JPWO2020247627A5 - - Google Patents
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- JPWO2020247627A5 JPWO2020247627A5 JP2021572444A JP2021572444A JPWO2020247627A5 JP WO2020247627 A5 JPWO2020247627 A5 JP WO2020247627A5 JP 2021572444 A JP2021572444 A JP 2021572444A JP 2021572444 A JP2021572444 A JP 2021572444A JP WO2020247627 A5 JPWO2020247627 A5 JP WO2020247627A5
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（Ｒ）－（＋）－アミスルプリドと（Ｓ）－（－）－アミスルプリドのエナンチオマー比が遊離塩基の重量で約８５：１５である、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリド、または薬学的に許容されるそれらの塩の不均等混合物の形態のアミスルプリド、ならびに
固体経口剤の総重量に対して約１０％から約５０％の量の持続放出性薬剤を含み、ここで、投与により、１２ミリ秒（ｍｓ）未満である基準値に対する対象集団の平均の最大ＱＴ間隔延長を提供する、固体経口剤。 A solid oral dosage form comprising amisulpride for treating bipolar depression, said treatment comprising administering to a subject as a solid oral dosage form from about 200 mg to about 400 mg of amisulpride by weight of free base per day; The solid oral formulation is
(R)-(+)-amisulpride and (S)-( where the enantiomeric ratio of (R)-(+)-amisulpride to (S)-(-)-amisulpride is about 85:15 by weight of free base -) - amisulpride in the form of unequal mixtures of amisulpride or a pharmaceutically acceptable salt thereof, and a sustained-release drug in an amount of about 10% to about 50% based on the total weight of the solid oral dosage form , wherein administration provides a subject population mean maximum QT interval prolongation relative to a baseline value of less than 12 milliseconds (ms).
（ｉｉ）固体経口剤が錠剤である；
（ｉｉｉ）基準値に対する集団の平均の最大ＱＴ間隔延長が、投与後１２時間の期間での基準値に対する集団の平均の最大ＱＴｃＦ間隔延長である；
（ｉｖ）基準値に対する集団の平均の最大ＱＴ間隔延長が、１１ミリ秒（ｍｓ）未満である；
（ｖ）基準値に対する集団の平均の最大ＱＴ間隔延長が、１０ミリ秒（ｍｓ）未満である；
（ｖｉ）遊離塩基の重量で１日当たり約２００ｍｇのアミスルプリドが投与される、例えば、基準値に対する集団の平均の最大ＱＴ間隔延長が、９ミリ秒（ｍｓ）未満である；
（ｖｉｉ）持続放出性薬剤が、マトリックス形成剤を含む、例えば、マトリックス形成剤が、１つまたは複数のセルロースエーテルを含む；
（ｖｉｉｉ）持続放出性薬剤が、固体経口剤の総重量に対して約２０％から約４０％の量である；
（ｉｘ）持続放出性薬剤が、固体経口剤の総重量に対して約２０％から約３０％の量のヒドロキシプロピルメチルセルロースを含む；
（ｘ）Ｄ２受容体占有率が表３８および本明細書に実質的に記載されている陽電子放射断層撮影法（ＰＥＴ）を使用して測定される場合、投与により、投与の約２７時間後に、約２０％から約６０％の対象集団のドーパミンＤ２受容体の平均占有率を提供する；
（ｘｉ）投与により、
ａ．固体経口剤と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物により達成される集団の幾何平均Ｃｍａｘの約８０％未満である、アミスルプリドの集団の幾何平均血漿Ｃｍａｘ、および
ｂ．固体経口剤と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物により達成される投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）の約８０％未満である、アミスルプリドの集団の幾何平均ＡＵＣ ０－２４
を提供し、所望により、即時放出組成物が、表２５に実質的に記載されている、医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物である；
（ｘｉｉ）投与により、固体経口剤組成物の初回投与後に約１９００（ｎｇ ＊ ｈ／ｍｌ）未満であるアミスルプリドの投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）を提供する；
（ｘｉｉｉ）投与により、固体経口剤組成物の投与１週間後に約２５００（ｎｇ ＊ ｈ／ｍｌ）未満であるアミスルプリドの投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）を提供する；
（ｘｉｖ）投与により、固体経口剤組成物の初回投与後に約４４００（ｎｇ ＊ ｈ／ｍｌ）未満であるアミスルプリドの投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）を提供する；または
（ｘｖ）投与により、固体経口剤組成物の投与１週間後に約５４００（ｎｇ ＊ ｈ／ｍｌ）未満であるアミスルプリドの投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）を提供する、
請求項１に記載の固体経口剤。 (i) administration is once daily ;
(ii) the solid oral dosage form is a tablet;
(iii) the population mean maximum QT interval prolongation relative to baseline is the population mean maximum QTcF interval prolongation relative to baseline over the 12 hour post-dose period;
(iv) the population mean maximal QT interval prolongation relative to baseline is less than 11 milliseconds (ms);
(v) the population mean maximal QT interval prolongation relative to baseline is less than 10 milliseconds (ms);
(vi) about 200 mg of amisulpride by weight of free base per day is administered, e.g., the population mean maximal QT interval prolongation relative to baseline is less than 9 milliseconds (ms);
(vii) the sustained-release drug comprises a matrix-forming agent, e.g., the matrix-forming agent comprises one or more cellulose ethers;
(viii) the sustained-release drug is in an amount of about 20% to about 40% of the total weight of the solid oral dosage form;
(ix) the sustained-release formulation comprises hydroxypropylmethylcellulose in an amount of about 20% to about 30%, based on the total weight of the solid oral dosage form;
(x) when D2 receptor occupancy is measured using Positron Emission Tomography (PET) as substantially described in Table 38 and herein, upon administration, at about 27 hours after administration, providing a mean occupancy of dopamine D2 receptors in a subject population of about 20% to about 60%;
(xi) administering
a. a population geometric mean plasma Cmax of amisulpride that is less than about 80% of the population geometric mean Cmax achieved with an immediate release composition having the same total daily dose of amisulpride as a solid oral dosage form; and
b. of amisulpride that is less than about 80% of the population geometric mean AUC from 0 to 24 hours post-dose (AUC 0-24 ) achieved by an immediate release composition having the same total daily dose of amisulpride as a solid oral dosage form; Population Geometric Mean AUC 0-24
and optionally wherein the immediate release composition is an immediate release composition having the same total daily amount of amisulpride as the pharmaceutical composition substantially as described in Table 25;
(xii) administration provides a population geometric mean AUC (AUC 0-24 ) from 0 to 24 hours after administration of amisulpride that is less than about 1900 (ng * h/ml) after the first administration of the solid oral dosage composition; ;
(xiii) administration provides a population geometric mean AUC (AUC 0-24 ) from 0 to 24 hours after administration of amisulpride that is less than about 2500 (ng * h/ml) one week after administration of the solid oral dosage composition; do;
(xiv) administration provides a population geometric mean AUC (AUC 0-24 ) from 0 to 24 hours after administration of amisulpride that is less than about 4400 (ng * h/ml) after the first administration of the solid oral dosage composition; ;or
(xv) administration provides a population geometric mean AUC (AUC 0-24 ) from 0 to 24 hours after administration of amisulpride that is less than about 5400 (ng * h/ml) one week after administration of the solid oral dosage composition; do,
The solid oral preparation according to claim 1 .
（Ｒ）－（＋）－アミスルプリドと（Ｓ）－（－）－アミスルプリドのエナンチオマー比が遊離塩基の重量で約８５：１５である、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリド、または薬学的に許容されるそれらの塩の不均等混合物の形態のアミスルプリド、ならびに
錠剤の総重量に対して約１０％から約５０％の量の持続放出性薬剤を含み、ここで、投与により、アミスルプリド１０ｍｇ当たり約０．４ミリ秒（ｍｓ）未満である、基準値に対する対象集団の平均の最大ＱＴ間隔延長を提供し、所望により、
（ｉ）投与が１日１回である；
（ｉｉ）基準値に対する集団の平均の最大ＱＴ間隔延長が、投与後１２時間の期間での基準値に対する集団の平均の最大ＱＴｃＦ間隔延長である；
（ｉｉｉ）基準値に対する集団の平均の最大ＱＴ間隔延長が、アミスルプリド１０ｍｇ当たり約０．３５ミリ秒（ｍｓ）未満である；
（ｖｉ）基準値に対する集団の平均の最大ＱＴ間隔延長が、アミスルプリド１０ｍｇ当たり約０．３ミリ秒（ｍｓ）未満である；
（ｖ）持続放出性薬剤が、マトリックス形成剤を含む、例えば、マトリックス形成剤が、１つまたは複数のセルロースエーテルを含む、例えば、持続放出性薬剤が、錠剤の総重量に対して約２０％から約４０％の量のヒドロキシプロピルメチルセルロースを含む；
（ｖｉ）Ｄ２受容体占有率が、表３８および本明細書に実質的に記載されている陽電子放射断層撮影法（ＰＥＴ）を使用して測定される場合、投与により、投与の約２７時間後に、約２０％から約６０％の対象集団のドーパミンＤ２受容体の平均占有率を提供する；
（ｖｉｉ）投与により、約２未満である集団のアミスルプリドのＣｍａｘ／Ｃｍｉｎ比を提供し、ＣｍａｘおよびＣｍｉｎの値は投与後９時間以内に測定される；
（ｖｉｉｉ）投与により、
ａ．医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物により達成される集団の幾何平均Ｃｍａｘの約８０％未満である、アミスルプリドの集団の幾何平均血漿Ｃｍａｘ、および
ｂ．医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物により達成される投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）の約８０％未満である、アミスルプリドの集団の幾何平均ＡＵＣ ０－２４
を提供する、例えば、即時放出組成物が、表２５に実質的に記載されている、医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物である；
（ｉｘ）投与により、固体経口剤組成物の初回投与後に約１９００（ｎｇ ＊ ｈ／ｍｌ）未満であるアミスルプリドの投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）を提供する；
（ｘ）投与により、固体経口剤組成物の投与１週間後に約２５００（ｎｇ ＊ ｈ／ｍｌ）未満であるアミスルプリドの投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）を提供する；
（ｘｉ）投与により、固体経口剤組成物の初回投与後に約４４００（ｎｇ ＊ ｈ／ｍｌ）未満であるアミスルプリドの投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）を提供する；または
（ｘｉｉ）投与により、固体経口剤組成物の投与１週間後に約５４００（ｎｇ ＊ ｈ／ｍｌ）未満であるアミスルプリドの投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）を提供する、
錠剤。 A tablet comprising amisulpride for treating bipolar depression, said treatment comprising administering to a subject from about 200 mg to about 400 mg of amisulpride by weight of free base per day as a tablet, said tablet comprising:
(R)-(+)-amisulpride and (S)-( where the enantiomeric ratio of (R)-(+)-amisulpride to (S)-(-)-amisulpride is about 85:15 by weight of free base -)- amisulpride in the form of unequal mixtures of amisulpride or a pharmaceutically acceptable salt thereof, and a sustained-release drug in an amount of about 10% to about 50% relative to the total weight of the tablet, wherein providing a subject population mean maximum QT interval prolongation relative to baseline that is less than about 0.4 milliseconds (ms) per 10 mg of amisulpride, and optionally,
(i) administration is once daily;
(ii) the population mean maximum QT interval prolongation relative to baseline is the population mean maximum QTcF interval prolongation relative to baseline over the 12 hour post-dose period;
(iii) the population mean maximum QT interval prolongation relative to baseline is less than about 0.35 milliseconds (ms) per 10 mg of amisulpride;
(vi) the population mean maximum QT interval prolongation relative to baseline is less than about 0.3 milliseconds (ms) per 10 mg of amisulpride;
(v) the sustained-release drug comprises a matrix-forming agent, e.g., the matrix-forming agent comprises one or more cellulose ethers, e.g., the sustained-release drug accounts for about 20% of the total weight of the tablet; Hydroxypropyl methylcellulose in an amount of about 40% from
(vi) by administration, at about 27 hours after administration, when D2 receptor occupancy is measured using Positron Emission Tomography (PET) as substantially described in Table 38 and herein; , which provides a mean occupancy of dopamine D2 receptors in a subject population of about 20% to about 60%;
(vii) administration provides a population Cmax/Cmin ratio of amisulpride that is less than about 2, and Cmax and Cmin values are measured within 9 hours after administration;
(viii) by administering
a. a population geometric mean plasma Cmax of amisulpride that is less than about 80% of the population geometric mean Cmax achieved with an immediate release composition having the same total daily amount of amisulpride as the pharmaceutical composition; and
b. of amisulpride that is less than about 80% of the population geometric mean AUC from 0 to 24 hours post-dose (AUC 0-24 ) achieved by an immediate release composition having the same total daily amount of amisulpride as the pharmaceutical composition; Population Geometric Mean AUC 0-24
wherein the immediate release composition is an immediate release composition having the same total daily amount of amisulpride as the pharmaceutical composition substantially as described in Table 25;
(ix) administration provides a population geometric mean AUC (AUC 0-24 ) from 0 to 24 hours after administration of amisulpride that is less than about 1900 (ng * h/ml) after the first administration of the solid oral dosage composition; ;
(x) administration provides a population geometric mean AUC (AUC 0-24 ) from 0 to 24 hours after administration of amisulpride that is less than about 2500 (ng * h/ml) one week after administration of the solid oral dosage composition; do;
(xi) administration provides a population geometric mean AUC (AUC 0-24 ) from 0 to 24 hours after administration of amisulpride that is less than about 4400 (ng * h/ml) after the first administration of the solid oral dosage composition; ;or
(xii) administration provides a population geometric mean AUC (AUC 0-24 ) from 0 to 24 hours after administration of amisulpride that is less than about 5400 (ng * h/ml) one week after administration of the solid oral dosage composition; do,
tablets .
