JP7247122B2 - ベリノスタットの新規経口製剤 - Google Patents
ベリノスタットの新規経口製剤 Download PDFInfo
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- JP7247122B2 JP7247122B2 JP2019572383A JP2019572383A JP7247122B2 JP 7247122 B2 JP7247122 B2 JP 7247122B2 JP 2019572383 A JP2019572383 A JP 2019572383A JP 2019572383 A JP2019572383 A JP 2019572383A JP 7247122 B2 JP7247122 B2 JP 7247122B2
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- belinostat
- amorphous
- pvp
- solid dispersion
- polymer
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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Description
ベリノスタット(Belinostat)はスルホンアミド‐ヒドロキサミド構造を有するヒストンデアセチラーゼ阻害剤(HDAC阻害剤)である。ベリノスタットの化学名は:(2E)‐N‐ヒドロキシ‐3‐[3‐(フェニルスルファモイル)フェニル]プロプ‐2‐エナミドである。その構造式は以下のとおりである:
第一の目的によると、本発明は、以下:
a)ベリノスタット、薬学的に許容されるまたはその薬学的に許容される塩、溶媒和物もしくはエステル;
b)少なくとも1つの非イオン化可能(中性)非セルロースポリマー;および
c)任意選択で、少なくとも1つの添加剤、
を含むベリノスタットの非晶質固体分散体(ASD)を提供する。
a)ベリノスタット薬学的に許容されるまたはその薬学的に許容される塩、溶媒和物もしくはエステル;
b)少なくとも1つのポリビニルラクタムポリマー;および
c)任意選択で、少なくとも1つの添加剤、
を含むベリノスタットの非晶質固体分散体に関係する。
ある実施形態によると、前記ポリマーは水溶性である。ある実施形態によると、前記ポリマーは直鎖ポリマーである。「直鎖ポリマー」とは、本明細書中で使用される場合、前記鎖に沿った接続のように端と端をつなぎ合わせた反復単位の長い紐から成る直鎖ポリマーを指す。
Povidone K12(BASFによって製造されたKollidon(登録商標)12PF)、Povidone K17(BASFによって製造されたKollidon(登録商標)17PF;ISPによって製造されたPlasdone(登録商標)C‐15)、Povidone K25(BASFによって製造されたKollidon(登録商標)25;ISPによって販売されたPlasdone(登録商標)K‐25)、Povidone K30(BASFによって製造されたKollidon(登録商標)30、ISPによって製造されたPlasdone(登録商標)K‐29/32)、低過酸化物グレードを有するPovidone K30(Kollidon(登録商標)30LP)、Povidone K90(BASFによって製造されたKollidon(登録商標)90F;ISPによって販売されたPlasdone(登録商標)K‐90、K‐90DおよびK‐90M)を含めた、それらの分子量を特徴づける様々な公称K値を有する医薬グレード生成物である。
式(I)の代表的なポリマーは以下で詳述される:
特にPVP K30とPVP VA64、およびその混合物から選択される。
ある実施形態によると、ベリノスタットの非晶質固体分散体はまた、少なくとも1つの添加剤を含んでもよい。
‐約5~80%(重量)のベリノスタット;および
‐約20~95%(重量)の前記非イオン化可能非セルロースポリマー、例えばポリビニルラクタムポリマーなど;
特に約15~50%のベリノスタット(重量)および約50~85%(重量)の前記非イオン化可能非セルロースポリマー、例えばポリビニルラクタムポリマーなど、
を含み得る。
ベリノスタット二量体((E)‐3‐(3‐(N‐フェニルスルファモイル)フェニル)‐N‐(((E)‐3‐(3‐(N‐フェニルスルファモイル)‐フェニル)アクリロイル)オキシ)アクリルアミド)は以下の式のものである:
‐放出試験で、0.2%未満のベリノスタット酸および/またはベリノスタット二量体;および/または
‐ICH(医薬品規制調和国際会議)条件下での保存中の少なくとも18カ月、好ましくは少なくとも24カ月、最も好ましくは少なくとも36カ月にわたる保存後に、2%未満のベリノスタット酸および/またはベリノスタット二量体、
