The Study Of Nifeviroc As Vaginal Microbicide Candidate

Nifeviroc is a novel anti-HIV drug, and would be a potential compounds of microbicide candidate, we design inclusion complex of Nifeviroc with Hydroxypropyl-β-cy-clodextrin to improve its solubility and stability for vaginal administration. Firstly, to establish an HPLC method for determination of Nifeviroc in hydroxypropyl-β-cyclodextrin inclusion complex and for study the stability of Nifeviroc. Secondly, to study the stability of Nifeviroc of inclusion complex in different condition and in vaginal gel, and the controlled release properties of the inclusion complex gels. Thirdly, to study the systemic and local acute toxicity and vaginal irritation of Nefiviroc Gels.The separation was performed on a GL Sciences Inertsil ODS column (4.6×250mm,5μm) maintained at 30℃and by a UV detector set at 265 nm. Methanol(A phase)-buffer (B phase)(60:40,v:v) was used as mobile phase to carry out isometric elution at a flow rate 1.0ml/min, and content determination was used by external standard method. Nifeviroc and related impurity could be baseline separated. The stability of inclusion complex in both different media conditions and methylcellulose gel were assessed. As required for in vivo application of microbicides, in vitro release and permeate studies of drug in gels were tested. Last, Bliss's method was used to test the lethal doses(LD50) in mice. The vaginal acute toxicity in SD rats was studied and vaginal irritation was observed on mature rabbits by Eckstein method and on mature mouse.A linear relationship between the peak area and concentration of Nifeviroc was achieved in the range of 20.10-180.90μ.g/ml with r=0.9999. The average recovery ratio was 100.5%(n=9). The complex of Nifeviroc-β-cyclodextrin could be stabiliity within 24 h in pH4.5 at 37℃. The low dose of the complex incorporated in carrier vehicle were degradation apparently during one month, but the high dose kept stability. Methylcellulose gel could provided a compatible formulation for the delivery of the lipophilic Nifeviroc. In the experimental dose, LD50 of the gels belongs to moderate toxicity, the vaginal irritation is acceptable.This method is convenient, accurate, sensitive and reliable. Hydroxypropyl-(3-cyclodextrin inclusion complex can improve the stability of Nifeviroc. Nifeviroc could be a micirobicide candidate, andβ-cy-clodextrin would be deliver system of Nifeviroc for vaginal administration. Nifeviroc vaginal gel would have the feasibility of clinical evaluation...