JP2022538797A - 生物学的送達ビヒクルのための組成物及び方法 - Google Patents
生物学的送達ビヒクルのための組成物及び方法 Download PDFInfo
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- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 26
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- KWVJHCQQUFDPLU-YEUCEMRASA-N 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KWVJHCQQUFDPLU-YEUCEMRASA-N 0.000 claims description 9
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- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 9
- 235000012000 cholesterol Nutrition 0.000 claims description 9
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 claims description 9
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 9
- YKIOPDIXYAUOFN-YACUFSJGSA-N (2-{[(2r)-2,3-bis(icosanoyloxy)propyl phosphonato]oxy}ethyl)trimethylazanium Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCCCC YKIOPDIXYAUOFN-YACUFSJGSA-N 0.000 claims description 8
- PIFFQYJYNWXNGE-UHFFFAOYSA-N 2,4-diacetylphloroglucinol Chemical compound CC(=O)C1=C(O)C=C(O)C(C(C)=O)=C1O PIFFQYJYNWXNGE-UHFFFAOYSA-N 0.000 claims description 8
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 claims description 8
- NRLNQCOGCKAESA-KWXKLSQISA-N [(6z,9z,28z,31z)-heptatriaconta-6,9,28,31-tetraen-19-yl] 4-(dimethylamino)butanoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCC(OC(=O)CCCN(C)C)CCCCCCCC\C=C/C\C=C/CCCCC NRLNQCOGCKAESA-KWXKLSQISA-N 0.000 claims description 8
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 8
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- HIHOWBSBBDRPDW-PTHRTHQKSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] n-[2-(dimethylamino)ethyl]carbamate Chemical compound C1C=C2C[C@@H](OC(=O)NCCN(C)C)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HIHOWBSBBDRPDW-PTHRTHQKSA-N 0.000 claims description 7
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
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- 150000001720 carbohydrates Chemical class 0.000 claims description 6
- 229940099352 cholate Drugs 0.000 claims description 6
- OGQYPPBGSLZBEG-UHFFFAOYSA-N dimethyl(dioctadecyl)azanium Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC OGQYPPBGSLZBEG-UHFFFAOYSA-N 0.000 claims description 6
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 claims description 6
- DGABKXLVXPYZII-SIBKNCMHSA-M hyodeoxycholate Chemical compound C([C@H]1[C@@H](O)C2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)CC1 DGABKXLVXPYZII-SIBKNCMHSA-M 0.000 claims description 6
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- DSNRWDQKZIEDDB-GCMPNPAFSA-N [(2r)-3-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-2-[(z)-octadec-9-enoyl]oxypropyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC DSNRWDQKZIEDDB-GCMPNPAFSA-N 0.000 claims description 5
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- NYDLOCKCVISJKK-WRBBJXAJSA-N [3-(dimethylamino)-2-[(z)-octadec-9-enoyl]oxypropyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(CN(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC NYDLOCKCVISJKK-WRBBJXAJSA-N 0.000 claims description 4
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Abstract
Description
