JP3407895B2 - Method for evaluating skin irritation of patches and patches - 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 for sticking to a skin surface to protect a wound or to absorb a drug through the skin, and a method for evaluating skin irritation of a patch preparation.

[0002]

2. Description of the Related Art Conventionally, in this type of patch and patch preparation, it is known that a polymer alone forms an adhesive layer, and the presence of this adhesive layer improves the adhesiveness to the skin. It was possible to fix the patch and patch preparation on the skin.

However, the above patch and patch preparation are
Since it is necessary to firmly fix it on the skin surface for a long time, the skin adhesive force is too strong, and when peeling and removing it from the skin surface after use, it causes pain due to physical irritation due to exfoliation of the skin surface, and sometimes, In some cases, significant pain occurred. In order to solve this problem, the present applicant has previously made a polymer layer in which an acrylic acid ester-based polymer contains an excess amount of a liquid component compatible with the polymer in excess of a usual amount to crosslink and gel the polymer layer. It has been found that the reduction of the cohesive force can be prevented, the stress applied to the skin surface at the time of peeling the preparation can be relieved and dispersed, and the skin adhesion and skin irritation can be well balanced, and a patent application has been filed ( See JP-A-3-220120).

[0004]

However, the patch and patch preparation of the invention described above are excellent ones capable of solving the problems of the conventional patch and patch preparation, but do not always exhibit the above effects, When peeled off from the skin surface after use, pain and exfoliation of the keratin may still occur. The present invention can solve the above problems, has excellent long-term adhesiveness to the skin, and is a skin irritation for determining a patch and a patch preparation that can be smoothly peeled without physical skin irritation (pain) during peeling. The purpose is to provide a sex evaluation method.

[0005]

Means for Solving the Problems As a result of further intensive studies by the present inventors in order to achieve the above-mentioned object, the skin adhesiveness and skin irritation of the patch and patch preparation were found to be the crosslinked state of the adhesive layer. They found that they correlate and completed the present invention. That is, the evaluation method of claim 1 is a method for evaluating the skin irritation of an adhesive patch having a pressure-sensitive adhesive layer made of a polymer cross-linked on one surface of a support, wherein the adhesive layer surfaces of the adhesive patch are After bringing them into close contact, move the roller with a load of 850 g from the top.
300mm / m in the 180 degree direction after being put back and pasted
When the 180-degree angle constant speed peel strength test is performed by peeling at a speed of in , the adhesive force is 20 to 180 g / 12 m
It is an evaluation method characterized in that a patch having an m-width is determined to be a patch having low skin irritation. In addition, claim 2
The evaluation method of is a method of evaluating the skin irritation of a patch preparation having a pressure-sensitive adhesive layer containing a drug, which consists of a polymer cross-linked on one surface of the support, and the adhesive layer surfaces of the patch preparation are tested. A roller with a load of 850g from above
-Move back and forth once to stick the pasted object 300 in 180 degree direction
When peeling is performed at a speed of mm / min, when the 180-degree angle constant speed peel strength test is performed, the adhesive force is 20 to 180 g.
This is an evaluation method characterized in that a patch preparation showing a / 12 mm width is judged to be a patch preparation having low skin irritation.

[0006]

The function of the patch and patch preparation of the present invention is as follows:
Together the above sticking adhesive layer to each other obtained by the crosslinking process
When the 180-degree constant-velocity peeling strength test is carried out in this manner, it is determined whether or not it exhibits a specific adhesive force. Based on this criterion, excellent long-term adhesiveness to the skin and Since it is possible to judge whether or not it exhibits appropriate adhesiveness, it is possible to obtain a patch or patch preparation that has good adhesiveness (adhesion) and does not cause keratinocyte exfoliation and physical skin irritation (pain). .

Explaining the present invention in more detail, the support used for the patch and patch preparation to which the evaluation method of the present invention is applied is not particularly limited, but liquid components contained in the cross-linked pressure-sensitive adhesive layer and It is preferable that the drug does not pass through the support and is lost from the back surface so that the content does not decrease, that is, those in which these pressure-sensitive adhesive layer constituent components are made of an impermeable material.

Examples of such impermeable supports include polyester, nylon, saran, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, ethylene-ethyl acrylate copolymer, polytetrafluoroethylene, A single film such as Surlyn or a metal foil, or a laminated film thereof may be used.

