Hydrogels as potential nano scale drug delivery systems

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                           Hydrogels as Potential Nano-Scale
                                      Drug Delivery Systems
                         Mohammad Reza Saboktakin, Ph. D of Nano Chemistry
                                                                              Islamic Republic

1. Introduction
Man has always been plagued with ailments and diseases of both the body and the mind.
However, dedicated research from scientists all over the world has made it possible to treat,
prevent and eradicate many of these diseases that plague man[1]. The field of
pharmaceutical science has been developing steadily over the years, and has today become
invaluable in helping to keep us healthy and prevent disease. An avenue of research that
has progressed a great deal in the past few decades is the treatment of diseases via
biomolecules such as drugs, proteins etc. Initially, these could only be administered in
limited manner, due to limitations of drug delivery through harmful environments in the
body[2]. Thus mobility reduced the effectiveness of administered drugs. Progress came with
the development of biomaterial carriers which could be encapsulated, or immobilized with
drugs, allowing the drug to safely reach the required site without harm. These carriers
allowed for the release of drug in sites which were previously inaccessible. The nature of
these carriers progressed over the years from ceramics, to natural, to synthetic materials.
Factors such as integrity, biocompatibility and flexibility were considered, and lead to the
use of hydrophilic three dimensional matrics as carrier materials[3]. These are a class of
materials known as Hyrogels.
These three dimensional polymer matrices are capable of imbibing large amounts of water,
and biological fluids. This property of hydrogels is the reason behind its varied applications
ranging from food additives to pharmaceuticals and clinical applications. Synthetic hydrogels
prepared from a varied range of monomers have found many applications especially in tissue-
engineering scaffolds, as carriers for implantable devices, and drug delivery devices. Synthetic
hydrogels provide an effective and controlled way in which to administer protein and peptide
based drugs for treatment of a number of diseases. A successful drug delivery device relies not
only on competent network design, but also on accurate mathematical modeling of drug
release profiles. Hydrogels have ordered polymer networks, with well-defined chemistries
yielding well-defined physicochemical properties and easily reproducible drug release
profiles[4]. In order to accurately understand and model drug release profiles from a material,
it becomes essential to have a quantitative mathematical understanding of material properties,
interaction parameters, kinetics, and transport phenomena within the material in question. The
network structure also plays a key role in diffusional behavior, mesh size and stability of
incorporated drug[9]. It is this well-defined order that enables accurate network design by
identifying key parameters and mechanisms that govern the rate and extent of drug release.

576                                                                                 Biopolymers

Hydrogels have thus become a premier materials used for drug delivery formulations and
biomedical implants, due to its biocompatibility, network structure, and molecular stability of
the incorporated bioactive agent[5].
Hydrogels, The swellable polymeric materials, have been widely investigated as the carrier
for drug delivery systems. These biomaterials have gained attention owing to their peculiar
characteristics like swelling in aqueous medium, pH and temperature sensitivity or
sensitivity towards other stimuli. Hydrogels being biocompatible materials have been
recognized to function as drug protectors, especially for peptides and proteins, from in vivo
environment. Also these swollen polymers are helpful as targetable carriers for bioactive
drugs with tissue specificity.
During the past decade, novel polymeric micropheres, polymer micelles, and hydrogel-type
materials have been shown to be effective in enhancing drug targeting specificity, lowering
systemic drug toxicity, improving treatment absorption rates, and providing protection for
pharmaceuticals against biochemical degradation. These are all goals of drug delivery. In
addition, several other experimental drug delivery systems show signs of promise,
including those composed of biodegradable polymers, dendrimers(so-called star polymers),
electroactive polymers, and modified C-60 fullerense(Also known as "Buckyballs")[6].
Polymer drug delivery nano-scale systems are based on " Nano carriers" which are composed
of mixing polymeric chemical compounds with drugs to forms complex, large molecules,
which " carry" the drug across physiological barriers. Illustrative examples of these
polymeric compounds are poly(rhylene-glycol)-poly(alpha, beta-asparic acid), carboxylates,
and heterobifunctional polyethylene glycol, in addition to others.
Another type of nanotechnology revolves around the use of "Hydrogel" as nano carriers of
drugs. The principle behind this technology is to use a chemical compound which traps a
drug and then releases the active compound by "Swelling" or expanding inside of specific
tissues, thus allowing a higher concentration of the drug in a biodegradable format.
Hydrogels are very specialized systems and are generally formulated to meet specific needs
for the delivery of individual drugs.
During the past two decades, research into hydrogel delivery systems in nano – scale has
focused primarily on systems containing polyacrylic acid(PAA) backbones. PAA hydrogels
are known for their super-absorbency and ability to form extended polymer networks
through hydrogen bonding [7]. In addition, they are excellent bioadhesives, which means
that they can adhere to mucosal linings within the gastrointestinal tract for extended
periods, releasing their encapsulated medications slowly over time .
One example of the complexity of these systems is a glucose-sensitive hydrogel that could
be used to deliver insulin to diabetic patients using an internal pH trigger. This system
features an insulin-containing " Reservoir" formed by a poly[methacrylic acid –g-
poly(ethylene glycol)]hydrogel membrane into which glucose oxidase has been
immobilized. The membrane itself is housed between nonswelling, porous "Molecular

2. Properties of hydrogels
Hydrogels ate water swellen polymer matrics, with a tendency to imbibe water when placed
in aqueous environment. This ability to swell, under biological conditions, makes it an ideal
material for use in drug delivery and immobilization of protein, peptides, and other
biological compounds. Due to their high water content, these gels resemble natural living

Hydrogels as Potential Nano-Scale Drug Delivery Systems                                    577

tissue more than any other type of synthetic biomaterials . These networks, have a three
dimensional structure, crosslinked together either physically (entanglements, crystallites), or
chemically(tie-points, junctions). This insoluble crosslinked structure allows immobilization
of active agents, biomolecules effectively, and allows for its release in well-defined specific
manner. Thus the hydrogels biocompatibility and crosslinked structure are responsible for
its varied applications[8].

3. Mechanical properties
For non biodegradable applications, it is essential that the carrier gel matrix maintain
physical and mechanical integrity. mechanical stability of the gel is, therefore, an important
consideration when designing a therapeutic system. For example, drugs and other
biomolecules must be protected from the harmful environments in the body such as,
extreme pH environment before it is released at the required site. To this end, the carrier gel
must be able to maintain its physical integrity and mechanical strength in order to prove an
effective biomaterial. The strength of the material can be increased by incorporating
crosslinking agents, comonomers, and increasing degree of crosslinking . There is however
an optimum degree of crosslink, as a higher degree of crosslinking also leads to brittleness
and less elasticity. Elasticity of the gel is important to give flexibility to the crosslinked
chains, to facilitate movement of incorporated bioactive agent. Thus a compromise between
mechanical strength and flexibility is necessary for appropriate use of these materials.

4. Biocompatible properties
It is important for synthetic materials, such as hydrogels, to be biocompatible and nontoxic
in order for it to be a useful biomedical polymer. Most polymers used for biomedical
application must pass a cytotoxicity and in-vivo toxicity tests. Most toxicity problems
associated with hydrogels arise due to unreacted monomers, oligomers and initiators that
leach out during application. Thus an assessment of the potential toxicity of all materials
used for fabrication of gel is an integral part of determining sutiability of the gel for
biological applications . To lower chances of toxic effects, the use of initiators is being
eliminated, with the advent of gamma irradiation as polymerization technique. Steps are
also taken to eliminate contaminants from hydrogels by repeated washing and treatment.
Also, kinetics of polymerization has been studied, so as to achieve higher conversion rates,
and avoid unreacted minomers and side products.

