JP2007089792A - Percutaneous administration apparatus - Google Patents
Percutaneous administration apparatus Download PDFInfo
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- JP2007089792A JP2007089792A JP2005282531A JP2005282531A JP2007089792A JP 2007089792 A JP2007089792 A JP 2007089792A JP 2005282531 A JP2005282531 A JP 2005282531A JP 2005282531 A JP2005282531 A JP 2005282531A JP 2007089792 A JP2007089792 A JP 2007089792A
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- protrusion
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- A—HUMAN NECESSITIES
- A45—HAND OR TRAVELLING ARTICLES
- A45D—HAIRDRESSING OR SHAVING EQUIPMENT; EQUIPMENT FOR COSMETICS OR COSMETIC TREATMENTS, e.g. FOR MANICURING OR PEDICURING
- A45D44/00—Other cosmetic or toiletry articles, e.g. for hairdressers' rooms
- A45D44/22—Face shaping devices, e.g. chin straps; Wrinkle removers, e.g. stretching the skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
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- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Media Introduction/Drainage Providing Device (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は，新規な経皮投与装置に関する。より詳しく説明すると，本発明は，経皮系ドラッグデリバリーシステム（ＤＤＳ）用の微細突起を有する経皮投与装置などに関する。 The present invention relates to a novel transdermal administration device. More specifically, the present invention relates to a transdermal administration device having fine protrusions for a transdermal drug delivery system (DDS).
薬剤の投与方法として，経口投与と注射による投与が主であった。しかし，経口投与は，消化器系を経由するので，患部へ効果的に到達しないなどの問題がある。また，注射による投与は，通常痛みを伴うなどの問題や，皮膚が損傷するなどの問題がある。また，薬剤の投与方法として，塗り薬や貼り薬などの経皮投与がある。これらの経皮投与は，簡便であり，かつ投与量を容易に調整できるという利点がある。しかし，これらの方法では，角質内に化合物を迅速に浸透させることは困難である。 The main methods of drug administration were oral and injection. However, since oral administration passes through the digestive system, there are problems such as not reaching the affected area effectively. In addition, administration by injection usually has problems such as pain and damage to the skin. In addition, as a method for administering the drug, there is a transdermal administration such as a coating agent or a patch. These transdermal administrations are advantageous in that they are simple and the dosage can be easily adjusted. However, with these methods, it is difficult to rapidly penetrate the compound into the stratum corneum.
近年，マイクロニードルなどによる経皮系ＤＤＳの開発が進み，実用段階に入っている（下記特許文献１参照）。しかし，マイクロニードルなどによる経皮投与では，皮膚が損傷するという問題がある。また，皮膚に穴などの傷が生ずるので、傷から菌が進入する可能性があるなどの問題がある。
本発明は，新規な経皮投与装置を提供することを目的とする。 An object of the present invention is to provide a novel transdermal administration device.
本発明は，化粧料などを効果的に投与できる新規な経皮投与装置を提供することを上記とは別の目的とする。 Another object of the present invention is to provide a novel transdermal administration device capable of effectively administering cosmetics and the like.
本発明は，痛みを伴わず，かつ皮膚に傷を残さない，新たな剤型を提供することを上記とは別の目的とする。 Another object of the present invention is to provide a new dosage form that does not cause pain and does not leave a wound on the skin.
本発明は，上記の課題のうち少なくともひとつ以上を解決するためのものであり，基本的には，突起部を角質層内に貫通させなくても，表皮を引き伸ばすことができれば，表皮の保護特性を低下させることができるので，突起に付着しているか又は突起に含まれる化粧料，医薬，糖類などの化合物を投与することができるという知見に基づくものである。 The present invention is to solve at least one of the above problems. Basically, if the epidermis can be stretched without penetrating the stratum corneum, the protective properties of the epidermis are achieved. Therefore, it is based on the knowledge that compounds such as cosmetics, medicines, and sugars attached to or contained in the protrusion can be administered.
本発明は，突起部が皮膚の角質層を貫通しないが，加圧されて薄くなった角質層などを通して，突起部に付着するか突起部に含まれる化合物を投与できるという，新規な経皮投与装置を提供することを目的とする。 The present invention provides a novel transdermal administration in which the protrusion does not penetrate the stratum corneum of the skin, but the compound attached to the protrusion or contained in the protrusion can be administered through the stratum corneum that has been pressed and thinned. An object is to provide an apparatus.
美容液などは効果的に投与することが期待されるが，本発明は，顔など特定の位置の皮膚を引き伸ばした状態で，化粧料などを投与できるので，化粧料などを効果的に投与できる新規な経皮投与装置を提供することができる。 It is expected that cosmetic liquids and the like are effectively administered. However, the present invention can administer cosmetics and the like with the skin at a specific position such as the face stretched, so that cosmetics and the like can be effectively administered. A novel transdermal administration device can be provided.
本発明の経皮投与装置は，通常の加圧において皮膚の角質層を貫通しないので，痛みを伴わず，かつ皮膚に傷を残さない，新たな剤型を提供することができる。 Since the transdermal administration device of the present invention does not penetrate the stratum corneum of the skin under normal pressure, it can provide a new dosage form that does not cause pain and does not leave a wound on the skin.
１．経皮投与装置
図1は，本発明の経皮投与装置の概略構成図である。図1に示されるように，本発明の経皮投与装置(1)は，基板(2)と，前記基板上に設けられた1又は複数の突起部(3)を具備する。具体的には，基板(2)と，前記基板上に設けられた１又は複数の突起部(3)を具備し，前記突起部は糖類又は生分解性ポリマーを主成分とし，前記突起部の高さは１０μｍ〜３ｍｍであり，前記突起部の先端が平坦か，丸みを帯びているか，又は平坦形状でありさらに１又は複数の微小突起を有する，経皮投与装置である。なお，図中，符号4は，突起部の先端部に設けられてもよい微小突起である。
1. Transdermal Administration Device FIG. 1 is a schematic configuration diagram of a transdermal administration device of the present invention. As shown in FIG. 1, the transdermal administration device (1) of the present invention comprises a substrate (2) and one or more protrusions (3) provided on the substrate. Specifically, it comprises a substrate (2) and one or a plurality of protrusions (3) provided on the substrate, the protrusions mainly comprising a saccharide or a biodegradable polymer, The transdermal administration device has a height of 10 μm to 3 mm, the tip of the protrusion is flat, rounded, or flat, and has one or more microprojections. In the figure, reference numeral 4 denotes a minute protrusion that may be provided at the tip of the protrusion.
前記突起部の高さは１０μｍ〜３ｍｍであり，好ましくは先端に向かうに従って先が細くなっている形状のものである。突起部の先端形状として，平坦か，丸みを帯びているか，又は平坦形状があげられる。このような形状を有するので，通常の使用状況の下では，突起部が角質層を貫通しないので，表皮にダメージを与える事態を防止でき，表皮を伸ばすことができるので効果的に化合物を投与できる。 The protrusion has a height of 10 μm to 3 mm, and preferably has a shape that tapers toward the tip. Examples of the tip shape of the protrusion include a flat shape, a rounded shape, and a flat shape. Because of this shape, under normal conditions of use, the protrusions do not penetrate the stratum corneum, preventing damage to the epidermis and extending the epidermis, so that the compound can be administered effectively. .
