JP2017514792A - 超音波前駆体の調製方法 - Google Patents
超音波前駆体の調製方法 Download PDFInfo
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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
- 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
-
- 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
- A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Acoustics & Sound (AREA)
- Physics & Mathematics (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
Abstract
Description
(i)両親媒性の膜形成材料を含む混合物からガスを含む小胞の分散液を形成する工程と、
(ii)ガスを含む小胞の分散液を凍結乾燥する工程と、
(iii)工程(ii)の凍結乾燥生成物を無菌水性液によって再構成して、ガスを含む小胞の水性分散液を形成する工程と、
(iv)工程(i)又は工程(iii)の水性分散液生成物或いは工程(ii)の凍結乾燥生成物を処理して、実質的に凝集体を含まない、ガスを含む小胞の無菌水性分散液を形成する工程と
を含む。
(i)各々のバイアル中のマイクロバブルの最適な収量及び濃度;
(ii)バイアル間の含有量の均一性の制御
である。
第1の態様では、本発明は、スクロース中の、水素化卵ホスファチジルセリンで安定化したペルフルオロブタンのマイクロバブルの凍結乾燥組成物を含む超音波造影剤前駆体の調製方法を提供し、方法は
(i)水溶液中の、水素化卵ホスファチジルセリンで安定化したペルフルオロブタンマイクロバブルの水性懸濁液を提供する工程と、
(ii)マイクロバブルのサイズを2〜5μmの範囲のメジアン径に調整する工程と、
(iii)サイズを調整した工程(ii)の懸濁液を無菌スクロース水溶液で希釈して、5〜20% w/vの最終スクロース濃度を得る工程と、
(iv)工程(iii)の組成物のアリコートをバイアルに計量分配して、充填バイアルを得る工程と、
(v)工程(iv)の計量分配が終了した後、5分未満の保持時間内に、各々の充填バイアルを−40℃〜−70℃の温度に冷却する工程と、
(vi)望ましい数の冷却された充填バイアルが得られるまで、必要に応じて工程(iv)及び(v)を繰り返す工程と、
(vii)工程(v)及び(vi)の冷却された充填バイアルを凍結乾燥する工程と、
(viii)工程(viii)の凍結乾燥バイアルのヘッドスペースガスをペルフルオロブタンでバックフィリングする工程と、
(ix)工程(vii)のバイアルをクロージャーで密封する工程と
を含む。
(i)超音波処理;
(ii)高剪断乳化;
(iii)膜乳化;
(iv)同軸電気流体力学的微粒化(CEHDA);及び
(v)マイクロ流体デバイス;
(vi)インクジェット印刷。
(a)1サイクル以上の浮選及び再懸濁、又は
(b)分画遠心法、又は
(c)粗大細孔によるクロスフロー濾過、又は
(d)フィールドフロー分画。
(i)凍結乾燥の前のマイクロバブルメジアン径;及び
(ii)「保持時間」−これは5分未満、好ましくは3分未満の期間に最小化されるべきである−
が2つとも制御されねばならないことを見出した。
第1の態様の方法は、14〜18μl/mLの範囲のミクロスフェア濃度、及び2.7〜3.5μmの範囲のマイクロバブルのサイズ分布(メジアン径)を提供する。
(a)1サイクル以上の浮選及び再懸濁、又は
(b)分画遠心法、又は
(c)それらの組合せ
によって実施される。
(i)第1の態様の方法を実施して、第1の態様に定義される造影剤前駆体を含むバイアルを得る工程と、
(ii)工程(i)の前駆体のバイアルを再構成するのに適した無菌水溶液の容器を提供して造影剤を得る工程と
を含む。
(i)第1の態様の方法を実施して、第1の態様に定義される造影剤前駆体を含むバイアルを得る工程と、
(ii)工程(i)の前駆体のバイアルを無菌水溶液で再構成する工程と
を含む。
FD:凍結乾燥。
