| Objective:Rectal drug administration has been effectively utilized to treat local diseases as well as to deliver drugs systemically as an alternative to oral administration. As one of the important administration routes,rectal drug delivery has been receiving extensive interests. Nimesulide(MIM),a significantly selective COX-2 inhibitor,which exerts potent pyretolysis,analgesic and anti-in?ammatory effects when administered orally,rectally or topically,shows various drawbacks that embrace low aqueous solubility,poor bioavailability. In particular,in the case of which a rapid onset of action is requested,such as analgesics or pyretolysis.However,the applications of numerous pharmaceutical formulations(such as traditional suppository,enteroclysis) are limited because of problems of themselves,which presents the necessity in designing new rectal dosage forms which can overcome these problems to some extent.In situ gels refer to the polymer solutions being administrated as liquid,which undergoes a phase transition to a non-crosslinked semisolid gel upon exposure to physiological environments. In situ thermosensitive gels with modulated gelation temperature(Tgel)were developed,and the drug release as well as the pharmacokinetics in rabbit after the in situ gels applied rectally was also studied. The purpose of this dissertation was to develop a thermosensible in situ gel including NIM for rectal administration and provide some references for formulations development of poorly soluble drugs like NIM.Method:The properties about NIM were studied as an essential part of preformulation. The dissolubility and the apparent n-octanol/buffer partition coefficient of NIM at different pH were determined with shake flask method.On the basis of scientific literatures,Poloxamer 407,a thermosensible high molecular material,was introduced into rectal drug delivery system; and the formulation screening was performed by taking sol-gel transition temperature and in vitro release as indices.Formulations containing NIM or not were prepared by"cold method". The Tgel was determined by"magnetic bar method". Compared with NIM raw powders,the release behaviors of NIM thermosensitive gels were performed by dialysis bag-paddle method at 37±0.5℃and maintaining the speed of rotation at 100 rpm with 500ml borate buffer (pH 9.18)as a release medium; samples were obtained at predetermined intervals,and then determined by UV method. The data obtained from the in vitro release experiments were analyzed by the following commonly used equation: Zero equation,First equation,Higuchi equation and Peppas equation.Retention in the rabbits'rectum:Six albino rabbits were divided into two groups randomly,and two kinds of optimal thermosensitive gels[Formulation A (P407-HPMC-PEG400(18:0.5:10))and Formulation B (P407-Alginate-PEG4000(18:0.5:1.2))] were administered at a dose of 20mg·kg-1 into the rectum 4 cm above the anus using a plastic syringe to see if there was any leakage.The stability test:The optimal thermosensitive gels formula were stored in the sealed vial at room temperature against light and at strong light(4500±200Lx),and then the permanent stability and the photosensitive property were investigated by determination of its appearance and content at different times.Pharmacokinetics study in vivo:Six albino rabbits were grouped randomly and administered NIM conventional suppositories(control group)while the thermosensitive gel(study group) were administered into the rectum 4 cm above the anus using a plastic syringe at a dose of 20mg·kg-1. After the administration,a RP-HPLC method with ultraviolet detection was developed for the determination of NIM in rabbit serum at different times. The pharmacokinetic parameters were calculated by 3p97 program.Result:The results of dissolubility studies at different pH indicated that NIM was more soluble at alkaline pH than acidic. Unfortunately,it was still poor even at pH as high as 10.0(only 1.491mg?mL-1 at 37℃), which indicated the pH for this preparation must be alkaline. At the same time,the apparent n-octanol/buffer partition coefficient was also pH-dependent but decreased with pH increasing. The Log Papp was 2.25 and 1.64 at pKa and pH 7.4,respectively.By taking sol-gel transition temperature and in vitro release as indices,the optimal formulation of NIM thermosensible gel were P407-Alginate-PEG4000(18:0.5:1.2)and P407-HPMC-PEG400 (18:0.5:10)which had a gelation temperature of 35℃.The accumulative release of NIM from this thermosensible gel in vitro was much faster than NIM raw powders(increase from 55% to 91% at 8h).The correlation coefficients calculated for each of model indicated that NIM release was better described by the Peppas model. The non-Fickian(anomalous) release kinetics according to Peppas equation might indicate that the release of NIM followed coupled erosion-diffusion mechanism(release exponent,n=0.6365).In vivo retention in the rectum:Only formulation B (P407-Alginate- PEG4000(18:0.5:1.2))retained in the rabbits'rectum without any leakage. The result of stability study displays that the thermosensitive gels have a good stability at ambient temperature away from light,But they were a little unstable to stable light. So it was better for this preparation to be stored in a place of light-resistant.Pharmacokinetics study in vivo : Compared with the control group,the study group had a shorter tmax,but a higher Cmax(180min,26.188μg·mL-1and 240min,19.398μg·mL-1 respectively).According to t test,the absorption rate of the study group was much faster at every specified time as Cmax was significantly higher before 240min(P<0.02).Pharmacokinetic behavior of both formulations were conformed to two compartment model with first order absorption by the weight of 1/C/C according to 3p97. In comparison with the absorption half life(t1/2(a)) obtained for the control group(135.40min),the t1/2(a) for the study group was much shorter(31.42min), whereas the mean retain time(MRT) (484.82min and 500.82min for the control and the study,respectively) and the elimination half-lives(t1/2(β))(231.05min for the control and 262.35min for the study)were both close. The area under the serum concentration vs. time curve(AUC0→t)for the study group increased about 24.07% in contrast with that of the control group(16493.88μg·min/mL and 13293.65μg·min/mL,respectively). However, differences were not statistically significant (P=0.14) probably because of the high inter-individual variability. No significant difference was found between both the apparent volume of distribution (V(c))(P=0.149)and the clearance rates (CL(s)) (P=0.126),351.35min,1.243 mL/min/kg and 244.05min,1.690 ml/min/kg for the study group and the control group, respectively.Conclusions:The results of both in vitro and in vivo showed that the NIM thermosensitive gel containing sodium alginate and PEG4000 prepared in this study appeared to be one of the preferred formulations which had an appropriate Tgel and stability. Pharmacokinetic characteristic of this thermosensitive gel in rabbits displayed a faster release and the absorption of NIM can be achieved by loading it into P407 thermosensitive gel system.Therefore,the thermosensitive gels may substantially increased the bioavailability of NIM and showed great potential in rectal application.
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