JP6333802B2 - ベンジルアルコールを含む医薬組成物 - Google Patents
ベンジルアルコールを含む医薬組成物 Download PDFInfo
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- JP6333802B2 JP6333802B2 JP2015501760A JP2015501760A JP6333802B2 JP 6333802 B2 JP6333802 B2 JP 6333802B2 JP 2015501760 A JP2015501760 A JP 2015501760A JP 2015501760 A JP2015501760 A JP 2015501760A JP 6333802 B2 JP6333802 B2 JP 6333802B2
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Description
本願は、2012年3月19日に出願された、出願中の米国仮特許出願第61/612,726号から優先権を主張するものであり、この内容は、それらの全体が参照することにより組み入れられる。
本発明はベンジルアルコールを含む注射用医薬組成物に関する。これらの組成物は、抗精神病製剤の送達に有用である。
これらの医薬組成物は、様々な形態をとることができる。そのような形態として、完全に分散したおよび凝集した系を挙げられるが、これに限定されない。
(a)水不溶性抗精神病薬;
(b)ベンジルアルコール;
(c)カルボン酸が8〜14個の炭素原子を含むカルボン酸ソルビタンエステルのポリオキシエチレン誘導体;および
(d)水性媒体;
を含み、水性で凝集した注射可能な懸濁液を形成する医薬組成物である。
Raは、存在しなく、Rbは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、もしくは−C(O)R1であり;または
Rbは、存在しなく、Raは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、もしくは−C(O)R1であり;
Rcは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、または−C(O)R1であり;
各々のR1は、水素、置換もしくは非置換脂肪族および置換もしくは非置換アリールからなる群から独立して選択され;ならびに
それぞれのR2は、置換もしくは非置換アリールおよび置換もしくは非置換ヘテロアリールから成る群から選択され;
Y−は、薬剤的に許容可能な対イオン;そして
R3a、R3b、およびR3cは、独立して、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、−C(O)R1、または−C(O)OC(R4)(R5)−OC(O)(G12)mR6であり;
R1は、水素、置換もしくは非置換芳香族および置換もしくは非置換アリールからなる群から独立して選択され;
各々のR4およびR5は、水素、C1−C3アルキル、アリール、または置換アリールから独立して選択され;
G12は、NH、CH2、−S−、または−O−から選択され;
mは、0または1であり;
R6は、C13−C26−アルキル、置換C13−C26−アルキル、C13−C26−アルケニル、置換C13−C26−アルケニル、C13−C26−アルキニル、置換C13−C26−アルキニル、C13−C26−シクロアルキル、および置換C13−C26−シクロアルキル、アリール−C13−C26−アルキル、置換アリール−C13−C26−アルキル、C1−C10−アリール、置換C1−C10−アリール、ヘテロアリール−C13−C26−アルキル、置換ヘテロアリール−C13−C26−アルキル;任意置換C13−C26−アルキルアリール、任意置換C13−C26−アルケニルアリール、および任意置換C13−C26−アルキニルアリールから選択され;そして
Y−は、薬剤的に許容可能な対イオンである。)
(a)おおよそ15〜35重量%のアリピプラゾール、またはオランザピン、または式I、式II、式III、式IV、式V、式VIの化合物、またはその薬剤的に許容可能な塩、水和物、もしくは溶媒和物;
(b)おおよそ1〜4重量%のベンジルアルコール;
(c)おおよそ0.05〜0.8重量%のポリソルベート20;そして
(d)水性担体
を含む注射可能な医薬組成物である。
(a)をおおよそ18〜26重量%;
(b)おおよそ2.25重量%のベンジルアルコール;
(c)おおよそ0.2重量%のポリソルベート20;そして
(d)水性担体
を含む。
(a)をおおよそ20〜24重量%;
(b)おおよそ2.25重量%のベンジルアルコール;
(c)おおよそ0.2重量%のポリソルベート20;そして
(d)水性担体
を含む。
本発明において提供するのは、抗精神病薬、ベンジルアルコール、および8〜14個(例えば、11〜13個)の炭素原子を含むカルボン酸のソルビタンエステルのポリオキシエチレン誘導体を含む注射可能な医薬組成物である。この組成物は、水不溶性抗精神病薬を注射可能で凝集した医薬組成物に製剤化するのに特に有用である。ある実施形態では、該ポリオキシエチレン誘導体は、ポリソルベート20である。該医薬組成物は、更に、リン酸緩衝生理食塩水のような水性媒体、ならびに本明細書に記載した任意の医薬成分を含むことができる。
(1)表面張力の低減、これは、高表面張力より、低表面張力の液の方が、表面や粒子が容易に濡れるので、湿潤化に役立ち得る。液の表面張力は、より多くの界面活性剤を添加すると低下する。
(2)ミセル形成(すなわち、水不溶性成分の溶解を可能にする溶液中の球状または非球状界面活性剤構造);および/または
(3)懸濁液の物理的安定性の増加
(a)おおよそ15〜35重量%のアリピプラゾール、またはオランザピン、または式I、式II、式III、式IV、式V、式VIの化合物、またはその薬剤的に許容可能な塩、水和物、もしくは溶媒和物;
(b)おおよそ1〜4重量%のベンジルアルコール;
(c)おおよそ0.05〜0.8重量%のポリソルベート20;そして
(d)水性担体
を含む注射可能な医薬組成物である。
(a)おおよそ18〜26重量%のアリピプラゾール、またはオランザピン、または式I、式II、式III、式IV、式V、式VIの化合物、またはその薬剤的に許容可能な塩、水和物、もしくは溶媒和物;
(b)おおよそ2.25重量%のベンジルアルコール;
(c)おおよそ0.2重量%のポリソルベート20;そして
(d)水性担体
を含む。
(a)おおよそ20〜24重量%のアリピプラゾール、またはオランザピン、または式I、式II、式III、式IV、式V、式VIの化合物、またはその薬剤的に許容可能な塩、水和物、もしくは溶媒和物;
(b)おおよそ2.25重量%のベンジルアルコール;
(c)おおよそ0.2重量%のポリソルベート20;そして
(d)水性担体
を含む。
(a)おおよそ15〜35重量%のアリピプラゾール、化合物A−4、または化合物A−7;
(b)おおよそ1〜4重量%のベンジルアルコール;
(c)おおよそ0.05〜0.8重量%のポリソルベート20;そして
(d)水性担体
を含む注射可能な医薬組成物である。
(a)おおよそ18〜26重量%のアリピプラゾール、化合物A−4、または化合物A−7;
(b)おおよそ2.25重量%のベンジルアルコール;
(c)おおよそ0.2重量%のポリソルベート20;そして
(d)水性担体
を含む。
(a)おおよそ20〜24重量%のアリピプラゾール、化合物A−4、または化合物A−7;
(b)おおよそ2.25重量%のベンジルアルコール;
(c)おおよそ0.2重量%のポリソルベート20;そして
(d)水性担体
を含む。
上述したように、本発明で提供する医薬組成物は、対象への抗精神病薬剤の投与に有用である。本明細書で使用される、「抗精神病薬」という語は、精神病治療に使用される全ての製剤をいう。抗精神病薬は、広範囲の他の診断に伴う精神病に対処するためにも使用されるが、抗精神病薬が処方される通常の状態としては、統合失調症、躁病、および妄想性障害を挙げられる。抗精神病薬は、また、(精神病の症状を呈しないときでさえ、)双極性障害の治療に適した気分安定剤としても作用する。本発明で提供する医薬組成物は、特に、水不溶性抗精神病薬を注射可能な組成物に製剤化するのに有用である。
Raは、存在しなく、Rbは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、もしくは−C(O)R1であり;または
Rbは、存在しなく、Raは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、もしくは−C(O)R1であり;
Rcは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、または−C(O)R1であり;
各々のR1は、水素、置換もしくは非置換脂肪族および置換もしくは非置換アリールからなる群から独立して選択され;ならびに
各々のR2は、置換もしくは非置換アリールおよび置換もしくは非置換ヘテロアリールから成る群から選択され;
