| Recently, the treatment of ocular ailments mostly needs local applications of drugs into the ocular cavity and tissues. However, highly sensitivity and effective protection mechanisms of eyes make the application of many pharmaceutical carriers limited. Thus, there is an urgent requirement for researchers to design effective drug carriers for local ocular delivery. In this study, a thermo-sensitive polymer (poloxamer) was introduced into ocular delivery system, which made preparations free-pouring liquid at room temperature and semi-solid gel after administration under body temperature. It could effectively avoid the drawbacks of conventional ophthalmic preparations and attain the purpose of medication.In our investigation, chloramphenicol was taken as the model drug and the chloramphenicol-loaded solid lipid nanoparticles were prepared. Such factors as the amount of oil phase and F188 and the proportion of drugs to oil phase for preparing nanoparticles were optimized by the Box-Behnken design by means of the experimental design software Design Expert (version7.1.3, beta), with the turbidity (NTU), encapsulation efficiency (EE%) and drug loading (DL%) as the criterion. The optimum technology parameters were seeked by analyzing the equations. Eventually an optimal design of chloramphenicol-solid lipid nanoparticles formulation of oil phase (glyceryl monostearate) 10%, F188 8% and chloramphenicol 13.55% of total oil phase was achieved, the product of which exhibited significantly delayed release.On the basis, Chloramphenicol-solid lipid nanoparticles as a drug, was prepared into ophthalmic thermo-sensitive gels with poloxamer 407 and poloxamer 188 as major substrates using cold dissolution method. Then the relationship between the concentration of the substrates and the phase-transition temperature of gels was investigated using a stirrer method. In the end, the basic prescription of the thermo-sensitive gels was 25% F407/ 6% F188.The high efficiency liquid chromatography method (HPLC) was used to detect the content of chloramphenicol in these gels. The chloramphenicol standard curve was prepared and the spotting recovery test was carried out. Furthermore, the in vitro dissolution kinetics and the drug release mechanisms were detected. The results showed that the corrosion of the thermo-sensitive gels corresponded to Hixon-Crowell model. Meanwhile, the HPLC method applied to test the chloramphenicol content in the thermo-sensitive gels was simple and rapid and the results were reliable.Besides, in this paper, the in vitro release profile, in vitro rabbit corneal permeability and the eye irritation situation of the rabbits were investigated by HPLC method.Rabbits were selected as laboratory animals for pharmacokinetics study in vivo. Results were expressed using high performance Liquid Chromatography (HPLC) with Ultraviolet detector. Six-point standard curve was established for CAP in rabbit aqueous humors, in order to calculate the concentration of them. The pharmacokinetics parameters were calculated by DAS software.The results in vitro and in vivo showed that the chloramphenicol-nanoparticulate gels could prolong the residence time of drug in the ocular cavity. It was tolerated well and there were no obvious toxic effects to ocular tissues. The chloramphenicol-nanoparticulate gels, which upon exposure to physiological conditions would shift the gel phase, could significantly extend release and increase the precorneal residence time of the drug, thus enhangced the ocular bioavailability. They could achieve high clinical application value and would be expected to become a new drug delivery system for the treatment of ocular diseases, and showed great potential in ophthalmic application. |
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