referred to as "IPM"), 1,3-butylene glycol (hereinafter referred to as "1,3-BG"), polyethylene glycol 400 (hereinafter referred to as "PEG400") Note) was used. Table 7
Shows the solubility of estradiol of each solubilizer.

Excess estradiol is dissolved in these solubilizers to prepare a solution of each estradiol saturated solubilizer (3
(7 ° C) was prepared and placed in a 2-chamber type diffusion cell in a WISTER rat (male, 5 weeks old, about 160 g).
The abdominal skin (hair clipper hair removal) was attached, each estradiol saturated solubilizing agent solution prepared was used as a donor, and physiological saline containing 20% polyethylene glycol was used as a receptor, and estradiol permeated to the receptor side through the skin was detected by HPLC. did. The results are shown in Figure 2.

As shown in FIG. 2, the permeability of estradiol is independent of IPM, PG, 1,3-BG and P.
EG400 was good in that order. Judging only from the viewpoint of permeability, IPM is suitable, but since IPM cannot form a liquid bubble structure, it was decided that the solubilizing agent in the following examples was also mainly PG. IPM is not a solubilizer,
It was confirmed to be effective as an absorption enhancer.

Example 6. Estradiol-containing plaster 2 An estaradiol-containing plaster was prepared by the compounding formulation shown in Table 8 below by the production method shown in Example 1. An in vitro skin permeability test was also conducted.

[0060]

[Table 8]

The obtained plaster was cut to a pore size of 3.14 cm ² (dosage 18 ml), mounted on a Franz type cell, and abdominal skin of a hairless mouse (female, 5 weeks old, about 20 g) was used. The dissolution test was performed using a physiological saline solution containing 20% PEG. The elution temperature was 37 ° C. The results are shown in Table 9 below and FIG. As shown in Table 9 and FIG. 3, all of the estradiol plasters (when dried) having a PG content of 20% by weight showed high skin permeability.

[0062]

[Table 9]

The solubility of estradiol in PG was 86.7 mg / g at 37 ° C., and all the formulations shown in Table 8 exceeded the solubility. Therefore, a part of estradiol is retained in the PG as crystals. By the way, it is desired to obtain the desired estradiol-containing plaster that can be effective for 2 days (48 hours) with one application. Therefore, the formulation of estradiol was as shown in Table 10 below.

[0064]

[Table 10]

A flexible non-woven fabric made of polyester (area weight: 51.0 g / m ² , thickness: 7 μm) was used for the support, and each sheet (5 × 3.14 cm ² ) and estradiol 5.0 mg, P
G 25 mg and SIS copolymer adhesive base 95 mg were used.

[0066]

As described above, the present invention provides a plaster consisting of a release paper, a plaster layer spread on the release paper, and a support coated on the surface of the plaster layer. Since the plaster layer is a SIS copolymer adhesive base having a release paper side on which liquid bubbles made of a solubilizing agent containing an active ingredient are dispersed, a paste such as flurbiprofen is used. It is possible to obtain a plaster which gives a dramatic percutaneous absorption not only with an active ingredient having a good skin absorption but also with an active ingredient having a small transdermal absorption such as estradiol.

In the present invention, since the solubilizing agent contains the above-mentioned active ingredient exceeding the solubility in the solubilizing agent, crystals of the active ingredient are also retained in the liquid foam structure. This crystal dissolves and replenishes the active ingredient, which decreases with permeation from the sticking surface. Therefore, continuous transdermal absorption can be performed.

In the present invention, if the solubilizing agent is contained in an amount of more than 10% with respect to the adhesive base, it can be added by adding it to the organic solvent solution of the SIS copolymer adhesive base and stirring it. A good liquid bubble structure of the solubilizer can be formed.

