JPH054915A - Plaster - Google Patents

Abstract

PURPOSE:To obtain a plaster, capable of suppressing occurrence of curling and thereby excellent in applicability and further shape stability even when a tacky plaster layer containing a medicine or an additive readily causing permeation to a support is provided. CONSTITUTION:A plaster having a tacky plaster layer containing a medicine or an additive having a solubility parameter within the range of 7-11 and a support in which the aforementioned tacky plaster layer is laminated to one surface. The aforementioned support has a structure in which the second and third layers swelling with the medicine or the additive are directly or indirectly formed on both sides of the first layer unswelling with the medicine or the additive.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a patch for transdermal administration of a drug, and more particularly to a patch excellent in stability and patchability as a preparation.

[0002]

2. Description of the Related Art As a dosage form used for transdermal administration of drugs, ointments, lotions, plasters and the like have been used for a long time, but in recent years, patches called tapes or patches. Is getting attention. The patch is formed by forming an adhesive plaster layer containing a drug or an additive on one surface of a support made of a flexible material such as a synthetic resin film or a non-woven fabric.

When the patch is used, the drug or the like can be continuously administered, and the administration can be easily stopped by peeling off the patch as needed. Therefore, there is an advantage that the dose of a drug intended for systemic action can be easily controlled, side effects due to rapid drug absorption can be reduced, and the number of drug administrations can be reduced. In addition, the patch is easier to handle than an ointment, and stains of clothes are less likely to occur during application.

In the adhesive patch having various advantages as described above, in order to make full use of these advantages, the support is required to satisfy the following conditions.
First, the support is required to be able to stably maintain the drugs and additives in the adhesive plaster layer. Further, it is desirable that the support itself does not change its shape or discolor.
Further, those having sufficient flexibility are required. Even if it is excellent in stability, if it is inflexible, it may give a patient a feeling of discomfort during application, or the adhesion to the skin may be impaired, resulting in insufficient drug administration. It is also necessary to select an appropriate support according to the type of drug, additive, etc.

Conventionally, a flexible material such as a synthetic resin film or a non-woven fabric has been used as a support for forming a patch. As the synthetic resin film, one made of polyethylene, polypropylene, polyethylene terephthalate or the like is used. Further, in JP-A-62-82967, a support formed from a resin composition comprising a hydrocarbon-based elastomer and a polyolefin, and in JP-A-62-153215, a vinyl chloride-ethylene copolymer and ethylene- A support formed from a resin composition comprising a carbon monoxide-vinyl acetate copolymer and a hydrous aluminosilicate, JP-A-1-224313.
In Japanese Patent Application Laid-Open No. 1-249719, a support formed by adhering a vinyl chloride resin film and a polyethylene terephthalate film to a support formed from a resin composition comprising a vinyl chloride polymer and an ethylene-vinyl acetate copolymer. JP-A-2-247118 also discloses a support in which polyethylene terephthalate is adhered to a flexible polyurethane-polyvinyl chloride graft copolymer film. However, none of the supports used in the conventional patches have sufficiently satisfied the above various conditions.

When the drug or additive contained in the adhesive plaster layer easily penetrates into the support and swells easily, the drug or additive tends to migrate to the support with time. there were. As a result, the patch curls over time,
In particular, curling tends to occur such that the adhesive plaster layer side is on the inner surface, which sometimes makes it difficult to stick to the skin surface.

[0007]

SUMMARY OF THE INVENTION The object of the present invention is to provide an adhesive plaster layer containing a drug or additive that penetrates into a support and easily swells as described above. It is an object of the present invention to provide a patch that can prevent curling, and thus has excellent patchability and shape stability.

[0008]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the inventors of the present invention have shown that they are non-swelling agents or additives contained in an adhesive plaster layer as a support. If a support is constructed by providing, directly or indirectly, swellable second and third layers for the drug or additive on both surfaces of the first layer, The present invention has been completed by finding that the curl can be prevented, and that it is excellent in both shape stability and flexibility, and thus can realize good sticking property.

