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Formulation development of linagliptin solid lipid nanoparticles for oral bioavailability enhancement: role of P-gp inhibition

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Abstract

Linagliptin (LGP), a novel anti-diabetic drug, is a DPP-4 inhibitor used in the treatment of type II diabetes. One of the major disadvantages of LGP is its low oral bioavailability (29.5%) due to first-pass metabolism and P-gp efflux. In an attempt to increase the oral bioavailability, LGP solid lipid nanoparticles (LGP-SLNs) were developed with poloxamer 188 and Tween 80 as P-gp inhibitors. LGP-SLNs were formulated using palmitic acid, poloxamer 188 and Tween 80 as lipid, surfactant and co-surfactant, respectively, by hot homogenization ultrasonication method and optimized using 32 full factorial designs. Particle size, entrapment efficiency (%EE) and drug release at 24 h were evaluated as responses. An optimized batch of LGP-SLNs (L12) was evaluated for intestinal transport of LGP by conducting in situ single-pass intestinal perfusion (SPIP), everted gut sac and Caco-2 permeability study. The pharmacokinetic and pharmacodynamic evaluation of L12 was carried out in albino Wistar rats. The mean particle size, polydispersity index, zeta potential and %EE of L12 were found to be 225.96 ± 2.8 nm, 0.180 ± 0.034, − 5.4 ± 1.07 mV and 73.8 ± 1.73%, respectively. %CDR of 80.96 ± 3.13% was observed in 24 h. The permeability values of LGP-SLNs in the absorptive direction were 1.82-, 1.76- and 1.74-folds higher than LGP-solution (LGP-SOL) in SPIP, everted gut sac and Caco-2 permeability studies, respectively. LGP-SLNs exhibited relative bioavailability of 300% and better reduction in glucose levels in comparison with LGP-SOL in rats. The enhanced oral bioavailability exhibited by LGP-SLNs bioavailability may be due to P-gp efflux inhibition and lymphatic targeting. Improved bioabsorption can cause reduction in dose, dose-related side effects and frequency of administration. Thus, LGP-SLNs can be considered promising carriers for oral delivery but clinical studies are required to confirm the proof of concept.

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Acknowledgements

The authors would like to acknowledge Dr. Tarjani Sheth, Department of English, Uka Tarsadia University, for the preparation of this manuscript.

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  1. Maliba Pharmacy College, Uka Tarsadia University, Gopal Vidyanagar, Bardoli Mahuva Road, Dist. Surat, Tarsadi, Gujarat, 394350, India

    Pranav Shah, Kejal Chavda, Bhavin Vyas & Shailaja Patel

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Caco-2 permeability test

The Caco-2 cell monolayer model bears close resemblance to human intestinal barrier properties. Therefore, this model finds widespread applications in prediction of in vivo permeability and absorption. Bidirectional (AP → BL and BL → AP) transport analysis using the Caco-2 cell monolayer model is the gold standard to evaluate substrates and inducers/inhibitors of P-gp transporters [72]. In order to compare the intestinal permeability, LGP-SOL and LGP-SLNs were evaluated using the Caco-2 cell monolayers (Fig. 9). The cells were cultured in the Transwell® for 21 days for monolayer formation, which was confirmed by a TEER cut-off value of 250 Ω cm2. As shown in Fig. 9, the observed mean Papp (AP → BL) values of LGP-SOL and LGP-SLNs were 0.87 × 10−6 and 2.09 × 10−6 cm/s, respectively.

Absorptive permeability Papp (AP → BL) of LGP from LGP-SLNs was significantly (p < 0.01) increased (2.4-fold) than LGP-SOL. The possible explanation for the enhancement of transepithelial permeability of LGP by LGP-SLNs formulation is due to poloxamer 188 and Tween 80, both of which are known P-gp inhibitors and hence assisted in increasing the intestinal permeability of LGP [73] .

The observed mean Papp (BL → AP) values of LGP-SOL and LGP-SLNs were 1.59 × 10−6 and 2.04 × 10−6 cm/s, respectively. The secretory permeability of LGP-SOL was 1.83-folds higher than absorptive permeability, suggesting higher efflux permeability compared with its influx component. The ratio of Papp (BL → AP) (secretion component) and Papp (AP → BL) (absorption component) is defined as efflux ratio (ER). The ER of LGP-SOL and LGP-SLNs were 1.828 and 0.976, respectively. An ER higher than unity suggested a net efflux transport, whereas ER near to unity indicated that LGP excretion from LGP-SLNs is reduced and the amount absorbed is increased. Thus, it was confirmed that the addition of poloxamer 188 and Tween 80 in the preparation of LGP-SLNs increased the intestinal permeability of the LGP. These results are in confirmation with our findings of single-pass perfusion and everted sac studies.

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Shah, P., Chavda, K., Vyas, B. et al. Formulation development of linagliptin solid lipid nanoparticles for oral bioavailability enhancement: role of P-gp inhibition. Drug Deliv. and Transl. Res. 11, 1166–1185 (2021). https://doi.org/10.1007/s13346-020-00839-9

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