Structure and Release Behavior of PMMA/Silica

Composite Drug Delivery System

MEI LIN,1,2 HAITAO WANG,1 SHENG MENG,1 WEI ZHONG,1 ZHULAI LI,2 RUI CAI,1 ZHUO CHEN,1 XIAOYU ZHOU,1
QIANGGUO DU1
1

The Key Laboratory of Molecular Engineering of Polymers, Ministry of Education and Department of Macromolecular
Science, Fudan University, Shanghai 200433, China
2

School of Pharmacy, Fujian Medical University, Fuzhou 350004, China

Received 22 May 2006; revised 12 August 2006; accepted 26 September 2006

Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20809

ABSTRACT: The preparation, characterization, and in vitro release of aspirin from

polymethylmethacrylate (PMMA)/silica composites prepared via a solgel route are
reported. The in vitro drug release test revealed that the release rate of aspirin in PBS
increased with the silica content in the composites; on the contrary, the increase of the
content of 3-(trimethoxysilyl) propyl methacrylate (MSMA), a coupling agent, decreased
the drug release rate. The drug release rate/composite structure relationship was studied
using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy
(SEM), and swelling ratio (SR) measurement. The results indicated that the interface
between polymer matrix and inorganic fillers has significant influence on the drug
release behavior of the composite materials. In addition, models of mass transfer based on
Fickian diffusion law at constant temperature and pressure were employed to analyze the
results of the in vitro drug release experiments. The drug release behaviors of the
composite samples fitted well with the Fickian diffusion model. The values of k, which is
in direct proportion to drug release rate, increased with the increasing content of silica
while decreased with that of MSMA in the composite samples. 2006 Wiley-Liss, Inc. and
the American Pharmacists Association J Pharm Sci 96:15181526, 2007

Keywords:

PMMA; silica; controlled release; sol-gel; composite

INTRODUCTION
There is growing scientific interest in developing
innovative biomaterials for biomedical applications. Among a wide range of polymeric materials,
poly (methyl methacrylate) (PMMA) has been
extensively studied in the past decades. It is
biocompatible and biostable materials, and has
already been used in bone-defect restoration.
For instance, Kelmn and other researchers have
utilized PMMA for approximately 20 years in
Europe for the management of open fractures,
chronic osteomyelitis, total joint arthroplasty, and
Correspondence to: Wei Zhong and Qiangguo Du (Telephone:
86-21-65642392; Fax: 86-21-65640293;
E-mail: weizhong@fudan.edu.cn; qgdu@fudan.edu.cn)
Journal of Pharmaceutical Sciences, Vol. 96, 15181526 (2007)
2006 Wiley-Liss, Inc. and the American Pharmacists Association

1518

so on.1 However, its bio-inertness has restricted

its application; no chemical or biological bonding
occurs at the interface between the PMMA and
bone. A novel approach to modification of PMMA
with the addition of bioactive glasses/ceramics
fillers has been proposed.2,3 In those polyacrylates-based composite materials, bioactive glasses
are able to bond to living tissues without fibrous
capsule formation, and can form an amorphous
calcium phosphate layer with an apatite-like structure when in contact with biological fluids.46
On the other hand, the wound closure and
implanted materials often induce infection and
inflammatory response. Hence, the incorporation
of anti-inflammatory drugs into these materials
for local controlled release appears to be a very
interesting alternative. In some reports, using
polyacrylate composite materials, people are

