JP6539675B2 - タキサンを含む無定形固体分散体、それを含む錠剤、及びそれを製造する方法 - Google Patents
タキサンを含む無定形固体分散体、それを含む錠剤、及びそれを製造する方法 Download PDFInfo
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- JP6539675B2 JP6539675B2 JP2016559161A JP2016559161A JP6539675B2 JP 6539675 B2 JP6539675 B2 JP 6539675B2 JP 2016559161 A JP2016559161 A JP 2016559161A JP 2016559161 A JP2016559161 A JP 2016559161A JP 6539675 B2 JP6539675 B2 JP 6539675B2
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Description
(a)タキサンまたはその医薬的に許容可能な塩、医薬的に許容可能なポリマー、及び医薬的に許容可能な界面活性剤を溶媒に溶解させて溶液を生産する段階、並びに
(b)前記(a)段階で得られた溶液を乾燥させる段階。
(a)タキサンまたはその医薬的に許容可能な塩、医薬的に許容可能なポリマー、及び医薬的に許容可能な界面活性剤を溶媒に溶解させて溶液を生産する段階;
(b)前記(a)段階で得られた溶液を乾燥させて固体分散体を生産する段階;
(c)前記固体分散体を顆粒外賦形剤と共に混合する段階;並びに
(d)(c)段階の前記混合物を圧縮させる段階。
本発明においては、タキサンの生体内(in vivo)伝達に使用される固体分散体を提供する。1つの具体例において、前記固体分散体は、タキサンまたはその医薬的に許容可能な塩、医薬的に許容可能なポリマー、及び医薬的に許容可能な界面活性剤を含む。
本発明の固体分散体に採用可能なタキサンは、パクリタキセル(Taxol)、ドセタキセル(Taxotere)、カバジタキセル、ラロタキセル、オルタタキセル、テセタキセル、及びそれらの組み合わせを含むが、それらに限定されるものではない。一具体例において、タキサンは、パクリタキセルまたはドセタキセルである。さらなる具体例において、タキサンは、パクリタキセルである。
前記固体分散体内に、添加剤として採用可能な医薬的に許容可能なポリマーは、親水性担体ポリマーでもあるが、それは、セルロース基盤ポリマー(例えば、ヒドロキシプロピルメチルセルロース(HPMC、ヒプロメロース)、エチルセルロース、ヒドロキシエチルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルセルロース、ヒプロメロースフタレート、酢酸セルロース、酢酸フタル酸セルロース、メチルセルロース、エチルセルロース、セルロース、カルボキシメチルセルロース、微結晶性(microcrystalline)セルロース、ケイ化(silicified)微結晶性セルロースなど)、澱粉基盤ポリマー(例えば、ヒドロキシプロピル澱粉、(完全な予備ゼラチン化(pregelatinized)及び部分的なゼラチン化がなされる、とうもろこし、じゃがいも、米、小麦のような任意の源泉からの澱粉を含む)澱粉)、ポリエチレングリコール、ポリアクリル酸、ポリアクリルアミド、ポリエチレンエチレン、ポリビニルピロリドン、ポリビニルアルコール、ポリグリコール化グリセリド、ポリメタクリレート、ヒドロコロイド(例えば、カラギーナン、キトサン、アルギン酸、ヒアルロン酸、ペクチン酸など)を含むが、それらに限定されるものではない。
