Biocompatible and biodegradable nanoparticles for enhancement of anti-cancer activities of phytochemicals.

Many phytochemicals show promise in cancer prevention and treatment, but their low aqueous solubility, poor stability, unfavorable bioavailability, and low target specificity make administering them at therapeutic doses unrealistic. This is particularly true for (-)-epigallocatechin gallate, curcumin, quercetin, resveratrol, and genistein. There is an increasing interest in developing novel delivery strategies for these natural products. Liposomes, micelles, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers and poly (lactide-co-glycolide) nanoparticles are biocompatible and biodegradable nanoparticles. Those nanoparticles can increase the stability and solubility of phytochemicals, exhibit a sustained release property, enhance their absorption and bioavailability, protect them from premature enzymatic degradation or metabolism, prolong their circulation time, improve their target specificity to cancer cells or tumors via passive or targeted delivery, lower toxicity or side-effects to normal cells or tissues through preventing them from prematurely interacting with the biological environment, and enhance anti-cancer activities. Nanotechnology opens a door for developing phytochemical-loaded nanoparticles for prevention and treatment of cancer.

Nanoencapsulation enhances epigallocatechin-3-gallate stability and its antiatherogenic bioactivities in macrophages.

We have successfully synthesized (-)-epigallocatechin-3-gallate (EGCG) encapsulated nanostructured lipid carriers (NLCE) and chitosan-coated NLCE (CSNLCE) using natural lipids, surfactant, chitosan, and EGCG. Nanoencapsulation dramatically improved EGCG stability. CSNLCE significantly increased EGCG content in THP-1-derived macrophages compared with nonencapsulated EGCG. As compared to 10 µM nonencapsulated EGCG, both NLCE and CSNLCE at the same concentration significantly decreased macrophage cholesteryl ester content. NLCE and CSNLCE significantly decreased mRNA levels and protein secretion of monocyte chemoattractant protein-1 (MCP-1) levels in macrophages, respectively. These data suggest that nanoencapsulated EGCG may have a potential to inhibit atherosclerotic lesion development through decreasing macrophage cholesterol content and MCP-1 expression.

Anticancer activities of (-)-epigallocatechin-3-gallate encapsulated nanoliposomes in MCF7 breast cancer cells.

The chemopreventive actions exerted by green tea are thought to be due to its major polyphenol, (-)-epigallocatechin-3-gallate (EGCG). However, the low level of stability and bioavailability in the body makes administering EGCG at chemopreventive doses unrealistic. We synthesized EGCG encapsulated chitosan-coated nanoliposomes (CSLIPO-EGCG), and observed their antiproliferative and proapoptotic effect in MCF7 breast cancer cells. CSLIPO-EGCG significantly enhanced EGCG stability, improved sustained release, increased intracellular EGCG content in MCF7 cells, induced apoptosis of MCF7 cells, and inhibited MCF7 cell proliferation compared to native EGCG and void CSLIPO. The CSLIPO-EGCG retained its antiproliferative and proapoptotic effectiveness at 10 µM or lower, at which native EGCG does not have any beneficial effects. This study portends a potential breakthrough in the prevention or even treatment of breast cancer by using biocompatible and biodegradable CSLIPO-EGCG with enhanced chemopreventive efficacy and minimized immunogenicity and side-effects.

A novel gastric-resident osmotic pump tablet: in vitro and in vivo evaluation.

A novel famotidine gastric-resident osmotic pump tablet was developed. Pharmaceutical iron powder was used as a gas-formation and density-increasing agent. Central composite design-response surface methodology was used to investigate the influence of factors, i.e., polyethylene oxide (Mw 1,000,000) content, NaCl content, iron powder content and weight gain, on the responses including ultimate cumulative release and correlation coefficient of drug release profile. A second-order polynomial equation was fitted to the data and actual response values are in good accordance with the predicted ones. The optimized formulation displays a complete drug delivery and zero-order release rate. Gamma scintigraphy was selected as the method to monitor in vivo gastric residence time of the (99m)Tc-labeled system in Beagle dogs. It was observed that the system can retain in stomach for an extended period of 7h after administration compared with conventional tablets. The present investigation suggests that water-insoluble drug can be delivered from single-layer osmotic pump tablets completely due to the push power of the hydrogen gas generated by the reaction of the iron and gastric fluid. And iron powder can increase the system density which is over 2.5 g cm(-3), making the system resident in stomach to prolong the drug delivery time in absorption zone.