一実施形態において、送達ビヒクルは、コンジュゲートされた脂質をさらに含み、コンジュゲートされた脂質は、安定化成分にコンジュゲートされた脂質を含む。いくつかの場合において、安定化成分は親水性ポリマーを含む。いくつかの場合において、親水性ポリマーは、ポリエチレングリコール、ポリ(2-アルキル-2-オキサゾリン)、ポリビニルアルコール、又はこれらの任意の組合せを含む。いくつかの場合において、親水性ポリマーは、約50kDa~約500kDaの分子量を有する。いくつかの場合において、親水性ポリマーはポリエチレングリコール(PEG)を含み、コンジュゲートされた脂質は、ペグ化された脂質を含む。いくつかの場合において、ペグ化された脂質は、DSPE-PEG、DSG-PEG、DMG-PEG、又はDPPE-PEGを含む。いくつかの場合において、ペグ化された脂質は、DSPE-PEG又はDMG-PEGを含む。いくつかの場合において、コンジュゲートされた脂質の濃度は25モル%未満である。いくつかの場合において、コンジュゲートされた脂質の濃度は5モル%未満である。いくつかの場合において、コンジュゲートされた脂質の濃度は約0.5モル%~約20モル%である。いくつかの場合において、送達ビヒクルは非カチオン性脂質を含み、非カチオン性脂質の濃度は約5モル%~約75モル%である。いくつかの場合において、脂質ナノ粒子は、正又は中性に近い正味電荷を有する。
カーゴ及びナノ粒子を含む送達ビヒクルであって、ナノ粒子は、約5.5~8.0のpHで正電荷を帯びている第1の部位及び約5.5~8.0のpHで負電荷を帯びている第2の部位を含み、第1の部位と第2の部位は、正電荷及び負電荷が散在しないように分離されており、ナノ粒子は、粘液バリアを通過して上皮細胞に到達することが可能である送達ビヒクルが本明細書で提供される。一態様において、上皮細胞への到達は、送達ビヒクルが細胞表面から20ミクロン以内に接近すること、上皮細胞表面に結合すること、あるいは上皮細胞によって吸収されることを含む。一態様において、ナノ粒子は、脂質、ポリマー、又はそれらの組合せを含む。一態様において、第1の部位は第1の相に含まれ、第2の部位は第2の相に含まれ、第1の相と第2の相は互いに物理的に分離されている。一態様において、第1の相は液体である。一態様において、第2の相はゲルである。一態様において、第1の相はゲルである。一態様において、第2の相は液体である。いくつかの場合において、送達ビヒクルは安定性成分をさらに含む。いくつかの場合において、安定性成分はポリエチレングリコール(PEG)である。いくつかの場合において、第1の部位は、不飽和脂質又は短尾部脂質を含む。いくつかの場合において、不飽和脂質は、カチオン性脂質又はイオン化可能なカチオン性脂質を含む。いくつかの場合において、カチオン性脂質は、多価カチオン性脂質又は一価カチオン性脂質を含む。いくつかの場合において、カチオン性脂質は、N1-[2-((1S)-1-[(3-アミノプロピル)アミノ]-4-[ジ(3-アミノ-プロピル)アミノ]ブチルカルボキサミド)エチル]-3,4-ジ[オレイルオキシ]-ベンズアミド(MVL5)、1,2-ジオレオイル-3-トリメチルアンモニウムプロパン(DOTAP)、N4-コレステリル-スペルミンHCl(GL67)、これらのいずれかの塩、及びこれらの任意の組合せからなる群から選択される。一態様において、第1の相中の1つ以上の脂質はペグ化されている。一態様において、第1の部位は、1,2-ジオレイルオキシ-3-(ジメチルアミノ)プロパン(DODMA)、6Z,9Z,28Z,31Z)-ヘプタトリアコンタ-6,9,28,31-テトラエン-19-イル3-(ジメチルアミノ)プロパノアート(MC2)、又はこれらの任意の組合せの少なくとも1つをさらに含む。一態様において、第2の部位は、1,2-ジステアロイル-sn-グリセロ-3-ホスホ-L-セリン(DSPS)、1,2-ジパルミトイル-sn-グリセロ-3-ホスホ-L-セリン(DPPS)、デポ酢酸メドロキシプロゲステロン(DMPA)、ジフェニルホスホリルアジド(DPPA)、1,2-ジステアロイル-sn-グリセロ-3-ホスファチジン酸ナトリウム(DSPA)、1,2-ジパルミトイルホスファチジルグリセロールジパルミトイルホスファチジルグリセロール(DPPG)、又は2,4-ジアセチルフロログルシノール(DAPG)の少なくとも1つを含む。一態様において、第2の部位は、2-ジステアロイル-sn-グリセロ-3-ホスホコリン(DSPC)、1,2-ビス(ジメチルホスフィノ)エタン(DMPE)、1,2-ビス(ジフェニルホスフィノ)エタン(DPPE)、1,2-ジステアロイルホスファチジルエタノールアミン(DSPE)、ジパルミトイルホスファチジルコリン(DPPC)、1,2-ジアラキドイル-sn-グリセロ-3-ホスホコリン20:0 PC(DAPC)、又は1,2-ジラジル-3-ホスファチジルエタノールアミン20:0 PE(DAPE)の少なくとも1つをさらに含む。一態様において、第2の部位は、デオキシコール酸塩、及び2-ジステアロイル-sn-グリセロ-3-ホスホコリン(DSPC)、1,2-ビス(ジメチルホスフィノ)エタン(DMPE)、1,2-ビス(ジフェニルホスフィノ)エタン(DPPE)、1,2-ジステアロイルホスファチジルエタノールアミン(DSPE)、ジパルミトイルホスファチジルコリン(DPPC)、1,2-ジアラキドイル-sn-グリセロ-3-ホスホコリン20:0 PC(DAPC)、又は1,2-ジラジル-3-ホスファチジルエタノールアミン20:0 PE(DAPE)の少なくとも1つを含む。一態様において、第1の相は37℃未満の転移温度を有し、第2の相は37℃超の転移温度を有する。一態様において、第1の相は37℃超の転移温度を有し、第2の相は37℃未満の転移温度を有する。一態様において、37℃未満の転移温度を有する相は、DODMA、MVL5、MC2、カチオン性脂質、又はイオン化可能なカチオン性脂質を含む。一態様において、37℃超の転移温度を有する相はDSPCを含む。いくつかの場合において、pH7.4における第2の部位中のアニオン性電荷に対する第1の部位中のカチオン性電荷の比は、約0.25~約3.0である。いくつかの場合において、この比は約0.75~約1.25である。いくつかの場合において、第1の相は、MVL5及びイオン化可能なカチオン性脂質を含む。いくつかの場合において、イオン化可能なカチオン性脂質は、DODMA、MC2、MC3、及びKC2からなる群から選択される。いくつかの場合において、イオン化可能なカチオン性脂質はDODMA又はMC2であり、送達ビヒクル中のMVL5:イオン化可能なカチオン性脂質のモル%比は、約6.25%:18.75%、12.5%:12.5%、又は18.75%:6.25%である。いくつかの場合において、送達ビヒクル中のMVL5:イオン化可能なカチオン性脂質の比は約12.5%:12.5%である。いくつかの場合において、第2の相はデオキシコール酸塩を含む。
送達ビヒクル又は医薬組成物を投与することを含んだ、消化管にカーゴを送達する方法であって、送達ビヒクルが消化管に到達し、送達ビヒクルが消化管中に存在する胆汁酸塩からカーゴを保護する方法が本明細書で提供される。いくつかの場合において、送達ビヒクルは粘液バリアを容易に通過する。いくつかの場合において、送達ビヒクルは、消化管内の上皮細胞に到達することが可能である。いくつかの場合において、上皮細胞への到達は、送達ビヒクルが細胞表面から20ミクロン以内に接近することを含む。いくつかの場合において、送達ビヒクルは上皮細胞の表面に接触する。一態様において、送達ビヒクルが上皮細胞に接触した後、カーゴは上皮細胞によって吸収される。いくつかの場合において、送達ビヒクル又は医薬組成物は、それを必要とする対象に経口又は非経口的に投与される。いくつかの場合において、カーゴは、核酸、タンパク質、抗体、ペプチド、小分子、又は生物製剤を含む。いくつかの場合において、核酸は治療剤をコードし、上皮細胞はカーゴを吸収した後に治療剤を発現する。いくつかの場合において、治療剤は上皮細胞により分泌される。