Y−は、薬剤的に許容可能な対イオン;そして
Raは、CH2OC(O)R1であり、R1は、置換または非置換脂肪族から選択される。)
R3a、R3b、およびR3cは、独立して、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、−C(O)R1、または−C(O)OC(R4)(R5)−OC(O)(G12)mR6であり;
R1は、水素、置換もしくは非置換芳香族および置換もしくは非置換アリールからなる群から独立して選択され;
各々のR4およびR5は、水素、C1−C3アルキル、アリール、または置換アリールから独立して選択され;好ましくは、水素またはメチルであり;
G12は、NH、CH2、−S−、または−O−から選択され;
mは、0または1であり;
R6は、C13−C26−アルキル、置換C13−C26−アルキル、C13−C26−アルケニル、置換C13−C26−アルケニル、C13−C26−アルキニル、置換C13−C26−アルキニル、C13−C26−シクロアルキル、および置換C13−C26−シクロアルキル、アリール−C13−C26−アルキル、置換アリール−C13−C26−アルキル、C1−C10−アリール、置換C1−C10−アリール、ヘテロアリール−C13−C26−アルキル、置換ヘテロアリール−C13−C26−アルキル;任意置換C13−C26−アルキルアリール、任意置換C13−C26−アルケニルアリール、および任意置換C13−C26−アルキニルアリールから選択され;そして
Y−は、薬剤的に許容可能な対イオンである。)
式(III)のひとつの実施形態では、R3aは、−C(O)OCH2OC(O)R6であり、R6は、C13〜C26−アルキルから選択される。式(III)の特定の実施形態では、R3aは、−C(O)OCH2OC(O)(CH2)14CH3(化合物O−56)である。式(III)の別の特定の実施形態では、R3aは、−C(O)OCH2OC(O)(CH2)16CH3(化合物O−111)である。式(III)の更に別の特定の実施形態では、R3aは、−C(O)OCH2OC(O)(CH2)18CH3(化合物O−112)である。化合物O−56、O−111およびO−112は、下記のように表される:
本発明における医薬組成物は、その必要性にある患者の様々な障害の治療に利用することができる。例えば、開示した組成物は、心臓バイパス手術および移植後の脳欠損、脳卒中、脳虚血、脊髄外傷、頭部外傷、周生期低酸素症、心停止、低血糖性神経損傷、認知症(AIDS−誘発性認知症を含む)、アルツハイマー病、ハンチントン舞踏病、筋萎縮性側索硬化症、眼損傷、網膜症、認知障害、特発性および薬剤誘発パーキンソン病、筋肉痙攣および震えを含む筋痙直に関連した障害、てんかん、痙攣、長期てんかん重積症に続発する脳欠損、片頭痛(migraine)(片頭痛(migraine headache)を含む)、尿失禁、薬物耐性、薬物離脱(アヘン剤、ニコチン、タバコ製品、アルコール、ベンゾジアゼピン系薬剤、コカイン、鎮静剤、睡眠剤等の物質を含む)、精神病、統合失調症、不安症(全般性不安障害、パニック障害、社会恐怖症、強迫性障害、および外傷後ストレス障害(PTSD))、注意欠陥障害(ADD)、注意欠陥移動性障害(ADHD)、気分障害(うつ病、躁病、双極性障害を含む)、概日リズム障害(時差ボケおよび交代勤務を含む)、三叉神経痛、難聴、耳鳴、眼の黄斑変性、嘔吐、脳浮腫、疼痛(急性および慢性疼痛状態、激痛、難治性疼痛、神経因性疼痛、炎症痛、および外傷後疼痛を含む)、遅発性ジスキネジア、睡眠障害(過眠症を含む)、注意欠陥/移動性障害および行動障害のような障害から選択される状態を治療するために使用することができる。
本発明を、更に、次に示す実施例および仮想例によって例示する。これらの実施例および仮想例により、更に限定されるものと解釈すべきではない。
ベンジルアルコール(1.5〜3%)およびポリソルベート20(0.1〜0.8%)の添加は、注射性能および沈降物の高さに影響する。表1参照(一定量の薬剤投入=21.9wt%(180mg/mL 化合物A−4)。注射性能は、様々なサイズの篩選別を通した材料を注射することにより評価し、最高点を7とし最低点を0として0〜7の範囲で採点する。表1を参照のこと:
アリピプラゾールプロドラッグの合成
アリピプラゾール(20g、45mmol)、トリエチルアミン(1mL、7.1mmol)、ホルムアルデヒド(37%水溶液、70mL)、およびジメチルホルムアミド(200mL)の混合物を80℃に20時間加熱した。反応混合物を冷却し、酢酸エチル(400mL)で希釈して、水/食塩水(1:1、500mLで3回)で洗浄した。有機相をMgSO4で乾燥し、ろ過後、真空で蒸発乾固して、白色固体のヘミアミナール体のA−1(18.6g、25%のアリピプラゾールを含有、A−1に基づいた収率65%)を得た。
2−メチル−4−(4−メチルピペラジン−1−イル)−5H−ベンゾ[b]チエノ[2,3−e][1,4]ジアゼピン−5−カルボン酸クロロメチル[A]の合成
オランザピン(18.0g、57.7mmol)およびトリエチルアミン(16mL、0.12mol)のジクロロメタン(250mL)中溶液を35℃に温めて、透明な溶液が一旦形成されたら、反応液を5℃に冷やした。これに、クロロギ酸クロロメチル(7.6mL、86.5mmol)を20分以上かけて添加した。反応液を室温で30分間撹拌し、室温に温まるまで放置した。室温で15分後に、反応混合物をジクロロメタン(100mL)で希釈し、飽和NaHCO3水溶液(75mL)および水(350mL)で洗浄した。有機相をMgSO4で乾燥し、ろ過した。そのから、有機相を真空下45℃で、約150mLの体積になるまで濃縮した。その混合物を酢酸エチル(30mL)で希釈し、更に、約20〜30mLになるまで、真空で蒸発させた。その混合物を室温に冷却して生じた固体の沈殿物をろ過し、酢酸エチルで洗浄した。35℃で90分間真空乾燥した後、黄色固体の2−メチル−4−(4−メチルピペラジン−1−イル)−5H−ベンゾ[b]チエノ[2,3−e][1,4]ジアゼピン−5−カルボン酸クロロメチル[A](17.1g、73%)を得た。1H NMR(300MHz、CDCl3)δ7.62−7.14(4H、m)、6.27−6.22(1H、m)、5.84−5.69(1H、m)、5.47−5.23(1H、m)、3.89−3.63(4H、m)、2.66−2.22(10H、m)。
2−メチル−4−(4−メチルピペラジン−1−イル)−5H−ベンゾ[b]チエノ[2,3−e][1,4]ジアゼピン−5−カルボン酸クロロメチル[A](1当量)のジメチルホルムアミド([A]1g当たり13mL))中溶液に炭酸セシウム(1当量)および適切な脂肪族カルボン酸(2当量)を添加した。反応混合物を、出発物質[A]が消費されるまで(出発物質の減少はTLCで判断)、60℃で2〜6時間加熱した。反応混合物を冷却し、NaHCO3飽和水溶液([A]1g当たり50mL)およびジエチルエーテル([A]1g当たり75mL)で希釈した。15分間撹拌した後、混合物をセライトに通してろ過し、有機相を分離した。これを、MgSO4で乾燥し、蒸発させた。残渣を、30%THFのEtOAc溶液を溶出液として、シリカのカラムクロマトグラフィーにより精製して、画分を含む生成物をひとつに合わせて、蒸発させた。残渣をヘキサンから同時蒸発させた。
2−メチル−4−(4−メチルピペラジン−1−イル)−10H−ベンゾ[b]チエノ[2,3−e][1,4]ジアゼピン−10−カルボン酸クロロメチル[C]
−78℃のオランザピン(5.0g、16mmol)のテトラヒドロフラン(50mL)中溶液に、テトラメチルエチレンジアミン(2.4mL、16mmol)を添加し、次いで、2M n−BuLiヘキサン(8.0mL、16mmol)を5分以上かけて添加した。反応混合物を15分間撹拌し、それから、クロロギ酸クロロメチル(2.1mL、24mmol)を添加し、その反応混合物を更に30分間撹拌した。それから、反応混合物を室温に温めて、1時間撹拌して、水(50mL)で反応を停止した。この混合物を塩水(50mL)で希釈して、酢酸エチル(50mL)で抽出した。有機相をMgSO4で乾燥し、蒸発させて、その残渣を更に0.2:1:1のメタノール/ジクロロメタン/酢酸エチルを溶出液としてシリカのカラムクロマトグラフィーにより精製し、2−メチル−4−(4−メチルピペラジン−1−イル)−10H−ベンゾ[b]チエノ[2,3−e][1,4]ジアゼピン−10−カルボン酸クロロメチル[C]を得た。(5.6g、1H NMRとLCMSによる純度、ほぼ50%)これを、更に精製することなく、次の反応に直接使用した。1H NMR(300MHz、CDCl3)δ7.02−7.30(4H、m)、6.45(1H、s)、5.78−5.92(1.5H、m)、5.52−5.60(0.5H、m)、3.50−3.70(4H、m)、2.35−2.55(7H、m)、2.32(3H、s)。[M+H]+=405.0。
