ARTICLE IN PRESS

Biomaterials 26 (2005) 2733–2739

www.elsevier.com/locate/biomaterials

Radiation synthesis of interpolymer polyelectrolyte complex and its

application as a carrier for colon-specific drug delivery system
Amr El-Hag Ali Said
Polymer Chemistry Department, National Center for Radiation Research and Technology, 3 Ahmed El-Zomor St., El-Zohor Distr,
P.O. Box 29, Nasr City, Cairo, Egypt
Received 20 April 2004; accepted 27 July 2004
Available online 18 September 2004

Abstract

Novel pH-sensitive interpolymer polyelectrolyte complex was synthesized by gamma radiation-induced copolymerization of
acrylic acid (AAc) and dimethyl aminoethyl methacrylate (DMAEMA). pH-dependent swelling showed different phase transitions
depending on the copolymer composition and also showed the interpolymer polyelectrolyte complex formation at pH values ranged
from pH 3 to pH 4. FT-IR and TGA was employed to study the complex formation. The influence of copolymer composition and
pH value of the surrounding medium on the type of water diffusion in the glassy polymer was discussed. The ability of the prepared
copolymer to be used as drug carrier for colon-specific drug delivery system was estimated using ketoprofen as a model drug.
r 2004 Elsevier Ltd. All rights reserved.

Keywords: Dimethyl aminoethyl methacrylate; PH-sensitive; Interpolymer complex; Colon-specific; Drug release

1. Introduction Polymeric hydrogels are suitable to serve as drug

delivery systems. They are non-toxic and high swellable
The majority of oral drug delivery systems are matrix- three-dimensional network structure [9]. Intelligent
based systems, such matrices are prepared by compres- hydrogels could be of great importance in the field of
sion of a mixture of powder polymer and drug [1,2]. The designing new versatile drug carriers. Intelligent hydro-
drug released from the polymeric matrix either by the gels respond to the presence of water, pH [10],
diffusion through the swellable hydrophilic polymer or temperature [11] or biological trigger [12]. pH-respon-
by erosion of such polymer [3]. Proteins are generally sive hydrogels are prepared by including weak polybase
not delivered orally due to their very low biostability, or polyacid within the polymeric hydrogel. The presence
they digested through the gastrointestinal track into of such groups causes the conformational transition
amino acids [4,5]. Designing of controlled drug delivery from collapsed to swollen states at certain pH value.
systems have become an integral part of the new pH-responsive hydrogels could be designed to control
medicine development. Site specific drug delivery and target the drug to a specific site such as colon
system, which is a promising division of controlled drug depending on the range of pHs domains in the body [13].
delivery systems, offer many advantages over the Polyelectrolytes, which are very special class of
ordinary methods for drug administration such as the pH sensitive polymers, are polymers with covalently
release of the drug as close as possible to the target site, bound ionic groups. Corresponding to the nature of
drug protection and optimization of drug absorption, the ionic groups, they are classified as polyanions,
etc. [6–8]. polycations or polyampholytes. Interactions between
oppositely charged polyelectrolytes has attracted a
Tel.: 02022747413; fax: 02022749298. considerable interest because of the possibilities of appli-
E-mail address: [email protected] (A. El-Hag Ali Said). cations of their products—polyelectrolyte complexes

0142-9612/$ - see front matter r 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.biomaterials.2004.07.049
 ARTICLE IN PRESS
2734 A. El-Hag Ali Said / Biomaterials 26 (2005) 2733–2739

