JP2018530547A - in situ架橋性多糖類組成物及びその使用 - Google Patents
in situ架橋性多糖類組成物及びその使用 Download PDFInfo
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- JP2018530547A JP2018530547A JP2018516501A JP2018516501A JP2018530547A JP 2018530547 A JP2018530547 A JP 2018530547A JP 2018516501 A JP2018516501 A JP 2018516501A JP 2018516501 A JP2018516501 A JP 2018516501A JP 2018530547 A JP2018530547 A JP 2018530547A
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- polysaccharide
- derivative
- situ
- precursor solution
- polysaccharide derivative
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- 230000003442 weekly effect Effects 0.000 description 1
- 229960003434 xenysalate Drugs 0.000 description 1
- HLDCSYXMVXILQC-UHFFFAOYSA-N xenysalate Chemical compound CCN(CC)CCOC(=O)C1=CC=CC(C=2C=CC=CC=2)=C1O HLDCSYXMVXILQC-UHFFFAOYSA-N 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- KYBJXENQEZJILU-UHFFFAOYSA-N zolamine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=NC=CS1 KYBJXENQEZJILU-UHFFFAOYSA-N 0.000 description 1
- 229950006211 zolamine Drugs 0.000 description 1
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Abstract
Description
上記を鑑み、本発明の目的は、in situ架橋性組成物を提供することである。該組成物は、細針から容易に押し出すことが可能であり、投与後in situで所望の特性(例えば、機械的、化学的、レオロジー、生物学的及び免疫学的特性に関する特性)を有する架橋ヒドロゲルを形成し、様々な美容及び治療用途において、軟部組織を増大させ、充填し、置換する。
(a)第1の多糖類誘導体の第1の前駆体溶液と、これとは別に、第2の多糖類誘導体の第2の前駆体溶液と、を準備する工程であって、第1の多糖類誘導体を求核基により官能化し、及び第2の多糖類誘導体を求電子基により官能化し、並びに第1及び第2の両前駆体溶液を滅菌する工程と、
(b)第1の前駆体溶液及び第2の前駆体溶液を混合することで、in situ架橋性混合溶液とする工程と、
(c)混合溶液を患者体内の標的部位に注入する工程であって、第1の多糖類誘導体の求核基及び第2の多糖類誘導体の求電子基を、共有結合をin situ形成することにより、標的部位において架橋ヒドロゲルを形成する工程と、を含む、方法を提供する。
[多糖類]−C(=O)−NH−NH−R1−C(=O)−NH−NH2
[式中、R1は、共有結合、C(=O)、C(=O)−O−R2、(C=O)−R2であり、R2は、直鎖状又は分岐鎖状C1、C2、C3、C4、C5若しくはC6アルキル基又はアルケニル基である]のジヒドラジド部分である。特に本明細書にて使用するのに好ましいのは、カルボジヒドラジド(CDH)である。CDHがヒドラジド部分として使用され、多糖類のカルボキシル基と結合すると、得られた修飾多糖類は、以下のペンダントヒドラジド末端部分、すなわち、多糖類−C(=O)−R[式中、RはNH−NH−C(=O)−NH−NH2である。]を有する。
Mw=ΣiNiMi 2/ΣiNiMi
式中、Niは、分子質量がMiである分子の数である。
[η]=K×Ma
式中、[η]は固有粘度であり、単位はm3/kgである。Mは分子量であり、K=2.26×10−5、かつa=0.796である。
(a)第1の多糖類誘導体の第1の前駆体溶液と、これとは別に、第2の多糖類誘導体の第2の前駆体溶液と、を準備する工程であって、第1の多糖類誘導体を求核基により官能化し、第2の多糖類誘導体を求電子基により官能化し、並びに第1及び第2の両前駆体溶液を滅菌する工程と、
(b)第1の前駆体溶液及び第2の前駆体溶液を混合することで、in situ架橋性混合溶液とする工程と、
(c)混合溶液を患者体内の標的部位に注入する工程であって、第1の多糖類誘導体の求核基及び第2の多糖類誘導体の求電子基を、共有結合をin situ形成させることにより、標的部位において架橋ヒドロゲルを形成させる工程と、を含む。方法を提供する。