In the production method of the present invention, in the production method of a plaster in which a plaster is spread on a release paper, the plaster is dried, and then a support is applied to the surface of the plaster; , The SIS copolymer adhesive base is dissolved in an organic solvent, and the solubilizer solution containing the active ingredient is stirred in the solution to disperse it in the form of a liquid foam; the dispersed solution is spread on a release paper. It is spread, the organic solvent is dried, and a support is attached to the surface. This has the effect of obtaining a plaster in which the liquid foam structure of the active ingredient and the solubilizer is dispersed in the SIS copolymer adhesive base.

[Brief description of drawings]

FIG. 1 is an explanatory diagram of a plaster showing a structure of a plaster of one example of the present invention. FIG. A is a schematic diagram showing a cross section of the present plaster, and FIG. B is a schematic diagram in which the inside of the circle in FIG.

FIG. 2 is a diagram showing the results of a skin permeability test of estradiol using various solubilizers. The vertical axis represents cumulative transmission amount (μg / cm ² ) and the horizontal axis represents elapsed time (hr).

FIG. 3 is a diagram showing the results of a skin permeability test of an estradiol-containing plaster. The vertical axis is the cumulative transmission amount (μg / c
m ² ), the horizontal axis is the aging time (hr).

[Table 7]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification symbol FI A61K 47/34 A61K 47/34 A61P 5/30 A61P 5/30 25/04 25/04 29/00 29/00 (72) Invention Person Masahiro Matsudaira 173 Mizuhashi Hatake, Toyama City, Toyama Prefecture, etc. 173, R & D Department, Daikyo Pharmaceutical Co., Ltd. (72) Inventor Junichi Ishiguro, 173 Mizuhashi Hatake, Toyama City, Toyama Prefecture, etc. 173, Research & Development Department, Daikyo Pharmaceutical Industry Co., Ltd. (56) 6-24969 (JP, A) JP 5-148145 (JP, A) JP 4-103528 (JP, A) JP 57-209217 (JP, A) JP 60-16916 (JP, A) Japanese Unexamined Patent Publication No. 3-227920 (JP, A) Special Table 10-504313 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 9/00 A61K 47/00

Claims (4)

(57) [Claims] 1. A plaster comprising a release paper, a plaster layer spread on the release paper, and a support adhered on the surface of the plaster layer, wherein the plaster layer is styrene- Isoprene-styrene block
The adhesive base consisting mainly of the copolymer is dissolved in an organic solvent.
It is obtained by drying the organic solvent after spreading on the release paper.
The solubilizing agent solution containing the active ingredient was dissolved in the organic solvent on the release paper side of the adhesive base containing the styrene-isoprene-styrene block copolymer as the main component.
Diameter was stirred at lysates were become by dispersing liquid bubble consisting of a solubilizing agent containing the active ingredient of 2Myuemu～40myuemu, the solubilizer is propylene glycol, 1,3-butylene
Either glycol or polyethylene glycol 400
Or one or more selected from the above adhesive bases
A plaster characterized by being contained in an amount exceeding 10% by weight . 2. The plaster according to claim 1, wherein the solubilizing agent contains the active ingredient exceeding the solubility in the solubilizing agent. 3. The plaster according to claim 1, wherein the active ingredient contains estradiol or flurbiprofen. 4. A method for producing a plaster in which a plaster is spread on a release paper, the plaster is dried, and then a support is applied to the surface of the plaster, wherein styrene-isoprene-is used as the plaster layer. An adhesive base containing a styrene block copolymer as a main component is dissolved in an organic solvent, and a solubilizing agent solution containing an active ingredient is stirred in this solution to disperse it in the form of a liquid foam having a diameter of 2 μm to 40 μm . was spread lysates were the dispersion on release paper, the organic solvent is dried, it is intended to deposit a support surface, as the solubilizing agent solution, propylene glycol, 1,3-Bed
Ji glycol, of polyethylene glycol 400
Any one selected from the above or two or more of them is used, and the solubilizing agent liquid is treated with an adhesive base obtained by drying the organic solvent.
And a content of more than 10% by weight .