AAPS PharmSciTech

, Volume 19, Issue 5, pp 2155–2173 | Cite as

Dry Gel Containing Optimized Felodipine-Loaded Transferosomes: a Promising Transdermal Delivery System to Enhance Drug Bioavailability

  • Mohammed Ali Kassem
  • Mona Hassan Aboul-EinienEmail author
  • Mai Magdy El Taweel
Research Article


Felodipine has a very low bioavailability due to first-pass metabolism. The aim of this study was to enhance its bioavailability by transdermal application. Felodipine-loaded transferosomes were prepared by thin-film hydration using different formulation variables. An optimized formula was designed using statistical experimental design. The independent variables were the used edge activator, its molar ratio to phosphatidylcholine, and presence or absence of cholesterol. The responses were entrapment efficiency of transferosomes, their size, polydispersity index, zeta potential, and percent drug released after 8 h. The optimized formula was subjected to differential scanning calorimetry studies and its stability on storage at 4°C for 6 months was estimated. This formula was improved by incorporation of different permeation enhancers where ex vivo drug flux through mice skin was estimated and the best improved formula was formulated in a gel and lyophilized. The prepared gel was subjected to in vivo study using Plendil® tablets as a reference. According to the calculated desirability, the optimized transferosome formula was that containing sodium deoxycholate as edge activator at 5:1 M ratio to phosphatidylcholine and no cholesterol. The thermograms of this formula indicated the incorporation of felodipine inside the prepared vesicles. None of the tested parameters differed significantly on storage. The lyophilized gel of labrasol-containing formula was chosen for in vivo study. The relative bioavailability of felodipine from the designed gel was 1.7. In conclusion, topically applied lyophilized gel containing felodipine-loaded transferosomes is a promising transdermal delivery system to enhance its bioavailability.


dry gel factorial study felodipine transdermal delivery transferosomes 


Compliance with Ethical Standards

The study protocol meets the international requirements for the care and use of laboratory animals and it was approved by The University Protection of Experimental Animals Committee and by the Ethics Committee of Faculty of Pharmacy, Cairo University.


