JP2016166179A - 安定化スタチン製剤 - Google Patents
安定化スタチン製剤 Download PDFInfo
- Publication number
- JP2016166179A JP2016166179A JP2016030191A JP2016030191A JP2016166179A JP 2016166179 A JP2016166179 A JP 2016166179A JP 2016030191 A JP2016030191 A JP 2016030191A JP 2016030191 A JP2016030191 A JP 2016030191A JP 2016166179 A JP2016166179 A JP 2016166179A
- Authority
- JP
- Japan
- Prior art keywords
- statin
- formulation
- pharmaceutically acceptable
- complexing agent
- lyophilized
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Abstract
Description
以下の実施例は、本発明の種々の態様を説明する。これらはいかなる意味においても請求の範囲を制限することを意図するものではない。
実施例1−3は、pHの影響、緩衝剤の強度、および種々の混合方法を評価するために可溶化方法を比較するものである。実施例1では、サンプルをpH5.5、6.5、7.5、および8.5で100mMの第二リン酸ナトリウム(Na2HPO4)中に作製した。サンプルはボルテックス撹拌のみ行った。実施例2では、サンプルをpH5.5、6.5、7.5、および8.5で100mMのNa2HPO4中に作製し、ボルテックス撹拌と超音波処理を行った。実施例3では、サンプルをpH7.5または8.5で25または50mMのNa2HPO4中に作製した。
種々のpH調整方法を用いて製剤中のAS-Caの溶解度を実施例4および5で比較し、複合体化の効率を評価した。実施例4では、NaOHを用いてpHを9に調整し、次いでリン酸を添加してpHを7.0−8.5まで下げた。実施例5では、0.85% o-リン酸または0.1M NaOHでpHを7.0−8.5の間に調整した。
実施例9および10では、HPβ-CDの代替候補として、スルホブチル-エーテル-β-シクロデキストリン(「SBE-β-CD」)を、SBE-β-CDとのAS-Ca複合体化によって評価した。リン酸ナトリウム塩対超純水のSBE-β-CDによるAS-Caの可溶化に対する効果も種々のpHで評価した。
a.40/10、4.0mlのプロピレングリコールおよび1.0mlのエタノール
b.30/10、3.0mlのプロピレングリコールおよび1.0mlのエタノール
c.20/10、2.0mlのプロピレングリコールおよび1.0mlのエタノール
d.40/5、4.0mlのプロピレングリコールおよび0.5mlのエタノール
e.40/0、4.0mlのプロピレングリコールおよび0.0mlのエタノール
サンプルをそれぞれ5分間ボルテックス撹拌し、次いで15分間超音波処理した。サンプルは最初に0.1M NaOHでpH9.00に調整し、ボルテックス撹拌し、次いで超音波処理した。サンプルのpHを0.85% o-リン酸でpH8.50に調整し、サンプルを再度ボルテックス撹拌および超音波処理した。超純水でサンプルを1.0mlとし、濾過し、次いでHPLCで分析した(表7を参照のこと)。
カルシウム三水和物型の代替物としてアトルバスタチン遊離酸の溶解度(「AS」)を調べた。
pH11.0でプロピレングリコール/エタノール(4/1)からなる非水性製剤を調べて、観察される分解が減少した。しかしながら、この製剤は生理食塩水中に1:1希釈すると沈澱した。安定性を改善するために、AS-CaのHPβ-CDとの予備的に凍結乾燥した製剤を調べた。この製剤の初期の安定性から、溶液中にサンプルを含んだままのものよりも安定性の改善が示された。
Claims (27)
- 少なくとも約3.32mg/mlの可溶化されたスタチン濃度を提供する、十分量の薬学上許容される錯化剤(complexing agent)と約7〜約9のpHを有する水溶液中で複合体化された有効量の薬学上許容される水不溶性スタチンを含有する液状医薬製剤。
- 複合体化されたスタチンが凍結乾燥されている、請求項1記載の製剤。
