JP2019218389A - 代謝障害を治療するための組成物および方法 - Google Patents
代謝障害を治療するための組成物および方法 Download PDFInfo
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- JP2019218389A JP2019218389A JP2019157580A JP2019157580A JP2019218389A JP 2019218389 A JP2019218389 A JP 2019218389A JP 2019157580 A JP2019157580 A JP 2019157580A JP 2019157580 A JP2019157580 A JP 2019157580A JP 2019218389 A JP2019218389 A JP 2019218389A
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Abstract
Description
本発明は、概して、ビグアナイド化合物を用いた代謝障害の治療、および遅延放出製剤を使用して患者にビグアナイド化合物を投与することによって、そのような化合物の胃腸忍容性を改善することに関する。
高血糖症(hyperglycemia)、高血糖症(hyperglycaemia)、または高血糖(high blood sugar)は、過量の、例えば約125mg/dLを超えるグルコースが血漿中を循環する状態である。正常を若干上回るレベルの慢性高血糖症は、ある期間にわたって、腎臓損傷、神経損傷、心血管損傷、網膜への損傷、または足および下肢への損傷を含む、多種多様の重篤な合併症を生じ得る。糖尿病性神経障害は、長期の高血糖症の結果であり得る。
対象におけるメトホルミン等のビグアナイド化合物の全身性生物学的利用能を最小化し、なおさらに、有意に有益な代謝効果、例えば、高血糖の低減を提供する方法および組成物が本明細書に企図される。従来の理解に反して(例えば、上記のMulherinらを参照されたい)、本開示のビグアナイド化合物は、事実上、腸内分泌細胞の管腔または上皮側(すなわち、胃腸管側)との相互作用を含み得る作用の機序を通してGLP−1の放出を生じ、全身性生物学的利用能は、したがって、なお有意義な治療効果を達成しながら最小化され得る。有利に、主題の方法および組成物はGI忍容性を著しく改善し、また、さもなければ禁忌となる患者がここで効果的に治療され得るように、乳酸アシドーシス等の有害作用の可能性を低減する。
本明細書で使用される場合「胃腸管」および「腸」という用語は、胃および腸管を指す。「小腸」または「腸管の上部」は、十二指腸、空腸、および回腸を含み、「大腸」または「腸管の下部」は、盲腸、結腸、および直腸を含む。「遠位」小腸には、空腸および回腸を含む。
本明細書で開示される組成物および方法は、メトホルミンおよび他のビグアナイドに関する。背景として、メトホルミンは、ビグアナイドとして既知の分類の化合物の最も単純な構造変異体の1つである。構造的展望から、メトホルミンは、ファーマコフォアまたはより大きい生物学的活性化学構造の断片に似ている。
を含み、式中、
R1、R2、R3、R4、R5、R6、およびR7は独立して、
H、OH、
O−Rx(式中、Rxが、アルキル、シクロアルキル、アルキルシクロアルキル、アシル、エステル、チオエステルである);
置換されていてもよいアルキル(例えば、酸素、ケイ素、硫黄で置換されていてもよく、またはOH、O−アルキル、SH、S−アルキル、NH2、NH−アルキルで置換されていてもよいC1〜C12直鎖または分枝鎖アルキル);シクロアルキル(例えば、C3〜C7シクロアルキル);アルキルシクロアルキル(例えば、C4〜C12アルキルシクロアルキル);ヘテロシクロアルキル(例えば、該ヘテロ環は、O、S、またはNから選択される1つまたは2つのヘテロ原子を含み、C2〜C6ヘテロシクロアルキルが含まれる);アルキルヘテロシクロアルキル(例えば、該ヘテロ環が、O、S、またはNから選択される1つまたは2つのヘテロ原子を含み、C3〜C11アルキルヘテロシクロアルキルが含まれ、Nが複素環式環に存在するとき、窒素原子は、アミド、カルバミン酸塩、または尿素の形態であり得ることを含む);置換されていてもよいアルケニル(例えば、酸素、ケイ素、硫黄で置換されていてもよく、OH、O−アルキル、SH、S−アルキル、NH2、NH−アルキルで置換されていてもよいC1〜C12直鎖または分枝鎖アルケニル);置換されていてもよいアルキニル(例えば、酸素、ケイ素、硫黄で置換されていてもよく、OH、O−アルキル、SH、S−アルキル、NH2、NH−アルキルで置換されていてもよいC1〜C12直鎖または分枝鎖アルキニル);
置換されていてもよいアリール(例えば、フェニル、置換フェニル、ナフチル、置換ナフチル);置換されていてもよいアルキルアリール(例えば、アルキルフェニル、アルキル置換フェニル、アルキルナフチル、アルキル置換ナフチル);置換されていてもよいヘテロアリール(例えば、それらすべてが置換されていてもよい、ピリジル、フラニル、チオフェニル、ピロリル、オキサゾリル、イソオキサゾリル、チアゾリル、ジアゾリル、ピラゾリル、トリアゾリル);置換されていてもよいアルキルヘテロアリールから選択され、かつ
あるいはR6およびR7は、一緒に結合を形成し、それらが結合している窒素原子を含む環をともに形成し得、
あるいはR1およびR2は、それらが結合している窒素原子を含む3〜8員複素環式環をともに形成し得、
あるいはR4およびR5は、それらが結合している窒素原子を含む、アジリジン、ピロリル、イミダゾリル、ピラゾリル、インドリル、インドリニル、ピロリジニル、ピペラジニル、およびピペリジルの群から選択される環をともに形成し得る。
H、メチル、エチル、プロピル、またはイソプロピルから選択されてもよく、
および残りの置換基のそれぞれ:R1、R2、R4、およびR5、またはR1、R2、およびR6、またはR1、R2、およびR6、またはR1およびR2、またはR1はそれぞれ独立して、
