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RU2015155368A - Липосомные композиции, используемые для доставки лекарственных средств - Google Patents

Липосомные композиции, используемые для доставки лекарственных средств Download PDF

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Publication number
RU2015155368A
RU2015155368A RU2015155368A RU2015155368A RU2015155368A RU 2015155368 A RU2015155368 A RU 2015155368A RU 2015155368 A RU2015155368 A RU 2015155368A RU 2015155368 A RU2015155368 A RU 2015155368A RU 2015155368 A RU2015155368 A RU 2015155368A
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Prior art keywords
composition according
anion
liposome
group
inner space
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RU2015155368A
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English (en)
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RU2015155368A3 (ru
RU2757110C2 (ru
Inventor
Килунг Хонг
Дэрил С. ДРЮММОНД
Дмитрий В. КИРПОТИН
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Мерримак Фармасьютикэлс, Инк.
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Claims (29)

1. Композиция, представляющая собой липосому в среде, имеющую внутреннее пространство, отделенное от среды мембраной, включающей один или несколько липидов, причем внутреннее пространство липосомы содержит замещенный аммоний, имеющий формулу
Figure 00000001
где N представляет собой аммонийный атом азота, каждый из R1, R2, R3, R4 представляет собой независимо атом водорода или органическую группу, имеющую каждая независимо не более 8 атомов углерода и в целом (в сумме) не более 18 атомов углерода включительно, причем, по меньшей мере, один из R1, R2, R3, R4 является органической группой, где органическая группа независимо представляет собой алкил, алкилиден, гетероциклический алкил, циклоалкил, арил, алкенил, циклоалкенил или их гидроксизамещенное производное, необязательно включающее атомы S, О или N, образующие эфирную, сложноэфирную, тиоэфирную, амино- или амидную связь, и где, по меньшей мере, три из R1, R2, R3, R4 являются органическими группами, или, по меньшей мере, одна из органических групп имеет вторичный или третичный атом углерода, непосредственно связанный с аммонийным атомом азота, и где указанное внутреннее пространство включает также анион.
2. Композиция по п. 1, отличающаяся тем, что среди органических групп каждая независимо содержит не больше 6 атомов углерода.
3. Композиция по п. 1, отличающаяся тем, что органические группы суммарно содержат не более 16 атомов углерода.
4. Композиция по п. 1, отличающаяся тем, что органические группы суммарно содержат не более 12 атомов углерода.
5. Композиция по п.1, отличающаяся тем, что замещенный аммоний образует истинный раствор в воде.
6. Композиция по п. 1, отличающаяся тем, что практически весь замещенный аммоний содержится во внутреннем пространстве липосомы.
7. Композиция по п. 1, отличающаяся тем, что замещенный аммоний является фармацевтически инертным.
8. Композиция по п. 1, отличающаяся тем, что замещенный аммоний выбран из группы, состоящей из изопропилэтиламмония, изопропилметиламмония, диизопропиламмония, третбутилэтиламмония, дициклогексиламмония, морфолиния, пиридиния, пиперидиния, пирролидиния, пиперазиния, третбутиламмония, 2-аммоний-2-метилпропанол-1,2-аммоний-2-метилпропандиола-1,3-трис-(гидроксиэтил)-аммоний метана, N,N'-диэтил-этаноламмония, Ν,Ν',N''-трис-(2-гидроксиэтил)аммония, Ν,N'-трис-(2-гидроксиэтил)этиламмония, триметиламмония, триэтиламмония, диэтилметиламмония, диизопропилэтиламмония, триизопропиламмония, N-метилморфолиния, 1-(2-гидроксиэтил)пиперидиния, 1-метилпирролидиния, 1,4-диметилпиперазиния, тетраметиламмония, тетраэтиламмония и тетрабутиламмония.
9. Композиция по п. 1, отличающаяся тем, что концентрация замещенного аммония во внутреннем пространстве липосомы выше, чем концентрация замещенного аммония в среде, содержащей липосомы.
10. Композиция по п. 10, отличающаяся тем, что концентрация замещенного аммония во внутреннем пространстве составляет, по меньшей мере, около 0,05 М, 0,1 М, 0,2 М, 0,5 М, 0,6 M или 0,7 М.
11. Композиция по п. 10, отличающаяся тем, что концентрация замещенного аммония во внутреннем пространстве составляет около 0,65 М.
