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- JPWO2021209739A5 JPWO2021209739A5 JP2022562608A JP2022562608A JPWO2021209739A5 JP WO2021209739 A5 JPWO2021209739 A5 JP WO2021209739A5 JP 2022562608 A JP2022562608 A JP 2022562608A JP 2022562608 A JP2022562608 A JP 2022562608A JP WO2021209739 A5 JPWO2021209739 A5 JP WO2021209739A5
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- 150000003839 salts Chemical class 0.000 claims description 61
- 238000000034 method Methods 0.000 claims description 49
- 239000002552 dosage form Substances 0.000 claims description 42
- 208000006682 alpha 1-Antitrypsin Deficiency Diseases 0.000 claims description 30
- 230000001404 mediated effect Effects 0.000 claims description 30
- 208000023504 respiratory system disease Diseases 0.000 claims description 26
- 239000007909 solid dosage form Substances 0.000 claims description 26
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 16
- QNQZWEGMKJBHEM-UHFFFAOYSA-N 6-methyl-5-(2-methylpyrazol-3-yl)-n-[(5-methylsulfonylpyridin-2-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(C=2N(N=CC=2)C)C=C1C(=O)NCC1=CC=C(S(C)(=O)=O)C=N1 QNQZWEGMKJBHEM-UHFFFAOYSA-N 0.000 claims description 13
- 230000036470 plasma concentration Effects 0.000 claims description 8
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 4
- 206010014561 Emphysema Diseases 0.000 claims description 4
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 4
- 230000001154 acute effect Effects 0.000 claims description 4
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 4
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 201000009267 bronchiectasis Diseases 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 206010033675 panniculitis Diseases 0.000 claims description 4
- 206010039083 rhinitis Diseases 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 208000035939 Alveolitis allergic Diseases 0.000 claims description 2
- 201000002909 Aspergillosis Diseases 0.000 claims description 2
- 208000036641 Aspergillus infections Diseases 0.000 claims description 2
- 241000711573 Coronaviridae Species 0.000 claims description 2
- 206010011224 Cough Diseases 0.000 claims description 2
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 2
- 208000027445 Farmer Lung Diseases 0.000 claims description 2
- 206010020751 Hypersensitivity Diseases 0.000 claims description 2
- 206010035664 Pneumonia Diseases 0.000 claims description 2
- 241000725643 Respiratory syncytial virus Species 0.000 claims description 2
- 208000036142 Viral infection Diseases 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- 230000000954 anitussive effect Effects 0.000 claims description 2
- 206010006451 bronchitis Diseases 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 201000009151 chronic rhinitis Diseases 0.000 claims description 2
- 208000022195 farmer lung disease Diseases 0.000 claims description 2
- 230000009610 hypersensitivity Effects 0.000 claims description 2
