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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5921_Библиотеки_им_академика_М_И_Перельмана
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form strong hydrogen and π-bonds, it is less hydrophobic than the arginine
sidechain, which may explain why its stabilization capacity is lower.
Interestingly, both arginine and histidine are partially amorphous during
drying, which facilitates molecular level interactions between excipient and
protein amino acids. This may further explain their ability to enhance
stability.
In another study, Faghihi et al. screened several amino acids in spraydried IgG formulations at 20% and 50% (w/w). The stability, emitted dose
(ED), and FPF of the powders were studied. The authors concluded that
phenylalanine and cysteine were the best at reducing aggregation during
processing and storage. The authors suggest that phenylalaine stabilizes
antibodies via hydrophobic and π-stacking interactions with its planar phenyl
sidechain. Interestingly, arginine appeared to denature the antibody more
than other amino acids based on a decrease in beta-sheet content in FTIR,
which seems to contradict other studies and suggests that excipient selection
may be dependent upon antibody identity. Concentration did not impact
stability, but higher amino acid concentration led to larger mean particle sizes
and lower FPF. Of the samples tested, the cysteine formulation had the
highest ED and FPF (95 and 70%, respectively) and generated corrugated
raisin-like particles. Phenylalanine had slightly lower ED (93%) and FPF
(62%) and led to a porous, dimpled surface [47].
3.2 Surface-ActiveExcipients
Surfactants are another well-studied excipient class for mAb formulation.
These are added primarily under the hypothesis that they can minimize
physical stress during drying by excluding protein molecules from the airwater interface of droplets. Faghihi et al. reported that cysteine and
polysorbate 20 (PS20) synergistically improved the stability of trehalose/IgG
formulations compared to either cysteine or PS20 alone [30]. Maa et al.
demonstrated that anti-IgE antibody aggregation during spray drying could
be ameliorated by the inclusion of PS20 [31]. Additionally, they reported that
increasing amounts of PS20 led to smoother antibody/lactose particles,
consistent with the idea that PS20 partitions to the surface of the drying
particle, excluding other molecules from the interface. Batens et al. reported
that inclusion of PS20 in the formulation signiicantly reduced aggregates
during spray drying [48]. However, these excipients can act as destabilizing
plasticizers within amorphous solids after spray-drying, so it is likely best
practice to minimize the amounts in order to maintain physical stability.
Endogenous surfactants formed in the lung are critical to proper lung
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function [49], and the impact of additional surfactants from DPI formulations
on this system is not currently known.
De-aggregation of powder inside a device to primary particles engineered
for light is a critical process for delivery by DPI. Upon inhalation, individual
particles must fully aerosolize and disperse, as aggregates will be too large to
reach the deep lung. Dispersibility of primary particles is improved by
reducing cohesive forces between adjacent particles. Most literature studies
aim to achieve this by some combination of increasing surface roughness
(thus reducing contact areas) [50] and/or by reducing the surface energy of
the particles [51]. Dispersibility-enhancing excipients can improve aerosol
performance of powders by facilitating de-aggregation of the powders as they
are inhaled into the lung [52].
The role of L-leucine in improving dispersibility and aerosol properties of
spray-dried powders for inhalation has been investigated extensively in the
literature [53–55]. A recent review by Alhajj et al. discusses this in detail and
summarizes regulatory considerations for this excipient [56]. Briely,
nucleation of L-leucine nanocrystals from a nearly-saturated spray solution
occurs during the droplet drying process, resulting in a leucine-enriched
surface of the particles. This imparts increased surface roughness, as well as
localization of the leucine crystals at the particle’s interface. These act in
combination to improve the dispersibility of the resulting inhalation
powders. A related excipient, tri-leucine, is also a powerful surface-active
compound that is reported to improve dispersibility [57].
3.3 InteractionofSpray-DryingProcessand
Formulation
The interplay of formulation and spray drying process parameters is critical
to development of a pulmonary powder that meets target product proile
speciications for deep-lung deposition. In the case of a biotherapeutic API
such as a mAb, formulation and process conditions play an additional role in
preventing the aggregation and/or degradation of the fragile active. Proteins
are sensitive to temperature exposure, and spray drying uses a heated drying
gas to produce powder. This apparent conlict is mostly resolved by the
impact of evaporative cooling on the temperature of the droplet during spray
drying. During much of the drying process, the droplet’s temperature is equal
to the wet bulb temperature, rather than the boiling point of the solvent [58].
In this way, temperature exposure can be limited, and API degradation can be
avoided for many systems. Additional destabilizing forces include
dehydration, shear from atomization, and air-liquid interfacial stress [26].
