JP7476161B2 - 凍結乾燥リポソーム - Google Patents
凍結乾燥リポソーム Download PDFInfo
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- JP7476161B2 JP7476161B2 JP2021196626A JP2021196626A JP7476161B2 JP 7476161 B2 JP7476161 B2 JP 7476161B2 JP 2021196626 A JP2021196626 A JP 2021196626A JP 2021196626 A JP2021196626 A JP 2021196626A JP 7476161 B2 JP7476161 B2 JP 7476161B2
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- liposomes
- composition
- liposome
- lyophilization
- cytarabine
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- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
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- 230000002209 hydrophobic effect Effects 0.000 description 1
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- 230000009456 molecular mechanism Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- 238000005191 phase separation Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
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- 230000000007 visual effect Effects 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
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Description
本出願は、2011年10月21日に出願された米国特許出願61/550,047号に対して優先権を主張し、その内容は、全体が参照によって本開示に援用される。
本発明は、長期間保存され得る少なくとも2つの治療薬または診断薬を含有する凍結乾燥リポソームを製造する方法および組成物に関連する。1つの局面において、本発明は、低コレステロールリポソームであって、必要に応じて外部媒体中に凍結保護物質を含み、リポソームの凍結/解凍および脱水の損傷に対する抵抗性を有し、それゆえリポソームのサイズおよび完全性を維持するリポソームに関する。
リポソームは、水溶性コアを囲む少なくとも1つの脂質二重層を有している閉鎖小胞である。リポソーム内の空間および脂質層は、薬物、化粧品、診断薬、遺伝物質および生理活性化合物を含む様々な物質を捕捉し得る。無毒性の脂質がリポソームの基盤として機能するので、それらは一般的に低い毒性を示す。低い毒性ならびに薬剤の血漿循環の寿命を増加させるリポソームの能力は、医薬活性剤を送達するのに特に有用なビヒクルとしてのリポソームを生じさせる。多くの場合、リポソーム送達薬剤は、結果として減少した毒性とともに優れた臨床効果をもたらす。
凍結乾燥後の再構成の際リポソームの完全性を維持するために、特に封入薬剤の保持を確実にするために、凍結保護物質がリポソーム内外両方に必要とされることが一貫して報告されている。本発明者らは、1つだけでなく2つまたはそれ以上の活性薬剤を封入するリポソームの凍結乾燥を成功させるために、内側の凍結保護物質を必要としない安定なリポソームを同定した。
本発明は、例えば、以下の項目も提供する。
(項目1)
凍結乾燥ゲル相リポソーム組成物であって、ここで、該ゲル相リポソームが、少なくとも25℃の溶融相温度(TC)を示し、少なくとも2つの治療薬および/または診断薬と安定に会合し、実質的に内側の凍結保護物質を含有せず、そして、
ここで、該ゲル相リポソーム組成物が再構成される場合、該リポソームの平均直径が、凍結乾燥前の該組成物と比較して維持され、該薬剤が該リポソーム中に保持される、組成物。
(項目2)
封入された前記薬剤が固定された割合であり、前記組成物が再構成される場合、前記薬剤の割合が、凍結乾燥前の該組成物と比較して25%以下変化する、項目1に記載の組成物。
(項目3)
前記リポソームが、少なくとも37℃である相転移温度(TC)を有する、項目1に記載の組成物。
(項目4)
前記リポソームの平均直径が、凍結乾燥前に測定された該値と比較して、前記リポソームの凍結乾燥後および再構成の際、25%以下増加する、項目1に記載の組成物。
