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Nano Physical Pharmaceutics of Nanogel Delivery System
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Chapter 6
Nano Physical Pharmaceutics of
Microsphere Delivery System
Zhiwen Qiu,
a
Wanru Tao,a Man Wang,a Hanwen Sun,b and Wei Li
a
a
Department of Nanomedicine, Naval Medical University,
Shanghai 200433, China
b
College of Medicine and Nursing, Dezhou University,
Shandong 253023, China
liwei_dds@163.com
6.1 Classification of Microspheres
Microspheres refer to tiny spherical entities formed during the
dissolution or dispersion of drugs in a matrix of polymer materials
and shall be categorized as matrix-type skeleton particles [1].
as nanospheres or nanoparticles, which belong to the colloid
category [1]. After being made into microspheres, drugs can
reducing the number of administrations, and improving the
Nano Physical Pharmaceutics
Edited by Wei Li
Copyright © 2025 Jenny Stanford Publishing Pte. Ltd.
ISBN 978-981-4968-52-2 (Hardcover), 978-1-003-51393-3 (eBook)
www.jennystanford.com
198
Nano Physical Pharmaceucs of Microsphere Delivery System
such as improving the stability of the drug, preventing the
inactivation of drugs in the stomach or reducing the irritation to
the stomach, facilitating the application and storage of liquid
drugs, and realizing the sustained release of drugs. With the
development of new technologies, the new process and new
materials, long-acting biodegradable injection microspheres have
become one of the important research areas of new pharmaceutical
preparations [2, 3].
According to the synthesized materials, they can be divided
into natural polymer microspheres, semi-synthetic polymer
microspheres and synthetic polymer microspheres. The natural
polymers used include carbohydrates (glucan, starch, chitin and
chitosan), acacia gum, alginate, protein (hyaluronic acid, gelatin
types of substances, which are generally degradable in vivo and
safe. The semi-synthetic polymers contain carboxymethyl cellulose
salts, methyl cellulose, ethyl cellulose, etc., which have low toxicity,
high viscosity and increased solubility after the salt formation.
However, due to hydrolyze, they cannot be processed at high
temperatures and need to be prepared as they are used. The new
biodegradable polymers in synthetic polymers have become an
important carrier of microsphere preparations, among which
polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic
acid (PLGA), polylactic acid and polyethylene glycol segmented
copolymer (PLA-PEG), e-caprolactone and lactide segmented
copolymer, polycarbonate, etc. are commonly used, which have
forming and sphere-forming properties [4–6].
Based on the structures of microspheres, they can be divided
into solid microspheres with the entire microspheres as a dense
structure, hollow microspheres with a hollow interior, and porous
microspheres with multiple holes on the surface. Compared with
the other two, hollow microspheres have unique advantages in
the controlled release and sustained release of drugs. However,
the preparation is currently only in the experimental research
stage due to the complicated preparation method and high cost,
their bright application prospects. Biodegradable polymer porous
Preparation of Microspheres
199
microspheres can be degraded in vivo
thus having been widely applied in controlled drug release, tissue
6.2 Preparation of Microspheres
The selection of microspheres carriers shall generally put the
following factors into consideration: stable in nature, non-toxic
and non-irritating properties, certain strength, elasticity and
plasticity, the ability to completely wrap drugs and achieve a
reasonable release speed, and the fact that after compounding
process of microspheres is exhibited in Fig. 6.1.
phase separation method, solvent evaporation method, spray
drying method, salting-out method, ultrasonic method, supercritical
used in the preparation of microspheres with various structures
are listed below.
Figure 6.1 Schematic diagram of preparation of drug-loaded microspheres.
6.2.1 Emulsification: Chemical Cross-Linking Method
mixing the drug with the carrier solution and dispersing it in an
immiscible medium to form a similar water-in-oil or oil-in-water
type emulsion, and then forming microspheres by cross-linking.
This method involves the cross-linking of groups in polymer
materials with the participation of cross-linking agents (such as
formaldehyde and glutaraldehyde) to form microspheres, which
generally uses the amino groups in the material to condense
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Nano Physical Pharmaceucs of Microsphere Delivery System
with the aldehyde group in the cross-linking agent to solidify
microspheres [11].
Compared with the traditional solvent evaporation technology
and spray drying technology, the microspheres prepared by
structure and a more ideal drug loading capacity. Whereas,
microspheres prepared by the traditional method have a low
fact that drugs can only be adsorbed on the surface of microspheres,
nature of materials, the synthesis concentration, pH value of
Among them, the concentration ratio of the materials and the
drugs is the main factor that determines the drug encapsulation
6.2.2 Solvent Evaporation
(such as organic solvents like methylene chloride, chloroform or
ethyl acetate) containing carrier material and water insoluble
(W/O) or water-in-oil-in-water (W/O/W) emulsion. The organic
solvents in the emulsion are removed by evaporation using
elevated temperature, reduced pressure extraction or continuous
stirring, and then prepared into drug microspheres by washing,
centrifugation and freeze-drying. Cellulose derivatives, polyesters
and polymeric anhydrides can be used as materials for the liquid
drying method [13, 14].
