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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5919_Библиотеки_им_академика_М_И_Перельмана.pdf
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Chapter 6
Polymer-Based Drug Delivery Systems: Design
and Characterization
Afroz Jahan, Milindmitra K. Lonare, Sanweer Khatoon, and K. Kasturi Devi
Abstract
Over the past two decades, significant advancements have been made in the field of polymeric drug delivery
systems. These systems are defined as formulations or devices that enable the introduction of therapeutic
substances into the body. The development of biodegradable and bio-reducible polymers has been instrumental in the creation of new drug delivery systems, offering promising future prospects for practical
applications. Natural polymers (arginine, chitosan, etc.) have been extensively explored for polymeric drug
delivery systems due to their biocompatibility and biodegradability. Synthetic polymers (poly(ethylenimines), biodegradable and bio-absorbable polymers, etc.) have also been studied for their potential in drug
delivery. Efforts have been made to develop targeted polymeric drug delivery systems that can specifically
deliver drugs to desired sites, reducing side effects and improving therapeutic outcomes. The rapid
development of polymeric drug delivery systems based on natural and synthetic polymers is revolutionizing
the pharmaceutical field. Significant progress has been made in using biocompatible and bio-related
copolymers and dendrimers for cancer treatment, particularly as delivery systems for potent anticancer
drugs. Combining insights from synthetic and biological fields is expected to lead to new paradigms in the
design of polymeric drug and gene delivery systems, enhancing their efficacy and safety.
Key words Polymeric drug delivery systems, Reservoir-Based Systems, Stimuli-Responsive Systems,
Polymeric hydrogels
1 Introduction
Developing a new drug is a demanding and costly process. Furthermore, recent drugs often fail clinical trials due to their ineffective
performance and tendency to cause severe side effects by damaging
normal tissues. Traditional medications are unstable, toxic, and
offer short-lived therapeutic benefits, compounded by solubility
issues. The therapeutic outcomes of drugs hinge on their biochemical properties and how they are released. Modern drug delivery
systems (DDSs) play a crucial role in ensuring the controlled,
targeted release of drugs to specific body areas, thus addressing
these challenges. Unlike conventional methods, DDSs enable
111
112 Afroz Jahan et al.
precise control over the timing, location, and rate of drug release,
ensuring drugs are delivered effectively to targeted organs. This
innovation not only enhances treatment efficacy but also boosts
patient confidence [
DDS involves using carriers or transmitters to deliver therapeutic agents to specific tissues or organs. Polymer-based drug delivery
systems have emerged as a pivotal area of research in biomedical
fields, offering enhanced drug efficacy while minimizing side
effects. Liposomes, micelles, and PNPs (polymeric nanoparticles)
are prominent drug carriers known for their ability to encapsulate
various therapeutic agents or diagnostics [
Polymers are optimal tools providing drug delivery mechanisms through the unique features of pharmacokinetics, circulation
time, biocompatibility, and biodegradability. These polymers are
chosen based on their physical, chemical, and biological properties,
ensuring effective therapeutic function with minimal adverse effects
8, 9]. Initially developed for biodegradable surgical sutures, syn-
[
thetic biodegradable polymers such as polystyrene (PGA, PLGA,
PLA) have evolved to offer controlled drug release and reduced
toxicity [
encapsulation, and controlled release capabilities, are preferred carriers in DDSs [
ficient, good corrosion resistance, excellent moldability, the ability
to achieve a fine surface finish, capability for precise dimensional
manufacturing, and be cost-effective. It should ideally not have
poor tensile strength, low mechanical properties, or poor temperature resistance. The transparency or ability to be produced in
different colors is a neutral characteristic that can be advantageous
depending on the specific application.
10]. PNPs, with their high biodegradability, efficient drug
An ideal polymer should possess low density, low friction coef-
1–5].
6, 7].
11, 12].
2 Classification of Polymers
Polymers are classified into following categories as depicted in
Scheme
1.
3 Design and Characterization of Polymeric Drug Delivery Systems
In polymer-based drug delivery systems, polymers play a crucial
role in achieving controlled (zero-order) or sustained (first-order)
release of drugs, thereby maintaining therapeutic drug levels over
time and reducing dosing frequency [
broadly categorized into matrix, reservoir, and conjugated systems.
