JP2022106971A - ペプチドエポキシケトン免疫プロテアソーム阻害剤の結晶塩 - Google Patents
ペプチドエポキシケトン免疫プロテアソーム阻害剤の結晶塩 Download PDFInfo
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Abstract
Description
、(式中、X-は対イオンである)。いくつかの実施形態において、X-は、マレイン酸イオン、フマル酸イオン、シュウ酸イオン、リンゴ酸イオン、硫酸イオン、メタンスルホン酸イオン、2-ナフタレンスルホン酸イオン、リン酸イオン、ハロゲン化物イオン、酒石酸イオン、クエン酸イオン、トシラートイオン、プロピオン酸イオン、および/または安息香酸イオンを含む。種々の場合において、塩は塩水和物である。
一態様において、本開示は、以下の構造を有する化合物Gの結晶塩を提供する
が挙げられる。いくつかの実施形態において、Xはジアニオン(X2-)であり得る。これらの実施形態において、架橋塩は、化合物Gの2つの分子の各々とイオン結合を形成するX2-の1つの分子と形成することができる。
いくつかの実施形態において、X-はマレイン酸イオンである。これらの実施形態において、化合物Gの結晶塩はモノマレイン酸塩(下に示す)であり得る。化合物Gのモノマレイン酸塩は、586.7g/molの分子量、5のpKaを有し、白色から黄色の固体として見える。化合物Gのモノマレイン酸塩は、100mg/mlを超える高い水溶解度を示す。そのような高い溶解度は、形態Aを非経口医薬組成物において高濃度で使用することを可能にするため有利である。
いくつかの実施形態において、X-はフマル酸イオンである。これらの実施形態において、化合物Gの結晶塩はモノフマル酸塩(下に示す)であり得る。化合物Gのモノフマル酸塩の特定の結晶形は形態Gである。
いくつかの実施形態において、X-はシュウ酸イオンである。場合によっては、化合物Gの結晶塩はモノシュウ酸塩であり得る。種々の場合において、シュウ酸イオンは2つの異なる化合物G分子上のモルホリノ基と反応して架橋塩を形成する。化合物Gのシュウ酸塩は、方法の項に後述するパラメータ(例えば、XRPD、DSC、TGA、および/またはDVS)のうちの1つ以上によって特徴付けることができる。
いくつかの実施形態において、X-はリンゴ酸イオンである。場合によっては、化合物Gの結晶塩はモノリンゴ酸塩であり得る。種々の場合において、リンゴ酸イオンは2つの異なる化合物G分子上のモルホリノ基と反応して架橋塩を形成する。化合物Gのリンゴ酸塩は、方法の項に後述するパラメータ(例えば、XRPD、DSC、TGA、および/またはDVS)のうちの1つ以上によって特徴付けることができる。
いくつかの実施形態において、X-は硫酸イオンである。化合物Gの硫酸塩は、方法の項に後述するパラメータ(例えば、XRPD、DSC、TGA、および/またはDVS)のうちの1つ以上によって特徴付けることができる。
いくつかの実施形態において、X-はメタンスルホン酸イオンである。化合物Gのメタンスルホン酸塩は、方法の項に後述するパラメータ(例えば、XRPD、DSC、TGA、および/またはDVS)のうちの1つ以上によって特徴付けることができる。
いくつかの実施形態において、X-は2-ナフタレンスルホン酸イオンである。化合物Gの2-ナフタレンスルホン酸塩は、方法の項に後述するパラメータ(例えば、XRPD、DSC、TGA、および/またはDVS)のうちの1つ以上によって特徴付けることができる。
いくつかの実施形態において、X-はリン酸イオンである。化合物Gのリン酸塩は、方法の項に後述するパラメータ(例えば、XRPD、DSC、TGA、および/またはDVS)のうちの1つ以上によって特徴付けることができる。
いくつかの実施形態において、X-はハロゲン化物(例えば、塩化物、臭化物、ヨウ化物、フッ化物)イオンである。化合物Gのハロゲン化物塩は、方法の項に後述するパラメータ(例えば、XRPD、DSC、TGA、および/またはDVS)のうちの1つ以上によって特徴付けることができる。
