Advertisement

AAPS PharmSciTech

, 20:103 | Cite as

Spray-Dried PulmoSphere™ Formulations for Inhalation Comprising Crystalline Drug Particles

  • Jeffry G. WeersEmail author
  • Danforth P. Miller
  • Thomas E. Tarara
Review Article Theme: Paul Myrdal Memorial Issue - Pharmaceutical Formulation and Aerosol Sciences
Part of the following topical collections:
  1. Theme: Paul Myrdal Memorial Issue - Pharmaceutical Formulation and Aerosol Sciences

Abstract

Over the past 20 years, solution-based spray dried powders have transformed inhaled product development, enabling aerosol delivery of a wider variety of molecules as dry powders. These include inhaled proteins for systemic action (e.g., Exubera®) and high-dose inhaled antibiotics (e.g., TOBI® Podhaler™). Although engineered particles provide several key advantages over traditional powder processing technologies (e.g., spheronized particles and lactose blends), the physicochemical stability of the amorphous drug present in these formulations brings along its own unique set of constraints. To this end, a number of approaches have been developed to maintain the crystallinity of drugs throughout the spray drying process. One approach is to spray dry suspensions of micronized drug(s) from a liquid feed. In this method, minimization of drug particle dissolution in the liquid feed is critical, as dissolved drug is converted into amorphous domains in the spray-dried drug product. The review explores multiple formulation and engineering strategies for decreasing drug dissolution independent of the physicochemical properties of the drug(s). Strategies to minimize particle dissolution include spray blending of particles of different compositions, formation of respirable agglomerates of micronized drug with small porous carrier particles, and use of common ions. The formulations extend the range of doses that can be delivered with a portable inhaler from about 100 ng to 100 mg. The spray-dried particles exhibit significant advantages in terms of lung targeting and dose consistency relative to conventional lactose blends, while still maintaining the crystallinity of drug(s) in the formulated drug product.

