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

OBJECTIVE: 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 two-fold 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.

Nanoemulsion improves hypoglycemic efficacy of berberine by overcoming its gastrointestinal challenge.

Berberine (BBR) is an important natural product with poor gastrointestinal behavior includes low permeability, P-glycoprotein efflux, and mass elimination in the intestine. The aim of this study was to develop a novel nanoemulsion (NE) to improve the hypoglycemic efficacy of BBR. NE was prepared and characterized by morphology and droplet size detection, stored stability, in vitro intestinal lipolysis and metabolism, Caco-2 cells transport, in situ single-pass intestinal perfusion, oral bioavailability in rats, and hypoglycemic efficacy in high-fat diet and streptozocin-induced mice. BBR-loaded NE exhibits small droplet size (30.56 ±â€¯0.35 nm) and good stability. NE could remain intact after lipolysis and protect BBR against the intestinal metabolism mediated by CYP2D6 and CYP3A4. Cells transport and intestinal perfusion studies revealed that NE decreases the P-glycoprotein efflux of BBR by 2-fold and enhances its permeability by 5.5-fold. Consequently, NE increased the oral bioavailability of BBR in rats by 212.02%. Compared to BBR control, blood glucose level of diabetic mice by NE was decreased by 3-fold. This novel NE provides a promising carrier to improve the hypoglycemic efficacy of BBR by overcoming its gastrointestinal deficiency, which may offer a product for the therapy of diabetes.