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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5642_Библиотеки_им_академика_М_И_Перельмана
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remodelling caused by ibrosis in COPD and idiopathic pulmonary
ibrosis evokes an increase in the air-blood barrier thickness due to
tissue hypertrophy.
4 ProductionandDesign ofPeptide-Load
InhalableParticlesforDPI
To manufacture inhalable particles with desirable inhalation
performance and suficient peptide delivery, the production method
and particle design are crucial for determining the potential of the DPI
system. The particle manufacturing approach can be categorized using
an intuitive approach based on whether the starting material is a solid
particle (top-down method) or a liquid (bottom-up method) (Table 2).
The manufacturing approach and composition have a signiicant
impact on the powder properties and the physical and chemical
stability of the included peptides. Thus, powderization techniques
should be carefully selected based on the physicochemical properties
and stability of the target peptide.
Table2 Particle production methods for inhalable powders
Category Technique Characteristic Reference
Top-downapproaches
Milling Ball/beads milling High shear stress
Necessity of separating
solid milling media
Concerns of
contamination with
foreign particulate
Jet milling Commercially
established method for
small molecular drugs
for inhalation
No solid milling media
No subsequent
separation process
[33, 53,
78]
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Category Technique Characteristic Reference
Homogenization High-pressure
homogenization
Necessity of
evaporation step after
micronization
Commercially used for
non-inhalation drugs
Bottom-upapproaches
Solvent
evaporation
Spray-drying Commercially
established method as
single-step particle
formation process
Controlling size,
morphology, density,
surface composition
[3, 8]
Spray freeze-drying Variant of spray-drying
process
Two-step process
(freezing and
lyophilization)
Production of fragile
particles with very low
density
No thermal stress, but
poor scalability and
complex process
[58, 59,
76]
Supercritical luid method
(rapid expansion):
Supercritical luidassisted atomization
Use SCF CO2 as
atomizing medium
No use of organic
solvent
[31, 64]
Antisolvent Supercritical luid method
(antisolvent)
Use SCF CO2 as an antisolvent to precipitate
ine particles
[36, 37]
4.1 PreparationMethod
4.1.1 Top-DownMethod
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In top-down approaches, target bulk particles are mechanically broken
down into micron-sized particles or aggregated in the respirable size
range (e.g., milling and high-pressure homogenization). Among the
top-down approaches, jet milling is a well-established method for the
production of DPI systems because it is faster, more scalable, and offers
a better-controlled particle size distribution than homogenization or
ball milling. Additionally, because of the media-less milling process,
there is no requirement for the separation of micronized particles from
the milling media. During jet milling, coarse particles of the raw feed
are injected into the milling chamber with a forceful stream of highpressure gas and then pulverized by repetitive inter-particle collisions
and attritions [41]. However, similar to other top-down approaches,
there are stability concerns due to the susceptibility of
macromolecules in the environment, and the heat and mechanical
stresses generated by high-energy conditions and harsh physical
grinding. High pressure is also known to cause denaturation of
peptides and proteins [77]. Depending on the operating conditions of
jet milling, the milling process contributes to the loss of potency of
target peptides due to the mechanical stresses of the jet-milling
process. Although top-down approaches are commonly used for the
micronization of many types of small-molecule drugs, optimized
micronizing conditions should be considered in the case of biologics
such as peptides.
4.1.2 Bottom-UpMethod
In contrast to top-down approaches, there are various bottom-up
approaches, leading to the diversity of starting materials, including
simple solutions, cosolvent solutions, oil in water (O/W) or water in oil
(W/O) emulsions, suspensions, or more complex colloidal luids,
suggesting lexibility for designing functional particles. The particles
are generated by single-step solvent evaporation, such as spray-drying,
and more complex processes, such as precipitation using an
antisolvent. Compared to top-down approaches, the molecular,
colloidal, or powder nature of bottom-up approaches can be wellcontrolled, such as particle morphology and size, surface properties,
and crystallinity. Additionally, the combined use of pharmaceutical
excipients in bottom-up approaches allows further characterization of
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the physicochemical, chemical, and physical stability and inhalation
performance of DPI.
Spray drying is a well-established powderization technology for the
preparation of solid particle formulations [24]. This process consists of
three steps: atomization of the sample solution into ine droplets,
drying by hot air, and collection of the generated powder. This
technique has been used to develop formulations of small-molecule
drugs with poor water solubility; however, it is increasingly used to
provide powder formulations of macromolecules and
biopharmaceuticals [24]. The freeze-drying method is commonly used
for solidiication of peptide solutions. Compared with the freeze-drying
method, the spray-drying method can generate ine particles with ine
aerosolization performance for DPI and can control the powder
properties in terms of morphology, size distribution, shape, and
surface texture with scalability. During the spray-drying process, it is
possible to expose some stresses, including mechanical stress, heat
stress, and adsorption at the air-liquid interface during atomization.
