JP2012090767A - Soluble three-layer microneedle array patch for vaccine antigen epidermis delivery - Google Patents
Soluble three-layer microneedle array patch for vaccine antigen epidermis delivery Download PDFInfo
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Abstract
Description
本発明は、高い効率で抗体価を得るための溶解性3層マイクロニードル・アレイの構造に関する。 The present invention relates to a structure of a soluble three-layer microneedle array for obtaining an antibody titer with high efficiency.
マイクロニードルは、皮膚に刺しても痛みを感じないほどに微細化された針であり、皮膚の最も外側に位置して外界からの細菌やウィルスの進入から体内を防御している角質層を物理的に突破して、従来の技術では経皮的に投与を行っても吸収が望めない薬物、化粧品用化合物あるいは吸収率が極めて低い薬物、化粧品用化合物の吸収率を改善する製剤技術である。マイクロニードルの材質としては、従来の注射針と同じ金属の他、シリカ等も用いられている(特許文献1〜52)。 Microneedles are finely sized needles that do not feel pain when stabbed into the skin, and physically protect the stratum corneum that is located on the outermost side of the skin and protects the body from the entry of bacteria and viruses from the outside world. It is a formulation technique that improves the absorption rate of drugs, cosmetic compounds, or drugs with a very low absorption rate, which cannot be absorbed even when administered transdermally by conventional techniques. As the material of the microneedle, silica or the like is used in addition to the same metal as the conventional injection needle (Patent Documents 1 to 52).
マイクロニードル・アレイは、注射針と同様の中空構造を有し、薬液を注入するタイプであったり、ポリ乳酸などの生分解性高分子製のマイクロニードル・アレイであったりする。さらに、水溶性物質を基剤とする溶解型のマイクロニードルも開発されている。すなわち、水溶性物質の基剤に目的物質を保持させておき、皮膚に挿入した後、基剤が皮膚内の水分により溶解することにより、目的物質を経皮的に投与することができる。例えば、麦芽糖を基剤とするマイクロニードルが開示されている(特許文献1〜3、40〜43)。また、マイクロニードルを介して薬物を注入する装置、器具、あるいはマイクロニードルの素材、形状、製法などに関する特許も多数公知である(特許文献4、特許文献7〜50)。 The microneedle array has a hollow structure similar to that of an injection needle and is a type for injecting a chemical solution or a microneedle array made of a biodegradable polymer such as polylactic acid. Furthermore, dissolution type microneedles based on water-soluble substances have also been developed. That is, the target substance can be administered transcutaneously by holding the target substance in a base of a water-soluble substance and inserting it into the skin, and then the base dissolves with moisture in the skin. For example, microneedles based on maltose are disclosed (Patent Documents 1 to 3, 40 to 43). Many patents relating to devices, instruments, or microneedle materials, shapes, manufacturing methods, etc. for injecting drugs via microneedles are also known (Patent Document 4, Patent Documents 7 to 50).
本発明者は上記麦芽糖を基剤とするマイクロニードルの欠点を克服したマイクロニードルとして、水溶性の洩糸性高分子物質を基剤とするマイクロニードルを特許出願した(特許文献5)。当該発明は、遺伝子組み換え蛋白薬、ワクチン、遺伝子DNAなどの高分子薬、水溶性の難・低経皮吸収性薬物など皮膚透過性が低いために従来の経皮投与では十分な効果が期待できない薬物の皮膚透過性を高めたものである。 The present inventor has filed a patent application for a microneedle based on a water-soluble leaky polymer substance as a microneedle overcoming the disadvantages of the microneedle based on maltose (Patent Document 5). Since the invention has low skin permeability such as genetically modified protein drugs, vaccines, high molecular weight drugs such as genetic DNA, water-soluble difficult / low transdermal absorbable drugs, sufficient effects cannot be expected with conventional transdermal administration. Increases skin permeability of drugs.
