Radiation Physics and Chemistry 64 (2002) 331336

Stimulus responsive drug release from polymer gel.

Controlled release of ionic drug from polyampholyte gel
Kouichi Sutani
a,
*, Isao Kaetsu
a
, Kumao Uchida
b
, Yoshio Matsubara
a
a
Interdisciplinary Graduate School of Science and Technology, Kinki University, Kowakae 3-4-1, Higashi-Osaka, Osaka 577-8502, Japan
b
Faculty of Science and Technology, Kinki University, Kowakae 3-4-1, Higashi-Osaka, Osaka 577-8502, Japan
Received 28 March 2001; accepted 25 September 2001
Abstract
2-(Dimethylamino)ethyl methacrylate or Methacryloyloxyethyltrimethylammonium chloride as a cationic monomer
was copolymerized by UV with anionic monomer such as acrylic acid (AAc), into a polyampholyte. The pH responsive
swelling behaviour and the pH and electro-responsive drug release functions of polyampholyte were investigated. The
result showed that a copolymer of cation rich composition swelled at acidic condition, and shrank at alkaline condition.
On the other hand, an anion rich copolymer showed a reverse phenomenon. Polyampholyte proved to interact with an
ionic drug both by ionic binding and physical adsorption. r 2002 Elsevier Science Ltd. All rights reserved.
Keywords: UV copolymerization; Ionic drug; Polyampholyte; Controlled release; pH responsiveness; Electro-responsiveness
1. Introduction
The phase transition phenomenon of polyelectrolyte
was theorized by Dusek and Patterson (1968). Tanaka
(1978, 1981) found phase transition of partially hydro-
lyzed poly(acrylamide) in acetone-water. Since then,
stimulus responsive polymers including polyelectrolyte
have been studied actively.
Two types of phase transition polymer have been
reported. One is the gels having both hydrophilic and
hydrophobic chemical structures such as poly NIPAAm
(N-isopropylacrylamide) (Hirokawa and Tanaka, 1984;
Ito, 1989) and cellulose derivative (Guo et al., 1998;
Sarkar and Walker, 1995), which show temperature
responsive phase transitions. The other is a polyelec-
trolyte such as poly(acrylic acid) (Kaetsu et al., 1992)
which shows pH-(Tanaka et al., 1980) and electro-
responsiveness (Kishi and Osada, 1989; Kwon et al.,
1991) owing to ionic interaction and conformation
change.
The authors of this paper have studied and developed
intelligent drug release systems using solenoid, shape
memory metal and stimulus-responsive hydrogels as the
sensors and actuators (Kaetsu, 1987; Kaetsu et al.,
1988). Then, the intelligent drug delivery systems (DDS)
using polyelectrolyte as a polymeric sensor and actuator
was synthesized by UV and radiation polymerization
(Kaetsu et al., 1993; Uchida et al., 1993; Kaetsu et al.,
1999). This kind of polymer repeats the reversible
volume changes with pH changes and ono switching
of electric eld.
We used mainly anionic polymer for intelligent DDS.
Various natural polyelectrolytes such as polysacchar-
ide have also been studied by UV and radiation
entrapment from the view point of good biocompat-
ibility and biological safety (Sutani et al., 2001a, b).
There are natural polyampholytes such as proteins
and blends of natural polyelectrolytes (Sutani et al.,
2001a, b). Furthermore, it is expected that polyampho-
lyte shows stimulus-responsive behaviour according to
the ionic balance in its composition. Therefore, we are
interested in an intelligent DDS using polyampholytes
*Corresponding author. Tel.: +81-6-6730-5880 Ext. 4373;
fax: +81-6-6723-2721.
E-mail addresses: sutani@post1.ned.kindai.ac.jp (K. Suta-
ni), kaetsu@ned.kindai.ac.jp (I. Kaetsu), uchida@ned.kin-
dai.ac.jp (K. Uchida).
0969-806X/02/$ - see front matter r 2002 Elsevier Science Ltd. All rights reserved.
PII: S 0 9 6 9 - 8 0 6 X( 0 1 ) 0 0 5 0 5 - 9
prepared by UV and radiation. In this paper, pH
responsive and electro-responsive swelling and drug
release were studied using a polyampholyte copolymer.