なお，突起部の高さは用途に応じて適宜調整すればよいが，１０μｍ〜３ｍｍがあげられ，１００μｍ〜２ｍｍでもよく，２００μｍ〜１ｍｍでもよい。特に顔などに化粧料を投与するために投与装置を用いる場合は，表皮が薄いので，突起部の長さを短くすることが望ましく，具体的には２０μｍ〜５００μｍとすればよい。 In addition, what is necessary is just to adjust the height of a projection part suitably according to a use, but 10 micrometers-3 mm are mention | raise | lifted, 100 micrometers-2 mm may be sufficient, and 200 micrometers-1 mm may be sufficient. In particular, when an administration device is used to administer cosmetics to the face or the like, the epidermis is thin, so it is desirable to shorten the length of the protrusion, specifically 20 μm to 500 μm.
図２は，突起部の先端が平坦である場合における，本発明の経皮投与装置の概略構成図である。突起部の先端が平坦である場合の「平坦」とは，たとえば，少なくとも突起部の先端を中心とした１０μｍ四方の領域において，基準長さを１μｍとしたときの算術平均粗さ（Ｒａ）が，０．０１μｍ以上１μｍ以下であるものがあげられ，０．０１μｍ以上０．５μｍ以下でもよい。また，少なくとも突起部の先端を中心とした１０μｍ四方の領域において，最大高さ（Ｒｙ）が５μｍ以下となるものがあげられ，４μｍ以下であればより好ましく，３μｍ以下であればさらに好ましい。このような平坦な領域を有することで，突起部が表皮に侵入する自体を効果的に防止できる。なお，平坦な領域は，たとえば，突起部の先端を中心とした１０μｍ四方の領域があげられるが，１μｍ２以上１０００μｍ２以下であってもよく，１０μｍ２以上５００μｍ２以下であってもよい。 FIG. 2 is a schematic configuration diagram of the transdermal administration device of the present invention when the tip of the protrusion is flat. “Flat” when the tip of the protrusion is flat is, for example, the arithmetic average roughness (Ra) when the reference length is 1 μm in at least a 10 μm square region centered on the tip of the protrusion. , 0.01 μm or more and 1 μm or less, and may be 0.01 μm or more and 0.5 μm or less. In addition, at least in a 10 μm square region centered on the tip of the protrusion, the maximum height (Ry) is 5 μm or less, more preferably 4 μm or less, and even more preferably 3 μm or less. By having such a flat region, the protrusion itself can effectively be prevented from entering the epidermis. The flat region is, for example, a 10 μm square region centered on the tip of the protrusion, but may be 1 μm 2 or more and 1000 μm 2 or less, or 10 μm 2 or more and 500 μm 2 or less.
突起部の先端が丸みを帯びている場合の「丸み」とは，たとえば，突起部の頂点部がなだらかに変化していることを意味する。なお，本明細書において，直径２ｒの丸みとは，突起部の太さが２ｒの位置において，その中心から，突起部の頂点までの距離がｒ以下の場合を意味する。たとえば，直径２０μｍの丸みとは，突起部の平均直径が２０μｍの位置において，その部位の中心から，突起部の頂点までの距離が１０μｍ以下の場合を意味する。このように突起部の先端が丸みを帯びている場合，突起部の先端が表皮に完全には突き刺さらず，表皮を引き伸ばす効果がある。なお，突起部の先端が丸みを帯びている場合の「丸み」は，たとえば，直径２０μｍ以上の丸みがあげられるが，直径が２０μｍ以上１ｍｍ以下でもよく，直径が３０μｍ以上２００μｍ以下でもよい。 “Rounding” when the tip of the protrusion is rounded means, for example, that the apex of the protrusion changes gently. In the present specification, the roundness having a diameter of 2r means that the distance from the center to the apex of the protrusion is not more than r at the position where the thickness of the protrusion is 2r. For example, the roundness with a diameter of 20 μm means that the distance from the center of the portion to the apex of the protrusion is 10 μm or less at the position where the average diameter of the protrusion is 20 μm. Thus, when the tip of the projection is rounded, the tip of the projection does not completely pierce the epidermis and has an effect of stretching the epidermis. The “roundness” when the tip of the protrusion is rounded is, for example, round with a diameter of 20 μm or more, but the diameter may be 20 μm or more and 1 mm or less, and the diameter may be 30 μm or more and 200 μm or less.
図３は，突起部の先端が，平坦形状であり，さらに１又は複数の微小突起(4)を有する場合における，本発明の経皮投与装置の概略構成図である。突起部の先端が，平坦形状であり，さらに１又は複数の微小突起を有する場合，微小突起の先端が，直径２０μｍ以上の丸みを有するものが好ましい。この場合において，「平坦」及び「丸み」は先に定義したものを適宜採用できる。また，微小突起として，たとえば，先に説明した突起部の１／１００〜１／２の大きさのものがあげられ，１／１０〜１／３の大きさのものでもよい。 FIG. 3 is a schematic configuration diagram of the transdermal administration device of the present invention in the case where the tip of the protrusion has a flat shape and further has one or a plurality of minute protrusions (4). When the tip of the protrusion has a flat shape and further has one or more fine protrusions, it is preferable that the tip of the fine protrusion has a roundness of 20 μm or more in diameter. In this case, “flat” and “roundness” can be appropriately defined as described above. Moreover, as a microprotrusion, the thing of the magnitude | size of 1 / 100-1 / 2 of the protrusion part demonstrated previously is mention | raise | lifted, for example, the thing of the magnitude | size of 1/10-1/3 may be mentioned.
図４は，複数の突起部を有する本発明の経皮投与装置の概略構成図である。図４に示されるように，前記複数の突起部は，好ましくは，基板の格子点の位置に設けられるものがあげられる。図５は，基板が網状のものである本発明の経皮投与装置の概略構成図である。基板として，図５に示されるように，網のように網目のあるものを用いてもよい。この場合，たとえば，突起部は網目の位置に設けられればよい。 FIG. 4 is a schematic configuration diagram of the transdermal administration device of the present invention having a plurality of protrusions. As shown in FIG. 4, the plurality of protrusions are preferably provided at the positions of the lattice points of the substrate. FIG. 5 is a schematic configuration diagram of the transdermal administration device of the present invention in which the substrate has a net-like shape. As the substrate, as shown in FIG. 5, a substrate having a mesh such as a mesh may be used. In this case, for example, the protrusion may be provided at the position of the mesh.
前記突起部は，通常使用において皮膚の角質層を貫通しないものが好ましい。ここで「通常使用」とは，本発明の経皮投与装置を皮膚において軽くたたく程度の加圧を意味する。具体的には，用途に応じて１ｇ重／ｃｍ２〜１００ｇ重／ｃｍ２程度（より具体的には，たとえば，１０ｇ重ｃｍ２）の加圧条件を意味する。 The protrusions preferably do not penetrate the stratum corneum of skin during normal use. Here, “normal use” means pressurization to the extent that the percutaneous administration device of the present invention is tapped on the skin. Specifically, depending on the application 1g heavy / cm 2 to 100 g weight / cm 2 of about (more specifically, for example, 10 g heavy cm 2) refers to the pressure conditions.
基板は，前記突起部を支持できるものであれば特に限定されず，公知の基板を用いることができる。基板としてテープのようなかとう性（フレキシビリティ）のあるものを用いてもよいし，プラスチックのような定型性を有するものを用いてもよい。基板と突起部とは同じ素材を用いたものを用いてもよい。基板の大きさや厚さは用途に応じて適宜調整すればよい。基板と突起部と一体成形されてもよいし，別々に成形されてもよい。基板の厚さは用途に応じて適宜調整すればよいが，たとえば０．１ｍｍ〜５ｍｍがあげられ，０．１ｍｍ〜１ｍｍでもよく，０．２ｍｍ〜０．８ｍｍでもよい。 The substrate is not particularly limited as long as it can support the protruding portion, and a known substrate can be used. A substrate having flexibility such as a tape may be used, or a substrate having a regularity such as plastic may be used. You may use what used the same raw material for a board | substrate and a projection part. What is necessary is just to adjust the magnitude | size and thickness of a board | substrate suitably according to a use. The substrate and the protrusion may be integrally formed, or may be separately formed. The thickness of the substrate may be adjusted as appropriate according to the application, but may be 0.1 mm to 5 mm, for example, 0.1 mm to 1 mm, or 0.2 mm to 0.8 mm.