さらに本発明者は水溶性の洩糸性高分子物質であるコンドロイチン硫酸、デキストラン、ヒアルロン酸などを基剤とするマイクロニードルの工業的製造法を発明して特許出願を行った(特許文献6)。マイクロニードルデバイスおよびマイクロニードル送達装置に関する特許も考案されている(特許文献9)。さらに本発明者は多層マイクロニードル・アレイを表面に形成したパッチ剤を考案した(特許文献51)。 Furthermore, the inventor has invented an industrial manufacturing method of microneedles based on chondroitin sulfate, dextran, hyaluronic acid and the like, which are water-soluble leaky polymer substances, and filed a patent application (Patent Document 6). . Patents relating to microneedle devices and microneedle delivery devices have also been devised (Patent Document 9). Furthermore, the inventor has devised a patch having a multilayer microneedle array formed on the surface (Patent Document 51).
また、本発明者は、ワクチン抗原などの高分子、インスリンなどのペプチド・蛋白薬を目的物質とし、コンドロイチン硫酸、デキストラン、ヒアルロン酸、などを基剤に用いて、長さ約500μm、底部直径約300μmの溶解性マイクロニードルを例えば1平方センチメートルのパッチ上に10行10列で100本構築したマイクロニードル・アレイの製造法を発明した(特許文献52)。さらにマイクロニードル・アレイを構築するのに適した多孔性の基盤を発明した(特許文献53)。また、マイクロニードル・アレイ・パッチを皮膚に対して垂直に挿入するための投与器具と一体化した密封包装投与システムに関する特許も出願した(特許文献54)。 In addition, the present inventor uses macromolecules such as vaccine antigens and peptide / protein drugs such as insulin as target substances and uses chondroitin sulfate, dextran, hyaluronic acid, etc. as a base, and has a length of about 500 μm and a bottom diameter of about A manufacturing method of a microneedle array was constructed in which 100 300 μm soluble microneedles were constructed in 10 rows and 10 columns on, for example, a 1 cm 2 patch (Patent Document 52). Furthermore, a porous base suitable for constructing a microneedle array was invented (Patent Document 53). A patent was also filed regarding a sealed package administration system integrated with an administration device for inserting a microneedle array patch perpendicular to the skin (Patent Document 54).
マイクロニードルの大きさに関しては数多くの研究が行われており、本発明者も水溶性の洩糸性高分子物質であるコンドロイチン硫酸やデキストランを用いて種々の長さの溶解性マイクロニードルを作成してきたが、操作性および皮膚への突刺時における強度の点から鑑みて、実用上、長さ500μm、底部の直径300μmのマイクロニードル・アレイがほぼ最適であるとの結論に至った。皮膚の生理学的構造として、ヒトの角質層の厚さは10-20μm、表皮層の厚さは50-150μmであるといわれている(非特許文献1および2)。また、真皮層は皮膚の表面から数mmの深さまで存在する。 Numerous studies have been conducted on the size of microneedles, and the present inventor has also prepared soluble microneedles of various lengths using chondroitin sulfate and dextran, which are water-soluble leaky polymer substances. However, in view of operability and strength at the time of piercing the skin, it was concluded that a microneedle array having a length of 500 μm and a bottom diameter of 300 μm is practically optimal. As the physiological structure of the skin, it is said that the thickness of the human stratum corneum is 10-20 μm and the thickness of the epidermis layer is 50-150 μm (Non-patent Documents 1 and 2). The dermis layer exists to a depth of several millimeters from the skin surface.