(項目5)
前記リポソームの平均直径が、凍結乾燥前に測定された該値と比較して、前記リポソームの凍結乾燥後および再構成の際、15%以下増加する、項目4に記載の組成物。
(項目6)
前記リポソームの平均直径が、凍結乾燥前に測定された該値と比較して、前記リポソームの凍結乾燥後および再構成の際、10%以下増加する、項目5に記載の組成物。
(項目7)
各薬剤の少なくとも75%が、前記リポソームの再構成の際保持される、項目1に記載の組成物。
(項目8)
各薬剤の少なくとも85%が、前記リポソームの再構成の際保持される、項目7に記載の組成物。
(項目9)
各薬剤の少なくとも90%が、前記リポソームの再構成の際保持される、項目8に記載の組成物。
(項目10)
前記リポソームのサイズ分布が、前記リポソームの凍結乾燥後および再構成の際、25%以下変化する、項目1に記載の組成物。
(項目11)
前記リポソームのサイズ分布が、前記リポソームの凍結乾燥後および再構成の際、15%以下変化する、項目10に記載の組成物。
(項目12)
前記リポソームのサイズ分布が、前記リポソームの凍結乾燥後および再構成の際、10%以下変化する、項目11に記載の組成物。
(項目13)
前記リポソームが、20mol%以下のコレステロールを含み、少なくとも1mol%のホスファチジルグリセロール(PG)および/またはホスホイノシトール(PI)を含む、項目1~12のいずれか一項に記載の組成物。
(項目14)
凍結保護物質が、前記リポソームの外側に存在する、項目1~12のいずれか一項に記載の組成物。
(項目15)
前記凍結保護物質が、スクロースである、項目14に記載の組成物。
(項目16)
前記薬剤が、少なくとも1.0だけ異なるlog分配係数を有する、項目1~12のいずれか一項に記載の組成物。
(項目17)
前記薬剤が、抗悪性腫瘍薬である、項目1~12のいずれか一項に記載の組成物。
(項目18)
前記抗悪性腫瘍薬の少なくとも1つが、ヌクレオシドアナログであり、または
前記抗悪性腫瘍薬の少なくとも1つが、アントラサイクリンである、項目17に記載の組成物。
(項目19)
前記抗悪性腫瘍薬が、ダウノルビシンおよびシタラビンである、項目18に記載の組成物。
(項目20)
ダウノルビシン:シタラビンの比が、モルベースで1:5である、項目19に記載の組成物。
(項目21)
前記抗悪性腫瘍薬が、イリノテカンおよびフロクスウリジンである、項目18に記載の組成物。
(項目22)
イリノテカンおよびフロクスウリジンのモル比が、モルベースで1:1である、項目21に記載の組成物。
(項目23)
項目1~12のいずれか一項に記載の組成物を調製する方法であって、少なくとも25℃の溶融相温度(TC)を示し、少なくとも2つの治療薬および/または診断薬と安定に会合し、実質的に内側の凍結保護物質を含有しないゲル相リポソームを含む水性媒体を凍結乾燥に付すことを含む、方法。
(項目24)
ゲル相リポソームを含む前記媒体が、前記媒体のガラス転移温度(Tg)未満である温度で凍結される、項目23に記載の方法。
(項目25)
被験者に治療薬および/または診断薬を投与するための薬学的組成物を調製する方法であって、薬学的担体中に項目1~12のいずれか一項に記載されたリポソーム組成物を再構成し、再構成された組成物を得ることを含む、方法。
(項目26)
動物の被験体に治療薬および/または診断薬を投与する方法であって、項目25に記載された再構成組成物を、該被験体に投与することを含む、方法。
(項目27)
前記投与が、非経口的である、項目26に記載の方法。
(項目28)
前記被験体が、ヒトである、項目26または27に記載の方法。
、図1~4に示されるように体積加重基準で評価され得る。
CPX-1の凍結乾燥
1:1のイリノテカンおよびフロクスウリジンを、DSPC/DSPG/コレステロール(7:2:1モル比率)リポソームおよび指定されたCPX-1中に、ともに封入する。凍結乾燥したCPX-1は、結果として安定した薬物負荷リポソームとなり、その結果、再構成された剤形から活性医薬成分の最小の漏出があった。CPX-1において使用されるイリノテカン塩酸塩は、3.94の予測されるLog分配係数(LogP)を有する。フロクスウリジンは、-1.14の予測されるLogPを有する。
凍結乾燥リポソームにおいて、時間とともに変わらない粒径サイズプロフィール
二重にロードされるCPX-1およびCPX-351リポソームのサイズ分布に対する、凍結、凍結乾燥および保存の影響を調べるために、実験を行った。CPX-351は、ジステアロイルフォスフォコリン(DSPC):ジステアロイルフォスファチジルグリセロール(DSPG):およびコレステロール(CHOL)がモル比で7:2:1であるリポソーム中に、モル比が1:5のダウノルビシンおよびシタラビンを有する製剤である。ダウノルビシンは、1.68の予測されるLogPを有する。シタラビンは、-2.17の予測されるLogPを有する。
凍結乾燥リポソームにおいて、時間とともに変わらない薬物封入パーセント
二重にロードされたCPX-1またはCPX-351リポソームからの薬物漏出の程度に対する、凍結および/または凍結乾燥ならびに保存の影響を調べるために、実験を行った。
