Study On Elemene Self-microemulsion Drug Delivery System

Cancer is one of the deadliest killers in human life,and the cure for cancer is still elusive.The main reason is that the naked drug or conventional cytotoxic drugs have strong toxic side effects caused by drug leakage before the traditional drug delivery system reaches a specific site.Overcoming the multi-drug resistance of traditional anti-cancer drugs in cancer treatment has been a research hotspot.Therefore,it is a great significance to construct drug delivery system that can kill diseased cells to overcome adverse reactions.A novel lipid drug delivery system was designed by combining acid-sensitive polymer with nanomaterial carrier.The poorly water-soluble drug is dissolved and encapsulated in solid carrier to achieve the effect of controlling drug release and improving its bioavailability.In this study,?-elemene?Ele?was used as a model drug to prepare a mesoporous silica nanoparticle?MSNs?nano-drug delivery system with polyacrylic acid?PAA?terminated macromolecules with pH-stimulated response.This system effectively combines the advantages of both mesoporous silica nanoparticle solid carrier and self-microemulsion drug delivery system.MSNs have good biocompatibility,stable structure,controllable morphology and affinity for tumor cells,and are often used in cancer treatment.The surface is covered with polyacrylic acid to make it have good biocompatibility and pH acid sensitivity,which not only increases the uptake of drugs by cells,but also has stable properties under normal physiological conditions?neutral environment?.It could be easily broken down only in the acidic condition,so that the drug could exert its curative effect in the tumor site in the acidic environment,thereby solving the problem of drug multidrug resistance.The ultraviolet spectrophotometer was used to study the physicochemical properties of?-elemene,providing a basis for the study of the optimal prescription formulation and in vitro release test;The dissolution effect of different excipients on model drugs was investigated,and suitable excipients to improve its solubility were initially screened.The formulation process was investigated by drawing a pseudo-ternary phase diagram,and the internal factors of the formulation process were further screened by the star point design-response surface method;Finally,the optimal prescription of?-elemene self-microemulsion was determined as:?-elemene?21%?,isopropyl myristate?16%?,polyoxyethylene 35 castor oil?42%?and 1,2-propanediol?21%?.Through the single factor investigation method,the external factors affecting the preparation of the prescription were studied.The emulsified oil method was used to prepare the optimal prescription.The microemulsion morphology observed under a transmission electron microscope?TEM?was spheroidal shape with good dispersibility and the mean particle size of 25.61±1.8 nm,PDI of 0.12±0.01.The test results are consistent with the results of the nano laser particle size analyzer.Through the preliminary physical stability experiment,there is no obvious difference between the average particle size and dispersion of the sample,indicating that the formulation has good stability.A pH-responsive solid self-microemulsion drug delivery system was constructed by the solid carrier adsorption method.Cetyltrimethylammonium bromide?CTAB?was used as the template and tetraethyl orthosilicate?TEOS?was used as the silicon source,mesoporous silica nanoparticles were synthesized under appropriate experimental conditions.Amino-modified mesoporous silica nanoparticles were prepared by3-aminopropyltriethoxysilane?APTES?silane modification method.Then,surface modification of the drug-loaded mesoporous silica nanoparticles was performed to achieve the effect of pH response.Self-assembled mesoporous silica nanoparticles have a regular channel structure.The nitrogen adsorption test results showed that the specific surface area and mesopore pore size of the synthesized mesoporous silica nanometer rice particles were both large.The synthetic samples were measured by means of drug loading test,automatic specific surface area and porosity measurement,scanning electron microscope,transmission electron microscope and Fourier infrared spectroscopy.The results indicated that polyacrylic acid was successfully loaded on the surface of mesoporous silica particles loaded with drugs.Morphologically,they were all spheroids with uniform particle size and good dispersion.In vitro release experiments using the dialysis bag method showed that Ele/MSNs-PAA has pH acid sensitivity and can achieve targeted drug release.This is beneficial for Ele/MSNs-PAA to effectively carry the drug to the tumor site in the acidic environment,thereby reducing its release under normal physiological conditions and greatly increasing the bioavailability of the drug.The vivo pharmacokinetic parameters of?-elemene suspension group,SMEDDS group and Ele/MSNs-PAA group were studied using mice.The t1/2?of the SMEDDS group and the Ele/MSNs-PAA group were 10.88±1.83 h and 8.246±2.06 h,respectively,which was about 5 times shorter than the?-elemene suspension?48.78±3.56 h?.It was concluded that compared with the?-elemene suspension group,the SMEDDE group and the Ele/MSNs-PAA group were able to rapidly penetrate into the tissue.In terms of AUC and C_max,the AUC and C_max values of the?-elemene suspension group?28.75±2.14 mg/L*h and 4.792±5.42 mg/L,respectively?were lower than those of the SMEDDS group?65.20±2.27 mg/L*h,9.792±4.41 mg/L?,The AUC and C_max values of SMEDDS group were lower than those of the Ele/MSNs-PAA group?102.29±2.84 mg/L*h,15.01±3.09 mg/L,respectively?.These results indicated that the absorption of?-elemene was better in the SMEDDS group and the Ele/MSNs-PAA group than in the?-elemene suspension group.It is proved that the preparation designed and synthesized in this subject has high stability and can realize controllable administration in vivo,thereby effectively improving the bioavailability of ?-elemene.