Canagliflozin (CFZ), a novel SGLT II antagonist, exhibits erratic absorption after oral administration. The current study entails development and evaluation of spray dried lipid based formulation (solid SMEDDS) for enhancing oral bioavailability and anti-diabetic activity of CFZ.
Solid SMEDDS developed through spray drying containing Neusilin US2 as an adsorbent. The formed solid SMEDDS were characterized for physicochemical and solid state attributes. Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) were used to confirm the spherical morphology. In vitro dissolution, ex vivo permeability and in vivo pharmacokinetic studies were conducted to determine the release rate, permeation rate and absorption profile of CFZ, respectively. Pharmacodynamic studies were done as per standard protocols.
The optimized solid SMEDDS exhibited acceptable practical yield and flow properties and is vouched with enhanced amorphization, nanoparticulate distribution and acceptable drug content. The spherical morphology of solid SMEDDS and reconstituted SMEDDS were confirmed in SEM and TEM, respectively. In vitro dissolution studies revealed multi-fold release behavior in CFZ in various dissolution media, whereas, remarkable permeability was observed in jejunum segment of rat intestine. Pharmacokinetic studies of CFZ in solid SMEDDS demonstrated 2.53 and 1.43 fold enhancement in Cmax and 2.73 and 1.98 fold in AUC 0-24h, as compared to pure API and marketed formulation, respectively. Pharmacological evaluation of solid SMEDDS revealed enhanced anti-diabetic activity of CFZ through predominant SGLT II inhibition in rats, as evident from evaluation of biochemical levels, urinary glucose excretion studies and SGLT II expression analysis.
The current work describes significant improvement biopharmaceutical properties of CFZ in solid SMEDD formulation.
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Said S, Hernandez GT. Sodium glucose co-transporter 2 (SGLT2) inhibition with canagliflozin in type 2 diabetes mellitus. Cardiovasc Hematol Agents Med Chem. 2013;11:203–6.
Davidson JA, Kuritzky L. Sodium glucose co-transporter 2 inhibitors and their mechanism for improving glycemia in patients with type 2 diabetes. Postgrad Med. 2014;126:33–48.
Whalen K, Miller S, Onge ES. The role of sodium glucose co-transporter 2 inhibitors in the treatment of type 2 diabetes. Clin Ther. 2015;37:1150–66.
Singh D, Tiwary AK, Bedi N. Canagliflozin loaded SMEDDS: formulation optimization for improved solubility, permeability and pharmacokinetic performance. J Pharm Investig. 2018;49:67–85.
Obadalova I, Dammer O, Jaroslava S, Krejcik L, Ridvan L, Marcela T. Complexes of canagliflozin and cyclodextrins US Patent (WO2016041530A1) (2016).
Qian J, Meng H, Xin L, Xia M, Shen H, Li G, et al. Self-nanoemulsifying drug delivery systems of myricetin: formulation development, characterization, and in vitro and in vivo evaluation. Colloids Surf B: Biointerfaces. 2017;160:101–9.
Quan G, Niu B, Singh V, Zhou Y, Wu CY, Pan X, et al. Supersaturable solid self-microemulsifying drug delivery system: precipitation inhibition and bioavailability enhancement. Int J Nanomedicine. 2017;12:8801–11.
Bhandari S, Rana V, Tiwary AK. Anti-malarial solid self-emulsifying system for oral use: in vitro investigation. Ther Deliv. 2016;8(4):201–13.
Custodio JM, Wu CY, Benet LZ. Predicting drug disposition, absorption/ elimination/ transporter interplay and the role of food on drug absorption. Adv Drug Deliv Rev. 2008;60:717–33.
Singh D, Tiwary AK, Bedi N. Role of porous carries in the biopharmaceutical performance of solid smedds of canagliflozin. Recent Pat Drug Deliv Formul. 2018;12:179–98.
Yi T, Wan J, Xu H, Yang X. A new solid self-microemulsifying formulation prepared by spray drying to improve the oral bioavailability of poorly water soluble drugs. Eur J Pharm Biopharm. 2007;70:439–44.
Panigrahi KC, Jena J, Jena GK, Patra CN, Rao MB. QbD-based systematic development of Bosentan SNEDDS: formulation, characterization and pharmacokinetic assessment. J Drug Dev Sci Technol. 2018;47:31–42.
Beg S, Sandhu PS, Batra RS, Khurana RK, Singh B. QbD-based systematic development of novel optimized solid self-nanoemulsifying drug delivery systems (SNEDDS) of lovastatin with enhanced biopharmaceutical performance. Drug Deliv. 2015;22:765–84.