2. Methods
2.1. Synthesis of ionic polymer
The cationic monomer, 2-(Dimethylamino)ethyl
methacrylate (DMMA) or methacryloyloxyethyltri-
methylammonium chloride (MADQUAT) and the
anionic monomer, acrylic acid (AAc) were used. Metanil
yellow was used as an acidic drug and methylene blue
was used as a basic drug. 2-hydroxyethyl methacrylate
(HEMA) was used for formation of drug matrix. The
ionic monomer, ionic drug and vinyl monomer were
provided as special pure grade product by Wako Pure
Chemical Industries, Ltd. and used without further
purication. The crosslinker, polyethyleneglycol #400
dimethacrylate (9G) was provided by Sinnakamura
Chemical Industrial Co., Ltd., Wakayama, Japan. The
polymerization initiator, 1-hydroxy cycrohexyl phenyl
ketone (IRAGACURE184) was provided by Aldrich
Chemical Company Inc. The mixture of ionic monomer
(0.10 mol), vinyl monomer (100 mol), crosslinker
(1.0 mol), as well as polymerization initiator (0.1 mol)
was poured into photopolymerization mold and irra-
diated. The polymerization was carried out using
gamma-ray from
60
Co source (dose rate: 1.5 10
3
Gy/
h, dose: 1.5 10
4
Gy) or UV light from high-pressure
mercury lamp (400 W, time of irradiation was equal to
72 h). The resulting matrix was heated for 1 h, at
temperature 1501C to cure the unreacted monomer.
2.2. Water content at various pH
The polymer was placed in water and swelled at
36.51C. pH was adjusted using 0.01 N-hydrochloric acid
solution or 0.01 N-sodium hydrate solution. Water
content of hydrogel was calculated by Eq. (1).
water content %
W
wet
W
dry
W
wet
100; 1
where W
wet
is the weight of swelled hydrogel, and W
dry
is the weight of dry hydrogel.
2.3. The ionic drug adsorption and ionic drug release in
the ionic polymer
Metanil yellow or methylene blue as an ionic drug was
added to the water solution. These drugs were absorbed
into a swelled hydrogel for 24 h. The amount of drugs
absorbed in the hydrogels were estimated by the
dierence of drug concentration in the solutions before
and after the contact with hydrogels.
For the release experiment, hydrogels were immersed
in a distilled water for 24 h in order to liberate physically
entrapped drugs and then in isotonic aqueous solution
of NaCl to liberate the ionically bound drug. The
released amount of drugs were measured spectrometri-
cally.
2.4. pH responsive weight change and ionic drug release
from the polymer
After the physically adsorbed drug was taken away
with a distilled water, the ionic polymer gel was put into
solutions of various pH values, which were adjusted
variously with 0.01 N-hydrochloric acid solution or
0.01 N-sodium hydrate solution at 36.51C. The weight
of the swelled polymer and the amount of released drug
were measured in those pH conditions. The operation
was repeated at certain intervals.
2.5. Electro-responsive weight change of polymer and
ionic drug release from the polymer
After the removal of physically adsorbed drug, the
ionic polymer gel was held between two Pt electrodes
connected with a battery. Strength of the electric eld
was evaluated by the voltage with a battery. Then an
electric eld was introduced for a certain period. The
weight of swelled polymer and the amount of released
drug were measured. The operation was repeated at
certain intervals.
3. Results and discussion
3.1. Water content at various pH conditions
Fig. 1 shows the relation of pH and swelling (water
content) in ionic copolymers. The composition of ionic
copolymers was varied widely between cationic homo-
monomer((DMMA) and anionic homo-monomer(AAc).
The hydrogel swelled in acidic condition and shrank in
alkaline condition, when the copolymer was DMMA
rich composition. The hydrogel swelled in alkaline
condition and shrank in acidic condition, when the
copolymer was an AAc rich composition. The hydrogel
swelled in acidic and alkaline conditions, and shrank in
neutral pH, when the copolymer consisted of equal
DMMA and AAc. The hydrogel including no ionic
monomer showed no change in swelling. The AAc rich
copolymer gel expanded in alkaline conditions, because
poly(AAc) was dissociated into carboxyl anion in
alkaline conditions, which caused the ionic repulsion
between anionic groups and resulted in the conforma-
tional stretching. On the other hand, the polymer shrank
in acidic condition owing to the coiled conformation due
to ionic anity.
