JP2022532213A - Mrna担持脂質ナノ粒子を調製する改善されたプロセス - Google Patents
Mrna担持脂質ナノ粒子を調製する改善されたプロセス Download PDFInfo
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- JP2022532213A JP2022532213A JP2021568011A JP2021568011A JP2022532213A JP 2022532213 A JP2022532213 A JP 2022532213A JP 2021568011 A JP2021568011 A JP 2021568011A JP 2021568011 A JP2021568011 A JP 2021568011A JP 2022532213 A JP2022532213 A JP 2022532213A
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- mrna
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- 229910052700 potassium Inorganic materials 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
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- 230000009261 transgenic effect Effects 0.000 description 1
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Abstract
Description
本出願は、2019年5月14日に出願された米国仮特許出願第62/847,837号に対する優先権を主張するものであり、すべての目的のためにその全体が参照により本明細書に援用される。
本発明がより容易に理解されるように、ある特定の用語が以下で最初に定義される。以下の用語および他の用語に対する追加の定義は、明細書全体を通して記述される。
本発明は、任意のmRNAを封入するために使用され得る。mRNAは、DNAからリボソームに情報を運ぶRNAのタイプと一般的に考えられる。典型的には、真核生物において、mRNAプロセシングは、5’末端に「キャップ」を付加すること、および3’末端の「尾部」に不可することを含む。典型的なキャップは、7-メチルグアノシンキャップであり、これは最初に転写されたヌクレオチドに結合した5’-5’-三リン酸塩を介して連結されたグアノシンである。キャップの存在は、大半の真核細胞に見られるヌクレアーゼへの耐性を提供するのに重要である。尾部の付加は、典型的にはポリアデニル化現象であり、これによりポリアデニリル(polyadenylyl)部分がmRNA分子の3’末端に加えられる。この「尾部」の存在は、エキソヌクレアーゼ分解からmRNAを保護するのに役立つ。メッセンジャーRNAは、タンパク質を構成する一連のアミノ酸にリボソームによって翻訳される。
コドン最適化ヒトOTCコード配列
AUGCUGUUCAACCUUCGGAUCUUGCUGAACAACGCUGCGUUCCGGAAUGGUCACAACUUCAUGGUCCGGAACUUCAGAUGCGGCCAGCCGCUCCAGAACAAGGUGCAGCUCAAGGGGAGGGACCUCCUCACCCUGAAAAACUUCACCGGAGAAGAGAUCAAGUACAUGCUGUGGCUGUCAGCCGACCUCAAAUUCCGGAUCAAGCAGAAGGGCGAAUACCUUCCUUUGCUGCAGGGAAAGUCCCUGGGGAUGAUCUUCGAGAAGCGCAGCACUCGCACUAGACUGUCAACUGAAACCGGCUUCGCGCUGCUGGGAGGACACCCCUGCUUCCUGACCACCCAAGAUAUCCAUCUGGGUGUGAACGAAUCCCUCACCGACACAGCGCGGGUGCUGUCGUCCAUGGCAGACGCGGUCCUCGCCCGCGUGUACAAGCAGUCUGAUCUGGACACUCUGGCCAAGGAAGCCUCCAUUCCUAUCAUUAAUGGAUUGUCCGACCUCUACCAUCCCAUCCAGAUUCUGGCCGAUUAUCUGACUCUGCAAGAACAUUACAGCUCCCUGAAGGGGCUUACCCUUUCGUGGAUCGGCGACGGCAACAACAUUCUGCACAGCAUUAUGAUGAGCGCUGCCAAGUUUGGAAUGCACCUCCAAGCAGCGACCCCGAAGGGAUACGAGCCAGACGCCUCCGUGACGAAGCUGGCUGAGCAGUACGCCAAGGAGAACGGCACUAAGCUGCUGCUCACCAACGACCCUCUCGAAGCCGCCCACGGUGGCAACGUGCUGAUCACCGAUACCUGGAUCUCCAUGGGACAGGAGGAGGAAAAGAAGAAGCGCCUGCAAGCAUUUCAGGGGUACCAGGUGACUAUGAAAACCGCCAAGGUCGCCGCCUCGGACUGGACCUUCUUGCACUGUCUGCCCAGAAAGCCCGAAGAGGUGGACGACGAGGUGUUCUACAGCCCGCGGUCGCUGGUCUUUCCGGAGGCCGAAAACAGGAAGUGGACUAUCAUGGCCGUGAUGGUGUCCCUGCUGACCGAUUACUCCCCGCAGCUGCAGAAACCAAAGUUCUGA(配列番号1)
コドン最適化ヒトASS1コード配列
AUGAGCAGCAAGGGCAGCGUGGUGCUGGCCUACAGCGGCGGCCUGGACACCAGCUGCAUCCUGGUGUGGCUGAAGGAGCAGGGCUACGACGUGAUCGCCUACCUGGCCAACAUCGGCCAGAAGGAGGACUUCGAGGAGGCCCGCAAGAAGGCCCUGAAGCUGGGCGCCAAGAAGGUGUUCAUCGAGGACGUGAGCCGCGAGUUCGUGGAGGAGUUCAUCUGGCCCGCCAUCCAGAGCAGCGCCCUGUACGAGGACCGCUACCUGCUGGGCACCAGCCUGGCCCGCCCCUGCAUCGCCCGCAAGCAGGUGGAGAUCGCCCAGCGCGAGGGCGCCAAGUACGUGAGCCACGGCGCCACCGGCAAGGGCAACGACCAGGUGCGCUUCGAGCUGAGCUGCUACAGCCUGGCCCCCCAGAUCAAGGUGAUCGCCCCCUGGCGCAUGCCCGAGUUCUACAACCGCUUCAAGGGCCGCAACGACCUGAUGGAGUACGCCAAGCAGCACGGCAUCCCCAUCCCCGUGACCCCCAAGAACCCCUGGAGCAUGGACGAGAACCUGAUGCACAUCAGCUACGAGGCCGGCAUCCUGGAGAACCCCAAGAACCAGGCCCCCCCCGGCCUGUACACCAAGACCCAGGACCCCGCCAAGGCCCCCAACACCCCCGACAUCCUGGAGAUCGAGUUCAAGAAGGGCGUGCCCGUGAAGGUGACCAACGUGAAGGACGGCACCACCCACCAGACCAGCCUGGAGCUGUUCAUGUACCUGAACGAGGUGGCCGGCAAGCACGGCGUGGGCCGCAUCGACAUCGUGGAGAACCGCUUCAUCGGCAUGAAGAGCCGCGGCAUCUACGAGACCCCCGCCGGCACCAUCCUGUACCACGCCCACCUGGACAUCGAGGCCUUCACCAUGGACCGCGAGGUGCGCAAGAUCAAGCAGGGCCUGGGCCUGAAGUUCGCCGAGCUGGUGUACACCGGCUUCUGGCACAGCCCCGAGUGCGAGUUCGUGCGCCACUGCAUCGCCAAGAGCCAGGAGCGCGUGGAGGGCAAGGUGCAGGUGAGCGUGCUGAAGGGCCAGGUGUACAUCCUGGGCCGCGAGAGCCCCCUGAGCCUGUACAACGAGGAGCUGGUGAGCAUGAACGUGCAGGGCGACUACGAGCCCACCGACGCCACCGGCUUCAUCAACAUCAACAGCCUGCGCCUGAAGGAGUACCACCGCCUGCAGAGCAAGGUGACCGCCAAGUGA(配列番号2)
