JP6830662B2 - 薬剤送達用デバイス - Google Patents
薬剤送達用デバイス Download PDFInfo
- Publication number
- JP6830662B2 JP6830662B2 JP2017545834A JP2017545834A JP6830662B2 JP 6830662 B2 JP6830662 B2 JP 6830662B2 JP 2017545834 A JP2017545834 A JP 2017545834A JP 2017545834 A JP2017545834 A JP 2017545834A JP 6830662 B2 JP6830662 B2 JP 6830662B2
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- Prior art keywords
- drug
- gel
- insulin
- gel composition
- drug delivery
- 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.)
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Description
[1]生体適合性及び薬剤透過性を有する多孔質体と、多孔質体の内面側に充填された刺激応答性ゲル組成物と、多孔質体の内面側においてゲル組成物に囲まれた薬剤とを備えることを特徴とする薬剤送達用デバイス。
[2]多孔質体が中空糸である、[1]記載の薬剤送達用デバイス。
[3]中空糸が限外濾過膜であり、限外濾過膜の分画分子量が10,000以下である、[2]記載の薬剤送達用デバイス。
[4]多孔質体の外径が、100〜2,000μm、内径が50〜1,950μm、長さが0.1〜100mmの範囲である、[1]〜[3]のいずれか記載の薬剤送達用デバイス。
[5]生体適合性を有するとともに薬剤放出部が設けられた薬剤放出体と、薬剤放出体の内面側に充填された刺激応答性ゲル組成物と、薬剤放出体の内面側においてゲル組成物に囲まれた薬剤とを備え、薬剤放出部は、ゲル組成物の内外における薬剤の濃度差に基づいた拡散により薬剤を放出することを特徴とする薬剤送達用デバイス。
[6]ゲル組成物が、グルコース濃度応答性ゲル組成物である、[1]〜[5]のいずれか記載の薬剤送達用デバイス。
[7]グルコース濃度応答性ゲル組成物が、フェニルボロン酸系単量体を単量体として含む共重合体ゲル組成物である、[6]記載の薬剤送達用デバイス。
[8]共重合体ゲル組成物が、N-イソプロピルメタクリルアミド(NIPMAAm)、フェニルボロン酸系単量体(AmECFPBA)、及び架橋剤としてN,N'-メチレンビスアクリルアミド(MBAAm)を用いて重合されたものである、[7]記載の薬剤送達用デバイス。
[9]薬剤がインスリンである、[1]〜[8]のいずれか記載の薬剤送達用デバイス。
[10]薬剤がゲル組成物中に混合されている、[1]〜[9]のいずれか記載の薬剤送達用デバイス。
[11]多孔質体又は薬剤放出体が体内に挿入可能である、[1]〜[10]のいずれか記載の薬剤送達用デバイス。
本明細書は本願の優先権の基礎となる日本国特許出願番号2015-209192号の開示内容を包含する。
上記の通り、本発明の一実施形態は、生体適合性及び薬剤透過性を有する多孔質体と、多孔質体の内面側に充填された刺激応答性ゲル組成物と、多孔質体の内面側においてゲル組成物に囲まれた薬剤とを備えることを特徴とする薬剤送達用デバイスを提供する。また、別の実施形態では、生体適合性を有するとともに薬剤放出部が設けられた薬剤放出体と、薬剤放出体の内面側に充填された刺激応答性ゲル組成物と、薬剤放出体の内面側においてゲル組成物に囲まれた薬剤とを備え、薬剤放出部は、ゲル組成物の内外における薬剤の濃度差に基づいた拡散により薬剤を放出することを特徴とする薬剤送達用デバイスを提供する。
