JP6817497B2 - ペメトレキセドの静脈内注入剤形 - Google Patents
ペメトレキセドの静脈内注入剤形 Download PDFInfo
- Publication number
- JP6817497B2 JP6817497B2 JP2020520324A JP2020520324A JP6817497B2 JP 6817497 B2 JP6817497 B2 JP 6817497B2 JP 2020520324 A JP2020520324 A JP 2020520324A JP 2020520324 A JP2020520324 A JP 2020520324A JP 6817497 B2 JP6817497 B2 JP 6817497B2
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- Prior art keywords
- layer
- pemetrexed
- container
- polyamide
- flexible plastic
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- 239000006207 intravenous dosage form Substances 0.000 title description 7
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Description
本発明は、ペメトレキセドの静脈内注入剤形およびその調製プロセスに関する。
ペメトレキセドは、悪性胸膜中皮腫および非小細胞肺癌の治療に使用される。ペメトレキセドは、未知およびまだ解明されていない、酸化、加水分解、二量体化などのような異なるメカニズムによって分解を受けることが知られている(Jansen PJ et al、Journal of Pharmaceutical Sciences、Volume 105、Issue 11、November 2016、Pages、3256−3268を参照)。不安定性を考慮して、最初の市販品であるALIMTA(登録商標)は、静脈内注入用の無菌凍結乾燥粉末として供給され、単回投与バイアルで利用可能であり、Eli Lillyによって米国で販売されている。ALIMTA(登録商標)は病院において再構成する必要があるため、すぐに注入できる静脈内注入剤形ではない。
a.ペメトレキセドまたはその薬学的に許容される塩およびオスモゲント(osmogent)を非経口水性媒体に溶解するステップ、
b.ステップ(a)の溶液をフレキシブル注入容器に充填するステップ、
c.充填されたフレキシブル注入容器を密封するステップ、
d.二次包装/容器でフレキシブル注入容器を囲み、二次包装/容器を密封するステップ、
e.ステップ(d)の容器を湿熱滅菌に供するステップ、
を含み、ここで上記の各ステップにおいて、低酸素条件は、溶液ならびに/またはフレキシブル注入容器のヘッドスペース、ならびにフレキシブル一次注入容器および二次包装/容器との間の空間に維持される。上記刊行物は、50mlから1000mlのペメトレキセドの大容量の水溶液を含むすぐに注入できる静脈内注入剤形を開示した。上記方法の1つの欠点は、注入剤形の最初の容器内の水溶液を、ステップeの後に視覚的に検査する必要があることであった。最初の容器の内容物の目視検査を可能にするために、二次包装/容器から最初の容器を取り除く必要がある。さらに、目視検査後、最初の容器を再度二次包装/容器に入れ、2つの容器の間の空間を不活性雰囲気に戻す必要がある。これらの要件により、プロセスが煩雑になる。室温で保存した場合に長期安定性があり、オートクレーブ処理が可能な、ペメトレキセドの大容量ですぐに注入できる静脈内注入剤形を提供する必要性が残っている。
本発明の目的は、簡単なプロセスによって安定したオートクレーブ可能な静脈内注入剤形を製造することである。特に、‘9000出願のプロセスに関する不利な点を回避すること、すなわち、最初の容器を二次包装で囲む必要がなく、脱酸素剤を配置する必要性も、最初の一次容器および二次包装の間の空間に不活性ガスを充填したりする必要性もなく、最初の容器をオートクレーブ処理を行うことが目的であった。
本発明は、以下を含む静脈内注入剤形を提供する:多層フレキシブルプラスチック注入容器中に存在する、1.0mg/mlから20.0mg/mlの範囲の濃度のペメトレキセドまたはその薬学的に許容される塩の水溶液、ここで多層フレキシブルプラスチック注入容器は、容器の最外層および最内層の間に挟まれた脱酸素剤層を有し、上記容器はポリアミドを含まず、ここでペメトレキセドの水溶液で充填された多層フレキシブルプラスチック注入容器はオートクレーブ可能である。
i).多層フレキシブルプラスチック注入容器に存在する、1.0mg/mlから20.0mg/mlの範囲の濃度のペメトレキセドまたはその薬学的に許容される塩の水溶液を含む静脈内注入剤形であって、ここで多層フレキシブルプラスチック注入容器は容器の最外層および最内層の間に挟まれた脱酸素剤層を有し、上記容器はポリアミドを含まず、ここでペメトレキセドの水溶液で充填された多層フレキシブルプラスチック注入容器はオートクレーブ可能である。
