JP2017518997A - 周囲温度における血小板の安定化 - Google Patents
周囲温度における血小板の安定化 Download PDFInfo
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- JP2017518997A JP2017518997A JP2016571743A JP2016571743A JP2017518997A JP 2017518997 A JP2017518997 A JP 2017518997A JP 2016571743 A JP2016571743 A JP 2016571743A JP 2016571743 A JP2016571743 A JP 2016571743A JP 2017518997 A JP2017518997 A JP 2017518997A
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Abstract
Description
本出願は、2014年6月10日に出願された米国仮特許出願第62/010,151号の利益を主張し、当該文献は参照によってその全体が本明細書中に組み込まれる。
A.pH緩衝液
特定の実施形態によれば、本明細書において記載された、1つ以上の血小板の実質的に安定した保存のための製剤および組成物は、1つ以上のpH緩衝液を含む。いくつかの実施形態では、pH緩衝液は、pH緩衝液が存在する水溶液のような溶液のpHの変化に抵抗する能力について当該技術分野で知られている、多くの化合物のいずれかである。安定した保存用の組成物に含まれる1つ以上のpH緩衝液の選択は、本明細書における開示および当該技術分野における日常的な業務に基づいて行なわれ、また、維持することが望ましいpH、生体サンプルの条件、利用される溶剤の状態、使用される製剤の他の成分、および他の基準を含む様々な因子によって影響され得る。例えば、典型的に、pH緩衝液は、緩衝液の特徴であるプロトン解離定数(pKa)約0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、または1.0のpH単位の範囲内のpHで利用される。
同様に、本明細書において記載されるように、特定の実施形態は、周囲温度における全血サンプル中の、生存している不活性化された血小板の実質的に安定した保存のために、組成物中に少なくとも1つのポリオールを含む。ポリオールは2つ以上の水酸基を含んでいる多価アルコールであり、一般的な公式H(CHOH)nHを有し、その際のnは2から7(7も含む)より選択した整数である。ポリオールは鎖長が異なり、大半のポリオールは五炭糖(5つの炭素糖)および六炭糖(6つの炭素糖)に由来している5−または6の炭素鎖を有する;一方で、より短い、およびより長い炭素鎖ポリオールも存在する。代表的なポリオールは、限定されないが、グリコール、グリセロール、エリスリトール、トレイトール、アラビトール、キシリトール、リビトール、アドニトール、マンニトール、ソルビトール、ガラクチトール、フシトール、イジトール、およびイノシトールを含む。実質的に安定した保存用の組成物に含まれる1つ以上の特定のポリオールの選択は、本明細書における開示および当該技術分野における日常的な業務に基づいて行なわれ、他の製剤の成分を含む様々な因子に影響され得る。いくつかの実施形態では、製剤に存在するポリオールは五炭糖ポリオールである。いくつかの実施形態では、ポリオールはアドニトールである。いくつかの実施形態では、ポリオールは20−100mMの間、または25−75mMの間の濃度で存在する。いくつかの実施形態では、ポリオールは五炭糖ポリオールであり、20−100mMの間、または25−75mMの間の濃度で存在する。いくつかの実施形態では、ポリオールはアドニトールであり、20−100mMの間、または25−75mMの間の濃度で存在する。
特定の実施形態では、表1中のものを含む周囲温度における全血サンプル中の1つ以上の不活性化された血小板の実質的に安定した保存のための製剤または組成物は、少なくとも1つのハロゲン化された二糖類誘導体を含む。いくつかの実施形態では、ハロゲン化された二糖類誘導体は、二塩素化または三塩素化した二糖類である。いくつかの実施形態では、そのような二塩素化または三塩素化した二糖類は、単独でまたは緩衝液のみの存在下で、思いがけず、不活性化された血小板を実質的に安定して保存することが出来る。