H−EPS:水素化卵ホスファチジルセリン;
ICH:医薬品規制ハーモナイゼーション国際会議;
i.v.:静脈内;
Min:分;
PA:ホスファチジン酸;
PFB:ペルフルオロブタン;
PS:ホスファチジルセリン;
Rpm:毎分回転数;
UoC:内容物の均一性;
WFI:注射水。
凍結乾燥し、27バッチのサイズを調整したPFBマイクロバブルの製造を、ローター・ステーター混合及び浮選の原理(装置及び生産設定だけがわずかに異なるが実施例1及び2に詳述される通り)による、凍結乾燥の前のサイズの調節を用いて実施した。これらのバッチ全てに関して、充填バイアルを凍結乾燥機に装填する前の保持時間は20分までであった。
v=6*10 4 *(2*ρ*g*r 2 )/(9*η)
に基づいて計算した。
Claims (12)
- スクロース中の、水素化卵ホスファチジルセリンで安定化したペルフルオロブタンのマイクロバブルの凍結乾燥組成物を含む超音波造影剤前駆体の調製方法であって、当該方法が、
(i)水溶液中の、水素化卵ホスファチジルセリンで安定化したペルフルオロブタンマイクロバブルの水性懸濁液を提供する工程と、
(ii)マイクロバブルのサイズを2〜5μmの範囲のメジアン径に調整する工程と、
(iii)サイズを調整した工程(ii)の懸濁液を無菌スクロース水溶液で希釈して、5〜20% w/vの最終スクロース濃度を得る工程と、
(iv)工程(iii)の組成物のアリコートをバイアルに計量分配して、充填バイアルを得る工程と、
(v)工程(iv)の計量分配が終了した後、5分未満の保持時間内に、各々の充填バイアルを−40℃〜−70℃の温度に冷却する工程と、
(vi)望ましい数の冷却された充填バイアルが得られるまで、必要に応じて工程(iv)及び(v)を繰り返す工程と、
(vii)工程(v)及び(vi)の冷却された充填バイアルを凍結乾燥する工程と、
(viii)工程(vii)の凍結乾燥バイアルのヘッドスペースガスをペルフルオロブタンでバックフィリングする工程と、
(ix)工程(viii)のバイアルをクロージャーで密封する工程と
を含む、方法。 - 凍結乾燥前駆体組成物が無菌である、請求項1記載の方法。
- 工程(iii)のスクロース濃度が8〜12% w/vである、請求項1又は請求項2記載の方法。
- 工程(ii)のサイズ調整が、
(a)1サイクル以上の浮選及び再懸濁、又は
(b)分画遠心法、又は
(c)それらの組合せ
によって実施される、請求項1乃至請求項3のいずれか1項記載の方法。 - 工程(iii)の後、分配工程(iv)に進む前に、サイズ分布及びマイクロバブル濃度がチェックされる、請求項1乃至請求項4のいずれか1項記載の方法。
- 工程(iv)において、複数のバイアルが平行して計量分配される、請求項1乃至請求項5のいずれか1項記載の方法。
- 工程(v)において、複数の充填バイアルが平行して冷却される、請求項1乃至請求項6のいずれか1項記載の方法。
- 工程(v)の保持時間が3分未満である、請求項1乃至請求項7のいずれか1項記載の方法。
- 工程(v)の保持時間が各充填バイアルについて同じである、請求項1乃至請求項8のいずれか1項記載の方法。
- 無菌水性媒体中、水素化卵ホスファチジルセリンで安定化したペルフルオロブタンのマイクロバブルの懸濁液を含む超音波造影剤の調製のためのキットの調製方法であって、
(i)請求項1乃至請求項9のいずれか1項記載の方法を実施して、請求項1乃至請求項3のいずれか1項記載の造影剤前駆体を含むバイアルを得る工程と、
(ii)工程(i)の前駆体のバイアルを再構成するのに適した無菌水溶液の容器を提供して造影剤を得る工程と
を含む、方法。 - 無菌水溶液が、100μM未満の総濃度の遊離アルミニウム、バリウム、マグネシウム、カルシウム及び亜鉛イオンを含む注射水である、請求項10記載の方法。
- 無菌水性媒体中、水素化卵ホスファチジルセリンで安定化したペルフルオロブタンのマイクロバブルの懸濁液を含む超音波造影剤の調製方法であって、
(i)請求項1乃至請求項9のいずれか1項記載の方法を実施して、請求項1乃至請求項3のいずれか1項記載の造影剤前駆体を含むバイアルを得る工程と、
(ii)工程(i)の前駆体のバイアルを無菌水溶液で再構成する工程と
を含む、方法。
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