JP5192722B2 - External patch - Google Patents

Description

  The present invention relates to an external patch comprising fentanyl as an active ingredient, and more particularly to a matrix-type external patch capable of percutaneously absorbing fentanyl over a long period of time.

  Fentanyl is a synthetic opioid analgesic and is mainly used as an injection for the treatment of acute postoperative pain and chronic cancer pain. In addition to an injection, a patch containing fentanyl has been developed (see Patent Document 1), which is already on the market in Japan, and is highly effective in clinical settings. This patch is a reservoir type that has a drug storage layer and a controlled release layer, has excellent sustained release of fentanyl, has a long action time on injections, and is suitable for the treatment of cancer pain control ing. However, the composition of the reservoir-type patch preparation comprises a support, a drug storage layer, a release control layer, an adhesive layer, and a liner, and its manufacturing method is complicated and requires high precision. Therefore, the reservoir type patch has a problem that the production cost is higher than that of a general patch. Furthermore, this patch has insufficient adhesiveness, and there has been a problem that peeling and turning will occur when it is applied continuously for 3 days.

  In order to solve such a problem, in recent years, a matrix-type fentanyl-containing patch has been developed. Since the matrix type patch has a simple configuration and a simple manufacturing method compared to the reservoir type patch, it can be manufactured at low cost. However, since matrix-type patches do not have a controlled release layer, compared with reservoir-type patches, in general, the drug can be transferred to the skin more rapidly, but the drug absorption can be sustained. It was low and needed to be improved.

  Accordingly, matrix-type fentanyl patches having various compositions have been developed. For example, patches containing fentanyl and an acrylic adhesive (see Patent Document 2), patches containing fentanyl and a silicone adhesive (Patent Document) 3), fentanyl, polyisobutylene, styrene-isoprene-styrene block copolymer, and a patch containing an alicyclic saturated hydrocarbon resin alone as a tackifying resin (see Patent Document 4), fentanyl, polyisobutylene, mineral oil And a patch containing an absorption accelerator (see Patent Document 5), two types of polyisobutylene having different molecular weights, a tackifier (tackifier), and an organic liquid (absorption accelerator) (see Patent Document 6) ) Etc. are disclosed.

  However, the acrylic pressure-sensitive adhesive used in the patch described in Patent Document 2 is generally a pressure-sensitive adhesive having good adhesiveness to the skin, but physical skin damage (corner) when peeling the patch. Because of the high occurrence of delamination, safety and compliance decline for cancer patients is a problem. In addition, the silicone adhesive used in the patch described in Patent Document 3 is generally poor in adhesiveness to the skin, causing peeling and turning at the time of application, stable administration of drugs to cancer patients, There is a problem that the effective blood concentration of the drug cannot be maintained.

  Furthermore, although the patch described in Patent Document 4 is excellent in adhesiveness to the skin, the alicyclic saturated hydrocarbon resin used as the tackifying resin is less compatible with fentanyl than other tackifying resins. Therefore, there has been a problem that fentanyl in the plaster layer is easily recrystallized and deposited over time. Moreover, although the patches of Patent Documents 5 and 6 have high stability and excellent skin permeability, there are problems that the adhesiveness to the skin during sweating or bathing, the occurrence of skin irritation, and the like are likely to occur.

JP 61-37725 A Publication No. 2004-524336 JP-T-2006-513160 International Publication No. 04/024155 International Publication No. 2004/035054 Pamphlet JP 2006-76994 A

  Accordingly, there is a need for the development of a matrix-type external patch that can be applied over a long period of time and can stably absorb fentanyl through the skin, and the present invention provides such an external patch. The task is to do.

  As a result of extensive research, the present inventors combined styrene-isoprene-styrene block copolymer and polyisoprene as a rubber component at a specific ratio, and added fentanyl to an adhesive base using a terpene resin as a tackifier. It discovered that the said subject could be solved by making it melt | dissolve, and completed this invention.

