JP7149449B2 - 経口用医薬組成物及びその製造方法 - Google Patents
経口用医薬組成物及びその製造方法 Download PDFInfo
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Description
[項1]pH依存性の溶解プロファイルを有する医薬活性成分と、無機又は有機の酸と、親水性ポリマーとを含む経口用医薬組成物。
[項2]医薬活性成分が、π共役系を有する芳香族化合物である、項1に記載の経口用医薬組成物。
[項3]医薬活性成分が、下記一般式Iで表される構造を有する化合物である、項1又は2に記載の経口用医薬組成物。
環Aは、1又は2以上の置換基を有していてもよい、5~16員の単環式又は縮合二環若しくは三環式の芳香族炭化水素基又は芳香族複素環式基を表し、
環Bは、1又は2以上の置換基を有していてもよい、5~12員の単環式又は縮合二環式の芳香族炭化水素基又は芳香族複素環式基を表し、
Lは、1又は2以上の置換基を有していてもよい、二価又は三価の連結基を表し、
pは、0又は1の整数を表し、
qは、1又は2の整数を表し、
rは、1又は2の整数を表す。)
[項4]医薬活性成分が、ART-001(セラベリシブ)、アルペリシブ、アファチニブ、ゲフィチニブ、ボスチニブ、アレクチニブ、パルボシクリブ、タセリシブ、及びコパンリシブから選択される1種又は2種以上の化合物である、項1~3の何れか一項に記載の経口用医薬組成物。
[項5]医薬活性成分のpH2.5での溶解性に対するpH6での溶解性の比率が、50%以下、又は30%以下、又は20%以下、又は10%以下、又は5%以下である、項1~4の何れか一項に記載の経口用医薬組成物。
[項6]無機又は有機の酸が、リン酸、塩酸、クエン酸、リンゴ酸、酒石酸、アスコルビン酸、フマル酸、コハク酸、アスパラギン酸、乳酸、酢酸、グルタミン酸、及びアジピン酸から選択される1種又は2種以上の酸である、項1~5の何れか一項に記載の経口用医薬組成物。
[項7]親水性ポリマーが、ポリビニルアルコール、ポビドン、ヒプロメロース、コポリビドン、ヒドロキシプロピルセルロース、ポリビニルアルコール・ポリエチレングリコール・グラフトコポリマー、ヒプロメロースフタル酸エステル、及びヒプロメロース酢酸エステルコハク酸エステルから選択される1種又は2種以上のポリマーである、項1~6の何れか一項に記載の経口用医薬組成物。
[項8]医薬活性成分の含有率が、2質量%以上、又は5質量%以上、又は10質量%以上、又は15質量%以上、また、40質量%以下、又は35質量%以下、又は30質量%以下、又は25質量%以下である、項1~7の何れか一項に記載の経口用医薬組成物。
[項9]医薬活性成分1質量部に対する無機又は有機の酸の含有割合が、0.1質量部以上、又は0.3質量部以上、又は0.5質量部以上、また、10質量部以下、又は7.5質量部以下、又は5質量部以下の範囲である、項1~8の何れか一項に記載の経口用医薬組成物。
[項10]医薬活性成分1質量部に対する親水性ポリマーの含有割合が、0.02質量部以上、又は0.05質量部以上、又は0.1質量部以上、また、5質量部以下、又は3質量部以下、又は2質量部以下の範囲である、項1~9の何れか一項に記載の経口用医薬組成物。
[項11]ドライシロップ剤である、項1~10の何れか一項に記載の経口用医薬組成物。
[項12]項1~11の何れか一項に記載の経口用医薬組成物を製造する方法であって、医薬活性成分、無機又は有機の酸、及び親水性ポリマーを含む混合物を湿式造粒し、乾燥することを含む方法。
[項13]項12に記載の方法により製造される経口用医薬組成物。
本発明の一態様は、pH依存性の溶解プロファイルを有する医薬活性成分を経口投与するための医薬組成物(適宜「本発明の医薬組成物」と称する。)に関する。本発明の医薬組成物は、斯かるpH依存性の溶解プロファイルを有する医薬活性成分に加えて、無機又は有機の酸と、親水性ポリマーとを含有する。
本発明の医薬組成物は、pH依存性の溶解プロファイルを有する医薬活性成分を含有する。
・(単環)フェニル基。
・(縮合二環)インデニル基、ナフチル基、アズレニル基。
・(縮合三環)アントラセニル基、フェナントナセニル基、フルオレニル基。
