The Studies On Cyclosporin A Solid Self-microemulsion

Cyclosporin A is a cyclic polypeptide, which consists of11amino acids. It is a potentimmunosuppressive agent which can selectively act on T lymphocyte. It can inhibit HelperT cells activation and IL-2responsiveness through binding to the immunization effect ofCyclophilin protein in cell. In clinical, Cyclosporin A is used for anti-rejection reactionafter liver, kinney and heart transplant, it can also be used to treat autoimmune diseaseswhen combining with adrenal cortex hormone.On the basis of CsA self-microemulsion, porous microspheres of ethyl cellulose wasprepared by using spherical crystallization technique, then solidified the liquid CsAmicroemulsion in conjunction with silica. In order to improve powder properties ofself-made CsA solid self-microemulsion and increase the drug loading, studies on CsAsolid self-microemulsion have begun.Quality research of the CsA self-microemulsion indicated: self-made CsAself-microemulsion was clear and transparent, the solution was light blue when dissolved indistilled water, and self-emulsifying rate was much higher. The particle size, zeta potentialof CsA self-microemulsion were28.82nm and-2.00mV in0.1mol·L^-1HCL. The formedmicroemulsion had smaller particle size and negative charge on surface, which could meetthe requirement of self-microemulsion. Therefore, the self-made CsA microemulsion canbe used for the latter experimental study.When preparing the ethyl cellulose porous microspheres, an evaluation index systemwas established mainly based on the microspheres’ appearance, size and distribution, yield,angle of repose, Carr’s index and porosity. On the basis of the single factors above, theorthogonal test was designed.The optimized result showed, the solvent system （includingmethylene chloride and sodium lauryl sulfate） was the most important affecting factors, thestirring rate was main determinant of particle size, the temperature had certain effect on theyield of aggregates, bulk density and particle size. These factors must be controled strictlyin the process of preparation.125ml of0.08%SDS solution was selected as the poor solvent, 6ml of methylene chloride was selected as good solvent as well as bridge solvent,EC/PEG40005:1,the stirring rate was500rpm while the temperature was settled at25℃.The experimenf used spherical crystallization technique to prepare porous microspheres ofethyl cellulose, and used silica dioxide to adsorb CsA self-microemulsion to solidified intoballs. The method was feasible and reproducible.A method was established to investigate powder property; and HPLC method was alsoestablished to determine the CsA content in CsA solid self-microemulsion and thedissolution and the monitor plasma concentration in rats.Powder properties of self-made CsA solid self-microemulsion was better （angle ofrepose29.4°±1.1,carr’s index17.73±0.83）, the particle size, zeta potential of theself-microemulsion and the solid self-microemulsion were similar, self microemulsion wasunspoiled in curing process. It was illustrated that CsA self-microemulsion was unspoiledfrom the solid self-microemulsion during the curing process. The released rate of thispreparation was more than87.0%in30min and more than95.0%in90min,so it releasedcompletely.When a single dose of the self-made CsA solid microemulsion and the saled Neoral were orally administered by rats, The pharmacokinetics parameters and the relativebioavailability were gained after process.The results were as follows: Cmaxwere（3.272±0.178）μg·mL^-1,（3.032±0.121）μg·mL^-1; AUC0â†'24hwere （13.326±0.262） μg·h·mL^-1,（13.718±0.574）μg·h·mL^-1; T_maxwere （0.806±0.044）h,（0.818±0.036）h, respectively. Acomparison between the CsA solid microemulsion and the reference preparation Neoral for the AUC, the relative bioavailability was97.14%. Statistical results show that there wasnot significant difference between the two preparations. Dissolution tests of CsA solidmicroemulsion indicated the goodness in in vivo and in vitro correlation.