Physicochemical and pharmacological evaluation of carvedilol-eudragit® RS100 electrosprayed nanostructures

Document Type : Original Article


1 Research Center for Pharmaceutical Nanotechnology, Biomedicines Institute, Tabriz University of Medical Sciences, Tabriz, Iran

2 Students Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

3 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

4 Pharmaceutical Analysis Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran


Objective(s): This study was carried out to boost the pharmacologic influence of carvedilol (CAR) (as a poorly water-soluble drug) by developing CAR-eudragit® RS100 (Eud) nanofibers and nanobeads benefiting an electrospraying approach.
Materials and Methods: CAR-Eud nanoformulations with varying ratios (1:5 and 1:10) at total solution concentrations of 10 %, 15 % and 20 % w/v were formulated.
Results: The solution concentration remarkably impressed the size and morphology of the samples; in which, the nanobeads (mean diameter of 135.83 nm) were formed at low solution concentrations and high concentrations led to nanofibers (mean diameter of 193.45 nm) formation. DSC thermographs and PXRD patterns along with FTIR spectrum precisely showed CAR amorphization and no probable chemical interactions between CAR and Eud in the electrosprayed nanosystems. The in vitro release considerations demonstrated that the nanoformulations with the drug: polymer ratios of 1:10 and 1:5 depict rapid dissolution rate compared to the physical mixtures (PMs) and the pure drug. The in vivo studies in Wistar male rats suggested that the electrosprayed nanoformulation (1:10; 20 %) reduced the isoproterenol (ISO) induced elevation of heart rate, necrosis and accumulation of neutrophils in the heart tissue more efficient than the pure drug and PM.
Conclusion: Our finding illustrated that the electrospraying as a profitable one-step procedure could be productively benefited to improve the physicochemical features and pharmacologic influences of CAR.


