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Nebivolol-Loaded Microsponge Gel for Healing of Diabetic Wound

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Abstract

An attempt was made to formulate nebivolol-loaded microsponge gel to access drug at wound area, incorporated into gel that possess optimum moist wound management environment during later stages of wound closure. Nebivolol, antihypertensive drug, exhibits vasodilating effects via nitric oxide pathway, slows diabetic neuropathy, and restores endothelial function in diabetic wounds. Microsponges were prepared by optimizing independent variables; drug to polymer ratio and internal phase volume and their effects on production yield, entrapment efficiency, and particle size. Formulations of microsponges were evaluated for drug content. Differential scanning calorimetry indicated reduction in crystallinity of NB during the formation of microsponges. In vitro study (drug to polymer 1:4 and 10 ml internal phase volume acetone) showed 80% drug released within 8 h. Spherical and porous microsponges confirmed by scanning electron microscopy were incorporated in the carbopol 934 (2%) gel base. Gel was characterized for pH, viscosity, and drug content. Less spreadability determined by texture analyzer demonstrated viscous nature of gel. In vitro diffusion study revealed entrapped drug in porous microsponges with slow release to heal wound. In vivo study performed using streptozotocin-induced diabetic rats and excision wound model showed wound healing and closure activity within day 10. Histology revealed inflammatory cell infiltrations and neovascularization in granulation tissues, ultimately healing wound. Microsponge gel prolonged drug release due to entrapped form in porous structure of microsponges with significant and fast wound healing and closure in diabetic rats. Microsponges with loaded drug fulfilled accessibility at wound area, while gel provided optimum moist wound management environment during later stages of wound closure.

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References

  1. Srivastava R, Kumar D, Pathak K. Colonic luminal surface retention of meloxicam microsponges delivered by erosion based colon-targeted matrix tablet. Int J Pharm. 2012;427:153–62.

    Article  CAS  PubMed  Google Scholar 

  2. Orlu M, Cevher E, Araman A. Design and evaluation of colon specific drug delivery system containing flubiprofen microsponges. Int J Pharm. 2006;318:103–17.

    Article  CAS  PubMed  Google Scholar 

  3. Amrutiya N, Amrita B, Madhu M. Development of microsponges for topical delivery of mupirocin. AAPS PharmSciTech. 2009;10:402–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Comoglu T, Gonul N, Baykara T. Preparation and in vitro evaluation of modified release ketoprofen microsponges. Il Farmaco. 2003;58:101–6.

    Article  CAS  PubMed  Google Scholar 

  5. Diegelmann RF, Evans MC. Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci. 2004;9:283–9.

    Article  CAS  PubMed  Google Scholar 

  6. Papanas N, Maltezos E. Becaplermin gel in treatment of diabetic neuropathic foot ulcers. Clin Interv Aging. 2008;3(2):233–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA. Diabetic neuropathic foot ulcers and amputation. Wound Repair Regen. 2005;13(3):230–6.

    Article  PubMed  Google Scholar 

  8. Tsourdi E, Barthel A, Rietzsch H, Reichel A, Bornstein SR. Current aspects in the pathophysiology and treatment of chronic wounds in diabetes mellitus. Biomed Res Int. 2013;385641:1–6. doi:10.1155/2013/385641.

  9. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. J Am Med Assoc. 2005;293(2):217–28.

    Article  CAS  Google Scholar 

  10. Fongemie J, Felix-Getzik E. A review of nebivolol pharmacology and clinical evidence. Drugs. 2015;75:1349–71. doi:10.1007/s40265-015-0435-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kalinowski L, Dobruck LW, Szczepanska-Konkel M. Third generation beta blockers stimulate nitric oxiderelease from endothelial cells through ATP efflux: a novel mechanism for antihypertensive action. Circulation. 2003;107:2747–52.

    Article  CAS  PubMed  Google Scholar 

  12. Mason RP, Kubant R, Jacob RF. Effect of nebivolol on endothelial nitric oxide and peroxynitrite release in hypertensive animals: role of antioxidant activity. J Cardiovasc Pharmacol. 2006;48:862–9.

    Article  CAS  PubMed  Google Scholar 

  13. Maffei A, Lembo G. Nitric oxide mechanisms of nebivolol. Ther Adv Cardiovasc Dis. 2009;3:317–27. doi:10.1177/1753944709104496.

    Article  PubMed  Google Scholar 

  14. Broeders MA, Doevendans PA, Bekkers BC. Nebivolol: a third generation beta-blocker that augments vascular nitric oxide release: endothelial beta (2)-adrenergic receptor-mediated nitric oxide production. Circulation. 2000;102:677–84.

    Article  CAS  PubMed  Google Scholar 

  15. Gulcan E, Ilhan D, Toker S. Nebivolol might be beneficial in the prevention and treatment of diabetic neuropathy. Am J Ther. 2008;23:181–6.

    Google Scholar 

  16. Gulcan E, Kucuk A, Kasim C, Murat T, Habib E, Lokman K, et al. Topical effect of nebivolol on wound in diabetic rats. Eur J Pharm Sci. 2012;47:451–5.

    Article  CAS  PubMed  Google Scholar 

  17. Taddei S, Virdis A, Ghiadoni L. Effects of antihypertensive drugs on endothelial dysfunction: clinical implications. Drugs. 2012;62:265–84.

  18. Hotkar MS, Avachat AM, Bhosale SS, Oswal YM. Preliminary investigation of topical nitroglycerin formulations containing natural wound healing agent in diabetes-induced foot ulcer. Int Wound J. 2015;12(2):210–217. doi:10.1111/iwj.12084.

  19. Lee AR. Enhancing dermal matrix regeneration and biomechanical properties of 2nd degree-burn wounds by EGF-impregnated collagen sponge dressing. Arch Pharm Res. 2005;28(11):1311–6.

