Scientia

Pharmaceutica

Review
Microparticles, Microspheres, and Microcapsules for
Advanced Drug Delivery
Miléna Lengyel 1 , Nikolett Kállai-Szabó 1 , Vince Antal 1 , András József Laki 2,3
and István Antal 1, *
1 Department of Pharmaceutics, Semmelweis University, Hőgyes E. str 7, 1092 Budapest, Hungary
2 Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, Práter str 50/A,
1083 Budapest, Hungary
3 Department of Biophysics and Radiation Biology, Semmelweis University, Tűzoltó str. 37-47,
1094 Budapest, Hungary
* Correspondence: [email protected]; Tel.: +36-12-170-914




Received: 11 July 2019; Accepted: 1 August 2019; Published: 9 August 2019


Abstract: Microparticles, microspheres, and microcapsules are widely used constituents of

multiparticulate drug delivery systems, offering both therapeutic and technological advantages.
Microparticles are generally in the 1–1000 µm size range, serve as multiunit drug delivery systems
with well-defined physiological and pharmacokinetic benefits in order to improve the effectiveness,
tolerability, and patient compliance. This paper reviews their evolution, significance, and formulation
factors (excipients and procedures), as well as their most important practical applications (inhaled
insulin, liposomal preparations). The article presents the most important structures of microparticles
(microspheres, microcapsules, coated pellets, etc.), interpreted with microscopic images too. The most
significant production processes (spray drying, extrusion, coacervation, freeze-drying, microfluidics),
the drug release mechanisms, and the commonly used excipients, the characterization, and the novel
drug delivery systems (microbubbles, microsponges), as well as the preparations used in therapy are
discussed in detail.

Keywords: multiparticulate formulations; polymer excipients; processes for microparticles in therapy;

structure and drug release; microfluidics; microbubbles; microsponge

1. Introduction
Microparticles, microspheres, and microcapsules are common constituents of multiparticulate drug
delivery systems offering numerous advantages based on their structural and functional abilities [1],
and their application is suitable for convenient and tolerable drug administration via several routes.
Depending on the formulation, they can be incorporated into different pharmaceutical dosage
forms such as solids (capsules, tablets, sachets), semisolids (gels, creams, pastes), or liquids (solutions,
suspensions, and even parenterals).
An advantage of microcarriers over nanoparticles is that they do not traverse into the interstitium
over the size of 100 nm transported by the lymph, and thus act locally [2]. Possibly toxic substances
can be carried encapsulated and liquids can be handled as solids in the form of dried microparticles.
In the case of multiparticulates, the dose is distributed in many small separate particles, which
carry and liberate a part of the dose, hence the malfunction of an individual subunit does not cause the
failure of the whole dosage.
Multiparticulate drug delivery systems offer outstanding advantages to experts and patients, such as:

- choice of dosage form for the desired drug delivery route (peroral tablets, parenteral injections);
- modified and targeted (even site-specific) drug release and delivery;

Sci. Pharm. 2019, 87, 20; doi:10.3390/scipharm87030020 www.mdpi.com/journal/scipharm

Sci. Pharm. 2019, 87, 20 2 of 31

- more expectable pharmacokinetics with reduced intra- or inter-subject variability;

- moreSci.homogenous distribution
Pharm. 2019, 87, x FOR PEER REVIEW in the physiological environment; 2 of 31

- stable fixed-dose combinations of drugs;

‐ choice of dosage form for the desired drug delivery route (peroral tablets, parenteral injections);
- dose‐ titration
modified andandless dose-dumping;
targeted (even site-specific) drug release and delivery;
- ‐
patient centricity
more expectable through better compliance
pharmacokinetics (e.g.,
with reduced patients
intra- with dysphagia)
or inter-subject variability; and adherence;
‐ more homogenous distribution in the physiological environment;
- individual therapy (e.g., for pediatric or geriatric population);
‐ stable fixed-dose combinations of drugs;
- improving
‐ dosestability
titration andof the
less medicinal
dose-dumping; preparations;
- ‐
isolating the constituents
patient to ensure
centricity through better compatibility;
better compliance (e.g., patients with dysphagia) and adherence;
- ‐ individual therapy (e.g., for pediatric or
innovative products with a prolonged life cycle through geriatric population);patent protection.
‐ improving stability of the medicinal preparations;
From‐ theisolating
viewpointthe constituents to ensure
of technology, better compatibility;provides several advantages: microparticles
microencapsulation
‐ innovative products with a prolonged life cycle through patent protection.
are formulated in order to protect the core from the environment; masking an unpleasant taste;
From theorviewpoint
preserving volatiles the viabilityof technology,
of the cells;microencapsulation provides several
separating incompatible advantages:
substances; protecting the
microparticles are formulated in order to protect the core from the environment; masking an
body from the side effects; and optimizing, prolonging, or targeting the effect of a drug.
unpleasant taste; preserving volatiles or the viability of the cells; separating incompatible substances;
The protecting
polymer the excipient
body fromprotects theeffects;
the side activeand pharmaceutical ingredient
optimizing, prolonging, (API) from
or targeting the environment
the effect of a
(oxidation, temperature, pH) or the body from the irritative, or mucosa-damaging effect of the drug
drug.
substance. The Thelesion
polymer excipient
(e.g., protectsofthe
bisectioning) theactive pharmaceutical
multiparticulate ingredient
solid dosage (API)
form from the
(i.e., micropellets
environment (oxidation, temperature, pH) or the body from the irritative, or mucosa-damaging
in spansule or compressed) affects only a small number of units, thus does not result in a significant effect
of the drug substance. The lesion (e.g., bisectioning) of the multiparticulate solid dosage form (i.e.,
change ofmicropellets
the bloodinlevel.
spansule or compressed) affects only a small number of units, thus does not result in
However, there
a significant are some
change limitations,
of the blood level. such as higher product costs due to the more expensive
excipients in However,
the formulations or to limitations,
there are some the more sophisticated equipment
such as higher product andtoprocesses,
costs due as well as stricter
the more expensive
excipientsIninaddition,
quality control. the formulations or to the more may
some constituents sophisticated
not meet equipment and processes,
the requirements forasbiocompatibility
well as
stricter quality control. In addition, some constituents may not meet the requirements for
and biodegradation.
biocompatibility and biodegradation.
2. Construction and Structure
2. Construction and Structure
Microparticles’ sizes range from 1 to 1000 µm and the well-known matrix or reservoir structure
Microparticles’ sizes range from 1 to 1000 µm and the well-known matrix or reservoir structure
they exist in have various different structures (Figure 1). Beyond the excipients used, the structure
they exist in have various different structures (Figure 1). Beyond the excipients used, the structure
and the shape
and thedetermines the function
shape determines asaswell.
the function well. Multiparticulate drug
Multiparticulate drug delivery
delivery systems
systems (micropellets,
(micropellets,
microgranules, microspheres,
microgranules, microcapsules,
microspheres, microsponges,
microcapsules, microsponges,liposomal
liposomal preparations)
preparations) attract
attract attention
attention
because of because
their wide of their
range ofwide range oftechnological
favorable favorable technological properties.
properties.

Figure 1. Schematic illustration of the different microparticle structures: (a) mononuclear/single

core/core-shell, (b) multi-wall, (c) polynuclear/multiple core, (d) matrix, (e) coated polynuclear core,
(f) coated matrix particle, (g) patchy microparticle, (h) dual-compartment microcapsule, (i) colloidosome,
(j) giant liposome, (k) irregular-shaped microparticle, (l) torus-shaped microparticle, (m) bullet-shaped
microparticle, (n) microtablet, and (o) cubic-shaped microparticle.
 Figure 1. Schematic illustration of the different microparticle structures: (a) mononuclear/single
core/core-shell, (b) multi-wall, (c) polynuclear/multiple core, (d) matrix, (e) coated polynuclear core,
(f) coated matrix particle, (g) patchy microparticle, (h) dual-compartment microcapsule, (i)
colloidosome,
Sci. Pharm. 2019, 87, 20 (j) giant liposome, (k) irregular-shaped microparticle, (l) torus-shaped microparticle,
3 of 31
(m) bullet-shaped microparticle, (n) microtablet, and (o) cubic-shaped microparticle.

Microparticles
Microparticlesmay be characterized
may as either
be characterized a homogenous
as either or heterogenous
a homogenous structure depending
or heterogenous structure
on
depending on the formulation and processing. Usually the spheroid shape is preferred since itfurther
the formulation and processing. Usually the spheroid shape is preferred since it makes the makes
processing
the further(e.g., coating)
processing easier.
(e.g., coating) easier.

2.1.
2.1. Microspheres
Microspheres and
and Microcapsules
Microcapsules
Microspheres
Microspheres cancan bebe characterized
characterized as
as matrix
matrix systems
systems inin which
which the
the drug
drug isis homogeneously
homogeneously
dispersed, either dissolved or homogenously suspended [3]. Microcapsules are heterogenous
dispersed, either dissolved or homogenously suspended [3]. Microcapsules are heterogenous particles
where a membrane shell is surrounding the core forming a reservoir (Figure 2) [4].
particles where a membrane shell is surrounding the core forming a reservoir (Figure 2) [4].

.
Figure2.2.Structures
Figure Structuresof
ofcalcium
calciumalginate
alginatemicroparticles:
microparticles: (a)
(a) microspheres,
microspheres, (b)
(b) microcapsules
microcapsules W/O/W
W/O/W
emulsion
emulsion in core surrounded by calcium alginate shell, and (c) “Janus particle” (the
in core surrounded by calcium alginate shell, and (c) “Janus particle” (theparticles
particles were
were
prepared
preparedby byaaBüchi
BüchiB-390
B-390Microencapsulator).
Microencapsulator).

