JP4312085B2 - Patch for ionic drug administration - Google Patents
Patch for ionic drug administration Download PDFInfo
- Publication number
- JP4312085B2 JP4312085B2 JP2004064910A JP2004064910A JP4312085B2 JP 4312085 B2 JP4312085 B2 JP 4312085B2 JP 2004064910 A JP2004064910 A JP 2004064910A JP 2004064910 A JP2004064910 A JP 2004064910A JP 4312085 B2 JP4312085 B2 JP 4312085B2
- Authority
- JP
- Japan
- Prior art keywords
- ion exchange
- exchange membrane
- drug
- living body
- membrane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000001647 drug administration Methods 0.000 title claims description 7
- 239000003814 drug Substances 0.000 claims description 113
- 229940079593 drug Drugs 0.000 claims description 110
- 239000003014 ion exchange membrane Substances 0.000 claims description 96
- 239000000463 material Substances 0.000 claims description 44
- 230000003746 surface roughness Effects 0.000 claims description 28
- 239000003456 ion exchange resin Substances 0.000 claims description 13
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 13
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- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 239000000853 adhesive Substances 0.000 claims description 11
- 230000001070 adhesive effect Effects 0.000 claims description 11
- 229920005992 thermoplastic resin Polymers 0.000 claims description 9
- 239000012466 permeate Substances 0.000 claims 1
- 239000012528 membrane Substances 0.000 description 45
- 210000004379 membrane Anatomy 0.000 description 41
- 238000000034 method Methods 0.000 description 40
- 239000000178 monomer Substances 0.000 description 37
- 238000005342 ion exchange Methods 0.000 description 34
- 239000000203 mixture Substances 0.000 description 25
- 150000002500 ions Chemical class 0.000 description 24
- 239000010410 layer Substances 0.000 description 22
- 238000004519 manufacturing process Methods 0.000 description 21
- 239000000243 solution Substances 0.000 description 17
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- 125000000524 functional group Chemical group 0.000 description 9
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- 238000005341 cation exchange Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
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- 239000004698 Polyethylene Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- NGPNWUWGVIIIDG-LEJBHHMKSA-L magnesium;[(2r)-2-[(1s)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2h-furan-3-yl] phosphate Chemical class [Mg+2].OC[C@H](O)[C@H]1OC(=O)C(O)=C1OP([O-])([O-])=O NGPNWUWGVIIIDG-LEJBHHMKSA-L 0.000 description 3
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- OSSNTDFYBPYIEC-UHFFFAOYSA-N 1-ethenylimidazole Chemical compound C=CN1C=CN=C1 OSSNTDFYBPYIEC-UHFFFAOYSA-N 0.000 description 2
- LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical compound CCCCC=C LIKMAJRDDDTEIG-UHFFFAOYSA-N 0.000 description 2
- IGGDKDTUCAWDAN-UHFFFAOYSA-N 1-vinylnaphthalene Chemical group C1=CC=C2C(C=C)=CC=CC2=C1 IGGDKDTUCAWDAN-UHFFFAOYSA-N 0.000 description 2
- KGIGUEBEKRSTEW-UHFFFAOYSA-N 2-vinylpyridine Chemical compound C=CC1=CC=CC=N1 KGIGUEBEKRSTEW-UHFFFAOYSA-N 0.000 description 2
- IWTYTFSSTWXZFU-UHFFFAOYSA-N 3-chloroprop-1-enylbenzene Chemical compound ClCC=CC1=CC=CC=C1 IWTYTFSSTWXZFU-UHFFFAOYSA-N 0.000 description 2
- WSSSPWUEQFSQQG-UHFFFAOYSA-N 4-methyl-1-pentene Chemical compound CC(C)CC=C WSSSPWUEQFSQQG-UHFFFAOYSA-N 0.000 description 2
- JCLFHZLOKITRCE-UHFFFAOYSA-N 4-pentoxyphenol Chemical compound CCCCCOC1=CC=C(O)C=C1 JCLFHZLOKITRCE-UHFFFAOYSA-N 0.000 description 2
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229920000557 Nafion® Polymers 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- XYLMUPLGERFSHI-UHFFFAOYSA-N alpha-Methylstyrene Chemical compound CC(=C)C1=CC=CC=C1 XYLMUPLGERFSHI-UHFFFAOYSA-N 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
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- 235000010378 sodium ascorbate Nutrition 0.000 description 2
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- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
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- 125000000542 sulfonic acid group Chemical group 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- FVQMJJQUGGVLEP-UHFFFAOYSA-N (2-methylpropan-2-yl)oxy 2-ethylhexaneperoxoate Chemical compound CCCCC(CC)C(=O)OOOC(C)(C)C FVQMJJQUGGVLEP-UHFFFAOYSA-N 0.000 description 1
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Images
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Description
本発明は、イオン性の薬剤を経皮投与する際に用いられる貼付材に関する。本貼付材は電圧を印加することなく生体に薬剤を浸透できる。 The present invention relates to a patch used for transdermal administration of an ionic drug. The patch can penetrate the living body without applying a voltage.
人間等の生体への薬剤の投与方法としては、経口投与方法や注射による投与方法が広く知られている。これらの方法に続く投与方法として、経皮投与方法に注目が集められている。経皮投与方法は、無痛状態で所望の患部に長時間に亘り薬剤を投与することが可能な方法である。また、経皮投与方法に用いる経皮投与剤は小型で、携帯が容易であるなどの様々な利点がある。このため、近年、様々な経皮投与剤の開発が行われている。 As a method for administering a drug to a living body such as a human, an oral administration method and an administration method by injection are widely known. As an administration method following these methods, attention has been drawn to a transdermal administration method. The transdermal administration method is a method capable of administering a drug over a long period of time to a desired affected area in a painless state. In addition, the transdermal administration agent used in the transdermal administration method has various advantages such as being small and easy to carry. For this reason, various transdermal administration agents have been developed in recent years.
従来、これら経皮投与剤は、薬剤溶液が親水性高分子や綿布などの薬剤保持材に含浸された薬剤層を有する。経皮投与剤の使用時には、この薬剤層が生体の皮膚に密着される。これにより、薬剤が皮膚を通過して生体に浸透される。 Conventionally, these transdermal administration agents have a drug layer in which a drug solution is impregnated with a drug holding material such as a hydrophilic polymer or cotton cloth. When the transdermal administration agent is used, this drug layer is in close contact with the skin of the living body. Thereby, the medicine passes through the skin and penetrates into the living body.
この投与方法においては、一般に、薬剤の濃度差が駆動力となって、生体内に薬剤が浸透される。しかしながら、通常の薬剤の皮膚や粘膜などの生体表面に対する浸透速度は小さい。このため、多量の薬剤を一度に生体へ投与できない問題がある。また、投与効率を高めるために経皮投与剤中の薬剤濃度を高めることが行われている。しかし、この方法による場合は、高価な薬剤を必要な投与量以上に薬剤層に含浸させる必要があるので、投与必要量を超える薬剤は無駄になる。更に、薬剤は溶液状態で生体に投与されるので、薬剤の溶解度が低い場合は、必要な投与量の薬剤溶液が得られない問題がある。 In this administration method, generally, the drug concentration penetrates into the living body by the difference in drug concentration as a driving force. However, the penetration rate of normal drugs into the surface of a living body such as skin or mucous membrane is small. For this reason, there is a problem that a large amount of medicine cannot be administered to a living body at one time. In addition, in order to increase the administration efficiency, the drug concentration in the transdermal administration agent is increased. However, according to this method, since it is necessary to impregnate the drug layer with an expensive drug more than the necessary dose, the drug exceeding the required dose is wasted. Furthermore, since the drug is administered to a living body in a solution state, there is a problem that a drug solution having a necessary dose cannot be obtained if the drug solubility is low.
イオン性薬剤の経皮投与の場合には、これらの欠点を解消するものとして、電気泳動を利用して薬剤イオンを生体内に浸透させるイオントフォレーシス法が知られている。さらに、薬剤の投与量を増すことを目的として、生体表面にイオン交換膜を置き、該イオン交換膜を通して薬剤イオンを生体に浸透させるイオントフォレーシスの新しい手法も提案されている（例えば、特許文献１〜４参照）。これらの提案において使用されるイオン交換膜は、製塩や、食品化合物の透析に用いられる織布を基材に用いた市販品である。 In the case of transdermal administration of an ionic drug, an iontophoresis method in which drug ions are permeated into a living body using electrophoresis is known as means for eliminating these drawbacks. Furthermore, for the purpose of increasing the dose of a drug, a new method of iontophoresis has been proposed in which an ion exchange membrane is placed on the surface of a living body, and drug ions are permeated into the living body through the ion exchange membrane (for example, patents). References 1-4). The ion exchange membrane used in these proposals is a commercial product using a woven fabric used for salt production and dialysis of food compounds as a base material.
このように、薬剤の経皮投与方法においては、薬剤の生体への投与量が低いという問題があった。また、イオントフォレーシス法では、薬剤の投与に際して、電圧を印加するための電極や電源を備えた複雑な構造の投与装置が必要である。このため、上記イオン交換膜を用いるイオントフォレーシスは、経皮投与法の重要な利点である携帯性、小型性に劣り、また装置が高価なものになる問題がある。 Thus, the method for transdermal administration of a drug has a problem that the dose of the drug to the living body is low. In addition, the iontophoresis method requires an administration device having a complicated structure including an electrode for applying a voltage and a power source when administering a drug. For this reason, iontophoresis using the ion exchange membrane has problems that it is inferior in portability and small size, which are important advantages of the transdermal administration method, and the device is expensive.
