JP7032406B2 - ダクチノマイシン組成物並びに骨髄異形成症候群及び急性骨髄性白血病の治療方法 - Google Patents
ダクチノマイシン組成物並びに骨髄異形成症候群及び急性骨髄性白血病の治療方法 Download PDFInfo
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Description
本出願は、2016年9月13日に出願された米国仮出願第62/394,104号、2017年1月9日に出願された米国仮出願第62/444,330号、及び2017年5月2日に出願された米国仮出願第62/500,459号の利益及び優先権を主張するものであり、これらの出願それぞれの内容はその全体が参照により本明細書に援用される。
(i)ダクチノマイシンの有機溶媒溶液を、ポリマーの有機溶媒溶液に、ポリマー:APIの比が10:1の比(重量/重量)になるまで加えることと、
(ii)(i)の溶液を均一になるまでボルテックスすることと、
(iii)9,000~10,000Daの分子量を有し80%加水分解された2%(w/w)のポリビニルアルコールを含有した水相に、水相を高速でボルテックスしながら、(ii)の溶液を(ii)の溶液と水相の体積比が約1:7になるまで滴加して、ナノ粒子乳濁液を形成することと、
(iv)(iii)の乳濁液をボルテックスすることと、
(v)(iv)の乳濁液を0℃で数分間超音波処理した後に、該乳濁液を2%(w/w)のポリビニルアルコールを含有した攪拌水相溶液に注ぎ、有機溶媒が蒸発するまで攪拌し続けることと、任意選択的に、
(vi)得られた組成物を14,000×rpmで約30分間の遠心分離により精製することと、
(vii)(vi)の上澄み液を捨てた後に、得られたナノ粒子をddH2Oで洗浄し、14,000×rpmで30分間遠心分離することと、
(viii)(viii)の生成物をddH2Oに再懸濁した後に、3500×rpmで5分間遠心分離することと、
(ix)(viii)の上澄み液を採取して、Amicon(登録商標)Ultra Centrifugalフィルタ(50kDカットオフ)により濃縮した後に、14,000×rpmで10分間遠心分離して遊離ダクチノマイシンを除去することと、を含むプロセスを提供する。
(a)抗炎症剤、
(b)抗酸化剤、及び
(c)該抗炎症剤と該抗酸化剤の組み合わせのうちの少なくとも一つとの投与であって、該ダクチノマイシンと、該抗炎症剤、該抗酸化剤、又はそれらの任意の組み合わせとが同時に投与される、投与を含む。
(a)抗炎症剤、
(b)抗酸化剤、及び
(c)該抗炎症剤と該抗酸化剤の組み合わせのうちの少なくとも一つとの投与であって、該ダクチノマイシンと、該抗炎症剤、該抗酸化剤、又はそれらの任意の組み合わせとが逐次的に投与される、投与を含む。
(a)抗炎症剤、
(b)抗酸化剤、及び
(c)該抗炎症剤と該抗酸化剤の組み合わせ、のうちの少なくとも一つとであり、
該ダクチノマイシンと、該抗炎症剤、該抗酸化剤、又はそれらの組み合わせとが、同時に投与される、方法を提供する。
(a)抗炎症剤、
(b)抗酸化剤、及び
(c)該抗炎症剤と該抗酸化剤の組み合わせ、のうちの少なくとも一つとであり、
該ダクチノマイシンと、該抗炎症剤、該抗酸化剤、又はそれらの組み合わせとが、逐次的に投与される、方法を提供する。
AML急性骨髄性白血病(AML)は、代替的に、急性骨髄性白血病(acute myelocytic leukemia)、急性骨髄性白血病(acute myelogenous leukemia)、急性顆粒球性白血病、又は急性非リンパ性白血病と称される容態の最も一般的な名前である。(Falini,B.et al.“Cytoplasmic nucleo-phosmin in acute myelogenous leukemia with a normal karyo-type”N.Engl.J.Med.2005;352:254-266;Cancer Genome Atlas Research Network.“Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia“N.Engl.J.Med.2013;368:2059-2074を参照)。
NPM1-変異型の急性骨髄性白血病(AML)は、成人においてAMLの3分の1のケースを占める特有の白血病である。NPM1は、正常な核小体の完全性及び機能に極めて重要なタンパク質である。(Falini,B.et al.“Acute myeloid leukemia with mutated nucleophosmin (NPM1):any hope for a targeted therapy?”Blood Rev.2011;25:247-254を参照)。
慢性リンパ性白血病(CLL)は、高齢者において最も一般的なタイプの白血病である。これは、血液、骨髄、リンパ節、及び脾臓にCD5/CD19/CD23陽性Bリンパ球が蓄積することによって特徴付けられる。この疾患の臨床経過は極めて変化に富んでおり、10年間にわたって自覚症状のないままである患者から、診断直後に積極的治療を必要とする患者までと様々である。
