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spray drying parameters as well as individual formulations
and particle size distributions would lead to
more robust product profiles, but these were out of
the scope of this study.
SEM and aerosol characterization techniques confirmed
that respirable powder properties were
achieved for both formulations within each simulspray.
The aerosol properties of the powders, measured
by APS and FSI, were consistent with targeted
delivery to the deep lung. This further emphasized
that the non-biased collection of the two formulations
occurred during manufacturing. An evaluation
of the active concentrations of the FSI fine particle
dose showed that the formulation ratios are
maintained during aerosolization. Additionally, the
BEV retained its anti-VEGF bioactivity, as demonstrated
by the ELISA quantification. This was of
particular interest for ERL and PTX simul-spray formulations,
in which the BEV might have been impacted
by ethanol or methanol vapor exposure.
Altogether, these results allay the major concerns
about simul-spray manufacturing.
Though not explored in this study, combination formulations
with deliberately different aerosol properties
could be prepared to expand the therapeutic
range of the actives. For example, one formulation
could be manufactured with smaller particle size to
target the alveolar region of the lung, while a second
could be sized to target the conducting airways. This
approach would not be without its engineering challenges,
particularly around the cyclonic collection of
powders with diverse aerodynamic properties.
4.1.3. Avoid Blending and Carrier Particles
Blending poorly flowing inhalation dry powders is
a substantial challenge in many cases. Once simulspray
drying is complete, no further blending operations
are necessary, and the powder can be filled
directly into blisters or capsules without the need for
additional excipients.
For a biotherapeutic such as the mAb used in this
study, milling is not an option. Materials are typically
supplied as liquid solutions, and even when
lyophilized, shear sensitivity is a challenge, which
would preclude milling. Even for compounds where
milling is feasible, spray drying may still be a preferred
particle engineering technology for inhalation
delivery as it allows for the manufacture of formulations
without the use of inert carrier particles.
This is particularly helpful when high doses (e.g., >5
mg) are required for treatment. For high-dose compounds,
eliminating the need for carrier particles
can help reduce the need for multiple actuations of
the dry powder inhaler, which is a high burden for
cystic fibrosis patients, for example.14
4.2. Significance of the Model Systems
The model systems chosen for this study were selected
due to their potential relevance to the treatment
of lung cancer. BEV is a VEGF-inhibitor monoclonal
antibody first marketed as Avastin.16
BEV is
approved for the treatment of late-stage non-smallcell
lung cancer (NSCLC). It is administered intravenously,
often in combination with chemotherapy,
immunotherapy, or other targeted therapies such as
EGFR-inhibitors.22,23
Our recent study on an inhaled
formulation of BEV manufactured by spray drying
demonstrated the successful reduction of tumors in
a rat model for NSCLC.17
Compounds to pair with BEV for this simul-spray
drying proof-of-concept study were inspired by a
review of inhaled chemotherapy by Rosiere et al.24
This work highlighted the potential of dry powder
inhalers to deliver chemotherapeutic agents directly
to the lung, circumventing many of the safety
challenges of nebulizer delivery. To this end, two
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