    Article  CAS  PubMed  Google Scholar 

  20. Christianne MRZ, Randa LA, Iman IS. In vitro and in vivo evaluation of hydroxyzine hydrochloride microsponges for topical delivery. AAPS PharmSciTech. 2011;12:989–1001.

    Article  Google Scholar 

  21. Goto S, Kawata M, Nakamura M, Maekawal K, Aoyama T, Eudragit E. L and S (acrylic resins) microcapsules as pH sensitive release preparations of ketoprofen. J Microencapsul. 1986;3:305–16.

    Article  CAS  PubMed  Google Scholar 

  22. Kawata M, Nakamura M, Goto S, Aoyama T. Preparation and dissolution pattern of Eudragit RS microcapsules containing ketoprofen. Chem Pharm Bull. 1986;34:2618–23.

    Article  CAS  PubMed  Google Scholar 

  23. Bhardwaj SB, Shukla AJ, Collins CC. Effect of varying drug loading on particle size distribution and drug release kinetics of verapamil hydrochloride microspheres prepared with cellulose esters. J Microencapsul. 1995;12:71–81.

    Article  CAS  PubMed  Google Scholar 

  24. Sha-sha L, Guo-feng L, Liu L, Xiao J, Zhang B, Zhi GL, et al. Evaluation of paenol skin target delivery from its microsponge formulation: in vitro skin permeation and in vivo microdialysis. PLoS One. 2013;8:e79881.

    Article  Google Scholar 

  25. Sareen R, Kavita N, Jain N, Dhar KL. Curcumin loaded microsponges for colon targeting in inflammatory bowel disease: fabrication, optimization, and in vitro and pharmacodynamic evaluation. Biomed Res Int. 2014;340701:1–7. doi:10.1155/2014/340701.

  26. Bueno FG, Moreira EA, Morais GR, Pacheco IA, Baesso ML, Leite-Mello EV, et al. Enhanced cutaneous wound healing in vivo by standardized crude extract of Poincianella pluviosa. PLoS One. 2016;11(3):e0149223. doi:10.1371/journal.pone.0149223.

  27. Jelvehgari M, Montazam H. Evaluation of mechanical and rheological properties of metronidazole gel as local delivery system. Arch Pharm Res. 2011;34:931–40. doi:10.1007/s12272-011-0610-5.

    Article  CAS  PubMed  Google Scholar 

  28. Pandit AP, Pol VV, Kulkarni VS. Xyloglucan based in situ gel of lidocaine HCl for the treatment of periodontosis. J Pharm. 2016. doi:10.1155/2016/3054321.

    Google Scholar 

  29. Hwang M, Kim J, Lee J, Kim Y, Kim J, Chang S, et al. Gentamicin-loaded wound dressing with polyvinyl alcohol/dextran hydrogel: gel characterization and in vivo healing evaluation. AAPS PharmSciTech. 2010;11(3):1092–1103. doi:10.1208/s12249-010-9474-0.

  30. Arunachalam KD, Subhashini S. Preliminary phytochemical investigation and wound healing activity of Myristica andamanica leaves in Swiss albino mice. J Med Plants Res. 2011;5:1095–106.

    Google Scholar 

  31. Landsman A, Agnew P, Parish L, Joseph R, Galiano RD. Diabetic foot ulcers treated with becaplermin and theragauze, a moisture-controlling smart dressing. J Am Podiatr Med Assoc. 2010;100:155–60.

    Article  PubMed  Google Scholar 

  32. Takzare N, Hosseini M, Hasanzadeh G, Mortazavi H, Takzare A, Habibi P. Influence of aloe vera gel on dermal wound healing process in rat. Toxicol Mech Methods. 2009;19:73–7.

    Article  CAS  PubMed  Google Scholar 

  33. Evans P. The healing process at cellular level: a review. Physiotherapy. 1980;66:256–9.

    CAS  PubMed  Google Scholar 

  34. Gulcan E. Could nebivolol be an alternative drug for the treatment of diabetic foot ulcers? J Am Podiatr Med Assoc. 2009;99:459.

    Article  PubMed  Google Scholar 

  35. Napavichayanun S, Yamdech R, Aramwit P. The safety and efficacy of bacterial nanocellulose wound dressing incorporating sericin and polyhexamethylene biguanide: in vitro, in vivo and clinical studies. Arch Dermatol Res. 2016;308:123–32. doi:10.1007/s00403-016-1621-3.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Authors thank Dolphin Pharma, Surat, India for providing gift sample of nebivolol and Evonik India Pvt. Ltd. Mumbai, India for gifting Eudragit RS 100.

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Authors and Affiliations

  1. Department of Pharmaceutics, JSPM Rajarshi Shahu College of Pharmacy and Research, Tathawade, Pune, 411 033, Maharashtra, India

    Ashlesha P. Pandit, Saurabh A. Patel, Vandana P. Bhanushali & Vinit S. Kulkarni

  2. Department of Pharmacology, JSPM Rajarshi Shahu College of Pharmacy and Research, Tathawade, Pune, 411 033, Maharashtra, India

    Vrushali D. Kakad

Authors
  1. Ashlesha P. Pandit
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  2. Saurabh A. Patel
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  3. Vandana P. Bhanushali
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  4. Vinit S. Kulkarni
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  5. Vrushali D. Kakad
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Correspondence to Ashlesha P. Pandit.

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Pandit, A.P., Patel, S.A., Bhanushali, V.P. et al. Nebivolol-Loaded Microsponge Gel for Healing of Diabetic Wound. AAPS PharmSciTech 18, 846–854 (2017). https://doi.org/10.1208/s12249-016-0574-3

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  • DOI: https://doi.org/10.1208/s12249-016-0574-3

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