JP6133883B2 - 薬物送達用の脂質ナノ粒子の生成方法 - Google Patents
薬物送達用の脂質ナノ粒子の生成方法 Download PDFInfo
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- JP6133883B2 JP6133883B2 JP2014540573A JP2014540573A JP6133883B2 JP 6133883 B2 JP6133883 B2 JP 6133883B2 JP 2014540573 A JP2014540573 A JP 2014540573A JP 2014540573 A JP2014540573 A JP 2014540573A JP 6133883 B2 JP6133883 B2 JP 6133883B2
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- lipid
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- 125000000830 polyketide group Chemical group 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 210000001938 protoplast Anatomy 0.000 description 1
- 238000007430 reference method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003290 ribose derivatives Chemical class 0.000 description 1
- OVVGHDNPYGTYIT-BNXXONSGSA-N rutinose Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)O1 OVVGHDNPYGTYIT-BNXXONSGSA-N 0.000 description 1
- 150000003308 rutinuloses Chemical class 0.000 description 1
- 150000003313 saccharo lipids Chemical class 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- SRLOHQKOADWDBV-NRONOFSHSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] 2-(2-methoxyethoxycarbonylamino)ethyl phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCCNC(=O)OCCOC)OC(=O)CCCCCCCCCCCCCCCCC SRLOHQKOADWDBV-NRONOFSHSA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- PZDOWFGHCNHPQD-VNNZMYODSA-N sophorose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O PZDOWFGHCNHPQD-VNNZMYODSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000002693 spinal anesthesia Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000185 sucrose group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000000647 trehalose group Chemical group 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- RULSWEULPANCDV-PIXUTMIVSA-N turanose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](C(=O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O RULSWEULPANCDV-PIXUTMIVSA-N 0.000 description 1