（Ｒ）－（＋）－アミスルプリドと（Ｓ）－（－）－アミスルプリドのエナンチオマー比が遊離塩基の重量で約８５：１５である、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリドの不均等混合物の形態のアミスルプリド、または薬学的に許容されるそれらの塩、ならびに
固体経口剤の総重量に対して約１０％から約５０％の量の持続放出性薬剤を含み、ここで、投与により、
投与後１２時間の期間にわたって１２ミリ秒（ｍｓ）未満である基準値に対する対象集団の平均の最大ＱＴｃＦ間隔延長、および
投与約２７時間後に約２０％から約６０％の対象集団のドーパミンＤ２受容体の平均占有率を提供し、所望により、
（ｉ）投与が１日１回である；
（ｉｉ）固体経口剤が錠剤である；
（ｉｉｉ）Ｄ２受容体占有率が、表３８および本明細書に実質的に記載されている陽電子放射断層撮影法（ＰＥＴ）を使用して測定される；
（ｉｖ）持続放出性薬剤が、マトリックス形成剤を含む、例えば、マトリックス形成剤が、１つまたは複数のセルロースエーテルを含む；
（ｖ）持続放出性薬剤が、固体経口剤の総重量に対して約２０％から約４０％の量のヒドロキシプロピルメチルセルロースを含む；
（ｖｉ）投与により、約２未満である集団のアミスルプリドのＣｍａｘ／Ｃｍｉｎ比を提供し、ＣｍａｘおよびＣｍｉｎの値が、投与後９時間以内に測定される；
（ｖｉｉ）投与により、
ａ．医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物により達成される集団の幾何平均Ｃｍａｘの約８０％未満である、アミスルプリドの集団の幾何平均血漿Ｃｍａｘ、および
ｂ．医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物により達成される投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）の約８０％未満である、アミスルプリドの集団の幾何平均ＡＵＣ ０－２４
を提供する、例えば、即時放出組成物が、表２５に実質的に記載されている、医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物である；
（ｖｉｉｉ）投与により、固体経口剤組成物の初回投与後に約１９００（ｎｇ ＊ ｈ／ｍｌ）未満であるアミスルプリドの投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）を提供する；
（ｉｘ）投与により、固体経口剤組成物の投与１週間後に約２５００（ｎｇ ＊ ｈ／ｍｌ）未満であるアミスルプリドの投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）を提供する；
（ｘ）投与により、固体経口剤組成物の初回投与後に約４４００（ｎｇ ＊ ｈ／ｍｌ）未満であるアミスルプリドの投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）を提供する；または
（ｘｉ）投与により、固体経口剤組成物の投与１週間後に約５４００（ｎｇ ＊ ｈ／ｍｌ）未満であるアミスルプリドの投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）を提供する、
固形経口剤。 1. A solid oral dosage form for treating bipolar depression, said treatment comprising administering to a subject as a solid oral dosage form about 200 mg to about 400 mg of amisulpride by weight of free base per day. but,
(R)-(+)-amisulpride and (S)-( where the enantiomeric ratio of (R)-(+)-amisulpride to (S)-(-)-amisulpride is about 85:15 by weight of free base -)- amisulpride in the form of an unequal mixture of amisulpride, or a pharmaceutically acceptable salt thereof, and a sustained-release drug in an amount of about 10% to about 50% based on the total weight of the solid oral dosage form , where by dosing
A subject population mean maximum QTcF interval prolongation relative to baseline that is less than 12 milliseconds (ms) over a period of 12 hours post-dose and about 20% to about 60% of the subject population dopamine D2 receptors at about 27 hours post-dose and, optionally, the average occupancy of
(i) administration is once daily;
(ii) the solid oral dosage form is a tablet;
(iii) D2 receptor occupancy is measured using Positron Emission Tomography (PET) as substantially described in Table 38 and herein;
(iv) the sustained-release drug comprises a matrix-forming agent, e.g., the matrix-forming agent comprises one or more cellulose ethers;
(v) the sustained release dosage form comprises hydroxypropyl methylcellulose in an amount of about 20% to about 40% by weight of the total solid oral dosage form;
(vi) administration provides a population Cmax/Cmin ratio of amisulpride that is less than about 2, and Cmax and Cmin values are measured within 9 hours after administration;
(vii) by administering
a. a population geometric mean plasma Cmax of amisulpride that is less than about 80% of the population geometric mean Cmax achieved with an immediate release composition having the same total daily amount of amisulpride as the pharmaceutical composition; and
b. of amisulpride that is less than about 80% of the population geometric mean AUC from 0 to 24 hours post-dose (AUC 0-24 ) achieved by an immediate release composition having the same total daily amount of amisulpride as the pharmaceutical composition; Population Geometric Mean AUC 0-24
wherein the immediate release composition is an immediate release composition having the same total daily amount of amisulpride as the pharmaceutical composition substantially as described in Table 25;
(viii) administration provides a population geometric mean AUC (AUC 0-24 ) from 0 to 24 hours after administration of amisulpride that is less than about 1900 (ng * h/ml) after the first administration of the solid oral dosage composition; ;
(ix) administration provides a population geometric mean AUC (AUC 0-24 ) from 0 to 24 hours after administration of amisulpride that is less than about 2500 (ng * h/ml) one week after administration of the solid oral dosage composition; do;
(x) administration provides a population geometric mean AUC (AUC 0-24 ) from 0 to 24 hours after administration of amisulpride that is less than about 4400 (ng * h/ml) after the first administration of the solid oral dosage composition; ;or
(xi) administration provides a population geometric mean AUC (AUC 0-24 ) from 0 to 24 hours after administration of amisulpride that is less than about 5400 (ng * h/ml) one week after administration of the solid oral dosage composition; do,
Solid oral preparation .
（Ｒ）－（＋）アミスルプリドの量が（Ｓ）－（－）－アミスルプリドの量より多い、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリドの不均等混合物の形態のアミスルプリド、または薬学的に許容されるそれらの塩；ならびに
１つまたは複数の薬学的に許容される賦形剤を含み、ここで、対象集団に投与した場合に、（ａ）アミスルプリド１０ｍｇ当たり約０．４５ミリ秒（ｍｓ）未満；または（ｂ）アミスルプリド１０ｍｇ当たり約０．４０ミリ秒（ｍｓ）未満；または（ｃ）アミスルプリド１０ｍｇ当たり約０．３５ミリ秒（ｍｓ）未満；または（ｄ）アミスルプリド１０ｍｇ当たり約０．３０ミリ秒（ｍｓ）未満；または（ｅ）アミスルプリド１０ｍｇ当たり約０．２５ミリ秒（ｍｓ）未満；または（ｆ）アミスルプリド１０ｍｇ当たり約０．２０ミリ秒（ｍｓ）未満；または（ｇ）アミスルプリド１０ｍｇ当たり約０．１５ミリ秒（ｍｓ）未満；または（ｈ）アミスルプリド１０ｍｇ当たり約０．１０ミリ秒（ｍｓ）未満；または（ｉ）アミスルプリド１０ｍｇ当たり約０．０５ミリ秒（ｍｓ）未満または（ｊ）アミスルプリド１０ｍｇ当たり約０．０２ミリ秒（ｍｓ）未満の投与後１２時間の期間での基準値に対する集団の平均の最大ＱＴ間隔延長を提供し、所望により、
（ｉ）基準値に対する集団の平均の最大ＱＴ間隔延長が、基準値に対する集団の平均の最大ＱＴｃＦ間隔延長である；または
（ｉｉ）（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリド、または薬学的に許容されるそれらの塩を組み合わせた量が、遊離塩基の重量で（ａ）約１００ｍｇ；または（ｂ）約１６０ｍｇ；または（ｃ）約２００ｍｇ；または（ｄ）約３００ｍｇ；または（ｅ）約４００ｍｇ；または（ｆ）約５００ｍｇ；または（ｇ）約６００ｍｇである、
医薬組成物。 A solid oral pharmaceutical composition comprising:
Form of unequal mixture of (R)-(+)-amisulpride and (S)-(-)-amisulpride, wherein the amount of (R)-(+)amisulpride is greater than the amount of (S)-(-)-amisulpride amisulpride, or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients, wherein (a) per 10 mg of amisulpride is about or (b) less than about 0.40 milliseconds (ms) per 10 mg of amisulpride; or (c) less than about 0.35 milliseconds (ms) per 10 mg of amisulpride; or (d) less than about 0.30 milliseconds (ms) per 10 mg amisulpride; or (e) less than about 0.25 milliseconds (ms) per 10 mg amisulpride; or (f) less than about 0.20 milliseconds (ms) per 10 mg amisulpride; or (g) less than about 0.15 milliseconds (ms) per 10 mg of amisulpride; or (h) less than about 0.10 milliseconds (ms) per 10 mg of amisulpride; or (i) less than about 0.05 milliseconds per 10 mg of amisulpride ( ms) or (j) less than about 0.02 milliseconds (ms) per 10 mg of amisulpride over a period of 12 hours post-dose, providing a population mean maximum QT interval prolongation relative to baseline , optionally
(i) the population mean maximum QT interval prolongation relative to baseline is the population mean maximum QTcF interval prolongation relative to baseline; or
(ii) a combined amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of the free base of (a) about 100 mg; or (b) about 160 mg; or (c) about 200 mg; or (d) about 300 mg; or (e) about 400 mg; or (f) about 500 mg; or (g) about 600 mg.
pharmaceutical composition .
（Ｒ）－（＋）－アミスルプリドの量が（Ｓ）－（－）－アミスルプリドの量より多い、（Ｒ）－（＋）アミスルプリドおよび（Ｓ）－（－）－アミスルプリドの不均等混合物の形態の２００ｍｇのアミスルプリド、または薬学的に許容されるそれらの塩；ならびに
１つまたは複数の薬学的に許容される賦形剤を含み、ここで、対象集団に投与した場合に、（ａ）約１０ミリ秒未満（ｍｓ）；または（ｂ）約９ミリ秒未満（ｍｓ）；または（ｃ）約８ミリ秒未満（ｍｓ）；または（ｄ）約７ミリ秒未満（ｍｓ）；または（ｅ）約６ミリ秒未満（ｍｓ）；または（ｆ）約５ミリ秒未満（ｍｓ）の投与後１２時間の期間での基準値に対する集団の平均最大ＱＴｃＦ間隔延長を提供し、所望により、基準値に対する集団の平均の最大ＱＴｃＦ間隔延長が、幾何平均Ｃｍａｘの基準値に対する集団の平均の最大ＱＴｃＦ間隔延長である、医薬組成物。 A solid oral pharmaceutical composition comprising:
Form of unequal mixture of (R)-(+)amisulpride and (S)-(-)-amisulpride, wherein the amount of (R)-(+)-amisulpride is greater than the amount of (S)-(-)-amisulpride of amisulpride, or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients, wherein when administered to a subject population: (a) about 10 or (b) less than about 9 milliseconds (ms); or (c) less than about 8 milliseconds (ms); or (d) less than about 7 milliseconds (ms); or (e) or ( f) a population mean maximum QTcF interval prolongation relative to baseline over a period of 12 hours post-dose of less than about 6 milliseconds (ms); or (f) less than about 5 milliseconds (ms); The pharmaceutical composition, wherein the population mean maximum QTcF interval prolongation is the population mean maximum QTcF interval prolongation relative to the baseline value for the geometric mean Cmax.
（Ｒ）－（＋）アミスルプリドの量が（Ｓ）－（－）－アミスルプリドの量より多い、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリドの不均等混合物の形態のアミスルプリド、または薬学的に許容されるそれらの塩；ならびに
１つまたは複数の薬学的に許容される賦形剤を含み、ここで、対象集団に投与した場合に、医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物と比較して、（ａ）即時放出組成物のものよりも少なくとも約７５％短い；または（ｂ）即時放出組成物のものよりも少なくとも約６５％短い；または（ｃ）即時放出組成物のものよりも少なくとも約６０％短い；または（ｄ）即時放出組成物のものよりも少なくとも約５５％短い；または（ｅ）即時放出組成物のものよりも少なくとも約５０％短い投与後１２時間の期間での基準値に対する集団の平均の最大ＱＴ間隔延長を提供し、所望により、
（ｉ）基準値に対する集団の平均の最大ＱＴ間隔延長が、基準値に対する集団の平均の最大ＱＴｃＦ間隔延長である；
（ｉｉ）即時放出組成物が、表２５に実質的に記載されている、医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物である；
（ｉｉｉ）（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリド、または薬学的に許容されるそれらの塩を組み合わせた量が、遊離塩基の重量で（ａ）約１００ｍｇ；または（ｂ）約１６０ｍｇ；または（ｃ）約２００ｍｇ；または（ｄ）約３００ｍｇ；または（ｅ）約４００ｍｇ；または（ｆ）約５００ｍｇ；または（ｇ）または約６００ｍｇである、
医薬組成物。 A solid oral pharmaceutical composition comprising:
Form of unequal mixture of (R)-(+)-amisulpride and (S)-(-)-amisulpride, wherein the amount of (R)-(+)amisulpride is greater than the amount of (S)-(-)-amisulpride amisulpride, or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients, wherein when administered to a subject population, the pharmaceutical composition and (a) at least about 75% shorter than that of the immediate release composition; or (b) at least about 65% shorter than that of the immediate release composition, compared to an immediate release composition having the same total amount of amisulpride. or (c) at least about 60% shorter than that of an immediate release composition; or (d) at least about 55% shorter than that of an immediate release composition; or (e) at least less than that of an immediate release composition. providing a population mean maximum QT interval prolongation relative to baseline over a period of 12 hours post-dose that is about 50% shorter , optionally
(i) the population mean maximum QT interval prolongation relative to baseline is the population mean maximum QTcF interval prolongation relative to baseline;
(ii) the immediate release composition is an immediate release composition having the same total daily amount of amisulpride as the pharmaceutical composition substantially as described in Table 25;
(iii) a combined amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of the free base of (a) about 100 mg; or (b) about 160 mg; or (c) about 200 mg; or (d) about 300 mg; or (e) about 400 mg; or (f) about 500 mg;
pharmaceutical composition .