ハロゲン化された二糖類誘導体は、例えば、米国の特許公開第2014/0065062号を確認されたい、および、スクラロース(1,6−ジクロロ−1,6−ジデオキシ−β−D−フルクトフラノシル−4−クロロ−4−デオキシ−α−D−ガラクトピラノシド)、三塩素化したマルトース、1,6−ジクロロ−1,6−ジデオキシ−β−D−フルクトフラノシル−4−クロロ−4−デオキシ−6−O−モノドデカノアート−α−D−ガラクトピラノシド、および1,6−ジクロロ−1,6−ジデオキシ−β−D−フルクトフラノシル−4−クロロ−4−デオキシ−6−O−モノテトラデカノアート−α−D−ガラクトピラノシドを含む。実質的に安定した保存の組成物に含まれる1つ以上のハロゲン化された二糖類誘導体の選択は、本明細書における開示および当該技術分野における日常的な業務に基づいて行なわれ、他の製剤の成分を含む様々な因子に影響され得る。いくつかの実施形態では、機能性炭水化物はスクラロースであり、約1.0−50.0mMで存在する。いくつかの実施形態では、機能性炭水化物はスクラロースであり、約10.0−30.0mMで存在する。いくつかの実施形態では、機能性炭水化物はスクラロースであり、約25.0mMで存在する。
本明細書において記載されたいくつかの実施形態では、表1中のものを含む製剤は機能性炭水化物を含む。典型的な機能性炭水化物はスクラルファートまたはオクタ硫酸スクロースを含み、また、本明細書の開示から、当業者は、利用される組成物の他の成分によって変動することもあるが、生存している、活性化が可能な血小板の安定した保存用の製剤および組成物で使用される他の機能性炭水化物を選択してもよいことを、認識するだろう。いくつかの実施形態では、表1で明らかにされるものを含む、本発明の製剤および組成物における機能性炭水化物の濃度は、約0.005−1.0mMである。いくつかの実施形態では、表1で明らかにされるものを含む、本発明の製剤および組成物における機能性炭水化物の濃度は、約0.25−0.5mMである。
いくつかの実施形態では、周囲温度における血小板の実質的に安定した保存のための製剤および組成物は、少なくとも1つの非還元糖を含む。いくつかの実施形態では、周囲温度における全血サンプル中の生存している不活性化された血小板の、実質的に安定した保存のための製剤および組成物は、少なくとも1つの非還元糖を含む。本明細書において使用されるように、「非還元糖」は機能的なアルデヒド基を欠く炭水化物分子を指す。典型的な非還元糖はスクロースおよびトレハロースを含む。いくつかの実施形態では、非還元糖はスクロースである。いくつかの実施形態では、非還元糖はトレハロースである。いくつかの実施形態では、トレハロースは約1.0−50mMの濃度で存在する。いくつかの実施形態では、トレハロースは約10.0−30mMの濃度で存在する。いくつかの実施形態では、トレハロースは約25mMの濃度で存在する。
いくつかの実施形態では、抗凝血剤は本明細書において記載される製剤または組成物に含まれる。このような抗凝血剤は、当該技術分野で既知である。典型的な抗凝血剤はエチレンジアミン四酢酸(EDTA)、ヒルジン、ヘパリン、およびクエン酸ナトリウムを含む。いくつかの実施形態では、抗凝血剤はヒルジンである。いくつかの実施形態では、ヒルジンは約1.0−50μg/mLの濃度で存在する。いくつかの実施形態では、ヒルジンは約1.0−25μg/mLの濃度で存在する。いくつかの実施形態では、ヒルジンは約10−20μg/mLの濃度で存在する。
いくつかの実施形態では、本発明の製剤、組成物、および方法は、少なくとも6時間の間、周囲温度において血小板の実質的に安定した保存を有利に提供する。いくつかの実施形態では、本発明の製剤、組成物および方法は、周囲温度における血液サンプル中の、自然循環型の、不活性化された状態の血小板の実質的に安定した保存を有利に提供し、ここで細胞は、少なくとも6時間の間、採取後に活性化される能力を保持する。他の実施形態では、血小板の少なくとも90%は、少なくとも6時間の間不活性化された状態で安定化される。他の実施形態では、血小板は、少なくとも7時間、少なくとも8時間、少なくとも9時間、少なくとも10時間、少なくとも11時間、少なくとも12時間、少なくとも13時間、少なくとも14時間、少なくとも15時間、少なくとも16時間、少なくとも17時間、少なくとも18時間、少なくとも19時間、少なくとも20時間、少なくとも21時間、少なくとも22時間、少なくとも23時間、または少なくとも24時間の間、不活性化された状態で安定化される。