・(縮合二環)インデニル基、インドリル基、イソインドリル基、インドリジニル基、インダゾリル基、ベンゾイミダゾリル基、アザインドリル基、アザインダゾリル基、ピラゾロピリミジニル基、プリニル基、ベンゾフラニル基、イソベンゾフラニル基、ベンゾチオフェニル基、ベンゾオキサゾリル基、ベンゾチアゾリル基、ベンゾイソオキサゾリル基、ベンゾイソチアゾリル基、キノリニル基、イソキノリニル基、キノリジニル基、キノキサリニル基、フタラジニル基、キナゾリニル基、ナフチリジニル基、ピリドピリミジニル基、ピリドピラジニル基、ベンゾピラニル基。
・(縮合三環)カルバゾリル基、ジベンゾフラニル基、アクリジニル基、フェナジニル基、フェノキサジニル基、フェノチアジニル基、フェノキサチイニル基。
・カルボニル基。
・アゾ基、ジアゾ基、(一級、二級、又は三級)アミノ基から更に1つ又は2つの水素原子を取り去って得られる二価又は三価の基、アミド基。
・スルフィド基、スルフィニル基、スルホニル基。
・オキシ基、ジオキシ基。
また、前記の連結基と環A及び環Bとの連結位置も特に制限されず、任意である。
本発明の医薬組成物は、無機又は有機の酸を含有する。本開示において無機又は有機の「酸」とは、プロトン(H+)を供与し得る無機又は有機の化合物(いわゆるブレンステッド酸)を意味する。理論に束縛されるものではないが、本発明の医薬組成物中では、斯かる酸が医薬活性成分の分子間に介在して存在することにより、その溶解プロファイルがpHによらず安定化するものと推測される。
本発明の医薬組成物は、親水性ポリマーを含有する。理論に束縛されるものではないが、本発明の医薬組成物中では、前記の酸に加えて、斯かる親水性ポリマーが医薬活性成分の分子間に介在してその再凝集や結晶化を防止することにより、その溶解プロファイルがpHによらず安定化するものと推測される。
本発明の医薬組成物は、更にその他の成分を含有していてもよい。その他の成分の具体例としては、制限されるものではないが、マンニトール、エリスリトール、粉末還元麦芽糖水アメ、結晶セルロース、トウモロコシデンプン等の賦形剤;クロスポビドン、クロスカルメロースナトリウム、デンプングリコール酸ナトリウム、部分アルファー化デンプン、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース等の崩壊剤;スクラロース、アスパルテーム、アセスルファムカリウム、サッカリンナトリウム、グリチルリチン酸モノアンモニウム、タウマチン等の甘味剤;流動化剤、着色剤、香料等のその他の添加物が挙げられる。これらの成分は、本発明の医薬組成物の剤形等に応じて、適宜選択して使用することが可能である。なお、本発明の医薬組成物は、これらの成分のうち何れか1種を単独で含んでいてもよく、2種以上を任意の組み合わせ及び比率で含んでいてもよい。なお、本発明の医薬組成物に使用可能な成分の詳細については、例えばUniversity of the Sciences in Philadelphia, “Remington: The Science and Practice of Pharmacy, 20th EDITION”, Lippincott Williams & Wilkins, 2000等の記載を適宜参酌することができる。
本発明の医薬組成物の剤形は限定されず、経口投与可能な剤形であれば任意である。例としては、日本薬局方に記載される各種の経口投与剤形、即ち錠剤、カプセル剤、顆粒剤、散剤、経口液剤、シロップ剤、経口ゼリー剤等が挙げられる。これらの剤形は、医薬活性成分や適応の種類に応じて、適宜選択すればよい。
本発明の医薬組成物を製造する方法は制限されず、剤形に応じた任意の公知の方法により製造すればよい。例えば、目的とする剤形に応じて、医薬活性成分、無機又は有機の酸、及び親水性ポリマー、並びに任意により用いられる他の成分を、公知の製剤手法を用いて混合し、適宜造粒等の処理を加えればよい。例えば顆粒製剤の場合には、乾式造粒法、湿式造粒法等の公知の造粒法を用いて原料混合物を造粒すればよい。錠剤の場合には、公知の造粒法によって得られた原料混合物の造粒物を圧縮して錠剤化し、得られた錠剤に必要に応じてコーティングを施せばよい。或いは、造粒工程を経ずに原料混合物を直接打錠法により直接打錠して製造してもよい。
・前記原料を任意の混合順で混合する工程。
・前記混合物を湿式造粒する工程。
・前記湿式造粒物を乾燥する工程。
