JP6305343B2 - 活性薬剤の送達のための分岐アルキルおよびシクロアルキルを末端とする生分解性脂質 - Google Patents
活性薬剤の送達のための分岐アルキルおよびシクロアルキルを末端とする生分解性脂質 Download PDFInfo
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- JP6305343B2 JP6305343B2 JP2014546118A JP2014546118A JP6305343B2 JP 6305343 B2 JP6305343 B2 JP 6305343B2 JP 2014546118 A JP2014546118 A JP 2014546118A JP 2014546118 A JP2014546118 A JP 2014546118A JP 6305343 B2 JP6305343 B2 JP 6305343B2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
R’は存在しないか、水素またはアルキル(例えば、C1〜C4アルキル)であり;
R1およびR2に関しては、
(i)R1およびR2は、各々独立して、任意選択で置換されているアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルキルアルキル、複素環、もしくはR10であるか;
(ii)R1およびR2は、それらが結合している窒素原子と一緒に、任意選択で置換されている複素環式環を形成しているか;または
(iii)R1およびR2のうちの一方は、任意選択で置換されているアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルキルアルキル、もしくは複素環であり、他方は、(a)隣接する窒素原子および(b)窒素原子に隣接する(R)a基と共に、4員〜10員の複素環式環もしくはヘテロアリール(例えば、6員環)を形成しており;
Rの各存在は、独立して、−(CR3R4)−であり;
R3およびR4の各存在は、独立して、水素、OH、アルキル、アルコキシ、−NH2、R10、アルキルアミノ、またはジアルキルアミノであり(1つの好ましい実施形態において、R3およびR4の各存在は、独立して、水素またはC1〜C4アルキルである);
R10の各存在は、独立して、PEG、ならびにポリ(オキサゾリン)、ポリ(エチレンオキシド)、ポリ(ビニルアルコール)、ポリ(グリセロール)、ポリ(N−ビニルピロリドン)、ポリ[N−(2−ヒドロキシプロピル)メタクリルアミド]およびポリ(アミノ酸)をベースとするポリマーから選択され、ここで、
(i)PEGまたはポリマーは、直鎖または分岐であり、(ii)PEGまたはポリマーは、n個のサブユニットが重合したものであり、(iii)nは、10〜200単位の間の数平均重合度であり、そして(iv)ここで、当該式の化合物は、2個以下のR10基(好ましくは1個以下のR10基)を有しており;
Qに向かう破線は存在しないか、または結合であり;
当該Qに向かう破線が存在しない場合は、その時は、Qは存在しないか、もしくは−O−、−NH−、−S−、−C(O)−、−C(O)O−、−OC(O)−、−C(O)N(R4)−、−N(R5)C(O)−、−S−S−、−OC(O)O−、−O−N=C(R5)−、−C(R5)=N−O−、−OC(O)N(R5)−、−N(R5)C(O)N(R5)−、−N(R5)C(O)O−、−C(O)S−、−C(S)O−もしくは−C(R5)=N−O−C(O)−であり;または
当該Qに向かう破線が結合である場合は、その時は、(i)bは0であり、かつ(ii)Qとそれに隣接する第3級炭素(C*)とは5個〜10個の環原子を有する置換もしくは非置換の単環式もしくは二環式の複素環式基を形成しており(例えば、複素環式基中のヘテロ原子は、OおよびS、好ましくはOから選択される);
R5の各存在は、独立して、水素またはアルキルであり;
XおよびYは、各々独立して、−(CR6R7)c−であり;
