JP6678676B2 - アリモクロモル製剤 - Google Patents
アリモクロモル製剤 Download PDFInfo
- Publication number
- JP6678676B2 JP6678676B2 JP2017533689A JP2017533689A JP6678676B2 JP 6678676 B2 JP6678676 B2 JP 6678676B2 JP 2017533689 A JP2017533689 A JP 2017533689A JP 2017533689 A JP2017533689 A JP 2017533689A JP 6678676 B2 JP6678676 B2 JP 6678676B2
- Authority
- JP
- Japan
- Prior art keywords
- piperidinyl
- propoxy
- pyridine
- hydroxy
- oxide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
本発明は、薬物動態が改善され、製造が標準化され、かつ患者遵守率が高いアリモクロモルの持続放出(ER)製剤を提供する。本明細書では、持続放出、徐放、遅延放出および制御放出は互換的に使用される。
一態様は、
N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩から選択される医薬品有効成分(API)と、
放出制御添加剤と
を含み、上記医薬品有効成分の持続放出をもたらす、
医薬製剤を提供することである。
薬学的有効量のN−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩と、
放出制御添加剤と
を含む、N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩の持続放出剤形である。
等量のN−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩を即放経口剤形および/またはボーラスIV注射剤によって1日3回投与した場合のCmaxに比して、1日1回または2回の投与でのCmaxを低下させること、
アリモクロモルのピーク血中濃度(Cmax)を曲線下面積(AUC)によって表される総曝露量に対して相対的に低下させること、
血中(または血清中)アリモクロモル濃度のピーク/トラフ比を小さくすること、
アリモクロモル曝露量を維持すると同時にピーク血漿中レベル(Cmax)を低下させること、
より少ない投与回数(1日1回または2回など)でアリモクロモル曝露量および/またはAUCを維持すると同時にピーク血漿中レベル(Cmax)を低下させること、
等量のN−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩を即放経口剤形および/またはボーラスIV注射によって投与した場合のTmaxに比してTmaxを増大させること、
等量のN−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩を即放経口剤形および/またはボーラスIV注射によって投与した場合のOCT2の阻害に比してOCT2の阻害を低下させること、
等量のN−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩を即放経口剤形および/またはボーラスIV注射によって投与した場合の血清中クレアチニンレベルに対する作用に比して血清中クレアチニンレベルに対する作用を低下させること、
等量のN−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩を即放経口剤形および/またはボーラスIV注射によって投与した場合の腎クレアチニンクリアランスに対する作用に比して腎クレアチニンクリアランスに対する作用を低下させること、
OCT2に対する医薬品有効成分の最大半量阻害(IC50)よりも低いCmaxを得ること。
Cmaxを低下させ、
OCT2の阻害を低下させ、
血清中クレアチニンレベルに対する作用を低下させ、かつ/または
Tmaxを増大させる。
N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩を投与してからその血清中濃度が最大値に達するまでの時間(Tmax)が、等量の同物質を即放経口剤形および/またはボーラスIV注射によって投与した場合のTmaxに比して増大し、
