JP2010540554A - 静脈内投与又は注射可能な医薬を経口投与剤形に変換する方法及び製剤 - Google Patents
静脈内投与又は注射可能な医薬を経口投与剤形に変換する方法及び製剤 Download PDFInfo
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Abstract
Description
(a)レシチン及びその誘導体のような両親媒性物質、ステロール(好ましくは植物性ステロール)、有効な医薬物質及び医薬排出タンパク阻害剤を、非極性溶媒(好ましくは酢酸エチル又はヘプタン)中で、その沸点において混合する;
(b)全成分の溶解度を維持するために高温で溶媒を留去した後、固体を回収する;
(c)固体を小片に破壊し、成分の1つの分解温度又は水の沸点のいずれか低い方より低い温度において、激しく撹拌しながら、水中に分散させる;
(d)乳状溶液を、最高圧力で作動するGaulin Dairyホモジナイザー(又は好適な均等物)を通過させる;及び、その後、
(e)乳状溶液を噴霧乾燥又は凍結乾燥して、錠剤又はカプセルに充填される固体を生成する(必要であれば、好適な添加剤を添加する)。任意に、好適な乾燥助剤(Maltrin、Capusile M又は好適な均等物)を添加する。
方法Iに記載のようにして、別々に、有効な医薬物質及び医薬排出タンパク阻害剤を調製する。ついで、噴霧乾燥した2つの粉末を乾燥混合して、1つの錠剤又はカプセルとする。
方法Iに記載のようにして、各々、有効な医薬物質及び医薬排出タンパク阻害剤を別個に調製する。有効な医薬を含有する粉末を、それ自体の錠剤又はカプセルに充填し、医薬排出タンパク阻害剤を含有する粉末を、別個に、それ自体の錠剤又はカプセルに充填する。この方法では、医薬排出タンパク阻害剤の投与を、有効な医薬物質の投与前の各種の時点で行うことができる。
固状パクリタキセル(20mg)、植物性ステロール(20mg)及びリゾレシチン(60mg)を、5個のプラスチックチューブの各々に入れ、各サンプルチューブにクロロホルム(1.0ml)を添加した。60℃の水浴で穏やかに加温しながら、窒素流下で、溶媒を除去し、ついで、残留する溶媒を除去するため、ポンプ吸引した。実験当日に、水(10ml)を添加し、混合物を、約0.32 cm(1/8インチ)のテーパ状先端を有するBranson Digital Sonifierにて、50%のパワーで30秒間超音波処理した。ついで、液状物を注射器で動物に投与した。注射器に水を加え、洗浄液をイヌに投与した。
パクリタキセルを上述のように処理した。ただし、超音波処理前に、水5.0mlを添加した。
固状サイクロスポリンA(80mg)、植物性ステロール(80mg)及びレシチン(160 mg)を、5個のプラスチックチューブの各々に入れ、各サンプルチューブにクロロホルム(1.0ml)を添加した。P-pg阻害剤を、パクリタキセルについての上記記載と同様に処理した。ただし、超音波処理前に水5.0mlを添加した。超音波処理の後、パクリタキセル溶液及びサイクロスポリン溶液を混合し、ミルク様の混合物を、実験当日に、注射によってイヌに投与した。
炭酸カルシウム(50mg)、Maltrin(登録商標)(75mg)及び二酸化ケイ素(3mg)を秤量し、「000」ゼラチンカプセルに入れた。別個に、パクリタキセル(20mg)を秤量し、前記カプセル内の他の成分に添加した。カプセルのヘッド片をボトム片に設置し、内容物を激しく振盪して、固体を撹拌した。
各製剤を投与した後、すべての血液サンプルを、ヘパリンナトリウム抗凝血剤チューブにおいて集め、加工して血漿とし、−80℃で凍結した。5匹のイヌの各々について、各時点における血漿中のパクリタキセルの濃度を、Bioanalytical Systems(McMinnville, OR)での高スループット液体クロマトグラフィー‐タンデム質量分析法によって測定した。図1に示すように、このCremophor Eフリーの液状製剤については、非製剤化パクリタキセルについてのものと比較すると、パクリタキセルの吸収において顕著な増大が認められた。吸収の変化を定量するため、各製剤系について、曲線下の面積(AUC0→∞)を算定し、結果を下記の表に示した。非製剤化パクリタキセルと比べて、製剤系単独では4.1倍の吸収増大(p=0.18)、製剤化パクリタキセル−サイクロスポリンA組み合わせでは、統計学的に有意な(p=0.008)41倍の増大が認められた。