2−メチル−4−(4−メチルピペラジン−1−イル)−10H−ベンゾ[b]チエノ[2,3−e][1,4]ジアゼピン−10−カルボン酸クロロメチル(C:1当量)のジメチルホルムアミド([C]1g当たり13mL)中溶液に、Cs2CO3(1当量)および適切な脂肪族カルボン酸(2当量)を添加した。反応混合物を、出発物質[A]が消費されるまで(出発物質の減少はTLCで判断)、65℃で2〜6時間加熱した。反応混合物を冷却し、NaHCO3飽和水溶液([C]1g当たり50mL)および酢酸エチル([C]1g当たり75mL)で希釈した。15分間撹拌した後、混合物をセライトに通してろ過し、有機相を分離した。これを、MgSO4で乾燥し、蒸発させた。残渣を、1:9のメタノール/酢酸エチルを溶出液として、シリカのカラムクロマトグラフィーにより更に精製して、画分を含む生成物を蒸発させた後、残渣をヘキサン(2x10mL/g[C])で同時蒸発させた。
Claims (30)
- (a)水不溶性抗精神病薬;
(b)ベンジルアルコール;
(c)カルボン酸が8〜14個の炭素原子を含むカルボン酸ソルビタンエステルのポリオキシエチレン誘導体;および
(d)水性媒体
を含み、
前記水不溶性抗精神病薬が、式Iの化合物、もしくは式IIの化合物、またはその薬剤的に許容可能な塩、水和物、もしくは溶媒和物:
Raは、存在しなく、Rbは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、もしくは−C(O)R1であり;または
Rbは、存在しなく、Raは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、もしくは−C(O)R1であり;
Rcは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、または−C(O)R1であり;
各々のR1は、水素、置換もしくは非置換脂肪族および置換もしくは非置換アリールからなる群から独立して選択され;ならびに
各々のR2は、置換もしくは非置換アリールおよび置換もしくは非置換ヘテロアリールから成る群から選択され;
Y−は、薬剤的に許容可能な対イオン;そして
であり、
前記カルボン酸ソルビタンエステルのポリオキシエチレン誘導体が、
水性で凝集した注射可能な懸濁液を形成し、前記成分(a)、(b)、および(c)が注射用に再度懸濁状態にできるように、フロックが沈降し、24時間の静置後に凝集していない組成物と比較して少なくとも20〜80%増加した沈降物の高さとなるよう、成分(a)を含むフロックを形成できる比率で成分(b)および(c)を含む、医薬組成物。 - 前記水不溶性抗精神病薬が、化合物A−4または化合物A−7:
- 前記成分(a)、(b)、および(c)は、1〜60秒以内の手による振とうで注射用に再懸濁状態にできる、請求項1に記載の組成物。
- 前記成分(c)に対する(b)の比率が、20ゲージ以上の注射針を使用して前記組成物の注射が可能になる比率である、請求項1〜3のいずれかに記載の組成物。
- 前記成分(c)に対する(b)の比率は、重量比4.5:1である、請求項1〜4のいずれかに記載の組成物。
- ソルビタンエステルのポリオキシエチレン誘導体(c)は、ポリソルベート20である、請求項1〜5のいずれかに記載の組成物。
- 約1〜4重量%のベンジルアルコールを含む、請求項1〜6のいずれかに記載の組成物。
- 約2.25重量%のベンジルアルコールを含む、請求項1〜7のいずれかに記載の組成物。
- 約0.1〜0.8重量%のポリソルベート20を含む、請求項1〜8のいずれかに記載の組成物。
- 約0.3〜0.6重量%のポリソルベート20を含む、請求項1〜9のいずれかに記載の組成物。
- 約0.5重量%のポリソルベート20を含む、請求項1〜10のいずれかに記載の組成物。
- 15〜35重量%の式Iの化合物もしくは式IIの化合物、またはその薬剤的に許容可能な塩、水和物、もしくは溶媒和物を含む、請求項1〜11のいずれかに記載の組成物。
- 18〜26重量%の式Iの化合物もしくは式IIの化合物、またはその薬剤的に許容可能な塩、水和物、もしくは溶媒和物を含む、請求項1〜12のいずれかに記載の組成物。
- 20〜24重量%の式Iの化合物もしくは式IIの化合物、またはその薬剤的に許容可能な塩、水和物、もしくは溶媒和物を含む、請求項1〜13のいずれかに記載の組成物。
- 22重量%の式Iの化合物もしくは式IIの化合物、またはその薬剤的に許容可能な塩、水和物、もしくは溶媒和物を含む、請求項1〜14のいずれかに記載の組成物。
- (a)15〜35重量%の式Iの化合物もしくは式IIの化合物、またはその薬剤的に許容可能な塩、水和物、もしくは溶媒和物;
Raは、存在しなく、Rbは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、もしくは−C(O)R1であり;または
Rbは、存在しなく、Raは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、もしくは−C(O)R1であり;
Rcは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、または−C(O)R1であり;
各々のR1は、水素、置換もしくは非置換脂肪族および置換もしくは非置換アリールからなる群から独立して選択され;ならびに
各々のR2は、置換もしくは非置換アリールおよび置換もしくは非置換ヘテロアリールから成る群から選択され;
Y−は、薬剤的に許容可能な対イオン;そして
(b)1〜4重量%のベンジルアルコール;
(c)0.05〜0.8重量%のポリソルベート20;そして
(d)水性担体
を含み、前記成分(a)、(b)、および(c)が注射用に再度懸濁状態にできるようにフロックが沈降し、24時間の静置後に凝集していない組成物と比較して少なくとも20〜80%増加した沈降物の高さとなるよう、成分(a)を含むフロックを形成できる比率で成分(b)および(c)を含む、注射可能な医薬組成物。 - (a)20〜26重量%の式Iの化合物もしくは式IIの化合物、またはその薬剤的に許容可能な塩、水和物、もしくは溶媒和物;
(b)2.25重量%のベンジルアルコール;
(c)0.2重量%のポリソルベート20;そして
(d)水性担体
を含む、請求項16に記載の注射可能な医薬組成物。 - (a)25.6重量%の式Iの化合物もしくは式IIの化合物、またはその薬剤的に許容可能な塩、水和物、もしくは溶媒和物;
(b)2.25重量%のベンジルアルコール;
(c)0.2重量%のポリソルベート20;そして
(d)水性担体
を含む、請求項16に記載の注射可能な医薬組成物。 - 水不溶性抗精神病薬の送達に伴う組織反応を調節するために処方されている、請求項1〜18のいずれか一項に記載の組成物。
- 前記組織反応の調節は注射部位の刺激を減少することである、請求項19に記載の組成物。
- 更に、緩衝剤を含む、請求項1〜20のいずれかひとつに記載の組成物。
- 前記緩衝剤がリン酸塩、クエン酸塩、酒石酸塩、または酢酸塩の緩衝剤である、請求項21に記載の組成物。
- (a)水不溶性抗精神病薬、約1〜4%の(b)ベンジルアルコール、約0.05〜1%の(c)ポリソルベート20、およびリン酸塩緩衝剤を含み、前記水不溶性抗精神病薬が、式Iの化合物もしくは式IIの化合物、またはその薬剤的に許容可能な塩、水和物、もしくは溶媒和物である:
Raは、存在しなく、Rbは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、もしくは−C(O)R1であり;または
Rbは、存在しなく、Raは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、もしくは−C(O)R1であり;
Rcは、−CH2OC(O)R1、−CH2OC(O)OR1、−CH2OC(O)N(R1)2、または−C(O)R1であり;
各々のR1は、水素、置換もしくは非置換脂肪族および置換もしくは非置換アリールからなる群から独立して選択され;ならびに
各々のR2は、置換もしくは非置換アリールおよび置換もしくは非置換ヘテロアリールから成る群から選択され;
Y−は、薬剤的に許容可能な対イオン;そして
前記成分(a)、(b)、および(c)が注射用に再度懸濁状態にできるようにフロックが沈降し、24時間の静置後に凝集していない組成物と比較して少なくとも20〜80%増加した沈降物の高さとなるよう、成分(a)を含むフロックを形成できる比率で成分(b)および(c)を含む、医薬組成物。 - 中枢神経系障害の治療において使用するための医薬組成物であって、前記治療が、請求項1〜23のいずれか一項に記載の組成物の有効量をその治療を必要とする個体に投与することを含む、医薬組成物。
- 前記障害が、不安症またはうつ病である、請求項24に記載の医薬組成物。
- 前記障害が双極性障害である、請求項24に記載の医薬組成物。
- 前記障害が自閉症に関連した過敏症である、請求項24に記載の医薬組成物。
- 前記障害が精神病状態である、請求項24に記載の医薬組成物。
- 前記精神病状態が、統合失調症または統合失調症様疾病である、請求項28に記載の医薬組成物。