（Ｒ）－（＋）－アミスルプリドの量が（Ｓ）－（－）－アミスルプリドの量より多い、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリドの不均等混合物の形態のアミスルプリド、または薬学的に許容されるそれらの塩；ならびに
１つまたは複数の薬学的に許容される賦形剤を含み、ここで、医薬組成物が対象集団に投与される場合に、投与後約２７時間で、
（ａ）医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物により達成されるドーパミンＤ２受容体占有率の少なくとも８５％；または
（ｂ）医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物により達成されるドーパミンＤ２受容体占有率の少なくとも９０％；または
（ｃ）医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物により達成されるドーパミンＤ２受容体占有率の少なくとも９５％である集団のドーパミンＤ２受容体の平均占有率
を提供し、所望により、
（ｉ）即時放出組成物が、表２５に実質的に記載されている、医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物である；または
（ｉｉ）（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリド、または薬学的に許容されるそれらの塩を組み合わせた量が、遊離塩基の重量で（ａ）約１００ｍｇ；または（ｂ）約１６０ｍｇ；または（ｃ）約２００ｍｇ；または（ｄ）約３００ｍｇ；または（ｅ）約４００ｍｇ；または（ｆ）約５００ｍｇ；または（ｇ）または約６００ｍｇである、
医薬組成物。 A solid oral pharmaceutical composition comprising:
unequal mixture of (R)-(+)-amisulpride and (S)-(-)-amisulpride, wherein the amount of (R)-(+)-amisulpride is greater than the amount of (S)-(-)-amisulpride Amisulpride, or a pharmaceutically acceptable salt thereof, in the form of amisulpride, or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients, wherein when the pharmaceutical composition is administered to a subject population, administration About 27 hours later,
(a) at least 85% of the dopamine D2 receptor occupancy achieved by an immediate release composition having amisulpride in the same total daily amount as the pharmaceutical composition; or (b) in the same total daily amount as the pharmaceutical composition. or (c) dopamine D2 receptor occupancy achieved by an immediate release composition having the same total daily amount of amisulpride as the pharmaceutical composition. providing an average dopamine D2 receptor occupancy of the population that is at least 95% of the D2 receptor occupancy;
(i) the immediate release composition is an immediate release composition having the same total daily amount of amisulpride as the pharmaceutical composition substantially as described in Table 25; or
(ii) a combined amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of the free base of (a) about 100 mg; or (b) about 160 mg; or (c) about 200 mg; or (d) about 300 mg; or (e) about 400 mg; or (f) about 500 mg;
pharmaceutical composition .
（Ｒ）－（＋）－アミスルプリドの量が（Ｓ）－（－）－アミスルプリドの量より多い、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリドの不均等混合物の形態のアミスルプリド、または薬学的に許容されるそれらの塩、ならびに
１つまたは複数の薬学的に許容される賦形剤を含み、ここで、対象集団に投与した医薬組成物が、医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物と比較して、アミスルプリドのＣｍｉｎとＣｍａｘとの間の差を最小限に抑えるのに有効であり、Ｃｍｉｎの値が、投与後約９時間以内に測定される、例えば、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリド、または薬学的に許容されるそれらの塩を組み合わせた量が、遊離塩基の重量で（ａ）約１００ｍｇ；または（ｂ）約１６０ｍｇ；または（ｃ）約２００ｍｇ；または（ｄ）約３００ｍｇ；または（ｅ）約４００ｍｇ；または（ｆ）約５００ｍｇ；または（ｇ）または約６００ｍｇである、医薬組成物。 A solid oral pharmaceutical composition comprising:
unequal mixture of (R)-(+)-amisulpride and (S)-(-)-amisulpride, wherein the amount of (R)-(+)-amisulpride is greater than the amount of (S)-(-)-amisulpride form of amisulpride, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition administered to the subject population comprises the pharmaceutical composition and Effective in minimizing the difference between Cmin and Cmax of amisulpride compared to an immediate release composition having the same total daily dose of amisulpride, with Cmin values approximately 9 hours after administration For example, the combined amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride, or a pharmaceutically acceptable salt thereof, measured within the weight of the free base ( or (c) about 200 mg; or (d) about 300 mg; or (e) about 400 mg; or (f) about 500 mg; or (g) or about 600 mg. pharmaceutical composition .
（Ｒ）－（＋）－アミスルプリドの量が（Ｓ）－（－）－アミスルプリドの量より多い、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリドの不均等混合物の形態のアミスルプリド、または薬学的に許容されるそれらの塩、ならびに
１つまたは複数の薬学的に許容される賦形剤を含み、ここで、前記組成物が対象集団に投与される場合に、（ａ）約２未満；または（ｂ）約１．９未満；または（ｃ）約１．８未満であるアミスルプリドのＣｍａｘ／Ｃｍｉｎ比を提供し、Ｃｍｉｎの値が投与後約９時間以内に測定され、所望により、
（ｉ）ＣｍａｘおよびＣｍｉｎの値が、集団の幾何平均値であり、値が投与後約９時間以内に測定される；
（ｉｉ）総量２００ｍｇのアミスルプリドを投与する固体経口剤が、（ａ）約３５０ｎｇ／ｍＬ未満；（ｂ）約３００ｎｇ／ｍＬ未満；または（ｃ）約２５０ｎｇ／ｍＬ未満の集団の幾何平均血漿Ｃｍａｘを提供する；
（ｉｉｉ）総量４００ｍｇのアミスルプリドを投与する固体経口剤が、（ａ）約５００ｎｇ／ｍＬ未満；（ｂ）約４７５ｎｇ／ｍＬ未満；または（ｃ）約４５０ｎｇ／ｍＬ未満の集団の幾何平均血漿Ｃｍａｘを提供する；または
（ｉｖ）（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリド、または薬学的に許容されるそれらの塩を組み合わせた量が、遊離塩基の重量で（ａ）約１００ｍｇ；または（ｂ）約１６０ｍｇ；または（ｃ）約２００ｍｇ；または（ｄ）約３００ｍｇ；または（ｅ）約４００ｍｇ；または（ｆ）約５００ｍｇ；または（ｇ）または約６００ｍｇである、
医薬組成物。 A solid oral pharmaceutical composition comprising:
unequal mixture of (R)-(+)-amisulpride and (S)-(-)-amisulpride, wherein the amount of (R)-(+)-amisulpride is greater than the amount of (S)-(-)-amisulpride form of amisulpride, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein when said composition is administered to a subject population, ( or (b) less than about 1.9; or (c) less than about 1.8, wherein the Cmin value is measured within about 9 hours after administration. , if desired,
(i) the Cmax and Cmin values are the geometric mean values of the population and the values are measured within about 9 hours after administration;
(ii) a solid oral dosage form administering a total dose of 200 mg of amisulpride provides a population geometric mean plasma Cmax of (a) less than about 350 ng/mL; (b) less than about 300 ng/mL; or (c) less than about 250 ng/mL. offer;
(iii) a solid oral dosage form administering a total amount of 400 mg of amisulpride provides a population geometric mean plasma Cmax of (a) less than about 500 ng/mL; (b) less than about 475 ng/mL; or (c) less than about 450 ng/mL. provide; or
(iv) a combined amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride, or a pharmaceutically acceptable salt thereof, by weight of the free base of (a) about 100 mg; or (b) about 160 mg; or (c) about 200 mg; or (d) about 300 mg; or (e) about 400 mg; or (f) about 500 mg;
pharmaceutical composition .
（Ｒ）－（＋）アミスルプリドの量が（Ｓ）－（－）－アミスルプリドの量より多い、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリドの不均等混合物の形態のアミスルプリド、または薬学的に許容されるそれらの塩；ならびに
持続放出性薬剤を含み、ここで、二段階インビトロ胃腸模擬溶出試験を使用して溶出性を試験した固体経口剤が、
（ａ）１時間後に約３０％未満のアミスルプリドを放出し、３時間後に約２０％超かつ約６０％未満のアミスルプリドを放出し、６時間後に約３０％超かつ約１００％未満のアミスルプリドを放出する；または
（ｂ）１時間後に約３０％未満のアミスルプリドを放出し、３時間後に２０％超かつ約６０％未満のアミスルプリドを放出し、６時間後に約３０％超かつ７５％未満のアミスルプリドを放出する；または
（ｃ）１時間後に約２０％未満のアミスルプリドを放出し、３時間後に約２０％超かつ約５０％未満のアミスルプリドを放出し、６時間後に約３０％超かつ約７５％未満のアミスルプリドを放出する；または
（ｄ）１時間後に約２０％未満のアミスルプリドを放出し、３時間後に約２０％超かつ約５０％未満のアミスルプリドを放出し、６時間後に約３０％超かつ約５０％未満のアミスルプリドを放出する；または
（ｅ）１時間後に約３０％以下のアミスルプリドを放出し、約３時間後に約３０％から約７５％のアミスルプリドを放出し、約１２時間後に約７５％超のアミスルプリドを放出する；または
（ｆ）１時間後に約３０％未満のアミスルプリドを放出し、３時間後に約２０％超かつ約６０％未満のアミスルプリドを放出し、６時間後に約３０％超かつ約１００％未満のアミスルプリドを放出し、約１０時間後に約７５％超のアミスルプリドを放出する；または
（ｇ）１時間後に約３０％未満のアミスルプリドを放出し、３時間後に約２０％超かつ約６０％未満のアミスルプリドを放出し、６時間後に約３０％超かつ約１００％未満のアミスルプリドを放出し、約８時間後に約７５％超のアミスルプリドを放出する；または
（ｈ）１時間後に約３０％未満のアミスルプリドを放出し、３時間後に約２０％超かつ約６０％未満のアミスルプリドを放出し、６時間後に約３０％超かつ約７５％未満のアミスルプリドを放出し、約１０時間後に約７５％超のアミスルプリドを放出する；または
（ｉ）１時間後に約２０％未満のアミスルプリドを放出し、３時間後に約２０％超かつ約６０％未満のアミスルプリドを放出し、６時間後に約３０％超かつ約１００％未満のアミスルプリドを放出し、約１０時間後に約７５％超のアミスルプリドを放出する；または
（ｊ）１時間後に約３０％未満のアミスルプリドを放出し、３時間後に約２０％超かつ約６０％未満のアミスルプリドを放出し、６時間後に約３０％超かつ約５０％未満のアミスルプリドを放出し、約１０時間後に約７５％超のアミスルプリドを放出する、例えば、
（Ａ）二段階胃腸模擬溶出試験が、第一段階で、約２のｐＨを有する５００ｍｌの水性媒体を含み、１時間後に、第二段階のｐＨが６．８になるように４００ｍｌの水性バッファー媒体を添加し；二段階インビトロ胃腸模擬溶出試験の両方の段階における温度が、約３７℃である；または
（Ｂ）二段階胃腸模擬溶出試験が、（ａ）米国薬局方（ＵＳＰ）第７１１章溶出試験の装置２；ＵＳＰ４１－ＮＦ３６一般章＜７１１＞溶出試験、および（ｂ）日本薬局方（ＪＰ）一般試験＜６．１０＞のうちの１以上に記載されているものに実質的に従ったパドル装置で実施される、
医薬組成物。 A solid oral pharmaceutical composition comprising:
Form of unequal mixture of (R)-(+)-amisulpride and (S)-(-)-amisulpride, wherein the amount of (R)-(+)amisulpride is greater than the amount of (S)-(-)-amisulpride amisulpride, or a pharmaceutically acceptable salt thereof; and a sustained-release drug, wherein the solid oral dosage form tested for dissolution using a two-stage in vitro gastrointestinal simulated dissolution test comprises:
(a) releasing less than about 30% amisulpride after 1 hour, releasing more than about 20% and less than about 60% amisulpride after 3 hours, and releasing more than about 30% and less than about 100% amisulpride after 6 hours; or (b) releasing less than about 30% amisulpride after 1 hour, releasing more than 20% and less than about 60% amisulpride after 3 hours, and more than about 30% and less than 75% amisulpride after 6 hours. or (c) releasing less than about 20% amisulpride after 1 hour, releasing more than about 20% and less than about 50% amisulpride after 3 hours, and more than about 30% and less than about 75% after 6 hours. or (d) releasing less than about 20% amisulpride after 1 hour, releasing more than about 20% and less than about 50% amisulpride after 3 hours, and more than about 30% and about release less than 50% of amisulpride; or (e) release about 30% or less of amisulpride after 1 hour, release about 30% to about 75% of amisulpride after about 3 hours, and release about 75% after about 12 hours. or (f) releasing less than about 30% amisulpride after 1 hour, releasing more than about 20% and less than about 60% amisulpride after 3 hours, and greater than about 30% after 6 hours and or (g) releasing less than about 30% amisulpride after 1 hour and greater than about 20% after 3 hours and about 75% after about 10 hours. releasing less than 60% amisulpride, releasing greater than about 30% and less than about 100% amisulpride after 6 hours, and releasing greater than about 75% amisulpride after about 8 hours; or (h) about 30% after 1 hour. % amisulpride, releasing greater than about 20% and less than about 60% amisulpride after 3 hours, releasing greater than about 30% and less than about 75% amisulpride after 6 hours, and about 75% after about 10 hours. or (i) releasing less than about 20% amisulpride after 1 hour, releasing more than about 20% and less than about 60% amisulpride after 3 hours, and more than about 30% after 6 hours. and releasing less than about 100% amisulpride after about 10 hours and releasing more than about 75% amisulpride after about 10 hours; or (j) releasing less than about 30% amisulpride after 1 hour and more than about 20% after 3 hours and releasing less than about 60% amisulpride, releasing greater than about 30% and less than about 50% amisulpride after 6 hours, and releasing greater than about 75% amisulpride after about 10 hours, e.g.