H;置換されていてもよいアルキル(例えば、酸素、ケイ素、硫黄でヘテロ置換されていてもよく、またはOH、O−アルキル、SH、S−アルキル、NH2、NH−アルキルで置換されていてもよいC1〜C12直鎖または分枝鎖アルキル);置換されていてもよいアルケニル(例えば、酸素、ケイ素、硫黄でヘテロ置換されていてもよく、またはOH、O−アルキル、SH、S−アルキル、NH2、NH−アルキルで置換されていてもよいC1〜C12直鎖または分枝鎖アルケニル);置換されていてもよいアルキニル(例えば、酸素、ケイ素、硫黄でヘテロ置換されていてもよく、またはOH、O−アルキル、SH、S−アルキル、NH2、NH−アルキルで置換されていてもよいC1〜C12直鎖または分枝鎖アルキニル);シクロアルキル(例えば、C3〜C7シクロアルキル);アルキルシクロアルキル(例えば、C4〜C12アルキルシクロアルキル);ヘテロシクロアルキル(例えば、該ヘテロ環が、O、S、またはNから選択される1つまたは2つのヘテロ原子を含み、C2〜C6ヘテロシクロアルキルが含まれる);アルキルヘテロシクロアルキル(例えば、該ヘテロ環が、O、S、またはNから選択される1つまたは2つのヘテロ原子を含み、C3〜C11アルキルヘテロシクロアルキルが含まれ、Nが複素環式環に存在するとき、窒素原子は、アミド、カルバミン酸塩、または尿素の形態であり得ることを含む);アリール(例えば、フェニル、置換フェニル、ナフチル、置換ナフチル);アルキルアリール(例えば、アルキルフェニル、アルキル置換フェニル、アルキルナフチル、アルキル置換ナフチル);ヘテロアリール(例えば、それらすべてが置換されていてもよい、ピリジル、フラニル、チオフェニル、ピロリル、オキサゾリル、イソオキサゾリル、チアゾリル、ジアゾリル、ピラゾリル、トリアゾリル);アルキルヘテロアリールから選択され、
あるいはR1およびR2は、それらが結合している窒素原子を含む3〜8員複素環式環をともに形成し得、
あるいはR4およびR5は、それらが結合している窒素原子を含む、アジリジン、ピロリル、イミダゾリル、ピラゾリル、インドリル、インドリニル、ピロリジニル、ピペラジニル、およびピペリジルの群から選択される環をともに形成し得る。
トリアゾール:
トリアジン:
ジヒドロトリアジン:
7環式ビグアナイド:
Aは、天然または非天然アミノ酸のプロトン化形態であり、
Bは、酸のジアニオンであり、
Cは、式Iの化合物のプロトン化形態である。
Aは、アラニン、アスパラギン酸、アスパラギン、アルギニン、グリシン、グルタミン、グルタミン酸リシン、フェニルアラニン、チロシン、セリン、スレオニン、トリプトファン、ロイシン、イソロイシン、ヒスチジン、メチオニン、プロリン、システイン、またはシスチンから選択される、天然アミノ酸のプロトン化形態であり、
Bは、シュウ酸、マロン酸、クエン酸、マレイン酸、フマル酸、酒石酸、アスパラギン酸、グルタミン酸等から選択される酸のジアニオンであり、かつ
Cは、式Iの化合物のプロトン化形態である。
メトホルミンを含む全身性ビグアナイドは腎臓によって実質的に排泄されると報告されているため、ビグアナイド化合物蓄積および乳酸アシドーシスの危険性は、腎機能の機能障害の度合いによって上昇する。メトホルミン等のビグアナイド化合物に対する他の禁忌には、乳酸排泄不全および低酸素状態が挙げられる。したがって、それらの禁忌を有する患者は、現在、従来のビグアナイド化合物で治療することはできない。
本発明の組成物および方法は、体重過多である、肥満、糖尿病前症、多嚢胞性卵巣症候群、脂質異常症、または脂質代謝の障害、ならびにインスリン依存(1型)もしくは非依存(2型)糖尿病等の高血糖状態、ならびに高血糖状態に関連するか、またはその結果である生理的状態もしくは障害を含む、代謝障害の治療および/または予防における有利な使用を発見する。このため、本発明の方法によって治療可能な高血糖状態はまた、慢性または急性高血糖(例えば、糖尿病)に関連する組織病理学的変化も含む。特定の例には、膵臓の変性(β細胞破壊)、腎臓細管石灰化、肝臓の変性、眼の損傷(糖尿病性網膜症)、糖尿病性足病変、口もしくは歯肉等の粘膜の潰瘍化、過剰な出血、遅延性血液凝固、または創傷治癒、ならびに冠動脈心疾患、脳卒中、末梢血管疾患、脂質異常症、高血圧症、および肥満症の危険性の上昇を含む。
本明細書に記載の化合物は、本明細書に記載の方法と組み合わせて、当業者に知られる標準の合成技術を使用して、または当該技術分野で既知の方法を使用して合成され得る。加えて、本明細書に提示される溶媒、温度、および他の反応状態は、当業者の習慣および知識によって異なり得る。
そのような化合物の類似体、塩、溶媒和化合物、多形体、水和物、N−酸化物、およびプロドラッグを含む、本開示のビグアナイド化合物は、肥満を含む様々な代謝障害、脂質異常症または脂質代謝の他の障害、ならびにII型糖尿病を含む高血糖症に関連付けられる高血糖状態および組織病理学的疾患を治療するために、それを必要とする対象に投与され得る。特に、本明細書で達成される全身性生物学的利用能および治療効果の驚くべき予想外の脱共役、ならびに毒性および安全性における結果的な改善を考慮して、そのような疾患および障害の予防および防止のためのそのような化合物の効果的な使用、ならびにより一般的な体重減少目的のための使用もまた明確に本明細書に企図される。
本明細書に記載の実施形態は、胃および近位小腸内での吸収を避け、Cmaxの急激な上昇に対応することによって、全身性生物学的利用能を最小化するために、小腸および/または腸管の下部、ならびに好ましくは遠位小腸の1つ以上の位置に送達されるように製剤化されるビグアナイド化合物(その任意の類似体、塩、溶媒和化合物、多形体、水和物、N−酸化物、またはプロドラッグを含む)を含む遅延放出組成物を投与することを含む治療方法を提供する。
