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. 2014 Jun 17:9:2943-53.
doi: 10.2147/IJN.S63395. eCollection 2014.

Nanosizing of a poorly soluble drug: technique optimization, factorial analysis, and pharmacokinetic study in healthy human volunteers

Ibrahim Elsayed  1 , Aly Ahmed Abdelbary  1 , Ahmed Hassen Elshafeey  2
Affiliations

Nanosizing of a poorly soluble drug: technique optimization, factorial analysis, and pharmacokinetic study in healthy human volunteers

Ibrahim Elsayed et al. Int J Nanomedicine. .

Abstract

Context: Diacerein (DCN) has low aqueous solubility (3.197 mg/L) and, consequently, low oral bioavailability (35%-56%). To increase both the solubility and dissolution rate of DCN while maintaining its crystalline nature, high pressure homogenization was used but with only a few homogenization cycles preceded by a simple bottom-up technique.

Methods: The nanosuspensions of DCN were prepared using a combined bottom-up/top-down technique. Different surfactants - polyvinyl alcohol, sodium deoxycholate, and sodium dodecyl sulfate - with different concentrations were used for the stabilization of the nanosuspensions. Full factorial experimental design was employed to investigate the influence of formulation variables on nanosuspension characteristics using Design-Expert(®) Software. Particle size (PS), zeta potential, saturation solubility, in vitro dissolution, and drug crystallinity were studied. Moreover, the in vivo performance of the optimized formula was assessed by bioavailability determination in healthy human volunteers.

Results: The concentration of surfactant had a significant effect on both the PS and polydispersity index values. The 1% surfactant concentration showed the lowest PS and polydispersity index values compared with other concentrations. Both type and concentration of surfactant had significant effects on the zeta potential. Formula F8 (containing 1% sodium deoxycholate) and Formula F12 (containing 1% sodium dodecyl sulfate) had the highest desirability values (0.952 and 0.927, respectively). Hence, they were selected for further characterization. The saturated solubility and mean dissolution time, in the case of F8 and F12, were significantly higher than the coarse drug powder. Techniques utilized in the nanocrystals' preparation had no effect on DCN crystalline state. The selected formula (F12) showed a higher bioavailability compared to the reference market product with relative bioavailability of 131.4%.

Conclusion: The saturation solubility, in vitro dissolution rate and relative bioavailability of DCN were significantly increased after nanocrystallization. Less time and power consumption were applied by the combination of bottom-up and top-down techniques.

Keywords: diacerein; factorial analysis; high pressure homogenization; nanocrystals; pharmacokinetic study.

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Figures

Figure 1
Figure 1
Response 3D plots for the effect of type (X1) and concentration (X2) of surfactant on the PS (A), PDI (B), ZP (C), and desirability (D) of diacerein nanosuspension formulas. Abbreviations: PS, particle size; SDS, sodium dodecyl sulfate; SDC, sodium deoxycholate; PVA, polyvinyl alcohol; PDI, polydispersity index; ZP, zeta potential.
Figure 2
Figure 2
Effect of lyophilization on the PS (A) and PDI (B) of formulas F8 and F12 in the presence and absence of cryoprotectant. Abbreviations: PS, particle size; PDI, polydispersity index.
Figure 3
Figure 3
Dissolution profile of DCN from nanocrystal formulas, F8 and F12, in comparison with the coarse drug powder, in phosphate buffer (pH 6.5). Abbreviation: DCN, diacerein.
Figure 4
Figure 4
DSC chromatograms of the drug (A), SDS (B), mannitol (C), physical mixture (D), and formula F12 (E). Abbreviations: DSC, differential scanning calorimetry; SDS, sodium dodecyl sulfate.
Figure 5
Figure 5
X-ray diffractograms of the drug (A), SDS (B), mannitol (C), physical mixture (D) and formula F12 (E). Abbreviation: SDS, sodium dodecyl sulfate.
Figure 6
Figure 6
Scanning electron micrographs of the lyophilized formula F12 with different magnifications. Note: Magnification; (A) ×1,500 and (B) ×3,000.
Figure 7
Figure 7
Linear presentation for rhein mean plasma concentration after single-dose administration of treatment A (DCN, 50 mg capsule) and treatment B (capsule containing lyophilized formula F12). Abbreviation: DCN, diacerein.
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