JP4439814B2 - 動脈性高血圧症、他の心血管疾患、及びその合併症を治療するためのアンギオテンシンiiat1受容体拮抗薬製剤の調製 - Google Patents
動脈性高血圧症、他の心血管疾患、及びその合併症を治療するためのアンギオテンシンiiat1受容体拮抗薬製剤の調製 Download PDFInfo
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- JP4439814B2 JP4439814B2 JP2002578949A JP2002578949A JP4439814B2 JP 4439814 B2 JP4439814 B2 JP 4439814B2 JP 2002578949 A JP2002578949 A JP 2002578949A JP 2002578949 A JP2002578949 A JP 2002578949A JP 4439814 B2 JP4439814 B2 JP 4439814B2
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Description
調製は、シクロデキストリンと、AT1受容体拮抗薬とを等モル比で行う。手短に言えば、β−シクロデキストリン及び/又はその誘導体を水中で攪拌、加熱しながら溶解する。次いで、当該量のロサルタンをこの水溶液に加える。溶解に続いて、混合液を液体窒素中で凍結し、凍結乾燥法にかけると乾燥固体が得られる。次いで、得られた固体を、赤外域での吸収分光、熱分析(TG/DTG及びDSC)及びX線回析を利用して物理化学的特徴付けを行う。β−シクロデキストリンの赤外スペクトルでは、3500cm−1付近でνOH、2910cm−1でνCH3(非対称)、及び1440cm−1でvC=Oのバンドが観察された。ロサルタンでは、3400cm−1付近でνNHに対応するバンド、2980cm−1でνCH3(非対称)、2770cm−1でνCH3(対称)、1600cm−1付近で芳香族のνC=C、1350cm−l付近でνCHのバンド、1500〜1600cm−1でνC=C+C=Nの振動様式の組合せに関連するバンド、760cm−1でCH3「rock(振動)」の動作に対応する強いバンドが確認された。包接化合物のIRスペクトルでは、CH3「rock」、2770cm−1でのνC−H(対称)、3400cm−lでのνN−Eのバンドは見られず、1500〜1600cm−1でイミダゾール及び芳香環のモードに関連するバンドが減少した。これらの観察から、包接化合物の形成が証明される。
ヒドロキシプロピル−β−シクロデキストリンとアンギオテンシンII AT1受容体との調製物をモル比1:1で調製した。手短に言えば、ヒドロキシプロピル−β−シクロデキストリン及び/又はその誘導体を水中で攪拌、加熱しながら溶解する。次いで、当該量のロサルタンをこの水溶液に加える。溶解に続いて、この混合液を液体窒素中で凍結し、凍結乾燥法にかけると乾燥固体が得られる。次いで、得られた固体を、赤外域での吸収分光、熱分析(TG/DTG及びDSC)及びX線回析を利用して物理化学的特徴付けを行う。ヒドロキシプロピル−β−シクロデキストリンの赤外スペクトルでは、3400cm−1でνO−H、2900cm−1付近でνC−H、1140cm−1でνC−O−C、及び1630cm−lでνOHの吸収バンドが示された。包接化合物のIRスペクトルでは、CH3「rock(振動)」、2770cm−lでのνC−H(対称)、及び3400cm−1でのνN−Hのバンドの不在が確認されたが、これは包接化合物の形成を証明する。
まず、ジクロロメタンに溶かしたポリ(乳酸−グリコール酸)(PLGA)から構成される有機相と、アンギオテンシンII AT1受容体の拮抗剤、例えばロサルタンから構成される水相とから構成される乳濁液を調製する。次いで、この乳濁液を30秒間超音波処理し、1%の(PVA)溶液に加えると、第2の乳濁液が生成する。この乳濁液を1分間攪拌して、ミクロ乳濁液の均質化を完了する。この系を溶媒が蒸発するまで、加熱せずに2時間攪拌下で維持する。この混合液を2、3回遠心分離機にかけ、水で3度洗浄して表面に吸着したPVAを除去し、最終的に水2mlで再懸濁して凍結乾燥する。次いで、この固体のミクロ球を熱分析及び走査型電子顕微鏡SEMによって特徴付ける。このミクロ球のDSC曲線は、PLGAポリマーで観察されたガラス転移に類似するガラス転移を示した。個々のSEM顕微鏡写真から、粒径は50ミクロンであった。また、ミクロ球の表面が多孔質であることも確認されている。使用した異なる系の較正曲線をUV−VIS分光法によって作成し、濃度と吸光度の関係を得てカプセル化能力を決定し、それによって取り込まれたロサルタンの量を定量した(表1を参照のこと)。
大腿動脈及び大腿静脈にカテーテルを埋め込んだラットに、ロサルタン投与の前、及び投与(0、2mg/Kg)の2、6、24、48時間後に、アンギオテンシンIIを傾斜用量(5、10及び20ng/100μL)で注入した。ロサルタンはシクロデキストリンに包接されていた(胃管栄養法)。シクロデキストリンに包接されたロサルタンは、48時間までAngIIの昇圧効果を約75%妨害した。ロサルタン単独では、約8時間AngIIの効果を妨害した。