上に記載されるように、本明細書で開示される方法は、禁忌となる患者におけるビグアナイド化合物の全身性生物学的利用能を最小化する。いくつかの実施形態において、ビグアナイド化合物は、平均全身性生物学的利用能を低下させた。低下された平均全身性生物学的利用能、いくつかの実施形態において、等量のビグアナイド化合物を有する即時放出または長時間放出製剤と比較して、より低い平均全身性生物学的利用能である。他の実施形態において、低下された平均全身性生物学的利用能は、平均全身性生物学的利用能が、等量のビグアナイド化合物を有する即時または長時間放出製剤と比較して、30%未満、25%未満、15%未満、10%未満、および5%未満の場合である。ある特定の実例では、平均全身性生物学的利用能は、15%未満である。
その全身性生物学的利用能を制限するために、ビグアナイド化合物を含む組成物は、血漿吸収を最小化する遅延放出用に適合される。腸内分泌細胞へのメトホルミン等のビグアナイド化合物の送達は、例えば、経口、直腸内、経鼻チューブ、腔内の腸管内注射等の非経口注射を含む、任意の既知の方法を介する。好ましい実施形態において、経口剤形が投与される。ビグアナイド化合物の経口送達は、遅延放出製剤の節に記載され、持効性放出系、腸溶コーティング、およびpH依存系等を含む。いくつかの実施形態において、本明細書に記載の化合物を含む組成物は、ビグアナイド化合物が、投与に続いて、十二指腸、空腸、回腸、腸管の下部、またはそれらの組み合わせ等の胃腸管のいくつかの場所に送達される場合、多成分系を利用する。例えば、ビグアナイド化合物を含む遅延放出製剤は、持効性、または遅延(腸内)放出成分の使用によって腸管の下部に送達することができる。そのような化合物の多成分系は、二重層もしくは三重層もしくは多層錠剤または被包性ミクロ錠剤、顆粒等のマルチ微粒子形状等の単位剤形、あるいは別々の剤形、例えば、同時にもしくは定期的な間隔で服用される別々の錠剤としてであってもよい。
放出の位置が全身性吸収を最小化するように制御される場合、遅延放出を得るために、多くのストラテジーが探究され得る。例えば、遅延放出は、製剤パラメーターおよび成分(例えば、適切な制御放出組成物およびコーティング)の適切な選択によって得ることができる。例には、単一または複数単位の錠剤またはカプセル組成物、油溶液、懸濁液、乳剤、マイクロカプセル、小球体、ナノ粒子、およびリポソームを含む。放出機構は、ビグアナイド化合物が定期的間隔で放出される、もしくは放出の位置が制御されるか、組み合わせ剤の放出が同時であり得るか、あるいは別の組み合わせ療法を他のものよりも早期放出することが好ましい場合、組み合わせにおけるビグアナイド化合物の遅延放出に影響し得るように、制御され得る。本明細書に記載の異なる送達系はまた、複数の間隔期間の開始で(例えば、経口投与後、約30分、約120分、約180分、および約240分)もしくは、異なる位置で(例えば、腸管の下部、腸管の上部、十二指腸、空腸、回腸、盲腸、結腸、および/または直腸における放出)、またはそれらの組み合わせで放出するように併用され得る。例えば、pH依存型系は、所望の放出特性を実現するために持効性放出系または本明細書に記載の任意の他の系と併用され得る。
1つの実施形態において、遅延放出機構は、投与に続いてある特定の時点で活性剤、例えばビグアナイド化合物を放出する「持効性」または経時的放出(「TR」)系である。持効性放出系は、当該技術分野でよく知られており、好適な持効性放出系には、任意の既知の賦形剤および/またはコーティングを含み得る。例えば、マトリックス、層、またはコーティング中の賦形剤は、環境中への活性薬剤の拡散を遅くすることによって活性薬剤の放出を遅延することができる。好適な持効性放出賦形剤には、アカシア(アラビアゴム)、寒天、ケイ酸マグネシウムアルミニウム、アルギン酸塩(アルギン酸ナトリウム)、ステアリン酸ナトリウム、ブラダーラック、ベントナイト、カルボマー、カラゲニン、Carbopol、セルロース、結晶セルロース、セラトニア、ツノマタ属、ブドウ糖、ファーセレラン、ゼラチン、ガティガム、グアーガム、ガラクトマンナン、ヘクトライト、ラクトース、スクロース、マルトデキストリン、マンニトール、ソルビトール、蜂蜜、トウモロコシデンプン、小麦デンプン、米デンプン、ジャガイモデンプン、ゼラチン、アラヤゴム、キサンタムガム(xanthum gum)、ベヘン酸グリセリル(例えば、Compritol 888 ato)、グリセリルジステアレート(例えば、Precirol ato 5)、ポリエチレングリコール(例えば、PEG 200−4500)、ポリエチレンオキシド、アジピン酸、トラガントガム、エチルセルロース(例えば、エチルセルロース100)、エチルヒドロキシエチルセルロース、エチルメチルセルロース、メチルセルロース、ヒドロキシエチルセルロース、ヒドロキシエチルメチルセルロース(例えば、KlOOLV、K4M、Kl5M)、ヒドロキシプロピルセルロース、ポリ(メタクリル酸ヒドロキシエチル)、酢酸セルロース(例えば、酢酸セルロースCA−398−10 NF)、酢酸フタル酸セルロース、酢酸プロピオン酸セルロース、酢酸酪酸セルロース、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、酪酸セルロース、硝酸セルロース、オキシポリゼラチン、ペクチン、ポリゲリン、ポビドン、炭酸プロピレン、ポリアンドライド(polyandride)、メチルビニルエーテル/無水マレイン酸コポリマー(PVM/MA)、ポリ(メトキシエチルメタクリル酸塩)、ポリ(メトキシエトキシメタクリル酸塩)、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム(CMC)、二酸化ケイ素、ビニルポリマー、例えば、ポリビニルピロリドン(PVP:ポビドン)、ポリ酢酸ビニル、もしくはポリ酢酸フタル酸ビニルおよび混合物、コリドンSR、アクリル誘導体(例えば、ポリアクリル酸塩、例えば、架橋ポリアクリル酸塩、メタクリル酸コポリマー)、Splenda(登録商標)(ブドウ糖、マルトデキストリン、およびスクラロース)、またはそれらの組み合わせが挙げられるが、これらに限定されない。持効性放出賦形剤は、活性薬剤とのマトリックス中、コーティングの一部として製剤の別の区画もしくは層の中、またはそれらの任意の組み合わせであり得る。様々な量の1つ以上の持効性放出賦形剤は、指定された放出時間を実現するために使用され得る。
