JP5810091B2 - 凍結乾燥方法、組成物、及びキット - Google Patents
凍結乾燥方法、組成物、及びキット Download PDFInfo
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Description
(a)完全に又はほぼ完全に結晶化された1以上の成分をその中に有する第一組成物を提供するために、約5時間又はそれより長く当該組成物の温度が約48℃又はそれ未満となるように、上記組成物を約54℃又はそれ未満に晒し;そして
(b)上記第一組成物を乾燥させて、凍結乾燥されたケーキを得ること
を含む。
幾つかの実施態様では、少なくとも1の活性成分は、タンパク質、核酸、及びそれらの組合せを含むが、それらに限定されない任意の活性成分でありうる。タンパク質としては、糖タンパク質(例えばAT III)、凝固因子、成長因子、サイトカイン、抗体、及びキメラ構築物が挙げられるが、これらに限られるものではない。本明細書において「タンパク質」という語句は、広い意味を意図されており、そして個別又は集合的な天然ヒト又は他の哺乳動物のタンパク質;及び/又は単一又は複数の遺伝子産物から生じるポリペプチドの同種又は異種組合せ;及び/又は特定の活性を示すタンパク質のフラグメント;及び/又はトランスジェニック技術を含む組換え技術により生成されるタンパク質及び/又はその活性フラグメントを指す。
1の実施態様では、少なくとも1の結晶化賦形剤は、アラニン、マンニトール、グリシン、及びNaClからなる群から選択される。
一般的に凍結乾燥法の特定の温度及び/又は温度範囲は、他に特記がない限り、凍結乾燥装置の棚(シェルフ)温度(shelf temperature)を指す。棚温度は、凍結乾燥機の棚(シェルフ)を通って流れる冷媒の制御温度を指し、これは凍結乾燥のあいだ、温度の点で制御されるものである。サンプルの温度(つまり、製品温度)は、最初の乾燥のあいだの蒸発/昇華率(蒸発冷却は、製品温度を棚温度よりも低くする)、棚温度、及び/又はチャンバー圧力に左右される。
1の実施態様では、第一温度は約−48℃であるか又はそれより低い。別の実施態様では、第一温度は約−54℃であるか又はそれより低い。別の実施態様では、時間は、少なくとも約30分、例えば約30分〜約20時間、約1〜約18時間、約2〜約16時間、約3〜約14時間、約4〜約10時間、約5〜約8時間、及び約6〜約7時間である。1の実施態様では、時間は約6時間である。
別の実施態様では、本方法はさらに、第一組成物を第二温度に第二時間のあいだ晒して、第二組成物を取得することを含み、ここで当該第二温度は第一温度より高い。
(a) 当該組成物を第一温度に、部分的又は完全に結晶化された少なくとも1の結晶化賦形剤を有する第一組成物を得るために十分な第一時間のあいだ晒す工程、
(b) 当該第一組成物を、第二温度に、第二時間のあいだ晒して第二組成物を得る工程、ここで第二温度は第一温度より高く、そして
(c)第二組成物を、第三温度に、第三時間のあいだ晒して第三組成物を得る工程、ここで第三温度は第二温度より低い、
を含む。
別の実施態様では、本発明の方法は、さらに乾燥フェーズを含む。乾燥フェーズは、第一乾燥フェーズと第二乾燥フェーズを含む。
(a) 上記組成物を第一温度に、部分的に又は完全に結晶化された少なくとも1の結晶化賦形剤を有する第一組成物を得るために十分な第一時間のあいだ晒し;そして
(b) 第一組成物を乾燥させて凍結乾燥ケーキを形成させる
を含む。
(a) 当該組成物を第一温度に、部分的又は完全に結晶化された少なくとも1の結晶化賦形剤を有する第一組成物を得るために十分な第一時間のあいだ晒す工程、
(b) 当該第一組成物を、第二温度に、第二時間のあいだ晒して第二組成物を得る工程、ここで第二温度は第一温度より高く、そして
(c)第二組成物を、第三温度に、第三時間のあいだ晒して第三組成物を得る工程、ここで第三温度は第二温度より低い、
(d) 第三組成物を乾燥させて凍結乾燥ケーキを形成させる
を含む、前記方法を提供する。
(a) 製剤を約−45℃未満の温度に、部分的又は完全に結晶化された少なくとも1の結晶化賦形剤を有する第一組成物を取得するために十分な時間のあいだ晒し;そして
(b) 第一組成物を乾燥させて凍結乾燥ケーキを形成する
を含む方法が提供される。
(a) 製剤を約−50℃未満の凍結温度に、部分的又は完全に結晶化された少なくとも1の結晶化賦形剤を有する第一組成物を取得するために十分な時間のあいだ晒し;そして
(b) 第一組成物を乾燥して、凍結乾燥ケーキを形成する
を含む前記方法に関する。
(a)製剤を、約−60℃未満の温度に、部分的に又は完全に凍結乾燥された少なくとも1の結晶化賦形剤を有する第一組成物を取得するために十分な時間のあいだ晒し;そして
(b)第一組成物を乾燥して、凍結乾燥ケーキを形成する
を含む方法を提供する。
さらなる態様では、本発明の医薬組成物を含むキットであって、さらに乾燥及び液体成分を含み、ここで乾燥及び液体成分は、キット内の分離した容器内に存在することができるか、又は成分の幾つかは1の容器内に混合されうるキット、例えば乾燥成分が第一容器内に存在し、液体成分が第二容器内に存在するキットが提供され、ここで当該容器が組合せた構成で存在してもよいしそうでなくてもよい。場合により、キットはさらに、多数の追加試薬を含むことができる。場合により、キットは、キットの成分を使用するための指示、例えば凍結乾燥された組成物を、適切な希釈液で構成するための指示、をさらに含むことができる。指示は、パッケージの挿入物としてキット内に存在してもよいし、キットや構成要素の容器のラベルに存在してもよい。
