JP2021165299A - 薬学的組成物、および1,2,4−オキサジアゾール安息香酸の塩 - Google Patents
薬学的組成物、および1,2,4−オキサジアゾール安息香酸の塩 Download PDFInfo
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Abstract
【解決手段】3−[5−(2−フルオロ−フェニル)−[1,2,4]オキサジアゾール−3−イル]安息香酸を含んでいる塩の形態、ならびにマグネシウム塩、カリウム塩、ナトリウム塩、トロメタミン塩、L−リジン塩、L−アルギニン塩、N−メチルグルカミン塩およびヒスチジン塩からなる群から選択される、塩、および、該塩の形態の有効量を、ナンセンス変異、すなわち未熟終結コドンと関連付けられている眼疾患を有している患者に投与することを包含している、ナンセンス変異、または未熟終結コドンと関連付けられている眼疾患を、処置するか、予防するか、または管理するための、方法を提供する。
【選択図】図1
Description
本明細書に使用されるとき、用語「未熟翻訳終結」は、アミノ酸に対応するコドンをストップコドンに変化させる変異の結果を指す。
薬学的組成物および本明細書に示されている塩の調製における使用のための化合物は、式(I):
本明細書に示されているのは、L−アルギニン、L−ヒスチジン、L−リジン、マグネシウムメトキシド、水酸化カリウム、水酸化ナトリウムまたはトロメタミンから選択される塩を包含している、化合物1の塩の形態である。より詳細には、化合物1の塩の形態は、L−リジン、ナトリウムまたはトロメタミンから選択される塩を包含している。本明細書に示されているのはまた、化合物1の塩の形態をインシチュに調製するための蒸発方法である。当該蒸発方法は、(1)塩の溶液および化合物1の溶液を混合する工程;(2)特定の温度におけるある流速を有しているガス流のもとに混合された溶液を蒸発させて、塩の形態を生じさせる工程;ならびに(3)塩を回収する工程を包含している。
一実施形態において、本明細書に示されているのは化合物1のマグネシウム塩である。
一実施形態において、本明細書に示されているのは化合物1のカリウム塩である。
一実施形態において、本明細書に示されているのは化合物1のナトリウム塩である。
一実施形態において、本明細書に示されているのは化合物1のトロメタミン塩である。
一実施形態において、本明細書に示されているのは化合物1のL−リジン塩である。
一実施形態において、本明細書に示されているのは、化合物1のL−アルギニン塩である。
一実施形態において、本明細書に示されているのは化合物1のL−ヒスチジン塩である。
有効量の化合物1を含んでいる薬学的組成物および単一の単位投与形態は、本明細書に示されている方法において使用され得る。個々の投与形態は、経口、経皮、粘膜(これらに限定されないが、眼、舌下、頬側、直腸、経鼻または経腟が挙げられる)、または非経口の投与(これらに限定されないが、皮下、筋肉内、静脈内、腹膜内、くも膜下腔内、脳室内、尿道内、胸骨内、頭蓋内、滑膜内、膀胱内、硝子体内、眼球内、角膜内または静脈内、ならびに類似の任意の他の注射手法または注入手法が挙げられる)に好適であり得る。好ましい薬学的組成物および単一の単位投与形態は、経口投与に好適である。一部の実施形態において、化合物は、出生前に経口的に(例えば、錠剤またはカプセル剤の投与形態において)投与され得る。一部の他の実施形態において、化合物1は、出生前に非経口的に(例えば静脈内の投与形態を介して)投与され得る。一部の実施形態において、化合物1は、局所的、経口的または非経口的に、出生後に投与され得る。一部の実施形態において、化合物1は、投与形態(例えば局所的な眼への投与形態(例えば局所的なゲル剤または点眼溶液剤))を用いて局所的に、出生前に投与され得る。
一部の実施形態において、化合物1を含んでいる、本明細書に示されている薬学的組成物は、出生後の局所投与のために調合されている。特定の実施形態において、本明細書に示されている薬学的組成物は、滅菌の等張性溶液(すなわち約3〜約8、約4〜約8(すなわち4.5)、約7〜8(すなわち7.4)のpH)として一般的に利用可能な、必要に応じて防腐剤をさらに含んでいる局所的な眼の溶液剤(点眼剤)として調合されている。
化合物1または薬学的に許容可能なその塩を、好適な薬剤を含んでいる層に担持している、眼の頂部に配置される眼科用パッチ、ならびに化合物1または薬学的に許容可能なその塩を含んでいる器具である、結膜嚢の下方または上方に配置される眼の挿入物の使用を包含している。