Main Subjects

1. Cardiovascular disease- World Heart Day 2017 [Internet]. World Health Organization. 2017. Available from:
2. Li J, Chen Z, Gao X, Zhang H, Xiong W, Ju J, et al. Meta-analysis comparing metoprolol and carvedilol on mortality benefits in patients with acute myocardial infarction. Am J Cardiol 2017; 120:1479-1486.
3. Patil SS, Roy K, Choudhary B, Mahadik KR. Fabrication of novel GMO/Eudragit E100 nanostructures for enhancing oral bioavailability of carvedilol. Drug Dev Ind Pharm 2016; 42:1300-1307.
4. Janakiraman AK, Sumathi B, Saleem TM, Ramkanth S, Kumar PO, Venkatachalam G. Design and evaluation of carvedilol nanocrystals sustained release tablets. J Appl Pharm Sci 2017; 7:061-068.
5. Aytac Z, Ipek S, Durgun E, Uyar T. Antioxidant electrospun zein nanofibrous web encapsulating quercetin/cyclodextrin inclusion complex. J Mater Sci 2018; 53:1527-1539.
6. Badr-Eldin SM, Ahmed TA, R Ismail H. Aripiprazole-cyclodextrin binary systems for dissolution enhancement: effect of preparation technique, cyclodextrin type and molar ratio. Iran J Basic Med Sci 2013; 16:1223-1231.
7. Jahangiri A, Barzegar-Jalali M, Javadzadeh Y, Hamishehkar H, Adibkia K. Physicochemical characterization of atorvastatin calcium/ezetimibe amorphous nano-solid dispersions prepared by electrospraying method. Artif Cells Nanomed Biotechnol 2017; 45:1138-1145.
8. Seo J-W, Hwang K-M, Lee S-H, Kim D-W, Park E-S. Preparation and characterization of adefovir dipivoxil–stearic acid cocrystal with enhanced physicochemical properties. Pharm Dev Technol 2017:1-10.
9. Zhang Y, Shang Z, Gao C, Du M, Xu S, Song H, et al. Nanoemulsion for solubilization, stabilization, and in vitro release of pterostilbene for oral delivery. AAPS PharmSciTech 2014; 15:1000-1008.
10. Soltani S, Zakeri-Milani P, Barzegar-Jalali M, Jelvehgari M. Design of eudragit RL nanoparticles by nanoemulsion method as carriers for ophthalmic drug delivery of ketotifen fumarate. Iran J Basic Med Sci 2016; 19:550-560.
11. Molaei M-A, Osouli-Bostanabad K, Adibkia K, Shokri J, Asnaashari S, Javadzadeh Y. Enhancement of ketoconazole dissolution rate by the liquisolid technique. Acta Pharm 2018; 68:325-336.
12. Hiendrawan S, Widjojokusumo E, Veriansyah B, Tjandrawinata RR. Pharmaceutical salts of carvedilol: polymorphism and physicochemical properties. AAPS PharmSciTech 2017; 18:1417-1425.
13. Adibkia K, Javadzadeh Y, Dastmalchi S, Mohammadi G, Niri FK, Alaei-Beirami M. Naproxen–eudragit® RS100 nanoparticles: Preparation and physicochemical characterization. Colloids Surf B 2011; 83:155-159.
14. Javadzadeh Y, Ahadi F, Davaran S, Mohammadi G, Sabzevari A, Adibkia K. Preparation and physicochemical characterization of naproxen–PLGA nanoparticles. Colloids Surf B 2010; 81:498-502.
15. Samiei M, Farjami A, Dizaj SM, Lotfipour F. Nanoparticles for antimicrobial purposes in endodontics: A systematic review of in vitro studies. Mater Sci Eng C 2016; 58:1269-1278.
16. Song Z, Shi J, Zhang Z, Qi Z, Han S, Cao S. Mesoporous silica-coated gold nanorods with a thermally responsive polymeric cap for near-infrared-activated drug delivery. J Mater Sci 2018; 53:7165-7179.
17. He X, Liang F, Wang F, Zou L, Wang J, Tang C, et al. Targeted delivery and thermo/pH-controlled release of doxorubicin by novel nanocapsules. J Mater Sci 2018; 53:2326-2336.
18. Rai VK, Mishra N, Agrawal AK, Jain S, Yadav NP. Novel drug delivery system: an immense hope for diabetics. Drug Deliv 2016; 23:2371-2390.
19. Gandhi AV, Thipsay P, Kirthivasan B, Squillante E. Adsorption onto mesoporous silica using supercritical fluid technology improves dissolution rate of carbamazepine—a poorly soluble compound. AAPS Pharm Sci Tech 2017; 18:3140-3150.
20. Tonglairoum P, Chaijaroenluk W, Rojanarata T, Ngawhirunpat T, Akkaramongkolporn P, Opanasopit P. Development and characterization of propranolol selective molecular imprinted polymer composite electrospun nanofiber membrane. AAPS Pharm Sci Tech 2013; 14:838-846.
21. Abedinoghli D, Charkhpour M, Osouli-Bostanabad K, Selselehjonban S, Emami S, Barzegar-Jalali M, et al. Electrosprayed nanosystems of carbamazepine – PVP K30 for enhancing its pharmacologic effects. Iran J Pharm Res 2018;17:1431-1443
22. Goh Y-F, Shakir I, Hussain R. Electrospun fibers for tissue engineering, drug delivery, and wound dressing. J Mater S 2013; 48:3027-3054.
23. Garjani A, Barzegar-Jalali M, Osouli-Bostanabad K, Ranjbar H, Adibkia K. Morphological and physicochemical evaluation of the propranolol HCl–Eudragit® RS100 electrosprayed nanoformulations. Artif Cells Nanomed Biotechnol 2018; 46:749-756.
24. Antaya H, Pellerin C. Preparation of the pure poly(ϵ-caprolactone)-urea complex by electrospray. Soft Matter 2011; 9:295-302.
25. Vellayappan MV, Venugopal JR, Ramakrishna S, Ray S, Ismail AF, Mandal M, et al. Electrospinning applications from diagnosis to treatment of diabetes. RSC Adv 2016; 6:83638-83655.
26. Payab S, Davaran S, Tanhaei A, Fayyazi B, Jahangiri A, Farzaneh A, et al. Triamcinolone acetonide–Eudragit® RS100 nanofibers and nanobeads: Morphological and physicochemical characterization. Artif Cells Nanomed Biotechnol 2016; 44:362-369.
27. Roman JA, Reucroft I, Martin RA, Hurtado A, Mao H-Q. Local release of paclitaxel from aligned, electrospun microfibers promotes axonal extension. Adv Healthc Mater 2016; 5:2628-2635.
