<p>A Non-Lipolysis Nanoemulsion Improved Oral Bioavailability by Reducing the First-Pass Metabolism of Raloxifene, and Related Absorption Mechanisms Being Studied</p>

Abstract

A non-lipolysis nanoemulsion (NNE) was designed to reduce the first-pass metabolism of raloxifene (RAL) by intestinal UDP-glucuronosyltransferases (UGTs) for increasing the oral absorption of RAL, coupled with in vitro and in vivo studies. Methods: In vitro stability of NNE was evaluated by lipolysis and the UGT metabolism system. The oral bioavailability of NNE was studied in rats and pigs. Finally, the absorption mechanisms of NNE were investigated by in situ single-pass intestinal perfusion (SPIP) in rats, Madin-Darby canine kidney (MDCK) cells model, and lymphatic blocking model. Results: The pre-NNE consisted of isopropyl palmitate, linoleic acid, Cremophor RH40, and ethanol in a weight ratio of 3.33:1.67:3:2. Compared to lipolysis nanoemulsion of RAL (RAL-LNE), the RAL-NNE was more stable in in vitro gastrointestinal buffers, lipolysis, and UGT metabolism system (p < 0.05). The oral bioavailability was significantly improved by the NNE (203.30%) and the LNE (205.89%) relative to the suspension group in rats. However, 541.28% relative bioavailability was achieved in pigs after oral NNE intake compared to the suspension and had twofold greater bioavailability than the LNE (p < 0.05). The RAL-NNE was mainly absorbed in the jejunum and had high permeability at the intestine of rats. The results of both SPIP and MDCK cell models demonstrated that the RAL-NNE was absorbed via endocytosis mediated by caveolin and clathrin. The other absorption route, the lymphatic transport (cycloheximide as blocking agent), was significantly improved by the NNE compared with the LNE (p < 0.05). Conclusion: A NNE was successfully developed to reduce the first-pass metabolism of RAL in the intestine and enhance its lymphatic transport, thereby improving the oral bioavailability. Altogether, NNE is a promising carrier for the oral delivery of drugs with significant first-pass metabolism.

Hybrid Lymphatic Drug Delivery Vehicles as a New Avenue for Targeted Therapy: Lymphatic Trafficking, Applications, Challenges, and Future Horizons

“…In this regard, Ye et al developed lipid nanoparticles (LNPs) as LDDS to increase raloxifene bioavailability through LS (Ye et al 2020 ). Similarly, Rangaraj et al prepared nanoscaled lipids materials as LDDS to enhance the bioavailability of Ibrutinib through the LS channel.…”

A randomized, open-label, single-dose, two-way crossover study to assess the pharmacokinetics between two tablets of fixed-dose combination formulation with raloxifene and cholecalciferol and concomitant administration of each agents in healthy male volunteers

“…One plausible factor responsible for the large intersubject %CV for the FDC formulation could be the formulation complexities. The aqueous solubility of raloxifene is poor [ 5 ]. Mitra et al [ 19 ] reported that dissolution from the FDC formulation could slow down if high drug loading is required owing to restrictions on its final size [ 19 ].…”

“…This drug reduces bone resorption and turnover, leading to increased bone mineral density. Raloxifene is used as a first-line drug to treat and prevent osteoporosis in postmenopausal women [ 5 ]. In 3,204 postmenopausal women with osteopenia or osteoporosis, raloxifene 60 mg administered once daily for 3 years significantly decreased the risk of new vertebral fractures compared to that in the placebo group [ 6 ].…”

An update on oral drug delivery via intestinal lymphatic transport

“…The harsh gastrointestinal environment owing to secretion of gastric acid, various surfactants and enzymes tends to degrade or inactivate certain labile entities including both small molecular drugs and biomacromolecules 9 , 10 , 11 , 12 . Some therapeutic compounds are stable and absorbable in the GIT, but are susceptible to first-pass hepatic metabolism and suffer from extremely low bioavailability 13 , 14 . Moreover, the enteric epithelia may also present as a formidable barrier to the entry of entities of less favorable properties 15 , 16 .…”