製剤はまた、胃等の酸性環境において、活性剤、例えばビグアナイド化合物を分解から保護し、取り込みのための標的領域、例えば回腸内への遅延放出を可能にする、腸溶コーティングでコーティングされてもよい。
追加の実施形態において、ビグアナイド化合物送達を対象とする方法および組成物は、まとめて「修飾放出」製剤として知られる、制御、持続、または長時間放出製剤をさらに用いてもよい。組成物は、修飾放出系によって、または当業者に既知の送達デバイスによって投与され得る。例には、米国特許第3,845,770号、同第3,916,899号、同第3,536,809号、同第3,598,123号、同第4,008,719号、同第5,674,533号、同第5,059,595号、同第5,591,767号、同第5,120,548号、同第5,073,543号、同第5,639,476号、同第5,354,556号、および同第5,733,566号に記載されるものが挙げられるが、これらに限定されない。そのような剤形は、様々な割合で所望の放出特性を提供するように、例えば、ヒドロプロピルメチルセルロース、他の高分子マトリックス、ゲル、透過膜、浸透圧性系、多層コーティング、微小粒子、リポソーム、小球体、またはそれらの組み合わせを使用して、1つ以上の活性成分の修飾放出を提供するために使用され得る。本明細書に記載のものを含む当業者に既知の好適な修飾放出製剤は、本発明の活性成分との使用ために容易に選択され得る。本発明は、このため、修飾放出にさらに適合された錠剤、カプセル、ゲルキャップ、およびカプレット等であるが、これらに限定されない経口投与に適した単一の単位剤形を包含する。
主題の組成物および方法における使用に適した経口剤形には、錠剤、硬カプセル、ゼラチンで作られた押込嵌めカプセル、およびゼラチン、およびグリセロールまたはソルビトール等の可塑剤で作られた軟密封カプセル、ならびにトローチ、薬飴、水性または油性懸濁液、分散性粉末もしくは顆粒、乳剤、シロップ、またはエリキシル剤が挙げられる。好適な経口剤形は、薬学的組成物の製造者にとって当該技術分野で既知の任意の方法に従って調製されてもよく、そのような組成物は、薬剤的に洗練され味の良い調製を提供するために、非限定的な例として、甘味剤、香味剤、着色剤、および保存料剤から選択される1つ以上の薬剤を含有してもよい。
本明細書に記載の組成物または製剤のいずれかは、薬剤学において任意に一般的に使用される賦形剤を含み、所望の剤形の活性薬剤(複数可)および放出特性性質との適合性に基づいて選択される。賦形剤には、結合剤、注入剤、流動補助剤(flow aid)/滑剤、崩壊剤、潤滑剤、安定剤、界面活性剤等が挙げられるが、これらに限定されない。本明細書に記載の賦形剤の要旨は、例えば、Remington:The Science and Practice of Pharmacy,Nineteeth Ed(Easton,PA:Mack Publishing Company,1995)、Hoover,John E.,Remington's Pharmaceutical Sciences,(Easton,PA:Mack Publishing Co 1975)、Liberman,H.A.and Lachman,L.,Eds.,Pharmaceutical Dosage Forms(New York, NY: Marcel Decker 1980)、およびPharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed(Lippincott Williams&Wilkins 1999)で見ることができ、参照によりそれらの全体が本明細書に組み込まれる。
本明細書に記載の実施形態の組成物は、本明細書に記載の状態のいずれかの治療のための既知の療法を用いて同時投与され得る。同時投与はまた、既知の療法のより低い投薬量、本明細書に記載の組成物、または両方の必要性をもたらす、相加または相乗効果を提供する。同時投与のさらなる利益には、既知の療法のいずれかに関連付けられる毒性の低下が挙げられる。
糖尿病の治療の評価
糖尿病の態様における本発明のビグアナイド化合物治療の効果は、当該技術分野で既知の、および糖尿病の患者を治療する医師によって一般的に実施される方法に従って、評価され得る。
肥満症の治療において、患者における体重および/または脂肪が減少されることが望ましい。体重を減少するとは、患者が、一連の治療にわたって彼の/彼女の全体重の一部を減らすことを意味する(一連の治療は、数日間、数週間、数か月間、または数年間であり得る)。代替として、体重を減少することは、脂肪質量対除脂肪質量の比率における減少として定義され得る(言い換えると、全体重における低下と必ずしも一致せずに、患者は脂肪量を減らし、除脂肪量を維持したか、または増加した)。この実施形態において施される有効量のビグアナイド化合物治療は、その一連の治療にわたって患者の体重を減少させるのに有効な量、または代替として、その一連の治療にわたって患者の脂肪質量の割合を低下させるのに有効な量である。ある特定の実施形態において、患者の体重は、一連の治療にわたって、少なくとも約1%、少なくとも約5%、少なくとも約10%、少なくとも約15%、または少なくとも約20%減少される。代替として、患者の脂肪質量の割合は、一連の治療にわたって、少なくとも1%、少なくとも5%、少なくとも10%、少なくとも15%、少なくとも20%、または少なくとも25%低下される。
いくつかの実施形態において、患者は、本明細書に記載の方法を使用して、代謝ホルモンの発現を事前に評価される。このため、個人に提供される療法を彼または彼女の特定の必要性に標的化することができる。実施形態において、患者のホルモンプロファイルは事前に評価され、医師が影響することを望む変化に応じて、ある特定の決定された量の化合物/代謝産物の組み合わせが投与される。評価プロセスは、繰り返されてもよく、治療は、治療の間の、または治療に続く任意の時間に従って調整され得る。