Sun C, Gui Y, Hu R, Chen J, Wang B, Guo Y, et al. Preparation and pharmacokinetics evaluation of solid self-microemulsifying drug delivery system (S-SMEDDS) of osthole. AAPS PharmSciTech. 2018;19:2301–10.
Yeom DW, Son HY, Kim JH, Kim SR, Lee SG, Song SH, et al. Development of solidified self-microemulsifying drug delivery system (SMEDDS) for atorvastatin calcium with improved dissolution and bioavailability. Int J Pharm. 2016;506:302–11.
Naseef MA, Ibrahim HK, Nour SA. Solid form of lipid-based self-nanoemulsifying drug delivery systems for minimization of diacerein adverse effects: development and bioequivalence evaluation in albino rabbits. AAPS PharmSciTech. 2018;19:3097–01.
Kamboj S, Sethi S, Rana V. A spray dried nelfinavir mesylate particles for enhanced oral bioavailability: systematic formulation optimization and in-vivo performance. Colloids Surf B: Biointerfaces. 2019;176:288–99.
Chaudhary S, Aqil M, Sultana Y, Kalam MA. Self-nanoemulsifying drug delivery system of nabumetone improved its oral bioavailability and anti-inflammatory effects in rat model. J Drug Dev Sci Technol. 2019;51:736–45.
Palsamy P, Subramanian S. Resveratrol, a natural hytoalexin normalizes hyperglycemia in streptozotocin-nicotinamide induced experimental diabetic rats. Biomed Pharmacother. 2008;62:598–05.
Tahara A, Takasu T, Yokono M, Imamura M, Kurosaki E. Characterization and comparison of sodium-glucose co-transporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects. J Pharmacol Sci. 2016;130:159–69.
Zhou J, Tan L, Xie J, Lai Z, Huang Y, Qu C, et al. Characterization of brusatol self-microemulsifying drug delivery system and its therapeutic effect against dextran sodium sulfate-induced ulcerative colitis in mice. Drug Deliv. 2017;24:1667–79.
Suthar V, Shital B, Gohel M. Solid self-emulsified nano-structures of lecanidipine hydrochloride: a potential approach to improve the fraction of dose absorbed. J Drug Dev Sci Technol. 2016;31:11–21.
Mura P, Valleri M, Cirri M, Mennini N. New solid self-microemulsifying systems to enhance dissolution rate of poorly water soluble drugs. Pharm Dev Technol. 2012;17:277–84.
Raut S, Karzuon B, Atef E. Using in situ Raman spectroscopy to study the drug precipitation inhibition and supersaturation mechanism of vitamin E TPGS from self-emulsifying drug delivery systems (SEDDS). J Pharm Biomed Anal. 2015;109:121–7.
Agarwal V, Siddiqui A, Ali H, Nazzal S. Dissolution and powder flow characterization of solid self-emulsified drug delivery system (SEDDS). Int J Pharm. 2009;366:44–52.
Vithani K, Hawley A, Jannin V, Pouton C, Boyd BJ. Solubilisation behavior of poorly water-soluble drugs during digestion of solid SMEDDS. Eur J Pharm Biopharm. 2018;130:236–46.
Krstić M, Popović M, Dobričić V, Ibrić S. Influence of solid drug delivery system formulation on poorly water-soluble drug dissolution and permeability. Molecules. 2015;20:14684–98.
Sun M, Zhai X, Xue K, Hu L, Yang X, Li G, et al. 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. 2011;43:132–40.
Chiu YY, Higaki K, Neudeck BL, Barnedd JL, Welage LS, Amidon GL. Human jejunal permeability of cyclosporine a: influence of surfactants on P-glycoprotein efflux in Caco-2-cells. Pharm Res. 2003;20:749–56.
Kumar M, Singh D, Bedi N. Mefenamic acid-loaded solid SMEDDS: an innovative aspect for dose reduction and improved pharmacodynamic profile. Ther Deliv. 2018;10:21–36.
Sato Y, Joumura T, Nashimoto S, Yokoyama S, Tekekuma Y, Yoshida H, et al. Enhancement of lymphatic transport of lutein by oral administration of a solid dispersion and a self-microemulsifying drug delivery system. Eur J Pharm Biopharm. 2018;127:171–6.
Garg V, Kaur P, Singh SK, Kumar B, Bawa P, Gulati M, et al. 2017. Solid self-nanoemulsifying drug delivery systems for oral delivery of polypeptide-k: formulation, optimization, in-vitro and in-vivo antidiabetic evaluation. Eur J Pharm Sci. 2017;109:297–15.