コドン最適化ヒトCFTRコード配列
AUGAGCACCGCCGUGCUGGAGAACCCCGGCCUGGGCCGCAAGCUGAGCGACUUCGGCCAGGAGACCAGCUACAUCGAGGACAACUGCAACCAGAACGGCGCCAUCAGCCUGAUCUUCAGCCUGAAGGAGGAGGUGGGCGCCCUGGCCAAGGUGCUGCGCCUGUUCGAGGAGAACGACGUGAACCUGACCCACAUCGAGAGCCGCCCCAGCCGCCUGAAGAAGGACGAGUACGAGUUCUUCACCCACCUGGACAAGCGCAGCCUGCCCGCCCUGACCAACAUCAUCAAGAUCCUGCGCCACGACAUCGGCGCCACCGUGCACGAGCUGAGCCGCGACAAGAAGAAGGACACCGUGCCCUGGUUCCCCCGCACCAUCCAGGAGCUGGACCGCUUCGCCAACCAGAUCCUGAGCUACGGCGCCGAGCUGGACGCCGACCACCCCGGCUUCAAGGACCCCGUGUACCGCGCCCGCCGCAAGCAGUUCGCCGACAUCGCCUACAACUACCGCCACGGCCAGCCCAUCCCCCGCGUGGAGUACAUGGAGGAGGAGAAGAAGACCUGGGGCACCGUGUUCAAGACCCUGAAGAGCCUGUACAAGACCCACGCCUGCUACGAGUACAACCACAUCUUCCCCCUGCUGGAGAAGUACUGCGGCUUCCACGAGGACAACAUCCCCCAGCUGGAGGACGUGAGCCAGUUCCUGCAGACCUGCACCGGCUUCCGCCUGCGCCCCGUGGCCGGCCUGCUGAGCAGCCGCGACUUCCUGGGCGGCCUGGCCUUCCGCGUGUUCCACUGCACCCAGUACAUCCGCCACGGCAGCAAGCCCAUGUACACCCCCGAGCCCGACAUCUGCCACGAGCUGCUGGGCCACGUGCCCCUGUUCAGCGACCGCAGCUUCGCCCAGUUCAGCCAGGAGAUCGGCCUGGCCAGCCUGGGCGCCCCCGACGAGUACAUCGAGAAGCUGGCCACCAUCUACUGGUUCACCGUGGAGUUCGGCCUGUGCAAGCAGGGCGACAGCAUCAAGGCCUACGGCGCCGGCCUGCUGAGCAGCUUCGGCGAGCUGCAGUACUGCCUGAGCGAGAAGCCCAAGCUGCUGCCCCUGGAGCUGGAGAAGACCGCCAUCCAGAACUACACCGUGACCGAGUUCCAGCCCCUGUACUACGUGGCCGAGAGCUUCAACGACGCCAAGGAGAAGGUGCGCAACUUCGCCGCCACCAUCCCCCGCCCCUUCAGCGUGCGCUACGACCCCUACACCCAGCGCAUCGAGGUGCUGGACAACACCCAGCAGCUGAAGAUCCUGGCCGACAGCAUCAACAGCGAGAUCGGCAUCCUGUGCAGCGCCCUGCAGAAGAUCAAGUAA(配列番号5)
