JP2016539131A - アラムコール塩 - Google Patents
アラムコール塩 Download PDFInfo
- Publication number
- JP2016539131A JP2016539131A JP2016535210A JP2016535210A JP2016539131A JP 2016539131 A JP2016539131 A JP 2016539131A JP 2016535210 A JP2016535210 A JP 2016535210A JP 2016535210 A JP2016535210 A JP 2016535210A JP 2016539131 A JP2016539131 A JP 2016539131A
- Authority
- JP
- Japan
- Prior art keywords
- salt
- acid
- aramcol
- amine
- arachidylamide
- 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.)
- Granted
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 125
- 238000000034 method Methods 0.000 claims abstract description 45
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 34
- 239000002253 acid Substances 0.000 claims description 65
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 52
- 239000002904 solvent Substances 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 35
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 32
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 23
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 20
- -1 amine salt Chemical class 0.000 claims description 18
- 150000001412 amines Chemical class 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 239000004472 Lysine Substances 0.000 claims description 15
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 13
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- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 claims description 12
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- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 claims description 10
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 10
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- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 claims description 9
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- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 8
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- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 8
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- IKXCHOUDIPZROZ-LXGUWJNJSA-N (2r,3r,4r,5s)-6-(ethylamino)hexane-1,2,3,4,5-pentol Chemical compound CCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO IKXCHOUDIPZROZ-LXGUWJNJSA-N 0.000 claims description 4
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- 229960003237 betaine Drugs 0.000 claims description 4
- 210000000941 bile Anatomy 0.000 claims description 4