1. Matrix-Based Systems: These
duce and extensively studied in drug release systems. In a
are among the simplest to pro-
13]. These systems are
Polymer-Based Drug Delivery Systems: Design and Characterization 113
Scheme 1 Classification of polymers based on origin of source, structure, and
molecular forces
matrix system, the drug can exist in a dissolved or dispersed
(amorphous/crystalline) state depending on the solubility of
the drug in the polymer and its concentration [14–16].
2. Reservoir-Based Systems:
contrast to matrix-based systems,
In
reservoir-based systems feature a solid drug core enclosed by a
polymeric membrane. The release profile is governed by the
rate of drug diffusion through the membrane. These systems
typically provide almost constant zero-order release as their
dimensions remain relatively stable over time. However, concerns such as membrane rupture leading to sudden release
(dose dumping) and the difficulty of retrieving the system
post-use limit their practicality.
3. Conjugated Systems: Covalently
linking drugs with polymers is
another strategy to control dr ug release profiles and extend
drug residence time in the body. Conjugates like poly(ethylene
glycol)-drug conjugates enhance circulation time, thereby
reducing both dosage and frequency of administration
17, 18]. Similarly, sequestering drugs within self-assembling
[
polymeric nanoparticles (e.g., cyclodextrins, block copolymers)
lead to drug-loaded micelles and nanoparticles. These systems
release drugs through mechanisms such as diffusion or degradation. Moreover, using specific linker chemistries (e.g., ‘S-S’
disulfide) for active agents conjugated to polymeric nanocarriers enables predefined loading and release kinetics from
nanoparticle-drug conjugates.
114 Afroz Jahan et al.
4 Responsive Polymers
There are various designs of polymeric drug delivery systems; however, the majority of them are responsive polymers. Hydrogels,
micelles, liposomes, polyplexes, or polymer-drug conjugates are
the responsive polymers most commonly used as polymeric drug
delivery systems.
4. Stimuli-Responsive Systems: Smart polymers are a class of materials comprised of a large variety of linear and branched (co)polymers or crosslinked polymer networks. A hallmark of
responsive polymers is their ability to undergo a dramatic physical or chemical change in response to an external stimulus.
Smart polymers (e.g., poly(N-isopropylacrylamide) (pNIPAM), poly((2-diethylamino)ethylmethacrylate) (PDEA)) can
create intelligent controlled release systems. These polymers
respond to environmental stimuli (e.g., temperature, pH) to
modulate drug release rates, offering precise control over therapeutic delivery [
19, 20].
4.1 Polymeric Hydrogels
Hydrogels are three-dimensional networks of water-soluble polymers, capable of absorbing and retaining large amounts of water.
They can be derived from natural or synthetic polymers and are
utilized extensively in controlled drug delivery systems due to their
biocompatibility and inertness to many drugs. Biodegradable
hydrogels, in particular, are employed as carriers for drug delivery
because they can release drugs gradually over time.
The high porosity of hydrogels plays a critical role in
controlling the release rate of drugs, which depends significantly
on the diffusion coefficient of the drug molecules through the gel
matrix. This porosity can be tailored by adjusting the degree of
cross-linking within the hydrogel network. Greater cross-linking
generally leads to reduced porosity and slower drug release, while
lower cross-linking enhances porosity and accelerates drug
release [
21].
Hydrogels e
xhibit r
apid swelling in aqueous environments,
which facilitates both the release of entrapped drug molecules and
the degradation of the polymer matrix. This characteristic is advantageous in drug delivery applications as it supports controlled and
sustained release of drugs over time. For further visualization and
understanding, refer to Fig.
1, which illustrates drug delivery
through hydrogels.
There are
various classifications of polymer-based hydrogels
including based on origin, composition, ionic charge, pore size,
physical appearance, configuration, crosslinking, external stimuli
response, and others. Few are discussed below.
