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406 | P a g e International Standard Serial Number (ISSN): 2319-8141
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International J ournal of Universal Pharmacy and Bio Sciences 3(2): March-April 2014
INTERNATIONAL JOURNAL OF UNIVERSAL
PHARMACY AND BIO SCIENCES
IMPACT FACTOR 1.89***
ICV 5.13***
Pharmaceutical Sciences REVIEW ARTICLE!!!

HYDROGEL : A SMART POLYMER: AN OVERVIEW
Ganesh Bamane*, Tejaswini Kakade, Akash Raval, Prasad Kevane, Sucheta Tikole
MSSCollege of Pharmacy Medha, Tal-Jaoli, Dist Satara, India.
YSPMS, YTC, Faculty of Pharmacy, Satara, India.

KEYWORDS:

Hydrogels, Polymerization.
Flexibility, Polymer
Matrix, Optimized Tools.
For Correspondence:
Ganesh Bamane*

Address:
MSSCollege of
Pharmacy Medha, Tal-
Jaoli, Dist Satara, India.
Email Id:
bamaneganesh88@gmail.
com

ABSTRACT
A naturally occurring or synthetic compound consisting of large
molecules made up of a linked series of repeated simple
monomers. polymerization is a process of reacting monomer
molecules together in a chemical reaction to form three-
dimensional networks or polymer chains. Hydrogels are liquid or
semisolid materials composed of long-chain molecules cross-
linked to one another to create many small empty spaces that can
absorb water or other liquids like a sponge. Hydrogels are highly
absorbent (they can contain over 99% water) natural or synthetic
polymers. Hydrogels also possess a degree of flexibility very
similar to natural tissue, due to their significant water content.
Hydrogels act as biomaterials. A hydrogel consists of a polymer
matrix containing water. It is used as a most promising polymer in
various drug delivery systems. Hydrogels can be seen as
optimised tools for facing various medicinal & pharmaceutical
problems by producing sustained & prolonged effects with
diminished side effects. Various hydrogels prepared are able to
produce the desired & required sustained effects.


1. Introduction to Polymer Science:
A naturally occurring or synthetic compound consisting of large molecules made up of a linked series of
repeated simple monomers.
1.1. Polymerization: In polymer chemistry, polymerization is a process of reacting monomer molecules
together in a chemical reaction to form three-dimensional networks or polymer chains. There are many
forms of polymerization and different systems exist to categorize them
1
.
A high molecular weight organic compound, natural or synthetic, whose structure can be represented by a
repeated small unit, the monomer (e.g. polyethylene, rubber, cellulose). Synthetic polymers are formed by
addition or condensation polymerization of monomers
2
.
Polymers are long linear chains consisting of a large (N >>1) number of monomer units. For synthetic
polymers usually N ~ 102 - 104; For DNA N ~ 109 -1010.
E.g. Polyethylene -CH
2
-CH
2
-CH
2
-CH
2
-

E.g. Polystyrene

E.g. Polyvinylchloride

1.2. Polymers as long molecular chains:
Electronic microphotograph of DNA macromolecule, partially released through the defects of a membrane.

Figure 1: Polymer chain


1.3. Physical Properties of Polymers are based on Three Main Factors:
1. Monomer units are connected into long chains. They do not have the freedom of independent
translational motion. Polymer systems are poor in entropy.
2. Number of monomer units is large N >> 1.
3. Polymer chains are flexible.
1.4. Change of the Main Emphasis in Polymer Science:
Before 1980: polymers as construction materials (plastics, resins, fibers, films, glues).
After 1980: polymers as functional materials (super absorbents, conducting polymers, polymers for optics,
and polymers for medicine).
1.5. Smart Polymers for Limiting Water Influxes:
The main aim of the work is to develop smart polymer materials that find the water inflow by themselves
and block it.
These materials should:
have low viscosity at injection
form a gel in contact with water
keep low viscosity in contact with oil
3
.
2. Hydrogel:
Hydrogels are liquid or semisolid materials composed of long-chain molecules cross-linked to one another
to create many small empty spaces that can absorb water or other liquids like a sponge. If the spaces are
filled with a drug, the hydrogel can dispense the drug gradually as the structure biodegrades. Widespread
research also is under way on using hydrogels as scaffolds for tissue engineering and tissue repair, where
the spaces in the gel might be filled with stem cells, tissue-growth factors or a combination of both
4
.
Hydrogels are highly absorbent (they can contain over 99% water) natural or synthetic polymers.
Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water
content
5
.
Among all the hydrogel systems investigated over the years, temperature- and pH-responsive hydrogels
have demonstrated great promise in drug delivery owing to their novel ability to change physical state.
Poly (N-isopropylacrylamide) (PNIPAAm) hydrogel is one of the well-known thermo sensitive materials
that has a lower critical solution temperature (LCST) or transition temperature at ~32C. 9, 10 Below the
LCST the hydrogel are swollen, and above the LCST the hydrogel will collapse (shrink). The change in
physical state is rapid and reversible, which makes the thermo responsive hydrogel an attractive means of

drug delivery. However, a potential drawback of PNIPAAm hydrogel is the limited amount of drug
released in response to a change in temperature. With a fast response to temperature stimuli, the drug can
be released from the hydrogel quickly and act as an on-off switching release system
6
.
Natural hydrogel materials are being investigated for tissue engineering; these materials include agarose,
methylcellulose, hyaluronam, and other naturally derived polymers.
2.1. Need:
Self-assembled hydrogels from small molecular building blocks provide highly tuneable materials for both
biological and non-biological applications. Biological applications of these systems include biosensing,
controlled drug release, three-dimensional cell culture and tissue engineering. In recent years, self-
assembling peptide hydrogels have received significant attention as they are believed to have potential as
next-generation biomaterials. For these materials to be successful in tissue engineering and three-
dimensional cell culture, self-assembly ideally occurs under physiological conditions (37 C, pH 77.5 and
an ionic strength of 0.15 M).
Many biological materials are based in some fashion on hydrogels, the crosslinked polymers that absorb
and hold water. Biological hydrogels contribute to processes as diverse as mineral nucleation during bone
growth and protection and hydration of the cell surface. The carbohydrate layer that coats all living cells,
often referred to as the glycocalyx, has hydrogel-like properties that keep cell surfaces well hydrated,
segregated from neighbouring cells, and resistant to non-specific protein deposition. With the molecular
details of cell surface carbohydrates now in hand, adaptation of these structural motifs to synthetic
materials is an appealing strategy for improving biocompatibility
7
.
2.2. Advantages:
Currently used as scaffolds in tissue engineering. When used as scaffolds, hydrogels may contain
human cells in order to repair tissue.
Environmentally sensitive hydrogels have the ability to sense changes of pH, temperature, or the
concentration of metabolite and release their load as result of such a change.
Hydrogel can be in sustained-release delivery systems.
It provides absorption, desloughing and debriding capacities of necrotics and fibrotic tissue.
Hhydrogels that are responsive to specific molecules, such as glucose or antigens can be used as
biosensors as well as in drug delivery system.
They can be used in contact lenses (silicone hydrogels, polyacrylamides).