R6およびR7の各存在は、独立して、水素、OH、アルキル、アルコキシ、−NH2、アルキルアミノ、またはジアルキルアミノであり(1つの好ましい実施形態において、R6およびR7の各存在は、独立して、HまたはC1〜C4アルキルである);
M1およびM2は、各々独立して、生分解性基(例えば、−OC(O)−、−C(O)O−、−SC(O)−、−C(O)S−、−OC(S)−、−C(S)O−、−S−S−、−C(R5)=N−、−N=C(R5)−、−C(R5)=N−O−、−O−N=C(R5)−、−C(O)(NR5)−、−N(R5)C(O)−、−C(S)(NR5)−、−N(R5)C(O)−、−N(R5)C(O)N(R5)−、−OC(O)O−、−OSi(R5)2O−、−C(O)(CR3R4)C(O)O−、または−OC(O)(CR3R4)C(O)−)であり;
aは、1、2、3、4、5または6であり;
bは、0、1、2、または3であり;
cの各存在は、独立して、2〜10(すなわち、2、3、4、5、6、7、8、9、または10)であり;そして
Z1およびZ2は、各々独立して、(i)C3〜C10シクロアルキル、(ii)C3〜C10シクロアルキル(C1〜C6アルキル)、または(iii)
1つの実施形態において、カチオン性脂質は、式Iの化合物である。別の実施形態において、カチオン性脂質は、式IIIの化合物である。以下の開示内容は、式Iの化合物の種々の実施形態である。
−OC(O)−、−C(O)O−、−SC(O)−、−C(O)S−、−OC(S)−、−C(S)O−、−S−S−、−C(R5)=N−、−N=C(R5)−、−C(R5)=N−O−、−O−N=C(R5)−、−C(O)(NR5)−、−N(R5)C(O)−、−C(S)(NR5)−、−N(R5)C(O)−、−N(R5)C(O)N(R5)−、−OC(O)O−、−OSi(R5)2O−、−C(O)(CR3R4)C(O)O−、または−OC(O)(CR3R4)C(O)−
である。
−OC(O)−、−C(O)−O−、−C(R5)=N−、−N=C(R5)−、−C(R5)=N−O−、−O−N=C(R5)−、−O−C(O)O−、−C(O)N(R5)−、−N(R5)C(O)−、−C(O)S−、−SC(O)−、−C(S)O−、−OC(S)−、−OSi(R5)2O−、−C(O)(CR3R4)C(O)O−、または−OC(O)(CR3R4)C(O)−
である。
−C(O)−O−、−OC(O)−、−C(R5)=N−、−C(R5)=N−O−、−O−C(O)O−、−C(O)N(R5)−、−C(O)S−、−C(S)O−、−OSi(R5)2O−、−C(O)(CR3R4)C(O)O−、または−OC(O)(CR3R4)C(O)−
である。
本明細書に記載される脂質粒子および組成物はまた、1種以上の中性脂質を含み得る。中性脂質は、存在する場合、生理的pHにおいて非荷電形態または中性の双性イオン性形態のいずれかで存在する多くの脂質化学種のうちの任意のものであり得る。そのような脂質としては、例えば、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タノールアミン、セラミド、スフィンゴミエリン、ジヒドロスフィンゴミエリン、セファリン、およびセレブロシドが挙げられる。1つの実施形態において、中性脂質成分は、2個のアシル基を有する脂質(例えば、ジアシルホスファチジルコリンおよびジアシルホスファチジルエタノールアミン)である。1つの実施形態において、中性脂質は、C10〜C20の範囲内の炭素鎖長を有する飽和脂肪酸を含む。別の実施形態において、中性脂質は、C10〜C20の範囲内の炭素鎖長を有するモノ不飽和脂肪酸またはジ不飽和脂肪酸を含む。好適な中性脂質としては、DSPC、DPPC、POPC、DOPE、DSPC、およびSMが挙げられるが、これらに限定されない。
さらなる態様において、本発明は、本明細書に記載されるカチオン性脂質のうちの1種以上を含む脂質粒子に関する。1つの実施形態において、脂質粒子は、式I〜VIIの1種以上の化合物を含む。