Process conditions and certain excipients can be used to both minimize
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degradation and maximize yield during spray-drying, setting the particles up
for improved stability.
Several seminal papers from Genentech examined the impacts of process
parameters and sugar excipients on mAb DPI critical quality attributes [31,
59, 36, 38, 44]. One recent publication aimed at room temperature bulk
storage optimized spray drying conditions for three model monoclonal
antibodies in parallel [38]. This study compared bench and lab-scale spray
dryers and found that larger-scale dryers created powders with lower water
content (~4% vs. ~8% for bench scale dryers) and ascribed this to a ~10-fold
longer residence time for droplets in the drying chamber.
They also noted that stainless steel is preferable to the glass components
found in some benchtop spray dryers, since static buildup on glass can lead to
particle accumulation on surfaces. The authors state that particle
accumulation on surfaces can also occur via tackiness, which is a complex
attribute inluenced by glass transition temperature of the particle matrix,
formulation, moisture level, and temperature. For instance, they reported that
an antibody:trehalose ratio of 1:2 created tacky particles and poor collection
yields, but ratios of 2:1 or 1:1 resulted in excellent yields of nontacky
powders. Interestingly, they also found that reconstituted spray-dried
powders exhibited substantially less turbidity and protein aggregation than
corresponding freeze dried formulations, though both had more than the
antibody solution prior to drying [38].
Brunaugh et al. employed an anti-streptavidin IgG1 as a model mAb for
dry powder inhalation delivery [60]. Spray drying, spray-freeze drying, and
lyophilization were compared using a formulation of 58.8% protein, 38.2%
sucrose, 1.74% histidine and 0.24% polysorbate 80. A Design of Experiments
(DoE) demonstrated optimized atomization conditions that produced
inhalation-size particles while limiting aggregation of the mAb. Aerosol
performance, secondary structure and aggregation of the dried powders on
stability were investigated. A low liquid feed rate, paired with high
atomization gas low rate and low feed concentration, were found to
discourage changes in secondary structure and aggregation.
Feasibility of spray drying an IgG1 model antibody for pulmonary delivery
was demonstrated by Schu le et al. in 2008 [61]. The formation of aggregates
was characterized as a function of spray drying processing conditions and
formulation composition. Most formulations were prepared with mannitol as
the primary excipient, though inclusion of trehalose was beneicial for
protein stabilization, and isoleucine was also beneicial for improving
aerodynamic and low properties. The authors found that reducing the
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humidity exposure of the formulation during stability was critical to reducing
aggregate formation on storage.
3.4 Spray-DryingScale-U p
A spray-dried inhalation formulation requires special considerations for
scale-up from feasibility batches to clinical and commercial scale. These
challenges are compounded by the sensitivity of a biotherapeutic API such as
a monoclonal antibody. This section discusses a few of these scale-up
challenges and approaches to address them.
Many of the scale-up challenges that apply to pharmaceutical spray drying
in general also apply for inhalation formulations of mAbs and other
biotherapeutics. Atomization of the feed solution into suficiently small
droplets for inhalation delivery becomes challenging at clinical and
commercial scale. A two-luid atomizer, in which an atomizing gas is used to
break up the liquid stream into ine droplets, is commonly used to make
particles targeted for pulmonary delivery. A number-up approach, in which
the liquid feed is divided between multiple nozzles spraying simultaneously
into the dryer, has been used to circumvent these issues [62]. Ultrasonic
spray atomizers, such as those found in the Buchi B-90 dryer [63], can
produce nearly monodisperse droplets at an appropriate size for inhalation
delivery but are not yet scalable to larger dryers. In future work, innovative
atomizer geometries should be considered to improve atomization eficiency
while minimizing shear exposure for delicate actives. Collection of spraydried powders is performed using a cyclone separator at large scale. Mosen et
al. raised the issue that some cyclones have a particle collection cutoff of
~2 μm, leading to incomplete capture of inhalation-sized particles [64]. In
recent years, high-eficiency cyclone geometries have been developed that
improved product recovery for <5-micron powders [65].
