ABSTRACT
Oral formulations of nanoemulsions (NE) were systematically designed, and then their effects on oral absorption of raloxifene (RAL), including their absorption mechanisms were investigated. RAL solubility in water and various excipients of NE and oil-water partition coefficient[P(O/W)] of RAL were examined. Next the optimal compatibility between emulsifiers and oils in NE were ascertained by emulsification ability. Proportions of each component and optimal RAL-NE were fully confirmed by a pseudo-ternary phase diagram and drug loading, respectively. RAL-NE quality was evaluated by particle size, zeta potential, morphology, entrapment efficiency and stability in simulated gastrointestinal fluid. A MDCK cell model was used to study the in vitro transport mechanism of RAL-NE. Oral bioavailability of RAL-NE was eventually performed in SD rats. RAL can be classified as BCSⅡ based on the solubility and P(O/W). The best formulation of RAL-NE was composed of linoleic acid (LOA):isopropyl palmitate (IPP):cremophor RH40 (RH40):alcohol as 1.67:3.33:3:2. Drug loading in pre-nanoemulsion was 15 mg·g-1 andentrapment efficiency of RAL in NE was (79.4 ±0.4)%. The particle size, zeta potential and drug content of RAL-NE were maintained in the simulated gastrointestinal fluid. The in vitro transport mechanism of RAL-NE in MDCK cells was mainly clathrin-mediated endocytosis. The oral bioavailability of RAL in RAL-NE relative to RAL-suspension was 171.9%. The best formulation of RAL-NE studied systematically was confirmed to significantly improve the RAL absorption by in vitro and in vivo evaluations (P < 0.05). This paper provides references for oral NE research and development.
ABSTRACT
OBJECTIVE:To study formulation design of raloxifene nanoemulsion. METHODS: The solubilities of raloxifene in excipients of nanoemulsion were investigated. On the basis, emulsifier and oil were selected by the emulsifying ability. The combination and optimum proportion among co-emulsifier, oil and emulsifier were determined by the pseudo-ternary phase diagram. The effect of raloxifene on nanoemulsion prescription was studied by drug loading. Finally chitosan and carboxylated chitosan were used to regulate the Zeta potential of raloxifene nanoemulsions. RESULTS: The optimum formulation ratio of LOA, IPP, RH40 and ethanol for loading 15 mg raloxifene is 0.167 g∶0.333 g∶0.3 g∶0.2 g, respectively. The Zeta potentials of the nanoemulsions can be changed by chitosan and carboxylated chitosan from -0.954 mV to 20 mV and -13 mV or so,respectively. The effect of different pH and dilution times on stability of formulations were slight. CONCLUSION: The formulations of raloxifene nanoemulsion including positive, negative and near zero Zeta potential were obtained, which have laid a foundation for absorption mechanism study of the raloxifene nanoemulsion.