実施例1
AT III溶液中において成分の結晶化を促進し、そして最終製品の物理的外観を改善する凍結条件を決定するために、ヒト血漿由来AT III(6.88mg/ml)、アラニン(100mM)、及びNaCl(150mM)を含むAT III製剤について凍結乾燥を行った。アラニン及びNaClの両方ともが、結晶化賦形剤である。この製剤について、物理的外観は、賦形剤の結晶化度に直接関連する。ケーキ構造を支持する固体マトリクスを提供するために、凍結のあいだできる限り完全にNaCl及びアラニンを結晶化すること望ましかった。
DSCの実行は、AT III製剤における賦形剤の結晶化性質を司る臨界因子を特徴決定することを狙っており、結晶化温度(Tx)、共結晶融点(Te)、及び結晶パーセントを測定した。
13ml成形バイアルを、AT III(〜6.88mg/ml)、アラニン(100mM(〜8.91mg/ml)、及びNaCl(150mM、〜8.7mg/ml)を含む10mlの滅菌ろ過溶液を充填した。AT IIIサンプルを−25℃で第一凍結し、2時間保持し、そして次に−54℃でさらに凍結し、6時間保持した。棚温度を次にゆっくり−30℃に、0.2℃/分の率で上昇し、そして2時間その温度に保持し、そして次にゆっくり0.2℃/分で−54℃に低下させた。第一乾燥を開始する前まで、製品を−54℃で2時間保持した。第一乾燥を0℃の棚温度、100mTorr制御されたチャンバー圧力で行った。第一乾燥を約32時間続け、その後に第二乾燥を開始した。第二乾燥を35℃の棚温度で、そして100mTorrのチャンバー圧力で13時間行った。
Claims (15)
- AT IIIとアラニン、マンニトール、グリシン、及びNaClからなる群から選択される少なくとも1の結晶化賦形剤とを含む組成物を凍結乾燥する方法であって、当該方法が当該組成物を、部分的又は完全に結晶化された少なくとも1の結晶化賦形剤を有する第一組成物を得るために乾燥前に第一時間である4〜10時間のあいだ第一温度である−54℃又はそれ未満に晒すことを含む、前記方法。
- 前記第一時間が、少なくとも5時間である、請求項1に記載の方法。
- 前記少なくとも1の結晶化賦形剤がアラニン及びNaClである、請求項1に記載の方法。
- 前記アラニン及びNaClが、前記組成物中において各100mMで存在する、請求項3に記載の方法。
- 前記第一温度と前記第一時間が、前記少なくとも1の結晶化賦形剤が完全又はほぼ完全に結晶化されるのに十分である、請求項1に記載の方法。
- 前記組成物が、さらに安定剤、緩衝剤、界面活性剤、抗酸化剤、及び二価カチオンからなる群から各々選択される1又は複数の賦形剤をさらに含む、請求項1に記載の方法。
- 前記組成物が、さらにリン酸緩衝剤、酢酸緩衝剤、クエン酸緩衝剤、及びクエン酸/リン酸緩衝剤、ヒスチジン、トリス−(ヒドロキシメチル)−アミノメタン、1,3−ビス−[トリス−(ヒドロキシ−メチル)メチルアミノ]−プロパン、ヒスチジン、ピペラジン−N,N’−ビス−(2−エタンスルホン酸)、3−{N−モルフォリノ)プロパンスルホン酸、N−2−ヒドロキシエチル−ピペラジン−N’−2−エタンスルホン酸、2−(N−モルフォリノ)エタンスルホン酸、及びN−2−アセトアミド−2−アミノエタンスルホン酸(ACES)からなる群から選ばれる緩衝剤をさらに含む、請求項1に記載の方法。
- 前記第一組成物を乾燥して、凍結乾燥されたケーキを取得することをさらに含む、請求項1に記載の方法。
- 前記凍結乾燥されたケーキが、少なくとも50%固体ケーキである、請求項8に記載の方法。
- 前記組成物が、医薬として許容される担体を含む液体医薬組成物である、請求項1に記載の方法。
- 前記第一組成物を第二温度に第二時間のあいだ晒して、第二組成物を取得することをさらに含み、ここで前記第二温度が前記第一温度より高い、請求項1に記載の方法。
- 前記第二組成物を第三温度に、第三時間のあいだ晒して、第三組成物を取得し、ここで第三温度が第二温度より低い、請求項11に記載の方法。
- 前記組成物を乾燥して、凍結乾燥ケーキを取得することをさらに含む、請求項12に記載の方法。
- 血漿由来AT III、NaCl、及びアラニンを含む液体組成物を凍結乾燥する方法であって、当該方法が以下の:
(a)上記組成物の温度が−48℃又はそれ未満となるように、当該組成物を−54℃又はそれ未満に5時間又はそれ以上晒して、完全に又はほぼ完全に結晶化された1又は複数の成分を有する第一組成物を提供する;及び
(b)第一組成物を乾燥して、凍結乾燥されたケーキを取得する
を含む、前記方法。 - 25℃〜40℃で1時間〜6ヶ月のあいだ貯蔵した後で、AT IIIの効力が、維持される、請求項14に記載の方法。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2015155455A (ja) * | 2009-11-24 | 2015-08-27 | グリフオルス・セラピユーテイクス・インコーポレーテツドGrifols Therapeutics,Inc. | 凍結乾燥方法、組成物、及びキット |
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