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Nano Physical Pharmaceucs of Microsphere Delivery System
M
a
Drug encapsulationefficiency M
(6.12)
o
where Mo is the total amount of the drug administered, and M
a
refers to the actual measured content of the drug in the drugloading microspheres [42].
6.4.3 Drug Release Behavior of Microspheres
The drug release from the microspheres can be simply described
as the following processes: the drug adsorbed on the surface of
and the drug encapsulated in it is released slowly. Studying the
for the development of microsphere preparations.
6.4.3.1 Mechanism of drug release by microspheres
The mechanisms of drug controlled release can generally be divided
control, (3) solvent activation control, (4) ion exchange control,
control, drugs are released due to the degradation of polymers
or the dissolution of the whole carrier. The drug release from the
microspheres can be simply described as the following processes.
The polymer is degraded due to hydrolysis, and the drug
encapsulated in it is released slowly shown in Fig. 6.4. For most
dissolution control are the two main mechanisms. At present,
polymer materials as carriers are mainly combined with drugs
in three forms: cumulative, homogeneous and polymer drugs.
Cumulative drug controlled release system is to embed drugs in
polymer membranes by physical methods, and drugs are released
NPP of Microspheres
215
Homogeneous drug controlled release system is to evenly mix
the drug in the polymer matrix, and the drug will be released
and release of the polymer. Polymer drugs refer to drugs and
polymers connected by chemical bonds, and drugs will also be
released due to the chemical bond-breaking reaction [43, 44].
Figure 6.4 Scheme illustrating the process of microsphere surface corrosion
for controllable drugs release.
If the drug is uniformly distributed or molecularly distributed
in the microsphere matrix, the release process can be expressed
by Equation 6.13:
n8
6 1
QKt
r
1
(6.13)
F
2
e
2
n
n1
Here F is the number of drugs released, Kr is the release rate
constant, D
r is the radius of microspheres, and Q is the release quantity at the
time of t.
If the drug is suspended in the microsphere matrix, it is an
inhomogeneous dispersion, and its release process is usually
expressed by Higuchi’s Equation (6.14):
3
2
3CD
2
11F )
2
(6.14)
(
3
F
st
Ar
Here Cs is the dissolution degree of the drug in the medium,
and A is the drug-loading rate per unit volume.
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Nano Physical Pharmaceucs of Microsphere Delivery System
If microspheres are used as a drug carrier, the concentration
in microspheres is almost constant during the release process,
dQ Q
)(
DS
n
(C
m
C )
dt n
Here Qn is the drug content of microspheres, S is the drug release
area of microspheres, n
Cm is the concentration of the drug in microspheres, and C is
the concentration of the drug in the release medium at the time
of t. When Cm> C, the parameters on the right side of the equation
are all constants, expressed by K, and integrated to obtain the
equation: Q = Kt.
some people also use Q = SCDK1ItrD1 to denote the zero-order
release of microspheres. Here Cis the initial concentration of
microspheres (C Cs), K1 is the interface velocity constant, I is the
interface thickness, and D1
of drugs. The actual drug release method is more complicated,
so usually, it is the result of several methods conducted
alternately, which may not be consistent with the theoretically
between group and individual drug release characteristics.
The factors controlling the drug release rate mainly include
the pore size distribution of the polymer, the interaction between
the polymer and drug molecules, the solubility of the drug in body
molecules, and the swelling and degradation of the polymer in
6.4.3.2 PLA microspheres delivery system
The sustained-release system of polylactic acid microspheres is
an ideal drug delivery system. However, this kind of microsphere
preparation is not commonly used in clinical practice. The main
technical problem causing this situation is that the preparation
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217
will quickly release a large amount of drugs before and after the
release,” the degree of which is generally measured through
release in the early stage of administration may cause the blood
concentration to approach or exceed the toxic level, resulting
become a problem faced by the researchers of the microspheres
Figure 6.5 The process and key parameters for structural tunning of
microsphere (such as PLA microsphere). Here, the inserted equaons are
also detailed in Sections 1.3 and 1.4 in Chapter 1.