押出力(注入力)を、1.0mLのガラスシリンジ(BD Hypak SCF、1mLの長さのRF−PRTC、ISO11040,内径6.35mm)及び30Gの針(TSK Laboratory)を装着した、テクスチャーアナライザ(TA.XT Plus、Texture Technologies,Corp.)によって測定した。押出力を、距離25mmにわたって、試験速度0.21mm/秒を使用して測定した(ターゲットモード:距離、力:100.0g)。試験前及び試験後の速度を、それぞれ0.21mm/秒及び10.0mm/秒とした。トリガとなる力を、2.0g(トリガタイプ:自動(力))で、歪みは10.0%とした。プラトーに到達した後の平均の力を押出力とした。
複素粘度(η*)並びに貯蔵及び損失弾性率(G’及びG’’)の測定
複素粘度(η*)並びに貯蔵及び損失弾性率(G’及びG’’)を、コーンプレート形状(径50mm、角度0.1°、CP50−1、ギャップ寸法0.1mm)を装着したレオメータ(Anton Paar Physica MCR302Rheometer、Anton Paar GmbH)を使用して25℃で測定した。試料を1Paの応力で振動させ、発振周波数を0.1〜10Hzで変化させた。
HAアルデヒド誘導体(HA−Ald)の合成
国際公開第2011/069475号に記載の方法に従って(例えば、実施例1を参照)、アルデヒド官能化HA誘導体を、HAのN−アセチルグルコサミン(GlcNAc)単位の一級C6ヒドロキシル基を選択的に酸化することによって調製した。つまり、TEMPO/共酸化剤系(TEMPO、2,2,6,6−テトラメチル−1−ピペリジニルオキシ)を使用して、ヒアルロン酸(HA)(Mw=1.0×106Da)を酸化した。透析後、溶液を凍結乾燥し、アルデヒド官能化HA(以下、「HA−Ald」と称する)を得た。
HAヒドラジド誘導体(HA−Ald)の合成
HA(6000.0mg、14.9mmolの二糖類繰り返し単位)を、室温で12時間をかけて、700.0mLの脱イオン水中に溶解させた。HOBt(2289.3mg、14.9mmol)を添加した後、固体EDC(1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(1428.9mg、7.84mmol)を添加した。pHを5.5〜6.5に調整し、溶液を1時間攪拌した。次に、カルボヒドラジド(CDH;4043.5mg、44.88mmol)を添加し、室温で10時間、攪拌を続けた。
HAヒドロゲルの形成及び特性測定
HAヒドロゲルを、蒸気滅菌(131℃、0.7分)した実施例1のHAアルデヒド誘導体(「HA−Ald」)、及び蒸気滅菌(131℃、0.7分)した実施例2のHAヒドラジン誘導体(「HA−Hyd」)の、室温(約25℃)での同量混合により、調製した。HA−Ald及びHA−Hyd誘導体を、別々にpH6.5〜7.5の、無菌性PBSに溶解し、それぞれ15mg/mL及び24.5mg/mLの濃度とした。続いて、1.0mLの、HA−Ald及びHA−Hyd前駆体溶液の各々(15mg/mL及び24.5mg/mLの濃度のそれぞれに対して別々に)を、体積比1:1で、1mLのルアーロックシリンジに充填した。使用した2個のシリンジの各々を、その各先端においてY字コネクタに連結し、2種の前駆体溶液を、針からの押し出しと同時に、効果的に混合可能とした。
概念実証を確証するための動物試験
予備的な動物実験
表2に示した2種の処方物を、ウサギにおけるヒドロゲルのin vivo形成に使用した。第1のヒドロゲル(「被験物質1」)を、HA−Hyd前駆体溶液(15mg/mL)及びHA−Ald前駆体溶液(15mg/mL)をウサギの皮膚に混注(1:1v/v)して入れた。第2のヒドロゲル(「被験物質2」)を、HA−Hyd前駆体溶液(24.5mg/mL)及びHA−Ald前駆体溶液(24.5mg/mL)をウサギの皮膚に混注(体積比1:1)して入れた。
12週間の試験をウサギにおいて実施し、上記の被験物質1の皮内注射(ID)及び上記の被験物質2の皮下注射(SC)後の皮膚反応の重症度を測定した。反応を、ID注射した対照物質1(Belotero Balance)及びSC注射した対照物質2(Belotero Volume Lidocaine)と比較した。注入4週間後、部位を肉眼で観察し、組織病理学的に分析し、各物質の皮膚反応を評価した。注入後と、次いで5日間は毎日、その後終了までは毎週、全部位を肉眼で観察した。
Claims (15)
- 美容用途において架橋ヒドロゲルをin situ形成させるための、第1の多糖類誘導体及び第2の多糖類誘導体の使用であって、前記第1の多糖類誘導体が求核基により官能化されており、前記第2の多糖類誘導体が求電子基により官能化されており、前記第1及び第2の両多糖類誘導体は滅菌されており、前記第1及び第2の多糖類誘導体の患者体内の標的部位への混注後、前記求核基及び前記求電子基が共有結合をin situ形成することにより、前記標的部位において架橋ヒドロゲルを形成する、使用。
- 共有結合の前記in situ形成が、混注後自発的に起き、及び/又は、共有結合の前記in situ形成によって、水以外の他の副生成物が放出されない、請求項1に記載の使用。
