JP2021516684A - サイズが制御された微小胞の調製 - Google Patents
サイズが制御された微小胞の調製 Download PDFInfo
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- JP2021516684A JP2021516684A JP2020545680A JP2020545680A JP2021516684A JP 2021516684 A JP2021516684 A JP 2021516684A JP 2020545680 A JP2020545680 A JP 2020545680A JP 2020545680 A JP2020545680 A JP 2020545680A JP 2021516684 A JP2021516684 A JP 2021516684A
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6925—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a microcapsule, nanocapsule, microbubble or nanobubble
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
−(i)気体流および(ii)微小胞−安定化材料を含む水性液体流を提供するステップ;
−前記気体流および前記液体流を、それぞれの流入チャネルを通して接触ゾーンに向けて方向付けるステップ;
−前記気体流および前記液体流を、接触ゾーンから、校正されたオリフィスを通して方向付けて、前記ガスが充填された微小胞を含む水性懸濁液を得るステップ;および
−前記微小胞を含む前記懸濁液を流出チャネルに向けて方向付けるステップ;
ここで前記気体流は、第1の気体および第2の気体を含み、前記第1の気体は高い水中溶解度を有し、前記第2の気体は低い水中溶解度を有し、前記気体流における前記第2の気体の体積パーセンテージは18%〜2%である。
ガスが充填された微小胞の安定化層の形成に適切な材料(すなわち微小胞−安定化材料)は、当技術分野で知られているものである。これらは、好ましくは、両親媒性材料を含む。本発明の方法での使用に適切な両親媒性材料は、例えば、リン脂質;リゾリン脂質;脂肪酸類、例えば、パルミチン酸、ステアリン酸、アラキドン酸またはオレイン酸;ポリマーを保有する脂質、例えば、キチン、ヒアルロン酸、ポリビニルピロリドンまたはポリエチレングリコール(PEG)、「ペグ化脂質」とも呼ばれる;スルホン化モノ− ジ−、オリゴ−または多糖類を保有する脂質;コレステロール、コレステロール硫酸またはヘミこはく酸コレステロール;ヘミこはく酸トコフェロール;エーテルを含む脂質またはエステル結合脂肪酸;重合脂質;リン酸ジアセチル;リン酸ジセチル;セラミド類;ポリオキシエチレン脂肪酸エステル類(例えば、ポリオキシエチレン脂肪酸ステアリン酸)、ポリオキシエチレン脂肪族アルコール類、ポリオキシエチレン脂肪族アルコールエーテル類、ポリオキシエチル化ソルビタン脂肪酸エステル類、グリセロールポリエチレングリコールリシノール酸、エトキシ化大豆ステロール類、エトキシ化ヒマシ油またはエチレンオキシド(EO)およびプロピレンオキシド(PO)ブロック共重合体;コレステロールグルクロニド、ラノステロールグルクロニド、7−デヒドロコレステロールグルクロニド、エルゴステロールグルクロニド、コレステロールグルコン酸、ラノステロールグルコン酸、またはエルゴステロールグルコン酸を含む、糖酸類のステロールエステル類;ラウリルグルクロニド、ステアロイルグルクロニド、ミリストイルグルクロニド、ラウリルグルコン酸、ミリストイルグルコン酸、またはステアロイルグルコン酸を含む、アルコール類および糖酸類のエステル;スクロースラウリン酸、フルクトースラウリン酸、スクロースパルミチン酸、スクロースステアリン酸、グルクロン酸、グルコン酸またはポリウロン酸を含む、脂肪酸類と糖類のエステル類;サルササポゲニン、スミラゲニン、ヘデラゲニン、オレアノール酸、またはジギトキシゲニンを含む、サポニン類;グリセロールまたは脂肪酸とのグリセロールモノエステル類(グリセロールモノパルミテート、グリセロールモノステアレート、グリセロールモノミリステートまたはグリセロールモノラウレートを含む);n−デシルアルコール、ラウリルアルコール、ミリスチルアルコール、セチルアルコール、またはn−オクタデシルアルコールを含む、長鎖アルコール類;6−(5−コレステン−3β−イルオキシ)−1−チオ−β−D−ガラクトピラノシド;ジガラクトシル−ジグリセリド;6−(5−コレステン−3β−イルオキシ)ヘキシル−6−アミノ−6−デオキシ−1−チオ−β−D−ガラクトピラノシド;6−(5−コレステン−3β−イルオキシ)ヘキシル−6−アミノ−6−デオキシル−1−チオ−β−D−マンノピラノシド;12−(((7’−ジエチルアミノクマリン−3−イル)カルボニル)メチルアミノ)オクタデカン酸;N−[12−(((7’−ジエチルアミノクマリン−3−イル)カルボニル)メチルアミノ)−オクタデカノイル]−2−アミノパルミチン酸;N−スクシニルジオレイルホスファチジルエタノールアミン;1,2−ジオレイル−sn−グリセロール;1,2−ジパルミトイル−sn−3−スクシニルグリセロール;1,3−ジパルミトイル−2−スクシニルグリセロール;1−ヘキサデシル−2−パルミトイルグリセロホスホエタノールアミンまたはパルミトイルホモシステイン;アルキルアミン類またはアルキルアンモニウム塩類、以下を含む、少なくとも1つの(C10−C20)、好ましくは(C14−C18)、アルキル鎖、例えば、N−ステアリルアミン、N,N’−ジステアリルアミン、N−ヘキサデシルアミン、N,N’−ジヘキサデシルアミン、N−ステアリルアンモニウム塩化物、N,N’−ジステアリルアンモニウム塩化物、N−ヘキサデシルアンモニウム塩化物、N,N’−ジヘキサデシルアンモニウム塩化物、ジメチルジオクタデシルアンモニウム臭化物(DDAB)、ヘキサデシルトリメチルアンモニウム臭化物(CTAB);第3級または第4級アンモニウム塩類、以下を含む、1つまたは好ましくは2つの(C10−C20)、好ましくは(C14−C18)、アシル鎖((C3−C6)アルキレン橋を通してN原子に連結される)、例えば、1,2−ジステアロイル−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−オレオイル−3−トリメチルアンモニウム−プロパン(DOTAP)、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);およびそれらの混合物または組み合わせを含む。
本発明の方法に従って校正されたガスが充填された微小胞を調製するための水性液体流は、例えば5.0〜20mg/mL、好ましくは7.5〜15mg/mLの濃度で、水性担体中に分散された両親媒性材料(上記に定義)を含む。
本発明の方法に従って校正された微小胞を調製するための気体流は、上記に例示されたガス状の化合物の混合物を、上記に例示されたそれぞれの体積比で含む。
本発明の方法に従って調製される微小胞は、特に超音波および磁気共鳴を含む、様々な診断および/または治療的技術において用いられ得る。
ガスが充填された微小胞の調製
市販のチップホルダー(Dolomite microfluidics、パートナンバー:3000024、3000109、3000021)内に取り付けられて、チップから気体および液体供給チューブ(Peek Upchurch,1/16インチ O.D,150μm I.D.)への漏れを防いだ接続を可能にする、市販のマイクロ流体フローフォーカシング装置(Dolomite microfluidics,小液滴チップ、14μmエッチング深さ、パートナンバー3200136)を用いて微小胞を合成した。微小胞形成チャネルは、17μmの幅および135μmの長さを有した。全体的なチャネル深さは14μmであった。チップおよびそのホルダーを、20倍拡大対物(Olympus,LMPLAN 20x)およびCCDカメラ(Lumenera,LM156M)を備える倒立顕微鏡上に取り付けられた、光学的に透明な温度制御された水浴内に置いた。恒温浴の温度は50℃に設定された(液体流中の両親媒性材料の混合物の転移温度よりもわずかに低い温度に対応する)。
DSPC:DPPE−PEG5000(9:1の各モル比)。混合物に関するTmは、55℃であると実験によって決定された。
圧力耐性およびLSガス濃度の決定
実施例1の調製を、LSガスとしてC4F10でC3F8を置き換えることによって繰り返した。5%C4F10ガスを用いた3回の調製および13%C4F10ガスを用いた2回の調製を、以下の手順に従って、ガスが充填された微小胞の圧力耐性に関して試験した。圧力耐性は、静水過圧の関数として光学的な吸光度の測定から決定される。0mmHg過圧で測定された吸光度の50%に相当する静水過圧(mmHgで表される;1mmHg=133.3パスカル)は、圧力耐性値、すなわちPc50と考えられる。
両親媒性材料の水性分散物の調製
異なる相転移温度(Tm)を有する両親媒性材料の2つの混合物を用いた:
M1:DSPC:DPPA:DPPE−PEG5000(Tm=55℃)
M2:DPPC:DPPA:DPPE−PEG5000(Tm=44℃)
両方とも、8:1:1のモル比。