前記固体分散体内の添加剤として採用可能な医薬的に許容可能な界面活性剤は、ポリソルベート(例えば、ポリソルベート20、ポリソルベート40、ポリソルベート80、ポリソルベート85、ポリソルベート60など)、ポリオキシル20ステアレート、ポリオキシル35ひまし油、ポロキサマー、ポリオキシエチレンソルビタンモノイソステアレート、ポリエチレングリコール40ソルビタンジイソステアレート、ポリオキシル40水素化ひまし油、ポロキサマー331、ポリオキシエチレン脂肪酸エステル、ポリオキシル40ひまし油、ポロキサマー188、ポリオキシエチレンポリオキシプロピレン1800、オレイン酸、デオキシコール酸ナトリウム、ラウリル硫酸ナトリウム、ソルビタンモノラウレート、ソルビタンモノオリエート、ソルビタンモノパルミテート、ソルビタントリオリエート、N−カルバモイルメトキシポリエチレングリコール2000−1,2−ジステアロール、ミリスチン酸、ステアレス(steareth)、ステアリン酸、ポリオキシル40ステアレート、ポリオキシル60ステアレート、スクロースステアレート、トコフェロール、ポリオキシルひまし油、トリグリセリド合成(synthetic)、トリミリスチン、トリステアリン、ステアリン酸マグネシウム、レシチン、ラウリル硫酸、ビタミンE、卵黄(egg yolk)ホスファチド、ドキュセートナトリウム、ジミリストイルホスファチジルグルリセロール、ジミリストイルレシチン、カプリオール(Capryol)90(プロピレングリコールモノカプリレート)、カプリオールPGMC(プロピレングリコールモノカプリレート)、デオキシコレート、コレステロール、クレモフォールEL、アルギン酸プロピレングリコール、クロバル(croval)A−10(PEG 60アーモンドグリセリド)、ラブラフィル1944(オレオイルマクロゴ−ル−6グリセリド)、ラブラフィル2125(リノレオイルマクロゴ−ル−6グリセリド)、ラブラソール(カプリロカプロイルマクロゴ−ル−8グリセリド)、ラウログリコール90(プロピレングリコールモノラウレート)、ラウログリコールFCC(プロピレングリコールラウレート)、ステアリン酸カルシウム、レシチンセントロミクスE、レシチンセントロフェーズ152、レシチンセントロール3F21B、POE 26グリセリン、オレパルイソステアリック(PEG−6イソステアレート)、プルロルジイソステアリック(ポリグリセロール−3−ジイソステアレート)、プルロルオレイックCC、POE 20ソルビタントリオリエート、タガットTO(ポリオキシエチレングリセロールトリオリエート)またはソルトール(マクロゴ−ル−15ヒドロキシステアレート)、またはそれらの混合物を含むが、それらに限定されるものではない。
無定形タキサン固体分散体を製造するための本発明の方法は、タキサンを十分な量の有機溶媒に溶解させる段階、並びに得られた溶液を、医薬的に許容可能なポリマー、及び医薬的に許容可能な界面活性剤を含む溶液と混合し、噴霧溶液を製造する段階を含む。前記溶媒は、その後、蒸発させてなくし、マトリックス内に、分散/溶解された前記薬剤が残る。前記固体マトリックスは、タキサンの溶解が最大化され、タキサンの生体利用率が改善されるように、微細に分散された(finely dispersed)(分子的分散)タキサンを有する。
(a)タキサンまたはその医薬的に許容可能な塩、医薬的に許容可能なポリマー、及び医薬的に許容可能な界面活性剤を溶媒に溶解させる段階;並びに
(b)前記(a)段階で得られた溶液を乾燥させる段階。
1.タキサン、医薬的に許容可能なポリマー、及び医薬的に許容可能な界面活性剤を含む噴霧溶液を製造する段階;
2.ノズルを介して、1)段階の溶液を噴霧させることにより、固体分散体を形成させて固体分散体を得る段階;並びに
3.それによって製造された固体分散体を収集する段階、及び必要によって乾燥させる段階。
段階1)において、固体分散体を生産するための噴霧溶液は、溶液A:タキサンを含む有機溶媒溶液、及び溶液B:医薬的に許容可能なポリマー、及び医薬的に許容可能な界面活性剤を含む水性有機溶媒を混合することによって製造される。
