JP6991592B2 - 中枢神経系送達のためのコクリエート化抗真菌化合物及びクリプトコッカス感染症の治療 - Google Patents

中枢神経系送達のためのコクリエート化抗真菌化合物及びクリプトコッカス感染症の治療 Download PDF

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JP6991592B2
JP6991592B2 JP2019500624A JP2019500624A JP6991592B2 JP 6991592 B2 JP6991592 B2 JP 6991592B2 JP 2019500624 A JP2019500624 A JP 2019500624A JP 2019500624 A JP2019500624 A JP 2019500624A JP 6991592 B2 JP6991592 B2 JP 6991592B2
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oral formulation
antifungal
cryptococcus
oral
flucytosine
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JP2019520407A (ja
JP2019520407A5 (enExample
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ラファエル ジェイ． マンニーノ
ルーイン ルー
ダグ エフ． クリング
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マティナス バイオファーマ ナノテクノロジーズ，インコーポレーテッド
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
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    • 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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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

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JP2019500624A 2016-07-12 2017-07-12 中枢神経系送達のためのコクリエート化抗真菌化合物及びクリプトコッカス感染症の治療 Active JP6991592B2 (ja)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201662361351P 2016-07-12 2016-07-12
US62/361,351 2016-07-12
US201762513800P 2017-06-01 2017-06-01
US62/513,800 2017-06-01
PCT/US2017/041750 WO2018013711A1 (en) 2016-07-12 2017-07-12 Encochleated antifungal compounds for central nervous system delivery and treatment of cryptococcus infections

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JP2019520407A JP2019520407A (ja) 2019-07-18
JP2019520407A5 JP2019520407A5 (enExample) 2020-05-28
JP6991592B2 true JP6991592B2 (ja) 2022-01-12

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US (3) US11123295B2 (enExample)
EP (1) EP3484447A4 (enExample)
JP (1) JP6991592B2 (enExample)
KR (2) KR20190029642A (enExample)
CN (2) CN109689028A (enExample)
AU (1) AU2017297402B2 (enExample)
CA (1) CA3027668A1 (enExample)
WO (1) WO2018013711A1 (enExample)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2659729C2 (ru) 2012-07-30 2018-07-03 Матинас Биофарма Нанотекнолоджис, Инк. Кохлеаты, полученные с использованием фосфатидилсерина сои
KR20200060424A (ko) 2017-09-20 2020-05-29 아토픽 메디컬, 엘엘씨. 호흡기 질환 및 점막 염증의 치료 및 개선을 위한 조성물 및 방법
WO2021030553A1 (en) * 2019-08-13 2021-02-18 Matinas Biopharma Nanotechnologies, Inc. Methods of treating cryptococcus infections
CN118370831A (zh) * 2023-01-20 2024-07-23 中国科学院微生物研究所 肌醇磷脂酰胺合成酶抑制剂与两性霉素b的联合用药及其用途

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002535267A (ja) 1999-01-22 2002-10-22 バイオデリバリー サイエンス インコーポレーテッド 新規ヒドロゲル単離コクリエート製剤、その調製方法および生物学的関連分子投与のための用途
JP2003529557A (ja) 2000-01-24 2003-10-07 バイオデリバリー サイエンス インコーポレーテッド コクリエート製剤、その調製方法および生物学的関連分子投与のための用途
JP2005529086A (ja) 2002-03-26 2005-09-29 バイオデリバリー サイエンシズ インターナショナル インコーポレーティッド 精製大豆ホスファチジルセリンによって作製される渦巻状物
JP2006514103A (ja) 2002-11-01 2006-04-27 バイオデリバリー サイエンシーズ インターナショナル インコーポレイティッド ジオデート送達媒体
WO2010091090A1 (en) 2009-02-03 2010-08-12 Biodelivery Sciences International, Inc. Cochleate compositions and methods of use
JP2014513135A (ja) 2011-05-05 2014-05-29 コーディネイティッド プログラム ディベロップメント，エルエルシー コクリエート組成物およびその製造および使用方法
JP2015528021A (ja) 2012-07-30 2015-09-24 コーディネイティッド プログラム ディベロップメント，エルエルシー ダイズホスファチジルセリンで作られたコクリエート