- 230000000642 iatrogenic effect Effects 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- 206010022000 influenza Diseases 0.000 claims description 2
- 201000009240 nasopharyngitis Diseases 0.000 claims description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 2
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 2
- 201000000306 sarcoidosis Diseases 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 125000005490 tosylate group Chemical class 0.000 claims description 2
- 201000008827 tuberculosis Diseases 0.000 claims description 2
- 241000701161 unidentified adenovirus Species 0.000 claims description 2
- 230000009385 viral infection Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 38
- -1 kit Substances 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
Description
１２．α－１アンチトリプシン欠損症によって媒介される呼吸器系疾患は、ＣＯＰＤ（慢性閉塞性肺疾患）である、先行実施形態のいずれかに記載の剤形、キットまたは方法。
本発明は、以下の態様を含む。
＜１＞
単一または複数の固体剤形（複数可）の１日２回の経口投与を含む、α－１アンチトリプシン欠損症によって媒介される呼吸器系疾患を処置するための方法であって、前記単一または複数の固体剤形（複数可）は、投与あたり合計１２０～３００ｍｇの６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩を含む、前記方法。
＜２＞
１２０～３００ｍｇの６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩を含む、固体剤形。
＜３＞
α－１アンチトリプシン欠損症によって媒介される呼吸器系疾患の処置に向けた、６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩の経口投与用の単一または複数の固体剤形（複数可）であって、前記単一または複数の固体剤形（複数可）は、投与あたり合計１２０～３００ｍｇの６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩を含む、前記単一または複数の固体剤形（複数可）。
＜４＞
α－１アンチトリプシン欠損症によって媒介される呼吸器系疾患の処置に向けた、６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩の経口投与用の単一または複数の固体剤形（複数可）であって、前記単一または複数の固体剤形（複数可）は、投与あたり合計１２０～３００ｍｇの６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩を含み、各用量の前記投与は、１日２回、少なくとも８時間の投与間隔で行われる、前記単一または複数の固体剤形（複数可）。
＜５＞
６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩の経口投与用の複数の固体剤形を含むキットであって、前記キットは、投与あたり合計１２０～３００ｍｇの前記６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩を順次投与するための指示書を含有し、各用量の前記投与は、α－１アンチトリプシン欠損症によって媒介される呼吸器系疾患の処置に向けて、１日２回、少なくとも８時間の投与間隔で行われる、前記キット。
＜６＞
経口投与用の複数の固体剤形を含むキットであって、前記剤形は、１２０～３００ｍｇの６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩を含み、前記キットは、α－１アンチトリプシン欠損症によって媒介される呼吸器系疾患の処置に向けた、順次、１日２回の各用量の投与に対する指示書を含有する、前記キット。
＜７＞
ＣＯＰＤを患うヒト患者に対する、単一または複数の固体剤形（複数可）の１日２回の経口投与を含む、α－１アンチトリプシン欠損症によって媒介される呼吸器系疾患を処置するための方法であって、前記単一または複数の固体剤形（複数可）は、投与あたり合計１２０～３００ｍｇの６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩を含む、前記方法。
＜８＞
有効成分が、６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドのトシレート塩を含むかまたはそれからなる、＜１＞～＜７＞のいずれかに記載の剤形、キットまたは方法。
＜９＞
前記６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドが、１２０～３００ｍｇ、好ましくは２４０～２８０ｍｇ、最も好ましくは２４０ｍｇの量で、前記剤形（複数可）中に存在する、＜１＞～＜８＞のいずれかに記載の剤形、キットまたは方法。
＜１０＞
錠剤（複数可）形態、またはカプセル剤（複数可）形態、好ましくは錠剤形態である、＜２＞～＜４＞のいずれかで定義される固体剤形。
＜１１＞
最小１日総用量が２４０ｍｇ、好ましくは４８０ｍｇである、＜１＞～＜１０＞のいずれかに記載の剤形、キットまたは方法。
＜１２＞
前記α－１アンチトリプシン欠損症によって媒介される呼吸器系疾患は、喘息、慢性閉塞性肺疾患（ＣＯＰＤ）、気管支炎、肺気腫、気管支拡張症、嚢胞性線維症、サルコイドーシス、農夫肺、過敏性肺炎、成人呼吸窮迫症候群（ＡＲＤＳ）、肺線維症、結核、アスペルギルス症、鎮咳活性、医原性の咳、急性及び慢性鼻炎、急性ウイルス感染症、肺高血圧症、ならびに呼吸器合胞体ウイルス、インフルエンザ、コロナウイルス及びアデノウイルスによる感染症からなる群より選択される、＜１＞～＜１１＞のいずれかに記載の剤形、キット、または方法。