  1. 1.
    Yedinak KC, Lopez LM. Felodipine: a new dihydropyridine calcium channel antagonist. DICP. 1991;25:1193–206.CrossRefPubMedGoogle Scholar
  2. 2.
    Walton T, Symes LR. Felodipine and isradipine: new calcium-channel-blocking agents for the treatment of hypertension. Clin Pharm. 1993;12:261–75.PubMedGoogle Scholar
  3. 3.
    Little WC, Cheng CP, Elvelin L, Nordlander M. Vascular selective calcium entry blockers in the treatment of cardiovascular disorders: focus on felodipine. Cardiovasc Drugs Ther. 1995;9(5):657–63. Scholar
  4. 4.
    Yusuf M, Sharma V, Pathak K. Nanovesicles for transdermal delivery of felodipine: development, characterization, and pharmacokinetics. Int J Pharm Investig. 2014;4(3):119–30. Scholar
  5. 5.
    Saltiel E, Ellrodt AG, Monk JP, Langley MS. Felodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. Drugs. 1988;36(4):387–428.CrossRefPubMedGoogle Scholar
  6. 6.
    Abramoweiz M. Felodipine—another calcium channel blocker for hypertension. Med Lett Drugs Ther. 1991;33:115–6.Google Scholar
  7. 7.
    Reddy PD, Balanjineyulu R, Swarnalatha D, Badarinath AV, Gopinath C. Design, development and in vitro characterization of felodipine mucoadhesive buccal tablets. J Pharm Res. 2015;9(2):170–6.Google Scholar
  8. 8.
    Arafa MF, El-Gizawy SA, Osman MA, El Maghraby GM. Xylitol as a potential co-crystal co-former for enhancing dissolution rate of felodipine: preparation and evaluation of sublingual tablets. Pharm Dev Technol. 2016;3:1–10. Scholar
  9. 9.
    Mishra AD, Khunt DM, Ghayal AH, Patel CN, Shah DR. Formulation and optimization of ethosomes for transdermal delivery of felodipine. Res J Pharm Technol. 2012;5(12):1509–17.Google Scholar
  10. 10.
    Cevc G, Blume G. Lipid vesicles penetrate into intact skin owing to the transdermal osmotic gradients and hydration force. Biochim Biophys Acta (BBA) Biomembr. 1992;1104(1):226–32.CrossRefGoogle Scholar
  11. 11.
    Shamma RN, Elsayed I. Transfersomal lyophilized gel of buspirone HCl: formulation, evaluation and statistical optimization. J Liposome Res. 2013;23(3):244–54. Scholar
  12. 12.
    Cevc G, Gebauer D, Stieber J, Schätzlein A, Blume G. Ultraflexible vesicles, transfersomes, have an extremely low pore penetration resistance and transport therapeutic amounts of insulin across the intact mammalian skin. Biochim Biophys Acta (BBA) Biomembr. 1998;1368(2):201–15.CrossRefGoogle Scholar
  13. 13.
    Cevc G, Blume G. Hydrocortisone and dexamethasone in very deformable drug carriers have increased biological potency, prolonged effect, and reduced therapeutic dosage. Biochim Biophys Acta (BBA) Biomembr. 2004;1663(1):61–73. Scholar
  14. 14.
    Hiruta Y, Hattori Y, Kawano K, Obata Y, Maitani Y. Novel ultra-deformable vesicles entrapped with bleomycin and enhanced to penetrate rat skin. J Control Release. 2006;113(2):146–54. Scholar
  15. 15.
    Cevc G, Vierl U, Mazgareanu S. Functional characterisation of novel analgesic product based on self-regulating drug carriers. Int J Pharm. 2008;360(1):18–28. Scholar
  16. 16.
    Al-mahallawi AM, Khowessah OM, Shoukri RA. Nano-transfersomal ciprofloxacin loaded vesicles for non-invasive trans-tympanic ototopical delivery: in-vitro optimization, ex-vivo permeation studies, and in-vivo assessment. Int J Pharm. 2014;472(1–2):304–14. Scholar
  17. 17.
    Scognamiglio I, De Stefano D, Campani V, Mayol L, Carnuccio R, Fabbrocini G, et al. Nanocarriers for topical administration of resveratrol: a comparative study. Int J Pharm. 2013;440(2):179–87. Scholar
  18. 18.
    Gupta AK, Madan S, Majumdar DK, Maitra A. Ketorolac entrapped in polymeric micelles: preparation, characterisation and ocular anti-inflammatory studies. Int J Pharm. 2000;209(1–2):1–14.CrossRefPubMedGoogle Scholar
  19. 19.
    Moore J, Flanner H. Mathematical comparison of curves with an emphasis on in-vitro dissolution profiles. Pharm Technol. 1996;20(6):64–74.Google Scholar
  20. 20.
    Vinod KR, Anbazhagan S, Suneel Kumar M, Sandhya S, Banji D, Rani PA. Developing ultra deformable vesicular transportation of a bioactive alkaloid in pursuit of vitiligo therapy. Asian Pac J Trop Dis. 2012;2(4):301–6. Scholar
  21. 21.
    Setti A, Takhelmayum PD, Reddy YPK, Sarikonda S, Rao JV, Pawar SC. Method development, validation and stability studies of felodipine by RP-HPLC and molecular interaction studies of felodipine and voltage gated L-type calcium channel. Int J Pharm Sci Rev Res. 2013;24(1):15–20.Google Scholar
  22. 22.
    El Zaafarany GM, Awad GAS, Holayel SM, Mortada ND. Role of edge activators and surface charge in developing ultradeformable vesicles with enhanced skin delivery. Int J Pharm. 2010;397(1–2):164–72. Scholar
  23. 23.
    Maestrelli F, González-Rodríguez ML, Rabasco AM, Mura P. Preparation and characterisation of liposomes encapsulating ketoprofen-cyclodextrin complexes for transdermal drug delivery. Int J Pharm. 2005;298(1):55–67. Scholar
  24. 24.
    Abdelbary G. Ocular ciprofloxacin hydrochloride mucoadhesive chitosan-coated liposomes. Pharm Dev Technol. 2011;16(1):44–56. Scholar
