JP6258264B2 - ヒトの血小板レベルを増加させるための組成物および方法 - Google Patents
ヒトの血小板レベルを増加させるための組成物および方法 Download PDFInfo
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- JP6258264B2 JP6258264B2 JP2015133015A JP2015133015A JP6258264B2 JP 6258264 B2 JP6258264 B2 JP 6258264B2 JP 2015133015 A JP2015133015 A JP 2015133015A JP 2015133015 A JP2015133015 A JP 2015133015A JP 6258264 B2 JP6258264 B2 JP 6258264B2
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Plural Heterocyclic Compounds (AREA)
Description
本発明は、ヒトの血小板レベルを増加させるための組成物および方法に関する。
血小板減少症は、循環系における血小板の欠乏によって特徴付けられる潜在的に深刻な症状である。それは、特に小さい毛細血管からの出血の危険の増加を伴い、その結果、血小板減少性紫斑病が生じる。血小板減少症の原因は多様であり、骨髄における血小板産生の減少および血液中の血小板残存量の減少が含まれる。特定の疾患に関係する血小板減少症、例えば特発性血小板減少性紫斑病および、他の疾患(悪性腫瘍および感染症、例えば肝炎が含まれる)の骨髄に対する間接的影響によって生じる血小板減少症が存在する。現在、血小板減少症の対処は主に血小板輸血に基づく。その有効性にもかかわらず、約30%の血小板輸血は深刻な合併症を伴う。それには、同種免疫、発熱副作用およびアレルギー反応、循環過負荷、急性肺損傷および細菌感染またはウイルス感染が含まれる。反復した血小板輸血を必要とする15〜25%の患者では、ヒト白血球抗原(HLA)同種免疫のせいで血小板応答は不十分である。したがって、血小板輸血の必要性を減らしたり、または排除できる安全な血小板新生剤は、患者の健康に有益であり、ヘルスケアコストをかなり減らすことができる。
本発明の目的は、ヒト被験体への投与後に血小板レベルを増加させるために有用な薬物動態パラメータをもたらす、1-(3-クロロ-5-{[4-(4-クロロチオフェン-2-イル)-5-(4-シクロヘキシルピペラジン-1-イル)チアゾール-2-イル]カルバモイル}ピリジン-2-イル)ピペリジン-4-カルボン酸(以下、「式Iの薬物」)の製剤を提供することである。
薬理学的研究が、以下の式Iの化合物:
式Iの薬物は、即時放出経口剤形中の製薬的に許容される賦形剤とともに経口剤形中に含ませることができる。本発明の即時放出剤形には、非限定的に、錠剤、軟または硬ゼラチンカプセル剤、液剤または懸濁剤が含まれる。
実施例
以下の実施例は本発明の種々の態様を説明する。それらは、全くいかなる様式においても特許請求の範囲を限定するものと解釈されることはない。
単回投与研究
健常なボランティアにおいて1-(3-クロロ-5-{[4-(4-クロロチオフェン-2-イル)-5-(4-シクロヘキシルピペラジン-1-イル)チアゾール-2-イル]カルバモイル}ピリジン-2-イル)ピペリジン-4-カルボン酸(式I)の用量の安全性、薬物動態、および薬理学を決定するための単一施設試験の無作為化した二重盲検の用量増加研究を実施した。式Iの薬物の開始用量は1 mg(遊離塩基で表す)であった。それに続く用量コホートは、3、10、20、50、75および100 mgを投与された。モノマレイン酸塩の形態の製剤原料をOra-Plus(登録商標)(精製水、微結晶性セルロース、カルボキシメチルセルロースナトリウム、キサンタンガム、クエン酸、リン酸ナトリウム、シメチコン、ソルビン酸カリウムおよびメチルパラベン)に懸濁した。Ora-Plus(登録商標)はPaddock Laboratories, Inc.(Minneapolis, MN)製の市販の経口懸濁用ビヒクルである。Ora-Plus(登録商標)は1:1懸濁液となるように精製水USPで希釈した後、経口投与用の調製として製剤原料粉末を懸濁した。投与前に30 mLのOra-Plus(登録商標)/水ビヒクルを各ボトルに加え、振とうした後、3、10、50および75mgの各用量コホートについて被験体に摂取させた。その後、追加の30 mLのビヒクルを、洗浄溶液としてボトルに加え、振とうした後、被験体に摂取させた。20mgおよび100mg用量コホートでは、60 mLのOra-Plus(登録商標)/水ビヒクルを、適切な用量の薬物を含有する2つの別々のボトルに加え(各ボトルに30 mL)、振とうした後、被験体に摂取させた。その後、追加の60 mLのビヒクルを、洗浄溶液として各ボトルに30 mlずつ加え、振とうした後、被験体に摂取させた。
実施例1から算出された予備的に得られた平均薬物動態値を以下の表1に示す。
健康な男性および女性ボランティアにおいて、二重盲検の、プラセボ対照を用いる用量増加研究を実施した。各用量コホートは、連続した14日間、1日1回、経口懸濁剤としてプラセボ処置または有効処置を受けた。上記実施例1に記載のように治験薬物の用量を調製し、投与した。この複数回投与研究において投与される用量は、実施例1で投与される用量の安全性および耐容性評価に基づくものであった。この研究での用量レベルは、常に、用量安全性および耐容性が実施例1で実証されている二番目の最大用量レベルよりも低い、少なくとも1用量のレベルのままであった。
