• EMAN A. MAZYED Department of Pharmaceutical Technology, Faculty of Pharmacy, Kaferelsheikh University, Kaferelsheikh, Egypt
  • SHERIN ZAKARIA Department of Pharmaceutical Technology, Faculty of Pharmacy, Kaferelsheikh University, Kaferelsheikh, Egypt


Objective: The present investigation aims to formulate and evaluate proniosomes of clopidogrel bisulphate for improving its dissolution characteristics.

Methods: The slurry method was used for the preparation of proniosomes of clopidogrel using cholesterol, sorbitan monostearate (Span 60) and maltodextrin as a carrier. Clopidogrel proniosomes were evaluated for their entrapment efficiency and in vitro drug release. The best formula (F1) that achieved maximum drug release was further evaluated by measurement of the angle of repose, morphological examination, determination of vesicle size, determination of zeta potential, Fourier transform infrared spectroscopy and differential thermal analysis. The in vivo behavior of the selected proniosomal formula (F1) was studied by measuring the antiplatelet activity in adult male mice.

Results: The entrapment efficiency of clopidogrel proniosomes was in the range of 83.04±1.99 to 90.14±0.30. % drug released from proniosomal formulations was in the range of 79.73±0.35 to 97.70±1.10 % within 4 h. Clopidogrel proniosomes significantly enhanced the in vitro release of clopidogrel compared with the plain drug that achieved 61.77±2.22 % drug release. F1 significantly (p ≤ 0.001) increased the bleeding time and bleeding volume and significantly (p ≤ 0.05) prolonged prothrombin time and decreased prothrombin activity and increased the international normalized ratio (INR) compared to plain clopidogrel.

Conclusion: The present investigation introduced proniosomes as a promising carrier for clopidogrel that could enhance its dissolution and pharmacological effect.

