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Demonstrated Solid-State Stability of Parathyroid Hormone PTH(1–34) Coated on a Novel Transdermal Microprojection Delivery System

Pharmaceutical Research volume 26, pages 2454–2463 (2009)Cite this article

Abstract

Purpose

This study assessed conditions necessary for at least a 2-year, ambient temperature storage stability of the peptide parathyroid hormone 1–34, or PTH(1–34), coated on a novel transdermal microprojection delivery system, or ZP-PTH.

Methods

Liquid coating characterization of high concentration PTH(1–34) formulations (>20% w/w) was assessed by viscosity and contact angle measurements along with RP-HPLC and SEC-HPLC. Solid-state coating morphology of PTH(1–34) on microprojection arrays was determined by SEM, and stability on storage was assessed after dissolution and testing with stability indicating assays. Internal vapor analysis was performed to detect and quantify volatile organics released by patch components into the headspace inside the final package.

Results

Aggregation and oxidation were the primary degradation mechanisms for solid-state PTH(1–34) in this transdermal delivery system. Although these two degradation pathways can be retarded by appropriate stabilizers and use of foil pouch packaging (nitrogen purged and desiccant), the solid-state drug formulation’s compatibility with patch components, particularly the plastic retainer ring, surprisingly dictated PTH(1–34) stability. Internal vapor analysis demonstrated that PTH(1–34) was particularly vulnerable to vapors such as moisture, oxygen, and outgassed formaldehyde, and each of these volatiles played a unique and significant role in PTH(1–34)’s degradation mechanism.

Conclusions

Identifying degradation mechanisms of volatile compounds on solid-state PTH(1–34) peptide stability allowed for the rationale for selection of final formulation, system components and packaging conditions. A >2-yr, ambient temperature storage stability was demonstrated for solid-state drug coated on a novel transdermal microprojection delivery system. This system was successfully tested in a Phase 2 clinical trial for the treatment of post-menopausal women with osteoporosis.

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REFERENCES

  1. McClung MR, San Martin J, Miller PD, Civitelli R, Bandeira F, Omizo M, et al. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med. 2005;165:1762–8.

    Article  CAS  PubMed  Google Scholar 

  2. Keaveny TM, Hoffman PE, Kepperdahl DL, Donely DW, Krohn K, Glass EV, et al. Comparison of the effects of teriparatide and alendronate on parameters of total hip strength assessed by finite element analysis (Abstract). J Bone Miner Res. 2007;22(Suppl 1):S75.

    Google Scholar 

  3. Keaveny TM, Hoffmann PF, Singh M, Palermo L, Bilezikian JP, Greenspan SL, et al. Femoral bone strength and its relation to cortical and trabecular changes after treatment with PTH, alendronate, and their combination as assessed by finite element analysis of quantitative CT scans. J Bone Miner Res. 2008;12:1974–82.

    Article  Google Scholar 

  4. Saag KG, Shane E, Boonen S, Marin F, Donely DW, Taylor KA, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med. 2007;357:2028–39.

    Article  CAS  PubMed  Google Scholar 

  5. Fraenkel L, Gulanski B, Wittink D. Patient treatment preferences for osteoporosis. Arthritis Rheum. 2006;5:729–35.

    Article  Google Scholar 

  6. Fraenkel L, Gulanski B, Wittink D. Patient willingness to take teriparatide. Patient Educ Couns. 2007;65(2):237–44.

    Article  PubMed  Google Scholar 

  7. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM. The effects of parathyroid hormone. Alendronate, or both in men with osteoporosis. N Engl J Med. 2003;349(13):1216–27.

    Article  CAS  PubMed  Google Scholar 

  8. Gopalakrishnan V, Hwang S, Loughrey H. Administration of ThPTH to humans using Macroflux® transdermal technology results in the rapid delivery of biologically active PTH. (Abstract). J Bone Miner Res. 2004;19(Suppl 1):S460.