That is, the patch of the present invention comprises an adhesive plaster layer containing a drug or additive having a solubility parameter in the range of 7 to 11 and the above-mentioned solubility parameter of 7 to 11
First non-swelling to drugs or additives in the range of
And a second or third layer which is directly or indirectly provided on both surfaces of the first layer and which has a solubility parameter in the range of 7 to 11 and which is swellable with respect to a drug or an additive.
And a support having the adhesive plaster layer provided on one surface thereof.

The swellable layer for the drug or additive of the present invention means that the drug or additive penetrates into the support or the drug or additive dissolves a part of the support. It means the layer in which the volume of the support is increased. Further, the non-swelling layer means a layer in which the penetration or dissolution of the drug or the additive into the support does not occur, or even if it occurs, the volume hardly increases.
The details of the configuration of the present invention will be described below.

Support The present invention relates to a second or third support which is swellable to a drug or an additive directly or indirectly on both sides of the first layer which is not swellable to the drug or the additive. It is characterized by having a structure in which the layers are laminated. In addition, the structure in which the second and third layers which are swellable with respect to the drug or the additive indirectly are provided on both surfaces of the first layer means that one or more other layers are provided on both surfaces of the first layer. It means a laminate of the second and third layers with the layer interposed therebetween.

In the present invention, the support is the first
The layered structure of at least three layers or more in which the second and third layers are provided on both sides of the layer is that the central first layer provides shape stability, and an adhesive containing a drug or an additive. The part where the adhesive plaster layer is laminated is made of a material which is swellable with respect to the drug or additive so that the strain between the adhesive plaster layer and the first layer excellent in shape retention is relaxed. This is to prevent curling due to migration of the drug to the support side with time.

As the non-swelling material for the drug or additive forming the first layer, a film made of a resin such as polyethylene terephthalate, polyamide, polyfluoroethylene, polyvinylidene chloride, polyvinyl alcohol or polyacrylonitrile. Is mentioned. All of these resin films have crystallinity, and therefore have excellent shape stability and high gas barrier properties.

Examples of the material that swells with respect to the drug or additive constituting the second and third layers include ethylene-vinyl acetate copolymer, soft polyvinyl chloride, polyolefin, ethylene-vinyl acetate copolymer, Acrylic polymer, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, polybutene, polyisoprene, ethylene-propylene copolymer,
Examples thereof include films made of resins such as polyvinyl formal and vinyl chloride-ethylene copolymer. These resins are amorphous or have low crystallinity, have excellent flexibility, and generally have low gas barrier properties.

Between the first layer and the second and third layers, a resin layer having a good affinity for both may be provided. In this way, by delaying the swelling of the second and third layers by the drug or the additive by providing the resin having excellent affinity for both between the first layer and the second and third layers. Can
Thereby, the strain in the support can be alleviated more effectively. Examples of such a structure include a structure in which a polyethylene layer is interposed between a first layer made of polyethylene terephthalate and second and third layers made of an ethylene-vinyl acetate copolymer.

Although the total thickness of the support varies depending on the balance with the thickness of the adhesive plaster layer and the feeling of use, it is 30 to 1
It is used in the range of 00 μm, and preferably 40 to 80 μm.
The thing of about m is used. Further, the thickness of each of the first to third layers constituting the support is appropriately selected within a range capable of imparting a balance with the thickness of the adhesive plaster layer and required elasticity. However, in order to suppress the above-described inward curl, when the layer on the side in contact with the adhesive plaster layer is the second layer, the third layer swelling to the drug or additive on the opposite side is used. Is set to be equal to or slightly thinner than the second layer.

In the case where the above-mentioned first to third layers are laminated to form a support, a method of adhering each layer with an adhesive or a method of melting the second and third layers on both surfaces of the first layer The method of laminating by doing so is used.

Drugs or Additives In the present invention, the adhesive plaster layer provided on one surface of the above-mentioned support contains a drug or an additive having a solubility parameter in the range of 7 to 11. This solubility parameter is measured by Solubility Parameters / A
Lan F. M. Barton; Chemical
Reviews, Vol. 75, no. 6p731-
(1975), and specifically, A Method for Estimating
Both the Solubility Para
meters and Mollar Volumes
of Liquids / Robert F. Fedor
s; POLYMER ENGINEERING AND
SCIENCE, FEBRARY, 1974, Vo
l. 14, No. 2 It is calculated according to the calculation method described in p147-.

