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Transdermal Delivery of Salmon Calcitonin Using a Dissolving Microneedle Array: Characterization, Stability, and In vivo Pharmacodynamics

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Abstract

Salmon calcitonin (sCT) is a polypeptide drug, possessing the ability to inhibit osteoclast-mediated bone resorption. Just like other bioactive macromolecules, sCT is generally administered to the patients by either injection for poor compliance or through nasal spray for low bioavailability, which limits its use as therapeutic drugs. In the present study, to overcome the limitations of the conventional routes, two new dissolving microneedle arrays (DMNAs) based on transdermal sCT delivery systems were developed, namely sCT-DMNA-1 (sCT/Dex/K90E) and sCT-DMNA-2 (sCT/Dex-Tre/K90E) with the same dimension, meeting the requirements of suitable mechanical properties. An accurate and reliable method was established to determine the needle drug loading proportion in sCT-DMNAs. The stability study exhibited that the addition of trehalose could improve the stability of sCT in DMNA under high temperature and humidity. Further, in vivo pharmacodynamic study revealed that DMNA patch could significantly enhanced relative bioavailability to approximately 70%, and the addition of trehalose was found to be beneficial for sCT transdermal delivery. Therefore, sCT-DMNA is expected to replace traditional dosage form, providing a secure, efficient, and low-pain therapeutic strategy for bone disorders.

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References

  1. Huang CLH, Sun L, Moonga BS, Zaidi M. Molecular physiology and pharmacology of calcitonin. Cell Mol Biol (Noisy-le-grand). 2006;52(3):33–43.

    CAS  Google Scholar 

  2. Naot D, Musson DS, Cornish J. The activity of peptides of the calcitonin family in bone. Physiol Rev. 2019;99(1):781–805. https://doi.org/10.1152/physrev.00066.2017.

    Article  CAS  PubMed  Google Scholar 

  3. Bandeira L, Lewiecki EM, Bilezikian JP. Pharmacodynamics and pharmacokinetics of oral salmon calcitonin in the treatment of osteoporosis. Expert Opin Drug Metab Toxicol. 2016;12(6):681–9. https://doi.org/10.1080/17425255.2016.1175436.

    Article  CAS  PubMed  Google Scholar 

  4. Allison SL, Davis KW. Calcitonin stewardship strategies. J Pharm Pract. 2019;32:584–5. https://doi.org/10.1177/0897190018770052.

    Article  PubMed  Google Scholar 

  5. Ito A, Yoshimura M. Mechanisms of the analgesic effect of calcitonin on chronic pain by alteration of receptor or channel expression. Mol Pain. 2017;13:1744806917720316. https://doi.org/10.1177/1744806917720316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Okabe K, Okamoto F, Kajiya H. Odontoclasts and calcitonin. Clin Calcium. 2012;22:19–26 CliCa12011926 (DOI Not Found).

    CAS  PubMed  Google Scholar 

  7. Bajracharya R, Song JG, Back SY, Han HK. Recent advancements in non-invasive formulations for protein drug delivery. Comput Struct Biotechnol J. 2019;17:1290–308. https://doi.org/10.1016/j.csbj.2019.09.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Putney SD, Burke PA. Improving protein therapeutics with sustained-release formulations. Nat Biotechnol. 1998;16:153–7. https://doi.org/10.1038/nbt0298-153.

    Article  CAS  PubMed  Google Scholar 

  9. Torres-Lugo M, Peppas NA. Transmucosal delivery systems for calcitonin: a review. Biomaterials. 2000;21:1191–6. https://doi.org/10.1016/S0142-9612(00)00011-9.

    Article  CAS  PubMed  Google Scholar 

  10. Sun L, Le Z, He S, Liu J, Liu L, Leong KW, et al. Flash fabrication of orally targeted nanocomplexes for improved transport of salmon calcitonin across the intestine. Mol Pharm. 2020;17:757–68. https://doi.org/10.1021/acs.molpharmaceut.9b00827.

    Article  CAS  PubMed  Google Scholar 

  11. Liu L, Yang H, Lou Y, Wu JY, Miao J, Lu XY, et al. Enhancement of oral bioavailability of salmon calcitonin through chitosan-modified, dual drug-loaded nanoparticles. Int J Pharm. 2019;557:170–7. https://doi.org/10.1016/j.ijpharm.2018.12.053.

    Article  CAS  PubMed  Google Scholar 

  12. Onishi H, Tokuyasu A. Preparation and evaluation of enteric-coated chitosan derivative-based microparticles loaded with salmon calcitonin as an oral delivery system. Int J Mol Sci. 2016;17(9):1546. https://doi.org/10.3390/ijms17091546.

    Article  CAS  PubMed Central  Google Scholar 

  13. Asafo-Adje TA, Chen AJ, Najarzadeh A, Puleo DA. Advances in controlled drug delivery for treatment of osteoporosis. Curr Osteoporos Rep. 2016;14(5):226–38. https://doi.org/10.1007/s11914-016-0321-4.