Preparation of medical electrodes using hydrogels composed of cross linked polymers
(polyethylene oxide, polyAMPS and polyvinylpyrrolidone).
Water gel explosives.
Granules for holding soil moisture in arid areas.
Dressings for healing of burn or other hard-to-heal wounds. Wound gels are excellent for helping to
create or maintain a moist environment.
Reservoirs in topical drug delivery; particularly ionic drugs, delivered by iontophoresis
8, 9
.
2.3. Disadvantages:
Current injectable hydrogels often require photo-irradiation, auxiliary crosslinking agents, and/or
organic solvents, which may damage the cells or proteins of interest.
Dextran hydrogels have a low initial swelling and are degradable under physiological conditions
with degradation time varying from 3 to 21 days depending on the delivery system, concentration &
dextran molecular weight.
However, a potential drawback of PNIPAAm hydrogel is the limited amount of drug released in
response to a change in temperature. With a fast response to temperature stimuli, the drug can be
released from the hydrogel quickly and act as an on-off switching release system
10
.
2.4. Hydrogels as biomaterials:
Hydrogels have attracted tremendous research interest over many years, in part for fundamental reasons
and in part because of the potential for a wide range of applications. Hydrogels have been successfully used
in biomedical fields due to their high water content and the consequent biocompatibility. Successful
examples include soft contact lenses, wound dressings, super absorbent, and drug-delivery systems. The
most recent and exciting applications of hydrogels are cell-based therapeutics and soft tissue engineering
11
.
The biomaterial used to grow the first living, tissue-engineered skin product was a collagen hydrogel.
Although the success of skin tissue engineering is encouraging, efforts to engineer other soft tissues have
not achieved similar success. The progress in large measure is limited by inappropriate properties of the
biomaterials currently available. To elicit desired cell response and coax cells to assemble into functional
tissues, the materials that support and contact the cells need to be carefully designed
12, 13
.

For hydrogels
used for cell-based therapeutics and soft tissue engineering, critical design parameters include both
physical properties (such as appropriate mechanical strength and integrity) and biological properties (such
as nontoxicity and ability to incorporate appropriate biological determinants (cell-binding domains, enzyme
recognition sites)
14
.

2.5. Genetically engineered protein hydrogels assembled through aggregation of leucine zipper
domains:
The concept of assembling artificial protein hydrogels through naturally occurring protein motifs opens a
new approach to creating unique hydrogels. Since the capacity for self-assembly is encoded in protein
sequences, gelation does not require chemical crosslinking reagents, which often compromise material
safety in biomedical applications. Artificial protein hydrogels constructed from a rod-coil-rod triblock
protein (designated AC10A) containing two leucine-zipper endblocks and a soluble random coil midblock
has been reported in our laboratory. Self-assembly of the leucine-zipper domains provides inter-chain
crosslinking and leads to networks that can be switched on and off by controlling pH and temperature. The
choice of residues for the leucine zipper domain was based on the residue pattern of the Jun oncogene
product and a database developed by Lupas et al. The midblock contains 90 amino acids, and features
periodic glutamic acids for solvent retention
15, 16
.
Hydrophobic interactions drive them to associate into oligomeric bundles. Among naturally occurring
coiled-coils, two, three, four, and five stranded bundles have been reported. Higher order of aggregation
has not been
found
18, 19
.
2.6. Transient Networks:
AC10A hydrogels are transient networks, in which network junctions form through physical associations
and are not permanent. Therefore these networks retain internal fluidity due to the finite lifetime of the
junctions. In other words, each chain can diffuse through the whole network on a certain time scale. The
dynamics of this internal fluidity can be exploited to control the diffusion of large molecules (such as
protein drugs) encapsulated in the network. Since the strength of physical associations can be tuned by
varying the solution conditions, transient networks are often reversible in response to environmental stimuli
such as temperature and pH.
The most extensively studied transient networks are those formed from hydrophobically modified
urethane-ethoxylate (HEUR) polymers
22, 23
. These polymers have a water-soluble midblock and two
hydrophobic associative endgroups (typically hydrocarbon or fluorocarbon groups). These transient
networks behave like solids on short time scales: under oscillatory shear, there is a plateau in storage
modulus (G) at high frequencies. On time scales longer than a characteristic relaxation time (r), these
materials behave like liquids: at low frequencies (x<1/r), the loss modulus (G) exceeds G. This solid-

to-liquid transition is called network stress relaxation, which is believed to be controlled by the dynamics
of the molecular motions of polymer chains.
Annables model proves valuable in understanding AC10A hydrogels as well. In the context of artificial
proteins, the model gives insight into the effects of ionic strength and pH, as well as mid-block length and
polymer concentration
26
.
3. Classification:
A) Classification Based on Preparation Method:
1. Homopolymer hydrogels (one type of hydrophilic polymer)
2. Copolymer hydrogels (two types of polymers, at least one hydrophilic)
3. Multipolymer hydrogels (more than three types of polymers)
4. Interpenetrating polymeric hydrogels (swelling a network of polymer 1 in polymer 2, making
intermeshing network of polymer 1 and polymer 2).
B) Classification Based on Ionic Charges:
1. Neutral hydrogels
2. Anionic hydrogels
3. Cationic hydrogels
4. Ampholytic hydrogels
C) Classification based on structure:
1. Amorphous hydrogels (chains randomly arranged)
2. Semicrystalline hydrogels (dense regions of ordered macromolecules, i.e. crystallites)
3. Hydrogen-bonded hydrogels
27,28
.