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 6, JUNE 2007

PMMA/SILICA COMPOSITE DRUG DELIVERY SYSTEM

succeeded in attaining an effective drug concentration at the inflammatory site without implanting extra materials, also, the effect of the inorganic
fillers on the drug release property of these
composites has been reported.69
It has been well documented that the interface
between polymer and inorganic fillers plays an
important role in the performance of polymerinorganic composite materials, such as gas permeability, selectivity, mechanical properties, and so
on.1012 It is often requested the interface between
the two materials in the composites should be well
adhesive. Organo-functional silanes, represented
as RSiX3, are often used as coupling agents to
enhance the adhesion between polymer and silica
filler.13 The methoxy or ethoxy groups, represented by X, can be hydrolyzed with water. The
silanol groups of hydrolyzed coupling agents can
be condensed with other silanol groups on a glass
or ceramic surface. The organo-functional group,
R, can be bonded chemically to a polymer matrix.
Thus, the adhesion between polymer and inorganic fillers was improved due to the chemical
bonds that formed at the interface.14 To our best
knowledge, how the interface inside organic
inorganic composite materials as well as the
coupling agents affect the drug release property
has not been studied. Understanding the interfacial interactions and structure is important to
better design and application of organicinorganic
composite drug delivery systems.
In present work, Aspirin was used as a model
drug and the drug release properties of PMMA/
silica composites were studied. Contrary to those
reported, composite drug delivery systems normally made by mixing of the polymer solution with
inorganic particles, the composites were prepared
via a solgel process by solvent mixing of PMMA
copolymers with silicic acid oligomer (SAO), a
novel silica precursor. The structure of the composite materials was characterized in order to study
the impact of the phase structure and interface
adhesion in the composite on their drug release
properties. In addition, models of mass transfer
employing Fickian diffusion law at constant
temperature and pressure were employed to
elucidate the experimental results.

trile (AIBN), and sodium silicate (Na2SiO3
9H2O)

were all analytical reagent grade and purchased
from Shanghai Chemical Reagents Company,
China National Medicines (Group), Shanghai,
China. 3-(Trimethoxysilyl) propyl methacrylate
(MSMA) was analytical reagent grade and purchased from ACROS Organics, Geel, Belgium and
used without further purification. MMA and THF
were purified by distillation and AIBN was used
after recrystallization from ethanol. Aspirin was
kindly provided by Fujian medical university.
Preparation of MMAMSMA Copolymer
The monomers, MMA and MSMA, and the
initiator, AIBN (0.2 wt% in the monomers), were
added to a reaction flask and were polymerized at
708C under nitrogen atmosphere for 12 h. The
resulting polymer was purified by precipitating in
methanol and then dried in vacuo at room
temperature. The weight ratio of [MSMA] to
([MMA] [MSMA]) was 0, 0.035, and 0.05,
respectively (denoted as PMMA, PMMA-3.5%
MSMA, and PMMA-5% MSMA, respectively).
The average molecular weight and polydispersity
(D) are listed in Table 1.
Preparation of Silica Precursor
Silicic acid oligomer (SAO) was prepared according to the method described in reference [15]
but slightly modified. Briefly, saturated sodium
silicate solution was adjusted to pH 2.0 with
1.0 mol/L H2SO4 aqueous solution under stirring
at ambient condition. Then the solution was
saturated with NaCl. The SAOTHF solution
was extracted from the solution with an equal
volume of THF.
Preparation of Drug-Loading and Drug-Free
PMMA/Silica Composite Films
A solgel route was adopted in the process of the
preparation of PMMA/silica composites with or
Table 1. The Average Molecular Weight and
Polydispersity of Synthesized Polymers

MATERIALS AND METHODS

Materials
Methyl methacrylate (MMA), tetrahydrofuran
(THF), sulfuric acid (H2SO4), azobisisobutyroniDOI 10.1002/jps

1519

Mw  104
Mn  104
Polydispersity

PMMA

PMMA-3.5%
MSMA

PMMA-5%
MSMA

7.0
4.3
1.64

7.9
4.6
1.71

7.4
4.2
1.75

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1520

LIN ET AL.

without aspirin embedded. Appropriate amounts

of silica precursor and aspirin (23 wt% of matrix
weight, if necessary) were introduced to a THF
solution of MMAMSMA copolymer and the
mixture was stirred magnetically at room temperature for 2 h to obtain a uniform and transparent solution. The solution was cast on a Teflon
disk and then dried at 808C for 12 h. Each sample
was punched with a cork borer into round disks
(R 7.0 mm, the film thickness is 0.25  0.02 mm).
PMMA/silica composite samples without drug
were prepared by the same method.
The composition of PMMA/SiO2 composite
samples can be learnt from their names. They
were named as PMMA x/y, where x denotes MSMA
weight content in copolymer and y denotes the
silica weight content in the composites. The silica
content was calculated from the silica content of
the SAOTHF solution.