As the support, a support having a thickness that does not impair the soft feeling of the patch and patch preparation, specifically, 1 to 25 μm, preferably 1 to 15 μm is used.

Further, it is preferable to use a laminate of the above support and a porous film because the anchoring effect improves the adhesive force between the adhesive layer and the support. As the porous film, specifically, paper, woven fabric, non-woven fabric, mechanically perforated sheet or the like can be used.

The thickness of this porous film is 10 to 500 μm in consideration of the above-mentioned anchoring property and flexibility of the patch and patch preparation, and in the case of a thin preparation such as plaster type or adhesive tape type. , 10-200
It is preferably in the range of μm.

When a woven or non-woven fabric is used as the porous film, the basis weight of the pressure-sensitive adhesive layer is 5 to 30 g / m.
² , preferably 8 to 20 g / m ² is preferable because the anchoring property is improved.

Further, in order to control the drug release property of the patch preparation, it is possible to make the support relatively breathable.

In the patch or patch preparation to which the evaluation method of the present invention is applied, since a pressure-sensitive adhesive layer made of a crosslinked polymer is formed on one side of a support, a proper skin adhesive force and cohesive force are obtained. It has and. The adhesive strength of this adhesive layer surface is obtained by bringing the adhesive layer surfaces of the patch or patch preparation into close contact with each other, and then applying a roller with a load of 850 g from above.
Reciprocating and pasted objects are 180 mm in the direction of 300 mm /
The adhesive strength is 20 to 180 g / 12 as measured by the 180-degree angle constant speed peel strength test, which is performed by peeling at a speed of min.
mm width, preferably 30 to 165 g / 12 m
It is determined that a material having an m width, more preferably 40 to 150 g / 12 mm width, is suitable for use as a patch or patch preparation having low skin irritation.

When the patch or patch preparation having a pressure-sensitive adhesive layer showing the above-mentioned adhesive strength is used, it has excellent adhesiveness and adhesion to the skin, and when it is peeled off after application to the skin, keratinocytes on the skin surface It is possible to peel smoothly without causing physical skin irritation (pain) due to peeling. Further, the pressure-sensitive adhesive layer has appropriate cohesiveness due to the cross-linking treatment, and is excellent in sticking to skin and releasability (no adhesive remains).

The polymer which is a film-forming component of the pressure-sensitive adhesive layer is not particularly limited, but rubber-based, acrylic-based, silicone-based, and other polymers can be used, and the acrylic-based polymer is particularly preferable. .

Examples of the acrylic polymer include (meth) acrylic acid alkyl ester polymers having a linear alkyl group or a branched alkyl group. As the (meth) acrylic acid alkyl ester-based polymer,
A polymer obtained by polymerizing a (meth) acrylic acid alkyl ester having an alkyl group with 4 or more carbon atoms, especially because the (meth) acrylic acid alkyl ester is used as a main component and is copolymerized with other copolymerizable monomers. Preference is given to using polymerized copolymers.

As the copolymerizable monomer to be copolymerized with the above-mentioned (meth) acrylic acid alkyl ester, a carboxyl group-containing monomer, a sulfoxyl group-containing monomer, a hydroxyl group-containing monomer, an amide-containing monomer, an alkylaminoalkyl group-containing monomer, (meth ) Acrylic acid alkoxyalkyl ester, alkoxy group (or ether bond in the side chain) -containing (meth) acrylic acid ester,
Examples thereof include vinyl-based monomers, and these can be used alone or in combination of two or more kinds for copolymerization.

The above-mentioned copolymerizable monomer is used for adjusting the cohesive force of the pressure-sensitive adhesive layer and for improving the solubility of the drug compounded in the pressure-sensitive adhesive layer. The type and amount of the monomer used depends on the purpose. It can be selected arbitrarily.

The liquid component used in the present invention has a property of being compatible with the above-mentioned polymer, and when contained in the pressure-sensitive adhesive layer, the pressure-sensitive adhesive layer is plasticized to give a soft feeling, and It has good adhesiveness to the skin and also has a role of reducing pain and skin irritation caused by the skin adhesive force when peeling the crosslinked adhesive layer from the skin surface.

As the liquid component, any liquid component having a plasticizing action may be used, but it is preferable to use a liquid component having an absorption promoting action in order to improve the transdermal absorbability of the coexisting drug.

