School of Chemical and Bioprocess Engineering, University College Dublin, Dublin 4, Ireland.
SSPC, The SFI Research Centre for Pharmaceuticals, School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College Dublin, Dublin 2, Ireland.
Mol Pharm. 2020 Sep 8;17(9):3412-3424. doi: 10.1021/acs.molpharmaceut.0c00467. Epub 2020 Aug 27.
Active pharmaceutical ingredient (API)-based ionic liquids (API-ILs) present an exciting new paradigm for the formulation of poorly water-soluble drugs. In this study, a model room temperature API-IL (1-butyl-3-methyl imidazolium ibuprofenate) was demonstrated to be not just highly soluble but fully miscible and hence have effectively unlimited solubility in water, compared to 0.021 mg mL solubility for the ibuprofen API. Solutions of the API-IL were found to be stable for up to 2 years, indicating that they have the potential to offer thermodynamic stability upon release, avoiding recrystallization issues that can limit the bioavailability of amorphous solid dispersions (ASDs) and some high-energy crystalline forms. The ibuprofen API-IL was successfully spray-dried into a polymer carrier in loadings of up to 75% w/w in order to transform it into a solid powder suitable for oral solid dosage (OSD) formulation. From modulated differential scanning calorimetry, hot-stage microscopy, powder X-ray diffraction, and attenuated total reflectance Fourier transform infrared spectroscopy measurements, the mechanism by which this high loading was achieved is based on the immiscibility between the polymer and API-IL, with the polymer encapsulating the phase-separated API-IL. Dissolution studies showed that solidification of the API-IL into microcapsules by spray drying in this manner had no detrimental effect on release characteristics. Failure to dissolve crystalline API forms into the polymer matrix eliminates the solubility enhancement of ASDs but not for highly soluble or fully miscible API-ILs. Furthermore, miscible API-IL/polymer dispersions at high loadings were found to possess less-favorable physical properties because of melting point depression, resulting, in some cases, in a failure to form a viable powder. As such, microencapsulated API-ILs at high loadings in immiscible or low-miscibility polymers that have solubility enhancement of the API-IL form, while providing solid powders for processing, represent a promising new platform for the formulation of poorly soluble compounds as OSDs.
基于活性药物成分 (API) 的离子液体 (API-IL) 为难溶性药物的制剂提供了一个令人兴奋的新范例。在这项研究中,与布洛芬 API 的 0.021mg/mL 溶解度相比,模型室温 API-IL(1-丁基-3-甲基咪唑丁酸盐)不仅具有高溶解度,而且完全混溶,因此在水中具有有效无限的溶解度。API-IL 的溶液发现稳定长达 2 年,表明它们有可能在释放时提供热力学稳定性,避免可能限制无定形固体分散体 (ASD) 和一些高能晶型生物利用度的再结晶问题。布洛芬 API-IL 成功地喷雾干燥到高达 75% w/w 的聚合物载体中,以将其转化为适合口服固体制剂 (OSD) 制剂的固体粉末。通过调制差示扫描量热法、热台显微镜、粉末 X 射线衍射和衰减全反射傅里叶变换红外光谱测量,实现这种高负载的机制基于聚合物和 API-IL 之间的不混溶性,聚合物封装相分离的 API-IL。溶解研究表明,通过喷雾干燥将 API-IL 固化成微胶囊的方式对释放特性没有不利影响。未能将结晶 API 形式溶解到聚合物基质中会消除 ASD 的溶解度增强,但对于高溶解度或完全混溶的 API-IL 则不会。此外,高负载下可混溶的 API-IL/聚合物分散体由于熔点降低而具有较差的物理性质,在某些情况下,无法形成可行的粉末。因此,在不混溶或低混溶性聚合物中以高负载量包埋 API-IL 的微胶囊具有 API-IL 形式的溶解度增强,同时为加工提供固体粉末,代表了作为 OSD 制剂的难溶性化合物的一个有前途的新平台。
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