JP2020517386A - 生分解性の骨用接着剤 - Google Patents
生分解性の骨用接着剤 Download PDFInfo
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- JP2020517386A JP2020517386A JP2019558497A JP2019558497A JP2020517386A JP 2020517386 A JP2020517386 A JP 2020517386A JP 2019558497 A JP2019558497 A JP 2019558497A JP 2019558497 A JP2019558497 A JP 2019558497A JP 2020517386 A JP2020517386 A JP 2020517386A
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Abstract
Description
(a) ポリマー主鎖、式Iの生体吸収性ポリマーまたはその混合物を準備すること、
(b) ポリマー主鎖、式Iの生体吸収性ポリマーまたはその混合物を溶剤に添加して、ポリマー溶液を形成すること、
(c) 前記ポリマー溶液に添加剤を添加または接触させること、
(d) 印刷ヘッドを介して前記ポリマー溶液を印刷して、多層の3D印刷された部品を形成すること、および
(e) 前記3D印刷された部品を硬化させること、
を含む前記方法が開示される。
(a) ポリマー主鎖、式Iの生体吸収性ポリマーまたはその混合物を準備すること、
(b) ポリマー主鎖、式Iの生体吸収性ポリマーまたはその混合物を溶剤に添加して、ポリマー溶液を形成すること、
(c) 前記ポリマー溶液に添加剤を添加または接触させること、
(d) 印刷ヘッドを介して前記ポリマー溶液を印刷して、多層のバイオプリントされた部品を形成すること、
(e) 前記バイオプリントされた部品を硬化させること
を含み、段階(b)または(c)のいずれかがさらに、生物活性剤を添加することを含む、前記方法が開示される。
本願の化合物および方法を開示し且つ説明する前に、本願に記載される態様は特定の方法、化合物、合成方法、物品、装置または用途に限定されず、当然のことながらそれらは変化できることが理解されるべきである。本願内で使用される用語は、特定の態様を説明する目的のためだけであり、特段定義されない限り、限定することは意図されていないことも理解されるべきである。
特段定義されない限り、本願内で使用される全ての技術用語および科学用語は、当業者によって慣例的に理解されるものと同じ意味を有する。矛盾する場合は、定義を含めて本書面が管理する。好ましい方法および材料を以下に記載するが、本願内に記載されたものと類似または均等な方法および材料を、本発明の実施または試験において使用できる。本願内で言及される全ての刊行物、特許出願、特許および他の参考文献は、参照をもってその全文が本願内に含まれるものとする。本願内で開示される材料、方法および例は、説明のためだけであり、限定することは意図されていない。
PEG−PLGA−PEG主鎖(ポリマー主鎖)の合成
図1に描かれるスキーム1はPEG−PLGA−PEG主鎖の製造に関する。D,Lラクチド(601.3g、4.17mol)およびグリコシド(149.0g、1.28mol)の溶融混合物に、ガラス漏斗を用いてグリコール酸(18.9g、0.25mol)を添加した。前記混合物を10分間撹拌し、次に2−エチルヘキサン酸スズ(II)(0.2309g、0.57mmol)のトルエン(5ml)中の溶液を、シリンジを用いて添加した。その添加の直後に、反応器の温度を170℃に設定した。3時間30分後、コハク酸無水物(124.3g、1.24mol)を添加し、溶融された混合物を170℃で2時間撹拌した。次に、反応器を最大限の真空度が達成されるまでゆっくりと排気し、真空下でさらに2時間保持した。反応器を窒素でパージした。前記のポリマーをパンに注ぎ入れ、液体窒素で冷却した。得られた粗製材料(736g)を、次に真空下、室温で乾燥させ(真空度は−28インチ/Hgである)、析出によって精製し(水/アセトン比20:1)、清浄な生成物をもたらした。全体の収率は70%であった。