実験動物の表皮層の厚さはラットで11.58±1.02μm、イヌで22.47±2.40μmであると報告されている(非特許文献3)。しかし、マイクロニードル・アレイ・パッチを指で加圧して皮膚に刺しても、500μmのマイクロニードルの全長を皮膚内へ挿入することはできない。ヘアレスラットおよび除毛したラットの皮膚への投与を行った実験では先端から約半分までが皮膚内に挿入された。一方、経皮ワクチンの場合、表皮層に多く分布するLangerhans細胞、さらに真皮層に多く分布するDendritic細胞のいずれの免疫系細胞が経皮的に投与された抗原蛋白を主として認識するのかという問題に関しては、免疫学分野において数多くの研究が行われてきているにもかかわらず、未だに結論に至っていない(非特許文献2から7)。多層マイクロニードル・アレイを利用したワクチンの経皮デリバリーに関する特許も出願されているが(特許文献55)、第1層であるマイクロニードルの先端部に抗原を高濃度で配置し、第2層を主として基剤で形成するという技術である。なお、当該特許文献においては、第1層と第2層の具体的な長さについては明示していない。 It has been reported that the thickness of the epidermis layer of experimental animals is 11.58 ± 1.02 μm in rats and 22.47 ± 2.40 μm in dogs (Non-patent Document 3). However, even if the microneedle array patch is pressed with a finger and stabbed into the skin, the entire length of the 500 μm microneedle cannot be inserted into the skin. In an experiment in which hairless and depigmented rats were administered to the skin, approximately half of the tip was inserted into the skin. On the other hand, in the case of transdermal vaccine, regarding the problem of which immune system cells of Langerhans cells distributed a lot in the epidermis layer and dendritic cells distributed abundantly in the dermis layer mainly recognize the antigen protein administered transdermally Despite numerous studies in the field of immunology, no conclusion has yet been reached (Non-Patent Documents 2 to 7). A patent on the transdermal delivery of a vaccine using a multilayer microneedle array has been filed (Patent Document 55), but the antigen is arranged at a high concentration at the tip of the microneedle which is the first layer, and the second layer is It is a technology that mainly uses a base. In this patent document, the specific lengths of the first layer and the second layer are not specified.
本発明者は、上記課題を解決すべく鋭意研究を重ね、本発明を完成した。すなわち、先にも述べたように操作性および強度の観点から実用的なマイクロニードルのサイズとしては、長さが約500μm、底部の直径が約300μmのマイクロニードルに集約される。本発明者が先に特許出願を行った水溶性の洩糸性高分子物質を基剤とする溶解性マイクロニードル・アレイ・パッチの密封包装投与システム(特許文献54)を用いれば、一定の加圧力でマイクロニードル・アレイ・パッチを皮膚へ投与することができ、再現性良くマイクロニードルの先端から同じ長さの部分を皮膚内へ挿入することができる。そこでマイクロニードル・アレイを3層構造とし、最先端である第1層には抗原を入れず基剤である水溶性の洩糸性高分子物質にて形成し、先端から第2番目の部分にはLangerhans細胞の多く分布する皮膚表皮層へデリバリーするためのワクチン抗原を配置し、3番目に相当する根元部分には基剤を配置することによりより高い効率でワクチンの効果を得ることに成功し、上記の問題を解決した。 The present inventor has intensively studied to solve the above problems and completed the present invention. That is, as described above, practical microneedles from the viewpoints of operability and strength are concentrated into microneedles having a length of about 500 μm and a bottom diameter of about 300 μm. If the present inventor has applied for a hermetic microneedle array patch sealed package administration system (Patent Document 54) based on a water-soluble, leaky polymer substance previously applied for, The microneedle array patch can be administered to the skin with pressure, and a portion of the same length from the tip of the microneedle can be inserted into the skin with good reproducibility. Therefore, the microneedle array has a three-layer structure, and the first layer, which is the most advanced, is formed of a water-soluble, leaky polymer substance that does not contain any antigen, and the second part from the tip. Succeeded in obtaining a vaccine effect with higher efficiency by placing a vaccine antigen for delivery to the skin epidermis layer where many Langerhans cells are distributed, and placing a base at the root part corresponding to the third. Solved the above problem.
より具体的には、本発明のマイクロニードルは、
ワクチン抗原を効率良く皮膚表皮層へデリバリーするための3層構造から成る溶解性マイクロニードル・アレイ・パッチである。
More specifically, the microneedle of the present invention is
It is a soluble microneedle array patch consisting of a three-layer structure for efficiently delivering a vaccine antigen to the skin epidermis layer.
また、前記溶解性3層マイクロニードル・アレイにおいて用いる基剤は水溶性の洩糸性高分子物質である溶解性マイクロニードル・アレイ・パッチである。 The base used in the soluble three-layer microneedle array is a soluble microneedle array patch which is a water-soluble leaky polymer substance.