本段階で、前記溶媒は、噴霧乾燥技術による蒸発によって除去されてもよい。用語「噴霧・乾燥(spray-drying)」は、一般的であって広範囲に、液体混合物を小液滴(droplet)に崩し(噴霧)(atomization)、前記液滴からの溶媒蒸発のための強い駆動力がある噴霧・乾燥装置内で、前記混合物から溶媒を迅速に除去することを含む工程を指すのに使用される。典型的な噴霧乾燥工程において、注入液体は、ポンプでポンピングされ、噴霧化(atomized)が可能である限り、溶液、スラリー、エマルジョン、ゲルまたはペーストでもある。
いったん前記噴霧が終われば、注入及び噴霧(atomization)が止まり、得られた固体分散体を収集し、必要であるならば、オーブンで40〜60℃、望ましくは、40〜50℃でさらに乾燥させる。
本発明の経口剤形は、望ましくは、カプセル剤、錠剤、ピル剤(pill)、分散体、溶液または懸濁液の形態である。本発明の剤形のための治療学的であって有効な経口投与量は、医療実務家の判断によって、標準臨床技術によって決定される。例えば、医学参照書籍及び医薬文献で提供される情報に加え、最適の投与量確認の一助とするために、周知のインビトロ(生体外)(in vitro)またはインビボ(生体内)(in vivo)分析法を使用することができる。
(a)タキサンまたはその医薬的に許容可能な塩、医薬的に許容可能なポリマー、及び医薬的に許容可能な界面活性剤を溶媒に溶解させて溶液を生産し、その後、前記溶液から前記溶媒を除外して固体分散体を生産する段階;
(b)段階(a)の前記固体分散体、顆粒内賦形剤及び顆粒外賦形剤を共に混合する段階;並びに
(c)段階(b)の前記混合物を圧縮させて錠剤を形成する段階。
(a)タキサンまたはその医薬的に許容可能な塩、医薬的に許容可能なポリマー、及び医薬的に許容可能な界面活性剤を溶媒に溶解させて溶液を生産し、その後、前記溶液から前記溶媒を除外して固体分散体を生産する段階;
(b)段階(a)の前記固体分散体と、顆粒内賦形剤とを共に混合する段階;
(c)段階(b)の前記混合物と顆粒外賦形剤とを混合する段階;並びに
(d)段階(c)の前記混合物を圧縮させて錠剤を形成する段階。
(b)前記固体分散体と顆粒外賦形剤とを共に混合する段階;並びに
(c)得られた混合物を圧縮させて錠剤を形成させる段階。
以下を含むタキサンを、必要とする個体に投与する方法が提供される:固体分散体として製造されたタキサンまたはその医薬的に許容可能な塩、医薬的に許容可能なポリマー、及び医薬的に許容可能な界面活性剤を含む医薬的経口固体投与剤形を提供する段階、並びに、治療的に有効量の前記医薬的剤形を必要とする個体に投与する段階。
表1に示された実施例1及び2の固体分散体を、従来の噴霧乾燥器を利用して、従来の噴霧乾燥で製造した。2つの異なるポリマー、HPMC及びPVPを使用して、パクリタキセル固体分散体を製造した。
表2に示された実施例3〜6の固体分散体を、前記従来の噴霧乾燥法を使用して製造した。多様なタイプの界面活性剤を使用して、パクリタキセル固体分散体を製造した。
表3に示された実施例7〜10の固体分散体を、前記従来の噴霧乾燥法を使用して、製造した。多様な量のポリマーを使用して、前記パクリタキセル固体分散体を製造した。
表4に示された実施例11の固体分散体を、実施例1で言及した従来の噴霧乾燥法を利用して製造した。最終固体分散体は、粉末混合物210mg当たり30mgのパクリタキセル相当量を含んでいた。
<実施例12−1>パクリタキセル含有固体分散体の製造
表5に示された実施例12−1の固体分散体を、流動層噴霧乾燥技術を利用して製造した。噴霧溶液は、パクリタキセル、PVP−K30、ポリソルベート80及びラウリル硫酸ナトリウムを、エタノール/水溶媒系に溶解させて製造した。前記溶液は、流動層システム(fluid bed system)において、表5に示されたような賦形剤混合物434g内に噴霧された。前記噴霧速度は、1つのトップガンを使用して、15〜25mL/分であった。静的注入口圧力(static inlet pressure)は、2.5−5バー(250−500kPa)であった。注入口温度は、65〜70℃であり、産物温度は30〜40℃であった。得られたパクリタキセル粉末混合物は、自由に流れ、最終混合物644mg当たり30mgのパクリタキセルを含んでいた。
