Transcript pH Sensitive Hydrogels In Controlled Release Systems

pH Sensitive Hydrogels
In Controlled Release Systems
By: Karin Stephenson
In partial fulfillment of Chem. 765
Advanced Polymers
Contents:
1.
2.
Definition of Hydrogels
Physical Properties of Hydrogels
 Pore Size Characterization using PAS
 Swelling Mechanisms – pH Sensitive Hydrogels
3.
4.
Introduction of Controlled Release Systems
Applications of Hydrogels in Controlled
Release Systems
 PEG Hydrogels in Drug Delivery
 pH Sensitive Hydrogels based on Chitosan and
D,L-Lactic Acid
Definition of a Hydrogel:

Hydrogels are three dimensional
networks of hydrophilic polymers that
are insoluble.
Xin, Qu. et al. “Synthesis and Characterization of pH sensitive Hydrogels Based on
Chitosan and D,L-Lactic Acid” Journal of Applied Polymer Science, v.74 3193-3202 (1999)
Applications of Hydrogels


Controlled Drug Release
Wound coverings
VigilonTM is a hydrogel used in sheet covering
wound materials. It is prepared from radiation
crosslinking of high molecular weight poly (ethylene
oxide) chains.
Hypol TM is used in foam wound healing materials
and in drug delivery. It is a crosslinked PEG foam.
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
Contact lenses
Adsorption
Chromatographic packing material
Properties of Hydrogels:

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Amorphous polymers
Tg values vary depending on the extent of
crosslinking.
Swelling is a result of a change in the external
environment.
Hydrogels can swell as a result of changes in pH,
temperature, ionic strength, solvent composition,
pressure and the application of electric fields.
R
O
O
O
N
N
H
H
H2O
R
R
NH2
O
+
H
H
R = polymer backbone
N,N-methyl bisacrylamide crosslinker (not hydrolytically stable)
Determination of Pore Sizes
Pore sizes are important to controlled
drug delivery.
 Current methods include:

– Gas diffusion, electron paramagnetic
resonance (EPR), and fluorescence
– Positron Annihilation Spectroscopy (PAS)
• Allows for the determination of electron density,
sizes and an indication of the number of pores
within the polymer.
pH Sensitive Hydrogels
R
R
NH3+
NH2
NH3+
NH2
R
R
O
pH<6.5 buffer

R= polymer backbone
Hydrophobic side chain
N
Hydrophobic side chain
N
O
pH>6.5 buffer
Crosslinking is based on hydrogen bonding,
and secondary hydrophobic interactions.
 Crosslinking is reversible
 Control over the pore sizes
Controlled Release Systems
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Release characteristics are dependent on the
chemical nature of the hydrogel
Hydrogel Requirements:
– Controlled or delayed diffusion of molecules
– Pore size compatibility with the biological molecule
– Solubility of the biological molecule
There are two general methods of controlled drug release
Poly(ethylene glycol) pH
Sensitive Hydrogels

Advantages of PEG:
*Biocompatibility
*Non-toxic
*Water soluble
*Rapid clearance from
the body
N. A. Peppas et al. Journal of Controlled Drug Release 62 (1999) 81-87
Synthesis of Peg Hydrogel for
Drug Delivery
HO
O
O
O
PEGMA
(PEG MW=1000)
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
n
n
O
O
PEGDMA
(PEG MW=1000)
PEGDMA and PEGMA (with PEG MW=1000)
macromonomers were polymerized via free radical
solution copolymerization in ratios ranging from 20:80
to 80:20
1-Hydroxycyclohexyl phenyl ketone was added as a
photoinitiator as 1 wt.% of total monomers.
N. A. Peppas et al. Journal of Controlled Drug Release 62 (1999) 81-87
Success of PEG Hydrogel

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Diltiazem is a small MW drug with an effective
hydrodynamic radius of 4.24Å
It was demonstrated that as the pore size increased
the diffusion rate of Diltiazem increased.
Fractional release
of diltiazem in 1M NaCl
(different feed ratios of
PEGDMA/PEGMA)
N. A. Peppas et al. Journal of Controlled Drug Release 62 (1999) 81-87
pH Sensitive Hydrogels based on
Chitosan and D,L-Lactic Acid
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Incorporation of a natural polymer into the gel aids in
the bioactivity and biodegradability of the polymer
The best method of combination is the graft
copolymerization of the synthetic polymer onto the
natural polymer.
These hydrogels are currently being tested in
controlled drug release mechanisms.
Chitosan has received a lot of attention recently
because it has been derivatized in the past and
maintained its biocompatibility
– Cosmetics and biotechnology
Graft Copolymerization of Lactic
Acid onto Chitosan
Ch2OH
Ch2OH
O
OH
n
Deacetylation
*
O
OH
*
n
88%
NH
NH2
O
O
H2O
D,L-Lactic Acid
Ch2OH
O
OH
*
n
NH
O
80 C
Ch2OH
-H2O
OH
O
OH
O
O
n
O
OH
H
n
*
NH3+
O
Xin, Qu. et al. Journal of Applied Polymer Science, V.74, 3186-3192 (1999)
Conclusions

Hydrogels are network polymers that swell
through a variety of mechanisms in an
aqueous environment
 They have shown to be useful in medical
applications as a mechanism of controlled
release
 Other mechanisms of swelling:
– pH, ionic strength, solvent composition, pressure
and even electric fields