Where Wwet and W0 are weights of the wet films

measured at time t, and initial weight of the dry
films before immersion, respectively.
In Vitro Drug Release Study
Each drug-loaded composite sample was soaked
in 5 mL of phosphate-buffered saline (PBS,
pH  7.4) and placed inside the incubator maintained at 37  0.18C with continuous shaking.
After specific intervals, the PBS buffer was
removed and replaced with fresh PBS buffer
solution. Aspirin content in the buffer solution
was measured by UV-Visible spectrophotometer
(Unico UV-2000) at the wavelength lmax
266 nm. All the drug release studies were carried
out in triplicate.

RESULTS AND DISCUSSION

Characterization

FT-IR Spectra

FT-IR spectra were recorded in thin polymer films

on a Nicolet Nexus 470 FTIR Spectrophotometer.
The morphologies of the fracture surface of the
PMMA/silica composite films were observed with a
scanning electron microscope (SEM, Tescan s. r. o,
Brno, Czech Republic). The molecular weight and
molecular weight distribution of the polymers
were determined by gel permeation chromatography (GPC, Agilent Technologies, USA). GPC
measurement was carried out at 308C at a flow
rate of 1 mL/min using THF as solvent. The
instrument was calibrated using Polystyrene as
standard. The glass transition temperature of
different composites was measured by a dynamic
mechanical analyzer (Netzsch DMA242). The
measurement was obtained at a heating rate of
38C/min and a frequency of 1 Hz. To estimate the
crosslinking effect of the inorganic moieties to
PMMA matrix, PMMA and the composite films
were extracted with THF for 10 days.16

Figure 1 shows the FT-IR spectra of PMMA

MSMA copolymer and composites with 5 wt%,
10 wt%, and 20 wt% silica, respectively. The
characteristic peaks of the stretching vibration
bands of the C O and CH bonds in the PMMA
segment at 1730 cm1 and 2950 cm1 were
observed. After introducing inorganic components, a broad and strong absorption band near
3400 cm1 corresponding to OH emerged. With
the peak of carbonyl groups at 1730 cm1 as
control, it can be seen that the peak at 960 cm1

The Swelling Ratio of Matrices

In a typical test, the films after having been
soaked in PBS solution for 20 days were weighted
after excess water was wiped off from the film
surface with filter paper. The swelling ratio (SR)
of matrices was calculated using the following
Eq. 1:
SR

Wwet  W0
 100
W0

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 6, JUNE 2007

Figure 1. FTIR spectra of composite samples with

different content of silica. (a) PMMA5/0, (b) PMMA5/5,
(c) PMMA5/10, (d) PMMA5/20.
DOI 10.1002/jps

PMMA/SILICA COMPOSITE DRUG DELIVERY SYSTEM

1521

corresponding to SiOH was enhanced with

increasing silica content, revealing that silica
was successfully introduced into polymer matrix
and the condensation of SiOH were not complete
during the thermal treatment.10,17 Typical absorption bands for SiOSi near 1150 cm1 also
become stronger with increasing addition of silica
indicating the formation of a more compact silica
network.14,17,18
Solvent Extraction Results
It is important to know whether, and to what
extent, the reaction between the silica particles
and the polymer matrix has occurred. Therefore,
THF extractions of PMMA/silica composite films
were performed for 10 days to evaluate the interaction between organic and inorganic phases. If
there were no strong interactions between PMMA
and the inorganic moieties, THF, a good solvent
for PMMA would dissolve the polymer and leave
the inorganic component whose weight will almost
equal to the amount of silica used in the composites. The resulting values of the residue percentage were listed in Table 2. The residue from the
extraction of PMMA0/20 composite was zero,
which meant that all the polymers were dissolved
and there left no visible object for weighing in
the solution. After 3.5% MSMA was introduced,
the residue jumped to 92.6% and increased with
increasing amount of MSMA in composites (96.8%
for PMMA5/20). That is to say, with the existence
of MSMA in the composites, strong chemical
bonds were formed between polymer and silica
particles. The crosslinking between organic and
inorganic phases was strengthened, and silica
particles were not easily drop off from composites with MSMA.