この基板又は突起部の主成分として，ポリ乳酸などの生体分解性ポリマー；ブドウ糖，マルトース，フルクトース，プルランなどの糖類があげられるが，好ましくはマルトース又はプルランである。さらに，それらを主成分として，薬剤又はその医薬的に許容される塩，化粧料などの化合物や，医薬的に許容される担体などを含むものであってもよい。薬理学的に許容される担体として，賦形剤，希釈剤，滑沢剤，結合剤，安定剤，及び矯臭剤から適宜選択されるものがあげられる。 Examples of the main component of the substrate or protrusion include biodegradable polymers such as polylactic acid; sugars such as glucose, maltose, fructose, and pullulan, with maltose or pullulan being preferred. Furthermore, it may contain a compound such as a drug or a pharmaceutically acceptable salt thereof, a cosmetic, a pharmaceutically acceptable carrier, etc., with these as a main component. Examples of the pharmacologically acceptable carrier include those appropriately selected from excipients, diluents, lubricants, binders, stabilizers, and flavoring agents.
先に説明したとおり，本発明の経皮投与装置は，糖類などの他に所定の化合物を含有してもよい。所定の化合物は，本発明の経皮投与装置により投与されることとなる。ただし，従来の注射などのように，表皮を突き破り所定の化合物が投与されるのではなく，好ましくは表皮が引き伸ばされた状態で，その表皮に化合物が接触するか，化合物を含有する突起部が溶解することにより皮膚に化合物が皮膚に付着し，表皮内へ浸透することにより所定の化合物が投与される。 As described above, the transdermal administration device of the present invention may contain a predetermined compound in addition to saccharides. The predetermined compound will be administered by the transdermal administration device of the present invention. However, the prescribed compound is not administered by piercing the epidermis as in conventional injections, etc. Preferably, the epidermis is stretched and the epidermis is in contact with the compound, or there is a protrusion containing the compound. By dissolving, the compound adheres to the skin, and the prescribed compound is administered by penetrating into the epidermis.
所定の化合物として，ペプチド類，核酸，薬剤又はその医薬的に許容される塩，化粧料，又は色素があげられ，ペプチド類として，ポリペプチドなどがあげられ，核酸として，ＤＮＡ，ＲＮＡがあげられ，薬剤として，公知の薬剤を適宜用いることができ，鎮痛剤，解熱剤，消毒薬，糖尿病の治療剤，サプリメントなどがあげられ，具体的には，シンバスタチン，アトルバスタチン，プラバスタチンなどの高脂血症薬；オメプラソール，ランソプラゾールなどの抗潰瘍剤；アムロジピン，ロサルタンなどの抗圧剤；エボエテンアルファ，エポエチンアルファなどの腎性貧血治療・予防剤；ロラタジン，セチリジン，フェキソフェナジンなどの抗ヒスタミン剤；セレコキシブ，ロフェコキシブなどのCox2阻害剤；オランバピンなどの精神***病薬；メトフォルミンなどの糖尿病薬；エストロゲン製剤などの更年期障害治療・予防剤；アモキシシリンなどの抗生物質；クロピドグレルなどの抗血小板薬；アレンドロン酸ナトリウムなどの骨粗鬆症薬；ガバペンチンなどの抗てんかん薬；ゾルビテムなどの睡眠薬；その他，７−クロロ−１，３−ジヒドロー１−メチル−５−フェニル−２Ｈ−１，４−ベンゾジアゼピン−２−オン（ジアゼパム），クロナゼパム，エスタゾラム，オキサゾラム，ハロキサゾラム，プロカイン，リドカイン（リンドカイン），シブカイン，プロプラノロール，ピンドロール，カルテオロール，レボトバ，レボフロキサシン，デキストロフメトルファン，オキサプロジン，チアミンジスルフィド，トリクロルメチアジド，ブロムペリドール，リトドリン，メリルエルゴメトリン，パクリタキセル，ドセタキセル，リンドカイン，インドメタシン，エストロディオール，ぺパリン又はインシュリンなどの薬剤や，ビタミンＣ，ビタミンＢ，ビタミンＥなどのビタミン類があげられる。これらの中では，リンドカイン，インドメタシン，エストロディオール，ぺパリン又はインシュリンなどを好適に用いることができる。後述の実施例で示されたとおり，本発明によれば，突起部による皮膚へのダメージが迅速に回復するので，本発明の経皮投与装置は，薬剤や化粧料（特に美容液）の投与装置として有効に利用できる。なお，所定の化合物として色素を用いれば，無痛の刺青や，比較的短期間で消える刺青，簡易マーキング装置などとしても利用できる。 Examples of the predetermined compound include peptides, nucleic acids, drugs or pharmaceutically acceptable salts, cosmetics, or pigments. Examples of peptides include polypeptides. Examples of nucleic acids include DNA and RNA. Well-known drugs can be used appropriately as drugs, including analgesics, antipyretics, antiseptics, diabetes treatments, supplements, etc. Specifically, hyperlipidemic drugs such as simvastatin, atorvastatin, pravastatin, etc. Anti-ulcer agents such as omeprazole and lansoprazole; anti-pressure agents such as amlodipine and losartan; therapeutic and preventive agents for renal anemia such as evoeten alfa and epoetin alfa; antihistamines such as loratadine, cetirizine and fexofenadine; celecoxib and rofecoxib Cox2 inhibitors such as; Schizophrenic drugs such as olambapine Antidiabetic agents such as estrogen preparations; antibiotics such as amoxicillin; antiplatelet drugs such as clopidogrel; osteoporosis drugs such as alendronate sodium; antiepileptic drugs such as gabapentin; Sleeping drugs; other, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (diazepam), clonazepam, estazolam, oxazolam, haloxazolam, procaine, lidocaine (lindocaine) , Sibucaine, propranolol, pindolol, carteolol, levotova, levofloxacin, dextrometholphan, oxaprozin, thiamine disulfide, trichlormethiazide, bromperidol, ritodrine, meryl Rugometorin, paclitaxel, docetaxel, lidocaine, indomethacin, S. Toro Dior, drugs and the like Bae heparin or insulin, vitamin C, vitamin B, vitamins such as vitamin E and the like. Among these, Lindocaine, indomethacin, estrodiol, pepperlin or insulin can be preferably used. According to the present invention, as shown in the examples described later, since the damage to the skin due to the protrusions is quickly recovered, the transdermal administration device of the present invention is capable of administering drugs and cosmetics (particularly cosmetic liquids). It can be effectively used as a device. If a dye is used as the predetermined compound, it can be used as a painless tattoo, a tattoo that disappears in a relatively short period of time, a simple marking device, or the like.