また、前記3層マイクロニードル・アレイ・パッチにおいてニードルの最先端部分に相当する第1番目の層は基剤である水溶性の洩糸性高分子物質により形成される溶解性マイクロニードル・アレイ・パッチである。 In the three-layer microneedle array patch, the first layer corresponding to the most distal portion of the needle is a soluble microneedle array formed by a water-soluble leaky polymer substance as a base. It is a patch.
また、前記3層マイクロニードル・アレイ・パッチにおいて先端から2番目の層にはワクチン抗原が配置されている溶解性マイクロニードル・アレイ・パッチである。 The three-layer microneedle array patch is a soluble microneedle array patch in which a vaccine antigen is arranged in the second layer from the tip.
また、前記3層マイクロニードル・アレイ・パッチにおいて先端から3番目の層は基剤である水溶性の洩糸性高分子物質により形成されている溶解性マイクロニードル・アレイ・パッチである。 In the three-layer microneedle array patch, the third layer from the tip is a soluble microneedle array patch formed of a water-soluble leaky polymer substance as a base.
また、前記の3層マイクロニードル・アレイ・パッチにおいてマイクロニードルのサイズが長さ500μm、底部の直径300μmである場合、最先端である第1番目の層の長さは先端から160μm、第2番目の層は先端から160〜220μmの部位、第3番目の層は先端から220〜500μmの部分に相当する溶解性マイクロニードル・アレイ・パッチである。なお、これらの数値はラットでの検証実験において得た数値であり、人間の場合には若干の変動がある。 In the three-layer microneedle array patch, when the size of the microneedle is 500 μm in length and the diameter of the bottom is 300 μm, the length of the first layer, which is the most advanced, is 160 μm from the tip, and the second The third layer is a soluble microneedle array patch corresponding to a portion 160 to 220 μm from the tip, and the third layer is a portion 220 to 500 μm from the tip. These numerical values are values obtained in the verification experiment using rats, and there are slight fluctuations in the case of humans.
3層構造を有する溶解性マイクロニードル・アレイを皮膚に突き刺すと、最先端部は溶解しながら皮膚の真皮内に入っていくので、3層構造からなるマイクロニードル・アレイにおいて先端から2番目の部分にワクチン抗原を配置することにより、皮膚表皮層に広範に分布する抗原認識細胞であるLangerhans細胞へのデリバリーを達成することができる。 When a soluble microneedle array having a three-layer structure is pierced into the skin, the most advanced part enters the dermis of the skin while dissolving, so the second part from the tip of the three-layer microneedle array By placing the vaccine antigen in the cell, it is possible to achieve delivery to Langerhans cells, which are antigen-recognizing cells widely distributed in the skin epidermis layer.
なお、マイクロニードル・アレイの先端から第3番目の層は皮膚に突き刺さらない部分になるので、抗原を配置する必要はない。 Since the third layer from the tip of the microneedle array is a portion that does not pierce the skin, there is no need to place an antigen.
長さが約500μm、底部の直径が約300μmのマイクロニードルの場合、具体的には、先端から160μmまでの第1層については基剤である水溶性の洩糸性高分子物質を用いて形成し、先端からの長さが160から220μmに相当する第2番目の層についてはワクチン抗原を配置することにより、皮膚表皮層への効率的な抗原のデリバリーが可能となった。先端からの長さが220μm以上の第3層であるマイクロニードルの根元部分については第1層と同様に水溶性の洩糸性高分子物質を用いて成形する。このような3層構造を有するマイクロニードル・アレイを構築したパッチとすることにより、上記の問題を解決することができる。なお、上記の長さに関する数値はラットでの検証実験の結果によるものであり、人間の皮膚に適用する場合には若干の変動がある。 In the case of a microneedle having a length of about 500 μm and a bottom diameter of about 300 μm, specifically, the first layer from the tip to 160 μm is formed using a water-soluble leaky polymer material as a base. The second layer corresponding to a length from the tip of 160 to 220 μm can be efficiently delivered to the skin epidermis layer by arranging the vaccine antigen. The root portion of the microneedle, which is the third layer having a length of 220 μm or more from the tip, is molded using a water-soluble leaky polymer material in the same manner as the first layer. By using a patch in which such a microneedle array having a three-layer structure is constructed, the above problem can be solved. In addition, the numerical value regarding said length is based on the result of the verification experiment in a rat, and when applying to human skin, there are some fluctuations.