As described above, the solubility parameter is 7 to 11
The drug or additive having a relatively high lipophilicity is contained in the drug or additive having a solubility parameter of more than 11, originally, the interaction with the support is small and the deterioration phenomenon of the preparation occurs. Because it is difficult. On the other hand, in the case of a drug or additive having a solubility parameter of 11 or less, penetration of the drug or additive or dissolution of the support is likely to occur when a conventional support is used, which causes deterioration of the preparation. On the other hand, when it is combined with the above-mentioned support of the present invention, such deterioration is less likely to occur and the effect of the present invention can be obtained.

Examples of the drug contained in the adhesive plaster layer in the present invention include anti-inflammatory agents, analgesics, antihistamines, hormones, vasodilators, antihypertensive agents, antibiotics,
Examples include antibacterial agents, muscle relaxants, antidepressants, anesthetics, vitamins and the like. Specific examples include L-menthol, glycyrrhetinic acid, aminopyrine, diphenhydramine, pentaerythritol tetranitrate, mianserin and the like. 1 to 3 of these drugs in the adhesive plaster layer.
It is compounded in the range of 0% by weight. This is because if it is less than 1% by weight, the effect of adding the drug cannot be obtained, and if it exceeds 30% by weight, the sticking property is adversely affected.

The additives include solubilizers, plasticizers,
As a tackifier, absorption promoter, stabilizer, etc., higher fatty acid, higher alcohol, fatty acid ester, alkylamine, etc. are contained. Specifically, stearic acid, myristic acid, oleic acid, linolenic acid, behenyl alcohol, oleyl alcohol, lauryl alcohol, cetyl acetate, isopropyl myristate, sorbitan (mono) laurate, glycerin (mono) oleate, liquid paraffin or diisopropyl. Examples include amines.
These additives are blended in the adhesive plaster layer in the range of 1 to 50% by weight. If it is less than 1% by weight, the effect of adding the additive cannot be obtained. If it exceeds 50% by weight, the effect of adding the additive is saturated, while
This is because the functions such as sticking property deteriorate.

In the adhesive plaster layer, a liquid drug or additive having a relatively high solubility in the above-mentioned dissolution parameter in the range of 7 to 11 is dissolved or dispersed in the adhesive base. As the adhesive base, one made of an appropriate material that has been conventionally used to form a patch can be used. Examples of such an adhesive base include an acrylic adhesive, a urethane adhesive or a rubber adhesive.

The content of the above-mentioned drug or additive in the adhesive plaster layer is usually contained in the adhesive plaster layer in the range of substantially less than the saturated solubility. Generally, when a drug or an additive having a saturated solubility or higher is contained, the drug or the additive is easily transferred from the adhesive plaster layer to the support side. However, even in such a case, curling or deformation with time can be effectively prevented by using the support of the present invention. Therefore, in the patch of the present invention, the above-mentioned drugs or additives may be blended in the adhesive plaster layer in a range exceeding the saturated solubility unless curling or other deformation with time occurs.

Formulation composition to which the present invention is applied The composition of the patch of the present invention other than the support is not particularly limited as long as it can effectively supply the drug into the body through the skin. Not done. For example, a single adhesive plaster layer system in which a drug is dispersed or dissolved in an adhesive base, a system in which a drug is encapsulated in microparticles and dispersed in an adhesive base, a release control film in a drug storage layer, and Examples thereof include a multi-layer system in which an adhesive base layer is combined as necessary, a system in which the surface contacting with the skin is divided into a drug storage area and an adhesive area.

In addition to the drug, a solubilizer, a plasticizer, a tackifier, an absorption enhancer, a stabilizer and the like may be blended with the drug, if necessary, or arranged as a layer different from the drug. May be. Usually, the surface of the adhesive plaster layer opposite to the surface in contact with the support is treated with a release paper for the purpose of protecting the adhesive plaster layer until it is applied to the skin. Are pasted together.

