Colloids and Surfaces B: Biointerfaces 91 (2012) 162–167

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Colloids and Surfaces B: Biointerfaces

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Poly(lactic acid)/N-maleoylchitosan core–shell capsules: Preparation and drug

release properties
Aiping Zhu ∗ , Fengjuan Li, Lijun Ji
College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, PR China

a r t i c l e i n f o a b s t r a c t

Article history: An oil in water interface radical polymerization was used to prepare felodipine-loaded polymerized-N-
Received 5 August 2011 maleoylchitosan (p-NMCS) and poly(lactic acid) (PLA)/p-NMCS capsules. Dynamic Light Scattering, Field
Received in revised form 26 October 2011 Emission Scanning Electron Microscopy and Transmission Electron Microscope characterization revealed
Accepted 28 October 2011
that both the p-NMCS and PLA/p-NMCS microcapsules had a ∼550 nm hydrodynamic diameter, regular
Available online 3 November 2011
spherical morphology and an obvious core–shell structure. The ratio of PLA to p-NMCS in PLA/p-NMCS
microcapsules was found affecting the drug loading content and entrapment efficiency. In vitro release
Keywords:
kinetic results indicated that the p-NMCS microcapsules had a fast release rate comparing with that of the
N-maleoylchitosan
PLA
PLA/p-NMCS core–shell microcapsules, suggesting the release mechanism of the p-NMCS microcapsules
Core–shell microcapsules was a diffusion-driven process, while the release mechanism of the PLA/p-NMCS microcapsules with high
Interfacial polymerization ratio of PLA to p-NMCS (not less than 1/1) was a combined diffusion and degradation-driven process.
Release kinetics © 2011 Elsevier B.V. All rights reserved.

1. Introduction adsorption. Polysaccharide coatings, such as heparin and dextran,

Over the past few decades, there has been an intensive research
on the development of drug delivery systems because they are able
to convert poorly soluble, poorly absorbed and labile biologically
active substances into promising drugs [1]. Quite often, the choices
for drug delivery platforms are liposomes, polymeric micelles,
polymeric solid particles, and lipid nanocarriers [2–9]. Owing to
their excellent biocompatibility, biodegradability, high encapsu-
lation capability for hydrophobic drugs and long-time sustained
drug release property, poly(lactic acid) (PLA) and poly(lactide-co-
glycolide) (PLGA) have been widely used to fabricate capsules for
drug delivery system [10,11]. However, uptake of conventional
microcapsules by the reticuloendothelial system after intravascular
administration limits their use [12]. Therefore, design of long-
circulating microcapsules or stealth microcapsules has emerged
as an attempt to escape recognition by phagocytic cells in the
blood. Because the in vivo fate of microcapsules is determined by
their surface properties and size [13,14], the most commonly used
strategy for designing stealth microcapsules is introducing flex-
ible hydrophilic coat onto hydrophobic surfaces, shielding them
against plasma protein adsorption, which is the first step of particle
clearance by blood phagocytes [15].
Hydrophilic polysaccharides have been recognized as suit-
able materials for shielding microcapsules against plasma protein
∗ Corresponding author. Tel.: +86 514 7975568; fax: +86 514 7975524.
E-mail address: apzhu@yzu.edu.cn (A. Zhu).
can reduce the uptake of particulate carriers by mononu-
clear phagocyte system (MPS) [16–18]. Particular attention has
been given to chitosan due to its attractive biocompatibility,
biodegradability, non-toxicity and low cost [19]. However, the
quite low solubility of chitosan limits its application in drug
delivery system. Fortunately, due to the presence of reactive
amino/hydroxyl groups, chitosan can be subjected to chemical
modification to obtain a derivative with desired characteris-
tics [20,21]. N-maleoylchitosan (NMCS) is a kind of amphiphilic
chitosan derivative with excellent solubility in water and bio-
compatibility [22]. p-NMCS nanocapsules have been formed by
polymerization of vinyl macromonomers within droplets dispersed
in a non-solvent (the so-called oil in water polymerization) [23–26].
On these premises, if microcapsules with thin p-NMCS shell and big
PLA core are designed, plasma protein absorption could be avoided
and drug release from these microcapsules could be modulated.
The first objective of the present study is to prepare stealth
microcapsules of PLA/p-NMCS encapsulating felodipine, a highly
selective Ca2+ antagonist used for the treatment of hyperten-
sion. The second objective is to study the effect of the ratio of
PLA to NMCS on the encapsulation efficiency and release kinet-
ics of PLA/p-NMCS microcapsules. We conceive that amphiphilic
NMCS macromonomers will polymerize on the interface of water
and oil droplet containing PLA and lipophilic drug. As a result,
polymerized-NMCS (p-NMCS) forms the hydrophilic shell and
hydrophobic PLA forms the core of the designed microcapsules with
the ability to encapsulate hydrophobic drugs effectively. Because
NMCS is a kind of amphiphilic chitosan derivative [23], it can

