Preparation Of Curcumin-hydroxypropyl-β-cyclodextrin Inclusion Complex And Investigation On Its Oral Bioavailability

Curcumin(CUR)is an active ingredient of herb Curcuma longa,which has anti-hyperlipidemia,anti-inflammatory,anti-microbial,anti-oxidation,anti-tumor and other pharmacological effects.Besides,CUR has little toxicity and low adverse reactions.CUR is liposoluble substance,which dissolves in ethanol,propylene glycol and other organic solvents.However,the clinic application of CUR is greatly hampered by its poor water solubility and low bioavailability.Therefore,in order to overcome the disadvantages of CUR and provide alternative dosage forms for clinical medication,this study investigated the inclusion technology of CUR.CDs have been extensively used to improve solubility and bioavailability of poorly water-soluble drugs because of low cost,little toxicity and easiness in drug-loading method.This topic using hydroxypropyl-β-cyclodextrin(HP-β-CD)asinclusionmaterials,curcumin-hydroxypropyl-β-cyclodextrin complex(CUR-HP-β-CD)inclusion complex is prepared by a simple method of water/ethanol cosolvency incubation-lyophilization to increase the solubility,stability and bioavailability of CUR.Objective:This report is aim to complete the preparation optimization and quality evaluation of CUR-HP-β-CD inclusion complex.At the same time,the in vitro antitumor effect and in vivo pharmacokinetic of CUR-HP-β-CD were studied.Method:CUR-HP-β-CD inclusion complex was prepared by cosolvent incubation-lyophilization method.Through investigating the effects of ingredient proportion of CUR to HP-β-CD,inclusion temperature,inclusion time and cosolvent ratio which were evaluated by inclusion rate,we used orthogonal test to optimize the preparation process of CUR-HP-β-CD;FT-IR,PXRD and DSC technologies were used to testify the formation of CUR-HP-β-CD.Phase solubility experiment was used to study the solubilization of HP-β-CD.The light stability,thermal stability,wet stability and pH stability of CUR and CUR-HP-β-CD were evaluated.MTT experiment was carried out to evaluate the anti-tumor efficacy of CUR and CUR-HP-β-CD on SGC-7901 and HHCC-7721 cells.For intravenous administration,the lyophilized CUR-HP-β-CD was dissolved in water and free CUR was dissolved in 50%(v/v)PEG400 solution.For oral administration,the lyophilized product was dissolved in water and free CUR powder was suspended in 0.5%carboxymethylcellulose sodium solution(0.5%CMC-Na).The plasma samples of different time points were procesed by ethyl acetate extraction method,detected by HPLC with a mobile phase consisted of0.5%acetic acid-methanol(80:20,v:v)to analyze pharmacokinetic parameters.Results:The optimized process for preparation of CUR-HP-β-CD is as follows:the molar ratio of CUR to HP-β-CD was of 1:3,the cosolvent ratio(ethanol/water)was of1:9,the reaction temperature was at 40°C and the reaction time was for 12 h.It was concluded that CUR-HP-β-CD was successfully prepared with the hydrophobic parts being incorporated into the cavity of cyclodextrin.The phase solubility diagram could be regarded as the A_L type indicating that CUR-HP-β-CD inclusion complex was combined with 1:1 stoichiometry.Besides,CUR-HP-β-CD was relatively stable under high temperature,strong light irradiation and high humidity environment.The solubility and dissolution rate of CUR-HP-β-CD were significantly higher than that of CUR.Both CUR-HP-β-CD and pure CUR exhibited significant inhibitory effects on SGC-7901 and HHCC-7721 cells in a dose-and time-dependent manner.It can be observed that there was no significantly difference between the pharmacokinetic parameters of CUR and CUR-HP-β-CD after intravenous administration.After the gavage,the oral bioavailability of CUR-HP-β-CD was 2.77-fold higher than that of free CUR.Conclusion:The encapsulation efficiency of CUR-HP-β-CD inclusion complex was greatly enhanced by the optimized process,besides that the solubility and stability of CUR was significantly improved after inclusion.The CUR-HP-β-CD maintained the anticancer activity of CUR and significantly enhanced oral bioavailability.Therefore,CUR-HP-β-CD inclusion complex can be used for anti-tumor therapy and may be a promising therapeutic preparation.