5. Classification of hydrogels
Hydrogels can be classified as neutral or ionic, based on the nature of sode groups . In
neutral hydrogels, the driving force for swelling is due to the water-polymer
thermodynamic mixing contribution to the overall free energy, along with elastic polymer
contribution. The swelling of ionic hydrogels is also affects by the ionic interactions between
charged polymers and free ions. Ionic hydrogels containing ionic groups, such as carboxylic
acid, imbibe larger amount of water, because of its increased hydrophilicity. Examples of
such gels are poly(acrylic acid), and polyamines. Hydrogels are also classified as
homopolymers or copolymers, based on the method of preparation[9]. Hydrogels can be
classified based on the physical structure of the network as amorphous, semicrystalline,

578                                                                             Biopolymers

hydrogen bonded structures, supermolecular structures and hydrocolloidal aggregates. An
important class of hydrogels are the stimuli responsive gels. These gels show swelling
behavior dependent radiation. These properties allow for usage in a number of applications,
such as seprartion membranes, biosensors, artificial muscles, and drug delivery devise.

6. Types of hydrogels
6.1 pH sensitive or ion sensitive hydrogels
These hydrogels respond to changes in pH of the external environment. These gels have
ionic groups (which are readily ionizable side groups)attached to impart peculiar
characteristics. Some of the pH sensitive polymers used in hydrogels preparations are
polymethyacrylic acid(PAA), polymethyl methacrylate (PMMA), polyacrylamide (PAAm),
polydimethylaminoethylmethacrylate(PDEAEMA) and polyethylene glycol. These
polymers though in nature are hydrophobic but swells in water depending upon the pH
prevalent in the external environment. Any change in pH of the biological environment
causes changes in the swelling behavior, for example, the hydrogel of caffeine is prepared
with polymer PDEAEMA at pH below 6. 6. As the polymer shows high swellability but
when pH changes to higher side, the polymer showed shrinkage leading to drug release.
The other pH sensitive hydrogels are copolymer of PMMA and polyhydroxyethyl methyl
acrylate(PHEMA) which are anionic copolymers, swell high in neutral or high pH but do
not swell in acidic medium. It was also observed that pH and ionic strength determines
kinetics of swelling of PHEMA and guar gum. Other drugs that have been delivered
through pH sensitive hydrogels are Tri polymer of N-vinyl-2-pyrrolidone methacrylamide
and itaconic acid, polydimethylaminoethylmethacrylate, polyethyleneglycol, copolymer of
poly methacrylic acid and polyethylene glycol, copolymer of cationic guar gum and acrylic
acid monomer. pH sensitive hydrogels have also been used to encapsulate proteins in
acrylamide polymer cross-linked with bisacrylamide acetal cross-linkers. At pH of around 5,
the pore size of the acetal cross-linked hydrogels increases leading to release of protein.
However at neutral pH, the acetal groups remain inact as cross linkers and protein do not
diffuse out easily[10].

6.2 Temperature sensitive hydrogels
The hydrogels being cross-linked polymers are temperature sensitive. These hydrogels are
pharmaceutically well accepted owing to large number of temperature sensitive drugs being
delivered in these dosage forms . The release as well as mechanical characteristics of drug
and hydrogels are altered with the change in the temperature of external environment.
Negative thermo-sensitive hydrogels contract upon heating above their low critical solution
temperature. Positive thermo-sensitive hydrogels contract upon cooling above their upper
critical solution temperature. In general, these hydrogels are hydrophobic polmers which
show variable network in response to temperature thus modulate the drug release. These
thermo- sensitive gels are specific, controllable and biocompatible drug delivery devices.
They could be biodegradable also. The drugs which are widely been explored for such
devices are usually from category of anticancer, antidiabetic, hormones or proteins and
peptides. Sometimes these gels are formed within the system and are particularly beneficial
for tissue targeting to inflamed or diseased areas. Drugs like insulin, heparin and
indometacin have delivered using these types of hydrogels. Tanaka developed the thermo-
sensitive hydrogels of PNIPAAm(polyisopropylacrylamide). The crosss-linked polymers

Hydrogels as Potential Nano-Scale Drug Delivery Systems                                    579

containing 75% NIPAAm(N-isopropyl acrylic amide)and rest of MAA(methacrylic acid )
showed temperature dependent swelling . However, the combined effect of temperature
and pH controls the drug release only when hydrogel gets swollen.
Thermo-sensitive macrocapsules of nanoparticles have been developed recently where the
matrix consists of temperature sensitive ethylcellulose polymer being coated with thermo-
sensitive membrane prepared by cross-linking poly NIPAAm hydrogel. The drug release is
expected to be high when high temperature causes collapsing of the membrane leading to
large void formation. These polymers exhibit phase separation at lower critical solution
temperature of about 32°C in aqueous solution. A novel thermo-sensitive hydrogel of
PNIPBAm{poly(N-isopropyl-3-butenamide)}was synthesized by Xu et al. . The synthesized
gel showed smaller pore size with the increase in concentration of cross-linker but the
swelling ratio was high with a gel containing low concentration of cross-linker. Another
thermo-sensitive hydrogel of polyorganophosphazene polymers bearing alpha – amino-
omega-methyl-poly ethylene glycol (AMPEG) and hydrophobic L-isoleucine ethyl ester side
groups so synthesized showed variable physical appearance from transparent sol to
translucent gel depending upon temperature and was utilized to entrap natural insulin
source for prolonged release. The same polymer has been used for controlled release of an
anticancer drug-doxorubicin. The drug showed sustained release over a period of 20 days
with no effect on gel characteristics like viscosity or gel strength and thus could be injected
for its depot therapy. Some of temperature sensitive hydrogels having pharmaceutical
applicability include : poly organophosphazene with α-amino omegamethylpolyethylene
glycol, copolymer of gelatin and PVA, Co-polymer of poly-PNIPA and poly-PNIPA-Co-AA,
NIPAAm-Co. AAm, NIPAAm-Co-AAm, polyepsilon caprolactone-co-lactide-polyethylene
glycol, chitosan. These hydrogels are not having thermo-sensitive response only, but they
are biodegradable also. That is why they are preferred for oral drug delivery. One such
example is novel biodegradable, thermo-sensitive hydrogel of poly(epsilon-caprolactone-co-
lactide-polyethylene glycol) copolymer used for iniectable drug delivery systems for
proteins and peptides[11].

6.3 Glucose sensitive hydrogels
These hydrogels are sugar sensitive and show variability in response depending upon the
presence of glucose. One of such pharmaceutical hydrogel system is the cross- linked
poly(methacrylamido phenylboronic acid)-co-acrylmide hydrogel which liberates the drug
in a controlled manner only when the concentration of glucose is high in the surrounding
environment causing swelling of hydrogel. Usually, glucose sensitive hydrogels are based
on implantable sensor which is sensitized to glucose concentration from 0-20 mM. Insulin
loaded hydrogels of cross-linked co-polymers of polyethyleneglycol and methacrylic acid
have been prepared by partitioning the insulin concentration. The micro particles of
hydrogels showed no leakage under acidic conditions while the release was highest at pH 7.
4 . A similar glucosesensitive hydrogel was prepared by photopolymerization of 2-
hydroxyethyl methacrylate and 3-acrylamido phenyl boronic acid. The liberation of insulin
was glucose concentration dependent. The hydrogels based on sulfonamide chemistry,
where the hydrogel showed maximum swelling at pH 7. 4 in a local glucose environment of
0-300 mg/dl for delivery of insulin, was an enzymatic approach. The hydrogel of poly(2-
hydroxyethyl methacrylate-co-N, N-dimethylaminoethyl methacrylate or poly HEMA-co-
DMAEMA polymer entrapped the insulin, glucose oxidase and catalase enzymes. Under the
environment of glucose, the glucose diffuses in the hydrogel from blood and gets converted

