Preparation Of Naringenin Phospholipid Complex And Its Pharmacokinetics In Rat Plasma

Naringenin is a kind of hydrophobic flavonoid,which is mainly found in citrus fruits such as grapefruit,sweet orange,lemon and tangerine.As one of the flavonoid active ingredients,naringenin has many pharmacological activities,such as anti-oxidant,anti-inflammatory,anti-tumor,lowering blood lipid,and antibacterial.However,the water solubility and liposolubility of naringin are poor,which makes it difficult to be absorbed and utilized by the digestive tract mucosa in vivo,and the oral bioavailability is extremely low,which limits its further application in food,medicine and clinical.In recent years,phospholipid complexation technology has been widely used to improve the bioavailability of poorly soluble flavonoids.In this study,naringenin phospholipid complex was prepared by solvent evaporation,and its structural characteristics,organic solvent residues,equilibrium solubility,oil-water partition coefficient,and in vitro dissolution were studied and analyzed.The effects of temperature,humidity and light on the stability of naringenin phospholipid complex were investigated by reference indexes such as appearance,mass fraction,particle size and potential,and the best storage and transportation conditions were sought.Finally,the pharmacokinetic behavior of naringenin and naringenin phospholipid complexes in rat plasma was investigated,and the effect of phospholipid complex on naringenin bioavailability was explored.The main results are as follows:1. Preparation,structural characterization and physicochemical properties of naringenin phospholipid complex?1?The naringenin phospholipid complex was prepared by solvent evaporation method,and it's drug loading efficiency is 31.79%±0.99%.The structure of naringenin phospholipid complex was characterized by UV,FTIR,DSC and XRD,The results show that naringenin phospholipid complex is a new phase,it is different from the physical mixture of naringenin and phospholipid,and is formed by intermolecular forces such as hydrogen bonds,van der Waals forces,and charge migration forces.Naringenin is dispersed in the phospholipid complex in an amorphous state.?2?A headspace gas chromatography method was developed for the determination of organic solvent residues in naringenin phospholipid complexes.The results show that the residual amounts of dichloromethane and ethyl acetate in the naringenin phospholipid complex are 0.0163%±0.0025%and 0.0408%±0.0019%,respectively,which all meet the standard of Chinese Pharmacopoeia.?3?The HPLC method for determining naringenin content was established.The equilibrium solubility,oil-water partition coefficient and in vitro dissolution of naringenin phospholipid complex were determined.The results show that the phospholipid complex can significantly increase the equilibrium solubility of naringin in water,n-octanol and different p H PBS buffer,Log P is reduced from 2.72±0.02 to 1.11±0.09,which more satisfies the absorption conditions in vivo.At the same time,the phospholipid complex can significantly improve the in vitro dissolution characteristics of naringenin,and the cumulative dissolution rate increased from 41.96%to 52.55%.2. Research on stability of naringenin phospholipid complexThe stability experimental results show that humidity is the main factor affecting the stability of naringenin phospholipid complex.Under high humidity environment,naringenin phospholipid complex absorbs moisture obviously and become viscous,which is difficult to weigh and store,at the same time,the particle size increases and the absolute value of potential decreases.Temperature has no effect on the drug loading of naringenin phospholipid complex,but high temperature will cause naringenin phospholipid complex to oxidize,darken the color and increase the particle size.Under light conditions,the naringenin phospholipid complex increases in particle size and decreases in absolute value of potential,while the mass fraction is significantly reduced.Therefore,the naringenin phospholipid complex should be stored at room temperature,without light and dry conditions.After 6 months of storage under these conditions,the naringenin phospholipid complex was stable.3. Study on pharmacokinetics of naringenin and its phospholipid complex in rat plasma?1?A HPLC analysis method of naringenin content in rat plasma was established.Methodological investigation show that the RSD of precision and stability are less than15%,and the extraction recovery is more than 80%,which meet the requirements of biological sample detection.Plasma naringenin has a good linear relationship in the range of 0.05?10?g/m L,and plasma endogenous substances has no interference with the determination.?2?SD rats were given 200 mg/Kg naringenin and naringenin phospholipid complex?in naringenin?by gavage.The plasma concentration-time curve was plotted and the pharmacokinetic parameters were calculated.The results show that the AUC_0-t,AUC_0-?,and C_maxof the naringenin phospholipid complex group are significantly larger than those of the naringenin group?P<0.01?,which are 2.13 times,2.12 times,and 2.31 times that of the naringenin group,respectively.T_1/2is 1.89 times that of the naringenin group,K_eand CL are significantly reduced,MRT_0-tis extended from?4.808±0.281?h to?7.123±0.508?h,and MRT_0-?is extended from?6.655±1.479?h to?9.261±1.859?h.Compared to naringenin,the relative bioavailability of naringenin phospholipid complex is?224.70±33.51?%.The results show that the formation of phospholipid complex increases the absorption of naringenin,delays the elimination rate of naringenin,increases the circulation time in the body,and thereby improves the bioavailability of naringenin.