JP6925970B2 - 副甲状腺機能低下症の治療 - Google Patents
副甲状腺機能低下症の治療 Download PDFInfo
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Description
副甲状腺ホルモンまたはその断片と、
SNAC(8−N−(2−ヒドロキシベンゾイル)アミノカプリル酸ナトリウム)と
を含む、医薬組成物が提供される。
副甲状腺ホルモンまたはその断片と、
SNAC(8−N−(2−ヒドロキシベンゾイル)アミノカプリル酸ナトリウム)と
を含む使用が提供される。
副甲状腺ホルモンまたはその断片と、
SNAC(8−N−(2−ヒドロキシベンゾイル)アミノカプリル酸ナトリウム)と
を含む組成物を、対象に経口投与することを含む方法が提供される。
副甲状腺ホルモンまたはその断片と、
SNAC(8−N−(2−ヒドロキシベンゾイル)アミノカプリル酸ナトリウム)と
を含む。
本明細書で用いられる語句「医薬組成物」(本明細書では、簡潔性のために「組成物」とも呼ばれる)は、副甲状腺ホルモン(PTH)(例えば、PTH(1−34)、PTH(1−84))と、SNACなどの他の化学的成分と、所望により、本明細書に記載のさらなる成分とを含む製剤を指す。医薬組成物の目的は、PTHの投与を容易にすることである。
本明細書に記載の実施形態のいずれかの態様のいくつかにおいて、組成物は少なくとも1つのプロテアーゼ阻害剤をさらに含む。
本明細書に記載の実施形態のいずれか1つにおける態様のいくつかにおいては、SNACを、場合により、SNAD(10−N−(2−ヒドロキシベンゾイル)アミノデカン酸ナトリウム)などの類似化合物で置き換えてもよい。以下に示される通り、SNADの構造は、脂肪酸部分の長さにおいてのみSNCAの構造と異なる。
本明細書に記載の実施形態に係わるいくつかの態様において、(場合により、本明細書に記載の対応する実施形態のいずれかによる、組成物単位剤形の形態の)組成物は、PTHとSNACと、場合により、(本明細書に記載の対応する実施形態のいずれかによる)プロテアーゼ阻害剤とに加えて、少なくとも1つの疎水性物質を含む。
本明細書に記載の実施形態の態様のいずれかによるいくつかの形態において、(本明細書に記載の対応する実施形態のいずれかによる)PTHおよびSNACを含む組成物は、少なくとも1つの固体粒子を含む薬物送達システムの一部を形成する。固体粒子は、PTHおよびSNACを含む組成物を含むコアと、水不溶性透水性コーティングおよび(本明細書で定義される)腸溶コーティングからなる群より選択されるコーティングとを含む。いくつかの態様において、コーティングは、コアの表面全体を被覆する。いくつかのそのような実施形態において、少なくとも1つの固体粒子を含む薬物送達システムは、(例えば、本明細書に記載の対応する実施形態のいずれかによる)長期放出製剤である。
本明細書に記載の実施形態の態様のいずれかによるいくつかの形態において、方法または治療は、保護剤の経口投与をさらに含む。
本明細書に記載の実施形態のいずれか1つにおけるいくつかの態様において、PTHおよびSNACを含む組成物(本明細書に記載の対応する実施形態のいずれかによるもの)は、ケーシングと、ケーシング内に含有されるPTHおよびSNACを含む組成物とを含む薬物送達システムの一部を形成する。
本明細書および当業界において、用語「副甲状腺機能低下症」とは、副甲状腺ホルモンの産生低下を特徴とする障害を指し、副甲状腺ホルモンの産生低下は、典型的には、副甲状腺の機能低下、例えば、副甲状腺の非存在または損傷(例えば、外科手術、自己免疫侵襲、マグネシウム欠乏、ヘモクロマトーシス、出生時の腺の非存在、および/または様々な遺伝的障害によるもの)に起因するものである。低い副甲状腺ホルモンレベルに伴う症状の例としては、これらに限定されるものではないが、(発作、不整脈および/または気道痙縮をもたらし得る)低い血中カルシウムレベル、知覚障害、筋痙攣およびテタニーが挙げられる。
次に、以下の実施例に参照するが、これらは上記説明と共に本発明の実施形態の一部を詳細に示すものであるが、本発明を限定するものではない。