Although spray-drying has fewer sources of stress to induce
denaturation of peptides than the mechanical top-down approach,
there is still some possibility of aggregation and denaturation of
peptides during the process. Thus, the atomizing conditions
(atomizing pressure, feed pump, and feed concentration) and drying
conditions (temperature of hot air and low rate) should be carefully
optimized depending on the target peptides.
Spray-freeze-drying is a variant of the spray-drying process used to
generate highly porous particles, such as freeze-dried cakes. In this
process, the droplets generated from the spray nozzles were directly
frozen using liquid nitrogen and then lyophilized [45]. This process can
be used to prepare inhalable spherical particles with high porosity,
thereby improving inhalation performance. However, the spray-freezedrying process is a very complex process with poor scalability; thus,
the applicability might be limited in some cases using highly heatsensitive compounds in conventional spray-drying systems.
Supercritical luid (SCF) technologies have also been applied to
prepare particles for inhalation [75]. Owing to relatively mild
conditions (relatively low critical temperature: 31.1 °C and pressure:
7.38 MPa), SCF carbon dioxide (SC-CO2) is commonly used to develop
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the formulations. During the particle production process, SC-CO2 can
act as an anti-solvent to precipitate peptide-loaded particles. This
process has been used to prepare dried protein and peptide
formulations, and to provide the possibility of producing small
microparticles suitable for inhalation. Briely, an aqueous sample
solution containing peptides, proteins, and ethanol was atomized
through a coaxial nozzle into a pressurized chamber illed with SC-CO2.
The drug-loaded particles were then precipitated from the water
droplet. Among the various SCF-based powderization systems, SCFassisted atomization (SAA), where SC-CO2 serves as the atomizing
medium, has been highlighted for its availability in aqueous solutions
without the use of any organic solvents [64]. Although there are still no
products for commercially available DPI manufactured by SCF systems,
some studies on the production of macromolecule-loaded powders,
including insulin, lysozyme, and albumin, have been reported [17, 23,
61, 64]. According to these studies, although biologics-loaded particles
can be successfully developed by the SCF approach, the stability and
inhalation performance of the prepared particles were dependent on
the physicochemical characteristics of the target peptides and process
conditions, such as temperature and pH conditions.
In addition to the conventional technique to prepare uniform
micron-sized particles for inhalation, some unique technologies have
been reported recently. The ine droplet drying (FDD) process is a
powderization technique that employs an inkjet head used in the
printing industry [62, 68]. In this process, the inkjet head uses a piezo
element as an actuator to produce uniform ine droplets, resulting in
uniform particles after drying the generated droplets. The size of the
produced particles could be precisely controlled at the single-micron
scale by changing the size of the nozzle holes. In a previous study,
salmon calcitonin was encapsulated in poly(lactic-co-glycolic acid)
using the FDD process for inhalation to sustain its pharmacological
action [62].
4.2 ExcipientstoEnhanceStabilityofPeptides
As mentioned above, there are many possible stresses that induce the
degradation, aggregation, and denaturation of target peptides during
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the manufacturing process of inhalable particles. The target
compounds should be protected from such stresses and stabilized
without affecting their biological activity. Immobilization of peptides
by solidiication and entrapment within the carrier matrix can simply
contribute to preserving biological action to prevent aggregation and
conformational changes. There are many kinds of excipients, such as
sugars, polyols, salts, amino acids, polymers, and surfactants, which
can be applied as stabilizing agents for peptides during the
manufacturing process (Table 3). However, the use of excipients for
stabilization of peptide-loaded DPI systems is more dificult than that
of oral formulations because only a limited range of compounds is
approved as a pharmaceutical excipient for pulmonary administration.
Table3 Excipients for using stabilization of peptide and proteins during spraydrying process
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Category Excipient Characteristic Reference
Sugars Glucose, fructose, maltose, sucrose,
trehalose, inulin, dextran
Water replacement
theory contributes
to the stabilization
of peptide by
molecular
interactions.
Entrapping peptide
into the glassy
matrix structure of
excipients,
stabilizing included
molecules by
restricting mobility.
