| Curcumin is the major active ingredient of the rhizome of Curcuma longa L, which has been extensively used as a dietary spice and a coloring agent, as well as a medicinal herb in the Chinese and Ayurvedic medical systems for the treatment of flatulence, jaundice, menstrual difficulties, hematuria, hemorrhage and colic. The studies on curcumin and its analogues have drawn increasing attentions in recent years, due to the promising clinical applications and low toxicity and have documented that curcumin possesses various biological and pharmacological activities, including anti-oxidation, anti-inflammation, tumor prevention and anti-depression, etc.. Nonetheless, the pharmaceutical formulation development of curcumin remains to be a challenge due to its poor physicochemical and biopharmaceutical properties. As a polyphenolic compound, curcumin is water insoluble and unstable at aqueous medium, and exhibits very poor oral bioavailability and rapid systemic elimination. In order to improve the bioavailability and/or modify the pharmacokinetic parameters, numerous drug delivery techniques by loading curcumin into liposomes, nanoparticles, solid dispersion or self-microemulsifying system, forming curcumin-phospholipids or cyclodextrins complex, and synthesizing structural analogues of curcumin have been investigated.Recently, a prodrug of curcumin, curcumin didecanoate (CurDD), was prepared by esterification of the hydroxyl groups of curcumin with capric acid so as to provide sustained plasma levels of curcumin and to achieve long-acting therapeutic effects following administration as a depot.Firstly, a high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of curcumin and its prodrug, curcumin didecanoate (CurDD), in rat plasma. The analytes were extracted by ethyl acetate following the addition of sodium dodecyl sulfate, and separated on a reverse phase C18 column using a gradient mobile phase system of acetonitrile-tetrahydrofuran-water containing 0.1% formic acid. Detection by UV absorption at 425 nm gave a lower limit of quantitation (LLOQ) of 5 ng/ml and 10 ng/ml for curcumin and CurDD in 50μl of plasma, respectively. Intra-and inter-day precision of quality control samples except those at LLOQ were within 15% for curcumin and CurDD, respectively, and the accuracy for both compounds were between-6.07 and 8.88%. Meanwhile, an HPLC-MS/MS method has been established for the determination of curcumin in rat plasma. The LLOQ of curcumin were determined to be 0.5 ng/ml. The linearity, precision, accuracy, extraction recoveries were fit for purpose of biological sample analysis.Secondly, the results of biotransformation of CurDD in vitro showed that CurDD can be transformed into curcumin, and the concentrations of curcumin were maintained at about 100ng/ml. Meanwhile, curcumin may be not only released by CurDD, but also degraded by itself. The results suggested that CurDD may be used as a depot of curcumin to maintain a stable concentration.Thirdly, a simple HPLC method was applied to determine the plasma concentrations of CurDD and/or curcumin after CurDD or curcumin was intravenously administered to rats at a dose of 1 mg/kg (calculated as curcumin). Following IV administration of curcumin, the plasma concentrations of curcumin rapidly decreased to the LLOQ within 20 min with a t1/2 of-7 min. After IV administration of CurDD, the concentrations of both CurDD and curcumin declined slowly. The plasma concentration of curcumin converted from CurDD was detectable up to 24 h with a t1/2 of～400 min. When the AUC data of curcumin obtained by direct IV administration were compared with those converted from CurDD, the latter were surprisingly 6-fold higher than the former. An HPLC-MS/MS method has also been developed and validated for the determination of curcumin after CurDD or curcumin was intramuscularly administered to rats at a dose of 50 mg/kg (calculated as curcumin). The study also found that when entered into the blood, CurDD was converted to curcumin and markedly extended the apparent elimination half-life. These results suggested that CurDD might be utilized as a prodrug to provide sustained plasma levels of curcumin over a long duration when administered as a depot.Fourthly, nano-suspensions of CurDD was prepared by planetary ball milling with the median particle size being less than 1μm. The preparation processes were optimized for various parameters of planetary ball milling affecting the particle size. Moreover, the physical properties and stability of the nano-suspensions have also been evaluated.Fifthly, it has been assessed that the percentage of the dose of CurDD remaining at the injection site after intramuscular administration of CurDD nano-and normal-suspensions in peanut oil. After 15d, only less than 20% of CurDD was remained at the injection site, whether CurDD nano-or normal-suspensions. Compared with CurDD normal-suspensions, CurDD nano-suspensions have extremely extended the dwell time of CurDD at the injection site.Finally, the concentration of curcumin didecanoate (CurDD) in brain tissues was determined as a function of time following intramuscular of CurDD nano-and normal-suspensions to rats at doses of 50 mg/kg(calculated as curcumin). When the brain concentration and AUC data obtained by CurDD nano-suspensions were compared with normal-suspensions, the former were significantly higher than the latter. |