本発明の経皮投与装置の好ましい別の態様は，突起部には，所定の化合物が塗布されることで，前記突起部の表面にはその化合物による層が形成され，その突起部をヒト又はヒト以外の動物（特に哺乳動物）に押し当てることで，前記動物内に前記糖類と化合物とが投与される経皮投与装置である。化合物を塗布する場合，突起部の全体に化合物（化合物を含む溶液であってもよい）を塗布してもよいし，先端部に塗布してもよい。また，塗布には，浸漬塗布，刷毛などによる塗布，スプレー塗布，化合物を付着させる塗布方法など公知の塗布方法を適宜利用することができる。また，突起部には，化合物が塗布され，前記基板及び突起部は，糖類と前記化合物とを含有し，前記突起部の少なくとも先端部は，動物に挿入され，溶解することにより前記動物内に前記糖類と化合物とが投与される経皮投与装置であってもよい。このように突起部に塗布される化合物は，６０℃以上の熱により効能が変化するものがあげられる。突起部に塗布される化合物と，経皮投与装置の原料とされる化合物とは同一でも異なってもよいが，好ましくは同一の化合物を用いるものである。別々の化合物を用いて，別々の薬効を期待してもよく，たとえば，塗布する化合物を鎮痛剤を含むものとし，経皮投与装置の原料とされる化合物に治療剤を含むものとしてもよい。また，５０℃以上の温度で薬効が１０％以上減少する薬剤と，塗布し，５０℃でも薬効が１０％以上減少しない薬剤を経皮投与装置の原料としてもよい。また，たとえば，突起部にＤＮＡなどの核酸（又はＤＮＡなどの核酸を含有する液）を塗布することによりＤＮＡを搭載すること望ましい。これによりＤＮＡなどの核酸を用いた予防剤，及び治療剤として本発明の経皮投与装置（経皮投与装剤）は利用されうることとなる。 In another preferred embodiment of the transdermal administration device of the present invention, a predetermined compound is applied to the protrusion, whereby a layer of the compound is formed on the surface of the protrusion, and the protrusion is human or It is a transdermal administration device in which the saccharide and the compound are administered into the animal by being pressed against an animal other than a human (particularly a mammal). When applying the compound, the compound (may be a solution containing the compound) may be applied to the entire protrusion, or may be applied to the tip. For the application, a known application method such as dip application, application with a brush, spray application, application method for attaching a compound or the like can be appropriately used. Further, the protrusion is coated with a compound, the substrate and the protrusion contain saccharides and the compound, and at least the tip of the protrusion is inserted into the animal and dissolved therein to dissolve in the animal. It may be a transdermal administration device in which the saccharide and the compound are administered. Examples of the compound applied to the protrusions in this way are those whose efficacy changes with heat of 60 ° C. or higher. The compound applied to the protrusion and the compound used as the raw material of the transdermal administration device may be the same or different, but preferably the same compound is used. Different compounds may be expected to have different medicinal effects. For example, the compound to be applied may contain an analgesic agent, and the compound used as the raw material of the transdermal administration device may contain a therapeutic agent. Moreover, it is good also as a raw material of a transdermal administration device to apply | coat with the chemical | medical agent whose medicinal effect reduces 10% or more at the temperature of 50 degreeC or more, and to apply | coat and does not reduce a medicinal effect 10% or more even at 50 degreeC. For example, it is desirable to mount DNA by applying a nucleic acid such as DNA (or a solution containing a nucleic acid such as DNA) to the protrusion. As a result, the transdermal administration device (transdermal administration device) of the present invention can be used as a preventive agent and a therapeutic agent using nucleic acids such as DNA.
なお，突起部に化合物を塗布する場合，医学的に許容される溶媒に化合物を溶解させたものを塗布すればよい。このような溶媒として，ヘキサン，ヘプタンのような脂肪族炭化水素類；トルエン，キシレンのような芳香族炭化水素類；クロロホルムのようなハロゲン化炭化水素類；酢酸メチル，酢酸エチル，酢酸プロピル，酢酸ブチル，炭酸ジエチルのようなエステル類；ジエチルエーテル，ジイソプロピルエーテル，テトラヒドロフラン，ジメトキシエタン，ジエチレングリコールジメチルエーテルのようなエーテル類；メタノ−ル，エタノ−ル，ｎ−プロパノ−ル，イソプロパノ−ル，ｎ−ブタノ−ル，イソブタノ−ル，ｔ−ブタノ−ル，イソアミルアルコ−ル，ジエチレングリコール，グリセリン，オクタノール，シクロヘキサノール，メチルセロソルブのようなアルコ−ル類；アセトニトリル，イソブチロニトリルのようなニトリル類；ホルムアミド，ジメチルホルムアミド，ジメチルアセトアミドのようなアミド類；のうち１種又は２種以上を混合して用いることができる。これらのうち，有機溶媒として，好ましくは，メタノール，エタノール，ｎ−プロパノール，イソプロパノール，ｎ−ブタノール，ペンタノール，酢酸エチル，又はアセトンであり；さらに好ましくはエタノール，ｎ−プロパノール，イソプロパノール，ｎ−ブタノール，ペンタノール，酢酸エチル，又はアセトンである。なお，有効成分として用いられる化合物の濃度として，０．０１重量％〜９０重量％があげられ，好ましくは１重量％〜８０重量％，さらに好ましくは１０重量％〜７０重量％である。 In addition, what is necessary is just to apply | coat what melt | dissolved the compound in the medically acceptable solvent when apply | coating a compound to a projection part. Examples of such solvents include aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as chloroform; methyl acetate, ethyl acetate, propyl acetate, and acetic acid. Esters such as butyl and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol Alcohol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; nitriles such as acetonitrile, isobutyronitrile; form Bromide, dimethyl formamide, amides such as dimethylacetamide; can be used alone or in combination of two or more of. Of these, the organic solvent is preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, pentanol, ethyl acetate, or acetone; more preferably ethanol, n-propanol, isopropanol, n-butanol. , Pentanol, ethyl acetate, or acetone. The concentration of the compound used as the active ingredient is 0.01% to 90% by weight, preferably 1% to 80% by weight, and more preferably 10% to 70% by weight.
３．経皮投与装置の製造方法
本発明の経皮投与装置の製造方法は，基板上に1又は複数の突起部とを具備し，前記突起部は高さが50μｍ〜3ｍｍであり，先端は丸みをもつ金型を用いて射出成型によって経皮投与装置を得る非侵襲経皮投与装置の製造方法である。詳細な工程や条件などは，たとえば，特開2003-238347号公報などに記載されるものを適宜用いればよい。金型（鋳型）は，公知の方法を用いて製造できる。この製造方法を用いれば，経皮投与装置を製造できる。また，金型のうち基板部に相当する部位を網状にするなどすれば，網状の基板を有する経皮投与装置を製造できる。
3. Method for manufacturing transdermal administration device The method for manufacturing the transdermal administration device of the present invention comprises one or a plurality of protrusions on a substrate, the protrusions having a height of 50 μm to 3 mm, and the tip is rounded. A method for manufacturing a non-invasive transdermal administration device, wherein a transdermal administration device is obtained by injection molding using a mold having a mold. As detailed processes and conditions, for example, those described in JP 2003-238347 A may be used as appropriate. The mold (mold) can be manufactured using a known method. If this manufacturing method is used, a transdermal administration device can be manufactured. In addition, if the part of the mold corresponding to the substrate portion is made into a net shape, a transdermal administration device having a net-like substrate can be manufactured.
