JP5489999B2 - 外科用ハイドロゲル - Google Patents
外科用ハイドロゲル Download PDFInfo
- Publication number
- JP5489999B2 JP5489999B2 JP2010522848A JP2010522848A JP5489999B2 JP 5489999 B2 JP5489999 B2 JP 5489999B2 JP 2010522848 A JP2010522848 A JP 2010522848A JP 2010522848 A JP2010522848 A JP 2010522848A JP 5489999 B2 JP5489999 B2 JP 5489999B2
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- Prior art keywords
- polymer
- derivatized
- hydrogel
- chitosan
- aldehyde
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Description
癒着の形成は、多くの外科手術で頻繁に生じる不快な結果である。癒着とは、通常は離れている創傷表面同士をつなぐ線維帯である。癒着は特に、ヘルニア修復、婦人科手術、結腸直腸手術などの腹部手術や骨盤手術後に普通にみられる。
(i)Kennedy R et al., Prevention of experimental postoperative adhesions by N,O-carboxymethyl chitosan, Surgery, 1996, 120, 866-70;
(ii)Costain DJ et al., Prevention of postsurgical adhesions with N,O-carboxymethylchitosan: Examination of the most efficacious preparation and the effect of N,O-carboxymethyl chitosan on postsurgical healing, Surgery, 1997; 121, 314-9;
(iii)Krause TJ et al., Prevention of pericardial adhesions with N,O-carboxymethylchitosan in the Rat Model, Journal of Investigative Surgery, 2001 ,14,93-97;
(iv)Diamond, Michael P. et al., Reduction of postoperative adhesions by N,O-carboxymethylchitosan: a pilot study, Fertil Steril 2003, 80, 631-636;
(v)Diamond Michael P et al., Reduction of post operative adhesions by N,O-carboxymethylchitosan: A Pilot Study, The Journal of the American Association of Gynecologic Laparoscopists, 2004, 11(1), 127;
(vii)Lee, Timothy D. G et al., Reduction in postoperative adhesion formation and re-formation after an abdominal operation with the use of N,O-carboxymethyl chitosan, Surgery, 2004, 135, 307-312。
本発明は、術創および他の創傷に適用可能なハイドロゲルに関する。このハイドロゲルは、混合時に架橋してポリマーネットワークを形成する2種類のポリマーの水溶液を組み合わせることで製造可能である。架橋が生じたら、得られるポリマーネットワークが水溶液にてハイドロゲルを生じる。このハイドロゲルは、たとえば、ポリマー溶液を標的部分に噴霧する、吹き掛ける、あるいは注ぐことによって、in situで形成可能である。あるいは、このハイドロゲルを事前に形成した上で標的部分に適用しても構わない。別の実施形態では、ポリマー成分を取り入れた創傷被覆材が湿っているときに、ハイドロゲルを形成できる。
