Department of Pharmacy, Science for Life Laboratory, Uppsala University, Uppsala 75123, Sweden.
Department of Pharmacy, University of Copenhagen, Copenhagen 2100, Denmark.
ACS Appl Mater Interfaces. 2022 May 18;14(19):21978-21988. doi: 10.1021/acsami.2c03556. Epub 2022 Apr 22.
Superparamagnetic iron oxide nanoparticles (SPIONs) generate heat upon exposure to an alternating magnetic field (AMF), which has been studied for hyperthermia treatment and triggered drug release. This study introduces a novel application of magnetic hyperthermia to induce amorphization of a poorly aqueous soluble drug, celecoxib, in situ in tablets for oral administration. Poor aqueous solubility of many drug candidates is a major hurdle in oral drug development. A novel approach to overcome this challenge is in situ amorphization of crystalline drugs. This method facilitates amorphization by molecular dispersion of the drug in a polymeric network inside a tablet, circumventing the physical instability encountered during the manufacturing and storage of conventional amorphous solid dispersions. However, the current shortcomings of this approach include low drug loading, toxicity of excipients, and drug degradation. Here, doped SPIONs produced by flame spray pyrolysis are compacted with polyvinylpyrrolidone and celecoxib and exposed to an AMF in solid state. A design of experiments approach was used to investigate the effects of SPION composition (ZnFeO and MnFeO), doped SPION content (10-20 wt %), drug load (30-50 wt %), and duration of AMF (3-15 min) on the degree of drug amorphization. The degree of amorphization is strongly linked to the maximum tablet temperature achieved during the AMF exposure ( = 0.96), which depends on the SPION composition and content in the tablets. Complete amorphization is achieved with 20 wt % MnFeO and 30 wt % celecoxib in the tablets that reached the maximum temperature of 165.2 °C after 15 min of AMF exposure. Furthermore, manganese ferrite exhibits no toxicity in human intestinal Caco-2 cell lines. The resulting maximum solubility of in situ amorphized celecoxib is 5 times higher than that of crystalline celecoxib in biorelevant intestinal fluid. This demonstrates the promising capability of SPIONs as enabling excipients to magnetically induce amorphization in situ in oral dosage forms.
超顺磁氧化铁纳米粒子 (SPIONs) 在暴露于交变磁场 (AMF) 时会产生热量，这已经在热疗和触发药物释放方面进行了研究。本研究介绍了磁热疗的一种新应用，即在口服片剂中就地诱导水中溶解度差的药物塞来昔布的非晶化。许多候选药物的水中溶解度差是口服药物开发的主要障碍。克服这一挑战的一种新方法是将结晶药物就地非晶化。该方法通过在片剂中的聚合物网络中使药物分子分散来促进非晶化，从而避免了在制造和储存常规无定形固体分散体时遇到的物理不稳定性。然而，目前该方法的缺点包括药物载药量低、赋形剂毒性和药物降解。在此，通过火焰喷雾热解法制备的掺杂 SPIONs 与聚乙烯吡咯烷酮和塞来昔布压缩在一起，并在固态下暴露于 AMF。使用实验设计方法研究了 SPION 组成 (ZnFeO 和 MnFeO)、掺杂 SPION 含量 (10-20wt%)、药物负载量 (30-50wt%) 和 AMF 持续时间 (3-15min) 对药物非晶化程度的影响。非晶化程度与 AMF 暴露期间达到的片剂最高温度密切相关 ( = 0.96)，这取决于片剂中的 SPION 组成和含量。在片剂中含有 20wt% MnFeO 和 30wt%塞来昔布时可以实现完全非晶化，在 15min AMF 暴露后达到 165.2°C 的最高温度。此外，在人肠 Caco-2 细胞系中，锰铁氧体没有毒性。原位非晶化塞来昔布的最大溶解度比生物相关肠液中结晶塞来昔布高 5 倍。这表明 SPIONs 作为赋形剂具有在口服剂型中磁致就地非晶化的有前途的能力。