(A) A two-stage gastrointestinal simulated dissolution test comprising, in the first stage, 500 ml of aqueous medium having a pH of about 2, and after 1 hour, 400 ml of aqueous buffer such that the second stage has a pH of 6.8. vehicle is added; the temperature in both stages of the two-stage in vitro gastrointestinal simulated dissolution test is about 37°C; or
(B) A two-stage gastrointestinal simulated dissolution test was performed using (a) Apparatus 2 of the United States Pharmacopeia (USP) Chapter 711 Dissolution Test; Performed on a paddle apparatus substantially in accordance with one or more of the General Tests <6.10>
pharmaceutical composition.
（Ｒ）－（＋）－アミスルプリドの量が（Ｓ）－（－）－アミスルプリドの量より多い、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリド不均等混合物の形態のアミスルプリド、または薬学的に許容されるそれらの塩；ならびに
持続放出性薬剤を含み、ここで、該固体経口剤が、米国薬局方（ＵＳＰ）第７１１章溶出試験の装置２；ＵＳＰ４１－ＮＦ３６一般章＜７１１＞溶出試験に記載されているパドル装置で、表５に記載されている二段階インビトロ溶出試験を使用してその溶出性を試験された場合に、（ａ）図１Ｃにおけるロット３Ｃのプロファイル；または（ｂ）図１Ｃにおけるロット２Ｃのプロファイル；または（ｃ）図１Ｄにおける実施例７Ａパート１もしくはパート２の試験に使用されるロット３Ｚのプロファイル；または（ｄ）図１Ｄにおける実施例７Ａ、パート１の摂食状態の試験に使用されるロット３Ｚのプロファイル；または（ｅ）図１Ｄにおける実施例７ＢのＭＡＤ／ＰＥＴ試験に使用されるロット３Ｚのプロファイル；または（ｆ）図１Ｄにおけるロット４Ｚのプロファイル；または（ｇ）図１Ｄにおけるロット５Ｚのプロファイル；または（ｈ）図１Ｄにおけるロット６Ｚのプロファイル；または（ｉ）０から６時間の期間にわたる、図１Ｅにおけるロット７Ｃのプロファイル；または（ｊ）０から６時間の期間にわたる、図１Ｅにおけるロット８Ｃのプロファイル；または（ｋ）実施例７Ｂ、実施例７Ａパート１の試験に使用されるロット３Ｚのプロファイル、または（ｌ）図１Ｄにおける実施例７Ａパート２の試験に使用されるロット３Ｚのプロファイルと実質的に同一の溶出プロファイルを有する、医薬組成物。 A solid oral pharmaceutical composition comprising:
The form of (R)-(+)-amisulpride and (S)-(-)-amisulpride unequal mixtures in which the amount of (R)-(+)-amisulpride is greater than the amount of (S)-(-)-amisulpride amisulpride, or a pharmaceutically acceptable salt thereof; and a sustained-release drug wherein the solid oral dosage form complies with United States Pharmacopeia (USP) Chapter 711 Dissolution Test Apparatus 2; USP 41-NF36 General (a) Lot 3C in FIG. or (b) the profile of Lot 2C in FIG. 1C; or (c) the profile of Lot 3Z used for testing of Example 7A Part 1 or Part 2 in FIG. 1D; or (d) Example 7A in FIG. , the profile of Lot 3Z used for the fed state study of Part 1; or (e) the profile of Lot 3Z used for the MAD/PET study of Example 7B in FIG. 1D; or (f) the lot in FIG. or (g) the profile of Lot 5Z in FIG. 1D; or (h) the profile of Lot 6Z in FIG. 1D; or (i) the profile of Lot 7C in FIG. j) Lot 8C profile in FIG. 1E over a period of 0 to 6 hours; or (k) Example 7B, Lot 3Z profile used in Example 7A Part 1 testing, or (l) run in FIG. A pharmaceutical composition having a dissolution profile substantially identical to that of Lot 3Z used in the study of Example 7A Part 2.
（Ｒ）－（＋）アミスルプリドの量が（Ｓ）－（－）－アミスルプリドの量より多い、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリドの不均等混合物の形態のアミスルプリド、または薬学的に許容されるそれらの塩；ならびに
持続放出性薬剤を含み、ここで、該医薬組成物が対象集団に投与される場合に、（ａ）図２２Ｂにおけるロット４Ｚのプロファイル；または（ｂ）図２２Ｃにおけるロット３Ｚのプロファイル；または（ｃ）図２２Ｄにおけるロット３Ｚ摂食状態のプロファイル；（ｄ）図２２Ｆにおけるロット４Ｚのプロファイル；または（ｅ）図２２Ｈにおけるロット３Ｚのプロファイル；または（ｆ）図２２Ｉにおけるロット３Ｚ摂食状態のプロファイル；または（ｇ）図２２Ｊにおけるロット３Ｚのプロファイル；または（ｈ）図２２Ｇにおけるロット５Ｚのプロファイル；または（ｉ）図２２Ｋにおけるロット６Ｚのプロファイルと実質的に同一の血漿中濃度プロファイルを提供する、医薬組成物。 A solid oral pharmaceutical composition comprising:
Form of unequal mixture of (R)-(+)-amisulpride and (S)-(-)-amisulpride, wherein the amount of (R)-(+)amisulpride is greater than the amount of (S)-(-)-amisulpride amisulpride, or a pharmaceutically acceptable salt thereof; and a sustained-release drug, wherein when the pharmaceutical composition is administered to a subject population, (a) the profile of Lot 4Z in FIG. 22B; or (b) Lot 3Z profile in FIG. 22C; or (c) Lot 3Z fed profile in FIG. 22D; (d) Lot 4Z profile in FIG. 22F; or (e) Lot 3Z profile in FIG. 22H; or (f) Lot 3Z fed profile in Figure 22I; or (g) Lot 3Z profile in Figure 22J; or (h) Lot 5Z profile in Figure 22G; or (i) Lot 6Z profile in Figure 22K. A pharmaceutical composition that provides substantially the same plasma concentration profile as
（Ｒ）－（＋）－アミスルプリドの量が（Ｓ）－（－）－アミスルプリドの量より多い、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリドの不均等混合物の形態のアミスルプリド、または薬学的に許容されるそれらの塩；ならびに
持続放出性薬剤を含み、ここで、該固体経口剤が対象集団に投与される場合に、
（ｉ）投与後約４時間から約６時間である、アミスルプリドの集団の幾何平均Ｔｍａｘ；
（ｉｉ）（ａ）投与から約４８時間の曲線下面積（ＡＵＣ０－４８）の約１９％未満；または（ｂ）投与から約４８時間の集団の平均曲線下面積（ＡＵＣ０－４８）の約１８％未満；または（ｃ）投与から４８時間の曲線下面積（ＡＵＣ０－４８）の約１７％未満；または（ｄ）投与から４８時間の曲線下面積（ＡＵＣ０－４８）の約１６％未満；または（ｅ）投与から４８時間の曲線下面積（ＡＵＣ０－４８）の約１５％未満；または（ｆ）投与から４８時間の曲線下面積（ＡＵＣ０－４８）の約１４％未満；または（ｇ）投与から４８時間の曲線下面積（ＡＵＣ０－４８）の約１３％未満；または（ｈ）投与から４８時間の曲線下面積（ＡＵＣ０－４８）の約１２％未満である、ＴｍａｘまでのＡＵＣ（ＡＵＣ０－Ｔｍａｘ）
を提供する、医薬組成物。 A solid oral pharmaceutical composition comprising:
unequal mixture of (R)-(+)-amisulpride and (S)-(-)-amisulpride, wherein the amount of (R)-(+)-amisulpride is greater than the amount of (S)-(-)-amisulpride Amisulpride, or a pharmaceutically acceptable salt thereof, in the form of:
(i) the population geometric mean Tmax of amisulpride from about 4 hours to about 6 hours after administration;
(ii) (a) less than about 19% of the area under the curve (AUC 0-48 ) at about 48 hours after dosing; or (b) the population mean area under the curve (AUC 0-48 ) at about 48 hours after dosing or (c) less than about 17% of the area under the curve (AUC 0-48 ) 48 hours after dosing; or (d) about 16 of the area under the curve (AUC 0-48 ) 48 hours after dosing. or (e) less than about 15% of the area under the curve (AUC 0-48 ) 48 hours after dosing; or (f) less than about 14% of the area under the curve (AUC 0-48 ) 48 hours after dosing. or (g) less than about 13% of the area under the curve (AUC 0-48 ) 48 hours after dosing; or (h) less than about 12% of the area under the curve (AUC 0-48 ) 48 hours after dosing , AUC up to Tmax (AUC 0−Tmax )
A pharmaceutical composition that provides
（ｉ）１つまたは複数の薬学的に許容される賦形剤が、持続放出性薬剤を含む；
（ｉｉ）１つまたは複数の薬学的に許容される賦形剤が、持続放出性薬剤を含み、ここで、持続放出性薬剤が、（ａ）固体経口剤の総重量に対して約１０％から約５０％；または（ｂ）固体経口剤の総重量に対して約３０％から約５０％；または（ｃ）固体経口剤の総重量に対して約２０％から約４０％；または（ｄ）固体経口剤の総重量に対して約２０％から約３０％の量である；
（ｉｉｉ）１つまたは複数の薬学的に許容される賦形剤が、持続放出性薬剤を含み、ここで、持続放出性薬剤が、（ａ）固体経口剤の総重量に対して約１０％から約５０％；または（ｂ）固体経口剤の総重量に対して約３０％から約５０％；または（ｃ）固体経口剤の総重量に対して約２０％から約４０％；または（ｄ）固体経口剤の総重量に対して約２０％から約３０％の量であり、固体経口剤が錠剤である；
（ｉｖ）１つまたは複数の薬学的に許容される賦形剤が、持続放出性薬剤を含み、ここで、持続放出性薬剤が、（ａ）固体経口剤の総重量に対して約１０％から約５０％；または（ｂ）固体経口剤の総重量に対して約３０％から約５０％；または（ｃ）固体経口剤の総重量に対して約２０％から約４０％；または（ｄ）固体経口剤の総重量に対して約２０％から約３０％の量であり、固体経口剤が錠剤であり、持続放出性薬剤が、マトリックス形成剤を含む、例えば、マトリックス形成剤が、１つまたは複数のセルロースエーテルを含む；
（ｖ）１つまたは複数の薬学的に許容される賦形剤が、持続放出性薬剤を含み、ここで、持続放出性薬剤が、（ａ）固体経口剤の総重量に対して約１０％から約５０％；または（ｂ）固体経口剤の総重量に対して約３０％から約５０％；または（ｃ）固体経口剤の総重量に対して約２０％から約４０％；または（ｄ）固体経口剤の総重量に対して約２０％から約３０％の量であり、固体経口剤が錠剤であり、持続放出性薬剤が、固体経口剤の総重量に対して約２０％から約４０％の量のヒドロキシプロピルメチルセルロースを含む；
（ｖｉ）固体経口剤が、固体経口剤の総重量に対して、
約３５％から約４５％のアミスルプリド、
約２０％から約４０％の薬学的に許容される充填剤、および
約２０％から約３５％の持続放出性薬剤
を含む；
（ｖｉｉ）対象集団に投与した場合に、
ａ．医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物により達成される集団の幾何平均Ｃｍａｘの約８０％未満である、アミスルプリドの集団の幾何平均血漿Ｃｍａｘ、および
ｂ．医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物により達成される投与後０から２４時間の集団の幾何平均ＡＵＣ（ＡＵＣ ０－２４ ）の約８０％未満である、アミスルプリドの集団の幾何平均ＡＵＣ ０－２４
を提供する、例えば、即時放出組成物が、表２５に実質的に記載されている、医薬組成物と１日当たりの総量が同一のアミスルプリドを有する即時放出組成物である；
（ｖｉｉｉ）対象集団に投与した場合に、投与の約２７時間後に、
（ａ）約２０％から約６０％の集団のドーパミンＤ２受容体の平均占有率、または
（ｂ）約３０％から約５０％の集団のドーパミンＤ２受容体の平均占有率を提供し、ここで、Ｄ２受容体占有率が、表３８および本明細書に実質的に記載されている陽電子放射断層撮影法（ＰＥＴ）を使用して測定される、例えば、（Ｓ）－（－）－アミスルプリドまたは薬学的に許容されるそれらの塩の量が、遊離塩基の重量で約１００ｍｇ未満である、
医薬組成物。 Claim 5, wherein the enantiomeric ratio of (R)-(+)-amisulpride and (S)-(-)-amisulpride, or a pharmaceutically acceptable salt thereof, is about 85:15 by weight of free base. 11. The pharmaceutical composition of any one of -10 , optionally comprising
(i) the one or more pharmaceutically acceptable excipients comprise a sustained release drug;
(ii) one or more pharmaceutically acceptable excipients comprising a sustained release agent, wherein the sustained release agent comprises (a) about 10% by weight of the total solid oral dosage form; or (b) from about 30% to about 50% by total weight of the solid oral dosage form; or (c) from about 20% to about 40% by total weight of the solid oral dosage form; or (d ) in an amount of about 20% to about 30%, based on the total weight of the solid oral dosage form;
(iii) the one or more pharmaceutically acceptable excipients comprise a sustained release agent, wherein the sustained release agent comprises (a) about 10% of the total weight of the solid oral dosage form; or (b) from about 30% to about 50% by total weight of the solid oral dosage form; or (c) from about 20% to about 40% by total weight of the solid oral dosage form; or (d ) in an amount of about 20% to about 30% based on the total weight of the solid oral dosage form, wherein the solid oral dosage form is a tablet;
(iv) one or more pharmaceutically acceptable excipients comprising a sustained release agent, wherein the sustained release agent comprises (a) about 10% of the total weight of the solid oral dosage form; or (b) from about 30% to about 50% by total weight of the solid oral dosage form; or (c) from about 20% to about 40% by total weight of the solid oral dosage form; or (d ) in an amount of about 20% to about 30% relative to the total weight of the solid oral dosage form, wherein the solid oral dosage form is a tablet, and the sustained-release dosage form comprises a matrix-forming agent, e.g., the matrix-forming agent contains 1 containing one or more cellulose ethers;
(v) one or more pharmaceutically acceptable excipients comprising a sustained release agent, wherein the sustained release agent comprises (a) about 10% by weight of the total solid oral dosage form; or (b) from about 30% to about 50% by total weight of the solid oral dosage form; or (c) from about 20% to about 40% by total weight of the solid oral dosage form; or (d ) in an amount of about 20% to about 30%, based on the total weight of the solid oral dosage form, wherein the solid oral dosage form is a tablet, and the sustained release dosage form is about 20% to about 30%, based on the total weight of the solid oral dosage form; Hydroxypropyl methylcellulose in an amount of 40%;
(vi) the solid oral dosage form is, relative to the total weight of the solid oral dosage form:
about 35% to about 45% amisulpride;
about 20% to about 40% of a pharmaceutically acceptable filler, and
about 20% to about 35% sustained release drug
including;
(vii) when administered to a subject population,
a. a population geometric mean plasma Cmax of amisulpride that is less than about 80% of the population geometric mean Cmax achieved with an immediate release composition having the same total daily amount of amisulpride as the pharmaceutical composition; and
b. of amisulpride that is less than about 80% of the population geometric mean AUC from 0 to 24 hours post-dose (AUC 0-24 ) achieved by an immediate release composition having the same total daily amount of amisulpride as the pharmaceutical composition; Population Geometric Mean AUC 0-24
for example, wherein the immediate release composition is an immediate release composition having the same total daily amount of amisulpride as the pharmaceutical composition substantially as described in Table 25;
(viii) about 27 hours after administration when administered to a subject population,
(a) an average dopamine D2 receptor occupancy of a population of about 20% to about 60%, or
(b) providing an average dopamine D2 receptor occupancy of about 30% to about 50% of the population, wherein the D2 receptor occupancy is positron as substantially described in Table 38 and herein; For example, the amount of (S)-(-)-amisulpride or a pharmaceutically acceptable salt thereof is less than about 100 mg by weight of free base, as measured using emission tomography (PET) ,
pharmaceutical composition.