動脈圧遠隔測定記録装置(Data Science System)を装着した体重(330〜350g)の雄ラットに麻酔をかけ、大腿静脈にカテーテルを埋め込んだ。ロサルタン(0、7mg)、この薬物を(0、7mg)含む、生分解性ポリマーに取り込ませたロサルタン、又はポリマーのみの皮下注射の前後に、AngII(5、10及び20ng/100μL)の注射を行った。AngIIの注射を2、8及び24時間後、次いで24時間間隔で15日間行った。生分解性ポリマー−ロサルタン−β−シクロデキストリンの組合せを用いて、AngIIの昇圧効果の著しい妨害を15日目まで実証することができた。賦形剤の投与による著しい変化は観察されなかった。ロサルタンは、単独で約8時間AngIIの効果を妨害した。
Claims (31)
- 水溶性のロサルタンと親水性のシクロデキストリンとを含む包接化合物を活性成分として含む医薬組成物であって、(i)当該シクロデキストリンはアシル化されておらず、かつ(ii)当該医薬組成物は経皮吸収用ではない、上記医薬組成物。
- 水溶性のロサルタンが、ロサルタンのモノカリウム塩である、請求項1記載の医薬組成物。
- シクロデキストリンが、6,7又は8個のグルコピラノース単位を有する、請求項1記載の医薬組成物。
- 親水性のシクロデキストリンが、α−シクロデキストリン、β−シクロデキストリン、γ−シクロデキストリン、ヒドロキシアルキル化されたシクロデキストリン及びアルキル化されたシクロデキストリンよりなる群から選択される、請求項1記載の医薬組成物。
- ヒドロキシアルキル化されたシクロデキストリンが、ヒドロキシプロピル−β−シクロデキストリンである、請求項4記載の医薬組成物。
- 前記組成物が制御された放出システムである、請求項1記載の医薬組成物。
- 前記組成物が、水溶性のロサルタン単独と比較して、水溶性のロサルタンの効果の持続時間において増大を示す、請求項1記載の医薬組成物。
- 前記組成物が、水溶性のロサルタン単独と比較して、水溶性のロサルタンの生物学的有効性において増大を示す、請求項1記載の医薬組成物。
- 前記組成物が、水溶性のロサルタンと親水性のシクロデキストリンとを含む包接化合物をカプセルに包む生分解性又は生体適合性ポリマーをさらに含む、請求項1記載の医薬組成物。
- ポリマーが分解性表面を有する、請求項9記載の医薬組成物。
- ポリマーが、ポリ(2−ヒドロキシエチル メタクリレート)、ポリアクリルアミド、ポリ(乳酸)(PLA)、ポリ(グリコール酸)(PGA)、ポリ(乳酸−グリコール酸)(PLGA)及びポリ(無水物)から選択される、請求項9記載の医薬組成物。
- 前記組成物が制御された放出システムである、請求項9記載の医薬組成物。
- 水溶性のロサルタンの効果の持続時間が増大された、請求項9記載の医薬組成物。
- 包接化合物を水溶性のロサルタンと親水性のシクロデキストリンとの間で形成することを含む、請求項1記載の医薬組成物の製造方法。
- 包接化合物を水溶性のロサルタンと親水性のシクロデキストリンとの間で形成すること、そして当該包接化合物を生分解性又は生体適合性ポリマーでカプセルに包むことを含む、請求項9記載の医薬組成物の製造方法。
- ポリマーが分解性表面を有する、請求項15記載の方法。
- 医薬的に許容可能な希釈剤又は添加剤をさらに含む、請求項1記載の医薬組成物。
- 前記組成物が、経口投与、筋肉注射、静脈内注射、皮下注射又は吸入投与用である、請求項17記載の医薬組成物。
- 前記組成物が、固体又は液体である、請求項17記載の医薬組成物。
- 前記組成物が、シクロデキストリンのない医薬組成物と比較して、水溶性のロサルタンの改善された生物学的有効性を増進する、請求項17記載の医薬組成物。
- 前記組成物が、シクロデキストリンのない医薬組成物と比較して、水溶性のロサルタンの改善された効果の持続時間を増進する、請求項17記載の医薬組成物。
- 水溶性のロサルタンと親水性のシクロデキストリンとを含む包接化合物の治療有効量及び医薬的に許容可能な希釈剤又は添加剤を含む、患者における動脈性高血圧症を治療するための医薬組成物であって、(i)当該シクロデキストリンはアシル化されておらず、かつ(ii)当該医薬組成物は経皮吸収用ではない、上記医薬組成物。
- 水溶性のロサルタンと親水性のシクロデキストリンとを含む包接化合物の治療有効量及び医薬的に許容可能な希釈剤又は添加剤を含む、患者における動脈性高血圧症の合併症を治療するための医薬組成物であって、(i)当該シクロデキストリンはアシル化されておらず、かつ(ii)当該医薬組成物は経皮吸収用ではない、上記医薬組成物。
- 合併症が、脳卒中、冠状動脈性疾患、脳血管性疾患、腎血管性疾患、心不全及び動脈硬化症よりなる群から選択される、請求項23記載の医薬組成物。
- 医薬的に許容可能な希釈剤又は添加剤をさらに含む、請求項9記載の医薬組成物。
- 前記組成物が、経口投与、筋肉注射、静脈内注射、皮下注射又は吸入投与用である、請求項25記載の医薬組成物。
- 前記組成物が、固体又は液体である、請求項25記載の医薬組成物。
- 前記組成物が、シクロデキストリンのない医薬組成物と比較して改善された生物学的有効性を有する、請求項25記載の医薬組成物。