biodegradable PLA microsphere, which is a well-known useful
carrier for drug delivery. The size, size distribution and stability
of such a system are mainly regulated by the chain length, the
ratio of hydrophilic chain to hydrophobic chain, and the mixing
methods used in the experiments. And the regulation mechanism
is shown in the inserted formula, which is discussed in
Sections 1.3 and 1.4 in Chapter 1. Drugs are uniformly dispersed
in the degradable microspheres, and the drugs adsorbed on the
surface or blended with PLA of the microspheres are released
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Nano Physical Pharmaceucs of Microsphere Delivery System
formed, so that the drug dissolves little by little. The drug release
is slow in the initial stage, and the drug release rate continues to
increase with the rapid degradation of the carrier in the later
stage. It is generally believed that the main reason for the burst
release of a microsphere controlled release system is that part
of the drug exists on or near the surface of microspheres, or
there are holes inside or on microspheres. Therefore, in the initial
release stage, the drug can be released directly or quickly
weight of polymer, the purity of the polymer, the physical and
chemical properties of the main drug, the preparation method
and parameters of microspheres, and the drug loading rate of
microspheres. According to the preliminary research on the causes
hinder burst release or reduce its degree mainly include directly
removing the drug on the surface of microspheres by physical
means, such as extraction and washing, changing the nature of
the microspheres matrix, changing main drugs’ physical and
chemical properties, using appropriate microspheres preparation
methods or adding additives [48].
The PLA/PEG microspheres were prepared by O/W solvent
evaporation method. The dried microspheres were immersed
in dilute gelatin solution at room temperature, collected and
dried. On the one hand, because of the high hydrophilicity of
polyethylene glycol (PEG), the introduction of PEG fragments
drugs in PLA/PEG microspheres. On the other hand, the
microspheres were dipped in the diluted gelatin solution to form
also control the drug release rate, which is much lower than the
bond may be formed between PEG and gel molecules. In addition,
the higher the gel concentration, the better the controlled release
of drugs. Therefore, the release rate can be controlled by
NPP of Microspheres
219
concentrations. The application of PLA microspheres in the
internal structure. The release curve is generally determined by
the porosity of the microspheres. The results provide not only a
new strategy for the preparation of shape-controllable PLA
microspheres but also a new possibility for the application of PLA
Microspheres have unique physical and chemical properties,
capacity. They are not only widely used in biopharmaceuticals,
but also play an important role in food safety detection, disease
diagnosis, and environmental monitoring.
6.4.4 Route of Administration of Microspheres
6.4.4.1 Cavity administration
but the solution was eliminated very quickly from the intraarticular cavity. Only by using high concentration and repeated
Inject microsphere drug directly into the joint cavity, and
control the particle size of the microsphere to reduce the degree
of drug leakage to the tissues or blood outside the joint cavity.
The larger the microsphere, the easier it will be swallowed by the
injection to delay the drug clearance time. Osteoarthritis (OA) is
the most common musculoskeletal disease in arthritis. Usually,
drugs are directly transported to the diseased joints to change the
axetil lipid globular carrier injection can reduce adverse reactions
of drugs into microspheres in the joint cavity can reduce the
number of treatments and provide a new choice for the treatment
of patients in the future.
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Nano Physical Pharmaceucs of Microsphere Delivery System
6.4.4.2 Injection administration
After the drug-loaded microspheres are administered in this
way, the administration frequency can be reduced, and the toxic
In the clinical treatment of tumors in the liver, spleen, kidney
and breast, the size of microspheres is controlled by intravenous
the macrophages of the reticuloendothelial system, so it is mainly
concentrated in the liver, the spleen and other tissues rich in
the capillary bed. And microspheres with a particle size smaller
among blood vessel cells (the width of cell membrane gaps of
can be combined with tablets, capsules and other dosage forms
to further improve the bioavailability during administration.
6.4.4.3 Administration by arterial embolism
Arterial embolism therapy refers to the direct injection of
of lesion (canceration) parts to embolize the small arteries
the growth of tumor cells and, through the continuous release of
drugs from the blocked area in microspheres, keep the treatment
concentration in tumor tissue for a long time and reduce the
distribution of drugs in other tissues as much as possible. In this
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221
drug microspheres makes them an ideal embolic dosage form in
transcatheter arterial embolization. Albumin, gelatin and starch
Arterial embolization treatment refers to the selective
injection of pharmaceutical preparations into the artery to
clinical observation on 43 patients with advanced bladder cancer
and hematuria and treated them with microsphere embolization.