3.1. Stimulus-Sensitive Hydrogels:
Table 1: Mechanisms of drug release according to stimulus

A hydrogel consists of a polymer matrix containing water. The amount of water in the polymer matrix can
be very large and can reach values of 99% by weight. The polymer matrix is made up of a very large
number of long molecular chains, also called backbones, which are held together by interconnections
between these chains, called crosslinks. The crosslinks keep the chains in the polymer matrixtogether, thus
circumventing the dissolution of the long molecular chains and increase the mechanical stability of the
hydrogel. The physics behind the effect of the gel network composition on the mechanical properties of the
network have been investigated by Flory and Rehner, which led to the Flory-Rehner equation. The long
molecular chains in turn are composed of small molecular units called monomers and comonomers which
have been attached to each other during the chemical synthesis of the polymer network. For a visual
representation of a hydrogel matrix.
The family of stimulus-sensitive hydrogels can largely be subdivided into two types of gels: pH-sensitive
hydrogels and temperature-sensitive hydrogels. Other types of gels exist and some examples will be given
below. Temperature- and pH-sensitive hydrogels are very different in their physical behavior and swelling
mechanism
29
.

3.1.1. Temperature-Sensitive Hydrogels:

Figure 2: The chemical structure of a hydrogel matrix. Water has been omitted for clarity.

Figure 3: (a) Backbones of the temperature-sensitive hydrogel in the swollen condition. (b) The backbones
in the aggregated condition. Note the reduction of the surface area exposed to water.
A common group of monomers, used in the synthesis of temperature-sensitive hydrogels, are the N-alkyl
acrylamides. A well-known monomer from this group is N-isopropyl acrylamide (NIPAAm). This
monomer has sidechains which have favorable interactions with water in the form of hydrogen bonds. This
causes a hydrogel made from this monomer, called a poly-NIPAAm hydrogel, to attract water molecules
and swell around room temperature
30
.

The efficiency of the hydrogen bonding process has a negative
temperature dependency and above a certain temperature, called the lower critical solution temperature
(LCST), the hydrogen bonds between the monomer side groups and water molecules will increasingly be
disrupted with increasing temperature.


3.1.2. pH-Sensitive Hydrogels:

Figure 4: Swell curve of a disc-shaped poly-NIPAAm hydrogel. Note the large diametral change with
temperature.

Figure 5: Ionisation behavior of acrylic acid and dimethyl aminomethacrylate. The degree of ionisation (I)
is plotted versus the pH. Acrylic acid is ionized at high pH and dimethyl aminomethacrylate at low pH.
Hydrogels that respond to pH (and ion concentration, as explained below) contain (co)monomers with
weak acidic or weak basic sidegroups. These sidegroups are ionizable and their charge will be a function of
the pH. Structure examples of pH-dependent monomers and their ionisation behavior. On the left the
ionisation versus pH is shown for the weak acidic monomer acrylic acid (AAc) and on the right this is

shown for the weak basic monomer dimethylamino ethylmethacrylate (DMAEMA). The swelling of a pH-
sensitive hydrogel is the result of the interplay of the pH and the ionic strength of the solution which the
hydrogel is exposed to. The ionizable monomers inside the hydrogel will dissociate as a function of the pH
and the resulting free counterions in the hydrogel exchange with salt ions from The chemical structure of a
hydrogel matrix
36
.
Water has been (a) Backbones of the temperature-sensitive hydrogel in the swollen condition. (b) The
backbones in the aggregated condition.
Inside the hydrogel a certain counter ion concentration will develop, that causes an osmotic pressure
difference to develop between the gel and the solution. Consequently the hydrogel will swell until the
elastic forces inside the hydrogel are in equilibrium with the osmotic force. An important condition in the
swelling of a pH-sensitive charge neutrality inside itself a hydrogel cannot give off an ion to the
surrounding solution without receiving a suitable counterion in return. When a hydrogel with an acidic
comonomer, e.g. polyhydroxy ethylmethacrylate-co-acrylic acid (poly-HEMA-co- AAc), is exposed to
pure water (at pH 7) no osmotic swelling will take place in the gel, although the pH of the solution is
higher than the pKa of the acrylic acid comonomers (the pKa of acrylic acid comonomers is around
37
.
3.1.2.1. pH-sensitive Modified Polyacrylamide Hydrogel:
A pH-sensitive modified polyacrylamide hydrogel was prepared by two steps and the modified
polyacrylamide was characterized by 1HNMR spectrum. The surface morphology and swelling behavior of
the hydrogels were investigated.
Polyacrylamide, hydrogel, pH-sensitive. Intelligent hydrogels which have the capability to respond to small
external stimulus changes, such as temperature, pH, photo field, and antigen, have attracted significant
attention from both academia and industry. pH-sensitive polymers are produced by pendant acidic and
basic functional groups in its backbone, these groups can accept or release protons, responsing to pH
changes of aqueous media. Kumaresh S. Soppimath have previously reported polyacrylamide grafting guar
gum based crosslinked anionic microgels as pH-sensitive drug delivery systems, and some other scientists
also studied the copolymer of acrylamide and acrylic acid as drug device
7
. However, the work on
hydrogels based on hydrolytic polyacrylamide was scarce, in the present work, we prepared the modified
polyacrylamide hydrogel, which exhibited the remarkable hydration-dehydraction change in response to
pH of aqueous media. Modified polyacrylamide was prepared as follows: an amount of partially hydrolytic
polyacrylamide(PAM), purchased from Jiangshu Nantian Flocclants Co. Ltd, with number average weight
5105 and hydrolytic degree 20%, was dissolved in deionized water to make the concentration 5 wt%, a

