Microphase separation in solid lipid dosage forms as the cause of drug release instability

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• 作者：Diogo Gomes Lopes^a ; ^b ; Ioannis Koutsamanis^a ; ^b ; Karin Becker^b ; Otto Scheibelhofer^a ; Peter Laggner^a ; ^c ; Detlev Haack^d ; Michael Stehr^e ; Andreas Zimmer^b ; Sharareh Salar-Behzadi^a ; ^{sharareh.salar-behzadi@rcpe.at}
• 关键词：Solid lipid excipients ; Drug release stability ; Hot-melt coating ; Polymorphism ; Microphase separation
• 刊名：International Journal of Pharmaceutics
• 出版年：2017
• 出版时间：30 January 2017
• 年：2017
• 卷：517
• 期：1-2
• 页码：403-412
• 全文大小：3883 K
• 卷排序：517

文摘

Although lipid excipients are of increasing interest for development of taste-masked and modified release formulations, the drug release instability and the lack of mechanistic understanding in that regard still prevent their larger-scale application. In this work, we investigated the physical stability of a binary (tripalmitin/polysorbate 65) lipid coating formulation with a known stable polymorphism. The coating composition was characterized using DSC to construct the phase diagram of binary system and polarized light microscopy to display the microstructure organization. The water uptake and the erosion of slabs cast from the coating formulations were investigated post-production and after storage. Subsequently, N-acetylcysteine particles were coated with the selected formulations and the drug release stability was investigated. Additionally, microstructure characterization was performed via SEM and X-ray diffraction. The drug release instability was explained by polysorbate 65 and tripalmitin phase growth during storage, especially at 40 °C, suggesting that polysorbate 65 can leak out of tripalmitin spherulitic structures, creating lipophilic and impermeable tripalmitin regions. The growth of polysorbate 65 phase leads to larger hydrophilic channels with reduced tortuosity. This work indicates that for obtaining stable drug release profiles from advanced lipid formulations, microphase separation should be prevented during storage.