| Baicalin (BC), as a kind of flavonoids, is the main effective component of radix scutellariae, and has widespread biopharmaceutics activities such as antibacterial, anti-inflammatory, antioxidant, diuresis, calm, step-down, immunosuppression and spasmolysis functions. As a potent bioactive agent, baicalin holds great promise in the application of pharmacy. In spite of superiorities, the use of BC in clinic is restricted owing to its low water-solubility induced weak stability, poor absorption and low bioavailability. To address this issue, plenty of formulations for solubilizing BC have been developed including solid lipid nanoparticles, gelling system, coprecipitate, phospholipid complex, solid nanocrystals and nanoemulsion. According to our research, mixed micelle formulations for improving the solubility and enhancing treatment effect of BC were not reported. Taking advantages of small particle size, high solubilization capacity, long circulation, hydrophilic shell and passive targeting ability, BC-loaded mixed micelles could improve the bioavailability of loading BC.Based on theory of synergistic effect, the mixed micelle system formed by multiple materials showed superior characteristics and attracted increasing attention. Mixed micelles successfully increased the solubility and bioavailability of hydrophobic drugs. Bile salts have the strong solubility and biocompatibility as anionic surface active agents, which play an important role in pharmaceutics. Sodium taurocholate (ST) combined by the carboxyl of bile acid and amino of taurine is extensively applied in pharmacy on account of surface-active advantage. Owing to non-toxicity, non-immunogenicity and biocompatibility, Pluronic P123 copolymer (poly (ethylene oxide)-b-poly (propylene oxide)-b-poly (ethylene oxide)) is employed as an appealing carrier material to solubilize and deliver drugs. According to literatures, both ST and P123 could form self-assembled micelles in aqueous solution as amphipathic molecule individually. To this end, it is expected that the mixed micelles composed of ST and P123 can incorporate insoluble drugs into the hydrophobic core. Recently, many researchers suggested the potential applications of mixed micelles in oral administration. In the present study, BC-loaded ST-P123-MMs were prepared by the thin-film dispersion method and optimized. Then the physicochemical properties of as-developed mixed micelles were characterized, such as particle size and zeta potential, morphology observation, phase analysis, and in vitro release study. Moreover, in situ intestine absorption and pharmacokinetics were also investigated to further confirm the superiority of BC-loaded ST-P123-MMs in enhancing the therapeutic effect in oral drug delivery system.1. Preparation and optimization of Baicalin-loaded mixed micelles by oral deliveryBased on properties of preparation methods and carrier materials, the thin-film hydration method was selected to prepare baicalin-loaded mixed micelles. After single factor experiments, feeding of P123 (X1, mg), feeding of ST (X2, mg), feeding of BC (X3, mg), hydration volume of deionized water (X4, mL) were further optimized by the uniform design. Taking the encapsulation efficiency as index, X1, X2, X3 were 100 mg,100 mg and 45 mg and X4 was 4 mL to constitute the optimal prescription.2. Characterization and release test in vitro of Baicalin-loaded mixed micelles by oral deliveryThe particles size and Zeta potential of baicalin-loaded mixed micelles were 14.16 nm and -10.80 mV, respectively. Under transmission electron microscopy (TEM), the mixed micelles showed obvious core-shell structure and spherical shape without conglutination. The results of phase analysis showed that the phase state of BC had changed and the drug was highly dispersed in the mixed micelles system. The critical micelle concentration (CMC) value was 6.70×10-3 g/L. Simulated gastric fluid and intestinal fluid were prepared as release media to simulate environment in vivo after oral administration. Results showed that the baicalin-loaded ST-P123-MMs manifested a certain delayed release.34% of BC was released from propylene glycol within 2 h and then 80% within 48 h. The release rate of BC from BC-loaded ST-P123-MMs was 15% within 2 h and then 55% within 48 h. The sustained release manner might be attributed to the fact that the drug inside the hydrophobic core of micelles was protected from the direct impact of external environment.3. In situ intestinal absorption test of Baicalin-loaded mixed micelles by oral delivery in ratsIntestinal absorption properties of baicalin and baicalin-loaded mixed micelles were investigated using in situ absorption test in rat intestine. The absorption rate equations of baicalin-perfusion fluid at low (27μg/mL), middle (54μg/mL), high (108μg/mL) concentration groups dose were lnXL=lnXo-0.0315t, lnXM =lnX0-0.0301t and lnXH=lnX0-0.0291t, respectively. There was no significant difference (P>0.05). Rate equations of baicalin-loaded mixed micelles solution were lnXL=lnX0-0.0770t, lnXM=lnX0-0.0906t and lnXH=lnX0-0.0843t at low (27μg/mL), middle (54μg/mL), high (108μg/mL) concentration groups, respectively. There was no significant difference (P>0.05). Percentage of absorption (P%) values of baicalin-perfusion fluid and baicalin-loaded mixed micelles in the range of 27-108 μg/mL had significant differences (P<0.01). These results revealed that baicalin-loaded mixed micelles could enhance absorption of baicalin in intestine obviously.4. Pharmacokinetics test of Baicalin-loaded mixed micelles by oral delivery in ratsBased on the results of in situ intestinal perfusion, pharmacokinetics test in vivo was conducted. Results showed that compared with baicalin suspension, the peak concentrations (Cmax) of baicalin increased from 8.95μg/mL to 13.37 μg/mL. And the area under the concentration-time curve (AUC) was improved from 322.51 μg/mL*h to 410.78μg/mL*h. Time to peak (Tmax) was delayed from 1.25 h to 8 h. There was significant difference (P<0.01). Taken together, mixed micelles can be considered as an attractive platform to improve the oral bioavailability of baicalin. |
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