Keywords: Clopidogrel, Maltodextrin, Proniosomes, Pharmacological effect


1. Sanjaymitra PVSS, Ganesh GNK. Dissolution and solubility enhancement strategies: current and novel prospectives. J Crit Rev 2018;5:1-10.
2. Jassim ZE, Hussein AA. Formulation and evaluation of clopidogrel tablet incorporating drug nanoparticles. Iran J Pharm Sci 2014;6:838–51.
3. Dua JS, Rana AC, Bhandari AK. Liposome: methods of preparation and applications. Int J Pharm Stud Res 2012;3:14–20.
4. Sharma Vijay K, Mishra DN, Sharma AK, Srivastava B. Liposomes: present prospective and future challenges. Int J Curr Pharm Rev Res 2010;1:6–16.
5. Ulrich AS. Biophysical aspects of using liposomes as delivery vehicles. Biosci Rep 2002;22:129–50.
6. Kumar D, Sharma D, Singh G, Singh M, Rathore MS. Lipoidal soft hybrid biocarriers of supramolecular construction for drug delivery. ISRN Pharm 2012. http://dx.doi.org/10.5402/ 2012/474830.
7. Yadav K, Yadav D, Saroha K, Nanda S, Mathur P, Syan N. Proniosomal gel: a provesicular approach for transdermal drug delivery. Der Pharm Lett 2010;2:189–98.
8. Yasam VR, Jakki SL, Natarajan J, Kuppusamy G. A review on novel vesicular drug delivery: proniosomes. Drug Delivery 2014;21:243–9.
9. Solanki A, Parikh J, Parikh R. Preparation, characterization, optimization, and stability studies of aceclofenac proniosomes. Iran J Pharm Res 2008;7:237–46.
10. Samy AM, Ramadan AA, Abu El-Enin ASM, Mortagi YIM. Formulation and optimization of itraconazole proniosomes using box behnken design. Int J Appl Pharm 2018;10:41-51.
11. Porter CJH, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discovery 2007;6:231-48.
12. Boddu M, Choppari V, Rapalli VK, Badam M. Formulation and evaluation of proniosomes of felodipine. Drug Des 2017;6:154.
13. Sengodan T, Sunil B, Vaishali R, Chandra RJ, Nagar S, Nagar O. Formulation and evaluation of maltodextrin based proniosomes loaded with indomethacin. Int J PharmTech Res 2009;1:517–23.
14. Marwa HA, Omaima AS, Hanaa AE, Hanan ME. Optimizing proniosomes for controlled release of ketoprofen using a box-behnken experimental design. Int J Pharm Sci Res 2011;2:2195.
15. Chauhan MK, Sahoo PK, Rawat AS, Duggal D, Kandwal M, Sandal N. Formulation, characterization and in vitro evaluation of tactically engineered proniosomes for successful oral delivery of ramipril. Der Pharm Lett 2015;7:93–7.
16. El Maghraby GM, Ahmed AA, Osman MA. Penetration enhancers in proniosomes as a new strategy for enhanced transdermal drug delivery. Saudi Pharm J 2015;23:67–74.
17. Moore JW, Flanner HH. Mathematical comparison of curves with an emphasis on in vitro dissolution profile. Pharm Technol 1996;20:64-74.
18. Samy AM, Ghorab MM, Shadeed SG, Mazyed EA. Formulation and evaluation of different transdermal drug delivery systems of ketoprfen. Int J Pharm Pharm Sci 2013;5 Suppl 2:600-7.
19. Nyol S, Gupta MM. Immediate drug release dosage form: a review. J Drug Delivery Ther 2013;3:155-61.
20. AhmedIbrahiem MM. Proniosomal oral tablets for controlled delivery and enhanced pharmacokinetic properties of Acemetacin. AAPS 2014;16:375-83.
21. Sivannarayana P, Rani AP, Saikishore V, Venu Babu C, Sri Rekha V. Transfersomes: ultra deformable vesicular carrier systems in transdermal drug delivery system. Res J Pharm Dos Forms Technol 2012;4:243-5.
22. Das B, Sen SO, Maji R, Nayak AK, Sen KK. Transferosomal gel for transdermal delivery of risperidone: formulation optimization and ex vivo permeation. J Drug Delivery Sci Technol 2017;38:59–71.
23. Gupta A, Prajapati SK, Balamurugan M, Singh M, Bhatia D. Design and development of a proniosomal transdermal drug delivery system for captopril. Trop J Pharm Res 2007;6:687–93.
24. Maheswari U, Mullaicharam AR. Development and in vitro evaluation of nanosuspension formulation containing acyclovir for the treatment of ocular infections. Res J Pharm Biol Chem Sci 2013;4:463–80.
25. Trivedi MK, Branton A, Trivedi D, Nayak G, Mishra R, Jana S. Characterization of physical, thermal and spectral properties of biofield treated 2-aminopyridine. Sci J Anal Chem 2015;3:127–34.
26. Eid RK, Essa EA, El Maghraby GM. Essential oils in niosomes for enhanced transdermal delivery of felodipine. Pharm Dev Technol 2018;23:1–9.
27. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 2010;8:e1000412.
28. 2010/63/EU EU directive. Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. Off J Eur Union L 2010;276:33–79.
29. de Vries JW, Schnichels S, Hurst J. DNA nanoparticles for ophthalmic drug delivery. Biomaterials 2018;157:98–106.
30. Ali SM, Sheikh S, Ahmad A, Moghis U. Pre-clinical and phase i clinical study of clopidogrel lipid suspension: intravenously injected formulation results in the faster onset of action and dose-dependent inhibition of platelet aggregation. J Pharmacol Clin Toxicol 2015;3:1–8.