580                                                                                  Biopolymers

to gluconic acid which raises the pH thus causes swelling of the hydrogel. Swelling of
hydrogel leads to liberation of insulin which controls the glucose level in the blood. Through
such controlled release devices not only the insulin release is controlled (by varying the
concentration of cross linking agent)but also, the morphology of hydrogel is regulated by
oxygen uptake.
Based on a similar approach of stimuli sensitive hydrogels, a conjugated polymer of
monomethoxy poly(ethylene glycol) with glucose containing polymer showed reversible gel
to sol phases depending on the concentration of glucose in the external environment. The
viscosity of the hydrogel decreased with the addition of glucose. A part from gel to sol
approach for glucose sensitive sensitive hydrogels, the other approach is competitively
binding insulin to concanavalin A, which is a lectin protein that reacts with specific sugar
residues present at terminals so that in the presence of glucose, insulin is displaced. Thus, in
general, glucose sensitive hydrogels are formed by immobilizing glucose oxidase enzyme
which catalyses beta D-glucose to gluconic acid and hydrogen peroxide. The release of
gluconic acid decreases pH of the external environment causing decrease in swelling
behavior. This enzyme can be present in bound form or it could be attached to the polymer
chain. The conducting behavior of gels which gives the idea of swelling vary with the ions
liberated due to formation of gluconic acid or by ionization of amines present in the
polymer(usually acrylates) used for preparation of hydrogels. Therefore, these smart
biomaterials show controlled delivery of solute usually proteins like insulin, lysozyme or
BSA(Bovine serum albumin)in response to external environment.
Apart from temperature, pH, glucose sensitive hydrogels, other stimuli like light, electric
field, chemicals and ions have been utilized in formation of responsive hydrogels. But these
have not gained considerable attention in the field of drug delivery[12].

6.4 Nanohydrogels
Nanohydrogels are the hydrogels which are prepared in water by self aggregation of
polymers of natural origin like dextran. These types of hydrogels are formed from natural
polysaccharides like dextran, pullulan, or cholesterol-containing polysaccharide. the
cholesterol-containing polysaccharide is stirred at 50°C for 12 h in aqueous buffer which
leads to swelling of the cholesterol-containing polysaccharide. After sonication at 25°C for
10 min, nanoparticles of hydrogelsare formed. The size and density of hydrogel
nanoparticles can be controlled by changing the degree of substitution of cholesterol groups
of such polysaccharides. These hydrogels are of nano dimensions usually of 20-30 nm and
are used for cell targeting as they release the entrapped drug by swelling caused by change
in the pH of the surrounding environment. Drugs like adriamycin has been deliverd to
tumor cells and the drug showed pH dependent release and the highest release was when
pH was below 6. 8 . These nanoparticles of hydrogels have been used for controlled release
of proteins like lysozyme, albumin, immunoglobulin. The amount of protein released is
dependent on the square root of time. Hyrogels especially of dextran are made
biodegradable by encapsulation of enzyme dextranase. The hydrogels of pullulan
nanoparticles have been used for cell targeting by encapsulating active drug in aqueous core
of Aerosol OT/n-hexane[13].
Similar hydrogels have been made by self-assembling nanoparticles of linoleic acid
modified chitosan. 1. 8% linoleic acid substituted chitosan has structural integrity and shows
loading capacity of 19. 85 to 37. 57% of bovine srum albumin. These nanoparticles and are
ideal for tissue targeting. the nanohydrogel of polysaccharide-mannose from saccharomyces

Hydrogels as Potential Nano-Scale Drug Delivery Systems                                  581

cerevisiae have been prepared or capsulating insulin or BSA. the incorporation of calcium
phosphate prevents the initial burst release thus these hydrogels are used for controlled
drug delivery.

7. Preparation methods of hydrogels
Hydrogels are polymeric networks. This implies that crosslinks have to be present in order
to avoid dissolution of the hydrophilic polymer chian in aqueous solution. Hydrogels are
most frequently used for controlled release of bioactive agents and for encapsulation of cell
and biomolecules. In many of these cases the three dimensional structure of the hydrogels
have to disintegrate into harmless non toxic products to ensure biocompatibility of the gel.
The nature of the degradation productions can be tailored by a proper selection of the
hydrogel building blocks. Keeping this consideration in mind, various chemical and
physical crosslinking gels have ionic or covalent bonds between polymer chains . Even
though this leads to more mechanical stability, some of the crosslinking agents used can be
toxic, and give unwanted reactions, thus rendering the hydrogel unsuitable for biological
use. These adverse effects can be removed with the use of physically crosslinked gels. In
physically crosslinked gels, dissolution I prevented by physical interations between
different polymer chains. Both of these methods are used today for preparation of synthetic
hydrogels and discussed in detail.

8. Chemically crosslinked gels
As stated earlier, chemically crosslinked gels are mechanically quite stable due to the ionic
and covalent bond which comprises these gels. However the addition of crosslinking agent
leads to adverse effects if the compound is toxic, which on liberation in the body becomes

quite harmful. the various methods for chemical crosslinking are as follows:
     Crosslinking of Polymers
In this method chemically crosslinked gels are formed by radical polymerization of low
molecular weight monomers, or homopolymers, or copolymers in the presence of
crosslinking agent. This reaction is mostly carried out in solution for biomedical
applications. Most hydrophilic polmers have pendant hydroxyl group, thus agents such as
aldehydes, maleic and oxalic acid, dimethylurea, diisocyanates etc that condense when
organic hydroxyl groups are used as crosslinking agents. the solvent used for these reactions
is usually water, but methanol, ethanol and benzyl alcohol have also been used. these
solvents can be used only if after formation of network structure, the solvent can be
exchanged with water.
A typical reaction scheme for this type of crosslinking is shown:

               CH2      CH          +PY                   CH2    CH         + XY
                                n                                       k
                        X                                        P

                                                          CH2    CH

582                                                                                        Biopolymers

9. Typical reaction scheme for Flory type crosslinked structure
End-linking and cross-linking reactions may also occur in the absence of cross-linking

agents if a free radical initiator can be used which forms free radicals in the backbone chain.
     Copolymerization/Crosslinking Reactions
Copolymerization reactions are used to produce polymer gels, many hydrogels are
produced in this fashion, for example poly(hydroxyalkyl methacrylates). Initiarors used in
these reactions are radical and anionic initiators. Various initiators are used, such as
Azobisisobutyronitrile(AIBN), benzyl peroxide etc. Solvents can be added during the
reaction to decrease the viscosity of the solution.
-    Kinetic mechanism
The whole crosslinking mechanism consists of four steps: initiation, propagation,
crosslinking, and termination. Termination can occur by combination, disproportionation,
and chain transfer to monomer. An example of a representative reaction scheme follows:

                                                 I ⎯⎯→ 2A

                                           A+M 1 ⎯⎯→ P1,0,0
                                                  k i1

Propagation and cross-linking

                                   Pp,q,r +Px,y,z ⎯⎯ Q p,q,r +Px,y-1,z+1

Termination by combination

                                   Pp,q,r +Px,y,z ⎯⎯⎯ M p+x,q+y,r+z
                                                   k tc11

Termination by disproportionation

                                 Pp,q,r +Px,y,z ⎯⎯⎯→ M p,q,r +M x,y,z
                                                 d111 k

Chain Transfer to monomer

                              Pp,q,r +M 1 ⎯⎯⎯ M p,q,r +M p , q , r + P1,0,0
                                           k f11

                          Pp,q,r +Px , y , z ⎯⎯⎯ M p.q .r + Px , y − 1, z + 1 + Q0 ,0 ,1
                                             k f 12