実施形態において、GLP−1、GLP−2、GIP、オキシントモジュリン、PYY、CCK、グリセンチン(glycentin)、インスリン、グルカゴン、グレリン、アミリン、ウログアニリン、C−ペプチド、および/またはそれらの組み合わせが挙げられるが、これらに限定されない、本発明の方法に関連して検査されるホルモンのレベルは、本文献に記載される標準方法に従って検出される。例えば、タンパク質は、免疫学的アッセイによって、および転写産物は核酸増幅技術によって測定され得る。当該技術分野で説明される機能アッセイがまた、必要に応じて使用されてもよい。実施形態において、検査される試料は、培養細胞、患者の細胞もしくは組織試料、患者の体液、例えば、血液もしくは血漿等を含む。同様に、本発明の方法に関して検査される分析物(例えば、グルコース、トリグリセリド、HDL、LDL、apoB等)のレベルは、任意の既知の方法に従って検出される。
実施例1.1:材料および方法
母集団:25.0〜35.0kg/m2のBMIを有する18〜65歳のおよそ18人の適格な男性および女性対象を本研究において無作為化した。適格であるため、各対象はまた、以下の基準も満たした:(a)母乳哺育ではない;(b)陰性妊娠検査結果(ヒト絨毛性性腺刺激ホルモン、βサブユニット)を有する;(c)外科的に無菌である、閉経後である、または出産可能性がある場合、試験の全期間中、適切な受胎調節を実施する;(d)以下の状態:(i)肝臓疾患;(ii)腎臓疾患;(iii)胃腸管疾患;(iv)糖尿病を含む、内分泌障害;(v)心血管疾患;(vi)発作性障害;(vii)臓器移植;および(viii)慢性感染を含むが、これらに限定されない、臨床的に有意な異常のない身体検査を有する;ならびに(e)プロトコール要求を理解する能力およびそれを支持する意志。
メトホルミンDR製剤は、錠剤が遠位小腸のpH6.5領域に達するまでGI管での薬物の放出を遅らせるために、そこに追加コーティング(密封コーティングおよび腸溶コーティング)が適用される、500mgのメトホルミン塩酸塩を含有する、米国から供給される市販のフィルムコーティングされた即時放出錠剤であった。その錠剤は、それぞれが500mgのメトホルミン塩酸塩を含有する、白色で両凸の、円形状のコーティングされた錠剤であった。その市販の錠剤の不活性成分には、ポビドン、ステアリン酸マグネシウム、ヒプロメロース、およびポリエチレングリコールを含んだ。追加コーティング系中の不活性成分には、ヒプロメロース、トリアセチン、タルク、メタクリル酸コポリマー(Eudragit(登録商標)L30 D−55)、ポリ(アクリル酸メチル−コ−メタクリル酸メチル−コ−メタクリル酸)7:3:1(Eudragit(登録商標)FS 30 D)、ラウリル硫酸ナトリウム、ポリソルベート80、モノステアリン酸グリセリン、およびクエン酸トリエチルを含んだ。
来院2および4で、無作為化スキームに従って、非盲検の施設薬剤師または研究職員によって試験薬が調剤された。来院2および4の終了時に、その次の試験来院(来院3または5)に彼らが戻るまでの割り当てられた試験薬および自己投与の指示書を持たせて、対象を診療所から退院させた。
[1]直接的ではない質問を通して服薬遵守および有害事象を評価し、対象に用量を増加させることを思い出させるための電話
[2]対象が子宮摘出術を受けたことがあるか、または閉経後である場合を除き、すべての女性対象において必要とされる妊娠検査。
[3]来院2および4においてGLP−1、PYY、血漿グルコース、インスリン、およびトリグリセリド;来院3および5においてGLP−1、PYY、血漿グルコース、インスリン、トリグリセリド、およびメトホルミン。
来院2および来院4における食事負荷の後。来院3および来院5における4日目の午後の用量および5日目の午前の用量。
[1]PYY、GLP−1、血漿グルコース、インスリン、およびトリグリセリドのアセスメントのための採取時点あたり6−mLの総血液量。
[2]対象は、20分間以内に標準化された朝食を消費することを指示される。
[1]PYY、GLP−1、血漿グルコース、インスリン、およびトリグリセリドのアセスメントのための採取時点あたり6−mLの総血液量。
[2]対象は、20分間以内に標準化された朝食を消費することを指示される。
[3]メトホルミンのアセスメントのための採取時点あたり2−mLの総血液量。
表1、2、および3に提示されるスケジュールに従って、ならびに上に記載されるように血液試料を収集した。分析方法により、空腹時および食後の腸ホルモンGLP−1およびPYYの血漿濃度、ならびに血漿グルコース、インスリン、およびトリグリセリドの濃度を測定した。各来院からの血液試料を処理し、将来のさらなるホルモンの探索分析のため、−70℃で保管した。
表1、2、および3に提示されるスケジュールに従って、ならびに上に記載されるように、血液試料を収集した。分析方法によって血漿メトホルミン濃度を測定した。各来院からの血液試料を処理し、将来のさらなるホルモンの探索分析のため、−70℃で保管した。
前節の表1、2、および3に提示されるスケジュールに従って、試料を収集した。
化学アセスメントは、尿素窒素、クレアチニン、総タンパク質、アルブミン、尿酸、総ビリルビン、アルカリホスファターゼ、アラニンアミノトランスフェラーゼ、アスパラギン酸塩アミノトランスフェラーゼ、γグルタミルトランスペプチダーゼ、クレアチンホスホキナーゼ、グルコース、ナトリウム、カリウム、塩化物、重炭酸塩、リン、乳酸塩、およびカルシウム(または他の承認された通例の化学パネル)を含んだ。
血液学アセスメントは、赤血球数、ヘモグロビン、ヘマトクリット値、白血球数、血小板、微分計数、平均細胞容積、平均赤血球ヘモグロビン量、および平均赤血球ヘモグロビン濃度(または他の承認された通例の血液学アセスメント)を含んだ。
尿検査アセスメントは、pH、比重、グルコース、血液、ケトン、およびタンパク質(または他の承認された通例の尿検査)を含んだ。
出産ステータスを問わず、すべての女性対象(対象が、閉経期後であったか、または子宮摘出術を受けたことがあった場合を除く)は、妊娠検査のための血液または尿を提供した。陰性結果が得られない限り、試験薬を投与しなかった。