いくつかの実施形態では、周囲温度で血液サンプル中の1つ以上の実質的に安定化させた血小板は、当業者により使用された周知の方法を用いて精製される。血液を血小板から取り除くための装置とキットは周知である(例えば、米国特許第5,234,593号、第6,315,706号、および第7,708,152号を参照)。特定の実施形態では、バッグ中での採血後に調製されたバッグPC(濃縮血小板)、および血液成分採取装置を用いて得られたアフェレーシスPCを使用して、血小板を精製する。こうした方法は遠心分離を使用して血液から血小板を分離する。いくつかの実施形態では、実質的に安定化させた、無処置の、代謝的に活性な生細胞は、天然の野性型膜タンパク質と受容体に対して生成された抗体を使用して、アフィニティークロマトグラフィーまたは蛍光標識細胞分取(FACS)分析によって有利に精製され、該方法は、こうした細胞タンパク質を変性させる他の保存用製剤を使用しては起こり得ない。
特定の実施形態では、適切な採血用の管、入れ物、または容器内に入れられる、本明細書で提供される製剤を含む製品が提供される。いくつかの実施形態では、製剤は、表1で説明されるものから選択される。いくつかの実施形態では、こうした製品は、採血時に1つ以上の血液成分を安定させることにより、1つ以上の血液成分の実質的に安定した保存のために使用される。特定の実施形態では、採血管は、あらかじめ決められた容量の全血を引き出すために大気圧未満の気圧を有する真空の採血管である。いくつかの実施形態では、こうした製品は本明細書に記載されるキットと方法で使用される。
特定の実施形態では、本明細書に記載される製品と添付文書のいずれか1つを含むキットが提供される。いくつかの実施形態では、キットの構成要素は、キットの内容物が殺菌・密閉されることで保存可能となるように、仕切り付きのプラスチック性のエンクロージャなどのパッケージング手段に入れられ、好ましくは密閉可能なカバーに入れられる。
本明細書では、いくつかの実施形態において、周囲温度で1つ以上の血小板を実質的に安定して保存するための方法が記載されている。いくつかの実施形態では、方法は、周囲温度で血液サンプル中の不活性化された状態の1つ以上の血小板を実質的に安定して保存するためのものである。
この実施例は、周囲温度で22時間にわたって保存した後に活性化し続けることができる不活性化された血小板を安定化させるための本発明の製剤について記載する。
Claims (42)
- 周囲温度における1つ以上の血小板の実質的に安定した保存のための製剤であって、1つ以上の血小板は少なくとも6時間の間安定化される、製剤。
- 1つ以上の血小板は、不活性化された状態で安定化される、請求項1に記載の製剤。
- 1つ以上の血小板は、血液サンプル中に存在する、請求項1または請求項2に記載の製剤。
- 1つ以上の血小板は、血液サンプルから単離される、請求項1および2のいずれか1つに記載の製剤。
- 血小板の少なくとも90%は、少なくとも6時間の間不活性化された状態で安定化される、請求項1乃至4のいずれか1つに記載の製剤。
- 血小板の少なくとも90%は、少なくとも9時間の間不活性化された状態で安定化される、請求項1乃至5のいずれか1つに記載の製剤。
- 製剤は、
(i)pH緩衝液;
(ii)抗凝血剤;
(iii)少なくとも1つの非還元糖またはポリオール;および
(iv)機能性炭水化物;
を含む、請求項1乃至6のいずれか1つに記載の製剤。 - 製剤は、グリコール、グリセロール、エリスリトール、トレイトール、アラビトール、キシリトール、リビトール、アドニトール、マンニトール、ソルビトール、ガラクチトール、フシトール、イジトールイノシトール、およびそれらの組み合わせからなる群から選択されるポリオールを含む、請求項1乃至7のいずれか1つに記載の製剤。
- 製剤は、五炭糖ポリオールまたは六炭糖ポリオールを含む、請求項1乃至7のいずれか1つに記載の製剤。
- 五炭糖ポリオールは、アドニトールである、請求項9に記載の製剤。
- 機能性炭水化物は、スクラルファートまたはオクタ硫酸スクロースである、請求項7乃至10のいずれか1つに記載の製剤。
- 機能性炭水化物は、オクタ硫酸スクロースである、請求項7乃至10のいずれか1つに記載の製剤。
- 非還元糖は、スクロースまたはトレハロースである、請求項7乃至12のいずれか1つに記載の製剤。
- 非還元糖は、トレハロースである、請求項7乃至12のいずれか1つに記載の製剤。
- 抗凝血剤は、EDTAまたはヒルジンである、請求項7乃至14のいずれか1つに記載の製剤。
- pH緩衝液は、2xリン酸緩衝生理食塩水またはトリス−HClである、請求項7乃至15のいずれか1つに記載の製剤。
- 周囲温度における1つ以上の血小板の実質的に安定した保存のための製剤であって、該製剤は、ハロゲン化された二糖類誘導体および抗凝血剤を含み、1つ以上の血小板は少なくとも6時間の間安定化される、製剤。