A classical microsphere structure contains solid or liquid API dispersed or dissolved in a matrix.
A classical microsphere structure contains solid or liquid API dispersed or dissolved in a matrix.
Microcapsules are reservoirs of microscopic size surrounded by a wall that is able to control the release
Microcapsules are reservoirs of microscopic size surrounded by a wall that is able to control the
from the reservoir.
release from the reservoir.
The size plays a role in the gastrointestinal performance: microparticles under 800 µm get
The size plays a role in the gastrointestinal performance: microparticles under 800 µm get
through the pylorus without the influence of gastric emptying, thus eliminating the interpersonal and
through the pylorus without the influence of gastric emptying, thus eliminating the interpersonal
intrapersonal (nutrition-based) differences.
and intrapersonal (nutrition-based) differences.
Particles larger than 100 nm stay at the site of administration until the phagosomal clearance.
Particles larger than 100 nm stay at the site of administration until the phagosomal clearance.
Lymphatic uptake and node accumulation is most significant between 10–80 nm [2]. The foreign body
Lymphatic uptake and node accumulation is most significant between 10–80 nm [2]. The foreign body
response is decreased by the application of spheres with a diameter of 1.5–2.5 mm compared to that of
response is decreased by the application of spheres with a diameter of 1.5–2.5 mm compared to that
smaller diameter spheres [5].
of smaller diameter spheres [5].
The surface charge has a key role in the aggregation of the particles. Aggregation hinders optimal
The surface charge has a key role in the aggregation of the particles. Aggregation hinders
administration and drug delivery (e.g., compromises content uniformity of doses, occludes normal
optimal administration and drug delivery (e.g., compromises content uniformity of doses, occludes
blood flow).
normal blood flow).
Porosity also has a significance in the in vivo performance in cell transplantation. Porous materials
Porosity also has a significance in the in vivo performance in cell transplantation. Porous
facilitate vascularization relative to non-porous biomaterials. A porosity of 30–40 µm leads to the
materials facilitate vascularization relative to non-porous biomaterials. A porosity of 30–40 µm leads
polarization of macrophages, causing elevated tissue repair [5].
to the polarization of macrophages, causing elevated tissue repair [5].
Several unique anisotropic colloidal microstructures have lately been created with
Several unique anisotropic colloidal microstructures have lately been created with special properties.
special properties.
2.1.1. Janus Particles
2.1.1. Janus Particles
These microparticles with a certain shape and phase anisotropy, created by alloying the distinct
These microparticles with a certain shape and phase anisotropy, created by alloying the distinct
properties (hydrophilic, hydrophobic) of the separated excipients, are used as multifunctional
properties (hydrophilic, hydrophobic) of the separated excipients, are used as multifunctional imaging
imaging probes and sensors [6,7]. The anisotropic response to external signals has also been exploited
probes and sensors [6,7]. The anisotropic response to external signals has also been exploited in the
in the preparation of color-changing traffic signals.
preparation of color-changing traffic signals.

2.1.2. Patchy
2.1.2. Patchy Particles
Particles

Spherical geometries with concave, convex, or flat patches on the polystyrene sphere’s surface have
also been created via colloidal fusion and concomitant shrinking (Figure 1). The patchy particles can
form clusters, and by patch-to-patch bonding between oil patches, can build supracolloidal architectures
(tetrahedral, hexagonal) that can withstand drying forces and show the ability to reversibly expand
Sci. Pharm. 2019, 87, 20 4 of 31

several times their original volume in a swelling agent [8]. Microfluidic techniques give rise to the
creation of anisotropic geometries.
Magnetic nanoparticles embedded into nonplanar, bullet-shaped microneedles give access to mild
invasive therapy [9].

2.2. Liposomes
Liposomes are lipid vesicles with one or more phospholipid bilayers and their structure comprises
small unilamellar vesicles (SUV: 20–100 nm), large unilamellar vesicles (LUV: >100 nm), multilamellar
vesicles (MLV: >500 nm), oligolamellar (OLV: 0.1–1 µm), giant unilamellar liposomes (GUV: > 1 µm),
and multivesicular vesicles (MVV: > 1 µm).
For ophthalmic delivery, they represent ideal drug delivery systems for both hydrophilic and
hydrophobic APIs by performing a cell-membrane like structure. The negative or positive charge can
contribute to the bioavailability: cationic liposomes (e.g., fabricated with didodecyldiethylammonium
chloride, stearylamine) exhibited better efficacy at the surface of cornea with a negative charge.
Liposomes can interact with the cells via several mechanisms: interaction with the cell surface
components, fusion with the membrane, endocytosis via phagocytic cells, or swap by bilayer
components. The methods of preparation are also versatile: solvent evaporation, double
emulsion-evaporation, or reverse-phase evaporation [10].

2.3. Colloidosomes
Colloidosomes are microcapsules that contain a hollow or hydrogel core and their wall is composed
of self-assembled colloidal particles. Their sizes range from 10–20 nm to micrometers. It was found
that colloidosomes have selective permeability where drugs can diffuse through their shells via size
exclusion [11]. They can be stabilized by solid excipients (e.g., Fe2 O3 , CaCO3 , colloidal anhydrous
silica) forming a Pickering emulsion [12]. Besides the emulsification, depending on the excipient
thermal annealing and chemical cross-linking take part in the immobilization of the active ingredient.

3. Types and Mechanism of Drug Release

The process of drug release of microparticulates, produced by special manufacturing technologies
and/or possibly containing special excipient(s), is the result of various phenomena and mechanisms
(dissolution/diffusion, osmotically driven release, erosion) (Figure 3). Generally, these mechanisms
take place side by side and one or the other mechanism provides a greater role during drug release [13].
In the microparticulate, when the active pharmaceutical ingredient is embedded in a polymer matrix
(Figure 3), the behavior of the polymer system is crucial during dissolution, but depends on many
factors (drug properties, formulation, release medium, etc.) [14].
In the case of a polymer matrix, the diffusion of the active ingredient can be through the intact
polymer network or through the pores filled with water. Water-soluble drugs may also dissolve in
the aqueous pore networks. Water uptake causes polymer chains to swell, indicating the formation
of new pores and/or osmotic pressure. During swelling, the volume increases, the effective diffusion
coefficient of the drug is increased, and more pharmacon molecules enter the aqueous part. Erosion of
the polymer matrix (bulk/surface) is also possible.
In the case of polymer coated microparticles, the film-forming polymer may dissolve in the
medium or act as a water-insoluble, permeable or semipermeable membrane. In the former case, the
diffusion is predominantly due to the release of the active ingredient. In the case of a semipermeable
coating, the osmotic phenomenon should be taken into account. It is also possible to use water-soluble
pore formers, which, by creating pores, accelerate the dissolution profile [15,16].
Sci. Pharm. 2019, 87, 20 5 of 31
Sci. Sci.
Pharm. 2019,
Pharm. 87, x87,
2019, FOR PEER
x FOR REVIEW
PEER REVIEW 5 of531of 31

Figure
Figure Release
3. Release mechanisms
mechanisms
3. Release in microencapsulated
mechanisms products.
in microencapsulated products.

In the
In the case
case
In the of
of smart
case smart
of smartdrug
drug delivery
delivery
drug microparticle
deliverymicroparticle
microparticle systems,
systems, thethe
the
systems, release
release of the
of
release thethe
of drug
drug occurs
occurs
drug viavia
via
occurs aa a
stimulus.
stimulus. It
stimulus. is possible
It isItpossible that
is possible one,
thatthat
one, two,
two,
one, or more
or more
two, (multiple)
(multiple)
or more stimuli
stimuli
(multiple) are
areare
stimuli required
required for dissolution
for for
required dissolution (Figure
(Figure
dissolution (Figure4).
4). 4).
TheThe
The stimulus
stimulus for
for drug
drug release
release may
may be
be internal
internal or
or external
external and
and be
be classified
classified as
as physical,
physical, chemical,
chemical,
stimulus for drug release may be internal or external and be classified as physical, chemical, or even or
or even
even
microbiological.
microbiological.
microbiological. Opening
Opening
Opening andand
and closing
closing signals
signals
closing of these
of
signals these systems
systems
of these areare
are
systems also
also possible,
possible,
also creating
creating
possible, feedback
feedback
creating feedback [17].
[17].
[17].

Figure
Figure 4.
4. Smart
Figure Smart release
4. Smart stimuli
release
release via
stimuli
stimuli microencapsulation.
via via microencapsulation.
microencapsulation.