材料:
8−アミノカプリル酸を、Alfa−Aesar社から入手した。
ステアリン酸マグネシウムを、Sigma−Aldrich社から入手した。
O−アセチルサリチロイルクロリドを、Sigma−Aldrich社から入手した。
ダイズトリプシン阻害剤(SBTI)を、Sigma−Aldrich社から入手した。
テリパラチドを、Bachem社から購入した。
重炭酸ナトリウムを、Merck社から入手した。
SNAC(8−N−(2−ヒドロキシベンゾイル)アミノカプリル酸ナトリウム)は、O−アセチルサリチロイルクロリドと8−アミノカプリル酸とを反応させることによって製造した。
乳棒と乳鉢を用いた幾何学的希釈によって、テリパラチドと、製剤の他の成分とを完全に混合することで、テリパラチド錠剤を製造した。8mmの両凸パンチおよびダイセットを具備した、手動で操作される単一パンチ打錠機(ドイツ国、Korsch製)を用い、圧力を20秒間印加することで、製剤成分の直接圧縮により円筒状の錠剤を製造した。
溶出および崩壊を、錠剤溶出/崩壊試験器(中国、PJ−3)を用いて測定した。錠剤の完全な溶出/崩壊に必要な時間を決定した。USPパドル法II(USP23)を溶出の測定に用いた。回転速度は50または100回転/分(それぞれの実験については以下に示される通り)であり、特定した溶出媒体の容量は900mlであり、それを37℃で維持した。崩壊の測定は、37℃に維持した800mlの媒体を用いてUSPプロトコールに従って実施した。完全な溶出は、ガラス容器底部に視認できる製剤が完全に存在しないことと定義した。完全な崩壊は、試験装置のスクリーン上に残存する錠剤のすべての残渣が明白に確認できるコアを有さない柔らかい塊である状態と定義した。
テリパラチド(副甲状腺ホルモン(1−34))を含む例示的な経口製剤の第I相臨床試験を、ハダサ・クリニカル・リサーチ・センター(Hadassah Clinical Research Center)で行った。試験を通して42人の健康なボランティアが含まれていた。
テリパラチドを含む例示的な経口製剤の第IIa相多施設臨床試験を、原発性副甲状腺機能低下症(PHP)が確立された(発症から1年を超える)19人の患者に対して行った。PHPは、13人の患者においては術後性であり、5人の患者においては自己免疫性であり、1人の患者においては遺伝性であった。
テリパラチド(1mg)の形態の副甲状腺ホルモン(PTH)、SNAC(8−N−(2−ヒドロキシベンゾイル)アミノカプリル酸ナトリウム)、ダイズトリプシン阻害剤(SBTI)およびステアリン酸マグネシウム(潤滑剤)からなる300mgの錠剤であって、エチルセルロース(EC)なしのもの、および41.67または62.5重量パーセントの顆粒化エチルセルロース(EC)を含むものを上記のように製造した。それぞれの製剤の組成を、以下の表3に提示する。
上記の錠剤で用いた顆粒化エチルセルロースではなく、微粉末状のエチルセルロース(100FPプレミアム)を用いて、さらなる錠剤を上記のように製造した。この錠剤は、テリパラチド(0.67mg)の形態の副甲状腺ホルモン(PTH)、SNAC、SBTIおよびステアリン酸マグネシウムからなり、30重量パーセントのエチルセルロース(EC)を含む、またはエチルセルロース(EC)を含まないものであった。
本発明のいくつかの態様による活性成分である、副甲状腺ホルモンおよびSNAC(8−N−(2−ヒドロキシベンゾイル)アミノカプリル酸ナトリウム)(それ自体、または本明細書に記載の対応する実施形態のいずれかに記載の医薬組成物として処方されたもの)を封入するケーシングを含む薬物送達システムは、場合により、図21に示されるように組み立てられる。
図23は、本発明のいくつかの態様によるケーシングの構造を示す。
同量のSNAC、トリプシン阻害剤およびテリパラチド(副甲状腺ホルモン(1−34))を有する2つの錠剤製剤を製造した。一方の製剤は、上記に加えて100mgの重炭酸ナトリウムを含有し、他方の製剤は、重炭酸ナトリウムを含有しない。錠剤は共に均一な混合物の形態にあった。