糖類を含む組成物は，経皮投与装置の原料となるものであり，糖類のみからなる組成物であってもよいし，糖類のほかに所定の化合物を有するものであってもよい。いずれにせよ，ある程度の流動性が必要なので，糖類を含む組成物は，溶液とされていることが好ましい。ただし，粉末状態の原料を混合したものを用いてもよい。溶液とする場合は，具体的には，糖類を加熱するか，水又は有機溶媒に糖類を加えるか，水又は有機溶媒に糖類を加えた後加熱すればよい。この際に加熱する温度として，10℃〜150℃があげられ，好ましくは40℃〜120℃であり，より好ましくは70℃〜90℃であり，さらに好ましくは75℃〜85℃である。水や有機溶媒を用いない場合は，加熱温度として50℃〜130℃があげられ,100℃〜120℃が好ましい。このような温度であれば，容易に糖分が溶解し，化合物も溶解することとなる。化合物が溶解しない場合は，公知の溶媒を加えてもよい。溶解時間は，適宜調整すればよく，1分〜1日があげられ，10分〜5時間でもよく，30分〜2時間でもよい。なお，水分や有機溶媒を用いると，固化する際にこれらが蒸発し，経皮投与装置の形状が変化する場合があるので，好ましくは糖類のみ又は糖類と所定の化合物のみを組成物とするものがあげられる。すなわち，本明細書において，組成物とは，所定の糖類のみを含むものをも含むものとする。 The composition containing saccharides serves as a raw material for the transdermal administration device, and may be a composition composed solely of saccharides, or may have a predetermined compound in addition to saccharides. In any case, since a certain degree of fluidity is required, it is preferable that the composition containing saccharides is a solution. However, you may use what mixed the raw material of a powder state. In the case of a solution, specifically, the saccharide is heated, the saccharide is added to water or an organic solvent, or the saccharide is added to water or an organic solvent and then heated. In this case, the heating temperature is 10 ° C to 150 ° C, preferably 40 ° C to 120 ° C, more preferably 70 ° C to 90 ° C, and further preferably 75 ° C to 85 ° C. When water or an organic solvent is not used, the heating temperature is 50 ° C to 130 ° C, preferably 100 ° C to 120 ° C. If it is such temperature, sugar will melt | dissolve easily and a compound will also dissolve | melt. If the compound does not dissolve, a known solvent may be added. What is necessary is just to adjust dissolution time suitably, 1 minute-1 day is raised, 10 minutes-5 hours may be sufficient, and 30 minutes-2 hours may be sufficient. In addition, when water or an organic solvent is used, these may evaporate when solidified, and the shape of the transdermal administration device may change. Therefore, the composition is preferably composed of only saccharides or only saccharides and a predetermined compound. Can be given. That is, in the present specification, the composition includes those containing only a predetermined saccharide.
化合物を混合する場合は，溶媒の温度を一定に保った状態で，攪拌しながら，又は攪拌せずに化合物を添加すればよい。このような工程は，常圧環境下において反応を進めればよく。たとえば，目視により原料が溶解した時点で，溶解工程を終了すればよい。また，所定の化合物が液体の場合は単に溶解させた糖類又は糖類を含む組成物に攪拌下所定の化合物を添加すればよい。化合物と糖類の割合は，投与量や経皮投与装置の強度などを考慮して適宜調整すればよく，化合物と糖類との重量比として，1:100〜1:1があげられ，1:10〜1:5であってもよい。この溶解したものを金型に入れてもよいし，いったん固化させたものを金型に入れてもよい。後者の場合，たとえば，常温，常圧とすることで，迅速に固化する。また，冷却することにより固化速度をあげてもよい。こかした塊を所定の大きさに分割し，分割したものを金型に入れて，金型を過熱し（又は金型を含む系を加熱し）溶解させればよい。より具体的には，金型又は系の温度として50℃〜130℃があげられ,好ましくは80℃〜120℃であり，90℃〜110℃とすればよく，加熱時間として1秒〜1時間があげられ，好ましくは5秒〜1分があげられる。 When mixing a compound, the compound may be added with or without stirring while keeping the temperature of the solvent constant. In such a process, the reaction may be carried out under a normal pressure environment. For example, the melting process may be terminated when the raw material is melted visually. When the predetermined compound is a liquid, the predetermined compound may be added to the composition containing saccharides or saccharides simply dissolved under stirring. The ratio of the compound and saccharide may be adjusted as appropriate in consideration of the dose and the strength of the transdermal administration device. The weight ratio of the compound and saccharide is 1: 100 to 1: 1, and 1:10 It may be ~ 1: 5. This dissolved material may be put in a mold, or once solidified, it may be put in a mold. In the latter case, for example, it is solidified quickly at normal temperature and normal pressure. Further, the solidification rate may be increased by cooling. The crushed lump is divided into a predetermined size, the divided piece is put in a mold, and the mold is heated (or the system including the mold is heated) to be melted. More specifically, the temperature of the mold or system is 50 ° C to 130 ° C, preferably 80 ° C to 120 ° C, 90 ° C to 110 ° C, and the heating time is 1 second to 1 hour. Preferably, 5 seconds to 1 minute is used.
液状の組成物を金型に注入する場合は，液状の組成物を，金型に注ぎ込めばよい。また，組成物を固化させるためには，常温，常圧下で放置してもよいし，冷却を行ってもよい。冷却を行う場合は，金型の外側から冷却してもよいし，金型を含む系全体を冷却してもよい。固化工程における圧力は，常圧で行えばよいが，溶媒を蒸発させることにより結晶化を行う場合は，減圧下（たとえば，0.1気圧〜0.9気圧にて）行うことが好ましい。結晶化時間として，10秒〜24時間があげられ，好ましくは1分〜1時間であり，より好ましくは1分〜30分である。 When pouring a liquid composition into a mold, the liquid composition may be poured into the mold. Further, in order to solidify the composition, it may be left at normal temperature and normal pressure, or may be cooled. When cooling is performed, the cooling may be performed from the outside of the mold, or the entire system including the mold may be cooled. The pressure in the solidification step may be normal pressure, but when crystallization is performed by evaporating the solvent, it is preferably performed under reduced pressure (for example, at 0.1 atm to 0.9 atm). The crystallization time is 10 seconds to 24 hours, preferably 1 minute to 1 hour, more preferably 1 minute to 30 minutes.
このようにして得られた投与装置は，好ましくは密閉容易に乾燥剤と共に封入する。水分があると，突起部が溶けるためである。なお，突起部の先端を丸くするためには，そのような形状を有する金型又は鋳型を用いてもよいが，比較的鋭利な先端を有するものを製造した後，所定時間（たとえば１分〜２０分），通常の湿度環境下にさらした後に，乾燥剤入りの密閉容器に封入すればよい。 The administration device thus obtained is preferably enclosed with a desiccant for easy sealing. This is because the protrusion melts when there is moisture. In order to round the tip of the protrusion, a mold or a mold having such a shape may be used, but after manufacturing a relatively sharp tip, a predetermined time (for example, 1 minute to 20 minutes), after exposure to a normal humidity environment, it may be sealed in a sealed container containing a desiccant.
４．経皮投与剤
本発明の経皮投与装置は，基板上に設けられた 1又は複数の突起部と具備し，前記基板及び突起部は，糖類と化合物とを含有し，一体として成形され，前記突起部の高さは50μｍ〜3ｍｍであり，前記突起部の先端部そのものは，動物に挿入されず，前記動物内に前記糖類と化合物とが投与される経皮投与剤として利用されうる。すなわち，本発明によれば，注射，塗布薬など同様の新たな経皮投与剤が提供されることとなる。この態様における化合物として，先に説明したもののうち，薬剤を効果的に用いることができる。
4). Transdermal administration agent The transdermal administration device of the present invention comprises one or a plurality of projections provided on a substrate, and the substrate and the projection contain a saccharide and a compound, are molded as a unit, The height of the protrusion is 50 μm to 3 mm, and the tip of the protrusion itself is not inserted into an animal and can be used as a transdermal administration agent in which the saccharide and the compound are administered into the animal. That is, according to the present invention, the same new transdermal administration agent such as injection and coating agent is provided. Among the compounds described above, a drug can be effectively used as the compound in this embodiment.
