JP6178414B2 - 少なくとも1種のヒアルロン酸及び少なくとも1種のショ糖オクタ硫酸水溶性塩を含有する水性媒体組成物 - Google Patents
少なくとも1種のヒアルロン酸及び少なくとも1種のショ糖オクタ硫酸水溶性塩を含有する水性媒体組成物 Download PDFInfo
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- JP6178414B2 JP6178414B2 JP2015516668A JP2015516668A JP6178414B2 JP 6178414 B2 JP6178414 B2 JP 6178414B2 JP 2015516668 A JP2015516668 A JP 2015516668A JP 2015516668 A JP2015516668 A JP 2015516668A JP 6178414 B2 JP6178414 B2 JP 6178414B2
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- hyaluronic acid
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- sucrose octasulfate
- water
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Description
本発明において、出願人企業は、ショ糖オクタ硫酸の水溶性塩の付加によって、ヒアルロニダーゼによるヒアルロン酸含有の組成物の分解という問題を解決することを目的とし、その一方で、製造プロセスにおける蒸気滅菌相中のそれらのレオロジー特性の安定性によって、経皮充填剤、粘弾性補充剤、化粧品製剤又は医薬品製剤の分野で使用されるこれら組成物の性能が保持される。
前記組成物は、物理的混合物であること、及び、ヒアルロン酸[HA]の含有量とショ糖オクタ硫酸の水溶性塩[SOS]の含有量の質量比[HA]/[SOS]が0.1以上であることを特徴とする、組成物に関する。
−少なくとも1種のヒアルロン酸の繊維の水和により、ヒドロゲルを得る段階、
−ショ糖オクタ硫酸の水溶性塩の溶液を、前の段階で得た前記ヒドロゲルと混合する段階、
−均質化する段階、及び
−蒸気オートクレーブ処理する段階
から成ることを特徴とする。
−顔面への審美用注射:経皮充填、皮膚欠損又は容積の欠損用(頬、顎、口唇);
−身体へのボリューム付与のための注射:胸部及び臀部の増大、Gスポット、膣形の増大、膣陰唇の復元又は陰茎の増大;
−変形性関節症の治療、不足滑液を交換又は補充するための関節部への注射;
−括約筋機能不全による尿失禁の治療における尿道注射;
−特に腹膜癒着を予防するための術後注射;
−レーザーを用いた強膜切断による遠視手術後の注射;
−硝子体腔への注射
において使用されるか又は潜在的に有益である注射可能な粘弾性製品及び多糖類に関して一般的に観察されるものである。
−微細な、適度な又は深い皺に対して充填するのに用いられ得、そして細針(例えば27ゲージ)を用いて注射され得るか;
−より大内径の、例えば22ないし26ゲージの、且つより長い(30ないし40mm)針を用いた注射でボリューム付与製品として使用され得;この場合、その粘着特性によって、注射部位に維持されることを可能にする。
−容積を充填するために;
−ある組織内に空間を生じさせ、これによりそれらの最適機能を促進するために;
−不足生理液を交換するために、
より広範に提供される本発明に従う組成物に限定してはならない。
当該実施例は、非架橋ヒアルロン酸及びショ糖オクタ硫酸カリウムを含有する本発明に従う組成物を示す。
当該実施例は、架橋ヒアルロン酸及びショ糖オクタ硫酸カリウムを含有する本発明に従う組成物の例を示す。
当該実施例は、非架橋ヒアルロン酸、ショ糖オクタ硫酸カリウム及びマンニトールを含有する本発明に従う組成物の例を示す。
当該実施例は、架橋ヒアルロン酸、ショ糖オクタ硫酸カリウム及びマンニトールを含有する本発明に従う組成物の例を示す。
当該実施例は、非架橋ヒアルロン酸、ショ糖オクタ硫酸カリウム及びリドカインを含有する本発明に従う組成物の例を示す。
当該実施例は、架橋ヒアルロン酸、ショ糖オクタ硫酸カリウム及びリドカインを含有する本発明に従う組成物の例を示す。
当該実施例は、眼球乾燥の治療用の、非架橋ヒアルロン酸及びショ糖オクタ硫酸カリウムを含有する本発明に従う組成物を示す。
当該実施例は、化粧品製剤を示す。
セテアリルアルコール 5%
エステル類(ジカプリリルエーテル、ミリスチン酸ミリスチル) 10%
実施例1で得られた非架橋ヒアルロン酸及び
ショ糖オクタ硫酸カリウム組成物 1%
グリセロール 5%
アルコール 5%
トコフェロール 0.2%
香料 0.1%
水 100%となる適量
当該実施例は、滅菌した化粧品製剤を示す。
[HA]/[SOS]比が4の、実施例1に従い得られた、
非架橋ヒアルロン酸及びショ糖オクタ硫酸カリウム組成物 1%
カルボマー 0.5%
キサンタンガム 2.5%
クエン酸 0.1%
2−フェニルエタノール 0.5%
グリセロール 1.2%
水 100%となる適量
蒸気オートクレーブに対する安定性
非架橋のヒアルロン酸を含有する本発明に従う組成物について、蒸気オートクレーブ段階後の滅菌された組成物の粘度ηを、25℃にて、制御された制約条件下、TAインストルメンツAR 2000 Ex レオメーターにて測定した。粘度値は、0.02s−1の制約で記録した。
実施例1に記載される手順に従い、非架橋ヒアルロン酸及び組成物中に1mg/gの濃度にある硫酸化オリゴ多糖類又は硫酸化単糖類を含有する9つの組成物を製造した。