本明細書中の全刊行物、特許、及び特許出願は、各個別の刊行物、特許、又は特許出願が、参照により組み込まれると具体的及び個別に示されるかのように同程度まで参照によりその全体として組み込まれる。本明細書中の用語と組み込まれた参照文献での用語の間に矛盾がある場合、本明細書中の用語が優先する。
消化(GI)管、膣、及び肺などの中の上皮組織及び細胞への治療剤などの薬剤の送達は特定の課題を提示する。これらの組織において、上皮細胞は粘膜層に覆われており、そのため治療剤は粘液に透過し、その中を動いて上皮細胞に達しなければならない。さらに、治療剤は、粘液の層内又はそれを通ると、意図される標的細胞の近傍に来なくてはならず、いくつかの場合において、細胞膜と相互作用するか、及び/又は細胞に入らなくてはならない。したがって、薬剤(本明細書で「カーゴ」とも称される)の送達は、粘液層に透過し、それを越えるだけでなく、意図される上皮細胞標的の届く範囲に来る送達ビヒクルにより改善される。また、消化管及び他の組織に関して、胃腸の天然に存在する胆汁酸などの過酷な環境は、送達の安定性及び意図される標的細胞へのカーゴの首尾よい送達のための課題を提示し得る。
本明細書で使用される通り、単数形「1つの(a)」、「1つの(an)」、及び「前記(the)」は、文脈が明らかに別なように示さない限り、複数形も含むものとする。さらに、用語「含む(including)」、「含む(includes)」、「有する(having)」、「有する(has)」、「有する(with)」、又はその変形体が詳細な説明及び/又は請求項中で使用される限り、そのような用語は、用語「含む(comprising)」と同様に包括的であるものとする。用語「約」又は「およそ」は、値がどのように測定又は決定されたか、例えば測定系の限界に部分的に依存する、当業者により決定される特定の値の許容できる誤差範囲内を意味し得る。例えば、「約」は、所与の値の±10%以内を意味し得る。特定の値が本願及び請求項に記載される場合、特記されない限り、用語「約」は、特定の値の許容できる誤差範囲を意味すると推測されるべきである。
本明細書で使用される用語「疎水性」及びその文法上の等価物は、水と容易に相互作用しない極性基を有する物質又は構造を指す。
本明細書中で提供される構造では、以下の括弧でくくられた下付き文字は下記の通り基をさらに定義する。「(Cn)」は、基の中の正確な数(n)の炭素原子を定義する。例えば、「(C2~10)」アルキルは、2~10個の炭素原子(例えば、2、3、4、5、6、7、8、9、又は10、又はそれらの中の誘導可能な範囲(例えば、3~10個の炭素原子)を有するアルキル基を示す。
いくつかの場合において、本明細書中で提供される送達ビヒクルは、粒子内の異なる部位中に、分離された正電荷及び負電荷を有するが、各部位は(部位に電荷を与える)異なるポリマーで構成されている。いくつかの場合において、本明細書中で提供される送達ビヒクルは正電荷を帯びた脂質及び負電荷を帯びた脂質を含み、部位は、液相及びゲル相中など相により分離されている。いくつかの場合において、送達ビヒクルは、正電荷を帯びた液相及び負電荷を帯びたゲル相、又は正電荷を帯びたゲル相及び負電荷を帯びた液相を含み得る。
いくつかの実施形態において、送達ビヒクル安定性は胆汁酸又は胆汁酸塩の組込みにより増加され得る。用語「胆汁酸」、「胆汁酸塩」、「胆汁酸/塩」は、特記されない限り、本明細書で互換的に使用される。本明細書で使用される胆汁酸へのあらゆる言及は、胆汁酸又はその塩への言及を含み得る。本明細書で使用される用語「胆汁酸」(及び「胆汁酸塩」「胆汁酸/塩」)は、非限定的な例として、コール酸、コール酸塩、デオキシコール酸、デオキシコール酸塩、ヒオデオキシコール酸、ヒオデオキシコール酸塩、グリココール酸、グリココール酸塩、タウロコール酸、タウロコール酸塩、ケノデオキシコール酸、ケノデオキシコール酸塩、リトコール酸、リトコール酸塩など又はその塩を含む、動物(例えばヒト)の胆汁に見られるステロイド酸(及びそのアニオン)、及びその塩を含み得る。いくつかの実施形態において、胆汁酸は、ウルソジオール、イソリトコール酸塩、アロイソリトコール酸塩、デヒドロリトコール酸塩、又は5-β-コラン酸である。タウロコール酸及びタウロコール酸塩は本明細書でTCAと称される。本明細書で使用される胆汁酸へのあらゆる言及は、胆汁酸、唯一の胆汁酸、1以上の胆汁酸、又は少なくとも1つの胆汁酸への言及を含み得る。さらに、薬学的に許容できる胆汁酸エステル、例えばアミノ酸(例えばグリシン又はタウリン)にコンジュゲートされた胆汁酸は、本明細書に記載される「胆汁酸」として使用され得る。他の胆汁酸エステルは、例えば、置換又は非置換のアルキルエステル、置換又は非置換のヘテロアルキルエステル、置換又は非置換のアリールエステル、置換又は非置換のヘテロアリールエステルなどを含み得る。例えば、用語「胆汁酸」は、それぞれグリシンかタウリンのいずれかにコンジュゲートされたコール酸、グリココール酸塩及びタウロコール酸塩(及びその塩)を含み得る。本明細書で使用される胆汁酸へのあらゆる言及は、天然により又は合成により調製された同一の化合物への言及を含み得る。さらに、本明細書で使用される成分(胆汁酸又はその他)へのあらゆる単一の言及が、唯一の、1つ以上の、又は少なくとも1つのそのような成分への言及を含み得ることが理解されるべきである。同様に、本明細書で使用される成分へのあらゆる複数の言及は、特に記載がない限り、唯一の、1つ以上の、又は少なくとも1つのそのような成分への言及を含み得る。
カーゴを有するものを含んだ本明細書中の送達ビヒクルは、脂質ナノ粒子中など1以上の脂質を含む。いくつかの実施形態において、脂質ナノ粒子は、少なくとも1つの飽和脂質と、不飽和カチオン性脂質又は不飽和非カチオン性脂質の少なくとも1つと、胆汁酸塩とを含む。いくつかの実施形態において、脂質ナノ粒子は少なくとも1つの飽和脂質を含み、飽和脂質は、少なくとも約37℃の相転移温度を有する飽和カチオン性脂質又は少なくとも約37℃の相転移温度を有する飽和非カチオン性脂質を含む。いくつかの態様において、脂質ナノ粒子は、非カチオン性脂質、多価カチオン性脂質、永久荷電カチオン性脂質、又はこれらの任意の組合せの少なくとも1つをさらに含む。いくつかの実施形態において、脂質ナノ粒子は、胆汁酸塩並びに多価カチオン性脂質及び非カチオン性脂質を含み、多価カチオン性脂質、非カチオン性脂質、又は多価カチオン性脂質及び非カチオン性脂質は、少なくとも約37℃の相転移温度を有する。いくつかの実施形態において、脂質ナノ粒子は、胆汁酸塩並びに少なくとも約37℃の相転移温度を有する飽和カチオン性脂質及び非カチオン性脂質を含む。いくつかの実施形態において、脂質ナノ粒子は、胆汁酸塩、並びに飽和カチオン性脂質、不飽和カチオン性脂質、及び非カチオン性脂質を含み、不飽和カチオン性脂質、非カチオン性脂質、又は不飽和カチオン性脂質及び非カチオン性脂質は少なくとも約37℃の相転移温度を有する。いくつかの実施形態において、送達ビヒクルは、約5.5~8.0のpHで正電荷を帯びている第1の部位及び約5.5~8.0のpHで負電荷を帯びている第2の部位を有し、第1の部位と第2の部位は、正電荷及び負電荷が散在しないように分離されており、一方又は両方の部位は脂質を含む。いくつかの実施形態において、第1の部位は、カチオン性又はイオン化可能なカチオン性脂質などの不飽和又は短尾部脂質、例えば、多価カチオン性脂質又は一価カチオン性脂質を含む。
本明細書中で提供される電荷分離及び上皮到達機能性を有する本明細書中の送達ビヒクルは、あらゆる種類のカーゴを、標的、例えば標的細胞に送達するために利用され得る。いくつかの場合において、カーゴは治療剤を含み得る。例示的な治療剤は、核酸、タンパク質、抗体、ペプチド、小分子、生物製剤、アンチセンスオリゴヌクレオチド、ペプチドミメティクス、リボザイム、化学療法薬分子などの化学剤、又はウイルス粒子、成長因子サイトカイン、免疫調節性剤、低分子薬を含むがこれらに限定されないあらゆる大きな分子、リポソーム内に組み込まれたDNAにより発現され得る蛍光色素ペプチドを含む蛍光色素、又はこれらの任意の組合せを含み得る。