In the later stage, bladder hemorrhage was stopped after the
the operation, indicating that arterial embolism can be used for
.
6.4.4.4 Magnetic microsphere administration
Magnetic polymer microspheres began to emerge at the end of the
(such as Fe, Co, Ni and their oxides). Because of its magnetism,
surrounding medium. These properties make it have a very broad
application prospect, so it has broad application prospect in cell
enzyme, immunoassay, targeted drugs, DNA separation and nucleic
inverse micro lotion polymerization method (point polymerization
method) to develop a monodisperse polyacrylamide microsphere
with visible and near-infrared light prepared by glutaraldehyde
cross-linking. Furthermore, polyacrylamide Fe3O4 composite
microspheres were successfully prepared by one-pot method
(PAM@FeNPs). The multi-component microspheres have the
has huge potential application in biomedicine imaging and drug
delivery system, and more importantly, provides an insight into
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Nano Physical Pharmaceucs of Microsphere Delivery System
6.4.4.5 Oral administration
Generally, due to the acidic environment in the stomach and
the presence of degrading enzymes, drugs are absorbed by the
stomach with bioavailability reduced. Especially for polypeptide
and protein drugs, it is very important to choose the appropriate
carrier for administration. Oral administration of drug microspheres can avoid the degradation of active drug molecules by
gastric acid and enzymes, improve the stability of drugs and reduce
the frequency of administration. Oral vaccine microspheres under
extensive research, such as the antigen-alginate microspheres,
have been prepared to protect the stability and activity of the
6.4.4.6 Mucosal administration
Mucosal drug delivery system (MDDS) is a new type of drug delivery
system. It mainly refers to the drug delivery mode in which drugs
and appropriate carrier materials are applied to the cavity mucosa
to play a local role or absorb into the systemic circulation to trigger
systemic treatment. Mucosal administration has the following
advantages: (1) Compared with oral administration, drugs enter
the systemic circulation through mucosal absorption, and can
through the liver; (2) The types and quantities of enzymes in
mucosa are limited, and the activity of enzymatic degradation
of drugs is relatively low; (3) Local administration can increase
the drug concentration at the active site and improve the
bioavailability; (4) Local application of medicine is convenient
for patients to operate independently and improve patients’
compliance. Guided by optimizing the clinical administration
mode and improving the comfort of patients in the treatment
process, based on the dry cross-linking mechanism and the drug
that can quickly and stably adhere to the wet oral mucosa and
load photosensitizers for local PDT, providing a new drug
delivery system that can replace the traditional local mucosal
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223
6.4.4.7 Ocular administration
The eye is one of the most sophisticated organs in the human body.
It has unique anatomical and physiological characteristics.
Generally, the eye is divided into anterior segment and posterior
segment by the lens plane. The ophthalmic drug delivery
preparation refers to the drug preparation that is directly used
in the eye to play a local therapeutic role or enters the body
circulation through the eye to play a therapeutic role [62].
Ocular administration is the main route of administration to treat
ocular local diseases. Compared with systemic administration,
it is more conducive to drug enrichment at the target site and can
of eye preparations sold in the market are traditional dosage
forms such as eye drops and ointment. The main defects are
low bioavailability, large adverse reactions and poor patient
compliance. In recent years, great progress has been made in the
clinical application of ophthalmic drug delivery systems. Many
new dosage forms aimed at prolonging the retention time of
drugs on the ocular surface, increasing the permeability of ocular
surface tissues and improving the bioavailability of ocular target
tissues have been marketed. The researchers used the spray drying
nasolacrimal duct and the retention time on the ocular surface,
providing a theoretical basis for the study of new ocular drug
delivery systems [63].
6.4.5 Biological Application of Microspheres
6.4.5.1 Sustained-release microsphere formulation
Peptide drugs. During the preparation of polypeptide drugloaded microspheres, due to its small molecular weight and
strong. Hydrophilic compounds tend to escape to the outer
steps, resulting in low embedding rate. Therefore, researchers
studied the characteristics of polypeptide drugs and prepared