Polymer-Based Drug Delivery Systems: Design and Characterization 115
Fig. 1 Schematic representation of drug-loaded polymeric hydrogel
Polymer-based hydrogels can be classified as natural, synthetic,
or a combination of both based on their origin. Natural polymerbased hydrogels are hydrogels composed of polymers derived from
natural sources, such as plants, animals, or microorganisms. These
polymers are biocompatible, biodegradable, and often exhibit
inherent bioactivity, making them suitable for a wide range of
biomedical applications [
22]. Natural polymers include collagen,
alginate, chitosan, hyaluronic acid, and gelatin. Natural polymerbased hydrogels offer advantages such as their similarity to the
natural extracellular matrix, which supports cell growth and tissue
regeneration. They can also provide a favorable microenvironment
for encapsulated cells or therapeutic agents [
Synthetic polymer-based hydrogels are hydrogels composed of
polymers that are chemically synthesized in the laboratory. These
polymers are typically derived from monomers through polymerization reactions, allowing for precise control over their chemical
structures, properties, and functionality. Synthetic polymer-based
hydrogels offer several advantages, including tunable properties,
reproducibility, and the ability to incorporate various functionalities
for specific applications [
25]. Some common synthetic polymers
used in the production of hydrogels are poly(acrylic acid) (PAA)
[26, 27], poly(N-isopropylacrylamide) (PNIPAAm) [28, 29], poly
(ethylene glycol) (PEG) [
[
32, 33], poly(HEMA) (hydroxyethyl methacrylate) [34], and
others [
35, 36].
Hybrid p
olymer-
based hydrogels, also known as semi-synthetic
30, 31], poly(vinyl alcohol) (PVA)
polymer-based hydrogels, are a type of hydrogel material that combines both natural and synthetic polymers to form a network struc-
37, 38]. These hydrogels are created by incorporating natural
ture [
polymers or biomolecules into a synthetic polymer matrix or by
chemically modifying natural polymers with synthetic components.
Polymer-based
hydrogels can also be classified based on their
composition, which includes homopolymer [
23, 24].
39, 40], copolymer
116 Afroz Jahan et al.
[41, 42], multipolymer [43, 44], and interpenetrating network
(IPN) hydrogels [
38, 45].
Homopolymer-based hydrogels are a type of hydrogel that is
composed of a single type of polymer. In other words, the hydrogel
network is formed by crosslinking repeating units of the same
polymer [
39]. These hydrogels are created by polymerizing a
monomer that consists of identical repeating units, leading to a
three-dimensional network structure [
40]. Homopolymer-based
hydrogels have the ability of certain polymers to absorb and retain
large amounts of water while maintaining their structural integrity.
Copolymer-based hydrogels are indeed composed of two or
more different monomers that undergo polymerization to form a
three-dimensional network [46, 47]. These hydrogels offer unique
properties that can be tailored based on the combination of monomers used in their synthesis [48, 49]. One example of a copolymerbased hydrogel is poly(ethylene glycol)-diacrylate (PEGDA).
PEGDA hydrogels are formed by copolymerizing PEGDA monomers with a crosslinking agent such as N,N′-
-methylenebisacrylamide (BIS).
Multipolymer-based hydrogels are hydrogels composed of
three or more different polymer chains. These hydrogels are
designed to leverage the beneficial proper ties of each individual
polymer, resulting in a unique combination of properties that can
be tailored for specific applications [
50, 51]. There are two com-
mon methods for preparing multipolymer hydrogels. The first
method involves blending different types of pre-synthesized polymers. This blending process allows for the combination of different
polymer chains to achieve the desired properties [
50, 51].
The second method for preparing multipolymer hydrogels is
through the copolymerization of two or more monomers. For
instance, a copolymer of poly(ethylene glycol) (PEG) and poly
(lactic acid) (PLA) can be synthesized. PEG, being a hydrophilic
polymer, enhances the water uptake of the hydrogel, while PLA, a
biodegradable polymer, controls the degradation rate of the hydrogel. By incorporating multiple polymer chains, multipolymer
hydrogels offer a broader range of properties compared to single
polymer-based hydrogels.
4.1.1 Characterization of Polymeric Hydrogels
Characterizing hydrogels involves assessing both their structural
and functional properties. Various microscopy techniques and
mechanical tests are employed to gather comprehensive data on
the material’s attributes.
Structural Analysis (a) Scanning Electron Microscopy (SEM): It is used to analyze
pore formation, pore size, crosslinking status, and the impact
of loaded compounds on the gel structure [52].