本明細書中で提供される送達ビヒクルは、カーゴを標的細胞に送達するために利用できる。いくつかの場合において、標的細胞は、消化管、生殖器管、循環系、呼吸器系、筋骨格系、排泄系、神経系、眼系、及びそれらの組合せに見られる。いくつかの場合において、好適な標的細胞は、皮膚、肺、心臓、肝臓、胃、尿路系、生殖系、腸、膵臓、腎臓、胸腺、甲状腺、及び/又は脳を含むがこれらに限定されない体のあらゆる主要器官に見られ得る。いくつかの場合において、標的細胞は消化管の一部であり、肛門、直腸、大腸、小腸、肝臓、胃、食道、又は口の中にある。いくつかの場合において、標的細胞は、腸内分泌細胞、肥満細胞、腸細胞、刷子細胞、パネート細胞、又は杯細胞である。いくつかの場合において、標的細胞は腸内分泌細胞であり、EC細胞、D細胞、CCK細胞、L細胞、P/D1細胞、又はG細胞である。いくつかの場合において、標的細胞は腸の上皮中にあり、腸の幹細胞、パネート細胞、杯細胞、腸細胞、トランジット増幅細胞、腸内分泌細胞、又はこれらの任意の組合せから選択される。いくつかの場合において、標的細胞は腸の幹細胞である。いくつかの場合において、標的細胞は腺窩細胞である。
本明細書中の送達ビヒクル組成物は、消化管(胃腸管)のものなどの粘膜組織内の上皮細胞への送達を与えると同時に肺、膣、及び眼などの他の粘膜組織で使用される。本明細書中の送達ビヒクルは、粘液層を通る透過と共に上皮細胞への到達を与える。いくつかの実施形態において、送達ビヒクルは、カーゴを消化管の上皮細胞に送達し、治療用、診断用、又はセラノスティック目的でカーゴ(本明細書に記載されるものなど)を送達する。
全体を通じて記載される組成物は医薬品に製剤でき、それを必要とするヒト又は哺乳動物を治療するのに使用できる。医薬品は、任意の追加の療法と共に共投与できる。
この実施例は、本開示の送達ビヒクルを調製する例示的な方法を提供する。送達ビヒクルの脂質成分DODMA(シグマアルドリッチ(Sigma Aldrich))、デオキシコール酸塩(シグマアルドリッチ(Sigma Aldrich))、MVL5(アバンティポーラリピッド(Avanti Polar Lipids))、DSPC(アバンティポーラリピッド(Avanti Polar Lipids))、DMG-PEG2000(アバンティポーラリピッド(Avanti Polar Lipids))、DOPC(アバンティポーラリピッド(Avanti Polar Lipids))、DiI(サーモフィッシャーサイエンティフィク(ThermoFisher Scientific))、DiO(サーモフィッシャーサイエンティフィク(ThermoFisher Scientific))をエタノールに溶解させ、例えば相転移温度が37℃より高い場合、それらの相転移温度より上に加熱した。例えば、DSPCを使用する場合、脂質及び水相を70℃に加熱した。DOPCを使用する場合、脂質及び水相を加熱せず、室温で使用した。核酸を、脂質の相転移温度より上に加熱された水性緩衝液に溶解させた。
封入された核酸を含む例示的な送達ビヒクルを調製するために、サイトメガロウイルス(CMV)プロモータ下でガウシアルシフェラーゼをコードする300μgのプラスミドDNAを、最終体積3mLの50mM酢酸ナトリウム緩衝液(pH4.8)に溶解させた。適切なモルのMVL5、DODMA、デオキシコール酸塩、MVL5、DSPC、DMG-PEG2000、及び/又はDOPCを、それらのモル及びカチオン性脂質:核酸比(調製された種々の製剤中の脂質のモル%に関しては表2参照)に応じてエタノール中で混合した。カチオン性脂質:ヌクレオチドモル比を約16に維持した。DiI及びDiOなどの蛍光標識された脂質を、使用する場合、ミックスに総脂質モルの0.5%で加えた。エタノール体積を1mLに増やした。
この試験において、例示的な送達ビヒクル(上記実施例1に記載のプロセスを利用して調製した)の核酸導入効率を評価した。50~80%のコンフルエンシーに培養したHEK細胞を核酸導入に使用した。脂質ナノ粒子(上記表2に列記)中に封入された1μgのガウシアルシフェラーゼを発現するプラスミドDNAを、24ウェルプレート中で1ウェルあたり使用した。核酸導入効率は、30μlの媒体を24時間後にとり、フラッシュルシフェラーゼアッセイ(ピアスガウシアルシフェラーゼアッセイキット(Pierce Gaussia Luciferase Kit))を実施することにより評価した。相対発光単位(RLU)の値の増加は、より高い核酸導入効率に対応した。
この試験において、高胆汁酸塩環境における例示的な送達ビヒクルの安定性を評価した。送達ビヒクル安定性を決定するために、このアッセイに使用した送達ビヒクルに、それぞれ0.5モル%のDiI及びDiOを組み込んだ。DiI及びDiOは、FRETペアである蛍光色素である。胆汁酸塩は、コール酸とデオキシコール酸塩の等量混合物を示された濃度で使用することにより模した(図2~4中)。送達ビヒクルが胆汁酸塩による崩壊を受けやすい場合、FRET強度の減少が起こるだろうと予測した。励起を465nmにし、発光を501nm及び570nmで読み取って、相対蛍光単位(RFU)を決定した。570nmでのRFU読取りを、501nmでの読取りにより割った。読取り値を、全く処理がない系のFRET強度に対して正規化した。データを図2、図3及び図4に示す。
この試験のために、脂質ナノ粒子(表2の製剤番号5)に封入された1μgのDNAを含む送達ビヒクルを、未処理(図5のレーン2)、(ii)7%トリトン-X100により処理(図5のレーン3)、(iii)7%トリトン-X100による処理に加えて70℃30分間(図5のレーン4)のいずれかでアガロースゲルのレーンにロードし、それに続いて電気泳動した。SYBRセーフ(SYBR Safe)を使用して、UV光によりDNAを検出した。DNAバンドは、胆汁酸塩安定系を含むカチオン性脂質のいずれでも見られず(レーン2、未処理)、封入及びDNAが送達ビヒクルから放出されなかったことを示した。しかし、DNAバンドは、洗剤及び熱を使用して系が乱された場合に見られ(レーン3及び4)、ビヒクルがこの環境中で不安定であり、DNAが処理時に放出されたことを示す。データを図5に示す。これは、特に消化管などの高胆汁酸塩環境中での効率よい保護のための、胆汁酸塩環境中で安定である送達ビヒクル内に封入されたカーゴ(DNAなど)を有することの利点を表した。
核酸カーゴの封入を下記の通り実施した。脂質をエタノールに溶解させ、それらの相転移温度より上に加熱した。核酸を、脂質の相転移温度より上に加熱した水性緩衝液に溶解させた。水性緩衝液pHを胆汁酸塩及びカチオン性脂質のpKa未満に設定した。このようにすると、核酸と共に製剤するときに、脂質は強カチオン性であった。脂質と核酸を、マイクロ流体チャネルを使用して混合した。pHを中性まで上げて、試料を濃縮し、透析を使用してエタノールを除去した。
製剤