proportional (1/1 mol/mol) of glycidyl methacrylate (GMA) was added, the solution was heated to 80.
Subsequently, the reaction was allowed to continue for another 15 h at this temperature. After the reaction
completed, the solution was poured into cold isopropyl alcohol (1/2 v/v), then the precipitate of modified
PAM was filtrated and washed by acetone for three times, dried in vacuum desiccator at 60 overnight.
Procedures of preparing modified PAM hydrogels were as follows: Firstly, the modified PAM was
dissolved in double distilled water to obtain a series of water solutions in the concentation range of 2-10 wt
%; Where after, a certain proportion (2 w/w) Ping An Song et al. of potassium persulfate triethanolamine
initiator system was charged into the solutions and the radical polymerization was carried out immediately.
The solutions were placed at room temperature for 24 hours. The hydrogels were immersed in distilled
water for a week to remove unreacted agents and the water was renewed every day. The prepared hydrogel
was dried in vacuum at 80C for about 24 h to obtain extracted xerogel. 1H-NMR spectra of modified
PAM were recorded on a Germany Bruker DRX-400 spectrometer (400 MHz for hydrogen) in D
2
O. The
surfaces morphology of modified polyacrylamide gels was observed with an XL-30 scanning electron
microscope (SEM). Each xerogel was immersed in distilled water at 298 K for studying the dynamic
swelling properties of xerogels. According to Vervoort et al.
8
, the equilibrium swelling ratio (Qeq ) was,
for each case, calculated according to equation (1), md and ms are the weight of xerogels and gels, which
were completely swollen to equilibrium, respectively.
Qeq =m s/ m d
The signals at 6.21 and 5.60 ppm in the 1H-NMR spectrum attributed to the vinyl protons and signal at
1.87 ppm attributed to the methyl protons. These signals confirmed that the modified PAM contained the
methacryloil groups.

Figure 6: SEM micrographs of dry modified PAM gels (a: 6 wt %, b: 10 wt %)
Figure 6 showed the SEM macrographs of two dried modified PAM gels with different concentrations. The
SEM showed that the apertures of gels became smaller with increasing the concentration (from 6 to 10 wt

%). The possible reason was that the increase effective crosslink density due to the increase of
concentration resulted in that the apertures of gels became smaller
39
.
4. Physical, Chemical and Toxicological Properties of Hydrogels:
4.1. Factors Affecting Swelling of Hydrogels:

Figure 7: Swelling of hydrogel
The crosslinking ratio is one of the most important factors that affect the swelling of hydrogels. It is
defined as the ratio of moles of crosslinking agent to the moles of polymer repeating units. The higher the
crosslinking ratio, the more crosslinking agent is incorporated in the hydrogel structure.Highly crosslinked
hydrogels have a tighter structure, and will swell less compared to the same hydrogels with lower
crosslinking ratios. Crosslinking hinders the mobility of the polymer chain, hence lowering the swelling
ratio.
The chemical structure of the polymer may also affect the swelling ratio of the hydrogels. Hydrogels
containing hydrophilic groups swell to a higher degree compared to those containing hydrophobic groups.
Hydrophobic groups collapse in the presence of water, thus minimizing their exposure to the water
molecule. As a result, the hydrogels will swell much less compared to hydrogels containing hydrophilic
groups.
4.2. Dynamics of Swelling:
The swelling kinetics of hydrogels can be classified as diffusion-controlled (Fickian) and relaxation-
controlled (non-Fickian) swelling. When water diffusion into the hydrogel occurs much faster than the
relaxation of the polymer chains, the swelling kinetics is diffusion-controlled. A nice mathematical analysis
of the dynamics of swelling is presented by Peppas and Colombo
40
.
4.3. Mechanical Properties:
Mechanical properties of hydrogels are very important for pharmaceutical applications. For example, the
integrity of the drug delivery device during the lifetime of the application is very important to obtain FDA
approval, unless the device is designed as a biodegradable system. A drug delivery system designed to
protect a sensitive therapeutic agent, such as protein, must maintain its integrity to be able to protect the

protein until it is released out of the system. Changing the degree of crosslinking has been utilized to
achieve the desired mechanical property of the hydrogel.
Increasing the degree of crosslinking of the system will result in a stronger gel. However, a higher degree
of crosslinking creates a more brittle structure. Copolymerization has also been utilized to achieve the
desired mechanical properties of hydrogels.
4.4. Cytotoxicity and in-vivo Toxicity:-
Cell culture methods, also known as cytotoxicity tests, can be used to evaluate the toxicity of hydrogels.
Three common assays to evaluate the toxicity of hydrogels include extract dilution, direct contact and agar
diffusion. Most of the problems with toxicity associated with hydrogel carriers are the unreacted
monomers, oligomers and initiators that leach out during application. Therefore, an understanding the
toxicity of the various monomers used as the building blocks of the hydrogels is very important. The
relationship between chemical structures and the cytotoxicity of acrylate and methacrylate monomers has
been studied extensively
41
.
Several measures have been taken to solve this problem, including modifying the kinetics of
polymerization in order to achieve a higher conversion, and extensive washing of the resulting hydrogel.
The formation of hydrogels without any initiators has been explored to eliminate the problem of the
residual initiator. The most commonly used technique has been gamma irradiation
42, 43, 44
.
Hydrogels of PVA have been also made without the presence of initiators by using thermal cycle to induce
crystallization
45
. The crystals formed act as physical crosslinks. These crystals will be able to absorb the
load applied to the hydrogels.
5. Methods of Preparation:
5.1. Example 1: Preparation of Empty Hydrogel-Isolated Cochleates from Dioleoylphosphatidylserine
Precipitated with Calcium
Step 1: Preparation of Small Unilamellar Vesicles from Dioleoylphosphatidylserine:-
A solution of dioleoyl phosphatidylserine (DOPS, Avanti Polar Lipids, Alabaster, Ala., USA) in
chloroform (10 mg/ml) was placed in a round-bottom flask and dried to a film using a Buchi rotavapor at
35C. The rotavapor was sterilized by flashing nitrogen gas through a 0.2 m filter. The following steps
were carried out in a sterile hood. The dried lipid film was hydrated with de-ionized water at the
concentration of 10 mg lipid/ml. The hydrated suspension was purged and sealed with nitrogen, then
sonicated in a cooled bath sonicator (Laboratory Supplies Corn., Inc.). Sonication was continued (for
several seconds to several minutes depending on lipid quantity and nature) until the suspension became