（ｉ）精神障害が、（ａ）鬱病性障害；または（ｂ）双極性障害；または（ｃ）双極性鬱病；または（ｄ）大鬱病性障害（ＭＤＤ）；または（ｅ）混合性の特徴を伴う大鬱病性障害（ＭＤＤ－ＭＦ）；または（ｆ）治療抵抗性鬱病（ＴＲＤ）；または（ｇ）統合失調症；または（ｈ）統合失調症の陰性症状である；または
（ｉｉ）精神障害が、双極性障害；双極性鬱病；またはその両方である、
固形経口剤。 16. A solid oral dosage form according to claim 15 for treating a psychiatric disorder comprising administering a solid oral dosage form according to claim 15, optionally comprising about 200 mg per day of amisulpride by weight of free base. Administering a solid oral dosage once daily in a total amount of from about 400 mg, e.g.
(i) the psychiatric disorder is (a) depressive disorder; or (b) bipolar disorder; or (c) bipolar depression; or (d) major depressive disorder (MDD); or (e) mixed features (f) treatment-resistant depression (TRD); or (g) schizophrenia; or (h) is a negative symptom of schizophrenia; or
(ii) the mental disorder is bipolar disorder; bipolar depression; or both;
Solid oral preparation .
（ｉ）持続放出性薬剤が、（ａ）固体経口剤の総重量に対して約１０％から約５０％；または（ｂ）固体経口剤の総重量に対して約３０％から約５０％；または（ｃ）固体経口剤の総重量に対して約２０％から約４０％；または（ｄ）固体経口剤の総重量に対して約２０％から約３０％の量である；
（ｉｉ）持続放出性薬剤が、（ａ）固体経口剤の総重量に対して約１０％から約５０％；または（ｂ）固体経口剤の総重量に対して約３０％から約５０％；または（ｃ）固体経口剤の総重量に対して約２０％から約４０％；または（ｄ）固体経口剤の総重量に対して約２０％から約３０％の量であり、固体経口剤が錠剤である；
（ｉｉｉ）持続放出性薬剤が、（ａ）固体経口剤の総重量に対して約１０％から約５０％；または（ｂ）固体経口剤の総重量に対して約３０％から約５０％；または（ｃ）固体経口剤の総重量に対して約２０％から約４０％；または（ｄ）固体経口剤の総重量に対して約２０％から約３０％の量であり、固体経口剤が錠剤であり、持続放出性薬剤が、マトリックス形成剤を含む；
（ｉｖ）持続放出性薬剤が、（ａ）固体経口剤の総重量に対して約１０％から約５０％；または（ｂ）固体経口剤の総重量に対して約３０％から約５０％；または（ｃ）固体経口剤の総重量に対して約２０％から約４０％；または（ｄ）固体経口剤の総重量に対して約２０％から約３０％の量であり、固体経口剤が錠剤であり、マトリックス形成剤が、１つまたは複数のセルロースエーテルを含む；
（ｖ）持続放出性薬剤が、固体経口剤の総重量に対して約２０％から約４０％の量のヒドロキシプロピルメチルセルロースを含む；
（ｖｉ）持続放出性薬剤が、（ａ）固体経口剤の総重量に対して約１０％から約５０％；または（ｂ）固体経口剤の総重量に対して約３０％から約５０％；または（ｃ）固体経口剤の総重量に対して約２０％から約４０％；または（ｄ）固体経口剤の総重量に対して約２０％から約３０％の量であり、固体経口剤が錠剤であり、固体経口剤が、１つまたは複数の（ａ）充填剤；（ｂ）結合剤；および（ｃ）滑沢剤を含む、例えば、滑沢剤が、ステアリン酸マグネシウムを含む、または、充填剤が、Ｄ－マンニトールを含み、固体経口剤が、錠剤の総重量に対して約０．５％から約２％の、ポリビニルアルコールを含む結合剤を含む；または
（ｖｉｉ）固体経口剤が、固体経口剤の総重量に対して、
約３５％から約４５％のアミスルプリド、
約２０％から約４０％の薬学的に許容される充填剤、および
約２０％から約３５％の持続放出性薬剤を含む、
医薬組成物。 Claim 11 , wherein the enantiomeric ratio of (R)-(+)-amisulpride and (S)-(-)-amisulpride, or a pharmaceutically acceptable salt thereof, is about 85:15 by weight of free base. 15. A pharmaceutical composition according to any one of claims 1 to 14 , optionally comprising
(i) the sustained release drug is (a) about 10% to about 50% by weight of the total solid oral dosage form; or (b) about 30% to about 50% by weight of the total solid oral dosage form; or (c) from about 20% to about 40% by total weight of the solid oral dosage form; or (d) from about 20% to about 30% by weight of the total solid oral dosage form;
(ii) the sustained release drug is (a) about 10% to about 50% by weight of the total solid oral dosage form; or (b) about 30% to about 50% by weight of the total solid oral dosage form; or (c) from about 20% to about 40% by total weight of the solid oral dosage form; or (d) from about 20% to about 30% by total weight of the solid oral dosage form, wherein the solid oral dosage form comprises is a tablet;
(iii) the sustained release drug is (a) about 10% to about 50% by weight of the total solid oral dosage form; or (b) about 30% to about 50% by weight of the total solid oral dosage form; or (c) from about 20% to about 40% by total weight of the solid oral dosage form; or (d) from about 20% to about 30% by total weight of the solid oral dosage form, wherein the solid oral dosage form comprises a tablet, wherein the sustained-release drug comprises a matrix-forming agent;
(iv) the sustained release drug is (a) about 10% to about 50% by weight of the total solid oral dosage form; or (b) about 30% to about 50% by weight of the total solid oral dosage form; or (c) from about 20% to about 40% by total weight of the solid oral dosage form; or (d) from about 20% to about 30% by total weight of the solid oral dosage form, wherein the solid oral dosage form comprises a tablet, wherein the matrix-forming agent comprises one or more cellulose ethers;
(v) the sustained release dosage form comprises hydroxypropyl methylcellulose in an amount of about 20% to about 40% based on the total weight of the solid oral dosage form;
(vi) the sustained release drug is (a) about 10% to about 50% by weight of the total solid oral dosage form; or (b) about 30% to about 50% by weight of the total solid oral dosage form; or (c) from about 20% to about 40% by total weight of the solid oral dosage form; or (d) from about 20% to about 30% by total weight of the solid oral dosage form, wherein the solid oral dosage form comprises is a tablet, wherein the solid oral dosage form comprises one or more of (a) a filler; (b) a binder; and (c) a lubricant, e.g., the lubricant comprises magnesium stearate, or , the filler comprises D-mannitol, and the solid oral dosage form comprises from about 0.5% to about 2%, based on the total weight of the tablet, of a binder comprising polyvinyl alcohol; or
(vii) the solid oral dosage form is, relative to the total weight of the solid oral dosage form:
about 35% to about 45% amisulpride;
about 20% to about 40% of a pharmaceutically acceptable filler, and
comprising from about 20% to about 35% sustained release drug;
pharmaceutical composition .
（ｉ）遊離塩基の重量で約１７０ｍｇの（Ｒ）－（＋）－アミスルプリドまたは薬学的に許容されるそれらの塩；および
遊離塩基の重量で約３０ｍｇの（Ｓ）－（－）－アミスルプリドまたは薬学的に許容されるそれらの塩を含む；または
（ｉｉ）遊離塩基の重量で約８５ｍｇの（Ｒ）－（＋）－アミスルプリドまたは薬学的に許容されるそれらの塩；および
遊離塩基の重量で約１５ｍｇの（Ｓ）－（－）－アミスルプリドまたは薬学的に許容されるそれらの塩を含む、
医薬組成物。 The combined amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride, or a pharmaceutically acceptable salt thereof, is (a) from about 50 mg to about or (b) from about 200 mg to about 600 mg by weight of free base; or (c) from about 100 mg to about 500 mg by weight of free base; or (d) from about 100 mg by weight of free base. or (e) from about 200 mg to about 400 mg by weight of the free base , optionally comprising:
(i) about 170 mg by weight of free base of (R)-(+)-amisulpride or a pharmaceutically acceptable salt thereof; and
about 30 mg of (S)-(-)-amisulpride or a pharmaceutically acceptable salt thereof by weight of free base; or
(ii) about 85 mg by weight of free base of (R)-(+)-amisulpride or a pharmaceutically acceptable salt thereof; and
about 15 mg of (S)-(−)-amisulpride or a pharmaceutically acceptable salt thereof by weight of free base;
pharmaceutical composition .
（ａ）アミスルプリド１０ｍｇ当たり約０．４５ミリ秒（ｍｓ）未満；または
（ｂ）アミスルプリド１０ｍｇ当たり約０．４０ミリ秒（ｍｓ）未満；または
（ｃ）アミスルプリド１０ｍｇ当たり約０．３５ミリ秒（ｍｓ）未満；または
（ｄ）アミスルプリド１０ｍｇ当たり約０．３０ミリ秒（ｍｓ）未満；または
（ｅ）アミスルプリド１０ｍｇ当たり約０．２５ミリ秒（ｍｓ）未満；または
（ｆ）アミスルプリド１０ｍｇ当たり約０．２０ミリ秒（ｍｓ）未満；または
（ｇ）アミスルプリド１０ｍｇ当たり約０．１５ミリ秒（ｍｓ）未満；または
（ｈ）アミスルプリド１０ｍｇ当たり約０．１０ミリ秒（ｍｓ）未満；または
（ｉ）アミスルプリド１０ｍｇ当たり約０．０５ミリ秒（ｍｓ）未満；または
（ｊ）アミスルプリド１０ｍｇ当たり約０．０２ミリ秒（ｍｓ）未満の投与後１２時間の期間での基準値に対する集団の平均の最大ＱＴ間隔延長を提供する、請求項８～１４のいずれか一項に記載の医薬組成物。 When administered to a target population,
(a) less than about 0.45 milliseconds (ms) per 10 mg of amisulpride; or (b) less than about 0.40 milliseconds (ms) per 10 mg of amisulpride; or (c) less than about 0.35 milliseconds (ms) per 10 mg of amisulpride. or (d) less than about 0.30 milliseconds (ms) per 10 mg of amisulpride; or (e) less than about 0.25 milliseconds (ms) per 10 mg of amisulpride; or (f) less than about 0.20 per 10 mg of amisulpride. or (g) less than about 0.15 milliseconds (ms) per 10 mg of amisulpride; or (h) less than about 0.10 milliseconds (ms) per 10 mg of amisulpride; or (i) per 10 mg of amisulpride or (j) less than about 0.02 milliseconds (ms) per 10 mg of amisulpride, providing a population mean maximal QT interval prolongation relative to baseline over a 12-hour post-dose period. The pharmaceutical composition according to any one of claims 8 to 14 .