CMVプロモータの下でガウシアルシフェラーゼをコードする375μgのプラスミドDNAを最終体積3mLの50mM酢酸ナトリウム緩衝液(pH4.8)に溶解させた。適切なモルのMVL5、DODMA、デオキシコール酸塩、MVL5、DSPC、GMO、DMG-PEG2000、及び/又はDOPCを、それらのモル及びカチオン性脂質:核酸比に応じてエタノール中で混合した。カチオン性脂質:ヌクレオチドモル比は16で一定に保った。脂質をDiI及びDiOにより蛍光標識する場合、各DiI及びDiOを総脂質モルの0.5%molでミックスに加えた。エタノール体積を1mLに増やした。試料を、ナノアセンブルベンチトップ(NanoAssemblr Benchtop)(プレシジョンナノシステムズ(Precision Nanosystems))上でシリンジ中に入れ、DSPC製剤では65℃に予備加熱し、又はDOPC製剤では室温であった。ナノアセンブルベンチトップ(NanoAssemblr Benchtop)マイクロ流体チップシステムを使用して6mL/分の流量で試料を混合した。pHを中和し、次いで、透析を一晩使用してエタノールを除去した。100kDa分子量カットオフを有するアミコンウルトラ(Amicon Ultra)-4(メルクミリポア社(Merck Millipore Ltd)、アイルランド)を使用して、試料を濃縮した。
マウスに、DiI及びDiO標識したナノ粒子中に封入したおよそ30マイクログラムのDNAを直腸内投与した。投薬の4時間後、マウスを犠死させ、腸をOCTに包埋し、ドライアイスで凍結させ、-80℃で保存した。組織を30マイクロメートルスライスの凍結切片にして、バイオテックサイテーション(BioTek Cytation)1を使用して画像化した。DiI蛍光をRFPチャネルで測定した。
MVL5/DODMA/DSPC/デオキシコール酸塩/DMG-PEG(粒子5~9)粒子を、DMG-PEGの量を増やしながら形成し、粒子の挙動をインビボで調査した。DMG-PEGの量を増やすと、腸の組織での分布が減少した。これは、ペグ化を増やして腸の上皮到達を増やすという現在の定説と矛盾する。発明者らは、増加したペグ化がその遮蔽特性により表面で正電荷の露出を減少させると考える。これは、図6(粒子5)、図7(粒子6)、図8(粒子7)、図9(粒子8)、及び図10(粒子9)に示されるように、粒子の二重の性質を減少させる。
図11A、図11B、図12A、図12B、図13A、図13B、図14A、及び図14Bに示されるように、DiI及びDiOを有するDSPC/デオキシコール酸塩/DMG-PEG)中でMVL5/DODMAの比を変更して、正電荷を増加させることの効果を調査した。粒子中の以下の比のMVL5/DODMAを形成した(0%/25%)、(6.25%/18.75%)、(12.5%/12.5%)、(18.75%、6.25%)、(25%/0%)。DODMAが中性pHでほとんど中性であり、一価であるので、デオキシコール酸塩の負電荷及びMVL5の多価電荷が、粒子の挙動を支配した。それにより、MVL5を増やすことは電荷を増やす。
送達ビヒクルを実施例1に記載の通り生成させ、実施例7に記載の通りインビボで試験した。双性イオン性が、PEGの存在なしに粘液透過を増加させることが以前に示された。二重相性ではなく双性イオン性が充分であるかどうかを調査するために、単一相のものであるように設計した粒子を製剤した。単一相粒子を製造するために、低相転移温度脂質(すなわちDOPC又はGMOを含む)を、DSPCの代わりにした。電荷を粒子の間で同じに保った。液相のみである粒子(DSPCの代わりにDOPC又はGMOを含む)は、腸の上皮細胞到達が著しく減少したか、又はほとんどないことが見出された。
先に実施例1に記載した方法を使用して、以下の製剤を製造した。モル比0.96:0.96:2.592:3.168:0.0768:0.0384:0.0384で、MVL5:MC2(バイオファインインターナショナル社(Biofine International LLC)、バンクーバー、ブリティッシュコロンビア州、カナダ):胆汁酸塩:DSPC:DMG-PEG2000:DiI:DiO。ここで、胆汁酸塩成分は、ウルソジオール、デオキシコール酸塩、リトコール酸塩、イソリトコール酸塩、アロイソリトコール酸塩、デヒドロリトコール酸塩、又は5β-コラン酸のいずれかであった。核酸は脂質ナノ粒子中に組み込まなかった。表4に与えられるものなど、代わりの製剤も生成させることができる。
Claims (100)
- (i)カーゴ及び(ii)脂質ナノ粒子を含む送達ビヒクルであって、
前記脂質ナノ粒子は少なくとも1つの飽和脂質と、胆汁酸塩とを含み、
前記少なくとも1つの飽和脂質が飽和カチオン性脂質であるか、あるいは前記脂質ナノ粒子が少なくとも1つのカチオン性脂質をさらに含む、送達ビヒクル。 - 前記脂質ナノ粒子は、不飽和カチオン性脂質又は不飽和非カチオン性脂質の少なくとも1つをさらに含み、任意選択で、前記脂質ナノ粒子中の前記少なくとも1つの不飽和カチオン性脂質又は不飽和非カチオン性脂質の濃度は、前記脂質ナノ粒子の総脂質濃度の50モル%未満である、請求項1に記載の送達ビヒクル。
- 前記飽和カチオン性脂質は少なくとも約37℃の相転移温度を有する、請求項1又は請求項2に記載の送達ビヒクル。
- 前記飽和脂質は、少なくとも約37℃の相転移温度を有する飽和非カチオン性脂質を含む、請求項1又は請求項2に記載の送達ビヒクル。
- 前記脂質ナノ粒子は、非カチオン性脂質、多価カチオン性脂質、永久荷電カチオン性脂質、又はこれらの任意の組合せの少なくとも1つをさらに含む、請求項1~4のいずれか一項に記載の送達ビヒクル。
- 前記多価カチオン性脂質は、MVL5、TMVLBG2、TMVLG3、TMVLBG1、GL67、又はこれらの任意の組合せの少なくとも1つを含む、請求項4に記載の送達ビヒクル。
- 前記多価カチオン性脂質はMVL5を含む、請求項6に記載の送達ビヒクル。
- 前記多価カチオン性脂質は総脂質濃度の約25モル%以下である、請求項6又は7に記載の送達ビヒクル。
- 前記永久荷電カチオン性脂質は、1,2-ジオレオイル-3-トリメチルアンモニウム-プロパン(DOTAP)、3β-[N-(N’,N’-ジメチルアミノエタン)-カルバモイル]コレステロール塩酸塩(DC-コレステロール・HCl)、又はこれらの任意の組合せを含む、請求項5に記載の送達ビヒクル。
- 前記飽和カチオン性脂質は、1,2-ステアロイル-3-トリメチルアンモニウム-プロパン、1,2-ジパルミトイル-3-トリメチルアンモニウム-プロパン、1,2-ジステアロイル-3-ジメチルアンモニウム-プロパン、ジメチルジオクタデシルアンモニウム、1,2-ジアルキル-sn-グリセロ-3-エチルホスホコリン、1,2-ジアルキル-3-ジメチルアンモニウム-プロパン、1,2-ジアルキル-3-トリメチルアンモニウム-プロパン、1,2-ジ-O-アルキル-3-トリメチルアンモニウムプロパン、1,2-ジアルキルオキシ-3-ジメチルアミノプロパン、N,N-ジアルキル-N,N-ジメチルアンモニウム、N-(4-カルボキシベンジル)-N,N-ジメチル-2,3-ビス(アルキルオキシ)プロパン-1-アミニウム、1,2-ジアルキル-sn-グリセロ-3-[(N-(5-アミノ-1-カルボキシペンチル)イミノジ酢酸)スクシニル]、N1-[2-((1S)-1-[(3-アミノプロピル)アミノ]-4-[ジ(3-アミノ-プロピル)アミノ]ブチルカルボキサミド)エチル]-3,4-ジ[アルキル]-ベンズアミド、1,2-ステアロイル-3-トリメチルアンモニウム-プロパン(DSTAP)、1,2-ジパルミトイル-3-トリメチルアンモニウム-プロパン(DPTAP)、1,2-ジステアロイル-3-ジメチルアンモニウム-プロパン(DSDAP)、又はこれらの任意の組合せの少なくとも1つを含む、請求項1~9のいずれか一項に記載の送達ビヒクル。