Magnetic Microcapsules
Magnetic Microcapsules
Magnetic
Magnetic microspheres
Magnetic microspheres supramolecular
areare supramolecular particles
particles thatthat
particles circulate through
circulate capillaries
through without
capillaries without
causing occlusion in the form of emboly (<4
(<4 µm)
µm) but
but show
show a ferromagnetic character
character
causing occlusion in the form of emboly (<4 µm) but show a ferromagnetic character such that such
such that they
they
cancan
be dragged into the target tissue with a magnetic field of 0.5–0.8 T [18]. Magnetic microparticles
be dragged into the target tissue with a magnetic field of 0.5–0.8 T [18]. Magnetic microparticles
for for
medical applications
medical applications have been
have developed,
been developed,such as magnetic
such as magneticresonance
resonanceimaging (MRI)
imaging andand
(MRI) drug
drug
delivery, and they are a promising choice in tumor therapy accompanied by hyperthermia.
delivery, and they are a promising choice in tumor therapy accompanied by hyperthermia. The The
Sci. Pharm. 2019, 87, 20 6 of 31

for medical applications have been developed, such as magnetic resonance imaging (MRI) and drug
delivery, and they are a promising choice in tumor therapy accompanied by hyperthermia. The release
can be fine-tuned by the strength of the applied magnetic heating: with a gentle magnetic effect, the
particles react with shrinkage and slow drug release, and with intense heating, the structure disruption
induces the shrinking, which leads to a burst release [19].
Their great advantage lies in the effective method of targeting the drug molecule to the desired
site to be treated (i.e., the tumor) with higher therapeutic efficacy and lower toxicity. The reduction of
dosing frequency enhances the patient’s compliance.
The production involves emulsion methods (multiple and phase separation polymerization,
solvent extraction, hot melt microencapsulation, dispersion copolymerization).

4. Formulation and Manufacturing

4.1. Composition and Excipients

The use of plant, animal, or microbial-origin biopolymers are propitious; semi-synthetic
cellulose derivatives and biodegradable or non-biodegradable synthetic polymers are used as well.
The formulation is usually based on polysaccharides or proteins, but waxes and lipids also play a role
in the construction. Nonpolymer excipients play a role in crosslinking the polymer chains (CaCl2 ,
glutaraldehyde, poly-l-lysine, etc.), thus forming and hardening the polymer network of the drug
delivery systems. The most commonly used polymers and their important microencapsulation-related
properties are summarized in Tables 1–5.

Table 1. Examples of proteins and waxes of plant or animal origin used in microencapsulation.

Physicochemical
Excipient Application and Benefits Limitations Ref.
Properties
At low pH coacervation
with negatively charged
Amphoteric polymers, high potential of
Influence of pH and
gelatin A (isoelectric crosslinking
ionic strength on
point (IEP) pH: 7–9.4 emulsifier, stabilizer (high
behavior
Gelatine gelatin B (IEP: viscosity), binder [20,21]
Need for preservation
pH 4.8–5.5) Thermoreversible gelling,
against possible prion
Swells, then dissolves implantable pulmonary
(BSE) contamination
in water delivery
pH-dependent, swelling,
dissolution, erosion
Hydrophilic, metal calcium caseinate
binding –reversible thermal
Casein Anaphylactic reactions [22]
Insoluble in water at its gelation solubility increase
IEP (pH 4.6) (coenzyme Q10)
Thermally irreversible
Thermal gelation, gel formation above
Insoluble at its IEP encapsulation of oils 70 ◦ C
Whey protein [23]
(pH 5.2) film formation: gas barrier, Denatures at higher
good tensile strength salt conc.
Anaphylactic reactions
IEP: 4.7 Chemical degradation,
Freely soluble in water Pulmonary delivery denaturation at high
Albumin [24]
negative charge at Alginate-albumin salt conc.,
pH 7.4 enzymes, heat
Sci. Pharm. 2019, 87, 20 7 of 31

Table 1. Cont.

Physicochemical
Excipient Application and Benefits Limitations Ref.
Properties
α, β, γ, δ, zein with
Brittle, rigid wall,
different Mw
Oral controlled release complex with a gelling
Zein amphiphilic character [25,26]
matrix and wall component to
IEP: 6.8
plasticize
hydrophobic
Partly soluble in water,
Oral controlled release
depending on the
Soy protein matrix and wall Sensitivity [27]
extraction process;
Emulsifier, foaming agent
IEP 4.5
Wall material,
Water-insoluble;
Gluten good elastic, good Gluten sensitivity [28]
IEP:7.5
thermoplastic properties
Edible, easy use, smooth
surface,
mp (melting point): hot melt extrusion
Bees-wax
62–64 ◦ C prolonged release for Oxidation [29]
(Apis mellifera)
HLBrequired = 12 hydrophilic substances,
protection from chemical
degradation
Good compatibility
Carnauba wax
mp: 78–85 ◦ C hot melt extrusion,
(Copernica Oxidation [30,31]
HLBrequired = 12 embedding water soluble
cerifera)
components, taste masking
Embedding water soluble
Paraffin (hard) ◦C components
mp: 50–61 Sensitivity [32]
(mineral) liquid paraffin in the
emulsification process

Table 2. Examples of polysaccharides of various origin used in microencapsulation.

Physicochemical
Excipient Applications and Benefits Limitations Ref.
Properties
Antifungal, antibacterial,
pH dependence
reduces LDL (low-density
(insoluble above
Soluble in weak acids lipoprotein), tissue
pH 6.5)
Chitosan Mucoadhesive regenerative, pulmonary
Addition of electrolytes [33–35]
(deacylated chitin) reacts with negatively delivery
precipitates chitosan in
charged surfaces Ionotropic gelation,
solution,
coacervation with anions,
hygroscopic
modified emulsification
Anionic character,
In microspheres nasal, Very hygroscopic,
Sodium soluble in water,
vaginal, ophthalmic when heated, [36,37]
hyaluronate high viscosity at low
delivery systems emits Na2 O
concentration
Starch from different
Spray drying, extrusion,
origins
Starch molecular inclusion,
Differ in particle size
(wheat, corn, coacervation with proteins,
and shape Hygroscopic [38]
potato, rice, hydrocolloid-forming,
Soluble in hot water
tapioca) release via swelling,
after a time of
diffusion, erosion
gelatinization
Water soluble,
nonionic, Controlled-release,
Needs preservation,
galactomannan colon-targeted release,
Guar gum borate hinders [39]
forms a thixotropic appetite suppressant,
swelling
solution, stable at thermoreversible
pH 4–10.5
Sci. Pharm. 2019, 87, 20 8 of 31

Table 2. Cont.

Physicochemical
Excipient Applications and Benefits Limitations Ref.
Properties
Controlled release in
Nonionic, combination
Locust bean gum galactomannan, pseudoplastic,
Low water solubility,
(LBG)/carob, dispersible in hot gelling with the addition [40]
hypersensitivity
ceratonia/ water, soluble at higher of borate, solubility not
temperature affected by pH or ionic
concentration
Elevation of temperature
Konjac gum Water soluble increases gelation, Indigestable [41,42]
antioxidant properties
λ−Carrageenan: highest
anionic charge, high
solubility, but no gelling, Acid-catalyzed
κ, ι−Carrageenan: elastic hydrolyses, especially
Anionic polymer, gel is formed with K+ , at higher temperature
K, ι, λ−, ι−Carrageenan: shear Ca2+ , thermoreversible gel and pH < 3
[43,44]
Carrageenan thinning thixotropic forming Administration of
gel forming Release by erosion >2 g/kg orally Induces
(physical intestinal ulcers, not
contact-Scentcaps® ), biodegradable
effective against HPV
(human papilloma virus)
swelling,
Agarose Soluble in hot water Thermoreversible gelation Poor biodegradability [45]
(at ≈37 ◦ C) with hysteresis
swelling ability (200–300×
pH dependence
Water soluble, anionic of its own weight from
(insoluble in acidic
coacervation with ions water)
medium)
(Ca2+ , Sr2+ , Ba2+ ), pH-dependent swelling
heat-sensitivity
Sodium alginate polycations (chitosan) nontoxic, nonirritant [46]
(hydrolysis)
or poly-l-lysine low density (capable of
microbial spoilage on
disintegrant, binder, floating in gastric juice)
storage
viscosity increasing Diffusion, erosion,
(depolymerization)
in situ forming hydrogels
Water soluble
Acid-resistance Di/trivalent cations
arabinogalactan and
emulsifier, cause drop in viscosity
Tragacanth swellable bassorin [47]
encapsulation of oils, because of
components,
stabilizer in emulsions precipitation
swells quickly in water
Emulsifier, spray-dry
encapsulation of flavor
Variation dependent
and of essential oils,
Gum arabic/ Water soluble, clear on source
30% solution has a
Acacia gummi solution of pH 4.5, pH, ionic strength [48–50]
relatively low viscosity,
(Ph. Eur.) protective colloid influences viscosity
Newtonian flow
(max at ≈pH 6–7)
permeable coating
dietary fiber
Gelation depends on the
degree of esterification,
cation (Ca,Zn)
Pectin Gelling occurs at low
concentration in solution,
(low or high pH (<3.5),
Negatively charged temperature and pH
methoxylated) presence of sugars [51,52]
molecule In situ gelling, sustained
(apple, citrus peel, necessary for gelation
delivery, dietary fiber,
beet) of HM pectin
drug delivery in colorectal
carcinoma (5-FU),
antiviral activity
Sci. Pharm. 2019, 87, 20 9 of 31

Table 3. Examples of polysaccharides of microbial fermentation used in microencapsulation.

Physicochemical
Excipient Applications and Benefits Limitations Ref.
Properties
No gelation at room temp,
cryogelation possible,
stable viscosity over wide
Soluble in warm and Hydrolysis
pH range, surface activity,
cold water, not affected Acceptable daily intake
Xanthan gum emulsion stabilizer, [53]
by pH (WHO) 10 mg/kg BW
controlled-release,
anionic polyelectrolyte Contains cellulase
colon-targeted
swelling, diffusion,
matrix erosion
Thermoreversible gelation
with cations
Anionic polyelectrolyte sol-gel transition under
Gellan gum Poor biodegragability [54]
soluble in water physiological conditions
bioadhesive
nasal administration
Neutral polymer, Colon-targeted delivery, At parenteral
solubility depends on formation of porous adiminitration:
Dextran [55,56]
degree of particle possible platelet
polymerization pulmonary delivery adhesiveness
Neutral polymer
Emulsifier
underivarized pullulan
Pullulan sustained-release Relatively high price [57,58]
has high water
preparations
solubility

Table 4. Examples of cellulose derivatives applied in microencapsulation.