以下に実施例をあげて具体的な実施形態を説明する。もちろん、本発明は以下の実施例に限定されるものではない。 Specific embodiments will be described below with reference to examples. Of course, the present invention is not limited to the following examples.
(実施例1)
1平方センチメートルあたりに深さ約500ミクロン、開口部直径約300ミクロンの逆円錐状細孔を有するシリコン製基盤の上に、375mgのコンドロイチン硫酸Cナトリウム(ナカライテスク)に精製水700μlを加えて作成した粘調液を塗布した。サランラップ(クレハ化学)を被せ、卓上遠心分離器(クボタ4000)を用いて毎分3500回転で樹脂基盤ごと15分間回転させ、遠心力を利用して加重下、充填した。サランラップを取り除き、30分間同条件で回転させ乾燥を行った。次に、モデルワクチン抗原として卵白アルブミン(シグマ社、米国)の20mg、微量のエバンスブルー(ナカライテスク)および35mgのコンドロイチン硫酸Cナトリウムに精製水170μlを加えて調製した粘性濃厚液を塗布した。卓上遠心分離器にて毎分3500回転で樹脂基盤ごと20分間回転させ、遠心力を利用して加重下、充填した。サランラップを取り除き、卓上遠心分離器にて同条件で30分間回転させ、乾燥を行った。樹脂基盤上の残留物を除去した後、コンドロイチン硫酸Cナトリウムの1gに精製水1mlを加えて作成した粘調液を樹脂基盤上の穴に塗布した。樹脂基盤ごと卓上遠心分離器にて3500回転で30分間回転させ、遠心力を利用して加重下、充填した。コンドロイチン硫酸Cナトリウムの粘調液を塗布した円形基盤を樹脂基盤の上に被せ、加重下で乾燥を行った。6時間後に円形基盤を引き離すことにより、3層マイクロニードル・アレイ・パッチを得た。調製した3層マイクロニードル・アレイ・パッチの10個を取り出し、ビデオマイクロスコープ(VH−Z、キーエンス製)で観察を行い、透明な第1層および青色に着色した第2層の長さを測定したところ次に示す結果を得た。
第1層、160.2±7.2μm
第2層、 58.7±4.2μm
Example 1
Prepared by adding 700 μl of purified water to 375 mg of sodium C chondroitin sulfate (Nacalai Tesque) on a silicon substrate having an inverted conical pore with a depth of about 500 microns per square centimeter and an opening diameter of about 300 microns. A viscous liquid was applied. It was covered with Saran Wrap (Kureha Chemical), and the resin base was rotated at 3500 rpm for 15 minutes using a desktop centrifuge (Kubota 4000), and filled under load using centrifugal force. Saran wrap was removed, and drying was performed by rotating under the same conditions for 30 minutes. Next, a viscous concentrated solution prepared by adding 170 μl of purified water to 20 mg of ovalbumin (Sigma, USA), a small amount of Evans Blue (Nacalai Tesque) and 35 mg of chondroitin sulfate C sodium salt as a model vaccine antigen was applied. The resin substrate was rotated at 3500 rpm for 20 minutes in a table centrifuge and filled under load using centrifugal force. The Saran wrap was removed, and it was rotated for 30 minutes under the same conditions in a desktop centrifuge and dried. After removing the residue on the resin substrate, a viscous liquid prepared by adding 1 ml of purified water to 1 g of chondroitin sulfate C sodium was applied to the hole on the resin substrate. The resin substrate was rotated at 3,500 rpm for 30 minutes in a table centrifuge and filled under load using centrifugal force. A circular substrate coated with chondroitin sulfate C sodium viscous liquid was placed on the resin substrate and dried under load. A three-layer microneedle array patch was obtained by pulling off the circular substrate after 6 hours. Ten of the prepared three-layer microneedle array patches are taken out and observed with a video microscope (VH-Z, manufactured by Keyence) to measure the length of the transparent first layer and the second layer colored blue. As a result, the following results were obtained.