一部の実施形態において、本明細書に示されている薬学的組成物は、実母または代理に対して経口投与を介した出生前の送達のために調製されている。一部の実施形態において、本明細書に示されている、経口投与用の薬学的組成物は、経口投与のために、固体、半固体または液体の形態において提供される。また、本明細書に使用されるとき、経口投与としては、頬側投与、舌投与および舌下投与が挙げられる。好適な経口投与形態としては、錠剤、舌下フィルム剤もしくは頬側フィルム剤(すなわち速溶剤)、チュアブル錠、カプセル剤、丸薬、ストリップ剤、トローチ剤、ロゼンジ剤、芳香製剤、サシェ、ペレット剤、薬用のチューインガム、原末剤、発泡性もしくは非発泡性の粉剤もしくは顆粒剤、経口噴霧剤、溶液剤、乳剤、懸濁剤、オブラート剤、散剤、エリキシル剤およびシロップ剤が挙げられるが、これらに限定されない。活性成分に加えて、薬学的組成物は、1つ以上の薬学的に許容可能な担体または賦形剤(結合剤、充填剤、希釈剤、崩壊剤、湿潤剤、界面活性剤、潤滑剤、滑剤、pH調整剤、着色剤、色移り防止剤、甘味剤、香味剤、乳化剤、懸濁分散剤、防腐剤、溶媒、非水性液体、有機酸および二酸化炭素源が挙げられるが、これらに限定されない)を含み得る。
of Boston、MA)およびアスベストなしのタルクが挙げられるが、これらに限定されない。好適な着色剤としては、承認されている法定の(approved certified)、アルミナ水和物に懸濁されている水溶性のFD&C色素および非水溶性のFD&C色素、ならびに着色レーキ、ならびにこれらの混合物が挙げられるが、これらに限定されない。着色レーキは、色素の非水溶性の形態を生じる、重金属の含水酸素に対する水溶性色素の吸着による組合せである。好適な香味剤としては、植物(例えば果実)から抽出された天然の香料、および心地よい味覚を生じさせる化合物(例えば、ペパーミントおよびサリチル酸メチル)の合成ブレンドが挙げられるが、これらに限定されない。
本明細書に示されている、化合物1を含んでいる薬学的組成物は、注射、注入または埋め込みによって非経口的に、局所投与または全身投与のために投与され得る。本明細書に使用されるとき、非経口投与としては、静脈内、動脈内、腹腔内、くも膜下腔内、脳内、尿道内、胸骨内、頭蓋内、筋肉内、滑膜内、膀胱内および皮下への投与が挙げられる。
本明細書に示されているのは、約2μm〜約12μmの体積加重平均直径D(4,3)を有している、化合物1の形態である。また、本明細書に示されているのは、約1μm〜約3μmの表面加重平直径D(3,2)を有している、化合物1の形態である。さらに本明細書に示されているのは、約5μm〜約26μmの範囲におけるD90粒径を有しており、約1μm〜約6μmの範囲におけるD50粒径を有しており、約0.1μm〜約1.5μmの範囲におけるD10粒径を有している、化合物1の形態である。
本明細書に示されている薬学的組成物は、当業者によく知られている包装材料を用いた製造物として提供され得る。薬学的な包装材料の例としては、ブリスター包装、ボトル、チューブ、吸入器、ポンプ、袋、バイアル、容器、シリンジ、点眼器、ならびに投与および処置の、選択される製剤および目的とされている様式に好適な任意の包装材料が挙げられるが、これらに限定されない。
本明細書に示されているのは、未熟翻訳終結またはナンセンス変異依存mRNA分解期機構の修飾によって寛解される疾患を処置するため、予防するため、または管理するための方法である。当該方法は、本明細書に示されている薬学的組成物の有効量または本明細書に示されている3−[5−(2−フルオロ−フェニル)−[1,2,4]オキサジアゾール−3−イル]安息香酸の塩の有効量を、未熟翻訳終結またはナンセンス変異依存mRNA分解機構の修飾によって寛解される疾患を有している患者に、投与することを包含している。
化合物1の可溶性、pKaおよび化学構造に基づいて、以下の表1に挙げられている塩/共結晶の前駆物は、塩の調製のために同時に選択されている。
表2:選択された塩/共結晶の性質決定(用語「塩 番号」は、示されている型の第1の塩または第2の塩の形成を指す)
遊離酸およびそれぞれの塩/共結晶の前駆物のストック溶液を、選択された溶媒において調製した(濃度がmol/Lにおいて示され、用語「N/A」が特定のストック溶液が調製されなかったことを示す、表3を参照すればよい)。表3に挙げられているストック溶液に加えて、水に溶媒和されているL−アルギニン、L−ヒスチジン、L−リジン、水酸化カリウムおよび水酸化ナトリウムのストック溶液を、0.050mol/Lの濃度にそれぞれ調製した。
溶媒の第2の集合を、相平衡(スラリー)実験のために選択した。0.05mLの溶媒を、蒸発実験の残余物に加えた。MTP’sを、Eppendorf Thermo-Mixerにおいて3日にわたって室温において振とうさせた。溶媒を、室温におけるN2流(〜0.4L/分)のもとに除去した。生じた固体を、視認およびラマン顕微鏡によって調べた。
