1. Introduction
Inhalable dry powder formulations propose great potential to improving lung cancer
treatment as they can be utilized for targeted pulmonary delivery of drugs directly to
the lungs. For many drugs, delivery via intravenous or oral administration routes
requires high systemic drug concentrations while a relatively low amount of the drug
actually reaches the lung. Through targeted inhalation, cell specificity to the lung may
be achieved, potentially reducing necessary administered dosage, decreasing drug
toxicity, thus limiting systemic side effects. Spray drying is a pharmaceutical
engineering process that produces a dry powder from a liquid by rapidly drying the
liquid with a hot gas. This allows for the formation of consistent, spherical particles
that are more easily distributed to deeper regions of the lung. Several particle
properties influence the aerosol performance including the aerodynamic diameter,
particle size distribution, particle morphology, and surface roughness. Iron Oxide
(Fe3O4) magnetic nanoparticles (MNPs) are capable of heating upon exposure to an
alternating magnetic field (AMF), and can be used to administer hyperthermia, the
heating of tissue above normal body temperature to around 41-45°C. In conjunction
with chemotherapy and radiation treatment, hyperthermia has been shown to increase
DNA damage, inhibit DNA repair, and increase drug efficacy and uptake.
Incorporation of these MNPs, along with common anti-cancer agents, into spray-dried
powder formulations shows promise in treating lung cancer. Side effects may be
minimized with decreased reliance on drug dose, and destruction to healthy tissue may
be reduced, given that the particles have adequate aerodynamic properties that will
allow specific targeting of the lungs.
Formulation and Characterization of Inhalable Spray Dried Powders with
Magnetic Nanoparticles and Anti-Cancer Agents for Lung Cancer Treatment
Marjorie L. Guy1, Nathanael Stocke2, J. Zach Hilt2
1College of Arts and Science, Department of Biology, University of Kentucky, Lexington, KY, USA
2 College of Engineering, Department of Chemical and Materials Engineering, University of Kentucky, Lexington, KY, USA
• Formulate inhalable dry powder systems containing common anti-cancer-agents
(ACAs), Cisplatin or Erlotinib, and/or MNPs along with the FDA-approved excipient
D-mannitol
• Characterize the physiochemical properties of spray dried powders
• In vitro testing of the aerodynamic performance of the inhalable dry powder systems
using Next Generation Impactor (NGI) technology
• Successful formulation of spray dried dry powders with common anti-cancer agents as well
as Iron Oxide magnetic nanoparticles
• NGI studies confirm increased aerosol performance of spray dried powders to disperse
throughout the regions of the simulated lung
• Characterization analyses signify high potential for advancement in increasing effectiveness
of lung cancer treatments
METHODS & RESULTSBACKGROUND
DSC: TA Instruments® Q200 DSC was used to determine thermal phase transitions of the
formulated powders and the raw components of each
• 2-5mg of powder into a Tzero Hermetic Alonoid pan with lid, DSC thermograms were
produced using 50mL/ minute nitrogen gas purge, a ramp rate of 5°C/min from 0-300°C
TGA was used to determine the iron oxide loading in the particle systems
• experimental parameters are as follows: ramp at 5°C/min to 120°C, isothermal for 20 min,
ramp at 5°C/min to 500°C, isothermal for 30 min, with a purge rate of 20mL/min.
• 2-5mg of sample were used in this analysis
System MNP loading (wt%)
MF15 37.55 %
MFE15-0.1 37.53 %
Differential Scanning Calorimetry (DSC) & Thermogravimetric Analysis
(TGA)
Heating Studies
• Spray-dried powders with 20 (MF20)
and 5 (MF5) wt% MNPs were
compared to the as synthesized
nanoparticles (MNPs)
• Spray dried powders were dissolved
in DI H2O and placed in an
alternating magnetic field to
determine heating capabilities upon
AMF exposure
• Results indicate that MNPs retain
their ability to heat after being
incorporated into spray-dried powders
Objectives
Next Generation Impactor (NGI)
Studies
• In vitro study of aerosol dispersion
performance of spray dried powders
• 10mg powders loaded into Spiriva capsules
(n=3) and inserted in Spiriva HandiHaler® dry
powder inhaler (DPI)
• Spray-dried powders showed enhanced
aerodynamic performance compared to raw
forms
• PXRD showed crys tallinity of
formulate powders
• Intense peaks represent crystalline
structure and long range order
Powder X-Ray Diffraction
(PXRD)
TGA
DSC
CONCLUSIONS
EM10
Electron Microscopy
• Scanning electron microscopy
(SEM) used to observe raw
and spray-dried powders
• Raw powders contain large
irregular crystals
• Spray-dried powders showed
spherical particle morphology
subsequent to spray drying
• Spray-dried powders show
relatively uniform particle
size distribution and smooth
surface
• Images show the effects of
spray drying to create
uniform, spherical particles
that are more effectively
aerosolized for deeper
distribution to the lungs
Raw Cisplatin
Erlotinib
CMS10
EM10
Powder Systems
• All powders had a solute
concentration of 0.1% (w/v)
• All powders* formulated w/ FDA-
approved excipient D-mannitol
• Powders with erlotinib and MNPs
used methanol as spray drying solvent
• Powders with cisplatin used DI-H2O
• MNPs used were uncoated Iron Oxide
• Powders containing Cisplatin included
Sodium chloride for increased stability
• Mixtures converted to dry powders via
Büchi Mini Spray Dryer B290
• DSC thermograms showed expected melting
points for D-mannitol (~165°C) and
erlotinib (~240°C)
• Decomposition of cisplatin occurred at
(~290°C)
• TGA showed iron oxide loadings higher
loading of MNPs than feed conditions
because of high density