本発明の医薬組成物は、医薬活性成分の種類に応じた疾患や状態の治療・予防・調節等の目的で、対象に対して経口投与される。本発明の医薬組成物の投与対象は特に制限されないが、例としてはヒト、ヒト以外の哺乳類、その他の動物等が挙げられる。本発明の医薬組成物の投与量や投与回数も特に制限されないが、例えば医薬活性成分の種類や活性、投与対象の種、年齢、体重、状態等に応じて、適宜調整すればよい。また、2種以上の医薬活性成分を個別に含む2種以上の本発明の医薬組成物を、同一対象に同時に又は連続して投与してもよく、ある医薬活性成分を含む本発明の医薬組成物と、別の医薬活性成分を含む別の医薬組成物を、同一対象に同時に又は連続して投与してもよい。特に、pH依存溶解性を有する第1の医薬活性成分と、溶解性がpHに依存しない第2の医薬活性成分とを同一対象に投与する場合には、pH依存溶解性を有する第1の医薬活性成分を製剤化した本発明の医薬組成物と、溶解性がpHに依存しない第2の医薬活性成分を製剤化した従来の医薬組成物とを組み合わせて、これらを対象に同時に又は連続して投与してもよい。なお、本発明の医薬組成物との組み合わせで投与される医薬組成物は、経口投与されるものであってもよいが、別の経路で投与されるものであってもよい。
様々なpH環境下におけるART-001の溶解プロファイルを、以下の手順により試験した。即ち、6規定塩酸又は10規定水酸化ナトリウム水溶液を用いて、pHを1~10の範囲内で種々調整した、50mMリン酸緩衝液(pH1、2、7、及び8)、クエン酸緩衝液(pH3、4、5、及び6)、ホウ酸緩衝液(pH9)、及び重炭酸緩衝液(pH10)に対して、過剰量のART-001を加え、室温下で攪拌した。溶解状態が平衡に到達した時点で一定量のサンプルを採取し、1000rpm、10分間の遠心分離を行ったのち、上清を採取しHPLCにて測定した。溶解始点及び溶解終点のpHも同時に測定し、記録した。
以下の手順によりART-001のドライシロップ製剤を調製した。
(1)42Mの篩を通したD-マンニトール(物産フードサイエンス(株))270g及び結晶セルロース(KG-1000、旭化成(株))30gを混合した。
(2)リン酸(国産化学(株))75g及びポピドン(PLASDONE K-25、ASHLAND)25gを精製水600gに溶解させた。
(3)ART-001(Carbogen Amcis AG)100gを前記(2)の溶液に加えて分散させた。
(4)前記(1)の混合物を流動層造粒乾燥機(FD-MP-01D/SFP型、(株)パウレック)に投入し、前記(3)の分散液を噴霧して造粒した。
(5)前記(4)で得られた造粒物を、60℃で乾燥した。
(6)前記(5)で得られた乾燥後の造粒物を30Mの篩により整粒した。
(7)前記(6)で得られた整粒物0.25gとクエン酸水和物(国産化学(株))0.15gを混合し、本発明の医薬組成物に該当する目的のドライシロップ製剤を得た。
(1)42Mの篩を通したD-マンニトール(物産フードサイエンス(株))270g及び結晶セルロース(KG-1000、旭化成(株))30gを混合した。
(2)リン酸(国産化学(株))75g及びポピドン(PLASDONE K-25、ASHLAND)25gを精製水600gに溶解させた。
(3)ART-001(Carbogen Amcis AG)100gを前記(2)の溶液に加えて分散させた。
(4)前記(1)の混合物を流動層造粒乾燥機(FD-MP-01D/SFP型、(株)パウレック)に投入し、前記(3)の分散液を噴霧して造粒した。
(5)前記(4)で得られた造粒物を、60℃で乾燥した。
(6)前記(5)で得られた乾燥後の造粒物を30Mの篩により整粒した。
(7)前記(6)で得られた整粒物0.25g、酒石酸(L(+)-酒石酸、国産化学(株))0.0583g及びL-グルタミン酸塩酸塩(富士フィルム和光純薬(株))0.035gを混合し、本発明の医薬組成物に該当する目的のドライシロップ製剤を得た。
(1)結晶セルロース(KG-1000、旭化成(株))48g及びポリビニルアルコール(部分けん化物)(ゴーセノール EG-05PW、三菱ケミカル(株))32gを混合した。
(2)42Mの篩を通したD-マンニトール(物産フードサイエンス(株))160gを前記(1)の混合物と混合した。
(3)リン酸(太平化学産業(株))120g及びポピドン(PLASDONE K-25、ASHLAND)40gを精製水960gに溶解させた。