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2263077A1 (en) * 1996-08-09 1998-02-19 Buckman Laboratories International, Inc. Treatment of fungal infections using a combination of an anti-fungal compound and an n-alkyl-heterocyclic compound
US5837254A (en) * 1996-11-14 1998-11-17 Chen; Yu Method of treating candida and cryptococcus fungal infections by administering gentian
AUPQ066399A0 (en) * 1999-05-31 1999-06-24 Fujisawa Pharmaceutical Co., Ltd. Antifungal combination use
US20050013854A1 (en) * 2003-04-09 2005-01-20 Mannino Raphael J. Novel encochleation methods, cochleates and methods of use
WO2004092123A2 (en) * 2003-04-10 2004-10-28 Microbia, Inc. Inhibitors of fungal invasion
US8252587B2 (en) * 2004-10-25 2012-08-28 Celerant Therapeutics, Inc. Methods of expanding myeloid cell populations and uses thereof
SI1867332T1 (sl) * 2005-04-07 2011-11-30 Toyama Chemical Co Ltd Farmacevtska sestava in postopek z rabo v kombinaciji s protiglivičnim sredstvom
BRPI0612843A2 (pt) * 2005-06-29 2010-11-30 The Research Foundation Of State University Of New York composição farmacêutica, métodos para fabricar a composição, e, uso de uma formulação
WO2009006311A2 (en) * 2007-06-29 2009-01-08 Wisconsin Alumni Research Foundation Structuring effect of cholesterol in peg-phospholipid micelles, drug delivery of amphotericin b, and combination antifungals
DE102008054431B3 (de) * 2008-12-09 2010-06-17 Pari Pharma Gmbh Aerosoltherapievorrichtung

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002535267A (ja) 1999-01-22 2002-10-22 バイオデリバリー サイエンス インコーポレーテッド 新規ヒドロゲル単離コクリエート製剤、その調製方法および生物学的関連分子投与のための用途
JP2003529557A (ja) 2000-01-24 2003-10-07 バイオデリバリー サイエンス インコーポレーテッド コクリエート製剤、その調製方法および生物学的関連分子投与のための用途
JP2005529086A (ja) 2002-03-26 2005-09-29 バイオデリバリー サイエンシズ インターナショナル インコーポレーティッド 精製大豆ホスファチジルセリンによって作製される渦巻状物
JP2006514103A (ja) 2002-11-01 2006-04-27 バイオデリバリー サイエンシーズ インターナショナル インコーポレイティッド ジオデート送達媒体
WO2010091090A1 (en) 2009-02-03 2010-08-12 Biodelivery Sciences International, Inc. Cochleate compositions and methods of use
JP2014513135A (ja) 2011-05-05 2014-05-29 コーディネイティッド プログラム ディベロップメント，エルエルシー コクリエート組成物およびその製造および使用方法
JP2015528021A (ja) 2012-07-30 2015-09-24 コーディネイティッド プログラム ディベロップメント，エルエルシー ダイズホスファチジルセリンで作られたコクリエート

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Clinical Infectious Diseases，2010年，Vol.50, No.3，pp.291-322

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JP2019520407A (ja) 2019-07-18
AU2017297402B2 (en) 2023-02-09
US11123295B2 (en) 2021-09-21
WO2018013711A1 (en) 2018-01-18
CA3027668A1 (en) 2018-01-18
US20210393526A1 (en) 2021-12-23
EP3484447A1 (en) 2019-05-22
CN114053417A (zh) 2022-02-18
US20200121601A1 (en) 2020-04-23
KR20230003167A (ko) 2023-01-05
US20240423916A1 (en) 2024-12-26
KR20190029642A (ko) 2019-03-20
CN109689028A (zh) 2019-04-26
AU2017297402A1 (en) 2019-01-03
EP3484447A4 (en) 2020-07-22

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