いくつかの実施形態において、X-は酒石酸イオンである。化合物Gの酒石酸塩は、方法の項に後述するパラメータ(例えば、XRPD、DSC、TGA、および/またはDVS)のうちの1つ以上によって特徴付けることができる。
いくつかの実施形態において、X-はクエン酸イオンである。化合物Gのクエン酸塩は、方法の項に後述するパラメータ(例えば、XRPD、DSC、TGA、および/またはDVS)のうちの1つ以上によって特徴付けることができる。
いくつかの実施形態において、X-はトシラートイオンである。化合物Gのトシル酸塩は、方法の項に後述するパラメータ(例えば、XRPD、DSC、TGA、および/またはDVS)のうちの1つ以上によって特徴付けることができる。
いくつかの実施形態において、X-はプロピオン酸イオンである。化合物Gのプロピオン酸塩は、方法の項に後述するパラメータ(例えば、XRPD、DSC、TGA、および/またはDVS)のうちの1つ以上によって特徴付けることができる。
いくつかの実施形態において、X-は安息香酸イオンである。化合物Gの安息香酸塩は、方法の項に後述するパラメータ(例えば、XRPD、DSC、TGA、および/またはDVS)のうちの1つ以上によって特徴付けることができる。
いくつかの実施形態において、本開示は、化合物Gの塩水和物、または化合物Gの遊離塩基一水和物を提供する。化合物Gの塩水和物または遊離塩基一水和物は、結晶性であり得、方法の項に後述するパラメータ(例えば、XRPD、DSC、TGA、および/またはDVS)のうちの1つ以上によって特徴付けることができる。
化合物Gの結晶塩、水和物、および塩水和物は、結晶分野で既知の様々な方法で形成することができる。化合物Gの結晶塩に関する以下の議論は、結晶塩水和物の形成、および遊離塩基化合物Gの結晶水和物に適用することができる。
本開示の別の態様は、本明細書に記載の結晶塩と、1つ以上の薬学的に許容される賦形剤とを含む医薬組成物(あるいは全体を通して製剤と呼ばれる)を提供する。「薬学的に許容される」という表現は、健全な医学的判断の範囲において、過剰な毒性、刺激、アレルギー反応、または他の問題もしくは合併症のない、妥当な利益/リスク比に見合った、ヒトおよび動物の組織と接触させて使用するのに適したリガンド、材料、組成物および/または剤形を指すために本明細書で用いられる。本明細書に記載の組成物は、任意の投与形態用に製剤化することができる。
本明細書に開示される結晶塩は、免疫プロテアソーム(iP)の阻害剤として作用することができる。場合によっては、本明細書に開示される結晶塩は、iPサブユニットLMP7を阻害する。LMP7の活性は、実施例に後述するようなプロテアソームサブユニットアッセイにおいて測定した場合、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%、または少なくとも80%阻害され得る。1つ以上のさらなるiPサブユニットが、LMP2、MECL-1、β1、β2、およびβ5等の本明細書に開示される結晶塩によって阻害され得る。種々の実施形態において、本明細書に開示される結晶塩は、LMP7ならびにLMP2およびMECL-1の一方または両方を阻害する。本明細書に開示される化合物は、サイトカインの活性または発現、例えばIL-2、MHC-I、IL-6、TNFα、およびIFN-βのうちの1つ以上を減少させることができる。したがって、本明細書に開示される化合物がIL-2、MHC-I、IL-6、TNFα、およびIFN-βのうちの1つ以上の発現または活性を少なくとも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%、または少なくとも80%阻害する方法が提供される。
