Вопросы изучения кинетики высвобождения лекарственных средств из имплантатов, формируемых in situ (обзор)

Введение. Имплантаты, формируемые in situ (in situ forming implants, ISFI), представляют собой жидкие лекарственные формы (ЛФ), образующие твердую полимерную матрицу непосредственно в месте введения в ответ на физиологические стимулы. Данные системы обеспечивают длительное локализованное высвобождение активных фармацевтических субстанций (АФС), что делает их перспективными для терапии различных заболеваний. Ключевой проблемой их фармацевтической разработки является отсутствие надежных прогностических моделей, связывающих in-vitro-кинетику с поведением in vivo.

Текст. В данном обзоре представлен систематический и критический анализ существующих методов in vitro для оценки высвобождения лекарственных средств из ISFI, подходов к выбору биорелевантных сред, математического моделирования, а также обоснованы основные направления для установления корреляции in vitro – in vivo (IVIVC). Были рассмотрены основные группы методов изучения высвобождения, такие как тест «Растворение» с использованием различных аппаратов, диализные методы и метод проб и разделения, а также более современные подходы, включая метод замены среды и диффузию в агарозной матрице. Показано, что выбор биорелевантной среды растворения, учитывающей специфику микроокружения в месте имплантации (синовиальная, гингивальная, интерстициальная, слезная жидкость, опухолевое микроокружение), является критически важным фактором для получения прогностически ценных данных. Проанализированы возможности классических (нулевого и первого порядка, Хигучи, Корсмайера – Пеппаса) и механистических математических моделей для описания сложной кинетики высвобождения, определяемой взаимосвязанными процессами диффузии, набухания и деградации полимерной матрицы. Центральное место занимает анализ прецедентов установления IVIVC для ISFI, от первой линейной корреляции до впервые в мире успешно разработанной и валидированной корреляции уровня А.

Заключение. Установление IVIVC для ISFI не является принципиально невозможным, но требует системного инжиниринга методов in vitro с акцентом на биомиметическую настройку геометрических параметров и состава среды. Ключевыми направлениями будущих исследований являются создание интегрированных тест-систем, включение в протоколы биологических факторов и применение методов неинвазивного мониторинга.

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