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Aerosolization, Drug Permeation and Cellular Interaction of Dry Powder Pulmonary Formulations of Corticosteroids with Hydroxypropyl-β-Cyclodextrin as a Solubilizer

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Abstract

Purpose

The purpose of this study was to assess the feasibility of hydroxypropyl-β-cyclodextrin as a solubilizer for the corticosteroids prednisolone and fludrocortisone acetate in dry powder inhalation formulations.

Methods

The dry particles were simultaneously produced and coated with nanosized L-leucine crystals using an aerosol flow reactor method. The aerosolization performances of carrier-free powders were studied using Easyhaler® and Twister™ at 2 and 4 kPa pressure drops over the inhalers. Drug permeation properties of the formulations were tested across a Calu-3 cell monolayer. Toxicity and reactive oxygen species induction were tested against Calu-3 and A549 cell lines.

Results

The hydroxypropyl-β-cyclodextrin in the powders promoted the dissolution of fludrocortisone the most, followed by that of prednisolone. Fine particle fractions were 52–70% from emitted doses which showed good repeatability with a coefficient variation of 0.9–0.17. In addition, hydroxypropyl-β-cyclodextrin enhanced the permeation of the corticosteroids. The powders showed no statistically significant toxicity nor reactive oxygen species induction in the tested cell lines.

Conclusions

This study demonstrated the preparation and function of fine powder formulations which combine improved dissolution of poorly soluble drugs with good aerosolization performance. These results are expected to promote particle engineering as a way to develop new types of therapeutic pulmonary powders.

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Abbreviations

BLPI:

Berner-type low pressure impactor

CD:

Cyclodextrin

CVED :

The coefficient of variations of the powder emission

ED:

Emitted dose

FLU:

Fludrocortisone-21-acetate

FPF:

Fine particle fraction

HP-β-CD:

Hydroxypropyl-β-cyclodextrin

L:

L-leucine

PRE:

Prednisolone

ROS:

Reactive oxygen species

References

  1. Patton JS. The lungs as a portal of entry for systemic drug delivery. Proc Am Thorac Soc. 2004;1:338–44. doi:10.1513/pats.200409-049TA.

    Article  CAS  PubMed  Google Scholar 

  2. Yang W, Johnston KP, Williams III RO. Comparison of bioavailability of amorphous versus crystalline itraconazole nanoparticles via pulmonary administration in rats. Eur J Pharm Biopharm. 2010;75:33–41.

    Article  CAS  PubMed  Google Scholar 

  3. Resatz S, Gold T, Wessel M. How to choose the right solubilization technology for your API. Drug Dev Deliv. 2015;15:35–40.

    Google Scholar 

  4. Uekama K, Fujinaga T, Hirayama F, Otagiri M, Yamasaki M, Seo H, et al. Improvement of the oral bioavailability of digitalis glycosides by cyclodextrin complexation. J Pharm Sci. 1983;72:1338–41.

    Article  CAS  PubMed  Google Scholar 

  5. Otero-Espinar FJ, Anguiano-Igea S, García-Gonzalez N, Vila-Jato JL, Blanco-Méndez J. Oral bioavailability of naproxen-β-cyclodextrin inclusion compound. Int J Pharm. 1991;75:37–44.

    Article  CAS  Google Scholar 

  6. Dhanaraju MD, Kumaran KS, Baskaran T, Moorthy MSR. Enhancement of bioavailability of griseofulvin by its complexation with β-cyclodextrin. Drug Dev Ind Pharm. 1998;24:583–7.

    Article  CAS  PubMed  Google Scholar 

  7. Malaekeh-Nikouei B, Sajadi Tabassi SA, Gerayeli G, Salmani MA, Gholamzadeh A. The effect of cyclodextrin mixtures on aqueous solubility of beclomethasone dipropionate. J Incl Phenom Macrocycl Chem. 2012;72:383–7.