粉末X線回折(「XRPD」)データは、PANalytical X’Pert3 X線(図1、21、および22~27)、Shimadzu XRD-7000(図5)、またはBruker D8Advance粉末X線回析計(図1、9、11、13~15、および19)で得られた。CuKα線(1.54Å)を用いて40kVおよび40mAで、0.02°のステップサイズで4~40°(2θ)から連続モードで試料を走査した(図1)。CuKα線(1.54Å)を用いて45kVおよび40mAで、0.013°のステップサイズで3~40°(2θ)から連続モードで試料を走査した(図21および23~27)。CuKα線(1.54Å)を用いて40kVおよび35mAで、0.02°のステップサイズで5~70°(2θ)から連続モードで試料を走査した(図5)。CuKα線(1.54Å)を用いて40kVおよび40mAで、0.02°のステップサイズで3~40°(2θ)から連続モードで試料を走査した(図1、9、11、13~15、および19)。
化合物Gを、それぞれ6つの異なる溶媒系中で6つの異なる酸と反応させ(合計36回のスクリーニング実験)、化合物Gの結晶塩が形成され得るかどうかを判定した。
化合物G(20mg、140μLの溶媒に予め溶解したもの)に1当量の酸(溶媒中40~240μLに予め溶解したもの)を加え、混合物を密封バイアル中で96時間にわたって放置した。以下の溶媒を用いた:トルエン、エタノール、メタノール、イソプロパノール、ヘキサン/酢酸エチル(1:1)、1,4-ジオキサン、アセトニトリル、1-ブタノール、酢酸エチル、アセトン、MTBE/酢酸エチル(1:1)、およびジエチルエーテル/酢酸エチル(1:1)。以下の酸を利用した:硫酸、メタンスルホン酸、トシル酸(一水和物)、2-ナフタレンスルホン酸、L-リンゴ酸、プロピオン酸、安息香酸、シュウ酸、およびリン酸。表4に示される組み合わせで固体沈殿物が観察された。
化合物Gのモノマレイン酸塩形態の調製は以下のようにスケールアップした。両方の出発材料を秤量してガラスバイアルに入れることにより、化合物G(約200mg)を1:1または1:2のモル比でマレイン酸と反応させた。一定体積のMTBEまたはアセトンを各ガラスバイアルに加え、得られた懸濁液を磁気プレート上で撹拌した。次いで、懸濁液を室温で真空乾燥させて形態Bを得た。
異なる乾燥条件(空気乾燥、真空乾燥、湿度サイクル)を用いて形態A(EtOAcから結晶化)を処理した。得られた結晶塩は、XRPD(図25および26)、DSC、およびTGAによって特徴付けを行った。真空乾燥後のマレイン酸塩も、1H NMRによって特徴付けを行い、遊離塩基/マレイン酸の化学量論を決定した。図26のXRPDの結果は、異なる乾燥条件下で全ての試料が同じ回折パターンを有していたことを示している。図4に示すように、動的蒸気収着試験(DVS)もまた、EtOAcからの形態Aを特徴付けるために適用された。これらの実験についての特徴付けデータを表6に要約する。
手順1:酢酸イソプロピル/エタノールを用いた化合物Gのモノマレイン酸塩の調製
化合物G(37.88kgのIPAc中3.6kg)にEtOH(11.5kg)を加えた。得られた溶液を50℃に加熱し、マレイン酸(EtOH中12.4重量%の溶液1.62kg)を15分で加え、続いて所望の化合物の種晶(18.0g)を加えた。懸濁液を50℃で0.5時間撹拌し、マレイン酸(EtOH中13.4重量%の溶液4.90kg)を3時間かけて加えた。混合物を50℃で4時間撹拌し、9.5時間かけて-3℃に冷却し、-2~3℃で2時間維持し、濾過し、-5~5℃のIPAc/EtOH(2:1、12.0kg)で洗浄した。湿潤ケーキを40~45℃で17時間真空乾燥させ、化合物Gのモノマレイン酸塩(3.86kg、純度99.0%)を得た。
形態A(3.56kg)に、15~25℃のIPAc(37.8kg)を加え、続いて3.5%NaHCO3(37.8kg)を加え、得られた懸濁液を1時間撹拌して溶液を得た。水層を除去し、有機層を15~25℃の5%Na2SO4(水溶液、36.9kg)で洗浄した。水層を除去し、有機層を45℃未満で4~7Lに濃縮した。有機層を15~25℃で酢酸エチル(32.0kg)で3回チェイスし、溶液を45℃未満で約7~11Lに濃縮した。次いで、酢酸エチル(28.8kg)を加え、溶液を45~55℃に加熱した。マレイン酸(720g)を19.4kgの酢酸エチルに溶解し、この溶液の1/10を45~55℃で30分かけて加えた。種晶(9.09g)を45~55℃で加え、混合物を30分間撹拌した。残りのマレイン酸溶液を45~55℃で1時間かけて加えた。混合物を45~55℃でさらに2時間撹拌し、次いで8時間かけて1℃に冷却した。混合物を-5~5℃で1時間撹拌し、次いで濾過し、酢酸エチル(13.0kg)で洗浄し、真空下40~50℃で26~28時間乾燥させて、3.42kgのマレイン酸塩(純度99.1%)を無色の固体として得た。XRPDパターンを図1に示し、特徴的なDSCデータを図2に示し、TGAデータを図3に示す。
