JP5117190B2 - 溶媒を含有しない非晶質ラパマイシン - Google Patents
溶媒を含有しない非晶質ラパマイシン Download PDFInfo
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- JP5117190B2 JP5117190B2 JP2007530211A JP2007530211A JP5117190B2 JP 5117190 B2 JP5117190 B2 JP 5117190B2 JP 2007530211 A JP2007530211 A JP 2007530211A JP 2007530211 A JP2007530211 A JP 2007530211A JP 5117190 B2 JP5117190 B2 JP 5117190B2
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- Prior art keywords
- rapamycin
- amorphous
- solution
- stent
- sirolimus
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Description
本出願は、出願日、2004年8月27日の米国仮特許出願シリアルナンバー第60/605,324号の利益を主張する。
〔1.発明の分野〕
本発明は、ステントを治療薬で被覆する方法に関し、更に詳しくは、ステントを被覆するための安定した非晶質治療薬だけでなく、他の用途のための安定した非晶質治療薬をも開発し利用することに関する。
多くの人が、心臓および他の主要器官に多量の血液を送る血管の進行性閉塞(progressive blockage)によって引き起こされる循環器系統の疾患を患っている。そのような人の血管の閉塞がより重症であると、しばしば、高血圧、虚血性障害、発作(stroke)または心筋梗塞を引き起こす。アテローム性病変(atherosclerotic lesions)は、冠状動脈血流(coronary blood flow)を制限するかまたは遮り、虚血性心臓疾患の主要原因となる。経皮経管冠動脈形成術(percutaneous transluminal coronary angioplasty)は、1つの医療処置であって、その目的が動脈を通過する血流量を増加させることである該医療処置である。経皮経管冠動脈形成術は、冠状血管狭窄(coronary vessel stenosis)のための主要処置である。この処置の使用が増大しているのは、冠動脈バイパス形成手術と比べて、該処置の成功率が相対的に高く、かつ、該処置の侵襲性が最小限に抑えられていることに起因する。経皮経管冠動脈形成術に関連する限界は、血管の急性冠閉塞である。この急性冠閉塞は、処置および再狭窄の後、直ちに生じることがある。再狭窄は、処置の後、徐々に生じる。更に、再狭窄は、伏在静脈バイパス移植術(saphenous vein bypass grafting)を受けた患者にとって慢性的問題である。急性閉塞の機構は、幾つかの要因を包含するようであり、血管の反跳(vascular recoil)に起因し、結果的に動脈が閉塞し、および/または、新たに開通した血管の損傷距離に沿って血小板とフィブリンとが堆積することがある。
本発明の方法は、植え込み可能な医療用具を治療薬で被覆すること、および、溶媒を実質的に含有しない非晶質形態の治療薬を創り出すことに、関連する困難さを克服するための方法を提供する。溶媒を実質的に含有しない非晶質形態の治療薬は、典型的にはより安定であり、また、典型的には、溶解度を増大させて該治療薬の摂取を改善する。
本発明は、ステントまたは他の植え込み可能な医療用具を1種以上の治療薬(例えば、ラパマイシン(rapamycin))で被覆する方法に向けられている。1つの典型的な方法を、図1の流れ図に開示する。該方法の第1の部分は、プライマー(primer)を施す工程を含む。その典型的な実施形態において、該方法の第1の工程は、表面調製および表面処理である(工程102)。この工程は、洗浄溶液を利用して、被覆されるべきステントから内毒素を除去する段階を含む。洗浄溶液には、かなり多数の種類の洗浄溶液、例えば、高pH溶液(例えば、ケイ酸塩を含有する水酸化カリウム溶液)、が包含されることがある。次の工程も、表面調製および表面処理の工程である(工程104)。この工程では、プライマー層を堆積させるための、複数のステントの表面を調製するために、シラン溶液を利用する。次の工程は、プライマーそれ自体を施す工程である(工程106)。典型的な実施形態では、蒸着法を利用して、ステントにパリレン(parylene)を施す。パリレンを施した後、直ちに、ステントを包装して秤量する(工程108)。ステントを秤量した後、直ちに、それらを容器またはバイアルに入れる。バイアルは、かなり多数の種類の適切な材料で形成することができる。典型的な実施形態において、バイアルは、ポリプロピレンで形成する。
(1)非晶質ラパマイシンを調製する方法において、
2−プロパノールにラパマイシンを溶解して溶液を形成する工程と、
前記溶液に水を添加することによって、非晶質ラパマイシンの沈降物を形成する工程と、
前記の非晶質ラパマイシンの沈降物を、所定の時間、乾燥させる工程と、