本明細書に記載される脂質粒子および組成物は、1種以上の抗酸化剤をさらに含み得る。抗酸化剤は、脂質粒子を安定させ、脂質粒子中に存在するカチオン性脂質および/または活性薬剤の劣化を防止、低減および/または阻止する。抗酸化剤は、親水性抗酸化剤、親油性抗酸化剤、金属キレート化剤、一次抗酸化剤、二次抗酸化剤、それらの塩、およびそれらの混合物であり得る。特定の実施形態において、抗酸化剤は、金属キレート化剤(例えば、EDTAまたはその塩)を、単独で、または1種、2種、3種、4種、5種、6種、7種、8種、もしくはそれ以上のさらなる抗酸化剤(例えば、一次抗酸化剤、二次抗酸化剤、または他の金属キレート化剤)と組み合わせて含む。1つの好ましい実施形態において、抗酸化剤は、金属キレート化剤(例えば、EDTAまたはその塩)を1種以上の一次抗酸化剤および/または二次抗酸化剤との混合物として含む。例えば、抗酸化剤は、EDTAまたはその塩と、一次抗酸化剤(例えば、α−トコフェロールまたはその塩)と、二次抗酸化剤(例えば、パルミチン酸アスコルビルまたはその塩)との混合物を含み得る。1つの実施形態において、抗酸化剤は、少なくとも約100mMのシトレートまたはその塩を含む。抗酸化剤の例としては、親水性抗酸化剤、親油性抗酸化剤、およびそれらの混合物が挙げられるが、これらに限定されない。親水性抗酸化剤の非限定的な例としては、キレート化剤(例えば、金属キレート化剤)(例えば、エチレンジアミン四酢酸(EDTA)、シトレート、エチレングリコール四酢酸(EGTA)、1,2−ビス(o−アミノフェノキシ)エタン−N,N,N’,N’−四酢酸(BAPTA)、ジエチレントリアミン五酢酸(DTPA)、2,3−ジメルカプト−1−プロパンスルホン酸(DMPS)、ジメルカプトコハク酸(DMSA)、cc−リポ酸、サリチルアルデヒドイソニコチノイルヒドラゾン(SIH)、ヘキシルチオエチルアミン塩酸塩(HTA)、デスフェリオキサミン、それらの塩、およびそれらの混合物)が挙げられる。さらなる親水性抗酸化剤には、アスコルビン酸、システイン、グルタチオン、ジヒドロリポ酸、2−メルカプトエタンスルホン酸、2−メルカプトベンズイミダゾールスルホン酸、6−ヒドロキシ−2,5,7,8−テトラメチルクロマン−2−カルボン酸、メタ重亜硫酸ナトリウム、それらの塩、およびそれらの混合物が含まれる。親油性抗酸化剤の非限定的な例としては、ビタミンE異性体(例えば、α−、β−、γ−、およびδ−トコフェロールならびにα−、β−、γ−、およびδ−トコトリエノール);ポリフェノール(例えば、2−tert−ブチル−4−メチルフェノール、2−fert−ブチル−5−メチルフェノール、および2−tert−ブチル−6−メチルフェノール);ブチル化ヒドロキシアニソール(BHA)(例えば、2−teri−ブチル−4−ヒドロキシアニソールおよび3−tert−ブチル−4−ヒドロキシアニソール);ブチルヒドロキシトルエン(BHT);tert−ブチルヒドロキノン(TBHQ);パルミチン酸アスコルビル;rc−プロピルガレート;それらの塩;およびそれらの混合物が挙げられる。好適な抗酸化剤およびそのような抗酸化剤を含有する製剤は、参照により本明細書に援用される国際公開第2011/066651号パンフレットに記載されている。
脂質粒子は、特に治療薬剤と関連させる場合、例えば薬学的に受容可能な希釈剤、賦形剤またはキャリア(例えば、生理食塩水またはリン酸緩衝液)をさらに含む、薬学的組成物として製剤化され得る。
カチオン性脂質、それを含有する脂質粒子、ならびにそのカチオン性脂質および/または脂質粒子を含有する薬学的組成物を製造する方法は、例えば、国際公開第2010/054406号パンフレット、同第2010/054401号パンフレット、同第2010/054405号パンフレット、同第2010/054384号パンフレット、同第2010/042877号パンフレット、同第2010/129709号パンフレット、同第2009/086558号パンフレットおよび同第2008/042973号パンフレット、ならびに米国特許出願公開第2004/0142025号明細書、同第2006/0051405号明細書および同第2007/0042031号明細書に記載されており、これらの特許文献の各々は、参照によりその全体が援用される。