THF(0.5mL)中の化合物G(100mg、0.170mmol)に、THF(0.5mL)中のマレイン酸0.085mmol、9.9mg)を加えた。混合物を一晩放置し、濾過して化合物Gのモノマレイン酸塩(50.5mg)を無色の固体として得た。
形態A(0.05g、0.0852mmol)にエタノール(0.5mL)を加え、溶液を5分間加熱還流し、一晩で20℃に冷却した。精製した化合物を無色の固体として単離した(42mg)。
表7に記載されるように、形態Aを45mg/mlの濃度で皮下投与用に製剤化した。各製剤を約3mg/kgの単回皮下用量としてカニクイザル(雄3匹/用量)に投与したときの形態Aのパーセントバイオアベイラビリティ(%F)も表7に見出すことができる。
方法A:約30mgの化合物Gを表8に示す溶媒に加え、次いで、50℃で700rpmの速度で振盪した。化合物の残渣を遠心分離(9,000rpmで5分間)により分離し、7日後に、表8および図7~13に示すように、XRPD、DSC、およびTGAによって調べた。
手順:2gの化合物Gをアセトン(20mL)中3%の水に加え、次いで50℃で700rpmの速度で一晩振盪した。残渣をXRPD、DSC、およびTGAによって調べた。
形態Aおよびその遊離塩基の安定性を、周囲条件(25℃および40%相対湿度「RH」)、ならびに高温および高湿度(40℃および75%RH)で1ヶ月の期間にわたって試験した。遊離塩基形態は、高温および高湿度で急速な分解を示した。しかしながら、同じ条件でかつ同じ期間にわたって、形態Aには有意な変化は観察されなかった。下の表10を参照されたい。したがって、形態Aは、その遊離塩基よりも安定性が高い。
Claims (88)
- X-は、マレイン酸イオン、フマル酸イオン、シュウ酸イオン、リンゴ酸イオン、硫酸イオン、メタンスルホン酸イオン、2-ナフタレンスルホン酸イオン、リン酸イオン、ハロゲン化物イオン、酒石酸イオン、クエン酸イオン、トシラートイオン、プロピオン酸イオン、または安息香酸イオンを含む、請求項1に記載の結晶塩。
- 塩水和物としての、請求項1または2に記載の結晶塩。
- X-はマレイン酸イオンを含む、請求項2または3に記載の結晶塩。
- 前記結晶塩はモノマレイン酸塩である、請求項4に記載の結晶塩。
- 約6.9、17.3、および17.8±0.2°2θにピークを含む、CuKα線を用いた粉末X線回折(「XRPD」)パターンを有する、請求項4または5に記載の結晶塩(「形態A」)。
- CuKα線を用いて、約4.9、6.8、および7.7±0.2°2θにピークをさらに含む、請求項6に記載の結晶塩。
- CuKα線を用いて、約10.9、12.4、13.5、14.2、16.1、16.4、18.5、21.0、22.0、23.4、23.7、24.5、および25.2±0.2°2θにピークをさらに含む、請求項7に記載の結晶塩。
- 実質的に図1に示すようなXRPDパターンを有する、請求項4~8のいずれか一項に記載の結晶塩。
- 実質的に図2に示すような示差走査熱量測定(「DSC」)サーモグラムを有する、請求項4~9のいずれか一項に記載の結晶塩。
- 約7.2、18.4、および22.0±0.2°2θにピークを含む、CuKα線を用いたXRPDパターンを有する、請求項4または5に記載の結晶塩(「形態B」)。
- CuKα線を用いて、約6.8、6.6、13.6、22.0、17.4、14.5、18.0、および5.0±0.2°2θにピークをさらに含む、請求項11に記載の結晶塩。
- 実質的に図13に示すようなXRPDパターンを有する、請求項4~5または11~12のいずれか一項に記載の結晶塩。
