Hydrogels are well known as networks of hydrophilic polymers, which can absorb

a significant amount of water (> 20% of their dry mass) without dissolving or losing
their structural integrity (1, 2). The networks can be formed by various methods: g-irra-
diation (
60
Co) (37) or UV irradiation (8, 9) on different biomaterials. Chemically cross-
linked hydrogels were developed in the last decades as carriers for drugs (10). The con-
trolled drug delivery devices assure a sustained release and targeted effect (11). The
great advantage of the drug-controlled release from the mentioned hydrogels is a possi-
bility for improvement of patient compliance (12). In recent years, the polyacrylic acid
(PAA) and its copolymers have been often used as carriers in drug release systems, be-
cause of their multifunctional nature, unique properties and good biocompatibility (13).
The aim of the present work is to investigate the possibility of applying PAA-based
hydrogels crosslinked by macrodiisocyanates (MDIC) (14) for retarded drug release.
25
Acta Pharm. 53 (2003) 2531 Original research paper
Hydrogels based on the chemically crosslinked
polyacrylic acid: Biopharmaceutical characterization
MILEN DIMITROV
1
NIKOLAI LAMBOV
1
*
STOICHO SHENKOV
2
VENETA DOSSEVA
2
VLADIMIR Y. BARANOVSKI
2
1
Department of Pharmaceutical
Technology, Faculty of Pharmacy
Medical University of Sofia, Bulgaria
2
Institute of Polymers, Bulgarian
Academy of Sciences, Sofia, Bulgaria
Received February 28, 2002
Accepted February 11, 2003
This study is an attempt at biopharmaceutical characte-
rization of hydrogels based on crosslinked polyacrylic
acid (PAA). Macrodiisocyanates (MDIC) or oligometha-
nediisocyanate (DO) were used as crosslinking agents.
The drug release rate from such hydrogels is determined
by a density of the net and is lowered by a decrease in
the PAA : MDIC mass ratio. The increase of the drug
concentration in the matrix improved the release pro-
cess. The drug release from the hydrogels was found to
be pH dependent.
Key words: hydrogels, polyacrylic acid network, crosslin-
king, macrodiisocyanates, drug release
* Correspondence, e-mail: [email protected]
EXPERIMENTAL
Excipients
All studied drugs (nicotine, paracetamol, ethophylline, theophyline) were provided
by Pharmachim (Bulgaria). Polyethylene glycols (PEG) with molecular masses 400, 600
and 1000, decamethylene diol (DMDO); polyoxytetramethylene glycol (PTMG) 1000
(also known as polytetrahydrofuran), were purchased from Sigma-Aldrich Chemie
GmbH (Germany).
Methods
The synthesis and chemical characterization of chemically crosslinked PAA hydro-
gels were described in a previous paper (14). Macrodiisocyanates (MDICs) were obtai-
ned by reaction of dioles (PEG 400, 600, 1000, PTMG 1000) and isophorone diisocyanates
in the molar ratio 1:2 according to the following scheme:
where
The polymer net used in the current research was obtained on the basis of PAA
crosslinked with oligomeric MDI. Oligourethanediisocyanate (DO) obtained through a
chemical reaction of decamethylenediol (DMDO) and isophoronediisocyanates in molar
ratio 2:3 was also applied as a crosslinking agent (15):
26
M. Dimitrov et al.: Hydrogels based on the chemically crosslinked polyacrylic acid: Biopharmaceutical characterization, Acta Pharm.
53 (2003) 2531.
R =
H
3
C
H
3
C CH
2
CH
3
'
CH
2 2
CH R =
2HO CH
2
10
OH
( )
+ 3 OCN R NCO
D DO
70 C
OCN R
[
]
NH C
O
O
(
CH
2
)
10
O
C
O
NH R
D
2
'
'
'
NCO
HO R ( O
)
n
H + 2 OCN R NCO
'
70 C
OCN R NH
'
C
O
O R ( O
)
n
C
O
NH R
'
MDIC
NCO
The drug loaded polymer networks based on PAA were obtained by dissolving the
drug in a mixture of MDI and PAA in various mass ratios in dimethylformamide (DMF)
(70 C for 24 hours, atmospheric pressure). The reaction was carried out until a constant
mass of reaction mixture. The drug content in the obtained polymer network was 1, 5, 10
or 15% (m/m).