SEM Images
Figure 2AC shows the scanning electron microscope (SEM) photographs of the fracture surface
of the PMMA/silica composite samples with
20 wt% silica but different amounts of MSMA.
The silica particle size of sample PMMA0/20
(Fig. 2A with 0% MSMA) is about 12 mm,
Table 2.

whereas that of composite PMMA3.5/20 (with

3.5% MSMA) is about 11.5 mm (Fig. 2B), and the
size of composite PMMA5/20 is even smaller
(Fig. 2C about 1 mm). By comparison of the three
samples (PMMA0/20, PMMA3.5/20, and PMMA5/
20), it can be observed that the silica particle size
in the composites decreases with the increasing
content of MSMA. The silica particle sizes of
the composites are all in micron scale, unlike the
sub-micron or even nano-scale silica particles
reported in other researches on PMMA nanocomposites.2,19 The reason may come from the
different way of the preparing of the silica sol in
this study. Those larger particles are easier to
observe and they are still able to make substantial
changes on the drug release behavior of the

THF Extraction Results of the Composite Films

Sample Name
Residue (%)

DOI 10.1002/jps

Figure 2. SEM pictures showing fracture surface

of the composite films with different silica and MSMA
contents. (A) PMMA0/20, (B) PMMA3.5/20, (C) PMMA5/
20, (D) PMMA5/10, (E) PMMA5/5.

PMMA0/20

PMMA3.5/20

PMMA5/20

92.6

96.8

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1522

LIN ET AL.

composites. It can also be observed that the

dispersion of the silica particles in the composites
becomes more even, narrower in size distribution,
and less aggregated with the addition of MSMA.
In addition, it is found that the surface of
PMMA0/20 composite was very clean which
indicate the weak adhesive between PMMA
matrix and silica. It seems that the interfacial
void is larger than those of the composite samples
containing MSMA, and silica particles are likely
to drop (Fig. 2A), while the surfaces of composites
having MSMA moieties are rough. Silica particles
firmly adhered to the polymer matrix (Fig. 2B,C),
especially the PMMA5/20 composite, and the
interface is blurry. This is due to the existence of
chemical bonds between the polymer matrix and
silica particles after the addition of MSMA. This
result is consistent with the results from solvent
extraction experiments. It confirms that the
compatibility and adhesion between PMMA and
silica can be improved by the addition of coupling
agent MSMA.
Figure 2CE are the SEM images of PMMA5/
20, PMMA5/10, PMMA5/5 composites, respectively. These three composite samples contained
same amount of MSMA (5 wt%) but different
amount of silica. It can be observed that the silica
particles on fractured surface become denser with
increasing silica content in the sample. That is to
say, having same amount of MSMA, the polymer/
inorganic interface area increase and the adhesive
force between the two phases may be weakened
with increasing amount of silica.
Swelling Measurement and Dynamic
Mechanical Analysis (DMA)
It is well known that water uptake or SR of the
matrix-type drug carriers would greatly influence
their drug release behaviors.20,21 In this study,
the SR of the prepared composite samples was
determined in order to know whether SR would
influence their drug release properties. Figure 3
presents the results of the SR of different PMMA/
silica composite samples after soaking in PBS
solution for 20 days. Composites without MSMA
reaches SR about 20%, while the composites with
MSMA only about 2%. It has been reported that
in organic/inorganic composite, water-uptake
mainly occurs in the organic phase matrix.22
Comparing these samples, it can be easily observed that MSMA strongly influenced the SR of
composites. Use of MSMA remarkably reduced
equilibrium water uptake for MSMA-modified
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 6, JUNE 2007