固状パクリタキセル(300 mg)、大豆ステロール(300 mg)及びリゾレシチン(900 mg)を30mlのガラスチューブに入れ、クロロホルム(3.0ml)を添加した。60℃の水浴で穏やかに加熱しながら、窒素流下で、溶媒を除去した。ついで、残留する溶媒を除去するため、ポンプ吸引した。水(15ml)を添加して固状物を軟化させ、ついで、混合物を、氷浴中で、40%のパワーで2分間超音波処理し、続いて、50%のパワーで2分間、さらに、60%のパワーで2分間超音波処理した。得られたミルク様の溶液を、ついで、凍結乾燥ジャーに移し、クロスカルメルロース及びヒュームドシリカを添加し、続いて、固状物を分散させるため、60%のパワーでさらに2分間超音波処理した。ついで、ミルク様の溶液を、ドライアイス−アセトン浴において外殻凍結し、凍結乾燥した。凍結乾燥した製剤化パクリタキセル(110 mg, パクリタキセル21mg)を、炭酸カルシウム、Maltrin(登録商標)及び二酸化ケイ素と共に乾燥造粒した。かさ密度の顕著な減少が認められた。流動可能な粉末を「000」カプセルに充填した。この造粒プロセスを、5個の別個のカプセルについて5回繰り返した。
固状サイクロスポリンA(500 mg)、大豆ステロール(500 mg)及びレシチン(1000 mg)を、2個の30mlガラスの各々に入れ、クロロホルム(3.0ml)を添加した。固状パクリタキセルについての上記記載と同様にして、成分の凍結乾燥混合物を調製した。サイクロスポリン混合物のかさ密度を増大させるため、91%イソプロパノール中に溶解した10%ポリビニルピロリドンを噴霧することによって、粉末を、炭酸カルシウムと共に湿式造粒した。混合物を48時間空気乾燥し、淡黄色の固状物を集め、#10篩を通過させた。より大きい粒状物をコーヒーミルにて粉砕し、固状物を再度篩通しした。カプセルに2段階で充填した。初めに、サイクロスポリン粒を秤量して「000」カプセルに充填し、続いて、キャップをしないまま、直立した状態に静置した。2段階目として、乾燥造粒したパクリタキセルを添加し、カプセルのヘッド片をしっかりと設置した。
炭酸カルシウム(50mg)、Maltrin(登録商標)(75mg)及び二酸化ケイ素(3mg)を秤量し、「000」ゼラチンカプセルに入れた。別個に、パクリタキセル(20mg)を秤量し、前記カプセル内の他の成分に添加した。カプセルのヘッド片をボトム片に設置し、内容物を激しく振盪して、固体を撹拌した。
各製剤を投与した後、すべての血液サンプルを、液状製剤について記載したように、処理し、分析した。図2に示すように、2個の固状製剤については、非製剤化パクリタキセルについてのものと比較すると、パクリタキセルの吸収において顕著な増大が認められた。吸収の変化を定量するため、各製剤系について、曲線下の面積(AUC0→∞)を算定し、結果を下記の表に示した。非製剤化パクリタキセルと比べて、製剤系単独では3.5倍の吸収増大(p=0.02)、製剤化パクリタキセル−サイクロスポリンA組み合わせでは、統計学的に有意な(p=0.008)26倍の増大が認められた。
Claims (40)
- 通常は難溶性の、疎水性、結晶性の医薬活性剤用の医薬送達組成物であって、乳化剤、植物性ステロール(スタノール)又は該ステロール(スタノール)から誘導されるエステル;医薬活性に有効な量の疎水性の医薬活性剤;及び少量ではあるが、阻害に有効な量の小腸排出タンパク阻害剤を含んでなる医薬送達組成物。
- 乳化剤が食品用又は医薬用として許容されたものである請求項1記載の医薬送達組成物。
- 乳化剤が、レシチン、リゾレシチン、モノ又はジグリセリド、モノ又はジグリセリドのジアセチル酒石酸エステル、リン酸モノグリセリド、アセチル化モノグリセリド、エトキシル化モノ又はジグリセリド、乳酸化モノグリセリド、プロピレングリコールエステル、ポリグリセリンエステル、ポリソルベート、ソルビタンエステル、ステアロイル乳酸ナトリウム又はカルシウム、コハク酸化モノグリセリド、脂肪酸のショ糖エステル、脂肪アルコール、脂肪酸のナトリウム塩、ツイーン又はこれらの組み合わせからなる群から選ばれるものである請求項2記載の医薬送達組成物。
- 植物性ステロール(ステアノール)又は植物性ステロール(ステアノール)エステルが、植物源又はトール油源に由来するものである請求項1記載の医薬送達組成物。
- 乳化剤が組成物の約7.5〜約95質量%であり、ステロールが組成物の約2〜約75質量%であり、有効な医薬が組成物の約2〜約50質量%であり、及び腸排出阻害剤が組成物の約2〜約50質量%である請求項1記載の医薬送達組成物。