0927-7765/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.colsurfb.2011.10.055
 A. Zhu et al. / Colloids and Surfaces B: Biointerfaces 91 (2012) 162–167
interact with PLA with its hydrophobic moieties and form stable
core–shell structure.
2. Materials and methods
2.1. Materials
Chitosan (CS, MW = 2.0 × 105 , degree of deacetylation = 85%)
powder was supplied by Zhejiang Yuhuan Ocean Biologicals Inc.,
China. The analytical grade reagents of maleic anhydride (MA),
acetic acid (HAc), chloroform and polyvinyl alcohol (PVA, aver-
age Mw 9000–10,000 Da 80% hydrolyzed) were obtained from
Sinopharm Chemical Reagents Co. Ltd., China. Deionized water was
from Milli-Q purification system. All other chemicals were of ana-
lytical grade and used directly without further purification.
2.2. Synthesis of NMCS
1 g chitosan powder was dissolved in 100 mL acetic acid aque-
ous (1%, v/v) solution and transferred to a three-necked flask. 0.5 g
maleic anhydride was dissolved in 5 mL acetone. The maleic anhy-
dride acetone solution was added to the reaction flask drop-wisely
over 20 min at 65 ◦ C. After that, the reaction was allowed to stand
at 65 ◦ C for another 8 h. Later, the reaction mixture was cooled to
room temperature and precipitated by adding excess amount of
acetone. After washing by 70% (v/v) acetone aqueous solution, 80%
(v/v) acetone aqueous solution and pure acetone, the precipitate
was collected and dried at 40 ◦ C under vacuum for 24 h. The yield
of NMCS was ∼85%.
2.3. Preparation of microcapsules
In a typical experiment of preparing felodipine-free PLA/p-
NMCS microcapsules, 0.1 g PLA dissolved in 5 mL chloroform and
0.5 g aqueous solution of 10% (w/v) PVA were added to 50 mL aque-
ous solution of 0.2% (w/v) NMCS. Chloroform and PLA mixture was
emulsified by PVA in the aqueous solution with a high-pressure
homogenizer (Ningbo Scienntz Biotechnology Co., Ltd., Zhejiang,
China) at a pressure of 10,000 psi for 10 min. The oil in water (o/w)
emulsion was obtained. The polymerization was initiated by inject-
ing 1 mL of K2 S2 O8 (KPS)/NaHSO3 (0.5 mg/0.5 mg) aqueous solution
under nitrogen at 50 ◦ C. After polymerization for 8 h, chloroform
was evaporated under vacuum. Finally, capsules obtained as a sus-
pension were collected by centrifugation at 15,000 rpm for 30 min,
being washed three times with distilled water, and then lyophilized
to obtain dry microcapsules and stored at 4 ◦ C until further use.
Felodipine-loaded PLA/p-NMCS capsules were prepared by a sim-
ilar process to that of blank microcapsules using initial polymer
loaded with drug of 10% (w/w). Felodipine was first dissolved
in chloroform followed by dissolution of PLA. The emulsification
and purification procedures were repeated as before. The resid-
ual chloroform was measured by headspace gas chromatography.
Schematic diagram of synthetic route for PLA/p-NMCS microcap-
sules was shown in Scheme 1(a).
2.4. Characterization of microcapsules
2.4.1. Microcapsule size and size distribution
The mean diameter and size distribution of microcapsules were
measured by a dynamic light scattering (DLS) system (DLS-5022F).
For all the batches, fresh microcapsules suspensions were diluted
100 times and size measurements were performed at 25 ◦ C and
scattering angle of 90◦ for 180 s and the light source was a 671 nm
He–Ne laser. The mean particle diameter was calculated using
differential size distribution processor (SDP) intensity analysis pro-
gram. The size distribution of the microcapsules was characterized
163
Scheme 1. (a) Schematic diagram of PLA/p-NMCS microcapsules synthesis and (b)
distribution of felodipine in PLA/p-NMCS microcapsules.
statistically by polydispersity index (PDI). The lower the value is,
the narrower the size distribution of the microcapsules is.
2.4.2. Microcapsule surface morphology
The surface morphological examination of the microcapsules
was performed by a field emission scanning electron microscope
(FESEM) (HITACHI-S4800). The microcapsules were placed on an
aluminum stub to obtain an uniform layer, coated with gold to a
thickness of about 100 Å using a gold sputter, and then observed
using FESEM. The morphology of the microcapsules was observed
using a transmission electron microscope (TEM) (TECHAI-12). For
sample preparation, a drop of sample solution (1 mg/mL in distilled
water) was placed on a 300-mesh copper grid coated with carbon.
Subsequently, the sample was dried and negatively stained by a 2%
(w/w) uranyl acetate solution.
2.4.3. Zeta potential measurements
Microcapsules were suspended in distilled water filtered by
films with pore size of 0.22 ␮m, and ␨-potential was measured on
a Malvern ZetaSIZER Nanoseries ZS (Malven Instruments, Woeces-
tershire, UK) in triplicate.
2.4.4. Encapsulation efficiency (EE)
A weight amount of microcapsules was digested in a 1 N NaOH
aqueous solution for 1 h to which ethanol was added followed by
acidification with 1 N HCl. Felodipine concentration was measured
by spectrophotometry at 361 nm (U-2001 UV/Visible spectropho-
tometer, Hitachi). The drug loading content and EE were calculated
using Eqs. (1) and (2):
weight of drug in capsules
Drug loading content (%) = × 100%
weight of capsules
(1)
weight of drug in capsules
EE (%) = × 100% (2)
weight of feed drug
2.4.5. In vitro drug release study
Drug loaded microcapsules were tested in triplicates for in vitro
drug release in a phosphate buffered saline solution (PBS, 10 mM,
pH 7.4). 150 mg of microcapsules were suspended in 3.5 mL of PBS
164 A. Zhu et al. / Colloids and Surfaces B: Biointerfaces 91 (2012) 162–167

