Ilie Alexandra-Roxana, Griffin Brendan T, Brandl Martin, Bauer-Brandl Annette, Jacobsen Ann-Christin, Vertzoni Maria, Kuentz Martin, Kolakovic Ruzica, Holm René
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. 2020 Sep 1;152:105452. doi: 10.1016/j.ejps.2020.105452. Epub 2020 Jul 3.
Supersaturated lipid-based drug delivery systems have recently been investigated for oral administration for a variety of lipophilic drugs and have shown either equivalent or superior oral bioavailability compared to conventional non-supersaturated lipid-based drug delivery systems. The aim of the present work was to explore supersaturated versus non-supersaturated lipid-based systems at equivalent lipid doses, on in vivo bioavailability in rats and on in vitro permeation across a biomimetic Permeapad membrane to establish a potential in vivo - in vitro correlation. A secondary objective was to investigate the influence of lipid composition on in vitro and in vivo performance of lipid systems. Results obtained indicated that increasing the celecoxib load in the lipid-based formulations by thermally-induced supersaturation resulted in increased bioavailability for medium and long chain mono-/di-glycerides systems relative to their non-supersaturated (i.e. 85%) reference formulations, albeit only significant for the medium chain systems. Long chain systems displayed higher celecoxib bioavailability than equivalent medium chain systems, both at supersaturated and non-supersaturated drug loads. In vitro passive permeation of celecoxib was studied using both steady-state and dynamic conditions and correlated well with in vivo pharmacokinetic results with respect to compositional effects. In contrast, permeation studies indicated that flux and percentage permeated of supersaturated systems, either at steady-state or under dynamic conditions, decreased or were unchanged relative to non-supersaturated systems. This study has shown that by using two cell-free Permeapad permeation models coupled with rat-adapted gastro-intestinal conditions, bio-predictive in vitro tools can be developed to be reflective of in vivo scenarios. With further optimization, such models could be successfully used in pharmaceutical industry settings to rapidly screen various prototype formulations prior to animal studies.
近年来，人们对用于多种亲脂性药物口服给药的过饱和脂质体药物递送系统进行了研究，与传统的非过饱和脂质体药物递送系统相比，其口服生物利用度相当或更高。本研究的目的是在等效脂质剂量下，探索过饱和与非过饱和脂质体系统对大鼠体内生物利用度以及对通过仿生Permeapad膜的体外渗透的影响，以建立潜在的体内-体外相关性。第二个目标是研究脂质组成对脂质体系统体外和体内性能的影响。所得结果表明，通过热诱导过饱和增加脂质体制剂中塞来昔布的载药量，相对于其非过饱和（即85%）参比制剂，中链和长链单/双甘油酯系统的生物利用度有所提高，尽管仅中链系统具有显著性差异。在过饱和和非过饱和药物载量下，长链系统的塞来昔布生物利用度均高于等效的中链系统。使用稳态和动态条件研究了塞来昔布的体外被动渗透，并在组成效应方面与体内药代动力学结果具有良好的相关性。相比之下，渗透研究表明，过饱和系统在稳态或动态条件下的通量和渗透百分比相对于非过饱和系统降低或未发生变化。本研究表明，通过使用两种无细胞Permeapad渗透模型并结合大鼠适应的胃肠道条件，可以开发出具有生物预测性的体外工具，以反映体内情况。通过进一步优化，此类模型可成功应用于制药行业，在动物研究之前快速筛选各种原型制剂。