If necessary, a primer layer may be provided between the support and the adhesive plaster layer to enhance the adhesion between the adhesive plaster layer and the support. .. The primer can be made of any material as long as it has an affinity for both the support and the adhesive plaster layer and does not impair the stability of the preparation, and such a primer can be used. Examples of the material include acrylic polymers, rubber polymers, urethane polymers, epoxy resins, and the like.

Production Method The patch of the present invention can be obtained by coating one side of the above-mentioned support with an adhesive base solution or dispersion in which a drug or the like is dissolved or dispersed, and drying. Also,
On another base member, an adhesive base solution or dispersion containing a drug or the like is applied to form an adhesive plaster layer,
You may comprise by transferring the said adhesive plaster layer on the said support body. In addition to the solvent coating method as described above, the hot-melt coating method can be used for coating.

[0028]

In the patch of the present invention, the first layer, which is non-swelling with respect to the drug or the additive, is provided in the center of the support, so that the shape stability is enhanced. In addition, since the second and third layers which are swellable with respect to the drug or the additive are directly or indirectly provided on both surfaces of the first layer, the solubility parameter is in the range of 11 or less, Even if an adhesive plaster layer containing a drug or an additive having a high penetrability into the body is laminated, the strain due to the migration of the drug or the additive to the support side is alleviated.

The reason is that, when an adhesive plaster layer containing a drug or an additive having a high permeability to the support is laminated, the drug or the additive penetrates into the second layer,
Even if a force that curls the support inwardly occurs due to the stress that causes the second layer to swell, the first layer and the third layer that have good shape stability are obtained. By the existence of the layer, the stress acts in a direction to be relaxed,
It is considered that inward curl is less likely to occur.

When the drug or additive not only penetrates into the second layer but also passes through the first layer and reaches the third layer, the third layer is swelled. It is considered that since the force that acts on the second layer balances with the force that tends to cause curling in the second layer, curling is further suppressed. Therefore, when the support of the present invention is used, curling of the patch with time can be effectively suppressed.

[0031]

EXAMPLES The present invention will be clarified further by describing examples of the present invention. First, the following materials were prepared to prepare patches of Examples and Comparative Examples described below.

[0032] As a material constituting the support substrate, in Examples 1 and 2 and Comparative Examples 1 to 4 were prepared films shown in Table 1 below.

[0033]

[Table 1]

Regarding the multilayer film in Table 1, the first described layer was the layer on the side where the adhesive plaster layer was provided.

As the pressure-sensitive adhesive for forming the pressure- sensitive adhesive plaster layer, the following 2
Different kinds of adhesives were prepared. Adhesive A (acrylic adhesive): 2-ethylhexyl methacrylate 180 g, 2-ethylhexyl acrylate 60 g and ethyl acetate 100 g were put in 1 liter of Kolben and heated to 80 ° C., then lauroyl peroxide 0.2 g was added to cyclohexane 100 g. What was melt | dissolved in was added over 6 hours, and it polymerized. As a result, an adhesive solution having a weight average molecular weight of 1.05 million and a solid content of 58% was obtained. Adhesive B (rubber-based adhesive) ... Styrene-isoprene-styrene block copolymer (manufactured by Shell Chemical Co., trade name: T
R1107) was used.

Drugs The following three drugs were prepared. Indomethacin (dissolution parameter = 12.9) Glycol salicylate (dissolution parameter = 15.3) L-menthol (dissolution parameter = 7.8)

Plasticizer isopropyl myristate (solubility parameter = 8.
5) Liquid paraffin (solubility parameter = 7.0-8.5) tackifier alicyclic saturated hydrocarbon (Arakawa Chemical Industries, Ltd., trade name: Alcon P80, solubility parameter = 8.0-9.0)

Example 1 A drug and a plasticizer as an additive and an adhesive solution were
The non-volatile components were blended so that the weight ratio was as shown in Table 2 below, the total non-volatile component concentration was adjusted to 30 wt% with ethyl acetate, and then the mixture was stirred and mixed with a mixer to uniformly dissolve the composition. It was This solution was applied to a surface with a release treatment to a thickness of 50μ.
m evenly coated on the polyester film, and after drying,
The support of Example 1 shown in Table 1 was laminated to obtain a patch having an adhesive plaster layer having a thickness of 80 μm.