本発明者等は、上記問題を解決するために鋭意研究を行ってきた。その結果、表面が平滑なイオン交換膜を生体表面に密着させて薬剤を経皮投与することで、電圧を印加しなくとも目的薬剤の投与量を著しく高めることができる事を見出し、本発明を完成するに至った。 The present inventors have conducted intensive research to solve the above problems. As a result, it was found that the dose of the target drug can be remarkably increased without applying voltage by applying the drug transdermally with an ion exchange membrane having a smooth surface in close contact with the living body surface. It came to be completed.
即ち、本発明は、電圧を印加することなく、生体表面から生体内にイオン性薬剤を浸透させることにより、生体にイオン性薬剤を投与するために用いる貼付材であって、該貼付材は、生体表面と接触させる部位の表面粗さ（Ｒｚ）が７μｍ以下のイオン交換膜と、該イオン交換膜内に含浸せしめられたイオン性薬剤とを有し、かつ該イオン交換膜が、熱可塑性樹脂からなる多孔質膜を基材とし、該基材内の空隙にイオン交換樹脂を含有してなるイオン交換膜であることを特徴とする、生体に対するイオン性薬剤投与用の貼付材である。
That is, the present invention is a patch used to administer an ionic drug to a living body by infiltrating the ionic drug from the surface of the living body into the living body without applying a voltage, and the ion exchange membrane surface roughness (Rz) following 7μm sites contacting the living body surface, possess an ionic agent which is impregnated in the ion exchange membrane, and the ion-exchange membrane, the thermoplastic resin the porous membrane as a base material made of, and wherein the ion exchange membrane der Rukoto that the voids in the base material comprising an ion exchange resin, an adhesive material for administration ionic medicine to a living body.
本発明のイオン性薬剤投与用の貼付材は、生体表面にイオン交換膜を密着させることにより、これまでの貼付材に比べて薬剤の高い投与量を達成できる。作用機構の詳細は不明であるが、イオン交換作用によりイオン交換膜内で薬剤が局部的に濃縮されることで生体内との濃度差が大きくなり、高い投与量が達成されるものと思われる。 The patch for ionic drug administration of the present invention can achieve a higher dose of the drug than the conventional patch by bringing the ion exchange membrane into close contact with the surface of the living body. The details of the mechanism of action are unknown, but the concentration of the drug locally in the ion exchange membrane due to the ion exchange action increases the concentration difference from the living body and seems to achieve a high dose. .
これらの高い投与量は、表面粗さが７μｍ以下のイオン交換膜を使用した場合にのみ達成される。このイオン交換膜は多孔質膜を基材として容易に製造できるが、織布を基材とするイオン交換膜に比べて表面が平滑なことで生体表面との密着性が高まって、大きい投与量が達成されるものと思われる。 These high doses are only achieved when using ion exchange membranes with a surface roughness of 7 μm or less. This ion-exchange membrane can be easily manufactured using a porous membrane as a base material, but its surface is smooth compared to an ion-exchange membrane based on a woven fabric, resulting in increased adhesion to the living body surface, resulting in a large dosage. Seems to be achieved.
表面粗さが７μｍ以下のイオン交換膜を用いる本発明のイオン性薬剤投与用の貼付材は、薬剤の経皮投与方法における各種特長に加え、これまでの経皮投与方法では得られなかった薬剤の極めて大きな投与量が達成可能となる。従って、本発明の貼付材は、美容用途、医療用途、サプリメント類を投与する健康増進用途など、これまで経皮投与方法の適用が検討されてきた全ての用途において極めて優れた効果を発揮する貼付材として好適に使用可能である。 The patch for ionic drug administration of the present invention using an ion exchange membrane having a surface roughness of 7 μm or less is a drug that has not been obtained by the conventional transdermal administration methods in addition to various features of the drug transdermal administration methods. Extremely large doses can be achieved. Therefore, the patch of the present invention is a patch that exhibits extremely excellent effects in all uses where application of the transdermal administration method has been studied so far, such as beauty use, medical use, and health promotion use for administering supplements. It can be suitably used as a material.
本発明の貼付材は、生体表面と接触させる部位の表面粗さ（Ｒｚ）が７μｍ以下のイオン交換膜と、該イオン交換膜内に含浸せしめられたイオン性薬剤と有すればよい。さらに必要に応じて、イオン交換膜の生体表面と接触する部位を有する側とは反対側にイオン性薬剤含有層が存在していたり、あるいは、イオン性薬剤の漏れ等を防ぐための各種部材を有していても良い。またイオン性薬剤はそれ単独で存在していても良いし、該薬剤を溶解させるための水、アルコール等の溶剤を含んでいてもよい。 The patch of the present invention may have an ion exchange membrane having a surface roughness (Rz) of 7 μm or less at a site to be brought into contact with the surface of the living body and an ionic drug impregnated in the ion exchange membrane. Further, if necessary, an ionic drug-containing layer is present on the side opposite to the side having the portion that contacts the living body surface of the ion exchange membrane, or various members for preventing leakage of the ionic drug, etc. You may have. Further, the ionic drug may be present alone or may contain a solvent such as water or alcohol for dissolving the drug.
本発明の貼付材は、生体に対して有用なイオン性薬剤を経口投与や注射による投与によらず、経皮的に生体内へ投与するために用いられるものである。 The patch of the present invention is used for transdermally administering an ionic drug useful for a living body into a living body, regardless of oral administration or administration by injection.
該イオン性薬剤は正イオンと負イオンとからなるものであって、この正イオン又は負イオンが生体内に入ることにより薬理効果を発揮する物質であれば特に制限されるものではない。例えば、正イオン側が薬理効果を有するイオン性薬剤としては、塩酸プロカイン、塩酸リドカイン、塩酸ジブカインなどの麻酔剤、マイトマイシン、塩酸ブレオマイシンなどの抗悪性腫瘍剤、塩酸モルフィネなどの鎮痛剤、酢酸メドロキシプロゲステロンなどのステロイド類、ヒスタミンなどが挙げられる。 The ionic drug is composed of positive ions and negative ions, and is not particularly limited as long as it is a substance that exhibits a pharmacological effect when the positive ions or negative ions enter the living body. For example, ionic drugs having a pharmacological effect on the positive ion side include anesthetic agents such as procaine hydrochloride, lidocaine hydrochloride and dibucaine hydrochloride, antineoplastic agents such as mitomycin and bleomycin hydrochloride, analgesics such as morphine hydrochloride, and medroxyprogesterone acetate. And steroids such as histamine.
一方、負イオン側が効果を発揮するイオン性薬剤としては、ビタミンＢ２、ビタミンＢ１２、ビタミンＣ、ビタミンＥ、葉酸などのビタミン剤、アスピリン、イブプロフェンなどの抗炎症剤、デキサメタゾン系水溶性製剤などの副腎皮質ホルモン、ベンジルペニシリンカリウムなどの抗生物質、インスリンなどが挙げられる。 On the other hand, the ionic drugs that are effective on the negative ion side include vitamin B2, vitamin B12, vitamin C, vitamin E, vitamins such as folic acid, anti-inflammatory agents such as aspirin and ibuprofen, and adrenal glands such as dexamethasone water-soluble preparations. Cortic hormones, antibiotics such as benzylpenicillin potassium, insulin and the like.
本発明の貼付材は、これらのイオン性薬剤が、生体表面と接触させる部位の表面粗さ（Ｒｚ）が７μｍ以下のイオン交換膜に含浸させられたものである。表面粗さが７μｍを超えるイオン交換膜を用いたり、あるいは、イオン交換膜を全く用いない場合には、（電圧付与を行わないと）イオン性薬剤の生体内への浸透がほとんどない。換言すれば、表面粗さ（Ｒｚ）が７μｍ以下のイオン交換膜を用いることにより、電圧を印加せずとも生体内へイオン性薬剤が浸透する。 The patch of the present invention is obtained by impregnating an ion exchange membrane having a surface roughness (Rz) of 7 μm or less at a site where these ionic drugs are brought into contact with the surface of a living body. When an ion exchange membrane having a surface roughness exceeding 7 μm is used, or when no ion exchange membrane is used, there is almost no penetration of the ionic drug into the living body (unless voltage is applied). In other words, by using an ion exchange membrane having a surface roughness (Rz) of 7 μm or less, the ionic drug penetrates into the living body without applying a voltage.
従来の電圧を印加するタイプの薬剤投与装置（イオントフォレーシス用装置）とは異なり、電圧を付与しなくともイオン性薬剤を生体内へと浸透させることができる原理は明らかではないが、表面粗さが小さい、即ち、表面が平滑であることにより、実効接触面積が極めて大きなものとなることに理由があるのではないかと推測している。 Unlike conventional drug administration devices that apply voltage (iontophoresis devices), the principle that allows an ionic drug to penetrate into a living body without application of voltage is not clear, but the surface It is speculated that there is a reason that the effective contact area becomes extremely large due to the small roughness, that is, the smooth surface.
なお、当該表面粗さ（Ｒｚ）は、ＪＩＳ―Ｂ０６０１−１９９４に規定される十点平均粗さである。 The surface roughness (Rz) is a ten-point average roughness defined in JIS-B0601-1994.
