Preparation and pharmacokinetics of tolvaptan loaded nanostructured lipid carriers
Objective To prepare tolvaptan loaded nanostructured lipid carriers(Tol-NLCs)for improving the oral bioavailability of tolvaptan.Methods Based on solubility,excipients were screened,including solid lipids(precirol ATO 5,campriitol 888 ATO,compritol HD5 ATO,glycerol monostearate,maisine CC),liquid lipids(labrafil M 1944 CS,peceol,gelucire 44/14,capryol 90)and surfactants(tween 80,cremophore EL,solutol HS15,poloxamer 188).Tol-NLCs were prepared using an emulsified ultrasound low-temperature curing method and the formulation was optimized using Box-Behankn effect surface methodology.The prepared Tol-NLCs were characterized by electron microscopy(TEM)observation,particle size distribution and Zeta potential measurement,and differential scanning calorimetry(DSC).At the same time,the in vitro drug release characteristics and transmembrane transport characteristics of Tol raw materials and Tol-NLCs were compared.Compare the in vivo pharmacokinetic characteristics of Tol suspension and Tol-NLCs after ig administration in rats.Results Based on the solubility,the optimal formula for Tol-NLCs was determined using glycerol valerate as a solid lipid,glycerol monooleate as a liquid lipid,and polyethylene glycol 15 hydroxystearate as a surfactant.Through optimization,the total lipid concentration was 40.0 mg·mL-1,the surfactant concentration was 25.0 mg·mL-1,and the ultrasound time was six minutes.Under transmission electron microscopy,the prepared Tol-NLCs can be observed to be spherical in shape and evenly distributed.The average particle size of Tol-NLCs is(106.2±14.7)nm,PDI is(0.196±0.004),and Zeta potential is(-26.6±0.6)mV.The drug exists in an amorphous form in Tol-NLCs.Tol-NLCs exhibit faster drug release in the early stage and slower drug release in the later stage in pH 6.8 phosphate buffer.The results of Caco-2 cell transmembrane transport showed that the Papp(AP→BL)value of Tol-NLCs was(11.16±0.58)× 10-6 cm·s-1,and the Papp(BL-AP)value was(4.51±0.46)×10-6 cm·s-1.Compared with Tol solution,Papp(AP→BL)showed a significant increase trend,while Papp(BL→AP)showed a significant decrease trend,indicating that Tol encapsulation in NLCs promoted drug absorption and inhibited the efflux of P-glycoprotein(P-gp).Compared with Tol suspension,the bioavailability of Tol increased by 2.5 times after ig of Tol-NLCs in rats.Conclusion Tol-NLCs prepared according to optimized prescription can significantly improve the bioavailability of drugs and have important value for the development of Tol dosage forms.
tovaptannanostructured lipid carriersbioavailabilityemulsification ultrasound low-temperature curing methodpharmacokineticscell transmembrane transport
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