JP3171935B2 - Patch with excellent sticking properties - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a patch which is used by sticking it to the skin surface. More specifically, the sticking operation is good, the skin is not irritated at the time of sticking, the feeling of wearing is excellent, and the drug is contained in the adhesive layer. The present invention relates to a patch which, when incorporated, also enhances percutaneous absorption of a drug.

[0002]

2. Description of the Related Art There have been proposed various types of patches to be used by sticking to the skin surface, such as a coating patch for protecting the skin surface and a patch for transdermally administering a drug to the body. Have been. In such patches, the application surface is the skin surface. Therefore, in the development, it is important to handle the application at the time of application, follow the movement of the skin surface (flexibility and elasticity), and to have low irritation to the skin. The required characteristics. In addition, in the case of a patch containing a drug, characteristics such as prevention of a decrease in the drug content due to the transfer of the drug to the support and excellent release (percutaneous absorption) of the drug from the adhesive layer are also improved. Required together.

[0003] In particular, these patches may be applied for a relatively long time, and those which do not exhibit discomfort or irritation to the skin after application to the skin are important required characteristics.

[0004] In order to meet such a demand, a patch has been conventionally proposed in which the thickness of the support is reduced as much as possible to reduce the irritation caused by the edge of the support and further impart skin followability. I have. In a patch containing a drug in the adhesive layer, a polyester support to which the drug does not migrate is generally used.
However, when the thickness of the support is reduced, the above-mentioned required properties can be satisfied, but the self-supporting property of the patch itself is lost, so that the handling property at the time of sticking is deteriorated, and the patch after the sticking becomes wrinkled or stuck. There is a problem that the adhesive surfaces sometimes stick together and cannot be stuck neatly.

Therefore, as a method for solving the above problem,
Use a patch made by temporarily attaching a self-supporting backing to the back of a thin support film, or increase the thickness of the support to a certain extent using a support made of a flexible material such as a polyurethane film. Patches and the like with improved handleability have been proposed.

The former patch is disclosed in JP-A-55-32553, JP-A-56-57235, and JP-A-56-1.
Many proposals have been made, such as Japanese Patent No. 58215, Japanese Patent Application Laid-Open No. 64-16719, and have excellent operability at the time of sticking. However, with this adhesive, if the adjustment of the adhesive force when temporarily attaching a self-supporting backing paper is insufficient, the mounting paper may be peeled off before pasting, or the adhesive itself may be peeled off when the backing paper is peeled off after pasting. May also be peeled off, and it is necessary to pay sufficient attention to the adjustment of the temporary adhesion.

On the other hand, in the latter patch, the thickness of the support is increased even if the support is made of a soft material, so that the irritation caused by the edge of the support may not be sufficiently reduced in a long-time application. .

Further, in place of the self-supporting backing paper, a support having a laminated structure in which a nonwoven fabric is adhered and laminated to impart self-supporting properties has been proposed in Japanese Patent Application Laid-Open No. 16716/1989. In the case of a patch containing a drug in an adhesive, it is thought that the skin surface to be applied is sealed and kept warm to increase the thermodynamic activity of the drug and improve the transdermal absorbability, as described above. If a nonwoven fabric is used in the support structure, the heat-sealing effect is reduced, so that it is hardly satisfactory from the viewpoint of percutaneous absorption of the drug.

[0009]

The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems. As a result, even if the support is a thin plastic film having no self-supporting property, By laminating a flexible independent foam sheet having a specific thickness on this film, the skin irritation can be reduced even when the thickness of the entire support is substantially increased, and the sticking operability and the feeling of wearing after sticking are reduced. I found it to be good.

[0010] Further, by using a polyester film as a plastic film and forming an adhesive layer on the film side, when a drug is contained in the adhesive layer, drug transfer to the support can be prevented, In addition, it has been found that transdermal absorbability is improved by a sealing and heat retaining effect after application to the skin surface, and the present invention has been completed.

[0011]

That is, according to the present invention, the thickness is set to 0.1 mm.
One side of a flexible closed cell foam sheet of 4 to 5 mm has a thickness of 0.1 mm.
Excellent sticking property characterized in that a pressure-sensitive adhesive layer having tackiness at room temperature is formed directly or indirectly on a polyester film surface of a support obtained by laminating a 5-6 μm polyester film. A patch is provided.