For conventional spray drying processes, spray solution preparation and
handling of protein APIs differs from small molecule APIs. Many protein
solutions are supplied frozen, thus, thawing time and appropriate container
geometry must be taken into account for larger batch sizes. mAb drug
substance is typically prepared in buffer solutions with or without stabilizing
excipients. Some amount of solution manipulation is often needed before
spray drying to yield the best powder for a dry powder headed for patient
dosing. As an example, Table 3 compares an IV formulation with a spray
drying solution for bevacizumab. In particular, buffer strength needs to be
reduced before spray drying so that the inal composition of the spray-dried
powder does not contain too much salt for good aerosol performance and to
minimize hygroscopicity, which would be challenging for product
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storage/stability. At a small scale, buffer exchange and excipient introduction
can be handled using a traditional dialysis process. However, at a larger scale,
the buffer quantities necessary for good dialysis practice (~100x the spray
solution volume) become untenable. Tangential low iltration can solve many
of these scaling issues while introducing options for process automation.
Table3 Example bevacizumab solution compositions for IV drug product and spray drying
liquid feed solution
Formulation Phosphate
buffer
mAb
concentration
Trehalose
concentration
Surfactant
concentration
L-leucine
concentration
Intravenous
solution
50 mM,
pH 6.3
30 mg/mL 60 mg/mL 0.04%wt PS 20 None
Spray drying
solution
1 mM,
pH 6.3
4 mg/mL 4 mg/mL None 2 mg/mL
Adapted from Shepard et al. [66]
3.5 DeviceandPackaging
Some challenges for dry powder inhaled mAb formulations include device and
packaging considerations. Many antibody-containing dry powder
formulations are sensitive to humidity exposure and must therefore be
packaged in blisters under controlled conditions. This can be achieved
through secondary packaging of capsules in a blister or through powder-illed
directly into a blister.
The device selection will be largely driven by stability considerations and
optimizing the patient’s treatment experience. In order to improve patient
compliance and reduce the number of device actuations, developers of
pharmaceutical inhalation products are often driven to higher powder doses
and higher active loading within the particle. Improvement in the product’s
delivery eficiency via device design and particle engineering can also help
reduce patient burden. This is especially true in the case of mAbs, where the
two main delivery options are dry powder inhaler and nebulization. One
driver to switch from nebulization to DPI is to reduce the time of dosing from
tens of minutes to only seconds. Additional advantages of DPI over nebulizer
include device portability, ease of use, and shelf stability for the therapeutic.
In the studies discussed here, a formulation with mAb loading of ~50% by
weight is feasible, with a typical maximum loading of 30 mg powder per
actuation. This corresponds to an approximate maximum mAb dose of 15 mg
per DPI actuation. For compounds that require very high pulmonary doses
(e.g., >50 mg), nebulization may still be preferred.
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Though there is currently a large selection of DPI devices on the market,
many were developed with small molecule APIs in mind, particularly using
milled crystalline API or an API/lactose-based carrier formulation. The
continued evolution and expansion of inhaled biologics treatments will no
doubt lead to a focus on developing these new products. After device
actuation, material can remain throughout a multi-use device that is exposed
to ambient humidity when the device is not in use, which could be
problematic for mAb formulations. This has raised the need for either proper
cleaning protocols for multi-use DPI devices or the development of single-use
devices. These considerations must be examined further as dry powder
inhaled mAb products move to later clinical phases.
4 PreclinicalandClinicalCaseStudies
Since foundational studies in spray-dried mAbs for inhalation performed by
Costantino and co-workers on rhuMAbE25 [67], progress has been made in
demonstrating preclinical feasibility, eficacy, and clinical safety of dry
powder inhaled mAbs prepared by spray drying. While hundreds of studies on
pulmonary delivery of spray-dried proteins and other biologics have been
conducted, as summarized in numerous review articles [68–72], the
literature is more constrained for monoclonal antibodies, perhaps due to the
high cost of making and isolating the antibodies themselves. In this section,
key preclinical studies of mAbs (and fragments thereof) are highlighted, as
well as a detailed discussion of the two exemplary clinical trials completed to
date.
Faghihi and colleagues spray-dried inliximab, an anti-TNFα mAb of
interest to treat inlammation, for local delivery to the lung via a dry powder
formulation [73]. Ten spray-dried formulations were tested with varying
ratios of trehalose-to-antibody and cysteine-to-antibody. A lead formulation
(approximately 46% trehalose, 16% cysteine, 38% antibody with 0.05%
Tween 20) was selected based on exhibiting good aerodynamic properties,
low initial aggregation, and low fragmentation on stability. An in vitro cellbased assay demonstrated biological activity was well-preserved in the
spray-dried lead formulation compared with the commercial inliximab IV
formulation. The anti-inlammatory effect of spray-dried mAb was
demonstrated in an allergen-induced mouse model, showing that lung TNFα
secretion was signiicantly reduced when mice were treated with inhaled
spray-dried inliximab formulation.