HEMA as the monomethacryl monomer and EGDMA as dimethylacryl monomer, I is the
initiator, and A is a molecule with initiated radical. Here P and Q represent living polymer
chains with monomethylacyl and dimethylacyl monomer terminal groups, respectively and
M is dead polymer chain. The subscripts p, q, r are used to describe primary chain, they
refer to monomethylacryl units, pendant methylacyl groups, and cross-links per chain

respectively[14] .
     Cross-linking by High Energy Radiation
High energy radiation, such as gamma and electron beam radiation can be used to
polymerize unsaturated compounds. Water soluble polymers derivatized with vinyl groups
can be converted into hydrogels using high energy radiation. For example, PEG derivatized

Hydrogels as Potential Nano-Scale Drug Delivery Systems                                    583

to PEGDA can form hydrogels once irradiated with UV radiations. Polymers without
additional vinyl groups can also be cross-linked via radiation. On exposure to gamma or
electron beam radiation, aqueous solutions of polymers form radicals on the polymer chains
(e. g by the hemolytic scission of C-H bonds). Also the radiolysis of water molecules
generates the formation of hydroxyl groups which can attack polymer chains also resulting
in the formation of microradicals. Recombination of these microradicals on different chains
results in the formation of covalent bonds and finally in a crosslinked structure. the swelling
and permeability characteristics of the gel depend on the extent of polymerization, a
function of polymer and radiation dose (in general crosslinking density increases with
increasing radiation dose). The advantage of using this process for gel formation is that in
can be done in water under mild conditions without the use of a crosslinking agent.
However there are some drawbacks to using this method, the bioactive material has to be
loaded after gel formation, as irradiation might damage the agent. Also in some gels like

PEG and PVA, the crosslinks consist of C-C bonds, which are not biodegradable.
     Cross-linking Using Enzymes
Recently a new method was published using an enzyme to synthesize PEG-based hydrogels.
A tetrahydroxy PEG was functionlized with addition of glutaminyl groups and networks
were formed by addition of transglutaminase into solution of PEG and poly(lysine-co-
phenylalanine). This enzyme catalyzed reaction between γ-carboxamide group of PEG and
the ε-amine group of lysine to obtain an amide linkage between polymers. The gel
properties can be tailored by changing ratios of PEG and lysine.

10. Physically cross-linked gels
Chemically crosslinked gels imply use of a cross-linking agent, which is often toxic. This
requires that the cross-linking agent be removed from gel, which can affect the gel integrity.
For these reasons, physically cross-linked gels are now coming into prominence. Several
methods have been investigated exploring preparation of physically cross-linked gels.

Below are mentioned some of the most widely used methods and their areas of application.
     Cross-linking by Ionic interactions
An example of cross-linking via ionic interactions is cross-linking of Alginate consists of
glucuronic acid residues and mannuronic residues and can be cross-linked by calcium ions.
Cross-linking can be carried out at normal temperature and pH. These gels are used as
matrix for encapsulation of cells and for release of proteins. Also Chitosan based hydrogels,
as well as dextran based hydrogels, cross-linked with potassium ions also other gels
synthesized with ionic interactions. In addition to anionic polymers being cross-linked with
methalic ions, hydrogels can also be obtained by complexation of polyanions and

     Cross-linking by Crystallization
An aqueous solution of PVA that undergoes a freeze-thaw process yiels a strong highly
elastic gel. Gel formation is attributed to the formation of PVA crystallites which act as
physical cross-linking sites in the network. The gel properties could be modified by varying
polymer concentration, temperature, and freezing and thawing cycle times. These gels have

been shown to be useful for drug release.
     Cross-linking by hydrogen Bonds
Poly(acrylic acid) and poly(methacrylic acid) form complexes with poly(ethylene glycol) by
hydrogen bonding the oxygen of the poly(ethylene glycol) and the carboxylic acid group of
poly(methacrylic acid). Also hydrogen bonding has been observed in poly(methacrylic acid-

584                                                                              Biopolymers

g-ethylene glycol). The hydrogen bonds are only formed when the carboxylic acid groups
are protonated. This also implies that the swelling of gels is pH dependent. Recently a
hydrogen system was developed using the principle of DNA hybridization via hydrogen
bonding . In this approach, oligodeoxyribounucleotides were coupled to a water soluble
polymer. Hydrogels were prepared by addition of a complementary oligodinucleotide
(ODN) either conjugated to the same water soluble polymer or, in its free form, to an

aqueous solution of the ODN derivatized water soluble copolymer.
     Cross-linking by Protein Interaction
Genetic engineering has also been used for the preparation of hydrogels. The major
advantage is that the sequence of peptides and, therefore its physical and chemical
properties can be precisely controlled by the proper design of the genetic code in synthetic
DNA sequences. Cappello and colleagues prepared sequential block copolymers containing
a repetition of silk-like and elastine-like blocks, in which the insoluble silk segments are
associated in the form of aligated hydrogen bonded beta strands or sheets. These hydrogels
can also be used for drug delivery with drug delivery release influenced by concentration,
polymer composition, and temperature. Crosslinking by antigen-antibody interaction was
also performed, in which an antigen (rabbit IgG) was grafted to chemically crosslinked
polyacrylamide in the presence of an additional crosslinker. Additionally hydrogels have
been prepared by immobilizing both the antigen and the antibody in the form of an
interpenetrating network polymer network . This approach might permit drug delivery in
response to specific antigen[16].

11. Monomers used for fabrication of hydrogels
The monomers used for fabrication of these biocaompatible hydrogels have expanded from
a handful of choices, to several novel materials with tailor-made proerties suited to
particular applications. The first synthesis of hydrogel was that of Wichterle and lin using
PHEMA(poly)hydroxyethyl methacrylate)) as monomer. Depending upon the application,
hydrogel monomers are chosen according to their properties, ease of delivery or
encapsulations, as well as cost and availability . One of the most traditional monomers used
for drug delivery of proteins is biodegradable PLGA(polymers of lactic and glycolic acid).
However, these hydrophobic materials have a tendency to denature protein as well as cause
inflammation due to degradation, These problems were overcome when researchers turned
towards hydrophilic monomers. Monomers such as acrylic acid, polyethylene glycol, and
methacrylic acid are all materials used in therapeutic applications. Researchers are today
trying to custom – make materials to suit specific applications. PNIPAAm (poly(N-
isopropylacrylamide), PVA(polyvinyl alcohol)are all synthesized by new preparation
techniques, for distinct applications. Table 1 provides monomers used in the synthesis of
hydrogels for pharmaceutical applications.

12. PEG(polyethylene glycol) as suitable material
It is known that hydrophilic monomers provide a distinct advantage in both fabrication and
application of hydrogels. the premier material used today for both drug delivery, cell
encapsulation and as adhesive promoters is poly(ethylene glycol)hydrogels. PEG has many
unique properties which make it an ideal choice. PEG and its "stealth" properties, that is
once its attached to certain formulations, it allows slow release of the formulation, thus

Hydrogels as Potential Nano-Scale Drug Delivery Systems                                 585

            Monomer Abbreviation                                 Monomer
    HEMA                                       Hydroxyethyl methacrylate
    HEEMA                                      Hydroxyethoxyethyl methacrylate
    HDEEMA                                     Hydroxydiethoxyethyl methacrylate
    MEMA                                       Methoxyethyl meacrylate
    MEEMA                                      Methoxyethoxyethyl methacrylate
    MDEEMA                                     Methoxydiethoxyethyl methacrylate
    EGDMA                                      Ethylene glycol dimethacrylate
    NVP                                        N-vinyl-2-pyrrolidone
    NIPAAm                                     N-isopropyl AAm
    VAc                                        Vinyl acetate
    AA                                         Acrylic acid
    MAA                                        Methacrylic acid
    HPMA                                       N-(2-hydroxypropyl methacrylamide)
    EG                                         Ethylene glycol
    PEGA                                       PEG acrylate
    PEGMA                                      PEG methacrylate
    PEGDA                                      PEG diacrylate
    PEGDMA                                     PEG dimethacrylate

Table 1.
enabling controlled release, as well as reduce uptake of harmful immunoglobins. This
allows longer dosage and reduces immunogenicity of substances such as adenosine
deaminase(ADA) and asparaginase. PEG is non toxic, thus ideal for biological applications,
and can be injected into the body without adverse effects. It is also an FDA approved
materials for use in humans. PEGylation is an important technique being developed for
drug delivery, involves attachment of PEG to proteins and drugs, and has great potential for
improving pharmokinetic and pharmodynamic properties of delivery drugs. Thus PEG has
varied used in the medical field, including drug delivery(e. g. ; treatment of hepatitis C),
laxatives, cell immobilization, (as adhesion promoters), biosensor materials, and
encapsulation of islets of langerhans for treatment of diabetes. It is also used as carrier
material for encapsulated cells for tissue engineering purposes. Thus PEG, with its
biocompatibility, flexibility and stealth properties is an ideal material for use in
pharmaceutical applications[17].

