Uniform and amorphous rifampicin microspheres obtained by freezing induced LLPS during lyophilization

详细信息    查看全文

• 作者：Chun Liu^a ; ^c ; Chao Kong^a ; ^c ; Guoliang Wu^a ; ^c ; Junhao Zhu^b ; ^c ; Babak Javid^b ; ^c ; Feng Qian^a ; ^c ; ^{qianfeng@biomed.tsinghua.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：LLPS ; liquid&ndash ; liquid phase separation ; RIF ; rifampicin ; TBA ; tert-butyl alcohol ; POM ; polarized microscope ; SEM ; scanning electron microscopy ; DLS ; dynamic light scattering ; PXRD ; powder X-ray diffraction ; Mtb ; mycobacterium tuberculosis ; TB ; tuberculosis ; AM桅 ; alveolar macrophage ; DPI ; dry powder inhaler ; DNA ; deoxyribonucleic acid ; RNA ; ribonucleic acid ; ATCC ; American type culture collection ; FBS ; fetal bovine serum ; PMA ; phorbol myristate acetate ; API ; active pharmaceutical ingredient
• 刊名：International Journal of Pharmaceutics
• 出版年：2015
• 出版时间：10 November 2015
• 年：2015
• 卷：495
• 期：1
• 页码：500-507
• 全文大小：2054 K

文摘

By lyophilization of rifampicin (RIF) solution in TBA/water with various solvent compositions, uniform and amorphous rifampicin (RIF) microspheres were produced. Using 55% TBA solution, the obtained RIF microspheres have a mono-dispersive size distribution with diameters range from 1 to 3 渭m. The RIF microspheres are found to be amorphous by X-ray diffraction, and are expected to dissolve much faster than the crystalline RIF upon inhalation. Mechanistic investigation revealed that the amorphous RIF microspheres were formed due to liquid–liquid phase separation (LLPS) occurred during the freezing of the TBA/water solution. We also observed that the RIF microspheres can be readily phagocytized by activated THP-1 cells within 15 min. The suitable size distribution, high solubility, and readiness for phagocytosis by macrophages, all suggest that the lyophilized amorphous RIF microspheres could be potentially used as an anti-tuberculosis inhalation therapy. In addition, similar process was used to lyophilize TBA/water solutions of several other drugs, including rifaximin, rifapentine, paclitaxel, and isoniazid. We found that for drugs with appropriate physiochemical properties, such as paclitaxel and rifaximin, mono-dispersive microspheres could be obtained as well, which demonstrated that freezing induced LLPS could be utilized as a novel particle engineering methodology to produce drug microspheres by lyophilization.