- スタチンが、ロバスタチン、シンバスタチン、メバスタチン、アトルバスタチン、セリバスタチンおよびリバスタチンからなる群から選択される、請求項1記載の製剤。
- 錯化剤がシクロデキストリンである、請求項1記載の製剤。
- 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記載の製剤。
- 可溶化スタチン濃度が約1mg/ml〜約25mg/mlである、請求項1記載の製剤。
- 錯化剤が製剤の少なくとも13.5%で含まれる、請求項1記載の製剤。
- 可溶化スタチン濃度が約5〜約15mg/mlである、請求項6記載の製剤。
- 可溶化スタチン濃度が約10mg/mlである、請求項6記載の製剤。
- スタチンが、ロバスタチン、シンバスタチン、メバスタチン、アトルバスタチン、セリバスタチンおよびリバスタチンからなる群から選択され、錯化剤がシクロデキストリンである、請求項1記載の製剤。
- 薬学上許容される水不溶性スタチンと、凍結乾燥粒子が薬学上許容される注射用溶液中で再構成されるときにスタチンを水溶性にするのに十分量の薬学上許容される錯化剤とを含有する、凍結乾燥粒子。
- 40℃で1ヵ月間保存して実質的に分解しない、請求項11記載の凍結乾燥粒子。
- 40℃で1ヶ月間保存した後の分解が約0.1%未満である、請求項12記載の凍結乾燥粒子。
- スタチンが、ロバスタチン、シンバスタチン、メバスタチン、アトルバスタチン、セリバスタチンおよびリバスタチンからなる群から選択される、請求項12記載の凍結乾燥粒子。
- 錯化剤がシクロデキストリンである、請求項12記載の凍結乾燥粒子。
- 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12記載の凍結乾燥粒子。
- 約1mg/ml〜約25mg/mlのスタチン濃度に再構成される、請求項12記載の凍結乾燥粒子。
- 約5〜約15mg/mlのスタチン濃度に再構成される、請求項12記載の凍結乾燥粒子。
- 約10mg/mlのスタチン濃度に再構成される、請求項12記載の凍結乾燥粒子。
- 薬学上許容されるスタチンおよび薬学上許容される錯化剤を含有する凍結乾燥粒子の調製方法であって、以下のステップ:
(a)錯化剤と好適な溶媒との混合物に水不溶性スタチンを添加し、
(b)混合し、
(c)薬学上許容される緩衝剤を用いてpHを約7〜約9のpH範囲に調整し、そして
(d)混合物を凍結乾燥して凍結乾燥粒子を得る、
を含む、上記方法。 - ヒト患者に注入するための有効量の薬学上許容される溶液中で凍結乾燥粒子を再構成する、請求項20記載の方法。
- スタチンが、ロバスタチン、シンバスタチン、メバスタチン、アトルバスタチン、セリバスタチンおよびリバスタチンからなる群から選択される、請求項20記載の方法。
- 錯化剤がシクロデキストリンである、請求項20記載の方法。
- 錯化剤が製剤の少なくとも13.5%で含有される、請求項20記載の方法。
- 少なくとも約3.32mg/mlの可溶化スタチン濃度が得られる、請求項20記載の方法。
- 以下のステップ:
(a)錯化剤と好適な溶媒との混合物に水不溶性スタチンを添加し、混合物を凍結乾燥して凍結乾燥粒子を得ることによって凍結乾燥粒子を調製し、
(b)薬学上許容される注射用溶液中で該凍結乾燥粒子を再構成し、そして
(c)好適量の溶液を投与して、治療の必要なヒト患者に有効量のスタチンを提供する、
を含む、治療方法。 - 患者の脂質レベルを低下させ、適切な抗炎症効果または他の治療効果を得るために有効な量でスタチンが投与される、請求項26記載の治療方法。
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KR101686881B1 (ko) * | 2014-07-25 | 2016-12-20 | 연세대학교 산학협력단 | 스타틴을 포함하는 갑상선 안병증의 예방 또는 치료용 약제학적 조성물 |
JP6355688B2 (ja) * | 2016-09-01 | 2018-07-11 | ペキン ユニバーシティ サード ホスピタルPeking University Third Hospital | 虚血性疾患の治療におけるスタチンの使用 |
KR102099627B1 (ko) | 2018-04-13 | 2020-04-10 | (주)바이오리치 | 냉이 추출물 및 신이 추출물을 유효성분으로 포함하는 지질 대사 개선용 조성물 |
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