  That is, the present invention provides a plaster layer on one side of a support, and in the patch containing the active ingredient fentanyl and an adhesive base in the plaster layer, styrene- Isoprene-styrene block copolymer and polyisoprene and a terpene resin as a tackifier, and the content of styrene-isoprene-styrene block copolymer is 0.2 mass times to 10 mass of the content of polyisoprene. It is a patch for external use characterized by being doubled.

  The external patch of the present invention contains fentanyl in a stable manner and has excellent adhesive properties, and thus has a continuous transdermal absorbability of fentanyl over a long period of time, for example, about 3 days. Moreover, since the amount of stratum corneum peeling at the time of peeling is low, fentanyl can be stably percutaneously absorbed even if it is continuously applied to the same site, which is highly safe.

  In addition, according to the present invention, for example, in the administration of fentanyl to cancer pain patients who need to set a fentanyl administration dose in accordance with the patient's symptoms, age, weight, sex, etc. The external patch contained therein can be obtained by a simple production method at a low cost.

  The external patch of the present invention is a matrix-type fentanyl patch formed by laminating a support and a paste layer, and fentanyl is used as an active ingredient in the paste layer, a rubber component and an adhesive as an adhesive base. Containing an imparting agent.

  The content of fentanyl, which is an active ingredient used in the present invention, is preferably 1 to 6% by mass (hereinafter simply expressed as%) in the plaster layer, particularly preferably 2 to 4%. In the present invention, it is preferable that such a content of fentanyl is present in a state dissolved in the plaster layer. If the content of fentanyl is less than 1%, sufficient transdermal absorbability of fentanyl may not be obtained. Further, if the content exceeds 6%, crystals of fentanyl precipitate during storage of the preparation, which may cause problems such as changes in the adhesive strength of the preparation and transdermal absorbability of fentanyl over time. .

  The adhesive base in the plaster layer constituting the external patch of the present invention contains a styrene-isoprene-styrene block copolymer and polyisoprene as rubber components.

  As the styrene-isoprene-styrene block copolymer, for example, commercially available products such as Kraton D-KX401CS and Kraton D-1107CP (manufactured by JSR Kraton Elastomer Co., Ltd.) can be used. Further, as the polyisoprene, synthetic isoprene rubber or natural rubber can be used. Examples of commercially available products include NIPOL IR2200 (manufactured by ZEON Corporation).

  As the rubber component used in the present invention, in addition to the styrene-isoprene-styrene block copolymer and polyisoprene, styrene / butadiene rubber, polyisobutylene, butyl rubber, etc. can be used. It is preferable to use only a styrene-isoprene-styrene block copolymer and polyisoprene from the viewpoint of suppression of skin damage at the time, formulation stability, and the like.

  The content of the styrene-isoprene-styrene block copolymer and polyisoprene in this rubber component is in a range where the styrene-isoprene-styrene block copolymer is 0.2 to 10 times the mass of polyisoprene. . If the content of styrene-isoprene-styrene block copolymer is less than 0.2 mass times the content of polyisoprene, the cohesiveness of the paste will be reduced, resulting in adhesive residue, and if it exceeds 10 mass times, It is not preferable because the adhesiveness to the skin becomes poor.

  The content of the rubber component is preferably 15 to 55% in the plaster layer. If the content of the rubber component is less than 15%, the cohesiveness of the plaster may be reduced, which may cause adhesive residue, and if the content exceeds 55%, the adhesive strength to the skin may be poor. There is not preferable.

  In the adhesive base, a terpene resin is used as a tackifier. As this terpene resin, for example, a commercial product such as YS resin PX1150N (manufactured by Yasuhara Chemical Co., Ltd.) can be used.