一実施形態では、ハイドロゲルが、(a)と(b)とを組み合わせて約1秒から約5分以内に生じて薬物を生成する。
(a)ジカルボキシル誘導体化キトサンポリマーと、
(b)アルデヒド誘導体化デキストランポリマーと、を含む、キットを提供するものである。
(a)ジカルボキシル誘導体化キトサンポリマーと、
(b)アルデヒド誘導体化デキストランポリマーと、を別々の容器に含む、キットを提供するものである。
一実施形態では、本発明のキットは、癒着形成しやすい組織の手術後の癒着を予防または低減する方法における使用説明書も含む。
1. 定義
本明細書で使用する場合、「キトサン」という用語は、ランダムに分散されたβ−(1,4)結合したD−グルコサミンおよびN−アセチル−D−グルコサミンからなる直鎖型の多糖を意味する。キトサンはキチンを脱アセチル化して生成可能なものである。α−キトサンとβ−キトサンのどちらも本発明で使用するのに適している。脱アセチル化度(%DA)はキトサンの溶解性や他の特性に影響する。市販のキトサンは一般に、脱アセチル化度が約50から100%である。完全に脱アセチル化したキトサンのモノマー単位を以下の式Iに示す。
本発明は、2種類の周知のポリマーであるキトサンとデキストランの誘導体化および架橋によって形成される新規なポリマーネットワークに関する。このポリマーは、水溶液中でハイドロゲルを生成しながらすみやかに三次元ポリマーネットワークを形成する。ハイドロゲルの特性については、2種類のポリマー成分の誘導体化と架橋を変更することで、特定の用途に合わせて微調整が可能である。
キトサンは広く利用でき、Sigma-Aldrich(www.sigma-aldrich.com)などのさまざまな提供元から業務入手可能である。
デキストランは、主にα−1,6リンケージで結合されたD−グルコース単位で構成される多糖である。ロイコノストック・メセンテロイデス(Leuconostoc mesenteroies)をスクロースで成長させて、高分子量の粗デキストランを業務入手する。得られる多糖を加水分解して、低分子量のデキストランを得る。
本発明は、アルデヒド誘導体化デキストランポリマーと架橋したジカルボキシ誘導体化キトサンポリマーを含む、ポリマーネットワークを提供するものである。一実施形態では、ジカルボキシ誘導体化キトサンポリマーがN−スクシニルキトサンポリマーである。一実施形態では、N−スクシニルキトサンポリマーが、N−スクシニルキトサンポリマーのアミン基およびアルデヒド誘導体化デキストランポリマーのアルデヒド基によってアルデヒド誘導体化デキストランポリマーと架橋している。好ましくは、N−スクシニルキトサンポリマーが、N−スクシニルキトサンである。
ジカルボキシ誘導体化キトサンポリマーは、アルデヒド誘導体化デキストランポリマーと反応し、三次元架橋ポリマーネットワークを生成する。このポリマーネットワークは、これが形成される水溶液との間でハイドロゲルを形成する。本発明のハイドロゲルは、自らを医療用途で、特に創傷治癒、手術による癒着の予防、出血の低減(止血)で使用するのに適したものとする特性を有する。
(a)アルデヒド誘導体化デキストランポリマーと架橋されてもよいし、
(b)ジカルボキシ基との間でアシル化されてもよく、あるいは、
(c)アセチル化(元のキチン材料から)されてもよい。
(a)キトサンの脱アセチル化度、
(b)キトサンのジカルボキシ誘導体化度、
(c)アルデヒド誘導体化デキストランの酸化度、
(d)水溶液中の濃度
のパラメータを操作することが可能である。
一態様では、本発明は、組織を本発明のハイドロゲルで治療することを含む、癒着形成しやすい組織の癒着を予防または低減する方法を提供するものである。
一実施形態では、本発明のハイドロゲルをin situで生成する。たとえば、溶液を標的部分に噴霧する、吹き掛ける、あるいは注ぐことによって、ジカルボキシ誘導体化キトサンポリマーおよびアルデヒド誘導体化デキストランポリマーの水溶液を同時に適用することが可能である。標的部分は、創傷(特に術創)であってもよいし、組織であってもよい。