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 4
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 3
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- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
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- 125000003158 alcohol group Chemical group 0.000 claims description 2
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- 229960003121 arginine Drugs 0.000 claims 1
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- 238000004806 packaging method and process Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 5
- IKKQPIUFYCCCCW-RXWWQTRFSA-N C(CCCCCCCCCCCCCCCCCCC)(=O)NC1[C@@H]([C@]2(CC[C@@H]3[C@]4(CCCCC4CC[C@H]3[C@@H]2C1)C(=O)O)C)[C@H](C)CCC Chemical compound C(CCCCCCCCCCCCCCCCCCC)(=O)NC1[C@@H]([C@]2(CC[C@@H]3[C@]4(CCCCC4CC[C@H]3[C@@H]2C1)C(=O)O)C)[C@H](C)CCC IKKQPIUFYCCCCW-RXWWQTRFSA-N 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
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- 239000004480 active ingredient Substances 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical group 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 238000004441 surface measurement Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000005259 triarylamine group Chemical group 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
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Abstract
Description
本発明は、アラムコールの新規な塩、例えばアミノアルコール、アミノ糖またはアミノ酸との塩、上記塩を含む医薬組成物、その調製方法および医療処置におけるその使用を提供する。
本発明は、アラムコール遊離酸と比較して高い生物学的利用度に相関する、高い溶解度、高い吸収量、および高い暴露量をはじめとする改善された生理化学的特性を示すアラムコールの塩に関する。
本発明のアラムコール塩を、以下の手順に従って調製した:アラムコール遊離酸を、水またはエタノール中で、対応する塩基と1:1の比で混合した。混合物を1℃/分の割合で50℃まで加熱した。混合物を50℃で2時間保持し、0.1℃/分の割合で20℃まで冷却した。塩が冷却後に沈殿しない場合には、粗反応混合物を3日間保持し、純度をHPLCで測定した。透明溶液をもたらしたアラムコール塩は、HPLCでさらなる不純物を示さなかった。結果を、表1に要約する。
本発明のアラムコール塩を、水中の溶解度についてさらに評価した。水性溶解度を、振とうフラスコ法を利用して20℃でテストした。各塩5mgを、計量した。透明溶液が得られるまで、水を段階的に添加した(表2、水中の溶解度)。各溶液のpHを、測定した(表2、溶解度の後のpH)。結果を、表2に要約する。
材料および方法
粉末X線回折(XRPD)
粉末X線回折試験を、Bragg−Brentano型のBruker社AXS D2 PHASER、装置番号1549を用いて実施した。30kV、10mAのCu陽極;サンプルステージ標準回転;κβフィルター(0.5%Ni)による単色化を用いた。スリット:固定発散スリット1.0mm(=0.61°)、第一の軸のソーラースリット2.5°、第二の軸のソーラースリット2.5°。検出器:開き角5°の受光スリットを有する一次元検出器LYNXEYE。標準の試料ホルダー((510)シリコンウエア中に0.1mmの穴)は、バックグランドシグナルに対して最小限の寄与率を有した。
34ポジションオートサンプラーを備えたMettler Toledo TGA/DSC1 Stare System(装置番号1547)を用いて、TGA/DSCを実施した。
DVSテストは、Surface Measurement System Ltd. DVS−1 No Video(装置番号2126)を用いて実施した。