本明細書で使用される場合、用語「カチオン性脂質」は、1つまたは2つの脂肪酸鎖または脂肪性脂肪族(fatty aliphatic)鎖と、生理的pHにおいてプロトン化されてカチオン性脂質を形成し得るアミノ酸含有頭部基とを有する脂質を包含する。一部の実施形態において、カチオン性脂質は、「アミノ酸コンジュゲートカチオン性脂質」と称される。
DSPC:ジステアロイルホスファチジルコリン;DPPC:1,2−ジパルミトイル−sn−グリセロ−3−ホスホコリン;POPC:1−パルミトイル−2−オレオイル−sn−ホスファチジルコリン;DOPE:1,2−ジレオイル(dileoyl)−sn−3−ホスホエタノールアミン;PEG−DMGとは、一般に、1,2−ジミリストイル−sn−グリセロール−メトキシポリエチレングリコール(例えば、PEG2000)をいう;TBDPSCl:tert−ブチルクロロジフェニルシラン;DMAP:ジメチルアミノピリジン;NMO:N−メチルモルホリン−N−オキシド;LiHDMS:リチウムビス(トリメチルシリル)アミド;HMPA:ヘキサメチルホスホルアミド;EDC:1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド;DIPEA:ジイソプロピルエチルアミン;DCM:ジクロロメタン;TEA:トリエチルアミン;TBAF:テトラブチルアンモニウムフルオリド。
中間体1の合成:
アセトン(300mL)中の5−ブロモ吉草酸エチル(25g)およびヨウ化ナトリウム(90g)の溶液を、室温で一晩撹拌した。この反応混合物を、水(200mL)で希釈し、ジエチルエーテル(200mL)で抽出した。有機画分を水で洗浄し、無水硫酸マグネシウム上で乾燥させ、濾過し、溶媒を除去して、5−ヨード吉草酸エチル(32g)を得た。
ナトリウムエトキシド(3.6g)を、無水エタノール(30mL)に溶解させた。ジエチルアセトンジカルボキシレート(12g)を添加し、溶液を加熱して還流させた。5−ヨード吉草酸エチル(16g)をゆっくりと添加し、溶液を1時間還流させた。エタノール(30mL)中のナトリウムエトキシド(3.6g)の溶液を添加し、続いて5−ヨード吉草酸エチル(16g)を添加した。溶液を一晩還流させた。この反応混合物を冷却し、水(200mL)で希釈し、ジエチルエーテル(200mL)で抽出した。有機画分を水で洗浄し、溶媒を除去した。残渣を酢酸(30mL)および濃塩酸(60mL)で処理し、次いで一晩還流させた。溶液を冷却し、水で希釈し、ジクロロメタンで抽出した。溶媒を除去し、残渣をアセトンから再結晶化させて、7−オキソ−トリデカン−1,13−二酸を白色粉末(5.9g)として得た。
1H NMR(400MHz,CDCl3)δ:4.08(t,J=6.8Hz,4H),3.42(t様,6.2Hz,2H),3.18(五重線様,5.5Hz,1H),2.51−2.44(m,2H),2.36(s,6H),2.29−2.22(m,2H),1.85(br.水(低磁場(low field)へのシフトは、アミノ基と水との間の相互作用によるものであり得る)),1.67−1.55(m,12H),1.55−1.41(m,8H),1.39−1.21(m,32H),0.89(2組の三重線,12H)。
C57BL/6マウス(Charles River Labs,MA)は、尾静脈注射によって、0.01mL/gの体積で、生理食塩水か、または所望の製剤中のsiRNAかのいずれかを受ける。投与後の様々な時点において、動物をイソフルオラン(isofluorane)吸入によって麻酔し、血液を眼窩後出血によって血清分離器管中に採取する。第VII因子タンパク質の血清レベルを、発色アッセイ(Coaset Factor VII、DiaPharma Group,OH、またはBiophen FVII、Aniara Corporation,OH)を用いて、製造業者のプロトコルに従って、各試料について測定する。標準曲線を、生理食塩水で処理した動物から採取した血清を用いて生成する。肝臓mRNAレベルが評価される実験においては、投与後の様々な時点において、動物を犠牲にし、肝臓を取り出し、液体窒素中で急冷凍する。冷凍した肝組織を、粉砕して粉末にする。組織溶解物を調製し、第VII因子およびアポBの肝臓mRNAレベルを分岐DNAアッセイ(QuantiGene Assay、Panomics,CA)を用いて測定する。