Physicochemical
Excipient Applications and Benefits Limitations Ref.
Properties
Emulsifier, pseudoplastic Complexation with
Soluble in cold water
Methylcellulose solution, pH-independent surface-active
Tsol-gel : 80 ◦ C [59]
(MC) gel formation above 50 ◦ C, components,
amphiphilic
high variety in Mw laxative
Anionic cellulose ether, Injectable
Carboxymethyl-
dispersible in water thermoreversible Microbial instability
cellulose sodium [60,61]
(forms a colloidal gel-forming, hygroscopicity
(CMC-Na)
solution) mucoadhesive
Incompatible with
alkaline substances,
Soluble in cold water,
Hydroxypropyl- High surface activity substituted phenol
compatible with waxes, [62]
cellulose (HPC) film-forming ability derivatives, anionic
oils, Tsol-gel : 55 ◦ C
polymers increase
viscosity
Reversible thermal
Hydroxypropyl- No complex with
Water soluble, gelation surface activity,
methylcellulose metallic salts or ionic [63]
nonionic emulsion stabilizer,
(HPMC) organics
film-forming ability
Film forming ability,
membrane-controlled
Water-insoluble, Organic solvent
Ethylcellulose diffusion, modified release, [64]
hydrophobic coating residuals
floating, gastroretentive
systems
Semipermeable coating,
Insoluble in water,
Cellulose acetate extended release Organic solvent
soluble in aceton-water [65]
butyrate formulations, diffusion, residuals
blends
matrix erosion
Sci. Pharm. 2019, 87, 20 10 of 31

Table 5. Synthetic polymers applied in microencapsulations.

Physicochemical
Excipient Applications and Benefits Limitations Ref.
Properties
Digestive tract
Insoluble in water Biodegradability, influences degradation,
Poly (lactic acid) degrades to CO2 and prolonged-release in im or parenteral
[64,65]
(PLA) H2 O over sc injections, implants, oral administration is
12–24 months solid dispersions favorable, initial burst
release may occur
Injectable or implantable
Insoluble in water systems (microparticles,
lactic acid-glycolic acid gels) for human and
Polylactic Degrades into
ratio influences veterinary use,
acid-glycolic acid by-products that can [66–69]
degradation ability to pH- responsive/non-pH
copolymer (PLGA) induce inflammation
thermoplastic gel -responsive polymer
forming degradation,
bone tissue engineering
Bioadhesive, targeted
Neutralization with Neutralization at
Polyacrylic acid delivery,
alkaline chemicals for preparation, [70]
(Carbopol) intranasal administration
gelling preservative needed
with microencapsulation
Soluble in organic pH-dependent solubility,
solvents, permeability
Polymethacrylates Water insolubility [71]
most of them are gastric or enteric targeted
miscible with water delivery possible
Poly-(N-
LCST: 35–40 ◦ C Thermoresponsive Not biodegradable [72,73]
isopropylacrylamide)
Plasticizer in wall of
Liquid or solid grades
compressible
depending on the Mw ,
Polyethylene microcapsules,
PEG (polyethylene Not biodegradable [74]
glycols oral insulin delivery
glycol) 1500 freezing
cell delivery in
point at 37–41 ◦ C
combination
Fumaryl High solubility at Self-assembled highly
Not biodegradable,
diketopiperazine pH ≥ 6, porous microparticles, [75]
excreted via urine
(FDKP) no biological activity Technosphere® carrier
LCST: lower critical solution temperature.

The combination of polymers of different properties is a common technique to improve the particle
characteristics and performance. Because of their opposite charges, alginate and chitosan at low pH
form a polyelectrolyte complex [76], thus decreasing the porosity of the polymer network and delay
the release of the API (Table 6).

Table 6. Synergistic polymer combinations.

Physicochemical
Polymer Active Ingredient Particle Size Ref
Mechanisms
Carbohydrate-Carbohydrate
Chitosan-alginate Leydig cells 230–370 µm Complex coacervation [77]
Microfluidics ionic
Agarose-alginate (CaCl2 ) Sertoli cells 250 µm [78]
gelation,
double
Gum arabic Xylitol 100 µm [79]
emulsion/coacervation
Cellulose acetate butyrate Sulfopropylated O/W emulsification,
40–120 µm [65]
(CAB) dextran microspheres solvent evaporation
Raspberry Emulsification,
Gelatin + gum arabic 150 µm [80]
anthocyanins coacervation
Sci. Pharm. 2019, 87, 20 11 of 31

Table 6. Cont.

Physicochemical
Polymer Active Ingredient Particle Size Ref
Mechanisms
Carbohydrate-Carbohydrate
S/O/W emulsification,
Maltodextrin + gum arabic Lavender oil 10–20 µm [50]
spray-drying
Emulsification, ionic
gelation,
CMC-Na + xanthan gum Diclofenac sodium 1000–1500 µm [81]
Interpenetrating
network
emulsification,
Buflomedil
LBG + PVA 350–750 µm Interpenetrating [40]
hydrochloride (BH)
network
electrostatic
Chitosan + pectin Insulin 0.24–2 µm [82]
self-assembly
Carbohydrate-Protein
Double
Gelatin + gum arabic Aspartame 100 µm emulsion/complex [83]
coacervation
Gelatin + chitosan Citronella oil 100 µm Coacervation [33]
whey Protein + emulsification, spray
Flaxseed oil ≈10 µm [84]
maltodextrin drying
Double layer
Whey protein + alginate Flaxseed oil <10 µm emulsification [85]
spray drying
Whey peptides
Alginate + gelatin (antihypertensive 1000 µm Dripping, coacervation [86]
activity
Bifidobacterium Extrusion coacervation
Alginate + zein 1200–1700 µm [87]
bifidum shell-core
Zein-sodium
Chitosan-zein Oral gene delivery 10 µm tripolyphosphate [88]
W/O emulsion
Poly (methyl vinyl
Poly-l-lysine ether-alt-maleic 400 µm prilling, coacervation [89]
anhydride) (PMM0 )
Poly (l-ornithine) + Superoxide dismutase, W/O/W, O/W,
500 µm [90]
alginate + PLA, PLGA ketoprofen solvent evaporation
Poly (l-ornithine) +
ursodeoxycholic acid, Complex coacervation,
Pancreatic ß-cells 700 µm [91]
Polystyrene sulfonate, vibrational jet
polyallilamine
Poly (ethylene glycol)
(PEG)-anthracene Coomassie blue no data Coacervation [92]
alginate
Vinyl-sulfone terminated Human foreskin
550 µm Simple coacervation [93]
PEG + alginate fibroblast
Alginate +
Theophylline 800 µm Complex coacervation [94]
Poly-ε-caprolactone
Polypropylene + PMMA + O/W solvent
Verapamil 150–200 µm [95]
ethylcellulose evaporation
PLGA-alginate Rifampicin 15–50 µm Microfluidics [96]

Funami et al. [97] proved that galactomannans, including guar gum, tara gum, LBG, or konjac gum
(glucomannan), influence both the short- and long-term retrogradation process of starch by controlling
the gelation, hindering the crystallization, and improving the water-holding capacity of starch.
Sci. Pharm. 2019, 87, 20 12 of 31

Farris et al. [88] developed a peroral gene delivery system, where DNA was encapsulated in
chitosan nanoparticles and the particles were protected from the gastric environment by embedding
the nanoparticles into zein matrix microparticles with a W/O emulsification method. Zein forms a
relatively brittle film; however, alginate was successfully administered to decrease the rigidity of the
wall [87].
Several studies show that copolymerization between synthetic and natural polymers
helps to increase biocompatibility and cell viability (agarose-Carbopol® , hyaluronic
acid-polyethyleneglycol) [98]. Hydrophobic excipients (poly-ε-caprolactone) can modify the release of
low-solubility drugs from alginate by forming hydrophobic interactions with the drug molecule, thus
prolonged release can be reached [94].
Controlled-release, porous, floating microparticles were formulated by combining
polypropylene-Eudragit® RS, ethylcellulose polymers [95].
Mahou et al. successfully studied the addition of vinyl-sulfone terminated polyethyleneglycol to
alginate and thus eliminated the use of polycations for human foreskin fibroblast cell encapsulation
from a cell culture medium [93].
Wells et al. reached prolonged drug release and light-sensitive drug delivery with the chemical
modification of PEG and chemical crosslinking with alginate.
Dalpiaz et al. studied the nasal absorption of zidovudine by deoxycholic-acid-conjugated chitosan
microparticles and found that the particles could get through the blood–brain barrier, in contrast with
active efflux transporters in rats [99].
Alginate microcapsules show shrinking and lower stability in an acidic medium. κ-carrageenan
locust bean gum gel beads show lower sensitivity to acidic conditions than alginate beads. A limitation
of their use is that the formation of κ-carrageenan locust bean gum beads requires a higher
amount of potassium or calcium ions, which in terms of a healthy diet, are not acceptable in
high amounts. In cell transplantation, alginate is applied because of its excellent biocompatibility
and biodegradability. Alginate, however, has some limitations: uneven porosity, poor mechanical
strength, weak wall-formation, and easy rupture on reaction to osmotic change have been reported.
To overcome these drawbacks, excipients such as the polyelectrolytes polystyrene sulfonate (PSS)
and polyallylamine (PAA) were examined in cell microencapsulation, which improved the physical
structure of polyelectrolyte gels and complexes by reducing pore size in the microcapsule membrane.
Osmotic or mechanical stress caused lower cell leakage of these microcapsules [91]. The incorporation
of PSS and PAA were shown to attract inflammatory cells and to trigger an immune response. The same
study showed that ursodeoxycholic acid increased mechanical stability and did not affect cell viability.
Poly-l-ornithine in combination with alginate has been shown to prevent post-transplant
inflammatory response and has protected the microcapsules in vivo over the first week after
grafting [90].
As artificial cell therapy, an alginate structure strengthened by poly-l-lysine was used for
encapsulation [100]. The alkylamino groups of the polyamide chain bonds via electrostatic interactions
with alginate, thus the matrix structure has reduced porosity and good immunoprotection.