First layer, 160.2 ± 7.2 μm
Second layer, 58.7 ± 4.2 μm
(実施例2)
実施例1で用いたのと同様の樹脂基盤の上に、卵白アルブミンの20mg、微量のエバンスブルーおよび35mgのコンドロイチン硫酸Cナトリウムに精製水170μlを加えて調製した粘性濃厚液を塗布した。サランラップを被せ、卓上遠心分離器にて毎分3500回転で樹脂基盤ごと45分間回転させ、遠心力を利用して加重下、充填した。サランラップを取り除き、15分間同条件で回転させ乾燥を行った。樹脂基盤上の残留物を除去した後、コンドロイチン硫酸Cナトリウムの1gに精製水1mlを加えて作成した粘調液を樹脂基盤上の穴に塗布した。シリコン樹脂基盤ごと卓上遠心分離器にて3500回転で30分間回転させ、遠心力を利用して加重下、充填した。コンドロイチン硫酸Cナトリウムの粘調液を塗布した円形基盤を樹脂基盤の上に被せ、加重下で乾燥を行った。6時間後に円形基盤を引き離すことにより、2層マイクロニードル・アレイ・パッチを得た。調製した2層マイクロニードル・アレイ・パッチの10個を取り出し、ビデオマイクロスコープで観察を行い、青色に着色した第1層の長さを測定したところ次に示す結果を得た。
第1層、153.7±7.4μm
(Example 2)
On a resin base similar to that used in Example 1, a viscous concentrated solution prepared by adding 170 μl of purified water to 20 mg of ovalbumin, a small amount of Evans Blue, and 35 mg of chondroitin sulfate C sodium salt was applied. It was covered with Saran wrap, rotated at 3,500 rpm for 45 minutes with the resin substrate in a desktop centrifuge, and filled under load using centrifugal force. The Saran wrap was removed and dried by rotating for 15 minutes under the same conditions. After removing the residue on the resin substrate, a viscous liquid prepared by adding 1 ml of purified water to 1 g of chondroitin sulfate C sodium was applied to the hole on the resin substrate. The silicon resin substrate was rotated at 3,500 rpm for 30 minutes in a table centrifuge and filled under load using centrifugal force. A circular substrate coated with chondroitin sulfate C sodium viscous liquid was placed on the resin substrate and dried under load. A double layer microneedle array patch was obtained by pulling off the circular substrate after 6 hours. Ten of the prepared two-layer microneedle array patches were taken out, observed with a video microscope, and the length of the first layer colored blue was measured. The following results were obtained.
First layer, 153.7 ± 7.4 μm
(実施例3)
実施例1および2で作成したマイクロニードル・アレイ・パッチ中の卵白アルブミン含量をLawry法を用いて蛋白量として測定した。その結果、
実施例1の3層マイクロニードル・アレイ・パッチ、 211.2±31.1μg
実施例2の2層マイクロニードル・アレイ・パッチ、 226.9±25.6μg
(Example 3)
The ovalbumin content in the microneedle array patches prepared in Examples 1 and 2 was measured as the amount of protein using the Lawry method. as a result,
Three-layer microneedle array patch of Example 1, 211.2 ± 31.1 μg
Two-layer microneedle array patch of Example 2, 226.9 ± 25.6 μg
(実施例4)
体重約300グラムの雄性ラットにペントバルビタール麻酔をかけ、手術台の上に仰向けに固定した。腹部の体毛を除毛した後、手術台に固定した。頸静脈より約0.2mL採血した後、実施例1および2で作製したモデル抗原である卵白アルブミンを含有する経皮ワクチンパッチを除毛したラットの腹部に押し当てることにより投与した。ポシティブコントロールとして卵白アルブミンの注射液を作成してラットに1000μgの投与量で皮下注射にて投与を行った。投与2週間後にペントバルビタール麻酔下、ラットより採血を行うとともに2回目の卵白アルブミンを含有する経皮ワクチンパッチおよび卵白アルブミン注射液のブースター投与を行った。1回目および2回目の投与後に回収したマイクロニードル・アレイ・パッチ中における卵白アルブミンの含有量を残存量としてLawry法にて測定したところ以下の結果を得た。
実施例1の3層マイクロニードル・アレイ・パッチ、7.0±2.6μg
実施例2の2層マイクロニードル・アレイ・パッチ、 7.1±2.0μg
従って、経皮的に投与された卵白アルブミン量を算出したところ次のような結果となった。
実施例1の3層マイクロニードル・アレイ・パッチ、 204.2±2.6μg
実施例2の2層マイクロニードル・アレイ・パッチ、 219.8±2.0μg
Example 4
