| Chronic Hepatitis B(CHB),one of the most devastating and severe threatening human health disease,which has become the important public hygiene problem in the world.More than 2 billion people were infected Hepatitis B Virus(HBV)worldwide.Some of them died from liver failure,HBV related cirrhosis and hepatocellular carcinoma.HBV hide in portal lymph node,where the most of conventional drug dosage forms can not enrich in portal lymph node to inhibiting or killing HBV.It is one of reason why CHB is outburst repeatedly in clinical.Nanoemulsion(NE),a type of TDDS,is defined as a system of surfactant,cosurfactant,oil and water,which is stable-transparent,thermodynamically and isotropic liquid solution with droplet size in the range of 0-200 nm.Current researches indicated that the NE have a significantly effect on the absorption of drugs via lymphatic transport.This is owing to NE contains more lipophilic components,coupled with small particle size and large surface area,which can dramatically improve the formulation affinity with lymphatic system.Baicalin(BA),a single active ingredient extracted from the dry root of Scutellaria baicalensis Georgi,which is the widespread used against treatment of CHB in China.Studies on pharmacology have shown that BA have broad functions such as arresting hepatic fibrosis and improve lipid metabolism.Objective:In this study,an efficient,stable and thermodynamic W/O NE was optimized and prepared.In order to improve the lymphatic transport and enhance the concentration in portal lymph node of BA.It is expected to provide a new choice for CHB clinical medication.Method:1.The preparation and quality evaluation on BAN In this experiment,PC(Soybean phospholipid),Span-60 and Span-80 were chosen as candidate surfactant.Polyethylene glycol 400(PEG 400),propylene glycol and ethanol were chosen as candidate cosurfactant.Isopropyl myristate(IPM),Isopropyl palmitate(IPP)and Glyceryl monooleate octyl decyl acid triglycerate(GTCC)were chosen as candidate oil phase.The pseudo-ternary phase diagram was used to select best blank NE formulation.The morphology of BAN was examined using transmission electron microscopy.The size distribution of BAN was measured by particle sizer.The Stability studies of BAN were measured by particle sizer and HPLC during the 3months at 4 °C and-20 °C.2.Pharmacokinetics study The pharmacokinetics experiment was carried out in SD rats.The HPLC method was established for determination of BA in rats plasma.The various pharmacokinetic parameters of BAN and BA suspension were compared.3.Lymphatic targeting study The HPLC method for detecting the content of BA was established.The absorption of BAN in lymphatic pathway was compared with BA suspension and BA oil suspension by using chylomicron flow block method.The concentration of BAN in portal lymph node was compared with BA suspension after oral administration.Results:1.The preparation and quality evaluation on BAN The optimal BAN formulation was PC: 22.7%,propylene glycol: 22.7%,IPM:45.5%,water: 9.1%.The particle size distribution of BAN was 66.95 ± 17.32 nm with a polydispersity index(PDI)of 0.134.Transmission electron microscopy revealed round or oval shapes and confirmed by particle size analysis.Stability results showed that no significant appearance changes and no difference in BA content during the 3 months at4 °C and-20 °C.2.Pharmacokinetics study Pharmacokinetics result showed that the AUC0-tvalue of BAN and BA suspension were 61.984 ± 4.645 mg/L*h and 5.881± 0.264 mg/L*h.The Cmax value of BAN and BA suspension were 3.01 ± 0.199 mg/L and 0.965 ± 0.100 mg/L.The Tmax value of BAN and BA suspension were 10 h and 2.5 h.The MRT0-t value of BAN and BA suspension were 18.895 ± 0.647 h and 10.497 ± 0.379 h.The VRT0-t value of BAN and BA suspension were 5.796 ± 0.444 L/kg and 53.794 ± 19.648 L/kg.The CLz/F value of BAN and BA suspension were 0.31 ± 0.023L/h/kg and 1.786 ± 0.927 L/h/kg.This results illustrated that NE can significantly enhance the rats plasma concentration of BA.3.Lymphatic targeting study The lymphatic transport results showed that Cmax value of BAN,BA suspension and BA oil suspension in lymph blocking group and control group were 3.010 ± 0.119mg/L vs 1.567 ± 0.220 mg/L,0.965 ± 0.079 mg/L vs 0.885 ± 0.072 mg/L,0.819 ± 0.100mg/L vs 0.578 ± 0.069 mg/L,respectively.The results showed that AUC0-t value of BAN,BA suspension and BA oil suspension in lymph blocking group and control group were 23.076 ± 1.244 mg/L*h vs 9.236 ± 0.940 mg/L*h,3.616 ± 0.434 mg/L*h vs 3.29 ±0.131 mg/L*h,5.648 ± 0.6170 mg/L*h vs 4.345 ± 0.369 mg/L*h,respectively.The lymphatic targeting efficiency of BAN,BA suspension and BA oil suspension were59.98%,23.07%,9.02%,respectively.The results illustrated that NE can significantly improve the absorption of BA through lymph pathway.The lymphatic transport results showed that BA suspension can transport to portal lymph node during with 2-4 h.BAN can enrich in portal lymph node during with 1-12 h.NE can dramatically enhance the concentration of BA in portal lymph node compared with suspension during with 12 h.The results demonstrated that BAN can enrich in portal lymph node via lymph pathway.Conclusion:In a word,the overall results confirmed that BAN had the stronger lymphatic transport activity in comparison with BA suspension.Furthemore,the NE formulation play an important role in the lymphatic transport. |
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