    Article  Google Scholar 

  14. Pontiroli AE. Peptide hormones: review of current and emerging uses by nasal delivery. Adv Drug Deliv Rev. 1998;29:81–7. https://doi.org/10.1016/S0169-409X(97)00062-8.

    Article  CAS  PubMed  Google Scholar 

  15. Manosroi J, Lohcharoenkal W, Götz F, Werner RG, Manosroi W, Manosroi A. Transdermal absorption and stability enhancement of salmon calcitonin by Tat peptide. Drug Dev Ind Pharm. 2013;39(4):520–5. https://doi.org/10.3109/03639045.2012.684388.

    Article  CAS  PubMed  Google Scholar 

  16. Amaro MI, Tewes F, Gobbo O, Tajber L, Corrigan OI, Ehrhardt C, et al. Formulation, stability and pharmacokinetics of sugar-based salmon calcitonin-loaded nanoporous/nanoparticulate microparticles (NPMPs) for inhalation. Int J Pharm. 2015;483(1–2):6–18. https://doi.org/10.1016/j.ijpharm.2015.02.003.

    Article  CAS  PubMed  Google Scholar 

  17. Tas C, Mansoor S, Kalluri H, Zarnitsyn VG, Choi SO, Banga AK, et al. Delivery of salmon calcitonin using a microneedle patch. Int J Pharm. 2012;423(2):257–63. https://doi.org/10.1016/j.ijpharm.2011.11.046.

    Article  CAS  PubMed  Google Scholar 

  18. Vemulapalli V, Bai Y, Kalluri H, Herwadkar A, Kim H, Davis SP, et al. In vivo Iontophoretic delivery of salmon calcitonin across microporated skin. J Pharm Sci. 2012;101(8):2861–9. https://doi.org/10.1002/jps.23222.

    Article  CAS  PubMed  Google Scholar 

  19. Gomaa YA, Garland MJ, McInnes F, El-K LK, Wilson C, Donnelly RF. Laser-engineered dissolving microneedles for active transdermal delivery of nadroparin calcium. Eur J Pharm Biopharm. 2012;82(2):299–307. https://doi.org/10.1016/j.ejpb.2012.07.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang Q, Yao G, Dong P, Gong Z, Li G, Zhang K, et al. Investigation on fabrication process of dissolving microneedle arrays to improve effective needle drug distribution. Eur J Pharm Sci. 2015;66:148–56. https://doi.org/10.1016/j.ejps.2014.09.011.

    Article  CAS  PubMed  Google Scholar 

  21. Yao G, Quan G, Lin S, Peng T, Wang Q, Ran H, et al. Novel dissolving microneedles for enhanced transdermal delivery of levonorgestrel: in vitro and in vivo characterization. Int J Pharm. 2017;534:378–86. https://doi.org/10.1016/j.ijpharm.2017.10.035.

    Article  CAS  PubMed  Google Scholar 

  22. Herwadkar A, Banga AK. Peptide and protein transdermal drug delivery. Drug Discov Today Technol. 2011;9(2):e71–e174. https://doi.org/10.1016/j.ddtec.2011.11.007.

    Article  CAS  Google Scholar 

  23. Cetin M, Youn YS, Capan Y, Lee KC. Preparation and characterization of salmon calcitonin-biotin conjugates. AAPS PharmSciTech. 2008;9(4):1191–7. https://doi.org/10.1208/s12249-008-9165-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sun P, Zhang X, Chen Y, Zang X. Application of the yeast-surface-display system for orally administered salmon calcitonin and safety assessment. Biotechnol Prog. 2010;26(4):968–74. https://doi.org/10.1002/btpr.413.

    Article  CAS  PubMed  Google Scholar 

  25. Karsdal MA, Byrjalsen I, Henriksen K, Riis BJ, Christiansen C. A pharmacokinetic and pharmacodynamic comparison of synthetic and recombinant oral salmon calcitonin. J Clin Pharmacol. 2009;49(2):229–34. https://doi.org/10.1177/0091270008329552.

    Article  CAS  PubMed  Google Scholar 

  26. Millest AJ, Evans JR, Young JJ, Johnstone D. Sustained release of salmon calcitonin in vivo from lactide: glycolide copolymer depots. Calcif Tissue Int. 1993;52(5):361–4. https://doi.org/10.1007/BF00310200.

    Article  CAS  PubMed  Google Scholar 

  27. Feng J, Fitz Y, Li Y, Fernandez M, Cortes PI., Wang D, et al. Catheterization of the carotid artery and jugular vein to perform hemodynamic measures, infusions and blood sampling in a conscious rat model. J Vis Exp. 2015;30(95). https://doi.org/10.3791/51881.

  28. Hartmann AE, Lewis LR. Evaluation of the ASTRA o-cresolphthalein complexone calcium method. Am J Clin Pathol. 1984;82(2):182–7. https://doi.org/10.1093/ajcp/82.2.182.

    Article  CAS  PubMed  Google Scholar 

  29. Cohen SA, Sideman L. Modification of the o-cresolphthalein complexone method for determining calcium. Clin Chem. 1979;25(8):1519–20.