- 1つ以上の血小板は、不活性化された状態で安定化される、請求項17に記載の製剤。
- 1つ以上の血小板は、血液サンプル中に存在する、請求項17または請求項18に記載の製剤。
- 1つ以上の血小板は、血液サンプルから単離されている、請求項17および18のいずれか1つに記載の製剤。
- 抗凝血剤は、ヒルジンである請求項17乃至20のいずれか1つに記載の製剤。
- ハロゲン化された二糖類誘導体は、スクラロース(1,6−ジクロロ−1,6−ジデオキシ−β−D−フルクトフラノシル−4−クロロ−4−デオキシ−α−D−ガラクトピラノシド)、トリクロロナートマルトース、1,6−ジクロロ−1,6−ジデオキシ−β−D−フルクトフラノシル−4−クロロ−4−デオキシ−6−O−モノドデカノアート−α−D−ガラクトピラノシド、1,6−シクロロ−1,6−ジデオキシ−β−D−フルクトフラノシル−4−クロロ−4−デオキシ−6−O−モノテトラデカノアート−α−D−ガラクトピラノシド、およびそれらの組み合わせから成る群から選択される、請求項17乃至21のいずれか1つに記載の製剤。
- 製剤は、本質的にヒルジンおよびスクラロース(1,6−ジクロロ−1,6−ジデオキシ−β−D−フルクトフラノシル−4−クロロ−4−デオキシ−α−D−ガラクトピラノシド)からなる、請求項17に記載の製剤。
- 請求項1乃至23のいずれか1つの製剤と混合させた1つ以上の血小板を含む、不活性化された状態で実質的に安定して保存された1つ以上の血小板の組成物。
- 1つ以上の血小板は、血液サンプル中に存在する、請求項24に記載の組成物。
- 1つ以上の血小板は、単離された血小板である、請求項24に記載の組成物。
- 製品であって、
採血管内に収容された請求項1乃至23のいずれか1つの製剤を含む、製品。 - 採血管は、真空の採血管である、請求項20に記載の製品。
- 請求項27または請求項28の製品、および添付文書を含む、キット。
- 周囲温度において1つ以上の血小板を実質的に安定して保存する方法であって、該方法は:被検体からの1つ以上の血小板を、請求項1乃至23のうちいずれか1つの製剤と混合する工程を含み、1つ以上の血小板は少なくとも6時間の間安定化される、方法。
- 1つ以上の血小板は、不活性化された状態で安定化される、請求項30に記載の方法。
- 1つ以上の血小板は、被検体からの血液サンプル中に存在する、請求項30または請求項31に記載の方法。
- 1つ以上の血小板は、被検体からの血液サンプルから単離される、請求項30および31のいずれか1つに記載の方法。
- 血小板の少なくとも90%は、少なくとも6時間の間不活性化された状態で安定化される、請求項30乃至33のいずれか1つに記載の方法。
- 血小板の少なくとも90%は、少なくとも9時間の間不活性化された状態で安定化される、請求項30乃至34のいずれか1つに記載の方法。
- 血小板の凝集を促進するために活性化剤を加えることによって、1つ以上の血小板を活性化させる工程をさらに含む、請求項30乃至35のいずれか1つに記載の方法。
- 活性化剤は、ADPである、請求項36に記載の方法。
- 血小板の凝集を促進するために活性化剤を加えることによって、1つ以上の血小板を活性化させる工程をさらに含む、請求項30乃至37のいずれか1つに記載の方法。
- 活性化剤は、ADPである、請求項38に記載の方法。
- 被検体は、動物である、請求項30乃至39のいずれか1つに記載の方法。
- 被検体は、哺乳動物である、請求項30乃至40のいずれか1つに記載の方法。
- 哺乳動物は、ヒトである、請求項41に記載の方法。
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US20230363375A1 (en) | 2023-11-16 |
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EP3942931A1 (en) | 2022-01-26 |
CN106572650A (zh) | 2017-04-19 |
WO2015191632A1 (en) | 2015-12-17 |
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EP3154338A4 (en) | 2017-11-15 |
JP6661554B2 (ja) | 2020-03-11 |
CN113826612B (zh) | 2022-11-22 |
EP3656215A1 (en) | 2020-05-27 |
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