The evaporation method is simple to operate and suitable
This program is usually divided into single the emulsion method
and the re-emulsion method, of which the latter is more widely
used. The single emulsion method can be divided into O/W and
O/O types. The former is suitable for fat-soluble drugs. Under
the same circumstances, the encapsulation rate of water-soluble
drugs is low, but it can be relatively improved by methods such
Preparation of Microspheres
201
as pre-emulsifying the water with the drug to saturate the
water phase. The re-emulsion method is often used to prepare
water-soluble drug microspheres. Generally, polymers are
dissolved in methylene chloride, chloroform and other organic
solvents, and then an aqueous solution of drugs or active
After that, they are dispersed in the outer aqueous phase and form
the W/O/W type double emulsion to solidify microspheres with
6.2.3 Phase Separation
Phase separation is a widely used method for preparing
microspheres. Its main principle is to dissolve polymer materials
the materials in the two solutions to obtain microspheres by
were optimized by adjusting and controlling the temperature, pH
value in the preparation process, as well as adding poor solvents
and polymers causing phase separation. The equipment required
is simple, together with a wide range of polymer materials, making
it suitable for various types of drug microencapsulation. However,
problems such as microcapsules or microspheres adhesion, and
aggregation are quite common (which is more serious in the
gelatin hydrophilic system) [13].
6.2.4 Salting-Out Method
caused by the addition of a large amount of neutral salt, i.e., most
or all of the free water in the original solution is transformed
molecules forced into contact with the hydrophobic groups
on the surface of materials to mask them become free water
molecules for further use (not the water molecules involved in the
solvation of the polar groups on the protein surface. Instead, they
are bound by electrostatic interaction, the link is much stronger
than those water molecules in contact with hydrophobic groups),
so they are removed to solvate the salt ion, leaving the exposed
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Nano Physical Pharmaceucs of Microsphere Delivery System
hydrophobic group. As the salt concentration increases, the
hydrophobic surface of the material is further exposed, and
the material aggregates and precipitates due to hydrophobic
interaction. The method of salting out uses the principle of
reversible expansion of polymer materials in solvents [18]. When
the polymer materials expand, drugs are added, then the pH is
adjusted, and the salting-out agent is added to precipitate the
polymer materials and drugs. After centrifugation and drying,
microspheres that carry drugs can be obtained. This method of
preparing drug-loading microspheres is relatively simple and
does not require special equipment. However, the disadvantage of
this method is that the concentration of the carrier material
during the preparation of microspheres cannot be too high;
otherwise, the salting-out agent cannot be evenly distributed,
which will easily cause the material to aggregate and form large
clusters. Since the drug is bound to the surface of microspheres
by adsorption, the extent of sustained drug release is also very
limited. In addition, the surface charge balance of microspheres
is easy to break when the pH changes in vivo, which changes
the solubility of microspheres and further accelerates the release
of drugs.
6.2.5 Spray Drying
Spray drying involves dispersing drugs in the solution of the
materials, and then spraying the mixture into the hot air stream
uses material drug suspension rheology and the nozzle design
to control the size and shape of microspheres. Compared with
other methods, this method requires short time, and is featured
with simple production process, easy operation and control,
high product purity, and good dispersibility. However, special
of microspheres are more complicated, including: the viscosity
of the mixed liquid, the uniformity, the concentration of drugs
and materials, the spray rate, the spray method and the hot air
temperature [13, 21, 22]. Spray drying has been applied to natural
polymer materials such as albumin and chitosan.
Preparation of Microspheres
203
Compared with the solvent evaporation method, this method
and the long-term contact between the drug and the organic
samples, and opens up a new way for the preparation of unstable
drug microspheres. In addition, due to the rapid volatilization
of the solvent during the drying process, the temperature of
the droplets can be kept lower than that of the drying air, thus
facilitating the preparation of temperature-sensitive drugs.
6.2.6 Ultrasound Method
Air albumin microspheres for acoustic contrast can be prepared
by using ultrasonic energy to heat the albumin solution to a
temperature close to denaturation, which will cause “cavitation” of
the micro air originally present in the solution and the air brought
in from outside. Under the action of sound waves, the existing
bubbles in the liquid expand and then burst to generate a large
number of microbubbles [13, 21]. These microbubbles undergo
further cavitation under the action of sound waves, thereby
splitting to generate more microbubbles. The cavitation process
is controlled by controlling the ultrasonic energy and sound
microspheres with good uniformity to meet the needs [23].
6.2.7 Supercritical Fluid Method
In the foregoing methods, a large amount of organic solvents are
used, and post-treatments such as washing and drying are required,
product quality [13, 24]. At present, the phase separation technology
system has been used in the preparation of microspheres. The
system mainly includes rapid expansion of supercritical solution
(RESS), gas anti-solvent recrystallization (GAS) and precipitation
meet the requirements of light-proof, air-isolated, waterproof,
sterile, etc., thus enabling production expansion [13].