経皮投与剤の製造方法は，上記した経皮投与装置の製造方法に従って製造できる。本発明の経皮投与剤による投与方法は，患部又は任意の皮膚に本発明の経皮投与剤をあてて軽く押すなどして，突起部を皮膚表面に加圧すればよい。 The manufacturing method of a transdermal administration agent can be manufactured according to the manufacturing method of a transdermal administration device mentioned above. In the administration method using the transdermal administration agent of the present invention, the protrusion may be pressed against the skin surface by applying the transdermal administration agent of the present invention to the affected area or arbitrary skin and pressing it lightly.
経皮投与装置を新規剤型として用いる場合，経皮投与装置に含まれる有効成分である所定の化合部の投与量は，対象疾患，投与対象などにより差異はあるが，例えば，一日につき化合物を約０．０１〜３０ｍｇ程度，好ましくは約０．１〜２０ｍｇ程度，より好ましくは約０．１〜１０ｍｇ程度を投与すればよい。糖類が溶解する温度で変性などを起こさない化合物を投与するためには，糖類と共に溶解させて経皮投与装置として用いればよい。また，糖類が溶解する温度で変性を起こすなど物性が大きく変化する化合物については，たとえば，皮膚に塗布した状態で，本発明の経皮投与装置を押し当てることにより投与してもよい。ヒト以外の動物の場合も，体重６０ｋｇ当たりに換算した，上記の量を投与することができる。投与回数は有効成分によって適宜調整すればよく１日あたり１回〜数回又は隔日など適当な周期とすればよい。 When a transdermal administration device is used as a new dosage form, the dose of a predetermined compound part, which is an active ingredient contained in the transdermal administration device, varies depending on the target disease, administration target, etc. About 0.01-30 mg, preferably about 0.1-20 mg, more preferably about 0.1-10 mg. In order to administer a compound that does not cause denaturation or the like at a temperature at which the saccharide dissolves, it may be dissolved with the saccharide and used as a transdermal administration device. In addition, a compound whose physical properties change greatly, such as degeneration at a temperature at which sugars dissolve, may be administered by pressing the transdermal administration device of the present invention while it is applied to the skin, for example. In the case of animals other than humans, the above-mentioned amount converted per 60 kg body weight can be administered. The frequency of administration may be appropriately adjusted depending on the active ingredient, and may be set to an appropriate cycle such as once to several times per day or every other day.
本発明の経皮投与装置は，顔，手，足又は頭皮（特に顔）に化粧料を投与するために好ましく用いることができる。いわゆる美容液などを顔に塗布する場合であっても顔の皮膚を傷つけることなく効果的に化粧料を浸透させることができる。糖類が溶解する温度で変性などを起こさない化合物を化粧料として投与するためには，糖類と共に溶解させて経皮投与装置として用いればよい。また，糖類が溶解する温度で変性を起こすなど物性が大きく変化する化合物を化粧料として投与するためには，たとえば，皮膚に塗布した状態で，本発明の経皮投与装置を押し当てることにより投与してもよい。 The transdermal administration device of the present invention can be preferably used for administering cosmetics to the face, hands, feet or scalp (particularly the face). Even when so-called cosmetic liquid is applied to the face, the cosmetic can be effectively penetrated without damaging the skin of the face. In order to administer a compound that does not undergo denaturation or the like at a temperature at which saccharides dissolve, it may be used as a transdermal administration device after being dissolved with saccharides. In addition, in order to administer a compound whose physical properties greatly change such as degeneration at a temperature at which saccharides dissolve, it can be administered by, for example, pressing the transdermal administration device of the present invention while it is applied to the skin. May be.
上記したとおり，所定の化合物を糖類などを共に溶解させ経皮投与装置を製造してもよいが，所定の化合物をヒト又はヒト以外の哺乳動物の表皮に化合物を塗布した後に，上記した経皮投与装置をその塗布した部位に当て，経皮投与装置を加圧することにより，経皮投与装置の突起部が表皮を伸ばすことによって，前記化合物を経皮投与するものは本発明の好ましい利用態様である。この利用態様では，特に美容液などの化粧料を効果的に投与することができる。 As described above, a transdermal administration device may be produced by dissolving a predetermined compound together with saccharides, etc., but after applying the compound to the epidermis of a human or a non-human mammal, the above-mentioned transdermal A preferred embodiment of the present invention is to administer the compound transdermally by applying the administration device to the applied site, pressurizing the transdermal administration device, and the protrusion of the transdermal administration device stretches the epidermis. is there. In this utilization mode, it is possible to effectively administer cosmetics such as a serum.
上記のとおり本明細書では，薬剤をヒト又はヒト以外の動物（特に哺乳動物）に投与するための上記した経皮投与装置の使用をも提供できる。さらに，上記した経皮投与装置を用いたヒト又はヒト以外の動物（特に哺乳動物）の特定疾患の予防又は治療方法をも提供できる。 As described above, the present specification can also provide use of the above-described transdermal administration device for administering a drug to a human or non-human animal (particularly a mammal). Furthermore, it is possible to provide a method for preventing or treating a specific disease in a human or non-human animal (particularly a mammal) using the transdermal administration device described above.
−経皮投与装置の製造−
(1) 経皮投与装置（経皮投与装剤）の作製
図４及び図５に示される経皮投与装置を製造した。なお，図４に示すような板状の基板を用いるものは，３ｍｍの格子点ごとに突起部を設けた。図５に示すような網状の基板のものは，網の太さを１ｍｍとし，網の目が２ｍｍ×２ｍｍとなるように設定した。この結果，突起部の密度は図４のものと同様となった。図６は，経皮投与装置の突起部の設計例を示す図である。突起部状に微小突起を３つ設けた。突起部及び基板の原料としてマルトースを用いた。粉末マルトースに粉末リドカイン（リドカインマルトースに対する重量比１０％）を均一に混合させた。その後，１１０℃で１時間過熱溶解させた。その後，溶解液を，冷却して１０重量％リドカイン含マルトース塊を製作した。適当に分割したマルトース塊を経皮投与装置製造用の金型に設置し，その金型を１００℃に１０秒間過熱昇温することにより，マルトース塊を溶解した。その後，常温，常圧にて５秒放置すると，冷却凝固された。その後，金型を分離し，脆い突起部を最初に金型から取り外した。このようにして，マルトースを主成分とする経皮投与装置を製作した。なお，本実施例では，突起部の大きさや微小突起の大きさを適宜変えた鋳型を作成し，突起部や微小突起の大きさが様々な経皮投与装置を製造した。得られた突起部の高さはたとえば，５００μｍであり，微小突起の高さは５０μｍのものや，高さが５００μｍで微小突起の高さが１００μｍのもの，図６に示されるように突起部の高さが８００μｍで，微小突起の高さが３００μｍのものなどを得た。
-Manufacture of transdermal administration device-
(1) Production of transdermal administration device (transdermal administration device) The transdermal administration device shown in FIGS. 4 and 5 was produced. In addition, what used the plate-shaped board | substrate as shown in FIG. 4 provided the projection part for every 3 mm lattice point. In the case of the net-like substrate as shown in FIG. 5, the thickness of the net was set to 1 mm, and the net size was set to 2 mm × 2 mm. As a result, the density of the protrusions was the same as that in FIG. FIG. 6 is a diagram showing a design example of the protrusion of the transdermal administration device. Three fine protrusions were provided in the shape of the protrusion. Maltose was used as a raw material for the protrusions and the substrate. Powdered lidocaine (10% by weight with respect to lidocaine maltose) was uniformly mixed with the powdered maltose. Then, it was dissolved by heating at 110 ° C. for 1 hour. Thereafter, the solution was cooled to produce a 10% by weight lidocaine-containing maltose mass. An appropriately divided maltose mass was placed in a mold for manufacturing a transdermal administration device, and the mold was heated to 100 ° C. for 10 seconds to dissolve the maltose mass. After that, it was cooled and solidified when left at room temperature and pressure for 5 seconds. Thereafter, the mold was separated, and the brittle protrusion was first removed from the mold. In this way, a transdermal administration device mainly composed of maltose was produced. In this example, a template was prepared by appropriately changing the size of the protrusions and the size of the microprojections, and transdermal administration devices with various sizes of the protrusions and microprojections were manufactured. The height of the obtained projection is, for example, 500 μm, the height of the microprojection is 50 μm, the height is 500 μm, and the height of the microprojection is 100 μm, as shown in FIG. And the like, and the height of the fine protrusions was 300 μm.