- 水溶性のロサルタンと親水性のシクロデキストリンとを含む包接化合物の治療有効量、水溶性のロサルタンと親水性のシクロデキストリンとを含む包接化合物をカプセルに包む生分解性又は生体適合性ポリマー及び医薬的に許容可能な希釈剤又は添加剤を含む、患者における動脈性高血圧症を治療するための医薬組成物であって、(i)当該シクロデキストリンはアシル化されておらず、かつ(ii)当該医薬組成物は経皮吸収用ではない、上記医薬組成物。
- 水溶性のロサルタンと親水性のシクロデキストリンとを含む包接化合物の治療有効量、水溶性のロサルタンと親水性のシクロデキストリンとを含む包接化合物をカプセルに包む生分解性又は生体適合性ポリマー及び医薬的に許容可能な希釈剤又は添加剤を含む、患者における動脈性高血圧症の合併症を治療するための医薬組成物であって、(i)当該シクロデキストリンはアシル化されておらず、かつ(ii)当該医薬組成物は経皮吸収用ではない、上記医薬組成物。
- 合併症が、脳卒中、冠状動脈性疾患、脳血管性疾患、腎血管性疾患、心不全及び動脈硬化症よりなる群から選択される、請求項30記載の医薬組成物。
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BRPI0105509B8 (pt) * | 2001-11-05 | 2021-05-25 | Univ Minas Gerais | formulações do peptídeo angiotensina-(1-7) usando as ciclodextrinas, lipossomas e o polímero plga |
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MXPA04009979A (es) | 2002-04-09 | 2004-12-13 | Flamel Tech Sa | Formulacion farmaceutica oral bajo forma de suspension acuosa de microcapsulas que permiten la liberacion modificada de amoxicilina. |
ATE321039T1 (de) | 2002-04-29 | 2006-04-15 | Teva Pharma | Verfahren zur herstellung von losartan und losartan-kaliumsalz |
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2001
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2002
- 2002-04-09 EP EP02713951A patent/EP1389106A1/en not_active Withdrawn
- 2002-04-09 CA CA002444145A patent/CA2444145C/en not_active Expired - Fee Related
- 2002-04-09 CN CN028106814A patent/CN1523985B/zh not_active Expired - Fee Related
- 2002-04-09 WO PCT/BR2002/000051 patent/WO2002080910A1/en not_active Application Discontinuation
- 2002-04-09 JP JP2002578949A patent/JP4439814B2/ja not_active Expired - Fee Related
- 2002-04-09 US US10/474,640 patent/US7858597B2/en not_active Expired - Fee Related
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2007
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2009
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US20080108575A1 (en) | 2008-05-08 |
EP1389106A1 (en) | 2004-02-18 |
CA2444145A1 (en) | 2002-10-17 |
US20040171584A1 (en) | 2004-09-02 |
JP2010047611A (ja) | 2010-03-04 |
BR0102252A (pt) | 2003-01-21 |
BR0102252B1 (pt) | 2013-10-22 |
WO2002080910A1 (en) | 2002-10-17 |
CN1523985B (zh) | 2010-05-12 |
US8293723B2 (en) | 2012-10-23 |
US20110091541A1 (en) | 2011-04-21 |
US7858597B2 (en) | 2010-12-28 |
CN1523985A (zh) | 2004-08-25 |
CA2444145C (en) | 2009-11-10 |
JP2004525167A (ja) | 2004-08-19 |
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