- 前記精神病状態が、急性躁病である、請求項28に記載の医薬組成物。
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Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3309151A1 (en) * | 2009-06-25 | 2018-04-18 | Alkermes Pharma Ireland Limited | Heterocyclic compounds for the treatment of neurological and psychological disorders |
HRP20240285T1 (hr) | 2011-03-18 | 2024-05-24 | Alkermes Pharma Ireland Limited | Farmaceutski pripravci koji sadrže sorbitan estere |
US9999670B2 (en) | 2012-03-19 | 2018-06-19 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions comprising benzyl alcohol |
US9993556B2 (en) | 2012-03-19 | 2018-06-12 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions comprising fatty glycerol esters |
NZ630643A (en) | 2012-03-19 | 2017-08-25 | Alkermes Pharma Ireland Ltd | Pharmaceutical compositions comprising fatty acid esters |
AR090775A1 (es) * | 2012-04-23 | 2014-12-03 | Otsuka Pharma Co Ltd | Preparado inyectable |
WO2014080285A2 (en) | 2012-09-19 | 2014-05-30 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions having improved storage stability |
MX2016011934A (es) | 2014-03-14 | 2017-04-13 | J Capon Daniel | Inmunoglobulina hibrida conteniendo un enlace no-peptidilico. |
BR112016021535A8 (pt) * | 2014-03-20 | 2021-07-20 | Alkermes Pharma Ireland Ltd | kit compreendendo formulações de aripiprazol tendo velocidades de injeção aumentadas útil para o tratamento de uma desordem do sistema nervoso central e uso |
CN106794251B (zh) * | 2014-08-18 | 2020-12-29 | 阿尔科姆斯制药爱尔兰有限公司 | 阿立哌唑前体药物组合物 |
US10016415B2 (en) | 2014-08-18 | 2018-07-10 | Alkermes Pharma Ireland Limited | Aripiprazole prodrug compositions |
CN109925300A (zh) * | 2017-12-19 | 2019-06-25 | 北京盈科瑞创新药物研究有限公司 | 一种福多司坦雾化吸入用溶液制剂及其制备方法 |
AU2019230014A1 (en) | 2018-03-05 | 2020-09-17 | Alkermes Pharma Ireland Limited | Aripiprazole dosing strategy |
CN110669057A (zh) * | 2018-07-02 | 2020-01-10 | 成都阿奇生物医药科技有限公司 | 一种奥氮平衍生物及其制备方法和用途 |
WO2022183196A1 (en) | 2021-02-24 | 2022-09-01 | Oakwood Laboratories, Llc | Microsphere formulations comprising lurasidone and methods for making and using the same |
Family Cites Families (128)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2418499A (en) | 1944-06-20 | 1947-04-08 | Du Pont | 2-alkoxymethylmercapto-thiazoles and thiazolines and a process for preparing the same |
GB849541A (en) | 1956-02-23 | 1960-09-28 | Rohm & Haas | Preparation of unsaturated cyclic urea derivatives |
DE1273533B (de) | 1962-09-08 | 1968-07-25 | Hoechst Ag | Verfahren zur Herstellung von N-(ª‡-Alkoxy-alkyl)-carbonsaeureamiden |
NL128370C (ja) | 1964-08-28 | |||
US3523121A (en) | 1967-03-09 | 1970-08-04 | Rohm & Haas | Certain 2-carbamoyl-3-isothiazolenes |
US3573308A (en) | 1969-04-03 | 1971-03-30 | Hoffmann La Roche | 3-lower alkoxy methyl-3,4-dihydro-4-hydroxy-4-aryl quinazolin-2(1h) ones and related compounds |
US3957808A (en) | 1969-09-03 | 1976-05-18 | Rohm And Haas Company | 3-alkoxyisothiazoles |
US3998815A (en) | 1974-06-24 | 1976-12-21 | Interx Research Corporation | 1-hydrocarbonoyloxymethyl-3-carbamoyl or 3-carboethoxy-pyridinium salts |
US4727151A (en) | 1974-06-24 | 1988-02-23 | Interx Research Corporation | Labile quaternary ammonium salts as prodrugs |
US4204065A (en) | 1975-09-22 | 1980-05-20 | Interx Research Corporation | Soft quaternary surface active agents and method of using same |
US4260769A (en) | 1977-04-22 | 1981-04-07 | Interx Research Corporation | 5,5-Diphenylhydantoins |
JPS54130587A (en) | 1978-03-30 | 1979-10-09 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivative |
JPS568318A (en) | 1979-06-28 | 1981-01-28 | Janssen Pharmaceutica Nv | Non oral long acting composition of haloperidol and bromperidol derivative |
DE3149010A1 (de) | 1981-12-10 | 1983-07-07 | A. Nattermann & Cie GmbH, 5000 Köln | (+)-2-(1-(2,6-dichlorphenoxy)-ethyl)-1,3- diazacyclopent-2-en, dessen herstellung und seine verwendung in pharamazeutischen praeparaten |
US4428935A (en) | 1982-05-24 | 1984-01-31 | Pfizer Inc. | Penicillanic acid dioxide prodrug |
