In-situ Gels and Hydrogels

Introduction
:
Hydrogels are crosslinked polymer networks that absorb
substantial amounts of aqueous solutions.
These crosslinks provide the network structure and
physical integrity.
Hydrogels can contain over 99.9% water.
The high water content of the materials contributes to
their biocompatibility.
2

What is a Hydrogel?
Three-dimensional networks of hydrophilic
polymer chains that do not dissolve but
can swell in water.
Cross-links produced through:
Chemical reaction to form covalent bonds
Entanglement of polymers
Hydrogen bonding and van der Walls forces

Properties
Both solid like and liquid like properties
high biocompatibility
Environmental stimuli respondent
(temperature, pH, light, specific molecules)

Ideal for controlled drug delivery

Advantages Of Hydrogels
Adaptable targeting system, allowing great
flexibility for many different drugs.
Offers more accurate drug placement.
Creating a more precise response and fewer
side effects.
Non-toxic and biocompatible, raising the level
of bio-safety for the patient.
Absence of Phagocytosis by macrophages.

Advantages of Hydrogels
Environment can protect cells and other substances (i.e.
drugs, proteins, and peptides)
Timed release of growth factors and other nutrients to
ensure proper tissue growth
Good transport properties
Biocompatible
Can be injected
Easy to modify

Disadvantages of Hydrogels
Low mechanical strength
Hard to handle
Difficult to load
Sterilization

 Because of these qualities it

gained different names like
intelligent gels or smart
hydrogels. The smartness of any
material is the key to its ability to
receive, transmit or process a
stimulus, and respond by
producing a useful effect.

Hydrogels are smart or intelligent

in the sense that they can recognize
the predominant stimuli and respond
by displaying changes in their
physical or chemical behavior,
resulting in the release of entrapped
drug in a controlled manner.

 Some hydrogels undergo continuous

or discontinuous changes in swelling
that are mediated by external stimuli
such as changes in pH, temperature,
ionic strength, solvent type, electric
and magnetic elds, light, and the
presence of chelating species.

10

Hydrogel : Swellable Polymeric Materials

Hydrogels are three dimensional networks of
hydrophilic polymers.
Extremely absorbent and possess a degree of flexibility
very similar to natural tissue .
Drug encapsulated in a hydrogel matrix is only released
after contact with organ-or tumor-specific molecules
(e.g. surface proteins).

 The majority of stimuli responsive

hydrogels were created using conventional
(traditional) methods of synthesis of a
relatively small number of synthetic
polymers, especially (meth) acrylate
derivatives and their copolymers.

12

Classication
- various criteria for the classification of hydrogels

Origin

Natural
Synthetic

Water content or degree

of swelling

Low swelling
Medium swelling
High swelling
Superabsorbent

Porosity

Nonporous
Microporous
Macroporous
Superporous

Cross-linking

Chemical (covalent bonding)

Physical (noncovalent bonding)

Biodegradability

Biodegradable
Nondegradable

Classication Of
Hydrogels:

14

Types of Hydrogel Polymers

Natural Polymers
Dextran, Chitosan, Collagen, Dextran
Sulfate
Advantages

Generally have high biocompatibility

Intrinsic cellular interactions
Biodegradable
Cell controlled degradability
Low toxicity byproducts

Disadvantages

Mechanical Strength
Batch variation
Animal derived materials may pass on viruses

Types of Hydrogel Polymers

Synthetic Polymers

PEG-PLA-PEG, Poly (vinyl alcohol)

Advantages

Precise control and mass produced

Can be tailored to give a wide range of properties (can
be designed to meet specific needs)
Low immunogenecity
Minimize risk of biological pathogens or contaminants

Disadvantages

Low biodegradability
Can include toxic substances

Combination of natural and synthetic

Collagen-acrylate, P (PEG-co-peptides)

Properties of Hydrogels
Swelling properties influenced by
changes in the environment
pH, temperature, ionic strength, solvent
composition, pressure, and electrical
potential