- 前記第1の多糖類誘導体が第1の無菌性前駆体溶液の形態で存在し、前記第2の多糖類誘導体が第2の無菌性前駆体溶液の形態で存在する、請求項1又は2に記載の使用。
- 前記第1及び第2の無菌性前駆体溶液が、1Hz及び25℃における振動レオロジー測定による測定で0.001Pa・s〜5.0Pa・sの複素粘度を各々有する、若しくは、1.0mLのガラスシリンジを使用し、押出速度0.21mm/秒で30Gの針を通過させた測定で0.01N〜15Nの注入力を各々有する、又は、これらの両方である、請求項3に記載の使用。
- 前記第1の前駆体溶液及び前記第2の前駆体溶液が、混注の際に、ただし、患者の体内に入る前に混合され、液体in situ架橋性組成物を形成し、前記液体in situ架橋性組成物が、好ましくは、1Hz及び25℃における振動レオロジー測定による測定で0.1Pa・s〜100Pa・sの複素粘度を有する、若しくは、1.0mLのガラスシリンジを使用し、押出速度0.21mm/秒で30Gの針を通過させた測定で0.01N〜20Nの注入力を有する、又は、これらの両方である、請求項3又は4に記載の使用。
- 前記第1の前駆体溶液中に存在する前記第1の多糖類誘導体の濃度が0.1重量%〜5.0重量%であり、及び前記第2の前駆体溶液中に存在する前記第2の多糖類誘導体の濃度が0.1重量%〜5.0重量%であり、並びに/又は患者体内の標的部位に注入される前記液体in situ架橋性組成物に含まれる、前記第1の多糖類誘導体対前記第2の多糖類誘導体の重量比が15:85〜85:15である、請求項3〜5のいずれか一項に記載の使用。
- 前記求核基がヒドラジド部分であり、前記求電子基がアルデヒド部分であり、前記アルデヒド部分が、好ましくは、前記多糖類骨格の繰り返しの糖類の環を壊すことなく、前記多糖類に導入されている、請求項1〜6のいずれか一項に記載の使用。
- 前記第1及び第2の多糖類誘導体が、独立して、カルボキシル化セルロース及びカルボキシル化セルロース誘導体、カルボキシメチルデキストラン、カルボキシメチルスターチ、ヒアルロン酸、アルギネート、ヘパロサン、ヘパリン、ヘパリンサルフェート、ペクチン、コンドロイチンサルフェート、デルマタンサルフェート、セルロース、キトサン又はキチンからなる群から選択される、請求項1〜7のいずれか一項に記載の使用。
- 前記第1の多糖類誘導体がヒドラジド官能化による第1のヒアルロン酸(HA)誘導体であり、前記第2の多糖類誘導体が、アルデヒド官能化による第2のヒアルロン酸(HA)誘導体であり、前記第1のHA誘導体は、好ましくはHAの糖類単位のカルボキシル基がヒドラジド部分によって官能化されている、若しくは、前記第2のHA誘導体は、好ましくは、−CH2OH基の−CHO基への変換によって生成されたアルデヒド部分によって官能化されている、又は、これらの両方である、請求項1〜8のいずれか一項に記載の使用。
- in situ架橋性組成物が、皮膚の皺及び皺線、眉間の皺線、鼻唇溝、頤の皺、マリオネットライン、下顎の輪郭、頬側交連、口周囲の皺、目尻の皺、皮膚陥凹み、傷痕、こめかみ、額の真皮支持、頬骨及び頬脂肪体、涙溝、鼻、唇、頬、頤、口周囲部、眼窩下部、及び顔面非対称の処置に使用される、請求項1〜9のいずれか一項に記載の使用。
- 治療用途の架橋ヒドロゲルの前記in situ形成のための、特に、腹圧性尿失禁、膣の乾燥、膀胱尿管逆流、声帯不全、及び声帯内方移動の処置に使用するための、請求項1〜9のいずれか一項に記載の、第1の多糖類誘導体及び第2の多糖類誘導体。
- 請求項9に記載の、第1のヒアルロン酸(HA)誘導体及び第2のヒアルロン酸(HA)誘導体の組み合わせ。
- 少なくとも、(a)請求項3〜9のいずれか一項に記載の第1の前駆体溶液が一方のバレルに、及び(b)請求項3〜9のいずれか一項に記載の第2の前駆体溶液がもう一方のバレルに予め充填された、マルチバレルシリンジシステム。
- (i)請求項3〜9のいずれか一項に記載の第1の前駆体溶液が入っている第1の容器と、(ii)請求項3〜9のいずれか一項に記載の第2の前駆体溶液が入っている第2の容器と、任意に、(iii)使用説明書と、を備える、架橋多糖類ヒドロゲルをin situ形成させるためのキット。
- 架橋ヒドロゲルを、美容又は治療用途において、in situ形成させるための方法であって、
(a)第1の多糖類誘導体の第1の前駆体溶液と、これとは別に、第2の多糖類誘導体の第2の前駆体溶液と、を準備する工程であって、前記第1の多糖類誘導体を求核基により官能化し、及び前記第2の多糖類誘導体を求電子基により官能化し、並びに前記第1及び第2の両前駆体溶液を滅菌する工程と、
(b)前記第1の前駆体溶液及び前記第2の前駆体溶液を混合することで、in situ架橋性混合溶液とする工程と、
(c)前記混合溶液を患者体内の標的部位に注入する工程であって、前記第1の多糖類誘導体の前記求核基及び前記第2の多糖類誘導体の前記求電子基を、共有結合をin situ形成することにより、前記標的部位において架橋ヒドロゲルを形成する工程と、を含む、方法。
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