Preparation of silymarin-loaded amphiphilic chitosan micelle and its in situ absorption in rat intestine / 药学学报

To improve the oral bioavailability of silymarin, the silymarin-loaded amphiphilic chitosan micelles (SM-OGC) were prepared. The absorption of SM-OGC in rat intestine was investigated. SM-OGC was prepared by dialysis method. The size and zeta potential of SM-OGC were investigated. Compared to silymarin suspension, the absorption of SM-OGC was investigated using in situ single pass perfusion model. The diameters and zeta potential SM-OGC were (162.4 +/- 3.0) nm and (+32.6 +/- 0.98) mV, respectively. The encapsulation efficiency was (39.17 +/- 0.98)% and the drug loading of SM-OGC was (28.15 +/- 0.43)%. The absorption of SM-OGC at different segments of intestine was significantly higher than that of silymarin suspension (P < 0.05). The apparent absorption rate (K(a)) and effective permeation coefficient (P(eff)) at the duodenum were the largest. K(a) and P(eff) had no significant difference between jejunum, ileum and colon. OGC micelles might significantly promote the absorption of silymarin in the intestine tract.

Preparation of doxorubicin-loaded chitosan polymeric micelle and study on its tissue biodistribution in mice / 药学学报

To prepare doxorubicin-loaded N-octyl-N'-succinyl chitosan polymeric micelle (DOX-OSC) and study the biodistribution of DOX-OSC in mice, DOX-OSC was prepared by dialysis method. By using doxorubicin injection (DOX-INJ) as control, DOX-OSC and DOX-INJ were administered to mice through caudal vein at a dose of 5 mg x kg(-1) body weight. The RP-HPLC method was established to determine the DOX levels in the plasma and other tissues of mice. The tissues distribution and targeting efficiency were evaluated by pharmacokinetic parameters (AUC, MRT) and targeting parameters (Re, Ce and Te). The drug loading and entrapment efficiency of DOX-OSC were (35.8 +/- 0.4)% and (75.3 +/- 1.1)%, respectively. The diameter and zeta potential of DOX-OSC were (174 +/- 12) nm and (-37.1 +/- 3.0) mV, respectively. The transmission electron microscope result showed DOX-OSC with spherical shape. The biodistribution results showed that the concentration of DOX of both DOX-OSC and DOX-INJ decreased rapidly in blood after iv administration. While free DOX levels in blood at 12-96 h were not detectable for DOX-INJ, in contrast, DOX level in blood at 96 h was still found for DOX-OSC. In contrast to DOX-INJ group, DOX-OSC showed a higher targeting efficiency in the liver and spleen. The AUCs of DOX in the liver and spleen were 20.0 and 47.4 times and the MRT were 11.2 and 37.2 times, respectively. And the levels of DOX-OSC in the heart and kidney tissues were significantly reduced. And the drug distribution of DOX-OSC in the heart and kidney tissues were 17.0% and 11.4%, respectively. Hence, DOX-OSC shows an excellent drug loading capabilities and a higher targeting efficiency in the liver and spleen. That the levels of DOX-OSC in the heart and kidney tissues are significantly reduced, might improve the treatment efficacy of DOX and decrease the side effects.

Solubilizing and sustained-releasing abilities and safety preliminary evaluation for paclitaxel based on N-octyl-O, N-carboxymethyl chitosan polymeric micelles / 药学学报

A series of novel self-assembled polymeric micelles based on carboxymethyl chitosan bearing long chain alkyl chains (N-octyl-O, N-carboxymethyl chitosan, OCC) was synthesized. PTX loaded OCC polymeric micelles (PTX-OCC) were prepared by dialysis method. The effects of the degree of substitutions (DS) of octyl groups on the solubilizing abilities of OCC for paclitaxel were studied. The PTX-OCC were characterized using drug loading content, drug encapsulation efficiency, dynamic light scattering, zeta potential and transmission electron microscopy (TEM). Take PTX injection (PTX-INJ) as control, the safety of PTX-OCC including hemolysis, hypersensitiveness in guinea pigs and acute toxicity in mice were also evaluated. OCC showed excellent loading capacities for paclitaxel with the DS of octyl groups in the range of 37.9% - 58.6%. Drug loading contents were up to 24.9% - 34.4% with drug encapsulation efficiency 56.3% - 89.3%, which both increased with the increasing of DS of octyl groups. The mean size of PTX-OCC was 186.4 - 201.1 nm which decreased with the increasing of DS of octyl groups. The zeta potential was -47.5 to -50.9 mV, which had no obvious relation with the DS of octyl groups. The TEM images showed a spherical shape. No burst release phenomena were observed and drug cumulative release was in the range of 60% -95% in 15 days. PTX-OCC with higher DS of octyl groups showed stronger sustained releasing ability. In terms of the induction of membrane damage and hypersensitiveness, PTX-OCC was superior to PTX-INJ. The LD50 and its 95% confidence interval of PTX-OCC were 134.4 (125.0 - 144.6) mg x kg(-1), which was 2.7 fold of PTX-INJ. The present PTX-OCC could be potentially useful as safety carriers for intravenous delivery.

Preparation of paclitaxel-loaded chitosan polymeric micelles and influence of surface charges on their tissue biodistribution in mice / 药学学报

<p><b>AIM</b>To prepare paclitaxel-loaded cationic chitosan micelles (PTX-CCM) and paclitaxel-loaded anionic chitosan micelles (PTX-ACM) and study the influence of surface charges on the biodistribution of paclitaxel-loaded chitosan polymeric micelles in mice.</p><p><b>METHODS</b>PTX-CCM and PTX-ACM were prepared by dialysis method and were administered to mice by caudal vein at a dose of 20 mg x kg(-1) body weight. The RP-HPLC method was established to determine the PTX concentrations in the plasma and other tissues of mice. The tissues distribution of PTX-CCM and PTX-ACM were evaluated by the pharmacokinetic parameters (AUC, MRT).</p><p><b>RESULTS</b>The diameter and zeta potential of PTX-CCM were 164 nm and +23.7 mV, while those of PTX-ACM were 180 nm and -28.0 mV, respectively. The drug loading and drug encapsulation efficiency for PTX-CCM were 26.4% (w/w) and 76.2% , while those of PTX-ACM were 34.6% (w/w) and 89.9%, respectively. The highest uptake of PTX-CCM and PTX-ACM in liver were 64.72% and 91.84% of dose, respectively. Meanwhile, MRT of both were 5.50 h and 51.39 h prolonged. The highest uptake of PTX-CCM and PTX-ACM in spleen were 7.08% and 5.16% of dose, respectively. Meanwhile, MRT of both were 9.04 h and 26.82 h. For PTX-CCM group, the AUC and C(max) of PTX in the lung were 2.71 times and 5.87 times of those of PTX-ACM group respectively. While in both PTX-CCM and PTX-ACM groups, the highest uptake of PTX in the heart were only 0.36% and 0.24% of dose, respectively and PTX in the kidney were only 0.75% and 0.33% of dose respectively.</p><p><b>CONCLUSION</b>PTX-CCM and PTX-ACM showed excellent drug loading capabilities with amount of cationic charges and anionic charges on their surface, respectively. Both PTX-CCM and PTX-ACM groups showed a higher targeting efficiency in the liver and spleen in vivo and accumulated in both tissues for relatively long time, especially in PTX-ACM group. In contrast to PTX-ACM, PTX-CCM showed a higher lung targeting efficiency in vivo while PTX-ACM had a stronger retention ability in the lung. Meanwhile in both groups the levels of PTX in the heart and kidney tissues were significantly lower which might decrease the side effects of PTX.</p>