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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5628_Библиотеки_им_академика_М_И_Перельмана.pdf
204
Nano Physical Pharmaceucs of Microsphere Delivery System
RESS:
is rapidly expanded in the expansion chamber to reduce the
solubility rapidly so that the solute can precipitate to form
microspheres. This method does not require the use of other
solvents, which is conducive to environmental protection.
However, CO
2
is relatively weak in polarity and can dissolve fewer
substances, so it is mainly applied to fat-soluble drugs.
GAS: Drugs and polymers are dissolved in an organic solvent,
the organic solvent but has poor solubility for the drug and
polymer is used to precipitate to obtain microspheres. It is
applicable to compounds that are slightly soluble or insoluble in
system, which will ensure a low level of the residual amount of
the solvents, as well as a narrow particle size distribution.
PCA: This method is similar to spray drying. The drug-
vapor phase to form fog droplets which will then be penetrated
dissolving capacity of the solvent, thereby causing the drug and
polymer to precipitate to form particles. In this way, relatively
monodisperse microspheres with small particle sizes can be
prepared [26].
6.3 Mechanism of Microsphere Formation
6.3.1 Stability of Nano-Microspheres and DLVO Theory
Microspheres are thermodynamically unstable systems. There is a
tendency for particles to coalesce with each other to reduce their
surface energy, that is, microspheres are featured with instability
which makes them easy to coagulate. Therefore, a stabilizer is
necessary when preparing microspheres. In addition, due to the
small particles of microspheres, the Brownian motion (which refers
to the never-ending irregular motion of particles suspended in
liquid or gas) is violent, so they are not easy to settle in the
Mechanism of Microsphere Formation
205
microspheres must have both stability and dynamic stability that
are not prone to coagulation. However, the stability that is not
prone to coagulation is more important, because although Brown
motion makes the microspheres have dynamic stability, it also
promotes the continuous collision among particles. If the particles
lose their stability against coagulation, the mutual collision will
cause agglomeration, and the result is that the particles are
enlarged, with the speed of Brownian motion decreased, and
eventually the microspheres will become a dynamically unstable
system. The process of particle aggregation from small to large
is called aggregation, and the large particles formed by the
of aggregation causes particles to precipitate out of the solution,
the aggregation process is called coagulation. In order to accelerate
the aggregation, other substances can be added as a coagulant,
such as electrolytes [13]. In addition, certain physical factors
may also cause the coagulation of microspheres, such as light,
electricity, and heat [13, 28].
When discussing the stability problem, we must consider
the force between particles (Fig. 6.2), which generally has the
gravity; (2) Electrostatic repulsion; (3) Born force or short
Landau, Verwey and Overbeek put forward DLVO theory based
on the mutual attraction and mutual repulsion force between
the stability of particle multiphase dispersion system. The following
mainly discusses the calculation of attraction and repulsion
The DLVO theory provides a method to calculate the repulsive
energy and attracting energy among colloidal particles, and based
on this, the stability of colloids is quantitatively processed, the
relationship between the coagulation value and the electrovalence
of counterions can be concluded, and the Schulze–Hardy rule
stability and coagulation of colloids from the perspective of
the interaction between the repulsive potential energy and the
attracting potential energy among colloidal particles. It is believed
that there are two interaction forces among charged colloidal
206
Nano Physical Pharmaceucs of Microsphere Delivery System
particles, that is, the electrostatic repulsion when the electrical
double layer overlaps, i.e., the long-range Van der Waals attracting
force among the particles, and their interaction determines
potential energy V
T
D
among particles in the dispersed system
is the sum of the repulsive potential energy (electrostatic repulsive
potential energy) V
ER
and the attracting potential energy (long-
range Van der Waals potential energy) VWA, namely:
V
T
D
=
VER + V
WA
(6.1)
6.3.2 Factors Affect the Potential Energy
particle size and shape of colloids, the distance among particles,
Hamaker constant A, the particle surface potential y, and the
electrolyte concentration n[31]. For a long time in the past,
the classic DLVO theory has been used to explain the cohesion
and dispersion behavior between colloidal particles. However,
special interaction forces between hydrophilic or hydrophobic
particles, which play a decisive role in the stability of the colloidal
dispersion system. The classic DLVO theory cannot explain the
cohesion and the dispersion of these systems, and an extended
DLVO theory is thus proposed as shown in Equation 6.2:
V = VER + VWA + VSR + VHR + VHA + V
MA
(6.2)
Here V
SR
refers to the space-repulsive potential energy, V
HR
refers to the hydration interaction repulsive energy, V
HA
refers to
the hydrophobic interaction attracting energy, and V
MA
refers to
the magnetic attraction potential energy. If the distance (H)
between the surfaces of two spherical particles with equal
volumes is much smaller than the particle radius (r), the mutual
gravitational potential energy (Aa) between the two particles can
be approximated based on Equation 6.3:
A
12
Ar
(6.3)
a
H
Mechanism of Microsphere Formation
207
where Aa is the gravitational potential energy, A is the Hamaker
constant, r is the particle radius, and H is the surface spacing
of spherical micelle particles. The Hamaker constant is related
to the properties of particles (such as the number of atoms per
unit volume, polarizability and solution pH), and is the
characteristic constant of substances, which are approximately
J [32].