図７は，本実施例１で得られたひとつの突起部につき微小突起を３つ有する経皮投与装置の図面に替わる写真である。図７に示されるように，ひとつの突起部につき微小突起を３つ有する経皮投与装置を製造することができた。図８は，図７における突起部の図面に替わる写真である。図8(a)は，突起部を示す図面に変わる写真であり，図8(b)はひとつの突起部の概要を示す図である。図８から，各突起部の底面は直径が約５００μｍであり，高さが約５００μｍであったことがわかる。さらに突起部の平坦形状を有する面は直径が約５００μｍであった。図９は，図８における微小突起を示すための図面に替わる写真である。図9(a)は，微小突起を示す図面に変わる写真であり，図9(b)はひとつの微小突起の概要を示す図である。図９に示されるように，この微小突起は，その高さが１００μｍであり，底面の直径が５０μｍであり，先端部の丸さが直径３０μｍの丸みを帯びていた。 FIG. 7 is a photograph replacing a drawing of the transdermal administration device having three fine protrusions per one protrusion obtained in Example 1. As shown in FIG. 7, a transdermal administration device having three microprotrusions per protrusion could be manufactured. FIG. 8 is a photograph replacing the drawing of the protrusion in FIG. FIG. 8 (a) is a photograph in place of a drawing showing a protruding portion, and FIG. 8 (b) is a view showing an outline of one protruding portion. FIG. 8 shows that the bottom surface of each protrusion has a diameter of about 500 μm and a height of about 500 μm. Further, the surface of the protrusion having a flat shape had a diameter of about 500 μm. FIG. 9 is a photograph replacing a drawing for showing the minute protrusions in FIG. FIG. 9 (a) is a photograph in place of a drawing showing a minute protrusion, and FIG. 9 (b) is a view showing an outline of one minute protrusion. As shown in FIG. 9, this microprotrusion had a height of 100 μm, a bottom surface diameter of 50 μm, and a round tip with a diameter of 30 μm.
次に，本発明の経皮投与装置の皮膚へのダメージを検証する実験を行った。図１０は，経皮投与装置をラットの皮膚に押し当て，ラットの皮膚の製を示す図面に代わる写真である。図１０(a)は，突起部を押し当て30秒後の写真であり，図１０(b)は突起部を押し当て1分後の写真である。図１０(a)に示されるとおり，皮膚に経皮投与装置を押し当てた際に，皮膚に色素（Tartrazine）が付着したことがわかる。また，図１０(b)に示されるとおり，突起部を押し当てた後1分後には，皮膚へのダメージが完全に回復されることがわかる。また，図10(b)に示されるとおり，機能剤（色素）が皮膚内に残留したことがわかる。 Next, an experiment was conducted to verify the damage to the skin of the transdermal administration device of the present invention. FIG. 10 is a photograph replacing a drawing which shows the production of the rat skin by pressing the transdermal administration device against the skin of the rat. FIG. 10 (a) is a photograph 30 seconds after the protrusion is pressed, and FIG. 10 (b) is a photograph 1 minute after the protrusion is pressed. As shown in FIG. 10 (a), it can be seen that when a transdermal administration device is pressed against the skin, a pigment (Tartrazine) has adhered to the skin. Further, as shown in FIG. 10 (b), it can be seen that the damage to the skin is completely recovered one minute after the protrusion is pressed. In addition, as shown in FIG. 10 (b), it can be seen that the functional agent (pigment) remained in the skin.
次に，本発明の経皮投与装置による薬剤の投与効率を検証する実験を行った。具体的には，化合物として10重量%のリドカインを含有する経皮投与装置を製造し，ラットの血中濃度を測定した。その結果を以下の表1に示す。なお，表中BLQは，測定基準値以下を示し，各濃度はng/mLを示す。 Next, an experiment was conducted to verify the drug administration efficiency by the transdermal administration device of the present invention. Specifically, a transdermal administration device containing 10% by weight of lidocaine as a compound was produced, and the blood concentration in rats was measured. The results are shown in Table 1 below. In the table, BLQ is below the measurement standard value, and each concentration is ng / mL.
表1から，ラットの血中濃度にリドカインが含まれ，本発明の経皮投与装置により効果的にリドカインを投与できることがわかる。 From Table 1, it can be seen that lidocaine is contained in the blood concentration of rats, and lidocaine can be effectively administered by the transdermal administration device of the present invention.
次に，本発明の経皮投与装置による薬剤が，効果的に浸透することを検証する実験を行った。具体的には，化合物として10重量%のリドカインを含有する突起部を1つ有する経皮投与装置を製造し，その突起部を突き刺した部分を中心とした10mm四方で深さが2mmのラットの皮膚を切り出し，高速液体クロマトグラフィー（HPLC）にて，リドカインの濃度を測定した。その結果を以下の表2に示す。なお，表中BLQは，測定基準値以下を示し，各濃度はngを示す。 Next, an experiment was conducted to verify that the drug by the transdermal administration device of the present invention penetrates effectively. Specifically, a transdermal administration device having one protrusion containing 10% by weight of lidocaine as a compound was produced, and a rat having a depth of 10 mm and a depth of 2 mm centered on the portion where the protrusion was pierced was used. The skin was cut out and the concentration of lidocaine was measured by high performance liquid chromatography (HPLC). The results are shown in Table 2 below. In the table, BLQ indicates the measurement standard value or less, and each concentration indicates ng.
表2から，本発明の経皮投与装置による薬剤は，投与後40分後には，突起部を押し当てた付近に多く存在したが，時間と共にラットの体内に浸透し，1時間20分以降は突起部を押し当てた付近の濃度が時間とともの減少したことがわかる。よって，上記の結果から，本発明の本発明の経皮投与装置によれば，効果的に薬剤成分を生体内に浸透させることができることがわかる。 From Table 2, the drug by the percutaneous administration device of the present invention was present in the vicinity of pressing the protrusion 40 minutes after administration, but penetrated into the rat body with time, and after 1 hour 20 minutes It can be seen that the concentration in the vicinity of the pressed portion decreased with time. Therefore, from the above results, it can be seen that according to the transdermal administration device of the present invention of the present invention, the drug component can effectively penetrate into the living body.