本明細書で使用される場合、「骨髄異形成症候群(MDS)」という用語及び/又は同様のものは、骨髄における不完全に形成された血球又は機能不全の血球によって引き起こされる、一つ又は複数の障害の群に言及するものである。
本開示は、ナノ粒子に封入されたダクチノマイシンの治療有効量を含む組成物であって、一つ又は複数のポリマーを含む、組成物を提供する。ポリマーとして、以下に限定されないが、ポリ(乳酸)(PLA)、ポリ(酪酸)、ポリ(吉草酸)、ポリ(カプロラクトン)(PCL)、ポリ(ヒドロキシ酪酸)、ポリ(ラクチド-コ-カプロラクトン)、ポリ(ラクチド-コ-グリコリド)(PLGA)、ポリメチルシアノアクリレート、及び、ポリ酸無水物類、ポリ(オルト)エステル類、又はそれらのポリウレタン類が挙げられ、ポリマーは任意選択的に、ポリエチレングリコール(PEG)又はポリエチレングリコールメチルエーテル(mPEG)、及び/又はそれらの任意の組み合わせをさらに含む。
A.ダクチノマイシンの保存溶液(25mg/mL)を有機溶媒で調製する。
B.ポリマーの保存溶液(例えば、Resomer(登録商標)R 202S及びR 203HなどのPLAポリマーを用いる場合には25mg/mL、又はResomer(登録商標)D5050 DLG mPEG 5000(35重量%、PEG)及び100 DL mPEG 5000(25重量%、PEG)を用いる場合には50mg/mL)を有機溶媒で調製する。
C.ダクチノマイシン溶液をポリマー溶液に、ポリマーとAPIの量の比が10:1(w/w)に達するまで加える。
D.最終溶液を均一になるまでボルテックスする。
E.界面活性剤水溶液(水相)を調製する。
F.ダクチノマイシンナノ粒子乳濁液は、ポリマー/ダクチノマイシン溶液を少量の水相に加えることによって形成するが、その間、ポリマー溶液全体が添加されて有機相:水相の体積比が約1:7に到達するまで、水相を高速でボルテックスする。
G.ボルテックスを続けた後、混合物を超音波処理器に約0℃で移し、所望のナノ粒子サイズ(例えば、約100nm~約200nm)が得られるまで数分間超音波処理する。
H.界面活性剤溶液の攪拌バルク水相に注ぎ、有機溶媒が完全に蒸発するまで室温で強力に攪拌する。
併用療法
実施例1:ダクチノマイシンの薬物動態
実施例2:アクチノマイシンD封入ナノ粒子の調製
実施例3:代表的なActDナノ粒子製剤
実施例4:ActDナノ粒子製剤の安定性
実施例6:遊離アクチノマイシンDとmPEG化ナノ粒子及び非mPEG化ナノ粒子に封入されたアクチノマイシンDとのラットにおける忍容性
実施例7:遊離アクチノマイシンDとmPEG化ナノ粒子及び非mPEG化ナノ粒子に封入されたアクチノマイシンDとのラットにおける薬物動態
Claims (14)
- ナノ粒子に封入されたダクチノマイシンの治療有効量を含む組成物であって、
20重量%~30重量%のmPEGを含み、分子量が25,000Da~35,000DaであるPLA-mPEGを含み、
前記ナノ粒子の平均サイズが約100nm~約200nmであり、
ダクチノマイシンの前記治療有効量が約1ng/mL~約20ng/mLのC max をもたらす、前記組成物。 - 界面活性剤をさらに含む、請求項1に記載の組成物。
- 前記ナノ粒子の平均サイズが、約100nm~約110nm、約105nm~約115nm、約110nm~約120nm、約115nm~約125nm、約120nm~約130nm、約125nm~約135nm、約130nm~約140nm、約135nm~約145nm、約130nm~約140nm、約135nm~約145nm、約140nm~約150nm、約145nm~約155nm、約150nm~約160nm、約155nm~約165nm、約160nm~約170nm、約165nm~約175nm、約170nm~約180nm、約175nm~約185nm、約180nm~約190nm、約185nm~約195nm、又は約190nm~約200nmである、請求項1又は2に記載の組成物。
- 前記組成物が、約5重量%~約15重量%のダクチノマイシンを含む、請求項1から3のいずれか1項に記載の組成物。
- 骨髄異形成症候群(MDS)を治療するための方法における使用のための、請求項1から4のいずれか1項に記載の組成物。
- 癌を治療するための方法における使用のための、請求項1から4のいずれか1項に記載の組成物であって、任意選択で、前記癌が、急性骨髄性白血病(AML)、慢性リンパ性白血病(CLL)、大腸癌、神経内分泌癌、食道癌、又は消化管間質腫瘍(GIST)である、組成物。
- 前記方法が、少なくとも一つの化学療法薬の治療有効量を投与することをさらに含み、前記化学療法薬が、トポイソメラーゼ阻害剤、白金系治療剤、アントラサイクリン系抗生物質、タキサン、チロシンキナーゼ阻害剤、ヌクレオシド類似体、FLT3阻害剤、及び高メチル化阻害剤からなる群から選択され、前記トポイソメラーゼ阻害剤、白金系治療剤、アントラサイクリン系抗生物質、タキサン、チロシンキナーゼ阻害剤、ヌクレオシド類似体、FLT3阻害剤、及び高メチル化阻害剤と、ダクチノマイシンとのモル比が、7:1、6:1、5:1、4:1、3:1、2:1、1:1、1未満:1、又はその間の任意の比である、請求項5または6に記載の組成物。