Can be biodegradable, bioerodible, and

bioabsorbable
Can degrade in controlled fashion

Properties of Hydrogels
Pore Size
Fabrication techniques
Shape and surface/volume ratio
H2O content
Strength
Swelling activation

Properties and Structures of Hydrogels

Swelling property is influenced by:
type and composition of monomers
other environmental factors such as :
temperature, pH, ionic strength
cross-linking
Mechanical

Rs = (Ws-Wd) / Wd

strength and
permeability

Rs = swelling ratio
Ws = weight of swollen
hydrogels
W = weight of dried hydrogels
Cross-linking and/ord copolymerization with hydrophobic comonomers

ensity, mechanical strength, swelling property

How theyre made.

Can cross link polymers via:

Heat
Pressure
Chemical reaction
Photopolymeriziation
Use light UV, visible
Radiation
Electron beams
Gama rays
X-rays

How theyre made.

Radical chain reaction used to form
cross links
Crosslinkers
Acrylate, double bond forms radical

Hydrogel Fabrication
Chemical
hydrogels
Covalently
crosslinked

Physical
hydrogels
Noncovalently
crosslinked
Hydrogen bonding
hydrophobic
interaction
crystallinity
stereocomplex
formation

Thermoset
hydrogels
Volume phase
transition
Reliable shape stability
and memory

Thermoplastic
hydrogels
ionic complexation
Sol-gel phase
transition
Limited shape stability
and memory

Hydrogel Fabrication
Physical crosslinking
Cross-linking without
chemical reaction
ionic interaction,
hydrogen bonding,
antigen-antibody
interaction,
supramolecular
Ionic hydrogel
association

Chemical and Physical

crosslinking

Hydrogel Fabrication
Chemical crosslinking
Polymerization of water soluble monomers in the presence
of bi- or multifunctional cross-linking agent
+

Copolymerizati
on
MonomeCrosslinke
r
r
or

Polymerizatio
n
Vinyl group-containing water-soluble
polymers

Hydrogel
network

Applications of Hydrogels in Drug Delivery

- Benets of controlled drug delivery

more effective therapies with reduced side effects
the maintenance of effective drug concentration
levels in the blood
patients convenience as medicines hence increased
patient compliance

- Release mechanisms of drug molecules

: diffusion, dissolution, osmosis, ion
exchange

Applications of Hydrogels in Drug

Delivery

Environment-Sensitive Hydrogels

respond to environmental change

: temperature, pH, specific molecule
reversible volume phase transition or sol-gel phase
transition
intelligent or smart hydrogel
Change in pH
for gel swelling

Drug release
through the swollen
network

Drug-loaded gel
Change in temperature
for gel collapse

Drug release by
the squeezing
action

ydrogel can be delivered by any of the following rou

27

Applications of Hydrogels
Soft contact lenses
Pills/capsules
Bioadhesive carriers
Implant coatings
Transdermal drug delivery
Electrophoresis gels
Wound healing
Chromatographic packaging material

Applications of Hydrogels in Drug

Delivery
- Benets of controlled drug delivery

more effective therapies with reduced side effects

the maintenance of effective drug concentration

levels in the blood

patients convenience as medicines hence increased

patient compliance

- Release mechanisms of drug molecules

: diffusion, dissolution, osmosis, ion
exchange

Applications of Hydrogels in Drug Delivery

- Diffusion controlled Drug Delivery
(1) Polymer matrix

Water-insoluble
Polymer matrices

time

(2) Reservoir system

Water-insoluble
Polymer membrane

time

Applications of Hydrogels in Drug Delivery

Environment-Sensitive Hydrogels
respond to environmental change
: temperature, pH, specific molecule
reversible volume phase transition or sol-gel phase
transition
intelligent or smart hydrogel
Change in pH
for gel swelling

Drug release
through the swollen
network

Drug-loaded gel
Change in temperature
for gel collapse

Drug release by
the squeezing
action

Uses
Biomaterial, coatings for medical devices,
contact lenses
Biologically compatible

Drug delivery
Degradable, swelling properties

Many other biological applications

Develop human tissues

Food- Jello

Basic difference in gel and hydrogel

Both gels and hydrogels might be similar
chemically, but they are physically distinct.
D. Jordan suitably described gels as The
colloidal condition, the gel, is one which is
easier to recognize than to dene
Technically, gels are semi-solid systems
comprising small amounts of solid,
dispersed in relatively large amounts of
liquid, having more solid-like than liquidlike character. Sometimes, hydrogels are
also described as aqueous gels because of
33
the prex hydro.