AxioCamERc5Sを備えたAxioVert 35M(装置番号1612)を用いて、顕微鏡試験を実施した。顕微鏡は、4つのレンズ:Zeiss A−Plan 5×/0.12、Zeiss A−Plan 10×/0.25、LD A−Plan 20×/0.30およびAchros TIGMAT 32×/0.40を備えていた。データ回収および評価は、Carl Zeiss Zen AxioVision Blue Edition Lite 2011 v1.0.0.0ソフトウエアを用いて実施した。
アラムコールのN−メチルグルカミン、トロメタミンおよびリシン塩の合成を、一般的方法1および2に従って遂行した。
XRPD分析を実施例3に記載された通り実施して、得られた塩が非晶質であることを実証した。アラムコールN−メチルグルカミン塩の代表的なXRPDスペクトルを、図1に示す。アラムコールリシン塩の代表的なXRPDスペクトルを、図2に示す。アラムコールトロメタミン塩の代表的なXRPDスペクトルを、図3に示す。
以下のテストを、塩について実施した:LC純度、Karl Fisher(試料中の微量の水を測定)および乾燥減量(LOD)(加熱により減少した質量%を測定)。結果は、塩の間で類似のパターンの水分量および質量減少%を示している(表7)。
アラムコールN−メチルグルカミン塩の吸着および脱離挙動を測定するために、DVS測定を実施した。相対湿度(RH)を1ステップあたり10%ずつ上昇させて、最終的に95%RHにすることにより、吸着を測定した。吸着サイクルの完了後に、材料を乾燥させた。XRPDを、DVSの前後に実施した。DVSは、RH変化に応答した段階的吸着と、総質量増加率16%を示しており、材料が吸湿性であることが示唆された。吸着は、可逆的および再現的であった。アラムコールN−メチルグルカミン塩の代表的なDVSスペクトルを、図8に示す。DVS後のXRPDパターンは、異なるピーク形状および強度を有する(異なる粒子径および形状のため)、非晶質材料を示した。
タップ密度およびかさ密度の測定は、粉末の流動特性および圧縮性を予測するのに用いられる。これらの2つの特性は、錠剤およびカプセルなどの固体投与剤形の製造にとって重要である。低値のタップ密度およびかさ密度を有する化合物は、打錠が困難になる場合があり、それゆえ流動特性を改善するためのさらなる加工を必要とし得る。
アラムコールのN−メチルグルカミン塩を、以下の条件による安定性の促進に供した。
a)閉鎖されたフラスコ内で溶液として40℃/75%RHに暴露
b)閉鎖された容器内で固相形態で40℃/75%RHに暴露
c)開放された容器内で固相形態で40℃/75%RHに暴露
アラムコール(遊離酸)は、水性媒体中で低い溶解度を有する(pH6.0の緩衝液中の溶解度0.001mg/mL未満、FeSSIF中の最大溶解度0.66mg/mL)。
アラムコール塩のインビボ透過性試験を、頸静脈および空腸にカニューレ挿入された雄Wisterラットにおいて実施した。胃の酸性pHにおけるアラムコール塩のプロトン化を回避するために、腸へのカニューレ挿入を実施した。PBS中に溶解したアラムコール塩(30mg/mL)を、空腸の近位側に挿入されたカニューレを介して、ラットの腸(空腸)へ100mg/kgの用量(遊離酸に基づく)で投与した。アラムコール遊離酸の懸濁液(PBS中に30mg/mL)を同じ経路で投与し、対照として用いた。所定のタイムポイント(投与前、投与後1時間、2時間、4時間、8時間、12時間、24時間)で、血液試料を頸静脈に挿入されたカニューレから採取した。アラムコール(遊離酸)の血漿濃度は、イスラエルのAnalyst Bioanalytical Laboratoriesにより、液体クロマトグラフィー・タンデム質量分析(LC−MS−MS)法を利用して測定された。PKパラメータは全て、ノンコンパートメント解析を利用して計算した。定量の下限(LOQ)(48.66ng/mL)以上の血漿濃度のみを、解析に使用した。投与前からLOQ以上になった最初の濃度までに生じた、LOQ未満の血漿濃度は、0として処理した。実際の採取時間を、全ての薬物動態分析に用いた。以下のPKパラメータを計算した:最大血漿濃度(Cmax)、Cmaxまでの時間(Tmax)、投与の時間から最後の血漿濃度までの血漿濃度−時間の曲線下面積(AUC0−t)、AUC/用量、排出半減期(t1/2)。CmaxおよびTmaxは、データから直接得た。0から濃度がLOQ以上である最後の試料までの曲線下面積。AUC0−tは、線形台形法を用いて計算した。
アラムコール塩を調製するために、約30種の医薬的に許容し得る塩基をスクリーニングした。それらのうち、アミンを基剤とする塩が、適切であることが見出され、特に3種のアラムコール塩が好ましい塩として選択された。本明細書で実証された通り、アラムコールのN−メチルグルカミン、リシンおよびトロメタミン塩が調製され、有利な特性を有することが示された。アラムコール塩一般に関する、および特に3種の好ましい塩に関する複数の予測されなかった知見を、本明細書の以下に要約する。
2)狭いpH範囲(7.0〜7.8)での実質的な溶解度差もまた、予測外であった。例えば3種のテストされた塩は、pH7と7.4で類似の溶解度を示す。しかし、脱塩水(pH7.8)中のN−メチルグルカミンの溶解度はpH7.4での5倍高く、他の2種の塩ではその差は相対的に低い。
3)溶液安定性の予測は不測である。例えば、N−メチルグルカミン塩は他の2種の塩に比較して相対的に高い溶液中の安定性を示す(表11)。例えば、pH=7.8(脱塩水)では、トロメタミン塩とリシン塩の両方の溶液が、24時間後に変化した(turned into gets)が、N−メチルグルカミン塩は、溶液のままであった。