- 前記飽和非カチオン性脂質は、1,2-ジアルキル-sn-グリセロ-3-ホスホコリン、1,2-ジアルキル-sn-グリセロ-3-ホスホエタノールアミン、1,2-ジアキリル-sn-グリセロ-3-ホスホリルグリセロール、1,2-ジアルキル-sn-グリセロ-3-ホスファチジルセリン、1,2-ジアルキル-sn-グリセロ-3-ホスフェート、モノグリセロールアルキラート、グリセリルヒドロキシアルキラート、ソルビタンモノアルキラート、1,2-ジアルキル-sn-グリセロ-3-ホスホエタノールアミン-N-メチル、1,2-ジアルキル-sn-グリセロ-3-ホスホメタノール、1,2-ジアルキル-sn-グリセロ-3-ホスホエタノール、1,2-ジアルキル-sn-グリセロ-3-ホスホエタノールアミン-N,N-ジメチル、1,2-ジアルキル-sn-グリセロ-3-ホスホプロパノール、1,2-ジアルキル-sn-グリセロ-3-ホスホブタノール、又はこれらの任意の組合せの少なくとも1つを含む、請求項4~9に記載の送達ビヒクル。
- 前記不飽和カチオン性脂質は、ジメチルジオクタデシルアンモニウム、1,2-ジアルキル-sn-グリセロ-3-エチルホスホコリン、1,2-ジアルキル-3-ジメチルアンモニウム-プロパン、1,2-ジアルキル-3-トリメチルアンモニウム-プロパン、1,2-ジ-O-アルキル-3-トリメチルアンモニウムプロパン、1,2-ジアルキルオキシ-3-ジメチルアミノプロパン、N,N-ジアルキル-N,N-ジメチルアンモニウム、N-(4-カルボキシベンジル)-N,N-ジメチル-2,3-ビス(アルキルオキシ)プロパン-1-アミニウム、1,2-ジアルキル-sn-グリセロ-3-[(N-(5-アミノ-1-カルボキシペンチル)イミノジ酢酸)スクシニル]、N1-[2-((1S)-1-[(3-アミノプロピル)アミノ]-4-[ジ(3-アミノ-プロピル)アミノ]ブチルカルボキサミド)エチル]-3,4-ジ[アルキル]-ベンズアミド、1,2-ジアルキルオキシ-N,N-ジメチルアミノプロパン、4-(2,2-ジオクタ-9,12-ジエニル-[1,3]ジオキソラン-4-イルメチル)-ジメチルアミン、O-アルキルエチルホスホコリン、MC3、MC2、MC4、3β-[N-(N’,N’-ジメチルアミノエタン)-カルバモイル]コレステロール、N4-コレステリル-スペルミン、7-(4-(ジメチルアミノ)ブチル)-7-ヒドロキシトリデカン-1,13-ジイルジオレアート(CL1H6)、又はこれらの任意の組合せの少なくとも1つを含む、請求項2~11のいずれか一項に記載の送達ビヒクル。
- 前記不飽和カチオン性脂質は少なくともMC2又はCL1H6を含む、請求項12に記載の送達ビヒクル。
- 前記不飽和非カチオン性脂質は、1,2-ジアルキル-sn-グリセロ-3-ホスホコリン、1,2-ジアルキル-sn-グリセロ-3-ホスホエタノールアミン、1,2-ジアキリル-sn-グリセロ-3-ホスホリルグリセロール、1,2-ジアルキル-sn-グリセロ-3-ホスファチジルセリン、1,2-ジアルキル-sn-グリセロ-3-ホスフェート、モノグリセロールアルキラート、グリセリルヒドロキシアルキラート、ソルビタンモノアルキラート、1,2-ジアルキル-sn-グリセロ-3-ホスホエタノールアミン-N-メチル、1,2-ジアルキル-sn-グリセロ-3-ホスホメタノール、1,2-ジアルキル-sn-グリセロ-3-ホスホエタノール、1,2-ジアルキル-sn-グリセロ-3-ホスホエタノールアミン-N,N-ジメチル、1,2-ジアルキル-sn-グリセロ-3-ホスホプロパノール、1,2-ジアルキル-sn-グリセロ-3-ホスホブタノール、又はこれらの任意の組合せの少なくとも1つを含む、請求項2~13のいずれか一項に記載の送達ビヒクル。
- 前記少なくとも1つの飽和脂質又はカチオン性脂質は多価カチオン性脂質である、請求項1に記載の送達ビヒクル。
- 非カチオン性脂質をさらに含む、請求項15に記載の送達ビヒクル。
- 前記多価カチオン性脂質、前記非カチオン性脂質、又は前記多価カチオン性脂質及び前記非カチオン性脂質は少なくとも約37℃の相転移温度を有する、請求項16に記載の送達ビヒクル。
- 前記多価カチオン性脂質は、MVL5、TMVLBG2、TMVLG3、TMVLBG1、及びGL67、又はこれらの任意の組合せの少なくとも1つを含む、請求項17に記載の送達ビヒクル。
- 前記非カチオン性脂質は飽和非カチオン性脂質を含む、請求項17又は請求項18に記載の送達ビヒクル。
- 前記飽和非カチオン性脂質は、1,2-ジアルキル-sn-グリセロ-3-ホスホコリン、1,2-ジアルキル-sn-グリセロ-3-ホスホエタノールアミン、1,2-ジアキリル-sn-グリセロ-3-ホスホリルグリセロール、1,2-ジアルキル-sn-グリセロ-3-ホスファチジルセリン、1,2-ジアルキル-sn-グリセロ-3-ホスフェート、モノグリセロールアルキラート、グリセリルヒドロキシアルキラート、ソルビタンモノアルキラート、1,2-ジアルキル-sn-グリセロ-3-ホスホエタノールアミン-N-メチル、1,2-ジアルキル-sn-グリセロ-3-ホスホメタノール、1,2-ジアルキル-sn-グリセロ-3-ホスホエタノール、1,2-ジアルキル-sn-グリセロ-3-ホスホエタノールアミン-N,N-ジメチル、1,2-ジアルキル-sn-グリセロ-3-ホスホプロパノール、1,2-ジアルキル-sn-グリセロ-3-ホスホブタノール、又はこれらの任意の組合せの少なくとも1つを含む、請求項19に記載の送達ビヒクル。
- 前記送達ビヒクルは、胆汁酸塩を含まない他の点では同一の送達ビヒクルと比べて、高胆汁酸塩環境中で安定である、請求項1~20のいずれか一項に記載の送達ビヒクル。
- 前記高胆汁酸塩環境は胃腸環境を含む、請求項21に記載の送達ビヒクル。
- 前記送達ビヒクルは、(i)胆汁酸塩を含まない他の点では同一の送達ビヒクルと比べて、少なくとも約5g/Lの胆汁酸塩を含む溶液中で増加した安定性を示し、前記安定性は、フェルスター共鳴エネルギー移動(FRET)アッセイにおいて、前記脂質ナノ粒子中に組み込まれた蛍光性脂質の相対蛍光強度により測定される、請求項21又は22に記載の送達ビヒクル。
- 前記送達ビヒクルは、(i)胆汁酸塩を含まない他の点では同一の送達ビヒクルと比べて、少なくとも約5g/Lの約50%コール酸と約50%デオキシコール酸塩の混合物を含む溶液中で増加した安定性を示し、前記安定性は、フェルスター共鳴エネルギー移動(FRET)アッセイにおいて、前記脂質ナノ粒子中に組み込まれた蛍光性脂質の相対蛍光強度により測定される、請求項23に記載の送達ビヒクル。
- N,N-ジオレイル-N,N-ジメチルアンモニウムクロリド(DODAC)、N-(2,3ジオレイルオキシ)プロピル)-N,N,Nトリメチルアンモニウムクロリド(DOTMA)、N,NジステアリルN,N-ジメチルアンモニウムブロミド(DDAB)、N-(2,3ジオレオイルオキシ)プロピル)-N,N,N-トリメチルアムントニウムクロリド(DODAP)、N-(1,2-ジミリスチルオキシプロパ-3-イル)-N,N-ジメチル-N-ヒドムキシエチルアンモニウムブロミド(DMRIE)、1,2ジオレオイル-sn-3-ホスホエタノールアミン(DOPE)、N-(1-(2,3ジオレイルオキシ)プロピル)N-(2-(スペルミンカルボキサミド)エチル)-N,N-ジメチルアンモニウムトリフルオロアセタート(DOSPA)、ジオクムデシルアミドグリシルカルボキシスペルミン(DOGS)、1,2-ジオレオイル-3-ジメチルアンモニウム-プロパン(DODAP)、DMDMA、1,2-ジリノレイルオキシ-N,N-ジメチルアミノプロパン(DLinDMA)、4-(2,2-ジオクタ-9,12-ジエニル-[1,3]ジオキソラン-4-イルメチル)-ジメチルアミン、DLin-K-C2-DMA、DLin-M-C3-DMA、2-{4-[(3β)-コレスタ-5-エン-3-イルオキシ]ブトキシ}-N,N-ジメチル-3-[(9Z,12Z)-オクタデカ-9,12-ジエニルオキシル]プロパン-1-アミン)(CLinDMA)、MC4、O-アルキルエチルホスホコリン、ジドデシルジメチルアンモニウムブロミド(DDAB)、N-(4-カルボキシベンジル)-N,N-ジメチル-2,3-ビス(オレオイルオキシ)プロパン-1-アミニウム(DOBAQ)、又はこれらの任意の組合せの少なくとも1つを含む、請求項1~24のいずれか一項に記載の送達ビヒクル。
