Advertisement

AAPS PharmSciTech

, Volume 12, Issue 1, pp 304–311 | Cite as

The Effects of Excipients and Particle Engineering on the Biophysical Stability and Aerosol Performance of Parathyroid Hormone (1-34) Prepared as a Dry Powder for Inhalation

  • Sunday A. Shoyele
  • Neeraj Sivadas
  • Sally-Ann Cryan
Research Article

Abstract

Pulmonary delivery of therapeutic peptides and proteins has many advantages including high relative bioavailability, rapid systemic absorption and onset of action and a non-invasive mode of administration which improves patient compliance. In this study, we investigated the effect of spray-drying (SD) and spray freeze-drying processes on the stability and aerosol performance of parathyroid hormone (PTH) (1-34) microparticles. In this study, the stabilisation effect of trehalose (a non-reducing sugar) and Brij 97 (a non-ionic surfactant) on spray-dried PTH particles was assessed using analytical techniques including circular dichroism (CD), fluorescence spectroscopy, modulated differential scanning calorimetry and an in vitro bioactivity assay. Physical characterisation also included electron microscopy, tap density measurement and laser light diffraction. The aerosol aerodynamic performance of the formulations was assessed using the Andersen cascade impactor. Based on these studies, a formulation for spray freeze-drying was selected and the effects of the two particle engineering techniques on the biophysical stability and aerosol performance of the resulting powders was determined. CD, fluorescence spectroscopy and bioactivity data suggest that trehalose when used alone as a stabilising excipient produces a superior stabilising effect than when used in combination with a non-ionic surfactant. This highlights the utility of CD and fluorescence spectroscopy studies for the prediction of protein bioactivity post-processing. Therefore, a method and formulation suitable for the preparation of PTH as a dry powder was developed based on spray-drying PTH with trehalose as a stabiliser with the bioactivity of SD PTH containing trehalose being equivalent to that of unprocessed PTH.

Key words

parathyroid hormone pulmonary delivery spray drying spray freeze-drying stability 

Notes

Acknowledgements

This research was supported by Science Foundation Ireland under grants SFI RFPENG0020 & SFI07/SRC/B1154.