を含む、方法。
(2)非晶質ラパマイシンにおいて、
2−プロパノールにラパマイシンを溶解して溶液を形成する工程と、
前記溶液に水を添加することによって、非晶質ラパマイシンの沈降物を形成する工程と、
前記の非晶質ラパマイシンの沈降物を、所定の時間、乾燥させる工程と、
を含む方法によって製造された、非晶質ラパマイシン。
(3)非晶質ラパマイシンにおいて、
約92℃〜約95℃の範囲のガラス転移温度を有する、非晶質ラパマイシン。
(4)非晶質ラパマイシンを調製する方法において、
2−プロパノールにラパマイシンを溶解して溶液を形成する工程と、
前記溶液に水を添加することによって、非晶質ラパマイシンの沈降物を形成する工程と、
を含む、方法。
(5)非晶質ラパマイシンにおいて、
2−プロパノールにラパマイシンを溶解して溶液を形成する工程と、
前記溶液に水を添加することによって、非晶質ラパマイシンの沈降物を形成する工程と、
を含む方法によって製造された、非晶質ラパマイシン。
2−プロパノールにラパマイシンを溶解して溶液を形成する工程と、
前記溶液に水を添加することによって、非晶質ラパマイシンの沈降物を形成する工程と、
前記非晶質ラパマイシンを、遊離基、残留溶媒および自動酸化開始剤にさらすことを減少させることによって、前記非晶質ラパマイシンの自動酸化を最小限に抑える工程と、
を含む、方法。
(7)実施態様6に記載の方法において、
低濃度ヒドロペルオキシド溶媒を使用することによって、前記非晶質ラパマイシンの自動酸化を最小限に抑える工程、
を更に含む、方法。
(8)実施態様6に記載の方法において、
不活性ガスによるブランケッティングによって溶存酸素を減少させることにより、前記非晶質ラパマイシンの自動酸化を最小限に抑える工程、
を更に含む、方法。
(9)実施態様6に記載の方法において、
前記非晶質ラパマイシンのガラス転移温度を上昇させることにより、自動酸化を最小限に抑える工程、
を更に含む、方法。
(10)実施態様6に記載の方法において、
前記溶液に溶解しているラパマイシンの濃度が、前記沈降物が形成される時間を決定する、方法。
前記沈降物を濾過し、洗浄し、乾燥する工程、
を更に含む、方法。
(12)非晶質治療薬において、
前記非晶質治療薬は、経口で、非経口で、血管内に、鼻腔内に、気管支内に、経皮的に、直腸から、または、前記治療薬で被覆されたステントを経て、投与することができ、
前記非晶質治療薬は、
溶媒に、ある量の結晶質治療薬を溶解させて溶液を形成する工程と、
前記溶液に作用物質を添加して、前記溶液から前記治療薬を沈降させる工程と、
前記沈降物を濾過する工程と、
前記沈降物を洗浄して、不純物を除去する工程と、
前記沈降物を乾燥させる工程と、
を含む、方法によって形成される、
非晶質治療薬。
(13)実施態様12に記載の方法において、
前記溶媒は、少なくとも1種の溶媒である、方法。
(14)実施態様12に記載の方法において、
前記結晶質治療薬は、結晶質シロリムスであり、
前記溶媒は、2−プロパノールである、
方法。
(15)実施態様14に記載の方法において、
前記作用物質は、水である、方法。
前記結晶質治療薬を前記溶媒に溶解するのを容易にするために、前記結晶質治療薬および前記溶媒を加熱し、かき混ぜて、前記溶液を形成する工程、
を更に含む、方法。
(17)実施態様12に記載の方法において、
前記結晶質治療薬の濃度が、前記溶液から前記沈降物を得る時間を決定する、方法。
(18)実施態様12に記載の方法において、
前記非晶質治療薬のガラス転移温度は、室温および室内圧力における前記非晶質治療薬を安定させる温度である、方法。
(19)実施態様12に記載の方法において、
前記結晶質治療薬は、ラパマイシンの変異体である、方法。
(20)実施態様19に記載の方法において、
前記のラパマイシンの変異体は、少なくとも、FKBP12および他のイムノフィリン類に結合する、全ての類似体、誘導体、および抱合体、を包含する、方法。
Claims (2)
- 非晶質ラパマイシンを形成する方法において、
2−プロパノールに結晶質ラパマイシンを溶解して溶液を形成する工程と、
前記溶液に水を添加することによって、非晶質ラパマイシンの沈降物を形成する工程と、
(i)不活性ガスによるブランケッティングによって溶存酸素を減少させること、および、(ii)真空条件と加熱とを適用して、残留溶媒の除去を促進し、前記ラパマイシンのガラス転移温度を上昇させることにより、前記非晶質ラパマイシンの自動酸化を最小限に抑える工程と、
を含む、方法。 - 請求項1に記載の方法において、
前記沈降物を濾過し、洗浄し、乾燥する工程、
を更に含む、方法。
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US60532404P | 2004-08-27 | 2004-08-27 | |
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PCT/US2005/030606 WO2006026531A1 (en) | 2004-08-27 | 2005-08-24 | Solvent free amorphous rapamycin |
