JP2005200429A - マクロライドの安定化 - Google Patents
マクロライドの安定化 Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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Abstract
【解決手段】 本発明は、結晶形の40-O-(2-ヒドロキシ)エチル-ラパマイシンの生成法、安定化法を開示し、該安定化は抗酸化剤を添加することにより達成される。さらに、40-O-(2-ヒドロキシ)エチル-ラパマイシンを含む医薬組成物も提供される。
【選択図】なし
Description
1.好ましくは単離ステップの開始において、抗酸化剤を精製マクロライドに添加することを含むポリ-エンマクロライド安定化方法
が提供される。
2.ポリ-エンマクロライドおよび抗酸化剤、好ましくは触媒量のそれらを、好ましくは固形で含む混合物、例えばバルク混合物
を提供する。
4.活性成分として、上記開示の安定化混合物を、1つまたはそれ以上の医薬的に許容される希釈剤または担体と共に含む、医薬組成物
が提供される。
温度 293(2)K
波長 1.54178Å
空間群 P21
単位細胞の大きさ
a 14.378.(2)Å
b 11.244(1)Å
c 18.310(2)Å
β 108.58(1)°
容積 2805.8(6)Å3
Z 2
密度(計算値) 1.134g/cm3
吸収係数 0.659mm−1
F(000) 1040
結晶の大きさ 0.59×0.11×0.03mm
データ回収用θ範囲 2.55から57.20°
回収反射 4182
独立反射 4037[R(int)=0.0341]
強度減衰 32%
改良方法 F2におけるフルマトリクス最小二乗法
データ/抑制/パラメーター 3134/1/613
F2における適合度 1.055
最終R指標[I>2シグマ(I)] R1=0.0574、wR2=0.1456
最も大きい回折ピークおよびホール 0.340および−0.184e/Å3
5.処置を必要とする対象において、急性または慢性の同種-または異種-移植拒絶、自己免疫疾患または炎症、喘息、増殖異常、または過増殖血管疾患を防止または処置する方法であって、当該対象に治療学的に有効量の結晶形40-O-(2-ヒドロキシ)エチル-ラパマイシンを投与することを含む方法、
6.医薬として、例えば上記開示の方法に使用のための結晶形40-O-(2-ヒドロキシ)エチル-ラパマイシン、
7.医薬的に許容される希釈剤または担体と共に結晶形40-O-(2-ヒドロキシ)エチル-ラパマイシンを含む医薬的組成物、
8.上記開示のような医薬的組成物および免疫抑制または免疫調節剤または抗炎症剤を含む医薬的組成物を含む、免疫抑制および炎症に使用するためのキットまたはパッケージ
を提供する。
0.5g無定形40-O-(2−ヒドロキシ)エチル-ラパマイシンを40℃で酢酸エチル2.0mlに溶解する。ヘプタン5.0mlを添加し、溶液を“乳濁状”とする。30℃に温めた後、当該溶液は、再び透明となる。0℃への冷却により、およびスクラッチすると共に油状物が析出する。試験管を封じ、10℃で一夜保存する。次いで、生じた白い大量の固体を濾過し、酢酸エチル/ヘキサン(1:2.5)の混合物0.5mlで洗浄し、生じた結晶を40℃、5mbarで16時間乾燥させる。次いで、融点146.5℃の結晶形40-O-(2-ヒドロキシ)エチル-ラパマイシンを得る。
無定形40-O-(2-ヒドロキシ)エチル-ラパマイシン250gをアルゴン気流中、ゆっくり攪拌しながら酢酸エチル1.0lに溶解する。この溶液を30℃に加熱し、次いで45分間、1.5lヘプタンを滴下する。上記開示のように調製した種晶0.25gを同一条件下、分けて加える。当該混合物を2時間にわたり30℃で攪拌し、結晶化混合物を1時間にわたり25℃に冷却し、次いで、30分間10℃に冷却し、濾過する。当該結晶を酢酸エチル/ヘキサン(2:3)混合物100mlで洗浄する。その後の乾燥は、50℃で約5mbarで行う。融点146.5℃
KBr中のIR:3452、2931、1746、1717、1617、1453、1376、1241、1191、1163、1094、1072、1010、985、896cm−1
座標による単一X線構造を以下の図1から3に示す。
40-O-(2-ヒドロキシ)エチル-ラパマイシン100gを無水エタノール600lに溶解する。BHT0.2gの添加後、生じた溶液を1時間以内に3.0lの水に攪拌しながら滴下する。生じた懸濁液を更に30分間攪拌する。その後の洗浄(5:1のv/v比の水/エタノール3×200ml)を伴う濾過により、含水性の白色生成物が生じ、更に、30℃、真空(1mbar)中で48時間更に乾燥する。当該生じた乾燥生成物は0.2%(w/w)BHTを含む。
化合物 オープンフラスコにおいて50℃
実施例2(0.2%BHT) 1.49
BHTなし >10
Claims (6)
- 結晶性非溶媒和形である、40-O-(2-ヒドロキシエチル)-ラパマイシン。
- 結晶格子がa=14.37Å、b=11.24Å、c=18.31Åであり、容積が2805Å3である、請求項1記載の40-O-(2-ヒドロキシエチル)-ラパマイシン。
- 40-O-(2-ヒドロキシエチル)-ラパマイシンをその結晶を含有する媒体から結晶化させ、生成した結晶を回収することを含む、本質的に純粋形の40-O-(2-ヒドロキシエチル)-ラパマイシンを製造する方法。
- 媒体が溶媒に脂肪族炭化水素CnH2n+2(n=5、6または7)を混合したものである、請求項3記載の方法。
- 溶媒が酢酸エチルである、請求項4記載の方法。