mRNAは、mRNAが脂質ナノ粒子に封入され得るように、脂質溶液と混合されるべき溶液中で提供され得る。好適なmRNA溶液は、様々な濃度で封入されるべきmRNAを含有する任意の水溶液であり得る。例えば、好適なmRNA溶液は、約0.01mg/ml、0.05mg/ml、0.06mg/ml、0.07mg/ml、0.08mg/ml、0.09mg/ml、0.1mg/ml、0.15mg/ml、0.2mg/ml、0.3mg/ml、0.4mg/ml、0.5mg/ml、0.6mg/ml、0.7mg/ml、0.8mg/ml、0.9mg/ml、または1.0mg/mlより高い濃度でmRNAを含有してもよい。いくつかの実施形態では、好適なmRNA溶液は、約0.01~1.0mg/ml、0.01~0.9mg/ml、0.01~0.8mg/ml、0.01~0.7mg/ml、0.01~0.6mg/ml、0.01~0.5mg/ml、0.01~0.4mg/ml、0.01~0.3mg/ml、0.01~0.2mg/ml、0.01~0.1mg/ml、0.05~1.0mg/ml、0.05~0.9mg/ml、0.05~0.8mg/ml、0.05~0.7mg/ml、0.05~0.6mg/ml、0.05~0.5mg/ml、0.05~0.4mg/ml、0.05~0.3mg/ml、0.05~0.2mg/ml、0.05~0.1mg/ml、0.1~1.0mg/ml、0.2~0.9mg/ml、0.3~0.8mg/ml、0.4~0.7mg/ml、または0.5~0.6mg/mlの範囲の濃度でmRNAを含有してもよい。いくつかの実施形態では、好適なmRNA溶液は、最高約5.0mg/ml、4.0mg/ml、3.0mg/ml、2.0mg/ml、1.0mg/ml、0.09mg/ml、0.08mg/ml、0.07mg/ml、0.06mg/ml、または0.05mg/mlの濃度でmRNAを含有してもよい。
本発明によれば、脂質溶液は、mRNAの封入のために脂質ナノ粒子を形成するのに適切な脂質の混合物を含有する。いくつかの実施形態では、好適な脂質溶液はエタノール系である。例えば、好適な脂質溶液は、純エタノール(すなわち、100%エタノール)に溶解された所望の脂質の混合物を含有してもよい。別の実施形態では、好適な脂質溶液はイソプロピルアルコール系である。別の実施形態では、好適な脂質溶液はジメチルスルホキシド系である。別の実施形態では、好適な脂質溶液は、エタノール、イソプロピルアルコール、およびジメチルスルホキシドを含むがこれらに限定されない好適な溶媒の混合物である。
本明細書で使用される場合、語句「カチオン性脂質」は、生理学的pHなどの選択されたpHで正味の正電荷を有する多数の脂質種のうちのいずれかを指す。いくつかのカチオン性脂質は文献に記載されており、その多くは市販されている。本発明の組成物および方法における使用のための特に好適なカチオン性脂質は、WO2010/053572(具体的には、段落[00225]に記載されているC12-200)およびWO2012/170930に記載されるものを含み、その両方は、参照により本明細書に援用される。ある特定の実施形態では、本発明の組成物および方法に適したカチオン性脂質は、例えば、(15Z,18Z)-N,N-ジメチル-6-(9Z,12Z)-オクタデカ-9,12-ジエン-l-イル)テトラコサ-15,18-ジエン-1-アミン(HGT5000)、(15Z,18Z)-N,N-ジメチル-6-((9Z,12Z)-オクタデカ-9,12-ジエン-1-イル)テトラコサ-4,15,18-トリエン-l-アミン(HGT5001)、および(15Z,18Z)-N,N-ジメチル-6-((9Z,12Z)-オクタデカ-9,12-ジエン-1-イル)テトラコサ-5,15,18-トリエン-1-アミン(HGT5002)などの、2012年3月29日に出願された米国仮特許出願第61/617,468号(参照により本明細書に援用される)に記載のイオン化可能なカチオン性脂質を含む。
各R2は、独立して、水素またはC1-3アルキルであり、
各qは、独立して、2~6であり、
各R’は、独立して、水素またはC1-3アルキルであり、
各RLは、独立して、C8-12アルキルである。
式中、
Rは
Rは
Rは
Rは
(例えば、Fenton,Owen S.,et al.“Bioinspired Alkenyl Amino Alcohol Ionizable Lipid Materials for Highly Potent In Vivo mRNA Delivery.”Advanced materials(2016)を参照のこと)。
