Abstract
Background
Valsartan exhibits poor aqueous solubility and dissolution rate limited absorption. The lower solubility in the upper part of gastrointestinal tract (pH-dependant solubility) where its absorption window exists further contributes to the low oral bioavailability of valsartan.
Objective
The present work was aimed to improve the in vivo pharmacokinetics of valsartan by preparing amorphous polymeric dispersions using Eudragit E 100 as carrier. Eudragit E 100 is a cationic polymer soluble in gastric fluid up to pH 5.0 and exhibits pH-dependent release. Hence, the dispersions prepared using Eudragit E 100 rapidly dissolves at lower pH presenting drug in molecularly dispersed and soluble form at its absorption site.
Methods
Polymeric solid dispersions were prepared in different drug-to-carrier ratios. The prepared dispersions were evaluated for drug–carrier interactions, solid-state transitions and drug-release properties with the help of Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and in vitro dissolution studies. The optimized formulation containing valsartan was tested in rats for bioavailability and pharmacokinetic parameters and compared with that of valsartan pure drug.
Results
The results from FTIR studies indicated no interactions between drug and excipients. DSC studies confirmed reduction in crystallinity of drug. The dissolution studies performed in 0.1 N HCl showed significant improvement (p < 0.05) in the dissolution of valsartan. In vivo pharmacokinetic studies showed 199 % relative bioavailability with significant improvement (p < 0.05) in area under the curve compared to valsartan pure drug.
Conclusion
Eudragit E 100 can be used to improve the dissolution of drugs that show low solubility at lower pH and thereby enhancing the bioavailability.
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References
Horter D, Dressman JB. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv Drug Deliv Rev. 2001;46(1–3):75–87 (Epub 2001/03/22).
Porter CJ, Pouton CW, Cuine JF, Charman WN. Enhancing intestinal drug solubilisation using lipid-based delivery systems. Adv Drug Deliv Rev. 2008;60(6):673–91 (Epub 2007/12/25).
Gu CH, Li H, Levons J, Lentz K, Gandhi RB, Raghavan K, et al. Predicting effect of food on extent of drug absorption based on physicochemical properties. Pharm Res. 2007;24(6):1118–30 (Epub 2007/03/27).
Mazayev VP, Fomina IG, Kazakov EN, Sulimov VA, Zvereva TV, Lyusov VA, et al. Valsartan in heart failure patients previously untreated with an ACE inhibitor. Int J Cardiol. 1998;65(3):239–46 (Epub 1998/09/18).
Ahad Abdul, Aqil Mohammed, Kohli Kanchan, Sultana Yasmin, Mujeeb Mohd, Ali A. Role of novel terpenes in transcutaneous permeation of valsartan: effectiveness and mechanism of action. Drug Dev Ind Pharm. 2011;37(5):583–896.
Chiou WL, Niazi S. Pharmaceutical applications of solid dispersion systems: dissolution of griseofulvin–succinic acid eutectic mixture. J Pharm Sci. 1976;65(8):1212–4 (Epub 1976/08/01).
Chiou WL, Riegelman S. Pharmaceutical applications of solid dispersion systems. J Pharm Sci. 1971;60(9):1281–302 (Epub 1971/09/01).
Serajuddin ATM. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. 1999;88(10):1058–66.
Lentz KA. Current methods for predicting human food effect. AAPS J. 2008;10(2):282–8 (Epub 2008/05/27).
Koga K, Kusawake Y, Ito Y, Sugioka N, Shibata N, Takada K. Enhancing mechanism of Labrasol on intestinal membrane permeability of the hydrophilic drug gentamicin sulfate. Eur J Pharm Biopharm. 2006;64(1):82–91 (Epub 2006/06/06).
Quinteros DA, Tartara LI, Palma SD, Manzo RH, Allemandi DA. Ocular delivery of flurbiprofen based on Eudragit((R)) E-flurbiprofen complex dispersed in aqueous solution: preparation, characterization, in vitro corneal penetration, and ocular irritation. J Pharm Sci. 2014;103(12):3859–68 (Epub 2014/10/09).
Patel BB, Patel JK, Chakraborty S. Solubility enhancement using poly(meth)acrylate based solid dispersions. Powder Tech. 2015;270:27–38.
Tang J, Xu N, Ji H, Liu H, Wang Z, Wu L. Eudragit nanoparticles containing genistein: formulation, development, and bioavailability assessment. Int J Nanomed. 2011;6:2429–35 (Epub 2011/11/11).
Biswal S, Sahoo J, Murthy PN. Physicochemical properties of solid dispersions of gliclazide in polyvinylpyrrolidone K90. AAPS PharmSciTech. 2009;10(2):329–34.
Leonardi Darío, Barrera María Gabriela, Lamas María Celina, Salomón CJ. Development of prednisone:polyethylene glycol 6000 fast-release tablets from solid dispersions: solid-state characterization, dissolution behavior, and formulation parameters. AAPS PharmSciTech. 2007;8(4):E1–8.