28. Ghaebi Panah N, Alizadeh P, Eftekhari Yekta B, Motakef-Kazemi N. Preparation and in vitro characterization of electrospun bioactive glass nanotubes as mesoporous carriers for ibuprofen. Ceram Int 2016; 42:10935-10942.
29. Payab S, Jafari-Aghdam N, Barzegar-Jalali M, Mohammadi G, Lotfipour F, Gholikhani T, et al. Preparation and physicochemical characterization of the azithromycin-Eudragit RS100 nanobeads and nanofibers using electrospinning method. J Drug Deliv Sci Technol 2014; 24:585-590.
30. Akduman C, Özgüney I, Kumbasar EPA. Preparation and characterization of naproxen-loaded electrospun thermoplastic polyurethane nanofibers as a drug delivery system. Mater Sci Eng C 2016; 64:383-390.
31. Jafari-Aghdam N, Adibkia K, Payab S, Barzegar-Jalali M, Parvizpur A, Mohammadi G, et al. Methylprednisolone acetate–Eudragit® RS100 electrospuns: Preparation and physicochemical characterization. Artif Cells Nanomed Biotechnol 2016; 44:497-503.
32. Balogh A, Cselkó R, Démuth B, Verreck G, Mensch J, Marosi G, et al. Alternating current electrospinning for preparation of fibrous drug delivery systems. Int J Pharm 2015; 495:75-80.
33. Krstić M, Radojević M, Stojanović D, Radojević V, Uskoković P, Ibrić S. Formulation and characterization of nanofibers and films with carvedilol prepared by electrospinning and solution casting method. Eur J Pharm Sci 2017; 101:160-166.
34. Balogh A, Farkas B, Faragó K, Farkas A, Wagner I, Van assche I, et al. Melt-blown and electrospun drug-loaded polymer fiber mats for dissolution enhancement: a comparative study. J Pharm Sci 2015; 104:1767-1776.
35. Huang S, Zhou L, Li M-C, Wu Q, Kojima Y, Zhou D. Preparation and properties of electrospun poly (vinyl pyrrolidone)/cellulose nanocrystal/silver nanoparticle composite fibers. Materials 2016; 9:523.
36. Nagy ZK, Balogh A, Drávavölgyi G, Ferguson J, Pataki H, Vajna B, et al. Solvent-free melt electrospinning for preparation of fast dissolving drug delivery system and comparison with solvent-based electrospun and melt extruded systems. J Pharm Sci 2013; 102:508-517.
37. Bal T, Sengupta S, Murthy PN. Formulation and evaluation of carvedilol microcapsules using Eudragit NE30D and sodium alginate. Braz J Pharm Sci 2013; 49:889-901.
38. Saini R, Singh SK, Verma PRP. Evaluation of carvedilol-loaded microsponges with nanometric pores using response surface methodology. J Exp Nanosci 2014; 9:831-850.
39. Morgan T. Clinical pharmacokinetics and pharmacodynamics of carvedilol. Clin Pharmacokinet 1994; 26:335-346.
40. Feuerstein G, Ruffolo Jr R. Carvedilol, a novel vasodilating beta-blocker with the potential for cardiovascular organ protection. Eur Heart J 1996; 17:24-29.
41. Jahangiri A, Davaran S, Fayyazi B, Tanhaei A, Payab S, Adibkia K. Application of electrospraying as a one-step method for the fabrication of triamcinolone acetonide-PLGA nanofibers and nanobeads. Colloids Surf B 2014; 123:219-224.
42. Nguyen DN, Clasen C, Van den Mooter G. Pharmaceutical applications of electrospraying. J Pharm Sci 2016; 105:2601-2620.
43. Keck CM, Müller RH. Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur J Pharm Biopharm 2006; 62:3-16.
44. Jermain SV, Brough C, Williams RO. Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery – An update. Int J Pharm 2018; 535:379-392.
45. Kajdič S, Vrečer F, Kocbek P. Preparation of poloxamer-based nanofibers for enhanced dissolution of carvedilol. Eur J Pharm Sci 2018; 117:331-340.
46. Wegmann M, Parola L, Bertera FM, Taira CA, Cagel M, Buontempo F, et al. Novel carvedilol paediatric nanomicelle formulation: in-vitro characterization and in-vivo evaluation. ‎J. Pharm. Pharmacol 2017; 69:544-553.
47. Liu D, Pan H, He F, Wang X, Li J, Yang X, et al. Effect of particle size on oral absorption of carvedilol nanosuspensions: in vitro and in vivo evaluation. Int J Nanomedicine 2015; 10:6425-6434.
48. Alderman EL, Harrison DC. Myocardial hypertrophy resulting from low dosage isoproterenol administration in rats. Proc Soc Exp Biol Med 1971; 136:268-270.
49. Patel V, Upaganlawar A, Zalawadia R, Balaraman R. Cardioprotective effect of melatonin against isoproterenol induced myocardial infarction in rats: A biochemical, electrocardiographic and histoarchitectural evaluation. Eur J Pharmacol 2010; 644:160-168.
50. Yousefi K, Fathiazad F, Soraya H, Rameshrad M, Maleki-Dizaji N, Garjani A. Marrubium vulgare L. methanolic extract inhibits inflammatory response and prevents cardiomyocyte fibrosis in isoproterenol-induced acute myocardial infarction in rats. BioImpacts 2014; 4:21-27.
51. Bristow MR. Mechanism of Action of Beta-Blocking Agents in Heart Failure. American J Cardiol 1997; 80:26L-40L.
52. Feuerstein G, Yue T-L, Ma X, Ruffolo RR. Novel mechanisms in the treatment of heart failure: Inhibition of oxygen radicals and apoptosis by carvedilol. Prog Cardiovasc Dis 1998; 41:17-24.
53. Venishetty VK, Chede R, Komuravelli R, Adepu L, Sistla R, Diwan PV. Design and evaluation of polymer coated carvedilol loaded solid lipid nanoparticles to improve the oral bioavailability: A novel strategy to avoid intraduodenal administration. Colloids Surf B 2012; 95:1-9.
54. Patil S, Babbar A, Mathur R, Mishra A, Sawant K. Mucoadhesive chitosan microspheres of carvedilol for nasal administration. J Drug Target 2010; 18:321-331.