(PECs) [14–17]. The combination of the polymer All samples were washed in excess water to remove
and electrolyte character produces new materials the unreacted component then air dried at room
with unique properties. At present, PECs are used as temperature. All of the samples used in this study
selective membranes [18], capsules and fibers [19,20], possess almost 100% gelation, i.e. no extractable
biomaterials [21], etc. monomers and/or polymers.
Radiation-induced copolymerization and crosslinking
of copolymers has been increasingly used for creation of 2.3. Preparation of buffer solutions of different pH’s
novel biomaterials. Radiation initiation of chemical
reactions offers several advantages over chemical In all 0.2 M (citric acid/trisodium citrate) and 0.2 M
methods: it is simple, additive free and sterilization of (sodium dihydrogen phosphate/disodium hydrogen
the product takes place simultaneously, i.e. the pro- phosphate) were used to prepare buffer solutions ranged
duced polymer will be sterilized and free of carcinogenic from 3 to 5 and 6 to 8, respectively [22]. 0.2 M HCl was
materials (initiators and/or crosslinkers). In this work, g- used to prepare solutions of pH 1.
rays as clean source of initiation and crosslinking was
employed to copolymerize acrylic acid as polyanion and
dimethyl aminoethyl methacrylate as polycation to 2.4. Swelling study
produce unique interpolymer polyelectrolyte complex
to be used as a drug carrier for colon-specific drug The prepared crosslinked gels were soaked in buffer
delivery system. The pH-sensitivity of the prepared solution of different pH values ranged from 1 to 8 at
copolymer hydrogel will be characterized. The interac- 37 1C. The swelling ratio (S) was determined from the
tion between the oppositely charged moieties in the following equation:
copolymer and complex formation will be investigated Ws  Wo
and the possibility of using such hydrogel as a drug S¼  100;
Wo
carrier will be estimated using Ketoprofen as a model
drug. Ketoprofen is an anti-inflammatory and analgesic where Ws and Wo are the weights of the swollen and the
agent of extensive use in the treatment of rheumatic dry hydrogel, respectively.
pains. It is an appropriate candidate for this type of drug
administration system due to its side effects that 2.5. Fourier-transform infrared (FT/IR) measurements
accompany its conventional administration.
Mattson 1000, Unicam, England in the range from
400 to 4000 cm1 was used to determine the FT/IR
2. Materials and methods spectra of dry copolymer swollen in buffer solutions of
different pH values.
2.1. Materials
2.6. Thermogravimetric analysis (TGA)
Acrylic acid (AAc) of purity 99.9% (Merck, Ger-
many) and Dimethyl aminoethyl methacrylate (DMAE- Shimadzu TGA system of Type TGA-50 under
MA) of purity 99.9% (Aldrich, Germany) were used as nitrogen atmosphere (20 ml/min) was used in this study.
received. Ketoprofen, pharmaceutical grade, kindly The temperature range was from ambient to 600 1C at
provided by Alexandria pharmaceuticals Co., Alexan- heating rate of 10 1C/min.
dria, Egypt. Citric acid, sodium citrate, sodium dihy-
drogen phosphate, and disodium hydrogen phosphate,
analytical reagents, were purchased from El-Nasr Co. 2.7. Ultraviolet (UV) measurements
for Chemical Industries, Egypt and used without further
purification. Determination of the released amount of Ketoprofen
as model drug was carried out at 260 nm using Milton
2.2. Preparation of AAc/DMAEMA gels Roy Spetronic 1201 spectrophotometer in the range
from 190 to 900 nm.
AAc/DMAEMA gels were obtained by gamma
irradiation-induced copolymerization of 20 wt% aqu- 2.8. Preparation of Ketoprofen-loaded gel
eous solutions of AAc and DMAEMA mixtures with
different molar ratio in small glass vials using 60Co Five mg of Ketoprofen was dissolved in 20 ml
gamma rays, 20 kGy, at a dose rate 10.28 kGy/h. After phosphate buffer of pH 7. The dry AAc/DMAEMA
copolymerization, the vials were broken, the formed copolymer hydrogels were soaked into the drug solution
polymeric cylinder were removed and cut into discs of at room temperature until equilibrium. The drug loaded
2 mm thickness and 5 mm diameter. gels were dried at room temperature for 48 h.
 ARTICLE IN PRESS
A. El-Hag Ali Said / Biomaterials 26 (2005) 2733–2739 2735