[14, 19, 21,
66]
Polyols Glycerol, mannitol, sorbitol Water replacement
theory contributes
to the stabilization
of peptide by
molecular
interactions.
Entrapping peptide
into the glassy
matrix structure of
excipients,
stabilizing included
molecules by
restricting mobility.
Amino
acids
Alanine, arginine, aspartic acid,
glycine, histidine, leucine,
isoleucine, lysine, phenylalanine,
proline
Forming hydrogen
bonding with
proteins and
peptides.
Inhibition of the
aggregation of
peptides by
competing with
adsorption at the
air–liquid interface.
Improved inhalation
performance and
moisture protection
[2, 15, 25,
26, 32]
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Category Excipient Characteristic Reference
by hydrophobic
amino acids.
Surfactants Polysorbate 20, polysorbate 80,
dipalmitoylphosphatidylcholine,
sodium glycocholate
Inhibition of the
aggregation of
peptides and
assisting in the
refolding by
preventing
adsorption at the
air–liquid interface.
[11, 43, 44]
Sugars and polyols are typically used as pharmaceutical excipients
to improve the lowability and stability of peptides. Sucrose, mannitol,
lactose, trehalose, sorbitol, and inulin are common excipients used for
the production of peptide-loaded particles [21]. These sugars and
polyols can theoretically stabilize the included peptides based on two
theories: (i) water replacement theory and (ii) vitriication theory (Fig.
2). Water replacement theory suggests that during the
solidiication/powderization process, these excipients can form
hydrogen bonds with active ingredients by replacing the hydrated
water of protein/peptide, leading to the entrapment of
macromolecules into the matrix structure of excipients. This may
reduce the chance of hydrolysis by removing surrounding water.
Vitriication theory suggests that entrapment of target
macromolecules into the glass-forming matrix former can contribute
to the restriction of mobility in a rigid structure, resulting in the
stabilization of highly structured proteins and peptides. Glassy
excipients with a high glass transition temperature can act as physical
barriers to improve thermostability. Non-reducing sugars, including
trehalose and sucrose, are preferable, and the combined use of sugars,
polyols, and other stabilizing excipients can stabilize proteins and
peptides during the manufacturing process.
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Fig.2 Vitriication and water replacement theories of peptide stabilization by
sugars and polyols
Amino acids are highly biocompatible and this class of compounds
have a wide range of chemical and physicochemical properties,
including hydrophilic, hydrophobic, neutral, cationic, anionic, and
antioxidant effects [32]. Amino acids with relatively small sizes,
including glycine, alanine, leucine, isoleucine, histidine, and arginine,
are typically used as stabilizers in DPI formulations. They can form
hydrogen bonds with proteins and peptides, possibly leading to
stabilization during powderization. Additionally, they can inhibit the
aggregation of peptides by competing with adsorption at the air-liquid
interface. The application of hydrophobic amino acids, L-leucine and
phenylalanine, can also reduce moisture-induced degradation and
improve the inhalation performance of dry powders by acting as
dispersibility enhancers. L-leucine can enhance the aerosolization
eficiency of spray-dried powders by reducing their surface
cohesiveness. Surfactants such as polysorbate 20, polysorbate 80, and
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dipalmitoyl phosphatidyl choline can also be used as stabilizers to
inhibit aggregation and assist in the refolding of proteins and peptides
by preventing adsorption at the air-liquid interface or ice-liquid
interface during the drying process.
5 PulmonaryDeliveryStrategiesforTherapeutic
Peptides
To achieve eficient delivery and an optimal therapeutic index of
therapeutic peptides (also peptide-loaded carriers), pharmaceutical
strategies should be carefully selected to overcome the biological
barriers mentioned above. Some approaches include controlling
mucodiffusiveness in the mucus layer, stabilization by molecular
modiication, and particle engineering of encapsulation [24, 55] (Table
4).
Table4 Pulmonary delivery strategies of peptide drugs
Strategy Function Example Reference
Controlling
mucodiffusiveness
Mucopenetrating PEGylated
carrier
[9, 50, 69]
Mucoadhesive Mucoadhesive
polymer
(chitosan,
alginate,
hyaluronic acid,
and cellulose
derivatives)
[5, 46, 51]
Chemical
modiication/derivatization
Stabilization Replacement of
amino acid
Chemical
modiication
Cyclization
[52, 53, 74,
56]
Encapsulation into carrier
particles
Stabilization and
designing functional
formulations
(controlled release,
Natural polymer
(gelatin,
hyaluronic acid,
albumin,
[20, 34, 39,
63, 65, 67]
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