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Mixing energy as an adjustment tool for aerodynamic behaviour of an inhaled product : In-vitro and in-vivo effects

Thalberg, Kyrre LU ; Matilainen, Laura ; Heinonen, Elina ; Eriksson, Patrik ; Husman-Piirainen, Johanna ; Autio, Maiju ; Lyberg, Ann Marie ; Göransson, Stefan ; Kirjavainen, Merja and Lähelmä, Satu (2024) In International Journal of Pharmaceutics 651.
Abstract

This paper describes the development of a fixed dose dry powder combination of indacaterol maleate (Inda) and glycopyrronium bromide (Glyco) in Easyhaler® inhaler for a comparative pharmacokinetic (PK) study, as well as the outcome of such a study. The development aim was to produce formulations with three different in vitro dispersibility profiles for both Inda and Glyco. This so-called ‘rake’ approach allows for quantitation of the candidate formulations relative to the reference product Ultibro® Breezhaler® in terms of the key PK parameters. Three formulations (A, B and C) were produced based on the mixing energy concept. For both APIs, formulation A (lowest mixing energy) displayed the highest fine particle fractions and formulation... (More)

This paper describes the development of a fixed dose dry powder combination of indacaterol maleate (Inda) and glycopyrronium bromide (Glyco) in Easyhaler® inhaler for a comparative pharmacokinetic (PK) study, as well as the outcome of such a study. The development aim was to produce formulations with three different in vitro dispersibility profiles for both Inda and Glyco. This so-called ‘rake’ approach allows for quantitation of the candidate formulations relative to the reference product Ultibro® Breezhaler® in terms of the key PK parameters. Three formulations (A, B and C) were produced based on the mixing energy concept. For both APIs, formulation A (lowest mixing energy) displayed the highest fine particle fractions and formulation C (highest mixing energy) the lowest. GMP manufacturing confirmed the performance of the three formulations. The candidate formulations were tested against the reference product in a single dose PK study in healthy volunteers. Clear differences in Inda plasma concentration profiles were observed between the treatments when administered concomitantly with charcoal, with Easyhaler A showing the highest Cmax value and Easyhaler C the lowest. Easyhaler B was bioequivalent to Ultibro Breezhaler with regard to the primary PK parameters of Inda, Cmax and AUC72h. For Glyco, Easyhaler formulations A, B and C provided lower peak concentrations than Ultibro Breezhaler. For AUC72h of Glyco, Easyhaler B was bioequivalent to the reference product. Additional measures for adjustment of formulation performance can be foreseen, whose effects can be predicted based on mixing energy theory.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Dry powder inhaler, Fine particle fraction (FPF), Glycopyrronium, Indacaterol, Mixing energy, Pharmacokinetic study
in
International Journal of Pharmaceutics
volume
651
article number
123755
publisher
Elsevier
external identifiers
  • scopus:85181901646
  • pmid:38163524
ISSN
0378-5173
DOI
10.1016/j.ijpharm.2023.123755
language
English
LU publication?
yes
id
455be346-1af2-42ed-9cf5-ec75bc2d0cb3
date added to LUP
2024-02-12 11:33:20
date last changed
2025-01-07 05:57:18
@article{455be346-1af2-42ed-9cf5-ec75bc2d0cb3,
  abstract     = {{<p>This paper describes the development of a fixed dose dry powder combination of indacaterol maleate (Inda) and glycopyrronium bromide (Glyco) in Easyhaler® inhaler for a comparative pharmacokinetic (PK) study, as well as the outcome of such a study. The development aim was to produce formulations with three different in vitro dispersibility profiles for both Inda and Glyco. This so-called ‘rake’ approach allows for quantitation of the candidate formulations relative to the reference product Ultibro® Breezhaler® in terms of the key PK parameters. Three formulations (A, B and C) were produced based on the mixing energy concept. For both APIs, formulation A (lowest mixing energy) displayed the highest fine particle fractions and formulation C (highest mixing energy) the lowest. GMP manufacturing confirmed the performance of the three formulations. The candidate formulations were tested against the reference product in a single dose PK study in healthy volunteers. Clear differences in Inda plasma concentration profiles were observed between the treatments when administered concomitantly with charcoal, with Easyhaler A showing the highest C<sub>max</sub> value and Easyhaler C the lowest. Easyhaler B was bioequivalent to Ultibro Breezhaler with regard to the primary PK parameters of Inda, C<sub>max</sub> and AUC<sub>72h</sub>. For Glyco, Easyhaler formulations A, B and C provided lower peak concentrations than Ultibro Breezhaler. For AUC<sub>72h</sub> of Glyco<sub>,</sub> Easyhaler B was bioequivalent to the reference product. Additional measures for adjustment of formulation performance can be foreseen, whose effects can be predicted based on mixing energy theory.</p>}},
  author       = {{Thalberg, Kyrre and Matilainen, Laura and Heinonen, Elina and Eriksson, Patrik and Husman-Piirainen, Johanna and Autio, Maiju and Lyberg, Ann Marie and Göransson, Stefan and Kirjavainen, Merja and Lähelmä, Satu}},
  issn         = {{0378-5173}},
  keywords     = {{Dry powder inhaler; Fine particle fraction (FPF); Glycopyrronium; Indacaterol; Mixing energy; Pharmacokinetic study}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{International Journal of Pharmaceutics}},
  title        = {{Mixing energy as an adjustment tool for aerodynamic behaviour of an inhaled product : In-vitro and in-vivo effects}},
  url          = {{http://dx.doi.org/10.1016/j.ijpharm.2023.123755}},
  doi          = {{10.1016/j.ijpharm.2023.123755}},
  volume       = {{651}},
  year         = {{2024}},
}