Figure 3. Swelling ratio of the composite films. Error

bars represent plus and minus one standard deviation.

samples. This reduction should be attributed to

the improved interfacial adhesion that avoided an
easy penetration of water molecules into the
modified composites and reduced water accumulation in interfacial voids.23,24 SEM photographs
(Fig. 2) of composites have shown that interfacial
void of composites without MSMA addition is
larger than those of composites containing
MSMA. The SR values correspond to the results
of SEM photographs. Also from Figure 3, the SR of
those samples without MSMA increased with
increasing silica content, this phenomenon can
be attributed to the weak interfacial adhesion and
the increased interfacial surface. It has been
reported that the increasing of water content
would increase the diffusion path of drug. The
lower water content, the lower drug release rate
is.25 So we may assume that the drug diffusion
rate of the series of composites without MSMA is
fastest since their SR value is much larger than
the other two series (composites with 3.5% MSMA
and 5% MSMA, respectively), and the drug
diffusion rates of the latter two series are similar
because of their similar SR values.
Normally, the glass transition temperature
(Tg) of polymer composites increase after adding
inorganic fillers, and the properties of composites
are often changed correspondingly.26 We also
measured the Tg of samples with different content
of silica while their MSMA content of the polymer
matrix is 5%. Measurements of dynamic mechanical analysis (DMA) provided information on
transitions occurring in materials. The DMA
results revealed that all the composite samples
had their storage moduli between 2 and 2.5 GPa at
room temperature. Increase in Tg of PMMAsilica
DOI 10.1002/jps

PMMA/SILICA COMPOSITE DRUG DELIVERY SYSTEM

1523

Figure 4. Tand curves of the composites with different silica contents.

composites compared to pure polymer has also

been observed. In Figure 4, the tand curves
indicate that the higher the silica content, the
higher Tg of the composites. The Tg of PMMA5/0
was about 102.28C, while the Tg of PMMA5/20 was
raised to 114.08C. This can be interpreted by the
reduction of the chain mobility caused by the
presence of silica particles as well as the coupling
agent MSMA.15,27 Diffusion rate of small molecules through polymer matrix is often lowered
with the increasing Tg for the increasing restriction of chain-segment mobility.28 Since Aspirin is
also a small molecule, Tg may influence the Asprin
release behaviors of PMMA/silica composites.
However, the Tg of each composite in this study
is above 1008C, which is much higher than the
temperature of release study. Therefore, the effect
of Tg difference may be less important for drug
release study. This will be further discussed in the
next section.
Drug Release Study
Saltzman and coworkers reported that the release
rate of dexamethasone in poly(ethylene-co-vinyl
acetate)(EVAc)/layered organosilicate nanocomposites was decreased with increasing amount of
inorganic moieties due to the changes in diffusion
characteristics resulting from the addition of
organosilicates.29 This is not the case in our
study. In Figure 5, the cumulative percentage of
aspirin released to PBS solution versus soaking
time was plotted for samples of the two series with
(Fig. 5B) and without MSMA (Fig. 5A), respecDOI 10.1002/jps

Figure 5. Release behavior of aspirin from composite

samples in PBS at 378C. Aspirin content in all the
samples are 23% (w/w). Error bars represent plus and
minus one standard deviation.

tively. The release profiles of these two series

were very similar: drug release rate increased
with the increase of silica content. This is not
always consistent with the SR results (Fig. 3) and
the change of Tg (Fig. 4). Normally those parameters like Tg reflect the chain-segment mobility
of the polymer matrix, it mainly influence the
bulk polymer diffusion properties. So there might
be other dominant factors for the drug release
property of the composite system containing both
polymer matrix and inorganic fillers. Joly et al.30
had studied the influence of silica content on gas
permeation of solgel polyimide/silica composite
system. They suggested that the gas permeability
increased with the silica content because silica
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1524