本明細書において、「多孔質体」とは、体内への挿入に適したサイズを有し、多数の細孔を有するものであり、好適には中空の糸状構造を有する中空糸、特に、薬剤の透過を可能とする分画分子量を有する限外濾過膜を含む。当分野において、中空糸は、ホローファイバー(hollow fiber)と呼ばれる場合もある。中空糸は、浄水等の工業用用途、透析等の医薬用及び研究用の用途等に使用されており、その用途に応じて様々な分画分子量を有するものが製造され、入手可能である。本発明のデバイスに用いる場合、中空糸の分画分子量は、特に限定するものではないが、例えば低分子薬剤の透過のためには数百以下、ペプチド及び抗体等のタンパク質の透過のためには約1,000,000以下とすることが好ましい。薬剤としてインスリンを利用する場合、分画分子量は約10,000以下とすることが好適である。
本明細書において、「薬剤放出体」とは、体内への挿入に適したサイズを有する中空構造のものを意図し、例えば医療用に使用可能なカテーテル、注射・注入用の針、マイクロニードルパッチ等を包含する。従って薬剤放出体は、血管内に挿入するか、又は皮膚に貼付して使用することができる。
本発明のデバイスにおいて送達することが想定される薬剤は、患者の状態に応じて送達が調節されるべき薬剤であり、低分子薬剤、ペプチド、抗体等のタンパク質医薬を含み得る。従って、特に限定するものではないが、例えば血中グルコース濃度に応じて投与することが必要となる糖尿病治療剤、例えばインスリンは好適に使用可能な薬剤の一例である。
本発明のデバイスに使用可能なゲル組成物は、外部からの刺激に応答して、例えばpH、光、温度、金属イオン、電場、磁場、化学物質(例えばグルコース)の濃度変化、酸化還元状態、又は抗原抗体反応等に依存して膨潤度が変化し、その結果、ゲル組成物中、又はゲル組成物充填部内部に存在する薬剤を透過させる機能を有するものである。本発明において使用可能な刺激応答性ゲルとしては、例えばグルコース濃度応答性ゲル組成物等を挙げることができる。本発明において使用可能なゲル組成物としては、例えばゲルハンドブック(エヌ・ティー・エス、1997年、長田義仁 梶原莞爾 編集代表)に記載されたものが挙げられる。
以下、図面を用いて本発明の薬剤送達用デバイスの構成をより具体的に説明する。
ゲル化剤(すなわち主鎖)としてN-イソプロピルメタクリルアミド(NIPMAAm)及びフェニルボロン酸系単量体(AmECFPBA)、架橋剤としてN,N'-メチレンビスアクリルアミド(MBAAm)、重合開始剤として2,2'-アゾビスイソブチロニトリルを仕込みモル比91.5/7.5/1/0.1で混合し、直径1mmのキャピラリー中でラジカル重合を行うことでゲルを調製した。
旭化成メディカル株式会社製のポリスルホンダイアライザー(APS-15SA 4537693003682)に用いられている中空糸1本をデバイスとして使用した(内径185μm、膜厚45μm)。本実施例では、デバイスに市販のヒト用シリコンカテーテル(4Fr:内径約600μm、プライムテック株式会社)を連結し、インスリンを供給するリザーバーとして機能させた。
実施例2と同様のシステムを使用して、旭化成メディカル株式会社製のポリスルホンダイアライザー(APS-15SA 4537693003682)に用いられている中空糸10本の両端を閉じたものを作製し、デバイスとして使用した。本実施例では、リザーバーを使用しない構成とした。
実施例2と同様のシステムを使用して、旭化成ケミカルズ株式会社製のMICROZA(AHP-0013 D)に用いられている中空糸1本をデバイスとして使用した(ポリアクリロニトリル製、内径800μm、長さ130mm)。本実施例では、リザーバーを使用しない構成とした。
2型糖尿病モデル動物であるAKITAマウス(7週齢、日本エスエルシー株式会社)を用い、図2A及び2Bに示す本発明のデバイスの効果を確認した。
実施例5と同様にして作製した側孔数24個のシリコンカテーテルデバイスを作製した。本実施例では、高濃度インスリン(22.5 mg/ml)、低濃度インスリン(3.5 mg/ml)又はPBSをデバイスに充填した。
ストレプトゾシン(STZ)誘導性1型糖尿病モデルマウス(9週齢、C57BL/6J)を用いて実施例6と同様の試験を行った。本実施例では、インスリン(3.6 mg/ml)又はPBSをデバイスに充填した。このマウスでは、16時間の絶食後においても血糖値が高いままであり、PBSを充填した対照群では血糖値の低下がほとんど観察されないのに対し、インスリン送達デバイス群では血糖値の顕著な低下が見られ、効果は観察した120分間の間持続した(図10A)。