References

  1. 1.
    Patton J. Pulmonary delivery of drugs for bone disorders. Adv Drug Deliv Rev. 2000;42(3):239–48.PubMedCrossRefGoogle Scholar
  2. 2.
    Barrett-Connor E. The economic and human costs of osteoporotic fracture. Am J Med. 1995;98(2A):3S–8S.PubMedCrossRefGoogle Scholar
  3. 3.
    Quattrocchi E, Kourlas H. Teriparatide: a review. Clin Ther. 2004;26(6):841–54.PubMedCrossRefGoogle Scholar
  4. 4.
    Tashjian JRA, Chabner B. Commentary on clinical safety of recombinant human parathyroid hormone 1-34 in the treatment of osteoporosis in men and postmenopausal women. J Bone Miner Res. 2002;17:1151–61.PubMedCrossRefGoogle Scholar
  5. 5.
    Shoyele S, Slowey A. Prospects of formulating proteins/peptides as aerosols for pulmonary drug delivery. Int J Pharm. 2006;314(1):1–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Akers M, Vasudevan V, Stickelmeyer M. Formulation development of protein dosage forms. In: Nail SL, Akers MJ, editors. Development and manufacture of protein pharmaceuticals. New York: Kluwer; 2002. p. 47.Google Scholar
  7. 7.
    Manning M, Patel K, Borchardt R. Stability of protein pharmaceuticals. Pharm Res. 1989;6(11):903–18.PubMedCrossRefGoogle Scholar
  8. 8.
    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.PubMedCrossRefGoogle Scholar
  9. 9.
    Pfutzner A, Flacke F, Pohl R, Linkie D, Engelbach M, Woods R, et al. Pilot study with Technosphere/PTH (1-34)-a new approach for effective pulmonary delivery of parathyroid hormone (1-34). Horm Metab Res. 2003;35(5):319–23.PubMedCrossRefGoogle Scholar
  10. 10.
    Codrons V, Vanderbist F, Verbeeck R, Arras M, Lison D, Préat V, et al. Systemic delivery of parathyroid hormone (1-34) using inhalation dry powders in rats. J Pharm Sci. 2003;92(5):938–50.PubMedCrossRefGoogle Scholar
  11. 11.
    Shoyele S, Cawthorne S. Particle engineering techniques for inhaled biopharmaceuticals. Adv Drug Deliv Rev. 2006;58(9–10):1009–29.PubMedCrossRefGoogle Scholar
  12. 12.
    Costantino H, Firouzabadian L, Wu C, Carrasquillo K, Griebenow K, Zale S, et al. Protein spray freeze drying. 2. Effect of formulation variables on particle size and stability. J Pharm Sci. 2002;91(2):388–95.PubMedCrossRefGoogle Scholar
  13. 13.
    Engstrom J, Simpson D, Lai E, Williams III R, Johnston K. Morphology of protein particles produced by spray freezing of concentrated solutions. Eur J Pharm Biopharm. 2007;65(2):149–62.PubMedCrossRefGoogle Scholar
  14. 14.
    Hillgren A, Aldén M. A comparison between the protection of LDH during freeze-thawing by PEG 6000 and Brij 35 at low concentrations. Int J Pharm. 2002;244(1–2):137–49.PubMedCrossRefGoogle Scholar
  15. 15.
    Jovanovic N, Bouchard A, Hofland G, Witkamp G, Crommelin D, Jiskoot W. Distinct effects of sucrose and trehalose on protein stability during supercritical fluid drying and freeze-drying. Eur J Pharm Sci. 2006;27(4):336–45.PubMedCrossRefGoogle Scholar
  16. 16.
    Ameri M, Maa Y. Spray drying of biopharmaceuticals: stability and process considerations. Drying Technol. 2006;24(6):763–8.CrossRefGoogle Scholar
  17. 17.
    Jeon J, Puleo D. Formulations for intermittent release of parathyroid hormone (1-34) and local enhancement of osteoblast activities. Pharm Dev Technol. 2008;13(6):505–12.PubMedCrossRefGoogle Scholar
  18. 18.
    Johnson K. Preparation of peptide and protein powders for inhalation. Adv Drug Deliv Rev. 1997;26(1):3–15.PubMedCrossRefGoogle Scholar
  19. 19.
    Maa Y, Nguyen P, Sweeney T, Shire S, Hsu C. Protein inhalation powders: spray drying vs spray freeze drying. Pharm Res. 1999;16(2):249–54.PubMedCrossRefGoogle Scholar
  20. 20.
    Yu Z, Johnston K, Williams III R. Spray freezing into liquid versus spray-freeze drying: Influence of atomization on protein aggregation and biological activity. Eur J Pharm Sci. 2006;27(1):9–18.PubMedCrossRefGoogle Scholar
  21. 21.
    Edwards D, Hanes J, Caponetti G, Hrkach J, Ben-Jebria A, Eskew M, et al. Large porous particles for pulmonary drug delivery. Science. 1997;276(5320):1868.PubMedCrossRefGoogle Scholar
  22. 22.
    Manavalan P, Johnson W. Protein secondary structure from circular dichroism spectra. J Biosci. 1985;8(1):141–9.CrossRefGoogle Scholar
  23. 23.
    Kanaori K, Takai M, Nosaka A. Comparative study of chicken and human parathyroid hormone-(1-34)-peptides in solution with SDS. Eur J Biochem. 2004;249(3):878–85.CrossRefGoogle Scholar
  24. 24.
    Demeule B, Lawrence M, Drake A, Gurny R, Arvinte T. Characterization of protein aggregation: the case of a therapeutic immunoglobulin. Biochimica et Biophysica Acta (BBA)-Proteins & Proteomics. 2007;1774(1):146–53.CrossRefGoogle Scholar
  25. 25.
    Capelle M, Gurny R, Arvinte T. High throughput screening of protein formulation stability: practical considerations. Eur J Pharm Biopharm. 2007;65(2):131–48.PubMedCrossRefGoogle Scholar
  26. 26.
    Costantino H, Firouzabadian L, Hogeland K, Wu C, Beganski C, Carrasquillo K, et al. Protein spray-freeze drying. Effect of atomization conditions on particle size and stability. Pharm res. 2000;17(11):1374–82.PubMedCrossRefGoogle Scholar
  27. 27.
    Lechuga-Ballesteros D. S, L. M., Vehring, R., Kuo M-C (eds). Use of a novel excipient to enable the preparation of stable and dispersible dry powder aerosol formulation by spray drying. In: 30th Annual Meeting and Symposium of the Controlled Release Society, Glasgow, Scotland; 2003Google Scholar
  28. 28.
    Chan H. Dry powder aerosol drug delivery—opportunities for colloid and surface scientists. Colloids Surf A. 2006;284:50–5.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2011

Authors and Affiliations

  • Sunday A. Shoyele
    • 1
  • Neeraj Sivadas
    • 2
  • Sally-Ann Cryan
    • 3
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyThomas Jefferson UniversityPhiladelphiaUSA
  2. 2.Freund Pharmatec Ltd, Unit 1IDA Business & Technology Park, TullamoreCo.OffalyIreland
  3. 3.School of PharmacyRoyal College of Surgeons in IrelandDublin 2Ireland

Personalised recommendations