本発明のハイドロゲルを、生物学的活性剤の部位特異的徐放キャリアとして用いることが可能である。したがって、一態様本発明は、組織を本発明のハイドロゲルで治療することを含む、1種以上の生物学的活性剤を組織まで送達する方法であって、ハイドロゲルが1種以上の生物学的活性剤を含有する方法を提供するものである。
別の態様では、本発明は、
(a)ジカルボキシル誘導体化キトサンポリマーと、
(b)アルデヒド誘導体化デキストランポリマーと、を含む、本発明の方法で用いるキットを提供するものである。
また、本発明は、湿ると本発明のハイドロゲルを放出できる創傷被覆材も提供するものである。創傷被覆材は、従来技術において周知の好適なドレッシングであればどのようなものであってもよい。一例として、絆創膏、ストリップ、パッド、ガーゼ、フィルム、ストッキング、テープがあげられる。
N−スクシニルキトサンポリマー(DMF法)
バッチA.無水コハク酸(2.15g、0.0215mol)を100mlのN,N−ジメチルホルムアミド(DMF)中でキトサン(1.5g、0.007mol)に加えた。この混合物を窒素下で3時間、150℃まで加熱した。
3時間攪拌しながらキトサン(Aldrich、実用グレード)(20g)を乳酸(20ml)および水(650ml)に溶解した。メタノール(650ml)を加え、混合物を35℃まで温めた。無水コハク酸(29g)を加え、混合物を35℃で4時間強く攪拌した。無水コハク酸は溶解するのに数時間を要した。水酸化ナトリウム溶液(水300mlに35g)を加え、混合物を1時間強く攪拌した。こうして得られた、部分的にゲル化した曇った混合物を1日間透析してメタノールを除去し、続いて強く攪拌して残っている最終ゲルを破砕し、蒸留水にて(12時間ごとに水を交換しながら)さらに3日間透析し、濾過した。凍結乾燥によって生成物(16.5g)を得た。
アルデヒド誘導体化デキストラン
バッチA.デキストラン(1g、MW60,000〜90,000)を20mlの蒸留水に溶解した。過ヨウ素酸ナトリウム(2g)を溶液に加え、これを室温にて3時間攪拌した。この溶液を3L容のビーカーで水を定期的に交換しながら一晩透析した。次に、この溶液を濃縮し、凍結乾燥させて、アルデヒド誘導体化デキストランを白色粉末として得た。
水溶液中にアルデヒド誘導体化デキストランポリマーと架橋したN−スクシニルキトサンを含むポリマーネットワーク
実施例1のN−スクシニルキトサン(30mg)を0.6mlの蒸留水に溶解させ、5%w/vの水溶液(溶液A)を生成した。アルデヒド誘導体化デキストランポリマー(30mg)を0.6mlの蒸留水に溶解して、5%w/v水溶液(溶液B)を生成した。
N−スクシニルキトサンの官能基レベルとハイドロゲルのゲル時間に対する塩基処理の効果
実施例1(DMF法−バッチC)に基づいてN−スクシニルキトサンを調製したが、キトサンとNaOHの溶液については以下の表1に示す温度で14時間加熱した。表1から、温度が高くなればなるほど脱アシル化度が大きくなり、結果として遊離アミン基の割合も多くなることが分かる。アセチルおよびN−スクシニル基に対する遊離アミン基の相対特性を‘Η nmrで求めた。
デキストランのアルデヒド誘導体化とハイドロゲルのゲル形成時間に対するmol%過ヨウ素酸塩の効果
実施例2に基づいてアルデヒド誘導体化デキストランを調製したが、ここでは異なるmol%の過ヨウ素酸塩を用いた。反応を室温にて2時間実施した。表2に、得られたアルデヒド誘導体化デキストランの分子量、アルデヒド基のmol%、アルデヒド誘導体化デキストランの溶液をN−スクシニルキトサンの溶液と混合した際にハイドロゲルが形成されるまでの時間を示す。
ヒツジにおける内視鏡的副鼻腔手術後の癒着に対するハイドロゲルの効果
20頭のヒツジ(merino cross wethers)で、十分に確立された内視鏡的副鼻腔手術創傷治癒プロトコールを用いて、標準化全層粘膜創傷を得た。各ヒツジの鼻の外壁に2つの傷を作り、それぞれの側に篩骨損傷を1つ作った。損傷を受けた領域を4つの処理群に無作為化し、(a)対照、(処理なし)、(b)SprayGel(商標)、(c)組換え組織因子、d)本発明のハイドロゲルのうちの1つで処理した。
Bonferroni補正した事後試験を用いる二元配置ANOVAを実施して、上皮の高さ、再上皮化、再線毛化、線毛グレードおよび鼻の外壁の癒着の比率とグレードを分析した。ウィルコクソン符号順位検定を用いて、篩骨癒着率のマッチドペアを解析した。統計的有意性についてはp<0.05に設定した。