( a) 1374

( b) 1663
3460 15941156
3313 2884 1084

( c) 1716
1634

( d) 1753

2992
2936
1753

4000 3500 3000 2500 2000 1500 1000 500

-1
wavenumber/cm

Fig. 1. FTIR spectra of (a) CS; (b) NMCS; (c) PLA and (d) PLA/p-NMCS microcapsules.

in a dialysis tubing (spectra Por 1 membrane, 6–8 kDa cut-off). This

dialysis tubing was placed in a screw-capped tube containing 10 mL
of PBS. The tubes were shaken at 100 rpm on a horizontal water
bath shaker (Orbit Shaker Bath, Labline) maintained at 37 ± 0.5 ◦ C.
At predetermined time intervals, the whole medium in the tube
was withdrawn and replaced by fresh PBS to maintain sink condi-
tions. The aliquots were assayed for the concentration of released
felodipine by spectrophotometry at 361 nm. This drug release pro-
files were repeated three times, and the cumulative drug release
percentage as a function of time was recorded.

3. Results and discussion

3.1. Characterization of polymers

To form PLA/p-NMCS core–shell structure, binding the
hydrophilic NMCS shell to the PLA core is necessary. The existence
of hydrophobic domains such as N-maleoyl and vinyl groups in the
NMCS molecules facilitated the adsorption of NMCS on the surface
of the oil droplets containing PLA to reduce their surface energy. The
adsorbed NMCS served as a stabilizer to effectively emulsify the
oil phase through steric hindrance and/or electrostatic repulsion.
Under initiation of KPS and NaHSO3 , the NMCS adsorbed on the
oil droplet surfaces can be then polymerized to form closed shells
around droplets. Meanwhile, those NMCS solubilized in water can
also be polymerized. Consequently, PLA core/crosslinked NMCS
shell microcapsules were obtained after evaporation of the oil
phase, CHCl3 . The residual chloroform measured by headspace gas
chromatography was 7.84 ppm.
Fig. 1 shows the FTIR spectra of (a) chitosan, (b) NMCS, (c)
PLA and (d) polymerized PLA/p-NMCS. From the spectrum of chi-
tosan (Fig. 1(a)), distinctive absorption bands appear at 3460 cm−1
(O–H stretch), 3318 cm−1 (N–H stretch), 2884 cm−1 (C–H stretch of
–CH2 ), 1663 cm−1 (C O stretch of acetyl), 1594 cm−1 (N–H bend)
and 1374 cm−1 (amide III). The absorption bands at 1156 cm−1
(asymmetric bridge-O-stretch) and 1084 cm−1 (skeletal vibration
involving C–O stretch) are characteristic of saccharine structure. In
the spectrum of NMCS (Fig. 1(b)), there is an obvious decrease in the
N–H stretching at 3318 cm−1 , which is attributed to the reaction of
maleic anhydrous and the amino group of chitosan. A new absorp-
tion peak at 1713 cm−1 (C O stretch) appears. Accompanying with
great decrease of the peak at 1594 cm−1 (N–H bend of amino
group), significant enhanced absorption peak at 1634 cm−1 (C C
double bond of C CCONH) is evident. Comparing with chitosan,
FTIR results clearly indicate the maleoyl-acylation successfully took
Fig. 2. DLS of (a) Felodipine-free and (b) Felodipine-loaded PLA/p-NMCS microcap-