    Article  CAS  Google Scholar 

  8. Rao VM, Haslam JL, Stella VJ. Controlled and complete release of a model poorly water-soluble drug, prednisolone, from hydroxypropyl methylcellulose matrix tablets using (SBE)7m-?-cyclodextrin as a solubilizing agent. J Pharm Sci. 2001;90:807–16.

    Article  CAS  PubMed  Google Scholar 

  9. Duan MS, Zhao N, Össurardóttir ÍB, Thorsteinsson T, Loftsson T. Cyclodextrin solubilization of the antibacterial agents triclosan and triclocarban: formation of aggregates and higher-order complexes. Int J Pharm. 2005;297:213–22.

    Article  CAS  PubMed  Google Scholar 

  10. Başaran B, Bozkir A. Thermosensitive and pH induced in situ ophthalmic gelling system for ciprofloxacin hydrochloride: hydroxypropyl-beta-cyclodextrin complex. Acta Pol Pharm. 69:1137–47.

  11. Müller BW, Brauns U. Hydroxypropyl-β cyclodextrin derivatives: influence of average degree of substitution on complexing ability and surface activity. J Pharm Sci. 1986;75:571–2.

    Article  PubMed  Google Scholar 

  12. Salem LB, Bosquillon C, Dailey LA, Delattre L, Martin GP, Evrard B, et al. Sparing methylation of β-cyclodextrin mitigates cytotoxicity and permeability induction in respiratory epithelial cell layers in vitro. J Control Release. 2009;136:110–6.

    Article  CAS  PubMed  Google Scholar 

  13. Azarbayjani AF, Lin H, Yap CW, Chan YW, Chan SY. Surface tension and wettability in transdermal delivery: a study on the in-vitro permeation of haloperidol with cyclodextrin across human epidermis. J Pharm Pharmacol. 2010;62:770–8.

    Article  CAS  PubMed  Google Scholar 

  14. Matilainen L, Toropainen T, Vihola H, Hirvonen J, Järvinen T, Jarho P, et al. In vitro toxicity and permeation of cyclodextrins in Calu-3 cells. J Control Release. 2008;126:10–6.

    Article  CAS  PubMed  Google Scholar 

  15. Ungaro F, d’Emmanuele di Villa Bianca R, Giovino C, Miro A, Sorrentino R, Quaglia F, et al. Insulin-loaded PLGA/cyclodextrin large porous particles with improved aerosolization properties: in vivo deposition and hypoglycaemic activity after delivery to rat lungs. J Control Release. 2009;135:25–34.

    Article  CAS  PubMed  Google Scholar 

  16. Kinnarinen T, Jarho P, Järvinen K, Järvinen T. Pulmonary deposition of a budesonide/gamma-cyclodextrin complex in vitro. J Control Release. 2003;90:197–205.

    Article  CAS  PubMed  Google Scholar 

  17. Cabral-Marques H, Almeida R. Optimisation of spray-drying process variables for dry powder inhalation (DPI) formulations of corticosteroid/cyclodextrin inclusion complexes. Eur J Pharm Biopharm. 2009;73:121–9.

    Article  CAS  PubMed  Google Scholar 

  18. Borgström L, Bondesson E, Morén F, Trofast E, Newman SP. Lung deposition of budesonide inhaled via Turbuhaler® : a comparison with terbutalinesulphate in normalsubjects. Eur Respir J. 1994;69–73.

  19. Lähde A, Raula J, Kauppinen EI. Simultaneous synthesis and coating of salbutamol sulphate nanoparticles with L-leucine in the gas phase. Int J Pharm. 2008;358:256–62.

    Article  PubMed  Google Scholar 

  20. Raula J, Lähde A, Kauppinen EI. A novel gas phase method for the combined synthesis and coating of pharmaceutical particles. Pharm Res. 2008;25:242–5.

    Article  CAS  PubMed  Google Scholar 

  21. Raula J, Rahikkala A, Halkola T, Pessi J, Peltonen L, Hirvonen J, et al. Coated particle assemblies for the concomitant pulmonary administration of budesonide and salbutamol sulphate. Int J Pharm. 2013;441:248–54.

