JP2018523728A - 殺菌性ポリマー及びその合成 - Google Patents
殺菌性ポリマー及びその合成 Download PDFInfo
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- JP2018523728A JP2018523728A JP2018503480A JP2018503480A JP2018523728A JP 2018523728 A JP2018523728 A JP 2018523728A JP 2018503480 A JP2018503480 A JP 2018503480A JP 2018503480 A JP2018503480 A JP 2018503480A JP 2018523728 A JP2018523728 A JP 2018523728A
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Abstract
Description
本明細書に提供される定義に関して、別途明示的に述べられるか、又は文脈から明らかでない限り、定義される用語及び語句は提供された意味を含む。特に断らない限り、又は文脈から明らかでない限り、以下の用語及び語句は、用語又は語句が関連技術分野の当業者によって把握される意味を排除するものではない。本発明の範囲は特許請求の範囲によってのみ限定されるので、定義は具体的な実施形態の記述を補助するために提供され、特許請求の範囲に記載された発明を限定するものではない。文脈によって特に要求されない限り、単数形の用語は複数形を含み、複数形の用語は単数形を含むものとする。
PASポリマーの合成は、いくつかの予期せぬ課題を生じ、その各々は本出願人により本発明の方法で対処された。例えば、5−HMAモノマーの精製の間の、水とメタノールを使用することによるこのモノマーの再結晶化は、2つの溶媒の特定の体積比率(0.5:2、水:メタノール)を必要とし、これにより生成物の完全な溶解及び再結晶を確実にする。
PASポリマーの合成に使用されるモノマーの1つである5−HMAの調製のための合成方法は、SanRoman,et al.[an initial study is shown in Elvira and San Roman,“Synthesis and stereochemistry of isomeric methacrylic polymers derived from 4− and 5−aminosalicylic acids”,Polymer,38,4743−4750,1997;and a follow−up study is disclosed in Elvira,Gallardo,Lacroix,Schacht,San Roman,“Incorporation of salicylic acid derivatives to hydrophilic copolymer systems with biomedical applications”,J Mater Sci Mater Med,12,535−542,2001]に記載された方法から適合できる。
開始剤として0.3モル%の4,4’−アゾビス(4−シアノ吉草酸)を用いて70℃、THF中でNIPAAm(68モル%)、NAS(14モル%)、PLA/HEMA(8モル%)、OEGMA(5モル%)及び5−HMA(5モル%)のフリーラジカル重合によってPASポリマーを合成した。24時間後、得られたポリマー溶液を32℃の水中で沈殿させて、未反応モノマーを除去した。次いで、沈殿したポリマーをエタノールに溶解し、同じ条件下で水中に再沈殿させた。次いで、得られたポリマーを40℃で48時間減圧乾燥した。
OEGMA含量5モル%の合成PASポリマーは水溶性であることが判明した。ポリマーのペプチド反応性を確認するために、GRGDS({GLY}{ARG}{GLY}{ASP}{SER})合成ペプチドをモデルペプチドとして使用した。GRGDSは、細胞外マトリックス中の多くの接着タンパク質の細胞結合部位を模倣し、拡散した細胞を球状にして、剥離を引き起こす。GRGDSペプチドは、骨機能に関与することが最も報告されているインテグリンであるV3及びIIb3に対する中間的な親和性を有する。PAS(150mg/mL)とGRGDS(1mg/mL)を混合し、4℃で8時間反応させた。次いで、得られたPAS−co−GRGDS(PASGel)溶液を、生理学的温度(例えば、37℃)まで温度を上昇させてヒドロゲルに変換した。
組織工学、薬物送達及び創傷被覆剤適用において、生体材料の組織接着性は、組織漏出等の臨床的合併症を防止するために非常に重要である。本出願人は、PASGelのこの特性を評価するために、ブタ皮膚を用いたex vivo ASTMD3164−03(2014)標準法を使用した。この分析のために、100μLのPASGelを用いて、0.5×0.5cm2の領域を充填して、2枚のブタ皮膚を接着させた。