N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩を投与した後のOCT2の阻害が、等量の同物質を即放経口剤形および/またはボーラスIV注射によって投与した場合のOCT2の阻害に比して低下し、
N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩を投与した後の血清中クレアチニンレベルに対する作用が、等量の同物質を即放経口剤形および/またはボーラスIV注射によって投与した場合の血清中クレアチニンレベルに対する作用に比して低下する
ように、それを必要とする患者にある量のN−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩から選択されるAPIを持続放出によって投与する方法もまた提供される。
本発明は、一態様では、N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド(アリモクロモル)、その立体異性体およびそれらの酸付加塩から選択される医薬品有効成分を含み、内部マトリックスと少なくとも1つの外部コーティングとを含み、上記医薬品有効成分の持続放出をもたらす、医薬製剤を提供する。
一実施形態では、本発明による医薬製剤は、APIを含む内部マトリックスなどの、マトリックス要素、および任意選択で外部コーティングを含む。一実施形態では、内部マトリックスは、錠剤、ミニタブレットまたはマイクロタブレットであり、錠剤は任意選択でコーティングされる。
一実施形態では、本発明による医薬製剤は、APIを含む内部マトリックスなどのマトリックス要素と、外部コーティングとを含む。一実施形態では、外部コーティングは医薬品有効成分を含まない。
a.N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩から選択される医薬品有効成分(API)を含み、少なくとも1つの放出制御添加剤と任意選択で1つまたは複数の追加の添加剤とを含む、内部マトリックスと、
b.任意選択で外部コーティングと
を含み、上記医薬品有効成分の持続放出をもたらす、医薬製剤が提供される。
本発明による医薬製剤は、一実施形態では、内部マトリックスまたは球状体基質などのマトリックス要素と、1つまたは複数の個別の層を含む外部コーティングとを含む。
一実施形態では、
N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩から選択される医薬品有効成分(API)と、
放出制御添加剤と
を含み、上記医薬品有効成分の持続放出をもたらし、持続放出顆粒の形態である、医薬製剤が提供される。
N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩から選択される医薬品有効成分(API)と、
放出制御添加剤と
を含む持続放出顆粒を含み、熱溶融押出によって得られる、医薬製剤が提供される。
a.N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩から選択されるAPIとHME添加剤とを混合する段階と;
b.上記APIおよび上記HME添加剤を加熱し押し出して、上記APIと上記HME添加剤とを含む押出物を得る段階と;
c.上記押出物を粉砕によるなどのサイズリダクションおよび任意選択でふるい分けによるなどのサイズ分級に供する段階と
を含む熱溶融押出によって製造されるか、得られる。
i)N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩から選択されるAPIと、65〜75℃の融点、例えば約70℃などの融点を有するHME添加剤とを準備する段階と、
ii)上記APIと上記HME添加剤とを混合する段階と、
iii)上記APIおよび上記HME添加剤を65〜75℃、例えば65〜70℃などの溶融温度に供する段階と、
iv)上記APIおよび上記HME添加剤を0〜10bar、例えば0〜8barなどの溶融圧で押し出して、上記APIと上記HME添加剤とを含む押出物を得る段階と、
v)好ましくは、上記APIと上記HME添加剤とを含む上記押出物を粉砕によるなどのサイズリダクションする段階と、
vi)任意選択で、サイズリダクションされた上記押出物をふるい分けによるなどのサイズ分級する段階と
を含む、方法が提供される。
本発明の製剤に含まれる医薬品有効成分(API)は、N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド(アリモクロモル)、その立体異性体およびそれらの酸付加塩から選択される。アリモクロモルについては、例えば国際公開第00/50403号に詳細に記載されている。