本明細書で使用される場合、語句「非カチオン性脂質」は、任意の中性脂質、両性イオン性脂質、またはアニオン性脂質を指す。本明細書で使用される場合、語句「アニオン性脂質」は、生理学的pHなどの選択されたpHで正味の負電荷を有する多数の脂質種のうちのいずれかを指す。非カチオン性脂質は、ジステアロイルホスファチジルコリン(DSPC)、ジオレオイルホスファチジルコリン(DOPC)、ジパルミトイルホスファチジルコリン(DPPC)、ジオレオイルホスファチジルグリセロール(DOPG)、ジパルミトイルホスファチジルグリセロール(DPPG)、ジオレオイルホスファチジルエタノールアミン(DOPE)、パルミトイルオレオイルホスファチジルコリン(POPC)、パルミトイルオレオイル-ホスファチジルエタノールアミン(POPE)、ジオレオイル-ホスファチジルエタノールアミン4-(N-マレイミドメチル)-シクロヘキサン-l-カルボキシレート(DOPE-mal)、ジパルミトイルホスファチジルエタノールアミン(DPPE)、ジミリストイルホスホエタノールアミン(DMPE)、ジステアロイル-ホスファチジル-エタノールアミン(DSPE)、1,2-ジエルコイル-sn-グリセロ-3-ホスホエタノールアミン(DEPE)、16-O-モノメチルPE、16-O-ジメチルPE、18-1-トランスPE、l-ステアロイル-2-オレオイル-ホスファチジエタノールアミン(SOPE)、またはこれらの混合物を含むが、これらに限定されない。いくつかの実施形態では、本発明での使用のための脂質の混合物は、非カチオン性脂質成分としてDSPCを含み得る。いくつかの実施形態では、本発明での使用のための脂質の混合物は、非カチオン性脂質成分としてDPPCを含み得る。いくつかの実施形態では、本発明での使用のための脂質の混合物は、非カチオン性脂質成分としてDOPEを含み得る。いくつかの実施形態では、本発明での使用のための脂質の混合物は、非カチオン性脂質成分としてDEPEを含み得る。
いくつかの実施形態では、好適な脂質溶液は、1つ以上のコレステロール系脂質を含む。例として、好適なコレステロール系カチオン性脂質として、例えば、DC-Choi(N,N-ジメチル-N-エチルカルボキサミドコレステロール)、1,4-ビス(3-N-オレイルアミノ-プロピル)ピペラジン(Gao,et al.Biochem.Biophys.Res.Comm.179,280(1991);Wolf et al.BioTechniques 23,139(1997);米国特許第5,744,335号)、またはICEが挙げられる。いくつかの実施形態では、コレステロール系脂質は、重量またはモルで、好適な脂質溶液中の総脂質の少なくとも約5%、10%、20%、30%、40%、50%、60%、または70%を構成する。いくつかの実施形態では、コレステロール系脂質は、重量またはモルで、好適な脂質溶液中の総脂質の約30~50%(例えば、約30~45%、約30~40%、約35~50%、約35~45%、または約35~40%)を構成する。
いくつかの実施形態では、好適な脂質溶液は、1つ以上のPEG化脂質を含む。例えば、ポリエチレングリコール(PEG)修飾リン脂質およびN-オクタノイル-スフィンゴシン-l-[スクシニル(メトキシポリエチレングリコール)-2000](C8 PEG-2000セラミド)を含む誘導体化したセラミド(PEG-CER)などの誘導体化した脂質の使用も、本発明によって企図される。企図されるPEG修飾脂質は、C6-C20長のアルキル鎖を有する脂質に共有結合した、長さ最大2kDa、最大3kDa、最大4kDa、または最大5kDaのポリエチレングリコール鎖を含むが、これらに限定されない。いくつかの実施形態では、PEG修飾またはPEG化脂質は、PEG化コレステロールまたはPEG-2Kである。好適な脂質溶液は、1,2-ジミリストイル-rac-グリセロ-3-メトキシポリエチレングリコール-2000(DMG-PEG2K)などのPEG修飾脂質を含み得る。いくつかの実施形態では、特定の有用な交換可能な脂質は、より短いアシル鎖(例えば、C14またはC18)を有するPEGセラミドである。