凝固カスケードにおける重要なタンパク質である第VII因子(FVII)は、肝臓(肝細胞)において合成され、血漿中に分泌される。血漿中FVIIレベルは、単純なプレートベースの比色アッセイによって測定され得る。そういうものであるから、FVIIは、肝細胞由来タンパク質のsiRNA媒介性ダウンレギュレーションを測定するため、ならびに核酸脂質粒子およびsiRNA(例えば、表19に示すsiRNA)の血漿濃度および組織分布をモニタリングするための、好都合なモデルである。
粒子を含有するカチオン性脂質を、事前形成小胞法を用いて作製する。カチオン性脂質、DSPC、コレステロールおよびPEG−脂質を、それぞれ40/10/40/10のモル比でエタノールに可溶化する。脂質混合物を、水性緩衝液(50mMクエン酸塩、pH4)に、それぞれ30%(vol/vol)および6.1mg/mLの最終エタノールおよび脂質濃度になるように、混合しながら添加し、押出前に2分間、室温で平衡させる。水和した脂質を、Nicomp分析により測定して70〜90nmの小胞直径が得られるまで、Lipex Extruder(Northern Lipids、Vancouver,BC)を用いて22℃にて、2枚積重ねた80nm細孔径のフィルター(Nuclepore)に通して押出す。これには、一般に、1〜3回の通過を要する。小さな小胞を形成しない一部のカチオン性脂質混合物については、より低いpHの緩衝液(50mMクエン酸塩、pH3)を用いてその脂質混合物を水和させてDSPC頭部基上のホスフェート基をプロトン化することが、安定な70〜90nm小胞を形成するのを助ける。
試験製剤を、以下のインライン混合法を用いて調製した。
一方は脂質を含有しそして他方はsiRNAを含有する、それぞれ異なった別個の原液を調製する。脂質A、DSPC、コレステロールおよびPEG脂質を含有する脂質原液(stock)を、90%エタノールに可溶化させることにより調製する。残りの10%は、低pHクエン酸塩緩衝液である。脂質原液の濃度は、4mg/mLである。このクエン酸塩緩衝液のpHは、使用される融合性脂質(fusogenic lipid)の種類によってpH3〜5の間で変化し得る。siRNAもまた、4mg/mLの濃度でクエン酸塩緩衝液に可溶化させる。小規模用に、5mLの各原液を調製する。
Claims (26)
- 式(I):
R’は存在せず;
R1およびR2は、各々独立して、アルキル、アルケニル、アルキニル、シクロアルキル、またはシクロアルキルアルキルであり;
Rの各存在は、独立して−(CR3R4)−であり;
R3およびR4の各存在は、独立して、水素であり;
Qに向かう破線は存在せず;
Qは、−O−、−NH−、−S−、−C(O)−、−C(O)O−、−OC(O)−、−C(O)N(R4)−、−N(R5)C(O)−、−S−S−、−OC(O)O−、−O−N=C(R5)−、−C(R5)=N−O−、−OC(O)N(R5)−、−N(R5)C(O)N(R5)−、−N(R5)C(O)O−、−C(O)S−、−C(S)O−もしくは−C(R5)=N−O−C(O)−であり;
R5の各存在は、独立して、水素またはアルキルであり;
XおよびYは、各々独立して、−(CR6R7)c−であり;
R6およびR7の各存在は、独立して、水素であり;
