| Curcumin, a well-known bioactive ingredient extracted from the roots of Curcuma longa, curcumn aromatica and curcumae zedoariae, is mainly composed of curcumin, a small amount of Demethoxcurcumin, Bisdemethoxycurcumin, the volatile oil mixture and other ingredients. Recent studies have shown that curcumin possesses wide range of potent pharmacological effects in anti-free radical anti-oxidation, anti-inflammatory, reducing blood viscosity, hypolipidemic, anti-atherosclerotic, anti-tumor activity etc., while it has low toxicity. The research of curcumin has become a hot topic at home and abroad in recent years. After carrying out a large number of clinical trials, curcumin is recognized as a good drug with low toxicity and side effects and low-priced, which has efficacy in the treatment of cancer. Curcumin has been classified as a third-generation anti-cancer chemopreventive drug by the United States National Institute of Oncology, and was included in the United States Pharmacopoeia in 2000. It should be said that curcumin would have very potential development of clinical application.Curcumin is slightly soluble in water. And it has been reported that the oral bioavailability of curcumin is low. The transformation of curcumin will be occurred during in the intestinal, while little was absorpted in the prototype into the blood. Therefore, the main purposes of the present study were to increase its bioavailability after oral administration, and to extend the retention time of curcumin in the gastrointestinal tract. So two kinds of liposomes, including conventional liposomes (CL), carbopol coated liposomes (CCL), were designed on the basis of the prescription.Before the design of the liposomal formulations for curcumin, the solubilities of curcumin in various organic solvent and at various pH aqueous media and the true n-octanol/water partition coefficient were determined. Meanwhile, the anti-lipid oxide of curcumin in vitro and oxidation index and the component of oral soybean phospholipid were investigated. The results indicated those as follows:Curcumin is a weak acid, and the solubilities in various organic solvents were high. But its solubility was markedly affected by the pH of the environment. Its real n-octanol/water partition coefficient was 2.69. Curcumin has strong anti-oxidation, which was a positive correlation with the amount of curcumin; oral phospholipid content of the phosphatidylcholine (PC) is much lower than the injected phospholipid.The UV spectrophotometry (UV) and high performance liquid chromatography (HPLC) which were used to determine content of curcumin were established and compared. The results showed that the results of both methods had no significant difference. The entrapment efficiency (EE) of curcumin liposomes was determined by microcolumn centrifuge method. The conventional liposomes containing curcumin (CL) were prepared by film dispersion method. Based on this, Single factor experiments and orthogonal experimental design were used to optimize the formulation and investigate the effects of various factors on EE of CL. The results indicated that the concentration of PC, the mass ratio drug to lipid, the mass ratio PC and cholesterol, different medium (different pH values) had larger effect on EE than the other factors. The high EE above 80% could be obtained in the optimized formulation.To increase oral bioavailability of curcumin, carbopol, a certain polymeric absorption enhancer with bio-adhesion property, was used to prepare carbopol coated curcumin liposomes. Meanwhile, the ways and means to improve oral absorption and bioavailability of small molecule insoluble drugs were further explored. The results showed those as follows:The particle size of CCL increased with the increasing concentration of carbopol solution used in the coating, suggesting the formation of coating layer on the surface of the liposomes. Liposomes coated 5.00 g·L-1 carbopol derived from the best physical stability among all of CCLs coated with carbopol of different concentration during the six-month storage at 4℃. The carbopol coating did not change EE significantly. The liposomes kept spherical and no significant aggregation was observed by transmission electron microscopy after coated with 5.00 g·L-1 carbopol. The stability of CCL in the artificial gastric juice showed that the drug release overall slower than CL. Also CCL showed a certain degree of biological adhesion property, and the bioadhesive of carbopol coating was larger than chitosan coating at the same concentration.Then the physicochemical characteristics of CL and CCL were evaluated in vitro. The liposomes were spheroidal and uniform, and the volume diameters of curcumin liposomes suspension were (228±12.5) nm and (459±24.8) nm respectively; The pH value was not changed notably, closed to 6.5; the EE of these were (88.8±1.28)% and (86.6±1.72)% differently.CL and CCL initial stability and security were studied. The results of stability tests indicated that CL and CCL need to improve stability further. In addition, the volume diameters of CCL became larger in the process of long-term storage at 4℃; there was not significant change in other indicators. Provocative tests in rat small intestine were introduced to carry out CCL safety inspection. The security investigation indicated that CCL were non-irritant, safe and did not appear adverse effects predictable in the short-term.To study the pharmacokinetics behaviour of liposomal curcumin, a stable, rapid, and accurate HPLC method was developed for the determination of curcumin in rat plasma. After oral administrated to rats respectively, the pharmacokinetics data in rats of curcumin suspension (CS), CL, CCL were compared. The results obtained from oral pharmacokinetics study indicated that the pharmacokinetic processes in rats for the three preparations were all accorded with two compartmental models. Compared with curcumin suspension, curcumin in liposomes had higher bioavailability. CCL significantly increased the oral bioavailability in rats after oral administration, while the relative bioavailability F (%) was 281%, which was 2.22 times as compared with the CL... |
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