LIN ET AL.

created a particlepolymer interface, and this

interface provided the gate for small molecules
to desorption out. Our results were consistent
with their conclusion. As we can see from the SEM
images, with the increase of silica content, the
number of inorganic particles became larger, and
then more interfacial areas were formed which led
to easier water penetration and faster diffusion of
aspirin into PBS. Thus, the contribution of the
interface effect to the drug release mechanism
may be possible.
In order to further confirm the influence of
polymer/inorganic interface on drug release rate,
the drug release rate of composite samples with a
fixed content of silica (10%) but different amount of
MSMA were studied and the results were summarized in Figure 6. It can be seen that the drug
release rate decreased with the increasing content
of MSMA. There are two possible mechanisms:
First is the interfacial effect. From Figure 3, the SR
values of two series containing different amount of
MSMA were much lower than those of the other
series of samples without coupling agent. Evidence
can also be found from Figure 2 and Table 2. The
samples with MSMA had higher crosslinking
densities, they had blurred interface between
polymer matrix and silica particles, indicating
the better adhesion between two phases. And this
would decrease diffusion path of drug and leads to
slower drug release rate. The other mechanism is
the crosslinking effect of the MSMA to the polymer
matrix. Besides the improvement of interfacial
adhesion between polymer matrix and silica,

MSMA has also crosslinking effect to the polymer

chains. With higher MSMA content, the mobility
of the polymer chains were limited, this may result
in decreased diffusion rate of small molecules like
drug within the polymer matrix. This might be the
reason why the drug release of samples with 3.5%
and 5% coupling agent were different while their
SR values were nearly equivalent according to
Figure 3.
Drug Release Kinetics
The in vitro drug release data were analyzed to
study the drug release kinetics. This release
system follows the Fickian model for diffusion
from film. The equation resulting from this model
is given as Eq. (2):29,31,32
Mt
1
kt2
M0

Where Mt/M0 is the fraction of drug released, t is

the release time, k is a constant characteristic of
each sample.
The value of the diffusion coefficient, D, can be
calculated according to the relation:
r
D
k4
3
pl2
Where l corresponds to the thickness of film.
This model is valid for release of less than 60% of
initial load. From Eq. (2), a plot of the fraction of
aspirin released versus the square root of time
produced a straight line with a slope corresponding to the value of k. The values of k of different
composites were summarized in Table 3. The
values of R2 which are all close to 1 indicated that

Table 3. Summary of Release Kinetic Data of Aspirin

from PMMA/SiO2 Composites
Samples

Figure 6. Release of aspirin from composites with

10% silica as a function of time in PBS solution at 378C.
All matrices containing 23%(w/w) aspirin. Error bars
represent plus and minus 1 SD.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 6, JUNE 2007

PMMA0/0
PMMA0/5
PMMA0/10
PMMA0/20
PMMA3.5/0
PMMA3.5/5
PMMA3.5/10
PMMA3.5/20
PMMA5/0
PMMA5/5
PMMA5/10
PMMA5/20

k (day1)

R2

0.0442
0.0572
0.0692
0.0950
0.0299
0.0351
0.0495
0.0496
0.0266
0.0234
0.0444
0.0450

0.998
0.993
0.990
0.992
0.997
0.998
0.991
0.972
0.997
0.998
0.994
0.991

DOI 10.1002/jps

PMMA/SILICA COMPOSITE DRUG DELIVERY SYSTEM

the drug release behavior of most PMMA/silica

composite samples in this study followed the
Fickian model. The larger value of k corresponds
to the faster rate of drug released from composites.
Those values of k well supported the mechanisms
of drug release presented in the above discussion.
It can be seen from Table 3 that the values of k
increased with the increasing content of silica
while decreased with that of MSMA. The adverse
effect of interface and crosslinking led to almost
equivalent k values of PMMA0/0 and PMMA5/10
(0.0442 vs. 0.0444, respectively), which meant
equal drug rates of aspirin from the two samples.

