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Enhancement of cellular uptake, transport and oral absorption of protease inhibitor saquinavir by nanocrystal formulation.

He Y, Xia DN, Li QX, Tao JS, Gan Y, Wang C - Acta Pharmacol. Sin. (2015)

Bottom Line: The dissolution, cellular uptake, and transport across a Caco-2 monolayer of the nanocrystal formulation were significantly improved compared to those of the coarse crystals.Pharmacokinetic study showed that the maximal plasma concentration (Cmax) was 2.16-fold of that for coarse crystalline SQV suspension, whereas the area under the curve (AUC) of nanocrystal SQV suspension was 1.95-fold of that for coarse crystalline SQV suspension.The nanocrystal drug delivery system significantly improves the oral absorption of saquinavir.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Chongqing Medical University, Chongqing 400016, China.

ABSTRACT

Aim: Saquinavir (SQV) is the first protease inhibitor for the treatment of HIV infection, but with poor solubility. The aim of this study was to prepare a colloidal nanocrystal suspension for improving the oral absorption of SQV.

Methods: SQV nanocrystals were prepared using anti-solvent precipitation-high pressure homogenization method. The nanocrystals were characterized by a Zetasizer and transmission electron microscopy (TEM). Their dissolution, cellular uptake and transport across the human colorectal adenocarcinoma cell line (Caco-2) monolayer were investigated. Bioimaging of ex vivo intestinal sections of rats was conducted with confocal laser scanning microscopy. Pharmacokinetic analysis was performed in rats administered nanocrystal SQV suspension (50 mg/kg, ig), and the plasma SQV concentrations were measured with HPLC.

Results: The SQV nanocrystals were approximately 200 nm in diameter, with a uniform size distribution. The nanocrystals had a rod-like shape under TEM. The dissolution, cellular uptake, and transport across a Caco-2 monolayer of the nanocrystal formulation were significantly improved compared to those of the coarse crystals. The ex vivo intestinal section study revealed that the fluorescently labeled nanocrystals were located in the lamina propria and the epithelium of the duodenum and jejunum. Pharmacokinetic study showed that the maximal plasma concentration (Cmax) was 2.16-fold of that for coarse crystalline SQV suspension, whereas the area under the curve (AUC) of nanocrystal SQV suspension was 1.95-fold of that for coarse crystalline SQV suspension.

Conclusion: The nanocrystal drug delivery system significantly improves the oral absorption of saquinavir.

No MeSH data available.


Related in: MedlinePlus

(A) Cellular uptake of saquinavir (SQV) coarse crystals and nanocrystals at different time points observed under confocal laser scanning microscope; (B) quantitatively analysis of fluorescence intensity of cells (n=3) (bP<0.05).
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fig5: (A) Cellular uptake of saquinavir (SQV) coarse crystals and nanocrystals at different time points observed under confocal laser scanning microscope; (B) quantitatively analysis of fluorescence intensity of cells (n=3) (bP<0.05).

Mentions: Figure 5A shows the CLSM images of Caco-2 cells incubated with the SQV nanocrystal suspension and the coarse SQV crystal suspension for different lengths of time. The fluorescent intensity of the SQV nanocrystal suspension was higher than the coarse crystals, indicating increased drug uptake. After 2 h, individual high-intensity red fluorescent particles could be observed in the cytoplasm of the cells exposed to the nanocrystal suspension. These particles were most likely to be “the nanocrystals.” However, very few individual particles were observed in the cytoplasm of the cells exposed to the coarse crystal suspension detected at the same excitation intensity and exposure time as that of nanocrystals. The fluorescence intensity of the cells incubated with nanocrystals was 2.19-fold higher than the coarse crystals, and revealed the significant advantage of nanocrystal uptake by the Caco-2 cells (Figure 5B).


Enhancement of cellular uptake, transport and oral absorption of protease inhibitor saquinavir by nanocrystal formulation.

He Y, Xia DN, Li QX, Tao JS, Gan Y, Wang C - Acta Pharmacol. Sin. (2015)

(A) Cellular uptake of saquinavir (SQV) coarse crystals and nanocrystals at different time points observed under confocal laser scanning microscope; (B) quantitatively analysis of fluorescence intensity of cells (n=3) (bP<0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4561971&req=5

fig5: (A) Cellular uptake of saquinavir (SQV) coarse crystals and nanocrystals at different time points observed under confocal laser scanning microscope; (B) quantitatively analysis of fluorescence intensity of cells (n=3) (bP<0.05).
Mentions: Figure 5A shows the CLSM images of Caco-2 cells incubated with the SQV nanocrystal suspension and the coarse SQV crystal suspension for different lengths of time. The fluorescent intensity of the SQV nanocrystal suspension was higher than the coarse crystals, indicating increased drug uptake. After 2 h, individual high-intensity red fluorescent particles could be observed in the cytoplasm of the cells exposed to the nanocrystal suspension. These particles were most likely to be “the nanocrystals.” However, very few individual particles were observed in the cytoplasm of the cells exposed to the coarse crystal suspension detected at the same excitation intensity and exposure time as that of nanocrystals. The fluorescence intensity of the cells incubated with nanocrystals was 2.19-fold higher than the coarse crystals, and revealed the significant advantage of nanocrystal uptake by the Caco-2 cells (Figure 5B).

Bottom Line: The dissolution, cellular uptake, and transport across a Caco-2 monolayer of the nanocrystal formulation were significantly improved compared to those of the coarse crystals.Pharmacokinetic study showed that the maximal plasma concentration (Cmax) was 2.16-fold of that for coarse crystalline SQV suspension, whereas the area under the curve (AUC) of nanocrystal SQV suspension was 1.95-fold of that for coarse crystalline SQV suspension.The nanocrystal drug delivery system significantly improves the oral absorption of saquinavir.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Chongqing Medical University, Chongqing 400016, China.

ABSTRACT

Aim: Saquinavir (SQV) is the first protease inhibitor for the treatment of HIV infection, but with poor solubility. The aim of this study was to prepare a colloidal nanocrystal suspension for improving the oral absorption of SQV.

Methods: SQV nanocrystals were prepared using anti-solvent precipitation-high pressure homogenization method. The nanocrystals were characterized by a Zetasizer and transmission electron microscopy (TEM). Their dissolution, cellular uptake and transport across the human colorectal adenocarcinoma cell line (Caco-2) monolayer were investigated. Bioimaging of ex vivo intestinal sections of rats was conducted with confocal laser scanning microscopy. Pharmacokinetic analysis was performed in rats administered nanocrystal SQV suspension (50 mg/kg, ig), and the plasma SQV concentrations were measured with HPLC.

Results: The SQV nanocrystals were approximately 200 nm in diameter, with a uniform size distribution. The nanocrystals had a rod-like shape under TEM. The dissolution, cellular uptake, and transport across a Caco-2 monolayer of the nanocrystal formulation were significantly improved compared to those of the coarse crystals. The ex vivo intestinal section study revealed that the fluorescently labeled nanocrystals were located in the lamina propria and the epithelium of the duodenum and jejunum. Pharmacokinetic study showed that the maximal plasma concentration (Cmax) was 2.16-fold of that for coarse crystalline SQV suspension, whereas the area under the curve (AUC) of nanocrystal SQV suspension was 1.95-fold of that for coarse crystalline SQV suspension.

Conclusion: The nanocrystal drug delivery system significantly improves the oral absorption of saquinavir.

No MeSH data available.


Related in: MedlinePlus