Study On Preparation And Preliminary Pharmacodynamics Of The Levofloxacin Hydrochloride Ear Thermosensitive Gels

Levofloxacin hydrochloride has high water solubility, high activity, lowtoxicity and clinical efficacy is higher, at present, commonly used inclinical routine otic solution, ointment in treatment of otitis externa, earinfections. Ear drops is convenient for administration, but easy to drain,needs frequent administration; ointment is not easy to drain, has sustainedrelease effect, but the administration is not convenient, not easy topermeate into the ear canal lesion depth treatment role play.Therefore, if the drug to prepare thermosensitive gel model, can in aliquid form of external auditory canal administration, occurs rapidly in theear canal phase transition to form a semi-solid gel, adhesion to the ear canalsurface, to extend the residence time in the ear canal, so as to reduce thefrequency of administration, and delay the drug release, increasebioavailability, overcomes the ear drops daily frequent dosing problem.Therefore, we selected the poloxamer P407and P188as drug carrier, theLevofloxacin Hydrochloride made levofloxacin ear temperature sensitivegel preparation, established its quality standard, and carries on the quality control, to investigate the in vitro erosion and drug release behavior and earretention study and preliminary pharmacodynamics study.Part1Preparation of the Levofloxacin Hydrochloride EarThermosensitive Gels The gel matrix is used in the preparation ofthermosensitive gel using poloxamer P407and P188, effects of differentprescriptions on gelation temperature sensitive gel. Preparation ofthermosensitive gel by cold method, concentration of P407and P188optimized by uniform design, determination of the gel temperature tubeinversion method. The experimental results show that, with increase ofP407concentration in the prescription, gelation temperature decreased andthe influence of gel; gelation temperature P188and P407instead of the gel;gelation temperature of other excipients and drug formulation of the gel toalso have certain effect.Part2Study on Stagnation of the Levofloxacin Hydrochloride EarThermosensitive Gels In order to stay the prepared gel, the ear endoscopyand magnetic resonance are investigated in the rabbit ear canal morphologyand retention time from the visual and radiographic angle. The preparedtemperature sensitive gel solution into rabbit ear, respectively in0h,1h,3hand8h were observed, results showed that, the gel quickly change in rabbitear energy, formation of semi-solid gel adhesion in the ear canal, theresidence time of more than8h. Part3Quality evaluation of the Levofloxacin Hydrochloride EarThermosensitive Gels To investigate the ear appearance, temperaturesensitive gel differential, pH value, content determination and stability. Theexperimental results show that, the gel is colorless or yellowish greentransparent liquid, retention time of the peak of the gel solution and controlsolution peak consistent blank gel solution, no absorption at293nmwavelength. The gel solution pH value is between5.5~6.5, the method forcontent determination of accuracy, precision, recovery rate all meet therequirements of methodology, the detection limit of0.54ng, levofloxacinhydrochloride in1～1000μ g ml1range of concentration and peakarea had a good linear relationship, y=5.0759x-22.7152(r=0.99992）, onthe determination of loxapine LVFX without interference. The gel has goodstability, but the need to avoid light preservation. And initially establishedthe quality standard of the gel.Part4Erosion and Drug Released Behavior of the LevofloxacinHydrochloride Ear Thermosensitive Gels Using HPLC to establish themethod for determination of the content of levofloxacin hydrochloride, amembraneless method and dialysis bag method was used to investigate thecorrosion behavior of gel and release behavior. The experimental resultsshow that, levofloxacin hydrochloride otic solution and drugtemperature-sensitive gel release followed zero-order kinetics equation, thetwo have a good linear relationship（r=0.9995）. A cumulative erosionpercentile and LVFX gel release percentage equal, when the gel erosion began, LVFX began to release; when the gel is completely dissolved,LVFX is completely free, takes about8h. Comparing the gel preparationand its aqueous solution, have obviously sustained effect.Part5Study on the safety and preliminary efficacy of theLevofloxacin Hydrochloride Ear Thermosensitive Gels UsingPseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli to rabbitear model was made, after the success of modeling, the negative isphysiological saline, Levofloxacin Hydrochloride Ear Drops as the positivecontrol, the bacterial clearance rate as evaluation index, and to observe therabbit ear. The experimental results show that, the ear temperature sensitivegel in rabbit ear has no significant stimulation, no swelling, edema,hyperemia. Preliminary efficacy studies, the LVFX ear temperaturesensitive gel times than the commercially available using the reduction inthe number of ear drops, and efficacy, no significant difference (P>0.05).This topic using poloxamer P407and P188as gel matrix ofthermosensitive gel, preparation of ear temperature sensitive gel systemusing LVFX as model drug, the uniform design method was adopted for thefirst time to prepare LVFX ear temperature sensitive gel. Establishment ofLVFX ear temperature sensitive gel solution and in vitro release method,confirms the gel erosion and drug release followed zero-order kineticsequation, the corrosion rate of gel is the main factor to determine the drugrelease rate, there was a good linear relationship between the two （r=0.9995）; confirmed the LVFX ear temperature sensitive gel and LVFXcompared to aqueous solution had obviously sustained effect; animalexperiment was adopted for the first time by endoscopy and nuclearmagnetic resonance spectroscopy confirmed that LVFX ear temperaturesensitive gel in the ear can retention time more than8h, and commerciallyavailable hydrochloric acid is left ofloxacin ear drops efficacy, organizationand good biocompatibility, no stimulation. This subject is temperaturesensitive gel in the ear canal locally applied in the establishment of themeans of preliminary, laid the theoretical foundation for the formulation ofthe ear canal application.