K. Sutani et al. / Radiation Physics and Chemistry 64 (2002) 331336 332
Assuming the dissociation constant (pK
a
) of AAc to
be almost similar to the pK
a
of monomer, 4.26
(Kilparrick and Morse, 1953), the pH value and degree
of dissociation can be calculated according to Eq. (2).
Table 1 shows the result of calculation.
a
1
10
pK
a
-pH
1
2
where a is the degree of dissociation, and pK
a
is the
dissociation constant.
The result of the calculation agreed with the experi-
mental curve (for example, AAc 10 mol composition) in
Fig. 1. When the pH value is less than 3.3, the degree of
dissociation is 0.0909 and the polymer scarcely dis-
sociates. But, in the region of pH 46, the degree of
dissociation increases rapidly to increase carboxyl anion.
In pH region higher than 7, the polymer completely
dissociates. As the pH moves from acidic to alkaline,
H
+
ion from carboxyl group combines with OH

in
alkali and dissociation into carboxyl anion occurs
completely. On the other hand, when pH moves to
acidic condition, concentration of H
+
increases, and
combines with carboxyl anion to retard the dissociation.
The degree of dissociation of DMMA can be
calculated also according to Eq. (2), since the dissocia-
tion constant (pK
a
) of DMMA is 8.44 (Emova et al.,
1998). In the DMMA rich copolymer, the dimethylami-
no group dissociates according to pH conditions in the
opposite way compared to the AAc rich copolymer.
When the copolymer has equimolar anionic and
cationic composition, the copolymer shrank at neutral
pH condition. In this case, ion complex forms between
the anionic and cationic units in the copolymer, and the
least ionic repulsion occurs. But, some ionic groups exist
separately and cannot form ionic complex. This might
be the reason why small shrinkage was observed.
3.2. Behaviour of ionic polymer for ionic drug adsorption
and ionic drug release
Fig. 2 shows the drug release from ionic polymer in
two kinds of solutions. First, drug was released in
distilled water, and secondly, drug release was carried
out in an isotonic sodium chloride solution. The
physically entrapped drug was released at an early stage
into distilled water, and metanil yellow, an anionic drug
was also released from anionic polymer (AAc). How-
ever, the highest max drug release was 50%, because
drug was occluded into the inner part of polymer and
could not be released from the network. On the other
Fig. 1. Eect of pH on the water content of the copolymer gels
based on HEMA, pH sensitive monomers and crosslinker 9G.
Ratio of DMMA to AAc (in mol) in HEMA (100 mol),
DMMAAAc (total 10 mol) and 9G (1 mol) system;
DMMA:AAc; (E) 10.0:0, (.) 7.5:2.5, (m) 5.0:5.0, (K)
2.5:7.5, () 0:10.0, (*) 0:0.
Table 1
Degree of dissociation of AAc with respect to pH (Eq. (2))
pH Degree of dissociation
1.26 0.0010
2.26 0.0099
3.26 0.0909
4.26 0.5000
5.26 0.9091
6.26 0.9901
7.26 0.9990
8.26 0.9999
Fig. 2. Dierence in drug releases from ionic polymer gel based
on HEMA, pH sensitive monomers and crosslinker 9G, in
distilled water and in isotonic sodium chloride solution.
Monomer composition: HEMA 100 mol, pH-sensitive mono-
mer (MADQUAT, AAc, DMMA) 10 mol, 9G 1 mol; pH
sensitive monomer: (K) MADQUAT, (m) AAc, (E) DMMA;
Ionic drug:metanil yellow (acidic drug).
K. Sutani et al. / Radiation Physics and Chemistry 64 (2002) 331336 333
hand, the cationic polymer, MADQUAT or DMMA
had ionic binding with the acidic drug, metanil yellow,
showing ionic interaction. No drug release occurred in
distilled water, but drug was released in an isotonic
sodium chloride solution, because the polymer with drug
was soaked in salt solution and the ionic drug was
separated from polymer network by displacement with
ionic salt and released out of polymer.
The model scheme is shown in Fig. 3 for the acidic
drug release from cationic polymer. Two kinds of drug
state are assumed. There are the chemical binding
between polymer and drug, and the physical adsorption
of drug in the polymer network. The release mechanism
of drug in the physical adsorption state is the diusion
out of polymer due to the concentration gradient in
distilled water. But no release of ionically bound drug
occurs.