2.9. Release of Ketoprofen swelling degree dramatically decreases by increasing

the AAc content in the copolymer. Oppositely, at high
AAc/DMAEMA gels loaded with Ketoprofen were pH value (pH 8), DMAEMA rich copolymer possesses
allowed to swell in buffer solutions of pH 1 and 7. At relatively low degree of swelling. Such swelling degree
first, the loaded gel were put in 25 ml of 0.2 M HCl (pH dramatically increases by increasing the AAc content in
1) for 3.5 h, then transferred to 100 ml 0.2 M phosphate the copolymer. Meanwhile, at pH 3 and 4, the degree of
buffer (pH 7) for 21.5 h. 1-ml sample was withdrawn on swelling increases by increasing the AAc content but it
time intervals to follow the release process. did not show such dramatic behavior. Also, the
equilibrium swelling is lower than that of DMAEMA
rich copolymer at pH 1 and lower than that of AAc rich
3. Results and discussions copolymer at pH 8.
The above-mentioned results could be explained in
3.1. Effect of copolymer composition on pH-dependent the light of the ionization of ionic groups present in the
swelling behavior network structure that the swelling of the hydrogel
increases due to increasing the osmotic pressure and
The copolymer composition influences significantly charge repulsion within the hydrogel. The swelling
on the swelling behavior of the prepared copolymer. Fig. ability of DMAEMA rich copolymer at pH 1 would
1a shows the effect of comonomer composition on the be mainly attributed to the hydration of the protonated
equilibrium swelling of the produced copolymer hydro- amino groups. The decrease in the degree of swelling
gels at pH 1, 3, 4 and 8. At low pH value (pH 1), the resulted from the increase in the AAc content due to the
DMAEMA rich copolymer hydrogel (DMAEMA increase in the number of the associated carboxylic
25 mol%) possesses high degree of swelling. Such groups.
Contrary, at high pH value, the relatively low swelling
ability of DMAEMA rich copolymer would be mainly
attributed the restriction applied by the presence of
5000
amino groups (which possesses lower hydrophilicity) on
the hydration of the dissociated carboxylic groups. The
Swelling degree (%)

4000
degree of swelling increases by increasing the AAc
content due to the increase in the number of dissociated
3000
carboxylic groups.
Fig. 1b shows the pH dependent equilibrium swelling
2000
of AAc/DMAEMA copolymer of different comonomer
compositions. As shown in the figure, pure PAAc show
1000
pH-dependent phase transition starts at pH 3 before
which there is no swelling whereas the degree of swelling
0
75 80 85 90 95 100 increases by increasing the pH value. In the same time,
(a) AAc content inthe copolymer (mol%) the increment of DMAEMA content in the copolymer
results in the appearance of double-side pH-dependent
6000 phase transition at both pH 3 and 4. At pH values lower
than pH 3, copolymer possesses high degree of swelling
5000 and it increase by lowering the pH value. At pH values
higher than pH 4, copolymer possesses high degree of
Swelling degree (%)

4000 swelling and it increase by increasing the pH value. At

pH values ranged from pH 3 to 4, the AAc/DMAEMA
3000
copolymer possesses the lowest degree of swelling.
2000 At low pH values, ionization of amino groups takes
place leading to the increase in the swelling degree of the
1000 DMAEMA-rich hydrogel due to the protonation of the
amino groups. By increasing the pH value, such degree
0 of ionization decreases and as a result, the hydration
0 2 3 4 5 6 7 8
(b) pH degree reduced leading to the decrease in the swelling
degree. At the pH values ranged from pH 3 to 4, ionic
Fig. 1. (a) Effect of (AAc/DMAEMA) copolymer composition on
interactions occur between the two oppositely charged
their equilibrium swelling in buffer solutions of different pH: (K)
pH 1, (J) pH 3, (.) pH 4 and (,) pH 8. (b) pH-dependent equilibrium functional groups and lead to the formation of
swelling of (AAc/DMAEMA) copolymer of different AAc content interpolymer polyelectrolyte complex. Complex forma-
(mol%): (K) 75, (J) 80, (.) 85 and (,) 100. tion consequently decreases the swelling degree that the
 ARTICLE IN PRESS
2736 A. El-Hag Ali Said / Biomaterials 26 (2005) 2733–2739