Rが
図2に描かれるスキーム2は式Aの製造に関する。50mlの丸底フラスコ内で、塩酸ドパミン(0.356g、1.88mmol)を、トリエチルアミン(TEA、0.26ml、1.88mmol)の存在下でジクロロメタン中に溶解し、10分間、室温で撹拌した。別のフラスコ内で、カルボン酸末端化PEG−PLGA−PEG(IV)(3g、0.75mmol)および1,3−ジシクロヘキシルカルボジイミド(DCC、0.387g、1.88mmol)を、ジクロロメタン(DCM、10ml)中で溶解した。次に、その2つの溶液を合わせて、4−ジメチルアミノピリジン(DMAP、0.23g、1.88mmol)を添加した。次に、この溶液を12時間、還流条件下で撹拌した。形成された析出物のジシクロヘキシル尿素をろ過して取り出し、反応混合物を冷たいジエチルエーテル中に注いだ。析出物をろ過し、エタノールで洗浄し、真空下、室温で2日間乾燥させて、生成物Vをもたらした。
Rが
図3に描かれるスキーム3は式Bの製造に関する。機械撹拌機を備えた500mlの反応器内で、カルボン酸末端化PEG−PLGA−PEG(IV)(10g、2.5mmol)および1,3−ジシクロヘキシルカルボジイミド(DCC、1.9g、9.15mmol)を、ジクロロメタン(DCM、100ml)中で溶解した。この溶液に、NHS(1.05グラム、9.15mmol)を添加した。この溶液を12時間、還流条件下で撹拌した。形成された析出物のジシクロヘキシル尿素をろ過して取り出し、反応混合物を冷たいジエチルエーテル中に注いだ。析出物をろ過し、エタノールで洗浄し、真空下、室温で2日間乾燥させて、生成物VIをもたらした。
Rが
図4に描かれるスキーム4は式Cの製造に関する。PTFEの丸底フラスコ内で、基材III(2g、0.53mmol)およびトリエチルアミン(0.3ml、2.1mmol)を20mLのテトラヒドロフラン中で溶解した。その透明な溶液に、トリエトキシシリルプロピルイソシアネート(0.26mL、1.05mmol)を滴下し、その反応混合物を還流温度で12時間撹拌した。次に、反応を平衡させて室温にした。6mlのエタノールを添加し、その溶液を室温で16時間撹拌した。その後、溶剤を減圧下で蒸発させた。残留油を6mlのDCM中で溶解し、その溶液をジエチルエーテル中に注いだ。析出物を単離し、真空下で8時間乾燥させて、1.8グラムの白い固体をもたらした(生成物VIII)。
Rが
図5に描かれるスキーム5は式Dの製造に関する。機械撹拌機を備えた500mlの反応器内で、カルボン酸末端化PEG−PLGA−PEG(IV)(10g、2.5mmol)および1,3−ジシクロヘキシルカルボジイミド(DCC、1.9g、9.15mmol)を、ジクロロメタン(DCM、100ml)中で溶解した。この溶液に、NHS(1.05グラム、9.15mmol)を添加した。この溶液を12時間、還流条件下で撹拌した。形成された析出物のジシクロヘキシル尿素をろ過して取り出し、反応混合物を冷たいジエチルエーテル中に注いだ。析出物をろ過し、エタノールで洗浄し、真空下、室温で2日間乾燥させて、生成物VIをもたらした。
表1は、生体吸収性ポリマーについてのNMRデータに関する。
骨類似物基材は、BoneSim Laboratories製のウシ海綿骨1200シリーズから得られた(密度: 1.2g/cc、寸法10×10×40mm、シアノアクリレート結合剤5〜7%)。).うざい1.2 boratories,100〜200mgの生分解性ポリマーを0.1〜1mLのジクロロメタン中に溶解し、透明な溶液をもたらした。次に、形成された溶液を1mlのシリンジ(Henke Sass Wolf 1ml NORM−JECT(登録商標)−Tuberkulin)内に装入した。第2の5mlシリンジ(Henke Sass Wolf 5ml(6ml) NORM−JECT(登録商標))にジエチルエーテルを装入した。2つの液体をシリンジから、第1の骨類似物基材の表面上へと押出し、受動的に混合させて粘性のゲルが形成された。そのゲルを第1の骨類似物基材上の15×10mmの表面上で広げ、16時間、減圧(約5Torr)下で乾燥させた。その後、第2の骨類似物基材(第1のものと同じ寸法を有する)を、第1の骨類似物基材の上の、ゲルが広げられた15×10mmの表面上に設置した。1.2kgの重りを、2つの一緒に接着された骨類似物基材の上に少なくとも16時間置いた。次に、製造された試料を、重ね剪断手順を使用して試験した。