安全性に関するバイタルサインおよび他の観察における臨床的に有意な異常を、根本的な原因が診断されるか、または回復が生じるまで研究者によって経過観察し、必要に応じてさらなる検査で評価した。
バイタルサイン測定は、収縮期および拡張期血圧、心拍数、および体温の設定を含んだ。対象がおよそ5分間の休憩をした後、座位の対象においてバイタルサインを測定した。少なくとも30秒後血圧測定を繰り返し、2つの読み取りの平均を記録した。
試験設計および事象タイムラインが、図1〜2に示される。結果として得られる対象の処置および母集団(表4)ならびに対象18人の人口統計学的およびベースライン特徴(表5)が、以下の表4および5において示される。
標準プロトコールを使用して、2つの標準化された食事(t=0分に約500キロカロリーの標準化された朝食、およびt=300分に約1000キロカロリーの標準化された昼食)に応答して、およそ10時間にわたる循環PYY、GLP−1、グルコース、およびインスリン濃度上の各治療の効果に関して、対象を評価した。およそ11時間のサンプリング期間にわたってメトホルミン薬物動態もまた評価した。
メトホルミンDR製剤は、錠剤が遠位小腸のpH6.5領域に達するまでGI管での薬物の放出を遅らせるために、そこに追加コーティング(密封コーティングおよび腸溶コーティング)が適用された、500mgのメトホルミン塩酸塩を含有する、米国から供給される市販のフィルムコーティングされた即時放出錠剤であった。その錠剤は、それぞれが500mgのメトホルミン塩酸塩を含有する、白色で両凸の、円形状のコーティングされた錠剤である。その市販の錠剤の不活性成分には、ポビドン、ステアリン酸マグネシウム、ヒプロメロース、およびポリエチレングリコールを含んだ。追加のElcelyxコーティング系中の不活性成分には、ヒプロメロース、トリアセチン、タルク、メタクリル酸コポリマー(Eudragit(登録商標)L30 D−55)、ポリ(アクリル酸メチル−コ−メタクリル酸メチル−コ−メタクリル酸)7:3:1(Eudragit(登録商標)FS 30 D)、ラウリル硫酸ナトリウム、ポリソルベート80、モノステアリン酸グリセリン、およびクエン酸トリエチルを含んだ。
試験薬は、朝食および夕食の前に無傷の錠剤(丸ごと嚥下される)として経口的に水とともに投与された。対象は、研究施設職員によって1日目に提供された指示書に従って、1日目の午後から4日目の午前まで彼らの割り当てられた試験薬を自己投与した。各治療期間に対する試験薬の最後2回の用量(4日目の午後および5日目の午前)は、認定された研究施設職員によって対象に投与された。胃腸副作用を低減するために、すべての治療レジメンは、最初3回の用量に対して500mg/用量で治療を開始し、続いて残りの試験期間に対して無作為化された用量(500mg/用量、1000mg、または1500mg/用量)に増加した。研究施設職員は、直接的ではない質問を通して服薬遵守および有害事象を評価し、適切な場合、彼らに用量の増大を思い出させるため、各治療期間の投薬の2日目に電話で対象に連絡した。
薬物動態評価
薬物動態プロファイル
図8は、治療から5日目の平均血漿メトホルミン濃度および時点を示す。5日目のt=0におけるメトホルミンIRの投薬前平均濃度は350ng/mLであり、それは文献に公開される定常状態のトラフ濃度と一致した。t=−1分におけるメトホルミンIRの投与後、メトホルミンの濃度の急激な上昇があり、それは投薬の90分後に1249ng/mLのピークに達し、その後残りのサンプリング期間において安定した低下が続いた。
表7および図9は、5日目における治療によるメトホルミン対メトホルミンIRの相対的生物学的利用能を示す。メトホルミンIR製剤と比較して、t=0から試験薬投与後の最終濃度までのメトホルミン曝露(AUC0−t)は、1000mg メトホルミンDRで45.2%(54.8の%平均比率;p<0.0001)、および500mg メトホルミンDRで56.6%(43.4の%平均比率;p<0.0001)統計的に有意に低下された。メトホルミンIRと比較して、Cmaxはまた、1000mg メトホルミンDRで34.9%(65.1の%平均比率;p<0.0001)、および500mg メトホルミンDRで47.7%(52.3の%平均比率;p<0.0001)統計的に有意に低下された。
略号:NA=該当なし;t=用量投与後の最後の数量化濃度
注釈:対象内のCV%は、AUC0-tに対して24.2、Cmaxに対して26.3であった。
[1] (1000mg Met IR、1000mg Met DR、または500mg Met DR)/1000mg Met IR。
総PYY
図10および表8は、ベースラインおよび治療から5日目の平均血漿PYY総濃度プロファイル、ならびにそれぞれ、時点および対応する薬力学パラメーターの分析を示す。ベースライン血漿PYY総濃度は、ほとんどの時点において治療間で同様であった。加えて、すべてのメトホルミン治療は、AUC0−tおよび1.26〜1.55の範囲のCmaxに対するパーセント比率(5日目/1日目)とともに、PYY総曝露およびピーク濃度(すべてに対してp<0.01)を統計的に有意に増加した。空腹時血漿PYY総濃度はまた、各治療に対して5日目のベースラインから統計的に有意に上昇された(表9、すべてに対してp<0.01)。これらの結果は、試験された治療のすべてが、2つの標準化された食事に対して同様のPYY総反応を誘発したことを示す。
略号:BL=ベースライン(1日目);EOT=治療の終わり(5日目);geo.=幾何学;t=用量投与後の最後の数量化濃度
[1] 各治療のEOT(5日目)/BL(1日目)
図11および表10は、ベースラインおよび治療から5日目の平均血漿GLP−1活性濃度プロファイル、ならびにそれぞれ、時点および対応する薬力学パラメーターの分析を示す。ベースライン血漿GLP−1活性濃度は、ほとんどの時点において治療間で同様であった。加えて、すべてのメトホルミン治療は、AUC0−tおよび1.42〜1.88の範囲のCmaxに対するパーセント比率(5日目/1日目)とともに、GLP−1活性曝露およびピーク濃度(すべてに対してp<0.01)を統計的に有意に増加した。空腹時血漿GLP−1総濃度はまた、各治療に対して5日目のベースラインから統計的に有意に上昇された(表11、すべてに対してp<0.05)。これらの結果は、試験された治療のすべてが、2つの標準化された食事に対して同様のGLP−1活性反応を誘発したことを示す。