functional groups responsible for swelling (carboxylic increased to be almost similar to that at pH 1 which
groups of AAc and amino groups of DMAEMA) indicates that the complexed carboxylic groups got free.
are involved in the complex formation [16,23,24]. FT-IR data confirmed the complex formation at pH 4
The further increase in the pH value increases the between AAc and DMAEMA in their copolymer.
ionization degree of carboxylic groups and deprotona- Similar electrostatic interaction was observed by Cerrai
tion of the amino groups leading to destroying the et al. [25,26], Anh et al. [27] and Hu et al. [28].
formed interpolymer polyelectrolyte complex and as a Thermogravimetric analysis was employed to study
result increasing the degree of swelling. the effect of interpolymer complex formation on the
FT-IR was used to follow the effect of pH on the thermal behavior of the copolymer. Fig. 3 shows the
interpolymer complex formation. Fig. 2 shows FTIR thermograms of dried AAc/DMAEMA (75/25 mol%)
spectra of AAc/DMAEMA (75/25 mol %) dry copoly- copolymer swollen at buffer solutions of pH 1, 4 and 8.
mer swollen at buffer solution of pH 1, 4 and 8. The at pH 1. The copolymer showed the four famous
carbonyl band of PAAc appeared at 1728 cm1 for the degradation steps of PAAc which are: the loss of the
copolymer swollen at buffer solution of pH 1. The band water associated with the copolymer, an intermolecular
appeared at 1642 cm1 could be assigned to the dehydration and anhydride formation, decarboxylation
intermolecular hydrogen bonding between carboxylic and finally back bone degradation at 155, 245, 260 and
groups, whereas for the AAc/DMAEMA copolymer 410 1C, respectively [15]. Meanwhile, the TGA thermo-
swollen at pH 4, such band, at 1642 cm1, was shifted gram of the copolymer swollen at pH 4 showed different
down to a lower value at 1623 cm1 and became of thermal behavior, that in addition of the four degrada-
higher intensity and more broad. Meanwhile, the tion steps a major degradation steps appeared at 200 1C
carbonyl band of PAAc was also slightly shifted down which might be attributed to amidation reaction due to
and became of lower intensity. The foregoing results the complex formed between carboxylic groups of AAc
could be attributed to the intermolecular complexation and the amino groups of DMAEMA which facilitate
between oppositely charged carboxylic groups of AAc such process [26]. On the other hand, the TGA
and amino groups of DMAEMA, which consume a thermograms showed that the dried copolymer swollen
large number of carboxylic groups in such complexation at buffer solution of pH 8 possesses higher thermal
process. On the other hand, the FT-IR spectrum of stability than both copolymers swollen at buffer
AAc/DMAEMA copolymer swollen at pH 8 showed the solutions of pH 1 and 4. It showed the liberation of
dissociation of the interpolymer complex formed at pH water associated with the copolymer at 140 1C followed
4, that the peak at 1623 cm1 was shifted back to by decarboxylation at 260 1C and finally back bone
1635 cm1 which is very near to its value at pH 1 and its degradation at 400 1C. The absence of the intermole-
intensity and broadness became less than that at pH 4. cular dehydration degradation step might be attributed
Also, the intensity of the carbonyl group at 1720 to the change in the molecular structure of the
carboxylic groups. Such a structural change is the so-
called scrambled-egg structure that sterically inhibits the
cyclization reaction between the COO groups in AAc
(a)
chains and improves its thermal stability [26].

100
Tr a n s m i t t a n c e (%)

(b)
80
Weight loss (%)

60

(c) 40

20

0
2000 1900 1800 1700 1600 1500 0 100 200 300 400 500 600
Wave number cm -1 Temperature oC

Fig. 2. FT-IR spectra in the region between 2000 and 1500 cm1 of dry Fig. 3. Thermogravimetric behavior of dry (AAc/DMAEMA) copo-
(AAc/DMAEMA) copolymer swollen in buffer solutions of different lymer swollen in buffer solutions of different pH: (–––) pH 1, (yy)
pH: (a) pH 1, (b) pH 4 and (c) pH 8. pH 4 and (- - - -) pH 8.
 ARTICLE IN PRESS
A. El-Hag Ali Said / Biomaterials 26 (2005) 2733–2739 2737

3.2. Swelling kinetics

Hydrogels, which are hydrophilic network polymers

and glassy in the dehydrated form, have the ability to
release the entrapped drug in aqueous medium and
regulating such release by controlling water diffusion.
The release of water-soluble drug from such dehydrated
hydrogel takes place by simultaneous absorption of
water and desorption of drug via a swelling controlled
diffusion mechanism. Studying swelling kinetics would
give good prediction of the diffusion behavior and the
ability of the hydrogel to be used as drug delivery
system.
Diffusion of water to the glassy polymeric matrix
generally exhibits a behavior ranging from Fickian to
Case II extremes depending on the experimental
conditions and thermodynamic compatibility between
water and copolymer hydrogel [29]. Diffusion type can Fig. 5. Representation of the fractional swelling of (AAc/DMAEMA)
be distinguished by fitting the fractional swelling of (75/25 mol%) copolymer in buffer solutions of different pH against
water (F) to the following empirical relation [29]: time: (K) pH 1, (J) pH 4 and (.) pH 8.