  As the tackifier, a tackifier other than the terpene resin can be used in combination, but the content of the terpene resin with respect to the entire tackifier is preferably 30% or more. When the content of the terpene resin is less than 30%, precipitation of fentanyl crystals over time or reduction in transdermal absorbability of fentanyl may be observed. Examples of the tackifier that can be used in combination include alicyclic saturated hydrocarbon resins, petroleum resins, and rosin resins. Among these, alicyclic saturated hydrocarbon resins and / or hydrogenated rosin glycerin esters are preferable. Used. Commercially available products of alicyclic saturated hydrocarbon resin and hydrogenated rosin glycerin ester include Alcon P-100 and KE-311 (both manufactured by Arakawa Chemical Industries, Ltd.), respectively.

  The content of this tackifier is preferably 20 to 60% in the plaster layer. If the content of the tackifier is less than 20%, the adhesiveness to the skin may be poor. On the other hand, if the content of the tackifier exceeds 60%, the cohesiveness of the paste decreases, which may cause adhesive residue, and the transdermal absorbability of fentanyl may decrease, which is not preferable. .

  In addition to the rubber component and tackifier, a softener can be further blended in the adhesive base of the plaster layer. As the softener, liquid paraffin and / or polybutene can be used. Examples of commercially available liquid paraffin that can be used include HICOAL M-352 (manufactured by Kaneda Corporation), and examples of commercially available polybutene include HV300F (manufactured by Nippon Oil Corporation).

  The softener content in the plaster layer is preferably 10 to 50%. If the content of the softening agent is less than 10%, an appropriate adhesive strength may not be obtained, and physical skin irritation at the time of the release of the preparation may occur, which is not preferable. On the other hand, if the content exceeds 50%, the cohesiveness of the plaster is lowered, which may cause a residue of adhesive, which is not preferable.

  Furthermore, an absorption enhancer for promoting the transdermal absorbability of fentanyl can be blended in the plaster layer. Examples of the absorption accelerator include alcohols such as glycerin, propylene glycol, polyethylene glycol, oleyl alcohol, sorbitan fatty acid esters such as sorbitan monooleate, amides such as dimethylacetamide, oleic acid, lauric acid, myristic acid, palmitic acid Higher fatty acids such as menthol and limonene, higher fatty acid esters such as isopropyl myristate and propyl oleate, surfactants such as polyoxyethylene alkyl ether, polyoxyethylene lauryl ether and glycerin fatty acid ester, N -Pyrrolidones such as methyl-2-pyrrolidone are preferred.

  The external patch of the present invention can be produced according to a known method. For example, fentanyl and other adhesive base components are dissolved in an organic solvent such as hexane and toluene, and this dissolved product is released into a release sheet, release paper or support. After spreading on the body and evaporating the solvent in the solution to form a plaster layer, it can be produced by a method (solvent method) in which a patch is obtained by laminating a support or a release sheet or release paper.

  Examples of the support include films, papers, porous bodies, woven fabrics, non-woven fabrics, foams and laminates thereof made of polyethylene, polypropylene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester, polyurethane, etc. Are preferably used.

  The release film or release paper is used to coat the plaster layer, for example, a film made of a polymer material such as polyester, or a paper coated with silicone oil or the like is selected. It is preferable to use it.

The external patch of the present invention preferably has an area of 2.5 to 60 cm ² when applied to the skin. If the area is less than 2.5 cm ² , therapeutically sufficient fentanyl transdermal absorbability may not be obtained, and handling properties are also deteriorated. If the area exceeds 60 cm ² , an uncomfortable feeling during application may occur, which may reduce the compliance of cancer patients.

  The external patch of the present invention obtained as described above can be retained in the plaster layer in a state where fentanyl is dissolved, and the adhesive strength and the fentanyl transdermal absorbability are reduced with the crystallization of crystals over time. And has a therapeutically sufficient amount of fentanyl percutaneously absorbable, and has sustained efficacy by maintaining an effective blood concentration for a long time.

  EXAMPLES Hereinafter, although an Example and a test example are given and this invention is demonstrated further in detail, this invention is not restrict | limited at all by these Examples.

Example 1:
An external patch (Invention product 1) was obtained using the following formulation and production method.