Polymer-Based Drug Delivery Systems: Design and Characterization 117
(b) Laser Scanning Confocal Microscopy (LSCM): It is used for
evaluating pore dimensions and shape. It is capable of complementary characterizations such as assessing hydrogel loading/unloading of solutes, solute dispersion/mobility, and
distribution of solid loading materials [
53].
(c) Atomic Force Microscopy (AFM): It provides topological and
roughness information, as well as functional data like the
elastic modulus of the gel. It correlates gel modulus with cell
differentiation and migration, polymer cross-linkage degree,
and solute mobility.
(d) Alternative Techniques: Bright Field Microscopy is less com-
monly used due to hydrogels’ optical clarity and threedimensional nature. Nuclear magnetic resonance (NMR)
spectroscopy is used to determine the number of lamellae in
hydrogels. Small angle X-ray scattering (SAXS) provides information on the gel’s internal structure at a nanometer
scale [
54].
Functional Analysis (a) Absorption Capacity and Rate: It is used to measure how
much and how quickly the hydrogel absorbs solutes.
(b) Absorbency Under Load: It determines the hydrogel’s ability
to absorb fluids under mechanical pressure [
55].
(c) Solute Retention and Release: It is dynamic probing of drug
concentration in the medium over time. It can be performed
by various methods like:
• High-Performance Liquid Chromatography (HPLC):
Common for peptides.
• Electrochemical Probing: Used for
gases like
• Fluorescence/Colorimetric/Absorbance Tests:
various solutes [
56].
H
S.
2
Used
for
4.2 Polymeric Micelles
Polymeric micelles are nano-sized structures with a core-shell architecture formed through the self-assembly of amphiphilic block
copolymers. These copolymers consist of both hydrophilic and
hydrophobic segments, making them suitable for delivering drugs
that have poor solubility in water. The core of polymeric micelles is
composed of hydrophobic blocks such as poly(propylene glycol) or
poly(caprolactone). These hydrophobic cores can encapsulate
hydropho
drugs, protecting them from degradation and
bic
enhancing their solubility in aqueous environments. Surrounding
the core is a shell made up of hydrophilic polymer blocks like
2).
polyethylene glycol (PEG) (Fig.
This shell stabilizes the micelle
structure and helps prevent recognition by the immune system,
thereby prolonging circulation time in the bloodstream.
118 Afroz Jahan et al.
Fig. 2 Schematic representation of drug-loaded polymeric micelle. Polymeric micelles offer several advantages: (i) They improve the solubility and stability of hydrophobic drugs. (ii) They can be tailored to release
drugs in a controlled manner. (iii) They enhance drug bioavailability and reduce side effects
4.2.1 Characterization of Polymeric Micelle
Critical Micelle Concentration Determination (CMC)
To understand and predict the behavior of micelles in a biological
environment, comprehensive characterization is crucial. The characterization process involves a variety of techniques to assess the
chemical composition, self-association, physicochemical properties,
and in vitro and in vivo behaviors of the block copolymers used to
form micelles [
57].
The critical micelle concentration (CMC) is a key parameter in the
characterization of polymer micelles (PMs). It indicates the concentration at which amphiphilic molecules self-assemble into
micelles in a solution. The CMC reflects the balance between the
hydrophobic and hydrophilic segments of the block copolymers
and is influenced by the characteristics of the hydrophobic groups,
the molecular weight of the hydrophilic part, and the distribution
of the hydrophilic part within the amphiphilic polymer [
58]. The
various methods for determining CMC are:
(a) Light Scattering: Measures changes in the scattering of light
by micelles as they form, providing an indirect indication
of CMC.
(b) Surface Tension: Monitors the surface tension of the solution,
which changes significantly at the CMC due to micelle
formation.
(c) Electrical Conductivity: Observes changes in the electrical
conductivity of the solution, which varies with the formation
of micelles.
(d) Photometric Methods:
optical probes to measure changes
Use
in absorbance or transmittance that occur at the CMC.
(e) Fluorometric Methods:
Employ fluorescent probes that
respond to the formation of micelles, allowing for precise
CMC determination through changes in fluorescence intensity or wavelength shift [
59].