M1およびM2は、各々独立して、−OC(O)−、−C(O)O−、−SC(O)−、−C(O)S−、−OC(S)−、−C(S)O−、−S−S−、−C(R5)=N−、−N=C(R5)−、−C(R5)=N−O−、−O−N=C(R5)−、−C(O)(NR5)−、−N(R5)C(O)−、−C(S)(NR5)−、−N(R5)C(O)−、−N(R5)C(O)N(R5)−、−OC(O)O−、−OSi(R5)2O−、−C(O)(CR3R4)C(O)O−、または−OC(O)(CR3R4)C(O)−から選択される生分解性基であり;
aは、1、2、3、4、5または6であり;
bは、0、1、2、または3であり;
cの各存在は、独立して、2〜10であり;そして
Z1およびZ2は、各々独立して、(i)C3〜C10シクロアルキル、(ii)C3〜C10シクロアルキル(C1〜C6アルキル)、または(iii)
化合物またはその塩。 - M1およびM2が、各々独立して、−OC(O)−または−C(O)O−である、請求項1に記載の化合物。
- R1およびR2が、各々アルキルである、請求項1または2に記載の化合物。
- R1およびR2が、各々メチルである、請求項1〜3のいずれか一項に記載の化合物。
- aが3であり、かつbが0である、請求項1〜4のいずれか一項に記載の化合物。
- XおよびYが、各々独立して、−(CH2)c−である、請求項1〜5のいずれか一項に記載の化合物。
- Z1およびZ2が、各々独立して、C3〜C10シクロアルキルである、請求項1〜6のいずれか一項に記載の化合物。
- Z1およびZ2が、各々シクロへキシルまたはデカヒドロナフタレニルである、請求項7に記載の化合物。
- 請求項1〜11のいずれか一項に記載の化合物の薬学的に受容可能な塩。
- 中性脂質と、凝集を低減できる脂質と、請求項1〜11のいずれか一項に記載の化合物とを含む、脂質粒子であって、前記凝集を低減できる脂質が、PEG修飾脂質、モノシアロガングリオシドGm1、またはポリアミドオリゴマーから選択される、脂質粒子。
- 前記中性脂質がDSPC、DPPC、POPC、DOPE、またはSMから選択され、前記凝集を低減できる脂質がPEG脂質であり、そして前記脂質粒子がステロールをさらに含む、請求項13に記載の脂質粒子。
- 前記化合物が20%および60%のモル百分率で存在し、前記中性脂質が5%〜25%のモル百分率で存在し、前記ステロールが25%〜55%のモル百分率で存在し、そして前記PEG脂質がPEG−DMA、PEG−DMG、またはそれらの組み合わせでありかつ0.5%〜15%のモル百分率で存在する、請求項13または14に記載の脂質粒子。
- 活性薬剤をさらに含む、請求項13〜15のいずれか一項に記載の脂質粒子。
- 前記活性薬剤が、プラスミド、免疫刺激性オリゴヌクレオチド、siRNA、アンチセンスオリゴヌクレオチド、マイクロRNA、アンタゴmir、アプタマー、およびリボザイムから選択される核酸である、請求項16に記載の脂質粒子。
- 前記脂質粒子が、3時間未満のインビボ半減期(t1/2)を有する、請求項13〜17のいずれか一項に記載の脂質粒子。
- 請求項13〜18のいずれか一項に記載の脂質粒子と、薬学的に受容可能なキャリアとを含む、薬学的組成物。
- 細胞における標的遺伝子の発現を調節するための組成物であって、請求項16に記載の脂質粒子を含む、組成物。
- 前記活性薬剤が、siRNAである核酸である、請求項20に記載の組成物。
- ポリペプチドの過剰発現により特徴付けられる疾患または障害を処置するための組成物であって、請求項16に記載の脂質粒子を含み、前記活性薬剤は、siRNA、マイクロRNA、およびアンチセンスオリゴヌクレオチドからなる群から選択される核酸であり、かつ前記siRNA、マイクロRNA、またはアンチセンスオリゴヌクレオチドは、前記ポリペプチドをコードするポリヌクレオチドまたはその相補体に特異的に結合するポリヌクレオチドを含む、組成物。
- ポリペプチドの過少発現により特徴付けられる疾患または障害を処置するための組成物であって、請求項16に記載の脂質粒子を含み、前記活性薬剤は、前記ポリペプチドまたはその機能的変異体もしくは断片をコードするプラスミドである、組成物。