略号:BL=ベースライン(1日目);EOT=治療の終わり(5日目);geo.=幾何学;t=用量投与後の最後の数量化濃度
[1] 各治療のEOT(5日目)/BL(1日目)。
図12および表12は、ベースラインおよび治療から5日目の平均血漿グルコース濃度プロファイル、ならびにそれぞれ、時点および食事による対応する薬力学パラメーターの分析を示す。
略号:BL=ベースライン(1日目);EOT=治療の終わり(5日目);t=用量投与後の最後の数量化濃度。
[1] 各治療のEOT(5日目)/BL(1日目)。
略号:BL=ベースライン(1日目);EOT=治療の終わり(5日目);t=用量投与後の最後の数量化濃度。
[1] 各治療のEOT(5日目)/BL(1日目)。
表15および16は、それぞれベースラインおよび5日目のインスリンの薬力学パラメーター、ならびにベースラインおよび5日目の空腹時血漿インスリン濃度を示す。治療のいずれに対してもインスリン曝露、ピーク濃度、または空腹時濃度に統計的に有意な変化はなかった(すべてに対してp>0.05)。低循環グルコース濃度にもかかわらずインスリン濃度の維持は、インクレチン効果を示す。
略号:BL=ベースライン(1日目);EOT=治療の終わり(5日目);t=用量投与後の最後の数量化濃度。
[1] 各治療のEOT(5日目)/BL(1日目)。
表17は、SOC、基本語(preferred term)、および開始時点での最新治療による、治療により発現した有害事象を要約する。
メトホルミンIRによる眩暈および頭痛等の神経系障害もまた、DR投薬のいずれかよりも頻繁であった。全体的にみて、メトホルミンDRによる、メトホルミンIRよりも少ない胃腸および神経系障害有害事象が報告され、近位小腸を迂回することによって達成されたメトホルミンに対する低下された全身性曝露が、忍容性を改善したことを示す。
本試験において、1000mgの即時放出メトホルミン(メトホルミンIR)、500mgのメトホルミンDR、および1000mgのメトホルミンDR、または500mgのメトホルミンIRおよび1000mgのメトホルミンDRの組み合わせによるBID投薬(朝食前および夕食前)の5日目の定常状態である11時間にわたって、血漿中のメトホルミン濃度を測定した(図1)。すべての対象は2型糖尿病を有し、治療間に1週間の休薬を伴う無作為化クロスオーバー設計における各治療を受けた。
午前と午後の用量の間における薬物動態の差をより良く特徴づけるため、健常対象において夕食および朝食時に与えられる500および1000mgの用量のメトホルミンDRの36時間PKプロファイルを得るように実施例3の試験を設計した。対象はまた、別々の治療期間の間に、夕食および朝食とともに1000mgのメトホルミンIRを受け、夕食とともに2000mgのメトホルミン長時間放出(メトホルミンXR)を受けた。すべての対象は、治療間に1週間の休薬を伴う無作為化クロスオーバー設計における各治療を受けた。
SS:統計的に有意である(p値<0.0001)
治療A:1000mg メトホルミンIR BID(2x500mg メトホルミンHCl錠剤[即時放出])
治療B:500mg メトホルミンDR BID(1x500mg メトホルミンHCl錠剤[遅延放出pH6.5腸溶コーティング])
治療C:1000mg メトホルミンDR BID(2x500mg メトホルミン HCl錠剤[遅延放出pH6.5腸溶コーティング])
SS:統計的に有意である(p値<0.0001)
治療B:500mg メトホルミンDR BID(1x500mg メトホルミンHCl錠剤[遅延放出pH6.5腸溶コーティング])
治療C:1000mg メトホルミンDR BID(2x500mg メトホルミン HCl錠剤[遅延放出pH6.5腸溶コーティング])
治療D:2000mg メトホルミンXR QD(4x500mg メトホルミンHCl錠剤[長時間放出])
以下に、本発明の基本的な諸特徴および種々の態様を列挙する。
[1]
ビグアナイド投与の胃腸忍容性を改善する、および/またはビグアナイド投与から生じる胃腸合併症を低減する方法であって、治療的有効量のビグアナイド化合物を遅延放出製剤でそれを必要とする患者に投与することを含む、前記方法。
[2]
代謝障害の治療を必要とする患者におけるその治療方法であって、治療的有効量のビグアナイド化合物を遅延放出製剤で前記患者に投与することを含み、前記患者が前記ビグアナイド化合物に対する禁忌を有する、前記方法。
[3]
前記患者が、低酸素状態、乳酸排泄不全、および前記ビグアナイド化合物の排泄不全から成る群から選択される禁忌を有する、[2]に記載の方法。
[4]
前記患者が低酸素状態を有する、[3]に記載の方法。
[5]
前記患者が乳酸排泄不全を有する、[3]に記載の方法。
[6]
前記患者が前記ビグアナイド化合物の排泄不全を有する、[3]に記載の方法。
[7]
前記患者が、前記ビグアナイド化合物の排泄不全をもたらす中等度の腎機能障害、重度の腎機能障害、または末期の腎疾患を有する、[3]に記載の方法。
[8]
前記患者が慢性腎臓疾患を有する、[3]に記載の方法。
[9]
前記その方法を必要とする患者が高血糖症を有する、[1]〜[8]のいずれか一項に記載の方法。
[10]
前記高血糖症が慢性である、[9]に記載の方法。
[11]
前記高血糖症がII型糖尿病によって引き起こされる、[9]または[10]に記載の方法。
[12]
糖尿病を有する腎不全の対象を治療する方法であって、治療的有効量のビグアナイド化合物を遅延放出製剤で前記対象に投与することを含む、前記方法。
[13]
うっ血性心不全、低酸素状態、および/または進行した肝臓疾患を有する糖尿病の対象を治療する方法であって、治療的有効量のビグアナイド化合物を遅延放出製剤で前記対象に投与することを含む、前記方法。
[14]
糖尿病前症を有する対象における糖尿病の開始を低減する方法であって、治療的有効量のビグアナイド化合物を遅延放出製剤で前記対象に投与することを含む、前記方法。