表6に示されたように、パクリタキセル以外のタキサンを含む実施例12−2〜12−4の固体分散体を、流動層噴霧乾燥技術を利用して製造した。噴霧溶液は、ドセタキセル(カバジタキセルまたはテセタキセル)、PVP−K30、ポリソルベート80及びラウリル硫酸ナトリウムを、エタノール/水溶媒系に溶解させて製造した。前記溶液は、流動層システムにおいて、表6に示されたような賦形剤混合物434g内に噴霧された。前記噴霧速度は、1つのトップガンを使用して、15〜25mL/分であった。静的注入口圧力は、2.5−5バー(250−500kPa)であった。注入口温度は、65〜70℃であり、産物温度は30〜40℃であった。得られたパクリタキセル粉末混合物は、自由に流れ、最終混合物644mg当たり30mgのパクリタキセルを含んでいた。
表7に示された成分を利用して、パクリタキセル含有液体剤形を製造した。具体的には、活性成分として、パクリタキセルは、磁石撹拌棒を利用して、界面活性剤としてのツイン80に完全に溶解された。
表8に示されたように、実施例11の固体分散体を利用して錠剤を製造した。
<実施例14−1>実施例12−1の固体分散体含有錠剤の製造
表9に示されたように、実施例12−1の固体分散体を利用して錠剤を製造した。
表10に示されたように、実施例12−2〜12−4の固体分散体を利用して錠剤を製造した。
表11に示されたように、実施例12−1で言及された流動層噴霧乾燥技術を利用して、比較例2の錠剤を製造した。噴霧溶液は、パクリタキセル、ラウリル硫酸ナトリウム及びPVP−K30を、エタノール/水溶媒系に溶解させて製造した。前記溶液は、流動層システムにおいて、表11に示されたように、賦形剤混合物(微結晶性セルロース、クロスカルメロースナトリウム及びラウリル硫酸ナトリウム)300g内に噴霧された。前記噴霧速度は、1つのトップガンを使用して、15〜25mL/分であった。静的注入口圧力は、2.5−5バー(250−500kPa)であった。注入口温度は、65〜70℃であり、産物温度は30〜40℃であった。得られた粒子は、賦形剤表面にコーティングされた無定形パクリタキセルを含み、自由に流れるものであった。得られた粒子は、自由に流れ、30mgのパクリタキセル相当量を含んでいた。
表12に示された成分を利用して、パクリタキセル含有在来の錠剤を製造した。
パドル速度50rpmであり、37±0.5℃で、溶解媒質としてpH1.2バッファ300mLであり、USPXXIII、溶解装置(dissolution apparatus)IIを利用して、実施例1及び2の固体分散体の溶解度を調査した。パクリタキセルの固体分散体(パクリタキセルとして90mg)を溶解試験機(Labfine社製、韓国)に導入した。規定の時間間隔で、5mLずつを収集して濾過し、HPLC法によって、パクリタキセルの含量を分析した。新鮮な溶解媒質の均等な体積(5mL)を交替させ、サンプリングによる損失を補償し、研究の間続けてシンク条件を維持した。媒質内のパクリタキセルの理論的濃度は、300PPM(300mL媒質内に90mgパクリタキセル)である。結果を図1に示す。
試験例1で論議したところと同一条件を利用して、実施例3〜6の固体分散体の溶解度を調査した。SLSに加え、パクリタキセルの溶解度に対する多様なタイプの界面活性剤の効果を図2に示す。
試験例1で論議したところと同一条件を利用して、実施例7〜10の固体分散体の溶解度を調査した。パクリタキセルの溶解度に対するポリマー量の効果が、本研究で調査された。固体分散体を製造するために、30〜270mg範囲のPVP−K30ポリマー含量を使用した。結果を図3に示す。使用されたパクリタキセル対PVP−K30の重量比は、1:9(30:270)、1:6(30:180)、1:3(30:90)及び1:1(30:30)であった。