In the current research, the obtained polymeric material was divided into 6 sym-
metric, equal, separate pieces, each with a 35 mm diameter. Included drug was quantita-
tively determined in every piece. The total amount of the drug release from all six sam-
ples corresponded fully to the initial amount of the drug included in the polymeric sys-
tem. The drugs were spectrometrically determined on a Hewlett-Packard 8452 A spec-
trophotometer (USA) (nicotine: l
max
= 260 nm, paracetamol: l
max
= 240 nm, ethophylli-
ne: l
max
= 276 nm, theophylline: l
max
= 270 nm).
The buffer solutions of pH 2, 5 and 7.4 were prepared by appropriate combinations
of 0.2 mol L
1
solutions of hydrochloric acid, potassium biphthalate and potassium mo-
nobasic phosphate (16).
The drug release rate was determined by the paddle over disk method according to
USP (16) using the Erweka DT8 (Germany) assembly. Dissolution medium was: 900 mL
distilled water, gastric fluid without enzymes, or intestinal fluid at a stirring rate of 50
rpm.
RESULTS AND DISCUSSION
In a previous study (14), the authors described in detail the methods for the synthe-
sis and studied the structure and characteristics of the polymer nets based on PAA and
MDI containing polyethylene glycol chains. This paper aims to study the possibility of
incorporating different drugs in a polymer net and investigating the influence of both
the drugs and the polymer network on the drug release rate.
Drugs of various chemical structures and dissolution in water (paracetamol, etho-
phylline, nicotine and theophylline) were used as model drugs. The results obtained for
27
M. Dimitrov et al.: Hydrogels based on the chemically crosslinked polyacrylic acid: Biopharmaceutical characterization, Acta Pharm.
53 (2003) 2531.
Time (h)
D
r
u
g
r
e
l
e
a
s
e
d
(
%
)
PEG 1000
PTMG 1000
DMDO 1000
0 1 2 3 4 5 6
100
90
80
70
60
50
40
30
20
10
0
Fig. 1. Influence of the type of the
crosslinking agent on the release rate
of paracetamol. PAA : MDI = 1:1; 5%
paracetamol of total network mass;
each point represents the mean SD,
n = 12.
the studied drugs allow us to assume that the chemical structure and dissolution in wa-
ter do not have a significant influence on the drug release rate from the polymeric net-
work. The main factors that determine the drug release from hydrogel systems are the
network density and the amount of the loaded drug (17).
The results presented in Fig. 1 explain the effect of the crosslinking agent type: in-
crease of the hydrophobicity of the crosslinking agent slowed down the release of the
drug. For example, with a crosslinking agent prepared from polyethylene glycol (PEG)
1000 the highest amount of paracetamol was released (67% after six hours), wheras with
a crosslinking agent prepared from DMDO 1000 the lowest amount of paracetamol was
released (10.5% after six hours).
With the increase of the molecular mass of the crosslinking agent, the released
amount of nicotine increased (Fig. 2): almost direct proportionality was followed. With
MDI prepared form PEG 400 the released nicotine amounted to 42% after six hours, and
from PEG 1000 it amounted to 66%.
In the process of obtaining MDI diols of different chemical composition (PEG,
PTMG) and DO, all of equal molecular mass about 1000 were used their chemical nature
determined the different hydrophobicity of the chains. From Fig. 1 it is obvious that the
chemical structure of the diol used to obtain MDI influenced the drug release, which de-
creased in the following sequence: PEG 1000 > PTMG 1000 > DMDO 1000.
The MDICs of different lengths chain determined by the different molecular mass of
PEG (400, 600, 1000) were used as crosslinking agents. Fig. 2 shows that the drug release
rate depends on the molecular mass of the crosslinking agent. With an increase of the
chain length, the net density decreases, swelling increases, and the rate and the degree
of the drug release also increase.
As it can be seen from Fig. 3, the amount of drug released increases with the in-
crease of the mass ratio PAA : MDI. As expected, the increase in the amount of MDI
crosslinking agent led to an decrease of the drug release rate.
The increase of the amount of the drug loaded enhanced the release process (Fig. 4).
28
M. Dimitrov et al.: Hydrogels based on the chemically crosslinked polyacrylic acid: Biopharmaceutical characterization, Acta Pharm.
53 (2003) 2531.
0 1 2 3 4 5 6
0
10
20
30
40
50
60
70
80
90
100
PEG 1000
PEG 600
PEG 400
D
r
u
g
r
e
l
e
a
s
e
d
(
%
)
Time (h)
Fig. 2. Influence of molecular mass
of the crosslinking agent on the re-
lease rate of nicotine. PAA : MDI =
1:1, drug amount 5% of total net-
work mass; each point represents the
mean SD, n = 12.