- 実質的に図16に示すようなDSCサーモグラムを有する、請求項4~5または11~13のいずれか一項に記載の結晶塩。
- 約7.4、13.2、および20.1±0.2°2θにピークを含む、CuKα線を用いたXRPDパターンを有する、請求項4または5に記載の結晶塩(「形態C」)。
- CuKα線を用いて、約6.6、13.6、6.9、16.9、3.7、17.9、および19.9±0.2°2θにピークをさらに含む、請求項15に記載の結晶塩。
- 実質的に図7に示すようなXRPDパターンを有する、請求項4~5または15~16のいずれか一項に記載の結晶塩。
- 実質的に図8に示すようなDSCサーモグラムを有する、請求項4~5または15~17のいずれか一項に記載の結晶塩。
- 約4.9、7.7、10.9、12.4、13.6、および15.3±0.2°2θにピークを含む、CuKα線を用いたXRPDパターンを有する、請求項4または5に記載の結晶塩(「形態D」)。
- CuKα線を用いて、約6.8、17.4、3.4、ならびに17.7および±0.2°2θにピークをさらに含む、請求項19に記載の結晶塩。
- 実質的に図9に示すようなXRPDパターンを有する、請求項4~5または19~20のいずれか一項に記載の結晶塩。
- 実質的に図10に示すようなDSCサーモグラムを有する、請求項4~5または19~21のいずれか一項に記載の結晶塩。
- 約6.4、7.3、および19.8±0.2°2θにピークを含む、CuKα線を用いたXRPDパターンを有する、請求項4または5に記載の結晶塩(「形態E」)。
- CuKα線を用いて、約3.3、6.8、16.5、12.1、21.5、4.0、ならびに13.0および±0.2°2θにピークをさらに含む、請求項23に記載の結晶塩。
- 実質的に図11に示すようなXRPDパターンを有する、請求項4~5または23~24のいずれか一項に記載の結晶塩。
- 実質的に図12に示すようなDSCサーモグラムを有する、請求項4~5または23~25のいずれか一項に記載の結晶塩。
- 約6.3、19.0、および19.6±0.2°2θにピークを含む、CuKα線を用いたXRPDパターンを有する、請求項4または5に記載の結晶塩(「形態F」)。
- CuKα線を用いて、約7.1、17.5、17.9、22.0、13.5、18.2、ならびに15.5および±0.2°2θにピークをさらに含む、請求項27に記載の結晶塩。
- 実質的に図19に示すようなXRPDパターンを有する、請求項4~5または27~28のいずれか一項に記載の結晶塩。
- 実質的に図20に示すようなDSCサーモグラムを有する、請求項4~5または27~29のいずれか一項に記載の結晶塩。
- X-はフマル酸イオンを含む、請求項2または3に記載の結晶塩。
- 前記結晶塩はモノフマル酸塩である、請求項31に記載の結晶塩。
- 約6.4、7.2、13.8、16.0、17.4、18.5、18.7、20.0、20.9、21.9、24.5、および25.8±0.2°2θにピークを含む、CuKα線を用いたXRPDパターンを有する、請求項31または32に記載の結晶塩(「形態G」)。
- 実質的に図21に示すようなXRPDパターンを有する、請求項31~33のいずれか一項に記載の結晶塩。
- 実質的に図22に示すようなDSCサーモグラムを有する、請求項31~34のいずれか一項に記載の結晶塩。
- X-はシュウ酸イオンを含む、請求項2または3に記載の結晶塩。
- X-はリンゴ酸イオンを含む、請求項2または3に記載の結晶塩。
- X-は硫酸イオンを含む、請求項2または3に記載の結晶塩。
- X-はメタンスルホン酸イオンを含む、請求項2または3に記載の結晶塩。
- X-は2-ナフタレンスルホン酸イオンを含む、請求項2または3に記載の結晶塩。
- X-はリン酸イオンを含む、請求項2または3に記載の結晶塩。
- X-はハロゲン化物イオンを含む、請求項2または3に記載の結晶塩。
- X-は酒石酸イオンを含む、請求項2または3に記載の結晶塩。
- X-はクエン酸イオンを含む、請求項2または3に記載の結晶塩。