上述のmRNA溶液を上述の脂質溶液と混合することによってmRNAを封入するLNP(mRNA-LNP)を形成して、mRNA-LNP形成に適したLNP形成溶液を生成するプロセスは、以前に記載されている。例えば、名称「Encapsulation of messenger RNA」の米国特許第9,668,980号は、この開示の全体が本明細書に援用され、mRNA溶液および脂質溶液を混合することによって脂質ナノ粒子中にメッセンジャーRNA(mRNA)を封入するプロセスを提供し、mRNA溶液および/または脂質溶液は、混合の前に、周囲温度よりも高い予め決められた温度まで加熱されて、mRNAを封入する脂質ナノ粒子を形成する。代替的には、mRNA溶液および脂質溶液は、mRNA溶液、脂質溶液、およびLNP形成溶液のうちのいずれの1つ以上も加熱することなく、mRNA-LNP形成を提供するLNP形成溶液中に混合され得る。
本発明は、部分的に、mRNA封入LNPが形成されるLNP形成溶液へのmRNA溶液および脂質溶液の混合物、ならびに医薬品製剤溶液を構成する溶液(例えば、10%トレハロース)へのLNP形成溶液のその後に続く交換の後、LNPにおけるmRNAの封入は、mRNA-LNPを含む医薬品製剤溶液、同様にLNP形成溶液に封入されなかったいくらかの遊離mRNAを加熱することによってさらに強化され得る。
本発明に従うプロセスは、より高い効力および有効性をもたらし、それによってより低い用量を可能にし、それによって治療指数を正の方向にシフトさせる。いくつかの実施形態では、本発明に従うプロセスは、均質で小さな粒子サイズをもたらす。いくつかの実施形態では、本発明に従うプロセスは、均質で200nm以下の小さな粒子サイズをもたらす。いくつかの実施形態では、本発明に従うプロセスは、均質で150nm以下の小さな粒子サイズをもたらす。いくつかの実施形態では、本発明によるプロセスは、従来の技術のプロセスと比較して、均質で小さな粒子サイズ、同様に顕著に改善された封入効率および/またはmRNA回収率をもたらす。
以下の実施例に記載されている製剤は、別段規定されない限り、以前に記載されるように、様々な核酸材料を封入するよう設計された1つ以上のカチオン性脂質、ヘルパー脂質(例えば、非カチオン性脂質および/またはコレステロール脂質)ならびにPEG化脂質を用いる、変動する割合の多成分の脂質混合物を含有する。
本実施例は、プロセスAを適用し、続いて、mRNA-LNPおよび遊離mRNAを含むLNP形成溶液を医薬品製剤溶液と交換し、その医薬品溶液を加熱することによる、脂質ナノ粒子内のmRNAの強化された封入のための、現在の例示的なプロセスを示す。本明細書で使用される場合、プロセスAは、例えば、第1に脂質を脂質ナノ粒子へと予め形成することなく、mRNAを脂質の混合物と混合することによってmRNAを封入する従来的な方法を指し、全体が参照により援用される米国特許出願第US2018/0008680号に記載される。
本実施例は、プロセスA、その後の医薬品製剤溶液中での加熱によって産生されたmRNA封入脂質ナノ粒子の封入において相当な増加があることを確証する。さらに、本実施例のデータは、本発明に従って調製された脂質ナノ粒子に封入されたhEPO mRNAの投与後のマウスにおけるヒトEPO(hEPO)のインビボ発現を示す。
本実施例は、プロセスA、その後の医薬品製剤溶液中での加熱によって産生されたmRNA封入脂質ナノ粒子の封入において相当な増加があり、多種多様なカチオン性脂質にわたって適用可能であることを確証する。さらに、本実施例のデータは、本発明に従って調製された脂質ナノ粒子に封入されたmRNAの肺投与後のマウスにおけるmRNAのインビボ発現を示す。
当業者は、日常的な実験作業のみを使用して、本明細書に記載される本発明の具体的な実施形態の多くの均等物を認識するか、または確認できるであろう。本発明の範囲は、上記の記載を限定することを意図しないが、むしろ以下の特許請求の範囲に記述されるとおりである。
Claims (27)
- 脂質ナノ粒子(LNP)にメッセンジャーRNA(mRNA)を封入するプロセスであって、