Shen Y, Lu F, Hou J, Guo S. Incorporation of paclitaxel solid dispersions with poloxamer188 or polyethylene glycol to tune drug release from poly(-caprolactone) films. Drug Dev Ind Pharm. 2013;39(8):1187–96 (Epub 2012/07/19).
Chella N, Kumar Yada K, Vempati R. Preparation and evaluation of ethyl cellulose microspheres containing diclofenac sodium by novel W/O/O emulsion method pharm. Sci Res. 2010;2(12):884–8.
Ahuja N, Katare OP, Singh B. Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers. Eur J Pharm Biopharm. 2007;65(1):26–38.
Malana MA, Zohra R. The release behavior and kinetic evaluation of tramadol HCl from chemically cross linked Ter polymeric hydrogels. Daru J Fac Pharm Tehran Univ Med Sci. 2013;21(1):10.
Das S, Murthy PN, Nath L, Chowdhury P. Kinetic modelling on drug release from controlled drug delivery systems. Acta Polo Pharm Drug Res. 2010;67(3):217–23.
Chella N, Tadikonda R. Melt dispersion granules: formulation and evaluation to improve oral delivery of poorly soluble drugs—a case study with valsartan. Drug Dev Ind Pharm. 2014. (Epub 2014/05/07).
Gregory C. Slack, Snow NH. HPLC sample preparation. In: Satinder Ahuja, Rasmussen H, editors. HPLC method development for pharmaceuticals. London: Academic press; 2007. pp. 237–263.
Aghazadeh-Habashi A, Sattari S, Pasutto F, Jamali F. High Performance liquid chromatographic determination of glucosamine in rat plasma. J Pharm Pharmaceut Sci. 2002;5(2):176–80.
Ma Q, Sun H, Che E, Zheng X, Jiang T, Sun C, et al. Uniform nano-sized valsartan for dissolution and bioavailability enhancement: influence of particle size and crystalline state. Int J Pharm. 2013;441(1–2):75–81 (Epub 2012/12/26).
Gao P, Shi Y. Characterization of supersaturatable formulations for improved absorption of poorly soluble drugs. AAPS J. 2012;14(4):703–13 (Epub 2012/07/17).
Yoshida T, Lai TC, Kwon GS, Sako K. pH- and ion-sensitive polymers for drug delivery. Expert Opin Drug Deliv. 2013;10(11):1497–513 (Epub 2013/08/13).
Kumar D, Sailaja Chirravuri SV, Shastri NR. Impact of surface area of silica particles on dissolution rate and oral bioavailability of poorly water soluble drugs: a case study with aceclofenac. Int J Pharm. 2014;461(1–2):459–68 (Epub 2013/12/26).
Krishnamoorthy V, Nagalingam A, Priya Ranjan Prasad V, Parameshwaran S, George N, Kaliyan P. Characterization of olanzapine-solid dispersions. Iran. J Pharm Res. 2011;10(1):13–24 (Epub 2011/01/01).
Valizadeh H, Nokhodchi A, Qarakhani N, Zakeri-Milani P, Azarmi S, Hassanzadeh D, et al. Physicochemical characterization of solid dispersions of indomethacin with PEG 6000, Myrj 52, lactose, sorbitol, dextrin, and Eudragit E100. Drug Dev Ind Pharm. 2004;30(3):303–17 (Epub 2004/04/28).
Jung JY, Yoo SD, Lee SH, Kim KH, Yoon DS, Lee KH. Enhanced solubility and dissolution rate of itraconazole by a solid dispersion technique. Int J Pharm. 1999;187(2):209–18 (Epub 1999/09/30).
Goddeeris C, Willems T, Houthoofd K, Martens JA, Van den Mooter G. Dissolution enhancement of the anti-HIV drug UC 781 by formulation in a ternary solid dispersion with TPGS 1000 and Eudragit E100. Eur J Pharm Biopharm. 2008;70(3):861–8 (Epub 2008/08/12).
Yan YD, Sung JH, Kim KK, Kim DW, Kim JO, Lee BJ, et al. Novel valsartan-loaded solid dispersion with enhanced bioavailability and no crystalline changes. Int J Pharm. 2012;422(1–2):202–10 (Epub 2011/11/17).
Acknowledgments
The authors would like to thank Evonik industries for Eudragit E 100 gift sample.
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No sources of funding were used to conduct this study.
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The authors report no conflict of interest.
Ethical Approval
The animal experimentation was approved by Institutional Animal Ethics Committee (IAEC) of National Institute of Pharmaceutical Educational and Research (NIPER), Hyderabad, India and performed in accordance with the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) guidelines for the safe use and care of experimental animals.
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Chella, N., Daravath, B., Kumar, D. et al. Formulation and Pharmacokinetic Evaluation of Polymeric Dispersions Containing Valsartan. Eur J Drug Metab Pharmacokinet 41, 517–526 (2016). https://doi.org/10.1007/s13318-015-0290-5
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DOI: https://doi.org/10.1007/s13318-015-0290-5