Another object is to provide a patch for preventing or treating various diseases by percutaneously absorbing a drug contained in the pressure-sensitive adhesive layer.

The patch of the present invention is characterized by the structure of the support, and is obtained by laminating a soft independent foam sheet having a thickness of 0.4 to 5 mm and a polyester film having a thickness of 0.5 to 6 μm. It has a structure.

The polyester film is preferably as thin as possible in order to reduce irritation caused by the edge of the support. From the practical point of view, it is preferable to use an extremely thin film of about 1 to 5 μm, and more preferably about 2 to 4 μm. When the thickness is less than 0.5 μm, it is difficult to obtain the support of the present invention by laminating with a flexible independent foam described later, and it is not practical. The stiffness possessed is manifested, and when applied to the skin surface, a rough feeling (uncomfortable feeling) is caused. In the patch of the present invention, by laminating the polyester film in the support structure, the drug can be prevented from migrating into the support even if the drug is contained in the adhesive layer,
Furthermore, the application surface is sealed, so-called sealed bandage therapy (ODT).
Therapy) and the transdermal absorption of the drug is improved.

Further, the flexible closed foam laminated with the above-mentioned polyester film imparts a suitable self-supporting property to the patch of the present invention to improve the operability at the time of sticking to the skin surface, This is to improve the wearing feeling after wearing.
Therefore, in order to exhibit such an effect and a sealing and heat retaining effect described later, the thickness of the flexible independent foam sheet is 0.4 to 5 m.
m, it is preferable to use one having a size of about 0.5 to 3 mm from a practical viewpoint.

In addition, the above-mentioned flexible closed-cell foam has a characteristic that when the patch of the present invention is applied to the skin surface, it breaks when pulled at a pulling speed of 50 mm / min from the viewpoint of skin followability (flexibility and stretchability). The elongation per unit area is preferably 50% or more, more preferably 100% or more. Further, the foaming ratio is 2 to 50 times, preferably 5 to 30 in view of self-supporting property at the time of sticking operation, feeling of wearing after sticking, and sealing and heat retaining effect.
It is desirable to use double soft closed cells.

As the polyester used for the polyester film, those mainly composed of polyethylene terephthalate are preferred from the viewpoints of safety (non-toxicity) for living bodies, practicality, and versatility. Specifically, an ethylene terephthalate homopolymer, a copolymer containing an ethylene terephthalate unit as a main unit and other ester units, a mixture of an ethylene terephthalate homopolymer and a polymer composed of other ester units, and the like can be used. Other ester units used in the copolymerization or mixture, for example, as a dicarboxylic acid component, isophthalic acid, diphenyl dicarboxylic acid, diphenyl ether dicarboxylic acid, diphenyl sulfone dicarboxylic acid, aromatic dicarboxylic acids such as naphthalenedicarboxylic acid, and adipine Acids, aliphatic dicarboxylic acids such as sebacic acid, etc., and alkylene glycols such as trimethylene glycol, tetramethylene glycol, hexamethylene glycol, aromatic diols such as hydroquinone, resorcinol and bisphenol A as diol components; (Hydroxyethoxyphenyl) sulfone,
An aliphatic diol such as bis (hydroxyethoxyphenyl) propane, diethylene glycol, or the like can be used.

On the other hand, as the soft closed-cell foam, a foam using a thermoplastic elastomer is preferable. As the thermoplastic elastomer, for example, polyolefin elastomers such as polyethylene, polypropylene, and polypropylene / polyethylene oxide / polypropylene copolymer; Polyurethane elastomers such as polyether polyurethane and polyester polyurethane, polyester elastomers such as polybutylene terephthalate / polybutylene glycol / polybutylene terephthalate, polyvinyl chloride elastomers, polyamide elastomers, styrene / butadiene (or isoprene)
/ Styrene block copolymer elastomer, ethylene /
Vinyl acetate copolymer, 1,4-polyisoprene rubber,
1,2-polybutadiene, natural rubber, and the like are used, and among these, polyethylene, 1,2-polybutadiene, polyether polyurethane, polyester polyurethane, and polychlorinated from the viewpoint of versatility and safety when affixed to the skin surface. Vinyl, ethylene / vinyl acetate copolymer and the like are preferably used.