(a)脂質溶液中の1つ以上の脂質を、mRNA溶液中の1つ以上のmRNAと混合して、脂質ナノ粒子(LNP)形成溶液中の前記LNP(mRNA-LNP)内に封入されたmRNAを形成するステップと、
(b)前記LNP形成溶液を医薬品製剤溶液と交換して、医薬品製剤溶液中にmRNA-LNPを提供するステップと、
(c)前記医薬品製剤溶液中で前記mRNA-LNPを加熱するステップと、を含み、
ステップ(c)から生じる前記mRNA-LNPの封入効率が、ステップ(b)から生じる前記mRNA-LNPの前記封入効率よりも大きい、プロセス。 - ステップ(a)において、前記1つ以上の脂質が、1つ以上のカチオン性脂質、1つ以上のヘルパー脂質、および1つ以上のPEG修飾脂質を含む、請求項1に記載のプロセス。
- 前記脂質が、1つ以上のコレステロール脂質(例えば、コレステロール)をさらに含む、請求項2に記載のプロセス。
- ステップ(a)において、前記1つ以上のカチオン性脂質が、cKK-E12、OF-02、C12-200、MC3、DLinDMA、DLinkC2DMA、ICE(イミダゾール系)、HGT5000、HGT5001、HGT4001、HGT4002、HGT4003、HGT4004、HGT4005、DODAC、DDAB、DMRIE、DOSPA、DOGS、DODAP、DODMAおよびDMDMA、DODAC、DLenDMA、DMRIE、CLinDMA、CpLinDMA、DMOBA、DOcarbDAP、DLinDAP、DLincarbDAP、DLinCDAP、KLin-K-DMA、DLin-K-XTC2-DMA、3-(4-(ビス(2-ヒドロキシドデシル)アミノ)ブチル)-6-(4-((2-ヒドロキシドデシル)(2-ヒドロキシウンデシル)アミノ)ブチル)-1,4-ジオキサン-2,5-ジオン(標的23)、3-(5-(ビス(2-ヒドロキシドデシル)アミノ)ペンタン-2-イル)-6-(5-((2-ヒドロキシドデシル)(2-ヒドロキシウンデシル)アミノ)ペンタン-2-イル)-1,4-ジオキサン-2,5-ジオン(標的24)、N1GL、N2GL、V1GLおよびそれらの組み合わせから選択される、先行請求項のいずれか一項に記載のプロセス。
- ステップ(a)において、前記1つ以上のヘルパー脂質が、ジステアロイルホスファチジルコリン(DSPC)、ジオレオイルホスファチジルコリン(DOPC)、ジパルミトイルホスファチジルコリン(DPPC)、ジオレオイルホスファチジルグリセロール(DOPG)、ジパルミトイルホスファチジルグリセロール(DPPG)、ジオレオイルホスファチジルエタノールアミン(DOPE)、パルミトイルオレオイルホスファチジルコリン(POPC)、パルミトイルオレオイル-ホスファチジルエタノールアミン(POPE)、ジオレオイル-ホスファチジルエタノールアミン4-(N-マレイミドメチル)-シクロヘキサン-l-カルボキシレート(DOPE-mal)、ジパルミトイルホスファチジルエタノールアミン(DPPE)、ジミリストイルホスホエタノールアミン(DMPE)、ジステアロイル-ホスファチジル-エタノールアミン(DSPE)、1,2-ジエルコイル-sn-グリセロ-3-ホスホエタノールアミン(DEPE)、16-O-モノメチルPE、16-O-ジメチルPE、18-1-トランスPE、l-ステアロイル-2-オレオイル-ホスファチジエタノールアミン(SOPE)、またはそれらの組み合わせから選択される、請求項2~4のいずれか一項に記載のプロセス。
- ステップ(a)において、前記1つ以上のPEG修飾脂質が、C6-C20長のアルキル鎖を有する脂質に共有結合した、長さ最大2kDa、最大3kDa、最大4kDaまたは最大5kDaのポリエチレングリコール鎖を含む、請求項1に記載のプロセス。
- 前記脂質溶液の脂質成分が、
(a)カチオン性脂質、
(b)ヘルパー脂質、
(c)コレステロール系脂質、および
(d)PEG修飾脂質からなる、先行請求項のいずれか一項に記載のプロセス。 - 前記カチオン性脂質対ヘルパー脂質対コレステロール系脂質対PEG修飾脂質のモル比が、約20~50:25~35:20~50:1~5である、請求項8に記載のプロセス。