IT1212743B (it) | 1983-05-17 | 1989-11-30 | Dompe Farmaceutici Spa | Sali quaternari di derivati di benzo[ 1,4 ]diazepinonici,pirido [1,4]benzodiazepinonici,prido [1,5]benzodiazepinonici e loro atti vita' farmacologica |
JPS602331A (ja) | 1983-06-20 | 1985-01-08 | Yoshino Kogyosho Co Ltd | 飽和ポリエステル樹脂製壜の成形方法 |
US4760057A (en) | 1983-06-23 | 1988-07-26 | Merck & Co., Inc. | (Acyloxyalkoxy)carbonyl derivatives as bioreversible prodrug moieties for primary and secondary amine functions in drugs |
DK302883D0 (da) | 1983-06-30 | 1983-06-30 | Hans Bundgaard | Allopurinol prodrugs |
DE3544134A1 (de) | 1984-12-15 | 1986-06-19 | Mitsubishi Chemical Industries Ltd., Tokio/Tokyo | Verfahren zur herstellung von n-((alpha)-alkoxyethyl) pyrrolidon |
GB8513754D0 (en) | 1985-05-31 | 1985-07-03 | Jones T R | Anti-cancer quinazoline derivatives |
DK588486A (da) | 1985-12-09 | 1987-06-10 | Otsuka Pharma Co Ltd | Anvendelse af en forbindelse til behandling af hypoxi |
GB8607683D0 (en) | 1986-03-27 | 1986-04-30 | Ici Plc | Anti-tumor agents |
US4925860A (en) | 1987-08-05 | 1990-05-15 | E. I. Du Pont De Nemours And Company | Stable pharmaceutical composition of 3-(hydroxymethyl)-5,5-diphenylhydantoin disodium phosphate ester |
US5006528A (en) | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
WO1991000863A1 (en) | 1989-07-07 | 1991-01-24 | Pfizer Inc. | Heteroaryl piperazine antipsychotic agents |
US5350747A (en) | 1989-07-07 | 1994-09-27 | Pfizer Inc | Heteroaryl piperazine antipsychotic agents |
US5229382A (en) | 1990-04-25 | 1993-07-20 | Lilly Industries Limited | 2-methyl-thieno-benzodiazepine |
JP2800953B2 (ja) | 1990-07-06 | 1998-09-21 | 住友製薬株式会社 | 新規なイミド誘導体 |
US5206386A (en) | 1991-03-20 | 1993-04-27 | Isp Investments Inc. | Controlled release N-substituted pyrrolidone esters and process for the use thereof |
MX9201991A (es) | 1991-05-02 | 1992-11-01 | Jonh Wyeth & Brother Limited | Derivados de piperazina y procedimiento para su preparacion. |
TW226016B (ja) | 1991-12-30 | 1994-07-01 | Sterling Winthrop Inc | |
US5462934A (en) | 1992-03-09 | 1995-10-31 | Takeda Chemical Industries | Condensed heterocyclic ketone derivatives and their use |
AU4534593A (en) | 1992-06-12 | 1994-01-04 | Affymax Technologies N.V. | Compositions and methods for enhanced drug delivery |
HUT72307A (en) | 1993-03-08 | 1996-04-29 | Eisai Co Ltd | Phosphonic acid derivatives |
TW376319B (en) | 1993-04-28 | 1999-12-11 | Janssen Pharmaceutica Nv | Pharmaceutical composition containing risperidone pamoate and having a long acting activity for treating psychoses induced by the release of dopamine |
DE4439493A1 (de) | 1994-10-25 | 1996-05-02 | Schering Ag | Neue Chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln |
JP3571795B2 (ja) | 1995-04-18 | 2004-09-29 | 株式会社日本触媒 | N−(1−アルキルオキシアルキル)カルバメート類の気相分子内脱アルコール反応用触媒およびn−ビニルカルバメート類の製造方法 |
US7833543B2 (en) | 1995-06-07 | 2010-11-16 | Durect Corporation | High viscosity liquid controlled delivery system and medical or surgical device |
CN1494907A (zh) | 1996-03-25 | 2004-05-12 | 治疗疼痛的药物组合物 | |
DE19619819A1 (de) | 1996-05-16 | 1997-11-20 | Boehringer Mannheim Gmbh | Neue Thiazolidindione, Verfahren zu ihrer Herstellung und diese enthaltenden Arzneimittel |
CZ299790B6 (cs) | 1996-08-22 | 2008-11-26 | Skyepharma Canada Inc. | Kompozice mikrocástic ve vode nerozpustné látky, farmaceutická kompozice, zpusob prípravy stabilních cástic, mikrocástice ve vode nerozpustné nebo slabe rozpustné slouceniny, kompozice obsahující tyto mikrocástice a zpusob prípravy mikrocástic |
US6133248A (en) | 1997-06-13 | 2000-10-17 | Cydex, Inc. | Polar drug of prodrug compositions with extended shelf-life storage and a method of making thereof |
CA2304568C (en) | 1997-09-30 | 2008-08-12 | Eli Lilly And Company | Olanzapine pamoate formulations |
UA72189C2 (uk) | 1997-11-17 | 2005-02-15 | Янссен Фармацевтика Н.В. | Фармацевтична композиція, що містить водну суспензію субмікронних ефірів 9-гідроксирисперидон жирних кислот |
