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Inhalable Spray-Freeze-Dried Powder with L-Leucine that Delivers Particles Independent of Inspiratory Flow Pattern and Inhalation Device

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ABSTRACT

Purpose

The purpose of this study was to develop inhalable particles that can reach deep into the lungs efficiently independent of inhalation patterns of patients and inhalation devices. We prepared porous particles including L-leucine (Leu), a dispersive agent, by a spray-freeze-drying (SFD) method and examined the influence of inspiratory flow patterns and inhalation devices with various inhalation resistances.

Methods

Four types of SFD powder with different Leu contents (0–10%) were prepared. Scanning electron microscopy and laser diffraction were used to measure the morphology and size distribution of the powders. In-vitro inhalation characteristics were determined using a twin-stage liquid impinger equipped with an inspiratory flow pattern simulator. The effects of Leu on the adhesion force and electrostatic property of the particles were evaluated.

Results

The inhalation performance of the powders was improved by the addition of Leu. The powders with Leu showed a high inhalation performance regardless of inspiratory flow patterns and devices. The addition of Leu decreased the adhesion force and increased the surface potential of the powders.

Conclusions

The SFD particles with Leu showed high inhalation performance regardless of the inhalation patterns and devices, which was attributed to the decreased adhesion force between particles and increased dispersibility.

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Abbreviations

ANOVA:

Analysis of variance

AUC:

Area under the flow rate-time curve

D50:

Geometric mean diameter

DPI:

Dry powder inhaler

FIR:

Flow increase rate

FlNa:

Sodium fluorescein

Leu:

L-leucine

Man:

D-(-)-mannitol

MMAD:

Mass median aerodynamic diameter

OE:

Output efficiency

PBS:

Phosphate buffer solution

PFR:

Peak flow rate

pMDI:

Pressurized metered-dose inhaler

SEM:

Scanning electron microscopy

SFD:

Spray-freeze-drying

St 2:

Stage 2 deposition

TSLI:

Twin-stage liquid impinger

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported by Adaptable and Seamless Technology Transfer Program through target-driven R&D, Japan Science and Technology Agency (JST). We thank Hitachi Automotive Systems, Co., Ltd., for supplying inspiratory flow meter and inhalation devices.

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Authors and Affiliations

  1. Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 468-8503, Japan

    Hiroko Otake, Tomoyuki Okuda, Daiki Hira, Haruyoshi Kojima & Hirozazu Okamoto

  2. Department of Pharmacy, Shiga University of Medical Science Hospital, Setatsukiwa-cho, Ohtsu, 520-2192, Japan

    Daiki Hira

  3. Nano Seeds Corporation, 2266-99 Anagahora, Shimoshidami, Moriyama-ku, Nagoya, 463-8560, Japan

    Yasuhiro Shimada

Authors
  1. Hiroko Otake
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  2. Tomoyuki Okuda
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  3. Daiki Hira
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  4. Haruyoshi Kojima
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  5. Yasuhiro Shimada
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  6. Hirozazu Okamoto
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Corresponding author

Correspondence to Hirozazu Okamoto.

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Otake, H., Okuda, T., Hira, D. et al. Inhalable Spray-Freeze-Dried Powder with L-Leucine that Delivers Particles Independent of Inspiratory Flow Pattern and Inhalation Device. Pharm Res 33, 922–931 (2016). https://doi.org/10.1007/s11095-015-1838-4

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  • DOI: https://doi.org/10.1007/s11095-015-1838-4

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