13. Applications of hydrogels
Water-swollen cross-linked hydrogels have varied applications in fields such as food
additives, pharmaceutical as well as biomedicine. The pioneering work on cross-linked
HEMA hydrogels was done by Wichterle and Lim in 1954. From their reseach and discovery
of the hydrophilic and biocompatible properties of hydrogels, there emerged a new class of
hydrogel technologies based on biomaterial application. Lim and Sun in 1980 demonstrated

586                                                                                 Biopolymers

the successful use of calcium alginate microcapsulates for cell encapsulation. Later natural
polymers such as collagen, and shark cartilage were incorporated into hydrogels as wound
dressings. Natural and synthetic polymers are used encapsulation of cells, as well as
encapsulation of islets in a semipermeable membrane. Hydrogels have been used to prevent
adhesions and prevent thrombosis after surgery, and as cell adhesion resistant surfaces.
Microfabricated hydrogel arrays are also used for biosensing . Hydrogels now play an
important role in tissue engineering scaffolds, biosensor and bioMEMS devices and drug
Among these applications, hydrogel-based drug delivery devices have become a major area
of study, and several commercially available producs are already in the market. Proteins,
peptides, DNA based drugs can all be delivered via hydrogel carrier devices. The various
properties of hydrogels such as biocompatibility, hydrophilicity, flexibility all make it ideal
for use as drug delivery matrix.
Hydrogels show good compatibility with blood and other body fluids, thus are used as
materials for contact lenses, burn wound dressings, membranes, and as coating applied to
living surfaces. Natural and synthetic polymers have applications as wound dressings,
encapsulation of cells, and recently are being used in the new field of tissue engineering as
matrices for repairing and regenerating a wide variety of tissues and organs. When parts, or
whole tissues, organs fail, treatments include repair, replacement with a natural or synthetic
substitute, or regeneration. Implants have been reasonably successful;however tissue
engineering holds great promise for regeneration. Hydrogels are now being considered as
ideal matrices for tissue engineering[18].

14. Drug delivery
The current growth of hydrogel applications in drug delivery and biosensors is ascribed in
part to the biocompatibility of hydrogels, and in part to fast and reversible volume changes in
response to external stimuli such as temperature, pH, electric and magnetic fields, or analyte
concentration. Thus these hydrogels are sometimes called " Stimulus" responsive polymers.
One approach is to use pH sensitivity to mediate changes in swelling . A pH – sensitive
hydrogel undergoes very large and reversible volume changes in response to pH changes
within the hydrogel. Two main types of pH –sensitive hydrogels are acidic hydrogels and
basic hydrogels. Acidic hydrogels by definition will be ionized and hence swollen at high
pH, and uncharged and unswollen at low pH. Swelling behavior of a basic hydrogel has the
opposite dependence on pH. The pH sensitivity is caused by pendant acidic and basic
groups such as carboxylic acids, Sulfonic acids, primary amines, and quaternary ammonium
salts. Carboxylic acid groups for example are charged at high pH and uncharged at low pH,
whereas the reverse is true for primary amine groups and quaternary ammonium salts.
In a biosensor, the swelling and shrinking of the hydrogel is usually made to be responsive
to charges in the level of a biological indicator or molecule of interest. This is generally
achieved by incorporating into the hydrogel an enzyme, receptor, antibody, or other agent
which binds the molecule of interest. Oxioreductase enzymes are one category of such
agents, which find particular use in biosensors. The characteristics of oxidoreductase
enzymes of particular value in sensor applications is the production of oxygen by the
enzyme reaction.
Among the oxidoreductase currently being investigated for use in biosensors are glucose
oxidase(for sensing blood sugar levels), cholesterase(for sensing cholesterol levels), alcohol

Hydrogels as Potential Nano-Scale Drug Delivery Systems                                      587

dehydrogenase(for sensing alcohol levels), and penicillinase(for sensing penicillin levels).
Besides those named here, there are over 100 known oxidoreductase enzymes, and at least
some of these are likely to find future use in biosensors[19].
A pH – sensitive hydrogel containing glucose oxidase (GOx) enzyme is called a glucose-
sensitive hydrogel(GSH) due to its responsiveness to environmental glucose concentrations.
Thermally stable GOx is a flavin-containing glycoprotein which catalyzes a reaction which is
very specific for glucose, and which produces gluconic acid and hydrogen peroxide in the
presence of glucose and oxygen as shown below. Therefoere, increases in the environmental
glucose concentration lower the pH value within the GSH.
Several attempts have been made to utilize this catalytic reaction in glucose biosensors.
Glucose biosensors based on amperometric methods are the most highly developed. In the
amperometric method, an electrode is used which produces a current proportional to the
diffusional flux of hydrogen peroxide to the electrode surface, or, alternatively, proportional
to the diffusional flux of oxygen to the electrode surface. At steady state, the diffusional flux
of hydrogen peroxide to the electrode surface equals the rate at which hydrogen peroxide is
produced by the GOx reaction in the hydrogel adjacent to the electrode. However, unlike
the hydrogels considered here, the hydrogels in amperometric glucose biodensors do not
swell in response to pH changes.
An important physical property of pH-sensitive GSHs is the ability to change volume in
response to changes in environmental glucose concentrations, due to changes in pH within
the hydrogel caused by the reaction of the GOx enzyme. This physical phenomenon has
been applied in insuline delivery devices to control insulin permeability through GSHs.
pH-sensitive glucose hydrogels are useful in devices using either amperometric means or
pressure transducers to detect glucose concentrations. For such applications, two major
problems with the GOx enzymatic process have been identified: insufficient oxygen supply
for the reaction, and the decay of the GOx activity with time due to peroxide inducted
For both insulin delivery devices and glucose biosensors, GOx stability is essential for long
term use in vivo. For insulin delivery devices and the pressure based glucose biosensors, a
rapid swelling kinetic is also important, to provide the best performance. The use of
hydrogels containing oxidoreductase enzymes in biosensors and controlled drug delivery
systems and more particularly to the inclusion of catalase in such biosensors and drug
delivery systems has been reported. The invention comprises a hydrogels containing an
analyte-sensitive enzyme which, with the catalase being present in amounts ranging from
about 100 units/ml to about 1000 units/ml. The term " Hydrogel" is intended to encompass
any polymer matrix suitable for use in hydrated conditions. In one embodiment, the analyte
is glucose and the analyte-sensitivie enzyme is glucose oxidase. In addition to glucose
oxidase, the invention is applicable any analyte-sensitive enzyme which generates hydrogen
peroxide as part of the reaction. these include monoamine oxidase as well as many
oxidoreductases. The invention further encompasses biosensors incorporating these
hydrogels . The hydrogels may preferably be formulated such that swelling of the gel
permits flow of a drug such as insulin out of the gel. Thus, in a further embodiment the
invention encompasses analyte responsive drug delivery devices containing hydrogels
which meet the above description. The hydrogels may be used with biosensors or drug –
delivery devices which use pressure transducers or amperometric means to register analyte
concentration. Hydrogels according the invention may also be used with devices employing
gas reservoirs or semipermeable membranes. The invention further includes methods for
using catalase in hydrogels, biosensors and analyte-responsive drug delivery devices[21].