4.2. Processes for the Particle Formation

From the point of view of the industrial performance, the most important methods for
microencapsulation are the air suspension method, spray-drying, and coacervation. Figure 5
summarizes the most important techniques.
Sci. Pharm. 2019, 87, 20 13 of 31
Sci. Pharm. 2019, 87, x FOR PEER REVIEW 14 of 31

Figure 5. Preparation processes

Figure 5. processes through
through droplet
droplet formation
formation at
at an
anorifice.
orifice.

4.2.1.
4.2.1. Coacervation
Coacervation
Coacervation
Coacervation related
related to
to the
the formation
formation ofof calcium
calcium alginate
alginate can
can bebe considered
considered aa classical
classical method
method
for
for the
the preparation
preparation of
ofmicrospheres
microspheresand andmicrocapsules.
microcapsules. Calcium-ions
Calcium-ions formform crosslinks
crosslinks between
between the
the
α-L-guluronicacid
α-l-guluronic acidand
andβ-d-mannuronic
β-D-mannuronic acid units
acid of alginate,
units thusthus
of alginate, organizing the polymer
organizing chains
the polymer into
chains
an “eggbox-structure.”
into This chemical
an “eggbox-structure.” bonding gives
This chemical the possibility
bonding gives theof forming stable
possibility of microspheres
forming stableor
core-shell structured microcapsules (Figures 6 and 7).
microspheres or core-shell structured microcapsules (Figures 6 and 7)
 4.2.1. Coacervation
Coacervation related to the formation of calcium alginate can be considered a classical method
for the preparation of microspheres and microcapsules. Calcium-ions form crosslinks between the
α-L-guluronic acid and β-D-mannuronic acid units of alginate, thus organizing the polymer chains
into
Sci. an2019,
Pharm. “eggbox-structure.”
87, 20 This chemical bonding gives the possibility of forming 14stable of 31
microspheres or core-shell structured microcapsules (Figures 6 and 7)

Sci. Pharm. 2019, 87, x FOR PEER REVIEW 15 of 31

Figure 6.6.(a)
Figure (a)Scheme
Scheme forfor
the the
interaction between
interaction calcium
between and alginate
calcium forming forming
and alginate an eggbox-like structure.
an eggbox-like
(b) Internal structure of the microsphere using scanning electron microscopy (SEM, magnification:
structure. (b) Internal structure of the microsphere using scanning electron microscopy (SEM,
130×, scale bar indicates
magnification: 130×, scale500 µm).
bar indicates 500 µm).

Figure 7. Images of a liquid core calcium alginate microcapsule prepared by vibration nozzle technique
(prepared
Figure 7. by Büchi of
Images B-390 Microencapsulator)
a liquid core calcium followed
alginate by coacervation:
microcapsule (a) oil-filled
prepared hollow particles,
by vibration nozzle
(b) calcium alginate shell after removal of oil core, and (c) calcium alginate
technique (prepared by Büchi B-390 Microencapsulator) followed by coacervation: shell cut in half
(a) (average
oil-filled
wall thickness:
hollow 8 µm)
particles, (Images:alginate
(b) calcium Nikon shell
SMZ after
1000 removal
Microscope).
of oil core, and (c) calcium alginate shell cut
in half (average wall thickness: 8 µm) (Images: Nikon SMZ 1000 Microscope).
Coacervation is defined as the separation of liquid phases in colloidal solutions [101]. During
coacervation, the active
Coacervation ingredient
is defined as thecan be dispersed
separation in thephases
of liquid coatinginpolymer
colloidalsolution
solutionsand[101].
at a specific
During
environmental
coacervation, the influence
active (ionic, pH, thermal
ingredient change), phase
can be dispersed in theseparation occurs, solution
coating polymer while theandcoreatmaterial is
a specific
encapsulated by the wall-forming polymer. Simple coacervation is based on incompatibilities
environmental influence (ionic, pH, thermal change), phase separation occurs, while the core material between
the polymers. Inby
is encapsulated most
thecases, it is caused
wall-forming by salting-out
polymer. (di- or trivalent
Simple coacervation cation,on
is based as incompatibilities
it happens with
alginate and Ca 2+ or Ba2+ , pectin and Ca2+ ). The particle size mainly depends on the excipients’
between the polymers. In most cases, it is caused by salting-out (di- or trivalent cation, as it happens
properties
with alginate(viscosity,
and Casurface
2+ or Batension)
2+, pectinand
andstirrer
Ca2+). setup [102,103].
The particle size mainly depends on the excipients’
During(viscosity,
properties complex coacervation,
surface tension) polyelectrolyte polymers
and stirrer setup with opposite charges form an insoluble
[102,103].
complex andcomplex
During meanwhile encapsulate
coacervation, the active ingredient.
polyelectrolyte polymers pH is important
with in complex
opposite charges formcoacervation,
an insoluble
as the isoelectric point of the polymers has to be taken into consideration.
complex and meanwhile encapsulate the active ingredient. pH is important in complex coacervation,
as theHydrophobic components
isoelectric point are often
of the polymers encapsulated
has to be taken intowithconsideration.
coacervation. In the case of hydrophilic
components, a double emulsion process followed by a
Hydrophobic components are often encapsulated with coacervation. coacervation provesInto becase
the successful way to
of hydrophilic
form a core–shell
components, structure
a double microcapsule
emulsion process[79]. As a result
followed of coacervation,
by a coacervation the product
proves contains way
to be successful a high
to
amount of solvent, which needs to be evaporated from the product.
form a core–shell structure microcapsule [79]. As a result of coacervation, the product contains a high
amountFor of
drying, besides
solvent, whichthe common
needs processes, lyophilization
to be evaporated from the product. (freeze-drying) offers a choice. This
is anForexpensive method,the
drying, besides but effective
common for heat-sensitive
processes, lyophilization actives. Shrinkingoffers
(freeze-drying) of the particles
a choice. can
This is
be partly avoided; the end product, however, has a high porosity, which is an
an expensive method, but effective for heat-sensitive actives. Shrinking of the particles can be partlyadvantage in fast
release
avoided; preparations to promote
the end product, the water
however, has uptake,
a high but is an obvious
porosity, which is drawback in the formulation
an advantage of
in fast release
sustained-release preparations.
preparations to promote the water uptake, but is an obvious drawback in the formulation of
sustained-release preparations.

4.2.2. Air Suspension Method/Fluid-Bed Coating

(Wurster (1959)) [104] has successfully administered fluidization in macroencapsulation for the
Sci. Pharm. 2019, 87, 20 15 of 31

4.2.2. Air Suspension Method/Fluid-Bed Coating

(Wurster (1959)) [104] has successfully administered fluidization in macroencapsulation for the
coating of solid particles, but it was also administered to encapsulate small particles in the size range
of 74–250 µm by Hinkes et al. [105]. The great advantage is that during the process, the particles are
suspended in an air (or inert gas) stream, in constant mixing, relative independently from each other
and the wall material solution or dispersion is sprayed on their surface, then dried inside the coating
chamber. The particle size can be tuned by the well-controllable process parameters: properties of the
core (density, hygroscopicity, surface area, particle size and shape, melting point, wettability, solubility,
volatility, compressibility, crystallinity, hardness, cohesiveness, adsorption, friability and flowability of
the core material). Concentration and quantity of wall material, inlet, outlet air temperature, and spray
settings are also critical for the process.

4.2.3. Extrusion through a Nozzle

Extrusion through a nozzle is a common method in the formation of gel particles. Many factors
influence the formation of microgels: the concentration, feeding rate, and surface tension of the
polymer solution, solvent, temperature, and nozzle diameter [3,106,107]. The solidification of the
formed microgel particles is performed in an additional step. For solidification of the gel, coacervation
(either simple or complex) is an optimal choice. The formed particles are collected in a solidification
liquid (ionic or polymer solution). The size and shape control of particles is dependent on various
factors. The distance, concentration, surface tension of the solidification liquid, and the time of the
process have a significance in the particle size and the physical properties of the beads (gel strength,
porosity, etc.). The most important limitations of the extrusion are the viscosity of the polymer because
of potential blockage of the nozzle; as such, the settings for optimal, narrow particle size distribution,
and shape are required. For the scale-up of the process, multiple-nozzle solutions have been presented.

4.2.4. Vibrational Jet/Electrostatic Extrusion

The particle formation via extrusion is completed by various processes: vibrational jet technique
means that a changing frequency vibration separates the laminar jet into beads). At the electrostatic
extrusion [108] the jet is subjected to an electric field, where having reached a certain voltage (5–6 kV),
particles are created, the repulsive forces additionally hinder their aggregation. The applied elevated
electric potential does not cause cell death [109].