  25. 25.
    Annadurai G, Ling LY, Lee JF. Statistical optimization of medium components and growth conditions by response surface methodology to enhance phenol degradation by Pseudomonas putida. J Hazard Mater. 2008;151(1):171–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Chauhan B, Gupta R. Application of statistical experimental design for optimization of alkaline protease production from Bacillus sp. RGR-14. Process Biochem. 2004;39(12):2115–22.CrossRefGoogle Scholar
  27. 27.
    Kaushik R, Saran S, Isar J, Saxena R. Statistical optimization of medium components and growth conditions by response surface methodology to enhance lipase production by Aspergillus carneus. J Mol Catal B Enzym. 2006;40(3–4):121–6.CrossRefGoogle Scholar
  28. 28.
    Lee EH, Kim A, Oh YK, Kim CK. Effect of edge activators on the formation and transfection efficiency of ultradeformable liposomes. Biomaterials. 2005;26(2):205–10.CrossRefPubMedGoogle Scholar
  29. 29.
    Basha M, Abd El-Alim SH, Shamma RN, Awad GEA. Design and optimization of surfactant-based nanovesicles for ocular delivery of Clotrimazole. J Liposome Res. 2013;23(3):203–10. Scholar
  30. 30.
    Salama HA, Mahmoud AA, Kamel AO, Abdel Hady M, Awad GA. Brain delivery of olanzapine by intranasal administration of transfersomal vesicles. J Liposome Res. 2012;22(4):336–45. Scholar
  31. 31.
    Stan CD, Tătărîngă G, Gafiţanu C, Drăgan M, Braha S, Popescu MC, et al. Preparation and characterization of niosomes containing metronidazole. Farmacia. 2013;61(6):1178–85.Google Scholar
  32. 32.
    Dora CP, Singh SK, Kumar S, Datusalia AK, Deep A. Development and characterization of nanoparticles of glibenclamide by solvent displacement method. Acta Pol Pharm. 2010;67(3):283–90.PubMedGoogle Scholar
  33. 33.
    Zeisig R, Shimada K, Hirota S, Arndt D. Effect of sterical stabilization on macrophage uptake in vitro and on thickness of the fixed aqueous layer of liposomes made from alkylphosphocholines. Biochim Biophys Acta. 1996;1285(2):237–45.CrossRefPubMedGoogle Scholar
  34. 34.
    Aburahma MH, Abdelbary GA. Novel diphenyl dimethyl bicarboxylate provesicular powders with enhanced hepatocurative activity: preparation, optimization, in vitro/in vivo evaluation. Int J Pharm. 2012;422(1–2):139–50. Scholar
  35. 35.
    Ruckmani K, Sankar V. Formulation and optimization of zidovudine niosomes. AAPS PharmSciTech. 2010;11(3):1119–27. Scholar
  36. 36.
    Singh R, Lillard JW. Nanoparticle-based targeted drug delivery. Exp Mol Pathol. 2009;86(3):215–23.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Singh G, Pai RS, Devi VK. Optimization of pellets containing solid dispersion prepared by extrusion/spheronization using central composite design and desirability function. J Young Pharm. 2012;4(3):146–56. Scholar
  38. 38.
    Basalious EB, Shawky N, Badr-Eldin SM. SNEDDS containing bioenhancers for improvement of dissolution and oral absorption of lacidipine. I: development and optimization. Int J Pharm. 2010;391(1–2):203–11. Scholar
  39. 39.
    Mura S, Manconi M, Sinico C, Valenti D, Fadda AM. Penetration enhancer-containing vesicles (PEVs) as carriers for cutaneous delivery of minoxidil. Int J Pharm. 2009;380(1):72–9. Scholar
  40. 40.
    El Maghraby GMM, Williams AC, Barry BW. Interactions of surfactants (edge activators) and skin penetration enhancers with liposomes. Int J Pharm. 2004;276(1):143–61. Scholar
  41. 41.
    Mura P, Faucci MT, Bramanti G, Corti P. Evaluation of transcutol as a clonazepam transdermal permeation enhancer from hydrophilic gel formulations. Eur J Pharm Sci. 2000;9(4):365–72. Scholar
  42. 42.
    Rhee Y, Choi JG, Park ES, Chi SC. Transdermal delivery of ketoprofen using microemulsions. Int J Pharm. 2001;228(1):161–70.CrossRefPubMedGoogle Scholar
  43. 43.
    Wang Q, Hu C, Zhang H, Zhang Y, Liu T, Qian A, et al. Evaluation of a new solid non-aqueous self-double-emulsifying drug-delivery system for topical application of quercetin. J Microencapsul. 2016;33(8):785–94. Scholar
  44. 44.
    Kadir R, Stempler D, Liron Z, Cohen S. Delivery of theophylline into excised human skin from alkanoic acid solutions: a “push-pull” mechanism. J Pharm Sci. 1987;76(10):774–9. Scholar
  45. 45.
    Forslind B, Engström S, Engblom J, Norlén L. A novel approach to the understanding of human skin barrier function. J Dermatol Sci. 1997;14(2):115–25. Scholar
  46. 46.
    Li F, Yang R, Weng Y, Tang X. Preparation and evaluation of lyophilized liposome-encapsulated bufadienolides. Drug Dev Ind Pharm. 2009;35(9):1048–58. Scholar
  47. 47.
    Chen C, Han D, Cai C, Tang X. An overview of liposome lyophilization and its future potential. J Control Release. 2010;142(3):299–311. Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Mohammed Ali Kassem
    • 1
  • Mona Hassan Aboul-Einien
    • 1
    Email author
  • Mai Magdy El Taweel
    • 1
  1. 1.Department of Pharmaceutics and Industrial Pharmacy, Faculty of PharmacyCairo UniversityCairoEgypt

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