(How to)
Component Weight parts 1. Fentanyl 1.0
2. Styrene-isoprene- 14.0
2. Styrene block copolymer Polyisoprene 10.0
4). Terpene resin ^{* 1} 34.0
5. Alicyclic saturated hydrocarbon resin ^{* 2} 14.0
6). Liquid paraffin 27.0
7). Total 100.0
* 1 YS resin PX1150N (manufactured by Yasuhara Chemical)
* 2 Alcon P-100 (Arakawa Chemical Industries)

(Production method)
A styrene-isoprene-styrene block copolymer, polyisoprene, terpene resin, alicyclic saturated hydrocarbon resin, and liquid paraffin were stirred and mixed in toluene, fentanyl was added, and the mixture was further stirred and mixed to obtain a uniform solution. . Next, this dissolved material is coated on a release film using a doctor knife coating machine, then air-dried, a support is bonded to the coated surface, and further cut to a size of 10.5 cm ² to obtain an external patch. Obtained.

Example 2
An external patch (Product 2 of the present invention) was obtained using the following formulation and production method.

(How to)
Component Weight parts 1. Fentanyl 2.0
2. Styrene-isoprene- 14.0
2. Styrene block copolymer Polyisoprene 10.0
4). Terpene resin ^{* 1} 34.0
5. Alicyclic saturated hydrocarbon resin ^{* 2} 14.0
6). Liquid paraffin 26.0
7). Total 100.0

(Production method)
An external patch was prepared by the same production method as in Example 1.

Example 3
An external patch (Product 3 of the present invention) was obtained using the following formulation and production method.

(How to)
Component Weight parts 1. Fentanyl 4.0
2. Styrene-isoprene- 14.0
2. Styrene block copolymer Polyisoprene 10.0
4). Terpene resin ^{* 1} 34.0
5. Alicyclic saturated hydrocarbon resin ^{* 2} 14.0
6). Liquid paraffin 24.0
7). Total 100.0

(Production method)
An external patch was prepared by the same production method as in Example 1.

Example 4:
An external patch (Product 4 of the present invention) was obtained using the following formulation and production method.

(How to)
Component Weight parts 1. Fentanyl 6.0
2. Styrene-isoprene- 14.0
2. Styrene block copolymer Polyisoprene 10.0
4). Terpene resin ^{* 1} 34.0
5. Alicyclic saturated hydrocarbon resin ^{* 2} 14.0
6). Liquid paraffin 22.0
7). Total 100.0

(Production method)
An external patch was prepared by the same production method as in Example 1.

Example 5:
An external patch (Product 5 of the present invention) was obtained using the following formulation and production method.

(How to)
Component Weight parts 1. Fentanyl 4.0
2. Styrene-isoprene-25.0
2. Styrene block copolymer Polyisoprene 5.0
4). Terpene resin ^{* 1} 48.0
5. Liquid paraffin 16.0
6). Polybutene 2.0
7). Total 100.0

(Production method)
An external patch was prepared by the same production method as in Example 1.

Example 6:
An external patch (Product 6 of the present invention) was obtained using the following formulation and production method.

(How to)
Component Weight parts 1. Fentanyl 4.0
2. Styrene-isoprene- 12.0
2. Styrene block copolymer Polyisoprene 3.0
4). Terpene resin 18.0
5. Hydrogenated rosin glycerin ester ^{* 3} 42.0
6). Polybutene 21.0
8). Total 100.0
* 3 KE-311 (Arakawa Chemical Industries)

(Production method)
An external patch was prepared by the same production method as in Example 1.

Example 7:
An external patch (Product 7 of the present invention) was obtained using the following formulation and production method.

(How to)
Component Weight parts 1. Fentanyl 4.0
2. Styrene-isoprene- 30.0
2. Styrene block copolymer Polyisoprene 3.0
4). Terpene resin ^{* 1} 16.0
5. Hydrogenated rosin glycerin ester ^{* 3} 37.0
6). Liquid paraffin 10.0
7). Total 100.0

(Production method)
An external patch was prepared by the same production method as in Example 1.

Example 8:
An external patch (Product 8 of the present invention) was obtained using the following formulation and production method.

(How to)
Component Weight parts 1. Fentanyl 4.0
2. Styrene-isoprene-5.0
2. Styrene block copolymer Polyisoprene 25.0
4). Terpene resin ^{* 1} 26.0
5. Alicyclic saturated hydrocarbon resin ^{* 2} 8.0
6). Liquid paraffin 32.0
7). Total 100.0

(Production method)
An external patch was prepared by the same production method as in Example 1.

Example 9:
An external patch (Invention product 9) was obtained using the following formulation and production method.

(How to)
Component Weight parts 1. Fentanyl 4.0
2. Styrene-isoprene- 30.0
2. Styrene block copolymer Polyisoprene 25.0
4). Terpene resin ^{* 1} 10.0
5. Alicyclic saturated hydrocarbon resin ^{* 2} 5.0
6). Hydrogenated rosin glycerin ester ^{* 3} 5.0
7). Liquid paraffin 21.0
8). Total 100.0

(Production method)
An external patch was prepared by the same production method as in Example 1.

Example 10:
An external patch (Invention product 10) was obtained using the following formulation and production method.

(How to)
Component Weight parts 1. Fentanyl 4.0
2. Styrene-isoprene-23.0
2. Styrene block copolymer Polyisoprene 3.0
4). Terpene resin ^{* 1} 10.0
5. Alicyclic saturated hydrocarbon resin ^{* 2} 5.0
6). Hydrogenated rosin glycerin ester ^{* 3} 5.0
7). Liquid paraffin 30.0
8). Polybutene 20.0
9. Total 100.0

(Production method)
An external patch was prepared by the same production method as in Example 1.

  The patches for external use obtained in Examples 1 to 10 were excellent in sticking property but had a low amount of exfoliated horny layer at the time of peeling, and no crystallization of fentanyl crystal was observed over time.

Comparison Example 1:
An external patch (Comparative product 1) was obtained using the following formulation and manufacturing method.

(How to)
Component Weight parts 1. Fentanyl 4.0
2. Styrene-isoprene-24.0
2. Styrene block copolymer Terpene resin ^{* 1} 34.0
4). Alicyclic saturated hydrocarbon resin ^{* 2} 14.0
5. Liquid paraffin 24.0
6). Total 100.0

(Production method)
An external patch was prepared by the same production method as in Example 1.

Comparative Example 2:
An external patch (Comparative product 2) was obtained using the following formulation and manufacturing method.

(How to)
Component Weight parts 1. Fentanyl 4.0
2. Styrene-isoprene- 12.0
2. Styrene block copolymer Terpene resin ^{* 1} 17.0
4). Alicyclic saturated hydrocarbon resin ^{* 2} 7.0
5. Liquid paraffin 60.0
6). Total 100.0

(Production method)
An external patch was prepared by the same production method as in Example 1.

Comparative Example 3:
An external patch (Comparative product 3) was obtained using the following formulation and manufacturing method.

(How to)
Component Weight parts 1. Fentanyl 4.0
2. Styrene-isoprene-25.0
2. Styrene block copolymer Polyisoprene 5.0
4). Alicyclic saturated hydrocarbon resin ^{* 2} 48.0
5. Liquid paraffin 16.0
6). Polybutene 2.0
7). Total 100.0

(Production method)
An external patch was prepared by the same production method as in Example 1.

Comparative Example 4:
An external patch (Comparative product 4) was obtained using the following formulation and manufacturing method.

(How to)
Component Weight parts 1. Fentanyl 4.0
2. Styrene-isoprene-25.0
2. Styrene block copolymer Polyisoprene 5.0
4). Hydrogenated rosin glycerin ester ^{* 3} 48.0
5. Liquid paraffin 16.0
6). Polybutene 2.0
7). Total 100.0

(Production method)
An external patch was prepared by the same production method as in Example 1.

