JP2016006083A - 噴霧乾燥した血液製剤とその製造方法 - Google Patents
噴霧乾燥した血液製剤とその製造方法 Download PDFInfo
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Abstract
Description
本発明は、従来の凍結乾燥(フリーズドライ)の代替として噴霧乾燥を用いて乾燥した血液製剤の調製方法と、この方法により製造した生成物に関する。本発明を用いると乾燥生成物の回収率を上げることができる。最終生成物を水と混合するときに再構成率が上昇するだけでなく、天然の血漿の少なくとも3倍の濃度を示す。
噴霧乾燥は、流動ガスの流れの中で溶液を噴霧して急速溶媒蒸発(すなわち、脱水)させる技術である。出来上がったものは、残留溶質から構成される微粒子のサブ秒の時間スケールでの形成物である。材料4、食品5、及び製薬6,7産業における産業プロセスとして、数十年間噴霧乾燥を用いている(以前の報告については、Bergsoe8などを参照されたい)。最近では、吸入剤9、高度な担体治療用の微細構造10−12の製剤、及び新しい種類の微細材料13−15用の微粒子として、噴霧乾燥はタンパク質治療の調製を容易にしている。究極の微粒子のサイズと組成を決定する動的、相移転、物質移動、熱伝達、及び他の物理的なプロセスは、良く理解されており(最近の報告については、Vehring16などを参照されたい)、材料科学研究において噴霧乾燥の研究は、非常に盛んな分野である。この研究の主要部からの重要な知見は、水溶液系においては揮発プロセス中で気化熱が粒子の温度を下げるということである。従って、タンパク質活性を維持するために、タンパク質の熱変性を最小限に抑えることができる。
噴霧乾燥した血漿の濃度。溶媒洗剤で処理したヒトのプール血漿(Kedrion S.p.A.,Barga,イタリア)と10種類の動物中のブタの血漿(チャペルヒルのノースカロライナ大学、フランシス・オーエン血液調査研究所より寄贈された)を、さまざまな装置のパラメータを実行して噴霧乾燥し、又は標準的な凍結乾燥サイクルで凍結乾燥して、さまざまなサイズの脱水微粒子を得ることができる。次いで、さまざまな量の低濃度のグリシンを含むpH2.4の滅菌水でこの生成物を再水和して、脱水プロセス間のプロトンの損失を補填し、比較して濃度の上限を定めた。実験の詳細は以下の通りである。
以下の一連の実験は、血漿を噴霧乾燥して、脱水した微粒子を得ることができ、天然凝固因子レベルと凝固パラメータで血漿を当初の容量に再水和できることを示す。溶媒洗剤でプールした血漿を標準的な噴霧乾燥(Butchi社のB−270を用いて120℃で1時間あたり415リットルのN2)して、図1に示す生成物を得た。得られた微粒子のくぼみのある球状の形状は、他のタンパク質を噴霧乾燥したときに得られる形に類似し、これは水の除去及び濃度の初期運動の結果として、タンパク質表面シェルが形成されることを示している(例えば、Vehring16を参照されたい)。しかし、この形状は波状表面のテクスチャを示す凍結乾燥した血漿に対して独特である。
この実施例の目的は、全ての成分(血小板粒子、緩衝塩、充填剤(ヒト血清アルブミンなど))の濃度が、噴霧乾燥器へ入った懸濁液と同じになるように、噴霧乾燥した誘導化血小板(商標名STASIXで販売され、ノースカロナイナ州のEntegrion社より入手できる)を再水和することである。三段階でこれを達成した。
1.噴霧乾燥前の光学密度を測定して、基準A280値を得る。
a)液体の噴霧乾燥前のサンプルを解凍して、デスクトップの微量遠心管を5に設定し二分間遠心して遠心分離する。上澄みを保持する。
b)この上澄み1/10をクエン酸生理食塩水へ三倍に希釈して、ナノドロップ分光計でA280値を計測する。
a)マイクロチューブ中の20乃至50mgの粒子部分をいくつか(だいたい4つ)に検量する。質量を記録する。一のチューブを蒸留水で10%(w/v)の懸濁液に再水和する。更に分析用に残りのチューブを保存する。
b)粒子を上記のように遠心分離して、上澄みを保持する。
c)各再水和サンプルの上澄み1/10をクエン酸食塩水に三倍に希釈して、A280値を測定する。
a)希釈係数(1/10)により希釈した噴霧乾燥前の上澄みからA280値を分けて、三つの値を平均し理論的な基準A280値又はA280,refを得る。
b)希釈係数(1/10)によって10%の再水和の上澄みからA280値を分けて、三つの値を平均しA280,10%といわれる理論的な不希釈のA280値を得る。