clear (suspension A) and there were no liposomes apparently visible under a phase contrast microscope
with a 1000 magnification. Laser light scattering (weight analysis, Coulter N4 Plus) indicated that the
mean diameter was 35.749.7 nm.
Step 2: Preparation of Hydrogel-Isolated Cochleates:-
The liposome suspension obtained in step 1 was mixed with 40% w/w dextran-500,000 (Sigma) in a
suspension of 2/1 v/v Dextran/liposome. This mixture was injected with a syringe into 15% w/w PEG-
8,000 (Sigma) (PEG 8000/(suspension A)) under magnetic stirring to result in suspension B. The rate of the
stirring was 800-1,000 rpm. A CaCl
2
solution (100 mM) was added to the suspension to reach the final
concentration of 1 mM.
Stirring was continued for one hour, and then a washing buffer containing 1 mM CaCl
2
and 150 mM NaCl
was added to suspension B at the volumetric ratio of 1:1. The suspension was vortexed and centrifuged at
3000 rpm, 2-4C. for 30 min. After the supernatant was removed, additional washing buffer was added at
the volumetric ratio of 0.5:1, followed by centrifugation under the same conditions. The resultant pellet
was reconstituted with the same buffer to the desired concentration. Laser light scattering (weight analysis,
Coulter N4 Plus) indicates that the mean diameter for the cochleate is 407.285 nm.
5.2. Example 2:- Preparation of Amphotericin B-loaded Hydrogel-Isolated Cochleates Precipitated with
Calcium
Step 1: Preparation of Small Unilamellar AmB-Loaded, Vesicles from Dioleoylphosphatidylserine:-
A mixture of dioleoyl phosphatidylserine (DOPS) in chloroform (10 mg/ml) and AmB in methanol (0.5
mg/ml) at a molar ratio of 10:1 was placed in a round-bottom flask and dried to a film using a Buchi
rotavapor at 40C. The rotavapor was sterilized by flashing nitrogen gas through a 0.2 m filter. The
following steps were carried out in a sterile hood. The dried lipid film was hydrated with de-ionized water
at the concentration of 10 mg lipid/ml. The hydrated suspension was purged and sealed with nitrogen, then
sonicated in a cooled bath sonicator. Sonication was continued (for several seconds to several minutes
depending on lipid quantity and nature) until the suspension became clear yellow (suspension A) and there
were no liposomes apparently visible under a phase contrast microscope with a 1000 magnification.
Step 2: Preparation of AmB-loaded, Hydrogel-Isolated Cochleates:-
The liposome suspension obtained in Step 1 was then mixed with 40% w/w dextran-500,000 in a
suspension of 2/1 v/v Dextran/liposome. This mixture was then injected via a syringe into 15% w/w PEG-
8,000 (PEG 8000/ (suspension A)) under magnetic stirring to result in suspension B. The rate of the stirring

was 800-1,000 rpm. A CaCl
2
solution (100 mM) was added to the suspension to reach the final
concentration of 1 mM.
Stirring was continued for one hour, and then a washing buffer containing 1 mM CaCl
2
and 150 mM NaCl
was added to suspension B at the volumetric ratio of 1:1. The suspension was vortexed and centrifuged at
3000 rpm, 2-4 C. for 30 min. After the supernatant was removed, additional washing buffer was added at
the volumetric ratio of 0.5:1, followed by centrifugation under the same conditions. The resulting pellet
was reconstituted with the same buffer to the desired concentration. Laser light scattering (weight analysis,
Coulter N4 Plus) indicated that the AmB-cochleates mean diameter was 407.3233.8 nm
46
.

6. APPLICATIONS:

6.1 General:
6.1.1. Hydrogel Nanopartiles:
Cross-linked polymer particles in colloidal-size range that response to external environment,
such as pH, temperature, light, ionic strength, osmotic pressure, and solvent composition.
High hydrophilicity and biocompatibility
Response to a variety of external stimuli
Temperature, pH, light, ionic strength, magnetic fields. e.g. Amphiphilic hydrogel nanoparticles.

Figure 8: Hydrogel Exhibit a temperature and concentration-dependent gelation in water which is
interpreted as a colloidal glass formation
47
.
6.1.2. Impact of Ultrasound:
Impact of ultrasound waves on aqueous solution of special group of compounds called sonosensitizers
promotes formation of Reactive Oxygen Species (ROS) which in turn may have lethal effect on living
cells. By applying sonosensitizers exhibiting preferential accumulation in neoplasm tissue and subjecting

such tissue to ultrasound it is potentially possible to fight tumours in a very precise, effective and non-
invasive way.
6.2. Pharmaceutical Applications:
6.2.1. Hydrogel Dressings for Wound Healing:
Hydrogel slides applied for routine healing of different kinds of wounds, mainly burn wounds, trophic
ulcerations, bedsores, etc. Major medical properties include pain soothing, protection against excessive loss
of body fluids, serving as an efficient antiseptic and particle barrier, sterility. Hydrogel dressings are not
antigenic or allergic.
6.2.2. Intervertebral Disc Implants:The aim of the project is to make up an artificial hydrogel based
structure well imitating high tensile properties, durability, elasticity and swelling-reswelling ability of the
real intervertebral disc.
6.2.3. Regulation of Molecular Weight of Chitosan and Other Polysaccharides: Chitosan as well as
other polysaccharides irradiated with electron beam or gamma rays undergo degradation. As a result the
molecular weight of these polymers is decreased, and molecular weight distribution is changed towards the
most probable (Gaussian distribution).
6.2.4. Polymeric Scaffolds for Bone Tissue Reconstruction:
A hybrid material combining the responsive properties of hydrogels with the mechanical properties of a
sturdy ion track membrane can find an application in many separation devices. The combination of a
stimuli-responsive hydrogel with an ion track membrane leads to a stimuli-responsive membrane with
pores able to open/close above a certain threshold temperature.
6.2.5. Sonodynamic Therapy:
The hydrogel rod-shape devices consist of active substances immobilized in polymer network. When inside
the body swelling hydrogel releases active compounds at precisely predefined rate delivering them to the
right place in right amounts. The system has been clinically applied with extraordinary results for healing
the endometrium cancer as well as for inducing childbirth.
6.2.6. Hybrid Organs - Encapsulation of Living Cells:
Tissue engineering techniques generally require the use of porous scaffold, which serves as three
dimensional template for initial cell attachment and subsequent tissue formation both in vitro and in vivo.
The scaffold provides the necessary support for cell to attach, proliferate, and maintain their differentiated
function. Its architecture defines the ultimate shape of the new grown soft or hard tissue. Most promising
materials for such systems are porous composites consisted with biocompatible biodegradable polymers.