- X-はトシラートイオンを含む、請求項2または3に記載の結晶塩。
- X-はプロピオン酸イオンを含む、請求項2または3に記載の結晶塩。
- X-は安息香酸イオンを含む、請求項2または3に記載の結晶塩。
- 化合物Gとマレイン酸とのモル比は、約1:0.5~1:2の範囲である、請求項48に記載の方法。
- 前記モル比は1:1である、請求項49に記載の方法。
- 前記溶媒は、メタノール(「MeOH」)、エタノール(「EtOH」)、イソプロパノール(「IPA」)、酢酸エチル(「EtOAc」)、酢酸イソプロピル(「IPAc」)、テトラヒドロフラン(「THF」)、メチルtert-ブチルエーテル(「MTBE」)、アセトン/n-ヘプタン、アセトン、ジエチルエーテル(「Et2O」)/EtOAc、ヘキサン/EtOAc、MTBE/EtOAc、トルエン、1,4-ジオキサン、アセトニトリル(「ACN」)、1-ブタノール、上記の水性混合物、およびそれらの組み合わせからなる群から選択される、請求項48~50のいずれか一項に記載の方法。
- 前記溶媒は、EtOAc、IPAc、EtOH、それらの水性混合物、またはそれらの組み合わせを含む、請求項51に記載の方法。
- 前記混合は、0℃~80℃の範囲の温度で行われる、請求項48~52のいずれか一項に記載の方法。
- 前記混合は、40℃~60℃の範囲の温度で行われる、請求項53に記載の方法。
- 前記混合は、最長約6時間行われる、請求項48~55のいずれか一項に記載の方法。
- 前記懸濁液を0℃に冷却することをさらに含む、請求項48~55のいずれか一項に記載の方法。
- 前記懸濁液を濾過してケーキを形成することをさらに含む、請求項56に記載の方法。
- 前記ケーキを洗浄すること、乾燥させること、または洗浄することおよび乾燥させることの両方をさらに含む、請求項57に記載の方法。
- 前記ケーキを再結晶化させることをさらに含む、請求項58に記載の方法。
- (i)前記ケーキから化合物Gを再形成すること、ならびに
(ii)前記再形成された化合物G、マレイン酸、および溶媒を混合して結晶塩を形成すること、をさらに含む、請求項58に記載の方法。 - 請求項1~47のいずれか一項に記載の結晶塩と、1つ以上の賦形剤とを含む、製剤。
- 液体製剤としての請求項61に記載の製剤。
- 凍結乾燥製剤としての請求項61に記載の製剤であって、前記凍結乾燥製剤は液体形態に再構成され得る、製剤。
- 前記結晶塩は、結晶塩の遊離塩基の重量に基づいて、約1mg/ml~約150mg/mlの範囲の濃度で前記液体製剤または再構成された凍結乾燥製剤中に存在する、請求項62または63に記載の製剤。
- 前記濃度は、約10mg/ml~約70mg/mlの範囲である、請求項64に記載の製剤。
- 前記濃度は、約30mg/ml~約50mg/mlの範囲である、請求項65に記載の製剤。
- 前記1つ以上の賦形剤は、界面活性剤、張性剤、緩衝剤、およびそれらの組み合わせからなる群から選択される、請求項61~66のいずれか一項に記載の製剤。
- 前記凍結乾燥製剤は、凍結保護剤、増量剤、またはその両方をさらに含み得る、請求項67に記載の製剤。
- 前記界面活性剤は、ポリソルベート、ポリオキシルヒマシ油、ポリ(アルキレン)グリコール、カプリロカプロイルポリオキシグリセリド、ポリオキシアルキレンブロックコポリマー、およびそれらの組み合わせである、請求項67に記載の製剤。
- 前記張性剤は、塩、ポリオール、またはそれらの組み合わせである、請求項67に記載の製剤。
- 前記液体製剤または前記再構成された凍結乾燥製剤は等張性である、請求項61~70のいずれか一項に記載の製剤。
- 前記緩衝剤は、クエン酸塩、リン酸塩、ヒスチジン、コハク酸塩、酢酸塩、マレイン酸塩、グルコン酸塩、およびそれらの組み合わせからなる群から選択される、請求項67に記載の製剤。
- 前記液体製剤または前記再構成された凍結乾燥製剤は、約3.0~約8.0の範囲のpHを示す、請求項61~70のいずれか一項に記載の製剤。
- 前記pHは、約4.0~約6.5の範囲である、請求項73に記載の製剤。