sules. Inset images indicated FESEM images of PLA/p-NMCS microcapsules. Data
represent mean ± S.D. for n = 5 independent observations.
place at the amino position of chitosan. In the spectrum of PLA
(Fig. 1(c)), the absorption bands at 1753 cm−1 (C O stretch) is
attributed to the characteristic structure of carboxyl group in PLA.
The spectrum of PLA/p-NMCS (Fig. 1(d)) reveals the disappearance
of the characteristic C C bond stretching peak at 1634 cm−1 in com-
parison with that of NMCS, and the increase in the C–H stretch at
2992 cm−1 and 2936 cm−1 compared with that of PLA. FTIR results
indicate that NMCS has been polymerized in the presence of a ther-
mal initiator and the PLA/p-NMCS composite has been successfully
obtained.
3.2. Microcapsules size and size distribution
Fig. 2 shows the DLS results of blank and drug loaded PLA/p-
NMCS microcapsules. Inset images indicated FESEM images of
PLA/p-NMCS microcapsules, showing microcapsules demonstrate
regular spherical morphology. Table 1 lists the particle size and
size distribution of blank PLA/p-NMCS, drug loaded NMCS and drug
loaded PLA/p-NMCS at the same preparation conditions identified
by DLS measurement. The microcapsule hydrodynamic diameter of
the blank PLA/p-NMCS, drug loaded NMCS and drug loaded PLA/p-
NMCS is 548, 548 and 554 nm respectively, while the polydispersity
index is 0.241, 0.223 and 0.225, respectively. From the DLS and
FESEM results, it is safe to conclude that the size and size distribu-
tion of the microcapsules are not affected by the drug loading or
 A. Zhu et al. / Colloids and Surfaces B: Biointerfaces 91 (2012) 162–167 165

Table 1 Table 2
Hydrodynamic diameter and its distribution of drug-free PLA/p-NMCS and drug- The drug-loading content and the drug encapsulation efficiency of NMCS and PLA/p-
loaded NMCS and PLA/p-NMCS microcapsules. NMCS microcapsules.

Samples Diameter (nm)b PDI Samples The drug-loading The drug

content (%) encapsulation
a
Drug-free PLA/P-NMCS microcapsules 548 ± 7.2 0.241
efficiency (%)
Drug-loaded NMCS microcapsules 548 ± 10.6 0.223
Drug-loaded PLA/P-NMCSa microcapsules 554 ± 9.8 0.225 PLA/p-NMCSa microcapsules 9.3 ± 1.2 94.9 ± 0.7
PLA/p-NMCSb microcapsules 9.2 ± 0.9 92.9 ± 1.8
All values indicate mean ± S.D. for n = 5 independent observations.
PLA/p-NMCSc microcapsules 8.3 ± 2.6 85.6 ± 3.7
For all cases the emulsifier content was 0.1 wt%.
NMCS microcapsules 7.6 ± 1.8 77.6 ± 5.3
PDI: Polydispersity index.
a
The ratio of PLA to NMCS was 1:1. All values indicate mean ± S.D. for n = 5 independent observations.
b For all cases the emulsifier content was 0.1 wt%.
Hydrodynamic.
a
The ratio of PLA to NMCS was 3:1.
b
The ratio of PLA to NMCS was 1:1.
c
The ratio of PLA to NMCS was 1:3.
composition of the microcapsules significantly when the emulsifi-
cation agent concentration and the ratio of oil/water are fixed.
3.5. Zeta potential measurements and suspension stability

