JP2017206502A - 関節内補充療法のためのポリマー溶液 - Google Patents
関節内補充療法のためのポリマー溶液 Download PDFInfo
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- JP2017206502A JP2017206502A JP2017086965A JP2017086965A JP2017206502A JP 2017206502 A JP2017206502 A JP 2017206502A JP 2017086965 A JP2017086965 A JP 2017086965A JP 2017086965 A JP2017086965 A JP 2017086965A JP 2017206502 A JP2017206502 A JP 2017206502A
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- 239000002775 capsule Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 239000004568 cement Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
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- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
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- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 1
- 230000005251 gamma ray Effects 0.000 description 1
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- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229960001067 hydrocortisone acetate Drugs 0.000 description 1
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 1
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- 229960001680 ibuprofen Drugs 0.000 description 1
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- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
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- 235000011837 pasties Nutrition 0.000 description 1
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 1
- 238000012667 polymer degradation Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229940119265 sepp Drugs 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
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Abstract
【解決手段】関節内補充療法のため、特に関節症の治療のためのポリマー溶液であって、a)少なくとも1種の少なくとも部分的に水溶性の多糖または多糖誘導体、b)ポリスチレンスルホン酸の少なくとも1種の水溶性のアルカリ塩またはアルカリ土類塩、およびc)水を含有する、ポリマー溶液。更に3−ヒドロキシプロピオン酸及び、消炎剤、免疫抑制剤並びに細胞増殖抑制剤とを含有する、ことが好ましい、ポリマー溶液。
【選択図】なし
Description
a)少なくとも1種の少なくとも部分的に水溶性の多糖もしくは多糖誘導体、または少なくとも1種の少なくとも部分的に水溶性の多糖と少なくとも1種の少なくとも部分的に水溶性の多糖誘導体の混合物、