KEY WORDS

PulmoSphere™ spray blending respirable agglomerates inhalation 

Notes

References

  1. 1.
    Snyder HE, Lechuga-Ballesteros D. Spray drying: theory and pharmaceutical applications. In: Augsburger LL, Hoag SW, editors. Pharmaceutical dosage forms: tablets, volume 1: unit operations and mechanical properties. New York: Informa Healthcare; 2008. p. 227–60.CrossRefGoogle Scholar
  2. 2.
    Vehring R, Foss WR, Lechuga-Ballesteros D. Particle formation in spray drying. J Aerosol Sci. 2007;8:728–46.CrossRefGoogle Scholar
  3. 3.
    Vehring R. Pharmaceutical particle engineering via spray drying. Pharm Res. 2008;25:999–1022.CrossRefGoogle Scholar
  4. 4.
    Edwards DA, Hanes J, Caponetti G, Hrkach J, Ben-Jebria A, Eskew M-L, et al. Large porous particles for pulmonary drug delivery. Science. 1997;276:1868–72.CrossRefGoogle Scholar
  5. 5.
    Lipp MM, Batycky R, Moore J, Leinonen M, Freed MI. Preclinical and clinical assessment of inhaled levodopa for off-episodes in Parkinson’s disease. Sci Transl Med. 2016;8:360ra136.CrossRefGoogle Scholar
  6. 6.
    Lord JD. AeroVanc: a novel dry powder inhaler for the treatment of methicillin-resistant Staphylococcus aureus infection in cystic fibrosis patients. Proc Respir Drug Deliv 2014. 2014;3:563–8.Google Scholar
  7. 7.
    Adi H, Young PM, Chan H-K, Stewart P, Agus H, Traini D. Co-spray dried antibiotics for dry powder lung delivery. J Pharm Sci. 2008;97:3356–66.CrossRefGoogle Scholar
  8. 8.
    Rabbani NR, Seville PC. The influence of formulation components on the aerosolization properties of spray-dried powders. J Control Release. 2005;110:130–40.CrossRefGoogle Scholar
  9. 9.
    Shoyele SA, Cawthorne S. Particle engineering techniques for inhaled biopharmaceuticals. Adv Drug Deliv Rev. 2006;58:1009–29.CrossRefGoogle Scholar
  10. 10.
    Healy AM, Amaro MI, Paluch KJ, Tajber L. Dry powders for oral inhalation free of lactose carrier particles. Adv Drug Deliv Rev. 2014;75:32–52.CrossRefGoogle Scholar
  11. 11.
    Stevenson C, Bennett D. Development of Exubera® insulin pulmonary delivery system. In: das Neves J, Sarmento B, editors. Mucosal delivery of biopharmaceuticals. New York: Springer Science; 2014. Chapter 21.Google Scholar
  12. 12.
    Geller D, Weers J, Heuerding S. Development of a dry powder formulation of tobramycin using PulmoSphere technology. J Aerosol Med Pulm Drug Del. 2011;24:175–82.CrossRefGoogle Scholar
  13. 13.
    Sadrzadeh N, Miller DP, Lechuga-Ballesteros D, Harper NJ, Stevenson CL, Bennett DB. Solid-state stability of spray-dried insulin powder for inhalation: chemical kinetics and structural relaxation modeling of Exubera above and below the glass transition temperature. J Pharm Sci. 2010;99:3698–710.CrossRefGoogle Scholar
  14. 14.
    Miller DP, Tan T, Tarara T, Nakamura J, Malcolmson R, Weers J. Physical characterization of tobramycin inhalation powder I: rational design of a stable engineered-particle formulation for delivery to the lungs. Mol Pharm. 2015;12:2582–93.CrossRefGoogle Scholar
  15. 15.
    Miller D, Tan T, Nakamura J, Malcolmson R, Tarara T, Weers J. Physical characterization of tobramycin inhalation powder II. State diagram of an amorphous engineered particle formulation. Mol Pharm. 2017;14:1950–60.CrossRefGoogle Scholar
  16. 16.
    Haynes A, Geller D, Weers J, Ament B, Pavkov R, Malcolmson R, et al. Inhalation of tobramycin using simulated cystic fibrosis patient profiles. Pediatr Pulmonol. 2016;51:1159–67.CrossRefGoogle Scholar
  17. 17.
    Ung KT, Rao N, Weers JG, Huang D, Chan H-K. Design of spray-dried insulin microparticles to bypass deposition in the extrathoracic region and maximize total lung dose. Int J Pharm. 2016;511:1070–9.CrossRefGoogle Scholar
  18. 18.
    Ung KT, Weers J, Huang D, Rao N, Son Y-J. Targeted delivery of spray-dried formulations to the lungs. WO 2017/042696 A1. 2017.Google Scholar