パドル速度50rpmであり、37±0.5℃で、溶解媒質としてpH1.2バッファ300mLであり、USPXXIII、溶解装置IIを利用して、実施例11及び12−1の固体分散体の溶解度を調査した。比較のために、比較例1の液体剤形(パクリタキセル90mgに相当)も溶解媒質に直接加えた。
試験例1で論議したところと同一条件を利用して、実施例13及び14−1、並びに比較例2及び3の錠剤の溶解度を調査した。実施例13及び14−1、並びに比較例2及び3(パクリタキセル90mgに相当)のパクリタキセル含有各剤形の3種錠剤を溶解試験機(Labfine社製、韓国)に導入した。全ての剤形の溶解度プロファイルを図5に示す。
従来の噴霧乾燥技術によって製造された実施例13の錠剤、前記流動層噴霧乾燥技術によって製造された実施例14−1の錠剤、最も高いポリマー比及びSLSだけの比較例2の錠剤、及び比較例3の在来の錠剤に対して、米国薬典(USP:United States Pharmacopoeia)によって崩壊試験を行った。各錠剤の崩壊時間を表13に示す。
従来の噴霧乾燥技術によって製造された実施例13の噴霧乾燥された錠剤、流動層噴霧乾燥工程によって製造された実施例14−1の噴霧乾燥された錠剤、及びパクリタキセルAPIに対して、スキャン速度6゜/分であり、CuX線40kV及び100mAの条件下で、M18XHF−SRA(Macsciences Co.,Ltd.,日本)を利用して、XRDで評価した。
生体内犬の生体利用率、及び薬動学的研究を行い、実施例13及び14−1、並びに比較例3の錠剤の生体利用率の上昇を調査した。
以下のプロトコルによる加速された条件によって、実施例14−1の錠剤を保存した。各活性成分の分解産物量を測定し、複合体剤形の安定性を比較した。結果を表16に示す。
−保存条件:40℃、7.5%RHでHDPE瓶内に収容
−試験期間:初期の1ヵ月及び3ヵ月
−分析目標:パクリタキセル及び関連化合物
パクリタキセル及びその関連化合物の分析条件
カラム:液体クロマトグラフィー(例えば、Symmetry C18、3um粒子サイズ)用オクタデシルシリルシリカゲルで充填されたステンレスカラム(内部径約4.6mm及び長さ15cm)
移動相:A:アセトニトリル:水(7:3);B:アセトニトリル
検出器:UV吸収検出器(227nmで吸収)
流速:1.2mL/min
注入体積:10μL
カラム温度:35℃
濃度勾配システム:
Claims (32)
- タキサンまたはその医薬的に許容可能な塩、
ポリビニルピロリドン、
ポリソルベート、及び
ラウリル硫酸ナトリウム
を含む無定形固体分散体。 - 前記タキサンは、パクリタキセル、ドセタキセル、カバジタキセル、ラロタキセル、オルタタキセル、テセタキセル、及びその組み合わせ体からなる群から選択される任意の一つであることを特徴とする、請求項1に記載の無定形固体分散体。
- 前記タキサンはパクリタキセルであることを特徴とする、請求項1に記載の無定形固体分散体。
- 前記ポリビニルピロリドンはポリビニルピロリドンK−30であることを特徴とする、請求項1に記載の無定形固体分散体。
- 前記ポリビニルピロリドン及びタキサンの重量比が、2:1〜9:1であることを特徴とする、請求項1に記載の無定形固体分散体。
- 前記ポリビニルピロリドン及びタキサンの重量比が、2.5:1〜3.5:1であることを特徴とする、請求項5に記載の無定形固体分散体。
- 前記ポリソルベートはポリソルベート80であることを特徴とする、請求項1に記載の無定形固体分散体。
- 前記ポリソルベート対前記ラウリル硫酸ナトリウムの重量比が、1:5〜5:1であることを特徴とする、請求項1に記載の無定形固体分散体。
- 前記タキサン対前記ポリソルベート及び前記ラウリル硫酸ナトリウムの組み合わされた重量の重量比が、1:1〜1:3であることを特徴とする、請求項1に記載の無定形固体分散体。
- 前記ポリソルベート及び前記ラウリル硫酸ナトリウムの組み合わされた重量対前記ポリビニルピロリドンの重量比が、1:1〜1:5であることを特徴とする、請求項1に記載の無定形固体分散体。