リドカイン１％あるいは２％含有マルトースの塊を製造した。１ｃｍ幅に100個の長さ500μｍの突起部付きの経皮投与装置を製造した。この経皮投与装置を用いて，ヒトの皮膚表面に突起部を押し当てたところ，投与箇所中心として，約２ｃｍ円形領域において，麻酔効果を確認できた。 Mass of maltose containing 1% or 2% lidocaine was produced. 100 transdermal administration devices with projections having a length of 500 μm each having a width of 1 cm were manufactured. When this protrusion was pressed against the human skin surface using this transdermal administration device, an anesthetic effect could be confirmed in a circular area of about 2 cm as the center of the administration site.
女性ホルモンの一種であるエストロディオールを２％含有させたマルトースを素材とする，１ｃｍ幅に25個の長さ500μｍの突起部付きの経皮投与装置を製造した。この経皮投与装置を用いて上腕皮膚に投与したところ，更年期障害を被る女性に無痛で投与調整ができることが確認できた。 A transdermal administration device with 25 pieces of 500 μm long protrusions 1 cm wide was produced using maltose containing 2% of estrodiol, a female hormone. Using this transdermal administration device, it was confirmed that administration to the upper arm skin was possible without pain for women suffering from menopause.
ペパリン２％含有マルトースを素材として，１ｃｍ幅に100個の長さ500μｍの突起部（針）付き経皮投与装置を製造した。この経皮投与装置を用いて，皮膚表面に投与したところ，投与箇所中心に１ｃｍ円形領域において，炎症の軽減が確認できた。 Using a maltose containing 2% of pepperine as a raw material, 100 transdermal administration devices with protrusions (needles) having a length of 500 μm in 1 cm width were manufactured. When this transdermal administration device was used to administer the skin surface, it was confirmed that inflammation was reduced in a 1 cm circular region at the center of the administration site.
経皮投与装置を常温，常湿，常圧雰囲気下においた際の，突起部の先端が丸くなる様子を検証した。図１１は，２０分間放置した場合の，突起部を示す図面に替わる写真である。図１１に示すとおり，当初突起部の先端が鋭いものを製造しても，一定時間放置すると，溶解して，先端が丸くなることがわかる。図１１の場合は，突起部が，直径５０μｍの丸みを有していた。突起部の先端部分の丸みと，時間との関係を以下の表３に示す。 When the transdermal administration device was placed in a normal temperature, normal humidity, and normal pressure atmosphere, we verified how the tip of the protrusion rounded. FIG. 11 is a photograph replacing a drawing showing a protrusion when left for 20 minutes. As shown in FIG. 11, it can be seen that even if a tip having a sharp tip is initially manufactured, if it is left for a certain period of time, it melts and the tip becomes round. In the case of FIG. 11, the protrusion has a roundness with a diameter of 50 μm. Table 3 below shows the relationship between the roundness of the tip of the protrusion and the time.
表３に示されるとおり，突起部の先端が鋭い鋳型を用いて経皮投与装置を製造し，一定時間放置した後に，乾燥容器に密封することで，所定の丸みを帯びた先端部の突起部を有する経皮投与装置を得ることができることがわかる。 As shown in Table 3, the transdermal administration device was manufactured using a mold having a sharp tip, and after standing for a certain period of time, it was sealed in a dry container, so that the protrusion with a predetermined rounded tip It can be seen that a transdermal administration device having the following can be obtained.
本発明の経皮投与装置は，新たな医療装置，化粧装置，サプリメント供給装置などとして利用されうる。また，本発明の金型は上記のような装置を製造するための製造業などにおいて好適に利用されうる。 The transdermal administration device of the present invention can be used as a new medical device, cosmetic device, supplement supply device and the like. Moreover, the metal mold | die of this invention can be utilized suitably in the manufacturing industry etc. for manufacturing the above apparatuses.
1 経皮投与装置
2 基板
3 突起部
4 微小突起
1 Transdermal administration device
2 Board
3 Protrusion
4 Micro protrusion
Claims (14)
前記基板上に設けられた１又は複数の突起部を具備し，
前記突起部は糖類又は生分解性ポリマーを主成分とし，
前記突起部の高さは１０μｍ〜３ｍｍであり，
前記突起部の先端が平坦か，丸みを帯びているか，又は平坦形状であり，さらに１又は複数の微小突起を有する，
経皮投与装置。 A substrate,
Comprising one or more protrusions provided on the substrate;
The protrusion is mainly composed of sugar or biodegradable polymer,
The height of the protrusion is 10 μm to 3 mm,
The tip of the projection is flat, rounded, or flat, and has one or more microprojections;
Transdermal administration device.
前記微小突起の先端が，直径２０μｍ以上の丸みを有する請求項１に記載される経皮投与装置。 The tip of the protrusion has a flat shape, and further has one or a plurality of minute protrusions,
The transdermal administration device according to claim 1, wherein the tip of the microprojection has a roundness with a diameter of 20 µm or more.
前記複数の突起部は，基板上の格子点の位置に設けられる請求項１に記載される経皮投与装置。 The protrusion is a plurality of protrusions,
The transdermal administration device according to claim 1, wherein the plurality of protrusions are provided at positions of lattice points on the substrate.
前記突起部は，複数の突起部であり，
前記複数の突起部は，基板の網目の位置に設けられる請求項１に記載される経皮投与装置。 The substrate is a mesh substrate;
The protrusion is a plurality of protrusions,
The transdermal administration device according to claim 1, wherein the plurality of protrusions are provided at mesh positions of the substrate.
前記突起部は，通常使用において皮膚の角質層を貫通しない請求項１に記載される経皮投与装置。 In addition to the saccharide or the biodegradable polymer, the protrusion includes a predetermined compound,
The transdermal administration device according to claim 1, wherein the protrusion does not penetrate the stratum corneum of the skin in normal use.
前記所定の化合物は，リドカイン，インドメタシン，エストロディオール，ぺパリン，インシュリン，ビタミン類，ホルモン類，又はヒアル酸，及びコラーゲンから選ばれる１種又は２種以上の化合物であり，
前記突起部は，通常使用において皮膚の角質層を貫通しない請求項１に記載される経皮投与装置。 In addition to the saccharide or the biodegradable polymer, the protrusion includes a predetermined compound,
The predetermined compound is one or more compounds selected from lidocaine, indomethacin, estrodiol, pepperine, insulin, vitamins, hormones, or hyaluric acid, and collagen,
The transdermal administration device according to claim 1, wherein the protrusion does not penetrate the stratum corneum of the skin in normal use.
前記突起部は，糖類により構成される代わりに，
糖類と所定の化合物とにより構成され，
前記所定の化合物は，リドカイン，インドメタシン，エストロディオール，ぺパリン，インシュリン，ビタミン類，ホルモン類，又はヒアル酸，及びコラーゲンから選ばれる１種又は２種以上の化合物であり，
前記突起部は，通常使用において皮膚の角質層を貫通しない請求項１に記載される経皮投与装置。 A surface of the protrusion has a predetermined compound layer,
Instead of being composed of saccharides,
Consists of a saccharide and a predetermined compound,
The predetermined compound is one or more compounds selected from lidocaine, indomethacin, estrodiol, pepperine, insulin, vitamins, hormones, or hyaluric acid, and collagen,
The transdermal administration device according to claim 1, wherein the protrusion does not penetrate the stratum corneum of the skin in normal use.
請求項１に記載される経皮投与装置をその塗布した部位に当て，
請求項１に記載される経皮投与装置を加圧する，
前記化合物の経皮投与方法。
After applying a given compound to the epidermis of a human or non-human mammal,
Applying the transdermal administration device according to claim 1 to the applied site;
Pressurizing the transdermal administration device according to claim 1;
A method for transdermal administration of said compound.
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