F ¼ ðM t =M 1 Þ ¼ Ktn ;
and turned to non-Fickian at High pH values (pH 4 and
where (Mt) is the absorbed water at time (t), M is the pH 8) which indicates the ability of the copolymer to
absorbed water at equilibrium, K is system characteriz- protect the loaded drug at pH 1 and to release it at
ing constant and n is an exponent characteristic the higher pH values. On the other hand, DMAEMA-rich
diffusion mode. For n ¼ 0:5; water follows the well- copolymer (75/25 mol %) (AAc/DMAEMA) possesses
known Fickian diffusion mechanism. For n40:5; non- non-Fickian diffusion at both pH 8 and pH 1, which
Fickian diffusion behavior is generally observed. Final- indicates the ability of the copolymer to release the
ly, for n ¼ 1; Case-II transport mechanism is followed. loaded drug at low pH values as well as high pH values.
Figs. 4 and 5 show the effect of pH value of the For controlled diffusion process, the fraction of
surrounding medium on swelling rate and the type of swelling due to the water uptake (F) can be also
water diffusion to the glassy copolymer and Table 1 expressed by the following equation [30]:
summarizes diffusion data of (AAc/DMAEMA) copo-
lymers of different compositions concluded from similar F ¼ 4ðDt=ph2 Þ1=2 ;
figures. It is clear that, AAc-rich copolymer (95/5 mol%) where D is the apparent diffusion coefficient for the
(AAc/DMAEMA) possesses Fickian diffusion at pH 1 transport of water towards the interior of the hydrogel,
h is the xerogel thickness and t is the time. This equation
is a solution of Fick’s second law under simple
boundary conditions such as swelling in water and
biological fluids or simple geometric forms such as discs,
cylinders and spheres. Plotting of fraction water uptake
(F) against the square root of time (t1/2), Fig. 6, linearity
is obtained in the first stage of the process, correspond-
ing to the values of F o0:5 allow the calculation of the
apparent diffusion coefficient from the slop of the
straight line. Table 2 summarizes the effect of copolymer
composition and surrounding pH value on the apparent
diffusion coefficient (D). The table shows that the
copolymer composition plays an important role at both
pH 1 and 8. At pH 1, D values increase from 0.1 to 0.8
by the increase in DMAEMA content from 10 to
30 mol% whereas, at pH 8, D values slightly increase
Fig. 4. Time dependent swelling of dry (AAc/DMAEMA)(75/ from 0.3 to 0.42 by the increase in AAc content from 70
25 mol%) copolymer in buffer solutions of different pH: (K) pH 1, to 90 mol%. At pH 4, all AAc/DMAEMA hydrogels
(J) pH 4 and (.) pH 8. possess the lowest D values regardless their composition.
 ARTICLE IN PRESS
2738 A. El-Hag Ali Said / Biomaterials 26 (2005) 2733–2739

Table 1 Table 2
Effect of (AAc/DMAEMA) copolymer composition and medium pH Effect of (AAc/DMAEMA) copolymer composition and medium pH
on their swelling kinetics on their apparent diffusion coefficient

AAc content (mol%) Diffusion parameters AAc content (mol%) Apparent diffusion coefficient

pH 1 pH 4 pH 8 pH 1 pH 4 pH 8

K n r2 K n r2 K n r2 D r2 D r2 D r2

70 –4.2 0.72 98 –3.3 0.5 99 –4.5 0.63 99 70 0.8 98 0.15 99 0.5 98

80 –4.7 0.74 98 –2.7 0.42 99 –5.0 0.67 99 80 0.26 99 0.02 85 0.35 98
90 –3.2 0.49 99 –4.2 0.6 99 –4.8 0.65 99 90 0.1 98 0.21 99 0.43 99

Fig. 7. Release profile of ketoprofen from (AAc/DMAEMA) copo-

lymers of different AAc content in buffer solution of pH 1 for 3.5 h
followed by buffer solutions of pH 7 up to 24 h: (K) 75, (J) 80, (.) 90
and (,) 100.

