Study On Ophthalmic Preparation Of Flurbiprofen

As one of the important fields of controlled release, ophthalmic drug delivery system has received extensive interests .The sensitivity and protection mechanisms of the eye promote more effective drug delivery systems with better compliancy to be developed, which presents great challenge in designing ophthalmic dosage forms. In this dissertation, flurbiprofen（FP） was selected as model drug, then an ophthalmic solution of FP and an in situ thermosensitive gelling ophthalmic drug delivery system for FP were developed and evaluated in vitro and in vivo,respectively. Main sections were included in this paper:1. UV spectrophotometry was used for the investigation of the pharmaceutical preformulation of FP.The solubility and oil/water partition coefficient of FP were correlated with the pH value of aqueous media. With the increasing value of pH, the solubility of FP increased, while the oil/water partition coefficient decreased. In vitro analytical methods of determining the content of Flurbiprofen and preservative, related substances test, drug release, across isolated cornea for FP ophthalmic drug delivery system have been established and tested .The method is simple, rapid, and accurate.2. Refer to USP and in accordance with quality control of CP2005,FP ophthalmic solutionwas prepared. The formulation screening was performed using modulated gelation temperature（GT） and permeability of across isolated cornea as indices, FP in situ thermosensitive gellingwas prepared.The reversible gelation behaviors of poloxamer 407 （P407）solutions showed strongconcentration dependency; no desired GT could be obtained by using P407 alone. GT wasadjusted by incorporating P188.GT was enhanced after being diluted by STF. The fitted equationwas established for the GT with the concentration of poloxamer solutions after diluted by STF.The permeability of FP across isolated rabbit cornea was measured using in vitro method undervarious penetration enhancers. The diffusion behaviors of FP across isolated rabbit corneapossessed zero-order kinetic characteristic. An apparent permeation coefficient the commercialreference product （Ocufen）, ophthalmic solution and an in situ thermosensitive gelling of FPwere 9.40±0.85、8.36±1.24、6.06±0.98(×10^-5cm·s^-1) respectively.2% HP-β-CD improved the apparent permeability of in situ thermosensitive gelling of FP as much as 10.53±1.99(×10^-5cm·s^-1). 0.5%EDTA did not improve the apparent permeability of FP.3. The main pharmaceutical properties of ophthalmic drug delivery system for FP such as gel erosion and drug release, viscosity, stability and irritancy were studied. According to the in vivo characteristic of ocular administration, a membraneless model was used to study the gel erosion and drug release simultaneously. Correlation analysis demonstrated that drug release, which followed zero-order kinetics. Thermocompression sterilization didn’t influence the gel erosion and drug release. The stability and irritancy of the ophthalmic solution of FP and in situ thermosensitive gel of FP complied with the requirement for ophthalmic appiicatiun, and no emergent irritation was observed.4. The tears were obtained by filter method. HPLC method was performed to detect the concentration of FP in tears.The area under the tears concentration vs.time curve for in situ thermosensitive gels increased more than 4.67 folds and meanretention time （MRT） for in situ thermosensitive gels increased more than 3.09 folds. Then situ thermosensitive gels showed great potential in ophthalmic application.