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Development and Characterization of Nanostructured Mists with Potential for Actively Targeting Poorly Water-Soluble Compounds into the Lungs

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ABSTRACT

Purpose

To formulate nanoemulsions (NE) with potential for delivering poorly water-soluble drugs to the lungs.

Method

A self nanoemulsifying composition consisting of cremophor RH 40, PEG 400 and labrafil M 2125 CS was selected after screening potential excipients. The solubility of carbamazepine, a poorly water-soluble drug, was tested in the formulation components. Oil-in-water (o/w) NEs were characterized using dynamic light scattering, electrophoretic light scattering, transmission electron microscopy (TEM) and differential scanning calorimetry. NEs were nebulized into a mist using a commercial nebulizer and characterized using laser diffraction and TEM. An aseptic method was developed for preparing sterile NEs. Biocompatibility of the formulation was evaluated on NIH3T3 cells using MTT assay. In vitro permeability of the formulation was tested in zebra fish eggs, HeLa cells, and porcine lung tissue.

Results

NEs had neutrally charged droplets of less than 20 nm size. Nebulized NEs demonstrated an o/w nanostructure. The mist droplets were of size less than 5 μm. Sterility testing and cytotoxicity results validated that the NE was biocompatible and sterile. In vitro tests indicated oil nanodroplets penetrating intracellularly through biological membranes.

Conclusion

The nanoemulsion mist has the potential for use as a pulmonary delivery system for poorly water-soluble drugs.

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Abbreviations

CBZ:

carbamazepine

CLSM:

confocal laser scanning microscope

DAPI:

4′,6-diamidino-2-phenylindole

DLS:

dynamic light scattering

DMEM:

Dulbecco’s Modified Eagle Medium

ELS:

electrophoretic light scattering

FBS:

fetal bovine serum

FTM:

fluid thioglycollate medium

He-Ne laser:

Helium-Neon laser

km ratio:

surfactant/co-surfactant ratio

MH:

Mueller Hinton

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NE:

nanoemulsions

OCT:

optimal cutting temperature

PBS:

phosphate buffered saline

SCD:

soybean casein digest medium

SNE:

self-nanoemulsifying

SNEDDS:

self-nanoemulsifying drug delivery system

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Acknowledgments and Disclosures

This research was performed with support from start-up funds made available by the Department of Pharmacy Practice at the University of Toledo College of Pharmacy and Pharmaceutical Sciences. We are grateful to Dr. Joseph Lawrence, Center for Sensor and Materials Characterization, University of Toledo College of Engineering for his assistance during the TEM work. We also thank Ms. Maki Takahashi, Department of Pharmacology, University of Toledo College of Pharmacy and Pharmaceutical Sciences for her help with cell cultures.

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Authors and Affiliations

  1. Department of Pharmacy Practice College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio, USA

    Jerry Nesamony, Ashish Kalra, Mohamed S. Majrad, Sai Hanuman Sagar Boddu & Rose Jung

  2. Department of Pharmacology College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio, USA

    Frederick E. Williams, Alaina M. Schnapp & Surya M. Nauli

  3. Department of Surgery, College of Medicine and Biomedical Sciences, University of Toledo HSC, Toledo, Ohio, USA

    Andrea L. Kalinoski

  4. Division of Industrial Pharmacy, Department of Pharmacy Practice College of Pharmacy and Pharmaceutical Sciences, University of Toledo HSC, 3000 Arlington Avenue, MS1013, Toledo, Ohio, 43614, USA

    Jerry Nesamony

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  1. Jerry Nesamony
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Correspondence to Jerry Nesamony.

Electronic Supplementary Material

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Supplemental figure 1

Schematic diagram depicting generation of the nanostructured mist (JPEG 9 kb)

High resolution image (TIFF 1060 kb)

Supplemental figure 2

3-day CLSM images obtained by virtual optical cross sectioning through a zebra fish egg exposed to 100 mg/ml Sudan IV loaded NE for 6 h (JPEG 11 kb)

High resolution image (TIFF 1160 kb)

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Nesamony, J., Kalra, A., Majrad, M.S. et al. Development and Characterization of Nanostructured Mists with Potential for Actively Targeting Poorly Water-Soluble Compounds into the Lungs. Pharm Res 30, 2625–2639 (2013). https://doi.org/10.1007/s11095-013-1088-2

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