    Article  CAS  PubMed  Google Scholar 

  22. Raula J, Lähde A, Kauppinen EI. Aerosolization behavior of carrier-free L-leucine coated salbutamol sulphate powders. Int J Pharm. 2009;365:18–25.

    Article  CAS  PubMed  Google Scholar 

  23. Raula J, Kuivanen A, Lähde A, Kauppinen EI. Gas-phase synthesis of L-leucine-coated micrometer-sized salbutamol sulphate and sodium chloride particles. Powder Technol. 2008;187:289–97.

    Article  CAS  Google Scholar 

  24. Gliński J, Chavepeyer G, Platten J-K. Surface properties of aqueous solutions of L-leucine. Biophys Chem. 2000;84:99–103.

    Article  Google Scholar 

  25. Matubayasi N, Miyamoto H, Namihira J, Yano K, Tanaka T. Thermodynamic quantities of surface formation of aqueous electrolyte solutions. V. Aqueous solutions of aliphatic amino acids. J Colloid Interface Sci. 2002;250:431–7.

    Article  CAS  PubMed  Google Scholar 

  26. Paajanen M, Katainen J, Raula J, Kauppinen EI, Lahtinen J. Direct evidence on reduced adhesion of Salbutamol sulphate particles due to L-leucine coating. Powder Technol. 2009;192:6–11.

    Article  CAS  Google Scholar 

  27. Eerikäinen H, Watanabe W, Kauppinen EI, Ahonen PP. Aerosol flow reactor method for synthesis of drug nanoparticles. Eur J Pharm Biopharm. 2003;55:357–60.

    Article  PubMed  Google Scholar 

  28. Zhu Y, Lee KW. Experimental study on small cyclones operating at high flowrates. J Aerosol Sci. 1999;30:1303–15.

    Article  CAS  Google Scholar 

  29. Kauppinen E, Kurkela J, Brown D, Jokiniemi J, Mattila T. Method and apparatus for studying aerosol sources. Google Patents; 2002. Available from: http://www.google.com.au/patents/WO2002059574A1?cl=en.

  30. Kurkela JA, Kauppinen EI, Brown DP, Jokiniemi JK, Muttonen E. A new method and apparatus for studying performance of inhalers. Respir Drug Deliv. 2002;VIII.

  31. Hillamo RE, Kauppinen EI. On the performance of the berner low pressure impactor. Aerosol Sci Technol. 1991; 33–47.

  32. Rahikkala A, Junnila S, Vartiainen V, Ruokolainen J, Ikkala O, Kauppinen E, et al. Polypeptide-based aerosol nanoparticles: self-assembly and control of conformation by solvent and thermal annealing. Biomacromolecules. 2014;15:2607–15.

    Article  CAS  PubMed  Google Scholar 

  33. Haghi M, Young PM, Traini D, Jaiswal R, Gong J, Bebawy M. Time- and passage-dependent characteristics of a Calu-3 respiratory epithelial cell model. Drug Dev Ind Pharm. 2010;36:1207–14.

    Article  CAS  PubMed  Google Scholar 

  34. Grainger CI, Greenwell LL, Lockley DJ, Martin GP, Forbes B. Culture of Calu-3 cells at the air interface provides a representative model of the airway epithelial barrier. Pharm Res. 2006;23:1482–90.

    Article  CAS  PubMed  Google Scholar 

  35. Bimbo LM, Mäkilä E, Laaksonen T, Lehto V-P, Salonen J, Hirvonen J, et al. Drug permeation across intestinal epithelial cells using porous silicon nanoparticles. Biomaterials. 2011;32:2625–33.

    Article  CAS  PubMed  Google Scholar 

  36. Ali HSM, York P, Blagden N, Soltanpour S, Acree WE, Jouyban A. Solubility of budesonide, hydrocortisone, and prednisolone in ethanol + water mixtures at 298.2 K. J Chem Eng Data. 2010;55:578–82.

