RU2016113283A - Жидкие составы белков, содержащие средства для снижения вязкости - Google Patents
Жидкие составы белков, содержащие средства для снижения вязкости Download PDFInfo
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Claims (41)
1. Фармацевтический состав для инъекции, содержащий
(i) один или несколько белков;
(ii) одно или несколько средств для снижения вязкости, причем средства для снижения вязкости являются объемными полярными органическими соединениями, выбранными из группы, состоящей из гидрофобных соединений, а также активных и неактивных фармацевтических ингредиентов, разрешенных для инъекции;
(iii) фармацевтически приемлемый растворитель;
где, когда белки комбинируют с растворителем, и средства для снижения вязкости находятся в объеме, подходящем для инъекции, состав имеет абсолютную вязкость от приблизительно 1 сП до приблизительно 50 сП при 25°C, как измеряют, используя вискозиметр с конусом и плоскостью; и абсолютная вязкость состава является меньшей, чем абсолютная вязкость другого такого же состава, содержащего эквивалентное количество фосфата натрия вместо средства для снижения вязкости;
где абсолютная вязкость в каждом случае является экстраполированной вязкостью при нулевой скорости сдвига.
2. Состав по п. 1, где белок(белки) имеют молекулярную массу между приблизительно 70 до 100 кДа, между приблизительно 100 кДа до приблизительно 250 кДа, или от приблизительно 250 кДа до приблизительно 500 кДа.
3. Состав по любому из пп. 1 и 2, где белки имеют молекулярную массу от приблизительно 120 кДа до приблизительно 250 кДа.
4. Состав по любому из пп. 1-3, где по меньшей мере один из белков представляет собой фермент, антитело или фрагмент антитела, гибридный белок или ПЭГилированный белок.
5. Состав по любому из пп. 1-4, где белок(белки) присутствуют в комбинированном количестве от приблизительно 100 мг до приблизительно 2000 мг на 1 мл (мг/мл); необязательно больше чем приблизительно 150 мг/мл.
6. Состав по любому из пп. 1-5, где состав содержит по меньшей мере два различных белка предпочтительно, где оба белка имеют молекулярную массу по меньшей мере приблизительно 50 кДа.
7. Состав по любому из пп. 1-6, где первоначальная абсолютная вязкость при такой же концентрации белка, как и перед добавлением средства для снижения вязкости, превышает приблизительно 50 сП, превышает приблизительно 80 сП или превышает приблизительно 100 сП.
8. Состав по любому из пп. 1-7, где жидкий состав является водным, имеющим pH между приблизительно 5,0 и приблизительно 8,0,
9. Состав по любому из пп. 1-8, содержащий средство для снижения вязкости, присутствующее в концентрации от приблизительно 0,01 M до приблизительно 1,0 M.
10. Состав по любому из пп. 1-9, содержащий средство для снижения вязкости, присутствующее в количестве менее чем 0,3 M или менее чем 0,15 M.
11. Состав по любому из пп. 1-10, содержащий один или несколько фармацевтически приемлемых эксципиентов для подкожной или внутримышечной инъекции, выбранных из группы, состоящей из сахаров или сахароспиртов, буферных агентов, консервантов, носителей, антиоксидантов, хелатирующих агентов, природных или синтетических полимеров, криопротекторов, лиопротекторов, поверхностно-активных веществ, объемообразующих агентов и стабилизаторов.
12. Состав по п. 11, где один или несколько эксципиентов выбраны из группы, состоящей из полисорбатов, полоксамера 188, лаурилсульфата натрия, полиола, выбранного из группы, состоящей из сахароспиртов, таких как маннит и сорбит), поли(этиленгликолей), глицерина, пропиленгликолей и поли(виниловых спиртов).
13. Состав по п. 11, где поверхностно-активное вещество присутствует в количестве менее чем приблизительно 10 мг/мл.
14. Состав по п. 12, содержащий полиол, присутствующий в количестве от приблизительно 2 мг/мл до приблизительно 900 мг/мл.
15. Состав по любому из п.п. 1-14, где абсолютная вязкость составляет от приблизительно 5 сП до приблизительно 50 сП при 25°C.