Claims (31)
- 3β−アラキジルアミド−7α,12α−ジヒドロキシ−5β−コラン−24−酸とアミンとの塩。
- 前記アミンがアンモニア、第一級アミン、第二級アミン、第三級アミン、第四級アンモニウム化合物、アミノアルコール、アミノ糖およびアミノ酸からなる群から選択される、請求項1に記載の塩。
- 前記アミンがアミノアルコール、アミノ糖およびアミノ酸からなる群から選択される、請求項2に記載の塩。
- アンモニウム、ベンザチン、トリメチルグリシン(ベタイン)、エタノールアミン、ジエタノールアミン、ジエチルアミン、アルギニン、リシン、コリン、デアノール、2−ジエチルアミノエタノール、N−メチルグルカミン(メグルミン)、N−エチルグルカミン(エグルミン)およびトロメタミン塩からなる群から選択される、請求項1に記載の塩。
- 3β−アラキジルアミド−7α,12α−ジヒドロキシ−5β−コラン−24−酸リシン塩。
- 3β−アラキジルアミド−7α,12α−ジヒドロキシ−5β−コラン−24−酸トロメタミン塩。
- 3β−アラキジルアミド−7α,12α−ジヒドロキシ−5β−コラン−24−酸N−メチルグルカミン塩。
- 結晶形態である、請求項1〜7のいずれか1項に記載の塩。
- 非晶質形態である、請求項1〜7のいずれか1項に記載の塩。
- (a)3β−アラキジルアミド−7α,12α−ジヒドロキシ−5β−コラン−24−酸を溶媒の存在下でアミンと混合するステップ;
(b)場合により前記混合物を前記溶媒の沸点以下の温度に加熱するステップ;
(c)場合により前記混合物を冷却するステップ;および
(d)こうして得られた3β−アラキジルアミド−7α,12α−ジヒドロキシ−5β−コラン−24−酸のアミン塩を単離するステップ、
を含む、請求項1〜9のいずれか1項に記載の塩を調製する方法。 - (a)3β−アラキジルアミド−7α,12α−ジヒドロキシ−5β−コラン−24−酸を溶媒の存在下でアミンと混合するステップ;
(b)場合により前記混合物を前記溶媒の沸点以下の温度に加熱するステップ;
(c)逆溶媒を添加するステップ;
(c)場合により前記混合物を冷却するステップ;および
(d)こうして得られた3β−アラキジルアミド−7α,12α−ジヒドロキシ−5β−コラン−24−酸のアミン塩を単離するステップ、
を含む、請求項1〜9のいずれか1項に記載の塩を調製する方法。 - 前記溶媒が水である、請求項10または11に記載の方法。
- 前記溶媒がアルコールである、請求項10または11に記載の方法。
- 前記溶媒が酢酸エチルである、請求項10または11に記載の方法。
- 前記溶媒がアセトンまたは酢酸エチルである、請求項11に記載の方法。
- 前記アミンがアンモニア、第一級アミン、第二級アミン、第三級アミン、第四級アンモニウム化合物、アミノアルコール、アミノ糖およびアミノ酸からなる群から選択される、請求項10または11に記載の方法。
- 前記3β−アラキジルアミド−7α,12α−ジヒドロキシ−5β−コラン−24−酸と前記アミンとの比が約1:1である、請求項10または11に記載の方法。
- 前記混合物を加熱するステップが約50℃の温度まで実施される、請求項10または11に記載の方法。
- 前記混合物を冷却するステップが約5℃の温度まで実施される、請求項10または11に記載の方法。
- 前記こうして得られた3β−アラキジルアミド−7α,12α−ジヒドロキシ−5β−コラン−24−酸の塩を単離するステップが前記溶媒を蒸発させることを含む、請求項10または11に記載の方法。
- 前記こうして得られた3β−アラキジルアミド−7α,12α−ジヒドロキシ−5β−コラン−24−酸の塩を単離するステップが前記塩の沈殿物を形成させることおよび前記反応混合物から前記沈殿物を分離することを含む、請求項10または11に記載の方法。
- 治療有効量の請求項1〜9のいずれか1項に記載の塩と場合により少なくとも1種の医薬的に許容し得る担体、希釈剤、ビヒクルまたは賦形剤とを含む医薬組成物。
- 錠剤、丸薬、カプセル、ペレット、顆粒、粉末、ロゼンジ、サシェ、カシェ、パッチ、エリキシル、懸濁剤、分散剤、エマルジョン、溶液、シロップ、エアロゾル、軟膏、軟および硬ゼラチンカプセル、坐剤、滅菌注射液、ならびに滅菌包装粉末からなる群から選択される形態である、請求項22に記載の医薬組成物。
- 血中コレステロールレベルを低下させることもしくは脂肪肝を処置することにおける使用のため、または非アルコール性脂肪性肝炎(NASH)を処置するための、請求項22に記載の医薬組成物。
- 胆汁中のコレステロール胆石を溶解することにおける使用のためおよびそのような胆石の形成を予防するための、請求項22に記載の医薬組成物。
- 動脈硬化を処置することにおける使用のための、請求項22に記載の医薬組成物。
- 糖代謝の変化に関連する疾患または障害を処置することにおける使用のための、請求項22に記載の医薬組成物。
- 前記糖代謝の変化に関連する疾患または障害が高血糖、糖尿病、インスリン抵抗性および肥満からなる群から選択される、請求項27に記載の医薬組成物。
- アミロイド斑沈着により特徴づけられる脳疾患の進行を処置、予防、または阻止することにおける使用のための、請求項22に記載の医薬組成物。
- 前記アミロイド斑沈着により特徴づけられる脳疾患がアルツハイマー病である、請求項29に記載の医薬組成物。
- 経口、経皮または局所経路を介して投与するのに適している、請求項22に記載の医薬組成物。
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