12. Композиция по п. 1, отличающаяся тем, что анион является двухвалентным анионом, трехвалентным анионом, поливалентным анионом, полимерным анионом, полианионизированным полиолом или полианионизированным сахаром.
13. Композиция, представляющая собой липосому в среде, имеющую внутреннее пространство, отделенное от среды мембраной, включающей один или несколько липидов, причем внутреннее пространство включает анион, выбранный из группы, состоящей из полианионизированного полиола или полианионизированного сахара, и липосома включает трансмембранный градиент, эффективный для удерживания вещества внутри липосомы.
14. Композиция по п. 13, отличающаяся тем, что трансмембранный градиент представляет собой ионный градиент, градиент иона аммония, рН градиент, градиент электрохимического потенциала, градиент растворимости или градиент замещенного иона аммония, содержащего, по меньшей мере, одну C-N связь.
15. Композиция по любому из пп. 1-14, отличающаяся тем, что анион включает
(i) остаток полиола, выбранного из группы, состоящей из моносахарида, дисахарида, линейного полигидроксилированного соединения, циклического полигидроксилированного соединения, алифатического спирта, имеющего более чем одну гидроксильную группу, алициклического спирта, имеющего более чем одну гидроксильную группу, гетероциклического спирта, имеющего более чем одну гидроксильную группу, и
(ii) связанные с остатком полиола, по меньшей мере, две сильноанионные функциональные группы.
16. Композиция по п. 15, отличающаяся тем, что по меньшей мере, одна из сильноосновных функциональных групп представляет собой эфир серной кислоты, эфир фосфорной кислоты, эфир борной кислоты, группу сульфокислоты, группу фосфоновой кислоты, группу тиокарбоновой кислоты, группу дитиокарбоновой кислоты, их производное или аналог.
17. Композиция по п. 15, отличающаяся тем, что указанный остаток выбран из группы, состоящей из арабинозы, рибозы, ксилозы, глюкозы, галактозы, сорбозы, фруктозы, мальтозы, сахарозы, лактозы, трегалозы, этиленгликоля, пропиленгликоля, глицерина, треитола, эритритола, пентаэритритола, рибитола,, арабитола, сорбитола, маннитола, лактитола, мальтитола, фруктитола, глюцитола, ксилитола или инозитола.
18. Композиция по п. 15, отличающаяся тем, что полианион является полисульфатированной сахарозой, имеющей от 3 до 8 сульфатных групп на молекулу.
19. Композиция по п. 15, отличающаяся тем, что полисульфатированная сахароза представляет собой сахарозооктасульфат.
20. Композиция по п. 15, отличающаяся тем, что полианион представляет собой инозитол гексафосфат.
21. Композиция по п. 15, отличающаяся тем, что концентрация аниона внутри липосомы составляет, по меньшей мере, около 0,05, 0,1, 0,2, 0,5, 0,6 0,7 или 1,0 грамм-эквивалент/л.
22. Композиция по п. 21, отличающаяся тем, что концентрация аниона внутри липосомы составляет около 0,65 грамм-эквивалента/л или около 1,0 грамм-эквивалента/л.
23. Композиция по пп. 1-14, дополнительно включающая вещество, отличное от упомянутого замещенного аммония и упомянутого аниона.
24. Композиция по п. 23, отличающаяся тем, что указанное вещество является полностью катионным веществом, терапевтическим агентом или детектируемым маркером.
25. Композиция по п. 23, отличающаяся тем, что указанное вещество содержится во внутреннем пространстве в концентрации, которая превосходит концентрацию этого вещества в среде.
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US20160030342A1 (en) 2016-02-04
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US20160095817A1 (en) 2016-04-07
KR101376895B1 (ko) 2014-03-25
FR17C1027I1 (ru) 2017-09-08
US11052079B2 (en) 2021-07-06
HUE068934T2 (hu) 2025-02-28
CA2566007A1 (en) 2005-11-17
EP1746976A4 (en) 2010-09-29
FIC20250005I1 (fi) 2025-01-20
US9730891B2 (en) 2017-08-15
JP4971142B2 (ja) 2012-07-11
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US9782349B2 (en) 2017-10-10
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US20160081928A1 (en) 2016-03-24
RU2006142766A (ru) 2008-06-20
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AU2005240131C1 (en) 2014-05-08
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US20070116753A1 (en) 2007-05-24
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CN107811971B (zh) 2021-10-29
CA2821167C (en) 2016-06-28
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