This effect is not pronounced up to 5% of drug loading; the difference is negligible
between 1% and 5%. The released amounts increased by almost two and three times
with drug loading of 10 and 15%, respectively. The main reason for the observed effect
might be the higher concentration gradient being responsible for a more efficient diffu-
sion of the drug molecules through the hydrogel phase, while all other conditions were
the same. Hence, changing the drug loading offers a real possibility of controlling the
drug release.
Fig. 5 demonstrates that the amounts of the drug released at pH 5 and pH 7.4 are
different. This is explained by the fact that a hydrophobic complex between PAA and
PEG units is formed at pH 5 (18). The existence of compact hydrophobic domains in the
polymeric network hampers the drug release. However, at pH 7.4 a great part of PAA
carboxylic groups are ionized. This leads to destruction of the complex and swelling of
the network, resulting in full release of the drug. At pH 2 the complex is as stable as in
the case of pH 5, but the amount of the drug released is bigger. The most probable rea-
29
M. Dimitrov et al.: Hydrogels based on the chemically crosslinked polyacrylic acid: Biopharmaceutical characterization, Acta Pharm.
53 (2003) 2531.
Time (h)
D
r
u
g
r
e
l
e
a
s
e
d
(
%
)
1%
0 1 2 3 4 5 6
100
90
80
70
60
50
40
30
20
10
0
5%
10%
15%
Fig. 4. Influence of the amount of pa-
racetamol in the matrix on the release
rate, PAA: MDI = 1:1; each point rep-
resents the mean SD, n = 12.
Time (h)
D
r
u
g
r
e
l
e
a
s
e
d
(
%
)
PAA : MDI = 1:0.3
0 1 2 3 4 5 6
100
90
80
70
60
50
40
30
20
10
0
PAA : MDI = 1:0.6
PAA : MDI = 1:1
PAA : MDI = 1:2
Fig. 3. Influence of mass ratio PAA :
MDI of the crosslinking agent on the
release rate of paracetamol, drug
amount 5% of total network mass;
each point represents the mean SD,
n = 12.
son for this is the fact that in artificial stomach juice, namely at pH 2, the hydrolysis of
the PAA network takes place at a higher rate and to a higher degree.
CONCLUSIONS
The chemically cross-linked hydrogels containing various drugs have been investi-
gated. It can be summarized that the basic factors influencing the drug release are the
type and the molecular mass of the crosslinking agents, the mass ratio PAA: MDI, drug
concentration and the pH of the eluent. The studied systems provide retarded drug re-
lease and appear to be potential candidates for use in the pharmaceutical practice. Simi-
lar phenomena have been observed for all the drugs studied.
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M. Dimitrov et al.: Hydrogels based on the chemically crosslinked polyacrylic acid: Biopharmaceutical characterization, Acta Pharm.
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(
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)
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0 1 2 3 4 5 6
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40
30
20
10
0
pH = 5
pH = 7.4
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S A @ E T A K
Hidrogeli na bazi kemijski umre`ene poliakrilne kiseline:
Biofarmaceutska karakterizacija
MILEN DIMITROV, NIKOLAI LAMBOV, STOICHO SHENKOV, VENETA DOSSEVA i VLADIMIR Y. BARANOVSKI
U radu su biofarmaceutski karakterizirani hidrogelovi na bazi umre`ene poliakrilne
kiseline (PAA). Kao sredstva za umre`avanje upotrebljeni su makrodiizocijanati (MDIC)
ili oligometandiizocijanati (DO). Osloba|anje ljekovite tvari iz takvih hidrogelova odre-
|eno je gusto}om umre`enja i ovisi o pH medija. Osloba|anje se smanjuje sa smanje-
njem omjera PAA i MDIC, a pove}ava s pove}anjem koncentracije ljekovite tvari.
Klju~ne rije~i: hidrogeli, poliakrilna kiselina, umre`enje, makrodiizocijanati, osloba|anje lijeka
Department of Pharmaceutical Technology, Faculty of Pharmacy, Medical University of Sofia, Bulgaria
Institute of Polymers, Bulgarian Academy of Sciences, Sofia, Bulgaria
31
M. Dimitrov et al.: Hydrogels based on the chemically crosslinked polyacrylic acid: Biopharmaceutical characterization, Acta Pharm.
53 (2003) 2531.