Oral Drug Delivery Innovation, Lonza Global R&D, Melbourne, Australia.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
Pharm Res. 2021 Jun;38(6):1125-1137. doi: 10.1007/s11095-021-03063-3. Epub 2021 Jun 7.
Successful oral peptide delivery faces two major hurdles: low enzymatic stability in the gastro-intestinal lumen and poor intestinal membrane permeability. While lipid-based formulations (LBF) have the potential to overcome these barriers, effective formulation of peptides remains challenging. Lipophilic salt (LS) technology can increase the apparent lipophilicity of peptides, making them more suitable for LBF.
As a model therapeutic peptide, octreotide (OCT) was converted to the docusate LS (OCT.DoS), and compared to the commercial acetate salt (OCT.OAc) in oral absorption studies and related in vitro studies, including parallel artificial membrane permeability assay (PAMPA), Caco-2, in situ intestine perfusion, and simulated digestion in vitro models. The in vivo oral absorption of OCT.DoS and OCT.OAc formulated in self-emulsifying drug delivery systems (SEDDS) was studied in rats.
LS formulation improved the solubility and loading of OCT in LBF excipients and OCT.DoS in combination with SEDDS showed higher OCT absorption than the acetate comparator in the in vivo studies in rats. The Caco-2 and in situ intestine perfusion models indicated no increases in permeability for OCT.DoS. However, the in vitro digestion studies showed reduced enzymatic degradation of OCT.DoS when formulated in the SEDDS formulations. Further in vitro dissociation and release studies suggest that the enhanced bioavailability of OCT from SEDDS-incorporating OCT.DoS is likely a result of higher partitioning into and prolonged retention within lipid colloid structures.
The combination of LS and LBF enhanced the in vivo oral absorption of OCT primarily via the protective effect of LBF sheltering the peptide from gastrointestinal degradation.
成功的口服肽递药面临两个主要障碍：在胃肠道腔中的低酶稳定性和差的肠黏膜通透性。虽然基于脂质的制剂（LBF）有可能克服这些障碍，但肽的有效制剂仍然具有挑战性。亲脂性盐（LS）技术可以增加肽的表观亲脂性，使其更适合 LBF。
以奥曲肽（OCT）作为模型治疗性肽，将其转化为月桂基磺酸钠盐（OCT.DoS），并在口服吸收研究和相关的体外研究中与商业乙酸盐（OCT.OAc）进行比较，包括平行人工膜渗透测定法（PAMPA）、Caco-2 细胞、原位肠灌注和模拟体外消化模型。在大鼠中研究了以自乳化药物递送系统（SEDDS）形式配制的 OCT.DoS 和 OCT.OAc 的体内口服吸收。
LS 制剂提高了 LBF 赋形剂中 OCT 的溶解度和载药量，并且 OCT.DoS 与 SEDDS 联合使用时，在大鼠体内研究中显示出比乙酸盐对照物更高的 OCT 吸收。Caco-2 和原位肠灌注模型表明，OCT.DoS 的通透性没有增加。然而，体外消化研究表明，当将 OCT.DoS 配制在 SEDDS 制剂中时，其酶降解减少。进一步的体外解离和释放研究表明，SEDDS 结合 OCT.DoS 增强了 OCT 的生物利用度，可能是由于其更有效地分配到脂质胶体结构中并延长保留时间。
LS 和 LBF 的结合主要通过 LBF 对肽的保护作用，从而增强了 OCT 的体内口服吸收，使其免受胃肠道降解的影响。