    Article  CAS  Google Scholar 

  37. Maynard RL. The Merck index: 12th edition 1996. Occup Environ Med. 1997;54:288.

    Article  PubMed Central  Google Scholar 

  38. Chew NYK, Chan H. Use of solid corrugated particles to enhance powder aerosol performance. Pharm Res. 2001;18:1570–7.

    Article  CAS  PubMed  Google Scholar 

  39. Djedaïni F, Perly B. Nuclear magnetic resonance investigation of the stoichiometries in β-cyclodextrin:steroid inclusion complexes. J Pharm Sci. 1991;80:1157–61.

    Article  PubMed  Google Scholar 

  40. Crowe A, Tan AM. Oral and inhaled corticosteroids: differences in P-glycoprotein (ABCB1) mediated efflux. Toxicol Appl Pharmacol. 2012;260:294–302.

    Article  CAS  PubMed  Google Scholar 

  41. Bimbo LM, Peltonen L, Hirvonen J, Santos HA. Toxicological profile of therapeutic nanodelivery systems. Curr Drug Metab. 2012;13:1068–86.

    Article  CAS  PubMed  Google Scholar 

  42. Nel A, Xia T, Mädler L, Li N. Toxic potential of materials at the nanolevel. Science. 2006;311:622–7.

    Article  CAS  PubMed  Google Scholar 

  43. Lutter R, Van Lieshout B, Folisi C. Reduced antioxidant and cytoprotective capacity in allergy and asthma. Ann Am Thorac Soc. 2015;12:S133–6.

    PubMed  Google Scholar 

  44. Nadeem A, Chhabra SK, Masood A, Raj HG. Increased oxidative stress and altered levels of antioxidants in asthma. J Allergy Clin Immunol. 2003;111:72–8.

    Article  CAS  PubMed  Google Scholar 

  45. Repine JE, Bast A, Lankhorst I. State of the art oxidative stress in chronic obstructive. Am J Respir Crit Care Med. 1997;156:341–57.

    Article  CAS  PubMed  Google Scholar 

  46. Vartiainen V, Bimbo LM, Hirvonen J, Kauppinen EI, Raula J. Drug permeation and cellular interaction of biodegradable amino acid-coated combination drug powders for pulmonary delivery. Int J Pharm. 2016;504:89–97.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

The Academy of Finland (project nos. 140362 and 276377), Orion Research Foundation, The Finnish Cultural Foundation, Biocentrum Helsinki, Finnish Medical Foundation, and the Jane and Aatos Erkko Foundation are acknowledged for financial support. The provision of facilities by Aalto University at OtaNano - Nanomicroscopy Center (Aalto-NMC) is acknowledged.

Author information

Authors and Affiliations

  1. Faculty of Medicine, University of Helsinki, Clinicum, P.O. Box 22, FI-00014, Helsinki, Finland

    Ville Vartiainen

  2. Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5E), FI-00014, Helsinki, Finland

    Luis M. Bimbo & Jouni Hirvonen

  3. School of Science, Aalto University, P.O. Box 15100, FI-00076, Aalto, Finland

    Esko I. Kauppinen & Janne Raula

Authors
  1. Ville Vartiainen
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  2. Luis M. Bimbo
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  3. Jouni Hirvonen
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  4. Esko I. Kauppinen
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  5. Janne Raula
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Corresponding authors

Correspondence to Luis M. Bimbo or Janne Raula.

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Vartiainen, V., Bimbo, L.M., Hirvonen, J. et al. Aerosolization, Drug Permeation and Cellular Interaction of Dry Powder Pulmonary Formulations of Corticosteroids with Hydroxypropyl-β-Cyclodextrin as a Solubilizer. Pharm Res 34, 25–35 (2017). https://doi.org/10.1007/s11095-016-2035-9

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  • DOI: https://doi.org/10.1007/s11095-016-2035-9

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