eBook: Formulation of Dry Powder Inhaler - 9

anti-VEGF activity assay described above. All three
formulations inhibited VEGF expression similar to
that of a bevacizumab solution control.
The three formulations were also subjected to an
accelerated stability challenge, where samples were
stored for 2 weeks in a closed vial with desiccant at
40°C/75% relative humidity (RH). The same tests described
above were repeated. The largest changes
were found for the 20% formulation, and only small
changes were observed for 10% and 40% formulations.
Based on these results, the 40% bevacizumab
spray-dried powder was selected as the lead formulation
for the remainder of this study due to its good
stability and high active loading. All further references
to spray-dried powders refer to this formulation.
Real-Time Stability Study Design
A real-time stability study was conducted, storing the
bevacizumab spray-dried powder at two conditions:
5°C and 25°C/60% RH. A sample of the spray-dried
powder (150 mg) was sealed in a glass vial. Samples
(10 mg each) were also filled into size 3 capsules
(Vcaps Plus HPMC capsules, Capsugel) in triplicate for
the 6-month stability sample and sealed in a glass vial.
The vials were heat-sealed in a Mylar® bag containing
2 g of silica gel desiccant. Samples were removed for
analysis after storage for 1, 3, and 6 months.
In Vivo Study Design
An in vivo study was designed for the bevacizumab
spray-dried powder using an orthotopic nude rat
model for NSCLC.26
All protocols were reviewed and
approved by an Institutional Animal Care and Use
Committee (IACUC) at LBRI. Research was conducted
under an IACUC-approved protocol in compliance
with the Animal Welfare Act, PHS Policy, and other
federal statutes and regulations relating to animals
and experiments involving animals. The facilities
where this research was conducted are accredited
by the Association for Assessment
and Accreditation of Laboratory Animal Care. The
study tested the effect on tumor size for bevacizumab
spray-dried powder delivered by inhalation (INH)
and bevacizumab administered by intraperitoneal
(IP) injection, with and without cisplatin, a chemotherapy
medication. The NSCLC cell line Calu-3 was
intratracheally instilled into the lungs of seven study
groups of X-irradiated rats, targeting 1.5 × 107
per installation.27 No treatment was given for the
cells
first 4 weeks of the study, enabling growth of the tumor
cells. The study design is shown in Table 2.
Table 2. In Vivo Study Design with NSCLC Orthotopic Nude Rat Model
Study Group Primary treatment (weeks 4-8) Maintenance therapy (weeks 8-12)a Rats
Cisplatin
1a
2b
3
4
5
6
7
No
Yes (IP)
No
Yes (IP)
No
Yes (IP)
Yes (IP)
aNegative control
bPositive control (standard of care for NSCLC)
Bevacizumab Bevacizumab
No
Yes (IP)
Yes (INH)
Yes (INH)
No
Yes (IP)
Yes (INH)
No
No
No
No
No
Yes (INH)
Yes (INH)
15
15
15
15
20
15
15
Endpoints
8-week lung weight
Survival
12-week lung weight
9

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