3.3. Morphology
To further investigate the detailed structure of the PLA/p-NMCS
capsules, TEM images of blank PLA/p-NMCS capsules are shown in
Fig. 3. The diameter of these microcapsules ranged from 150 nm to
450 nm. From Fig. 3(b), the high magnification of the PLA/p-NMCS
capsules, the core–shell structure can be seen obviously. According
to the formation mechanism of microcapsule, it is easy to know
that the inner big core should be composed of PLA and the outer
thin layer is the p-NMCS. Since felodipine drug had no effect on the
size and morphology of capsules, it can be speculated that most
of the hydrophobic drugs inclined to localize in the hydrophobic
PLA.
3.4. Encapsulation efficiency (EE)
The drug-loading content and drug encapsulation efficiency
of NMCS and PLA/p-NMCS microcapsules were measured and
listed in Table 2. The results indicate that both the drug-loading
content and drug encapsulation efficiency of the NMCS micro-
capsules are lower than those of PLA/p-NMCS microcapsules. And
the higher the ratio of PLA to NMCS is, the higher the values of
drug-loading content and drug encapsulation efficiency are. This
result suggests that the hydrophobic PLA core is beneficial for the
improvement of hydrophobic drug loading efficiency, while the
amphiphilic p-NMCS outer shell can ensure the good suspension
of PLA/p-NMCS microcapsules in the physiological environment
and give the prolonger blood circulation properties of the
microcapsules.
In contrast to the negative surface potential (−6.98 ± 0.5 mV)
of NMCS, the unwashed PLA/p-NMCS core–shell microcapsules
(−1.85 ± 0.8 mV) was almost neutral. After sufficient washing, the
surface potential of the PLA/p-NMCS core–shell microcapsules
increased to −6.68 ± 0.6 mV, the same as that of NMCS. It sug-
gests that the neutral emulsifier, PVA, adsorbed onto the surfaces
of the insufficiently washed microcapsules. Since most of the PVA
could be removed, risk of potential side effects introduced by the
emulsifier can be neglected. DLS revealed that these microcapsules
possess good stability against coagulation during storage.
3.6. In vitro sustained release
It has been reported that drugs are mainly released from
polysaccharide capsules through their diffusion across the per-
meable microcapsule walls to the leaching media [27,28]. Rapid
release of low molecular weight hydrophobic drugs from polysac-
charide capsules is due to the hydrophilic character of the
polysaccharide walls. On the other hand, synthetic hydrophobic
polyester carriers often possess a long-time sustained drug release
property. Therefore, if the wall composition of the resultant micro-
capsules, such as the present microcapsules with thin p-NMCS shell
and big PLA core, can be designed, drug release from capsules can
be modulated.
The in vitro drug release profiles from the felodipine-loaded
NMCS and PLA/p-NMCS microcapsules were examined using a dial-
ysis membrane bag and the amounts of felodipine released to
outer aqueous medium (or leaching solution) were measured. In all
cases, the felodipine concentrations in outer aqueous medium are

Fig. 3. TEM images of PLA/p-NMCS nanoparticles: (a) low magnification; (b) high magnification.
166 A. Zhu et al. / Colloids and Surfaces B: Biointerfaces 91 (2012) 162–167

a 100
Table 3
The platform duration of drug release of PLA/p-NMCS microcapsules.
NMCS
PLA:NMCS=1:3 Ratio of PLA to NMCS Duration (h)
80 PLA:NMCS=1:1
Cumulative release (%)