- 230000009452 underexpressoin Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000004017 vitrification Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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Description
本出願は、2011年11月4日に出願された米国仮出願第61/556,124号の利益を主張し、これはその全体が参照によって本明細書に組み込まれる。
本明細書に提供される説明は、例えば核酸、タンパク質、およびペプチドなどの負に荷電した治療用ポリマーを含む、脂質に封入される治療用分子を作製するための方法に関する。本明細書に提供される説明は、脂質に封入された核酸分子を作製するための方法を含む。この方法は、リポソームに封入された治療用分子からなる粒子の大規模製造に特に適している。この方法は、生成された粒子が0.2未満の多分散性指数(PDI)を有する50〜150nmのサイズ分布であるという、予想外で驚くべき結果を提供する。この方法は、エタノールなどの水混和性有機溶媒に溶解した脂質を、水性溶液中に溶解した負に荷電した治療用ポリマーと混合し、有機溶媒を除去することにより、封入するという手段を提供する。脂質および負に荷電した治療用ポリマーの絶対的および相対的な濃度は、小さな粒子を生成するのに十分である。記載の方法により生成された粒子は、0.2未満のPDIの粒子集団を得るために、例えば押出しなどの機械的処理を必要としない。
本明細書の範囲内であるのは、式Iで表されるカチオン性脂質である:
Z=アルキルリンカー、C2〜C4アルキル、
Y=アルキルリンカー、C1〜C6アルキル、
R1およびR2は、各々独立して、C10〜C30アルキル、C10〜C30アルケニル、またはC10〜C30アルキニル、C10〜C30アルキル、C10〜C20アルキル、C12〜C18アルキル、C13〜C17アルキル、C13アルキル、C10〜C30アルケニル、C10〜C20アルケニル、C12〜C18アルケニル、C13〜C17アルケニル、C17アルケニルであり;R3およびR4は、各々独立して、水素、C1〜C6アルキル、または−CH2CH2OH、C1〜C6アルキル、C1〜C3アルキルであり;nは1〜6であり;およびXは、任意の窒素対イオンなどの対イオンであり、この用語は、当技術分野において容易に理解される。好ましい窒素対イオンはハロゲンを含み、塩化物および臭化物が特に好ましい。別の好ましい対イオンは、メシレート(−SO3CH3)である。
本明細書の範囲内であるのは、式II:
Z=アルキルリンカー、C2〜C4アルキル、−CH2SCH2CH2−、
Y=アルキルリンカー、C1〜C6アルキル、
R1およびR2は、各々独立して、C10〜C30アルキル、C10〜C30アルケニル、またはC10〜C30アルキニル、C10〜C30アルキル、C10〜C20アルキル、C12〜C18アルキル、C13〜C17アルキル、C13アルキル、C10〜C30アルケニル、C10〜C20アルケニル、C12〜C18アルケニル、C13〜C17アルケニル、C17アルケニルであり;R3およびR4は、各々独立して、水素、C1〜C6アルキル、または−CH2CH2OH、C1〜C6アルキル、C1〜C3アルキルである;
で表されるイオン化可能カチオン性脂質である。
中性脂質の例としては、限定はされないが、リン脂質、アミノ脂質、およびスフィンゴ脂質が挙げられる。中性脂質は、両親媒性脂質を含む。リン脂質の代表例としては、限定はされないが以下が挙げられる:ホスファチジルコリン、ホスファチジルエタノールアミン、ホスファチジルセリン、ホスファチジルイノシトール、ホスファチジン酸、パルミトイルオレオイルホスファチジルコリン、リゾホスファチジルコリン、リゾホスファチジルエタノールアミン、ジパルミトイルホスファチジルコリン、ジオレオイルホスファチジルコリン、ジステアロイルホスファチジルコリン、またはジリノレオイルホスファチジルコリン。リンを欠いている他の化合物、例えばスフィンゴ脂質、スフィンゴ糖脂質ファミリー、ジアシルグリセロールおよび3−アシルオキシ酸なども、両親媒性脂質として指定されたグループに含まれる。さらに、上記の両親媒性脂質は、トリグリセリドおよびステロールなどの他の脂質と混合することができる。
二重層安定化成分は、ポリエチレングリコール(「PEG」)が、ホスファチジルエタノールアミンなどの脂質頭部基に結合したものである。別の二重層安定化成分は、PEGがセラミドに結合したものである。PEGはホスファチジルエタノールアミンあるいはセラミドに、当業者に知られており使用される標準的なカップリング反応を用いてに結合することができる。さらに、予備形成されたPEG−ホスファチジルエタノールアミン結合体(「PEG−PE」)も市販されている。