Optimized preparation of vinpocetine proliposomes by a novel method and in vivo evaluation of its pharmacokinetics in New Zealand rabbits.

Free-flowing proliposomes which contained vinpocetine were prepared successfully to increase the oral bioavailability of vinpocetine. In this study the proliposomes were prepared by a novel method which was reported for the first time and the formulation was optimized using the centre composite design (CCD). The optimized formulation was Soybean phosphatidylcholine: 860 mg; cholesterol: 95 mg and sorbitol: 8000 mg. After the proliposomes were contacted with water, the suspension of vinpocetine liposomes formed automatically and the entrapment efficiency was approximately 86.3% with an average particle size of about 300 nm. The physicochemical properties of the proliposomes including SEM, TEM, XRD and FTIR were also detected. HPLC system was applied to study the concentration of vinpocetine in the plasma of the New Zealand rabbits after oral administration of vinpocetine proliposomes and vinpocetine suspension. The pharmacokinetic parameters were calculated by the software program DAS2.0. The concentration-time curves of vinpocetine suspension and vinpocetine proliposomes were much more different. There were two absorption peaks on the concentration-time curves of the vinpocetine proliposomes. The pharmacokinetic parameters of vinpocetine and vinpocetine proliposomes in New Zealand rabbits were T(max) 1 h and 3 h (there was also an absorption peak at 1 h); C(max) 163.82+/-12.28 ng/ml and 166.43+/-21.04 ng/ml; AUC(0-infinity) 1479.70+/-68.51 ng/ml h and 420.70+/-35.86 ng/ml h, respectively. The bioavailability of vinpocetine in proliposomes was more than 3.5 times higher than the vinpocetine suspension. The optimized vinpocetine proliposomes did improve the oral bioavailability of vinpocetine in New Zealand rabbits and offer a new approach to enhance the gastrointestinal absorption of poorly water soluble drugs.

A novel time-controlled release system based on drug-resin complexes and elementary osmotic pump.

A novel time-controlled system based on elementary osmotic pump tablet containing a drug-resin complexes (DRCs) core is presented. In the traditional osmotic pump tablets (OPTs), the lag time was always minimized. On the contrary, in the DRCs osmotic pump tablet (DRCOPT), the lag time was increased to achieve time-controlled delivery. The system led to a zero-order drug release after an initial lag time. Polyethylene oxide (PEO) N80 was used as suspension agent and NaCl was applied as ion-exchange, osmotic pressure (electrolyte supplementary) agent, respectively. To examine the mechanism of this system, drug release behaviors were investigated under conditions of various osmotic pressures. A new method of combination of conductivity and HPLC was applied to determine the different fractions of NaCl in producing osmotic pressure, ion-exchange and electrolyte supplement. The pharmacokinetic studies conducted in beagle dogs showed that a steadier and controlled drug release behavior was obtained compared with the traditional formulations. On the basis of prescription of the DRCOPT, a good in-vitro-in-vivo correlation (IVIVC, R(2)=0.9541) was achieved. In addition, a lag time of 4 h was observed in in vivo experiment, which indicated that the DRCOPT can be used in therapeutic regimens with the characteristics of chronotherapy.

[Tissue distribution of solid lipid nanoparticles loaded garlic oil in rats].