However, when the polymer was put into isotonic
sodium chloride solution, the ionic drug was dissociated
from the polymer and released. This release was not
controlled by the diusion mechanism as in the release
of physically entrapped drug and showed almost
constant drug release.
3.3. pH responsive weight change and ionic drug release
from the ionic polymer
Fig. 4 shows the release of methylene blue. Methylene
blue was released from the ionic polymer of various
ratio of anionic and cationic compositions. The amount
of drug release from the copolymer of equimolar anionic
and cationic composition was higher than from the
anion rich copolymer. In anion poor copolymer, drug
release was prevented. These results support the model
described in Section 3.2. The release result of metanil
yellow was contrary to that of methylene blue due to the
opposite charge in the drug.
The drug was released constantly for 8 h, however, the
drug release was not controlled by diusion mechanism.
In the diusion mechanism, drug release shows linear
increase in the beginning, and then later exponential
release. But this system showed a dierent release
behaviour.
Fig. 5 shows pH responsive changes of water content
in the ionic polymer. The polymer swelled at acidic
conditions and shrank at alkaline conditions when the
copolymer was a cation rich composition. On the other
hand, the polymer swelled at alkaline condition and
shrank at acidic condition in the anion rich copolymer.
Expansion and shrinkage should repeated reversibly in
response to pH changes. It is concluded that such ionic
copolymers can be used for the pH responsive intelligent
drug delivery.
Fig. 3. Model scheme for the mechanism of ionic drug release
from ionic polymer. non-ion sol.Fdistilled water, ion sol.Fi-
sotonic sodium chloride solution.
Fig. 4. Release of basic drug from copolymer gels based on
HEMA, pH sensitive monomers and crosslinker 9G. Ratio of
MADQUAT to AAc in HEMA (100 mol), MADQUATAAc
(total 10 mol) and 9G (1 mol) system; (K) 5.0:5.0, (m) 5.0:0, (.)
0:5.0, (E) 7.5:2.5, () 2.5:7.5; Ionic drugFmethylene blue
(basic drug); Drug release solventFisotonic sodium chloride
solution.
Fig. 5. pH responsive changes of water content in ionic
copolymer gels based on HEMA, pH sensitive monomers and
crosslinker 9G. Ratio of AAc to MADQUAT (in mol) in
HEMA (100 mol), AAcMADQUAT (total 10 mol) and 9G
(1 mol) system; () 7.5:2.5, (J) 2.5:7.5.
K. Sutani et al. / Radiation Physics and Chemistry 64 (2002) 331336 334
3.4. Electro-responsive weight change from the ionic
polymer
Fig. 6 shows electro-responsive changes of water
content in the ionic copolymer. The polymer shrank at
the on-state of electric eld and swelled at the o-state of
electric eld when the copolymer was rich of cationic
and anionic compositions.
The mechanism of electro-responsive changes was
presumed as follows. When the ionic polymer was anion
rich, the polymer dissociated into cation and polymer
anion. Under electric eld, the cation species moved to
the cathode, and combined with OH

from the
electrolyzed water, to form NaOH, and was released
from the polymer matrix. The polymer anion could not
diuse, but the polymer anion was attracted ionically to
the anode. The polymer was transformed and shrank to
squeeze out water from the gel.
The polymer swelled again by relaxation, when the
electric eld was switched o.
Therefore, the ionic polymer can be used as electro-
responsive intelligent materials for drug delivery sys-
tems.
4. Conclusion
It was shown that the cation rich polyampholyte
copolymer swelled in acidic condition, and shrank in
alkaline condition. The anion rich copolymer showed
the opposite swelling behaviour compared to the cation
rich copolymer.
The drug release was quite dierent between the
chemical binding drug and physical adsorption drug.
The drug release can be controlled better in the chemical
binding drug. The combination of ionic polymer and
ionic drug was advantageous.
The polyampholyte and ionic drug complex could
show pH- and electro-responsive drug release.
References
Dusek, K., Patterson, D., 1968. Transition in swollen polymer
networks induced by intramolecular condensation. J.
Polym. Sci. Part A 2 (6), 12091216.
