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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) Time-profiles of permeation of saquinavir (SQV) through a monolayer of Caco-2 cells; (B) Apparent permeability coefficient (Papp) of SQV across a Caco-2 cell monolayer (n=3). cP<0.01.
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fig6: (A) Time-profiles of permeation of saquinavir (SQV) through a monolayer of Caco-2 cells; (B) Apparent permeability coefficient (Papp) of SQV across a Caco-2 cell monolayer (n=3). cP<0.01.

Mentions: To evaluate the effect of the particle size of the crystals (coarse crystals vs nanocrystals) on SQV transport through cell monolayers, we determined the drug transport across Caco-2 cell monolayers from the AP side to the BL side. In all the experiments, the TEER measurements showed no cellular damage. Figure 6A shows the time profiles of SQV permeation through the Caco-2 cell monolayers. The amount of drug in the receiving chamber (BL side) increased with time for both formulations. It was clear that the amount of drug in the receiving chambers of monolayers treated with the nanocrystals was much higher than the amount in the receiving chambers of monolayers treated with the coarse crystals at each time point. These results indicated that the drug transport for the nanocrystals was faster than the coarse crystals.


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) Time-profiles of permeation of saquinavir (SQV) through a monolayer of Caco-2 cells; (B) Apparent permeability coefficient (Papp) of SQV across a Caco-2 cell monolayer (n=3). cP<0.01.
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Related In: Results  -  Collection

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

fig6: (A) Time-profiles of permeation of saquinavir (SQV) through a monolayer of Caco-2 cells; (B) Apparent permeability coefficient (Papp) of SQV across a Caco-2 cell monolayer (n=3). cP<0.01.
Mentions: To evaluate the effect of the particle size of the crystals (coarse crystals vs nanocrystals) on SQV transport through cell monolayers, we determined the drug transport across Caco-2 cell monolayers from the AP side to the BL side. In all the experiments, the TEER measurements showed no cellular damage. Figure 6A shows the time profiles of SQV permeation through the Caco-2 cell monolayers. The amount of drug in the receiving chamber (BL side) increased with time for both formulations. It was clear that the amount of drug in the receiving chambers of monolayers treated with the nanocrystals was much higher than the amount in the receiving chambers of monolayers treated with the coarse crystals at each time point. These results indicated that the drug transport for the nanocrystals was faster than the coarse crystals.

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