Male rats weighing approximately 300 grams were anesthetized with pentobarbital and fixed on their back on the operating table. After removing the abdominal body hair, it was fixed to the operating table. About 0.2 mL of blood was collected from the jugular vein, and then administered by pressing the transdermal vaccine patch containing ovalbumin, which is a model antigen prepared in Examples 1 and 2, against the abdomen of the depilated rat. As a positive control, an ovalbumin injection solution was prepared and administered to rats by subcutaneous injection at a dose of 1000 μg. Two weeks after administration, blood was collected from rats under anesthesia with pentobarbital, and a second transdermal vaccine patch containing ovalbumin and an ovalbumin injection solution were boosted. When the content of ovalbumin in the microneedle array patch collected after the first and second administrations was measured as a residual amount by the Lawry method, the following results were obtained.
Three-layer microneedle array patch of Example 1, 7.0 ± 2.6 μg
Two-layer microneedle array patch of Example 2, 7.1 ± 2.0 μg
Therefore, when the amount of ovalbumin administered transdermally was calculated, the following results were obtained.
Three-layer microneedle array patch of Example 1, 204.2 ± 2.6 μg
Two-layer microneedle array patch of Example 2, 219.8 ± 2.0 μg
2週間後および4週間後にラットから採血を行って得た血漿試料を用いてELISA法(Rat
anti-ovalbumin Ig ELISA kit, ALPHA DIAGNOSTICS社)にて血漿中の卵白アルブミン抗体価を測定したところ以下の結果を得た。
2週間後の血漿試料
実施例1の3層マイクロニードル・アレイ・パッチ投与群、54.99±7.08単位/ml
実施例2の2層マイクロニードル・アレイ・パッチ投与群、8.93±2.78単位/ml
皮下注射による投与群、98.34±3.82 単位/ml
4週間後の血漿試料
実施例1の3層マイクロニードル・アレイ・パッチ投与群、1578.57±182.59単位/ml
実施例2の2層マイクロニードル・アレイ・パッチ投与群、351.27±156.52単位/ml
皮下注射による投与群、655.70±118.01単位/ml
以上より、先端から2番目の層にモデル抗原蛋白である卵白アルブミンを含有する本発明の3層マイクロニードル・アレイ・パッチは2層マイクロニードル・アレイ・パッチよりも循環血漿中の高い抗体価を誘導し、経皮ワクチンとしての優秀性が示された。
ELISA method (Rat) using plasma samples collected from rats after 2 weeks and 4 weeks
Anti-ovalbumin Ig ELISA kit (ALPHA DIAGNOSTICS) was used to measure the ovalbumin antibody titer in plasma, and the following results were obtained.
Plasma sample after 2 weeks Three-layer microneedle array patch administration group of Example 1, 54.99 ± 7.08 units / ml
Double-layer microneedle array patch administration group of Example 2, 8.93 ± 2.78 units / ml
Administration group by subcutaneous injection, 98.34 ± 3.82 units / ml
Plasma samples after 4 weeks Three-layer microneedle array patch administration group of Example 1, 1578.57 ± 182.59 units / ml
Double-layer microneedle array patch administration group of Example 2, 351.27 ± 156.52 units / ml
Administration group by subcutaneous injection, 655.70 ± 118.01 units / ml
From the above, the three-layer microneedle array patch of the present invention containing ovalbumin as a model antigen protein in the second layer from the tip has a higher antibody titer in circulating plasma than the two-layer microneedle array patch. Induced and demonstrated superiority as a transdermal vaccine.