Fig. 6. Representation of swelling of (AAc/DMAEMA) (75/25 mol%)

copolymer in buffer solutions of different pH against time: (K) pH 1, destroyed in the upper gastrointestinal track. To accept
(J) pH 4 and (.) pH 8.
the copolymer as carrier for Colon-specific drug delivery
system it should not release the drug and protect it at
The increment in D values at pH 1 by the increase in stomach, pH 1, and start to release the drug at colon
DMAEMA content and at pH 8 by the increase in AAc and small intestine, pH 7.
content could be attributed to the hydrophilic character
of the hydrogel. When the hydrophilic character of the 3.3.1. Release of Ketoprofen
hydrogel increases, either by the protonation of amino The release experiments was carried out at buffer
groups at pH 1 or by the dissociation of carboxylic solution of pH 1 which is almost similar to that of
groups at pH 8, its swelling in aqueous medium turns stomach medium for 3.5 h and at buffer solution of pH 7
out to be quicker. On the other hand, the decrement in which is similar to that of the intestine medium for 18 h.
D values at pH 4 may be attributed to the increase in Fig. 7 shows the drug release behavior of AAc/
crosslinking density results from the interpolymer DMAEMA copolymer hydrogel of different composi-
complex formation. These results come in good agree- tions as a function of time at pH 1 and 7. The figure
ment with the forgoing results in our study to confirm shows that there is no significant drug release at pH 1
the formation of interpolymer complex between car- whereas the drug release occurs as soon as the
boxylic and amino groups of AAc and DMAEMA, copolymer transferred to buffer solution of pH 7. The
respectively at pH 4. results show that the drug release is not only pH
dependent but it also shows the influence of the
3.3. Colon-specific drug delivery copolymer composition on the release rate and total
released drug. As AAc content increase in the copoly-
Colon-specific drug delivery is useful in several mer, the release rate and total released drug increases.
therapeutic areas such as topical treatment of colonic These results could be attributed to the swelling
diseases and oral delivery of proteins and drugs behavior of the copolymer hydrogel.
 ARTICLE IN PRESS
A. El-Hag Ali Said / Biomaterials 26 (2005) 2733–2739 2739