両親媒性材料(純粋なDPPCまたはDSPC、および、DPPC:DPPA:DPPE−PEG5000またはDSPC:DPPA:DPPE−PEG5000の混合物)の転移温度を、Tzeroアルミニウム坩堝(TA Instruments,New Castle,DE USA)を備える市販の示差走査熱量計DSC−Q2000を用いて決定した。温度および熱の流れを含むシステム校正を、インジウム金属を用いて行なった(融合エンタルピー28.71 J/g±0.5 J/g;融解開始温度156.6℃±0.25℃)。
ガスが充填された微小胞の調製
実施例1に記載したのと同一のマイクロ流体チップを用いて微小胞を合成した。シリンジポンプ(Harvard PHD 4400)を用いて液体並流速度を制御した。ガス(SF6)を、圧力センサー(Omega,DPG1000B−30G)に接続された圧力調整器(Omega,PRG101−25)を用いて圧力制御した。個々の微小胞は、記録された光学画像から自動的に検出されて、Matlabソフトウェア(The Mathworks Inc.,Natick,MA)を用いて、PC上で、オフラインでそれらのサイズを測定した。実施例1とは異なり、2つの異なる液体並流速度を試験して(45μL/分または55μL/分)、フローフォーカシング装置を、滴下レジーム下またはより好ましい噴射レジーム下で、それぞれ運転した。
図9a〜9eは、5〜15mg/mLの範囲の両親媒性材料の濃度で(それぞれ、図9a〜9e)、マイクロ流体チップ(図2に示されるものと同様)を含む異なる温度の恒温浴で、上記のように調製されたDSPC/DPPA/DPPE−PEG5000懸濁液(Tm55℃)の液体並流を用いて得られた結果を示す。四角(■)は、滴下レジーム下で行われた実験を示し、三角(▲)は、より好ましい噴射レジーム下で行われた実験を示す。
微小胞の分散度に対する下流冷却の効果を評価するために、異なる冷却条件を試験した。
Claims (16)
- ガスが充填された微小胞の懸濁液を調製する方法であって、
−(i)気体流および(ii)両親媒性微小胞安定化材料を含む水性液体流を提供するステップ;
−前記気体流および前記液体流を、それぞれの流入チャネルを通して接触ゾーンに向けて方向付けるステップ;
−前記気体流および前記液体流を、接触ゾーンから、校正されたオリフィスを通して方向付けて、前記ガスが充填された微小胞を含む水性懸濁液を得るステップ;および
−前記微小胞を含む前記懸濁液を流出チャネルに向けて方向付けるステップ;
を含み、
ここで前記気体流は、第1の気体および第2の気体を含み、前記第1の気体は高い水中溶解度を有し、前記第2の気体は低い水中溶解度を有する生体適合性フッ素化ガスであり、前記気体流における前記第2の気体の体積パーセンテージは、18%〜2%である、
方法。 - 請求項1に記載の方法であって、
前記気体流における前記第1の気体の体積パーセンテージは、15%以下である、
方法。 - 請求項1に記載の方法であって、
前記気体流における前記第1の気体の体積パーセンテージは、13%以下である、
方法。 - 請求項1から3のいずれかに記載の方法であって、
前記第2の気体の体積パーセンテージは、少なくとも5%である、
方法。 - 請求項1から4のいずれかに記載の方法であって、
前記第1の気体は、0.01よりも高い、水中溶解度(ブンゼン係数「α」として定義される)を有する、
方法。 - 請求項5に記載の方法であって、
前記第1の気体は、0.5よりも高い水中溶解度を有する、
方法。 - 請求項1から6のいずれかに記載の方法であって、
前記第2の気体は、0.008以下の水中溶解度を有する、
方法。 - 請求項7に記載の方法であって、
前記第2の気体は、0.001以下の水中溶解度を有する、
方法。 - 請求項1から8のいずれかに記載の方法であって、
前記第2の気体は、ペルフルオロ化ガスである、
方法。 - 請求項9に記載の方法であって、
前記ペルフルオロ化ガスは、SF6、CF4、C2F6、C3F8、C4F8、C4F10およびそれらの混合物からなる群から選択される、
方法。 - 請求項1から10のいずれかに記載の方法であって、
前記第1の気体は、空気、窒素、二酸化炭素およびそれらの混合物からなる群から選択される、
方法。 - 請求項11に記載の方法であって、
前記気体は、二酸化炭素である、
方法。 - 請求項1から12のいずれかに記載の方法であって、
得られる、ガスが充填された微小胞は、体積で少なくとも45%の、低い水中溶解度を有する気体の最終量を含む、
方法。 - 請求項13に記載の方法であって、
低い水中溶解度を有する気体の前記最終量は、少なくとも60%である、
方法。 - 請求項1から14のいずれかに記載の方法であって、
前記両親媒性微小胞安定化材料は、リン脂質である、
方法。 - 請求項15の方法であって、
前記両親媒性材料は、5.0〜20mg/mLの濃度で水性担体中に分散される、
方法。
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