Advertisement

AAPS PharmSciTech

, Volume 19, Issue 8, pp 3723–3733 | Cite as

Evaluation of Nasal Inlet Ports Having Simplified Geometry for the Pharmacopeial Assessment of Mass Fraction of Dose Likely to Penetrate Beyond the Nasopharynx: a Preliminary Investigation

  • Gerallt Williams
  • Chris Blatchford
  • Jolyon P. Mitchell
Research Article
  • 42 Downloads

Abstract

Nasal cavity breakthrough to the airways of the lungs is associated with nasally inhaled droplets whose size is smaller than ca. 10 μm aerodynamic diameter that behave as an aerosol rather than a spray in terms of their transport. The purpose of the present laboratory-based study was to evaluate a nasal product quality control procedure involving a new inlet for the quantification of mass of such droplets emitted by commercially available aqueous nasal spray pump products by cascade impactor. This inlet is more representative of the adult nasal vestibule in terms of entry angle for the spray as well as internal volume for plume expansion. Sampling was also undertaken via a spherical 1-L glass expansion vessel as inlet, previously established for quantification of these aerosol droplets. The selected solution- and suspension-formulated products containing azelastine and fluticasone propionate respectively were shown to contain < 1% of the total spray mass per actuation associated with droplets < 14.1 μm aerodynamic diameter. These measurements were consistent with laser diffraction-based measurements of the entire droplet size distribution. Comparable measures of aerosol droplet mass fraction were obtained when the spray was sampled by the cascade impactor method using either the 1-L glass expansion chamber or the new metal inlet as entry for the spray produced by either product evaluated. We conclude that the metal inlet has the potential to be adopted as a suitable induction port in the assessment of nasal product quality, where currently no standardized inlet exists.

KEY WORDS

nasal ports spray aqueous spray pulmonary breakthrough pulmonary breakthrough 

Notes

Acknowledgements

The authors acknowledge the support of Mark Copley of Copley Scientific Ltd., Nottingham, UK for preparing the engineering drawings for the stainless steel nasal inlet port to 3M Health Care UK’s design and demonstrating its manufacturability. They further acknowledge the technical advice given by Paul Kippax of Malvern Panalytical Ltd., Malvern, UK in connection with the application of laser diffractometry to the assessment of aerosol droplets associated with the products described in this article. Finally, they thank the following organizations for experimental work and associated technical advice during the course of the study:

• 3M Health Care Ltd., UK

• Aptar Pharma R&D, France

• Boehringer-Ingelheim AG & Ko. KG, Germany

• Covance Ltd, UK

• US Food and Drug Administration Laboratories, St Louis, MO, USA

• GlaxoSmithKline plc, UK

• Intertek Melbourn, UK

• Next Breath LLC, MD, USA

• National Institute for Public Health and the Environment (RIVM), Netherlands

References

  1. 1.
    Doub WH, Adams WP, Wokovich AM, Black JC, Shen M, Buhse LF. Measurement of drug in small particles from aqueous nasal sprays by Andersen Cascade Impactor. Pharm Res. 2012;29(11):3122–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Tsuda A, Henry FS, Butler JP. Particle transport and deposition: basic physics of particle kinetics. Compr Physiol. 2013;3(4):1437–71.CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Liu X, Doub WH, Guo C. Assessment of the influence factors on nasal spray droplet velocity using phase-Doppler anemometry (PDA). AAPS PharmSciTech. 2011;12(1):337–43.CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, June 1999, Draft Guidance for Industry, Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action. (Superseded by April 2003 Draft Guidance with same name.) [cited 6/20/2011]. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070111.pdf.
  5. 5.
    US Pharmacopeial Convention: United States Pharmacopeia 41/ National Formulary 36, Chapter <601> Aerosols, nasal sprays, metered-dose inhalers, and dry powder inhalers. Rockville, MD, 2018.Google Scholar
  6. 6.
    European Directorate for Quality in Medicines (EDQM): European pharmacopeia 9.0, monograph 0676. Nasal Preparations, Strasburg, France. EDQM 2017 (January).Google Scholar
  7. 7.
    Trows S, Wuchner K, Spycher R, Steckel H. Analytical challenges and regulatory requirements for nasal drug products in Europe and the U.S. Pharmaceutics. 2014;6:195–219.CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Mitchell JP, Nagel MW, Nichols SC, Nerbrink O. Laser diffractometry as a technique for the rapid assessment of aerosol particle size from inhalers. J Aerosol Med. 2006;19(4):409–33.CrossRefPubMedGoogle Scholar
  9. 9.
    European Medicines Agency (EMEA). Guideline on the pharmaceutical quality of inhalation and nasal products. 2006; EMEA/CHMP/QWP/49313/2005 Final. London, UK. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003568.pdf. accessed August 9 2017.
  10. 10.
    Canada H. Guideline on the pharmaceutical quality of inhalation and nasal products. Health products and food branch. In: File 06-106624-547. Ottawa, Canada; 2005.Google Scholar
  11. 11.
    Hinds WC. Aerosol technology: properties, behavior and measurement of airborne particles. 2nd ed. New York, USA: John Wiley & Sons Ltd.; 1999.Google Scholar
  12. 12.
    Mitchell JP, Nagel MW. Cascade impactors for the size characterization of aerosols from medical inhalers: their uses and limitations. J Aerosol Med. 2003;16(4):341–77.CrossRefPubMedGoogle Scholar
  13. 13.
    Newman SP, Steed KP, Hooper G, Brickwell J. Scintigraphic assessment of the oropharyngeal and nasal depositions of fusafungine from a pressurized inhaler and from a novel pump spray device. J Pharm Pharmacol. 1995;47:818–21.CrossRefPubMedGoogle Scholar
  14. 14.
    Yu CD, Jones RE, Henesian M. Cascade impactor method for the droplet size characterization of a metered-dose nasal spray. J Pharm Sci. 1984;73:344–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Task Group on Lung Dynamics. Deposition and retention models for internal dosimetry of the human respiratory tract. Health Phys. 1966;12:173–207.Google Scholar
  16. 16.
    Kelly JT, Asgharian B, Kimbell JS, Wong BA. Particle deposition in human nasal airway replicas manufactured by different methods. Part I: inertial regime particles. Aerosol Sci Technol. 2004;38(11):1063–71.CrossRefGoogle Scholar
  17. 17.
    Cheng YS. Aerosol deposition in the extrathoracic region. Aerosol Sci Technol. 2003;37(8):659–71.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Yu CD, Jones RE, Henesian M. Cascade impactor method for the droplet size characterization of a metered-dose nasal spray. J Pharm Sci. 1984;73(3):344–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Doub WH, Adams WP. Measurement of drug in small particles/droplets from aqueous nasal spray by cascade impaction. Poster session T3415 presented at Annual Meeting of the American Association of Pharmaceutical Scientists; Nov. 12, 2002. Toronto, Ontario.Google Scholar
  20. 20.
    Nichols SC, Brown DR, Smurthwaite M. New concept for the variable flow rate Andersen cascade impactor and calibration data. J Aerosol Med. 1998;11:133–8.CrossRefGoogle Scholar
  21. 21.
    Trinidade IEK, Oliviera A, Gomes C, Sampaio-Texiera ACM, Trinidade HK. Adult nasal volumes assessed by acoustic rhinometry. Braz J Otorhinolaringol. 2007;73(1):32–9.CrossRefGoogle Scholar
  22. 22.
    Inhalanda Working Party of the European Pharmacopeia. Private communication. 2010.Google Scholar
  23. 23.
    Aiache JM, Beyssac E. Modification of the Twin Impinger for the measurement of particle size from nasal sprays. Pharmeuropa. 1997;9(3):561–5.Google Scholar
  24. 24.
    Hallworth GW, Westmoreland DG. The Twin Impinger: a simple device for assessing the delivery of drugs from metered dose pressurized aerosol inhalers. J Pharm Pharmacol. 1987;39:966–72.CrossRefPubMedGoogle Scholar
  25. 25.
    Williams G, Bickmann D, Blatchford C, Doub B, Mitchell J, Nichols S, Schiewe J, Suman J, Weda M. Towards standardizing methodology for quantifying the emitted fine mass fraction of active pharmaceutical ingredient (API) from nasal products (NPs). Drug delivery to the lungs-24. The Aerosol Society, Edinburgh, UK. 2013, pp. 89–92.Google Scholar
  26. 26.
    Marple VA, Roberts DL, Romay FJ, Miller NC, Truman KG, Van Oort M, Olsson B, Holroyd MJ, Mitchell JP, Hochrainer D. Next generation pharmaceutical impactor. Part 1: design. J Aerosol Med 2003;16(3):283–299.Google Scholar
  27. 27.
    Marple VA, Olson BA, Santhanakrishnan K, Mitchell JP, Murray SC, Hudson-Curtis BL. Next generation pharmaceutical impactor: a new impactor for pharmaceutical inhaler testing. Part III. Extension of archival calibration to 15 L/min. J. Aerosol Med. 2004;17(4):335–43.CrossRefPubMedGoogle Scholar
  28. 28.
    Marple VA, Olson BA, Santhanakrishnan K, Mitchell JP, Murray SC, Hudson-Curtis BL. Next generation pharmaceutical impactor. Part II. Archival calibration. J. Aerosol Med. 2003;16(3):301–24.CrossRefGoogle Scholar
  29. 29.
    Schwab JA, Zenkel M. Filtration of particulates in the human nose. Laryngoscope. 1998;108(1 Pt 1):120–4.CrossRefPubMedGoogle Scholar
  30. 30.
    Djupesland P. Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review. Drug Deliv Transl Res. 2013;3:42–62.CrossRefPubMedGoogle Scholar
  31. 31.
    Derbyshire H, Patel N, Wheeler A. Improving nasal drug delivery with HFA nasal aerosols. The Aerosol Society, Edinburgh, UK: Drug Delivery to the Lungs; 2013. p. 213–6.Google Scholar
  32. 32.
    Intertek S o p. AM560/01. Melbourn, UK; 2018.Google Scholar
  33. 33.
    Pharma A, procedure S o. MO42/01. Le Vaudreuil, France; 2018.Google Scholar
  34. 34.
    Pu Y, Goodey A, Fang X, Jacob K. A comparison of the deposition patterns of different nasal spray formulations using a nasal cast. Aerosol Sci Technol. 2014;48(9):930–8.CrossRefGoogle Scholar
  35. 35.
    Kippax P. Malvern Panalytical Ltd., Malvern, UK. Private communication. 2018.Google Scholar
  36. 36.
    Bonam M, Christopher D, Cipolla D, Donovan B, Goodwin D, Holmes S, et al. Minimizing variability of cascade impaction measurements in inhalers and nebulizers. AAPS PharmSciTechnol. 2008;9(2):404–13.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Gerallt Williams
    • 1
  • Chris Blatchford
    • 2
  • Jolyon P. Mitchell
    • 3
  1. 1.Scientific Affairs, Prescription Division, Aptar PharmaLe VaudreuilFrance
  2. 2.3M United Kingdom plcLoughboroughUK
  3. 3.Jolyon Mitchell Inhaler Consulting Services Inc.LondonCanada

Personalised recommendations