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US8715771B2 (en) * | 2003-02-26 | 2014-05-06 | Abbott Cardiovascular Systems Inc. | Coated stent and method of making the same |
US20060258698A1 (en) | 2005-02-09 | 2006-11-16 | Sreenivasu Mudumba | Liquid formulations for treatment of diseases or conditions |
US8663639B2 (en) | 2005-02-09 | 2014-03-04 | Santen Pharmaceutical Co., Ltd. | Formulations for treating ocular diseases and conditions |
US8492400B2 (en) | 2006-02-09 | 2013-07-23 | Santen Pharmaceutical Co., Ltd. | Stable formulations, and methods of their preparation and use |
JP5506378B2 (ja) | 2006-03-23 | 2014-05-28 | 参天製薬株式会社 | 血管透過性に関連する疾患または病気のための製剤および方法 |
US20090011117A1 (en) * | 2007-07-03 | 2009-01-08 | Endotronix, Inc. | Methods for texturing a surface of an endovascular implant |
JP2011525849A (ja) | 2008-06-25 | 2011-09-29 | ボストン サイエンティフィック サイムド,インコーポレイテッド | 治療剤を含む医療機器 |
IT1400977B1 (it) | 2010-07-01 | 2013-07-05 | Euticals Spa | Nuovi complessi di inclusione farmaceutici, solidi, solubili in acqua e le loro soluzioni acquose per uso orale, oftalmico, topico o parenterale, contenenti un macrolide ed alcune ciclodestrine. |
DK2948134T3 (da) | 2013-01-24 | 2020-06-02 | Palvella Therapeutics Inc | Sammensætninger til transdermal indgivelse af mtor-inhibitorer |
JP6472155B2 (ja) * | 2013-04-01 | 2019-02-20 | テルモ株式会社 | ステントおよびステントデリバリーシステム |
WO2015181826A1 (en) | 2014-05-27 | 2015-12-03 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Crystalline coating and release of bioactive agents |
US9827135B2 (en) | 2015-09-15 | 2017-11-28 | Savage Medical, Inc. | Devices and methods for anchoring a sheath in a tissue cavity |
IL267869B2 (en) | 2017-01-06 | 2023-10-01 | Palvella Therapeutics Inc | Non-aqueous preparations of mTOR inhibitors and methods of use |
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BE1009856A5 (fr) | 1995-07-14 | 1997-10-07 | Sandoz Sa | Composition pharmaceutique sous la forme d'une dispersion solide comprenant un macrolide et un vehicule. |
US6384213B1 (en) * | 1998-10-23 | 2002-05-07 | Ranbaxy Laboratories Limited | Process for preparing a pure, pharmacopoeial grade amorphous form of cefuroxime axetil |
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US20040093064A1 (en) * | 2002-11-12 | 2004-05-13 | Gjalt Bosma | Drug eluting stent graft combination |
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