588                                                                                    Biopolymers

Drug delivery has been a subject of intense studies over recent years. The goal is to achieve
sustained(or slow) and /or controlled drug release and thereby improve efficacy, safety,
and/or patient comfort. A sustained and /or controlled release of the drug agents is
achieved by the retardation of drug diffusion by and/or gradual disintegration of the
polymer matrix following application.
In-situ gelation is a process of gel formation at the site of application after the composition or
formulation has been applied to the site. In the field of human and animal medicine, the
sites of application refers to various injection sites, topical application sites, and others
where the agents are brought into contact with tissues or body fluids. As a drug delivery
agent, the in-situ gel has an advantage related to the gel or polymer network being formed
in-situ providing sustained release of the drug agent. At the same time, it permits the drug
to be delivered in a liquid form. The in-situ gelation compositions using ionic
polysaccharides have been reported, which consist of a drug, a polymer and a gel forming
ionic polysaccharide which consist of two components, an ionic polysaccharide and a cross-
linking ion capable of cross-linking the former. The in-situ formation is induced by the
application of the cross-linking ions.
Thus, a great need exists for a simpler and more efficient in-situ gelling composition that
employs only a low polymer concentration for the purposes of drug delivery. Pectin is a
biodegradable acidic carbohydrate polymer. Pectin is commonly found in plant cell walls.
The cell wall of a plant is devided into three layers consisting of the middle lamella, the
primary wall and the secondary cell wall. The middle lamella is richest in pectin. The
chemistry and biology of pectin have been extensively reviewed.
Current commercial pectins are mainly from citrus and apples. However, besides cirtrus
and applies pectins can also be isolated from many other plants. All vetetacble and fruits
that have been examined contain pectins. Pectins from sugar beets, sunflowers, potatoes,
and grapefruits are just a few other well known examples. A pectic substance to provide a
biodegradable in-situ gelling composition for animal and human use was prepared. The
composition transformed from a liquid into a gel following administration to the target site.
Preferably the pectic substance was Aloe pectin. This composition could control, or sustain,
the release of a physiologically active agent in the body of an animal . It provided a
transparent polymer solution wherein no dramatic increase in gel cloudiness was created
beyond certain concentration ranges. Preferably the composition was capable of creating an
in-situ gel at low concentrations. The polymer solution was transparent wherein a thickener
is added. Preferably the composition is capable of creating an in-situ gel at low
concentrations to be delivered in the liquid form and provide a composition for drug
delivery a therapeutic or diagnostic agent incorporated into the formulation or composition.
These agents can be small molecules as well as large ones such as proteins like insulin.
Preferably the composition is capable of forming an in-situ gel at low concentrations[22].
Two classes of polymers that are currently receiving widespread attention in biosensor
development are hydrogels and conducting electroactive polymers. the integration of two
materials to produce electroactive hydrogel composites are reported that physically entrap
enzymes within their matrics for biosensor construction and chemically stimulated
controlled release. Enhanced biosensing capabilities of these membranes have been
demonstrated in the fabrication of glucose, cholesterol and glucose amperometric
biosensors. All biosensors displayed extended linear response ranges(10-5 -10-2 M), rapid
response times (< 60 sec. ), retained storage stabilities of up to 1 year, and excellent screening
of the physiological interferents ascorbic acid, uric acid, and acetaminophen. When the

Hydrogels as Potential Nano-Scale Drug Delivery Systems                                  589

cross-linked hydrogel components of these composite membranes were prepared with the
amine containing dimethylaminoethyl methacrylate monomer the result was polymeric
devices that swelled in response to pH changes(neutral to acidic). Entrapment of glucose
oxidase within these materials made them glucose responsive through the formation of
gluconic acid. When insulin was co-loaded with glucose oxidase into these "bio smart"
devices, there was a twofold increase in insulin release rate when the devices were
immersed in glucose solutions. This demonstrates the potential of such systems to function
as a chemically-synthesized artificial pancreas.
Glucose-sensitive hydrogel membranes have been synthesized and characterized for their
rate – of delivery of macromolecules. The mechanism for changing this rate is based on
variable displacement of the affinity interaction between dextran and concanavalin A(con
A). Membranes were constructed from cross-linked dextrans to which con A was coupled
via a spacer arm. Changes in the porosity of the resulting hydrogel in the presence of
glucose led to changes in the diffusion rate observed for a range of proteins. Gels of
specified thickness were cast around to nylon gauze support (pore size, 0. 1 mm) to improve
mechanical strength. Diffusion of proteins through the gel membrane was determined using
a twin-chamber diffusion cell with the concentrations being continuously minitored using a
UV spectrophotometer. Changes in the transport properties of the membranes in response
to glucose were explored and it was found that, while 0. 1M D-glucose caused a substantial,
but saturatrable, increase in the rates of diffusion of both insulin and lysozyme, controls
using glycerolor L-glucose(0. 1M) had no significant effect. Sequential addtition and
removal of external glucose in a stepwise manner showed that permeability changes were
reversible. As expected, diffusion rates were inversely proportional to membrane thickness.
A maximum increase in permeability was observed at pH 7. 4 at 37 degrees C. The results
demonstrate that this hydrogel membrane functions as a smart material allowing control of
solute delivery in response to specific changes in its external environment[23].
A novel UV polymerized glucose-response mixture containing concanavalin A (con A) and
dextran was synthesized and characterized as a " smart" biomaterial to form the basis of a
closed-loop delivery device. Dextran and con A precursors were modified with acrylic side
groups and then UV polymerized to produce covalently bonded mixtures which were
examined by FTIR. The viscoelastic properties of these polymerized mixtures containing
glucose concentrations between 0% and 5% w/w were also examined using oscillatory
rheometry within the linear viscoelstic range across a frequency range of 0. 01-50 Hz. As the
formulation glucose concentration was raised, a graded decrease in storage modulus, loss
modulus and complex viscosity when compared at 1 Hz was observed. Increasing the
mixture irradiation time produced viscosity profiles at higher values throughout the glucose
concentration range. The subsequent testing of such formulations in in vitro diffusion
experiments revealed that the leaching of the mixture components is formulation dependent
and is restricted significantly in the covalently bonded mixtures. Insulin delivery in
response to glucose in the physiologically relevant glucose concentration range was
demonstrated using the novel polymerized mixture at 37 degrees C. The performance of this
covalently cross-linked glucose-responsive biomaterial has been improved in terms of
increased mixture stability with reduced component leaching . This could, therefore be used
as the basis of the design of a closed-loop drug delivery device for therapeutic agents used
for the management of diabetes mellitus[24].
Treatment of diseases has always been a major issue for researchers for as long as mankind
has existed. As technology has advanced, proteins, peptides, and other materials have been
identified as " drugs" which can be used to treat physiological life processes, pain, and

590                                                                                   Biopolymers

discomfort. Drugs can vary in their characteristics to the extent that drugs used to treat the
same symptoms might differ in characteristics such as hydrophilicity, chemical composition,
size and effectiveness. An increasing understanding of cellular at the biology at the
molecular level and breakthroughs in proteomics have led to concept of gene delivery.
Drugs have to reach the site of action following administration(oral intravenous,
transdermal etc. ) in a specific manner and in specific quantity. This is the basis of the drug
delivery field. Drug delivery aims at delivering the right drug at the right place, at right
concentration for the period of time. Sometimes direct delivery of such drugs is difficult,
due to the treacherous route of delivery or discomfort caused to the patient. for such cases,
strategies have been developed for delivering drug with a carrier. the drug carrier, whether
it be an implantable device, or long chain polymer must be biocompatible with the drug and
the body. Drug delivery systems alter the biodistribution and pharmakinetics of the drug .
Therefore one must take into account obstacles such as drug solubility, enzyme degradation,
toxicity, inability to cross biological barriers as well as adverse environmental conditions. In
order to make the delivery of the drug effective without causing an immune response in the
body, proper design and engineering of the drug delivery system is essential[25].