本発明のイオン性薬剤投与用の貼付材で用いるイオン交換膜は生体表面と接触させる部位の表面粗さ（Ｒｚ）が７μｍ以下のものであれば公知の如何なるイオン交換膜であっても特に制限されず使用できる。より好ましくは表面粗さ（Ｒｚ）が５μｍ以下、さらに好ましくは３μｍ以下、特に好ましくは１μｍ以下のイオン交換膜の使用である。なお、本発明において、該イオン交換膜は、生体と接触する部位の表面粗さが上記範囲内にあれば良く、それ以外の、生体と接触する部位以外の部分の表面形状は特に制限されず、表面粗さ（Ｒｚ）が７μｍより大きくても構わない（以下では、生体表面と接触させる部位の表面粗さ（Ｒｚ）が７μｍ以下のイオン交換膜を、表面粗さ（Ｒｚ）が７μｍ以下のイオン交換膜、あるいは単にイオン交換膜と称する場合がある）。 The ion exchange membrane used in the patch for ionic drug administration of the present invention is not particularly limited as long as it is any known ion exchange membrane as long as the surface roughness (Rz) of the site to be brought into contact with the biological surface is 7 μm or less. It can be used without being. More preferably, an ion exchange membrane having a surface roughness (Rz) of 5 μm or less, more preferably 3 μm or less, and particularly preferably 1 μm or less is used. In the present invention, it is sufficient that the surface roughness of the portion that comes into contact with the living body is within the above range, and the surface shape of the portion other than the portion that comes into contact with the living body is not particularly limited. The surface roughness (Rz) may be larger than 7 μm (in the following, an ion exchange membrane having a surface roughness (Rz) of 7 μm or less at a site to be brought into contact with the living body surface, and the surface roughness (Rz) of 7 μm or less. May be referred to as an ion exchange membrane, or simply an ion exchange membrane).
本発明の貼付材に用いる、上記イオン交換膜の有するイオン交換基の極性は、目的とするイオン性薬剤の極性により選択され、イオン性薬剤の薬効イオンの荷電と同荷電のイオンを交換する膜が用いられる。即ち、目的薬剤の薬効イオンが正に荷電している場合にはカチオン交換基を有する膜（カチオン交換膜）が、また、目的薬剤の薬効イオンが負に荷電している場合にはアニオン交換基を有する膜（アニオン交換膜）が使用される。 The membrane used for the patch of the present invention, the polarity of the ion exchange group of the ion exchange membrane is selected according to the polarity of the target ionic drug, and exchanges ions having the same charge as the medicinal ions of the ionic drug. Is used. That is, a membrane having a cation exchange group (cation exchange membrane) when the medicinal ion of the target drug is positively charged, and an anion exchange group when the medicinal ion of the target drug is negatively charged. A membrane having an anion (anion exchange membrane) is used.
当該イオン交換基としては、水溶液中で負又は正に荷電し得る官能基であれば特に限定されない。このようなイオン交換基となり得る官能基を具体的に例示すれば、カチオン（陽イオン）交換基としては、スルホン酸基、カルボン酸基、ホスホン酸基等が挙げられ、一般的に、強酸性基であるスルホン酸基が特に好ましい。また、アニオン（陰イオン）交換基としては、１〜３級アミノ基、４級アンモニウム基、ピリジル基、イミダゾール基、４級ピリジニウム基、４級イミダゾリウム基等が挙げられ、一般的に、強塩基性基である４級アンモニウム基や４級ピリジニウム基が好適に用いられる。 The ion exchange group is not particularly limited as long as it is a functional group that can be negatively or positively charged in an aqueous solution. Specific examples of such functional groups that can be ion exchange groups include cation (cation) exchange groups such as sulfonic acid groups, carboxylic acid groups, and phosphonic acid groups. The sulfonic acid group which is a group is particularly preferred. Examples of anion (anion) exchange groups include primary to tertiary amino groups, quaternary ammonium groups, pyridyl groups, imidazole groups, quaternary pyridinium groups, and quaternary imidazolium groups. A quaternary ammonium group or a quaternary pyridinium group which is a basic group is preferably used.
本発明における上記イオン交換膜としては、イオン性薬剤の含浸量を多くして生体への投与量を増すために、固定イオン濃度が０．３〜１５．０ｍｍｏｌ／ｇ−水であることが好ましく、０．６〜１２．０ｍｍｏｌ／ｇ−水であることがより好ましい。 The ion exchange membrane in the present invention preferably has a fixed ion concentration of 0.3 to 15.0 mmol / g-water in order to increase the impregnation amount of the ionic drug and increase the dose to the living body. 0.6-12.0 mmol / g-water is more preferable.
このような固定イオン濃度のイオン交換膜を得るためには、イオン交換容量及び含水率を調整すればよい。固定イオン濃度は、イオン交換容量／含水率であるから、イオン交換容量が大きいほど固定イオン濃度も大きくなる。イオン交換容量は一般に、イオン交換基の量を多くするほど大きくなる。上記固定イオン濃度を得るためには、イオン交換容量で０．１〜６．０ｍｍｏｌ／ｇ−乾燥膜、特に０．３〜４．０ｍｍｏｌ／ｇ−乾燥膜であるものを用いることが好ましい。また、含水率が低いほど、固定イオン濃度は高くなる。しかし、含水率があまりに低いとイオン性薬剤のイオン交換膜内での移動抵抗が増大する傾向がある。イオン交換膜の含水率は、イオン交換膜の乾燥質量に対して５質量％以上、好適には１０質量％以上であるのが好ましい。一般的には含水率が５〜９０質量％、好ましくは１０〜５０質量％のイオン交換膜を用いることが好適である。このような範囲の含水率を得るためには、イオン交換基の種類、イオン交換容量及び架橋度等を適宜選択することにより制御することができる。 In order to obtain an ion exchange membrane having such a fixed ion concentration, the ion exchange capacity and water content may be adjusted. Since the fixed ion concentration is the ion exchange capacity / water content, the larger the ion exchange capacity, the higher the fixed ion concentration. In general, the ion exchange capacity increases as the amount of ion exchange groups increases. In order to obtain the fixed ion concentration, it is preferable to use a membrane having an ion exchange capacity of 0.1 to 6.0 mmol / g-dry membrane, particularly 0.3 to 4.0 mmol / g-dry membrane. Also, the fixed ion concentration increases as the moisture content decreases. However, when the water content is too low, the migration resistance of the ionic drug in the ion exchange membrane tends to increase. The water content of the ion exchange membrane is preferably 5% by mass or more, and preferably 10% by mass or more, based on the dry mass of the ion exchange membrane. In general, it is suitable to use an ion exchange membrane having a moisture content of 5 to 90 mass%, preferably 10 to 50 mass%. In order to obtain a moisture content in such a range, it can be controlled by appropriately selecting the type of ion exchange group, ion exchange capacity, degree of crosslinking, and the like.
さらに、本発明におけるイオン交換膜としては、ある程度以上の厚さがあった方が、物理的な強度が高く好ましいが、一方で、膜厚が薄い方が生体への追随性が良好であるため、膜厚が５〜１５０μｍのものを用いることが好ましく、１０〜１２０μｍのものを用いることがより好ましい。また、この膜厚範囲のものは、製造も容易である。 Furthermore, as the ion exchange membrane in the present invention, it is preferable that the thickness is more than a certain degree because the physical strength is high, but on the other hand, the smaller the thickness, the better the followability to the living body. The film thickness is preferably 5 to 150 μm, and more preferably 10 to 120 μm. In addition, the film thickness range can be easily manufactured.
このようなイオン交換膜としては、生体に対して有害な不純物を含まない限り、如何なる製造方法で得られたものでも良いが、表面粗さが７μｍ以下のものを容易に製造できる点で、多孔質フィルムや不織布等の表面が平滑な多孔質膜を基材（補強材、支持材とも呼ばれる）とし、該多孔質膜の空隙内にイオン交換樹脂を充填することによって得られるものであることが好ましい。多孔質膜を基材とすることにより、織布を基材とするよりも遙かに容易に表面が平滑なものを製造することができ、また基材を用いない（キャスト法など）場合よりも極めて容易な製造工程で膜の製造が可能で、また強度に優れたイオン交換膜の製造が可能である。またこのようなイオン交換膜におけるイオン交換樹脂の充填率は、後述の多孔質膜の空孔率とも関係するが、一般的には５〜９５重量％であり、薬剤イオンの透過を容易にして、かつイオン交換膜の強度を高めるために１０〜９０重量％であることが好ましい。 Such an ion-exchange membrane may be obtained by any manufacturing method as long as it does not contain impurities harmful to the living body, but is porous in that it can easily manufacture a surface roughness of 7 μm or less. A porous film having a smooth surface, such as a porous film or a non-woven fabric, as a base material (also referred to as a reinforcing material or a support material), and being obtained by filling an ion-exchange resin in the voids of the porous film preferable. By using a porous membrane as a base material, it is possible to produce a material with a smooth surface much more easily than when using a woven fabric base material, and also when using no base material (such as a casting method). However, it is possible to manufacture a membrane by an extremely easy manufacturing process and to manufacture an ion exchange membrane having excellent strength. The filling rate of the ion exchange resin in such an ion exchange membrane is related to the porosity of the porous membrane described later, but is generally 5 to 95% by weight, which facilitates the permeation of drug ions. And in order to raise the intensity | strength of an ion exchange membrane, it is preferable that it is 10 to 90 weight%.
当該多孔質膜を基材とするイオン交換膜の最も代表的な製造方法を具体的に述べると以下の通りである。即ち、表面の平滑な多孔質膜に、スチレン等のイオン交換基を導入可能な重合性単量体を浸透させた後、表面をポリエステルフィルム等の平滑な材料で覆った状態で重合させて重合体とし、さらにそこへイオン交換基を導入する方法で製造ができる。 The most typical production method of an ion exchange membrane based on the porous membrane is specifically described as follows. That is, after a porous monomer having a smooth surface is infiltrated with a polymerizable monomer capable of introducing an ion exchange group such as styrene, the surface is covered with a smooth material such as a polyester film and polymerized. It can be produced by a method of combining and further introducing an ion exchange group therein.
