| Objective:We prepare 5-fluorouracil hyaluronic acid microspheres by emulsification crosslinking method with hyaluronic acid as the carrier,coated with acrylic resin,in ord-er to locate the drug to release in the colon area for the increased treatment of colon cancer.Methods:5-fluorouracil hyaluronic acid microspheres were preparated by emulsifica-tion crosslinking technology.Encapsulation efficiency and particle size of the micro-spheres were evaluation index,combined with preparation conditions.The statist-ical method of single factor screened crosslinker.The two indicators(encapsulation efficien-cy and particle size)as the evaluation criteria of the formation of 5-fluorouracil miro-spheres were investigated,and two sets of orthogonal experiment were designed for preferably optimal prescription.According to the preparation process,the volume ratio(v:v)of water phase and oil phase was factor(A),the mass ratio(m:m)of the emulsifier Span80 and oil phase was factor(B),the structural unit substances volume ratio(n:n)of crosslinkers and hyaluronic acid was factor(C).Each factor take three levels using L9(34)orthogonal table test to study.The best prescription was verificated by validation experiments.Preparation of 5-fluorouracil hyaluronic acid microspheres using Preopti-mal prescription were coated with eudragit latex.In vitro release rate of 5-fluorouracil standard,5-fluorouracil hyaluronic acid microspheres and coated 5-fluorouracil Hyalur-onic Acid microspheres in three different media(artificial gastric juice,artificial small intestinal juice and artificial colon fluid)were Compared.HPLC was determined metho-d with rats animal model,to study the control group of 5-fluorouracil and experim-ental groups of the homemade colon-coated hyaluronic acid microspheres in vivo pharmacokinetic process.The pharmacokinetic parameters of the two groups were analyzed and bioavailability between the two groups were comparedResults:The final choice of crosslinkers filtered by the single factorsstatistical meth-ods,was the adipic dihydrazide and glutaraldehyde with molar ratio of 1:2.The volume ratio(v:v)of 5-luorouracil hyaluronic acid microspheres prescription for the water phase and oil phase was 1:2.The mass ratio(m:m)of the Span80 emulsifier and oil phase is finally obtained after the orthogonal test and verification experiments wasl:100,the structural unit substance amount ratio(n:n)of crosslinker and hyaluronic acid was 5:1.The microspheres were spherical with diameters 2-3 μm and encapsulated was about 20-50%(w/w)in all of the formulations.The release of 5F-u in artificial gastric juice in two hours has had reached 61.18±1.89%,the release of two hours in artificial small intestinal fluid has reached 85.81±0.98%.Compared to pure 5-Fu dry powder up to 99.60±0.92%,the release of 5-Fu from coated 5-Fu-HA microsphers in artificial gastric juice in two hours had only reached 16.17±1.80%.The release of 5-Fu from coated 5-Fu-HA microspheres in four hours in artificial small intestinal fluid and in four hours in artificial colon fluid had reached 73.80±0.30%and 98.45±0.30%,respectively.These compositions were selected as an optimal formulaicantly higher than that of 5-Fu powder alone,indicating that the 5-Fu-HA microspheres for the oral delivery system in thepharmacokinetic study.The Cmax and tmax of 5-Fu in 5-Fu powder and coated 5-Fu-HA microsphere were 28.76 ±11.11mg/ml and 1.167±0.2357 h;42.88±13.40mg/ml and 8.667±0.9428 h(P<0.05);Furthermore,the MRT and AUC of 5-Fu in 5-Fu powder and coated 5-Fu-HA micro-sphere were 1.926±0.4077h and 12.63±2.315mg/ml;9.046±1.380h and 83.21 ± 12.22 mg/ml(P<0.05),respectiveely.Compared with the control group,the relative bioavai-lability of the coated 5-Fu-HA microsphere group was 190.82%.Conclusion:Our results demonstrated that coated 5-Fu-HA microsphere increased 5-Fu bioavailability,and provides a preliminary research on 5-Fu oral drug delivery systems. |
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