15. Hydrogels in drug delivery
Localized drug delivery can be achieved by introducing the drug directly at the target site.
the major class of biomaterials considered as implantable drug delivery systems are
hydrogels. These hydrophilic networks are capable of absorbing great amounts of water
while maintaining structural integrity. Their structural similarity to the extracellular matrix
makes it biocompatible. These synthetic polymers have generated wide interests and are
now at the forefront of drug delivery research.
In order to incorporate a performed gel into the body, an opening must be created, with at
least the same dimension as that of the gel. This leads to potential risk and discomfort to the
patient. Thus focus has shifted to developing injectable materials with ability to form three
dimensional matrices under physiological matrices. This in situ formation can be achieved
through specific chemical cross-linking reactions. Gel structuring is triggered by
environmental stimuli(pH, temperature, solvent exchange etc. ). Synthetic hydrogels, with
their ability to imbibe water, flexibility, and biocompatibility, are ideal carriers for the
development for novel pharmaceutical formulations and for the delivery of drugs, proteins,
and as targeting agents for drug delivery . The network structure and the nature of
components play a key role in the diffusional behavior, molecular mesh size changes, and
stability of the incorporated bioactive agent[26]. The use of hydrogels allows not only
delivery of drugs, but also controlled release, in the manner required by the pharmaceutical
scientists. For example, drugs can be delivered only when needed, may be directed to
specific site, and can be delivered at specific rates required by the body. In the last 20 tears,
advanced drug delivery formulations have been examined in great detail. Reviews related
to the various applications of hydrogels in drug delivery and various sites available in the
body for such are readily available.

16. Properties useful in drug delivery
Hydrigels posses several properties that make them an ideal material for drug delivery.
First, hydrogels can be tailored ro respond to a number of stimuli. This enables sustained
drug delivery corresponding to external stimuli such as pH or temperature. These pH

Hydrogels as Potential Nano-Scale Drug Delivery Systems                                     591

sensitive gels are useful in oral drug delivery as they can protect proteins in the digestive
track. pH responsiveness is also useful for lysosomal escape during gene delivery. Second,
hydrogels can also be synthesized to exhibit bioadhesiveness to facilitate drug targeting,
especially through mucus membranes, for non-invasive drug administration. finally,
hydrogels also have a " stealth"characteristic in vivo circulation time of delivery device by
evading the host immune response and decreasing phagocytic activity[27].

17. Applications of Hydrogels in drug delivery
Advances in recombinant protein technology have identified several protein and peptide
therapeutics for disease treatment. However, the problem which plagued researchers as how
to effectively deliver these biomolecules. Due to their large molecular weight, and three
dimensional structure, the most commomly used route for drug administration is by
intravenous or subcutaneous injection. Unfortunately proteins and peptides are prone to
proteolytic degradation, thus they experience short plasma circulation times and rapid renal
clearance, leading to multiple daily injections or increased dosage in order to maintain the
required drug therapeutic levels. Multiple injections are difficult for the patient, while high
dises might be toxic, and induce serious immune response. Hydrophobic polymeric controlled
release formulations, such as PLGA, offer a sustained release mechanism in which drug
release rates can manipulated by changing polymer molecular weight and composition. These
polymers however induce adverse effects to the encapsulated proteins or peptides during
network preparation and delivery, as well as trigger the immune response. Hydrophilic
hydrogels, on the other hand, provide relatively mild network fabrication technique and drug
encapsulation conditions, making them the ideal material for use indrug delivery. Thus
hydrogels are primarily used for encapsulation of bioactive materials and their subsequent
controlled release. If designed properly, hydrogels can be used in a variety of applications
such as sustained, targeted, or stealth biomolecule delivery. Hydrogel based delivery devices

can be used for oral. ocular, epidermal and subcutaneous application[28].
     drug Delivery in GI Tract
The ease of administration of drugs, and the large surface area for absorption makes the GI
tract most popular rote for drug delivery. It is however, also a very complex rote, so that
versatile approaches are needed to deliver drugs for effective therapy. Hydrogel-based
devices can be designed to deliver drugs locally to specific sites in the GI tract. For example,
Patel and Amiji proposed stomach-speicific antibiotic drug delivery systems for the
treatment of Helicobacter pylori unfection in peptic ulcer disease. They developed cationic
hydrogels with pH sensitive swelling and drug release properties for antibiotic delivery in
the acidic environment of the stomach. There are still many drawbacks for peroral delivery
of peptides and proteins to GI tract, like protein inactivation by digestive enzymes in the GI
tract and poor epithelial permeability of the drugs. However, certain hydrogels may
overcome some of these problems by appropriate molecular design of formulation, for
example Akiyama reported novel peroral dosage forms of hydrogel formulations with
protease inhibitory activities[29].
Recently oral insulin delivery using pH responsive complexation hydrogels was reported.
the hydrogels used were crosslinked copolymers of PMMA with graft chains of
polyethylene glycol . These hydrogels protect the insulin in the harsh, acidic environment of
the stomach before releasing the drug in the small intestine.

592                                                                                   Biopolymers

The colonic region has also been considered as a possible absorption site for orally
administered proteins and peptides, mostly due to a lower proteolytic activity in
comparison to that in the small intestine. Several hydrogels are currently being investigated
as potential devices for colon-specific drug delivery. These include chemically or physically
cross-linked polysaccharides such as dextran, guar gumand insulin. They are designed to be
highlyswollen or degraded in the presence of colonic enzymes or microflora, providing

colon-specificity in drug delivery[30].
      Rectal Delivery
This route has been used to deliver many types of drugs for treatment of diseases associated
with the rectum, such as hemorrhoids. This route is an ideal way to administer drugs
suufering heavy first-pass metabolism. There are however, some drawbacks associated with
rectal delivery. For example, due to discomfort arising from given dosage forms, there is
substantial variability in patient's acceptance of treatment. Also, if drugs diffusing out of the
suppositories are delivered in an uncontrolled manner, they are unable to be retained at a
specific position in the rectum, and tend to migrate upwards to the colon. This leads to
variation of availability of drugs, especially those that undergo extensive first-pass
elimination. Hydrogels offer a way in which to overcome these limitations, provided that
the hydrogels show bioadhesive properties. It was reported that increased bioavailability of
propanol subject to extensive first-pass metabolism was observed by adding certain
mucoadhesive polymeric compounds to poloxamer-based thermally gelling suppositories.
the polymeric compounds tested were polycarbophil and sodium alginate. Miyazaki et al.
investigated the potential application of xyloglucan gels with a thermal gelling property as
matrices for drug delivery. Another important issue in rectal drug delivery is to avoid rectal
irritation. The products discussed above, indicated no such mucosal irritation after drug