[15]
対象において体重減少を誘発する方法であって、治療的有効量のビグアナイド化合物を遅延放出製剤で前記対象に投与することを含む、前記方法。
[16]
前記ビグアナイド化合物が、同量の前記ビグアナイド化合物を有する即時放出製剤と比較すると、前記遅延放出製剤において約40、50、または60%の低下された相対的生物学的利用能を有する、[1]〜[15]のいずれか一項に記載の方法。
[17]
前記投与は、前記製剤が500mgで1日2回投与されるとき、約14,000、13,000、または12,000ng*h/mL未満の平均血漿AUC 0〜36 を生成する、[1]〜[15]のいずれか一項に記載の方法。
[18]
前記投与は、前記製剤が500mgで1日2回投与されるとき、約800、700、または600ng/mL未満の平均C max を生成する、[1]〜[15]のいずれか一項に記載の方法。
[19]
前記ビグアナイド化合物が、小腸への送達に標的化され、前記製剤が、5.0または5.5以上のpHで腸溶性にコーティングされた経口剤形を含む、[1]〜[18]のいずれか一項に記載の方法。
[20]
前記ビグアナイド化合物が、遠位小腸への送達に標的化され、前記製剤が、6.0または6.5以上のpHで腸溶性にコーティングされた経口剤形を含む、[19]に記載の方法。
[21]
前記経口剤形が、前記ビグアナイド化合物の少なくとも一部分について修飾放出成分をさらに含む、[19]または[20]に記載の方法。
[22]
前記経口剤形が、500mg未満の前記ビグアナイド化合物を含む、[19]または[20]に記載の方法。
[23]
前記ビグアナイド化合物が、メトホルミン、フェンホルミン、ブホルミン、およびイメグリミンから成る群から選択される、[1]〜[22]のいずれか一項に記載の方法。
[24]
DPP−IV阻害剤の投与をさらに含む、[1]〜[23]のいずれか一項に記載の方法。
[25]
抗肥満または抗糖尿病薬の投与をさらに含む、[1]〜[24]のいずれか一項に記載の方法。
Claims (25)
- ビグアナイド投与の胃腸忍容性を改善する、および/またはビグアナイド投与から生じる胃腸合併症を低減する方法であって、治療的有効量のビグアナイド化合物を遅延放出製剤でそれを必要とする患者に投与することを含む、前記方法。
- 代謝障害の治療を必要とする患者におけるその治療方法であって、治療的有効量のビグアナイド化合物を遅延放出製剤で前記患者に投与することを含み、前記患者が前記ビグアナイド化合物に対する禁忌を有する、前記方法。
- 前記患者が、低酸素状態、乳酸排泄不全、および前記ビグアナイド化合物の排泄不全から成る群から選択される禁忌を有する、請求項2に記載の方法。
- 前記患者が低酸素状態を有する、請求項3に記載の方法。
- 前記患者が乳酸排泄不全を有する、請求項3に記載の方法。
- 前記患者が前記ビグアナイド化合物の排泄不全を有する、請求項3に記載の方法。
- 前記患者が、前記ビグアナイド化合物の排泄不全をもたらす中等度の腎機能障害、重度の腎機能障害、または末期の腎疾患を有する、請求項3に記載の方法。
- 前記患者が慢性腎臓疾患を有する、請求項3に記載の方法。
- 前記その方法を必要とする患者が高血糖症を有する、請求項1〜8のいずれか1項に記載の方法。
- 前記高血糖症が慢性である、請求項9に記載の方法。
- 前記高血糖症がII型糖尿病によって引き起こされる、請求項9または請求項10に記載の方法。
- 糖尿病を有する腎不全の対象を治療する方法であって、治療的有効量のビグアナイド化合物を遅延放出製剤で前記対象に投与することを含む、前記方法。
- うっ血性心不全、低酸素状態、および/または進行した肝臓疾患を有する糖尿病の対象を治療する方法であって、治療的有効量のビグアナイド化合物を遅延放出製剤で前記対象に投与することを含む、前記方法。
- 糖尿病前症を有する対象における糖尿病の開始を低減する方法であって、治療的有効量のビグアナイド化合物を遅延放出製剤で前記対象に投与することを含む、前記方法。
- 対象において体重減少を誘発する方法であって、治療的有効量のビグアナイド化合物を遅延放出製剤で前記対象に投与することを含む、前記方法。
- 前記ビグアナイド化合物が、同量の前記ビグアナイド化合物を有する即時放出製剤と比較すると、前記遅延放出製剤において約40、50、または60%の低下された相対的生物学的利用能を有する、請求項1〜15のいずれか1項に記載の方法。
- 前記投与は、前記製剤が500mgで1日2回投与されるとき、約14,000、13,000、または12,000ng*h/mL未満の平均血漿AUC0〜36を生成する、請求項1〜15のいずれか1項に記載の方法。
- 前記投与は、前記製剤が500mgで1日2回投与されるとき、約800、700、または600ng/mL未満の平均Cmaxを生成する、請求項1〜15のいずれか1項に記載の方法。
- 前記ビグアナイド化合物が、小腸への送達に標的化され、前記製剤が、5.0または5.5以上のpHで腸溶性にコーティングされた経口剤形を含む、請求項1〜18のいずれか1項に記載の方法。
- 前記ビグアナイド化合物が、遠位小腸への送達に標的化され、前記製剤が、6.0または6.5以上のpHで腸溶性にコーティングされた経口剤形を含む、請求項19に記載の方法。
- 前記経口剤形が、前記ビグアナイド化合物の少なくとも一部分について修飾放出成分をさらに含む、請求項19または20に記載の方法。
- 前記経口剤形が、500mg未満の前記ビグアナイド化合物を含む、請求項19または20に記載の方法。
- 前記ビグアナイド化合物が、メトホルミン、フェンホルミン、ブホルミン、およびイメグリミンから成る群から選択される、請求項1〜22のいずれか1項に記載の方法。
- DPP−IV阻害剤の投与をさらに含む、請求項1〜23のいずれか1項に記載の方法。
- 抗肥満または抗糖尿病薬の投与をさらに含む、請求項1〜24のいずれか1項に記載の方法。
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