本明細書で引用した全ての刊行物、特許及び特許出願はそのまま引用により本明細書に組み入れられるものとする。
2 カテーテル
3 リザーバー
4 側壁
5 側孔
6 ゲル充填部
7 薬剤充填部
8 針
9 リザーバー
10 皮膚
11、21、31 カテーテル
12、22 側孔
32 開口部
Claims (8)
- 生体適合性及び薬剤透過性を有する中空糸と、中空糸の内面側に充填されたグルコース濃度応答性ゲル組成物と、中空糸の内面側においてゲル組成物に囲まれた薬剤とを備え、ゲル組成物で中空糸外壁側に近い区画と遠い区画を形成し、近い区画に遠い区画よりも高濃度の薬剤を存在させ、グルコース濃度に応答して膨潤したゲル組成物内の薬剤が中空糸の外部へ持続的に放出されるようにしたことを特徴とする薬剤送達用デバイス。
- 中空糸が限外濾過膜であり、限外濾過膜の分画分子量が10,000以下である、請求項1記載の薬剤送達用デバイス。
- 中空糸の外径が100〜2,000μm、内径が50〜1,950μm、長さが0.1〜100mmの範囲である、請求項1または2記載の薬剤送達用デバイス。
- グルコース濃度応答性ゲル組成物が、フェニルボロン酸系単量体を単量体として含む共重合体ゲル組成物である、請求項1〜3のいずれか1項記載の薬剤送達用デバイス。
- 共重合体ゲル組成物がN-イソプロピルメタクリルアミド(NIPMAAm)、フェニルボロン酸系単量体(AmECFPBA)、及び架橋剤としてN,N'-メチレンビスアクリルアミド(MBAAm)を用いて重合されたものである、請求項4記載の薬剤送達用デバイス。
- 薬剤がインスリンである、請求項1〜5のいずれか1項記載の薬剤送達用デバイス。
- 薬剤がゲル組成物中に混合されている、請求項1〜6のいずれか1項記載の薬剤送達用デバイス。
- 中空糸が体内に挿入可能である、請求項1〜7のいずれか1項記載の薬剤送達用デバイス。
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PE20180325A1 (es) | 2015-04-21 | 2018-02-13 | Univ North Carolina State | Sistema de suministro de insulina sensible a la glucosa usando nanocompuestos sensibles a la hipoxia |
WO2018085809A1 (en) | 2016-11-07 | 2018-05-11 | North Carolina State University | Patch loaded with dual-sensitive vesicles for enhanced glucose-responsive insulin delivery |
CN111629746B (zh) * | 2017-11-21 | 2024-04-16 | 北卡罗来纳州立大学 | 具有超快响应的用于葡萄糖触发胰岛素递送的电荷可切换聚合物储库 |
JPWO2019182099A1 (ja) * | 2018-03-22 | 2021-03-18 | 国立大学法人 東京医科歯科大学 | 糖反応性複合ゲル組成物、その製造方法、前記糖反応性複合ゲル組成物を含むインスリン送達マイクロニードルおよびその製造方法 |
US11819570B2 (en) | 2018-06-01 | 2023-11-21 | National University Corporation Tokai National Higher Education And Research System | Temperature-resistant sugar-responsive gel |
CN109675185A (zh) * | 2019-01-02 | 2019-04-26 | 浙江大学 | 一种苯硼酸水凝胶基糖敏微针贴及其制备方法 |
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