Comparing the Inhalable and Parenteral Forms of Erythropoietin in Enhancement of Reticulocytes Count

Document Type : Original Article (s)

Authors

1 Professor, Department of Pharmaceutics, School of Pharmacy AND Novel Drug Delivery Systems Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

2 Professor, Department of Pharmacology, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran

3 Student of Pharmacy, School of Pharmacy AND Novel Drug Delivery Systems Research Center AND Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: In patients with renal failure, frequent use of erythropoietin is necessary for long times due to serious anemia. The aim of the present study was production of an inhalable dry powder of erythropoietin and comparison it with its parenteral form in erythrocytes count enhancement.Methods: The inhalable powder was prepared using spray-drying of the mixture of poly (methyl-vinyl ether-maleic anhydride), 2-hydroxy propyl-alpha-cyclodextrin and terhalose. The freeze-dried aqueous solution of erythropoietin was mixed with the spray-dried powder in 1:4 ratio. The particle size and drug content uniformity were determined in the final dried powder. There were 3 groups of rats each containing 6 animals. One group received 840 IU as subcutaneous (sc) injection of regular solution of the drug. The other was treated with blank pulmonary powder and the last group with 840 IU of the spray dried pulmonary powder. Six days before starting the treatment, all animals were fed with 1 % (w/w) ferrous sulfate as gavage. Blood sampling was carried out from eye retro-orbital vein at 0, 1, 4 and 7 days after treatment and the reticulocytes were counted by hemocytometer.Findings: There was not any significant difference between control, inhalable and parenteral groups at days of 0 and 1 after administration. At the day 4, there was significant difference between all three groups and reticulocytes count was higher in the inhalable group than the parenteral (P < 0.001) and the control groups (P < 0.010). At the 7th day, the results were similar to the 4th day but the reticulocytes count of ininhalable group was significantly higher than the control and parenteral groups (P < 0.001 for both).Conclusion: The spray-dried inhalable powder of erythropoietin was more effective than subcutaneous injection form in enhancing the reticulocytes count for a longer time and may be a good replacement for the parenteral form of this drug.

