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406 | P a g e International Standard Serial Number (ISSN): 2319-8141

Full Text Available On www.ijupbs.com

I nternational Journal of Uni versal Pharmacy and Bio Sciences 3(2): March-Apr il 2014

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCESIMPACT 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

MSS’College of Pharmacy Medha, Tal-Jaoli, Dist – Satara, India.

YSPM’S, YTC, Faculty of Pharmacy, Satara, India.

KEYWORDS:

Hydrogels, Polymerization.Flexibility, Polymer

Matrix, Optimized Tools.

For Correspondence:

Ganesh Bamane*

Address:

MSS’College of

Pharmacy Medha, Tal-

Jaoli, Dist – Satara, India.

Email Id: [email protected]

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.

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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 -CH2-CH2-CH2-CH2-

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

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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 arefilled 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 ~32ºC. 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

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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 ºC, pH 7 – 7.5 andan 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).

http://en.wikipedia.org/wiki/Biosensor

http://en.wikipedia.org/wiki/Contact_lens

http://en.wikipedia.org/wiki/Silicone

http://en.wikipedia.org/wiki/Polyacrylamide

http://en.wikipedia.org/wiki/Polyacrylamide

http://en.wikipedia.org/wiki/Silicone

http://en.wikipedia.org/wiki/Contact_lens

http://en.wikipedia.org/wiki/Biosensor

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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 (τr), these

materials behave like liquids: at low frequencies (ωx<1/τr), the loss modulus (G″) exceeds G′. This solid -

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to-liquid transition is called network stress relaxation, which is believed to be controlled by the dynamics

of the molecular motions of polymer chains.

Annable’s 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, makingintermeshing 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.

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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.

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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 -alky

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. Thiscauses 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.

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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

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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 acidiccomonomer, 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

5×105 and hydrolytic degree 20%, was dissolved in deionized water to make the concentration 5 wt%, a

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%). 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 crossli nking 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 hydrophilicgroups.

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

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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

crystallization45. 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

35°C. The rotavapor was sterilized by flashing nitrogen gas through a 0.2 μm 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

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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 35.7±49.7 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 CaCl2 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 CaCl2 and 150 mM NaC

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 atthe 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 407.2±85 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 (0.5mg/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 40°C. The rotavapor was sterilized by flashing nitrogen gas through a 0.2 μm 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

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was 800-1,000 rpm. A CaCl2 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 CaCl2 and 150 mM NaC

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 407.3±233.8 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

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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 asother 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.

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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

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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 itshigh 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.

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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 chitosan±poly (ethylene oxide)

(PEO) IPN. pH-dependent swelling properties and the release of two common antibiotics, amoxicillin and

metronidazole, entrapped in the chitosan±PEO 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

chitosan±PEO 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 anddrugrelease 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 gelatin±PEO 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

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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 22±27°C, 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 toits 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

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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 hydroge

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 Harris72. 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 beencarried 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.

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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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