- 前記ポリビニルピロリドンは、前記無定形固体分散体の総量に対して10重量%〜80重量%の量で存在することを特徴とする、請求項1に記載の無定形固体分散体。
- 前記ポリビニルピロリドンは、前記無定形固体分散体の総量に対して40重量%〜60重量%の量で存在することを特徴とする、請求項11に記載の無定形固体分散体。
- 前記ポリソルベート及び前記ラウリル硫酸ナトリウムの組み合わされた重量が、前記無定形固体分散体の総量に対して10重量%〜50重量%であることを特徴とする、請求項1に記載の無定形固体分散体。
- 前記ポリソルベート及び前記ラウリル硫酸ナトリウムの組み合わされた重量が、前記無定形固体分散体の総量に対して30重量%〜40重量%であることを特徴とする、請求項13に記載の無定形固体分散体。
- 前記ポリビニルピロリドン対前記タキサンの重量比が、約3:1であり、前記タキサン対前記ポリソルベート及び前記ラウリル硫酸ナトリウムの組み合わされた重量の重量比が、約1:2であることを特徴とする、請求項1に記載の無定形固体分散体。
- 請求項1〜請求項15のうちいずれか1項に記載の無定形固体分散体、顆粒内賦形剤及び顆粒外賦形剤を含む錠剤。
- 前記無定形固体分散体は、前記錠剤の総重量に対して15重量%〜50重量%の量で存在することを特徴とする、請求項16に記載の錠剤。
- 前記無定形固体分散体は、前記錠剤の総重量に対して20重量%〜30重量%の量で存在することを特徴とする、請求項17に記載の錠剤。
- 前記顆粒内賦形剤及び顆粒外賦形剤は、充填剤、崩壊剤、潤滑剤、界面活性剤、及びそれらの混合物からなる群からそれぞれ選択されることを特徴とする、請求項16に記載の錠剤。
- 前記顆粒内賦形剤は、微結晶性セルロース、クロスカルメロースナトリウム、ラウリル硫酸ナトリウム、及びそれらの混合物からなる群から選択されることを特徴とする、請求項16に記載の錠剤。
- 前記顆粒外賦形剤は、微結晶性セルロース、クロスカルメロースナトリウム、フマル酸ステアリルナトリウム、及びそれらの混合物からなる群から選択されることを特徴とする、請求項16に記載の錠剤。
- 下記段階を含む請求項1〜請求項15のうちいずれか1項に記載の無定形固体分散体を製造する方法:
(a)タキサンまたはその医薬的に許容可能な塩、ポリビニルピロリドン、ポリソルベート、及びラウリル硫酸ナトリウムを溶媒に溶解させる段階、並びに
(b)前記(a)段階で得られた溶液を乾燥させる段階。 - 前記(b)段階は噴霧乾燥を含むことを特徴とする、請求項22に記載の方法。
- 前記タキサンは有機溶媒に溶解されていることを特徴とする、請求項22に記載の方法。
- 前記ポリビニルピロリドン、前記ポリソルベート、及び前記ラウリル硫酸ナトリウムは、水性有機溶媒に溶解されていることを特徴とする、請求項22に記載の方法。
- 前記水性有機溶媒はエタノール及び水の混合物を含むことを特徴とする、請求項25に記載の方法。
- 下記段階を含む請求項16〜請求項21のうちいずれか1項に記載の錠剤を製造する方法:
(a)タキサンまたはその医薬的に許容可能な塩、ポリビニルピロリドン、ポリソルベート、及びラウリル硫酸ナトリウムを溶媒に溶解させる段階;
(b)前記(a)段階で得られた溶液を乾燥させて固体分散体を生産する段階;
(c)前記固体分散体を顆粒外賦形剤と共に混合する段階;並びに
(d)得られた混合物を圧縮させて錠剤を形成する段階。 - 前記(b)段階は噴霧乾燥を含むことを特徴とする、請求項27に記載の方法。
- 前記噴霧乾燥は流動層において行われることを特徴とする、請求項28に記載の方法。
- 前記流動層は顆粒内賦形剤を含むことを特徴とする、請求項29に記載の方法。
- 前記ポリビニルピロリドン、前記ポリソルベート、及び前記ラウリル硫酸ナトリウムは、水性有機溶媒に溶解されていることを特徴とする、請求項27に記載の方法。
- 前記水性有機溶媒はエタノール及び水の混合物を含むことを特徴とする、請求項31に記載の方法。
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