Comparative Example 5:
An external patch (Comparative product 5) was obtained using the following formulation and production method.

(How to)
Component Weight parts 1. Fentanyl 4.0
2. Styrene-isoprene-26.0
2. Styrene block copolymer Terpene resin ^{* 1} 20.0
4). Alicyclic saturated hydrocarbon resin ^{* 2} 30.0
5. Liquid paraffin 20.0
6). Total 100.0

(Production method)
An external patch was prepared by the same production method as in Example 1.

  The external patches of Comparative Examples 3 and 5 were not sufficiently stickable, and the patch of Comparative Example 4 had good patchability but a slightly large amount of exfoliation.

Comparative Example 6:
An external patch (Comparative product 6) was obtained using the following formulation and production method.

(How to)
Component Weight parts 1. Fentanyl 4.0
2. Acrylic ester-vinyl acetate copolymer (solid content) 96.0
3. Total 100.0

(Production method)
Fentanyl is added to a commercially available acrylic ester-vinyl acetate copolymer (trade name: DURO-TAK87-4287, manufactured by National Starch & Chemical Co., solid content: 39%, solvent: ethyl acetate), and mixed by stirring to achieve uniform dissolution. I got a thing. Next, this dissolved material is coated on a release film using a doctor knife coating machine, then air-dried, a support is bonded to the coated surface, and further cut to a size of 10.5 cm ² to obtain an external patch. Obtained.

Comparative Example 7:
An external patch (Comparative product 7) was obtained using the following formulation and production method.

(How to)
Component Weight parts 1. Fentanyl 4.0
2. Silicone adhesive (solid content) 96.0
3. Total 100.0

(Production method)
Fentanyl was added to a commercially available silicone pressure-sensitive adhesive (trade name: BIO-PSA7-4201, manufactured by Dow Corning Healthcare, solid content: 70%, solvent: heptane), and mixed with stirring to obtain a uniform dissolved product. Next, this dissolved material is coated on a release film using a doctor knife coating machine, then air-dried, a support is bonded to the coated surface, and further cut to a size of 10.5 cm ² to obtain an external patch. Obtained.

Test Example 1
Adhesion test:
For inventive products 3 and 5, and comparative products 1, 2, 6 and 7, placebo (fentanyl blank) was prepared and a usability test was performed. In the test, the test substance was applied to the breasts of 12 healthy adult men for 3 days, and the applied condition at that time and the adhesive residue of the paste on the skin at the time of peeling were evaluated according to the following criteria. The results are shown in Table 1.
(Scoring method of pasting status)
◎: Less than 10% peeling and turning ○: 10% to less than 20% peeling and turning △: 20% to less than 50% peeling and turning ×: More than 50% peeling and turning (scoring method for remaining glue)
None: There is no adhesive paste remaining .: There is adhesive paste remaining.

  The inventive products 3 and 5 and the comparative product 6 (acrylic pressure-sensitive adhesive) have peeling and curling of less than 10%, and it has been clarified that the adhesiveness in humans is excellent. In comparative product 1 (rubber component is styrene-isoprene-styrene block copolymer only) and comparative product 7 (silicone-based adhesive), peeling and curling during application were observed in 20% or more and less than 50%, The sticking property was low. Comparative product 2 (rubber component is only styrene-isoprene-styrene block copolymer and the blending amount of liquid paraffin is 60% by mass) has 50% or more peeling and curling during application, and it can be applied to skin. Was even lower. Moreover, the adhesive residue at the time of peeling was recognized.