当該多孔質膜は、表裏を連通する細孔を多数有するフィルムもしくはシート状のものであれば特に制限されるものではないが、上記のような物性のイオン交換膜とし易く、また物理的強度に優れたものとすることが容易な点で、孔の平均孔径は０．００５〜５．０μｍ、特に０．０１〜２．０μｍであることが好ましく、空隙率（気孔率とも呼ばれる）は２０〜９５％、特に３０〜９０％であるのが好ましく、透気度（ＪＩＳ Ｐ−８１１７）は１０００秒以下、特に５００秒以下であるのが好ましい。また、用いる多孔質膜の厚みは、イオン交換膜が前記した厚さとなるように５〜１５０μｍであるものが好ましく、１０〜１２０μｍがより好ましい。 The porous membrane is not particularly limited as long as it is a film or sheet having a large number of pores communicating with the front and back, but it is easy to make an ion exchange membrane having the above physical properties, and has a physical strength. The average pore diameter of the pores is preferably 0.005 to 5.0 μm, particularly preferably 0.01 to 2.0 μm, and the porosity (also referred to as porosity) is 20 to 20 in that it is easy to make excellent. It is preferably 95%, particularly 30 to 90%, and the air permeability (JIS P-8117) is preferably 1000 seconds or less, particularly preferably 500 seconds or less. Further, the thickness of the porous membrane to be used is preferably 5 to 150 μm, more preferably 10 to 120 μm so that the ion exchange membrane has the thickness described above.
また、当該多孔質膜の材質は特に制限されるものではないが、その製造が容易であるばかりでなく、本発明の貼付材を後述する袋状物の形態とする際に、該袋状物を融着により簡単に製造ができる点で、熱可塑性樹脂からなる多孔質フィルムであるのが好ましい。 Further, the material of the porous membrane is not particularly limited, but not only the production thereof is easy, but the bag-like material is used when the patch of the present invention is in the form of a bag-like material described later. Is preferably a porous film made of a thermoplastic resin in that it can be easily manufactured by fusing.
当該多孔質フィルムを構成する熱可塑性樹脂としては、エチレン、プロピレン、１−ブテン、１−ペンテン、１−ヘキセン、３−メチル−１−ブテン、４−メチル−1−ペンテン、５−メチル−１−ヘプテン等のα−オレフィンの単独重合体または共重合体等のポリオレフィン樹脂；ポリ塩化ビニル、塩化ビニル−酢酸ビニル共重合体、塩化ビニル−塩化ビニリデン共重合体、塩化ビニル−オレフィン共重合体等の塩化ビニル系樹脂；ポリテトラフルオロエチレン、ポリクロロトリフルオロエチレン、ポリフッ化ビニリデン、テトラフルオロエチレン−ヘキサフルオロプロピレン共重合体、テトラフロオロエチレン−ペルフロオロアルキルビニルエーテル共重合体、テトラフルオロエチレン−エチレン共重合体等のフッ素系樹脂；ナイロン６、ナイロン６６等のポリアミド樹脂；ポリイミド樹脂等からなるものが制限なく採用できるが、機械的強度、化学的安定性、耐薬品性に優れ、後述するポリスチレン系のイオン交換樹脂との馴染みがよいことからポリオレフィン樹脂を用いるのが好ましい。ポリオレフィン樹脂としては、ポリエチレン、ポリプロピレンが特に好ましく、ポリエチレンが最も好ましい。
Examples of the thermoplastic resin constituting the porous film include ethylene, propylene, 1-butene, 1-pentene, 1-hexene, 3-methyl-1-butene, 4-methyl-1-pentene, and 5-methyl-1. -Polyolefin resin such as homopolymer or copolymer of α-olefin such as heptene; polyvinyl chloride, vinyl chloride-vinyl acetate copolymer, vinyl chloride-vinylidene chloride copolymer, vinyl chloride-olefin copolymer, etc. Vinyl chloride resin: polytetrafluoroethylene, polychlorotrifluoroethylene, polyvinylidene fluoride, tetrafluoroethylene-hexafluoropropylene copolymer, tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer, tetrafluoroethylene- Fluorine resin such as ethylene copolymer;
このような多孔質フィルムは、一般に、熱可塑性樹脂組成物及び有機液体よりなる樹脂組成物をシート若しくはフィルム状に成形した後に有機液体を溶剤によって抽出すること、或いは無機フィラー及び／又は有機フィラーを充填したシートを延伸すること等により容易に得ることができる。さらには、例えば特開２００２−３３８７２１号公報等に記載の方法によって得ることもできるし、あるいは、市販品（例えば、旭化成「ハイポア」、宇部興産「ユーポア」、東燃タピルス「セテラ」、日東電工「エクセポール」、三井化学「ハイレット」等）として入手することも可能である。 Such a porous film is generally obtained by forming a resin composition comprising a thermoplastic resin composition and an organic liquid into a sheet or film and then extracting the organic liquid with a solvent, or by using an inorganic filler and / or an organic filler. It can be easily obtained by stretching the filled sheet. Furthermore, it can be obtained by the method described in, for example, JP-A-2002-338721, or a commercially available product (for example, Asahi Kasei “Hypore”, Ube Industries “Eupor”, Tonen Tapils “Setera”, Nitto Denko “ Exepole ", Mitsui Chemicals" Hillet ", etc.) are also available.
また、多孔質膜内に充填されているイオン交換樹脂は特に限定されず、スチレン、ビニルピリジン、ビニルイミダゾール等の芳香族ビニル化合物を重合させた重合体（以下、これらをポリスチレン系（の樹脂）とも称す）や、ポリ（メタ）アクリル酸系のもの、あるいはＮａｆｉｏｎ（デュポン社）に代表されるパーフルオロスルホン酸樹脂や、ポリスルホン、ポリエーテルスルホン、ポリエーテルエーテルケトン、ポリフェニレンオキサイド、ポリイミドなどのいわゆるエンジニアリングプラスチック類、ポリスチレン−ポリ（エチレン−ブチレン）−ポリスチレントリブロック共重合体などのエラストマー類に前記のイオン交換基を導入した樹脂が使用できる。 The ion exchange resin filled in the porous membrane is not particularly limited, and a polymer obtained by polymerizing an aromatic vinyl compound such as styrene, vinyl pyridine, vinyl imidazole (hereinafter referred to as polystyrene-based resin). Also called perfluorosulfonic acid resins represented by Nafion (DuPont), polysulfone, polyethersulfone, polyetheretherketone, polyphenylene oxide, polyimide, etc. Resins in which the ion exchange groups are introduced into elastomers such as engineering plastics and polystyrene-poly (ethylene-butylene) -polystyrene triblock copolymers can be used.
より高い薬剤投与効率を得るためには、このようなイオン交換樹脂としては、架橋型のイオン交換樹脂を採用することが好ましい。さらに、製造工程の簡便さや、化学的安定性、各種イオン交換基の導入が簡単である等の点から、ポリスチレン系の架橋型イオン交換樹脂であることが好ましい。 In order to obtain higher drug administration efficiency, it is preferable to employ a cross-linked ion exchange resin as such an ion exchange resin. Furthermore, a polystyrene-based cross-linked ion exchange resin is preferable from the viewpoints of simplicity of the production process, chemical stability, and easy introduction of various ion exchange groups.
当該ポリスチレン系のイオン交換樹脂は、一般的には、スチレン、α−メチルスチレン、３−メチルスチレン、４−メチルスチレン、２，４−ジメチルスチレン、ｐ−ｔｅｒｔ−ブチルスチレン、α−ハロゲン化スチレン、ビニルナフタレン等の陽イオン交換基の導入可能な官能基を有する芳香族ビニル化合物、あるいはスチレン、ビニルトルエン、クロロメチルスチレン、ビニルピリジン、ビニルイミダゾール、α−メチルスチレン、ビニルナフタレン等の陰イオン交換基が導入可能な官能基を有する芳香族ビニル化合物を重合させ、ついで公知の方法でイオン交換基を導入することにより製造することができる。 The polystyrene ion exchange resin is generally styrene, α-methylstyrene, 3-methylstyrene, 4-methylstyrene, 2,4-dimethylstyrene, p-tert-butylstyrene, α-halogenated styrene. , Aromatic vinyl compounds having functional groups capable of introducing cation exchange groups such as vinyl naphthalene, or anion exchange such as styrene, vinyl toluene, chloromethyl styrene, vinyl pyridine, vinyl imidazole, α-methyl styrene, vinyl naphthalene, etc. It can be produced by polymerizing an aromatic vinyl compound having a functional group into which a group can be introduced, and then introducing an ion exchange group by a known method.
また、上記イオン交換樹脂は架橋型のものであることが好ましく、上記イオン交換基の導入可能な官能基を有する芳香族ビニル化合物を重合させる際に、架橋性単量体を用いることが好ましい。当該架橋性単量体としては特に制限されるものではなく、例えば、ジビニルベンゼン類、ジビニルスルホン、ブタジエン、クロロプレン、ジビニルビフェニル、トリビニルベンゼン等の多官能性ビニル化合物、トリメチロールメタントリメタクリル酸エステル、メチレンビスアクリルアミド、ヘキサメチレンジメタクリルアミド等の多官能性メタクリル酸誘導体が用いられる。 The ion exchange resin is preferably a cross-linked type, and a crosslinkable monomer is preferably used when the aromatic vinyl compound having a functional group into which the ion exchange group can be introduced is polymerized. The crosslinkable monomer is not particularly limited, and examples thereof include polyfunctional vinyl compounds such as divinylbenzenes, divinylsulfone, butadiene, chloroprene, divinylbiphenyl, trivinylbenzene, and trimethylolmethane trimethacrylate. Polyfunctional methacrylic acid derivatives such as methylenebisacrylamide and hexamethylenedimethacrylamide are used.