実施例3に記載される手順に従い、非架橋ヒアルロン酸、マンニトール及び組成物中に1mg/gの濃度にある硫酸化オリゴ多糖類又は硫酸化単糖類を含有する5種類の組成物を製造した。
ヒアルロン酸及びショ糖オクタ硫酸カリウムを含有する物理的混合物の分光学的特性
実施例4の組成物について、1H NMR解析を行った。蒸気オートクレーブによる滅菌の前後に、実施例4の組成物について分光学的同定を行った。
−図1は、水溶液中のショ糖オクタ硫酸カリウム単独の1H NMRスペクトルであり、
−図2は、滅菌前後の実施例4の組成物の1H NMRスペクトルの重ね合わせである。
ショ糖オクタ硫酸のアノマープロトンの呈示
酵素分解試験
刊行物“Comparison of the sensitivity of 11 crosslinked hyaluronic acid gels to bovine testis hyaluronidase”,I.Sall及びG.Ferard,Polymer Deg.and Stability,(2007),92,915−919及び国際公開第2009/068215号明細書に記載される試験に基づき、分解試験を開発した。
得られた半減期を下記表4に与える。
酸化分解試験
蒸気オートクレーブにより滅菌された実施例4に従う組成物について、及び同様の条件下で蒸気オートクレーブにより滅菌された参照組成物について、酸化分解試験を行った。ショ糖オクタ硫酸カリウムの水溶液を同量のリン酸緩衝剤水溶液に替えたことにより、参照組成物を処方した。
得られた半減期を下記表5に与える。
参照ゲルである、20mg/gの架橋NaHAゲル(IPN様ゲル、スタイレージ M(Stylage(登録商標)M)ブランドで販売)を有する(種々の濃度にある)KSOSの製剤についての試験例
実施例8に従い、参照組成物に対する弾性要素G’の損失のパーセンテージを測定し、そして30ゲージ1/2の皮下注射針を用い、参照ゲルの注射可能な力及びショ糖オクタ硫酸カリウムを含有するゲルの注射可能な力の差を測定した。
結果を下記表6に与える。
下記表8に記載される濃度及び比にある、架橋ヒアルロン酸を含有するゲルを有するKSOSの製剤についての試験例
実施例2に記載の手順に従いゲルを製造し、そしてその後、実施例8に従いレオロジーを同定した。
Claims (16)
- 少なくとも1種のヒアルロン酸及び少なくとも1種のショ糖オクタ硫酸の水溶性塩を含有する、水性媒体中の滅菌組成物であって、
前記組成物は、物理的混合物であること、及び、ヒアルロン酸[HA]の含有量とショ糖オクタ硫酸の水溶性塩[SOS]の含有量の質量比[HA]/[SOS]が0.1以上であることを特徴とする、組成物。 - プロトン1H NMR分光法により分析したときに、ショ糖オクタ硫酸塩のアノマープロトンの化学シフト値が、溶液中のショ糖オクタ硫酸単独の塩のアノマープロトンの化学シフト値と同一であることを特徴とする、請求項1に記載の組成物。
- 前記ヒアルロン酸の分子量Mwが、0.01MDaないし5MDaの範囲にあること、及び/又は、前記ヒアルロン酸の含有量が、組成物に対し2mg/gないし50mg/gであることを特徴とする、請求項1又は2に記載の組成物。
- 少なくとも1種の非架橋ヒアルロン酸を含有することを特徴とする、請求項1ないし3のうちいずれか1項に記載の組成物。
- 少なくとも1種の架橋ヒアルロン酸をさらに含有することを特徴とする、請求項1ないし4のうちいずれか1項に記載の組成物。
- 前記ショ糖オクタ硫酸の水溶性塩は、ショ糖オクタ硫酸のナトリウム塩又はショ糖オクタ硫酸のカリウム塩であること、及び、前記ショ糖オクタ硫酸の水溶性塩の含有量が、組成物に対し0.01mg/gないし40mg/gであることを特徴とする、請求項1ないし5のうちいずれか1項に記載の組成物。
- 抗酸化剤、局所麻酔薬、又はビタミン類から、単独で又は組み合わせて選択される少なくとも1種の有効成分をさらに含有することを特徴とする、請求項1ないし6のうちいずれか1項に記載の組成物。
- 前記抗酸化剤は、ポリオール群から選択されることを特徴とする、請求項7に記載の組成物。
- 前記局所麻酔薬は、リドカイン(lidocaine)、プロカイン(procaine)、メピバカイン(mepivacaine)、ロピバカイン(ropivacaine)、ブピバカイン(bupivacaine)及び医薬的に許容され得るそれらの塩から成る群より選択されることを特徴とする、請求項7に記載の組成物。
- 請求項1ないし9に記載の組成物及び少なくとも1種の化粧品的に許容され得る賦形剤を含有することを特徴とする、化粧品製剤。
- 請求項1ないし9に記載の組成物の製造方法であって、少なくとも、
少なくとも1種のヒアルロン酸の繊維の水和により、ヒドロゲルを得る段階、
ショ糖オクタ硫酸の水溶性塩の溶液を、前の段階で得た前記ヒドロゲルと混合する段階、
均質化する段階、及び
蒸気オートクレーブ処理する段階
から成ることを特徴とする、製造方法。 - 少なくとも1回の架橋段階をさらに含むことを特徴とする、請求項11に記載の組成物の製造方法。
- 粘弾性補充組成物としての使用のための、請求項1ないし9に記載の組成物。
- 経皮充填剤としての請求項1ないし9に記載の組成物の使用。
- 眼球乾燥の治療のための請求項1ないし9に記載の組成物。
- 滅菌されたシリンジ内に又は滅菌された単回投与用容器内に充填された、請求項1ないし9に記載の組成物を含むキット。
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