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. 2020 May;15(3):336-346.
doi: 10.1016/j.ajps.2018.11.009. Epub 2019 Feb 14.

Enhanced intestinal lymphatic absorption of saquinavir through supersaturated self-microemulsifying drug delivery systems

Kanghee Jo  1 , Hyeongmin Kim  1 , Prakash Khadka  1 , Taejun Jang  1 , Soo Jin Kim  1 , Seong-Ha Hwang  1 , Jaehwi Lee  1
Affiliations

Enhanced intestinal lymphatic absorption of saquinavir through supersaturated self-microemulsifying drug delivery systems

Kanghee Jo et al. Asian J Pharm Sci. 2020 May.

Abstract

The therapeutic potential of saquinavir, a specific inhibitor of human immunodeficiency virus (HIV)-1 and HIV-2 protease enzymes, has been largely limited because of a low solubility and consequnt low bioavailability. Thus, we aimed to design a supersaturated self-microemulsifying drug delivery system (S-SMEDDS) that can maintain a high concentration of saquinavir in gastro-intestinal fluid thorugh inhibiting the drug precipitation to enhance the lymphatic transport of saquinavir and to increase the bioavailability of saquinavir considerably. Solubilizing capacity of different oils, surfactants, and cosurfactants for saquinavir was evaluated to select optimal ingredients for preparation of SMEDDS. Through the construction of pseudo-ternary phase diagram, SMEDDS formulations were established. A polymer as a precipitation inhibitor was selected based on its viscosity and drug precipitation inhibiting capacity. The S-SMEDDS and SMEDDS designed were administered at an equal dose to rats. At predetermined time points, levels of saquinavir in lymph collected from the rats were assessed. SMEDDS prepared presented a proper self-microemulsification efficiency and dispersion stability. The S-SMEDDS fabricated using the SMEDDS and hydroxypropyl methyl cellulose 2910 as a precipitation inhibitor exhibited a signficantly enhanced solubilizing capacity for saquinavir. The drug concentration in a simulated intestinal fluid evaluated with the S-SMEDDS was also maintained at higher levels for prolonged time than that examined with the SMEDDS. The S-SMEDDS showed a considerably enhanced lymphatic absoprtion of saquinavir in rats compared to the SMEDDS. Therefore, the S-SMEDDS would be usefully exploited to enhance the lymphatic absorption of hydrophobic drugs that need to be targeted to the lymphatic system.

Keywords: Lipid-based formulation; Lymphatic drug delivery; Precipitation inhibitor; Saquinavir; Self-microemulsifying drug delivery system; Supersaturation.

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Figures

Image, graphical abstract
Graphical abstract
Figure Fig. 1.
Fig. 1
Pseudo-ternary phase diagrams of formulations composed of Capryol™ 90 (oil), Labrasol® (surfactant) and propylene glycol (cosurfactant) dispersed in distilled water. The surfactant mixtures (Smix) used consisted of surfactant and cosurfactant at three different ratios of (A) 1:1, (B) 2:1, and (C) 3:1. The gray area indicates that the formulations formed oil-in-water microemulsions.
Figure Fig. 2.
Fig. 2
The time taken for self-emulsification of self-microemulsifying drug delivery system formulations of A, B, and C, which were composed of Capryol™ 90, Labrasol®, and propylene glycol at three different weight ratios of 20:40:40, 20:53:27, and 20:60:20, respectively. Asterisk (*) indicates a statistical significance of P < 0.05.
Figure Fig. 3.
Fig. 3
Changes in droplet size (A and B) and zeta potential (C and D) of oil phase of self-microemulsifying drug delivery systems (200 mg) evaluated for 24 h after dilution of the formulations in distilled water (25 mL). Fig. 3(a) and (c) present changes in original values of the droplet size and zeta potential, and Fig. 3(b) and (d) show percentile changes in the droplet size and zeta potential. A, B, and C indicate the self-microemulsifying drug delivery system formulations consisting of Capryol™ 90, Labrasol®, and propylene glycol at three different weight ratios of 20:40:40, 20:53:27, and 20:60:20, respectively. Asterisk (*) indicates a statistical significance of P < 0.05.
Figure Fig. 4.
Fig. 4
Solubility of saquinavir evaluated in self-microemulsifying drug delivery systems. A, B, and C indicate the self-microemulsifying drug delivery system formulations composed of Capryol™ 90, Labrasol®, and propylene glycol at three different weight ratios of 20:40:40, 20:53:27, and 20:60:20, respectively. Asterisk (*) indicates a statistical significance of P < 0.05.
Figure Fig. 5.
Fig. 5
Solubility of saquinavir in self-microemulsifying drug delivery system (formulation A) and supersaturated self-microemulsifying drug delivery systems (formulation Sa3 and Sb4). Asterisk (*) indicates a statistical difference of P < 0.05.
Figure Fig. 6.
Fig. 6
In vitro release behavior of saquinavir from S-SMEDDS (Sa3 and Sb4), S-SMEDDS (formulation A) and saquinavir bulk powder.
Figure Fig. 7.
Fig. 7
Result of the drug precipitation inhibiting ability of S-SMEDDS (formulation Sa3 and Sb4) evaluated in a simulated intestinal fluid in comparison with SMEDDS (formulation A) and saquinavir bulk powders. Changes in concentration of saquinavir in the simulated intestinal fluid were monitored for 90 min after adding the samples equivalent to 200 mg of saquinavir to 10 ml of the simulated intestinal fluid.
Figure Fig. 8.
Fig. 8
(A) Concentration and (B) cumulative amount of saquinavir in lymph obtained from rats evaluated during in vivo lymphatic drug absorption study. For the experiment, S-SMEDDS (formulation Sb4), SMEDDS (formulation A), and saquinavir suspension were administered to rats at an equal dose. Data are presented as mean ± standard error of mean (n = 5). Asterisk (*) and sharp (#) represents P < 0.05 versus saquinavir suspension and SMEDDS, respectively.
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