また、上記各成分の他に、必要に応じて上記イオン交換基が導入可能な官能基を有する単量体や架橋性単量体と共重合可能な他の炭化水素系単量体や可塑剤類が添加されたものでよい。こうした他の単量体としては、例えば、アクリロニトリル、アクロレイン、メチルビニルケトン等が用いられる。また、可塑剤類としては、ジブチルフタレート、ジオクチルフタレート、ジメチルイソフタレート、ジブチルアジペート、トリエチルシトレート、アセチルトリブチルシトレート、ジブチルセバケート等が用いられる。 In addition to the above components, other hydrocarbon monomers and plasticizers that can be copolymerized with monomers having a functional group into which the ion exchange groups can be introduced and crosslinkable monomers as required. It may be added with a kind. Examples of such other monomers include acrylonitrile, acrolein, methyl vinyl ketone, and the like. Further, as the plasticizers, dibutyl phthalate, dioctyl phthalate, dimethyl isophthalate, dibutyl adipate, triethyl citrate, acetyl tributyl citrate, dibutyl sebacate and the like are used.
これら単量体を重合させる際に用いる重合開始剤としては、従来公知のものが特に制限なく使用できる。こうした重合開始剤の具体例としては、オクタノイルパーオキシド、ラウロイルパーオキシド、ｔ−ブチルパーオキシ−２−エチルヘキサノエート、ベンゾイルパーオキシド、ｔ−ブチルパーオキシイソブチレート、ｔ−ブチルパーオキシラウレート、ｔ−ヘキシルパーオキシベンゾエート、ジ−ｔ−ブチルパーオキシド等の有機過酸化物が挙げられる。またその他、イオン交換膜（樹脂）を製造するために用いられる公知の添加剤を配合してもよい。 As a polymerization initiator used when polymerizing these monomers, conventionally known polymerization initiators can be used without particular limitation. Specific examples of such polymerization initiators include octanoyl peroxide, lauroyl peroxide, t-butylperoxy-2-ethylhexanoate, benzoyl peroxide, t-butylperoxyisobutyrate, t-butylperoxy Examples thereof include organic peroxides such as laurate, t-hexyl peroxybenzoate, and di-t-butyl peroxide. Moreover, you may mix | blend the well-known additive used in order to manufacture an ion exchange membrane (resin).
これら単量体組成物を構成する各成分の配合割合は、一般には、イオン交換基が導入可能な官能基を有する単量体１００重量部に対して、架橋性単量体を０．１〜５０重量部、好適には１〜４０重量部、これらの単量体と共重合可能な他の単量体を０〜１００重量部使用するのが好適である。また、重合開始剤は、イオン交換基が導入可能な官能基を有する単量体１００重量部に対して、０．１〜２０重量部、好適には０．５〜１０重量部配合するのが好ましい。 The mixing ratio of each component constituting these monomer compositions is generally such that the crosslinkable monomer is 0.1 to 100 parts by weight of the monomer having a functional group into which an ion exchange group can be introduced. It is preferred to use 50 to 100 parts by weight, preferably 1 to 40 parts by weight, and 0 to 100 parts by weight of other monomers copolymerizable with these monomers. The polymerization initiator is blended in an amount of 0.1 to 20 parts by weight, preferably 0.5 to 10 parts by weight, based on 100 parts by weight of the monomer having a functional group capable of introducing an ion exchange group. preferable.
当該重合、およびイオン交換基の導入は、前記多孔質フィルム内に充填する前に行っても良いが、高性能の膜を効率よく製造できるという観点から、上記イオン交換基が導入可能な官能基を有する単量体、架橋性単量体、重合開始剤および必要に応じて配合される他の成分からなる単量体組成物（以下、単量体組成物）を、前記多孔質フィルムの有する空隙内に含浸させた後、単量体組成物を重合し、次いで生成した重合体に陽イオン交換基や陰イオン交換基を導入する方法が好ましい。 The polymerization and introduction of the ion exchange group may be performed before filling the porous film, but from the viewpoint that a high-performance membrane can be efficiently produced, the functional group into which the ion exchange group can be introduced. The porous film has a monomer composition (hereinafter referred to as a monomer composition) composed of a monomer having a monomer, a crosslinkable monomer, a polymerization initiator, and other components blended as necessary. A method of polymerizing the monomer composition after impregnating the voids and then introducing a cation exchange group or an anion exchange group into the produced polymer is preferred.
多孔質フィルムの有する空隙内への上記単量体組成物の含浸（充填）方法は特に限定されず、例えば、単量体組成物を多孔質フィルムに塗布したり、スプレーしたり、あるいは単量体組成物中に多孔質フィルムを浸漬したりすることによって行なうことができる。上記単量体組成物の塗布等に際しては、多孔質フィルムの空隙に該単量体組成物が良好に充填されるように減圧下で両者を接触さたり、接触後に加圧処理を行なうなどの方法を採用してもよい。また、基材となる多孔質フィルムに充填された単量体組成物を重合する場合には、ポリエステル等のフィルムに挟んで加圧しながら常温から昇温して重合することにより、得られる膜の表面粗さを７μｍ以下とすることが容易にできる。加圧条件は０．０１〜１．０ＭＰａが好適である。その他の重合条件は、使用した重合開始剤の種類や単量体組成物の組成等に応じて適宜決定すればよい。 The method of impregnating (filling) the monomer composition into the voids of the porous film is not particularly limited. For example, the monomer composition is applied to the porous film, sprayed, or a single amount. It can be performed by immersing a porous film in the body composition. When applying the monomer composition, etc., the porous composition may be contacted with each other under reduced pressure so that the monomer composition is satisfactorily filled in the void, or a pressure treatment is performed after the contact. A method may be adopted. In addition, when polymerizing the monomer composition filled in the porous film serving as the base material, the temperature of the resulting film is polymerized by raising the temperature from room temperature while pressing between polyester films. The surface roughness can be easily set to 7 μm or less. The pressure condition is preferably 0.01 to 1.0 MPa. Other polymerization conditions may be appropriately determined according to the type of polymerization initiator used and the composition of the monomer composition.
ついでこの多孔質フィルムに充填、重合せしめられて得た重合体に対して、公知のイオン交換基導入処理を施してイオン交換膜とする。イオン交換基導入処理の方法は公知の方法を適宜選択して採用すればよく、例えば、陽イオン交換膜を得る場合にはスルホン化、クロルスルホン化、ホスホニウム化、加水分解等の処理を行なえばよく、また陰イオン交換膜を得る場合にはアミノ化、アルキル化等の処理を行なえばよい。 Subsequently, the polymer obtained by filling and polymerizing the porous film is subjected to a known ion exchange group introduction treatment to obtain an ion exchange membrane. As a method for introducing an ion exchange group, a known method may be appropriately selected and employed.For example, when a cation exchange membrane is obtained, a treatment such as sulfonation, chlorosulfonation, phosphoniumation, hydrolysis and the like may be performed. In addition, when an anion exchange membrane is obtained, treatments such as amination and alkylation may be performed.
むろん本発明の貼付材におけるイオン交換膜としては、表面粗さが７μｍ以下であれば、上記以外の製造方法によって製造されたイオン交換膜を用いても良く、多孔質膜にイオン交換基を有する重合体を浸透させたり、イオン交換基を有する重合性単量体を浸透させ、該重合性単量体を重合させる方法等で製造されたもの等でもなんら問題はない。 Of course, as the ion exchange membrane in the patch of the present invention, an ion exchange membrane produced by a production method other than the above may be used as long as the surface roughness is 7 μm or less, and the porous membrane has an ion exchange group. There is no problem even if it is produced by a method in which a polymer is permeated, a polymerizable monomer having an ion exchange group is permeated, and the polymerizable monomer is polymerized.