Test example 2
Stratum corneum peel test:
A placebo (fentanyl blank) was prepared for the inventive products 3 and 5 and the comparative products 6 and 7, and a stratum corneum peeling test was performed on human patch. In the test, the test substance was applied to the left and right breasts of 10 healthy adult men for 3 days according to an arbitrary assignment method, and the amount of stratum corneum peeling at the time of peeling was measured. The measurement was performed by immersing the peeled test substance and the unattached product of each test substance in a staining solution (a solution obtained by dissolving gentian violet and brilliant green in distilled water to make 100 mL) for 3 minutes to stain the stratum corneum. A sodium dodecyl sulfate solution (1 → 100, 10 mL) was accurately added to the stained test substance and left overnight to extract the stained stratum corneum. This solution was used as a sample solution. Absorbance at a wavelength of 595 nm was measured by an absorbance measurement method. In addition, the same operation was performed for the unattached product of each test substance (n = 3), and the average value was calculated from the obtained absorbance to obtain the absorbance of the unattached product of each test substance. From the absorbance of the stratum corneum extract of each test substance, the absorbance value of each test substance unattached product was subtracted to obtain the stratum corneum peeling amount. The results are shown in Table 2.

  The stratum corneum peeling amount of the products 3 and 5 of the present invention is about 50% of the comparative product 6 (acrylic pressure-sensitive adhesive) that showed the same adhesive strength in Test Example 1, and the comparative product 7 (silicone-based material) having low adhesive strength. It was almost the same as the adhesive. In the pain alleviation treatment of cancer patients, it is considered that fentanyl patch is administered continuously, and there is a possibility of administration to the same application site. For this reason, fentanyl is excessively absorbed through the skin due to a decrease in the skin barrier function due to continuous administration of the patch, which may increase the occurrence of side effects. Therefore, as for external preparations containing fentanyl as an active ingredient, in preparations for controlling the amount of drug absorbed in the body and managing pain, preparations that maintain the skin condition normally and always stably absorb the drug are required. It is done. The products 3 and 5 of the present invention are preparations having a low amount of exfoliated stratum corneum at the time of exfoliating the preparation, and can be expected to improve safety and compliance with cancer patients.

Test Example 3
Confirmation of fentanyl crystal precipitation time The inventive product 3, the inventive product 5, the comparative product 3, the comparative product 4 and the comparative product 5 were stored at 25 ° C. for 6 months, and the crystal precipitation state of fentanyl in each preparation was confirmed. In the test, the test substances packaged one by one in a transparent polyacrylonitrile packaging material were stored in a thermostatic chamber at 25 ° C., and the time when the crystals of fentanyl were precipitated was visually confirmed. All test substances were tested in 6 cases. The results are shown in Table 3.

  Inventive products 3, 5 (terpene resin) and comparative product 4 (hydrogen rosin glycerin ester) did not precipitate fentanyl crystals even after 6 months at 25 ° C., whereas comparative product 3 (alicyclic ring) Since the precipitation of fentanyl crystals was confirmed after 2 months at 25 ° C., the compatibility between the alicyclic saturated hydrocarbon resin and fentanyl was found in other tackifiers. It became clear that it was lower. Comparative product 5 (the ratio of terpene resin to alicyclic saturated hydrocarbon resin is 40 to 60) was compatible with fentanyl because there was no precipitation of fentanyl crystals after 25 months at 6 months. It was suggested that even when an alicyclic saturated hydrocarbon resin having a low viscosity is used, by combining with a terpene resin, precipitation of fentanyl crystals can be suppressed, and a patch excellent in formulation stability can be obtained.

Test Example 4
Drug residue test:
Twelve rabbits (Japanese white, male, 18 weeks old, body weight of about 3 kg) whose hair on the back skin had been removed in advance were used, and the products 3 and 5 of the present invention and the comparative products 3, 4 and 6 were arbitrarily assigned. According to the method, it was applied to the right and left back skins of rabbits and peeled after 72 hours. The fentanyl content in the preparation was quantified by liquid chromatography for the peeled preparation and the unapplied preparation, and the skin migration rate of fentanyl was calculated from the obtained quantitative results. The results are shown in Table 4.