- 前記脂質溶液の脂質成分が、
(a)カチオン性脂質、
(b)ヘルパー脂質、
(c)PEG修飾脂質からなる、請求項1~6のいずれか一項に記載のプロセス。 - 前記カチオン性脂質が、コレステロール系またはイミダゾール系カチオン性脂質である、請求項9に記載のプロセス。
- 前記カチオン性脂質対ヘルパー脂質対コレステロール系脂質対PEG修飾脂質のモル比が、約55~65:30~40:1~15である、請求項9または10に記載のプロセス。
- 前記mRNAが、タンパク質またはペプチドをコードする、先行請求項のいずれか一項に記載のプロセス。
- ステップ(c)において、前記医薬品製剤溶液が、熱源からの熱を前記溶液に印加することによって加熱され、前記溶液が、周囲温度よりも高い温度で10~20分間維持される、先行請求項のいずれか一項に記載のプロセス。
- 前記周囲温度よりも高い温度が、約60~70℃である、請求項13に記載のプロセス。
- ステップ(c)後の前記封入効率が、ステップ(b)後の前記封入効率を超える少なくとも5%以上を提供する、先行請求項のいずれか一項に記載のプロセス。
- ステップ(c)後の前記封入効率が、ステップ(b)後の前記封入効率から少なくとも10%以上改善される、先行請求項のいずれか一項に記載のプロセス。
- ステップ(a)において、前記脂質溶液が、エタノールに溶解された脂質を含む、先行請求項のいずれか一項に記載のプロセス。
- ステップ(a)において、前記mRNA溶液が、クエン酸緩衝液に溶解されたmRNAを含む、先行請求項のいずれか一項に記載のプロセス。
- 前記医薬品製剤溶液が、凍結保護剤を含む薬学的に許容可能な賦形剤を含む水溶液である、先行請求項のいずれか一項に記載のプロセス。
- 前記医薬品製剤溶液が、糖を含む水溶液である、先行請求項のいずれか一項に記載のプロセス。
- 前記糖が、トレハロース、スクロース、マンノース、ラクトース、およびマンニトールのうちの1つ以上からなる群から選択される、請求項20に記載のプロセス。
- 前記糖が、トレハロースを含む、請求項21に記載のプロセス。
- ステップ(b)において、前記医薬品製剤溶液が、約10重量対体積%のトレハロースを含む水溶液である、先行請求項のいずれか一項に記載のプロセス。
- エタノールおよびクエン酸塩の両方が、前記医薬品製剤溶液に存在しない、先行請求項のいずれか一項に記載のプロセス。
- 前記脂質溶液がエタノールを含み、前記mRNA溶液がクエン酸塩を含み、エタノールおよびクエン酸塩の両方が前記医薬品製剤溶液に存在しない、先行請求項のいずれか一項に記載のプロセス。
- 前記mRNA溶液が、pH5.0未満のpHを有する、先行請求項のいずれか一項に記載のプロセス。
- 前記医薬品製剤溶液が、pH5.0~pH7.0のpHを有する、先行請求項のいずれか一項に記載のプロセス。
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PCT/US2020/032943 WO2020232276A1 (en) | 2019-05-14 | 2020-05-14 | Improved process of preparing mrna-loaded lipid nanoparticles |
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IL288020A (en) | 2022-01-01 |
EP3968952A1 (en) | 2022-03-23 |
CN114126588A (zh) | 2022-03-01 |
CA3140423A1 (en) | 2020-11-19 |
AU2020274758A1 (en) | 2021-12-23 |
US20220218612A1 (en) | 2022-07-14 |
BR112021022909A2 (pt) | 2022-01-25 |
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