ステロイドには、コレスタン(例えば、コレステロール)、コランおよび胆汁酸(例えば、ケノデオキシコラートおよびコラート)、エルゴステロール、ラノステロール、コルチコステロイド(例えば、グルココルチコイド)、プレグナン(例えば、プロゲステロン)、およびフィトステロールが含まれる。これらは、例えばポリエチレングリコールなどの親水性部分との結合体の形態においても、含めることができる。好適なステロイドは、コレステロールである。
標的脂質の例は、式(A)の化合物である:
L−X−R A
式中、
・脂質(L)は、DSPE、DOPE、およびDCからなる群から選択され;
・リンカー(X)は、不在、PEG550、PEG2000、PEG−グルタミン酸(−Glu)、Glu、C6、グリシン、およびGluNH、N1,N19−ビス(3−(2−(2−(3−アミノプロポキシ)エトキシ)エトキシ)プロピル)−4,7,10,13,16−ペンタオキサノナデカン−1,19−ジアミドからなる群から選択され;および
・レチノイド(R)は、トレチノイン、アダパレン、レチノール、4−ヒドロキシ(フェニル)レチンアミド(4−HPR)、レチノイン酸(ビタミンA)、9−(2,6,6−トリメチルシクロヘキス−1−エン−1−イル)ノナン酸、3,7−ジメチル−9−(2,6,6−トリメチルシクロヘキス−1−エン−1−イル)ノナン酸、3,7−ジメチル−9−(2,2,6−トリメチルシクロヘキシル)ノナン酸、および任意の部分的または完全飽和レチノイドまたはその誘導体からなる群から選択される。
R−X−R B
式中、
・リンカー(X)は、N1,N19−ビス(3−(2−(2−(3−アミノプロポキシ)エトキシ)エトキシ)プロピル)−4,7,10,13,16−ペンタオキサノナデカン−1,19−ジアミド(「ビスアミド−PEG」)またはN1,N19−ビス(16,20−ジアミノ−15−オキソ−4,7,10−トリオキサ−14−アザイコシル)−4,7,10,13,16−ペンタオキサノナデカン−1,19−ジアミド(「lys−ビスアミド−PEG−lys」)であり;および
・レチノイド(R)は、トレチノイン、アダパレン、レチノール、4−ヒドロキシ(フェニル)レチンアミド(4−HPR)、およびレチノイン酸(ビタミンA)、9−(2,6,6−トリメチルシクロヘキス−1−エン−1−イル)ノナン酸、3,7−ジメチル−9−(2,6,6−トリメチルシクロヘキス−1−エン−1−イル)ノナン酸、3,7−ジメチル−9−(2,2,6−トリメチルシクロヘキシル)ノナン酸、および任意の部分的または完全飽和レチノイドまたはその誘導体からなる群から選択される。
本説明は、活性剤を有するか有さない脂質粒子を含有する組成物を含み、ここで活性剤が存在する場合、これは脂質粒子と関連している。特定の態様において、活性剤は治療剤である。特定の態様において、活性剤は、脂質粒子の水性内部内に封入された、負に荷電した治療用ポリマーである。他の態様において、活性剤は、脂質粒子の1または2以上の脂質層内に存在する。他の態様において、活性剤は、脂質粒子の脂質表面外部または内部に結合している。
脂質−核酸粒子中に封入されたsiRNAのパーセントで表したsiRNA封入効率(EE)を決定するために、RiboGreenアッセイを次のように利用する。この手順を用いて、溶液中の二本鎖および一本鎖RNAまたはDNAの濃度を決定することができる。
EE=(Triton試料−リポソーム試料)/(Triton試料)
サイズは、形成される粒子のサイズ(直径)を示す。サイズ分布は、Malvern Zetasizer Nano-ZS動的光散乱(DLS)測定器を用いて決定することができる。
リポソームの調製
脂質混合物は、水混和性有機溶媒、好ましくは無水エタノール中に溶解することができる。多くの態様において、有機溶媒は、それが市販されている形態で使用される。
本明細書に記載の方法は、例えばRNA分子などの負に荷電した治療用ポリマーを有する脂質粒子を調製するのに有用である。本明細書に記載の方法において、脂質の混合物を、ポリマーの水性溶液と組み合わせる。ポリマーは、得られた脂質粒子に効率的に封入されている。
本開示は部分的に、再構成された場合に最小量の大きな凝集体を有する、凍結乾燥された医薬組成物に関する。かかる大きな凝集体は、約0.2μmを超える、または約0.5μmを超える、または約1μmを超えるサイズを有する可能性があり、再構成された溶液中に望ましくない場合がある。凝集体サイズは、参照により本明細書に組み入れられる米国薬局方32<788>に示されたものを含む、様々な技術を用いて測定することができる。試験は、光遮蔽粒子計数試験、顕微鏡的粒子計数試験、レーザー回折、および単一粒子光学検知を含むことができる。一態様において、所与の試料中の粒子サイズは、レーザー回折および/または単一粒子光学検知を用いて測定される。動的光散乱(DLS)を用いて粒子サイズを測定してもよいが、この手法はブラウン運動に依存するため、いくつかの大きな粒子を検出できない可能性がある。レーザー回折は、粒子と懸濁媒体の間の屈折率の差に依存する。この手法は、サブミクロンからミリメートル範囲の粒子を検出することができる。大きな粒子の比較的小さい量(例えば、約1〜5重量%)は、ナノ粒子懸濁液中で決定することができる。単一粒子光学センシング(SPOS)は、希薄懸濁液の光遮蔽を用いて、約0.5pmの個々の粒子をカウントする。測定試料の粒子濃度を知ることにより、凝集体の重量パーセントまたは凝集体濃度(粒子数/mL)を算出することができる。