4.2.5. Spinning Disk and Cutting Wire

These devices mechanically aid the particle formation and disaggregation [110].

4.2.6. Spray Drying

Spray drying is widely used in the industry for microencapsulation of volatiles, probiotics, and
viable cells. Besides the obvious drawback (high loss, low yield), the numerous advantages make this
technology very popular (uniform particle size, all steps carried out in one apparatus, use of organic
solvents, the capability of encapsulating heat-labile materials). The emulsion is sprayed into a chamber,
where warm air dries the particles, and as a result, regular shaped, micron-sized, uniform particles
are created.
The extruded wax particles can be solidified using congealing, which offers a solution for
embedding hydrophilic component to perform sustained release via the slow erosion of the wall in the
biological medium.

4.2.7. Supercritical Fluid Precipitation

This technique is capable of constructing very uniform particles, but its use is more significant in
nanoencapsulation [111].
Sci. Pharm. 2019, 87, 20 16 of 31

4.2.8. Freeze-Drying
Freeze-drying is successfully used in the microencapsulation of protein APIs. The process consists
of freezing, sublimation, primary drying, and secondary drying. At the freezing step, the eutectic point
of the components is taken into consideration. Lyoprotectants or cryoprotectants (trehalose, dextran)
can stabilize API molecules during the process by replacing water, forming a glassy matrix, reducing
molecular mobility by establishing hydrogen or van der Waals bonds between the molecules [112].
Despite its high cost, it is an advantageous process for heat-sensitive molecules.
Freeze-drying provides solidification, which then allows particles to be reconstituted in an aqueous
medium (Figure
Sci. Pharm. 2019, 87, x8).
FOR PEER REVIEW 17 of 31

Figure 8. Calcium alginate microparticles: (a) initial (prepared using a Büchi B-390 Microencapsulator),
(b) freeze-dried,
Figure and (c)alginate
8. Calcium reconstituted in a pH 6.8 phosphate
microparticles: (a) initialbuffer (60 min). using a Büchi B-390
(prepared
Microencapsulator), (b) freeze-dried, and (c) reconstituted in a pH 6.8 phosphate buffer (60 min).
Table 7 summarizes the most important methods along with the parameters of the initial and final
form of microparticles.
Table 7. Classification of main procedures to prepare microparticles, spheres, and microcapsules.

Typical
Table 7. Classification of main Initial
procedures Approximate
to prepare Structure
microparticles, spheres, and microcapsules.Final
Method
Form of the Core Size (µm) Matrix Core/Shell State
Typical Initial Approximate Structure
Method wet
Final State
Form of the Core Size (µm) Matrix Core/Shell
C Interfacial In emulsion or (slurry),
h Interfacial In emulsion or 0.1–500 X wet (slurry),
polymerization
polymerization
suspension
suspension
0.1–500 X can be
can be dried
e Chemical dried
In situ In emulsion or wet (slurry),
m 1–1000 X wet
polymerization suspension can be dried
ic In emulsion or or
In emulsion wet, (slurry),
can be
al In situ polymerization
left 1–1000
2–5000 X X X
suspension
suspension dried
can be
Dripping-
Droplet dried
(Vibrating wet, can be
In emulsion or
formulation/extrusion; 10–5000 X X wet, can
Coacervation nozzle-single; coextrusion 2–5000 X X dried
multiple) suspension be dried
Dripping- (Vibrating
Solvent Droplet
In emulsion or wet, can be
P Physicochemical evaporation suspension
0.1–5000 X X wet, can
dried
nozzle-single; formulation/extru 10–5000 X X
h be dried
multiple) Spray drying sion; coextrusion
Droplet
1–100 X dry
ys (from solution) formulation/spraying
In emulsion or wet, can
ic Solvent evaporation Droplet 0.1–5000 X X
Spray chilling suspension
formulation/spraying
1–100 X X be
drydried
oc
Droplet
h Spray drying Fluid(from
bed
coating/drum formulation/spray
Solid core particle 1–100
100–5000 X X drydry
e solution) coating ing
m
Droplet
ic
Spray chilling formulation/spray 1–100 X X dry
al
ing
Fluid bed
Solid core particle 100–5000 X dry
coating/drum coating

4.2.9. Microfluidics in Microparticle Fabrication

Sci. Pharm. 2019, 87, 20 17 of 31

4.2.9. Microfluidics in Microparticle Fabrication

Microfluidics also presents promising results regarding microparticle production [113]. A wide
range of microfluidic plates have been created concerning their various structure, material, and
size [114]. Various methods are used for the engineering of microparticles such as continuous
flow-based and electrowetting-based droplet generators.
Sci. Pharm. 2019, 87, x FOR PEER REVIEW 18 of 31
Microfluidic Droplet Generators (MFDG)
Microfluidic dropletgenerators
Microfluidic droplet generators (MFDG)
(MFDG) withwith a T-junction,
a T-junction, co-flowing
co-flowing junction,
junction, and flow-
and flow-focusing
focusing
geometriesgeometries
are ableare to able to create,
create, depending
depending on the
on the settings,
settings, monodispersespherical
monodisperse sphericaloror spheroid
droplets [114].
[114].TheThemicrofluidic-based
microfluidic-based droplet generation
droplet can be
generation canimplemented
be implementedusing active
usingor passive
active or
methods.
passive In the passive
methods. method,method,
In the passive droplets can becan
droplets produced in squeezing,
be produced dripping,
in squeezing, jetting,
dripping, tip-
jetting,
streaming, andand
tip-streaming, tip-multibreaking
tip-multibreaking modes, depending
modes, depending ononthe
thecompetition
competitionbetween
betweencapillary,
capillary, viscous,
viscous,
and inertial forces [115]. In active control, droplet generation can be manipulated by either applying
additional forces from electrical, magnetic, and centrifugal controls, or modifying intrinsic forces via
tuning fluid
fluidvelocity
velocityandand material
material properties
properties including
including viscosity,viscosity,
interfacialinterfacial tension,
tension, channel channel
wettability,
wettability, and fluid
and fluid density [115]. density [115].
Coaxially assembled devices, in combination with emulsification
emulsification methods,
methods, led
led to the production of
monodisperse
monodisperse microcapsules
microcapsules or or Janus particles [116]. The polymerization
polymerization occurs
occurs using a concomitant
concomitant
chemical
chemical or physical reaction
or physical reaction based
based on the nature
nature of
of the
the polymer
polymer [117].
[117]. Figure 99 presents
presents particle
particle
formation
formation through
through a PDMS
PDMS (polydimethylsiloxane)
(polydimethylsiloxane) hydrodynamic
hydrodynamicfocusing
focusingapparatus
apparatusof of aa W/O/W
alginate
alginate system
system in oil asas aa carrier
carrier liquid.
liquid. The
The alginate
alginate droplets
droplets were
were solidified
solidified via
via coacervation
coacervation (own
experiments).
experiments).

9. (a)(a)
Figure 9.
Figure Particle
Particle generation
generation withwith microfluidics
microfluidics with awith a flow-focusing-based
flow-focusing-based microfluidic
microfluidic droplet
droplet generator (MFDG). Particle formation was carried out with an
generator (MFDG). Particle formation was carried out with an own-developed hydrodynamic- own-developed
hydrodynamic-focusing-based
focusing-based microfluidic
microfluidic device. device.
(b) Emulsion (b) Emulsion
coacervated particlecoacervated particle
fabricated using fabricated
microfluidics.
using microfluidics.
Wu et al. [96] demonstrated that in the case of monodisperse rifampicin-PLGA core-shell
Wu et al. [96] demonstrated that in the case of monodisperse rifampicin-PLGA core-shell
microcapsules, the burst-release can be decreased with increased encapsulation efficiency, and the
microcapsules, the burst-release can be decreased with increased encapsulation efficiency, and the
release can be controlled by increasing the wall thickness.
release can be controlled by increasing the wall thickness.
4.2.10. Lithography
4.2.10. Lithography
Contact lithography was originally developed for the semiconductor industry. It is, however,
Contact lithography was originally developed for the semiconductor industry. It is, however,
successfully applied in the replication of nonspherical particles of 500–1000 µm in size. The pattern
successfully applied in the replication of nonspherical particles of 500–1000 µm in size. The pattern is
is transferred from a photomask to a photopolymerizable material (e.g., polyethylene-glycol-
transferred from a photomask to a photopolymerizable material (e.g., polyethylene-glycol- diacrylate)
diacrylate) using light [118]. Continuous flow lithography has better particle resolution and
using light [118]. Continuous flow lithography has better particle resolution and improved throughput.
improved throughput. The monomer solution is pumped through a microfluidic device, where
The monomer solution is pumped through a microfluidic device, where photopolymerization occurs.
photopolymerization occurs. The polymer particles (sometimes of extreme shape) are collected after
having left the device [9,119] and have been used for the controlled synthesis of bullet-shaped, 12.4-
µm long, magnetic and non-magnetic microparticles using stop-flow lithography, which gives the
possibility of executing mild invasive drug delivery via microneedles.

5. Characterization
Sci. Pharm. 2019, 87, 20 18 of 31

The polymer particles (sometimes of extreme shape) are collected after having left the device [9,119] and
have been used for the controlled synthesis of bullet-shaped, 12.4-µm long, magnetic and non-magnetic
microparticles using stop-flow lithography, which gives the possibility of executing mild invasive drug
delivery via microneedles.