＜１３＞
前記α－１アンチトリプシン欠損症によって媒介される呼吸器系疾患は、ＣＯＰＤ（慢性閉塞性肺疾患）である、＜１＞～＜１２＞のいずれかに記載の剤形、キットまたは方法。
＜１４＞
前記α－１アンチトリプシン欠損症によって媒介される呼吸器系疾患は、肺気腫である、＜１＞～＜１３＞のいずれかに記載の剤形、キットまたは方法。
＜１５＞
前記α－１アンチトリプシン欠損症によって媒介される呼吸器系疾患は、気管支拡張症である、＜１＞～＜１４＞のいずれかに記載の剤形、キットまたは方法。
＜１６＞
前記α－１アンチトリプシン欠損症によって媒介される呼吸器系疾患は、喘息である、＜１＞～＜１５＞のいずれかに記載の剤形、キットまたは方法。
＜１７＞
前記単一または複数の固体剤形（複数可）は、合計２２０～３００ｍｇの６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩を含む、＜１＞～＜１６＞のいずれかに記載の剤形、キットまたは方法。
＜１８＞
最小１日総用量が４４０ｍｇ、好ましくは４８０ｍｇである、＜１＞～＜１７＞のいずれかに記載の剤形、キットまたは方法。
＜１９＞
最小１日総用量が３６０ｍｇ、好ましくは４８０ｍｇである、＜１＞～＜１８＞のいずれかに記載の剤形、キットまたは方法。
＜２０＞
＜１＞～＜１９＞のいずれかで言及されるようなα－１アンチトリプシン欠損症によって媒介される呼吸器系疾患を処置するための方法を必要とする患者におけるその方法であって、１２０ｍｇの６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩をＢＩＤで前記患者に投与することを含む、前記方法。
＜２１＞
＜１＞～＜２０＞のいずれかで言及されるようなα－１アンチトリプシン欠損症によって媒介される呼吸器系疾患を処置するための方法を必要とする患者におけるその方法であって、２４０ｍｇの６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩をＢＩＤで前記患者に投与することを含む、前記方法。
＜２２＞
α－１アンチトリプシン欠損症によって媒介される呼吸器系疾患（例えば、ＣＯＰＤ）を処置するための方法を必要とする、従来のＡＡＴ療法では応答が示されなかった患者におけるその方法であって、アルベレスタットまたはその塩を有効量で前記患者に投与することを含む、前記方法。
＜２３＞
α－１アンチトリプシン欠損症によって媒介される疾患（例えば、ＣＯＰＤまたは脂肪織炎）を処置するための方法を必要とする患者におけるその方法であって、アルベレスタットまたはその塩を以下：
－アルベレスタットまたはその塩を、第１の一定期間、用量６０ｍｇで１日２回投与すること、
－アルベレスタットまたはその塩を、それ以降、用量１２０ｍｇで１日２回投与すること、
ここで、前記第１の期間は５～２０日間、好ましくは約１週間（７日間）である、
を含む投与量漸増計画で投与することを含む、前記方法。
＜２４＞
α－１アンチトリプシン欠損症によって媒介される疾患（例えば、ＣＯＰＤまたは脂肪織炎）を処置するための方法を必要とする患者におけるその方法であって、アルベレスタットまたはその塩を以下：
－アルベレスタットまたはその塩を、第１の一定期間、用量６０ｍｇで１日２回投与すること、
－アルベレスタットまたはその塩を、第２の一定期間、用量１２０ｍｇで１日２回投与すること、
－アルベレスタットまたはその塩を、第３の一定期間、用量１８０ｍｇで１日２回投与すること、及び
－アルベレスタットまたはその塩を、それ以降、用量２４０ｍｇで１日２回投与すること、
ここで、前記第１、第２及び第３の期間は５～２０日間、好ましくは約１週間（７日間）である、
を含む投与量漸増計画で投与することを含む、前記方法。
＜２５＞
前記アルベレスタットまたはその塩の投与により、前記患者における血漿中濃度Ｃ
ｍｉｎ
が少なくとも３００ｎＭになる、＜１＞～＜２４＞のいずれかに記載の剤形、キットまたは方法。
＜２６＞
前記アルベレスタットまたはその塩の投与により、前記患者における血漿中濃度Ｃ
ｍａｘ
が少なくとも１０００ｎＭになる、＜１＞～＜２５＞のいずれかに記載の剤形、キットまたは方法。
＜２７＞
前記アルベレスタットまたはその塩の投与により、前記患者において、血漿中濃度Ｃ
ｍｉｎ
が少なくとも３００ｎＭになり、かつ、血漿中濃度Ｃ
ｍａｘ
が少なくとも１０００ｎＭになる、＜１＞～＜２６＞のいずれかに記載の剤形、キットまたは方法。
＜２８＞
投与あたり１２０ｍｇのアルベレスタットまたはその塩が投与される、＜１＞～＜２７＞のいずれかに記載の剤形、キットまたは方法。
＜２９＞
投与あたり２４０ｍｇのアルベレスタットまたはその塩が投与される、＜１＞～＜２８＞のいずれかに記載の剤形、キットまたは方法。
12. A dosage form, kit or method according to any of the preceding embodiments, wherein the respiratory disease mediated by alpha-1 antitrypsin deficiency is COPD (chronic obstructive pulmonary disease).
The present invention includes the following aspects.
<1>
A method for treating respiratory diseases mediated by alpha-1 antitrypsin deficiency comprising twice daily oral administration of single or multiple solid dosage form(s). One or more solid dosage form(s) may contain a total of 120 to 300 mg of 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl) pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof.
<2>
120-300 mg of 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[ A solid dosage form comprising 3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof.