Keywords

References

  1. Maxwell PH, Pugh CW, Ratcliffe PJ. The pVHL-hIF-1 system. A key mediator of oxygen homeostasis. Adv Exp Med Biol 2001; 502: 365-76.
  2. United States Renal Data System. 2009 Annual Report United States Renal Data System [Online]. [cited 2011 Oct 8]; Available from: URL: http://www.usrds.org
  3. Katzung B, Masters S, Trevor A. Basic and clinical pharmacology 12th ed. New York, NY: McGraw-Hill; 2011. p. 591-2.
  4. Brunton L, Chabner B, Knollman B. Goodman and Gilman's the pharmacological basis of therapeutics 12th ed. New York, NY: McGraw Hill; 2010. p. 1068-73.
  5. Maitani Y, Moriya H, Shimoda N, Takayama K, Nagai T. Distribution characteristics of entrapped recombinant human erythropoietin in liposomes and its intestinal absorption in rats. Int J Pharm 1999; 185(1): 13-22.
  6. Venkatesan N, Uchino K, Amagase K, Ito Y, Shibata N, Takada K. Gastro-intestinal patch system for the delivery of erythropoietin. J Control Release 2006; 111(1-2): 19-26.
  7. Venkatesan N, Yoshimitsu J, Ito Y, Shibata N, Takada K. Liquid filled nanoparticles as a drug delivery tool for protein therapeutics. Biomaterials 2005; 26(34): 7154-63.
  8. Venkatesan N, Yoshimitsu J, Ohashi Y, Ito Y, Sugioka N, Shibata N, et al. Pharmacokinetic and pharmacodynamic studies following oral administration of erythropoietin mucoadhesive tablets to beagle dogs. Int J Pharm 2006; 310(1-2): 46-52.
  9. Shimoda N, Maitani Y, Machida Y, Nagai T. Effects of dose, pH and osmolarity on intranasal absorption of recombinant human erythropoietin in rats. Biol Pharm Bull 1995; 18(5): 734-9.
  10. Pitt CG, Platz RM. Pulmonary administration of erythropoietin [US Patent No. 5354934]. 1994.
  11. Bitonti AJ, Dumont JA, Low SC, Peters RT, Kropp KE, Palombella VJ, et al. Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway. Proc Natl Acad Sci U S A 2004; 101(26): 9763-8.
  12. Bitonti AJ, Dumont JA. Pulmonary administration of therapeutic proteins using an immunoglobulin transport pathway. Adv Drug Deliv Rev 2006; 58(9-10): 1106-18.
  13. Patton JS. Mechanisms of macromolecule absorption by the lung Advanced Drug Delivery Reviews, 1996; 19(1): 3-36.
  14. Azarmi S, Roa WH, Lobenberg R. Targeted delivery of nanoparticles for the treatment of lung diseases. Adv Drug Deliv Rev 2008; 60(8): 863-75.
  15. Brain JD. Inhalation, deposition, and fate of insulin and other therapeutic proteins. Diabetes Technol Ther 2007; 9(Suppl 1): S4-S15.
  16. Bi R, Shao W, Wang Q, Zhang N. Solid lipid nanoparticles as insulin inhalation carriers for enhanced pulmonary delivery. J Biomed Nanotechnol 2009; 5(1): 84-92.
  17. Grainger CI, Alcock R, Gard TG, Quirk AV, van AG, de Swart RL, et al. Administration of an insulin powder to the lungs of cynomolgus monkeys using a Penn Century insufflator. Int J Pharm 2004; 269(2): 523-7.
  18. Kobayashi S, Kondo S, Juni K. Pulmonary delivery of salmon calcitonin dry powders containing absorption enhancers in rats. Pharm Res 1996; 13(1): 80-3.
  19. Jalalipour M, Najafabadi AR, Gilani K, Esmaily H, Tajerzadeh H. Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats. J Pharm Sci 2008; 97(12): 5176-85.
  20. Giosue S, Casarini M, Ameglio F, Zangrilli P, Palla M, Altieri AM, et al. Aerosolized interferon-alpha treatment in patients with multi-drug-resistant pulmonary tuberculosis. Eur Cytokine Netw 2000; 11(1): 99-104.
  21. Geller D, Thipphawong J, Otulana B, Caplan D, Ericson D, Milgram L, et al. Bolus inhalation of rhDNase with the AERx system in subjects with cystic fibrosis. J Aerosol Med 2003; 16(2):
  22. -82.
  23. Rooijen N, Sanders A, The macrophage as target or obstacle in liposome-based targeting strategies. Int J Pharm 1998; 162(1-2): 45–50.
  24. Hussain A, Arnold JJ, Khan MA, Ahsan F. Absorption enhancers in pulmonary protein delivery. J Control Release 2004; 94(1): 15-24.
  25. Yoncheva K, Lizarraga E, Irache JM. Pegylated nanoparticles based on poly(methyl vinyl ether-co-maleic anhydride): preparation and evaluation of their bioadhesive properties. Eur J Pharm Sci 2005; 24(5): 411-9.
  26. Major A, Mathez-Loic F, Rohling R, Gautschi K, Brugnara C. The effect of intravenous iron on the reticulocyte response to recombinant human erythropoietin. Br J Haematol 1997; 98(2): 292-4.
  27. Zhang Y, Wang X, Lin X, Liu X, Tian B, Tang X. High azithromycin loading powders for inhalation and their in vivo evaluation in rats. Int J Pharm 2010; 395(1-2): 205-14.
  28. Onoue S, Yamamoto K, Kawabata Y, Hirose M, Mizumoto T, Yamada S. Novel dry powder inhaler formulation of glucagon with addition of citric acid for enhanced pulmonary delivery. Int J Pharm 2009; 382(1-2): 144-50.
  29. Shao Z, Li Y, Mitra AK. Cyclodextrins as mucosal absorption promoters of insulin III: pulmonary route of delivery. Eur J Pharm Biopharm1994; 40: 283-8.
  30. Garcia-Contreras L, Morcol T, Bell SJ, Hickey AJ. Evaluation of novel particles as pulmonary delivery systems for insulin in rats. AAPS PharmSci 2003; 5(2): E9.
  31. Wolff RK. Safety of inhaled proteins for therapeutic use. J Aerosol Med 1998; 11(4): 197-219.
  32. Cefalu WT, Balagtas CC, Landschultz WH, Gelfand RA. Sustained efficacy and pulmonary safety of inhaled insulin during 2 years of outpatient therapy. Diabetes Research and Clinical Practice 2000; 50(Suppl 1): 73.
  33. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol 2003; 56(6): 588-99.
  34. Johnson MA, Newman SP, Bloom R, Talaee N, Clarke SW. Delivery of albuterol and ipratropium bromide from two nebulizer systems in chronic stable asthma. Efficacy and pulmonary deposition. Chest 1989; 96(1): 6-10.
Journal of Isfahan Medical School
Volume 31, Issue 264 - Serial Number 264
November and December 2014
Pages 2031-2041

Files

History

  • Receive Date: 20 October 2013
  • Revise Date: 01 November 2024
  • Accept Date: 06 April 2022

Share

How to cite

Statistics