ii).多層フレキシブルプラスチック注入容器に存在する、1.0mg/mlから20.0mg/mlの範囲の濃度のペメトレキセドまたはその薬学的に許容される塩の水溶液を含む静脈内注入剤形であって、ここで多層フレキシブルプラスチック注入容器は容器の最外層および最内層の間に挟まれた脱酸素剤層を有し、上記容器はポリアミドを含まず、ここでペメトレキセドの水溶液で充填された多層フレキシブルプラスチック注入容器はオートクレーブ可能であり、ここで静脈内注入剤形の脱酸素剤層は、エチレンビニルアルコール共重合体およびエチレン−酢酸ビニル共重合体からなる群から選択されるポリマーで構成されている。
iii).多層フレキシブルプラスチック注入容器に存在する、1.0mg/mlから15.0mg/mlの範囲の濃度のペメトレキセドまたはその薬学的に許容される塩の水溶液を含む静脈内注入剤形であって、ここで多層フレキシブルプラスチック注入容器は容器の最外層および最内層の間に挟まれた脱酸素剤層を有し、上記容器はポリアミドを含まず、ここで脱酸素剤層はエチレンビニルアルコール共重合体およびエチレン−酢酸ビニル共重合体からなる群から選択されるポリマーで構成され、ここで静脈内注入剤形の最外層は、ポリエチレンテレフタレート、ポリプロピレンテレフタレート、ポリブチレンテレフタレート、およびポリエチレンナフタレートからなる群から選択されるポリマーで構成され、および/またはここで静脈内注入剤形の最内層は、ペメトレキセドの水溶液と直接接触しており、ポリエチレンおよびシクロオレフィンからなる群から選択されるポリマーで構成され、ここでペメトレキセドの水溶液で充填された多層フレキシブルプラスチック注入容器はオートクレーブ可能である。
本明細書で使用される「オートクレーブ可能」という用語は、本発明による多層フレキシブルプラスチック注入容器が、ペメトレキセドの水溶液の化学的および物理的安定性に影響を与えることなくオートクレーブ処理に耐えることができることを意味する。用語化学的安定性によると、本発明によるオートクレーブ処理された静脈内注入剤形が、室温で少なくとも1年間保存されるとき、不純物A、BおよびCのレベルがそれぞれ0.24重量%を超えず、総不純物のレベルがペメトレキセドの2.0重量%を超えないことを意味する。用語「物理的安定性」によると、本発明による静脈内注入剤形に含まれるペメトレキセドの水溶液を、オートクレーブにかけ、室温で少なくとも1年間保存したときに、水溶液がポリアミド−11環状モノマーおよび/またはポリアミド−11環状二量体および/またはポリアミド−11環状三量体の粒子を含まないことがわかることを意味する。他の粒子は、もし存在する場合、米国薬局方条約、改訂公報2011などの規制当局によって非経口製品に指定された粒子状物質の数の制限内にあることがわかっている。米国薬局方条約は、容器内の調製物の容量に基づいて粒子状物質の数の制限を指定している。呼び容量が100mlまたはより少ない容量の容器の場合、製品の有効期限中、サイズが10μm以上の粒子の数は容器あたり6000カウントを超えてはならず、製品の有効期限中、サイズが25μm以上の粒子の数は容器あたり600カウントを超えてはならない。また、100mlを超える呼び容量の容器の場合、サイズが10μm以上の粒子の数は、製品の有効期限中の溶液1ミリリットルあたり25粒子を超えてはならず、サイズが25μm以上の粒子の数は製品の有効期限中の容器1ミリリットルあたり3粒子を超えてはならない。粒子状物質の数は、微視的粒子数または光遮断粒子数などの、当技術分野で公知の技法によって決定することができる。
(i)シスプラチンと組み合わせた非扁平上皮非小細胞肺癌、特に局所進行性または転移性非扁平上皮非小細胞肺癌患者の初期治療のため
(ii)カルボプラチンおよびペンブロリズマブと組み合わせた非扁平上皮非小細胞肺癌、特に転移性非扁平上皮、非小細胞肺癌患者の初期治療のため
(iii)単剤としての非扁平上皮非小細胞肺癌、特に4サイクルの白金ベースの第一選択の化学療法後に疾患が進行していない局所進行または転移性の非扁平上皮非小細胞肺癌患者の維持療法のため
(iv)単剤としての非扁平上皮非小細胞肺癌、特に以前の化学療法後の再発性転移性非扁平上皮非小細胞肺癌の患者の治療のためおよび/または
(v)シスプラチンと組み合わせた中皮腫、特に疾患が切除不能であるか、そうでなければ治癒的手術の候補ではない悪性胸膜中皮腫の患者の初期治療のため。
b)溶液を窒素でパージするステップ、
c)(b)の水溶液を多層フレキシブルプラスチック注入容器に充填するステップであって、多層は、少なくとも3層、最外層、中間脱酸素剤層、および最内層を含み、ここで多層フレキシブルプラスチック注入容器には、ポリアミドを含まない、ステップ
d)ヘッドスペースを不活性ガスで充填し、容器を密閉するステップ、
e)ステップ(d)の充填した容器を、120℃から125℃の範囲の温度で、約10分から25分の範囲の期間、約2.5から3.5バールGの滅菌圧力でオートクレーブするステップであって、ここでオートクレーブ中に容器が二次包装で包装またはオーバーラップされていない、ステップ