CONCLUSION
In this study, PMMA/silica composite materials
with various MSMA proportion and silica content
have been prepared via solgel process. The
influence of MSMA proportion and silica content
on their drug release properties has been evaluated using aspirin as a model drug. The swelling
test and SEM results supported the hypothesis
that the interface between the polymer matrix
and silica particles played a key role in drug
release property of the composite system in PBS.
The drug release behaviors of the composite
samples fitted well with the Fickian diffusion
model. The drug release rate increased with the
increasing content of silica while decreased with
the amount of coupling agent in the composite
samples. The drug release rate of this composite
system can be modulated by adjusting the content
of both inorganic fillers and the coupling agent.

REFERENCES
1. Sivakumar M, Panduranga RK. 2000. Synthesis
and characterization of poly(methyl methacrylate)
functional microspheres. React Function Polym
46:2937.
2. Rhee SH. 2002. Preparation of a bioactive poly
(methyl methacrylate)/silica nanocomposite. J Am
Ceram Soc 85:13181320.
3. Ohtsuki C, Miyazaki T, Kyomoto M, Tanihara M,
Osaka A. 2001. Development of bioactive PMMAbased cement by modification with alkoxysilane
and calcium salt. J Mat Sci-Mat Med 12:895
899.
4. Ohtsuki C, Miyazaki T, Tanihara M. 2002. Development of bioactive organic-inorganic hybrid for
bone substitutes. Mat Sci Eng C 22:2734.

DOI 10.1002/jps

1525

5. Rhee SH, Hwang MH, Si HJ, Choi JY. 2003.

Biological activities of osteoblasts on poly(methyl
methacrylate)/silica composite containing calcium
salt. Biomaterials 24:901906.
6. Ladron de Guevara-Fernandez S, Ragel CV, ValletReg M. 2003. Bioactive glass-polymer materials
for controlled release of ibuprofen. Biomaterials 24:
40374043.
7. Schiraldi C, DAgostino A, Oliva A, Flamma F, Rosa
AD, Apicella A, Aversa R, Rosa MD. 2004. Development of composite materials based on hydroxyethylmethacrylae as supports for improving cell
adhesion and proliferatin. Biomaterials 25:3645
3653.
8. Vallet-Reg M, Granado S, Arcos D, Gordo M,
Cabanas MV, Ragel CV, Salinas AJ, Doadrio AL,
San Roman J. 1998. Preparation, characterization,
and in vitro release of ibuprofen from Al2O3/PLA/
PMMA composites. J Biomed Mater Res 39:423428.
9. Ragel CV, Vallet-Reg M. 2000. In vitro bioactivity
and gentamicin release from glass-polymer-antibiotic composites. J Biomed Mater Res 51:424429.
10. Sun DH, Zhang R, Liu ZM, Huang Y, Wang Y, He J,
Han BX, Yang GY. 2005. Polypropylene/silica nanocomposites prepared by in-situ sol-gel reaction with
the aid of CO2. Macromolecules 38:56175624.
11. Cornelius CJ, Marand E. 2002. Composite silicapolyimide composite membranes: Gas transport
properties. J Membr Sci 202:97118.
12. Bandyopadhyay A, Bhowmick AK, Sarkar MD.
2004. Synthesis and characterization of acrylic
rubber/silica hybrid composites prepared by solgel technique. J Appl Polym Sci 93:25792589.
13. Jo H, Blum FD. 1999. Characterization of the
interface in polymer-silica composites containing
an acrylic silane coupling agent. Chem Mater 11:
25482553.
14. Wang HT, Zhong W, Xu P, Du QG. 2005. Polyimide/
silica/titania nanocomposites via a novel nonhydrolytic sol-gel route. Compos Part A-Appl Sci
Manufact 36:909914.
15. Wang HT, Zhong W, Du QG, Yang YL, Okamoto H,
Inoue S. 2003. Novel polyimide/silica nanocomposites from water glass. Polym Bull 51:6368.
16. Wang HT, Xu P, Zhong W, Shen L, Du QG. 2005.
Transparent poly(methyl methacrylate)/silica/zirconia nanocomposites with excellent thermal stabilities. Polym Degra Stabi 87:319327.
17. Gao Y, Choudhury NR, Dutta N, Matisons J,
Reading M, Delmotte L. 2001. Organic-inorganic
composite from ionomer via sol-gel reaction. Chem
Mater 13:36443652.
18. Shang XY, Zhu ZK, Yin J, Ma XD. 2002. Compatibility of soluble polyimide/silica composites
induced by a coupling agent. Chem Mater 14:7177.
19. Luna-Xavier JL, Guyot A, Bourgeat-Lami E.
2004. Preparation of nano-sized silica/poly(methyl
methacrylate) composite latexes by heterocoagula-