The liquid component is not particularly limited as long as it is compatible with the polymer, but glycols, fats and oils, organic solvents, liquid surfactants, plasticizers, hydrocarbons, ethoxylated compounds. Stearyl alcohol, glycerin ester, isopropyl myristate, isotridecyl myristate, ethyl laurate, N-methylpyrrolidone ethyl oleate, oleic acid, diisopropyl adipate, isopropyl palmitate, octyl palmitate, 1,3-butanediol, etc. To be

The amount of the above liquid components is 100 parts by weight of the polymer in consideration of the balance of the cohesiveness of the pressure-sensitive adhesive layer, the flexibility, the adhesiveness to the skin, the sticking property (paste residue), the skin irritation and the like. On the other hand, it is 20 to 200 parts by weight, preferably 40 to 180 parts by weight. When it exceeds 200 parts by weight, cohesive failure occurs in the pressure-sensitive adhesive layer, and when the patch or patch preparation is peeled off from the skin, a significant amount of the pressure-sensitive adhesive remains on the skin, which is not preferable. On the other hand, if the amount is less than 20 parts by weight, the plasticizing effect cannot be obtained and the adhesion to the skin is deteriorated, which is not preferable.

The above-mentioned pressure-sensitive adhesive layer can be formed by directly applying the above-mentioned pressure-sensitive adhesive composition onto a support material by a suitable method such as a roll coater, a reverse coater, a doctor blade or a bar.
Alternatively, a dry film thickness of the adhesive is 30 to 1 on the release liner.
After coating so as to have a thickness of 20 μm, this pressure-sensitive adhesive layer is adhered to a support material.

The patch or patch preparation used in the present invention exhibits appropriate adhesiveness to the skin, and when peeled off after application, in order to reduce physical skin irritation (pain) due to keratinocyte detachment, It is an essential requirement that the adhesive layer be crosslinked.

The cross-linking treatment is carried out by physical cross-linking by irradiation with radiation such as UV irradiation or electron beam irradiation, or chemicals using a cross-linking agent such as polyisocyanate compound, organic peroxide, organic metal salt, metal alcoholate or metal chelate compound. Crosslinking treatment is performed. However, in the patch preparation of the present invention, since the drug is mixed in the adhesive layer, it is necessary to select a cross-linking treatment method that does not decompose or react the drug.

When the pressure-sensitive adhesive layer is subjected to the crosslinking treatment by the above method, the liquid component contained in the pressure-sensitive adhesive layer can be prevented from flowing out, and the pressure-sensitive adhesive layer can be provided with an appropriate cohesive force as a patch.

The amount of the above-mentioned cross-linking agent added is such that the adhesiveness (sticking) to the skin is good without impairing the flexibility required for the patch or patch preparation, and the physical skin irritation (pain) upon peeling ) Need to be adjusted.
Specifically, it is 0.05 to 1 with respect to 100 parts by weight of the polymer.
It is preferable to add parts by weight. If it is less than 0.05 parts by weight, the adhesive force on the surface of the pressure-sensitive adhesive layer exceeds 180 g / 12 mm width, and physical skin irritation (pain) is severe when peeling the patch from the skin, which may cause significant damage to the skin. There is. If it exceeds 1 part by weight, the adhesive force on the surface of the pressure-sensitive adhesive layer becomes less than 20 g / 12 mm width, and the pressure-sensitive adhesive layer becomes inflexible and lacks adhesiveness to the skin, and can be used as a patch or patch preparation. Disappear.

Even if the polymer of the pressure-sensitive adhesive does not have a functional group that reacts with the above-mentioned crosslinking agent, it can be modified into a structure capable of crosslinking treatment by subjecting the substance to be crosslinked to alkali treatment or the like. .

The evaluation method of the present invention can be applied to a patch preparation obtained by incorporating a drug into the adhesive layer of the patch. The drug to be contained is arbitrarily selected according to the purpose of treatment, for example corticosteroids, analgesic and anti-inflammatory agents, hypnotics, tranquilizers, antihypertensive agents, antihypertensive diuretics, antibiotics, Anesthetic,
Antibacterial agents, antifungal agents, vitamins, coronary vasodilators, antihistamines, antitussives, sex hormones, antidepressants, cerebral circulation improvers, antiemetics, antitumor agents, biopharmaceuticals, etc. that can be transdermally absorbed These can be used, and if necessary, two or more kinds can be used in combination.