f)ステップ(e)のオートクレーブ処理された容器を目視検査に供するステップであって、検査済みの多層フレキシブルプラスチック注入容器を二次包装に包装するステップ
を含む。
a)ペメトレキセドまたはその薬学的に許容される塩を2.0から15.0mg/mlの濃度で含む水溶液を多層フレキシブルプラスチック注入容器に充填するステップであって、多層は少なくとも3層、最外層、脱酸素剤層および最内層を含み、ここで多層フレキシブルプラスチック注入容器はポリアミドを含まない、ステップ
b)ステップ(a)の充填した容器を、110℃から125℃の範囲の温度で、5分から60分の範囲の期間、約2.0から3.5バールGの範囲の滅菌圧力でオートクレーブ処理するステップであって、ここで容器はオートクレーブ中に二次包装で包装またはオーバーラップされない、ステップ
c)オートクレーブ処理された多層フレキシブルプラスチック注入容器を二次包装に包装するステップ。
この比較実施例は、溶液を窒素でパージ(purge)し、ヘッドスペース(headspace)を窒素で満たしている場合でも、オートクレーブすると全体の不純物が大幅に増加する、ペメトレキセド溶液に関連する問題を示す。
(i)ポリシクロヘキサンジメチルシクロヘキサンジカルボン酸エラストマー、官能化エチレンアルファオレフィン共重合体、エチレンアルファオレフィン共重合体、スチレン−エチレン−ブチレン−スチレンブロック共重合体、およびエチレンプロピレン共重合体(CPET−Tie−PE−Tie−EPCと称される)で構成される外側から内側に層を有する多層ポリオレフィンフィルムで構成された多層フレキシブルプラスチック容器。
(ii)スチレン−エチレン−ブチレン(SEB)ブロック共重合体を含むポリプロピレン重合体の外層、スチレン−エチレンブチレンブロック共重合体を含むポリプロピレンベースのポリオレフィン重合体で構成される中間層および内層の両方で構成される多層フレキシブルプラスチック容器。
(iii)シクロオレフィン重合体の内層、線状低密度ポリエチレン重合体の中間層、および低密度ポリエチレン重合体の外層で構成される多層フレキシブルプラスチック容器。
この比較実施例は、ポリアミドを含み、脱酸素剤層を有さない多層フレキシブルプラスチック注入容器の使用に関連する問題の発見を示した。
比較実施例IIの水溶液の物理的観察は、ロッド形状のサブビジブル(sub−visible)粒子の存在を示した。これらのサブビジブル粒子を、0.2μmポリエーテルスルホンフィルターを使用したろ過によって溶液から分離し、ラマン分光法により特性評価にかけた。これらの粒子のラマンスペクトルを、これらのろ過された粒子をラマンG3 IDの石英プレート上に置くことによって記録した。スペクトルを図3に示す。ポリアミド11環状モノマーおよびポリアミド11環状二量体の参照物質のラマンスペクトルを記録し、図1および図2それぞれに示した。図3に示す粒子のラマンスペクトルの700〜1260cm−1(官能基:C−C)、1410〜1460cm−1(官能基:CH3&CH2変角)、および1620〜1690cm−1(官能基:NH変角と混合した>C=O)の位置で観察される顕著なピークは、図1および図2それぞれに示すポリアミド11環状モノマーおよびポリアミド11環状二量体のポリアミド参照物質のラマンスペクトルの同じ位置で観察されるピークと一致し、粒子中のポリアミド11環状モノマーとポリアミド11環状二量体の存在を示した。
を以下の表4に示す。
この実施例は、本発明による注入剤形を例示している。剤形を、以下のステップに従って調製する。
Claims (5)
- 多層フレキシブルプラスチック注入容器中に存在する、1.0mg/mlから20.0mg/mlの範囲の濃度のペメトレキセドまたはその薬学的に許容される塩の水溶液を含む静脈内注入剤形であって、前記多層フレキシブルプラスチック注入容器が、前記容器の最外層および最内層の間に挟まれた脱酸素剤層を有し、前記容器はポリアミドを含まず、ペメトレキセドの前記水溶液で充填された前記多層フレキシブルプラスチック注入容器がオートクレーブ可能である、静脈内注入剤形。
- 前記脱酸素剤層が、エチレンビニルアルコール共重合体およびエチレン酢酸ビニル共重合体からなる群から選択されるポリマーで構成される、請求項1に記載の前記静脈内注入剤形。
- 前記最外層が、ポリエチレンテレフタレート、ポリプロピレンテレフタレート、ポリブチレンテレフタレートおよびポリエチレンナフタレートからなる群から選択されるポリマーで構成される、請求項1に記載の前記静脈内注入剤形。
- 前記最内層がペメトレキセドの前記水溶液と直接接触し、ポリエチレンおよびシクロオレフィンからなる群から選択されるポリマーで構成される、請求項1に記載の前記静脈内注入剤形。
- 0.20重量%より大きくない不純物Bまたは0.20重量%より大きくない不純物Cが水溶液中に存在し、前記溶液はオートクレーブ直後のポリアミド11環状二量体またはポリアミド11環状三量体の粒子を含まない、請求項1に記載の前記静脈内注入剤形。
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