- 乳化剤が組成物の約20〜約80質量%であり、ステロールが組成物の約10〜約60質量%であり、有効な医薬が組成物の約10〜約40質量%であり、及び腸排出阻害剤が組成物の約10〜約40質量%である請求項5記載の医薬送達組成物。
- 追加の疎水性の化合物としてビタミンEを含むものである請求項1記載の医薬送達組成物。
- 有効な医薬が、麻酔剤、抗喘息薬、抗生物質、抗鬱剤、抗糖尿病薬、抗癲癇薬、抗菌剤、抗痛風薬、抗腫瘍薬、抗肥満薬、抗原虫薬、解熱剤、抗ウイルス薬、抗精神病薬、カルシウム調節剤、心血管薬、コルチコステロイド、利尿剤、ドーパミン作動薬、消化管薬、ホルモン(ペプチド及び非ペプチド)、免疫抑制剤、脂質調節剤、植物性エストロゲン、プロスタグランジン、弛緩薬及び興奮剤、ビタミン/栄養剤、キサンチン及び生体異物からなる群から選ばれるものである請求項1記載の医薬送達組成物。
- 有効な医薬が生体異物である請求項8記載の医薬送達組成物。
- 生体異物が、タキ酸系抗ガン剤、カンプトテシン、アントラサイクリン系抗ガン剤、ビンカアルカロイド及びエピポドフィロトキシンからなる群から選ばれるものである請求項9記載の医薬送達組成物。
- 生体異物がパクリタキセルである請求項9記載の医薬送達組成物。
- 生体異物がトポテカンである請求項9記載の医薬送達組成物。
- 生体異物がドキソルビシンである請求項9記載の医薬送達組成物。
- 生体異物がビンブラスチンである請求項9記載の医薬送達組成物。
- 生体異物がエトポシドである請求項9記載の医薬送達組成物。
- 組成物のすべてが、代表的なシングル医薬経口投与送達系で提供される請求項1記載の医薬送達組成物。
- 小腸排出阻害剤が、ベラパミル、サイクロスポリンA、サイクロスポリンC、エリスロマイシン、キニン、フルフェナジン、レセルピン、プロゲステロン、タモキシフェン、ミトタン、アンナマイシン、ビリコダル、エラクリダル、タリキダル及びゾスキダルからなる群から選ばれるものである請求項1記載の医薬送達組成物。
- 有効な医薬及び小腸排出阻害剤を、相互に混合して医薬送達組成物を形成する前に、別個に、ステロール及び乳化剤と混合する請求項1記載の医薬送達組成物。
- 2つの経口剤として形成し、1つは、有効な医薬、ステロール及び乳化剤を含有するものであり、他の1つは、ステロール、乳化剤及び小腸排出阻害剤を含有するものである請求項1記載の医薬送達組成物。
- 有効な医薬及び乳化剤を乾燥して粉末とし、ついで、ステロール、乳化剤及び乾燥して粉末とした小腸排出阻害剤と混合したものである請求項1記載の医薬送達組成物。
- 錠剤又はカプセル剤から選ばれる経口剤である請求項1記載の医薬送達組成物。
- 経口投与組成物を飲料又は医療用食品に配合する請求項1記載の医薬送達組成物。
- 圧力少なくとも100 psigにおいて、少なくとも15秒間、圧縮又は押し出し成形することによって請求項1記載の医薬送達組成物から形成された錠剤。
- 通常は難溶解性の疎水性化合物用の医薬送達系を製造する方法であって、
非極性溶媒と共に、乳化剤又はその混合物;植物性ステロール(スタノール)又は植物性ステロール(スタノール)由来のエステル(脂肪酸エステルモイエティーが植物又はトール油に由来するものである);有効な医薬;及び小腸医薬排出タンパク阻害剤を混合し;
溶媒を除去して、混合した成分の固状残渣を生成し;
混合した成分のいずれかの分解温度未満の温度で、前記混合した成分の固状残渣に水を添加し;
水性混合物を均質化し;
均質化した混合物を乾燥し;及び
混合した成分の乾燥した固状残渣を、固状の医薬品用キャリヤーフォーマット内に備えることを含んでなる医薬送達系の製法。 - 非極性溶媒が、酢酸エチル、クロロホルム、ジクロロメタン、イソプロパノール、二酸化炭素及びヘプタンからなる群から選ばれるものである請求項24記載の方法。
- 非極性溶媒がその沸点状態にある請求項24記載の方法。
- 非極性溶媒を、温度を溶媒の沸点以上に上昇させることによって除去する請求項24記載の方法。
- 混合した成分の乾燥した固状残渣を、混合した成分のいずれかの分解温度未満の温度において、激しく撹拌しながら、水中に分散させる請求項24記載の方法。
- 最終の乾燥前に、混合した成分が分散された水を均質化する追加の工程を含む請求項24記載の方法。
- 溶媒を除去した後に形成された固体を、好適なミル、粉砕機又はプロセッサーにおいて粉砕して、分散可能な粉末を生成する請求項24記載の方法。
- 溶媒含量が0.5%未満の固状残渣が得られるまで溶媒の除去を続けて行う請求項24記載の方法。
- 請求項29記載の粉末を、混合した成分のいずれかの分解温度未満の温度において、激しく撹拌しながら、水に添加する請求項24記載の方法。
