| Objective: To design a camptothecin nanoemulsion/gel pellet based on oral colon-based drug delivery to improve the efficacy of camptothecin in the treatment of colon cancer,reduce its side effects,and improve patient compliance.Methods: The camptothecin loaded nanoemulsion was prepared by self-nanoemulsification method.The oil phase was screened by measuring the solubility of camptothecin in different oils.The emulsifier and coemulsifier were screened with reference to turbidity and solubility of oil in the different emulsifiers and/or co-emulsifiers.The laser dynamic scattering instrument was applied to determine nanoemulsion′s particle size and polydispersity index,and the transmission electron microscope was used to observe the microscopic morphology of nanoemulsion droplets.The medicinal polymers such as sodium alginate and carbomer were chosen to prepare nanoemulsion/gel composites based on the principle of electrostatic recombination.The outer polymer of camptothecin-loaded nanoemulsion/gel pellets was solidified by organic chelating technology.The single-factor investigation and Box-Behnken design combined with response surface method were adopted to optimize the formulation of camptothecin-loaded nanoemulsion/gel pellets.Fourier infrared spectroscopy was used to identify the formation of camptothecin-loaded nanoemulsion/gel pellets.The content of camptothecin,encapsulation efficiency and drug loading were determined by high-performance liquid chromatography.The swelling properties in different release media and the adhesion rate of camptothecin-loaded nanoemulsion/gel pellets on different digestion tract mucosa isolated from mice were investigated,respectively.The in vitro release mechanism of camptothecin-loaded nanoemulsion/gel pellets was analyzed by fitting different release models in different simulated digestive liquid.The stomach and intestine transportation and release characteristics were observed with fluorescent dye-loaded nanoemulsion/gel pellets by small animal imager after the pellets were orally administrated by rats.The in vitro inhibitory effect on human colon cancer cells of camptothecin-loaded nanoemulsion/gel pellets,camptothecin nanoemulsion and camptothecin were evaluated by MTT tests,respectively.Results: The camptothecin-loaded nanoemulsion consisted of each gram of oil phase contains camptothecin 1.5 mg per 1 g of oil,oil phase(propylene glycol monocaprylate)accounted for 20 %(w/w),the mixed emulsifier(polyoxyethylene 40 hydrogenated castor oil/diethylene glycol monoethyl ether = 1:1,w/w)accounted for42.0%(w/w),stabilizer oleic acid accounted for 2.0 %(w/w),deionized water accounted for 36.0 %(w/w).The camptothecin-loaded nanoemulsion/gel pellets consisted of the mixture of camptothecin-loaded nanoemulsion and gel(1:1,w/w),and the mixture of the gel solution containing 1.92 %(w/v)sodium alginate and 2.18 %(w/v)carbomer(1:1,w/w).The average particle size of the camptothecin–loaded nanoemulsion was 33.25 ± 6.40 nm,the polydispersity index was 0.06 ± 0.01,and the encapsulation efficiency was 98.65 ± 1.31%.The drug loading of the camptothecin-loaded nanoemulsion/gel pellets was 0.044 ± 0.003 %,and the encapsulation rate was 70.52 ± 1.55%;the swelling ratio in p H 7.4 phosphate buffer solution for 4 hours reached 420%;the average adhesion rate of gastric mucosa and small intestine mucosa was 11.67 % and 88.33 %,and the colonic mucosal adhesion rate was 98.33 %.The camptothecin-loaded nanoemulsion/gel pellets released less than 20 % in artificial gastric juice,and about 45 % before reaching the colon,most of which released slowly in the colon.The release of camptothecin-loaded nanoemulsion/gel pellets in the simulated digestive tract was an irregular transport mechanism that indicated the release mechanism was a combination of diffusion and swelling/erosion.The camptothecin-loaded nanoemulsion/gel pellets were aggregated in the stomach and mostly released after reaching the lower small intestine and the colon.The camptothecin-loaded nanoemulsion and camptothecin-loaded nanoemulsion/gel pellets showed stronger inhibitory effect on human colon cancer cells′ growth than the camptothecin.Conclusion: Camptothecin-loaded nanoemulsion/gel pellets can release most of camptothecin in the colon,which is expected to improve the efficacy of camptothecin in the treatment of colon cancer and reduce side effects. |