実施例1から算出された平均薬物動態値を以下の表3に示す。
摂食および絶食条件下で経口懸濁剤または錠剤として健康な男性および女性ボランティアに投与された式Iの薬物の10mg経口用量の薬物動態、相対的バイオアベイラビリティ、および安全性を評価するために、オープンラベルで、無作為化した、三元配置のクロスオーバー研究を行った。
[請求項1]
血小板レベルを増加させることにより、血小板減少症を治療するための経口剤形であって、治療有効量の式(I)の薬物:
該経口剤形が20 mgの薬物を含み、かつヒト被験体への一回量の投与後に、約60.0 ng/ml〜約160.0 ng/mlの平均最大血漿中濃度(Cmax)をもたらす、前記経口剤形。
[請求項2]
血小板レベルを増加させることにより、血小板減少症を治療するための経口剤形であって、治療有効量の式(I)の薬物:
該経口剤形が20 mgの薬物を含み、かつヒト被験体への一回量の投与後に、約1000 ng・hr/ml〜約5000 ng・hr/mlの平均AUC0−24をもたらす、前記経口剤形。
[請求項3]
血小板レベルを増加させることにより、血小板減少症を治療するための経口剤形であって、治療有効量の式(I)の薬物:
該経口剤形が、10 mgの薬物を含み、かつヒト被験体への一回量の投与後に、約30 ng/ml〜約80 ng/mlの平均最大血漿中濃度(Cmax)をもたらす、前記経口剤形。
[請求項4]
血小板レベルを増加させることにより、血小板減少症を治療するための経口剤形であって、治療有効量の式(I)薬物:
該経口剤形が、10 mgの薬物を含み、ヒト被験体への一回量の投与後に、約500 ng・hr/ml〜約2500 ng・hr/mlの平均AUC0−24をもたらす、前記経口剤形。
[請求項5]
ヒト被験体への一回量の投与後に、約10時間〜約25時間の排出半減期(T1/2)をもたらす、請求項1〜4のいずれか1項記載の経口剤形。
[請求項6]
その必要があるヒト患者において、ベースラインからの、少なくとも約25%の血小板数の増加をもたらす、請求項1〜5のいずれか1項記載の経口剤形。
[請求項7]
剤形が、錠剤、軟または硬ゼラチンカプセル剤、液剤、および懸濁剤からなる群から選択される、請求項1〜6のいずれか1項記載の経口剤形。
[請求項8]
剤形が錠剤である、請求項7記載の経口剤形。
[請求項9]
剤形が懸濁剤である、請求項7記載の経口剤形。
[請求項10]
式(I)の薬物がモノマレイン酸塩の形態である、請求項1〜9のいずれか1項記載の経口剤形。
Claims (11)
- 血小板減少症を治療するための経口製剤であって、
10〜20mgの式(I)の化合物または製薬的に許容されるその塩を含んでおり、
前記製剤は、ヒト被験体への一回量の投与後に、製剤中に含まれる各1mgの化合物に対して3ng/ml〜8ng/mlの平均最大血漿中濃度(Cmax)をもたらす、
経口製剤。
- 請求項1に記載の経口製剤であって、
10mgの式(I)の化合物または製薬的に許容されるその塩を含む、
経口製剤。 - 請求項1に記載の経口製剤であって、
20mgの式(I)の化合物または製薬的に許容されるその塩を含む、
経口製剤。 - 請求項2または3に記載の経口製剤であって、
前記化合物またはその塩は20mg以下の一日量で投与される、
経口製剤。 - 請求項1に記載の経口製剤であって、
前記製剤は、錠剤または懸濁剤の形態である、
経口製剤。 - 請求項1に記載の経口製剤であって、
前記製薬的に許容される塩は、鉱酸、有機酸、無機塩基との塩、有機塩基との塩、またはアンモニウム塩である、
経口製剤。 - 請求項6に記載の経口製剤であって、
前記製薬的に許容される塩は、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、p-トルエンスルホン酸、アスパラギン酸、グルタミン酸、ナトリウム、カリウム、マグネシウム、カルシウム、メチルアミン、エチルアミン、エタノールアミン、リシン、またはオルニチンの塩である、
経口製剤。 - 請求項1に記載の経口製剤であって、
式(I)に記載の化合物はモノマレイン酸塩の形態である、
経口製剤。 - 請求項1に記載の経口製剤であって、
血小板減少症は、特発性血小板減少性紫斑病(ITP)である、
経口製剤。 - 請求項1に記載の経口製剤であって、
血小板減少症は、肝不全における肝臓によるトロンボポエチン産生の減少に関連する、
経口製剤。 - 請求項1に記載の経口製剤であって、
血小板減少症は、血栓性血小板減少性紫斑病(TTP)、溶血性尿毒症症候群(HUS)、播種性血管内凝固症候群(DIC)、発作性夜間血色素尿症(PNH)、抗リン脂質症候群、全身性エリテマトーデス(SLE)、輸血後紫斑、新生児自己免疫性血小板減少症(NAITP)、脾機能亢進に起因する脾臓の血小板捕捉、デング熱、骨髄異形成症候群(MDS)の血小板減少症、化学療法誘発性血小板減少症、ビタミンB12または葉酸欠乏、白血病、肝不全における肝臓によるトロンボポエチン産生の減少、敗血症、全身性ウイルス感染または細菌感染、先天性無巨核球性血小板減少症(CAMT)、橈骨欠損血小板減少症候群、ファンコニ貧血、ベルナール・スーリエ症候群、メイ・ヘグリン異常、灰色血小板症候群(Grey platelet syndrome)、またはアルポート症候群である、
経口製剤。
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