本発明では、治療を必要とする個人に医薬品有効成分(API)を薬学的有効量で投与する。治療有効量の本発明によるAPIとは、所与の疾患または病態およびその合併症の臨床症状の治癒、予防、リスク軽減、緩和または部分的抑制に十分な量である。特定の治療目的に有効な量は、疾患の重症度および種類、ならびに対象の体重および全身状態に左右される。
本発明による医薬製剤は、治療を必要とする任意の個人に投与できる。治療を必要とする個人とは、本発明による医薬品有効成分での治療から利益を受けるか、受ける可能性のある任意の個人である。
一態様は、薬物として使用する本発明による医薬製剤を提供することである。
1.N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩から選択される医薬品有効成分を含み、内部マトリックスと少なくとも1つの外部コーティングとを含み、上記医薬品有効成分の持続放出をもたらす、医薬製剤。
b.20〜50%のHPMC、20〜25%w/wなど、例えば25〜30%w/w、30〜35%w/wなど、例えば35〜40%w/w、40〜45%w/wなど、例えば45〜50%w/wのHPMC、
c.10〜50%のMCC、例えば10〜50%w/w、10〜15%w/wなど、例えば15〜20%w/w、20〜25%w/wなど、例えば25〜30%w/w、30〜35%w/wなど、例えば35〜40%w/w、40〜45%w/wなど、例えば45〜50%w/wのMCC、
d.5〜30%のデンプン、5〜10%w/wなど、例えば10〜15%w/w、15〜20%w/wなど、例えば20〜25%w/w、25〜30%w/wなどのデンプン、
e.0.05〜1%のシリカ、0.05〜0.1%w/wなど、例えば0.1〜0.2%w/w、0.2〜0.3%w/wなど、例えば0.3〜0.4%w/w、0.4〜0.5%w/wなど、例えば0.5〜0.6%w/w、0.6〜0.7%w/wなど、例えば0.7〜0.8%w/w、0.8〜0.9%w/wなど、例えば0.9〜1.0%w/wのシリカ、
f.0.1〜5%のステアリン酸マグネシウム、0.1〜0.5%w/wなど、例えば0.5〜1.0%w/w、1〜2%w/wなど、例えば2〜3%w/w、3〜4%w/wなど、例えば4〜5%w/wのステアリン酸マグネシウム、
g.0.1〜10%のステアリン酸、0.1〜0.5%w/wなど、例えば0.5〜1.0%w/w、1〜2%w/wなど、例えば2〜3%w/w、3〜4%w/wなど、例えば4〜5%w/w、5〜6%w/wなど、例えば6〜7%w/w、7〜8%w/wなど、例えば8〜9%w/w、9〜10%w/wなどのステアリン酸、ならびに
h.任意選択で5〜30%の(EC)、5〜10%w/wなど、例えば10〜15%w/w、15〜20%w/wなど、例えば20〜25%w/w、25〜30%w/wなどのEC
を含むか、これよりなる内部マトリックスと、
ii)任意選択で、
a.5〜40%w/wの重量増加、10〜15%w/wなど、例えば15〜20%w/w、20〜25%w/wなど、例えば25〜30%w/w、30〜35%w/wなど、例えば35〜40%w/wの重量増加に適用される水性エチルセルロース(EC)、溶媒型ECおよび/または水性ポリメタクリル酸、ならびに
b.任意選択で外部シールコーティング
を含むか、これよりなる外部コーティングと
を含むか、これよりなる、項目1〜36のいずれかに記載の医薬製剤。
b.20〜50%のHPMC、
c.10〜50%のMCC、
d.5〜30%のデンプン、
e.0.05〜1%のシリカ、
f.0.1〜5%のステアリン酸マグネシウム、ならびに
g.0.1〜10%のステアリン酸
を含むか、これよりなる内部マトリックスと、
ii)a.5〜25%w/wの重量増加に塗布される水性エチルセルロース(EC)、溶媒型ECおよび/または水性ポリメタクリル酸、ならびに
b.任意選択で外部シールコーティング
を含むか、これよりなる外部コーティングと
を含むか、これよりなる、項目1〜37のいずれかに記載の医薬製剤。
b.1〜10%w/wの、1〜2%w/wなど、例えば2〜3%w/w、3〜4%w/wなど、例えば4〜5%w/w、5〜6%w/wなど、例えば6〜7%w/w、7〜8%w/wなど、例えば8〜9%w/w、9〜10%w/wなどのN−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド(アリモクロモル)、その立体異性体およびそれらの酸付加塩を有し、かつ1〜10%w/wのMethocel E6などのHPMC、1〜2%w/wなど、例えば2〜3%w/w、3〜4%w/wなど、例えば4〜5%w/w、5〜6%w/wなど、例えば6〜7%w/w、7〜8%w/wなど、例えば8〜9%w/w、9〜10%w/wなどのHPMCを有する薬物層と、