特に断りがない限り、表4に示されているすべての実験を、周囲の実験室条件のもとに実施した。Fluka、AldrichまたはABCRの分析等級溶媒を使用した。すべての溶媒(水を除く)を、使用前に3または4Åの孔径を有している分子ふるいに通して乾燥させた。
(6.1.マグネシウム塩1および2(Mg))
大規模化実験において、結晶性および非晶質の形態が認められた。
カリウム塩1を、THF/H2Oからの沈殿によって調製した。ラマンスペクトルは図3に示されている。図4におけるPXRDパターンは、部分的に結晶性のサンプルを示す。1H−NMR分析は、サンプルの化学的な完全性を確認した。
ナトリウム塩1を、MtOH/CH2Cl2からの蒸発によって調製した。ナトリウム塩1のラマンスペクトルが再現された(図5を参照すればよい)。図6におけるPXRDパターンは結晶性の塩を示す。1H−NMR分析は、サンプルの化学的な完全性を支持した。
トロメタミン塩1を、アセトン/MeOHからの蒸発によって調製した。ラマンスペクトルは図7に示されている。図8に示されているPXRDパターンは結晶性の形態を示す。1H−NMR分析は、トロメタミン、メタノールおよび微量の未知の不純物(例えば分解生成物)の存在下における化合物の遊離酸の化学的な完全性を確認した。サンプルが化合物1を含んでおり(1H−NMR)、トロメタミンは、さらなる成分の存在下において化学量論的な1:1の比率において存在しなかった(化合物1/0.5 TRO/0.5
MeOH/0.5 H2O)。DVSの結果は、試験されたサンプルにおける3%の全体の質量損失を示し、高い相対湿度におけるメタノールまたは水和物の形態の損失を示し、したがって、4%(メタノールの損失をともなう)、または2%(メタノールの損失および水による置換)の全体の質量損失に導く。
L−リジン塩1を、THF/H2Oからの蒸発によって首尾よく調製した。ラマンスペクトルは図11に示されている。図12におけるPXRDパターンは結晶性の塩を示す。1H−NMRはサンプルの化学的な完全性を支持した。
L−アルギニン塩を、EtOH/H2Oからの蒸発によって首尾よく調製した。L−アルギニン塩は図13に示されている。図14におけるPXRDパターンは結晶性の塩を示す。1H−NMR分析はサンプルの化学的な完全性を支持した。
L−ヒスチジン塩1を、THF/H2Oからの蒸発によって調製した。ラマンスペクトルは、Quick-Screenにおいて得られた基準のスペクトルと類似している(図15を参照すればよい)。図16に示されているPXRDパターンは、化合物1の形態AおよびL−ヒスチジンの混合物と同等である。
(7.1.FT−ラマン、PXRDおよび1H−NMR)
カリウム塩、ナトリウム塩、マグネシウム塩、L−リジン塩およびトロメタミン塩を、FT−ラマン、PXRDおよび1H−NMRによって性質決定した(項目10.を参照すればよい)。塩の形成、結晶性および化学的な完全性を確認した。塩のFT−ラマンスペクトルを、項目9.におけるDVSおよび水溶性決定の後に測定したスペクトルと比較した。また、「調製されたときの」サンプルおよび水における平衡の後の残余物のPXRDパターンを比較した。
選択されたサンプルの元素分析は一般的に、サンプルの分子式に適合する。L−リジン塩について、EMAは、単塩の存在を支持した(化学量論1:1、塩/共結晶前駆物:遊離酸)。カリウム塩の場合に、単塩の無水物がEMAによって観察された。これは、DVS測定と一致している。ナトリウム塩1について、EMAは、単塩につき1.5の水の水和物の形態を示した。これは、開始材料に水のないことを示したDVS測定による示唆より大きい。マグネシウム塩1について、EMAは、ヘミ塩(0.5:1、塩の前駆物:遊離酸)の4水和物が単塩の代わりに調製されたことを明らかにした。
DVS測定(50%→0%→95%→50%r.h.)を、カリウム塩1、ナトリウム塩1、トロメタミン塩1、L−リジン塩およびマグネシウム塩2のサンプルに対して実施した。
それぞれの塩を、水に懸濁させ、25℃および500rpmにおいて24時間にわたって振とうさせた。生じた懸濁物をろ過(0.1μmのフィルタ)した。得られた固体の残余物をFT−ラマンによって分析した。ろ過物のpHを測定し、遊離酸の濃度をHPLCによって決定した。値を表10に示す。マグネシウム塩2の可溶し得は顕著に低い。塩を、マグネシウム:遊離酸の化学量論1:1において、溶液から沈殿させた。ENAの結果は、0.5:1の化学量論(マグネシウム:遊離酸)を有しているヘミ塩に対応する。