      Ocular delivery
Drug delivery to the eye is difficult due to its protective mechanisms, such as effective tear
drainage, blinking, and low permeability of the cornea. Thus, eye drops containing drug
solution tends to be eliminated rapidly from the eye and the drugs show limited absorption,
leading to poor aphthalmic bioavailability. Due to the short retention time, a frequent dosing
regimen is necessary for required therapeutic efficacy. These challenges have motivated
researchers to develop drug delivery systems that provide prolonged residence time.
The earlier dosage forms, such as suspension and ointments colud be retained in the eye,
but sometimes gave patients an unpleasant feeling because of the nature of solids and semi-
solids. Hydrogels, because of their elastic properties can represent an ocular drainage-
reisitant device. In-situ forming hydrogels are attractive as an ocular drug delivery system
because of their facility in dosing as a liquid, and long term retention property as a gel after
Cohen et al. developed an in-situ gelling system of alginate with high gluronic acid contents
for the ophthalmic delivery of pilocarpine. This system extended the duration of the
pilocarpine to 10 hr, compared to 3 hr when pilocarpine nitrate was dosed as a solution.
Chetoni et al. reported silicone rubber hydrogel composite ophthalmic inserts. An in-vivo
study using rabbits showed a prolonged release of oxytetracycline from the inserts for
several days.
Vascular endothelial growth factor(VEGF) has been identified as akey regulator of
angiogenesis. It can act as an endothelial cell mitogen and increase vascular permeability
along with angiogenesis. Elevated VEGF level has been correlated with several ocular

Hydrogels as Potential Nano-Scale Drug Delivery Systems                                    593

diseases, such as age-related macular degeneration and diabetic retinopathy. On the basis of
these findings, in the past several years, considerable progress has been made in the
treatment of the wet form of age – related macular degeneration and diabetic retinopathy by
using anti-VEGF therapy. Several clinical trials employing ranibizumab, including
ANCHOR and MARINA, have demonstrated the success of anti-VEGF therapy.
Although intravitreal anti-VEGF therapy is a very promising treatment, the major drawback
is that the treatment must be repeatedevery 4 to 6 weeks. This is not a desirable method of
delivery for several reasons: patient discomfort;the need for repetitive injections with
inherent complications, including endophthalmitis, retinal tear and detachment, intraocular
hemorrhage, and cataract formation;and bolus administration of the agent. Currently, there
is no alternative method for delivery of the anti-VEGF agent into the eye;hence, there is a
great need and desire to develop a relatively noninvasive delivery method that is more
effective and longer lasting than the current clinical regimen. Since the development of
hydrogels in 1960, they have been of great interest to biomaterial scientists and tissue

      Transdermal Delivery
Drug delivery to the skin has been generally used to treat skin diseases or for disinfection of
the skin. In recent years, however a transdermal route for the delivery of drugs has been
investigated. Swollen hydrogels can be delivered for long duration and can be easily
removed. These hydrogels can also bypass hepatic first-class metabolism, and are more
comfortable for the patient. Hydrogel based delivery devices have been proposed by Sun et
al., such as composite membranes of crosslinked PHEMA with a woven polester support.
Also hydrogels have been reported which have been obtained by the copolymerization of
bovine serum albumin(BSA) and PEG. These hydrogels can be used as controlled release
devices in the field of wound dressing . Hubbell has also carried out extensive research on
in-situ photopolymerization made from terminally diacrylated ABA block copolymers of
lactic acid oligomers(A) and PEG(B) for barriers and local drug delivery in the control of
wound healing .
Current research in this field is now focused on electrically –assisted delivery using
iontophoresis and electroporation. Hydrogel-based formulations are being look at for
transdermal ionphoresis to obtain enhanced permeation of products in question such as,

hormones and nicotine[36-38].
      Subcutaneous Delivery
Among the varied possible pharmaceutical applications of hydrogels, the most substantial
application is probably in implantable therapeutics. Implantable devices that are
subcutaneously inserted tend to illicit immune response of the body, leading to
inflammation, carcinogenicity and immunogenicity. Thus biocompatibility becomes a major
issue, and all implantable materials must be compatible with the body. Hydrogels are an
ideal candidate for implantable materials. They also have other properties which make them
a vaiable choice, (1) minimal mechanical irritation upon in-vivo implantation due to their
soft, elastic properties(2) prevention of protein absorption and cell adhesion arising from the
low interfacial tension between water and hydrogels (3)broad acceptability for individual
drugs with swelling for release of incorporated drug in specific manner. Thus, hydrogels are
an ideal material to be used for delivery of proteins and peptides[40].
Hydrogel formulations for subcutaneous delivery of anticancer drugs have been proposed.
For example, crosslinked PHEMA was applied to cyratabine(Ara-C). Current studies on
implantable hydrogels are leading towards the development of biodegradable systems,

594                                                                                     Biopolymers

which don not require surgical removal once the drug has been administered.
Biodegradable PEG hydrogels are now at the forefront of this research, and several novel
systems have been developed. One type is synthesized via a polycondensation reaction
between functional PEG acids and brabched PEG polyols. Another type is PEG based
hydrogels having functional groups in which the protein drugs can be covalently attached
to the gel network via ester linkages. In this case, the release of the immobilized proteins
would be controlled by the hydrolysis of ester linkage between the gel and protein, followed
by diffusion of protein, and degradation of gel[41-45].

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596                                                                                 Biopolymers

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[39] Saboktakin, M. R. ;Tabatabaie, R. ;Maharramov, A. ; Ramazanov, M. A. ;(2010);"
         Synthesis and Characterization of New electrorheological Fluids by Carboxymethyl
         Starch Nanocomposites " ; Journal of Carbohydrate Polymers;79, 4, 1113-1116.
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         sensitive starch hydrogels via free radical graft copolymerization, synthesis and
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[41] Saboktakin, M. R. ;Tabatabaie, R. ;Maharramov, A. ; Ramazanov, M. A. ;(2009);
         ”Synthesis and Characterization of Superparamagnetic Nanoparticles Coated with
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         Synthesis and Characterization of Chitosan Hydrogels Containing 5-Aminosalicylic
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         Sciences, 2010, Accepted & in Press .
[43] Saboktakin, M. R. ;Tabatabaie, R. ;Maharramov, A. ; Ramazanov, M. A. ;(2010); "
         Synthesis and Characterization of Superparamagnetic Chitosan-Dextran Sulfate
         Hydrogels for Targeted Drug Delivery to the Colon ", Journal of Carbohydrate
         Polymers ; Accepted and in Press.
[44] Saboktakin, M. R. ;Tabatabaie, R. ;Maharramov, A. ; Ramazanov, M. A. ;(2010); "
         Synthesis and Characterization of Superparamagnetic Chitosan-Dextran Sulfate
         Hydrogels for Targeted Drug Delivery to the Colon ", Journal of Carbohydrate
         Polymers, Accepted and in Press.
[45] Saboktakin, M. R. ;Tabatabaie, R. ;Maharramov, A. ; Ramazanov, M. A. ;(2010); ""
         Synthesis and Characterization of Biodegradable Chitosan Beads as Nano Carriers
         for Local Delivery of Satranidazole" ; Journal of Carbohydrate Polymers, Accepted &
         in press .

                                      Edited by Magdy Elnashar

                                      ISBN 978-953-307-109-1
                                      Hard cover, 612 pages
                                      Publisher Sciyo
                                      Published online 28, September, 2010
                                      Published in print edition September, 2010

Biopolymers are polymers produced by living organisms. Cellulose, starch, chitin, proteins, peptides, DNA and
RNA are all examples of biopolymers. This book comprehensively reviews and compiles information on
biopolymers in 30 chapters. The book covers occurrence, synthesis, isolation and production, properties and
applications, modification, and the relevant analysis methods to reveal the structures and properties of some
biopolymers. This book will hopefully be of help to many scientists, physicians, pharmacists, engineers and
other experts in a variety of disciplines, both academic and industrial. It may not only support research and
development, but be suitable for teaching as well.

How to reference
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Mohammad Reza Saboktakin (2010). Hydrogels as Potential Nano-Scale Drug Delivery Systems, Biopolymers,
Magdy Elnashar (Ed.), ISBN: 978-953-307-109-1, InTech, Available from:

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