c)再水和したサンプルが、基準A280値と同じA280値をとるように、基準A280値方程式1に従いA280,ref値に対するA280,10%の比をとり、噴霧乾燥後の粉末の適した再水和質量(w/v)を得る。
*重量パーセントは、mg/mlを単位としており、例えば、8.9%(w/v)は89mg/mlに相当する。
a)10%の再水和懸濁液(細胞を遠心分離しない)1/10をクエン酸生理食塩水で三倍に希釈する。
b)各サンプルをA500で濁度を測定する。
c)Hiska血液学的分析器で直接細胞総数を測定する。
d)収量低下を考慮して計算する。
再水和して噴霧乾燥した誘導化血小板(再水和したSTASIX)の電子顕微鏡写真は、図6と図7に示した。
単回でサルに静脈注射して投与(だいたい5回以上)したときに、噴霧乾燥した誘導化血小板(上記のようにStasixを噴霧乾燥して再水和した)の毒性の評価をするように検査を設計した。動物の回復サブグループを7日間観察した。
この実施例では、アルデヒド安定化血小板を脱水する凍結乾燥の代替としての噴霧乾燥の有用性を検査する。その全体が参照により本明細書に組み込まれている米国特許第5,651,966号に記載されているReadらの手順を用いてヒトのアフェレーシス血小板を安定化した。
新鮮なブタの血液由来の分離した血漿を、新鮮な凍結した血漿(FFP)として保管又は冷凍乾燥した血漿(FDP)若しくは噴霧乾燥した血漿(SDP、前述の実施例で詳述したように調製した)として保存した。インビトロ検査:当初のFFPの量と同等(1倍SDP)又は1/3(3倍SDP)である蒸留水中でSDPを再構成した。プロトンビン時間(PT)、部分的トロンボプラスチン時間(PTT)、フィブリノゲンレベル、及び選択された凝固因子の活性の測定を分析は含んだ。インビトロ検査で、多発性外傷(大腿骨骨折、等級Vの肝臓損傷)と出血性ショック(アシドーシス、凝固障害、及び低体温症の「致命的三徴」を伴う60%の動脈性出血)にブタをさらし、FFP、FDP、又は3倍SDPで治療した(n=4乃至5/グループ)。ベースライン(BL)、ショック後(PS)、晶質後(PC)、治療(MO)で凝固プロファイル(PT、PTT、トロンボエラストグラフィー)を測定し、4時間モニタリング(M1−4)した。
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Claims (1)
- 再水和血漿を調製する方法であって、
(a)凝固因子を有する血漿サンプルを提供するステップと;
(b)前記血漿サンプルを噴霧乾燥して脱水血漿を生成するステップであって、当該脱水血漿中の凝固因子が前記血漿サンプル中の凝固因子と似ているステップと;
(c)前記脱水血漿を再水和して、前記血漿サンプル中の凝固因子と似た凝固因子を含む再水和血漿を得るステップであって、当該再水和血漿が具える濁度(A500)値が再水和した凍結乾燥血漿組成物の濁度値よりも低いステップと;
を具えることを特徴とする方法。
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MX2011010633A (es) | 2012-01-20 |
CN102448475A (zh) | 2012-05-09 |
US20120027867A1 (en) | 2012-02-02 |
EP2416790B1 (en) | 2018-05-23 |
AU2010234607A1 (en) | 2011-10-27 |
EP2416790A1 (en) | 2012-02-15 |
JP2012523414A (ja) | 2012-10-04 |
AU2010234607B2 (en) | 2014-01-16 |
US20220117897A1 (en) | 2022-04-21 |
WO2010117976A1 (en) | 2010-10-14 |
JP6336419B2 (ja) | 2018-06-06 |
ES2684130T3 (es) | 2018-10-01 |
EP2416790A4 (en) | 2013-01-16 |
BRPI1006722A2 (pt) | 2017-10-10 |
CA2757961C (en) | 2020-02-04 |
CO6390111A2 (es) | 2012-02-29 |
US20180153811A1 (en) | 2018-06-07 |
US11213488B2 (en) | 2022-01-04 |
CA2757961A1 (en) | 2010-10-14 |
US9867782B2 (en) | 2018-01-16 |
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