Fabrication of lipidic nanocarriers of loratadine for facilitated intestinal permeation using multivariate design approach

Abstract

In this investigation, multivariate design approach was employed to develop self-nanoemulsifying drug delivery system (SNEDDS) of loratadine and to exploit its potential for intestinal permeability. Drug solubility was determined in various vehicles and existence of self-nanoemulsifying region was evaluated by phase diagram studies. The influence of formulation variables X₁ (Capmul MCM C8) and X₂ (Solutol HS15) on SNEDDS was assessed for mean globule sizes in different media (Y₁–Y₃), emulsification time (Y₄) and drug-release parameters (Y₅–Y₆), to improve quality attributes of SNEDDS. Significant models were generated, statistically analyzed by analysis of variance and validated using the residual and leverage plots. The interaction, contour and response plots explicitly demonstrated the influence of one factor on the other and displayed trend of factor-effect on responses. The pH-independent optimized formulation was obtained with appreciable global desirability (0.9266). The strenuous act of determining emulsification time is innovatively replaced by the use of oil-soluble dye to produce visibly distinct globules that otherwise may be deceiving. TEM images displayed non-aggregated state of spherical globules (size < 25 nm) and also revealed the structural transitions occurring during emulsification. Optimized formulation exhibited non-Newtonian flow justified by the model-fit and also presented the stability to dilution effects and thermodynamic stress testing. The ex vivo permeation study using confocal laser scanning microscopy indicate strong potential of rhodamine 123-loaded loratadine-SNEDDS to inhibit P-gp efflux and facilitate intestinal permeation. To conclude, the effectiveness of design yields a stable optimized SNEDDS with enhanced permeation potential, which is expected to improve oral bioavailability of loratadine.

• Confocal laser scanning microscopy
• dye colored emulsification
• ex vivo intestinal permeation
• multivariate design
• self-nanoemulsifying drug delivery system
• transmission electron microscopy

Acknowledgements

The authors thank Vice-Chancellor, Birla Institute of Technology for providing the facilities and Dr. (Mrs.) S. M. Verma for helpful discussions. Authors are also thankful to CIF, BIT Mesra and SICART, Anand, Gujarat, India, for extending their facilities for characterization studies. The constructive comments and suggestion of anonymous reviewers is gratefully acknowledged.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Samridhi gratefully acknowledges the financial support in the form of INSPIRE-JRF (IF120784) provided by the Department of Science and Technology, Government of India (Ref. No. DST/INSPIRE fellowship/2012 dated 25 February 2013).

Supplementary material available online Supplementary Figure S1 (A-H) and Table S1.