b)ポリスチレンスルホン酸の少なくとも1種の水溶性のアルカリ塩またはアルカリ土類塩、および
c)水
を含有する。
a)少なくとも1種の少なくとも部分的に水溶性の多糖、または少なくとも1種の少なくとも部分的に水溶性の多糖誘導体、または少なくとも1種の少なくとも部分的に水溶性の多糖と少なくとも1種の少なくとも部分的に水溶性の多糖誘導体の混合物と、
b)ポリスチレンスルホン酸の少なくとも1種の水溶性のアルカリ塩またはアルカリ土類塩と、
c)水と、
d)任意に、3−ヒドロキシプロピオン酸と、
e)任意に、少なくとも1種の消炎剤と、
f)任意に、少なくとも1種の抗生物質と、
g)任意に、少なくとも1種の免疫抑制剤と、
h)任意に、少なくとも1種の細胞増殖抑制剤と
からなるポリマー溶液もまた、本発明である。
b)ポリスチレンスルホン酸の少なくとも1種の水溶性のアルカリ塩またはアルカリ土類塩、
c)水、および
d)3−ヒドロキシプロピオン酸
を含有するポリマー溶液もまた、本発明である。
NaHya:ヒアルロン酸のナトリウム塩(Mn約90万ダルトン)、
CMC:カルボキシメチルセルロースのナトリウム塩(Mn約90,000ダルトン)、
MC:メチルセルロース(SM−4000)、
HEC:ヒドロキシエチルセルロース(60SH−4000)、
PSS1:ポリスチレンスルホン酸のナトリウム塩(Mn約70,000ダルトン)、
PSS2:ポリスチレンスルホン酸のナトリウム塩(Mn約1,300,000ダルトン)。
合計5.0mlのpH7.4のリン酸緩衝液をビーズ付きの縁のあるバイアル(beaded rim vial)に入れた。合計0.25wt%、0.5wt%、1.0wt%および2.0wt%の多糖/多糖誘導体およびポリスチレンスルホン酸のナトリウム塩(PSS1およびPSS2)を室温にてそれらの緩衝液中に溶解した。ポリマー溶液を24時間後に視覚的に検査した。
さらに抗生物質ドキシサイクリンを含んだことを除いてポリマー溶液を実施例1と同様に調製した。ドキシサイクリン−ヒアレート(doxycycline−hyalate)(ドキシサイクリン塩酸塩−ヘミエタノラート半水和物)をこの目的のために使用した。ポリマー溶液を室温で24時間の保存後に視覚的に調べた。
さらに抗生物質硫酸ゲンタマイシンを含んだことを除いてポリマー溶液を実施例1と同様に調製した。硫酸ゲンタマイシン(580の活量係数)をこの目的のために使用した。ポリマー溶液を室温で24時間の保存後に視覚的に調べた。
さらに消炎剤リン酸デキサメタゾンを含んだことを除いてポリマー溶液を実施例1と同様に調製した。リン酸デキサメタゾンのナトリウム塩(NaDexP)をこの目的のために使用した。ポリマー溶液を室温で24時間の保存後に視覚的に調べた。
リン酸緩衝液pH7.4を使用してNaHyaの0.25wt%溶液を調製した。次いで10mg、1.0mg、0.1mg、および0.01mgのPSS1を各々40.0gの溶液に加えた。0.1mgおよび0.01mgのPSS1の添加のために、リン酸緩衝液中の10mgのPSS1の溶液を調製し、この溶液の対応するアリコートをNaHya溶液に加えた。リン酸緩衝液pH7.4中の26.7IU/μlのウシヒアルロニダーゼ(Kraeber、329IU/mg)を含有する溶液を調製した。次いで、このヒアルロニダーゼ溶液の150μlのアリコートを40gのNaHya−PSS1溶液に加えた。次いで溶液をUbbelohde 粘度計(キャピラリーI)において37℃にて15分間維持した。次いでポリマー溶液の通過時間を決定した。次いでポリマー溶液をUbbelohde粘度計において37℃に維持した。ポリマー溶液の通過時間を連続して1時間間隔で再び測定した。さらに、ヒアルロニダーゼを加えた0.25wt%のNaHya溶液の通過時間を参照として測定した。
リン酸緩衝液pH7.4を使用してNaHyaの0.25wt%溶液を調製した。次いで10mg、1.0mg、0.1mg、および0.01mgのPSS2を各々40.0gの溶液に加えた。0.1mgおよび0.01mgのPSS2の添加のために、リン酸緩衝液中の10mgのPSS2の溶液を調製し、この溶液の対応するアリコートをNaHya溶液に加えた。リン酸緩衝液pH7.4中の26.7IU/μlのウシヒアルロニダーゼ(Kraeber、329IU/mg)を含有する溶液を調製した。次いで、このヒアルロニダーゼ溶液の150μlのアリコートを40gのNaHya−PSS2溶液に加えた。次いで溶液をUbbelohde 粘度計(キャピラリーI)において37℃にて15分間維持した。次いでポリマー溶液の通過時間を決定した。この目的のためにポリマー溶液をUbbelohde粘度計において37℃に維持した。ポリマー溶液の通過時間を連続して1時間間隔で再び測定した。さらに、ヒアルロニダーゼを加えた0.25wt%のNaHya溶液の通過時間を参照として測定した。
