JP6568577B2 - 肝内胆汁うっ滞症の治療 - Google Patents
肝内胆汁うっ滞症の治療 Download PDFInfo
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- JP6568577B2 JP6568577B2 JP2017501116A JP2017501116A JP6568577B2 JP 6568577 B2 JP6568577 B2 JP 6568577B2 JP 2017501116 A JP2017501116 A JP 2017501116A JP 2017501116 A JP2017501116 A JP 2017501116A JP 6568577 B2 JP6568577 B2 JP 6568577B2
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- intrahepatic cholestasis
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- liver
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
- A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
Landscapes
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- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
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- Dermatology (AREA)
- Dispersion Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
胆汁うっ滞は、肝臓から十二指腸への胆汁の流れが遅延し、または阻害される状態である。胆汁うっ滞は、肝内胆汁うっ滞(肝臓内部において、胆汁の形成が様々な疾患などの症状、静脈内栄養の持続によって、あるいは一定の薬物(例えば、なんらかの抗生物質)の副作用として妨げられる);および肝外胆汁うっ滞(肝臓外部で生じ、典型的には、胆汁の流れが、例えば、胆管腫瘍、嚢胞、胆管結石、胆管狭窄症または胆管の圧力による胆管の機械的な一部もしくは全部の閉塞によって妨げられる)の利便的に2つのタイプに分けられ得るが;原発性硬化性胆管炎(PSC)は、肝内でもあり、肝外でもありうる。胆汁うっ滞の一般的な症状としては、疲労感、そう痒(痒み)、黄疸、および黄色腫(皮下においてコレステロールを豊富に含む物質の蓄積)が挙げられる。胆汁うっ滞の効果は、深く広範囲であり、全身疾患を伴う肝臓疾患を悪化させ、肝不全を生じ、肝臓移植が必要となる。
上述したように、UDCAは、胆汁うっ滞を減少させ、肝臓機能を向上させる作用のため、肝内胆汁うっ滞症の一般的な治療法である。しかしながら、2012年のPBCにおけるUDCAのコクランレビューでは、UDCAにより肝臓病変、黄疸、および腹水症のバイオマーカーの減少が示されるが、死亡率または肝臓移植に対するUDCAの利益について医学的文献における証拠は存在せず、その使用は体重増加とコストを伴うものであることが見出された。
MBX−8025は、式
肝内胆汁うっ滞症の治療における使用のためのMBX−8025またはMBX−8025塩;
肝内胆汁うっ滞症の治療のため、または肝内胆汁うっ滞症の治療剤の製造におけるMBX−8025またはMBX−8025塩の使用;
肝内胆汁うっ滞症の治療のためのMBX−8025またはMBX−8025塩を含む医薬組成物;
肝内胆汁うっ滞症を治療するためのMBX−8025またはMBX−8025塩を含む組成物を含むキット;ならびに
MBX−8025またはMBX−8025塩を投与することを特徴とする肝内胆汁うっ滞症の治療方法
である。
「肝内胆汁うっ滞症」およびそれらの治療は、段落[0002]から[0010]に記載される。
(1)肝内胆汁うっ滞症を発症するリスクを予防し、または減少させること、すなわち、肝内胆汁うっ滞症に罹りやすい傾向にありうるが、肝内胆汁うっ滞症の症状をまだ経験していないか、または示していない患者において肝内胆汁うっ滞症の臨床症状を発症させないこと(すなわち、予防);
(2)肝内胆汁うっ滞症を抑制すること、すなわち、肝内胆汁うっ滞症またはその臨床症状の発症を停止させ、または減少させること;ならびに
(3)肝内胆汁うっ滞症を緩和すること、すなわち、肝内胆汁うっ滞症を退縮させ、反転させ、または軽減させること、あるいはその臨床症状の回数、頻度、期間、または重症度を減少させること
のうちの1つまたはそれ以上が含まれる。ある対象のための治療上の有効量は、治療される対象の年齢、健康および身体的状態、肝内胆汁うっ滞症およびその程度、医学的状況の評価、および他の関連因子によって変動する。治療上の有効量は、日常的な試験を通して決定することができる比較的広範囲であることが予想される。
前記MBX−8025は、治療される対象および対象の状態の性質に適する経路によって投与されうる。投与経路には、注射(静脈内、腹腔内、筋肉内、および皮下注射を含む)、経粘膜もしくは経皮送達、局所適用、経鼻スプレー、坐薬などによる投与が含まれるか、または経口で投与されてもよい。製剤は、必要に応じて、リポソーム製剤、乳濁液、粘膜を通過する薬物を投与するように設計された製剤または経皮製剤であってもよい。これらの投与方法の各々に適する製剤は、例えば、"Remington: The Science and Practice of Pharmacy", 20th ed., Gennaro, ed., Lippincott Williams & Wilkins, Philadelphia, Pa., U.S.A中で見出されうる。MBX−8025は、経口的に利用可能であるため、一般的な製剤は、経口であり、一般的な剤形は、経口投与用の錠剤またはカプセル剤である。段落[0014]に記載されるように、MBX−8025は、臨床試験のためにカプセル剤に製剤化される。
Claims (11)
- (R)−2−(4−((2−エトキシ−3−(4−(トリフルオロメチル)フェノキシ)プロピル)チオ)−2−メチルフェノキシ)酢酸である化合物またはその塩を含む、対象における肝内胆汁うっ滞症の治療剤。
- 前記化合物が、(R)−2−(4−((2−エトキシ−3−(4−(トリフルオロメチル)フェノキシ)プロピル)チオ)−2−メチルフェノキシ)酢酸のL−リジン二水和物である、請求項1に記載の治療剤。
- 経口投与のための、請求項1または2に記載の治療剤。
- 前記化合物の用量が、(R)−2−(4−((2−エトキシ−3−(4−(トリフルオロメチル)フェノキシ)プロピル)チオ)−2−メチルフェノキシ)酢酸として算出した場合、20〜200mg/日である、請求項1〜3のいずれか1項に記載の治療剤。
- 前記化合物の用量が、(R)−2−(4−((2−エトキシ−3−(4−(トリフルオロメチル)フェノキシ)プロピル)チオ)−2−メチルフェノキシ)酢酸として算出した場合、50〜200mg/日である、請求項4に記載の治療剤。
- 前記化合物が、1日1回投与されるものである、請求項1〜5のいずれか1項に記載の治療剤。
- 前記肝内胆汁うっ滞症が、原発性胆汁性肝硬変、原発性硬化性胆管炎、進行性家族性肝内胆汁うっ滞症、またはアラジール症候群である、請求項1〜6のいずれか1項に記載の治療剤。
- 前記肝内胆汁うっ滞症が、原発性胆汁性肝硬変である、請求項7に記載の治療剤。
- 前記肝内胆汁うっ滞症が、原発性硬化性胆管炎である、請求項7に記載の治療剤。
- 前記肝内胆汁うっ滞症が、進行性家族性肝内胆汁うっ滞症である、請求項7に記載の治療剤。
- 前記肝内胆汁うっ滞症が、アラジール症候群である、請求項7に記載の治療剤。
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US10512622B2 (en) | 2017-07-14 | 2019-12-24 | Cymabay Therapeutics, Inc. | Treatment of intrahepatic cholestatic diseases |
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US20200155487A1 (en) * | 2018-11-16 | 2020-05-21 | Cymabay Therapeutics, Inc. | Treatment of obesity and its complications |
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