本明細書に開示された脂質粒子は、特に治療薬と関連付けられている場合には、医薬組成物として製剤化してもよく、これは例えば、薬学的に許容し得る希釈剤、賦形剤、または担体、例えば生理食塩水またはリン酸緩衝液などを、投与経路および標準的な医薬の実務に従って選択してさらに含む。当業者によって理解されるように、担体は、以下に説明する投与経路、標的組織の位置、送達される薬物、薬物送達の時間経過などに基づいて選択することができる。
本明細書に記載の脂質粒子は、核酸などの負に荷電した治療用ポリマーを、in vitroまたはin vivoで細胞へ送達するために使用することができる。本発明の脂質粒子および関連する医薬組成物を使用する様々な方法の以下の説明は、核酸−脂質粒子に関連する説明によって例示されるが、これらの方法および組成物は、かかる処置により利益を受けるであろう任意の疾患または障害の処置のための、任意の治療剤の送達用に容易に適合され得ることが、理解される。
本明細書において、用語「貯蔵寿命」は、脂質:RNAナノ粒子がその生物学的活性を失う前に貯蔵することができる期間(定義された条件の下、例えば4℃の緩衝液中で)を指すために使用される。本発明における貯蔵寿命を決定するためにアッセイされる生物学的活性は、脂質:RNAナノ粒子の、静脈内投与後にin vivoで哺乳動物細胞をトランスフェクトする能力である。
本発明はまた、本明細書に記載の脂質:RNAナノ粒子を調製するためのキットを提供する。かかるキットは、上述のように、容易に入手可能な材料および試薬から調製することができる。例えば、かかるキットは、以下の材料のいずれかを1または2以上含み得る:リポソーム、核酸(RNA、DNA、一本鎖または二本鎖)、親水性ポリマー、Fab’断片などの標的部分で誘導体化された親水性ポリマー、および指示書。多種多様なキットおよび成分を、本明細書に従い、キットの意図するユーザーおよびのユーザーの特定のニーズに応じて、調製することができる。例えばキットは、上述したように、複合体を特定の細胞型に標的化するための多数の標的部分のいずれか1つを含むことができる。
実施例
この例は、siRNAおよび脂質濃度の、粒子サイズに対する効果を記載する。
この例は、様々なプロセスパラメータの、RNA−脂質粒子形成に対する効果について記載する。いくつかのパラメータをこの実験の間にスクリーニングしたが、それには、温度、エタノール濃度、緩衝液、脂質:siRNA比、および脂質の溶液を分散させるために用いたノズルタイプを含む。
表6
これらの結果は、本明細書に記載の脂質/核酸粒子を調製するための方法を、Sempleらによる米国特許第6,858,225号に記載の方法(対照方法または対照方法により用いられる対照組成物)と比較した。これらは、例2の組成物に従って、または対照方法を用いて調製した。
例2に記載したプロセスを、永久荷電(HEDC)カチオン性脂質とイオン化可能(S104)カチオン性脂質分子の組み合わせを含む、異なる脂質組成を用いて実施した。HEDC、S104、DOPE、コレステロール、PEG−BML、およびdiVA−PEG750−diVAを、無水エタノールに20:20:30:25:5:2のモル比で溶解した。スケールアップの間、異なるsiRNA分子、異なるバッチ容積、および異なるsiRNA(薬物)/脂質比を評価した。表7は、条件の範囲から得られたナノ粒子を特徴づける結果をまとめたものである。
例2に記載したプロセスを、HEDC、S104、DOPE、コレステロール、PEG−BML、およびdiVA−PEG750−diVAを無水エタノールに20:20:30:25:5:2のモル比で溶解して実施した。スクロースを、本明細書に記載のように、小胞の調製に含めた。異なるバッチ容積を評価し、凍結解凍に供した。表8は、条件の範囲から得られたナノ粒子を特徴づける結果をまとめたものである。
例2に記載のプロセスを、サブマージ注入を用いて小胞を調製することにより修正して実施した。HEDC、S104、DOPE、コレステロール、PEG−BML、およびdiVA−PEG750−diVAを、無水エタノールに20:20:30:25:5:2のモル比で溶解した。表10は、表面添加処理と比較して、サブマージ添加プロセスから得られたナノ粒子を特徴づける結果をまとめたものである。結果は、脂質をサブマージ注入により水相に添加した場合に、平均粒子サイズが実質的に減少するという、驚くべき予想外の結果を示す。