シミュレートされた生理学的条件では、PASGelヒドロゲルがそれぞれ311±47kPa及び781±116kPaの圧縮及び引張り係数を示した。これらの機械的性能パラメータは、以前に開発された又は市販のヒドロゲルと比較して、最も重要である。例えば、軟骨修復のための臨床試験段階にあるNeocartヒドロゲルは、10kPa未満の圧縮弾性率を有する[Ahmed and Hincke,“Strategies for articular cartilage lesion repair and functional restoration”Tissue Eng Part B Rev;16,305−329,2010]、BioGlue[CryoLife:BioGlue(R) Summary of Safety and Effectiveness Surgical Adhesive Indications for Use Contraindications;FDA Rep 2013]、ProGel[ProGel summary of Safety and Effectiveness Data;FDA Rep 2008:1−26]、及びCrosseal[Crosseal Summary of Safety and Effectiveness Data;FDA Rep 2010]のような、外科的シーラントと比較して、PASGelはより弾性的で機械的に堅牢である。これらの機械的性能の両方は、内外の創傷被覆及び組織再生にとって重要である。
PASGelが潜在的に、とりわけ以下のように使用されるかどうかを調べるための試験が行われた:
・内部出血シーラント;深部組織のための外科用シーラント;及び/又は
・欠陥部位の充填又は物理的封じ込めによって血液漏出を防止するために使用されることが意図される物理的凝固剤。
Claims (45)
- 少なくとも3つのさらなるモノマー単位と組み合わせられる、少なくとも1つの殺菌性/鎮痛性/抗炎症性モノマー単位を含み、前記3つのさらなるモノマー単位が、温度活性化、水溶性、機械的強度、タンパク質/多糖結合能力、及びそれらの組み合わせからなる群から選択される特性を生起する、ポリマー。
- 前記殺菌性/鎮痛性/抗炎症性モノマー単位が、5−HMA、4−HMA、又はそれらの組み合わせから選択されるサリチル酸のメタクリル酸エステル誘導体を含む、請求項1に記載のポリマー。
- 前記少なくとも3つのさらなるモノマー単位が、
親水性エチレングリコール(OEGMA)成分の形態の水溶性モノマー単位;
ポリラクチド−co−2−ヒドロキシ−エチルメチルアクリレート(PLA/HEMA)の形態の機械的強度を付与するモノマー単位;
N−アクリロキシスクシンイミド(NAS)成分の形態のタンパク質/多糖類反応性モノマー単位;及び
N−イソプロピルアクリルアミド(NIPAAm)成分の形態の熱硬化性モノマー単位
からなる群から選択される、請求項1又は2に記載のポリマー。 - 親水性エチレングリコール(OEGMA)成分の形態の水溶性モノマー単位中に一定の水溶性を提供し、それにより、ポリマーの調製における有機溶媒の使用を実質的に回避する、請求項3に記載のポリマー。
- 機械的強度を付与するモノマー単位が、制御可能な機械的強度、可撓性及び弾性を与え、一定の用途の特定された要求のためにポリマーを調整する、請求項3又は4に記載のポリマー。
- 機械的強度を付与するモノマー単位が、ポリマーに組織接着挙動を与え、それにより、送達部位における前記ポリマーの沈着物の保持を容易にする、請求項3又は4に記載のポリマー。
- ポリラクチド−co−2−ヒドロキシ−エチルメチルアクリレート(PLA/HEMA)の形態の、機械的強度を付与するモノマー単位は、ヒドロゲルが、PLAの段階的な切断により、腎臓を介して生体吸収性である分解特性;及びヒドロゲルの周囲組織への移動及び漏出を防止するための組織接着性を提供する、請求項3から6のいずれかに記載のポリマー。
- 水溶性モノマー単位の及び機械的強度を付与するモノマー単位の量において、制御可能な生体吸収挙動が提供される、請求項3から7のいずれかに記載のポリマー。
- N−アクリロキシスクシンイミド(NAS)成分の形態のタンパク質反応性モノマー単位が、異なる生物学的活性ペプチド及び多糖類をヒドロゲルに結合させることによってペプチド反応性を提供し、細胞シグナル伝達及び組織形成速度を促進する、請求項3から8のいずれかに記載のポリマー。
- N−イソプロピルアクリルアミド(NIPAAm)成分の形態の熱硬化性モノマー単位が、約37℃で、その場での構造形成を誘導することによる熱硬化特性を提供する、請求項3から9のいずれかに記載のポリマー。
- 0℃から35℃で10mg/mLから700mg/mLの質量含有量で水溶液に溶解される、請求項3から10のいずれかに記載のポリマー。
- 温度を37℃以上に上昇させることによりその場でミクロ構造又はマクロ構造を形成する、請求項11に記載のポリマー。
- ポリマーの生物学的有効性が、細胞適合性試験及び微生物コロニー計数試験によって確認可能である、請求項1から12のいずれかに記載のポリマー。
- 得られる圧縮強度及び引張強度の、ポリマーの機械的特性が、それぞれ、約200kPaから約400kPa、及び約500kPaから約800kPaの範囲内である、請求項1から13のいずれかに記載のポリマー。
- 組織接着試験が、少なくとも約970kPaの接着せん断強度を示す、請求項1から14のいずれかに記載のポリマー。
- 以下の構造によって概略的に表される、請求項1から15のいずれかに記載のポリマー:
- 外科用シーラント、創傷治癒被覆剤、充填剤又は生体内組織再生足場として使用される、請求項1から16のいずれかに記載のポリマー。
- おおよその相対モル比で、約5モル%未満のOEGMAを含む、請求項1から17のいずれかに記載のポリマー。
- おおよそ相対モル比で、約8モル%を超えるPLA/HEMAを含む、請求項1から18のいずれかに記載のポリマー。
- ポリマーが、おおよその相対モル比で、約8モル%を超えるPLA/HEMAを含み、それにより約37℃でヒドロゲル形成を生起する、請求項19に記載のポリマー。
- おおよその相対モル比で、NIPAAm(68モル%);NAS(14モル%);PLA/HEMA(8モル%);OEGMA(5モル%);並びに5−HMA及び/又は4−HMA(5モル%)を含む、請求項1から20のいずれかに記載のポリマー。
- ポリマーが、生体内でポリマーを送達した後に、手術部位において対象の異物免疫応答及び慢性炎症による臨床合併症を生起しない、請求項1から21のいずれかに記載のポリマー。
- 約0日から約270日の期間にわたり、サリチル酸のメタクリル酸エステル誘導体からの殺菌性/鎮痛性/抗炎症性効果のバースト放出を防止するためのビヒクルを提供し、それにより、手術部位での時間ベースでの感染の発生率を減少させる、請求項1から22のいずれかに記載のポリマー。
- 約0から約270日の期間が約10から約260日;約20日から約250日;約30日から約240日;約40日から約230日;約50日から約220日;約60日から約210日;約70日から約200日;約80日から約190日;約90日から約180日;約100日から約170日;約110日から約160日;約110から約150日;約120日から約140日;又は約130日間である、請求項23に記載のポリマー。
- 前記ポリマーが、天然及び合成のペプチド又は多糖類と結合する、請求項1から24のいずれかに記載のポリマー。
- 生物学的組織の修復を補助するための1以上の細胞をさらに含む、請求項25に記載のポリマー。
- 前記1以上の細胞が前記ポリマー全体にわたって比較的均一に分布している、請求項26に記載のポリマー。
- ポリマー中の1以上の細胞の数が約102細胞/mLから約108細胞/mLである、請求項26又は27に記載のポリマー。
- ポリマー中の1以上の細胞の数が約103細胞/mLから約105細胞/mLである、請求項28に記載のポリマー。
- 一定のモル量の殺菌性/鎮痛性/抗炎症性モノマー単位と;それぞれ一定のモル量の水溶性モノマー単位;機械的強度を付与するモノマー単位;タンパク質反応性モノマー単位;及び熱硬化性モノマー単位のうちの少なくとも3種との、一定のモル量の開始剤のフリーラジカル重合を含む、請求項1から29のいずれかに記載のポリマーの合成方法。
- 約24時間までの期間にわたって進行して実質的に完了することを特徴とする請求項30に記載の方法。
- 約32℃の水中でポリマーを沈殿させて未反応モノマーを除去し、濾過する抽出工程をさらに含む、請求項30又は31に記載の方法。
- 沈殿したポリマーをエタノールに溶解し、約32℃の水中に再沈殿させる精製工程をさらに含む、請求項32に記載の方法。
- 使用前にポリマーを約40℃の温度で約48時間、減圧下で乾燥させる、請求項32又は33に記載の方法。
- 前記殺菌性/鎮痛性/抗炎症性モノマー単位が5−HMA及び/又は4−HMAであり;存在する場合、水溶性モノマー単位はNIPAAmであり;機械的強度を付与するモノマー単位はNASであり;タンパク質反応性モノマー単位はPLA/HEMAであり;熱硬化性モノマー単位はOEGMAである、請求項30から34のいずれかに記載の方法。
- 5−HMA及び/又は4−HMAの一定のモル量が約5モル%であり、存在する場合、NIPAAmの一定のモル量が約68モル%であり;NASの一定のモル量は約14モル%であり;PLA/HEMAの一定のモル量は約8モル%であり;OEGMAの一定のモル量は約5モル%である、請求項35に記載の方法。
- 医療用途における、請求項1から29のいずれかに記載のポリマーの使用。
- 前記ポリマーが、外科用シーラント、創傷治癒被覆剤、充填剤として使用されるか、又は生体内組織再生又は試験管内細胞増殖足場のために使用される、請求項37に記載の使用。
- 癌を含む医学的状態の治療における、請求項1から29のいずれかに記載のポリマーの使用。
- 前記癌が肺癌を含む、請求項39に記載の使用。
- 外科的シーリング、創傷の被覆、空洞の充填、又は生体内組織発生足場の提供の方法であって、そのような処置を必要とする対象に、有効量の請求項1から29のいずれかに記載のポリマーを投与することを含む方法。
- 癌を含む医学的状態の治療方法であって、請求項1から29のいずれかに記載の有効量のポリマーをそのような治療を必要とする対象に投与することを含む方法。
- 前記癌が肺癌を含む、請求項42に記載の方法。
- 請求項1から29のいずれかに記載のポリマーと;ポリマーを生物学的に適合するヒドロゲルと組み合わせるための指示書と;必要に応じてシリンジを含む、医療用キット。
- 実質的に本明細書に記載のポリマー、ポリマーの使用、ポリマーを使用する医療処置の方法、又はポリマーを含む医療キット。
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