- ジアシルホスファチジルコリン、ジアシルホスファチジルエバノールアミン、セラミド、スフィンゴミエリン、セファリン、セレブロシド、ジアシルグリセロール、又はこれらの任意の組合せの少なくとも1つを含む、請求項1~25のいずれか一項に記載の送達ビヒクル。
- ホスファチジルグリセロール、カルジオリピン、ジアシルホスファチジルセリン、ジアシルホスファチジン酸、N-ドデカノイルホスファチジルエタノールアミン、N-スクシニルホスファチジルエタノールアミン、N-グルタリルホスファチジルエタノールアミン、リジルホスファチジルグリセロール、パルミトイルオレイオルホスファチジルグリエロール(POPG)、又はこれらの任意の組合せの少なくとも1つを含む、請求項1~26のいずれか一項に記載の送達ビヒクル。
- ジステアロイルホスファチジルコリン(DSPC)、ホスファチジルコリン1,2-ジミリストイル-sn-グリセロ-3-ホスホコリン(DMPC)、1,2-ジステアロイル-sn-グリセロ-3-ホスホ-L-セリン(DSPS)、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(OPEC)、ジオレオイルホスバチジルグリセロール(DOPG)、ジパフニ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)、パルミトイルオルミル-ホスファチジルエタノールアミン(POPE)及びジオレオイル-ホスファチジルエタノールアミン4-(4-マレイミドメチル)シエロヘキサン-1-カルボキシラート(DOPE-teal)、ジパフニ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バノールアミン(DMPE)、ジステアロイル-ホスファチジルエタノールアミン(DSPE)、16-O-モノメチルPE、16-OジメチルPE、18-1-トランスPE、1-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(SOPS)、1,2-ジエライドイル-sn-グリセロ-3-ホホエタノールアミン(transDOPE)、又はこれらの任意の組合せの少なくとも1つを含む、請求項1~27のいずれか一項に記載の送達ビヒクル。
- 少なくともDSPC又はDMPCを含む、請求項28に記載の送達ビヒクル。
- コンジュゲートされた脂質をさらに含み、前記コンジュゲートされた脂質は、安定化成分にコンジュゲートされた脂質を含む、請求項1~29のいずれか一項に記載の送達ビヒクル。
- 前記安定化成分は親水性ポリマーを含む、請求項30に記載の送達ビヒクル。
- 前記親水性ポリマーは、ポリエチレングリコール、ポリ(2-アルキル-2-オキサゾリン)、ポリビニルアルコール、又はこれらの任意の組合せを含む、請求項31に記載の送達ビヒクル。
- 前記親水性ポリマーが約50kDa~約500kDaの分子量を有する、請求項32に記載の送達ビヒクル。
- 前記親水性ポリマーはポリエチレングリコール(PEG)を含み、前記コンジュゲートされた脂質は、ペグ化された脂質を含む、請求項32又は33に記載の送達ビヒクル。
- 前記ペグ化された脂質は、DSPE-PEG、DSG-PEG、DMG-PEG、又はDPPE-PEGを含む、請求項34に記載の送達ビヒクル。
- 前記ペグ化された脂質はDSPE-PEG又はDMG-PEGを含む、請求項35に記載の送達ビヒクル。
- 前記コンジュゲートされた脂質の濃度は25モル%未満である、請求項30~36のいずれか一項に記載の送達ビヒクル。
- 前記コンジュゲートされた脂質の濃度は5モル%未満である、請求項30~36のいずれか一項に記載の送達ビヒクル。
- 前記コンジュゲートされた脂質の濃度は約0.5モル%~約20モル%である、請求項30~36のいずれか一項に記載の送達ビヒクル。
- 前記非カチオン性脂質を含み、前記非カチオン性脂質の濃度は約5モル%~約75モル%である、請求項5~39のいずれか一項に記載の送達ビヒクル。
- 前記脂質ナノ粒子は、正又は中性に近い正味電荷を有する、請求項1~40のいずれか一項に記載の送達ビヒクル。
- コレステロールをさらに含む、請求項1~41のいずれか一項に記載の送達ビヒクル。
- カーゴ及びナノ粒子を含む送達ビヒクルであって、前記ナノ粒子は、約5.5~8.0のpHで正電荷を帯びている第1の部位、及び約5.5~8.0のpHで負電荷を帯びている第2の部位を含み、前記第1及び第2の部位は、前記正電荷及び負電荷が散在しないように分離されており、前記ナノ粒子は、粘液バリアを通過して上皮細胞に到達することが可能である、送達ビヒクル。
- 上皮細胞への到達は、前記送達ビヒクルが細胞表面から20ミクロン以内に接近すること、上皮細胞表面に結合すること、あるいは上皮細胞によって吸収されることを含む、請求項43に記載の送達ビヒクル。
- 前記ナノ粒子は、脂質、ポリマー、又はそれらの組合せを含む、請求項43又は44に記載の送達ビヒクル。
- 前記第1の部位は第1の相に含まれ、前記第2の部位は第2の相に含まれ、前記第1の相と前記第2の相は互いに物理的に分離されている、請求項43~45のいずれか一項に記載の送達ビヒクル。
- 前記第1の相が液体である、請求項46に記載の送達ビヒクル。
- 前記第2の相がゲルである、請求項47に記載の送達ビヒクル。
- 前記第1の相がゲルである、請求項46に記載の送達ビヒクル。
- 前記第2の相が液体である、請求項49に記載の送達ビヒクル。
- 安定性成分をさらに含む、請求項43~50のいずれか一項に記載の送達ビヒクル。
- 前記安定性成分はポリエチレングリコール(PEG)である、請求項51に記載の送達ビヒクル。
- 前記第1の部位は、不飽和脂質又は短尾部脂質を含む、請求項47に記載の送達ビヒクル。
- 前記不飽和脂質は、カチオン性脂質又はイオン化可能なカチオン性脂質を含む、請求項53に記載の送達ビヒクル。
- 前記カチオン性脂質は、多価カチオン性脂質又は一価カチオン性脂質を含む、請求項54に記載の送達ビヒクル。
- 前記カチオン性脂質は、N1-[2-((1S)-1-[(3-アミノプロピル)アミノ]-4-[ジ(3-アミノ-プロピル)アミノ]ブチルカルボキサミド)エチル]-3,4-ジ[オレイルオキシ]-ベンズアミド(MVL5)、1,2-ジオレオイル-3-トリメチルアンモニウムプロパン(DOTAP)、N4-コレステリル-スペルミンHCl(GL67)、これらのいずれかの塩、及びこれらの任意の組合せからなる群から選択される、請求項55に記載の送達ビヒクル。
- 前記第1の相中の1つ以上の脂質はペグ化されている、請求項56に記載の送達ビヒクル。
- 前記第1の部位は、1,2-ジオレイルオキシ-3-(ジメチルアミノ)プロパン(DODMA)、6Z,9Z,28Z,31Z)-ヘプタトリアコンタ-6,9,28,31-テトラエン-19-イル3-(ジメチルアミノ)プロパノアート(MC2)、又はこれらの任意の組合せの少なくとも1つをさらに含む、請求項43~57のいずれか一項に記載の送達ビヒクル。