(実施例5)
実施例1および2に示した方法でフルオレッセインイソチオシアネート(FITC)で蛍光標識を行った卵白アルブミンを含有する3層および2層マイクロニードル・アレイ・パッチを作成した。ペントバルビタール麻酔下で雄性ラット腹部の除毛皮膚に投与した後、経時的に切除して得た皮膚切片を用いて、蛍光照射下にてビデオマイクロスコープにて撮影を行った。実施例1で作成した3層マイクロニードル・アレイ・パッチをラットの皮膚に投与した後、30秒後には皮膚の表面に近い表皮層に強い蛍光が観察された。2分後においても表皮層に強い蛍光発光が観察され、FITC卵白アルブミンの表皮層へのデリバリーが確認された。実施例2で作成した2層マイクロニードル・アレイ・パッチをラットの皮膚に投与した後、30秒後および2分後において、皮膚表面から離れた真皮層に強い蛍光発光が観察され、卵白アルブミンの真皮層へのデリバリーが示された。
(Example 5)
Three-layer and two-layer microneedle array patches containing ovalbumin fluorescently labeled with fluorescein isothiocyanate (FITC) by the method shown in Examples 1 and 2 were prepared. After administration to the hair removal skin of the male rat abdomen under pentobarbital anesthesia, the skin section obtained by excision with time was used to photograph with a video microscope under fluorescence irradiation. After the three-layer microneedle array patch prepared in Example 1 was administered to the rat skin, strong fluorescence was observed in the epidermis layer close to the surface of the skin 30 seconds later. Even after 2 minutes, strong fluorescence was observed in the epidermal layer, and delivery of FITC ovalbumin to the epidermal layer was confirmed. After administration of the two-layer microneedle array patch prepared in Example 2 to the skin of a rat, after 30 seconds and 2 minutes, strong luminescence was observed in the dermis layer away from the skin surface, and ovalbumin Delivery to the dermis layer has been demonstrated.
より高い効率で経皮ワクチンの効果を得るためには、ワクチン抗原のデリバリー部位を免疫系細胞であるLangerhans細胞が主として分布する皮膚表皮層とするかそれともDendritic細胞が主として分布する真皮層とするか、いずれの部位が最適の部位であるかという問題は長年の論争の的となっていた。それゆえ、溶解性マイクロニードル・アレイ・パッチを経皮ワクチンのデリバリーに用いる場合、多層マイクロニードル・アレイ・パッチとし、いずれの層にワクチン抗原を配置するのが最適であるのかという課題を解決する必要があった。本発明により、長さ約500μm、底部の直径約300μmのマイクロニードルの先端から2番目の層に相当する先端から160から220μmの部分にワクチン抗原を配置すればワクチン抗原の表皮層へのデリバリーを達成でき、より効果的な薬理効果を引き出すことができることが明らかとなった。 In order to obtain a transdermal vaccine effect with higher efficiency, whether the vaccine antigen delivery site should be a skin epidermis layer in which Langerhans cells as immune system cells are mainly distributed or a dermis layer in which dendritic cells are mainly distributed The question of which part is the optimal part has been controversial for many years. Therefore, when a soluble microneedle array patch is used for delivery of transdermal vaccine, it is a multi-layer microneedle array patch and solves the problem of which layer of vaccine antigen is best placed There was a need. According to the present invention, if a vaccine antigen is placed in a portion 160 to 220 μm from the tip corresponding to the second layer from the tip of a microneedle having a length of about 500 μm and a bottom diameter of about 300 μm, the vaccine antigen can be delivered to the epidermis layer. It has been clarified that it can be achieved and a more effective pharmacological effect can be derived.
Claims (6)
When the size of the microneedle is 500 μm in length and the bottom diameter is 300 μm in the three-layer microneedle array patch according to claim 1, the length of the first layer which is the most advanced is 160 μm from the tip, and the second The layer is a soluble microneedle array patch corresponding to a portion 160 to 220 μm from the tip, and the third layer is a portion 220 to 500 μm from the tip. In addition, these figures are those in rat experiments, and there are some fluctuations in the case of humans.
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