鼻の外壁に経時的な癒着のある各群におけるヒツジの比率を図1に示す。全層損傷法を使用すると、対照群の癒着率が15%、組織因子群の癒着率が25%であったのに対し、SprayGel(商標)群の率は10%であった。ハイドロゲル群は癒着率が10%であったが、しかしながらこれは56日目に5%まで落ち、研究の最後までそのレベルに保たれた。ハイドロゲル群は、56日目、84日目、112日目に組織因子群よりも癒着の比率が有意に低かった(5%vs25%、p<0.05)。
SprayGel(商標)と本発明のハイドロゲルはいずれも、癒着予防特性を呈した。特に、ハイドロゲルは鼻の外壁と前篩骨の両方で組織因子に比して癒着形成を有意に低下させた。
前向きランダム化比較パイロット試験を実施した。フルハウスの内視鏡的副鼻腔手術を受けた6名の患者に対して無作為にハイドロゲル20mlを与え、対側には何の処置もほどこさなかった。それぞれの側で手術の終わりに内視鏡下で観察しながら溶液を噴霧して適用した。適用後の出血については、標準的な動画内視鏡法で記録し、事前に検証した2つの尺度で2分ごとに最大10分まで評価した。
ハイドロゲルでは、適用後4分、6分、8分、10分の時点で術野に臨床的に有意な改善が認められた(表5および図10および図11を参照のこと)。
ヒツジにおける内視鏡的副鼻腔手術後の止血に対するハイドロゲルの効果
この研究では、ヒツジバエ(Oestrus ovus)を外寄生させた21頭のヒツジ(merino cross wethers)を用いた。経鼻内視鏡でヒツジバエ感染を目視確認し、リーシュマン染色した鼻用のスワブで好酸球性副鼻腔炎を記録した。頸静脈にチオペントンナトリウムを注射(体重kgあたり19mg)して全身麻酔を導入した。次に、1.5〜2.0%ハロタンの吸入により麻酔を維持したまま気管内挿管した。マイクロデブリッダーを用いて前篩骨複合体と鼻腔壁との間に標準的な粘膜損傷を作る前に中鼻甲介を取り除いた(Medtronic ENT、Jacksonville、Florida)。ストップウォッチを用いて両側での損傷実施時間を30秒間で区切った。粘膜損傷直後に、Boezaart術野評価尺度(Boezaart AP、Van Der Merne J、Coetzee A、Comparison on sodium nitroprusside and esmolol induced controlled hypertension for functional endoscopic sinus surgery. (Can J Anaesth 1995, 42, page 373-376)(表6)を用いて独立した観察者によって基線術野グレードを求めた。
GraphPad PrismおよびSPSS 11.0を用いて術野グレードスコアを解析した。データが正規分布していないため、ウィルコクソン符号順位検定を用いる非母数データ用の一対比較試験を使用して、それぞれの側での手術グレードの差異を解析した。複数回の試験でのBonferroni補正を手術グレードのすべての解析に適用し、統計的有意性をp<0.05に設定した。スチューデントのT−検定を用いて、完全な止血に至るまでの時間の平均を比較した。
本研究のこの段階では、21頭のヒツジ(merino cross wethers)を用いた。基線出血時間に対照群vsハイドロゲルで有意な差異は認められなかった(2.4±0.67vs2.4±0.74)。ハイドロゲル側のほうが、適用後2分、4分、6分の時点で有意に止血された。対照群vsハイドロゲルの平均評価スコアと95%信頼区間は、2分−1.6(±0.92)vs0.9(±0.53)、4分−1.0(±0.66)vs0.24(±0.43)、6分−0.4(±0.59)vs0.048(±0.21)(p<0.05)(図12)であった。
ハイドロゲル側はすべて、6分までに完全に止血された。止血までの平均時間は、ハイドロゲル側で4.09(±1.61)vs対照群側で6.57(±2.20)(p=0.049)(図13)と、有意に改善された。対照群側で続いている出血は、8分の時点で3つの側、10分の時点で1つの側にあった。これに対し、ハイドロゲル側では6分を過ぎてからは出血は認められなかった。