US6180095B1 (en) | 1997-12-17 | 2001-01-30 | Enzon, Inc. | Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents |
JP2001527083A (ja) | 1997-12-31 | 2001-12-25 | ザ・ユニバーシティ・オブ・カンザス | 第二級および第三級アミン含有薬剤の水溶性プロドラッグおよびその製造方法 |
AU754557B2 (en) | 1998-08-26 | 2002-11-21 | Aventis Pharma Limited | Aza-bicycles which modulate the inhibition of cell adhesion |
FR2783519B1 (fr) | 1998-09-23 | 2003-01-24 | Sod Conseils Rech Applic | Nouveaux derives d'amidines, leur preparation, leur application a titre de medicaments et les compositions pharmaceutiques les contenant |
US7374779B2 (en) | 1999-02-26 | 2008-05-20 | Lipocine, Inc. | Pharmaceutical formulations and systems for improved absorption and multistage release of active agents |
US20060034937A1 (en) | 1999-11-23 | 2006-02-16 | Mahesh Patel | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
CA2311734C (en) | 2000-04-12 | 2011-03-08 | Bristol-Myers Squibb Company | Flash-melt oral dosage formulation |
MY128450A (en) | 2000-05-24 | 2007-02-28 | Upjohn Co | 1-(pyrrolidin-1-ylmethyl)-3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives |
US6656505B2 (en) | 2000-07-21 | 2003-12-02 | Alpharma Uspd Inc. | Method for forming an aqueous flocculated suspension |
US20030049320A1 (en) | 2000-12-18 | 2003-03-13 | Wockhardt Limited | Novel in-situ forming controlled release microcarrier delivery system |
US7053092B2 (en) | 2001-01-29 | 2006-05-30 | Otsuka Pharmaceutical Co., Ltd. | 5-HT1a receptor subtype agonist |
ATE280164T1 (de) | 2001-02-14 | 2004-11-15 | Warner Lambert Co | Benzothiadiazine als matrix metallproteinase inhibitoren |
JP2005511477A (ja) | 2001-03-19 | 2005-04-28 | プラエシス ファーマシューティカルズ インコーポレーテッド | 持続放出のための医薬調合物 |
US20060293217A1 (en) | 2001-03-19 | 2006-12-28 | Praecis Pharmaceuticals, Inc. | Pharmaceutical formulations for sustained release |
CA2443350A1 (en) | 2001-04-03 | 2002-12-05 | Aryx Therapeutics | Ultrashort-acting opioids for transdermal application |
MY129350A (en) | 2001-04-25 | 2007-03-30 | Bristol Myers Squibb Co | Aripiprazole oral solution |
AR033485A1 (es) | 2001-09-25 | 2003-12-26 | Otsuka Pharma Co Ltd | Sustancia medicinal de aripiprazol de baja higroscopicidad y proceso para la preparacion de la misma |
ES2316777T3 (es) | 2002-02-15 | 2009-04-16 | Glaxo Group Limited | Moduladores de receptores vainilloides. |
JP4667867B2 (ja) * | 2002-08-02 | 2011-04-13 | メルク・シャープ・エンド・ドーム・コーポレイション | 置換フロ[2,3−b]ピリジン誘導体 |
RU2342931C2 (ru) | 2002-08-20 | 2009-01-10 | Бристол-Маерс Сквибб Компани | Состав на основе комплекса арипипразола |
BR0314393A (pt) | 2002-09-17 | 2005-07-19 | Warner Lambert Co | Piperazinas heterocìclicas substituìdas para o tratamento de esquizofrenia |
US7148211B2 (en) | 2002-09-18 | 2006-12-12 | Genzyme Corporation | Formulation for lipophilic agents |
EP1605956B1 (en) | 2002-12-18 | 2015-11-11 | Centrexion Therapeutics Corporation | Administration of capsaicinoids for the treatment of osteoarthritis |
ES2311756T3 (es) | 2002-12-18 | 2009-02-16 | Algorx | Administracion de la capsiacina. |
DE10303669A1 (de) | 2003-01-28 | 2004-07-29 | Hans-Knöll-Institut für Naturstoff-Forschung e.V. | Tetraalkylammoniumsalze vom Kohlensäureestertyp, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen |
KR20070087266A (ko) | 2003-04-03 | 2007-08-28 | 세마포르 파머슈티컬즈, 아이엔씨. | 피아이-3 키나아제 억제제 프로드러그 |
PL1626721T3 (pl) | 2003-05-23 | 2017-05-31 | Otsuka Pharmaceutical Co., Ltd. | Pochodne karbostyrylu i stabilizatory nastroju do leczenia zaburzeń nastroju |
SI1651265T1 (sl) | 2003-07-24 | 2008-10-31 | Merial Ltd | Formulacije cepiva, ki obsegajo emulzijo olje v vodi |
US6987111B2 (en) | 2003-08-06 | 2006-01-17 | Alkermes Controlled Therapeutics, Ii | Aripiprazole, olanzapine and haloperidol pamoate salts |
US20050032811A1 (en) | 2003-08-06 | 2005-02-10 | Josiah Brown | Methods for administering aripiprazole |
US7160888B2 (en) | 2003-08-22 | 2007-01-09 | Warner Lambert Company Llc | [1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia |
TW200510721A (en) * | 2003-08-29 | 2005-03-16 | Toshiba Kk | Color reagent, concentration measuring kit, concentration measuring method and sensor chip for use therein |
ATE411797T2 (de) | 2003-10-23 | 2008-11-15 | Otsuka Pharma Co Ltd | Sterile injizierbare aripiprazol-formulierung mit kontrollierter freisetzung und verfahren |
BRPI0418255A (pt) | 2003-12-31 | 2007-04-17 | Warner Lambert Co | derivados de piperazina e piperidina n-substituìdos |
EP1718311A1 (en) | 2004-02-13 | 2006-11-08 | Pfizer Products Incorporated | Therapeutic combinations of atypical antipsychotics with corticotropin releasing factor antagonists |
US7169803B2 (en) | 2004-03-15 | 2007-01-30 | Bristol-Myers Squibb Company | N-substituted prodrugs of fluorooxindoles |
US7119214B2 (en) | 2004-04-13 | 2006-10-10 | Cephalon France | Thio-substituted tricyclic and bicyclic aromatic methanesulfinyl derivatives |
GB2413795A (en) | 2004-05-05 | 2005-11-09 | Cipla Ltd | Process for the preparation of rosiglitazone |
WO2006037090A2 (en) | 2004-09-28 | 2006-04-06 | Purdue Research Foundation | Drug-phosphate conjugates as prodrugs |
ES2526092T3 (es) | 2004-11-16 | 2015-01-05 | Alkermes Pharma Ireland Limited | Formulaciones de olanzapina en nanopartículas inyectables |
US20080233053A1 (en) | 2005-02-07 | 2008-09-25 | Pharmalight Inc. | Method and Device for Ophthalmic Administration of Active Pharmaceutical Ingredients |
WO2006090273A2 (en) | 2005-02-22 | 2006-08-31 | Warner-Lambert Company Llc | [1,8]naphthyridin-2-ones and related compounds with keto or hydroxyl linkers for the treatment of schizophrenia |
WO2006134864A1 (ja) | 2005-06-13 | 2006-12-21 | Dainippon Sumitomo Pharma Co., Ltd. | 可溶化型製剤 |
JP2009508859A (ja) * | 2005-09-15 | 2009-03-05 | エラン ファーマ インターナショナル リミテッド | ナノ粒子アリピプラゾール製剤 |
EP1777222A1 (en) | 2005-09-22 | 2007-04-25 | Galantos Pharma GmbH | Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment |
WO2007059111A2 (en) | 2005-11-14 | 2007-05-24 | Entremed, Inc. | Anti-angiogenic activity of 2-methoxyestradiol in combination with anti-cancer agents |
US20090068290A1 (en) | 2006-08-31 | 2009-03-12 | Michel Bourin | Bifeprunox doses for treating schizophrenia |
US20080085888A1 (en) | 2006-09-15 | 2008-04-10 | Breining Scott R | Therapeutic Combinations |
US20090291134A1 (en) | 2006-11-21 | 2009-11-26 | Jina Pharmaceuticals, Inc. | Endoxifen methods and compositions in the treatment of psychiatric and neurodegenerative diseases |
KR20090086627A (ko) | 2006-12-05 | 2009-08-13 | 노이로제스엑스, 인코포레이티드 | 프로드러그 및 그것의 제조 및 사용 방법 |
AU2007334343A1 (en) | 2006-12-15 | 2008-06-26 | Ordway Research Institute, Inc. | Treatments of therapy-resistant diseases comprising drug combinations |
EP1961412A1 (en) | 2006-12-27 | 2008-08-27 | LEK Pharmaceuticals D.D. | Self-microemulsifying drug delivery systems |
US20080186971A1 (en) | 2007-02-02 | 2008-08-07 | Tarari, Inc. | Systems and methods for processing access control lists (acls) in network switches using regular expression matching logic |
JP2010522198A (ja) | 2007-03-19 | 2010-07-01 | アカドイア プハルマセウチカルス インコーポレーテッド | 5−ht2aインバースアゴニスト及びアンタゴニストの抗精神病薬との併用 |
RU2468025C2 (ru) | 2007-04-04 | 2012-11-27 | Мерк Шарп Энд Домэ Корп. | Терапевтические агенты |
US20100292316A1 (en) | 2007-07-18 | 2010-11-18 | Research Development Foundation | Improved therapeutic methods and compositions comprising chroman ring compounds |
SA08290475B1 (ar) | 2007-08-02 | 2013-06-22 | Targacept Inc | (2s، 3r)-n-(2-((3-بيردينيل)ميثيل)-1-آزا بيسيكلو[2، 2، 2]أوكت-3-يل)بنزو فيوران-2-كربوكساميد، وصور أملاحه الجديدة وطرق استخدامه |
WO2009052467A1 (en) | 2007-10-19 | 2009-04-23 | Board Of Regents Of The University Of Texas System | Methods of identifying pi-3-kinase inhibitor resistance |
CL2008003305A1 (es) * | 2007-11-06 | 2009-06-05 | M/S Panacea Biotec Ltd | Composicion inyectable que comprende un agente activo seleccionado de un grupo definido; al menos un polimero bioerosionable, al menos un solvente no toxico y opcionalmente uno o mas excipientes; proceso de preparacion; uso para tratar enfermedades mentales o cancer. |