本発明の貼付材は上記表面粗さが７μｍ以下のイオン交換膜と、該イオン交換膜に含浸せしめられた前記イオン性薬剤とを必須とするが、その製造方法は特に制限されるものではない。一般的には、用いるイオン性薬剤を、該薬剤を溶解することの可能な溶剤、例えば水やエタノール等のアルコール類に溶解させて溶液とし、この溶液をイオン交換膜に浸透させることで製造ができる。また、必要であれば、用いた溶剤をこの浸透の後に揮発除去するなどして、イオン性薬剤濃度を調整しても良い。浸透させる方法としては、イオン交換膜を上記のようなイオン性薬剤の溶液に浸漬させる方法や、イオン交換膜に対し、イオン性薬剤溶液を塗布、スプレー等する方法が挙げられる。また、後述するイオン性薬剤含有層を設けることにより、該イオン性薬剤含有層とイオン交換膜との界面を通してイオン性薬剤がイオン交換膜内に供給され、これにより本発明の貼付材が形成される。 The patch of the present invention essentially comprises an ion exchange membrane having a surface roughness of 7 μm or less and the ionic drug impregnated in the ion exchange membrane, but the production method is not particularly limited. . In general, an ionic drug to be used can be produced by dissolving it in a solvent capable of dissolving the drug, for example, water or alcohol such as ethanol to make a solution and permeating this solution into an ion exchange membrane. it can. If necessary, the concentration of the ionic drug may be adjusted by volatilizing and removing the solvent used after the permeation. Examples of the permeation method include a method of immersing the ion exchange membrane in the ionic drug solution as described above, and a method of applying and spraying the ionic drug solution to the ion exchange membrane. Further, by providing an ionic drug-containing layer, which will be described later, the ionic drug is supplied into the ion-exchange membrane through the interface between the ionic drug-containing layer and the ion-exchange membrane, thereby forming the patch of the present invention. The
本発明の貼付材においては、上記表面粗さが７μｍ以下のイオン交換膜と、該イオン交換膜に含浸せしめられた前記イオン性薬剤のみからなる、換言すれば、イオン性薬剤を含浸させたイオン交換膜単独で構成することも可能である。しかし、薬剤の投与を経時的に持続させるために、該イオン交換膜の生体と接触する部位を有する側とは反対側に、イオン性薬剤含有層を設けることが好適である。上記したように、この場合には、予めイオン性薬剤を含浸させたイオン交換膜を用いなくとも、貼付材作成後、使用待機時あるいは使用時にイオン性薬剤はイオン交換膜内に浸透する。 The patch of the present invention comprises only an ion exchange membrane having a surface roughness of 7 μm or less and the ionic agent impregnated in the ion exchange membrane, in other words, an ion impregnated with the ionic agent. It is also possible to constitute the exchange membrane alone. However, in order to keep the administration of the drug over time, it is preferable to provide an ionic drug-containing layer on the side of the ion exchange membrane opposite to the side having the site in contact with the living body. As described above, in this case, without using an ion exchange membrane impregnated with an ionic agent in advance, the ionic agent penetrates into the ion exchange membrane after preparation of the patch and at the time of use standby or during use.
このイオン性薬剤含有層には、通常の経皮投与に用いられる薬剤含有層が何ら制限されることなく使用可能である。即ち、上記したイオン性の薬剤を水、エタノールなどの溶剤に溶解させた溶液そのもの、該溶液をポリビニルアルコールやポリビニルピロリドンなどのゲル、多孔質フィルム、ガーゼ、紙などに含浸させたものが使用可能である。 As the ionic drug-containing layer, a drug-containing layer used for normal transdermal administration can be used without any limitation. That is, a solution in which the above ionic drug is dissolved in a solvent such as water or ethanol, or a solution obtained by impregnating a gel such as polyvinyl alcohol or polyvinyl pyrrolidone, a porous film, gauze, or paper can be used. It is.
さらに、本発明の貼付材は、イオン交換膜やイオン性薬剤含有層の乾燥を防ぐ目的で最外層に溶剤難透過性の外装材を設けたり、生体表面との密着力を増すために貼付材の周縁部に粘着層を設けることも可能である。 Furthermore, the patch of the present invention is provided with a solvent-permeable outer packaging material on the outermost layer for the purpose of preventing drying of the ion exchange membrane or the ionic drug-containing layer, or for increasing adhesion to the surface of a living body. It is also possible to provide a pressure-sensitive adhesive layer on the peripheral edge.
上記溶剤難透過性の外装材としては、熱可塑性樹脂、特にポリオレフィン系のフィルムであることが好ましい。このようなものを用いることにより、イオン交換膜として前記熱可塑性樹脂を基材としたイオン交換膜と、接着剤等の接合用材料を用いずとも熱融着等による接合が容易となり、接着剤等の使用による不純物の混入を防止することができる。このようなフィルム状の外装材を用いる場合、その厚さは特に制限されるものではなく、一般的な厚さのフィルムを採用すれば良く、通常は５〜１５０μｍ程度である。 The solvent-permeable outer packaging material is preferably a thermoplastic resin, particularly a polyolefin film. By using such a material, the ion exchange membrane based on the thermoplastic resin as an ion exchange membrane can be easily joined by thermal fusion or the like without using a joining material such as an adhesive. It is possible to prevent contamination of impurities due to use of the above. When such a film-shaped exterior material is used, the thickness thereof is not particularly limited, and a film having a general thickness may be employed, and is usually about 5 to 150 μm.
ポリオレフィン系のフィルム等からなる外装材を有する貼着材の代表的な構造を図１に示す。即ち、貼付材１００は、生体の表面１と接触する側の表面粗さが７μｍ以下のイオン交換膜２と、フィルム状外装材４とからなり、これらの周縁部６を互いに接合することにより内部に密閉された中空部を有する袋状物の形態をしている。該袋状物内の中空部には、イオン性薬剤含有層３が設けられている。イオン交換膜２には、イオン性薬剤含有層３が含有するイオン性薬剤と同じイオン性薬剤が含浸されている。該フィルム状外装材４とイオン交換膜２との周縁部６は融着等により接合、密封されている。
FIG. 1 shows a typical structure of an adhesive material having an exterior material made of a polyolefin film or the like. That is, the
この貼付材１００のイオン交換膜２を生体の表面１に貼着することにより、該イオン性薬剤が生体との接触面から、生体内へと迅速に浸透していく。
By sticking the
フィルム状外装材４は、イオン性薬剤含有層３に含まれるイオン性薬剤やその他の成分が、保管時に貼付材を収納している包装材料や、貼付材の使用時の衣類へ付着したり、あるいは揮散したりすることを防止する。
The film-like packaging material 4 is such that the ionic drug and other components contained in the ionic drug-containing
なお、図１は、イオン性薬剤含有層３が存在した場合を示しているが、前述したように、この層３は存在していなくても良い。更に、該貼付材は、周縁部の生体と接する側の表面に粘着層等を有していても良く、また、その他、図示した以外の各種部材を有していても良い。
Although FIG. 1 shows the case where the ionic drug-containing
図１に示す袋状の貼付材１００を製造する方法は特に制限されず、如何なる方法によって製造しても良い。例えば、イオン交換膜とフィルム状外装材との周縁部の一部を残して互いに接合することにより、周縁部の一部が開口した袋状物を製造する。次いで開口部から袋状物の内部にイオン性薬剤含有物質を充填する。その後、該開口部をさらに接合して袋状物を密封する。または、イオン交換膜とフィルム状外装材とを用いてイオン性薬剤含有層を挟む。その後、イオン交換膜とフィルム状外装材との周縁部を一度に接合して密封しても良い。
The method for producing the bag-
前記したように、接合、密封する方法としては、製造が容易で、密封状態の保持性も高く、さらにはイオン性薬剤含有層に対する不純物混入の危険性が少ない点で、融着により接合、密封する方法が好ましい。該融着の方法は特に制限されるものではなく、熱可塑性樹脂からなるフィルムを融着するために用いられる公知の如何なる方法も採用できる。一般には、接合する部分に対して、外装材およびイオン交換膜の基材となっている熱可塑性樹脂の溶融温度より０〜１００℃高い温度を付与できる材料を押当てたり、あるいは５０〜３００Ｈｚの振動や１０〜５０ｋＨｚの高周波を印加して融着する。 As described above, the bonding and sealing methods are easy to manufacture, have high sealing retention, and have a low risk of mixing impurities into the ionic drug-containing layer. Is preferred. The method for fusing is not particularly limited, and any known method used for fusing a film made of a thermoplastic resin can be adopted. In general, a material that can be given a temperature higher by 0 to 100 ° C. than the melting temperature of the thermoplastic resin that is the base material of the exterior material and the ion exchange membrane is pressed against the part to be joined, or 50 to 300 Hz. Fusing by applying vibration or high frequency of 10-50 kHz.
貼付材の製造後、使用するまでの保管時に、内部のイオン性薬剤や溶剤等が貼付材の外部に漏出したり、あるいはイオン性薬剤に対して有害な環境（酸素、紫外線等）から遮断する目的で、イオン交換膜の生体と接触する部位が存在する面に脱離可能に保護フィルムを設けたり、貼付材全体をさらに袋状の包装材で密封しても良い。 During storage from the time of manufacture of the patch until use, the internal ionic chemical or solvent leaks out of the patch, or is blocked from the environment (oxygen, ultraviolet rays, etc.) harmful to the ionic chemical. For the purpose, a protective film may be provided on the surface of the ion exchange membrane where the part that comes into contact with the living body is detachable, or the entire patch may be further sealed with a bag-shaped packaging material.
本発明の貼付材の大きさは特に限定されるものではなく、目的や用途によって適宜決定すればよい。一般には、直径もしくは一辺の長さは、０．５〜５０ｃｍ程度、厚さは４０〜２３００μｍ程度である。この場合には、イオン交換膜及び必要に応じて用いられる外装材の厚さを前記のように５〜１５０μｍとし、イオン性薬剤又はイオン性薬剤含有層の厚さを３０〜２０００μｍとすればよい。また、上記フィルム状外装材を用いる場合、融着する周縁部の大きさも特に制限がなく、簡単に破断等して内部のイオン性薬剤又はイオン性薬剤含有層が漏れ出すことを防止するに足りる周縁部の大きさにすればよい。一般には、周縁部の幅は０．１〜５ｍｍ程度でよい。 The size of the patch of the present invention is not particularly limited, and may be appropriately determined depending on the purpose and application. Generally, the diameter or the length of one side is about 0.5 to 50 cm, and the thickness is about 40 to 2300 μm. In this case, the thickness of the ion exchange membrane and the exterior material used as necessary may be 5 to 150 μm as described above, and the thickness of the ionic drug or the ionic drug-containing layer may be 30 to 2000 μm. . In addition, when the film-shaped exterior material is used, the size of the peripheral edge to be fused is not particularly limited, and it is sufficient to prevent the internal ionic drug or the ionic drug-containing layer from leaking due to simple breakage or the like. What is necessary is just to make it the magnitude | size of a peripheral part. In general, the width of the peripheral edge may be about 0.1 to 5 mm.