[0039]

[Table 2]

[0040] except that instead of the support of Comparative Examples 1 to 4 shown in Comparative Examples 1-4 in Table 1, to obtain each adhesive patch of Comparative Example 1-4 in the same manner as in Example 1.

Example 2 A drug, a plasticizer, a tackifier, and an adhesive were blended so that the weight ratio of nonvolatile components was as shown in Table 3 below, and 15
The mixture was melt-mixed uniformly at 0 ° C. Then mix this mixture
The surface of the polyester film having a thickness of 50 μm is subjected to hot melt coating uniformly, and the support of Example 2 in Table 1 is laminated on the polyester film so that the thickness of the adhesive plaster layer is 80.
A patch of μm was obtained.

[0042]

[Table 3]

Evaluation The patches of Examples 1 and 2 and Comparative Examples 1 to 4 obtained as described above were evaluated in the following manner. Appearance observation at the time of severe test The patches of Examples 1 and 2 and Comparative Examples 1 to 4 were respectively
It was cut into 6 × 6 cm ² , put in an aluminum packaging material, and heat-sealed. Each packaging material was stored at 60 ° C. for 1 week, opened, the release paper was removed, and the appearance of the patch was visually observed. The results are shown in Table 4 below.

[0044]

[Table 4]

The meanings of the judgment reference symbols in Table 4 are as follows. --- No curling occurs. ± ... A slight curl was observed. +: Curling occurs so that one side of the patch forms 1/8 to 1/4 of the circumference. ++ Curling occurs so that one side of the patch forms 1/4 to 1/2 of the circumference. +++ ... A large curl occurs, where one side forms more than 1/2 of the circumference.

Shape change during severe test Example 1 and comparative examples 1 to 4 used in the severe test described above.
The vertical and horizontal lengths of the adhesive patch were measured after 2 weeks at 60 ° C., and the change rate with respect to the vertical and horizontal lengths immediately after production was obtained. The results are shown in Table 5 below.

[0047]

[Table 5]

As is clear from the results of Tables 4 and 5,
It can be seen that in the patches of Examples 1 and 2 and Comparative Example 3, although some outward curl was generated immediately after the production, generation of inward curl with time could be suppressed. On the other hand, it can be seen that in the patch of Comparative Example 1, the inward curl increases with time, and in Comparative Examples 2 and 4, the outward curl increases considerably with time.

As is clear from Table 5, Example 1
Also, it can be seen that the patches of Comparative Examples 1 and 2 have a very small dimensional change with time, whereas the patches of Comparative Examples 3 and 4 have a considerably large shape change with time. Therefore,
According to the embodiments of the present invention, it is found that not only curling over time can be suppressed, but also the stability of the shape can be improved.

[0050]

As described above, according to the present invention, the support swells the drug or the additive directly or indirectly on both surfaces of the first layer which is non-swelling to the drug or the additive. Since it has a structure in which the second and third layers having the property of being provided are provided, curling of the patch with time can be effectively suppressed, and the shape stability of the patch can be enhanced. Therefore, according to the present invention, even when a drug or an additive having a solubility parameter of 7 to 11 and excellent in lipophilicity is contained in the adhesive plaster layer, stability as a preparation and sticking property In any of the above cases, it becomes possible to provide an excellent patch.

Claims (1)

Claims: 1. An adhesive plaster layer containing a drug or additive having a solubility parameter in the range of 7 to 11, and a drug or additive having the solubility parameter in the range of 7 to 11. A non-swellable first layer, and a drug or additive formed directly or indirectly on both surfaces of the first layer and having the solubility parameter in the range of 7 to 11; A patch comprising a swellable second and third layer, and a support having the adhesive plaster layer provided on one surface thereof.