（ｉ）（ａ）１０分を超える急速眼球運動（ＲＥＭ）睡眠の減少；または（ｂ）約１５分から約４５分のＲＥＭ睡眠の減少；または（ｃ）約１５分から約３０分のＲＥＭ睡眠の減少；
（ｉｉ）（ａ）２０分を超える急速眼球運動（ＲＥＭ）睡眠への待ち時間；または（ｂ）３０分を超えるＲＥＭ睡眠への待ち時間；または
（ｉｉｉ）（ａ）５％を超える総睡眠時間に対する総急速眼球運動（ＲＥＭ）睡眠時間の減少；または（ｂ）６．５％を超える総睡眠時間に対する総ＲＥＭ睡眠時間の減少
により特徴付けられるＲＥＭ睡眠における時間の抑制をもたらす、請求項５～１４のいずれか一項に記載の医薬組成物。 When administered to a target population,
(i) (a) reduction in rapid eye movement (REM) sleep for more than 10 minutes; or (b) reduction in REM sleep for about 15 minutes to about 45 minutes; or (c) reduction in REM sleep for about 15 minutes to about 30 minutes. decrease ;
(ii) (a) latency to rapid eye movement (REM) sleep greater than 20 minutes; or (b) latency to REM sleep greater than 30 minutes; or
(iii) (a) decreased total rapid eye movement (REM) sleep time for >5% total sleep time; or (b) decreased total REM sleep time for >6.5% total sleep time
The pharmaceutical composition according to any one of claims 5 to 14 , which provides suppression of time in REM sleep characterized by:
（Ｒ）－（＋）－アミスルプリドと（Ｓ）－（－）－アミスルプリドのエナンチオマー比が、遊離塩基の重量で約８０：２０から約８８：１２であり、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリド、または薬学的に許容されるそれらの塩を組み合わせた量が、遊離塩基の重量で約１００ｍｇから約５００ｍｇである、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリドの不均等混合物の形態のアミスルプリド、または薬学的に許容されるそれらの塩；ならびに
錠剤の総重量に対して約１０％から約５０％の量の持続放出性薬剤
を含み、所望により、（Ｒ）－（＋）－アミスルプリドおよび（Ｓ）－（－）－アミスルプリド、または薬学的に許容されるそれらの塩を組み合わせた量が、遊離塩基の重量で約２００ｍｇであり、（Ｒ）－（＋）－アミスルプリドと（Ｓ）－（－）－アミスルプリドのエナンチオマー比が、遊離塩基の重量で８５：１５であり、好ましくは、錠剤が、
錠剤の総重量に対して約３５％から約４５％のアミスルプリド、
錠剤の総重量に対して約２０％から約４０％の薬学的に許容される充填剤、および
錠剤の総重量に対して約２０％から約３０％の持続放出性薬剤
を含み、より好ましくは、持続放出性薬剤が、ヒドロキシプロピルメチルセルロースを含み、さらにより好ましくは、ヒドロキシプロピルメチルセルロースが、アミスルプリドのメジアン径の５～１５倍のメジアン径を有する、または、充填剤が、Ｄ－マンニトールを含み、錠剤が、錠剤の総重量に対して約０．５％から約２％の、ポリビニルアルコールを含む結合剤を含む、
医薬組成物。 A pharmaceutical composition in the form of a tablet, the tablet comprising
the enantiomeric ratio of (R)-(+)-amisulpride to (S)-(-)-amisulpride is from about 80:20 to about 88:12 by weight of free base, and (R)-(+)-amisulpride (R)-(+)-amisulpride and (R)-(+)-amisulpride, and (S)-(-)-amisulpride, or a pharmaceutically acceptable salt thereof, in a combined amount of from about 100 mg to about 500 mg by weight of free base; (S)-(-)-amisulpride in the form of unequal mixtures of amisulpride, or a pharmaceutically acceptable salt thereof; and sustained release in an amount of about 10% to about 50% relative to the total weight of the tablet. The combined amount of the drug, optionally (R)-(+)-amisulpride and (S)-(-)-amisulpride, or a pharmaceutically acceptable salt thereof, is about 200 mg, the enantiomeric ratio of (R)-(+)-amisulpride and (S)-(-)-amisulpride is 85:15 by weight of free base, preferably the tablet comprises
about 35% to about 45% of amisulpride, based on the total weight of the tablet;
from about 20% to about 40% of a pharmaceutically acceptable filler, based on the total weight of the tablet; and
about 20% to about 30% of the sustained release drug relative to the total weight of the tablet
more preferably the sustained-release drug comprises hydroxypropylmethylcellulose, even more preferably the hydroxypropylmethylcellulose has a median diameter of 5 to 15 times the median diameter of amisulpride, or the filler is D-mannitol, wherein the tablet comprises a binder comprising polyvinyl alcohol from about 0.5% to about 2%, based on the total weight of the tablet;
pharmaceutical composition .
顆粒成分がアミスルプリドおよび結合剤を含み；および
顆粒外成分が持続放出性薬剤を含み、所望により、
（ｉ）顆粒成分が、１つまたは複数の（ａ）充填剤；および（ｂ）結合剤を含む、例えば、顆粒が、（ａ）約６０重量％から約８０重量％のアミスルプリド、約１０重量％から約３０重量％の充填剤、および約１重量％から約５重量％の結合剤；または（ｂ）約７０重量％から約８０重量％のアミスルプリド、約２０重量％から約２５重量％の充填剤、および約１重量％から約５重量％の結合剤を含む、または、顆粒成分が、顆粒成分の重量に対して、
約７３重量％から約７８重量％のアミスルプリド、
約１０重量％から約１２重量％のＤ－マンニトール、
約１０重量％から約１２重量％のアルファ化デンプン、および
約１重量％から約重量３％のポリビニルアルコールを含む；
（ｉｉ）顆粒外成分が、１つまたは複数の（ａ）充填剤；（ｂ）結合剤；および（ｃ）滑沢剤を含む；
（ｉｉｉ）錠剤（顆粒と顆粒外成分）が、（ａ）錠剤の総重量に対して約２０％から約７０％の持続放出性薬剤の顆粒；または（ｂ）錠剤の総重量に対して約１０％から約５０％の持続放出性薬剤を含む；
（ｉｖ）錠剤（顆粒と顆粒外成分）が、（ａ）錠剤の総重量に対して約６％から約６０％の、顆粒および顆粒外の両方で組み合わせた量の充填剤；または（ｂ）錠剤の総重量に対して約１０％から約５０％の、顆粒および顆粒外の両方で組み合わせた量の充填剤を含む；
（ｖ）錠剤（顆粒と顆粒外成分）が、錠剤の総重量に対して約１％から約２％の滑沢剤を含む、例えば、滑沢剤が、ステアリン酸マグネシウムである；または
（ｖｉ）錠剤（顆粒と顆粒外成分）が、
（ａ）錠剤の総重量に対して約３４％から約３９％のＤ－マンニトール、および錠剤の総重量に対して約１５％のヒドロキシプロピルメチルセルロース；または
（ｂ）錠剤の総重量に対して約２４％から約２９％のＤ－マンニトール、および錠剤の総重量に対して約２５％のヒドロキシプロピルメチルセルロース；または
（ｃ）錠剤の総重量に対して約４％から約９％のＤ－マンニトール、および錠剤の総重量に対して約４５％のヒドロキシプロピルメチルセルロース
を含む、
請求項２６に記載の医薬組成物。 the tablet comprises a granular component admixed with an extragranular component;
a granular component comprising amisulpride and a binder; and an extragranular component comprising a sustained release drug, optionally comprising
(i) the granule ingredients comprise one or more of (a) a filler; and (b) a binder, e.g. % to about 30% by weight filler, and about 1% to about 5% by weight binder; or (b) about 70% to about 80% by weight amisulpride, about 20% to about 25% by weight a filler, and from about 1% to about 5% by weight of a binder;
from about 73% to about 78% by weight of amisulpride;
about 10% to about 12% by weight D-mannitol;
about 10% to about 12% by weight pregelatinized starch; and
from about 1% to about 3% by weight of polyvinyl alcohol;
(ii) the extragranular component comprises one or more of (a) fillers; (b) binders; and (c) lubricants;
(iii) the tablet (granules and extragranular components) comprises (a) from about 20% to about 70% of the sustained release drug granules, based on the total weight of the tablet; or (b) about 10% to about 50% sustained release drug;
(iv) the tablet (granular and extragranular components) contains (a) a combined amount of both granular and extragranular fillers from about 6% to about 60%, based on the total weight of the tablet; or (b) Fillers in a combined amount, both granular and extragranular, of about 10% to about 50% based on the total weight of the tablet;
(v) the tablet (granules and extragranular components) comprises from about 1% to about 2% of a lubricant, based on the total weight of the tablet, e.g., the lubricant is magnesium stearate; or
(vi) tablets (granules and extragranular components)
(a) about 34% to about 39% D-mannitol by total tablet weight and about 15% hydroxypropyl methylcellulose by total tablet weight; or
(b) about 24% to about 29% D-mannitol by total tablet weight and about 25% hydroxypropyl methylcellulose by total tablet weight; or
(c) about 4% to about 9% D-mannitol, based on the total weight of the tablet, and about 45% hydroxypropyl methylcellulose, based on the total weight of the tablet;
including,
27. A pharmaceutical composition according to claim 26 .
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| US62/944,023 | 2019-12-05 | ||
| PCT/US2020/036118 WO2020247627A1 (en) | 2019-06-04 | 2020-06-04 | Modified release formulations and uses thereof |
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| JP7268026B2 (en) | 2017-12-05 | 2023-05-02 | サノビオン ファーマシューティカルズ インク | Non-racemic mixtures and uses thereof |
| US20220323409A1 (en) * | 2019-06-04 | 2022-10-13 | Sunovion Pharmaceuticals Inc. | Modified release formulations and uses thereof |
| BR112021024380A2 (en) | 2019-06-04 | 2022-04-19 | Sunovion Pharmaceuticals Inc | Modified release formulations and uses thereof |
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Family Cites Families (165)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH415963A (en) | 1964-09-04 | 1966-06-30 | Wander Ag Dr A | Compound for the production of tablets with protracted action |
| AT264666B (en) | 1965-06-10 | 1968-09-10 | Elektroprojekt Berlin Veb | Circuit arrangement for the automatic shutdown of reversing and one-way strip rolling stands |
| US3577514A (en) | 1968-06-10 | 1971-05-04 | Pfizer | Sustained release pharmaceutical tablets |
| FR2415099A1 (en) | 1978-01-20 | 1979-08-17 | Ile De France | NEW DERIVATIVES OF 4-AMINO-5-ALKYLSULFONYL ORTHO-ANISAMIDES, THEIR METHODS OF PREPARATION AND THEIR APPLICATION AS PSYCHOTROPES |
| US4590062A (en) | 1984-04-16 | 1986-05-20 | Tech Trade Corp. | Dry direct compression compositions for controlled release dosage forms |
| US4816264A (en) | 1986-06-06 | 1989-03-28 | Warner-Lambert Company | Sustained release formulations |
| IT1200178B (en) | 1986-07-23 | 1989-01-05 | Alfa Farmaceutici Spa | GALENIC FORMULATIONS WITH SCHEDULED SALE CONTAINING DRUGS WITH ANTI-FLOGISTIC ACTIVITY |
| JP2572673B2 (en) | 1990-07-25 | 1997-01-16 | エスエス製薬株式会社 | Sustained-release tablets |
| US5316772A (en) | 1990-12-19 | 1994-05-31 | Solvay & Cie, S.A. (Societe Anonyme) | Bilayered oral pharmaceutical composition with pH dependent release |
| US5591455A (en) | 1990-12-20 | 1997-01-07 | Warner-Jenkinson Company, Inc. | Wet powder film-forming compositions |
| ATE192335T1 (en) | 1990-12-20 | 2000-05-15 | Warner Jenkinson Co Inc | MOIST POWDER FILM-FORMING COMPOSITIONS |
| GB2256648B (en) | 1991-05-29 | 1995-08-30 | Colorcon Ltd | Wax polish composition |
| EP0520119A1 (en) | 1991-06-17 | 1992-12-30 | Spirig Ag Pharmazeutische Präparate | New oral diclofenac composition |
| TW245641B (en) | 1993-04-26 | 1995-04-21 | Takeda Pharm Industry Co | |
| AU3205497A (en) | 1996-05-23 | 1997-12-09 | G.D. Searle & Co. | Pharmaceutical compositions containing non-racemic verapamil and process for optimizing the pharmaceutical activity of r- and s-verapamil |
| IT1283124B1 (en) | 1996-06-12 | 1998-04-07 | Prodotti Antibiotici Spa | PHARMACEUTICAL FORMS AND COMPOSITIONS FOR THE TREATMENT OF BENIGN PROSTATIC HYPERTROPHY |
| FR2753376B1 (en) | 1996-09-18 | 1998-10-16 | Synthelabo | PHARMACEUTICAL COMPOSITIONS COMPRISING AMISULPRIDE AND THERAPEUTIC APPLICATIONS THEREOF |
| ID21762A (en) | 1996-09-24 | 1999-07-22 | Lilly Co Eli | FORMULATED PARTICLE FORMULATION |
| US5922352A (en) | 1997-01-31 | 1999-07-13 | Andrx Pharmaceuticals, Inc. | Once daily calcium channel blocker tablet having a delayed release core |
| US5837379A (en) | 1997-01-31 | 1998-11-17 | Andrx Pharmaceuticals, Inc. | Once daily pharmaceutical tablet having a unitary core |
| FR2762213B1 (en) | 1997-04-18 | 1999-05-14 | Synthelabo | PHARMACEUTICAL COMPOSITION WITH GASTRIC RETENTION |
| US6210710B1 (en) | 1997-04-28 | 2001-04-03 | Hercules Incorporated | Sustained release polymer blend for pharmaceutical applications |
| US20050281752A1 (en) | 1997-10-01 | 2005-12-22 | Dugger Harry A Iii | Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the central nervous system |
| AU1534699A (en) | 1997-12-05 | 1999-06-28 | Alza Corporation | Osmotic dosage form comprising first and second coats |
| US6169094B1 (en) | 1998-07-14 | 2001-01-02 | Sanofi-Synthelabo | Compositions of (S) (-)-amisulpride |
| CO5140079A1 (en) | 1998-10-14 | 2002-03-22 | Novartis Ag | PHARMACEUTICAL COMPOSITION OF SUSTAINED LIBERATION AND METHOD TO RELEASE A PHARMACEUTICALLY ACTIVE AGENT FROM SUSTAINED LIBERATION AND METHOD TO RELEASE A PHARMACEUTICALLY ACTIVE AGENT |
