JP6545334B2 - ムコ多糖症の治療におけるオジパルシルの使用 - Google Patents
ムコ多糖症の治療におけるオジパルシルの使用 Download PDFInfo
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- JP6545334B2 JP6545334B2 JP2018143573A JP2018143573A JP6545334B2 JP 6545334 B2 JP6545334 B2 JP 6545334B2 JP 2018143573 A JP2018143573 A JP 2018143573A JP 2018143573 A JP2018143573 A JP 2018143573A JP 6545334 B2 JP6545334 B2 JP 6545334B2
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- opipalcil
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- mucopolysaccharidosis
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Description
(1.培養細胞で得られた結果)
(1.1.ウシ大動脈内皮細胞)
6ウェルプレートでウシ大動脈内皮細胞(ECACC92010601)を培養し、35S硫酸ナトリウム(10μci/ml)と、DMSOで所定の濃度(1〜10μM;DMSO最終濃度:0.1%)に可溶化したオジパルシルとの存在下、24時間インキュベートした。その後、培養上清を回収して細胞層をリン酸バッファ(PBS)で洗浄し、上記培養上清及び洗浄液を試験管内でひとまとめにした。次いで、未標識のデルマタン硫酸(200μg)溶液を連行剤(entraining agent)として働かせるために加えた。Sephadex G25カラムを用いてゲル濾過することで、導入されなかった35Sを取り除いた。この際、GAGはカラムの排除画分(V0)に溶離していた。塩化セチルピリジニウム溶液(最終濃度:0.1%)を溶離液に加え、室温で24時間、GAGを析出した。その後、サンプルを遠心分離して上清を除去した。得られた析出物を2M塩化マグネシウムに再溶解し、5体積の95%エタノールでGAGを析出した。遠心分離後、アルコール性の析出物を0.9%塩化ナトリウムに再溶解し、カウンティングバイアルにシンチレーション流体を加えてから、分取画分の放射能を測定した。
正常ヒト皮膚繊維芽細胞(BIOalternatives PF2)を、96ウェルプレートで24時間培養した。上記培地を、所定濃度(1μM、3μM、10μM)のオジパルシルを含有する培地若しくは含有しない(コントロール)培地、又は、10ng/mlのTGF−βリファレンスを含有する(ポジティブコントロール)培地と置き換えた後、総GAG合成を評価するために3H−グルコサミン放射標識を加えて、上記細胞を72時間インキュベートした。インキュベート終了時、培養プレートのウェルにカオトロピックバッファを加えて、繊維芽細胞を溶解した。次いで、細胞溶解液のGAG全体をイオン交換クロマトグラフィー(Q−Sepharoseカラム)により精製した。液体シンチレーションにより、アニオン性画分に取り込まれた放射能を測定した。
オジパルシルを400mg/kgの用量でニュージーランドウサギに経口投与した。投与から4時間後、当該動物に麻酔をかけ、頸動脈へのカテーテル法により血液サンプルをクエン酸チューブに採取した。遠心分離後、血漿を除去、凍結した。Pronase Eを用いて、50℃で48時間、タンパク質を消化させた後、血漿GAGを単離した。トリクロロ酢酸を加えてタンパク質及びタンパク質残渣を析出させ、4℃で一晩インキュベートした。遠心分離後、上清を回収し、リン酸バッファ100体積に対して、4℃で48時間透析した。塩化セチルピリジニウム溶液(最終濃度:0.1%)を透析物に加えて、周囲温度で24時間、GAGを析出した。次いで、サンプルを遠心分離し、上清を除去した。得られた析出物を2M塩化ナトリウムに再溶解し、GAGを5体積の95%エタノールで析出した。遠心分離後、アルコール性析出物を0.9%塩化ナトリウムに再溶解し、Sephadex G25カラム(PD10)で脱塩した。
湿式造粒法によって得られた錠剤の成分(重量%)
オジパルシル:90%
結晶セルロース(国民医薬品集又は欧州薬局方):7%
ポビドン(ポリビニルピロリドン)(米国薬局方又は欧州薬局方):3%
水(米国薬局方又は欧州薬局方):湿式造粒するのに十分な量
Claims (8)
- オジパルシルを含む、ライソゾームにおけるコンドロイチン硫酸及び/又はデルマタン硫酸の蓄積を低減させるための医薬組成物。
- オジパルシルが1日あたり100mg〜5000mgの量で投与されるように用いられる、請求項1に記載の医薬組成物。
- 食物と共に投与される請求項1または2に記載の医薬組成物。
- 1種以上の医薬的に許容される賦形剤を含有する、請求項1〜3のいずれか1項に記載の医薬組成物。
- 経口剤形である請求項1〜4のいずれか1項に記載の医薬組成物。
- 固形製剤である請求項5に記載の医薬組成物。
- 錠剤である請求項5又は6に記載の医薬組成物。
- オジパルシルを100mg〜1000mg含有する請求項4〜7のいずれか1項に記載の医薬組成物。
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FR1359657 | 2013-10-04 | ||
FR1359657A FR3011468B1 (fr) | 2013-10-04 | 2013-10-04 | Utilisation de l'odiparcil dans le traitement d'une mucopolysaccharidose |
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JP2018143573A Active JP6545334B2 (ja) | 2013-10-04 | 2018-07-31 | ムコ多糖症の治療におけるオジパルシルの使用 |
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US6866844B2 (en) * | 2002-11-07 | 2005-03-15 | Biomarin Pharmaceutical Inc. | Precursor N-acetylgalactosamine-4-sulfatase, methods of treatment using said enzyme and methods for producing and purifying said enzyme |
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US9051342B2 (en) * | 2004-10-13 | 2015-06-09 | Ptc Therapeutics, Inc. | Pyrazole or triazole compounds and their use for the manufacture of a medicament for treating somatic mutation related diseases |
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