  19. 19.
    Weers JG, Miller DP. Formulation of dry powders for inhalation. J Pharm Sci. 2015;104:3259–88.CrossRefGoogle Scholar
  20. 20.
    Weers JG, Tarara TE. The PulmoSphere™ platform for pulmonary drug delivery. Ther Deliv. 2014;5:277–95.CrossRefGoogle Scholar
  21. 21.
    Weers JG, Clark AR. The impact of inspiratory flow rate on drug delivery to the lungs with dry powder inhalers. Pharm Res. 2017;34:507–28.CrossRefGoogle Scholar
  22. 22.
    Pedersen S. How to use a Rotahaler. Arch Dis Child. 1986;61:11–4.CrossRefGoogle Scholar
  23. 23.
    Li L, Sun S, Parumasivam T, Denman JA, Gegenbach T, Tang P, et al. L-leucine as an excipient against moisture on in vitro aerosolization performance of highly hygroscopic spray-dried powders. Eur J Pharm Biopharm. 2016;102:132–44.CrossRefGoogle Scholar
  24. 24.
    Zhou QT, Gegenbach T, Denman JA, Heidi HY, Yi J, Chan H-K. Synergistic antibiotic combination powders of colistin and rifampicin provide high aerosolization efficiency and moisture protection. AAPS J. 2014;16:37–47.CrossRefGoogle Scholar
  25. 25.
    Ahlneck C, Zografi G. The molecular basis for moisture effects on the physical and chemical stability of drugs in the solid-state. Int J Pharm. 1990;62:87–95.CrossRefGoogle Scholar
  26. 26.
    Kumar S, Shen J, Zolnik B, Sadrieh N, Burgess DJ. Optimization and dissolution performance of spray-dried naproxen nano-crystals. Int J Pharm. 2015;486:159–66.CrossRefGoogle Scholar
  27. 27.
    Barot BS, Parejiya PB, Patel TM, Parikh RK, Gohel MC. Development of directly compressible metformin hydrochloride by the spray-drying technique. Acta Pharma. 2010;60:165–75.CrossRefGoogle Scholar
  28. 28.
    Miller DP, Huang D, Rao N, Weers JG. Highly dispersible powders comprising inorganic salts. Proc Respir Drug Deliv. 2016;2:471–5.Google Scholar
  29. 29.
    Selby MD, de Koning PD, Roberts DF. A perspective on synthetic and solid-form enablement of inhalation candidates. Future Med Chem. 2011;3:1679–701.CrossRefGoogle Scholar
  30. 30.
    Yeadon M. The paradox of respiratory R&D, and why ‘inhaled-by-design’ heralds a new dawn in asthma and chronic obstructive pulmonary disease treatments. Future Med Chem. 2011;3:1581–3.CrossRefGoogle Scholar
  31. 31.
    Weers JG. Enhanced design of inhaled therapeutics: what does the future hold? Ther Deliv. 2016;7:145–8.CrossRefGoogle Scholar
  32. 32.
    Weers JG, Tarara T, Malcolmson R, Leung D. Embedded crystals in low density particles: formulation, manufacture, and properties. Proc Respir Drug Deliv X. 2006;2:296–304.Google Scholar
  33. 33.
    Faithfull NS, Weers JG. Partial liquid breathing of fluorochemicals. US Patent 5,490,498, 1996.Google Scholar
  34. 34.
    Dickson EW, Heard SO, Tarara TE, Weers JG, Brueggemann AB, Doern GV. Liquid ventilation with perflubron in the treatment of rats with Pneumococcal pneumonia. Crit Care Med. 2002;30:393–5.CrossRefGoogle Scholar
  35. 35.
    Ivey JW, Vehring R. The use of modeling in spray drying of emulsions and suspensions accelerates formulation and process development. Comp Chem Eng. 2010;34:1036–40.CrossRefGoogle Scholar
  36. 36.
    Duddu SP, Sisk SA, Walter YH, Tarara TE, Trimble K, Clark AR, et al. Improved lung delivery from a passive dry powder inhaler using an engineered PulmoSphere powder. Pharm Res. 2002;19:689–95.CrossRefGoogle Scholar
  37. 37.
    McShane PJ, Weers JG, Tarara TE, Haynes A, Durbha P, Miller DP, et al. Ciprofloxacin dry powder for inhalation (Ciprofloxacin DPI): technical design and features of an efficient drug-device combination. Pulm Pharmacol Ther. 2018;50:72–9.CrossRefGoogle Scholar
  38. 38.
    Weers J, Huang D, Tarara TE, Miller D. Deamorphization of spray-dried formulations via spray blending. US Patent 2015/0374623 A1. 2015.Google Scholar
  39. 39.