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 6, JUNE 2007

1526

20.

21.

22.

23.

24.

25.

LIN ET AL.

tion: Comparison of three synthetic routes. Polym

Inter 53:609617.
Chang CM, Bodmeier R. 1997. Swelling of and drug
release from monoglyceride-based drug delivery
systems. J Pharm Sci 86:747752.
Gulsen D, Chauhan A. 2006. Effect of water content
on transparency, swelling, lidocaine diffusion in
p-HEMA gels. J Membr Sci 269:3548.
Domingo C, Arcs RW, Lopez-Macipe A, Osorio R,
Rodrguez-Clemente R, Murtra J, Fanovich MA,
Toledano M. 2001. Dental composites reinforced
with hydroxyapatite: Mechanical behavior and
absorption/elution characteristics. J Biomed Mater
Res 56:297305.
Thwe MM, Liao K. 2003. Durability of bambooglass fiber reinforced polymer matrix composite
composites. Compos Sci Technol 63:375387.
Arbelaiz A, Fernandez B, Ramos JA, Retegi A,
Llano-Ponte R, Mondragon I. 2005. Mechanical
properties of short flax fibre bundle/polypropylene
composites: Influence of matrix/fibre modification,
fibre content, water uptake and recycling. Compos
Sci Technol 65:15821592.
Lara MG, Vitoria M, Bentley LB, Collett JH. 2005.
In vitro drug release mechanism and drug loading
studies of cubic phase gels. Intern J Pharm 293:
241250.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 6, JUNE 2007

26. Kawasumi M, Hasegawa N, Kato M, Usuki A,

Okada A. 1997. Preparation and mechanical properties of polypropylene-clay composites. Macromolecules 30:63336338.
27. Fragiadakis D, Pissis P, Bokobza L. 2005. Glass
transition and molecular dynamics in poly(dimethylsiloxane)/silica nanocomposites. Polymer 46:
60016008.
28. Bucknall DG. 2004. Influence of interfaces on thin
polymer film behaviour. Progress Mater Sci 49:
713786.
29. Cypes SH, Saltzman WM, Giannelis EP. 2003.
Organosilicate-polymer drug delivery systems:
Controlled release and enhanced mechanical properties. J Control Release 90:163169.
30. Joly C, Smaihi M, Porcar L, Noble RD. 1999.
Polyimide-silica composite materials: How does
silica influence their microstructure and gas permeation properties. Chem Mater 11:23312338.
31. Frank A, Rath SK, Venkatraman SS. 2005. Controlled release from bioerodible polymers: Effect
of drug type and polymer composition. J Control
Release 102:333344.
32. Reinhard CS, Radomsky ML, Saltzman WM,
Hilton J, Brem H. 1991. Polymeric controlled
release of dexamethasone in normal rat brain.
J Control Release 16:331340.

DOI 10.1002/jps