| Huperzine A(Hup-A) is an active constituent extracted and separated from the traditional chinese medicine Huperzia serrata(Thunb.) Trev, is a kind of acetylcholinesterase inhibitors. It has good curative effect of treating Alzheimer’s disease(AD) and improving memory. But, huperzine A, with poor solubility in water,and its oral bioavailability is very low. Self-microemulsifying drug delivery system(SMEDDS) is a kind of new drug delivery system. It has been used as a vehicle of difficult soluble drugs, so it can significantly enhance the oral absorption of drugs.Objective: To explore the formulation and preparation technology of the Huperzine A sustained-release solid self-microemulsifying system(S-SMEDDS), and to build the stable and controllable sustained-release solid self-microemulsion.Methods: On the basis of self-microemulsion prescription had been studied, to prepare and evaluate Hup-A self-microemulsion. The Hup-A self-microemulsion was solidified by spherical crystallization technique. Through the single factor exploration the effect of formulation and preparation technology for solid self-microemulsion. Several influential factors were the volume ratio of absolute alcohol and CH2Cl2, the amount of liquid paraffin, and the temperature. The yield, D50 and entrapment efficiency were used as evaluation indexes, the orthogonal design were used to optimize formulation and preparation technology. The obtained Hup-A sustained-release solid self-microemulsion was evaluated, and its preliminary stability was also studied. Next, the pharmacokinetic experiment of Hup-A sustained-release solid self-microemulsion was studied. By single-pass intestinal perfusion technique for intestinal absorption experiment. A chylomicron flow blocking approach was used to study lymphatic transport of different formulations. Finally, in vitro experiment of Hup-A self-microemulsion was studied.Results:(1) Hup-A self-microemulsion was clear and transparent. The microemulsion morphology were homogeneous and globe shapes after emulsification. It can meet the requirement of self-microemulsion, which can be further studied. The optimalformulation and preparation technology for sustained-release solid self-microemulsion as follows: the retardants were Eu RS PO: EC 1:1, the poor solvent was liquid paraffin125 m L, and good solvent system were absolute alcohol:CH2Cl2 5:3, the sustained-release solid self-microemulsion was stirred with magnetic stirrer at the speed of 400 r·min-1 for 30 min at 25 ℃. The microspheres were spherosome, and self-microemulsion was not damaged in the process of solidification. It shows that about15% and 63% release was determined after 1 h and 8 h while more than 90%accumulated release was reached within 24 h, and has sustained-release characteristics.Drug release from the in house formulation fitted well into Higuchi model. The test of primary stability indicated that the Hup-A S-SMEDDS have a better stability than other formulations, and it can keep stable at low temperature and seal conditions for 6 months.The properties have no obvious chang during storage.(2) In the pharmacokinetic study, The S-SMEDDS compared with tablet, the Tmax, t1/2and MRT were prolonged significantly, reached the sustained-release effect, which can play a long-lasting efficacy. The relative bioavailability was 262.92%. It indicated that Hup-A S-SMEDDS can significantly improve the bioavailability.(3) The in situ intestinal absorption experiment showed that the absorption rate of different concentrations is not significantly different, and it is passive transport. Hup-A SMEDDS can be absorbed in any part of intestine, and the absorption rate constant(Ka)and the apparent absorption coefficient(Papp) of ileum is significantly larger than that of others. The Ka and Papp of Hup-A in the SMEDDS were significantly higher than the suspension, but were smaller than water-in-oil emulsion. The proportion of lymphatic pathway transportation of water-in-oil emulsion and self-microemulsion were 46.91%and 40.03%, only 5.62% of tablet suspension. It indicated that tablet is mainly absorbed via the portal vein, and microemulsion also can transport through lymphatic pathway.Also shows that grease composition is much easier to transport through lymphatic pathway.(4) In vitro experiment, 0.1~10 μM Hup-A self-microemulsion can better protect PC12cells with H2O2-induced injury than Hup-A.Conclusion: The formulation and preparation technology of Hup-A S-SMEDDS were feasible, and the stability was good. Its bioavailability was significantly improved, and also has sustained-release characteristics. Meanwhile SMEDDS can promote drugs transportation through the lymphatic pathway. So it is a new drug delivery system with great investigating value and potentials. |
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