Drug Product Development, Janssen Research and Development, Johnson & Johnson, Beerse, Belgium; School of Pharmacy, University College Cork, Cork, Ireland.
School of Pharmacy, University College Cork, Cork, Ireland;.
Eur J Pharm Sci. 2021 Apr 1;159:105691. doi: 10.1016/j.ejps.2020.105691. Epub 2020 Dec 24.
Supersaturated lipid-based drug delivery systems are increasingly being explored as a bio-enabling formulation approach, particularly in preclinical evaluation of poorlywater-soluble drugs. While increasing the drug load through thermally-induced supersaturation resulted in enhanced in vivo exposure for some drugs, for others, such as cinnarizine, supersaturated lipid-based systems have not been found beneficial to increase the in vivo bioavailability. We hypothesized that incorporation of precipitation inhibitors to reduce drug precipitation may address this limitation. Therefore, pharmacokinetic profiles of cinnarizine supersaturated lipid-based drug delivery systems with or without precipitation inhibitors were compared. Five precipitation inhibitors were selected for investigation based on a high throughput screening of twenty-one excipients. In vivo results showed that addition of 5% precipitation inhibitors to long chain monoglyceride (LCM) or medium chain monoglyceride (MCM) formulations showed a general trend of increases in cinnarizine bioavailability, albeit only statistically significantly increased for Poloxamer 407 + LCM system (i.e. 2.7-fold increase in AUC compared to LCM without precipitation inhibitors). It appeared that precipitation inhibitors mitigated the risk of in vivo precipitation of cinnarizine from sLBDDS and overall, bioavailability was comparable to that previously reported for cinnarizine after dosing of non-supersaturated lipid systems. In summary, for drugs which are prone to precipitation from supersaturated lipid-based drug delivery systems, such as cinnarizine, inclusion of precipitation inhibitors mitigates this risk and provides the opportunity to maximize exposure which is ideally suited in early efficacy and toxicology evaluation.
超饱和脂质给药系统作为一种生物赋形剂方法，越来越多地被探索，特别是在难溶性药物的临床前评价中。虽然通过热诱导过饱和度增加药物负载可以提高一些药物的体内暴露量，但对于其他药物，如肉桂嗪，超饱和脂质给药系统并没有被发现有利于提高体内生物利用度。我们假设加入沉淀抑制剂以减少药物沉淀可能会解决这个问题。因此，比较了肉桂嗪超饱和脂质给药系统是否加入沉淀抑制剂的药代动力学特征。根据对 21 种赋形剂的高通量筛选，选择了五种沉淀抑制剂进行研究。体内结果表明，在长链单甘酯（LCM）或中链单甘酯（MCM）制剂中加入 5%的沉淀抑制剂通常会增加肉桂嗪的生物利用度，尽管只有泊洛沙姆 407+LCM 系统的增加具有统计学意义（即 AUC 与不含沉淀抑制剂的 LCM 相比增加了 2.7 倍）。沉淀抑制剂似乎减轻了肉桂嗪从 sLBDDS 中体内沉淀的风险，总体而言，生物利用度与之前报道的非超饱和脂质系统给药后的肉桂嗪相当。总之，对于易从超饱和脂质给药系统中沉淀的药物，如肉桂嗪，加入沉淀抑制剂可以降低这种风险，并提供了最大限度提高暴露量的机会，这在早期的疗效和毒理学评价中非常理想。