本発明の貼付材の使用方法は、通常、以下に示すものである。即ち、投与するイオン性薬剤を含浸したイオン交換膜が生体表面に直接密着するように、貼付材を生体表面へ貼り付ける（該イオン交換膜の接触面は表面粗さ（Ｒｚ）が７μｍ以下である）。貼付材の生体表面への貼り付け方法は、前記のように貼付材に粘着層を設けておいてこの粘着層を介して貼着ても良い。または、医療用絆創膏等を利用して貼着しても良い。また、貼付場所や貼付時間等は、用いるイオン性薬剤の種類や濃度、所望の投与量等により適宜決定される。 The method of using the patch of the present invention is usually as follows. That is, the patch is applied to the living body surface so that the ion exchange membrane impregnated with the ionic drug to be administered is in direct contact with the living body surface (the surface of the contact surface of the ion exchange membrane has a surface roughness (Rz) of 7 μm or less. is there). As for the method of attaching the adhesive material to the surface of the living body, an adhesive layer may be provided on the adhesive material as described above, and the adhesive material may be attached via this adhesive layer. Or you may stick using medical adhesive bandages. The location and time of application are appropriately determined depending on the type and concentration of the ionic drug used, the desired dose, and the like.
本発明を更に具体的に説明するため、以下、実施例及び比較例を掲げて説明するが、本発明はこれらの実施例に限定されるものではない。尚、実施例および比較例で用いたイオン交換膜の特性値は、以下の方法により測定した。 In order to describe the present invention more specifically, examples and comparative examples will be described below, but the present invention is not limited to these examples. In addition, the characteristic value of the ion exchange membrane used by the Example and the comparative example was measured with the following method.
（１）イオン交換容量および含水率；
イオン交換膜を１ｍｏｌ／ＬのＨＣｌ水溶液に１０時間以上浸漬した。
(1) ion exchange capacity and moisture content;
The ion exchange membrane was immersed in a 1 mol / L HCl aqueous solution for 10 hours or more.
その後、陽イオン交換膜の場合には、１ｍｏｌ／ＬのＮａＣｌ水溶液で水素イオン型をナトリウムイオン型に置換させ、遊離した水素イオンを水酸化ナトリウム水溶液を用いて電位差滴定装置（ＣＯＭＴＩＴＥ−９００、平沼産業株式会社製）で定量した（Ａｍｏｌ）。 Thereafter, in the case of a cation exchange membrane, the hydrogen ion type is replaced with a sodium ion type with a 1 mol / L NaCl aqueous solution, and the liberated hydrogen ions are converted into a potentiometric titrator (COMMITE-900, Hiranuma using a sodium hydroxide aqueous solution). (Amol).
一方、陰イオン交換膜の場合には、１ｍｏｌ／ＬのＮａＮＯ３水溶液で塩化物イオン型を硝酸イオン型に置換させ、遊離した塩化物イオンを硝酸銀水溶液を用いて電位差滴定装置（ＣＯＭＴＩＴＥ−９００、平沼産業株式会社製）で定量した（Ａｍｏｌ）。 On the other hand, in the case of an anion exchange membrane, a chloride ion type is replaced with a nitrate ion type with 1 mol / L NaNO 3 aqueous solution, and the liberated chloride ion is converted into a potentiometric titrator (COMMITITE-900, (Amol).
次に、同じイオン交換膜を１ｍｏｌ／ＬのＨＣｌ水溶液に４時間以上浸漬し、イオン交換水で十分水洗した後、その膜を取り出しティッシュぺーパー等で表面の水分を拭き取り湿潤時の重さ（Ｗｇ）を測定した。次に膜を６０℃で５時間減圧乾燥させその重量を測定した（Ｄｇ）。上記測定値に基づいて、イオン交換容量及び固定イオン濃度を次式により求めた。 Next, the same ion exchange membrane is immersed in a 1 mol / L HCl aqueous solution for 4 hours or more and thoroughly washed with ion exchange water. Then, the membrane is taken out and wiped with a tissue paper or the like to wipe moisture on the surface (weight when wet ( Wg) was measured. Next, the membrane was dried under reduced pressure at 60 ° C. for 5 hours, and its weight was measured (Dg). Based on the measured values, the ion exchange capacity and the fixed ion concentration were determined by the following equations.
イオン交換容量＝Ａ×１０００／Ｄ［ｍｍｏｌ／ｇ−乾燥重量］
含水率＝１００×（Ｗ−Ｄ）／Ｄ[％]
固定イオン濃度＝１００×イオン交換容量／含水率[ｍｍｏｌ／ｇ−水]
（２）膜抵抗；
セルの内部をイオン交換膜で仕切って形成した２室のそれぞれに白金黒電極を設けた構造の２室セルを用意した。イオン交換膜の両側の各室に３ｍｏｌ／ｌの硫酸水溶液を満たした。交流ブリッジ（周波数１０００サイクル／秒）により２５℃における電極間の抵抗を測定した。該電極間の抵抗値とイオン交換膜を設置しない場合の該電極間の抵抗値の差抵抗値を膜抵抗値とした。なお、上記測定に使用する膜は、あらかじめ３ｍｏｌ／ｌの硫酸水溶液中で平衡にしたものを用いた。
Ion exchange capacity = A × 1000 / D [mmol / g-dry weight]
Moisture content = 100 × (WD) / D [%]
Fixed ion concentration = 100 × ion exchange capacity / water content [mmol / g-water]
(2) membrane resistance;
A two-chamber cell having a structure in which a platinum black electrode was provided in each of two chambers formed by partitioning the inside of the cell with an ion exchange membrane was prepared. Each chamber on both sides of the ion exchange membrane was filled with 3 mol / l sulfuric acid aqueous solution. The resistance between the electrodes at 25 ° C. was measured by an AC bridge (frequency 1000 cycles / second). The difference resistance value between the resistance value between the electrodes and the resistance value between the electrodes when no ion exchange membrane was installed was taken as the membrane resistance value. Note that the membrane used for the above measurement was previously equilibrated in a 3 mol / l sulfuric acid aqueous solution.
（３）表面粗さ；
三次元粗さ測定器（小坂研究所製ＴＤＦ−３Ａ型）を用いて、イオン交換膜表面の表面粗さを測定した。得られた粗さ曲線において、評価長さを１１ｍｍとして測定した十点平均粗さ（Ｒｚ）をもってイオン交換膜の表面粗さとした。
(3) surface roughness;
The surface roughness of the ion exchange membrane surface was measured using a three-dimensional roughness measuring instrument (TDF-3A type manufactured by Kosaka Laboratory). In the obtained roughness curve, the 10-point average roughness (Rz) measured with an evaluation length of 11 mm was defined as the surface roughness of the ion exchange membrane.
（４）仮想皮膚系での薬剤透過量；
１０質量％のポリビニルアルコール（日本合成製ＮＨ−２０）の水溶液をろ紙（アドバンテック製化学分析用ろ紙５Ｃ）上に塗布した。塗布量は、溶媒除去後にポリビニルアルコールが２ｍｇ／ｃｍ２となるようにした。その後、室温で２４時間以上放置して水を揮散させて仮想皮膚を得た。次いで、図２に示すように、該仮想皮膚２０と測定対象とする被検膜（イオン交換膜等）２１とを密着させてセルの中央に設置した。薬液室２２に所定濃度の薬剤の水溶液を、仮想皮膚室２３には０．９質量％の塩化ナトリウム水溶液を満たした。次いで、薬液室２２内と仮想皮膚室２３内とを攪拌しながら、２５℃で所定時間透過試験を行った。試験終了後、直ちに仮想皮膚室２３内の液を抜き取り、これを測定試料とした。測定試料中の薬剤量を高速液体クロマトグラフを用いて測定した。
(4) Amount of drug permeation through virtual skin system;
An aqueous solution of 10% by mass of polyvinyl alcohol (Nippon Gosei NH-20) was applied on filter paper (Advantech Chemical Analysis Filter Paper 5C). The coating amount was such that polyvinyl alcohol was 2 mg / cm 2 after the solvent was removed. Thereafter, the skin was allowed to stand for 24 hours or more at room temperature to evaporate water to obtain virtual skin. Next, as shown in FIG. 2, the
（５）生体系での薬剤透過量；
仮想皮膚（ポリビニルアルコールを塗布したろ紙）の代わりに、生体皮膚としてミニブタ（Yucatane Micropig、５ヶ月齢、メス）の背部皮膚を用い、仮想皮膚系と同じ方法で薬剤透過量を測定した。
(5) Amount of drug permeation in biological system;
Instead of virtual skin (filter paper coated with polyvinyl alcohol), the back skin of a minipig (Yucatane Micropig, 5 months old, female) was used as living skin, and the amount of drug permeation was measured by the same method as the virtual skin system.