 Although the term hydrogel implies a

material already swollen in water, while in a
true sense hydrogel is a cross-linked network
of hydrophilic polymers. They possess the
ability to absorb large amounts of water and
swell, while maintaining their threedimensional (3D) structure.

34

 hydrogels display swelling in

aqueous media for the same
reasons that an analogous linear
polymer dissolves in water to form
an ordinary polymer solution. Thus,
the feature central to the
functioning of a hydrogel is its
inherent cross-linking.
Conventional gels can also develop
small levels of cross-links as a result
of a gain in energy under the
influence of shear forces, but these
35

 Because of the above quality

hydrogels is a polymer network,
these polymers produce systems
that extend a range of rigidities,
beginning with a sol and increasing
to jelly, gel and hydrogel. Thus,
hydrogel, sometimes referred to as
xerogel, is a more rigid form of gel

36

nvironmental-Sensitive Hydrogels used for Drug Delivery

Environmental
Factor
Temperature

Typical polymers

Main Mechanism

Applications

PNIPAAm, PDEAAm, PEO-PPO

block copolymers

Competition between hydrophobic

interaction and hydrogen bonding

On/off drug release,

squeezing device

Polyelectrolytes, PAA, PDEAEM

Ionization of polymer chains upon

pH change

pH-dependent oral drug

delivery

pH-sensitive hydrogels;
Concanavalin A-grafted polymers;
polymers containing phenylborate
groups

pH change caused by glucose

oxidase; reversible interaction
between glucose-containing
polymers and Concanavalin A;
reversible solgel transformation

Self-regulated insulin
delivery

Polyelectrolytes (pH-sensitive)

Reversible swelling or deswelling

in the presence of electric field

Actuator, artificial muscle,

on off drug release

Light

Copolymer of PNIPAAm and light

sensitive chromophore, such as
triphenylmethane and leuco
derivatives

Temperature change via the

incorporated photosensitive
molecules; dissociation into ion
pairs by UV irradiation

Optical switches,
ophthalmic drug delivery

Antigen

Semi-IPN with grafted antibodies

or antigens

Competition between polymergrafted antigen and free antigen

Modulated drug release in

the presence of a specific
antigen; sensor for
immunoassay and antigen

pH
Glucose

Electric signal

Specic applications of Hydrogels in Oral Drug Delivery

Summary
Hydrogels have played role in the development
of various controlled-release formulation
biocompatible and increasing the solubility of
poorly soluble drug
Hydrogels with novel properties will continue to
play important role in drug delivery
smart hydrogels and new controlled-release
formulation

In Situ Gel
It is a drug delivery system which is in a

solution form before the administration in the

body but it converts in to a gel form after the
administration.
There are various routes such as oral, ocular,

vaginal, rectal, I/V , intraperitoneal etc

40

Advantages
Ease of administration
Improved local bioavailability
Reduced dose concentration
Reduced dosing frequency
Improved patient compliance and comfort
Simple formulation and manufacturing so less

investment and
cost

41

There are various factors such as

Temp. modulation,
pH change,
presence of ions,
UV irradiation,
solvent exchange and from which drug release

in a sustained manner
Various biodegradable polymers used
are:
Gellan gum Poloxamer Pectin Chitosan
Poly(DL lactic acid) Poly(DL lactide-coglycolide) Poly-caprolactone Alginic acid
Xyloglucan
42