- 未粉砕の乾燥した固状残渣に直接水を導入する請求項24記載の方法。
- 水が、混合した成分のいずれかの分解温度未満の温度である請求項33記載の方法。
- 水性混合物を、Gaulinホモジナイザー、Frenchプレス、超音波処理器及びマイクロフルイダイザーから選ばれるホモジナイザーにおいて均質化する請求項24記載の方法。
- 均質化した水性混合物を、噴霧乾燥機及び凍結乾燥機からなる群から選ばれる乾燥機において乾燥する請求項24記載の方法。
- デンプン、二酸化ケイ素及びケイ酸カルシウムからなる群から選ばれる乾燥助剤を添加する請求項36記載の方法。
- 炭酸カルシウムのような好適な制酸剤を、乾燥した粉末に配合する請求項37記載の方法。
- 制酸剤を0.1〜10質量%で添加する請求項37記載の方法。
- 制酸剤を3.5質量%で添加する請求項39記載の方法。
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2007
- 2007-09-28 US US11/864,113 patent/US20090088393A1/en not_active Abandoned
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2008
- 2008-09-25 CA CA2701023A patent/CA2701023C/en not_active Expired - Fee Related
- 2008-09-25 WO PCT/US2008/077646 patent/WO2009045837A1/en active Application Filing
- 2008-09-25 MX MX2010003470A patent/MX2010003470A/es active IP Right Grant
- 2008-09-25 JP JP2010527135A patent/JP5496894B2/ja not_active Expired - Fee Related
- 2008-09-25 AU AU2008309010A patent/AU2008309010B2/en not_active Ceased
- 2008-09-25 EP EP08836498.9A patent/EP2205219B1/en not_active Not-in-force
- 2008-09-25 ES ES08836498.9T patent/ES2608818T3/es active Active
- 2008-09-25 BR BRPI0817237-4A patent/BRPI0817237A2/pt not_active Application Discontinuation
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2014
- 2014-08-06 US US14/452,993 patent/US20150031628A1/en not_active Abandoned
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Also Published As
Publication number | Publication date |
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US20150031628A1 (en) | 2015-01-29 |
ES2608818T3 (es) | 2017-04-17 |
WO2009045837A1 (en) | 2009-04-09 |
US20090088393A1 (en) | 2009-04-02 |
MX2010003470A (es) | 2010-04-27 |
AU2008309010A1 (en) | 2009-04-09 |
AU2008309010B2 (en) | 2012-07-19 |
EP2205219A1 (en) | 2010-07-14 |
CA2701023A1 (en) | 2009-04-09 |
JP5496894B2 (ja) | 2014-05-21 |
EP2205219B1 (en) | 2016-11-02 |
CA2701023C (en) | 2013-07-30 |
BRPI0817237A2 (pt) | 2015-06-16 |
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