    Weers JG, Huang D, Tarara TE, Miller DP. Deamorphization of spray-dried formulations via spray blending. Proc Respir Drug Deliv. 2016;3:481–4.Google Scholar
  40. 40.
    Weers J, Tarara T. Pulmonary delivery of a fluoroquinolone. US Patent 8,834,930. 2014.Google Scholar
  41. 41.
    Stass H, Delesen H, Nagelschmitz J, Staab D. Safety and pharmacokinetics of ciprofloxacin dry powder for inhalation in cystic fibrosis: a phase I, randomized, single-dose, dose-escalation study. J Aerosol Med Pulm Drug Deliv. 2015;28:106–15.CrossRefGoogle Scholar
  42. 42.
    Stass H, Nagelschmitz J, Kappeler D, Sommerer K, Kietzig C, Weimann B. Ciprofloxacin dry powder for inhalation in patients with non-cystic fibrosis bronchiectasis or chronic obstructive pulmonary disease and in healthy volunteers. J Aerosol Med Pulm Drug Deliv. 2017;30:53–63.CrossRefGoogle Scholar
  43. 43.
    Haynes A, Mundry T, Durbha P, Miller DP, Tarara T, Malcolmson R, et al. Design of ciprofloxacin dry powder for inhalation. Proc Respir Drug Deliv 2016. 2016;3:455–8.Google Scholar
  44. 44.
    Stass H, Nagelschmitz J, Willmann S, Delesen H, Gupta A, Baumann S. Inhalation of a dry powder ciprofloxacin formulation in healthy subjects: a phase 1 study. Clin Drug Invest. 2013;33:419–27.CrossRefGoogle Scholar
  45. 45.
    Dorkin HL, Staab D, Operschall E, Alder J, Criollo M. Ciprofloxacin DPI: a randomized placebo-controlled, phase IIb efficacy and safety study on cystic fibrosis. BMJ Open Respir Res. 2015;2:e000100.  https://doi.org/10.1136/bmjresp-2015-000100/2:e000100. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Wilson R, Welte T, Polverino E, De Soyza A, Greville H, O’Donnell A, et al. Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis: a phase II randomized study. Eur Respir J. 2013;41:1107–15.CrossRefGoogle Scholar
  47. 47.
    Ciprofloxacin DPI (BAY q3939). In: Briefing document for FDA Advisory Committee Meeting on 16 Nov 2017, NDA 209367. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM584651.pdf. Accessed 07 Sep 2018.
  48. 48.
    Young PM. High dose powders: a critical assessment of needs, formulation, and delivery technologies. Proc Respir Drug Deliv. 2018;1:201–8.Google Scholar
  49. 49.
    Brunaugh AD, Smyth HDC. Formulation techniques for high dose dry powders. Int J Pharm. 2018:489–98.  https://doi.org/10.1016/j.ijpharm.2018.05.036.
  50. 50.
    Borgström L, Bondesson E, Moren F, Trofast E, Newman SP. Lung deposition of budesonide inhaled via Turbuhaler®: a comparison with terbutaline sulphate in normal subjects. Eur Respir J. 1994;7:69–73.CrossRefGoogle Scholar
  51. 51.
    Kugler AR, Lee JD, Samford LK, Sahner DK, Eldon MA. Clinical pharmacokinetics (PK) following multiple doses of amphotericin B inhalation powder (ABIP). Focus on Fungal Infections (FoFI) 17. 2007: Abstract P-0032, pp. 225–226.Google Scholar
  52. 52.
    Duddu S, Palakodaty S, Lechuga-Ballesteros, D, Miller D, Kugler AR, Frantz C, Tan T, Malcolmson R, Washco K, Sweeney T, Tarara TE, Dwivedi S, Eldon MA. Compositions comprising amphotericin B, methods and systems. US Patent 7,326,691 B2. 2008.Google Scholar
  53. 53.
    Schwan WR. Differences in sensitivity of PA-1806 among iron transport mutants of Pseudomonas aeruginosa compared to Escherichia coli. Antimicrob Agents Chemother. 2000;44:3237–8.CrossRefGoogle Scholar
  54. 54.
    Tarara TE, Weers JG. Pharmaceutical formulations with an insoluble active agent. US Patent Application 2004/0156792 A1. 2004.Google Scholar
  55. 55.
    Safety, pharmacokinetics and efficacy study of QCC374 in PAH patients. Clinical Trial No. NCT02927366. 2017. https://clinicaltrials.gov/ct2/show/NCT02927366. Accessed 07 Sep 2018.
  56. 56.
    Weers JG, Clark AR, Rao N, Ung K, Khindri SK, Perry SA, et al. In vitro in vivo correlations observed with indacaterol-based formulations delivered with the Concept1 inhaler. J Aerosol Med Pulm Drug Deliv. 2015;28:268–80.CrossRefGoogle Scholar