5. Characterization

5.1. Morphology
Size plays a crucial role in the in vivo performance of microparticles. Particles larger than 100
nm stay at the site of administration until the phagosomal clearance. Lymphatic uptake and node
accumulation is most significant between 10–80 nm [2].

5.1.1. Particle Size Analysis

Particle size analysis of microparticles above the diameter of 3 µm is in most cases carried out
based on laser light diffraction (LD) method or using a Coulter counter. In LD, the distribution indicates
the span-value, and d0.1 , d0.5 , and d0.9 are the parameters that can be used to compare the results.
Span-value indicates the size distribution and is calculated based on the following equation:

d0.9 − d0.1
Span = (1)
d0.5

where 90% of the particles are under the diameter d0.9 , 10% of the particles are under the diameter d0.1 ,
and 50% are under the diameter d0.5 .
The polydispersity index (PDI) determined by dynamic laser light scattering indicates the size
distribution in the lower size region of microparticles.

5.1.2. AFM (Atomic Force Microscopy)

AFM is a technique providing information about the surface of microparticles in nanoscale by
profiling the surface [120].

5.1.3. Coulter Counter

A Coulter counter gives an absolute particle number per volume unit for various size ranges and
is very important in the particle analysis of microparticles for intravenous use [121].

5.1.4. Image Analysis

The shape determination can be more accurately achieved using microscopic (light or scanning
electron microscopy) image analysis. The shape is characterized by the roundness, aspect ratio (AR),
P2
and the Feret-diameter. Roundness (R) is calculated using R = 4πA , where P is the perimeter, and A is
Dmax
the projection area. The aspect ratio is calculated using AR = Do , where Do is the longest orthogonal
diameter perpendicular to Dmax .
The aerodynamic size distribution (indicator of the particle deposition during inhalation) can be
investigated using cascade impactors (powders, aerosols, and sprays). The deposition is not solely
based on the particle size, the flow depends on the particle shape and density as well [120].
Sci. Pharm. 2019, 87, 20 19 of 31

5.2. Physicochemical Properties

Zeta-Potential Analysis
The surface charge of the particles influences physical properties (e.g., tendency to aggregation);
it also has a tremendous role in their biological performance: negatively charged surfaces
(polysaccharide-based natural molecules, e.g., polyalginic acid, hyaluronic acid, polymethacrylic acid,
etc.) attract to tissues in inflammations and are hemocompatible. Positively charged microparticles
(chitosan, Poly-l-lysine), however, present a mucoadhesive character and are non-hemocompatible [122].
Zeta potential and particle size can be determined using photon correlation spectroscopy. The
dynamic light scattering measurement is based on the Brownian movement of the particles. Zeta
potential measurements present valuable data concerning the aggregation potential of surface charged
microparticles in a suspension (above ±30 mV stable suspended particles because of repulsion), and in
indicating whether the surface-charged molecule is encapsulated or adsorbed on the surface [123].

5.3. Physical Properties

5.3.1. Density
The density of particles determines the floating capacity and concomitant disintegration or
swelling of the particle. The pycnometric method with helium gas can be used to determine this
value [124].

5.3.2. Porosity
The porosity of microparticles has a significant role in the water uptake, swelling, reconstitution,
and release mechanisms. This parameter can be measured directly using mercury porosimeters [125].

5.3.3. Microcomputed Tomography

The indirect assessment of porosity can be deducted from a microcomputed tomography assay
based on the 3D internal trabecular separation for calcium-alginate microparticles [126].

5.3.4. Flowability and Compressibility Studies

The flowability, Carr’s index, Hausner ratio, and angle of repose are significant for particles
applied in the dry state. These tests can be executed as it is described in the official pharmacopoeias
(e.g., European Pharmacopoeia, Unites States Pharmacopoeia).

5.3.5. Mechanical Test

The tensile strength and the elasticity of microparticles can be tested with a texture analyzer,
where the compression force is detected relative to the distance, and the maximum compression force
and hardness can be calculated, which indicate the mechanical resistance of the shell or the matrix
structure [124].

5.3.6. Swelling
An equilibrium swelling study can be performed to observe the behavior of dry particles under
various conditions (Figure 10). The swelling index (S%) can be calculated using the swollen particle
diameter (ds ) and the initial particle diameter prior to reconstitution (di ), as follows:

ds − di
S(%) = × 100 (2)
di
 An equilibrium swelling study can be performed to observe the behavior of dry particles under
various conditions (Figure 10). The swelling index (S%) can be calculated using the swollen particle
diameter (ds) and the initial particle diameter prior to reconstitution (di), as follows:
Sci. Pharm. 2019, 87, 20 𝑆(%) = × 100 (2) 20 of 31

Figure 10. Swelling of air-dried O/W alginate (2%) microparticles (prepared using a Büchi B-390
FigureMicroencapsulator)
10. Swelling of air-dried
in a pH O/W alginate buffer:
6.8 phosphate (2%) microparticles (prepared
(a) initial, (b) after using
5 min, (c) aftera 15
Büchi
min, B-390
and (d) after
Microencapsulator)
30 min (the oilinphase
a pHcontained
6.8 phosphate
Sudanbuffer: (a) indicator).
III. as an initial, (b) Images:
after 5 min, (c) SMZ
Nikon after 1000
15 min, and (d)
Stereomicroscope.
after 30 min (the oil phase contained Sudan III. as an indicator). Images: Nikon SMZ 1000
5.3.7. Wetting Property
Stereomicroscope.
The wetting property of the excipients can be determined using contact angle measurements [127,128].
5.3.7. Wetting Property
5.4. Drug Entrapment Efficiency
The wetting property of the excipients can be determined using contact angle measurements
[127,128]. The success of drug loading can be expressed by the actual loading and the entrapment
(encapsulation) efficiency:
5.4. Drug Entrapment
The actualEfficiency
drug loading is:

drug (mg)
DL (%) = × 100 (3)
(drug + polymer) (mg)

The general formula for calculating the entrapment efficiency value is:

entrapped drug content (mg)

EE (%) = × 100 (4)
theoretical drug content (mg)

The ideal entrapment efficiency (100%) is influenced by various factors such as the type and
circumstances of the process [129].

5.5. Drug Release

5.5.1. In Vitro Dissolution Test for Multiparticulates

USP 42-NF 37 suggests different methods for the dissolution of multiparticulate preparations. The
apparatus and the volume are chosen based on the dosage form performance in the medium and the
volume. Compendial rotating basket (USP Apparatus 1), a reciprocating cylinder (USP Apparatus 3)
can be used for nondisintegrating coated beads, or a flow-through cell (USP Apparatus 4) can be used
for multiple dosage forms (beaded products), where sink conditions are provided.
Polymers of ionic character perform differently under various pH conditions. The independence
or dependence of drug release on the ionic strength of the medium can be proved using distinctive
pharmacopoeial methods. The medium ranges between the physiological pH 1.2–7.5 hydrochloric acid
or phosphate or acetate buffer with or without enzymes, depending on the route of administration or
the behavior of the polymer in the medium (e.g., swelling, ionization (IEP)). The use of surfactants is
possible, usually over its CMC value.
As a noncompendial apparatus, a mini-paddle-equipped small-volume apparatus, dialysis tubes,
or rotating bottle can be used.
The in vitro release mechanisms (diffusion, erosion, osmotic release, or a combination of the
previous) can be interpreted based on the models of Fick, Higuchi, Korsmeyer-Peppas, Weibull, and
Kopcha [130,131].
Sci. Pharm. 2019, 87, 20 21 of 31

5.5.2. Dissolution Test for Inhaled Particles

Inhaled particles deposit in the tracheobronchial tract depending on the size, density, and shape
of the particles. The mucus layer that provides the absorption site for drugs has a small volume
and the renewal of the absorption layer is different from that of the gastrointestinal tract; therefore,
the development of dissolution methods different from the traditional is used. USP 2, the rotating
paddle apparatus, can be used with certain modifications. The drug is set into a special cassette and an
apparatus capable of a 150 mL dissolution medium is used, agitated using mini paddles [132].
The dialysis bag method is also useable. The drug is set in the semipermeable dialysis bag,
which is immersed in the dissolution medium. The drug diffusion occurs between the two liquid
phases, and although both static and sink-conditions are maintained, the method does not simulate the
air–liquid transition.
5.5.3. In Vitro Performance of Intramuscular Injections
The in vitro dissolution study of the long-acting intramuscular injection, Risperdal® Consta® ,
where the small interstitial volume provides an alternative dissolution method, was carried out in
a flow-through cell apparatus equipped with glass beads of 1 mm diameter and a pump [133]. The
in vitro dissolution data of the accelerated test, performed at a temperature above the glass transition
temperature of the polymer, correlated well with the previously published in vivo data.
In both the modified Franz diffusion cell [134] and Transwell® [135] systems, drug powder is
poured on a semipermeable membrane, which is located above the acceptor medium and diffuses
through the membrane during the test. Small volume, agitation, and regularly withdrawn samples
(sink conditions) provide the in vitro simulation of the in vivo performance.
DissolveIt® apparatus [136] presents in vitro dissolution and absorption by mimicking the in vivo
performance with a membrane separating the simulated air–blood barrier in the tracheobronchial
region of the lung and a flowing blood simulant.
5.5.4. In Vitro Dissolution Test for Topical Microsponge Preparations
A Franz diffusion cell with silastic membranes and a sink condition providing solvents
as an acceptor medium has been applied to test benzoyl-peroxid-containing microsponge gel
preparations [64].
6. Other Studies

6.1. Spectrometry
Fourier-transform infrared (FT-IR) and powder X-ray diffractometry (PXRD) analysis can be
performed to follow the intramolecular changes during microencapsulation [81]. Nuclear magnetic
resonance (NMR) studies underline the conformational changes in polymers during complexation [137].