APPROACHES OF IN SITU GEL DRUG

DELIVERY
There are certain broadly dened

mechanisms used for triggering the in situ gel

formation of biomaterials:
Physiological stimuli (e.g., temperature and
pH),
Physical mechnism-changes in
biomaterials (e.g., swelling and solvent
exchange-Diffusion ),
Chemical reactions (e.g. ionic, enzymatic,
and photo-initiated polymerization)
43

In situ formation based on

Physiological stimuli
Thermally triggered systems
Temperature-sensitive hydrogels are probably the most

commonly studied class of environment sensitive polymer

systems in drug delivery research. The use of biomaterial
whose transitions from sol-gel is triggered by increase in
temperature, is an attractive way to approach in-situ
formation. The ideal critical temperature range for such
system is ambient and physiologic temperature, such that
clinical manipulation is facilitated and no external source of
heat other than that of body is required for triggering
gelation. A useful system should be tailorable to account for
small differences in local temperature, such as might be
encountered in appendages at the surface of skin or in the
oral cavity
They are classied into Positively thermosensitive
Negatively thermosensitive Thermally reversible gels

44

Positively thermosensitive
A positive temp sensitive hydrogel is having upper

critical solution temperature(UCST), such hydrogels

contracts upon cooling below this UCST Ex.
Poly(acrylic acid)(PAA), Poly(acrylamide) (PAAm),
Poly(acrylamideco- butyl methacrylate).

Negatively thermosensitive
It has lower critical solution temperature(LCST),
contracts upon heating above LCST
Ex. poly(N-isopropylacrylamide) (PNIPAAm)
PNIPAAm is a water soluble polymer at its low LCST,
but hydrophobic above LCST, which result on
precipitation of PNIPAAm from the solution at the LCST.
45

Mostly used Thermo reversible gels

are prepared from Pluronics

andTetronics
Pluronics are poly (ethylene oxide)-poly

(propylene oxide)-poly (ethylene oxide) (PEOPPOPEO) triblock co-polymer that are fluid at
low temperature, but forms thermo responsible
gel when heated as a consequences of a
disorder-order transition in micelle packing
which makes these polymers suitable for in situ
gelation.

46

pH triggered systems
All the pH-sensitive polymers contain pendant acidic or

basic groups that either accept or release protons in

response to changes in environmental pH .
The polymers with a large number of ionizable
groups are known as polyelectrolytes.
Swelling of hydrogel increases as the external pH
increases in the case of weakly acidic (anionic)
groups, but decreases if polymer contains weakly
basic (cationic) groups
The most of anionic pH-sensitive polymers are based on
PAA,Carbopol- carbomer or its derivative Likewise
polyvinyl acetal diethylaminoacetate (AEA) solutions with
a low viscosity at pH 4 form hydrogel at neutral pH
condition
Another ex. Are PMMA, PEG, CAP latex, Pseudolatex etc..47

IN SITU FORMATION BASED

ON PHYSICAL MECHANISM
Swelling
In situ formation may also occur when material absorbs

water from surrounding environment and expand to

cover desired space. One such substance is Myverol 1899 (glycerol monooleate), which is polar lipid that swells
in water to form lyotropic liquid crystalline phase
structures. It has some Bioadhesive properties and can
be degraded invivo by enzymatic action.
Solvent exchange-Diffusion
This method involves the diffusion of solvent from
polymer solution into surrounding tissue and results in
precipitation or solidication of polymer matrix. Nmethyl pyrrolidone (NMP) has been shown to be useful
solvent for such system.
48

IN SITU FORMATION BASED

ON CHEMICAL REACTIONS
Following chemical reaction

cause gelation
Ionic crosslinking
Enzymatic cross-linking
Photo-polymerization

49

Ionic crosslinking
Polymers may undergo phase transition in presence of

various ions. Some of the polysaccharides fall into the

class of ion-sensitive ones.
While K-carrageenan forms rigid, brittle gels in reply of
small amount of K +, i-carrageenan forms elastic gels
mainly in the presence of Ca2+.
Gellan gum commercially available as Gelrite is an
anionic polysaccharide that undergoes in situ gelling in
the presence of mono- and divalent cations, including
Ca2+, Mg2+, K+ and Na+.
Gelation of the low-methoxy pectins can be caused by
divalent cations, especially Ca2+. Likewise, alginic acid
undergoes gelation in presence of divalent/polyvalent
cations e. g. Ca 2+due to the interaction with guluronic
acid block in alginate chain
50

