Preparation And Investigation Of A Thermoresponsive Ophthalmic In Situ Gel Containing Terbinafine Hydrochloride(TH)-loaded Macrogol 15 Hydroxystearate Micelles

Background:Macrogol 15 hydroxystearate(HS 15)is widely used to solubilize poorly soluble drugs as a novel and soft non-ionic surfactant.HS 15 when above its CMC(0.06-0.1mM)can form 13 to 14 nm micelles in aqueous media at 37°C.In situ gelling system constituted one of the main means to enhance the bioavailability of ophthalmic pharmaceutical formulation through increasing pre-corneal drug retention.This purpose of this job was to prepare and investigate a thermoresponsive in situ gel including terbinafine hydrochloride(TH)-loaded macrogol 15 hydroxystearate(HS15)micelles with the expected sol-gel transformation temperature for ophthalmic use.Combining drug-loaded micelles with in-situ gels prolongs the drug's residence time of the pre-cornea,further increasing the bioavailability.Purpose:This purpose of this job was to prepare and investigate a thermoresponsive in situ gel including terbinafine hydrochloride(TH)-loaded macrogol 15 hydroxystearate micelles(HS15)for ocular use.Methods:TH-loaded HS15 micelles(TH-HNMs)were prepared through the simple co-solvent method.Then the gels(TH-HNMs-Gel)were created by the cold method.We take advantage of the central composite design and response surface methodology to estimate the influences of changing the concentrations of F127 and F68 on the sol-gel transition temperature.The optimized formulation was a free-flowing liquid at room temperature or under refrigeration conditions and transformed into a semi-solid gel at about 34.5? after dilution with simulated tear fluid.The Characterization of the TH-HNMs was measured by Zetasizer and transmission electron microscopy(TEM).The high performance liquid chromatography(HPLC)was employed to exam the in vitro cumulative release quantity of TH in the TH-HNMs-Gel and estimate the drug entrapment efficiency.Six rabbits was used to evaluated the ocular irritation of TH-HNMs-Gel.50?L of0.25%TH eye drops were administered to the right eye conjunctival sac.And the left eye was given saline as a control.The ocular surface integrity was observed using slit lamp at 1h,2h,4h,24 h,48h,72 h and scored according to the Draize score.Fifty-four rabbits were divided into two groups randomly.50?L of 0.25% TH-HNMs(control group)and TH-HNMs-Gel(experimental group)were topically applied to the right eye and the corneas were collected after 5,15,30,60,90,120,180,240 and 360 min.Then the TH concentration was determined by HPLC analysis.Results:Average size of TH-HNMs was 14.25±0.903 nm with a low PDI of 0.025.And an electrically neutral surface(-2.67±0.29 mV).The drug encapsulation efficiency of TH-HNMs-Gel was almost 100%.The release of TH from the micelles was pH dependent.93.43±1.52% of encapsulated TH released from the TH-HNMs-Gel in the PBS at pH 5.0.But within the same release time,there was only 0.201±0.018% of TH that released from the PBS at pH7.4.Ocular irritation test indicated thatTH-HNMs-Gel may be believed to be harmless for the delivery of ophthalmic drug.The peak concentration of TH of the experimental group and the control group in the normal rabbit cornea after administration was 13.51±0.85?17.16±2.09?g/g,which occurred 5 minutes post-dose.Although the concentration of th peak in the experimental group was slightly lower than that in the control group,the TH-HNMs-Gel in the experimental group showed a longer retention time.The AUC0-360 min of experimental groups was 1058.8g/g·min.It was 1.41 folds of the control group.Conclusion:The TH-HNMs-Gel with easily prepared,small and physically stable characteristics can enhance the ocular bioavailability and it holds great promise as an efficient carrier for topical ocular delivery of TH.