The above-mentioned thermoplastic elastomer can be made into a sheet of an independently foamed body in which cells are independently present by a conventionally known foaming means using a foaming agent or a foaming aid.

The support in the patch of the present invention comprises
So certain polyester film and flexible closed foam
The sheet is made by laminating sheets.
Adhesive on the film side with a gravure coater.
Dry coating amount is 1-3g / m ^TwoApply to the extent
And press-fit the foam sheet while heating if necessary
Can be obtained by: Adhesive used in this case
Polyester, acrylic, vinyl chloride
-Based, vinyl acetate, rubber, urethane, etc.
An adhesive can be used. The laminated structure of the support is
Not only a two-layer structure but also a foam sheet on at least one side
Since it may be a laminated structure, for example, a soft closed-cell foam
Sheet / polyester film / non-woven fabric (or continuous
(Foam). like this
Non-woven fabric layer or continuous foam layer on polyester film side
By laminating, the adhesive formed on the film side
It is preferable because it can improve the anchoring property with the agent layer.
No.

The patch of the present invention may be provided with an adhesive layer having tackiness at room temperature directly or indirectly via a binder layer for improving anchoring property on the polyester film side of the support as described above. It is formed. As the pressure-sensitive adhesive layer to be formed, if it is a pressure-sensitive adhesive for medical use that does not have skin irritation to the pressure-sensitive adhesive itself because it comes into contact with the skin surface,
An acrylic adhesive, a natural rubber adhesive, a synthetic rubber adhesive, a vinyl ether adhesive, a silicone adhesive, or the like can be used. Among these adhesives, from the viewpoints of stability of quality, easy adjustment of adhesive strength, release of drug, etc., 50 (alkyl) acrylate alkyl esters are used.
Acrylic pressure-sensitive adhesives obtained by polymerization of at least% by weight, and synthetic rubber-based pressure-sensitive adhesives such as polyisobutylene / polybutene and styrene / diene / styrene can be preferably used.

The adhesive layer of the present invention can be used as a patch preparation for transdermal absorption for treating or preventing various diseases by containing a drug. Such a drug may be any of a topical drug or a systemic drug as long as it exerts a pharmacological effect by percutaneous absorption. Specifically, corticosteroids, analgesic anti-inflammatory drugs, hypnotics, etc. Sedatives,
Mood stabilizers, antihypertensives, antihypertensive diuretics, antibiotics, anesthetics, antibacterials, antifungals, vitamins, coronary vasodilators, antihistamines, antitussives, sex hormones, antidepressants, cerebral circulation improvers, antiemetic , Drugs such as antitumor agents and biomedical drugs can be used. These drugs can be used in combination of two or more if necessary.

The content of these drugs can be appropriately set according to the kind of the drug and the purpose of administration, but is usually contained in the pressure-sensitive adhesive layer in an amount of 1 to 40% by weight, preferably about 2 to 30% by weight. If the content is less than 1% by weight, a therapeutically effective amount of the drug cannot be expected to be released, while if it exceeds 40% by weight, the therapeutic effect is limited and economically disadvantageous.

[0024]

As the patch of the present invention uses a support having a structure in which an extremely thin polyester film and a specific soft independent foam sheet are laminated, it has a moderate self-supporting property during the sticking operation and is handled. In addition to its excellent properties, it has the effect of significantly improving skin irritation after application. Also,
Since the flexible independent foam sheet is laminated on the support used for the patch of the present invention, it is rich in flexibility, elasticity, and elasticity,
The feeling of wearing after sticking is also good.

Further, in a patch containing a drug in the pressure-sensitive adhesive layer, the drug is prevented from migrating into the support by the polyester film, and there is almost no loss of the drug contained by the transfer. An appropriate ODT effect can be expected by sealing the skin surface. Moreover,
Since the soft independent foam sheet is laminated, it also has a heat retaining effect and can be expected to improve percutaneous absorption of a drug.

[0026]

EXAMPLES Examples of the present invention will be shown below, and will be described more specifically.

Example 1 An acrylic pressure-sensitive adhesive solution (solid content 25% by weight) obtained by copolymerizing 60 parts by weight of 2-ethylhexyl acrylate and 40 parts by weight of 2-methoxyethyl acrylate in an organic solvent. ) Was applied and dried on the separator so that the thickness after drying was 40 μm, to prepare an adhesive layer.