| FR2784583B1 (en) | 1998-10-16 | 2002-01-25 | Synthelabo | PHARMACEUTICAL COMPOSITION WITH GASTRIC RESIDENCE AND CONTROLLED RELEASE |
| HUP0104420A2 (en) | 1998-12-02 | 2002-08-28 | Darwin Discovery Ltd | Therapeutic composition containing a new form of tramadol and its use |
| US6897242B1 (en) | 1999-02-24 | 2005-05-24 | Judson J. Somerville | Non-racemic mixtures of d- and l- methadone and method of treating pain |
| CA2431041A1 (en) | 2001-01-02 | 2002-07-11 | Pharmacia & Upjohn Company | New drug combinations of norepinehrine reuptake inhibitors and neuroleptic agents |
| US20030096264A1 (en) | 2001-06-18 | 2003-05-22 | Psychiatric Genomics, Inc. | Multi-parameter high throughput screening assays (MPHTS) |
| ATE452642T1 (en) | 2001-06-19 | 2010-01-15 | Norbert Mueller | USE OF COX-2 INHIBITORS TO TREAT AFFECTIVE DISORDERS |
| DE10129320A1 (en) | 2001-06-19 | 2003-04-10 | Norbert Mueller | Use of cyclooxygenase-2 inhibitor in the preparation of a medicament for treating psychiatric disorders e.g. schizophrenia |
| US20110130390A1 (en) | 2001-06-19 | 2011-06-02 | Mueller Norbert | Use of COX-2 Inhibitors for the Treatment of Schizophrenia, Delusional Disorders, Affective Disorders, Autism or Tic Disorders |
| US20060167074A1 (en) | 2001-06-19 | 2006-07-27 | Norbert Muller | Methods and compositions for the treatment of psychiatric disorders |
| US7544681B2 (en) | 2001-09-27 | 2009-06-09 | Ramot At Tel Aviv University Ltd. | Conjugated psychotropic drugs and uses thereof |
| US7815936B2 (en) | 2001-10-30 | 2010-10-19 | Evonik Degussa Gmbh | Use of granular materials based on pyrogenically produced silicon dioxide in pharmaceutical compositions |
| DE10153078A1 (en) | 2001-10-30 | 2003-05-22 | Degussa | Use of granules based on pyrogenic silicon dioxide in pharmaceutical compositions |
| US8268352B2 (en) | 2002-08-05 | 2012-09-18 | Torrent Pharmaceuticals Limited | Modified release composition for highly soluble drugs |
| US7985422B2 (en) | 2002-08-05 | 2011-07-26 | Torrent Pharmaceuticals Limited | Dosage form |
| US8216609B2 (en) | 2002-08-05 | 2012-07-10 | Torrent Pharmaceuticals Limited | Modified release composition of highly soluble drugs |
| US20050250767A1 (en) | 2003-01-23 | 2005-11-10 | Weiner David M | Use of N-desmethylclozapine to treat human neuropsychiatric disease |
| US20050085463A1 (en) | 2003-01-23 | 2005-04-21 | Weiner David M. | Use of N-desmethylclozapine to treat human neuropsychiatric disease |
| EP1626703A2 (en) | 2003-05-22 | 2006-02-22 | Yeda Research And Development Co. Ltd. | Dopamine and agonists and antagonists thereof for modulation of suppressive activity of cd4+cd25+ regulatory t cells |
| FR2857263B1 (en) | 2003-07-09 | 2005-09-09 | Sanofi Synthelabo | NOVEL SOLID PHARMACEUTICAL COMPOSITION COMPRISING AMISULPRIDE |
| CA2537180A1 (en) | 2003-08-29 | 2005-03-10 | Cotherix, Inc. | Cicletanine in combination with oral antidiabetic and/or blood lipid-lowering agents as a combination therapy for diabetes and metabolic syndrome |
| US20050181049A1 (en) | 2003-11-19 | 2005-08-18 | Dong Liang C. | Composition and method for enhancing bioavailability |
| EP1547650A1 (en) | 2003-12-02 | 2005-06-29 | B & B Beheer NV | Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists |
| CA2547639A1 (en) | 2003-12-02 | 2005-06-16 | B&B Beheer Nv | Use of d4 and 5-ht2a antagonists, inverse agonists or partial agonists |
| WO2005082370A1 (en) | 2004-01-29 | 2005-09-09 | Pfizer Products Inc. | Combinations of an atypical antipsychotic and an aminomethylpyridyloxymethyl/benzisoxazole azabicyclic derivatives for treating cns disorders |
| WO2005084654A2 (en) | 2004-03-02 | 2005-09-15 | Pharmacia Corporation | Methods and compositions for treating or preventing psychiatric disorders with cox-2 inhibitors alone and in combination with antidepressant agents |
| US20060150989A1 (en) | 2005-01-12 | 2006-07-13 | Peter Migaly | Method of diagnosing, treating and educating individuals with and/or about depression |
| US20060167068A1 (en) | 2005-01-26 | 2006-07-27 | Seth Feuerstein | Method of treating self-injurious behavior with glutamate modulating agents |
| JP2008528532A (en) | 2005-01-28 | 2008-07-31 | シュヴァルツ・ファーマ・アーゲー | SPM927 for add-on treatment of schizophrenia |
| US20110015246A2 (en) | 2005-03-14 | 2011-01-20 | Agean Llc | Lofexidine enantiomers for use as a treatment for cns disease and pathologies and its chiral synthesis |
| CA2603939C (en) | 2005-04-08 | 2013-08-27 | Pfizer Products Inc. | Bicyclic [3.1.0] heteroaryl amides as type i glycine transport inhibitors |
| EP2676691B1 (en) | 2005-11-17 | 2016-07-06 | Zogenix, Inc. | Delivery of viscous formulations by needle-free injection |
| ATE552832T1 (en) | 2006-02-24 | 2012-04-15 | Shire Llc | ANTIDEPRESSANT PROPHARMACIES |
| EP2004150A1 (en) | 2006-03-27 | 2008-12-24 | Panacea Biotec Ltd. | Sustained release pharmaceutical composition on the basis of a release system comprising an acid-soluble polymer and a ph-dependent polymer. |
| EP2023898A1 (en) | 2006-05-10 | 2009-02-18 | Evonik Degussa GmbH | Use of roll compacted pyrogenically produced silicon dioxide in pharmaceutical compositions |
| WO2007133802A2 (en) | 2006-05-15 | 2007-11-22 | Acadia Pharmaceuticals Inc. | Pharmaceutical formulations of pimavanserin |
| WO2007137224A2 (en) | 2006-05-22 | 2007-11-29 | Vanda Pharmaceuticals, Inc. | Method of treatment |
| GB0618879D0 (en) * | 2006-09-26 | 2006-11-01 | Zysis Ltd | Pharmaceutical compositions |
| WO2008070296A2 (en) | 2006-10-17 | 2008-06-12 | The Research Foundation For Mental Hygiene, Inc. | System and method for diagnosis and treatment of neuropsychiatric disorders |
| US8394790B2 (en) | 2006-10-25 | 2013-03-12 | Ramot At Tel-Aviv University Ltd. | Psychotropic agents having glutamate NMDA activity |
| WO2008065500A2 (en) | 2006-11-30 | 2008-06-05 | Pfizer Products Inc. | Heteroaryl amides as type i glycine transport inhibitors |
| EP1944295A1 (en) | 2007-01-15 | 2008-07-16 | Laboratorios del Dr. Esteve S.A. | Non-racemic mixtures of (R)-N-piperidinyl-5-(4-chlorophenyl)1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide and (S)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide |
| EP1946777A1 (en) | 2007-01-16 | 2008-07-23 | Laboratorios del Dr. Esteve S.A. | Substituted pyrazoline for preventing weight gain |
| US9044471B2 (en) | 2007-02-01 | 2015-06-02 | Alan I. Green | Combinations of dopamine D2 receptor blockade with norepinephrine reuptake inhibition and with norepinephrine alpha 2 receptor blockade |
| US7825156B2 (en) * | 2007-02-02 | 2010-11-02 | Copharms | Method of treating bipolar depression with a benzamide derivative |
| WO2008116024A2 (en) | 2007-03-19 | 2008-09-25 | Acadia Pharmaceuticals Inc. | Combinations of 5-ht2a inverse agonists and antagonists with antipsychotics |
| GB0707127D0 (en) | 2007-04-13 | 2007-05-23 | Zysis Ltd | Pharmaceutical compositions |
| WO2008141057A1 (en) | 2007-05-08 | 2008-11-20 | Auspex Pharmaceuticals, Inc. | Deuterated pimavanserin 1- (4-flu0r0benzyl) -3- (4-isobutoxybenzyl) -1- ( l-methyl-piperidin-4-yl) -urea |
| EP2030619A1 (en) | 2007-06-18 | 2009-03-04 | A.Carlsson Research AB | Use of dopamine stabilizers |
| ES2528040T3 (en) | 2007-06-18 | 2015-02-03 | A.Carlsson Research Ab | Use of dopamine stabilizers |
| WO2009017453A1 (en) | 2007-07-30 | 2009-02-05 | Astrazeneca Ab | New therapeutic combination of an antipsychotic and a gsk3 inhibitor 958 |
| CA2699786C (en) | 2007-09-10 | 2019-08-13 | Vanda Pharmaceuticals, Inc. | Antipsychotic treatment based on snp genotype |
| WO2009035473A2 (en) | 2007-09-13 | 2009-03-19 | Sanfilippo Louis C | Method of treating binge eating disorder, obesity resulting from binge eating behavior and depressive disorders |
| US20090082342A1 (en) | 2007-09-21 | 2009-03-26 | Acadia Pharmaceuticals, Inc. | N-substituted piperidine derivatives as serotonin receptor agents |
| CN101888991A (en) | 2007-10-31 | 2010-11-17 | 财团法人乙卯研究所 | Retinoid prodrug compound |
| GB2456183A (en) | 2008-01-04 | 2009-07-08 | Gw Pharma Ltd | Anti-psychotic composition comprising cannabinoids and anti-psychotic medicament |
| US8906847B2 (en) | 2008-02-01 | 2014-12-09 | Ascendis Pharma A/S | Prodrug comprising a drug linker conjugate |
| US20090208979A1 (en) | 2008-02-14 | 2009-08-20 | Technion Research And Development Foundation Ltd. | Method for identifying antipsychotic drug candidates |
| US8138169B2 (en) | 2008-04-11 | 2012-03-20 | Comgenrx, Inc. | Combination therapy for bipolar disorder |
| US20090269770A1 (en) | 2008-04-24 | 2009-10-29 | Technion Research And Development Foundation Ltd. | Methods for evaluation prognosis and follow-up of drug treatment of psychiatric diseases or disorders |
| ES2546732T3 (en) | 2008-08-20 | 2015-09-28 | Brainco Biopharma, S.L. | STXBP1 as a psychiatric biomarker in a murine model system and its uses |
| US20100074973A1 (en) | 2008-08-27 | 2010-03-25 | Auspex Pharmaceuticals, Inc. | Thioxanthene modulators of dopamine d2 receptors |
| WO2010023690A2 (en) | 2008-08-28 | 2010-03-04 | Torrent Pharmaceuticals Ltd. | Prolonged release formulation of amisulpride |
| US20100069399A1 (en) | 2008-09-15 | 2010-03-18 | Auspex Pharmaceutical, Inc. | Arylpiperazine modulators of d2 receptors, 5-ht1a receptors, and/or 5-ht2a receptors |
| US20100119622A1 (en) | 2008-09-15 | 2010-05-13 | Auspex Pharmaceuticals, Inc. | 3h-benzooxazol-2-one modulators of d2 receptor and/or 5-ht1a receptor |
| WO2010033270A1 (en) | 2008-09-17 | 2010-03-25 | Auspex Pharmaceuticals, Inc. | Dibenzothiazepine modulators of dopamine, alpha adrenergic, and serotonin receptors |
| US20100119624A1 (en) | 2008-09-17 | 2010-05-13 | Auspex Pharmaceuticals, Inc. | Benzisoxazole modulators of d2 receptor and/or 5-ht2a receptor |
| US20100266711A1 (en) | 2008-09-29 | 2010-10-21 | Auspex Pharmaceuticals, Inc. | Thienobenzodiazepine modulators of d1 receptor, d2 receptor, and/or 5-ht2 receptor |
| US20100159033A1 (en) | 2008-09-29 | 2010-06-24 | Auspex Pharmaceuticals, Inc. | Benzisoxazole modulators of d2 receptor, and/or 5-ht2a receptor |
| WO2010056065A2 (en) | 2008-11-14 | 2010-05-20 | Ewha University-Industry Collaboration Foundation | Method for preparing microspheres and microspheres produced thereby |
| WO2010058314A1 (en) | 2008-11-18 | 2010-05-27 | Pfizer Inc. | Hydroxyquinolin-2(1h)-ones and derivatives thereof |
| CA2646779A1 (en) | 2008-11-25 | 2010-05-25 | Gerard Voon | Bioscience ix |
| US20100143507A1 (en) | 2008-12-09 | 2010-06-10 | Auspex Pharmaceuticals, Inc. | Carboxylic acid inhibitors of histone deacetylase, gaba transaminase and sodium channel |
| WO2010075275A1 (en) | 2008-12-23 | 2010-07-01 | Usworldmeds Llc | Selective release of non-racemic mixtures of two enantiomers from tablets and capsules |