- 前記液体製剤または再構成された凍結乾燥製剤は、対象への非経口投与に適している、請求項62~74のいずれか一項に記載の製剤。
- 前記非経口投与は、静脈内、筋肉内、腹腔内、または皮下である、請求項75に記載の製剤。
- 前記非経口投与は皮下である、請求項76に記載の製剤。
- 前記対象はヒトである、請求項65に記載の製剤。
- 前記製剤は、少なくとも55%のバイオアベイラビリティを示す、請求項61~78のいずれか一項に記載の製剤。
- 前記製剤は、少なくとも60%のバイオアベイラビリティを示す、請求項79に記載の製剤。
- 前記製剤は、少なくとも65%のバイオアベイラビリティを示す、請求項80に記載の製剤。
- 細胞を請求項1~47のいずれか一項に記載の結晶塩または請求項61~81のいずれか一項に記載の製剤と接触させることを含む、細胞の免疫プロテアソームを阻害する方法。
- 免疫プロテアソームLMP7が阻害される、請求項82に記載の方法。
- 前記接触はインビボである、請求項82または83に記載の方法。
- 前記接触させることは、異常な免疫プロテアソーム活性に関連する障害に罹患している対象に投与することを含む、請求項82に記載の方法。
- 前記障害は自己免疫疾患または炎症である、請求項85に記載の方法。
- 前記疾患は、疾患は、乾癬、皮膚炎、全身性強皮症、硬化症、クローン病、潰瘍性大腸炎;呼吸困難症候群、髄膜炎;脳炎;ぶどう膜炎;大腸炎;糸球体腎炎;湿疹、喘息、慢性炎症;アテローム性動脈硬化症;白血球接着不全;関節リウマチ;全身性エリテマトーデス(SLE);真性糖尿病;多発性硬化症;レイノー症候群;自己免疫性甲状腺炎;アレルギー性脳脊髄炎;シェーグレン症候群;若年発症糖尿病;結核、サルコイドーシス、多発性筋炎、肉芽腫症、血管炎;悪性貧血(アジソン病);白血球減少症を伴う疾患;中枢神経系(CNS)炎症性疾患;多臓器損傷症候群;溶血性貧血;重症筋無力症;抗原-抗体複合体媒介疾患;抗糸球体基底膜疾患;抗リン脂質症候群;アレルギー性神経炎;グレーブス病;ランバート・イートン筋無力症候群;類天疱瘡;天疱瘡;自己免疫性多腺性内分泌障害;ライター病;全身硬直症候群;ベーチェット病;病巨細胞性動脈炎;免疫複合腎炎;IgA腎症;IgMポリニューロパチー;免疫性血小板減少性紫斑病(ITP)または自己免疫性血小板減少症である、請求項86に記載の方法。
- 前記障害は、狼瘡、ループス腎炎、関節リウマチ、糖尿病、強皮症、強直性脊椎炎、乾癬、多発性硬化症、橋本病、髄膜炎、または炎症性腸疾患である、請求項86に記載の方法。
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EA033614B1 (ru) | 2012-05-08 | 2019-11-11 | Onyx Therapeutics Inc | Способы комплексообразования с циклодекстринами для введения пептидных протеасомных ингибиторов в фармацевтические составы |
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AR095426A1 (es) * | 2013-03-14 | 2015-10-14 | Onyx Therapeutics Inc | Inhibidores tripeptídicos de la epoxicetona proteasa |
KR102365509B1 (ko) * | 2013-03-14 | 2022-02-21 | 오닉스 세라퓨틱스, 인크. | 트리펩타이드 에폭시 케톤 프로테이스 억제제 |
EA030957B1 (ru) | 2013-03-14 | 2018-10-31 | Оникс Терапьютикс, Инк. | Дипептидные и трипептидные эпоксикетонные ингибиторы протеазы |
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