Using the pressure-sensitive adhesive layer prepared above as a support, a polyethylene terephthalate film (2 μm thick)
/ Adhesive patch of the present invention by transfer-pressing to a film surface of a laminate of a / polyethylene independent foam sheet (thickness 1 mm, expansion ratio 20 times, elongation per unit area at break at a pulling speed of 50 mm / min 200%) I got

Comparative Example 1 An adhesive patch having no foam sheet was prepared in the same manner as in Example 1 except that a single-layer polyethylene terephthalate film (thickness: 6 μm) was used as a support.

Example 2 High molecular weight polyisobutylene (viscosity average molecular weight 1,20
(000) 25 parts by weight, low molecular weight polyisobutylene (viscosity average molecular weight 35,000) 47 parts by weight, polybutene (viscosity average molecular weight 1,260) 8 parts by weight, and alicyclic petroleum resin 20 parts by weight. A rubber-based pressure-sensitive adhesive solution (solid content concentration: 25% by weight) was prepared by dissolving in hexane, and this was coated and dried on a separator so that the thickness after drying was 20 μm, to prepare a pressure-sensitive adhesive layer.

Using the pressure-sensitive adhesive layer prepared above as a support, a polyethylene terephthalate film (2 μm thick)
/ 1,2-polybutadiene independent foam sheet (thickness: 0.5 mm, expansion ratio: 5 times, elongation per unit area at break at a pulling speed of 50 mm / min, 400%) is transferred and pressure-bonded to the film surface. Thus, the patch of the present invention was obtained.

Comparative Example 2 A patch was prepared in the same manner as in Example 2 except that a foam sheet was not laminated, except that a single-layer polyethylene terephthalate film (thickness: 6 μm) was used as the support.

Example 3 Same as Example 1, except that ketoprofen, an anti-inflammatory analgesic, was added to the adhesive solution obtained in Example 1 so that the content in the adhesive was 20% by weight. To prepare a patch containing the drug.

Comparative Example 3 A drug-containing patch having no foam sheet laminated thereon was prepared in the same manner as in Example 3, except that a single-layer polyethylene terephthalate film (thickness: 6 μm) was used as the support.

Comparative Example 4 A polyethylene independent foam sheet (thickness: 1) was used as a support.
mm, expansion ratio 20 times, elongation per unit area at break at a pulling speed of 50 mm / min 200%), except that a polyester film was not laminated in the same manner as in Example 3. An adhesive patch was prepared.

Comparative Example 5 The procedure of Example 3 was repeated except that a pressure-sensitive adhesive layer was formed on the film side as a laminated film of a polyethylene terephthalate film (thickness: 2 μm) / polyethylene terephthalate nonwoven fabric (basis weight: 12 g / m ² ) as a support. Thus, a patch containing the drug was prepared.

Example 4 The procedure of Example 2 was repeated except that the beta-blocker metoprolol was added to the adhesive solution obtained in Example 2 so that the content in the adhesive was 10% by weight. In the same manner, a drug-containing patch was prepared.

Comparative Example 6 A drug-containing patch having no foam sheet laminated thereon was prepared in the same manner as in Example 4, except that a single-layer polyethylene terephthalate film (thickness: 6 μm) was used as the support.

Comparative Example 7 A 1,2-polybutadiene independent foam sheet (thickness 0.5 mm, expansion ratio 5 times, tensile speed 50 mm /
A drug-containing patch having no polyester film laminated thereon was prepared in the same manner as in Example 4 except that a single-layer film having an elongation at break of 400% per unit area per minute) was used.

Comparative Example 8 The procedure of Example 4 was repeated except that an adhesive layer was formed on the film side as a laminated film of a polyethylene terephthalate film (thickness: 2 μm) / polyethylene terephthalate nonwoven fabric (basis weight: 12 g / m ² ) as a support. Thus, a patch containing the drug was prepared.

Comparative Example 9 A polyethylene terephthalate film (thickness: 10 μm) / polyethylene independent foam sheet (thickness: 1) was used as a support.
A patch was prepared in the same manner as in Example 1 except that a laminate having a thickness of 200 mm, an expansion ratio of 20 times, and an elongation per unit area at breakage at a tensile speed of 50 mm / min of 200%) was used.