The content of the above-mentioned drug is appropriately set depending on the kind of the drug and the purpose of administration, but is generally 1 to 40% by weight, preferably 3 to 30% by weight of the pressure-sensitive adhesive composition. It is a degree. If the content is less than 1% by weight, the amount of drug absorbed into the body is small and no therapeutic effect is observed.
When it exceeds 40% by weight, the therapeutic effect is limited and it is economically disadvantageous, which is not preferable.

[0032]

EXAMPLES Examples will be shown below for further detailed description. In the following, parts and% mean parts by weight and% by weight. Example 1 An acrylic acid ester-based polymer solution was prepared by copolymerizing 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid in 50 parts of ethyl acetate under an inert gas atmosphere. To 100 parts of the polymer of this solution, 0.14 parts of trifunctional isocyanate (trade name Coronate HL, manufactured by Nippon Polyurethane Company) was added to obtain a viscous solution. This viscous solution was applied on a 75 μm-thick polyester release liner with a doctor blade so that the thickness after drying was 60 μm, dried at 100 ° C. for 5 minutes, and then a polyester nonwoven fabric (12 g / m ² ) A support having a 2 μm polyester film laminated thereon was bonded to obtain a patch.

Comparative Example 1 A patch was obtained in the same manner as in Example 1 except that the trifunctional isocyanate was not added and the pressure-sensitive adhesive layer was formed by the acrylic ester polymer solution alone.

Example 2 The same as Example 1 except that 41.8 parts of isopropyl myristate and 0.07 part of trifunctional isocyanate were mixed with 51.8 parts of the polymer of the acrylic ester polymer solution. Then, the patch was obtained.

Comparative Example 2 A patch was obtained in the same manner as in Example 2, except that the pressure-sensitive adhesive layer was formed without adding the trifunctional isocyanate. This patch was markedly cohesively broken and could not be subjected to all the tests described below.

Example 3 In Example 1, 40 parts of isopropyl myristate was added to 43 parts of the polymer of the acrylic acid ester-based polymer solution.
Parts, isosorbitodinitrate 17 parts, and trifunctional isocyanate 0.06 parts were all mixed in the same manner to obtain a patch preparation.

Example 4 A patch preparation was obtained in the same manner as in Example 3, except that 0.06 part of ethyl acetoacetate aluminum diisopropylate was used instead of 0.06 part of the trifunctional isocyanate.

Example 5 In an inert gas atmosphere, 75 parts of 2-ethylhexyl acrylate, 22 parts of N-vinyl-2-pyrrolidone and 3 parts of acrylic acid were copolymerized in 150 parts of ethyl acetate to form an acrylate ester system. A polymer solution was prepared. 0.2 part of trifunctional isocyanate was added to 100 parts of the polymer of this solution to obtain a viscous solution. Then, the same operation as in Example 1 was performed to obtain a patch.

Example 6 The same as Example 1 except that 40 parts of octyl palmitate and 0.12 parts of trifunctional isocyanate were added to 60 parts of the polymer of the acrylic acid ester-based polymer solution. The operation was performed to obtain a patch.

Comparative Example 3 A patch was obtained in the same manner as in Example 6, except that the compounding amount of the trifunctional isocyanate was changed to 0.72 part.

Comparative Example 4 A patch was obtained in the same manner as in Example 6, except that the compounding amount of the trifunctional isocyanate was changed to 0.024 part.

Example 7 In Example 5, with respect to 57.5 parts of the polymer of the acrylic acid ester-based polymer solution, 4 octyl palmitate was added.
A patch preparation was obtained in the same manner except that 0 part, 2.5 parts of estradiol and 0.115 part of a trifunctional isocyanate were added.

Experimental Example The samples obtained in Examples 1 to 7 and Comparative Examples 1 to 4 were stored at 70 ° C. for 2 days, and then the following tests were conducted. [Adhesive strength of pressure-sensitive adhesive layer] After cutting each sample into a width of 12 mm and peeling the liner,
After the two adhesive layers of each sample are brought into close contact with each other,
A roller having a load of 850 g was reciprocated once from the above to be laminated. Then, this laminated product is 300 mm in the 180 degree direction.
The adhesive strength was measured by peeling at a speed of / min. In addition, the said adhesive force was measured using the Shopper tension tester (made by Ueshima Seisakusho).

