Research On Octoxynol-9 Chitosan Thermosensitive Sustained-release Gel For Vagina

Octoxynol-9(N-9)and Nonoxynol-9 share some structural similarities with each other,they are spermicides in vaginal contraceptive preparations which belongs to category of nonionic surfactants,but N-9 was more toxic than O-9[1-2].Today's external used contraceptive preparations are easy to leak out,it is difficult to spread out and cover the surface of the vagina,the retention time in the vagina is short and resulting in the low bioavailability.Thermosensitive gel is a kind of in situ gel which has a unique solution-gel properties for the phase change in response to the change of temperature,thus get the characteristics of the convenient dosing,strong adhesive force and the long retention time,so it is especially suitable for mucosal drug delivery[3-4].Chitosan(CS)is also a kind of commonly used materials in thermosensitive gel which has good biodegradability ?biocompatibility?non-toxic and antibacterial,it is also an excellent biological adhesion material which can sustained release the drugs[5-6].Therefore,this research will combine the safer O-9 and CS with good adhesion to develop a new type of vaginal preparations with temperature sensitivity which can make the preparation widely covered the vigina surface,prolong the retention time of drugs and get the safer?effective and easier used new type of topical contraceptive preparations.The cold dissolving method was used to prepare O-9 vaginal thermosensitive gels((O-9)-VTG)based on Poloxamer 407/188 as thermosensitive materials and CS as bioadhensive materials.Tube inversion method was used to measure the gelling temperature(TGEL).Central composite design/response surface method was useded to optimize the formulation.Optimized formulation was confirmed as 16.3% P407,5.7% P188,5% glycerin and 0.6% Chitosan and the observed TGEL of optimized formulation was 33?A quantitative HPLC method was used to establish the quality control method of O-9 and the labeled amount of 3 batches(O-9)-VTG were 99.83%,100.69% and 99.31%(n = 3)Membraneless dissolution model was selected to determine gel erosion and in vitro release of(O-9)-VTG.The results indicated that the release profile of(O-9)-VTG was best fitted with zero order kinetics.With appearance,pH,TGEL and estradiol content as indexs to evaluated preliminary stability,the results show that(O-9)-VTG has good stability.Tube inversion method can be used to measure the gelling temperature,but can not characterize the phase transition behavior and the gel strength,so the rotational rheometer was used to determine the rheological properties of(O-9)-VTG.And measured the TGEL is 32.6?,the result is basically identical with tube inversion method.It is Newtonian fluid with low viscosity at room temperature(25?)which to be easier injected into the vagina and it became pseudoplastic fluid with high viscosity when placed in the vagina.The formulation could still transform into a gel at body temperature after being diluted with the simulation vaginal fluid(SVF).Taking vaginal samples after administration of(O-9)-VTG and O-9 gels,then determined the concentration of Octoxynol-9 in the samples and got the retention time of(O-9)-gel and(O-9)-VTG with DAS to deal with the data.It turned out that(O-9)-VTG has better retention capacity.To observe the spermicidal and antifertility effect,Sander-cramer method was used to observe the minimum effective spermicidal concentration(MEC)of(O-9)-VTG.It came that the MEC of(O-9)-VTG is 0.50 mg ml-1.Rats were administered with test substances through vagina and then mated with male rats(1:1).The results suggested that(O-9)-VTG and N-9 jelly both has good antifertility effect compared with natural control group and blank group.It is similar with N-9 jelly on spermicidal and contraceptive efficacy.Vaginal mucosa irritation test and acute toxicity test was conducted on female SD rats.Through the naked eye?vaginal pathological observation and Eckstein excitant evaluation standard to evaluate the irritation,It was shown that(O-9)-VTG has no apparent irritation and is also non-toxic in vaginal administration compared with the saline group.To sum up,(O-9)-VTG has good temperature sensitivity,quality stability and slow-release effect.It has long residence time in vagina and has good biocompatibility.This research has got the the safer?effective and easier used new type of topical contraceptive preparations.It will also provide some informations and bases for the further study of O-9 when used in vagina.