Vira’g L, Szabo’ C. The therapeutic potential of poly (ADP-ribose) polymerase inhibitors. Pharmacol Rev. 2002;54:375–29.
Masiello P, Broca C, Gross R, Roye M, Manteghetti M, Hillaire-Buys D, et al. Experimental NIDDM: development of a new model in adult rats administered streptozotocin and nicotinamide. Diabetes. 1998;47:224–9.
Rodríguez T, Alvarez B, Busquets S, Carbó N, López-Soriano FJ, Argilés JM. The increased skeletal muscle protein turnover of the streptozotocin diabetic rat is associated with high concentrations of branched chain amino acids. Biochem Mol Med. 1997;61:87–94.
Ji W, Zhao M, Wang M, Yan W, Liu Y, Ren S, et al. Effects of canagliflozin on weight loss in high-fat diet-induced obese mice. PLoS One. 2017;12(6):e0179960.
Oguma T, Kuriyama C, Nakayama K, Matsushita Y, Yoshida K, Kiuchi S, et al. The effect of combined treatment with canagliflozin and teneligliptin on glucose intolerance in Zucker diabetic fatty rats. J Pharmacol Sci. 2015;127:456–61.
Sha S, Devineni D, Ghosh A, Polidori D, Chien S, Wexler D, et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab. 2011;13:669–72.
Kuang H, Liao L, Chen H, Kang Q, Shu X, Wang Y. Therapeutic effect of sodium glucose co-transporter 2 inhibitor dapagliflozin on renal cell carcinoma. Med Sci Monit. 2017;23:3737–45.
Shima K, Zhu M, Kuwajima M. A role of nicotinamide-induced increase in pancreatic beta-cell mass on blood glucose control after discontinuation of the treatment in partially pancreatectomized OLETF rats. Diabetes Res Clin Pract. 1998;41:1–8.
Pepato MT, Migliorini RH, Goldberg AL, Kettelhut IC. Role of different proteolytic pathways in degradation of muscle protein from streptozotocin-diabetic rats. Am J Phys. 1996;271:E340–7.
Brodsky IG. Nutritional effects of dietary protein restriction in insulin dependent diabetes mellitus. J Nutr. 1998;128:337S–9S.
Singleton JR, Smith AG, Russell JW, Feldman EL. Microvascular complications of impaired glucose tolerance. Diabetes. 2003;52:2867–73.
Giugliano D, Ceriello A, Esposito K. Glucose metabolism and hyperglycemia. Am J Clin Nutr. 2008;87:217S–22S.
Huebschmann AG, Regensteiner JG, Vlassara H, Reusch JE. Diabetes and advanced glycoxidation end products. Diabetes Care. 2006;29:1420–32.
Steven S, Oelze M, Hanf A, Kröller-Schön S, Kashani F, Roohani S, et al. The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox Biol. 2017;13:370–85.
Sha S, Devineni D, Ghosh A, Polidori D, Hompesch M, Arnolds S, et al. Pharmacodynamic effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, from a randomized study in patients with type 2 diabetes. PloS One. 9:e105638.
Osorio H, Bautista R, Rios A, Franco M, Arellano A, Vargas-Robles H, et al. Effect of phlorizin on SGLT 2 expression in the kidney of diabetic rats. J Nephrol. 2010;23:541–6.
Tabatabai NM, Sharma M, Blumenthal SS, Petering DH. Enhanced expressions of sodium-glucose co transporters in the kidneys of diabetic zucker rats. Diabetes Res Clin Pract. 2009;83:e27–30.
The authors are highly grateful to Zydus Cadila Limited, India for providing ex gratia of CFZ for our research work. The authors acknowledge University Grants Commission (UGC), Delhi for University with Potential for Excellence (UPE) and Department of Science and Technology (DST), Government of India PURSE, CPEPA and FIST schemes for strengthening infrastructure of Guru Nanak Dev University, Amritsar. The authors are highly thankful to Alomone Labs, Israel for providing ex gratia sample of SGLT II primary antibody for our research work. Cooperation of Mr. Brahmjot Singh from Department of Pharmaceutical Sciences for helping in animal studies is deeply acknowledged.
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Singh, D., Singh, A.P., Singh, D. et al. Enhanced oral bioavailability and anti-diabetic activity of canagliflozin through a spray dried lipid based oral delivery: a novel paradigm. DARU J Pharm Sci (2020). https://doi.org/10.1007/s40199-020-00330-3