手順の開始前に骨基材を予め蒸留水に約10分間浸漬させたこと以外、前記乾燥条件下と同じ手順を使用した。
1mlのシリンジに、PEG 400中の生分解性ポリマー溶液を装入し、且つ5mlのシリンジに水中で15%(w/w)の過酸化水素を装入したこと以外、前記湿潤条件と同じ手順を使用した。
50mlのPE試験管内で、0.3gの式A、B、CまたはDの生体吸収性ポリマーを、0.6mlの無水DMSO中に溶解させた。撹拌プレートを用いて2時間撹拌した後、前記溶液は透明になった(溶液1:0.7ml)。生じる溶液を1mlのシリンジに装入した。他方で、10mlの脱イオン水および可能性のある任意の添加剤(例えばトリエチルアミン、ポリ−l−リシン、架橋剤等)を12mlのシリンジに装入した。
第2の骨類似物基材を、ステンレス鋼である金属基材で置き換えたこと以外、前記乾燥条件と同じ手順を使用した。
ポリマー溶液の6つの試料(各々、0.6gの式Dおよび20mlの0.1w/v%のポリ−L−リシンを含有)を、140rpmで終夜振盪した。該試料を水で洗浄し、実験の前に徹底的に乾燥させた。前記試料は各々、約0.5gの重量であった。次に、各々の試料を、30mLのリン酸緩衝食塩水(1×PBS)、pH7.4で満たされたファルコンの遠心管内に設置した。次に、試料を充填した管を、インキュベータ内に37℃で実験時間の間、設置した。各々の溶液のpHを一日おきに監視し、pHが7.2を下回ったら緩衝液を交換した。様々な時間間隔、具体的には1、2、3、4、6および8週で、管の1つを分析して、生じた分解を評価した。インキュベータから材料を取り出し、室温で1時間平衡させた。次に、その試料を3000rpmで10分間、遠心分離して、ポリマーから上澄み液を分離した。可溶性の分解生成物を含有する上澄み液を回収し、−20℃の冷凍庫でさらなる調査、例えばGPC、HPLC等のために保管した。PBS緩衝剤からの塩残留物を除去するために、残りの材料を脱イオン水で洗浄し、3000rpmで10分間、2回遠心分離した。次にその材料を回収し、一定の質量になるまで真空下で乾燥させた(通常、48時間)。質量損失を各々の時点で測定し、試料を−20℃(冷凍庫)で保管した後、GPCおよびNMRの調査に供した。
生体吸収性ポリマーの3D印刷
ポリマー溶液(0.6mlのDMSO中の0.3gの式D)を準備し、3Dプリンタ(3D Bioplotter Manufacturing Series、Envision Tec製)に適合するカートリッジ内で保管した。0.1%のポリ−l−リシン臭化水素酸塩水溶液(Sigma−Aldrich社から購入)を準備し、4℃で保管した。数層分の高さを有する1cm2の面積の組織のソリッドモデルを作り出した。次に、「スライス」作業を実施して、そのソリッドモデルを印刷のために準備する。そのスライス作業により、ソリッドの部品の形状が、プリンタが印刷しようとしている複数の層へと分けられた。ペトリ皿の取り付け台をプラットフォームに固定した。印刷表面として使用されるペトリ皿を、取り付け台の中に設置した。準備された印刷形状のファイルを、3Dプリンタのソフトウェアにインポートした。印刷のために使用されるポリマー溶液を指定し、印刷インフィルのために使用されるパターンを指定することにより、印刷の準備をした。直径0.4mmのチップを、ポリマー溶液のカートリッジに付け、そのカートリッジを3Dプリンタの印刷ヘッド内に設置した。ペトリ皿の印刷表面を、0.1%のポリ−l−リシン臭化水素酸塩溶液の均質な層を噴霧することによって準備した。ポリマー溶液を含有する印刷ヘッドを較正し、最初の印刷パラメータを見積もり、3Dプリンタソフトウェアにおける材料プロファイルへと配置した。作業者が印刷作業を開始した。3Dプリンタの印刷ヘッドがx方向およびy方向に動いて、部品の形状を印刷した。層の間で、ポリマーを最低30秒間、硬化させた。次に、印刷ヘッドを上昇させ(z)、次の層の形状を印刷した。部品全体が印刷されるまで、この工程を繰り返した。次に、その部品を乾燥させた。
