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Pharmaceutical Research

, Volume 30, Issue 6, pp 1698–1713 | Cite as

Optimization of the Fine Particle Fraction of a Lyophilized Lysozyme Formulation for Dry Powder Inhalation

  • Sarah Claus
  • Claudius Weiler
  • Joerg Schiewe
  • Wolfgang Friess
Research Paper

ABSTRACT

Purpose

A new dry powder inhalation technology creates inhalable particles from a coherent lyophilized bulk at the time of inhalation. The aim of this study was to evaluate several approaches to improve the fine particle fraction (FPF) and to understand underlying mechanisms.

Methods

Lysozyme was chosen as model drug. Phenylalanine and valine were added, and the freezing process was varied. Lyophilisate characteristics as well as aerosolization behavior was analyzed.

Results

The addition of the crystalline amino acids rendered a dose independent three-fold increase of the FPF. This is possibly due to enhanced fracture properties of the lyophilisates upon impact of the air stream and reduced particle agglomeration/cohesion caused by a rougher surface. This positive effect was well preserved over 3 months of storage. The structure of the lyophilisate was influenced by the freezing process which in turn affected the aerosolization behavior. Liquid nitrogen and vacuum-induced freezing performed best, doubling the FPF. The special cake morphology with elongated channels enabled easy disintegration. The resulting large porous particles comprise a low density being advantageous for a high FPF.

Conclusion

The variation of the lyophilization process and formulation utilizing excipients enabled an optimization of the FPF of the novel lyophilisate based DPI system.

KEY WORDS

dry powder inhalation fine particle fraction freeze-drying freezing process lyophilisate 

ABBREVIATIONS

ACI

Andersen Cascade Impactor

API

active pharmaceutical ingredient

DPI

dry powder inhaler

ED

emitted dose

FPF

fine particle fraction

Lys

lysozyme

MD

metered dose

Phe

L-phenylalanine

RH

relative humidity

SEM

scanning electron microscopy

Tg′

glass transition temperature of the max. freeze concentrated solution

Val

L-valine

XRD

x-ray diffractometry

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

This research project is supported by Boehringer Ingelheim Pharma GmbH & Co. KG. We thank Holger Holakovsky and Gilbert Wuttke for the possibility to do the high speed camera recordings. We also thank Alexandra Pickel for her analytical contribution to this study.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Sarah Claus
    • 1
  • Claudius Weiler
    • 2
  • Joerg Schiewe
    • 2
  • Wolfgang Friess
    • 1
  1. 1.Department of Pharmacy, Pharmaceutical Technology & BiopharmaceuticsLudwig-Maximilians-Universitaet MuenchenMunichGermany
  2. 2.Boehringer Ingelheim Pharma GmbH & Co. KGIngelheim am RheinGermany

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