<3>
6-Methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl) ) Pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-carboxamide or a salt thereof for oral administration in single or multiple solid forms. Dosage form(s), wherein the solid dosage form(s) contain a total of 120 to 300 mg of 6-methyl-5-(1-methyl-1H-pyrazol-5-yl) per dose. )-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or its salt said single or multiple solid dosage form(s).
<4>
6-Methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl) ) Pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-carboxamide or a salt thereof for oral administration in single or multiple solid forms. Dosage form(s), wherein the solid dosage form(s) contain a total of 120 to 300 mg of 6-methyl-5-(1-methyl-1H-pyrazol-5-yl) per dose. )-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or its salt said single or multiple solid dosage form(s), wherein said administration of each dose occurs twice a day with an interval of at least 8 hours.
<5>
6-Methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(tri fluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof for oral administration, said kit comprising a total of 120 to 300 mg of said 6-methyl per administration. -5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof, wherein said administration of each dose is effective for the treatment of respiratory diseases mediated by alpha-1 antitrypsin deficiency. Said kit for treatment, which is carried out twice a day with an administration interval of at least 8 hours.
<6>
A kit comprising a plurality of solid dosage forms for oral administration, the dosage forms comprising 120 to 300 mg of 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5 -(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof; Said kit containing instructions for the administration of each dose twice daily in sequence for the treatment of respiratory diseases mediated by alpha-1 antitrypsin deficiency.
<7>
for treating respiratory diseases mediated by alpha-1 antitrypsin deficiency, comprising twice daily oral administration of single or multiple solid dosage form(s) to human patients suffering from COPD. The method, wherein the solid dosage form(s) contain a total of 120 to 300 mg of 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{ [5-(Methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof, the method described above .
<8>
The active ingredient is 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[ The dosage form, kit or method according to any one of <1> to <7>, which comprises or consists of a tosylate salt of 3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide.
<9>
The above 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-( trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide is present in said dosage form(s) in an amount of 120 to 300 mg, preferably 240 to 280 mg, most preferably 240 mg, <1 The dosage form, kit, or method according to any one of > to <8>.
<10>
A solid dosage form as defined in any of <2> to <4>, which is in the form of tablet(s) or capsule(s), preferably in the form of a tablet.
<11>
The dosage form, kit or method according to any of <1> to <10>, wherein the minimum daily total dose is 240 mg, preferably 480 mg.
<12>
Respiratory diseases mediated by alpha-1 antitrypsin deficiency include asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, bronchiectasis, cystic fibrosis, sarcoidosis, farmer's lung, and hypersensitivity. Pneumonia, adult respiratory distress syndrome (ARDS), pulmonary fibrosis, tuberculosis, aspergillosis, antitussive activity, iatrogenic cough, acute and chronic rhinitis, acute viral infections, pulmonary hypertension, and respiratory syncytial virus, influenza. The dosage form, kit, or method according to any one of <1> to <11>, which is selected from the group consisting of infections caused by , coronavirus, and adenovirus.
<13>
The dosage form, kit, or method according to any one of <1> to <12>, wherein the respiratory disease mediated by α-1 antitrypsin deficiency is COPD (chronic obstructive pulmonary disease).
<14>
The dosage form, kit, or method according to any one of <1> to <13>, wherein the respiratory disease mediated by α-1 antitrypsin deficiency is emphysema.
<15>
The dosage form, kit, or method according to any one of <1> to <14>, wherein the respiratory disease mediated by α-1 antitrypsin deficiency is bronchiectasis.
<16>
The dosage form, kit, or method according to any one of <1> to <15>, wherein the respiratory disease mediated by α-1 antitrypsin deficiency is asthma.
<17>
The solid dosage form(s) contain a total of 220-300 mg of 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl) Any of <1> to <16>, including pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridin-3-carboxamide or a salt thereof The dosage form, kit or method described in any of the above.
<18>
The dosage form, kit or method according to any one of <1> to <17>, wherein the minimum daily total dose is 440 mg, preferably 480 mg.
<19>
The dosage form, kit or method according to any of <1> to <18>, wherein the minimum daily total dose is 360 mg, preferably 480 mg.
<20>
A method for treating a respiratory disease mediated by α-1 antitrypsin deficiency as mentioned in any of <1> to <19> in a patient in need thereof, comprising: 6-Methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-( [trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof BID to the patient.
<21>
A method for treating a respiratory disease mediated by α-1 antitrypsin deficiency as mentioned in any of <1> to <20> in a patient in need thereof, the method comprising: 240 mg 6-Methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-( [trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof BID to the patient.