Comparative Example 10 A polyethylene terephthalate film (2 μm thick) / polyethylene independent foam sheet (7 m thick) was used as a support.
A patch was prepared in the same manner as in Example 1, except that a laminate having a m of 20 times, an expansion ratio of 20 times, and an elongation at break of 30% at a tensile speed of 50 mm / min was used.

Comparative Example 11 A pressure-sensitive adhesive layer was formed on the foam sheet side of the support.
A patch was prepared in the same manner as in Example 3.

Comparative Example 12 Ethylene / vinyl acetate copolymer film (vinyl acetate content: 18%, thickness: 2 μm) / polyethylene independent foam sheet (thickness: 1 mm, expansion ratio: 20 times, tensile speed: 50 mm / min) Elongation per unit area per hour 2
(00%), a patch was prepared in the same manner as in Example 3 except that the laminate was used.

Comparative Example 13 A polyethylene terephthalate film (thickness: 2 μm) / 1,2-polybutadiene continuous foam sheet (thickness: 0.5 mm, expansion ratio: 5 times, tensile speed: 50 mm) was used as a support.
A patch was prepared in the same manner as in Example 4 except that a laminate having an elongation per unit area of 400% per minute at break / minute) was used.

The following tests were carried out using the patches obtained in the above Examples and Comparative Examples. The results are shown in Tables 1 and 2.

[Handlability] Each patch sample cut to a size of 25 cm ² was applied to the inside of the forearm of five volunteers, and the handleability at that time was evaluated according to the following criteria, and the average value was calculated. I asked.

3: There is no sticking between the adhesive surfaces during the sticking operation, and the sticking can be performed neatly. 2: It can be stuck neatly, but there is some difficulty in handling. 1: At the time of pasting, wrinkles enter, the adhesive surfaces stick together,
It is difficult to handle.

[Patching Feeling] Each patch sample cut to a size of 10 cm ² was pasted on the chest of five volunteers for 6 hours, and the sticking feeling at that time was evaluated according to the following criteria, and the average value was determined. 3: Good without discomfort.

2: Somewhat uncomfortable. 1: There is considerable discomfort.

[Skin irritation] Each patch sample cut to a size of 10 cm ² was applied to the inside of the forearm of five volunteers for 24 hours. Next, after peeling and removing each sample from the application surface, the state of the skin surface was observed after 30 minutes and 24 hours. The degree of skin irritation was determined based on the Japanese patch test criteria, and the average score was calculated.

(-) No response Rating 0 (±) Mild erythema Rating 0.5 (+) Erythema Rating 1.0 (++) Erythema and edema Rating 2.0

[Drug Residual Rate] Each patch sample containing a drug cut into a size of 10 cm ² was sealed with a packaging material, stored at 50 ° C. for one month, and the amount of drug contained in the patch was determined. Quantified. The drug residual ratio was calculated from the drug content after storage, assuming that the drug content before storage was 100%.

[Transdermal absorbability] Each patch sample containing a drug cut into a size of 10 cm ² was applied to the back of five volunteers for 24 hours. Next, each sample was peeled off from the application surface, the amount of drug remaining in the sample was measured, and the amount of decrease in drug content before application (percutaneous absorption)
Was calculated to calculate the skin transfer rate. In addition, the same test was performed on a sample stored at 50 ° C. for one month, and the change over time in skin transfer rate was also examined.

[0055]

[Table 1]

[0056]

[Table 2]

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int. Cl. ⁷ , DB name) A61L 15/00-15/58 A61F 13/00-13/14 A61K 9/00-9/70

Claims (4)

(57) [Claims] 1. A nonwoven fabric sheet having a thickness of 0.4 to 5 mm and a polyester film having a thickness of 0.5 to 6 μm laminated on one side of the flexible closed foam sheet to give an adhesive at room temperature to a polyester film surface of the support. A patch having excellent sticking properties, characterized by being formed directly or indirectly with a pressure-sensitive adhesive layer having the same. 2. The patch according to claim 1, wherein the elongation per unit area at break when the flexible independent foam is pulled at a pulling speed of 50 mm / min is 50% or more. 3. The patch according to claim 1, wherein the flexible closed foam has an expansion ratio of 2 to 50 times. 4. The pressure-sensitive adhesive layer comprising a drug.
The patch as described in the above.