c.0.1〜5%w/wの、0.1〜0.5%w/wなど、例えば0.5〜1%w/w、1〜2%w/wなど、例えば2〜3%w/w、3〜4%w/wなど、例えば4〜5%w/wのPVA系フィルムコートを有するシールコートと、
d.5〜30%w/wのECまたはポリアクリル酸、5〜10%w/wなど、例えば10〜15%w/w、15〜20%w/wなど、例えば20〜25%w/w、25〜30%w/wなどのECまたはポリアクリル酸を有する制御放出コートと、
e.任意選択で1〜10%w/wのPVA系フィルムコート、1〜2%w/wなど、例えば2〜3%w/w、3〜4%w/wなど、例えば4〜5%w/w、5〜6%w/wなど、例えば6〜7%w/w、7〜8%w/wなど、例えば8〜9%w/w、9〜10%w/wなどのPVA系フィルムコートを有するフィルムコートと
を含むか、これよりなる、項目1〜54のいずれかに記載の医薬製剤。
b.4%w/wのN−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド(アリモクロモル)、その立体異性体およびそれらの酸付加塩を有し、かつ5%w/wのMethocel E6などのHPMCを有する薬物層と、
c.1%w/wのPVA系フィルムコートを有するシールコートと、
d.5〜20%w/wのECまたはポリアクリル酸を有する制御放出コートと、
e.任意選択で3%w/wのPVA系フィルムコートを有するフィルムコートと
を含むか、これよりなる、項目1〜55のいずれかに記載の医薬製剤。
この試験の目的は、アリモクロモルとヒトSLC(取込み)輸送体:OATP1B1(OATP2、OATP−C)、OATP1B3(OATP8)、OAT1、OAT3、およびOCT2との相互作用に関するデータ(表1)を提供することであった。
アリモクロモルは、このアッセイに使用したアッセイ緩衝液に最大300μM溶解した。
アリモクロモルは、諸添加濃度でOCT2を介するプローブ基質蓄積を阻害し(用量依存性に)、最大阻害は98.36であった(図5)。IC50の計算値は9.72μMであった。アリモクロモルは、諸添加濃度でOATP1B1、OATP1B3、OAT1およびOAT3を介するプローブ基質蓄積に影響しなかった(図1、図2、図3および図4)。
OAT1(図6)、OAT3(図7)およびOCT2(図8)の基質実現可能性実験で、諸添加濃度(1μMおよび10μM)および諸時点(2分後および20分後)での細胞内への重要なアリモクロモルの蓄積倍数は観察されなかった(蓄積倍数は2未満であった)。アリモクロモルの最大蓄積倍数は、OAT1で0.77(1μMおよび2分後)、OAT3で0.86(1μM、2分後および20分後の両方)およびOCT2で1.28(1μMおよび20分後;表6)であった。陽性対照で、使用した細胞中の輸送体の機能が確認された。
被験物質、ストック溶液、化学薬品および機器
被験物質のアリモクロモル313.7799g/molを室温で保管した。溶解度は25℃(水)で14g/100mLおよび25℃(メタノール)で0.4g/100mLである。水中にストック溶液(1mM、10mMおよび30mM)を調製した。DMSO中に段階希釈液(7段階、特殊)を調製し、様々なアッセイで試験溶液として使用した(取込みアッセイでは100倍希釈)。基質実験の希釈倍数は1000倍であった。その他のアッセイでのアッセイ緩衝液中の溶媒濃度は1.1%(v/v)を超えなかった。
光学顕微鏡による評価(倍率5倍および10倍)と組み合わせた分光学的測定によってTAの水溶解度を求めた。無色の化合物は可視範囲(400〜700nm)で光を吸収せず、したがって、TAを分光光度計で測定する場合、この波長範囲でバックグランド補正した吸光度値がブランク吸光度値よりも大きいことは、沈降した粒子によって引き起こされると考えられる光散乱の存在を示す。溶解度評価の時間枠には、対応するin vitro実験のインキュベーション時間を含めた。
水中にTAのストック溶液および希釈系列(5段階、2倍希釈系列)を調製した。96ウェルプレート内でストック溶液を適切なアッセイ緩衝液と混合し、37℃で10分間インキュベートした後、500nmで溶液を評価した。緩衝液の吸光度測定値は通常、0.010〜0.030である。したがって、所与の濃度で可溶性であると見なされるには、TA溶液のバックグラウンド補正した吸光度が0.030吸光度単位未満でなければならない(ΔA=A溶液−Aブランク<0.030)。各溶液についてバックグラウンド補正した吸光度値を求めた。