<22>
In need of a method for treating a respiratory disease mediated by alpha-1 antitrypsin deficiency (e.g., COPD) in a patient who has not responded to conventional AAT therapy, the method comprises: The method comprises administering to the patient an effective amount of alberestat or a salt thereof.
<23>
A method for treating a disease mediated by alpha-1 antitrypsin deficiency (e.g., COPD or panniculitis) in a patient in need thereof, the method comprising administering alberestat or a salt thereof:
- administering alberestat or a salt thereof at a dose of 60 mg twice a day for a first period of time;
- administering alberestat or its salts at a dose of 120 mg twice daily thereafter;
Here, the first period is 5 to 20 days, preferably about 1 week (7 days).
said method, comprising administering in a dose escalation regimen comprising:
<24>
A method for treating a disease mediated by alpha-1 antitrypsin deficiency (e.g., COPD or panniculitis) in a patient in need thereof, the method comprising administering alberestat or a salt thereof:
- administering alberestat or a salt thereof at a dose of 60 mg twice a day for a first period of time;
- administering alberestat or a salt thereof at a dose of 120 mg twice a day for a second period of time;
- administering alberestat or a salt thereof at a dose of 180 mg twice a day for a third period; and
- administering alberestat or its salts at a dose of 240 mg twice daily thereafter;
Here, the first, second and third periods are 5 to 20 days, preferably about 1 week (7 days).
said method, comprising administering in a dose escalation regimen comprising:
<25>
The dosage form, kit, or method according to any one of <1> to <24> , wherein administration of the alberestat or a salt thereof results in a plasma concentration C min of at least 300 nM in the patient.
<26>
The dosage form, kit, or method according to any one of <1> to <25> , wherein administration of the alberestat or a salt thereof results in a plasma concentration C max of at least 1000 nM in the patient.
<27>
Any one of <1> to <26> , wherein administration of the alberestat or a salt thereof results in a plasma concentration C min of at least 300 nM and a plasma concentration C max of at least 1000 nM in the patient. Dosage forms, kits or methods as described.
<28>
The dosage form, kit, or method according to any one of <1> to <27>, wherein 120 mg of alberestat or a salt thereof is administered per administration.
<29>
The dosage form, kit, or method according to any one of <1> to <28>, wherein 240 mg of alberestat or a salt thereof is administered per administration.
Claims (29)
前記医薬組成物が、６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩を含み、
前記方法が、単一または複数の固体剤形（複数可）の１日２回の経口投与を含み、
前記単一または複数の固体剤形（複数可）は、投与あたり合計１２０～３００ｍｇの６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩を含む、医薬組成物。 A pharmaceutical composition for use in a method for treating a respiratory disease mediated by alpha-1 antitrypsin deficiency, the composition comprising:
The pharmaceutical composition comprises 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1 - [3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof,
the method comprises twice daily oral administration of single or multiple solid dosage form(s);
The solid dosage form(s) may contain a total of 120-300 mg of 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methyl A pharmaceutical composition comprising sulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof.
前記医薬組成物が、６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩を含み、
前記方法が、ＣＯＰＤを患うヒト患者に対する、単一または複数の固体剤形（複数可）の１日２回の経口投与を含み、
前記単一または複数の固体剤形（複数可）は、投与あたり合計１２０～３００ｍｇの６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩を含む、医薬組成物。 A pharmaceutical composition for use in a method for treating a respiratory disease mediated by alpha-1 antitrypsin deficiency, the composition comprising:
The pharmaceutical composition comprises 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1 - [3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof,
The method comprises twice daily oral administration of single or multiple solid dosage form(s) to a human patient suffering from COPD;
The solid dosage form(s) may contain a total of 120 to 300 mg of 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methyl A pharmaceutical composition comprising sulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof.
前記医薬組成物が、６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩を含み、
前記方法が、単一または複数の固体剤形（複数可）の１日２回の経口投与を含み、
前記方法が、１２０ｍｇの６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩をＢＩＤで前記患者に投与することを含む、医薬組成物。 A pharmaceutical composition for use in a method for treating respiratory diseases mediated by alpha-1 antitrypsin deficiency as mentioned in any one of claims 1 to 19, comprising:
The pharmaceutical composition comprises 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1 - [3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof,
the method comprises twice daily oral administration of single or multiple solid dosage form(s);
The method comprises: 120 mg of 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1; - A pharmaceutical composition comprising administering BID to the patient: -[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof.