| CA3037010A1 (en) | 2009-01-20 | 2010-07-29 | Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Cente | Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical |
| KR101597672B1 (en) | 2009-03-20 | 2016-02-25 | 앤태어스 파머, 인코퍼레이티드 | Hazardous agent injection system |
| CN101898991B (en) | 2009-05-31 | 2013-09-25 | 江苏天士力帝益药业有限公司 | Synthesis method of (S) (-)-amisulprideD-(-)-tartrate |
| EP2459227B1 (en) | 2009-07-31 | 2021-03-17 | Ascendis Pharma A/S | Prodrugs containing an aromatic amine connected by an amide bond to a carrier |
| GEP20115310B (en) | 2009-10-09 | 2011-10-25 | Medicinal preparation of amisulpride in the solid form and the method of its manufacture | |
| WO2011057199A1 (en) | 2009-11-06 | 2011-05-12 | Adenios, Inc. | Compositions for treating cns disorders |
| WO2011060363A2 (en) | 2009-11-16 | 2011-05-19 | Auspex Pharmaceuticals, Inc. | Cyclohexyl urea modulators of d2 receptors and/or d3 receptors |
| AR079814A1 (en) | 2009-12-31 | 2012-02-22 | Otsuka Pharma Co Ltd | HETEROCICLICAL COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND THEIR USES |
| GB201003766D0 (en) | 2010-03-05 | 2010-04-21 | Univ Strathclyde | Pulsatile drug release |
| GB201003734D0 (en) | 2010-03-05 | 2010-04-21 | Univ Strathclyde | Delayed prolonged drug delivery |
| GB201003731D0 (en) | 2010-03-05 | 2010-04-21 | Univ Strathclyde | Immediate/delayed drug delivery |
| GB201004020D0 (en) * | 2010-03-11 | 2010-04-21 | Acacia Pharma Ltd | New therapeutic use |
| WO2011143534A1 (en) | 2010-05-13 | 2011-11-17 | The Mclean Hospital Corporation | Methods for the treatment of psychiatric disorders |
| WO2011158084A1 (en) | 2010-06-17 | 2011-12-22 | Lupin Limited | An improved process for preparation of amisulpride |
| WO2012002583A1 (en) | 2010-07-02 | 2012-01-05 | Vanderbilt University | Method for treating schizophrenia and related diseases with a combination therapy |
| CN101987081B (en) | 2010-07-16 | 2012-08-08 | 钟术光 | Controlled release preparation |
| DE102010033527A1 (en) | 2010-08-05 | 2012-02-09 | Acino Pharma Ag | Quetiapine tablets |
| US20130224110A1 (en) | 2010-09-16 | 2013-08-29 | Cornell University | Use of adenosine receptor signaling to modulate permeability of blood-brain barrier |
| WO2012065110A2 (en) | 2010-11-12 | 2012-05-18 | Promentis Pharmaceuticals, Inc. | S-protected cysteine analogs and related compounds |
| JP2014502958A (en) | 2010-11-12 | 2014-02-06 | プロメンテイス・フアーマシユーテイカルズ・インコーポレイテツド | St-Butyl protected cysteine dipeptide analogues and related compounds |
| AU2011348085B2 (en) | 2010-12-23 | 2016-12-08 | Alkermes Pharma Ireland Limited | Multi- API loading prodrugs |
| WO2012118562A1 (en) | 2011-03-02 | 2012-09-07 | Rhine Pharmaceuticals, Llc | Compositions and methods for treating depression, adhd and other central nervous system disorders employing novel bupropion compounds, and methods for production and use of novel bupropion compounds and formulations |
| EP2508174A1 (en) | 2011-04-06 | 2012-10-10 | Ljiljana Sovic Brkicic | Pharmaceutical composition |
| WO2012158492A2 (en) | 2011-05-13 | 2012-11-22 | Dainippon Sumitomo Pharma Co., Ltd. | Treatment and management of cns disorders |
| AR086798A1 (en) | 2011-06-29 | 2014-01-22 | Otsuka Pharma Co Ltd | USEFUL QUINAZOLINIC DERIVATIVES TO TREAT CENTRAL NERVOUS SYSTEM DISORDERS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| US9457014B2 (en) | 2011-07-28 | 2016-10-04 | Promentis Pharmaceuticals, Inc. | Cysteine prodrugs |
| CN103906514A (en) * | 2011-09-13 | 2014-07-02 | 拜奥迈德瓦利探索有限公司 | Compositions and methods for treating metabolic disorders |
| WO2013122554A1 (en) | 2012-02-14 | 2013-08-22 | Mahmut Bilgic | Pellet formulations comprising esomeprazole |
| CN102600132B (en) | 2012-03-13 | 2014-05-14 | 齐鲁制药有限公司 | Oral preparation containing amisulpride |
| JOP20210047A1 (en) | 2012-10-25 | 2017-06-16 | Otsuka Pharma Co Ltd | Prophylactic and/or therapeutic agent for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental disease containing brexpiprazole or salt thereof |
| CA2903769A1 (en) * | 2013-03-11 | 2014-10-09 | Durect Corporation | Injectable controlled release composition comprising high viscosity liquid carrier |
| WO2014152965A2 (en) | 2013-03-14 | 2014-09-25 | The Children's Hospital Of Philadelphia | Schizophrenia-associated genetic loci identified in genome wide association studies and use thereof as novel therapeutic targets |
| US20170027958A1 (en) | 2013-04-02 | 2017-02-02 | Themis Medicare Limited | Fulvestrant compositions |
| UA119324C2 (en) | 2013-04-02 | 2019-06-10 | Теміс Медікер Лімітед | Compositions of pharmaceutical actives containing diethylene glycol monoethyl ether or other alkyl derivatives |
| US10098893B2 (en) | 2013-10-03 | 2018-10-16 | Northwestern University | Methods of administering a trace amine-associated receptor 1 (TAAR1) agonist to patients having the minor allele of the single nucleotide polymorphism rs2237457 |
| KR20230023817A (en) | 2013-12-03 | 2023-02-17 | 인트라-셀룰라 써래피스, 인코퍼레이티드. | Novel methods |
| JP2017506228A (en) | 2014-02-05 | 2017-03-02 | イェダ リサーチ アンド ディベロップメント カンパニー リミテッドＹｅｄａ Ｒｅｓｅａｒｃｈ Ａｎｄ Ｄｅｖｅｌｏｐｍｅｎｔ Ｃｏ．Ｌｔｄ． | MicroRNA for the treatment and diagnosis of serotonin releasing hormone, adrenergic releasing hormone, noradrenaline releasing hormone, glutamate releasing hormone and corticotropin releasing hormone related medical conditions and compositions comprising said microRNA |
| TW201613864A (en) | 2014-02-20 | 2016-04-16 | Takeda Pharmaceutical | Novel compounds |
| RU2020123764A (en) | 2014-04-04 | 2020-08-05 | Интра-Селлулар Терапиз, Инк. | ORGANIC COMPOUNDS |
| CN106456638A (en) | 2014-04-04 | 2017-02-22 | 细胞内治疗公司 | Organic compounds |
| EP2959895A1 (en) | 2014-06-27 | 2015-12-30 | Rheinisch-Westfälische Technische Hochschule Aachen (RWTH) | Compositions comprising Phenylalanine and Leucine for use in the diagnosis and treatment of neurological disorders and symptoms thereof |
| ES2562684B1 (en) | 2014-08-04 | 2017-02-06 | Consejo Superior De Investigaciones Científicas (Csic) | ANTIPSYCHOTIC TREATMENT MONITORING METHOD |
| US11174514B2 (en) | 2014-08-29 | 2021-11-16 | Northwestern University | Methods, kits, and devices utilizing HTR2C polymorphisms for diagnosing, prognosing, and treating psychiatric disorders in a patient |
| WO2016109359A1 (en) | 2014-12-29 | 2016-07-07 | Auspex Pharmaceuticals, Inc. | Cyclopropyl dihydrobenzofuran modulators of melatonin receptors |
| US20160193151A1 (en) | 2015-01-06 | 2016-07-07 | Maria Del Pilar Noriega Escobar | Dosage form incorporating an amorphous drug solid solution |
| CN104725292B (en) | 2015-03-23 | 2017-07-25 | 湖北荆江源制药股份有限公司 | A kind of preparation method of (S) () Amisulpride |
| GB201506116D0 (en) | 2015-04-10 | 2015-05-27 | Acacia Pharma Ltd | Kit and combination therapy for nausea and vomiting |
| ITUB20150635A1 (en) | 2015-04-14 | 2016-10-14 | Giuseppe Lotito | Use of an aceticolinesterase inhibitor and pharmaceutical compositions containing said inhibitor. |
| US11426366B2 (en) | 2015-05-15 | 2022-08-30 | Arizona Board Of Regents On Behalf Of The Universsity Of Arizona | Compositions and methods for treating motor disorders |
| CA2997378A1 (en) | 2015-09-18 | 2017-03-23 | Grunenthal Gmbh | Crystallization method and bioavailability |
| CN106890129A (en) * | 2015-12-18 | 2017-06-27 | 健乔信元医药生技股份有限公司 | The extended release dosage form of the general woods of ring benzyl |
| EP3423033A4 (en) | 2016-03-04 | 2020-01-01 | Sharon Anavi-Goffer | Self-emulsifying compositions of cb2 receptor modulators |
| WO2018015915A1 (en) | 2016-07-22 | 2018-01-25 | Cadila Healthcare Limited | A parenteral controlled release composition of an atypical antipsychotic agent |
| US10336679B2 (en) | 2016-10-24 | 2019-07-02 | Syneurx International (Taiwan) Corp. | Polymorphic forms of sodium benzoate and uses thereof |
| US20180118967A1 (en) * | 2016-10-31 | 2018-05-03 | Xerox Corporation | Metal Nanoparticle Ink Compositions For Printed Electronic Device Applications |
| US11377421B2 (en) | 2016-11-28 | 2022-07-05 | Lb Pharmaceuticals Inc. | Psychotropic agents and uses thereof |
| CN106995397B (en) * | 2016-12-12 | 2020-01-14 | 河北医科大学 | R-amisulpride medicinal salt, preparation method, crystal form and application thereof |
| CN107126422B (en) | 2017-03-02 | 2020-07-07 | 河北龙海药业有限公司 | Amisulpride tablet and preparation method thereof |
| CN107049981A (en) | 2017-04-11 | 2017-08-18 | 深圳市泛谷药业股份有限公司 | A kind of quick-release Amisulpride pharmaceutical composition and preparation method thereof |
| CA3061340A1 (en) | 2017-04-25 | 2018-11-01 | Temple Otorongo Llc | Pharmaceutical composition comprising tryptophan and phyllokinin derivative for use in treating psychiatric and psychological conditions |
| US10441544B2 (en) | 2017-10-10 | 2019-10-15 | Douglas Pharmaceuticals, Ltd. | Extended release pharmaceutical formulation |
| WO2019113084A1 (en) | 2017-12-05 | 2019-06-13 | Sunovion Pharmaceuticals Inc. | Crystal forms and production methods thereof |
| JP7268026B2 (en) | 2017-12-05 | 2023-05-02 | サノビオン ファーマシューティカルズ インク | Non-racemic mixtures and uses thereof |
| CN109010300A (en) | 2018-10-24 | 2018-12-18 | 湖南洞庭药业股份有限公司 | A kind of Amisulpride piece and preparation method thereof |
| US20220323409A1 (en) | 2019-06-04 | 2022-10-13 | Sunovion Pharmaceuticals Inc. | Modified release formulations and uses thereof |
| BR112021024380A2 (en) * | 2019-06-04 | 2022-04-19 | Sunovion Pharmaceuticals Inc | Modified release formulations and uses thereof |
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2020
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- 2020-06-04 SG SG11202113266YA patent/SG11202113266YA/en unknown
- 2020-06-04 WO PCT/US2020/036118 patent/WO2020247627A1/en active Application Filing
- 2020-06-04 US US16/892,641 patent/US11160758B2/en active Active
- 2020-06-04 KR KR1020227000263A patent/KR20220018004A/en unknown
- 2020-06-04 CA CA3142355A patent/CA3142355A1/en active Pending
- 2020-06-04 MX MX2021014774A patent/MX2021014774A/en unknown
- 2020-06-04 AU AU2020286441A patent/AU2020286441A1/en active Pending
- 2020-06-04 EP EP20819313.6A patent/EP3980009A4/en active Pending
- 2020-06-04 JP JP2021572444A patent/JP2022535893A/en active Pending
- 2020-06-04 CN CN202080055664.1A patent/CN114401717A/en active Pending
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2021
- 2021-09-30 US US17/490,616 patent/US11654113B2/en active Active
- 2021-11-24 IL IL288372A patent/IL288372A/en unknown
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2023
- 2023-03-07 US US18/118,479 patent/US20230404924A1/en active Pending
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