それぞれの取込み輸送体を安定に発現するCHO細胞、MDCKII細胞またはHEK293細胞を用いて取込み実験を実施した。取込み輸送体アッセイのパラメータを表3に示す。対照細胞系、細胞培養および播種に関する情報を表4にまとめる。
95:5の空気:CO2の雰囲気下、37±1℃で細胞を培養し、標準的な96ウェル組織培養プレートに表4に記載した細胞数で播種した。
表4に記載されるように95:5の空気:CO2の雰囲気下にて37±1℃で細胞を培養し、標準的な24ウェル組織培養プレートに2×105細胞/ウェルで播種した。各取込み輸送体を過剰発現する細胞および対照細胞を用いて2つのインキュベーション時点(2分後および20分後)および2つのTA濃度(1μMおよび10μM)でのTAの取込みを求めて、TAが細胞内に能動的に取り込まれるかどうかを明らかにした。相互作用を確認するため、各輸送体の既知の阻害剤の存在下でTAの輸送体特異的取込みを求めた。
各ウェルについて、移行したプローブ基質の量をcpmまたはRFUで求めた。以下の式から相対活性を計算した:
活性%=(A−B)/(C−D)×100
A:トランスフェクト細胞中でTAの存在下で移行した基質の量
B:対照細胞中でTAの存在下で移行した基質の量
C:トランスフェクト細胞中で溶媒の存在下で移行した基質の量
D:対照細胞中で溶媒の存在下で移行した基質の量。
トランスフェクト細胞と対照細胞中へのTAまたはプローブ基質の取込みの比を蓄積倍数値と定義した:
蓄積倍数=UPTTRP/UPTCTL
UPTTRP:トランスフェクト細胞中に蓄積されるTAまたはプローブ基質の量をタンパク質含有量で正規化した値[pmol/mgタンパク質]
UPTCTL:対照細胞中に蓄積されるTAまたはプローブ基質の量をタンパク質含有量で正規化した値[pmol/mgタンパク質]
基礎データの処理にはMicrosoft Excel 2010(Microsoft社、レドモンド、ワシントン州)を用い、カーブフィッティングおよび反応パラメータの決定にはGraphPad Prism 5.0(GraphPad Software社、サンディエゴ、カリフォルニア州)を用いた。
取込み輸送体アッセイの結果
1)取込み輸送体阻害アッセイの結果については、図1(OATP1B1)、図2(OATP1B3)、図3(OAT1)、図4(OAT3)および5(OCT2)を参照されたい。
2)取込み輸送体基質アッセイについては、図6(OAT1)、図7(OAT3)、図8(OCT2)を参照されたい。
この試験の目的は、許容される官能特性を有し嚥下が容易であり持続放出性を示すアリモクロモルの経口投与形式を開発することである。
計9種類の製剤混合物を検討し、以下にまとめた:
HPMCミニタブレット:混合物1、2および3はマトリックス中にHPMCとデンプンを様々な比で含有する
HPMC/ECミニタブレット:混合物4および5はマトリックス中にHPMC、デンプンおよびECを様々な比で含有する
ロウ系マトリックス:ロウ系基剤(濃度30%w/wまたは40%w/wのグリセロールジベンヘナート(Glycerol Dibenhenate)またはグリセロールジステアラート)を含有する混合物を計4種類調製した。ロウ系基剤を用いた場合、ミニタブレットはうまく作製されなかった。
ミニタブレットマトリックス中にHPMCを含めて、それがミニタブレットからの原薬の放出を遅らせ、したがって、それ自体が制御放出マトリックスとして作用することが可能かどうかを検討した。いずれの混合物も錠剤ホッパーの中に容易に流れ込み、2mmミニタブレットへとうまく圧縮され、適切な流動性を有することが示された。目に見えるキャッピングの徴候もラミネーションの徴候も観察されなかった。
混合物1〜混合物4の溶出プロファイルは同等であると示された;このため、最初に混合物1に関するコーティング試験を遂行した。以下のコーティング法を採用した:
5%、10%および20%の重量増加まで水性EC分散液(Surelease(商標))を使用
5%、10%および20%の重量増加まで溶媒型ECコーティングを使用
5%、10%および20%の重量増加まで水性ポリメタクリル酸系分散液(Eudragit NE30D(商標))を使用。
2種類の異なるコア(糖および微結晶性セルロース)および様々なコーティング材料(水性エチルセルロース、溶媒型エチルセルロースおよび水性ポリアクリル酸分散液)を用いて様々な溶出プロファイルを有するコーティング球状体を作製することを目的とした。2種類の球状体、すなわち可溶性糖球状体(Suglets(商標))および不溶性微結晶性セルロース球状体(Vivapur(商標))を薬物層形成基質として検討した。