前記医薬組成物が、６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩を含み、
前記方法が、単一または複数の固体剤形（複数可）の１日２回の経口投与を含み、
前記方法が、２４０ｍｇの６－メチル－５－（１－メチル－１Ｈ－ピラゾール－５－イル）－Ｎ－｛［５－（メチルスルホニル）ピリジン－２－イル］メチル｝－２－オキソ－１－［３－（トリフルオロメチル）フェニル］－１，２－ジヒドロピリジン－３－カルボキサミドまたはその塩をＢＩＤで前記患者に投与することを含む、医薬組成物。 A pharmaceutical composition for use in a method for treating respiratory diseases mediated by alpha-1 antitrypsin deficiency as mentioned in any one of claims 1 to 19 , comprising:
The pharmaceutical composition comprises 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1 - [3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof,
the method comprises oral administration of single or multiple solid dosage form(s) twice daily;
The method comprises the following steps: 240 mg of 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1 - A pharmaceutical composition comprising administering BID to the patient: -[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide or a salt thereof.
前記医薬組成物が、アルベレスタットまたはその塩を含み、
前記方法が、アルベレスタットまたはその塩を有効量で前記患者に投与することを含む、医薬組成物。 In need of a method for treating respiratory diseases mediated by alpha-1 antitrypsin deficiency (e.g., COPD) for use in patients who have not responded to conventional AAT therapy. A pharmaceutical composition comprising:
the pharmaceutical composition comprises alberestat or a salt thereof,
A pharmaceutical composition , wherein said method comprises administering to said patient an effective amount of alberestat or a salt thereof.
前記医薬組成物が、アルベレスタットまたはその塩を含み、
前記方法が、アルベレスタットまたはその塩を以下：
－アルベレスタットまたはその塩を、第１の一定期間、用量６０ｍｇで１日２回投与すること、
－アルベレスタットまたはその塩を、それ以降、用量１２０ｍｇで１日２回投与すること、
ここで、前記第１の期間は５～２０日間、好ましくは約１週間（７日間）である、
を含む投与量漸増計画で投与することを含む、医薬組成物。 A pharmaceutical composition for use in a method for treating a disease mediated by alpha-1 antitrypsin deficiency (e.g., COPD or panniculitis) in a patient in need thereof, comprising:
the pharmaceutical composition comprises alberestat or a salt thereof,
The method may include alberestat or its salts as follows:
- administering alberestat or a salt thereof at a dose of 60 mg twice a day for a first period of time;
- administering alberestat or its salts at a dose of 120 mg twice daily thereafter;
Here, the first period is 5 to 20 days, preferably about 1 week (7 days).
a pharmaceutical composition comprising: administering in a dose escalation regimen comprising:
前記医薬組成物が、アルベレスタットまたはその塩を含み、
前記方法が、アルベレスタットまたはその塩を以下：
－アルベレスタットまたはその塩を、第１の一定期間、用量６０ｍｇで１日２回投与すること、
－アルベレスタットまたはその塩を、第２の一定期間、用量１２０ｍｇで１日２回投与すること、
－アルベレスタットまたはその塩を、第３の一定期間、用量１８０ｍｇで１日２回投与すること、及び
－アルベレスタットまたはその塩を、それ以降、用量２４０ｍｇで１日２回投与すること、
ここで、前記第１、第２及び第３の期間は５～２０日間、好ましくは約１週間（７日間）である、
を含む投与量漸増計画で投与することを含む、医薬組成物。 A pharmaceutical composition for use in a method for treating a disease mediated by alpha-1 antitrypsin deficiency (e.g., COPD or panniculitis) in a patient in need thereof, comprising:
the pharmaceutical composition comprises alberestat or a salt thereof,
The method may include alberestat or its salts as follows:
- administering alberestat or a salt thereof at a dose of 60 mg twice a day for a first period of time;
- administering alberestat or a salt thereof at a dose of 120 mg twice a day for a second period of time;
- administering alberestat or a salt thereof at a dose of 180 mg twice a day for a third period; and - administering alberestat or a salt thereof at a dose of 240 mg twice a day thereafter;
Here, the first, second and third periods are 5 to 20 days, preferably about 1 week (7 days).
A pharmaceutical composition comprising: administering in a dose escalation regimen comprising:
28. A dosage form, kit or pharmaceutical composition according to any one of claims 22 to 27 , wherein 240 mg of alberestat or a salt thereof is administered per dose.
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