eBook: Formulation of Dry Powder Inhaler - 38

Lonza is investigating the ability to deliver monoclonal
antibody therapies (mAbs) locally for lung
indications. Currently, mAbs are delivered either as
subcutaneous injections or IV infusions. These treatments
are typically administered on a semi-frequent
basis, creating additional burden for patients who
must receive these drugs through in-person visits to
a medical provider. This, coupled with the dangers
inherent to systemic circulation and the expense
of these more invasive therapies, can lead to poor
patient adherence. An alternative, a nebulizer capable
of targeted drug delivery through inhalation, is
currently being investigated. Strong preclinical evidence
exists to indicate that nebulizers are an effective
means of delivering certain mAbs directly to the
lung; however, there remain a number of hurdles to
their widespread employment. Concerns exist regarding
the stability of these drugs, which are liquid
formulations, as well as those related to the relatively
high treatment burden for patients - though nebulizer
treatments can be administered at home, they
can take hours to complete.
In order to circumvent the challenges related to stability
and delivery presented by this strategy, Lonza
devised an alternative dosage form - dry powder -
and has investigated its use in combination with an
inhaler to facilitate swift drug delivery. For its model
system, Lonza formulated a dry powder for delivery
to the lung by way of a dry powder inhaler, utilizing
spray drying to perform that manufacture. The
team in Bend was able to demonstrate a 40 percent
active formulation that was stable for 12 months
at 25° C, and a high process yield of 90 percent. To
achieve this, Lonza relied on two excipients: trehalose,
a sugar that stabilizes the amorphous state
of the antibody and can help to replace hydrogen
bonding from water, and L-leucine, which enhances
crystallization at a particle's surface, improving the
aerosol properties of the drug within an inhaler and
Figure 1. The above chart illustrates that bevacizumab binds with VEGF
as effectively as the control over a wide range of concentrations, using
luciferase reporter assay kit for VEGF activity (Source: Lonza).
reducing the potential for particles clumping and
becoming trapped in the upper respiratory tract.
Critically, Lonza was able to demonstrate that its
bevacizumab spray drying formulation maintains its
anti-VEGF properties upon reconstitution by utilizing
a cell-based assay designed to quantify bevacizumab's
ability to repress VEGF. Decreased luminescence
in the assay indicated VEGF repression.
With this data, Lonza proceeded to conduct a rat model
study of non-small cell lung cancer to determine
the efficacy of this material. In this model system,
conducted in collaboration with Lovelace Biomedical,
CALU-3 tumor cells were intratracheally instilled into
the lungs of rats. After a four-week growth period to
allow the tumors to grow, treatment was administered
weekly from weeks four to eight. The endpoint
was the weight of the lung, which functions as a proxy
for the tumor burden within the rats. The study divided
rats into four groups: the first, its negative control
group, received no treatment at all. The second
group represented the current standard of care and
approximated the treatment humans receive - injected
cisplatin, a chemotherapy administered alongside
bevacizumab - as well as injected bevacizumab. The
third group received the dry powder bevacizumab
38

eBook: Formulation of Dry Powder Inhaler

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