[Skin application (adhesion)] Each sample was applied to the inside of the upper arm of 6 volunteers,
The skin adhesiveness (adhesion) after 24 hours was visually evaluated. The one with the best adhesion (the one with good adhesiveness)
Was evaluated as 5, and the case of significant peeling was evaluated as 1.

[Skin irritation (pain) at the time of peeling] After measuring the skin adhesiveness, the degree of skin irritation (pain) at the time of peeling the sample was measured in 5 steps. The average value was calculated by setting 1 as one having no skin irritation. In addition, the thing of the comparative example 1 was determined as 5 as a reference | standard.

[0046]

[Table 1]

As is clear from Table 1, according to the evaluation method of the present invention, the patch and patch preparation of the Example products have good skin patchability, and physical irritation (pain) when peeled from the skin. Almost nothing.

[0048]

The method for evaluating skin irritation of the present invention comprises:
The patch and patch preparation have an adhesive strength of 2 when the pressure-sensitive adhesive layers made of the crosslinked polymer are stuck together.
When the blending ratio of the constituents of this pressure-sensitive adhesive layer is adjusted so as to show a width of 0 to 180 g / 12 mm, it is excellent in long-term adhesiveness to the skin and sticking (adhesion), and further when peeling after sticking. It was found that physical skin irritation (pain) due to exfoliation of keratinocytes does not occur.

Further, by cross-linking the pressure-sensitive adhesive in the patch or patch preparation, the shape retention and cohesiveness of the pressure-sensitive adhesive layer are improved, so that the pressure-sensitive adhesive does not remain on the skin during peeling and the adhesive strength is improved. Since it falls within the above range, reduction of skin irritation can be expected.

In addition, the patch preparation containing the drug can release the drug to the skin surface to an appropriate degree, and the drug can be administered from the skin surface to the living body by transdermal absorption to treat or prevent various diseases. It is effective.

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hitomi Akemi 1-2-1, Shimohozumi, Ibaraki City, Osaka Prefecture Nitto Denko Corporation (72) Inventor Saburo Otsuka 1-1-1, Shimohozumi, Ibaraki City, Osaka Prefecture No. 2 Nitto Denko Corporation (72) Inventor Takamitsu Muraoka 1-2-1, Shimohozumi, Ibaraki City, Osaka Prefecture Nitto Denko Corporation (56) Reference JP-A-3-220120 (JP, A) Kaihei 3-223212 (JP, A) (58) Fields surveyed (Int.Cl. ⁷ , DB name) A61K 9/70 A61F 13/02 A61L 15/06

Claims (4)

(57) [Claims] 1. A method for evaluating skin irritation of a patch having a pressure-sensitive adhesive layer made of a cross-linked polymer on one surface of a support, wherein the pressure-sensitive adhesive layer surfaces of the patch are adhered to each other .
After that, a roller having a load of 850 g was reciprocated once from above, and the pasted product was 180 degrees at a speed of 300 mm / min.
Carried out by peeling, when the 180-degree angle constant rate peel strength test, evaluation and judging an adhesive preparation in which the adhesive force shows a 20~180g / 12mm width to be low skin irritation of the patch material Method. 2. A method for evaluating the skin irritation of a patch preparation, which comprises a cross-linked polymer on one side of a support and has a drug-containing pressure-sensitive adhesive layer, the method comprising: A roller with a load of 850g from above
-Move back and forth once to stick the pasted object 300 in 180 degree direction
When peeling is performed at a speed of mm / min, when the 180-degree angle constant speed peel strength test is performed, the adhesive force is 20 to 180 g.
An evaluation method characterized in that a patch preparation showing a / 12 mm width is determined to be a patch preparation having low skin irritation. 3. A pressure-sensitive adhesive, wherein the pressure-sensitive adhesive layer is composed of 25 to 200 parts by weight of a liquid component compatible with the polymer and 100 to 100 parts by weight of the polymer and 0.05 to 1.0 parts by weight of a crosslinking agent. The evaluation method according to claim 1, wherein the composition is formed into a film and crosslinked. 4. The drug is contained in an amount of 1 to 40% by weight based on 100 parts by weight of the pressure-sensitive adhesive composition.
Evaluation method described in.