16. Состав по любому из п.п. 1-15, где абсолютная вязкость является по меньшей мере приблизительно на 30% меньшей, чем абсолютная вязкость состава без средства для снижения вязкости, когда ее измеряют при одинаковых условиях, за исключением замены средства для снижения вязкости на соответствующий буфер с приблизительно одинаковой концентрацией.
17. Состав по любому из п.п. 1-16, где абсолютная вязкость является по меньшей мере приблизительно в 2 раза или 4 раза ниже, чем абсолютная вязкость состава без средства для снижения вязкости, когда ее измеряют при одинаковых условиях, за исключением замены средства для снижения вязкости на соответствующий буфер с приблизительно одинаковой концентрацией.
18. Состав по любому из пп. 1-17 во флаконе, контейнере или предварительно заполненном шприце с однократной дозой.
19. Состав по п. 18, где белок, средство для снижения вязкости и/или эксципиенты находятся в виде сухого вещества, предпочтительно лиофилизированного.
20. Состав по любому из пп. 1-19, где объем состава, когда средство для снижения вязкости, белок и растворитель комбинируют, составляет менее чем приблизительно 1,5 мл для ПК инъекции, и менее чем приблизительно 3 мл для ВМ инъекции.
21. Состав по любому из пп. 1-20, где состав является изотоническим сыворотке крови человека.
22. Состав по любому из пп. 1-21, который имеет реологическое поведение, по существу, как у ньютоновской жидкости, при условиях, при которых он мог бы вводиться субъекту, нуждающемуся во введении.
23. Состав по любому из пп. 1-22, достигающий терапевтически эффективной дозировки в сравнении с такой же дозой белка, вводимой посредством внутривенной инфузии.
24. Состав по любому из пп. 1-23, где средства для снижения вязкости присутствуют в концентрации, которая не вызывает клинически значимых признаков токсичности или раздражения участка инъекции, когда ее вводят посредством подкожной или внутримышечной инъекции.
25. Состав по любому из пп. 1-24, где абсолютную вязкость состава измеряют при скорости сдвига, равной по меньшей мере приблизительно 0,5 с-1, когда измерение проводят, используя вискозиметр с конусом и плоскостью.
26. Состав по любому из пп. 1-24, где абсолютную вязкость состава измеряют при скорости сдвига, равной по меньшей мере приблизительно 1,0 с-1, когда измерение проводят, используя микрожидкостный вискозиметр.
27. Способ введения терапевтически эффективного количества белка, включающий подкожные или внутримышечные инъекции состава по любому из пп. 1-26.
28. Способ по п. 27, где подкожную или внутримышечную инъекцию выполняют с использованием шприца, выбранного из группы, состоящей из нагретых шприцев, самосмешивающих шприцев, автоматических инъекторов, предварительно заполненных шприцев и их комбинаций.
29. Способ по п. 28, где шприц представляет собой нагретый шприц, и состав вводят при температуре между 25 и 40°C.
30. Способ по п. 27, где состав производит индекс первичного раздражения менее 3, когда оценку проводят, используя систему оценки в баллах по Дрейзу.
31. Способ по любому из пп. 27-30, где усилие при инъекции является по меньшей мере на 10 или 20% меньше, чем усилие при инъекции для другого такого же состава без средства для снижения вязкости, вводимого таким же образом.
32. Способ по любому из пп. 27-31, где инъекцию вводят с помощью иглы с диаметром между 27 и 31 калибром, и усилие при инъекции составляет менее 30 Н с использованием иглы 27 калибра.
33. Способ получения фармацевтического состава, включающий стадию объединения белка, растворителя и средства для снижения вязкости по любому из пп. 1-26 с образованием жидкого состава.
34. Способ по п. 33, где дозированная единица состава находится в предварительно заполненном шприце или картридже.
35. Способ облегчения очистки белка, включающий добавление к раствору белка эффективного количества средства для снижения вязкости по любому из пп. 1 или 7-10 для снижения абсолютной вязкости раствора белка.
36. Способ по п. 35, где раствор белка-средства для снижения вязкости очищают или концентрируют с использованием способа, выбранного из группы, состоящей из ультрафильтраци/диафильтрации, тангенциальной поточной фильтрации, центрифужного концентрирования и диализа.
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