6.2.7. Hydrogel Phantoms for Radiation Dosimetry:
Phantom gels based on monomers which are sensitive to very small doses of radiation are used to precisely
assess the spatial distribution of absorbed dose. The gels are of exceptional interest in radiotherapy
dosimetry and their application is intended to improve the process of planning the medical treatment of
patients who suffer from tumours
48
.
6.3. Drug Delivery:
Living cells embedded in the capsule shaped matrix of natural and synthetic semi-permeable membranes
are isolated from the recipient's immune system and allow for exchange of nutritive and secretary
substances. A collection of such structured devices implanted to the recipient's body may play a role of a
hybrid organ, e.g. an endocrine gland. Advanced works on construction of a hybrid pancreas have been
carried out.
6.3.1. Peroral Drug Delivery:
Drug delivery through the oral route has been the most common method in the pharmaceutical applications
of hydrogels. In peroral administration, hydrogels can deliver drugs to four major specific sites; mouth,
stomach, small intestine and colon. By controlling their swelling properties or bioadhesive characteristics
in the presence of a biological, hydrogels can be a useful device for releasing drugs in a controlled manner
at these desired sites. Additionally, they can also adhere to certain specific regions in the oral pathway,
leading to a locally increased drug concentration, and thus, enhancing the drug absorption at the release
site.
6.3.2. Drug Delivery in the Oral Cavity:
Drug delivery to the oral cavity can have versatile applications in local treatment of diseases of the mouth,
such as periodontal disease, stomatitis, fungal and viral infections, and oral cavity cancers. Long-term
adhesion of the drug containing hydrogel against copious salivary flow, which bathes the oral cavity
mucosa, is required to achieve this local drug delivery. For this purpose, many types of bioadhesive
hydrogel systems have been devised since the early 1980s. Some of these are already on the market. For
example, a bioadhesive tablet developed by Nagai et al. is commercially available under the brand name
Aftach
49
.

This product is composed of a double layer, with a bioadhesive layer made of hydroxypropyl
cellulose and poly (acrylic acid) and a lactose non-adhesive backing layer. It is a local delivery system of
triamcinolone acetonide for the treatment of aphthous ulcers.
A hydrogel-based ointment can also be utilized for the topical treatment of certain diseases in the oral
cavity. It can be used not only as a drug delivery device, but also as a liposome delivery vehicle. The

possible advantage of liposome delivery with this ointment is that the use of liposomal formulations with
encapsulated drug can lead to an increase of local, and a decrease of systemic, drug concentration, because
of the encapsulation of drugs with phospholipids. This may provide more desirable properties for topical
use, such as reduction of uncontrolled release of drugs into the blood circulation and certain undesirable
side effects, compared with the conventional ointment-drug formulations.
Petelin et al. investigated the pharmaceutical performance of three different hydrogel-based ointments as
possible vehicles for liposome delivery into the oral cavity tissues by electron paramagnetic resonance
(EPR).
The oral cavity can also provide a useful location as a transport route for heavily metabolized drugs, since
the drugs absorbed from this route bypass first-pass hepatic metabolism. Kitano et al. proposed a hydrogel
ointment containing absorption enhancers for the buccal delivery of 17 b-estradiol (E2) to treat
osteoporosis. It is well known that the oral administration of E2 results in very low availability due to its
high first-pass effect. Ethanol solution containing E2, and glyceryl monolaurate as an absorption enhancer,
and an aqueous solution of a commercial carboxyvinyl polymer and triethanolamine were mixed together
to produce the hydrogel ointment. In-vivo studies using hamsters demonstrated that the buccal
administration of E2 with this formulation allowed the maintenance of the E2 plasma level at over 300
change of buccal membrane was observed 7 h after application
51
.
Remunan-Lopez et al. reported new buccal bilayered tablets containing nifedipine and propranolol
hydrochloride intended for systemic drug administration. The tablets, comprising two layers, a drug-
containing mucoadhesive layer of chitosan with polycarbophil and a backing layer of ethylcellulose, were
obtained by direct compression. The double-layered structure design provided a unidirectional drug
delivery towards the mucosa, and avoided a loss of drug resulting from wash-out with saliva flow. The
striking feature of this device would be the utilization of an in-situ crosslinking reaction between cationic
chitosan and anionic polycarbophil, which progressed upon penetration of the aqueous medium into the
tablet. As a result of the crosslinking effect, the tablets showed controlled swelling and prolonged drug
release, and an adequate adhesiveness could be obtained
52
.
6.3.3. Drug Delivery in the GI Tract:
The GI tract is unquestionably the most popular route of drug delivery because of the facility of
administration of drugs for compliant therapy, and its large surface area for systemic absorption. It is,
however, the most complex route, so that versatile approaches are needed to deliver drugs for effective
therapy.