まず、各々30.0mLのリン酸緩衝液(pH値7.4)を使用してポリスチレンスルホン酸を含有する多糖の溶液を調製した。合計106cfuのバチルスアトロフェウス(Bacillus atropheus)の胞子懸濁液を、滅菌25mLプラスチックチューブ中の多糖溶液の各々5mLに加えた。次いで、vortexミキサーを使用して胞子を均質に懸濁した。続いて、0.5wt%、1.0wt%、および2.0wt%のβ−プロピオラクトンを、以前に胞子と混合した各々5.0mLの多糖溶液に加えた。次いで試料をvortexミキサーにおいて再び均質化した。β−プロピオラクトンで処理していない多糖溶液を陽性対照として使用した。室温で48時間の保存後、多糖溶液をDIN EN ISO 11737、パート2に従って滅菌について試験した。アッセイは2連で行った。
Claims (12)
- 関節内補充療法のため、特に関節症の治療のためのポリマー溶液であって、
a)少なくとも1種の少なくとも部分的に水溶性の多糖または多糖誘導体、
b)ポリスチレンスルホン酸の少なくとも1種の水溶性のアルカリ塩またはアルカリ土類塩、および
c)水
を含有する、ポリマー溶液。 - d)3−ヒドロキシプロピオン酸
を含有する、請求項1に記載のポリマー溶液。 - 前記溶液は目視により透明であることを特徴とする、請求項1または2に記載のポリマー溶液。
- 多糖もしくは多糖誘導体、または少なくとも2種の多糖の混合物、または少なくとも2種の多糖誘導体の混合物、または少なくとも1種の多糖と少なくとも1種の多糖誘導体の混合物と、ポリスチレンスルホン酸のアルカリ塩またはアルカリ土類塩の質量比が、1対1から1対0.01の範囲であることを特徴とする、請求項1〜3のいずれか一項に記載のポリマー溶液。
- 前記ポリマー溶液のポリマー含有量の合計が0.1から10wt%であることを特徴とする、請求項1〜4のいずれか一項に記載のポリマー溶液。
- 前記ポリマー溶液が、消炎剤、抗生物質、免疫抑制剤、および細胞増殖抑制剤をさらに含有することを特徴とする、請求項1〜5のいずれか一項に記載のポリマー溶液。
- 前記ポリマー溶液が、リン酸デキサメタゾン、リン酸トリアムシノロン、ドキシサイクリン、クロロテトラサイクリン、オキシテトラサイクリン、ドキソルビシン、シクロスポリン、メトトレキサート、レフルノミド、アザチオプリン、マイトマイシンC、タクロリムス、シロリムス、およびエベロリムスを含有することを特徴とする、請求項6に記載のポリマー溶液。
- a)少なくとも1種の少なくとも部分的に水溶性の多糖、または少なくとも1種の少なくとも部分的に水溶性の多糖誘導体、または少なくとも1種の少なくとも部分的に水溶性の多糖と少なくとも1種の少なくとも部分的に水溶性の多糖誘導体の混合物と、
b)ポリスチレンスルホン酸の少なくとも1種の水溶性のアルカリ塩またはアルカリ土類塩と、
c)水と、
d)任意に、3−ヒドロキシプロピオン酸と、
e)任意に、少なくとも1種の消炎剤と、
f)任意に、少なくとも1種の抗生物質と、
g)任意に、少なくとも1種の免疫抑制剤と、
h)任意に、少なくとも1種の細胞増殖抑制剤と
からなる、請求項1〜7のいずれか一項に記載のポリマー溶液。 - a)少なくとも1種の少なくとも部分的に水溶性の多糖、または少なくとも1種の少なくとも部分的に水溶性の多糖誘導体、または少なくとも1種の少なくとも部分的に水溶性の多糖と少なくとも1種の少なくとも部分的に水溶性の多糖誘導体の混合物と、
b)ポリスチレンスルホン酸の1種の水溶性のアルカリ塩またはアルカリ土類塩と、
c)水と
を、少なくとも0.5wt%のβ−プロピオラクトンと混合することを特徴とする、滅菌水性ポリマー溶液を生成する方法であって、このように調製されたポリマー溶液が4から40℃にて少なくとも24時間保存される、方法。 - 0.5から2.0wt%のβ−プロピオラクトンが滅菌の目的のために加えられることを特徴とする、請求項8に記載の方法。
- 関節内補充療法のための手段としての請求項1〜8のいずれか一項に記載のポリマー溶液の使用。
- 医薬品のための補助物としての請求項1〜8のいずれか一項に記載のポリマー溶液の使用。
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