生体吸収性ポリマーの口腔への施与
0.3gのポリマー主鎖を0.6mlのDMSO中に溶解させて溶液1を形成した。溶液2は0.6mlの水または0.6mlのリン酸緩衝生理食塩水(PBS)を含有した。溶液1および溶液2を、アプリケーターのチップのデュアルカニューレに接続された2つのシリンジを通じて同時に部位に施与した。溶液1が溶液2と接触することにより、溶解されたポリマー主鎖が生じ、溶液から析出してゲルを形成する。
生体吸収性ポリマーの口腔への施与
0.3gの式Dのポリマーを0.6mlのDMSO中に溶解させて溶液1を形成した。ポリ−l−リシン(PLL)(0.1w/v%のポリ−L−リシン溶液)を0.6mlの水または0.6mlのリン酸緩衝生理食塩水中に溶解させて、溶液2を形成した。溶液1および溶液2を、アプリケーターのチップのデュアルカニューレに接続された2つのシリンジを通じて同時に部位に施与した。溶液1が溶液2と接触することにより、式Dの溶解されたポリマーが生じ、溶液から析出してゲルを形成する。
(a) 項目1に記載の式Iのポリマー主鎖、生体吸収性ポリマーまたはその混合物を準備すること、
(b) 項目1に記載の式Iのポリマー主鎖、生体吸収性ポリマーまたはその混合物を溶剤に添加して、ポリマー溶液を形成すること、
(c) 前記ポリマー溶液に添加剤を添加または接触させること、
(d) 印刷ヘッドを介して前記ポリマー溶液を印刷して、多層の3D印刷された部品を形成すること、および
(e) 前記3D印刷された部品を硬化させること、
を含む、前記方法である。
(a) 項目1に記載の式Iのポリマー主鎖、生体吸収性ポリマーまたはその混合物を準備すること、
(b) 項目1に記載の式Iのポリマー主鎖、生体吸収性ポリマーまたはその混合物を溶剤に添加して、ポリマー溶液を形成すること、
(c) 前記ポリマー溶液に添加剤を添加または接触させること、
(d) 印刷ヘッドを介して前記ポリマー溶液を印刷して、多層のバイオプリントされた部品を形成すること、
(e) 前記バイオプリントされた部品を硬化させること
を含み、段階(b)または(c)のいずれかがさらに、生物活性剤を添加することを含む、前記方法である。
Claims (23)
- 請求項1に記載の式Iの生体吸収性ポリマーまたはその混合物と、
溶剤と、
非溶剤と
を含む、組成物。 - 前記組成物がさらに添加剤を含む、請求項2に記載の組成物。
- 前記添加剤が前記非溶剤中に溶解されている、請求項3に記載の組成物。
- 前記組成物がさらに抗微生物剤、抗菌剤またはそれらの混合物を含む、請求項2または3に記載の組成物。
- 前記溶剤がアセトン、クロロホルム、ジクロロメタン、ジメチルスルホキシド、ジメチルホルムアミド、ポリエチレングリコール、またはN−メチル−2−ピロリドンである、請求項2または3に記載の組成物。
- 前記非溶剤がエタノール、メタノール、水、シクロヘキサン、ヘキサン、ペンタン、過酸化水素、ジエチルエーテル、tert−ブチルメチルエーテル(TBME)、リン酸緩衝生理食塩水(PBS)またはそれらの混合物である、請求項2または3に記載の組成物。
- 前記添加剤が成長因子、ビタミン、生物学的製剤、抗生物質、抗ウイルス剤、アレンドロネート、オルパドロネート、エチドロネート、コレカルシフェロール(ビタミンD)、トコフェロール(ビタミンE)、ピリドキシン(ビタミンB6)、コバラミン(ビタミンB12)、血小板誘導成長因子(PDGF)、グリシン、リシン、ペニシリン、セファロスポリン、テトラサイクリン、ラミブジンおよびジドブジン、ポリエチレングリコール、ポリアミノ酸(典型的には、50個を上回る結合したアミノ酸、および例えばタンパク質および/またはポリペプチドを含む)、脂肪族ポリエステル(例えばポリ乳酸、ポリグリコール酸および/またはポリカプロラクトンを含む)、糖類(例えば糖を含む)、多糖類(例えばデンプン)、脂肪族ポリカーボネート、ポリアミン(例えばポリエチレンイミンを含む)、ポリ無水物、ステロイド(例えばヒドロコルチゾン)、グリセロール、アスコルビン酸、アミノ酸(例えばリシン、チロシン、セリンおよび/またはトリプトファン)またはペプチド(典型的には2〜50個結合したアミノ酸)、無機粒子(例えばバイオガラス、ヒドロキシアパタイト、セラミック粒子)、ポリエチレンイミン(PEI)、ポリ−l−リシン(PLL)、ポリ−d−リシン(PDL)、ポリ−d,l−リシン(PDLL)、ポリ−l−システイン、ポリ−d−システイン、ポリ−d,l−システイン、短いオリゴマーのl−リシン、d−リシン、l−システイン、d−システイン、アミノ官能化PEG、アミノ官能化無機粒子(バイオガラス、ヒドロキシアパタイト、リン酸四カルシウム)およびスズ触媒である、請求項3に記載の組成物。
- 請求項1に記載の式Iの生体吸収性ポリマーの製造方法であって、ポリマー主鎖と官能基前駆体とを混合して混合物を形成する段階、および前記混合物にリンカーを添加して生体吸収性ポリマーを形成する段階を含む、前記製造方法。
- 材料を接着するための接着剤としての、請求項1から8までのいずれか1項に記載の組成物の使用。
- 前記材料が生物学的組織である、請求項10に記載の使用。
- 前記材料が生物学的組織基材および骨基材である、請求項10に記載の使用。
- 前記材料が金属基材および骨基材である、請求項10に記載の使用。
- 前記材料が金属基材および生物学的組織である、請求項10に記載の使用。
- 前記材料が金属基材である、請求項10に記載の使用。
- 生物学的組織内の中空空間の充填方法であって、ある量の請求項2または3に記載の組成物を生物学的組織内の中空空間に施与することを含む、前記方法。
- 口腔内の生物学的組織内の中空空間の充填方法であって、ある量の請求項2または3に記載の組成物を口腔内の生物学的組織内の中空空間に施与することを含む、前記方法。
- ある量の請求項2または3に記載の組成物および生物活性剤を、デュアルカニューレチップを備えた2シリンジアプリケーターを使用して施与する方法。
- ポリマー主鎖、請求項1に記載の式Iの生体吸収性ポリマーまたはその混合物と、溶剤と、非溶剤とを含む歯科用メンブレン。
- ポリマー主鎖、請求項1に記載の式Iの生体吸収性ポリマーまたはその混合物と、溶剤と、非溶剤と、添加剤とを含む3D印刷された部品。
- ポリマー主鎖、請求項1に記載の式Iの生体吸収性ポリマーまたはその混合物を含有する3D印刷された部品の製造方法であって、
(a) ポリマー主鎖、請求項1に記載の式Iの生体吸収性ポリマーまたはその混合物を準備すること、
(b) ポリマー主鎖、請求項1に記載の式Iの生体吸収性ポリマーまたはその混合物を溶剤に添加して、ポリマー溶液を形成すること、
(c) 前記ポリマー溶液に添加剤を添加または接触させること、
(d) 印刷ヘッドを介して前記ポリマー溶液を印刷して、多層の3D印刷された部品を形成すること、および
(e) 前記の3D印刷された部品を硬化させること、
を含む、前記方法。 - ポリマー主鎖、請求項1に記載の式Iの生体吸収性ポリマーまたはその混合物と、溶剤と、非溶剤と、添加剤と、生物活性剤とを含む、バイオプリントされた部品。
- ポリマー主鎖、請求項1に記載の式Iの生体吸収性ポリマーまたはその混合物を含有するバイオプリントされた部品の製造方法であって、
(a) ポリマー主鎖、請求項1に記載の式Iの生体吸収性ポリマーまたはその混合物を準備すること、
(b) ポリマー主鎖、請求項1に記載の式Iの生体吸収性ポリマーまたはその混合物を溶剤に添加して、ポリマー溶液を形成すること、
(c) 前記ポリマー溶液に添加剤を添加または接触させること、
(d) 印刷ヘッドを介して前記ポリマー溶液を印刷して、多層のバイオプリントされた部品を形成すること、
(e) 前記バイオプリントされた部品を硬化させること
を含み、段階(b)または(c)のいずれかがさらに、生物活性剤を添加することを含む、前記方法。
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