EP2234617B1 (en) | 2007-12-19 | 2021-03-31 | Janssen Pharmaceutica NV | Dosing regimen associated with long acting injectable paliperidone esters |
AU2008345225A1 (en) | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
US9161943B2 (en) * | 2007-12-31 | 2015-10-20 | Industrial Technology Research Institute | Sustained release composition and manufacturing method thereof |
US8138169B2 (en) | 2008-04-11 | 2012-03-20 | Comgenrx, Inc. | Combination therapy for bipolar disorder |
MX2011002312A (es) | 2008-09-03 | 2011-04-26 | Vertex Pharma | Co-cristales y formulaciones farmaceuticas que comprenden los mismos. |
US20100203129A1 (en) | 2009-01-26 | 2010-08-12 | Egalet A/S | Controlled release formulations with continuous efficacy |
WO2010129843A1 (en) | 2009-05-08 | 2010-11-11 | Cytopathfinder, Inc. | Dihydronaphthyridinyl and related compounds for use in treating ophthalmological disorders |
WO2010151711A1 (en) | 2009-06-25 | 2010-12-29 | Alkermes, Inc. | Prodrugs of nh-acidic compounds |
EP3309151A1 (en) | 2009-06-25 | 2018-04-18 | Alkermes Pharma Ireland Limited | Heterocyclic compounds for the treatment of neurological and psychological disorders |
AU2010313290A1 (en) * | 2009-10-30 | 2012-05-17 | Janssen Pharmaceutica Nv | Dosing regimen associated with long-acting injectable paliperidone esters |
US20110166156A1 (en) | 2010-01-07 | 2011-07-07 | Alkermes, Inc. | Prodrugs for the Treatment of Schizophrenia and Bipolar Disease |
AU2010339691B2 (en) | 2010-01-07 | 2015-04-02 | Alkermes Pharma Ireland Limited | Prodrugs of heteraromatic compounds |
WO2011084851A1 (en) | 2010-01-07 | 2011-07-14 | Alkermes, Inc. | Asenapine produrugs |
US20110166128A1 (en) | 2010-01-07 | 2011-07-07 | Alkermes, Inc. | Diaryldiazepine Prodrugs for the Treatment of Neurological and Psychological Disorders |
CA2798172C (en) | 2010-01-07 | 2017-11-21 | Alkermes Pharma Ireland Limited | Quaternary ammonium salt prodrugs |
WO2011102316A1 (ja) | 2010-02-16 | 2011-08-25 | 浜松ホトニクス株式会社 | ガス濃度算出装置及びガス濃度計測モジュール |
NZ603268A (en) | 2010-05-04 | 2015-02-27 | Alkermes Pharma Ireland Ltd | Process for synthesizing oxidized lactam compounds |
AU2011270701B2 (en) | 2010-06-24 | 2015-05-14 | Alkermes Pharma Ireland Limited | Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives |
HRP20240285T1 (hr) | 2011-03-18 | 2024-05-24 | Alkermes Pharma Ireland Limited | Farmaceutski pripravci koji sadrže sorbitan estere |
NZ630643A (en) | 2012-03-19 | 2017-08-25 | Alkermes Pharma Ireland Ltd | Pharmaceutical compositions comprising fatty acid esters |
US9999670B2 (en) | 2012-03-19 | 2018-06-19 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions comprising benzyl alcohol |
US9993556B2 (en) | 2012-03-19 | 2018-06-12 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions comprising fatty glycerol esters |
WO2014080285A2 (en) | 2012-09-19 | 2014-05-30 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions having improved storage stability |
BR112016021535A8 (pt) | 2014-03-20 | 2021-07-20 | Alkermes Pharma Ireland Ltd | kit compreendendo formulações de aripiprazol tendo velocidades de injeção aumentadas útil para o tratamento de uma desordem do sistema nervoso central e uso |
-
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- 2013-03-13 US US13/801,344 patent/US9999670B2/en active Active
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AU2013235526A1 (en) | 2014-09-25 |
HK1206595A1 (en) | 2016-01-15 |
AU2013235526B2 (en) | 2017-11-30 |
ES2950418T3 (es) | 2023-10-09 |
US9999670B2 (en) | 2018-06-19 |
NZ630428A (en) | 2017-02-24 |
EP2827866A4 (en) | 2016-03-23 |
CA2867137A1 (en) | 2013-09-26 |
WO2013142205A1 (en) | 2013-09-26 |
EP2827866B1 (en) | 2023-05-03 |
JP2015510931A (ja) | 2015-04-13 |
US20130267505A1 (en) | 2013-10-10 |
EP2827866A1 (en) | 2015-01-28 |
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