Emova, D.Yu., Shibalovich, V.G., Nikolaev, A.F., Tribo,
E.N., 1998. Acidbase properties of monomeric and
polymeric ammonium salts of N,N-dimethylaminoethyl
methacrylate with inorganic acids. Russ. J. Appl. Chem.
71 (8), 14321436.
Guo, J.H., Skinner, G.W., Harcum, W.W., Barum, P.E., 1998.
Pharmaceutical applications of naturally occurring water-
soluble polymers. PSTT 1 (6), 254261.
Hirokawa, Y., Tanaka, T., 1984. Volume phase transition in a
nonionic gel. J. Chem. Phys. 81 (12), 63796380.
Ito, S., 1989. Phase transition of aqueous solution of poly(N-
alkylacrylamide) derivatives. Kobunshi Ronbunshu 46 (7),
437443.
Kaetsu, I., 1987. Biodegradable implant composites for local
therapy. J. Controlled Release. 6, 249263.
Kaetsu, I., Yoshida, M., Asano, M., Yamanaka, H., Imai, K.,
Nakai, K., Mashimo, T., Yuasa, H., 1988. Controlled
release for hormone therapies by LHRH analogue contain-
ing polymer needles and testosterone containing articial
testis. Drug Dev. Ind. Pharm. 14 (1517), 25192533.
Kaetsu, I., Uchida, K., Morita, Y., Okubo, M., 1992. Synthesis
of electro-responsive hydrogels by radiation polymerization
of sodium acrylate. Radiat. Phys. Chem. 40 (2), 157160.
Kaetsu, I., Uchida, K., Murai, Y., Morita, Y., Sutani, K., 1993.
Study on actuators for sensor-connected drug delivery
systems. Polym. Preprints, Japan 42 (8), 31743176.
Kaetsu, I., Uchida, K., Sutani, K., 1999. Intelligent feedback
release systems and the application to neuron network
model research. Radiat. Phys. Chem. 55 (56), 673676.
Kilparrick, M., Morse, J.G., 1953. The dissociation constants
of acids in salt solutions. VI. Carbocyclic carboxylic acids. J.
Am. Chem. Soc. 75, 18541856.
Kishi, R., Osada, Y., 1989. Reversible volume change of
microparticles in an electric eld. J. Chem. Soc. Faraday
Trans. 85 (3), 655662.
Kwon, I.C., Bas, Y.H., Kim, S.W., 1991. Electrically erodible
polymer gel for controlled release of drugs. Nature 354 (28),
291293.
Sarkar, N., Walker, L.C., 1995. Hydrationdehydration prop-
erties of methylcellulose and hydroxypropylmethylcellulose.
Carbohydr. polym. 27, 177185.
Sutani, K., Kaetsu, I., Uchida, K., 2001a. The synthesis and the
electric-responsiveness of hydrogels entrapping natural
polyelectrolyte. Radiat. Phys. Chem., 60, 513520.
Sutani, K., Kaetsu, I., Matsumura, H., Uchida, K., 2001b.
Stimulant response hyaluronic acid blend gel. Seitaizairyu,
19(2), 4248.
Tanaka, T., 1978. Collapse of gels and the critical endpoint.
Phys. Rev. Lett. 40 (12), 820823.
Fig. 6. Electro-responsive changes of water content in ionic
copolymer gels based on HEMA, pH sensitive monomers and
crosslinker 9G. Ratio of AAc to MADQUAT (in mol) in
HEMA (100 mol), AAcMADQUAT (total 10 mol) and 9G
(1 mol) system; () 7.5:2.5, (J) 2.5:7.5; VoltageF6 V.
K. Sutani et al. / Radiation Physics and Chemistry 64 (2002) 331336 335
Tanaka, T., 1981. Gels. Sci. Am. 244 (1), 110123.
Tanaka, T., Fillmore, D., Sun, S.T., Nishio, I., Swislow, G.,
Shah, A., 1980. Phase transitions in ionic gels. Phys. Rev.
Lett. 45 (20), 16361639.
Uchida, K., Kaetsu, I., Sutani, K., Tanaka, S., Okuda, K.,
1993. Release under electric eld in electromagnetic
composite system. Proc. Int. Symp. Control Rel. Bioact.
Mater. 20, 352353.
K. Sutani et al. / Radiation Physics and Chemistry 64 (2002) 331336 336