The Comparision Of The Effects Of Drugs And Nanoemulsions Properties On The Oral Absorption And Lymphatic Transport

Objective:To study and compare the effects of drug properties and properties of oil in nanoemulsion?NE?on oral absorption and lymphatic transport of drugs promoted by NE.Methods:The shake-flask method was used to determine the equilibrium solubility and oil-water partition coefficient?log P?of drug in water and various gastrointestinal p H buffers.Lipolytic triglycerides?soybean oil?SO?and medium-chain length triglyceride?MCT??,lipolytic monoester?Maisine 35-1?MAI?and ethyl oleate?EO??,and non-lipolytic oils?isopropyl palmitate?IPP?,lemon oil?LO?and linoleic acid?LOA??were selected as the oil phase for NE.The NE formulations and emulsified process were optimized.Cinnarizine?CIN?and Raloxifene?RAL?were used as the model drugs to evaluate the basic properties of drug-loaded NE.Lipolytic SO-NE and non-lipolytic IPP-NE were used to represent the lipolysis and non-lipolysis NE,respectively,for evaluating the stability of NE in simulated gastrointestinal fluid in vitro.The in vivo rats were used to compare the oral bioavilability which effected by the properties of CIN and RAL,and the oils of NEs.Cycloheximide?CHX?was injected as a chylomicron blocker to establish the blocking model for study the lymphatic transport of drugs.The relationship between lymphatic transport and oral absorption was illustrated.Results:?1?The comparision on the solubility and log P of CIN and RAL.At 37?,the equilibrium solubility of CIN decreased and the log P increased with the increase of p H.The CIN solubility in water was 0.84�0.03?g/mL and the log P was 3.05.The equilibrium solubility of RAL was arranged as following order,pH 5.0>pH 1.2>water>p H 6.8.There was positive correlation between log P of RAL and pH.The RAL solubility in water was 1.47�0.19?g/mL and log P water was 2.55.?2?The optimization of formulations and emulsified process,and the comparison of drug loaded NEs.The ratio of pre-nanoemulsion was oil:LOA:Cremophor RH40:ethanol=5:5:7:3?w/w?.The 2 mL water was added into 1 g pre-nanoemulsion at a 0.5 mL/min of water adding rate,40�C,and stirred at 1,000 rpm to prepare NE.The saturated solubility?S₀?of CIN was up to 160 mg/g in LOA-NE,and that was 85 mg/g to 100 mg/g in other NEs.The saturated drug loading in pre-nanoemulsion?S₀%?of CIN?50 mg/g?was arranged as follows,EO-NE and SO-NE?56%to58%?>MAI-NE,IPP-NE,LO-NE and MCT-NE?51%to 52%?>LOA-NE?31%?.The S₀ of RAL in SO-NE and IPP-NE were 15 mg/g and8 mg/g,respectively.The S₀%of RAL?7 mg/g?was 46%and 89%,respectively.The particles size of CIN-NEs were range of 35 to 110 nm and their PDI were below 0.3.The range of Zeta potential was-5.5 to-2.2mV,and conductivity of NEs were 0.16 to 0.24 mS/cm.The particle size of RAL-NE was 26 to 28 nm and the PDI was less than 0.3.The Zeta potential of RAL-NEs were-4.5 to-3.3 mV and the range of conductivity were 0.18 to 0.20 mS/cm.The pH of the drug loaded NEs were about 5.?3?The comparison on in vitro stability.CIN-NE and RAL-NE were stable in water dilution?25 to 100-fold?and in the simulated gastric fluid,the changes of particle size were not sighificant and without precipitation.The precentage content of CIN and RAL dissolved in the liquid phase had no significant changes?>80%?within 2 h.In the simulated intestinal fluid,the lipolysis rate and degree of SO-NE were higher than those of IPP-NE.In addition,the particle size of SO-NE was up to 160 nm,while that of IPP-NE was only 80 nm post-lipolysis.After 1 h of lipolysis and stirring for 8 h,the percentage content of drugs in SO-NE decreased to 30%,while that in IPP-NE was above 70%.?4?The comparison on the oral absorption of drugs.The relative oral bioavailability of CIN were arranged as below order,LO-NE?1535.7%?>SO-NE?821.8%??IPP-NE?804.2%?>EO-NE?626.9%?>MAI-NE?541.2%?>MCT-NE?475.6%??LOA-NE?478.6%?.The relative oral bioavailability of RAL was as follows,SO-NE?51.15%??IPP-NE?49.84%?.?5?The comparison on lymphatic transport of drugs.The elimination half-life of CHX was 4.19 h and the injecting dose of CHX was 1 mg/kg to establish the chylomicron blocking model.The differences of area under plasma concentration-time during 0 to 6 h(differences of AUC_0-6h)was used to represent the trend of lymphatic transport of CIN-NE and the order was arranged as follows,LO-NE?7.43�1.64 h*?g/mL?>EO-NE?4.95�0.21 h*?g/mL?>MAI-NE?4.07�0.31 h*?g/mL?>MCT-NE?2.96�0.49h*?g/mL?>LOA-NE?2.73�0.35 h*?g/mL?>IPP-NE?1.87�0.50h*?g/mL?>SO-NE?1.60�0.45 h*?g/mL?>SUSP?1.21�0.26h*?g/mL?.The order of lymphatic transport rate([AUC_0-6hNormal-AUC_0-6hBlocking]/AUC_0-6hNormal�100%)was as follow,SUSP,LOA-NE and EO-NE?92%?>MAI-NE?81%?>MCT-NE?76%?>LO-NE?59%?>IPP-NE?54%?>SO-NE?46%?.The difference of AUC_0-6h of RAL was as follows,IPP-NE?0.45�0.09 h*?g/mL?>SUSP?0.39�0.13 h*?g/mL?>SO-NE?-0.01�0.14 h*?g/mL?.The lymphatic transport rate of RAL was as follows,SUSP?90%?>IPP-NE?74%?>SO-NE?-3%?.The lipophilic CIN has higher lymphatic transport amount than RAL.?6?The relationship between lymphatic transport and bioavailability.The lymphatic transport was closely related to the promoted effects of NEs on oral absorption of CIN.Except the SO-NE and IPP-NE,the differences of AUC_0-6h of CIN-NEs were positive correlated with their oral bioavailability,namely,the lymphatic transport was positive correlated with oral bioavailability.CONCLUSION:?1?Due to the difference of aqueous solubility and log P of CIN and RAL,their S₀ and drug loading dose were significantly different.?2?NE can significantly improve the oral bioavailability of CIN,but the oils in NEs had various contirbutions on the CIN absorption.The the oral absorption of CIN can be better promoted by LO-NE,IPP-NE and SO-NE.?3?The lymphatic transport had a significant contribution on improvement of oral bioavailability of CIN.?4?The CIN-NEs with different oil properties,affect the trend and degree of lymphatic transport of drug and it was arranged as follows,essential oil>monoester>MCT>fatty acid>isopropyl ester>long-chain length triglyceride.?5?The oral absorption of RAL indicated that the improvement effect on oral bioavailability not only correlated with NE formulations,but also with the log P,S₀ and drug loading dose.