目的:この試験の目的は、微粉化されている化合物1および微粉化されていない化合物1の可溶性を評価することである。可溶性試験を、2つの代表的な溶剤、pH1(0.5%のラウリル硫酸ナトリウムを有している0.1NのHCl)およびpH7.4(0.1Mのリン酸緩衝化食塩水)において実施した。
使用された実験材料:(1)微粉化されている化合物1;(2)微粉化されていない化合物1;(3)氷酢酸;(4)トリエチルアミン;(5)アセトニトリル、HPLC等級;(6)10mLのシリンジ;および(7)0.45μmのPTEEシリンジフィルタ。
放射線標識した化合物1(14C−3−[5−(2−フルオロ−フェニル)−[1,2,4]オキサジアゾール−3イル]安息香酸)の、スピローグダウリーラットおよびロングエバンスラットに対する単回用量投与の後における、種々の組織(眼が挙げられる)における化合物1/代謝物の濃度を評価するために、2回の試験を実施した。
化合物1は、マウスPAX6遺伝子における天然に存在するナンセンス変異を含んでいる、Gregory-Evansによって開発された無虹彩のマウスモデル(不完全優性の小さな眼のモデル(PAXSey+/−))における角膜、水晶体および網膜における、疾患の進行を阻害し、先天性奇形を無効にした。
Claims (8)
- 3−[5−(2−フルオロ−フェニル)−[1,2,4]オキサジアゾール−3−イル]安息香酸を含んでいる塩の形態、ならびにマグネシウム塩、カリウム塩、ナトリウム塩、トロメタミン塩、L−リジン塩、L−アルギニン塩、N−メチルグルカミン塩およびヒスチジン塩からなる群から選択される、塩。
- 上記塩は、トロメタミン塩およびL−リジン塩からなる群から選択される、請求項1に記載の塩の形態。
- 請求項1に記載の塩の形態の有効量を含んでいる、薬学的組成物。
- 眼への投与に好適である、請求項3に記載の薬学的組成物。
- 請求項1に記載の塩の形態の有効量を、ナンセンス変異、すなわち未熟終結コドンと関連付けられている眼疾患を有している患者に投与することを包含している、ナンセンス変異、または未熟終結コドンと関連付けられている眼疾患を、処置するか、予防するか、または管理するための、方法。
- 上記眼疾患が、無虹彩、先天性脈絡膜欠如、網膜欠損症症候群、レーバー先天性黒内障、網膜色素変性症、バルデー−ビードル症候群、緑内障、中心窩形成不全、白内障、アッシャー症候群、中枢性聴覚処理障害、脈絡網膜変性症、先天性の水晶体混濁、高眼圧、滲出性の血管網膜症、緑内障、虹彩形成不全、角膜症(角膜変性症)、視神経形成不全、網膜剥離、続発性の斜視、および水晶体血管膜からなる群から選択される、請求項5に記載の方法。
- 請求項3に記載の薬学的組成物の有効量を、ナンセンス変異、すなわち未熟終結コドンと関連付けられている眼疾患を有している患者に投与することを包含している、ナンセンス変異、または未熟終結コドンと関連付けられている眼疾患を、処置するか、予防するか、または管理するための、方法。
- 上記眼疾患が、無虹彩、先天性脈絡膜欠如、網膜欠損症症候群、レーバー先天性黒内障、網膜色素変性症、バルデー−ビードル症候群、緑内障、中心窩形成不全、白内障、アッシャー症候群、中枢性聴覚処理障害、脈絡網膜変性症、先天性の水晶体混濁、高眼圧、滲出性の血管網膜症、緑内障、虹彩形成不全、角膜症(角膜変性症)、視神経形成不全、網膜剥離、続発性の斜視、および水晶体血管膜からなる群から選択される、請求項7に記載の方法。
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EP3113619A4 (en) | 2017-09-13 |
EA032779B1 (ru) | 2019-07-31 |
JP2017507158A (ja) | 2017-03-16 |
IL247653A0 (en) | 2016-11-30 |
US20180179170A1 (en) | 2018-06-28 |
TW201836605A (zh) | 2018-10-16 |
CN112979574A (zh) | 2021-06-18 |
US9873677B2 (en) | 2018-01-23 |
CN112979575A (zh) | 2021-06-18 |
KR20230024431A (ko) | 2023-02-20 |
TWI695717B (zh) | 2020-06-11 |
JP7335795B2 (ja) | 2023-08-30 |
KR102497273B1 (ko) | 2023-02-07 |
CA2942147C (en) | 2022-12-13 |
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