- 前記第2の部位は、1,2-ジステアロイル-sn-グリセロ-3-ホスホ-L-セリン(DSPS)、1,2-ジパルミトイル-sn-グリセロ-3-ホスホ-L-セリン(DPPS)、デポ酢酸メドロキシプロゲステロン(DMPA)、ジフェニルホスホリルアジド(DPPA)、1,2-ジステアロイル-sn-グリセロ-3-ホスファチジン酸ナトリウム(DSPA)、1,2-ジパルミトイルホスファチジルグリセロールジパルミトイルホスファチジルグリセロール(DPPG)、又は2,4-ジアセチルフロログルシノール(DAPG)の少なくとも1つを含む、請求項43~58のいずれか一項に記載の送達ビヒクル。
- 前記第2の部位が、2-ジステアロイル-sn-グリセロ-3-ホスホコリン(DSPC)、1,2-ビス(ジメチルホスフィノ)エタン(DMPE)、1,2-ビス(ジフェニルホスフィノ)エタン(DPPE)、1,2-ジステアロイルホスファチジルエタノールアミン(DSPE)、ジパルミトイルホスファチジルコリン(DPPC)、1,2-ジアラキドイル-sn-グリセロ-3-ホスホコリン20:0 PC(DAPC)、又は1,2-ジラジル-3-ホスファチジルエタノールアミン20:0 PE(DAPE)の少なくとも1つをさらに含む、請求項59に記載の送達ビヒクル。
- 前記第2の部位が、デオキシコール酸塩、及び2-ジステアロイル-sn-グリセロ-3-ホスホコリン(DSPC)、1,2-ビス(ジメチルホスフィノ)エタン(DMPE)、1,2-ビス(ジフェニルホスフィノ)エタン(DPPE)、1,2-ジステアロイルホスファチジルエタノールアミン(DSPE)、ジパルミトイルホスファチジルコリン(DPPC)、1,2-ジアラキドイル-sn-グリセロ-3-ホスホコリン20:0 PC(DAPC)、又は1,2-ジラジル-3-ホスファチジルエタノールアミン20:0 PE(DAPE)の少なくとも1つを含む、請求項43~58のいずれか一項に記載の送達ビヒクル。
- 前記第1の相は37℃未満の転移温度を有し、前記第2の相は37℃超の転移温度を有する、請求項47に記載の送達ビヒクル。
- 前記第1の相は37℃超の転移温度を有し、前記第2の相は37℃未満の転移温度を有する、請求項49に記載の送達ビヒクル。
- 37℃未満の転移温度を有する前記相は、DODMA、MVL5、MC2、カチオン性脂質、又はイオン化可能なカチオン性脂質を含む、請求項62又は請求項63に記載の送達ビヒクル。
- 37℃超の転移温度を有する前記相はDSPCを含む、請求項62又は請求項63に記載の送達ビヒクル。
- pH7.4における前記第2の部位中のアニオン性電荷に対する前記第1の部位中のカチオン性電荷の比は、約0.25~約3.0である、請求項43~65のいずれか一項に記載の送達ビヒクル。
- 前記比は約0.75~約1.25である、請求項66に記載の送達ビヒクル。
- 前記第1の相は、MVL5及びイオン化可能なカチオン性脂質を含む、請求項66又は67に記載の送達ビヒクル。
- 前記イオン化可能なカチオン性脂質が、DODMA、MC2、MC3、及びKC2からなる群から選択される、請求項68に記載の送達ビヒクル。
- 前記イオン化可能なカチオン性脂質はDODMA又はMC2であり、前記送達ビヒクル中のMVL5:イオン化可能なカチオン性脂質のモル%比は、約6.25%:18.75%、12.5%:12.5%、又は18.75%:6.25%である、請求項69に記載の送達ビヒクル。
- 前記送達ビヒクル中のMVL5:イオン化可能なカチオン性脂質の前記比は約12.5%:12.5%である、請求項70に記載の送達ビヒクル。
- 前記第2の相はデオキシコール酸塩を含む、請求項61~69のいずれか一項に記載の送達ビヒクル。
- 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(DMG-PEG)、又はその塩をさらに含む、請求項72に記載の送達ビヒクル。
- DMPE-PEG又はその塩をさらに含む、請求項72に記載の送達ビヒクル。
- 前記第1の部位はカチオン性脂質を含み、前記第2の部位はアニオン性化合物を含む、請求項43に記載の送達ビヒクル。
- 前記カチオン性脂質はMVL5である、請求項75に記載の送達ビヒクル。
- 前記アニオン性化合物は胆汁酸塩を含む、請求項75又は請求項76に記載の送達ビヒクル。
- 前記胆汁酸塩は、コール酸、コール酸塩、デオキシコール酸、デオキシコール酸塩、ヒオデオキシコール酸、ヒオデオキシコール酸塩、グリココール酸、グリココール酸塩、タウロコール酸、タウロコール酸塩、ケノデオキシコール酸、ケノデオキシコール酸塩、イソリトコール酸、イソリトコール酸塩、リトコール酸、及びリトコール酸塩からなる群から選択される、請求項1~32又は77のいずれか一項に記載の送達ビヒクル。
- 前記胆汁酸塩は、リトコール酸塩、デオキシコール酸塩、及びイソリトコール酸塩からなる群から選択される、請求項78に記載の送達ビヒクル。
- 前記胆汁酸塩はデオキシコール酸塩である、請求項78に記載の送達ビヒクル。
- 前記胆汁酸塩はイソリトコール酸塩である、請求項78に記載の送達ビヒクル。
- 前記胆汁酸塩は約10モル%~約80モル%の濃度である、請求項1~42又は78~81のいずれか一項に記載の送達ビヒクル。
- 前記カーゴは、前記脂質ナノ粒子により少なくとも部分的に取り囲まれている、請求項1~82のいずれか一項に記載の送達ビヒクル。
- 前記カーゴは治療剤を含む、請求項1~83のいずれか一項に記載の送達ビヒクル。
- 前記カーゴは、核酸、タンパク質、抗体、ペプチド、小分子、生物製剤、又はこれらの任意の組合せを含む、請求項1~84のいずれか一項に記載の送達ビヒクル。
- 前記カーゴは核酸であり、前記核酸は、DNA、修飾DNA、RNA、修飾RNA、miRNA、siRNA、アンチセンスRNA、又はこれらの任意の組合せを含む、請求項85に記載の送達ビヒクル。
- 細胞内移行のための成分をさらに含む、請求項1~86のいずれか一項に記載の送達ビヒクル。
- 前記成分は、ペプチド、炭水化物、又はリガンドである、請求項87に記載の送達ビヒクル。
- 細胞透過性ペプチド、リガンド、粘液透過性ポリマー、粘液透過性ペプチド、非粘液付着性細胞透過性ペプチド、又はこれらの任意の組合せをさらに含む、請求項1~88のいずれか一項に記載の送達ビヒクル。
- 請求項1~89のいずれか一項に記載の送達ビヒクルを含む医薬組成物。
- 消化管にカーゴを送達する方法であって、請求項1~89のいずれか一項に記載の送達ビヒクル又は請求項90に記載の医薬組成物を投与することを含み、前記送達ビヒクルが消化管に到達し、前記送達ビヒクルが前記消化管中に存在する胆汁酸塩から前記カーゴを保護する、方法。
- 送達ビヒクルは粘液バリアを容易に通過する、請求項91に記載の方法。
- 送達ビヒクルは、前記消化管内の上皮細胞に到達することが可能である、請求項91又は請求項92に記載の方法。
- 上皮細胞への到達は、前記送達ビヒクルが細胞表面から20ミクロン以内に接近することを含む、請求項93に記載の方法。
- 前記送達ビヒクルは上皮細胞の表面に接触する、請求項93に記載の方法。
- 前記送達ビヒクルが上皮細胞に接触した後、前記カーゴは上皮細胞によって吸収される、請求項95に記載の方法。
- 前記送達ビヒクル又は医薬組成物は、それを必要とする対象に経口又は非経口的に投与される、請求項91~96のいずれか一項に記載の方法。
- 前記カーゴは、核酸、タンパク質、抗体、ペプチド、小分子、又は生物製剤を含む、請求項91~97のいずれか一項に記載の方法。
- 前記核酸は治療剤をコードし、上皮細胞は前記カーゴを吸収した後に前記治療剤を発現する、請求項98に記載の方法。
- 前記治療剤は前記上皮細胞により分泌される、請求項99に記載の方法。
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