Quality-by-Design-Assisted Laboratory Scale-Up of Lipid Nanoparticles of Stearic Acid–Raloxifene Hydrochloride Conjugate: A Pathway for Enhanced Oral Bioavailability via Lymphatic Uptake

Despite exhibiting promising efficacy in managing postmenopausal osteoporosis, hormonal therapy, and breast cancer prevention, the usage of raloxifene hydrochloride (RLX) is limited in clinical settings due to its low aqueous solubility (345.2 ± 15.6 μg/mL) and 2% oral bioavailability. Oral administration of RLX results in the formation of an inactive glucuronide conjugate at free hydroxyl groups in the presence of hepatic and extrahepatic UDP-glucuronosyltransferases (UGTs). To circumvent RLX transformation, lipid-drug-conjugate-based lymphatic targeting may offer a suitable alternative. Therefore, we synthesized a stearic acid-raloxifene hydrochloride (SRC) conjugate and confirmed it using ATR-FT-IR, ¹H NMR, and HR-MS spectral techniques. Further, SRC was amalgamated with optimized lipid nanoparticles (SRC@LNPs4) to improve its stability under simulated physiological conditions. SRC@LNPs4 demonstrated remarkably improved stability of SRC compared to SRC alone when incubated with SGF, SIF, porcine lipoprotein lipase, and lipase-simulated plasma. Furthermore, biocompatibility analysis conducted with HT-29 cells ensured its safety for oral administration. Micrographic evaluation of rat intestines incubated with C6@LNPs indicated improved uptake of LNPs into enteric epithelia. Female Wistar rats orally administered with SRC@LNPs4 (∼10 mg/kg of RLX) exhibited a hike (unpaired <i>t</i>-test, <i>p</i> < 0.05) of 1.87-fold in the AUC_0-<i>_t</i> of SRC@LNPs4 (43.04 ± 0.50 h·μg/mL) compared to RLX (22.95 ± 4.30 h·μg/mL) Furthermore, the notable changes observed in the pharmacokinetic parameters of SRC@LNPs4 in rats previously injected with cycloheximide (CHX; 3 mg/kg) suggest that the drug is primarily absorbed into systemic circulation through lymphatic uptake. In conclusion, SRC@LNPs4 presents a valuable strategy to augment oral absorption and bioavailability via lymphatic targeting.