- 免疫応答を誘導するための組成物であって、請求項16に記載の脂質粒子を含み、前記活性薬剤は、免疫刺激性オリゴヌクレオチドである、組成物。
- 前記標的遺伝子が、第VII因子、Eg5、PCSK9、TPX2、アポB、SAA、TTR、RSV、PDGFβ遺伝子、Erb−B遺伝子、Src遺伝子、CRK遺伝子、GRB2遺伝子、RAS遺伝子、MEKK遺伝子、JNK遺伝子、RAF遺伝子、Erk1/2遺伝子、PCNA(p21)遺伝子、MYB遺伝子、JUN遺伝子、FOS遺伝子、BCL−2遺伝子、サイクリンD遺伝子、VEGF遺伝子、EGFR遺伝子、サイクリンA遺伝子、サイクリンE遺伝子、WNT−1遺伝子、β−カテニン遺伝子、c−MET遺伝子、PKC遺伝子、NFKB遺伝子、STAT3遺伝子、サーバイビン遺伝子、Her2/Neu遺伝子、SORT1遺伝子、XBP1遺伝子、トポイソメラーゼI遺伝子、トポイソメラーゼIIα遺伝子、p73遺伝子、p21(WAF1/CIP1)遺伝子、p27(KIP1)遺伝子、PPM1D遺伝子、RAS遺伝子、カベオリンI遺伝子、MIB I遺伝子、MTAI遺伝子、M68遺伝子、癌抑制遺伝子、およびp53癌抑制遺伝子からなる群から選択される、請求項20に記載の組成物。
- 前記標的遺伝子が、1つ以上の変異を含む、請求項20に記載の組成物。
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US20130123338A1 (en) * | 2010-05-12 | 2013-05-16 | Protiva Biotherapeutics, Inc. | Novel cationic lipids and methods of use thereof |
DK2575764T3 (en) * | 2010-06-03 | 2017-08-07 | Alnylam Pharmaceuticals Inc | BIODEGRADABLE LIPIDS FOR THE ACTIVATION OF ACTIVE AGENTS |
WO2013086322A1 (en) * | 2011-12-07 | 2013-06-13 | Alnylam Pharmaceuticals, Inc. | Branched alkyl and cycloalkyl terminated biodegradable lipids for the delivery of active agents |
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JP2018087250A (ja) * | 2011-12-07 | 2018-06-07 | アルニラム・ファーマシューティカルズ・インコーポレーテッド | 活性薬剤の送達のための分岐アルキルおよびシクロアルキルを末端とする生分解性脂質 |
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JP2015505838A (ja) | 2015-02-26 |
WO2013086322A1 (en) | 2013-06-13 |
EP2788316A1 (en) | 2014-10-15 |
US20150005363A1 (en) | 2015-01-01 |
AU2012347605A1 (en) | 2014-07-10 |
JP2023010780A (ja) | 2023-01-20 |
CA2856737A1 (en) | 2013-06-13 |
JP2018087250A (ja) | 2018-06-07 |
CA2856737C (en) | 2023-09-26 |
EP2788316B1 (en) | 2019-04-24 |
AU2012347605B2 (en) | 2017-09-21 |
CA3170051A1 (en) | 2013-06-13 |
US9463247B2 (en) | 2016-10-11 |
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