Claims (13)
- siRNA分子を封入した脂質ナノ粒子を調製するための方法であって、次のステップ:
水混和性有機溶媒中に溶解されたカチオン性脂質、ヘルパー脂質、ステロール、およびPEG脂質を含む、脂質の溶液を調製すること;
0.08〜0.8mg/mlの前記siRNA分子およびpH3.5〜6.5の水性緩衝液を含む、第1の水性溶液を調製すること;
前記脂質の溶液を、混合容器内で攪拌されている前記水性溶液中に、25〜45%(v:v)の有機溶媒を含む最終溶液が得られるまで、25〜55℃の温度にて、一定速度で1〜100分かけて注入し、0.06〜0.16(w:w)のsiRNA:脂質比、および1:2.5〜1:1のsiRNA:脂質の電荷比を有する、脂質ナノ粒子を生成すること;ならびに
前記有機溶媒を、中性pHにて第2の水性緩衝溶液に対するダイアフィルトレーションにより、前記混合物から除去すること、
を含む、前記方法。 - 第2の溶液が、多糖類をさらに含む、請求項1に記載の方法。
- 多糖類が、スクロース、トレハロース、マンニトール、ソルビトール、キシリトール、ラクトース、マルトースおよびイヌリンからなる群から選択される、請求項2に記載の方法。
- siRNA分子を封入した脂質ナノ粒子を凍結乾燥するステップをさらに含む、請求項1〜3のいずれか一項に記載の方法。
- 有機溶媒が、エタノールである、請求項1〜4のいずれか一項に記載の方法。
- カチオン性脂質が、脂質の40〜60モルパーセントである、請求項1〜5のいずれか一項に記載の方法。
- カチオン性脂質が、HEDC、HEDODCおよびHE−Et−DODCからなる群から選択される、請求項1〜6のいずれか一項に記載の方法。
- カチオン性脂質が、永久カチオン性脂質および/またはイオン化可能カチオン性脂質を含む、請求項1〜6のいずれか一項に記載の方法。
- 脂質の溶液が、
式(A)の化合物
L−X−R A
式中、
・脂質(L)は、DSPE、DOPE、およびDCからなる群から選択され;
・リンカー(X)は、不在、PEG550、PEG2000、PEG−グルタミン酸(−Glu)、Glu、C6、グリシン、およびGluNH、N1,N19−ビス(3−(2−(2−(3−アミノプロポキシ)エトキシ)エトキシ)プロピル)−4,7,10,13,16−ペンタオキサノナデカン−1,19−ジアミドからなる群から選択され;および
・レチノイド(R)は、トレチノイン、アダパレン、レチノール、4−ヒドロキシ(フェニル)レチンアミド(4−HPR)、レチノイン酸、9−(2,6,6−トリメチルシクロヘキス−1−エン−1−イル)ノナン酸、3,7−ジメチル−9−(2,6,6−トリメチルシクロヘキス−1−エン−1−イル)ノナン酸、3,7−ジメチル−9−(2,2,6−トリメチルシクロヘキシル)ノナン酸、および任意の部分的または完全飽和レチノイドからなる群から選択される、
式(B)の化合物
R−X−R B
式中、
・リンカー(X)は、N1,N19−ビス(3−(2−(2−(3−アミノプロポキシ)エトキシ)エトキシ)プロピル)−4,7,10,13,16−ペンタオキサノナデカン−1,19−ジアミドまたはN1,N19−ビス(16,20−ジアミノ−15−オキソ−4,7,10−トリオキサ−14−アザイコシル)−4,7,10,13,16−ペンタオキサノナデカン−1,19−ジアミドであり;および
・レチノイド(R)は、トレチノイン、アダパレン、レチノール、4−ヒドロキシ(フェニル)レチンアミド(4−HPR)、およびレチノイン酸、9−(2,6,6−トリメチルシクロヘキス−1−エン−1−イル)ノナン酸、3,7−ジメチル−9−(2,6,6−トリメチルシクロヘキス−1−エン−1−イル)ノナン酸、3,7−ジメチル−9−(2,2,6−トリメチルシクロヘキシル)ノナン酸、および任意の部分的または完全飽和レチノイドからなる群から選択される、
葉酸、ビタミンE、ペプチドリガンドおよび/またはモノクローナル抗体
からなる群から選択される化合物をさらに含む、請求項1〜8のいずれか一項に記載の方法。 - 第1の溶液および第2の溶液が、25〜55℃である、請求項1〜9のいずれか一項に記載の方法。
- 第1の緩衝溶液がシトラートを含む、請求項1〜10のいずれか一項に記載の方法。
- 脂質の溶液を、マルチノズルを通して空気−水界面に注入することにより、水性溶液に添加する、請求項1〜11のいずれか一項に記載の方法。
- 脂質の溶液を、サブマージ注入により水性溶液に添加する、請求項1〜12のいずれか一項に記載の方法。
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