  57. 57.
    Hartman M, Tarara TE, Teung P, Weers JG: Respirable agglomerates of porous carrier particles and micronized drug. US Patent 9,452,139, 2016.Google Scholar
  58. 58.
    Weers JG, Tarara T, Teung P, Walsh K, Rao N, Le J, et al. Solving the particle adhesion paradox: respirable agglomerates of micronized drugs and porous (microcarrier) particles. Proc Respir Drug Deliv. 2015;1:177–85.Google Scholar
  59. 59.
    Weers JG, Tarara TE, Gill H, English BS, Dellamary LA. Homodispersion technology for HFA suspensions: particle engineering to reduce dosing variance. Proc Respir Drug Deliv VII. 2000;1:91–7.Google Scholar
  60. 60.
    Weers JG, Schutt EG, Dellamary LA, Tarara TE, Kabalnov A. Stabilized preparations for use in metered dose inhalers. US Patent 6,309,623, 2001.Google Scholar
  61. 61.
    Dellamary LA, Tarara TE, Smith DJ, Woelk CH, Adractas A, Costello M, et al. Hollow porous particles in metered dose inhalers. Pharm Res. 2000;17:168–74.CrossRefGoogle Scholar
  62. 62.
    Hirst PH, Elton RC, Pitcairn GR, Newman SP, Weers JG, Clark AR, et al. In vivo lung deposition of hollow porous particles from a pressurized metered dose inhaler. Pharm Res. 2002;19:258–64.CrossRefGoogle Scholar
  63. 63.
    Tarara TE, Hartman M, Gill H, Kennedy A, Weers JG. Characterization of suspension-based metered dose inhaler formulations comprised of spray-dried budesonide crystals dispersed in HFA-134a. Pharm Res. 2004;21:1607–14.CrossRefGoogle Scholar
  64. 64.
    Vehring R, Lechuga-Ballesteros D, Joshi V, Noga B, Dwivedi SK. Co-suspensions of microcrystals and engineered microparticles for uniform and efficient delivery of respiratory therapeutics from pressurized metered dose inhalers. Langmuir. 2012;28:15015–23.CrossRefGoogle Scholar
  65. 65.
    Doty A, Schroeder J, Vang K, Sommerville M, Taylor M, Flynn B, et al. Drug delivery from an innovative LAMA/LABA delivery technology fixed-dose combination MDI: evidence of consistency, robustness, and reliability. AAPS PharmSci Tech. 2018;19:837–44.CrossRefGoogle Scholar
  66. 66.
    Taylor G, Warren S, Dwivedi S, Sommerville M, Mello L, Orevillo C, et al. Gamma scintigraphic pulmonary deposition study of glycopyrronium/formoterol metered dose inhaler formulated using co-suspension delivery technology. Eur J Pharm Sci. 2018;111:450–7.CrossRefGoogle Scholar
  67. 67.
    Bevespi Aerosphere® package insert. www.bevespi.com. Accessed 07 Sep 2018.
  68. 68.
    Reisner C, Fernandez C, Darken P, et al. Pearl’s PT010 triple combination provides comparable budesonide exposure to Symbicort and comparable glycopyrronium exposure to PT003. Eur Respir J. 2014;44:1891.Google Scholar
  69. 69.
    Morton DAV, Barling D. Developing dry powder inhaler formulations. ISAM textbook, Chapter 7.2, www.isam.org/textbook. Accessed 27 Nov 2018.
  70. 70.
    deBoer AH, Hagedoorn P, Hoppentocht M, Buttini F, Grasmeijer F, Frijlink HW. Dry powder inhalation: past, present and future. Expert Opin Drug Deliv. 2017;14:499–512.CrossRefGoogle Scholar
  71. 71.
    Hancock BC, Shamblin SL, Zografi G. Molecular mobility of amorphous pharmaceutical solids below their glass-transition temperatures. Pharm Res. 1995;12:799–806.CrossRefGoogle Scholar
  72. 72.
    Roos YH. Phase transitions in foods. San Diego: Academic Press; 1995. p. 360.Google Scholar
  73. 73.
    Maltz DS, Paboojian JS. Device engineering insights into TOBI Podhaler: A development case study of high efficiency powder delivery to cystic fibrosis patients. Proc Respir Drug Deliv Eur. 2011;1:55–66.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Jeffry G. Weers
    • 1
    Email author
  • Danforth P. Miller
    • 1
  • Thomas E. Tarara
    • 1
  1. 1.Respira Therapeutics, Inc.San MateoUSA

Personalised recommendations