OBJECTIVE: To investigate the tissue distribution of the diallyl disulfide (DADS) and diallyl trisulfide (DATS) in solid lipid nanoparticles loaded garlic oil (GO-SLN) in rats. METHOD: The gas chromatography-electron capture detection (GC-ECD) method was established to determined the DADS and DATS simultaneously in the biological samples of rats after administration of 0.5 mL garlic oil injection or GO-SLN (containing about 10 mg garlic oil) via jugular vein cannula. The conditions for gas chromatographic separation were as follows. The oven temperature was set at 110 degrees C and maintained for 15 min. Temperatures at the injection port and detector were 180 degrees C and 300 degrees C, respectively. Ultra-pure nitrogen (purity > 99.999%, Shenyang Kerui Special Gases Co. Ltd., China) was used as a carrier gas and made-up gas at flow-rates of 1 mL x min(-1) and 60 mL x min(-1), respectively. All injections were carried out in the split injection mode with a split ratio of 1:10. RESULT: The GC-ECD method was fit for determing the concentration of DADS and DATS in garlic oil. The distribution character of GO-SLN in rats had changed to some extent and the concentration of GO-SLN in tissues was higher than that of GO-Injection. CONCLUSION: The SLN can elevate the passive targeting of drugs and lengthen their action time in tissues.

Studies of the pharmacokinetics of paeoniflorin in two Jing-Zhi-Guan-Xin formulations after oral administration to beagle dogs.

Paeoniflorin is the principal bioactive component of Paeoniae Radix. The traditional chinese medicine compound recipe (TCMCR) tablets of Jing-Zhi-Guan-Xin (JZGX), which is composed of Radix Salviae Miltiorrhizae, Radix Paeoniae Rubrae, Rhizoma Chuan-xiong, Flos Carthami and Lignum Dalbergiae Odorafera, have been widely used in China and Japan. The plasma concentrations of paeoniflorin in beagle dogs after oral administration of two Jing-Zhi-Guan-Xin formulations (the dose used in the two formulations were both 200 mg paeoniflorin) were measured using a simple and rapid HPLC method. The mean terminal half-lives (t1/2) of JZGX tablet and JZGX elementary osmotic pump tablet (EOPT) formulations of paeoniflorin were 147.52 +/- 28.98 and 276.60 +/- 24.24 min, the maximum plasma concentrations (Cmax) of paeoniflorin were 210.49 +/- 23.89 and 94.36 +/- 14.01 ng/ml, times to reach maximum concentrations (tmax) were 130.00 +/- 30.98 and 280.00 +/- 48.99 min, the area under the plasma concentration-time curves (AUC0-infinity) were 43066.50 +/- 10119.51 and 42266.87 +/- 2654.90 ng min/ml, the mean residence times (MRT) were 212.87 +/- 41.82 and 399.14 +/- 34.98 min, respectively, and the relative bioavailability (Fr) of JZGX EOPT compared with JZGX tablet was 101.8 +/- 18.8%. These results, compared with the pharmacokinetic parameters of paeoniflorin after oral administration of Paeoniae Radix extract alone, indicated that the absorption of paeoniflorin after oral administration of the two JZGX formulations was significantly greater than that after oral administration of Paeoniae Radix extract alone.

Studies on controlled release effervescent osmotic pump tablets from Traditional Chinese Medicine Compound Recipe.

A controlled release effervescent osmotic pump tablet (EOPT) of Traditional Chinese Medicine Compound Recipe (TCMCR), named Fuzilizhong prescription which includes acidic drugs consisted of many known and unknown effective components and has been used for several thousands years, was successfully prepared with sodium chloride, sodium hydrogen carbonate and hydroxypropylmethylcellulose(HPMC) as osmotic agents. Since the osmotic pressure in EOPT with sodium chloride and sodium hydrogen carbonate increased greatly, which was induced mostly by gas carbon dioxide generating from the reaction of sodium hydrogen carbonate and the acidic drugs in TCMCR after the fluid being imbibed into the compartment through the semipermeable membrane and the in vitro accumulative dissolution percent from prescription 3 was up to 96.6% at 14 hour, the problem that water insoluble drugs can not to be elementary osmotic pump tablet for its low dissolution rate was solved in the paper. On the basis of prescription 3, the drug in effervescent osmotic pump tablet was released controllably after HPMC was selected as retarder and has a good in-vitro-in-vivo correlation(IVIVC, r=0.9550). Threrfore, it could be concluded that the formulation of TCMCR is appropriate to being made into EOPT, which improves acidic drugs composed of soluble and poorly soluble components release more greatly and controllably. From the point of this, water insoluble drugs can be designed to elementary osmotic pump tablet for more complete dissolution release.