The magnitude of the repulsion potential energy (V) between
particles with the same charge depends on the number of particle
charges and the distance between each other. If the surface
potential energy between parallel plates is:
1
1
V Kc
2
exp Kc
2
r 1
2
(6.4)
Here c is the electrolyte concentration, K1 and K2
values under certain conditions, and V decreases exponentially
with the increase of electrolyte concentration c, therefore, the
of microspheres. For two spherical particles with a distance
of H, assuming that the surface potential is low, the repulsive
potential energy can be approximately expressed as:
Vr K ej
2
exp (kH)
Here K is a constant, e is the dielectric constant of the
medium, jis the electric potential of the colloidal particle
surface, K is the reciprocal of the ion atmosphere radius in the
Debye-Hickel equation, His the minimum distance between the
surfaces of the two spheres, and r is the particle radius. It can
be seen from the equation that the repulsive potential energy
increases with the increase of the surface potential jand the
particle radius r, and decreases exponentially with the increase
of the distance among particles.
The total potential energy among particles should be the
sum of the attracting potential energy and the repulsive potential
208
Nano Physical Pharmaceucs of Microsphere Delivery System
energy, that is, V = Va+ Vr, and the value change is roughly. In the
potential energy curve, the height of the potential barrier is a sign
of the stability of microspheres. When the height is zero,
microspheres will become unstable. Find the point where
the potential barrier is reduced to zero due to the addition of
electrolyte, namely:
dV
, V
(6.6)
dH
The concentration c of electrolyte added at this time is the
coagulation concentration when V
expression of the DLVO theory with water as the medium is
obtained:
4
r
cK
26
AZ
6.3.3 Factors Affect the Stability of Microspheres
6.3.3.1 Properties of polymers
Aggregation or association is a process in which primary particles
under the action of force. The study of particle aggregation
in polymer solutions and dispersions has attracted extensive
attention of scientists. The aggregation of polymer chains can
form a variety of structures such as spheres, core–shell, columns
and vesicles with uniform density. Because the aggregation of
polymer chains has many important applications in industry, such
as the stability of lotion particles, the preparation of dyes and
pigments in the printing industry, etc. The aggregation of a polymer
single chain is more complex [33]. Wu et al. studied the thin layer
phase separation behavior on the surface of a homopolymer
from the time scale of permanent interpenetration of two
adjacent aggregates, aggregation does not play a leading role [34].
Our group’s research shows that the expressions of tC and tE are
as follows:
l
Mechanism of Microsphere Formation
209
role (
C E
shown in Fig. 6.2.
v
t
E
t
C
2
3 32 p/
N
af
D
2
l
D
1
where
l
velocity,
monomer,
is
〈
D〉
N is
the
range
of interaction; v
the
degree
of polymeri
〈
a
When
particles
on adjacent
the requir
time
collide
cannot
with each
be bonded
in the collision
properties
studies have
aggregation
group
of
shown
–6
of
on »the
surface
t
t
collide with each other, the polymer chains
microspheres
ed
for this tprocess
other
will entangle
is C. If t
is
t
t
« E , the
C
E
together. They are like two
process,
long
in the
polymer
which is determined
high
molecular
that
even
if the polymer
collapsed
is very
of such
slow.
polymer
chains
state, the
particles
is
the
the length
zation,
with
. The
time
two
[34].
concentration
f
If there
average 1 thermal
D
of P a
and
each
other,
when
particles
colliding
elastic
by the
P
particles
“glas
viscoelastic
Our
previous
is
no a hydrophilic
to
play
stabilizing
unit
is
the
and
s balls”
is very
as
viscoelastic particles.
210
Nano Physical Pharmaceucs of Microsphere Delivery System
6.3.3.2 Surface charge of microspheres
Based on the type of surfactants, monomers or initiators used,
the surface of microspheres is positively or negatively charged.
The greater the surface charge, the greater the repulsive force
among microspheres, and the more stable the microspheres in
an aqueous solution. Therefore, the electric potential is one
of the important indicators to characterize the stability of the
microsphere dispersion (see Fig. 6.3).
Figure 6.3 The micro-electronic properes and force among charged
parcles in soluon.
called the Van der Waals force (or London dispersion force).
