Design And Evaluation Of Effective Oral Nano-formulations Of Curcumin

Curcumin,an active component isolated from the rhizome of the plant Curcuma longa,exhibits wide pharmacological activities and little side-effects.It was classified as BCS Class ?molecule,with low solubility and permeability.It possessed poor stability and undergone fast metabolism when passing through intestinal and appearing in liver.All of these constrain its oral bioavailability.There are three kinds of oral nanocarriers,polymer based nanocarriers,lipid based nanocarriers and molecular based nanocarriers.Curcumin was set as model drug and two kinds of nano-formulations,self-assembled nanoparticles based on polymer and self-emulsifying drug delivery system based on lipid,were designed and developed.Pharmacokinetics and pharmacodynamics of the above two kinds of nano-formulations and Meriva,phytosome of curcumin based on molecular complex,were investigated to verify whether the three kinds of nano-formulations can increase oral bioavailability of curcumin.And absorption mechanisms of the nano-formulations were investigated and compared in order to bring insight into the key factors affecting oral absorption of curcumin.These can provide theoretical and practical basis for designing and preparing effective oral formulations of curcuminTwo kinds of amp hiphilic copolymers based on pullulan,PL(poly(D,L-lactide)-graft-pullulan)and PPLGA(poly(lactic-co-glycolic acid)-graft-pullulan)were designed and synthetized.Microwave assisted synthesis was first applied to synthetize PL.Reactive conditions were evaluated by molecular compositions and yield of PL.And the above methods were further used for the synthesis of PPLGA,which was further characterized.The results indicated that microwave-assisted synthesis shorten the copolymerization of PL,possess higher yield and give amphiphilic copolymers with different characters.Attributing to the thermo(temperature)-stimuli responsive character,curcumin-loaded self-assembled nanoparticles could control drug release as a function of the ambient temperature.PPLGA-1 whose LCST was 40? was selected as amphiphilic copolymers and solvent casting was used for preparing self-assembled nanoparticles based on polymer and loaded with curcumin.The results showed that particle size of CUR-PPLGA-N was 83.88±0.58nm(PDI:0.23±0.01)which can improve the solubility of curcumin to 2mg/ml,1.816×105-fold of free curcumin.Drug loading and encapsulation efficiency of CUR-PPLGA-N was 15.71 ±0.27%and 78.53±0.61%,respectively.CUR-SEDDS was also screened and prepared,which consisted of curcumin,P53 as oil,Cremphor EL as surfactant and Transcutol as co-surfactant.The curcumin concentration of CUR-SEDDS was 35mg/ml.CUR-SEDDS could generate nano-emulsions with particle size of 98.7±13nm after self-emulsifying in water.In order to confirm the advantages of two kinds of nano-formulations of curcumin,based on polymer and lipid,pharmacokinetics and bioavailability of them were investigated by setting CUR-Suspension(CUR-SU)as control and compared with Meriva based on molecular complex.Results indicated that the elimination of curcumin in the formulation of CUR-PPLGA-N is fast.The relative bioavailability Meriva,CUR-PPLGA-N and CUR-SEDDS was 415.4%?1576.9%and 3769.2%,Cmax was 18.333?58.333 and 70.000-fold of the counterpart of CUR-SU.The elimination half life of CUR-SEDDS is 2.872-fold of Meriva indicating that curcumin of this formulation eliminate slower than Meriva and CUR-PPLGA-N.CUR-SEDDS endowed curcumin with longer circulation time and is better than CUR-PPLGA-N based on polymer,which is better than Meriva based on molecular complex for improving oral availability of curuminSetting bifendate as positive control group,activities of CUR-PPLGA-N,CUR-SEDDS with high,medium,low dosage,Meriva and CUR-SU on inhibiting carbon tetrachloride-induced liver injury were investigated and compared according the levels of GPT and GOT in plasma,glutathione peroxidase in liver and liver histopathology.Results indicated that the activities of CUR-SEDDS based on lipid were significantly better than CUR-PPLGA-N based on polymer,Meriva based on molecular complex and bifendate.Two kinds of nano-formulations of curcumin had shown different potential in improving bio availability and effect of curcumin.In order to bring insight into the key factors affecting oral absorption of curcumin,everted rat gut sacs and Caco-2 cells were adopted for investigating absorption mechanism of CUR-PPLGA-N and CUR-SEDDS.The stabilities of CUR-PPLGA-N and CUR-SEDDS in simulated gastric fluid,simulated intestinal fluid and Krebs-Ringer' buffer were also investigated.Results showed that macropinosis could contribute to the uptake of CUR-PPLGA-N and CUR-SEDDS,raft/caveolae dependent endocytosis is also uptake route of the two formulations,clathrin-mediated endocytosis also contribute to the uptake and the uptake is time and energy dependent.CUR-PPLGA-N and CUR-SEDDS can increase the permeability of curcumin,and the latter one is more excellent.CUR-SEDDS had better stability in Kreb-Ringer's buffer,simulated gastric fluid,plasma and simulated intestinal fluid than CUR-PPLGA-N.This maybe the underlying reasons resulting formulations' differences in permeability,oral bio availability and pharmacodynamics.Increasing the stabilities in body fluid and permeability of curcumin upon improving its solubility,are key factors that affect the oral absorption of curcumin.