31. Murad JP, Espinosa EVP, Ting HJ, Khasawneh FT. Characterization of the in vivo antiplatelet activity of the antihypertensive agent losartan. J Cardiovasc Pharmacol Ther 2012;17:308–14.
32. Foerch C, Arai K, Jin G. Experimental model of warfarin-associated intracerebral hemorrhage. Stroke 2008;39:3397–404.
33. Lemini C, Jaimez R, Franco Y. Gender and inter-species influence on coagulation tests of rats and mice. Thromb Res 2007;120:415–9.
34. Gurrapu A, Jukanti R, Bobbala SR, Kanuganti S, Jeevana JB. Improved oral delivery of valsartan from maltodextrin based proniosome powders. Adv Powder Technol 2012;23:583–90.
35. Nii T, Ishii F. Encapsulation efficiency of water-soluble and insoluble drugs in liposomes prepared by the microencapsulation vesicle method. Int J Pharm 2005;298:198–205.
36. Singh CH. Formulation, characterization, stability and in vitro evaluation of nimesulide niosomes. Pharmacophore 2011;2:131–48.
37. Sankar V, Ruckmani K, Durga S, Jailani S. Proniosomes as drug carriers. Pak J Pharm Sci 2010;23:103–7.
38. Ibrahim MM, Tawfique SAH, Mahdy MM. Liposomal diltiazem HCl as ocular drug delivery system for glaucoma. Drug Dev Ind Pharm 2014;40:765–73.
39. Mokhtar ASZ and M. Multivariate optimization of formulation variables influencing flurbiprofen proniosomes characteristics. J Pharm Sci 2011;100:2212–21.
40. Asthana GS, Sharma PK, Asthana A. In vitro and in vivo evaluation of niosomal formulation for controlled delivery of clarithromycin. Scientifica (Cairo) 2016. Doi: 10.1155/ 2016/6492953.
41. Mokale VJ, Patil HI, Patil AP, Shirude PR, Naik JB. Formulation and optimisation of famotidine proniosomes: an in vitro and ex vivo study. J Exp Nanosci 2016;11:97–110.
42. USP30-NF25, U. P., US Pharmacopoeial Convention, Inc, Rock. USA; 2007.
43. Singh S, Trivedi S, Jain S. Design and development of proniosome based transdermal delivery of ondansetron hydrochloride. Int J Pharm Biol Res 2012;3:191–201.
44. Kazi KM, Mandal AS, Biswas N. Niosome: a future of targeted drug delivery systems. J Adv Pharm Technol Res 2010;1:374–80.
45. Das MK, Palei NN. Sorbitan ester niosomes for topical delivery of rofecoxib. Indian J Exp Biol 2011;49:438-45.
46. Keservani RK, Sharma AK, Jain S. Effect of different process variables on the preparation of baclofen niosomes. Int J Univ Pharm Life Sci 2011;1:301–10.
47. Balasubramaniam J, Bindu K, Rao VU, Ray D, Haldar R, Brzeczko AW. Effect of superdisintegrants on a dissolution of cationic drugs. Dissolution Technol 2008;15:18-25.
48. Patel P. Design and development of self microemulsifying drug delivery system of clopidogrel bisulphate. Int J Pharmamedix India 2013;1:539–53.
49. El-Sayed MM, Hussein AK, Sarhan HA, Mansour HF. Flurbiprofen-loaded niosomes-in-gel system improves the ocular bioavailability of flurbiprofen in the aqueous humor. Drug Dev Ind Pharm 2017;43:902–10.
50. Sun P, Yang HJ, Wang YQ, Liu KZ, Xu YW. Lipase-catalyzed synthesis and characterization of stearic acid dextrin ester. Res Heal Nutr 2013;1:7–11.
51. Rahman SA, Abdelmalak NS, Badawi A, Elbayoumy T, Sabry N, Ramly AEl. Formulation of tretinoin-loaded topical proniosomes for treatment of acne: in vitro characterization, skin irritation test and comparative clinical study. Drug Delivery 2015;22:731–9.
52. Das S. Study of decomposition behaviour of binders and the effect of binder type on strength and density of alumina samples, BTech Thesis, Department of Ceramic Engineering, National Institute of Technology Rourkela; 2011.
53. Patil BA. Formulation and development of industry feasible proniosomal transdermal drug delivery system of granisetron hydrochloride. Asian J Pharm 2015;9:113–9.
54. Patil HN, Hardikar SR, Bhosale AV. Formulation, development and evaluation of proniosomal gel of carvedilol. Int J Pharm Pharm Sci 2012;4:191–7.
55. Sahoo RK, Biswas N, Guha A, Sahoo N, Kuotsu K. Development and in vitro/in vivo evaluation of controlled release provesicles of a nateglinide–maltodextrin complex. Acta Pharm Sin B 2014;4:408–16.
56. Karabulut H, Toraman F, Evrenkaya S, Goksel O, Tarcan S, Alhan C. Clopidogrel does not increase bleeding and allogenic blood transfusion in coronary artery surgery. Eur J Cardio-Thoracic Surg 2004;25:419–23.
57. Wen MM, Farid RM, Kassem AA. Nano-proniosomes enhancing the transdermal delivery of mefenamic acid. J Liposome Res 2014;24:280–9.
58. Vasistha P, Ram A. Non-ionic provesicular drug carrier: an overview. Asian J Pharm Clin Res 2013;6 Suppl 1:38-42.
26 Views | 24 Downloads
How to Cite
MAZYED, E. A., & ZAKARIA, S. (2019). ENHANCEMENT OF DISSOLUTION CHARACTERISTICS OF CLOPIDOGREL BISULPHATE BY PRONIOSOMES. International Journal of Applied Pharmaceutics, 11(2), 77-85. https://doi.org/10.22159/ijap.2019v11i2.30575
Original Article(s)