Enzymatic cross-linking
In situ formation catalysed by natural enzymes has not

been investigated widely but seems to have some

advantages over chemical and photochemical approaches.
For example, an enzymatic process operates efficiently
under physiologic conditions without need for potentially
harmful chemicals such as monomers and initiators.
Intelligent stimuli-responsive delivery systems using
hydrogels that can release insulin have been investigated.
Cationic pH-sensitive polymers containing
immobilized insulin and glucose oxidase can swell in
response to blood glucose level releasing the
entrapped insulin in a pulsatile fashion.
Adjusting the amount of enzyme also provides a
convenient mechanism for controlling the rate of gel
formation, which allows the mixtures to be injected before
gel formation.
51

PHOTO-POLYMERIZATION
Photo-polymerization is commonly used for in situ

formation of biomaterials.
A solution of monomers or reactive macromer and
initiator can be injected into a tissues site and the
application of electromagnetic radiation used to
form gel
Acrylate or similar polymerizable functional
groups are typically used as the polymerizable
groups on the individual monomers and macromers
because they rapidly undergo photo-polymerisation
in the presence of suitable photoinitiator (2,2
dimethoxy-2-phenylacetophenone, is often
used as the initiator for ultraviolet photopolymerization, where as camphorquinone
and ethyl eosin initiators are often used in
52

PHOTOPOLYMERIZATION
Typically long wavelength ultraviolet and visible

wavelengths are used

Short wavelength ultraviolet is not used often
because it has limited penetration of tissue and
biologically harmful
Photopolymerizable systems when introduced to the
desired site via injection get photocured in situ with
the help of ber optic cables and then release the
drug for prolonged period of time.
The photo-reactions provide rapid polymerization
rates at physiological temperature. Furthermore, the
systems are easily placed in complex shaped volumes
leading to an implant formation.
53

Polymers used in In situ drug

delivery

Gellan gum
Poloxamer
Pectin
Chitosan
Poly(DL lactic acid)
Poly(DL lactide-co-glycolide)
Poly-caprolactone
Alginic acid
Xyloglucan

54

Synthetic polymers
Synthetic polymers are popular choice

mainly for parenteral preparations.

The trend in drug delivery technology has been
towards biodegradable polymers such as poly
(lactic acid), poly (glycolic acid), poly (lactidecoglycolide), poly (decalactone), poly caprolactone have been the subject of the most
extensive recent investigations
The feasibility of lactide/glycolide polymers as
excipients for the controlled release of bioactive
agents is well proven.
These materials have been subjected to extensive
animal and human trials without evidence of any
harmful side effects.

55

Synthetic polymers
Thermosetting systems are in the sol form when initially

constituted, but upon heating , they set into their nal

shape.
This sol-gel transition is known as curing. But if this
cured polymer is heated further, it may lead to
degradation of the polymer.
Curing mainly involves the formation of covalent cross links
between polymer chains to form a macromolecular network
An important example of thermosensitive polymer is
poly-(N-isopropyl acrylamide)-poly (NIPAAM), which is
used for the formation of in situ gels.
The polymers such as poly(DL-lactide), poly(DLlactide-co- glycolide) and poly(DL-lactide-co- caprolactone) form solvent-removal precipitating
polymeric systems.
56

Classification Of In Situ Drug Delivery

In situ gel forming systems have been classied in two

categories as below:
Based on Mechanism of Gelation
Based on Route of Administration
Based on Mechanism of Gelation a) pH Sensitive
Gel b) Gel Sensitive to electrical current c)
Thermosensitive Gel d) Enzyme Sensitive e) Presence of
Ions
Based on Route of Administration (Applicability
of In Situ Drug Delivery System) a) In situ forming
polymeric systems for oral administration b) In situ
forming polymeric systems for ocular delivery c) In situ
forming polymeric systems for rectal and vaginal
delivery d) In situ forming injectable drug delivery
systems e) In situ forming nasal drug delivery systems57