- 前記方法が、前記組成物を、全身的に、静脈内に、注入により、又は経口的に、対象に投与することを含む、請求項5から7のいずれか1項に記載の組成物。
- 前記組成物が、1週間、2週間、又は3週間にわたり1回又は2回投与され、場合により、前記方法が、投与期間の間に、1週間、2週間、3週間、又は4週間の休薬期間をさらに含む、請求項5から8のいずれか1項に記載の組成物。
- 対象が、粘膜炎を発症しているか又は発症するリスクがあり、場合により
i.前記対象が、粘膜炎の症状に対して、一つ又は複数の抗炎症剤及び/又は抗酸化剤を用いて同時に治療されている;または
ii.前記対象が、粘膜炎の症状に対して、一つ又は複数の抗炎症剤及び/又は抗酸化剤を用いて、前記組成物の投与前に前処置されている
請求項5から9のいずれか1項に記載の組成物。 - ダクチノマイシンの前記治療有効量が約0.05~約2.0mg・分/LのAUC∞をもたらす、請求項5から10のいずれか1項に記載の組成物。
- 前記ダクチノマイシンの約70%~約80%が、3日後に前記ナノ粒子から放出される、請求項5から11のいずれか1項に記載の組成物。
- 請求項1から4のいずれか1項に記載の組成物を調製するための方法であって、
(i)ダクチノマイシンの有機溶媒溶液を、ポリマーの有機溶媒溶液に、前記ポリマー:APIの比が10:1の比(重量/重量)になるまで加えることと、
(ii)(i)の溶液を均一になるまでボルテックスすることと、
(iii)9,000~10,000Daの分子量を有し80%加水分解された2%(w/w)のポリビニルアルコールを含有した水相に、前記水相を高速でボルテックスしながら、(ii)の溶液を(ii)の溶液と前記水相の体積比が約1:7になるまで滴加して、ナノ粒子乳濁液を形成することと、
(iv)(iii)の乳濁液をボルテックスすることと、
(v)(iv)の乳濁液を0℃で数分間超音波処理した後に、前記乳濁液を2%(w/w)のポリビニルアルコールを含有した攪拌水相溶液に注ぎ、有機溶媒が蒸発するまで攪拌し続けることと、任意選択的に、
(vi)得られた組成物を14,000×rpmで約30分間の遠心分離により精製することと、
(vii)(vi)の上澄み液を捨てた後に、得られたナノ粒子をddH2Oで洗浄し、14,000×rpmで約30分間遠心分離することと、
(viii)(viii)の生成物をddH2Oに再懸濁した後に、3500×rpmで約5分間遠心分離することと、
(ix)(viii)の上澄み液を採取して、Amicon(登録商標)Ultra Centrifugalフィルタ(50kDカットオフ)により濃縮した後に、14,000×rpmで約10分間遠心分離して遊離ダクチノマイシンを除去することと、を含む、前記方法。 - 前記組成物における遊離ダクチノマイシンの量が、ナノ粒子に封入されたダクチノマイシンの量の5重量%未満、4重量%未満、3重量%未満、2重量%未満、又は1重量%未満である、請求項13に記載の方法。
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CA3060306A1 (en) * | 2017-05-09 | 2018-11-15 | Dignity Health | Drug delivery composition and method of fabrication |
US20220339294A1 (en) * | 2019-09-09 | 2022-10-27 | Yale University | Nanoparticles for selective tissue or cellular uptake |
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US20210275463A1 (en) | 2021-09-09 |
AU2017327392A1 (en) | 2019-01-31 |
US11975111B2 (en) | 2024-05-07 |
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CA3031691A1 (en) | 2018-03-22 |
US10973773B2 (en) | 2021-04-13 |
US20180092857A1 (en) | 2018-04-05 |
JP2022066256A (ja) | 2022-04-28 |
WO2018053052A1 (en) | 2018-03-22 |
EP3512560A1 (en) | 2019-07-24 |
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