以内に維持される点において、得られた本発明の非晶質固体分散体は化学的に安定である。本発明の非晶質固体分散体は、インビトロ溶出試験法で試験したときに結晶性薬物を比較すると、高い溶解性および溶解特性を提供する。
非晶質固体分散体は、スプレードライ、ホットメルト押出(HME)、および非溶媒の添加による溶液からの沈殿を含めた、当該技術分野における任意の既知の方法で調製され得る。好ましくは、その方法はスプレードライ法である。
‐任意選択で前記任意選択の添加剤を伴った、溶媒中のベリノスタットと、前記非イオン化可能非セルロースポリマー、例えばポリビニルラクタムポリマーなど、との溶液を調製し;そして
‐前記溶液をスプレードライすること、
を含む。
次いで、乾燥ガスは、送風機、および電気ヒーターであってもよいヒーターを通過する。次いで、乾燥ガスは、ガスが天井ガスディスペンサを介して乾燥チャンバに導入される前に入口ガス温度を監視する入口ガス温度計を通過する。生成物品質を確保するために、余分な濾過を採用してもよい。
好適な溶剤としては、メタノール、アセトン、クロロホルム、エタノール、ジクロロメタン、水が挙げられる。
一般的に、固形物重量の5~50%にて溶液が調製される。
‐ベリノスタットおよび前記非イオン化可能非セルロースポリマー、例えばポリビニルラクタムポリマーなどを、任意選択の添加剤と最終的に混合し;そして
‐温度制御押出機を使用するのによって、混合物を押出成形すること、
を含む。
本発明によると、「患者」または「それを必要とする患者」という用語は、上記障害に罹患しているまたは罹患する可能性が高いヒトまたはヒト以外の哺乳類を意図する。好ましくは、患者はヒトである。
イヌPK試験を実施して、ベリノスタットの5つの異なった経口固体剤形の血漿中曝露量および生物学的利用能を比較した。製剤A、B、C、DおよびE(表1に詳述した組成物)を、イヌ1頭あたり50mgの固定用量(6.5~10.2mg/kgに相当)にて、断食状態の5頭の雌ビーグル犬(7.0~9.0Kg)に対して経口強制飼養によって投与した。動物には、それぞれ投与量の間に1週間のウォッシュアウト(washout)期間をとって、各製剤を用いて一度に投与した。絶対生物学的利用能計算のために、橈側皮静脈への低速ボーラス注入によって、静脈内投与を実施した。
ベリノスタットおよびポリマーの様々なASDを、以下の手順に従ってスプレードライによって調製した:
実施例2に記載の非晶質状態または結晶状態の新たに調製したスプレードライ分散液を、粉末X線回析(XRPD)によって評価した。同じ分析を、開放系条件において40℃および75%の相対湿度にて1週間の保存後に繰り返した。XRPDパターンを、銅陽極(Kα1=1.5060Å;Kα2=1.54439Å)、45kVおよび15mAに設定した発電機を用いて作動させ、3~40°2θの2θ範囲内において、連続走査モードで1分間あたり2.5°2θの速度にて走査したRigaku MiniFlex 600 X線回析計を用い、さらにD/teX Ultra高速検出装置を使用することで得た。
ヒドロキサミド官能基のため、ベリノスタットは容易に加水分解されるので、そのため、化学的に安定なASDを開発することは困難なことである。ASDのそれぞれのバッチの純度を、調製直後と加速安定性条件:40℃/75%のRHで開放系または閉鎖系、での1週間の保存後のサンプルに対してHPLC分析法によって試験した。閉鎖系条件では、ASDを、1gのSORB‐IT乾燥剤キャニスタを含有した閉鎖系ボトル(熱誘導シール)内に置いた。
結晶性薬物に対して超飽和を達成する製剤の能力および超飽和の持続可能性を評価するために、ベリノスタットのスプレードライ物の溶解を、非沈下条件下でインビトロにおいて試験した。
化学的安定性に関して、二量体不純物の形成は、使用されるポリマーに依存して変化しやすかった。
非イオン化可能(中性)非セルロースポリマー、例えばポリビニルラクタムポリマーなどを用いた本発明の様々なベリノスタット非晶質スプレードライ分散液のインビトロ溶解データは、非分散型結晶性ベリノスタットと比較して、大きな溶解性向上を示し、斯かる分散液が薬物の溶解速度を顕著に改善したことを示す。
上記の結果は、ポリビニルラクタムクラスのポリマーだけが、好適なTg、良好な物理的安定性および十分な溶解特性と共に、特に優れた化学的安定性につながることを示す。
ポリビニルラクタムポリマーは、低率の二量体生成と共に、十分な溶解を達成することが予想外にわかった。