The sum of the potential energy of these two interactions is
negatively correlated to the center-to-center distance. For the
highly charged microspheres suspended in a solution containing
the potential is still controversial. Generally speaking, the potential
energy must be added with the third term: the stronger long r.
2 kr kh
()
Ur
()Ze e
2
e
e1kr
h
Here h is the center-to-center distance of the two charged
microspheres, Z is the number of charges of each charged
microspheres, r is the radius of the charged microspheres, and e is
NPP of Microspheres
211
the dielectric constant of the dispersive medium. The magnitude
increase of the stray electrolyte concentration, which is due to the
6.4 NPP of Microspheres
6.4.1 Physicochemical Properties of Microspheres
6.4.1.1 Parcle size and apparent structure of microspheres
The shape, size and pore structure of microsphere particles
depend on a lot of experimental variables, such as temperature,
stirring speed, pH, stirring type, porogen, polymer and their
concentration. Therefore, it is very challenging to synthesize porous
particles with predetermined porosity.
conditions. In the copolymer system of GMA and DVB or EGDA
(Route 1), polymers with a higher content of GMA and PGMA are
separated from polydimethylsiloxane during the polymerization
process. The polydimethylsiloxane migrates inward, and monomers
and polymers migrate to the interfaces of the dispersed phase
capsule structure will be formed. Due to the relatively low thermal
gravity, micelles that migrate to the interface will deform, making
the surface of microspheres smooth. In the cross-linking system
St (Route 2), the phase separation occurs later, and monomers
micelles is larger and have a higher thermal weight. The
“eggshell” can be supported by micelles, and the surface of
microspheres has a spherical convex structure. In the P (GMA-StEGDA) system (Route 3), the phase separation occurs earlier due
to the poor compatibility of monomers and porogen. At the same
time, monomers show poor swelling capacity towards micelles,
so micelles prepared in this way are smaller. However, the T
g
is relatively moderate, which can not only form a support
frame, but also cause shrinkage and wrinkle deformation of the
“eggshell” [38].
212
Nano Physical Pharmaceucs of Microsphere Delivery System
The volume shrinkage of the “eggshell” shows the shape of
wrinkles, which should be directly related to two factors. On the
one hand, the micelle skeleton formed by phase separation acts
as a support, which determines the basic roughness. The
results show that the surface of P(St-EGDA) and P(St-DVB)
microspheres are spherical protrusions, and the compatibility
between St and dimethylsiloxane is better than that between
The performance of microspheres can be further improved
mixed particles can be changed within a controllable range to
adjust their optical, electrical, thermal, mechanical, electro-optical,
facilitates the adjustment of the interaction between microspheres,
and stabilizes the dispersion of these balls in a given medium.
In addition, in the subsequent steps, solvent extraction, hightemperature calcination and other ways can also be used to
remove the inner core, thereby generating a hollow sphere of the
coating material. In many cases, these hollow spheres may show
have an advantage over solid spheres because hollow spheres
have a lower density. Hollow spheres have nothing inside, which
also makes them particularly useful in other niche applications.
For example, it can be used as a container to carry various
6.4.1.2 Factors affecting the particle size of microspheres
Drug concentration. There are two ways to add drugs into
microspheres: one is to add drugs into microspheres during
the formation of microspheres. The other is to prepare blank
into the microspheres. With the increase of drug concentration
and drug loading of microspheres, the particle size will continue
to increase.
NPP of Microspheres
213
Effect of additives. By reducing the interfacial tension
between the dispersed phase and the dispersion medium, the
surfactant can vary the size of the emulsion drop in the preparation
microspheres.
Preparation method. The size of the microspheres depends
greatly on the preparation method, and the diameters of the
not necessarily the same. The same preparation method adopts
Mixing speed and emulsification time. Generally, the faster
the stirring speed is, the smaller the particle size is. The ultrasonic
treatment is smaller than the stirring method. The longer the
and the more uniform the particle size distribution is. In addition,
time of irradiation, curing time and temperature, cross-linking
agent, amount and type of catalyst.
6.4.2 Drug Loading and Encapsulation Efficiency of
Microspheres
The determination of drug content generally adopts the solvent
extraction method, in which the structure of microspheres is
broken to release drugs. The principle of solvent selection: maximize
the dissolution of drugs and minimize that of carrier materials;
ensure that solvents will not interfere with the determination.
Generally, an ultraviolet spectrophotometer or high-performance
liquid phase is used to detect the drug concentration [13, 41].
a
Loadingefficiency
L
(6.11)
()
L
t
where Lt is the total weight of the drug-loading microspheres, and
La is the actual measured content of the drug in the drug-loading
microspheres.