4. Conclusion [14] Nishi S, Kotak T. Complex-forming poly(oxyethylene)/poly

(acrylic acid) interpenetrating polymer networks. 2. Function as
a chemical valve. Macromolecules 1986;19:978–84.
A new interpolymer polyelectrolyte complex of
[15] Cerri P, Guerra GD, Maltinti S, Tricoli M. Physicochemical
AAc-co-DMAEMA was synthesized by g-radiation- properties of poly(allylammonium acrylate) complexes obtained
induced copolymerization and crosslinking. The pre- by radical template polymerization. Macromol Rapid Commun
pared copolymer showed a unique pH-sensitivity that 1994;15:983–90.
allows the copolymer to serve in different fields [16] Mun GA, Nurkeeva ZS, Khutoryanskiy VV, Yermukhambetova
depending on the copolymer composition. Investigating BB, Koblanov SM, Arkhipova IA. Radiation synthesis of
hydrogels based on copolymers of vinyl ethers of monoethano-
the ability of the prepared copolymer to be used as a lamine and ethyleneglycol and their interaction with poly (acrylic
carrier for colon-specific drug deliver system showed a acid). Radiat Phys Chem 2003;67:745–9.
promising result not only in the field of drug targeting [17] Thunemann AF, Muller M, Dautzenberg H, Joanny J-F, Lowen
but it also shows the possibility of controlling the H. Polyelectrolyte complexes. Adv Polym Sci 2004;166:113–71.
released amount and release rate by controlling the [18] Nam SY, Lee YM. Pervaporation and properties of chitosan-
poly(acrylic acid) complex membranes. J Membr Sci 1997;135:
comonomer composition. 161–71.
[19] Kono K, Ohno T, Kumei T, Takagishi T. Permeability
characteristic of polyelectrolyte complex capsule membranes:
References effect of preparation condition on permeability. J Appl Polym
Sci 1996;59:687–93.
[1] Banker GS, Anderson NR. Tablets. In: Lanchman L, Lieberman [20] Yamamoto H, Senoo Y. Polyion complex fiber and capsule
HA, Kanig JL, editors. The theory and practice of industrial formed by self-assembly of chitosan and gellan at solution
pharmacy. 1987. p. 293–345. interfaces. Macromol Chem Phys 2000;201(1):84–92.
[2] Peppas NA. Hydrogels in medicine and pharmacy, vol. 3. Boca [21] Barbani N, Lazzeri L, Cristallini C, Cascone MG, Polacco G,
Raton, FL: CRC Press; 1987. Pizzirani G. Bioartificial materials based on blends of collagen
[3] Park K. Controlled drug delivery: challenges and strategies. and poly(acrylic acid). J Appl Polym Sci 1999;72:971–6.
Washington, DC, USA: American Chemical Society; 1997. [22] Cruickshank R, Duguid JP, Marmion BP, Swain RHA, Churchill
[4] Pauletti G, Gangwar S, Knipp GT, Nerurkar MM, Okuma FW, L. Medical microbiology: (The practice of medical microbiology),
Tamura K, Siahaan TJ, Borchardt RT. Structural requirements vol. II. Edinburgh and New York, 1975.
for intestinal absorption of peptide drugs. J Control Rel [23] Kono K, Tabata F, Takagishi T. pH-responsive permeability of
1996;41:3–17. poly(acrylic acid)—poly(ethylenimine) complex capsule mem-
[5] Carinp GP, Mathiowitz E. Oral insulin delivery. Adv Drug Deliv brane. J Membr Sci 1993;76:233–43.
Rev 1999;35:249–57. [24] de la Torre MP, Enobakhare Y, Torrado G, Torrado S. Release
[6] Yeh PY, Berenson MM, Samowitz WS, Kopeckova P, Kopecek J. of amoxicillin from polyionic complexes of chitosan and poly
Site-specific drug delivery and penetration enhancement in the (acrylic acid) study of polymer/polymer and polymer/drug inter-
gastrointestinal tract. J Control Rel 1995;36:109–24. actions within the network structure. Biomaterials 2003;24:
[7] Tao SL, Lubeley MW, Desai TA. Synthesis of cytoadhesive 1499–506.
poly(methylmethacrylate) for applications in targeted drug [25] Cerrai P, Guerra GD, Maltinti S, Tricoli M. Physicochemical
delivery. J Biomed Mater Res: Part A 2003;67A(2):369–75. properties of poly(ally1ammonium acrylate) complexes obtained
[8] Bajpai SK, Bajpai M, Dengre R, Okano T. Chemically treated by radical template polymerization. Macromol Rapid Commun
hard gelatin capsules for colon-targeted drug delivery: a novel 1994;15:983–90.
approach. J Appl Polym Sci 2003;89(8):2277–82. [26] Cerrai P, Guerra GD, Tricoli M. Polyelectrolyte complexes
[9] Okano T, Yoshida R. Biomedical applications of polymeric obtained by radical polymerization in the presence of chitosan.
materials. Boca Raton, FL: CRC Press; 1993 Chapter 6. Macromol Chem Phys 1996;197:3567–79.
[10] Liu S, Liu M. Synthesis and characterization of temperature- and [27] Ahn JS, Choi HK, Cho CS, Chun M, Ryu J, Jung J, Kim Y, Cho
pH-sensitive poly(N,N-diethylacrylamide-co-methacrylic acid). CS. Release of triamcinolone acetonide from mucoadhesive
J Appl Polym Sci 2003;90(13):3563–8. polymer composed of chitosan and poly (acrylic acid) in vitro.
[11] Xiao XC, Chu LY, Chen WM, Wang S, Li Y. Positively thermo- Biomaterials 2002;23:1411–6.
sensitive monodisperse core-shell microspheres. Adv Funct Mater [28] Hu Y, Jiang X, Ding Y, Ge H, Yuan Y, Yang C. Synthesis and
2003;13(11):847–52. characterization of chitosan-poly (acrylic acid) nanoparticles.
[12] Park SE, Nho YC, Lim YM, Kim HI. Preparation of pH-sensitive Biomaterials 2002;23:3193–201.
poly(vinyl alcohol-g-methacrylic acid) and poly(vinyl alcohol-g- [29] Lee PI. Kinetics of drug release from hydrogel matrices. J Control
acrylic acid) hydrogels by gamma ray irradiation and their insulin Rel 1985;2:277–88.
release behavior. J Appl Polym Sci 2004;91(1):636–43. [30] Garcia O, Blanco MD, Martin JA, Tejon JM. 5-Fluorouracil
[13] Evans DF, Pye G, Bramley R, Clark AG, Dyson TJ, Hardcastle trapping in poly(2-hydroxyethyl methacrylate-co-acrylamide)
JD. Measurement of gastrointestinal pH profiles in normal hydrogels: in vitro drug delivery studies. Eur Polym J 2000;36:
ambulant human subjects. Gut 1988;29:1035–41. 111–22.