    Article  CAS  Google Scholar 

  30. Zhang T, Heimbach T, Lin W, Zhang J, He H. Prospective predictions of human pharmacokinetics for eighteen compounds. J Pharm Sci. 2015;104(9):2795–806. https://doi.org/10.1002/jps.24373.

    Article  CAS  PubMed  Google Scholar 

  31. Lock JY, Carlson TL, Carrier RL. Mucus models to evaluate the diffusion of drugs and particles. Adv Drug Deliv Rev. 2018;124(15):34–49. https://doi.org/10.1016/j.addr.2017.11.001.

    Article  CAS  PubMed  Google Scholar 

  32. Okamura E. Solution NMR to quantify mobility in membranes: diffusion, protrusion, and drug transport processes. Chem Pharm Bull. 2019;67(4):308–15. https://doi.org/10.1248/cpb.c18-00946.

    Article  CAS  Google Scholar 

  33. Crowe LM. Lessons from nature: the role of sugars in anhydrobiosis. Comp Biochem Physiol. 2002;131A:505–13. https://doi.org/10.1016/S1095-6433(01)00503-7.

    Article  CAS  Google Scholar 

  34. Crowe JH, Hoekstra FA, Crowe L. Anhydrobiosis. Annu Rev Physiol. 1992;54:579–99. https://doi.org/10.1146/annurev.ph.54.030192.003051.

    Article  CAS  PubMed  Google Scholar 

  35. Elbein AD, Pan YT, Pastuszak I, Carroll D. New insights on trehalose: a multi functional molecule. Glycobiology. 2003;13:17–27. https://doi.org/10.1093/glycob/cwg047.

    Article  Google Scholar 

  36. Oliveira IP, Martínez L. The shift in urea orientation at protein surfaces at low pH is compatible with a direct mechanism of protein denaturation. Phys Chem Chem Phys. 2019;22(1):354–67. https://doi.org/10.1039/c9cp05196a.

    Article  CAS  PubMed  Google Scholar 

  37. Diamant S, Eliahu N, Rosenthal D, Goloubin P. Chemical chaperones regulate molecular chaperones in vitro and in cells under combined salt and heat stresses. J Biol Chem. 2001;276:39586–91. https://doi.org/10.1074/jbc.M103081200.

    Article  CAS  PubMed  Google Scholar 

  38. Welch WJ, Brown CR. Influence of molecular and chemical chaperones on protein folding. Cell Stress Chaperones. 1996;1:109–15. https://doi.org/10.1379/1466-1268(1996)001<0109:iomacc>2.3.co;2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Singer MA, Lindquist S. Multiple effects of trehalose on protein folding in vitro and in vivo. Mol Cell. 1998;1:639–48. https://doi.org/10.1016/s1097-2765(00)80064-7.

    Article  CAS  PubMed  Google Scholar 

  40. Corradini D, Strekalova EG, Stanley HE, Gallo P. Microscopic mechanism of protein cryopreservation in an aqueous solution with trehalose. Sci Rep. 2013;3:1218. https://doi.org/10.1038/srep01218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Laskowska E, Kuczyńska-Wiśnik D. New insight into the mechanisms protecting bacteria during desiccation. Curr Genet. 2020;66(2):313–8. https://doi.org/10.1007/s00294-019-01036-z.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81502994), Key Projects of Outstanding Young Talents Support Program in universities of Anhui Province (Grant No. gxyqZD2020026), and Natural Science Foundation of Anhui Province (Grant No. 1608085QH179).

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Author notes

  1. Lu Zhang and Yingying Li contributed equally to this work.

Authors and Affiliations

  1. School of Pharmacy, Bengbu Medical College, No. 2600, Donghai Avenue, Bengbu, 233000, Anhui, China

    Lu Zhang, Yingying Li, Fang Wei, Hang Liu, Yushuai Wang, Weiman Zhao, Zhiyong Dong, Tao Ma & Qingqing Wang

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  1. Lu Zhang
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Contributions

Lu Zhang: conceptualization, methodology, software, investigation, writing—original draft.

Yingying Li: validation, formal analysis, visualization, software.

Fang Wei: validation, formal analysis, visualization.

Hang Liu: resources, writing—review and editing, supervision, data curation.

Yushuai Wang: resources, writing—review and editing, supervision, data curation.

Weiman Zhao: resources, writing—review and editing, supervision.

Zhiyong Dong: writing—review and editing.

Tao Ma: writing—review and editing.

Qingqing Wang: writing—review and editing.

Corresponding author

Correspondence to Qingqing Wang.

Ethics declarations

All operations were approved by the Animal Ethical Committee of Sun Yat-sen University and were in accordance with the National Institutes of Health guidelines for the care and use of laboratory animals.

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The authors declare that there are no competing interests.

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Zhang, L., Li, Y., Wei, F. et al. Transdermal Delivery of Salmon Calcitonin Using a Dissolving Microneedle Array: Characterization, Stability, and In vivo Pharmacodynamics. AAPS PharmSciTech 22, 1 (2021). https://doi.org/10.1208/s12249-020-01865-z

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