(a)少なくとも37℃の溶融相温度(TC)を示し、かつ、該リポソームのリポソーム膜が、20mol%以下のコレステロールを含み、かつ、少なくとも1mol%のホスファチジルグリセロール(PG)若しくはホスファチジルイノシトール(PI)、又はそれらの両方を含む、ゲル相リポソームであって、
ここで、少なくとも2つの治療薬および/または診断薬が該リポソームと安定に会合しているゲル相リポソーム;及び、
(b)該リポソームの外側に存在する凍結保護物質
を含み、
ここで、該リポソームが実質的に内側の凍結保護物質を含有せず、かつ、
該凍結乾燥ゲル相リポソーム組成物が医薬担体中で再構成される場合、該リポソームの平均直径が、凍結乾燥前の該組成物と比較して実質的に維持され、かつ、該薬剤が該リポソーム中に実質的に保持される、組成物であって、
各薬剤の少なくとも75%が、前記リポソームの再構成の際保持され、かつ、当該薬剤の保持が、5℃~25℃の保存で少なくとも6ヶ月間維持される、組成物。
ここで、前記リポソームは少なくとも37℃の溶融相温度(TC)を示し、かつ、該リポソームのリポソーム膜が、20mol%以下のコレステロールを含み、かつ、少なくとも1mol%のホスファチジルグリセロール(PG)若しくはホスファチジルイノシトール(PI)、又はそれらの両方を含み;かつ、該リポソームは、少なくとも2つの治療薬および/または診断薬と安定に会合し、かつ、実質的に内側の凍結保護物質を含有せず
外部に保護物質が存在する、方法。
Claims (12)
- 凍結乾燥されたゲル相リポソーム組成物であって、当該組成物は、
(a)少なくとも37℃である相転移温度(T C )を有するゲル相リポソーム、ここで、該リポソームの膜は、7:2:1のDSPC:DSPG:CHOLを成分として含み、かつ、該リポソームはダウノルビシン:シタラビンの比率が1:5である、という一定比率のダウノルビシンとシタラビンと安定に会合している;及び、
(b)該リポソームの外側に存在する、300mMの濃度のスクロースを含む凍結保護物質
を含み、
ここで、該リポソームは実質的に内側の凍結保護物質を含有しないものであり、
前記組成物が薬学的担体中に再構成される場合、前記リポソームの平均直径が、凍結乾燥前の該組成物と比較して15%以下増大し、かつ、ダウノルビシンとシタラビンがそれぞれ少なくとも約90%、リポソーム内に保持される、
前記組成物。 - 前記組成物が再構成される場合、前記ダウノルビシン:シタラビンの比率が、凍結乾燥前の該組成物と比較して10%以下変化する、請求項1に記載の組成物。
- 前記リポソームの平均直径が、凍結乾燥前に測定された該値と比較して、前記リポソーム組成物の凍結乾燥後および再構成の際、10%以下増加する、請求項1に記載の組成物。
- 前記平均直径が、5℃~25℃の保存で少なくとも6ヶ月間維持される、請求項3に記載の組成物。
- 前記リポソーム組成物が再構成の際、ダウのルビシン及びシタラビンのそれぞれの少なくとも95%が維持される、請求項1に記載の組成物。
- 平均直径が、5℃~25℃の保存で少なくとも6ヶ月間維持される、請求項5に記載の組成物。
- 前記リポソームのサイズ分布が、前記リポソーム組成物の凍結乾燥後および再構成の際、10%以下変化する、請求項1に記載の組成物。
- 請求項1に記載の組成物を調製する方法であって、少なくとも37℃である相転移温度(T C )を有するゲル相リポソームを含む水性媒体を外部の保護物質の存在下で凍結乾燥に付すことを含み、
ここで、前記リポソームにおいて、該リポソームの膜は、7:2:1のDSPC:DSPG:CHOLを成分として含み;かつ、ダウノルビシン:シタラビンの比率が1:5である、という一定の比率のダウノルビシンとシタラビンが該リポソームと安定に会合しており;かつ、実質的に内側の凍結保護物質を含有しない、方法。 - ゲル相リポソームを含む前記水性媒体が、前記媒体のガラス転移温度(Tg)未満である温度で凍結される、請求項8に記載の方法。
- 被験者にダウノルビシンとシタラビンを投与するための薬学的組成物を調製する方法であって、薬学的担体中で請求項1~6のいずれか1項に記載されたリポソーム組成物を再構成して再構成された組成物を得ることを含む、方法。
- 動物にダウノルビシンとシタラビンを投与する方法において使用するための請求項10に記載の方法により調製された組成物。
- 動物の癌を治療する方法において使用するための請求項10に記載の方法により調製された組成物。
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JP2007533670A (ja) | 2004-04-22 | 2007-11-22 | セレーター ファーマスーティカルズ、インク. | アントラサイクリン系薬剤及びシチジンアナログのリポソーム製剤 |
JP2010519224A (ja) | 2007-02-16 | 2010-06-03 | セラター・ファーマスーティカルズ・インコーポレーテッド | 造血器癌および増殖性疾患の治療のための固定した薬物比 |
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