Canagliflozin loaded SMEDDS: formulation optimization for improved solubility, permeability and pharmacokinetic performance
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The aim of the present investigation is to systematically optimize and develop microemulsion preconcentrates to improve the solubility and oral bioavailability profile of canagliflozin employing D-optimal mixture design. Preconcentrate constituents, i.e. oils, surfactants and co-surfactants were selected on the basis of solubility studies and their concentration range capable of influencing the formation of microemulsions was determined. D-optimal mixture design was employed for studying the interaction behavior of desired responses and optimized using desirability approach. The optimized formulation was evaluated for its in vitro, ex vivo and in vivo behavior to determine the dissolution rate, permeation rate and oral bioavailability of the drug. The optimized formulation containing Lauroglycol FCC (80 mg), Tween 80 (300 mg) and Transcutol P (120 mg) showed desired attributes of measured responses with minimum experimental variation and desirability value of 0.751. The morphological behavior showed uniform nano-structured globules with negligible aggregation as confirmed in transmission electron microscopy. Ex vivo permeation rate of the drug across excised intestinal segments (duodenum, jejunum, ileum and colon) was observed to be 3.51, 5.62, 4.52 and 2.98 folds higher, respectively, as compared to drug powder and marketed tablets Compared with the pure drug and commercial tablets, enhanced in vitro dissolution rate of optimized formulation was observed, resulting in 2.56 fold enhancement in Cmax and AUC0–24h following oral administration in fasting wistar rats. Establishment of level A IVIVC for the developed SMEDDS indicated excellent goodness of fit between the in vitro drug release and in vivo drug absorbed. Accelerated stability studies indicated stability of the optimized formulation over 3 months storage.
KeywordsSolubility Canagliflozin Preconcentrates SMEDDS Mixture design
The authors are highly thankful to Zydus Cadila Limited, Ahmedabad for providing gift sample of canagliflozin. Emerging Life Sciences Facility in Guru Nanak Dev University for carrying out characterization studies is highly acknowledged.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Research involving human and animal rights
All institutional and national guidelines for the care and use of laboratory animals were followed.
- Baek MK, Lee JH, Cho YH, Kim H, Lee GY (2013) Self-microemulsifying drug delivery system for improved oral bioavailability of pranilukast hemihydrate: preparation and evaluation. Int J Nanomed 8:167–176Google Scholar
- Burjak M, Rozman PT, Petek B, Markun B, Berjinc K, Jaklic MT, Ham JZ (2017) Pharmaceutical compositions comprising Canagliflozin. US Patent (WO 2016030502 A1)Google Scholar
- Committee for Medicinal Product for Human use, Assessment Report February (2014) http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002656/WC500166672.pdf. Accessed 24 Sep 2016
- Jankovic J, Djekic L, Dobricic V, Primorac M (2015) Evaluation of critical formulation parameters in design and differentiation of self-microemulsifying drug delivery system (SMEDDS) for oral delivery of acyclovir. Int J Pharm 456:1232–1244Google Scholar
- Kaseem AA, Mohsen AM, Ahmed RS, Essan TM (2016) Self-nanoemulsifying drug delivery system (SNEDDS) with enhanced solubilization of nystatin for treatment of oral candidiasis: design, optimization, in vitro and in vivo evaluation. J Mol Lipids 218:219–232Google Scholar
- Krishnamoorthy B, Rahman HS, Selvan TN, Parsad HR, Rajkumar M, Selvakumar SM, Vamshikrishna K, Gregory M, Vijayaraghavan C (2015) Design, formulation, in vitro, in vivo and pharmacokinetic evaluation of nisoldipine loaded self-nanoemulsifying drug delivery system. J Nanopart Res 17:34–42CrossRefGoogle Scholar
- Ma YG, Yuan XZ, Peng X, Wang H, Huang HJ, Bao S, Huan L, Xiao ZH, Zeng GM (2015) The pseudo ternary phase diagrams and properties of anionic-nonionic mixed surfactant reverse micellar systems. J Mol Lipids 203:181–186Google Scholar
- Shakeel F, Haq N, Raish M, Siddiqui NA, Alanazi FK, Alsarra IA (2016) Anti-oxidant and cytotoxic effects of vanillin via eucalyptus oil containing self-nanoemulsifying drug delivery system. J Mol Lipids 218:233–239Google Scholar
- Sun M, Zhai X, Xue K, Hu L, Yang X, Li G, Si L (2011) Intestinal absorption and intestinal lymphatic transport of sirolimus from self-microemulsifying drug delivery systems assessed using the single-pass intestinal perfusion (SPIP) technique and a chylomicron flow blocking approach: linear correlation with oral bioavailabilities in rats. Eur J Pharm Sci 43:132–140CrossRefGoogle Scholar
- Yeom DW, Song SY, Kim SR, Lee SG, Kang MY, Lee S, Choi YW (2015) Development and optimization of a self-microemulsifying drug delivery system for atorvastatin calcium by using D-optimal mixture design. Int J Nanomed 10:3865–3878Google Scholar