3つのスプレードライ分散液(ASD)の生物学的利用能を、前臨床イヌPK試験で評価した。以下の製剤、HPMCAS‐M、PVPVA64およびPVPK30中の25%のベリノスタットを、イヌ1頭あたり50mgの固定用量(~6.25mg/kgに相当)にて、断食状態の4頭の雄ビーグル犬(7.0~9.0Kg)への経口強制飼養によって投与した。それぞれ投与量の間に少なくとも1週間のウォッシュアウト期間を伴って、動物に、それぞれの製剤を一度に投与した。
Claims (9)
- 以下:
a)ベリノスタット(Belinostat)またはその薬学的に許容される塩、溶媒和物もしくはヒドロキシ基のアセチルエステルもしくはリン酸エステル;
b)少なくとも1つのポリビニルラクタムポリマー、ここで、前記ポリビニルラクタムポリマーは、PVP K30、PVP K12、PVP K90、PVP VA64およびその混合物から選択される;および
c)任意選択で、少なくとも1つの添加剤、
を含むベリノスタットの非晶質固体分散体。 - 以下:
a)5~80%のベリノスタット(重量パーセント);および
b)20~95%の前記ポリビニルラクタムポリマー(重量パーセント)、
を含む、請求項1に記載のベリノスタットの非晶質固体分散体。 - 前記添加剤が:pH調整剤、抗酸化剤、分散剤、可溶化剤、安定化剤、崩壊剤または任意のその混合物から成る群から選択される、請求項1又は2に記載のベリノスタットの非晶質固体分散体。
- 前記添加剤がヒスチジンである、請求項1~3のいずれか一項に記載のベリノスタットの非晶質固体分散体。
- 前記非晶質固体分散体が、以下:
‐放出試験で、0.2%未満のベリノスタット酸および/またはベリノスタット二量体;および/または
‐少なくとも18カ月間の保存で、2%未満のベリノスタット酸および/またはベリノスタット二量体、
を含む、請求項1~4のいずれか一項に記載のベリノスタットの非晶質固体分散体。 - 以下のステップ:
‐溶媒中に前記ポリビニルラクタムポリマーとベリノスタットとを含む溶液を調製し;
‐前記溶液をスプレードライすること、
を含む、請求項1~5のいずれか一項に記載のベリノスタットの非晶質固体分散体の製造方法。 - 請求項1~5のいずれか一項に記載のベリノスタットの非晶質固体分散体、および1もしくは複数の薬学的に許容される賦形剤を含む医薬組成物。
- 経口投与によって癌を治療および/または予防するために使用するための、請求項1~5のいずれか一項に記載のベリノスタットの非晶質固体分散体。
- リンパ腫を治療するための請求項8に記載の使用のための、ベリノスタットの非晶質固体分散体。
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US11266614B2 (en) | 2022-03-08 |
HUE057999T2 (hu) | 2022-06-28 |
IL271658B2 (en) | 2023-09-01 |
DK3644970T3 (da) | 2022-03-14 |
CN110996913A (zh) | 2020-04-10 |
EP3644970B8 (en) | 2022-03-16 |
ECSP19091293A (es) | 2020-05-29 |
BR112019028088A8 (pt) | 2022-11-08 |
SI3644970T1 (sl) | 2022-05-31 |
CL2019003801A1 (es) | 2020-09-11 |
CO2019014831A2 (es) | 2020-04-24 |
ES2909583T3 (es) | 2022-05-09 |
PL3644970T3 (pl) | 2022-04-25 |
LT3644970T (lt) | 2022-04-25 |
CA3067723A1 (en) | 2019-01-03 |
EP3644970A1 (en) | 2020-05-06 |
HRP20220309T1 (hr) | 2022-05-13 |
BR112019028088A2 (pt) | 2020-07-28 |
AU2018294561B2 (en) | 2023-12-07 |
IL271658B1 (en) | 2023-05-01 |
RS63046B1 (sr) | 2022-04-29 |
JP2020525499A (ja) | 2020-08-27 |
IL271658A (en) | 2020-02-27 |
MX2019015869A (es) | 2020-08-06 |
AU2018294561A1 (en) | 2020-01-16 |
US20200155485A1 (en) | 2020-05-21 |
ZA201908532B (en) | 2022-07-27 |
CY1125762T1 (el) | 2024-02-16 |
EP3644970B1 (en) | 2022-02-09 |
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