Like buccal delivery, hydrogel-based devices can be designed to deliver drugs locally to the specific sites
in the GI tract. For example, Patel and Amiji proposed stomach-specific antibiotic drug delivery systems
for the treatment of Helicobacter pylori infection in peptic ulcer disease. For localized antibiotic delivery in
the acidic environment of the stomach, they developed cationic hydrogels with pH-sensitive swelling and
drug release properties. The hydrogels were composed of freeze-dried chitosanpoly (ethylene oxide)
(PEO) IPN. pH-dependent swelling properties and the release of two common antibiotics, amoxicillin and
metronidazole, entrapped in the chitosanPEO semi- IPN were evaluated in enzyme-free simulated gastric
fluid (SGF; pH 1.2) and simulated intestinal fluid (SIF; pH 7.2). The swelling ratio of the hydrogels after 1
h in SGF wasfound to be 16.1, while that in SIF was only 8.60. Additionally, the freeze-dried
chitosanPEO semi-IPN demonstrated fast release of the entrapped antibiotics in SGF because of its highly
porous matrix structure resulting from freezedrying. More than 65 and 59% of the entrapped amoxicillin
and metronidazole, respectively were released from the hydrogels after 2 h in SGF. The rapid swelling and
drugrelease demonstrated by these hydrogel formulations may be beneficial for site-specific antibiotic
delivery in the stomach, because of the limitations of the gastric emptying time
53, 54
.
Amiji et al. also reported enzymatically degradable gelatinPEO semi-IPN with pH-sensitive swelling
properties for oral drug delivery. In this case, the incorporation of gelatin in the IPN made it possible to
swell in the acidic pH of the gastric fluid, due to the ionization of the basic amino acid residues of gelatin.
The IPN was found to be degraded by proteolytic enzymes, such as pepsin and pancreatin.
Undoubtedly, peroral delivery of peptides and proteins to the GI tract is one of the most challenging issues,
and thus, under much investigation. However, there are many hurdles, including protein inactivation by
digestive enzymes in the GI tract, and poor epithelial permeability of these drugs. However, certain
hydrogels may overcome some of these problems by appropriate molecular design or formulation
approaches. For example, Akiyama et al. reported novel peroral dosage forms of hydrogel formulations
with protease inhibitor activities using Carbopol (CP934), a poly(acrylic acid) product, which has been
shown to have an inhibitory effect on the hydrolytic activity of trypsin, and its neutralized freeze-dried
modification (FNaCP934). They demonstrated that two-phase formulations, consisting of the rapid gel-
forming FNaC934P and the efficient enzyme-inhibiting, but more slowly swelling, C934P, had the most
profound effect on trypsin activity inhibition
55
.
Recently, oral insulin delivery using pH-responsive complexation hydrogels was reported by Lowman et
al. The hydrogels used to protect the insulin in the harsh, acidic environment of the stomach before
releasing the drug in the small intestine were crosslinked copolymers of PMAA with graft chains of

polyethylene glycol (P(MAAg- EG)). The insulin-containing P (MAA-g-EG) microparticles demonstrated
strong dose-dependent hypoglycemic effects in in-vivo oral administration studies using both healthy and
diabetic rats. The blood glucose levels in these animals were decreased significantly for at least 8mg/ml
due to the absorption of insulin in the GI tract. It is worth noting that these effects were observed without
the addition of additives, such as absorption enhancers or protease inhibitors.
Due to a lower proteolytic activity in comparison to that in the small intestine, the colonic region has also
been considered as a possible absorption site for orally administered peptides and proteins. Several
hydrogels are currently being investigated as potential devices for colon-specific drug delivery. These
include chemically or physically crosslinked polysaccharides, such as dextran, amidated pectin, guar gum,
and inulin and azocross-linked poly(acrylic acid). They are designed to be highly swollen or degraded in
the presence of colonic enzymes or microflora, providing colon-specificity in drug delivery
56
.
6.3.4. Rectal Delivery:
The rectal route has been used to deliver many types of drugs, although patient acceptability is variable
due to the discomfort arising from administered dosage forms. Its primary applications have been for local
treatment of diseases associated with the rectum, such as hemorrhoids. Additionally, it is well known that
drugs absorbed from the lower part of the rectum drain into the systemic circulation directly. Thus, the
rectal route is a useful administration route for drugs suffering heavy first-pass metabolism. Conventional
suppositories hitherto adapted as dosage forms for rectal administration are solids at room temperature, and
melt or soften at body temperature. A problem associated with rectal administration using conventional
suppositories is that drugs diffusing out of the suppositories in an uncontrolled manner are unable to be
sufficiently retained at a specific position in the rectum, and sometimes migrate upwards to the colon. This
often leads to a variation of the bioavailability of certain drugs, in particular, for drugs that undergo
extensive first-pass elimination.
In this context, hydrogels may offer a valuable way to overcome the problem in conventional suppositories,
provided that they are designed to exhibit a sufficient bioadhesive property following their rectal
administration. For example, Ryu et al. reported that increased bioavailability of propranolol subject to
extensive first-pass metabolism was observed by adding certain mucoadhesive polymeric compounds to
poloxamer-based thermally gelling suppositories. Among the mucoadhesive polymeric compounds tested,
polycarbophil and sodium alginate provided the largest mucoadhesive force and the smallest intrarectal
migration to the suppositories, resulting in the largest bioavailability of propranolol (82.3 and 84.7%,
respectively).
57


Miyazaki et al. investigated the potential application of xyloglucan gels with a thermal gelling property as
vehicles for rectal drug delivery. Xyloglucan processed by the researchers has the sol-gel transition
temperature of around 2227C, and thus, it can be a gel at body temperature; on the other hand, it can be
easily administered since it can behave as a liquid at room temperature. In-vivo rectal administration of
xyloglucan gels containing indomethacin using rabbits showed a wellcontrolled drug plasma concentration-
time profile without reduced bioavailability, when compared to commercial indomethacin suppositories
58
.
Watanabe et al. reported that avoiding rectal irritation caused by vehicles is another important issue in
rectal drug delivery. Both Ryu's and Miyazaki's products, described above, revealed no evidence of
mucosal irritation after rectal administration. A significantly reduced irritation by rectal hydrogels prepared
with water-soluble dietary fibers, xanthan gum and locust bean gum
59
.
6.3.5. Ocular Delivery:
In ocular drug delivery, many physiological constraints prevent a successful drug delivery to the eye due to
its protective mechanisms, such as effective tear drainage, blinking and low permeability of the cornea.
Thus, conventional eye drops containing a drug solution tend to be eliminated rapidly from the eye, and the
drugs administered exhibit limited absorption, leading to poor ophthalmic bioavailability. Additionally,
their short-term retention often results in a frequent dosing regimen to achieve the therapeutic efficacy for a
sufficiently long duration. These challenges have motivated researchers to develop drug delivery systems
that provide a prolonged ocular residence time of drugs.
Cohen et al. developed an in-situ-gelling system of alginate with high guluronic acid contents for the
ophthalmic delivery of pilocarpine. This system significantly extended the duration of the pressure-
reducing effect of pilocarpine to 10 h, compared to 3 h when pilocarpine nitrate was dosed as a solution.
60