Shepard et al. demonstrated a spray-dried bevacizumab formulation for
delivery to the lung as a potential treatment for lung cancer [74].
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Bevacizumab, an anti-VEGF compound that can interrupt the formation of
new blood vessels in tumors, is approved for IV administration to lung cancer
patients, often in combination with chemotherapy. A bevacizumab
formulation with trehalose and L-leucine was shown to be physically stable
for 24 months at 25 °C as measured by the maintenance of good aerosol
properties and in vitro bioactivity [75]. The spray-dried formulation was
administered via inhalation in a nude rat model of non-small-cell lung cancer,
where it reduced tumor burden both in combination with chemotherapy (IV
cisplatin) and on its own. In a follow-up publication, dry powder bevacizumab
formulation was paired with cancer-relevant small molecules to produce a
combination DPI powder using a simultaneous spray drying process [76].
The irst clinical trial of a dry powder inhaled antibody antigen-binding
fragment (Fab) was conducted in 2016 on VR942 (NCT02473939) [77].
VR942, also named abrezekimab, is an anti-IL-13 compound indicated for the
treatment of asthma that is uncontrolled by corticosteroid therapy. The
spray-dried powder was formulated with trehalose, L-leucine, and phosphate
buffer as excipients, then administered using a unit-dose DPI device from
blisters, illed with either 0.5 mg active or 5.0 mg active. Daily doses of up to
20 mg for 10 days were generally well tolerated by healthy participants and
participants with asthma. The authors stated that the results of the study
justiied further evaluation of the drug in additional clinical trials, though no
further clinical trials have been published at the time of this chapter’s writing.
Ecleralimab, previously known as CSJ117, is an anti-TSLP antibody
fragment from Novartis indicated for asthma treatment. A spray-dried
inhalable formulation was formulated with leucine, trileucine, mannitol, and
trehalose as excipients. Though no peer-reviewed results were released for
this product, clinical trial results are available on Novartis’ website. A phase 1
study was completed in 2019, in which participants received 4 mg daily of
CSJ117 dry powder for 12 weeks (NCT03138811). Participants with asthma
underwent an allergen inhalation challenge, and forced expiratory volume
was quantiied afterward. Adequate safety and tolerability were
demonstrated, as well as an improved response to the allergen inhalation
challenge for those treated with CSJ117. Based on these promising results, a
phase 2 study is currently recruiting at the time of this chapter’s writing
(NCT04410523).
5 OutlookandConclusions
Interest in dry powder inhaled mAbs has grown stronger in recent years as
manufacturing technology has progressed, and the irst antibody fragment
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treatments have reached clinical trials. The pipeline of drugs for respiratory
illnesses is developing as well, with an increasing fraction of biotherapeutics
in the preclinical stages (currently ~30%). Though monoclonal antibodies are
the focus of this chapter, many of the same formulation strategies and
manufacturing considerations apply to mAb-adjacent actives such as
antibody fragments (Fabs) and nanobodies (VHHs) [78]. Here, we discuss our
opinions on the outlook for dry powder inhaled mAbs in the treatment of lung
disease and ask some open questions for future research.
In the many studies referenced above, a range of model IgG compounds,
new chemical entities (both mAb and Fab), and commercially approved mAbs
are used to demonstrate formulation and process approaches to DPI
development. The generalizability of formulation and manufacturing
strategies between different mAbs remains an open question. Due to the
structural similarity between mAb compounds, it is more likely that a
generalized formulation platform for mAbs is possible than it is for proteins
in general. Early-stage screening approaches to determine the sensitivity of
mAbs [79] and enzymes [80] have been proposed to address these questions
in a materials-sparing fashion.
In other sections of this book, the therapeutic advantages of inhaled
delivery of mAbs are discussed more generally. Many of the advantages of a
dry powder inhaled mAb formulation relate to stability and patient
experience. Dry powder inhalers are also convenient for patients, as they can
deliver up to 30 mg powder per actuation in just seconds, compared with
minutes-long nebulizer treatments. DPIs can be administered at home with
no special equipment, whether once-daily or multiple times a day. Patient
education for DPIs is straightforward compared with nebulizers or even
metered-dose inhalers, simplifying compliance.
Finally, dry-powder mAb formulations discussed above have often
demonstrated excellent physical stability, even at 25 °C. Avoiding cold-chain
storage enables simpler distribution to patients with less chance of
accidental spoilage, especially in rural areas or developing countries. This
could help expand patient access to eficacious treatments for lung diseases.
Continuing investigation of dry powder mAb delivery to the lung is warranted
to realize these promising beneits for patients in need.
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