(4)ART-001(Carbogen Amcis AG)160gを前記(3)の溶液に加えて分散させた。
(5)前記(2)の混合物を流動層造粒乾燥機(FD-MP-01D/SFP型、(株)パウレック)に投入し、前記(4)の分散液を噴霧して造粒した。
(6)前記(5)で得られた造粒物を、60℃で乾燥した。
(7)前記(6)で得られた乾燥後の造粒物を30Mの篩により整粒し、本発明の医薬組成物に該当する目的のドライシロップ製剤を得た。
前記手順で調製したART-001のドライシロップ製剤を、以下に詳述する手順でイヌに投与し、ART-001の血中薬物動態を検討した。なお、対照として、0.5%メチルセルロース(MC;信越化学工業株式会社製METOLOSE、SM-100)水溶液にART-001を懸濁させた製剤も調製し、同様にイヌに投与して、ART-001の血中動態を検討した。
前記手順で調製したART-001のドライシロップ製剤(本発明の医薬組成物)を、健康成人男性に単回投与又は反復投与し、その後のART-001の血中薬物動態を検討した。
Claims (7)
- ART-001(セラベリシブ)と、無機又は有機の酸と、親水性ポリマーとを含むドライシロップ剤である経口用医薬組成物であって、ここで無機又は有機の酸が、リン酸、塩酸、クエン酸、リンゴ酸、酒石酸、アスコルビン酸、フマル酸、コハク酸、アスパラギン酸、乳酸、酢酸、グルタミン酸、及びアジピン酸から選択される1種又は2種以上の酸である、経口用医薬組成物。
- 無機又は有機の酸として、少なくともリン酸、クエン酸、酒石酸、及びグルタミン酸から選択される酸を含む、請求項1に記載の経口用医薬組成物。
- 親水性ポリマーが、ポリビニルアルコール、ポビドン、ヒプロメロース、コポリビドン、ヒドロキシプロピルセルロース、ポリビニルアルコール・ポリエチレングリコール・グラフトコポリマー、ヒプロメロースフタル酸エステル、及びヒプロメロース酢酸エステルコハク酸エステルから選択される1種又は2種以上のポリマーである、請求項1又は2に記載の経口用医薬組成物。
- ART-001(セラベリシブ)の含有率が2~40質量%の範囲である、請求項1~3の何れか一項に記載の経口用医薬組成物。
- ART-001(セラベリシブ)1質量部に対する無機又は有機の酸の含有割合が0.1~10質量部の範囲である、請求項1~4の何れか一項に記載の経口用医薬組成物。
- ART-001(セラベリシブ)1質量部に対する親水性ポリマーの含有割合が0.02~5質量部の範囲である、請求項1~5の何れか一項に記載の経口用医薬組成物。
- 請求項1~6の何れか一項に記載の経口用医薬組成物を製造する方法であって、ART-001(セラベリシブ)、無機又は有機の酸、及び親水性ポリマーを含む混合物を湿式造粒し、乾燥することを含む方法。
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- 2021-07-01 US US18/013,616 patent/US20230364063A1/en active Pending
- 2021-07-01 CA CA3182166A patent/CA3182166A1/en active Pending
- 2021-07-01 WO PCT/JP2021/025019 patent/WO2022004859A1/ja active Application Filing
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JP2022174317A (ja) | 2022-11-22 |
TW202216117A (zh) | 2022-05-01 |
EP4176902A1 (en) | 2023-05-10 |
CN115989022A (zh) | 2023-04-18 |
US20230364063A1 (en) | 2023-11-16 |
CA3182166A1 (en) | 2022-01-06 |
KR20230034207A (ko) | 2023-03-09 |
WO2022004859A1 (ja) | 2022-01-06 |
JPWO2022004859A1 (ja) | 2022-01-06 |
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