    Google Scholar 

  9. Lane LE, Cosman F, Bolognese M, Zanchetta J, Sees K, Gaumer K, et al. Transdermal delivery of (hPTH 1–34) (ZP-PTH) is effective in increasing bone mineral density of the lumbar spine & hip in postmenopausal women with osteoporosis. (Abstract) Arthritis Rheum. 2008;58(9) late-breaking supplement p.1

    Google Scholar 

  10. Cormier M, Johnson B, Ameri M, Nyam K, Libiran L, Zhang DD, et al. Transdermal delivery of desmopressin using a coated microneedle array patch system. J Controlled Rel. 2004;97:503–11.

    CAS  Google Scholar 

  11. Widera G, Johnson J, Kim L, Libiran L, Nyam K, Daddona PE, et al. Effect of delivery parameters on immunization to ovalbumin following intracutaneous administration by a coated microneedle array patch system. Vaccine 2006;24:1653–64.

    Article  CAS  PubMed  Google Scholar 

  12. Matriano J, Cormier M, Johnson J, Young WA, Buttery M, Nyam K, et al. Macroflux microprojection array patch technology: a new and efficient approach for intracutaneous immunization. Pharm Res. 2002;19:63–70.

    Article  CAS  PubMed  Google Scholar 

  13. Lin WQ, Cormier M, Samiee A, Griffin A, Johnson B, Teng CL, et al. Transdermal delivery of oligonucleotides with microprojection patch (Macroflux®) technology. Pharm Res. 2001;18:1789–93.

    Article  CAS  PubMed  Google Scholar 

  14. Proos ER, Prescott JH, Staples MA. Long-term stability and in vitro release of hPTH(1–34) from a multi-reservoir array. Pharm Res. 2008;25(6):1387–95.

    Article  CAS  PubMed  Google Scholar 

  15. Cormier M, Neukermans AP, Block B, Theeuwes FT, Amkraut A. A device for enhancing transdermal agent delivery or sampling. EP0914178B1. 2003.

  16. Trautman JC, Wright CT, Cormier M. Method and apparatus for coating skin piercing microneedles. US Patent 6,855,372 (2002).

  17. Trautman JC, Wright CT, Cormier M. Method and apparatus for coating skin piercing microneedles. US Patent 7,435,299 (2002).

  18. Nabuchi Y, Fujiwara E, Kuboniwa H, Asoh Y, Ushio H. The stability and degradation pathway of recombinant human parathyroid hormone: deamidation of asparaginyl residue and peptide bond cleavage at aspartyl and asparaginyl residues. Pharm Res. 1997;14:1685–90.

    Article  CAS  PubMed  Google Scholar 

  19. Manning MC, Patel K, Borchardt RT. Stability of protein pharmaceuticals. Pharm Res. 1989;6:903–17.

    Article  CAS  PubMed  Google Scholar 

  20. Frelinger AL III, Zull JE. Oxidized forms of parathyroid hormone with biological activity. J Bio Chem. 1984;259:5507–13.

    CAS  Google Scholar 

  21. Frelinger AL III, Zull JE. The role of the methionine residues in the structure and function of parathyroid hormone. Arch Biochem Biophy. 1986;244:641–9.

    Article  CAS  Google Scholar 

  22. Zull JE, Smith SK, Wiltshire R. Effect of methionine oxidation and deletion of amino-terminal residues on the conformation of parathyroid hormone—circular dichroism studies. J Bio Chem. 1990;265:5671–6.

    CAS  Google Scholar 

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Authors and Affiliations

  1. Zosano Pharma, Inc., 34790 Ardentech Court, Fremont, California, 94555, USA

    Mahmoud Ameri, Peter E. Daddona & Yuh-Fun Maa

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  1. Mahmoud Ameri
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  2. Peter E. Daddona
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  3. Yuh-Fun Maa
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Correspondence to Yuh-Fun Maa.

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Ameri, M., Daddona, P.E. & Maa, YF. Demonstrated Solid-State Stability of Parathyroid Hormone PTH(1–34) Coated on a Novel Transdermal Microprojection Delivery System. Pharm Res 26, 2454–2463 (2009). https://doi.org/10.1007/s11095-009-9960-9

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  • DOI: https://doi.org/10.1007/s11095-009-9960-9

KEY WORDS

  • aggregation
  • drug-coating
  • formulation compatibility
  • internal vapor analysis
  • oxidation
  • parathyroid hormone
  • PTH(1–34)
  • transdermal microprojection delivery system