非水性および水性のエチルセルロース制御放出コーティングを用いた糖球状体のコーティング(実験6);
水性ポリアクリル酸系分散液(Eudragit E30D(商標))コーティングを用いた糖球状体のコーティング(実験8)。
薬物層形成溶液:4%w/wの薬物と5%w/wのHPMCとを含有する溶液100gを調製した。
シールコート:製造業者の指示に従って、3%w/w〜5%w/wのコーティング固体を含有する分散液100gを調製した。
制御放出溶液:60gのSurelease(商標)を水とともに100gへと添加することにより、15%w/wのコーティング固体(Surelease E−7−19040(商標))を含有する溶液100gを調製した。
フィルムコート:シールコートの通りに調製した。
アリモクロモル持続放出製剤の様々な溶出放出速度に関する熱溶融押出(HME)の評価。
Thermo Scientific Pharma 11同方向回転二軸スクリュ押出機を用いるアリモクロモル/C888粉末混合物から固形製品を作製する熱溶融押出によって、Compritol(登録商標)888(C888)中で活性な33重量%、50重量%および66重量%のアリモクロモル製剤を作製することを目的とした。
−溶融圧は0〜8barであった
−溶融温度は67〜69℃であった
−機器トルクは11〜12%であった
1つの被験物質(アリモクロモル)を5元クロスオーバー試験、すなわち、1つは現在用いられている製剤で、4つは改変した製剤で検討するGottingen雄ミニブタPO PK試験にて、本発明による放出制御製剤を試験する。Charles River laboratories(イギリス)にて生体試験を非GLP基準で実施する。用量レベルを確定する。
Claims (15)
- a.N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩から選択される医薬品有効成分と、
b.放出制御添加剤と
を含む、
前記医薬品有効成分の持続放出を提供する、経口剤形である、持続放出医薬製剤であって、
等量のN−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩を即放経口剤形によって投与した場合および/またはボーラスIV注射によって投与した場合と比較して、OCT2の阻害を低下させ、
前記医薬品有効成分は、1つの剤形または製剤単位で、1用量当たり5〜1000mgの総量で存在する、
持続放出医薬製剤。 - i)前記持続放出医薬製剤が10μM以下の、9μM未満など、例えば8μM未満、7μM未満など、例えば6μM未満、5μM未満など、例えば4μM未満、3μM未満など、例えば2μM未満、1μM未満などのCmaxを提供して、Cmaxを減少させ、
ii)Cmaxが、少なくとも10%、少なくとも20%、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%、少なくとも80%、少なくとも90%、または100%の倍率で低下され、
iii)前記医薬品有効成分の曝露量および/またはAUCを維持しながらCmaxが低下され、
iv)曲線下面積(AUC)によって表される総曝露量に対してCmaxが相対的に低下され、および/または
v)Cmaxが、OCT2に対する前記医薬品有効成分の最大半量阻害(IC50)よりも低い、
請求項1に記載の持続放出医薬製剤。 - Tmaxが、10〜20%、20〜30%、30〜40%、40〜50%、50〜60%、60〜70%、70〜80%、80〜90%、90〜100%、100〜125%、125〜150%、150〜200%、または200〜250%の倍率で増大される、請求項1または2に記載の持続放出医薬製剤。
- OCT2の阻害が、少なくとも10%、少なくとも20%、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%、少なくとも80%、少なくとも90%、または少なくとも100%の倍率で低下される、請求項1〜3のいずれか一項に記載の持続放出医薬製剤。
- 1日1回または1日2回投与される、請求項1〜4のいずれか一項に記載の持続放出医薬製剤。
- 前記前記持続放出医薬製剤が、
i)3〜5時間以内に前記医薬品有効成分の85%が放出される溶出速度を有する、または
ii)少なくとも6時間後に前記医薬品有効成分の85%が放出される溶出速度を有する、