  Fentanyl transfer rate to rabbit skin of inventive products 3 and 5 (terpene resin) and comparative product 3 (alicyclic saturated hydrocarbon resin) is about 70%, and fentanyl transfer rate of comparative product 6 (acrylic adhesive) The value was clearly higher than 40%, suggesting that the preparation is superior in transdermal absorbability of fentanyl. Comparative product 4 (hydrogenated rosin glycerin ester) had a fentanyl skin migration rate of 50%, which was clearly lower than that of a formulation containing other tackifiers. Compared with other tackifiers, the compatibility with fentanyl was higher, suggesting that the absorbency of fentanyl was reduced.

Test Example 5
Blood dynamics test:
1. Twelve rabbits (Japanese white breed, male, 18 weeks old, body weight of about 3 kg) whose hair on the back skin has been removed beforehand were cut into 10.5 cm ² and the commercial fentanyl patch. 5 mg was affixed to the back skin of rabbits, one each and 6 each, and peeled after 72 hours. Blood was collected from the rabbit ear vein 4, 8, 12, 24, 48 and 72 hours after the start of the test. Plasma fentanyl concentration was quantified by liquid chromatography / mass spectrometry (LC / MS). The time-dependent behavior of plasma fentanyl concentration obtained by quantification is shown as an average value ± standard deviation. The results are shown in FIG.

  The time course of the plasma fentanyl concentration of the product 3 of the present invention showed the same behavior as that of the commercially available fentanyl patch. In addition, since the commercially available fentanyl patch shows a stable fentanyl concentration in plasma for 3 days even in humans (Mizuguchi et al., Clinical Evaluation of Fentanyl Patch for Cancer Pain (KJK-4263) (1), Pharmaceutical Journal, vol37, No. 8, 2001), even when the fentanyl patch of the present invention was applied to humans, it was suggested that a stable plasma fentanyl concentration was maintained for 3 days.

  The patch of the present invention can be produced at low cost without requiring special processing, and can be held in the plaster layer for a long time in a state where fentanyl is dissolved. The drug has a transdermal absorbability of fentanyl in a sufficient amount for treatment, and there is no sudden increase in drug blood concentration. It can be obtained. Furthermore, by suppressing skin damage when the patch is peeled off, safety and compliance for cancer patients when repeatedly administered to the same site can be improved. Therefore, it is extremely useful as a patch for alleviating pain such as cancer pain.

6 is a graph showing the time-dependent behavior of plasma fentanyl concentration of the product 3 of the present invention and the commercially available fentanyl patch in the blood kinetic test of Test Example 5.

Claims (7)

In a patch comprising a plaster layer provided on one side of a support and containing the active ingredient fentanyl and an adhesive base in the plaster layer, a styrene-isoprene-styrene block copolymer as a rubber component in the adhesive base. It contains a polymer and polyisoprene and a terpene resin as a tackifier, and the content of the styrene-isoprene-styrene block copolymer is 0.2 to 10 times the content of the polyisoprene. Features of external patches ( excluding those containing propylene glycol, 1,3-butylene glycol or polyethylene glycol 400 ).   The content of fentanyl in the plaster layer is 1 to 6% by mass, the content of the rubber component is 15 to 55% by mass, and the content of the tackifier is 20 to 60% by mass. The external patch according to Item.   The external patch according to claim 1 or 2, wherein the content of the terpene resin relative to the entire tackifier is 30% by mass or more.   The external patch according to claim 3, further comprising a resin selected from the group consisting of an alicyclic saturated hydrocarbon resin, a petroleum resin, and a rosin resin as a tackifier.   The external patch according to any one of claims 1 to 4, wherein the adhesive base further contains liquid paraffin and / or polybutene as a softening agent.   The external patch according to claim 5, wherein the content of the softener in the plaster layer is 10 to 50% by mass. External patch according to any one of claims paragraph 1 - paragraph 6, wherein the area of the patch during skin application is 2.5~60cm ^2.

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