- 有効成分である請求項1または2記載の40-O-(2-ヒドロキシエチル)-ラパマイシンと、1種またはそれ以上の医薬的に許容される希釈剤または担体を含有する、医薬的組成物。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9826882.4A GB9826882D0 (en) | 1998-12-07 | 1998-12-07 | Organic compounds |
GB9826882.4 | 1998-12-07 | ||
GBGB9904934.8A GB9904934D0 (en) | 1998-12-07 | 1999-03-04 | Organic compounds |
GB9904934.8 | 1999-03-04 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2000586368A Division JP3805625B2 (ja) | 1998-12-07 | 1999-12-06 | マクロライドの安定化 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2005200429A true JP2005200429A (ja) | 2005-07-28 |
JP5043308B2 JP5043308B2 (ja) | 2012-10-10 |
Family
ID=26314797
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2000586368A Expired - Lifetime JP3805625B2 (ja) | 1998-12-07 | 1999-12-06 | マクロライドの安定化 |
JP2005106512A Expired - Lifetime JP5043308B2 (ja) | 1998-12-07 | 2005-04-01 | マクロライドの安定化 |
JP2005378514A Expired - Lifetime JP5165199B2 (ja) | 1998-12-07 | 2005-12-28 | マクロライドの安定化 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2000586368A Expired - Lifetime JP3805625B2 (ja) | 1998-12-07 | 1999-12-06 | マクロライドの安定化 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
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JP2005378514A Expired - Lifetime JP5165199B2 (ja) | 1998-12-07 | 2005-12-28 | マクロライドの安定化 |
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US (5) | US6605613B2 (ja) |
EP (4) | EP1137439B2 (ja) |
JP (3) | JP3805625B2 (ja) |
KR (2) | KR20060096477A (ja) |
CN (2) | CN1261163C (ja) |
AR (3) | AR026102A1 (ja) |
AT (1) | ATE365051T1 (ja) |
AU (1) | AU759219B2 (ja) |
BE (1) | BE1012869A3 (ja) |
BR (1) | BR9915986A (ja) |
CA (3) | CA2651609A1 (ja) |
CO (1) | CO4980847A1 (ja) |
CY (1) | CY1106870T1 (ja) |
CZ (2) | CZ303006B6 (ja) |
DE (1) | DE69936352T3 (ja) |
DK (1) | DK1137439T4 (ja) |
ES (1) | ES2288033T5 (ja) |
FR (1) | FR2786771B1 (ja) |
GB (2) | GB9826882D0 (ja) |
HK (1) | HK1038889B (ja) |
HU (2) | HU230174B1 (ja) |
ID (1) | ID29250A (ja) |
IL (1) | IL143092A0 (ja) |
IT (1) | IT1319701B1 (ja) |
MY (2) | MY127579A (ja) |
NO (2) | NO332698B1 (ja) |
NZ (2) | NZ511936A (ja) |
PE (1) | PE20001333A1 (ja) |
PL (2) | PL208854B1 (ja) |
PT (1) | PT1137439E (ja) |
RU (1) | RU2243769C2 (ja) |
SG (1) | SG151072A1 (ja) |
SI (1) | SI1137439T2 (ja) |
SK (2) | SK287325B6 (ja) |
TR (2) | TR200201428T2 (ja) |
TW (2) | TWI248938B (ja) |
WO (1) | WO2000033878A2 (ja) |
ZA (1) | ZA200104360B (ja) |
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