Chetoni et al. reported silicone rubber hydrogel composite ophthalmic inserts. Poly (acrylic acid) or poly
(MAA) IPN was grafted on the surface of the inserts to achieve a mucoadhesive property. The ocular
retention of IPN-grafted inserts was significantly higher with respect to ungrafted ones. An in-vivo study
using rabbits showed a prolonged release of oxytetracycline from the inserts for several days.
62

6.3.6. Transdermal Delivery:
Drug delivery to the skin has been traditionally conducted for topical use of dermatological drugs to treat
skin diseases, or for disinfection of the skin itself. In recent years, a transdermal route has been considered
as a possible site for the systemic delivery of drugs. The possible benefits of transdermal drug delivery
include that drugs can be delivered for a long duration at a constant rate, that drug delivery can be easily
interrupted on demand by simply removing the devices, and that drugs can bypass hepatic first-pass

metabolism. Furthermore, because of their high water content, swollen hydrogels can provide a better
feeling for the skin in comparison to conventional ointments and patches. Versatile hydrogel-based devices
for transdermal delivery have been proposed so far. Sun et al. devised composite membranes comprising of
crosslinked PHEMA with a nonwoven polyester support. Depending on the preparation conditions, the
composite membranes can be tailored to give a permeation flux ranging from 4 to 68 mg/cm
2
per hr for
nitroglycerin
63
. Comprehensive studies on in-situ photopolymerizable hydrogels 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 have been carried out by Hubbell
66
.
6.3.7. Subcutaneous Delivery:
As described through Sections, hydrogels posses a wide variety of possible pharmaceutical applications.
Among them, their substantial application may be found in implantable therapeutics. Subcutaneously
inserted exogenous materials may more or less evoke potentially undesirable body responses, such as
inflammation, carcinogenicity and immunogenecity.
Therefore, biocompatibility is a prerequisite that makes materials implantable. Due to their high water
content, hydrogels are generally considered as biocompatible materials.
They also provide several promising properties:
(1) Minimal mechanical irritation upon in-vivo implantation, due to their soft, elastic properties;
(2) Prevention of protein adsorption and cell adhesion arising from the low interfacial tension between
water and hydrogels;
(3) Broad acceptability for individual drugs with different hydrophilicities and molecular sizes;
(4) Unique possibilities (crosslinking density and swelling) to manipulate the release of incorporated
drugs.Some of these may offer an advantage for the delivery of certain delicate drugs, such as peptides and
proteins
67
.
Giammona et al. developed new hydrogels originating from the chemical reticulation of a,b-
polyasparthydrazide (PAHy) by glutaraldehyde. PAHy is a new watersoluble macromolecule, synthesized
from a polysuccinimide by reaction with hydrazine. Histological analysis revealed that this hydrogel was
inert when implanted subcutaneously into rats
68
.
Several hydrogel formulations for the subcutaneous delivery of anticancer drugs have been also proposed.
For example, crosslinked PHEMA with good biocompatibility was applied to cystabine (Ara-C) and
methotrexate. Poly (AAm-co-monomethyl or monopropyl itaconate) developed by Blanco's group was
employed for the controlled release of Ara-C and 5-fuorouracil
69, 70
.

Current studies on implantable hydrogels have been directed towards the development of biodegradable
systems requiring no follow-up surgical removal once the drug supply is depleted. A bioerodible hydrogel
based on a semi-IPN structure composed of a poly (1-caprolactone) and PEG macromer terminated with
acrylate groups was devised by Cho et al
71
. Long-term constant release over 45 days of clonazepam
entrapped in the semi-IPN was achieved in vivo. Recently, two types of novel degradable PEG hydrogels
for the controlled release of proteins were developed by Zhao and Harris
72
. One type is prepared by a
polycondensation reaction between difunctional PEG acids and branched PEG polyols. Upon hydrolysis of
the resulting ester linkages, these gels degrade into only PEG and PEG derivatives. The other is PEG-based
hydrogels having functional groups in which protein drugs can be covalently attached to the gel network
via ester linkage. Thus, the release of the protein drugs immobilized would be controlled by the hydrolysis
of the ester linkage between the gel and the protein, followed by the diffusion of the protein out of the gel,
and by the degradation of the gel. Extensive research efforts on degradable dextran hydrogels have been
carried out by Hennink and his coworkers. These hydrogels are based on acrylate derivatives of dextran. In
their studies, the application of the hydrogels to the controlled release of protein was thoroughly investi-
gated. Biodegradable crosslinked dextran hydrogels containing PEG (PEG-Dex) was reported by
Moriyama and Yui. Insulin release from these hydrogels was regulated by the surface degradation of PEG-
Dex microdomain structured.
7. MARKET PRODUCTS:
7.1. Tegagel Gel
7.2. Intrasite Gel
7.3. Nu-Gel Wound
7.4. Solosite Pump
7.5. Solosite Tube
8. CONCLUSION:
Hydrogels can be seen as optimised tools for facing various medicinal & pharmaceutical problems by
producing sustained & prolonged effects with diminished side effects. Various hydrogels prepared are able
to produce the desired & required sustained effects. In case of opthalmic drug delivery, elastic property of
hydrogels provides a reduction in lacrimal drainage.
Trasdermal preparations used to produce a constant preparation of a flux into skin for a longer period of
time. The super absorbent property of hydrogels helps in absorbing urine for the diapers of the children.
Thus, hydrogels provides various advantages in this changing educational &scientific world.

9. FUTURE PROSPECTS:
Recent research trends in transdermal applications are focusing on electrically-assisted delivery, using
iontophoresis and electroporation. Several hydrogel-based formulations are being investigated as vehicles
for transdermal iontophoresis to obtain the enhanced permeation of luteinizing hormone releasing
hormone, sodium nonivamide acetate, nicotine and enoxacin. On the other hand, a methyl cellulose-based
hydrogel was used as a viscous ultrasonic coupling medium for transdermal sonophoresis assisted with an
AC current, resulting in an enhanced permeation of insulin and vasopressin across human skin in vitro.
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