6.2. Thermoanalytical Methods

Thermogravimetry (TG) and differential scanning calorimetry (DSC) give valuable data of the
thermal behavior of the polymer. The measurable glass transition temperature plays a significant role
in the production and the release mechanisms as well.
In the case of mucoadhesive systems, the tensile strength test, shear strength test, and the peel-off
test or in vitro wash-off test can be performed [61].
6.3. Biocompatibility
A tetrazolium-based colorimetric assay, such as an MTT (methylthiazolyldiphenyl-tetrazolium
bromide) assay, proved good to screen the cytotoxicity of hydrophylic polymers [138].
7. Applications in the Therapeutical Practice
Several types of multiparticulate sytems and product examples are detailed in Table 8 according
their type, dosage form with route of administration, drug and key excipient, and indication for use.
Sci. Pharm. 2019, 87, 20 22 of 31

Table 8. Types of multiparticulate systems in use.

Type Dosage Form Key Excipient Drug Indication Product Example

Micropellets Peroral pellets in capsule HPC Lansoprazole Proton pump inhibitor Lansoprazole®
Enteric-coated Delayed-release orally
Methacrylic acid, polyacrylate Lansoprazole Proton pump inhibitor Prevacid® SoluTab™
microgranules disintegrating tablets
Compressing pellets into an Cardioselective beta
Coated pellets HPC, EC Metoprolol succinate Betaloc® ZOK
extended release tablet blockers
Methacrylic acid-ethyl acrylate,
Microtablets Peroral minitablets in capsule Lipase, amylase, Enzyme supply Pangrol®
MCC
Dry powder
inhalation Fumaryl diketopiperazine Insulin Diabetes AfrezzaTM
(Technospheres® )
Microspheres Im suspension injection Poly-d, l-lactid-co-glycolide Risperidone Schizophrenia Risperdal® consta
Acromegaly,
Microspheres Powder for injection Poly-d, l-lactide-co-glycolide Bromocriptine Parlodel® LAR
parkinsonism
Powder and solvent for Acromegaly pancreatic
Microspheres Poly-d, l-lactide-co-glycolide Octreotide Sandostatin LAR®
suspension and injection tumors
Prolonged-release suspension
Microspheres Poly-d, l-lactide-co-glycolide Exenatide Diabetes type 2 Bydureon®
for injection
Lyophilized microspheres Suspension depot injection Poly-d, l-lactid-co-glycolide Leuprolide acetate Endometriosis Lupron® depot
Liposome inhalation Cholesterol,
Liposomes Amikacin Antibacterial Arikayce®
suspension dipalmitoylphosphatidylcholine
Powder for suspension for
Liposomes (DepoFoam™) Cholesterol, DOPC, DPPG Cytarabine Neoplastic meningitis Depocyte®
injection
Powder for suspension for Cholesterol, DOPC, DPPG,
Liposomes (DepoFoam™) Morphine Epidural analgesia DepoDur®
injection tricaprylin, triolein
Microbubbles Intravenous injection Albumin Perflutren Ultrasound contrast agent Albunex®
PEG 4000, DSPC, DPPG-Na,
Microbubbles Intravenous injection Sulfur hexafluoride Ultrasound contrast agent Lumason/SonoVue®
palmitic acid
Microbubbles Intravenous injection DPPA, DPPC, MPEG5000 DPPE Perflutren Ultrasound contrast agent Definity®
Methyl methacrylate/glycol
Microsponge Topical gel Tretinoin Acne vulgaris Retin A® micro gel
dimethacrylate crosspolymer
Methyl methacrylate glycol
Multiple acne/solar
Microsponge Topical cream dimethacrylate crosspolymer, 5-fluorouracil Carac® cream 0.5%
keratoses
dimethicone.
Sci. Pharm. 2019, 87, 20 23 of 31

Solid multiparticulates usually involve coated pellets or microtablets in order to ensure gastric
resistance (e.g., for acid labile proton pump inhibitor compounds) or to prolong the duration of
action and optimize the pharmacokinetic profile. Smart carrier systems react to changing pH, electric
impulse, magnetic field, and/or temperature, and have been developed in many platforms (pellets,
microgranules, microspheres).
Patient-centric medication involves the development of patient-friendly devices (e.g., DPI—Dry
Powder Inhaler) and administration routes. Inhalatives, ODTs, and nasal administration could be an
opportunity to reach a systemic effect. There is broad research on this field, however, there is only a
limited number of preparations approved by the authorities
Sustained-release injectable depot systems are capable of forming a reservoir at the site of
administration and release the API over a longer period. This property is advantageous in the
treatment of psychotic patients, or in the medication of children with acute diseases.

7.1. Insulin for Inhalation (Technosphere® )

AfrezzaTM is an immediate-release insulin formulation for Type 1 and Type 2 diabetes patients with
an optimal bioavailability (25%). The pulmonary applied preparation consists of microparticles (2–3 µm)
of self-assembled fumaryl diketopiperazine (FDKP) (Mw = 452.46 Da) molecules. In this preparation,
FDKP nanocrystals are formed via a pH-induced crystallization process, and the nanocrystals are
self-assembled into a spherical microparticle, like a deck of playing cards. The front and back sides of
the “cards” provide the spheres with a high surface area, and the distance between the layers provide
the extremely high porosity, low density, and convenient aerodynamic character to deposit into the
distant alveolar regions where the API dissolves rapidly at the alveolar surfactant pH. Depending on
the API molecular weight, local (>100,000 Da) or systemic absorption is possible. Special inhalers
(Dreamboat® or Cricket® ) are designed for optimal application [139].

7.2. Depocyte® (Parenteral Suspension)

Depocyte® , a liposomal product, is a pyrogen-free, parenteral suspension containing cytarabine
developed for the treatment of neoplastic meningitis (NM) via controlled release. Depocyte® is a
slow-release formulation created using DepoFoam™ technology, which includes microscopic spherical
particles (3–30 µm) and is suitable for encapsulating hydrophilic compounds in a “honeycomb-like
structure” of separated water-containing chambers. Lipid membranes separate each adjacent chamber.
Drug release is carried out over an extended time via erosion and/or reorganization of the particles’
lipid membranes. The honeycomb architecture of multivesicular DepoFoam™ particles gives allows for
a comparatively high drug loading. The injection comprising 96% aqueous foam and 4% biodegradable
lipid [140] has to be administered intrathecally every two weeks and it is metabolized by the usual
metabolic pathways for triglycerides, phospholipids, and cholesterol.

7.3. DepoDur™
Epidural morphine sulfate sustained-release liposome injection DepoDur™ is a single-dose
preparation administered at the lumbar level by the epidural route before operations. The lipid foam
contains multivesicular lipid-based particles with aqueous chambers that encapsulate the active drug.
The foam releases morphine during a 48-h period via erosion, namely the rupture of the microvesicles
(of 17–23 µm in median diameter).

7.4. Microsponge Delivery System (MDS)

Topical delivery of drugs can be achieved with microparticles of very high porosity. These
structures (of particle size of 5–300 µm) can entrap and release drugs with a controlled rate as a
response to special triggers—skin temperature change, rubbing, moisture, friction, etc.—while they
do not penetrate into the skin and perform a local effect. MDSs can achieve a very high embedding
Sci. Pharm. 2019, 87, 20 24 of 31

capacity (50–60%), and as their pore size is very small (≈0.25 µm), bacteria cannot penetrate inside, they
do not need preservatives to obtain stability. They are usually administered in the form of a gel, and the
aforementioned physical and physicochemical tests have to be accomplished with rheological studies
(viscoelasticity) [141]. The disadvantage is that by the production only organic solvent technologies
proved to be effective.

7.5. Microbubbles
Microbubbles are used as ultrasound contrasting agents, gene delivery vesicles, O2 carriers,
are thrombolytic, and facilitate the transport through the blood–brain barrier without inducing a
tissue-damaging effect [142]. Microbubble formulations contain an emulsifier, phospholipids, or protein
components, which, following sonication, entrap gases (O2 , perfluorocarbons, or sulfur hexafluoride).
The product can be preserved in a lyophilized form. The maximum size may not exceed 10 µm to
avoid embolism in vivo [143].
The in vivo performance of microbubbles is influenced by the complement system of the immune
system, which is responsible for the removal of drug molecules, bacterial cells, and microbubbles
from the circulation. Studies pointed out that PEGylation reduces the immunogenicity of BSA (bovine
serum albumin) microbubbles [143].

8. Summary
In the past few decades, numerous microparticulate formulations gained therapeutical and
diagnostical significance. A great number of polymers have been tested, of which several have been
proved effective.
To accomplish the traditional coacervation, new methods have been developed (freeze-drying,
spray drying, microfluidic flow-focusing, lithography, etc.). The various created structures offer
a large potential for the fine-tuning of drug release mechanisms and the optimization of the
pharmacokinetic profile.

Author Contributions: Formulation, characterization, polymer excipients, and use (M.L.); processes, release
mechanisms (N.K.-S.); preparation, samples, and photos (V.A.); microfluidics (A.J.L.); and content, structure, and
therapeutical aspects (I.A.).
Funding: This review article received no external funding.
Acknowledgments: The authors thank Ágnes Sárádi-Kesztyűs for technical assistance.
Conflicts of Interest: The authors declare no conflict of interest.

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