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Study On The Oral Absorption Of (S)NEDDS With And Without Pancreatic Lipase

Posted on:2015-09-25Degree:MasterType:Thesis
Country:ChinaCandidate:H Y WuFull Text:PDF
GTID:2284330452953766Subject:Pharmacy
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Purpose: The aim of the present study was to design self-nanoemulsion drug deliverysystems (SNEDDS) for the poorly water-soluble drugs of BCSⅡ, and study the oralabsorption mechanism of SNEDDS using in vitro cell model, in vitro lipolysis model and invivo rat model with lipolysis and without lipolysis condition.Methods:(1) Preparation and evaluation of nanoemulsion drug delivery systems (NEDDS).Solubility of GRI、IND、KET、PHE in various oils, surfactants and co-surfactants weredetermined and pseudo-ternary phase diagrams were constructed to identify thecomposition and proportion. The particle sizes of the resultant formulation with drugloaded were determined using a laser diffraction size and the stability within24h wasstudied.(2) Constructed MDCK cell model to study the cell monolayer’s transportcharacteristics of GRI、IND、KET、PHE and its NEDDSs by comparing the cumulativepermeate quantity percentage (CP%) and apparent permeability coefficients (Papp).(3) Preparation and evaluation of cinnarizine medium chain SNEDDS(CIN-MCT-SNEDDS). The excipients of formulation were chosen base on the mixeduniformity of excipients. Pseudo-ternary phase diagrams were constructed and thesolubility of CIN in various oils, surfactant and co-surfactant were measured to determineoptimal MCT-SNEDDS formulation. Self-emulsifying rate, transmittance, particle sizewere measured and the stability within24h of MCT-SNEDDS with different drug loadingswas study to evaluate the optimal MCT-SNEDDS.(4) Building and optimization of in vitro lipolysis model. Building in vitro lipolysismodel with reference and the conditions including the concentration of lipase, NaTDC/PC,NaOH, Trizma maleate and the adding way of Ca2+were studied with the indexes of the MCT-SNEDDS lipolysis rate and degree.(5) Study on the drug dynamic distribution and solubility in different phases oflipolysis medium during the lipolysis of CIN-MCT-SNEDDS. In vitro lipolysis ofCIN-MCT-SNEDDS was conducted and sampling at predetermined time. Bench-topcentrifuge and ultracentrifuge were used to separate different phases of lipolysis mediumand the drug concentrations were measured with HPLC. The drug solubility of aqueousphase was compared between with lipolysis and without lipolysis of CIN-MCT-SNEDDS.(6) The pharmacokinetic study in SD rats of CIN-SUSP and CIN-MCT-SNEDDS.Blood samples were collected through the orbital vein prior to dosing and at thepredetermined time of0.167,0.5,1.0,1.5,2.0,3.0,4.0,6.0,8.012.0and24h post-dosingof test formulations. The plasma was separated immediately with acetonitrile. The CINconcentrations in plasma were determined with HPLC. Drawing the plasma concentrationversus time profiles, and area under the curve (AUC) of CIN was calculated by the lineartrapezoidal model.Results:(1) Preparation and evaluation of NEDDS. The optimal formulation was preparedusing MCT oil: Tween80/Span80(HLB=11): water=8:10:3.5. The optimal formulationwith drug loaded was clear bluish, the particle size was less80nm and there was no drugprecipitation within24h.(2) MDCK model study. NEDDS could significantly increase the solubility of GRI、IND、KET and PHE, but the CP%and Pappwere notably decreased when compared to itssaturated aqueous solutions.(3) Preparation and evaluation of CIN-MCT-SNEDDS. The optimal formulation wasprepared using MCT oil: Cremophor RH40: Ethanol=3:5:2and could form the clear andmono-phasic nanoemulsion system with a particle size less than29nm in3min whendispersing in water, pH6.8digestion buffer and NaTDC/PC mixed micelle.CIN-MCT-SNEDDS with25mg CIN was stability and no drug precipitation within24hwhen dispersing in the above solutions.(4) In vitro lipolysis model optimization. The conditions of optimized lipolysis modelas following: NaCl:50Mm, Trizma maleate:50mM, Ca2+:5mM (once adding), NaTDC/PC: 5mM/1.25mM, lipase activity:800TBU/mL, NaOH:1M.(5) The order of the solubility of CIN in various solvents was pH1.2HCl> aqueousphase of lipolysis medium> NaTDC/PC mixed micelle> digestion buffer≈water.Aqueous phase and pellet phase of lipolysis medium were obtained with bench-topcentrifuge and ultracentrifuge. There was no significant difference between bench-topcentrifuge and ultracentrifuge to separate the different phase of lipolysis medium. CINconcentration in aqueous phase was decrease with the proceeding of MCT-SNEDDSlipolysis, and the amount of drug precipitation was increased corresponding. Comparedwith lipolysis condition, there was no drug precipitation of CIN-MCT-SNEDDS withoutlipolysis. However, the drug concentration in aqueous phase after60min lipolysis ofCIN-MCT-SNEDDS was about3times higher than its solubility in aqueous phase oflipolysis medium.(6) Study of pharmacokinetics. A double peak phenomenon was observed on theplasma profiles. The primary pharmacokinetics parameters of CIN-MCT-SNEDDS asfollowing: C1max:0.44μg/mL, C2max:0.63μg/mL, T1max:2h, T2max:8h, AUC0~24:6.27μg.h/mL, and all of them were significantly larger than CIN-SUSP. The relativebioavailability of CIN-MCT-SNEDDS was179.66%. However, the T2maxwas delayed.Conclusions: NEDDS could improve the solubility of poorly water-soluble drugs, but thepermeability didn’t increase corresponding. The veracity of using typical in vitro cellmodel to study the absorption of NEDDS was limited since the complex environment ingastrointestinal after oral administration. Drug was released from oil phase graduallyduring lipolysis and solubilizing in aqueous phase which facilitating the drug absorption.MCT-SNEDDS could enhance the bioavailability of CIN and delay absorption which wasevidenced by in vivo pharmacokinetics study. In vitro lipolysis model conducted toevaluate and predict drug oral absorption was reliable and showed good in vivo in vitrorelations.
Keywords/Search Tags:Poorly water-soluble drugs, Nanoemulsion drug delivery systems, MDCK cellmodel, In vitro lipolysis model, intestinal digestion, Pharmacokinetics, Bioavailability, Absorption mechanism
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