本研究のこの段階では、20頭のヒツジを用いた。術後1日目、31日目、71日目、141日目に、対照群側の平均痂皮とハイドロゲル溶解スコアに有意な差異は認められなかった。対照群vsハイドロゲルの平均痂皮/ハイドロゲル溶解スコアならびに95%信頼区間は、1日目−2.0(±0.00)vs1.9(±0.31)、3日目−1.6(±0.60)vs1.65(±0.59)、7日目−0.47(±0.61)vs0.53(±0.70)、14日目−0.00(±0.00)vs0.05(±0.22)(図14)であった。
ヒツジの慢性副鼻腔炎モデルでは、本発明のハイドロゲルは、粘膜損傷の2分、4分、6分後に対照群に比して止血を有意に改善する。また、対照群と比較すると、同様の痂皮溶解特性を呈する。有意な止血作用のある創傷治癒に対する周知の好ましい効果と組み合わせて、本発明のハイドロゲルは、ESSを受けている患者におけるESS後の術後創傷被覆材として大きな可能性を秘めている。
本発明は、創傷治癒と癒着の予防を助けるために創傷に適用可能な水ベースの生分解性ハイドロゲルを提供するものである。このハイドロゲルは、止血に対しても好ましい効果があり、絆創膏やフィールドドレッシングに適用して、出血性の外傷創傷および術後の出血を止める助けとすることが可能である。
Claims (10)
- アルデヒド誘導体化デキストランポリマーと架橋したジカルボキシ誘導体化キトサンポリマーを含む、ポリマーネットワーク。
- 前記ジカルボキシ誘導体化キトサンポリマーが、前記ジカルボキシ誘導体化キトサンポリマーのアミン基および前記アルデヒド誘導体化デキストランポリマーのアルデヒド基を介して前記アルデヒド誘導体化デキストランポリマーと架橋される、請求項1に記載のポリマーネットワーク。
- ハイドロゲルの形態である、請求項1または請求項2に記載のポリマーネットワーク。
- 2%から10%w/vのジカルボキシ誘導体化キトサンポリマーと2%から10%w/vのアルデヒド誘導体化デキストランポリマーとを含む、請求項3に記載のポリマーネットワーク。
- 前記ジカルボキシ誘導体化キトサンポリマーが、N−スクシニルキトサンである、請求項1〜4のいずれか一項に記載のポリマーネットワーク。
- 血漿タンパク質、ホルモン、酵素、抗生物質、防腐剤、抗悪性腫瘍薬、抗真菌薬、抗ウイルス薬、抗炎症薬、成長因子、ステロイド、細胞懸濁液、細胞毒、および細胞増殖阻害剤から選択される1種以上の生物学的活性剤をさらに含む、請求項3〜5のいずれか一項に記載のポリマーネットワーク。
- 請求項3〜6のいずれか一項に記載のポリマーネットワークの製造方法であって、ジカルボキシ誘導体化キトサンポリマーの水溶液とアルデヒド誘導体化デキストランポリマーの水溶液とを混合することを含む方法。
- 癒着形成の影響を受けやすい組織の癒着を予防または低減するため、創傷治癒を加速または促進するため、あるいは創傷の出血を止めるための組成物であって、請求項1〜6のいずれか一項に記載のポリマーネットワークを含む組成物。
- 請求項1〜6のいずれか一項に記載のポリマーネットワークを含む、耳、鼻および喉の外科手術用組成物。
- 請求項1〜6のいずれか一項に記載のポリマーネットワークを製造するためのキットであって、
(a)ジカルボキシル誘導体化キトサンポリマーと、
(b)アルデヒド誘導体化デキストランポリマーと、
(c)前記キットを、癒着形成の影響を受けやすい組織の癒着を予防または低減するため、創傷治癒を加速または促進するため、あるいは創傷の出血を止めるために用いるための使用説明書
を含む、キット。
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US8809301B2 (en) | 2014-08-19 |
JP2010537711A (ja) | 2010-12-09 |
US20130244974A1 (en) | 2013-09-19 |
KR101610268B1 (ko) | 2016-04-07 |
WO2009028965A1 (en) | 2009-03-05 |
EP2195039A1 (en) | 2010-06-16 |
CN101848739A (zh) | 2010-09-29 |
AU2008293135B2 (en) | 2014-08-07 |
EP2195039A4 (en) | 2013-01-09 |
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