請求項1〜5のいずれか一項に記載の持続放出医薬製剤。 - 内部マトリックスと少なくとも1つの外部コーティングとを含み、前記内部マトリックスが前記医薬品有効成分を含む、請求項1〜6のいずれか一項に記載の持続放出医薬製剤。
- 内部球状体基質と1つまたは複数の個別の層を含む外部コーティングとを含むコーティング球状体であり、前記外部コーティングが前記医薬品有効成分を含む、請求項1〜6のいずれか一項に記載の持続放出医薬製剤。
- 前記経口剤形が、N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩と放出制御添加剤とを含む持続放出顆粒の形態である、請求項1〜6のいずれか一項に記載の持続放出医薬製剤。
- 前記医薬品有効成分が、
a.N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリドのラセミ体、
b.N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリドの光学活性立体異性体、
c.N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリドの鏡像異性体、
d.(+)−R−N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、
e.(−)−(S)−N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、
f.N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリドの酸付加塩、
g.N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリドクエン酸塩、
h. N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリマレイン酸塩、
i.(+)−R−N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリドクエン酸塩、
j.(−)−S−N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリドクエン酸塩、
k.(+)−R−N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリドマレイン酸塩、および
l.(−)−S−N−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリドマレイン酸塩
からなる群より選択される、請求項1〜9のいずれか一項に記載の持続放出医薬製剤。 - 1つまたは複数のさらなる医薬品有効成分を、別個にまたは一緒に含む、請求項1〜10のいずれか一項に記載の持続放出医薬製剤。
- OCT2の阻害が、等量のN−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩を即放経口剤形によって投与した場合と比較して回避または低減される薬剤としての使用のための、請求項1〜11のいずれか一項に記載の医薬製剤。
- OCT2に対する前記医薬品有効成分の最大半量阻害(IC50)よりも低いCmaxを維持することにより、OCT2の阻害が回避または低減される、請求項12に記載の持続放出医薬製剤。
- 小児患者;血清中クレアチニンの上昇がみられる患者;非炎症性腎障害(ネフローゼ)および炎症性腎障害(腎炎)を含む腎疾患(腎障害)を有する患者;1型糖尿病、2型糖尿病および高血圧症から選択される疾患を有する患者;からなる群より選択される患者に用いられ、OCT2の阻害が、等量のN−[2−ヒドロキシ−3−(1−ピペリジニル)−プロポキシ]−ピリジン−1−オキシド−3−カルボキシイミドイルクロリド、その立体異性体およびそれらの酸付加塩を即放経口剤形によって投与した場合と比較して回避または低減される薬剤としての使用のための、請求項1〜13のいずれか一項に記載の持続放出医薬製剤。
- スフィンゴリピドーシス、ガングリオシドーシスおよび白質ジストロフィーを含めた脂質蓄積障害(またはリピド―シス)、ムコ多糖症、糖タンパク質蓄積障害(または糖タンパク代謝異常症)およびムコリピドーシスからなる群より選択されるリソソーム蓄積症;または筋萎縮性側索硬化症(ALS);を治療用の、請求項1〜14のいずれか一項に記載の持続放出医薬製剤。
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