製造例１
クロロメチルスチレン３８０ｇ、ジビニルベンゼン２０ｇ、ｔ−ブチルパーオキシエチルヘキサノエート２０ｇからなる単量体組成物を調整し、この単量体組成物４２０ｇを５００ｍｌのガラス容器に入れた。この単量体組成物中に２０ｃｍ×２０ｃｍの多孔質膜（質量平均分子量２５万のポリエチレン製、膜厚２５μｍ、平均孔径０．０３μｍ、空隙率３７％）を大気圧下、２５℃で１０分浸漬し、この多孔質膜に単量体組成物を含浸させた。続いて、上記多孔質膜を単量体組成物中から取り出し、厚さ１００μｍのポリエステルフィルムでこの多孔質膜の両側を被覆した後、平滑なステンレス板２枚の間に挟み込み、０．２９ＭＰａ（３ｋｇ／ｃｍ２）の窒素加圧下、８０℃で５時間加熱重合した。次いで、得られた膜状物をトリメチルアミン１５質量％、水６０質量％、アセトン２５質量％よりなるアミノ化浴に浸漬し、室温で５時間反応せしめ４級アンモニウム型陰イオン交換膜を得た。
Production Example 1
A monomer composition consisting of 380 g of chloromethylstyrene, 20 g of divinylbenzene, and 20 g of t-butylperoxyethyl hexanoate was prepared, and 420 g of this monomer composition was placed in a 500 ml glass container. In this monomer composition, a 20 cm × 20 cm porous film (made of polyethylene having a mass average molecular weight of 250,000, a film thickness of 25 μm, an average pore diameter of 0.03 μm, a porosity of 37%) is subjected to atmospheric pressure at 25 ° C. for 10 minutes. The porous membrane was immersed and impregnated with the monomer composition. Subsequently, the porous membrane was taken out from the monomer composition, and after covering both sides of the porous membrane with a polyester film having a thickness of 100 μm, it was sandwiched between two smooth stainless steel plates, and 0.29 MPa ( Polymerization was performed by heating at 80 ° C. for 5 hours under a nitrogen pressure of 3 kg / cm 2 ). Next, the obtained membrane was immersed in an amination bath composed of 15% by mass of trimethylamine, 60% by mass of water, and 25% by mass of acetone, and reacted at room temperature for 5 hours to obtain a quaternary ammonium type anion exchange membrane.
得られた陰イオン交換膜のイオン交換容量、含水率、固定イオン濃度、膜抵抗、膜厚、表面粗さを測定した。結果を表１に示す。 The ion exchange capacity, water content, fixed ion concentration, membrane resistance, film thickness, and surface roughness of the obtained anion exchange membrane were measured. The results are shown in Table 1.
製造例２〜５
単量体組成物、及び多孔質膜を表１に示した組成に代えた以外は製造例１と同様にして陰イオン交換膜を製造した。得られた膜の物性を表１に示す。
Production Examples 2-5
An anion exchange membrane was produced in the same manner as in Production Example 1 except that the monomer composition and the porous membrane were changed to the compositions shown in Table 1. Table 1 shows the physical properties of the obtained film.
製造例６
製造例１と同様にして、表１に示す単量体組成物を多孔質膜に含浸させ、続いて、多孔質膜を単量体組成物中から取り出した。１００μｍのポリエステルフィルムで多孔質膜の両側を被覆した後、これをステンレス製の平板２枚の間に挟み込み、０．２９ＭＰａ（３ｋｇ／ｃｍ２）の窒素加圧下、４５℃で３時間、ついで７５℃で５時間加熱重合した。次いで、得られた膜状物をヨウ化メチルとｎ−ヘキサンの１：３（質量比）の混合液中に３０℃で２４時間浸漬し、４級ピリジニウム型陰イオン交換膜を得た。
Production Example 6
In the same manner as in Production Example 1, the porous membrane was impregnated with the monomer composition shown in Table 1, and then the porous membrane was taken out from the monomer composition. After covering both sides of the porous membrane with a 100 μm polyester film, the porous membrane was sandwiched between two stainless steel flat plates, and nitrogen pressure of 0.29 MPa (3 kg / cm 2 ) was applied at 45 ° C. for 3 hours, and then 75. Polymerization was carried out at 5 ° C. for 5 hours. Subsequently, the obtained film-like material was immersed in a 1: 3 (mass ratio) mixture of methyl iodide and n-hexane at 30 ° C. for 24 hours to obtain a quaternary pyridinium-type anion exchange membrane.
得られた陰イオン交換膜のイオン交換容量、含水率、固定イオン濃度、膜抵抗、膜厚、表面粗さを測定した結果を表１に示す。 Table 1 shows the results of measuring the ion exchange capacity, water content, fixed ion concentration, membrane resistance, film thickness, and surface roughness of the obtained anion exchange membrane.
実施例１〜６
陰イオン性の薬剤であるアスコルビン酸リン酸エステルマグネシウム塩の１０ｍｍｏｌ／Ｌ溶液を用いて仮想皮膚系での薬剤透過量を測定した。用いたイオン交換膜と薬剤透過量とを表２に示す。
Examples 1-6
The amount of drug permeation through the virtual skin system was measured using a 10 mmol / L solution of ascorbic acid phosphate magnesium salt, which is an anionic drug. Table 2 shows the ion exchange membrane used and the amount of drug permeation.
比較例１
織布を基材とする陰イオン交換膜であるネオセプタＡＭＸ（トクヤマ製；膜物性は表１に記載）を用いた以外は、実施例１と同様にして薬剤透過量を測定した。結果を表２に示す。
Comparative Example 1
The amount of drug permeation was measured in the same manner as in Example 1 except that Neoceptor AMX (manufactured by Tokuyama; membrane properties are listed in Table 1), which is an anion exchange membrane based on a woven fabric, was used. The results are shown in Table 2.
比較例２
測定対象イオン交換膜を使用せず、仮想皮膚のみを用いて実施例１と同様にして薬剤透過量を測定した。結果を表２に示す。
Comparative Example 2
The drug permeation amount was measured in the same manner as in Example 1 using only virtual skin without using the ion exchange membrane to be measured. The results are shown in Table 2.
実施例７
アスコルビン酸リン酸エステルマグネシウム塩の１０ｍｍｏｌ／Ｌ溶液に代えて、アスコルビン酸ナトリウム塩の１０ｍｍｏｌ／Ｌ溶液を用いて製造例１で得た膜の仮想皮膚系での薬剤透過量を測定した。結果を表３に示す。
Example 7
Instead of a 10 mmol / L solution of ascorbic acid phosphate magnesium salt, a 10 mmol / L solution of sodium ascorbate was used to measure the amount of drug permeation in the virtual skin system of the membrane obtained in Production Example 1. The results are shown in Table 3.
比較例３
織布を基材とするイオン交換膜として、陰イオン交換膜であるネオセプタＡＭＸ（トクヤマ製；膜物性は表１に記載）を用いた以外は、実施例７と同様にして薬剤透過量を測定した。結果を表３に示す。
Comparative Example 3
The drug permeation amount was measured in the same manner as in Example 7 except that Neoceptor AMX (made by Tokuyama; membrane properties are listed in Table 1), which is an anion exchange membrane, was used as the ion exchange membrane based on woven fabric. did. The results are shown in Table 3.
比較例４
測定対象イオン交換膜を使用せず、仮想皮膚のみを用いて実施例７と同様にして薬剤透過量を測定した。結果を表３に示す。
Comparative Example 4
The drug permeation amount was measured in the same manner as in Example 7 using only virtual skin without using the ion exchange membrane to be measured. The results are shown in Table 3.
実施例８〜１３、比較例５、６
陽イオン性の薬剤である、ヒスタミン二塩酸塩の１０ｍｍｏｌ／Ｌ溶液を用いて仮想皮膚系での薬剤透過量を測定した。用いたイオン交換膜と薬剤透過量の結果を表４に示す。なお、実施例１３で用いたＮａｆｉｏｎ１１２（デュポン社製；膜物性は表１に記載）は非架橋の陽イオン交換膜である。
Examples 8 to 13, Comparative Examples 5 and 6
The amount of drug permeation through the virtual skin system was measured using a 10 mmol / L solution of histamine dihydrochloride, which is a cationic drug. Table 4 shows the results of the ion exchange membrane used and the drug permeation amount. Note that Nafion 112 (manufactured by DuPont; membrane properties are listed in Table 1) used in Example 13 is a non-crosslinked cation exchange membrane.
実施例１４、比較例７、８
陰イオン性の薬剤であるアスコルビン酸ナトリウムの１０ｍｍｏｌ／Ｌ溶液を用いて生体皮膚系での薬剤透過量を測定した。用いたイオン交換膜と薬剤透過量の結果を表５に示す。
Example 14, Comparative Examples 7 and 8
Using a 10 mmol / L solution of sodium ascorbate, which is an anionic drug, the amount of drug permeation through the living skin system was measured. Table 5 shows the results of the ion exchange membrane used and the drug permeation amount.
実施例１５、比較例９
陰イオン性の薬剤であるアスコルビン酸りん酸エステルマグネシウム塩の１０ｍｍｏｌ／Ｌ溶液を用いて生体皮膚系での薬剤透過量を測定した。用いたイオン交換膜と薬剤透過量の結果を表６に示す。
Example 15 and Comparative Example 9
The amount of drug permeation through the living skin system was measured using a 10 mmol / L solution of ascorbic acid phosphate magnesium salt, which is an anionic drug. Table 6 shows the results of the ion exchange membrane used and the drug permeation amount.
１：生体面
２：生体との接触面の表面粗さ（Ｒｚ）が７μｍ以下のイオン交換膜
３：イオン性薬剤含有層
４：フィルム状外装材
５：貼付材周縁部の接合部
６：周縁部
２０：仮想皮膚または生体皮膚
２１：被検膜
２２：薬液室
２３：仮想皮膚室
１００：貼付材
1: Biological surface 2: Ion-
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| US8295922B2 (en) | 2005-08-08 | 2012-10-23 | Tti Ellebeau, Inc. | Iontophoresis device |
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