Applicability Of In Situ Drug

Delivery System in
In situ forming polymeric systems for Oral

administration.
In situ forming polymeric systems for Ocular
drug delivery.
In situ forming polymeric systems for Rectal
and Vaginal delivery.
In situ forming Injectable drug delivery
systems.
In situ forming Nasal drug delivery
systems.
58

EVALUATION AND
CHARACTERIZATIONOF IN SITU
GEL / HYDROGEL SYSTEM
1.Clarity
The clarity of formulated solutions determined by

visual inspection under black and white background

2.Viscosity and rheology
The viscosity and rheological properties of the
polymeric formulations, either in solution or in gel
made with articial tissue fluid (depending upon the
route of administrations) were determined with
Brookeld rheometer or some other type of
viscometers such as Ostwalds viscometer.
No difficulties are envisaged during their
administration by the patient, especially during
parenteral and ocular administration.

59

3.Determination of
Mucoadhesive force
Modied balance method or TensilometerGel

Strength
This parameter can be evaluated using a
rheometer.
Depending on the mechanism of the gelling of
gelling agent used, a specied amount of gel
is prepared in a beaker, from the sol form .
This gel containing beaker is raised at a
certain rate, so pushing a probe slowly
through the gel.
The changes in the load on the probe can be
60

4.Sol-gel Transition
Temperature And Gelling
Time
For in situ gel forming systems incorporating

thermoreversible polymers, the sol-gel

transition temperature may be dened as that
temperature at which the phase transition of
sol meniscus is rst noted when kept in a
sample tube at a specic temperature and
then heated at a specied rate .
Gel formation is indicated by a lack of
movement of meniscus on tilting the tube.
Gelling time is the time for rst detection of
gelation as dened above.
61

5.Texture analysis
The rmness, consistency and cohesiveness of formulation

are assessed using texture analyzer which mainly indicates

the syringeability of sol so the formulation can be easily
administered in-vivo.
Higher values of adhesiveness of gels are needed to maintain
an intimate contact with surfaces like tissues.
Fourier transform infra-red spectroscopy and thermal analysis
During gelation process, the nature of interacting forces can
be evaluated using this technique by employing potassium
bromide pellet method.
Differential scanning calorimetry is used to observe if there
are any changes in thermograms as compared with the pure
ingredients used thus indicating the interactions.
Thermogravimetric analysis can be conducted for in situ
forming polymeric systems to quantitate the percentage of
water in hydrogel
62

6.In Vitro Drug Release Studies

For the in situ gel formulations to be administered by oral,

ocular or rectal routes, the drug release studies are carried

out by using the plastic dialysis cell.
The cell is made up of two half cells, donor compartment
and a receptor compartment. Both half cells are separated
with the help of cellulose membrane. The sol form of the
formulation is placed in the donor compartment.
The assembled cell is then shaken horizontally in an
incubator.
The total volume of the receptor solution can be removed at
intervals and replaced with the fresh media. This receptor
solution is analyzed for the drug release using analytical
technique.
For injectable in situ gels , the formulation is placed into
vials containing receptor media and placed on a shaker
water bath at required temperature and oscillations rate.
Samples are withdrawn periodically and analyzed
63

COMMERCIAL FORMULATIONS OF IN
SITUPOLYMERIC SYSTEMS
Timoptic-XE
ReGel:depot technology
Cytoryn TM

64

CONCLUSION
The primary requirement of a successful controlled

release product focuses on increasing patient

compliance which the in situ gels offer.
Exploitation of polymeric in- situ gels for controlled
release of various drugs provides a number of
advantages over conventional dosage forms.
Sustained and prolonged release of the drug, good
stability and biocompatibility characteristics make
the in situ gel dosage forms very reliable.
Use of biodegradable and water soluble polymers for
the in situ gel formulations can make them more
acceptable and excellent drug delivery systems.
65