非盲検比較薬物動態試験を、10人の健康なボランティアに対して実施した。異なる来院時に、各ボランティアは、0.75mgのテリパラチド、即ち、組換え型の副甲状腺ホルモン(1−34)(PTH(1−34))を含有する同じ経口錠剤を与えられた。1回目の来院において、錠剤を150mlの水と共に投与したが、2回目の来院において、錠剤を150mlの3mg/ml重炭酸ナトリウム水溶液と共に投与した。
Claims (9)
- 副甲状腺機能低下症の治療に用いるための医薬組成物であって、治療を必要とする対象に経口摂取によって投与するためのものであって、錠剤として処方されており、
100〜3000μgの範囲内の副甲状腺ホルモンまたはその断片と、
少なくとも1つのプロテアーゼ阻害剤と、
50〜99.4重量パーセントの範囲内の濃度のSNAC(8−N−(2−ヒドロキシベンゾイル)アミノカプリル酸ナトリウム)と
を含み、
経口摂取による少なくとも1日2回の投与用である、医薬組成物。 - 前記断片がテリパラチドを含む、請求項1に記載の医薬組成物。
- 前記少なくとも1つのプロテアーゼ阻害剤が、少なくとも1つのトリプシン阻害剤を含む、請求項1または2に記載の医薬組成物。
- 前記少なくとも1つのトリプシン阻害剤が、ライマメトリプシン阻害剤、アプロチニン、ダイズトリプシン阻害剤およびオボムコイドトリプシン阻害剤からなる群より選択される、請求項3に記載の医薬組成物。
- 前記少なくとも1つのトリプシン阻害剤が、ダイズトリプシン阻害剤を含む、請求項3に記載の医薬組成物。
- 前記副甲状腺ホルモンまたはその断片の量が、750〜3000μgの範囲内である、請求項1〜5のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が、経口摂取による1日3回または4回の投与用である、請求項1〜6のいずれか一項に記載の医薬組成物。
- 1日当たり400μg〜2000μgの範囲内の量の前記副甲状腺ホルモンまたはその断片を経口摂取により投与するための、請求項1〜7のいずれか一項に記載の医薬組成物。
- 前記経口摂取は、直近の食物摂取の少なくとも4時間後に行うものである、請求項1〜8のいずれか一項に記載の医薬組成物。
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JP2021128296A JP2021176914A (ja) | 2015-02-09 | 2021-08-04 | 副甲状腺機能低下症の治療 |
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US201562113638P | 2015-02-09 | 2015-02-09 | |
US201562113673P | 2015-02-09 | 2015-02-09 | |
US201562113625P | 2015-02-09 | 2015-02-09 | |
US201562113619P | 2015-02-09 | 2015-02-09 | |
US201562113604P | 2015-02-09 | 2015-02-09 | |
US201562113600P | 2015-02-09 | 2015-02-09 | |
US201562113629P | 2015-02-09 | 2015-02-09 | |
US62/113,619 | 2015-02-09 | ||
US62/113,600 | 2015-02-09 | ||
US62/113,604 | 2015-02-09 | ||
US62/113,625 | 2015-02-09 | ||
US62/113,629 | 2015-02-09 | ||
US62/113,638 | 2015-02-09 | ||
US62/113,673 | 2015-02-09 | ||
PCT/IL2016/050151 WO2016128970A1 (en) | 2015-02-09 | 2016-02-09 | Treatment of hypoparathyroidism |
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