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Heat-Stable Dry Powder Oxytocin Formulations for Delivery by Oral Inhalation

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Abstract

In this work, heat stable dry powders of oxytocin (OT) suitable for delivery by oral inhalation were prepared. The OT dry powders were prepared by spray drying using excipients chosen to promote OT stability including trehalose, isoleucine, polyvinylpyrrolidone, citrate (sodium citrate and citric acid), and zinc salts (zinc chloride and zinc citrate). Characterization by laser diffraction indicated that the OT dry powders had a median particle size of 2 μm, making them suitable for delivery by inhalation. Aerodynamic performance upon discharge from proprietary dry powder inhalers was evaluated by Andersen cascade impaction (ACI) and in an anatomically correct airway (ACA) model, and confirmed that the powders had excellent aerodynamic performance, with respirable fractions up to 77% (ACI, 30 L/min). Physicochemical characterization demonstrated that the powders were amorphous (X-ray diffraction) with high glass transition temperature (modulated differential scanning calorimetry, MDSC), suggesting the potential for stabilization of the OT in a glassy amorphous matrix. OT assay and impurity profile were conducted by reverse phase HPLC and liquid chromatography-mass spectrometry (LC-MS) after storage up to 32 weeks at 40°C/75%RH. Analysis demonstrated that OT dry powders containing a mixture of citrate and zinc salts retained more than 90% of initial assay after 32 weeks storage and showed significant reduction in dimers and trisulfide formation (up to threefold reduction compared to control).

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Abbreviations

OT:

Oxytocin

Tg:

Glass transition temperature

PVP:

Polyvinylpyrrolidone

MDSC:

Modulated differential scanning calorimetry

ACI:

Andersen cascade impactor

PIP:

Peak inspiratory pressure

ACA:

Anatomically correct airway

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Authors and Affiliations

  1. Mannkind Corporation, One Casper Street, Danbury, Connecticut, 06810, USA

    Karine Fabio, Kieran Curley, Joseph Guarneri, Benoit Adamo, Brendan Laurenzi, Marshall Grant, Kelly Kraft & Andrea Leone-Bay

  2. Mintaka Foundation, Geneva, Switzerland

    Robin Offord

Authors
  1. Karine Fabio
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  2. Kieran Curley
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  3. Joseph Guarneri
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  4. Benoit Adamo
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  5. Brendan Laurenzi
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  6. Marshall Grant
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  7. Robin Offord
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  8. Kelly Kraft
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  9. Andrea Leone-Bay
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Corresponding author

Correspondence to Karine Fabio.

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Fabio, K., Curley, K., Guarneri, J. et al. Heat-Stable Dry Powder Oxytocin Formulations for Delivery by Oral Inhalation. AAPS PharmSciTech 16, 1299–1306 (2015). https://doi.org/10.1208/s12249-015-0314-0

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  • DOI: https://doi.org/10.1208/s12249-015-0314-0

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