PLA:NMCS=3:1 1/3 Too short to determine

1/1 15
3/1 24
60

40 PLA to NMCS. The platform duration of the PLA/p-NMCS microcap-

sules dependent on the ratio of PLA to NMCS is shown in Table 3.
The release kinetics of drug is dependent on the matrix com-
20 ponent, properties, morphological character and the interaction
between the loaded drug and matrix, etc. [29]. For example, the
drug release from polymeric micelles is affected by several factors,
0
0 50 100 150 200 250 300 350 such as particle size and morphology, block composition, molecular
weight, and degradation rate [30]. Drug release from capsules gen-
Time (h) erally involves three different mechanisms: (1) diffusion from the
capsules surface on which drugs have been adsorbed due to great
100
b (NMCS) specific surface of microcapsules, (2) diffusion through the swollen
(PLA:NMCS=1:3) rubbery matrix entrapping drugs, and (3) release due to polymer
80 (PLA:NMCS=1:1) erosion. To understand the release of felodipine from p-NMCS or
(PLA:NMCS=3:1) PLA/p-NMCS microcapsules, it is necessary to know the interaction
Cumulative release (%)

between the drug and the capsule walls. Scheme 1(b) confirms the
60 possible drug distribution in the present microcapsules. In p-NMCS
microcapsules, the entrapped drugs should distribute uniformly,
and the interaction between the hydrophobic drug and amphiphilic
40 p-NMCS should be weak. However, in the case of PLA/p-NMCS
microcapsules, it is very different from the p-NMCS microcapsules.
Firstly, the drug distribution is not uniform in the whole PLA/p-
20 NMCS multiple microcapsules. The hydrophobic drugs are inclined
to localize rather in hydrophobic PLA than in amphiphilic p-NMCS
or on the interface between p-NMCS and PLA. Secondly, the inter-
0 action between drug and PLA should be stronger than that between
0 2 4 6 8 10 12 14
drug and p-NMCS.
0.43
[Time (h)] To understand the mode of drug release from these capsules,
c 100 the data was fitted to the following power law equation:
(NMCS)
(PLA:NMCS=1:3) Mt
= Kt n × 100% (3)
80 (PLA:NMCS=1:1) M∞
(PLA:NMCS=3:1)
Cumulative release (%)

where Mt and M∞ are the absolute cumulative amounts of

60
40
20
0 and (c), it can be seen that the fitting data presents linear rela-
0 20 40 60 80 100 120 140 160
0.85
[Time (h)]
Fig. 4. (a) Felodipine release profiles from microcapsules at 37 ◦ C in PBS. (b) Calcu-
lated experimental data based on the power law model for microcapsules n = 0.43
and (c) calculated experimental data based on the power law model for microcap-
sules n = 0.85. Data represent mean ± S.D. for n = 5 independent observations.
maintained less than felodipine’s solubility. The in vitro release
profiles of the felodipine-loaded NMCS and PLA/p-NMCS micro-
capsules with three different ratios of PLA to NMCS are shown in
Fig. 4(a). Comparing with the release profile of the NMCS microcap-
sules, a slower release rate was observed in the profile of the PLA/p-
NMCS microcapsules. Moreover, it is interesting to find that there
appeared platforms in all the profiles of the PLA/p-NMCS microcap-
sules and the duration increased with the decrease of the ratio of
drug released at time t and infinite time, respectively; K is the
release constant; exponent n describes the kinetic and the release
mechanism, which depends on the geometry of the system. For
diffusion-degradation controlled drug release system, n for spher-
ical particles is usually between 0.43 and 0.85. When n is close
to 0.43, diffusion is the major driving force, and this is normally
called the Fickian diffusion. When n is close to 0.85, the drug release
is mainly controlled by degradation [31,32]. The result obtained
by fitting the experimental data to Eq. (3) is shown in Fig. 4(b)
tion when n is 0.43 for p-NMCS microcapsules but not when n
is 0.85. These results suggest that the diffusion mechanism is the
driven force for felodipine released from p-NMCS microcapsules.
The fitting result of felodipine released from PLA/p-NMCS multi-
ple microcapsules with a 1/3 ratio of PLA to NMCS is similar to
that of p-NMCS microcapsules. When n is equal to 0.43, the fitting
data almost demonstrates linear relation. This result suggests that
low ratio of PLA to p-NMCS does not affect the diffusion-driven
drug release mechanism of the multiple microcapsules. There is
almost no platform appeared in the fitting data of the PLA/p-NMCS
multiple microcapsules with a 1/3 ratio of PLA to NMCS in compar-
ison with that of other PLA/p-NMCS multiple microcapsules with
a higher ratio of PLA to NMCS. This phenomenon may be resulted
from the diffusion-driven drug release mechanism. However, as
can be seen from microcapsules with a 1/1 and 3/1 ratio of PLA
to NMCS, respectively, the fitting data does not present the linear
 A. Zhu et al. / Colloids and Surfaces B: Biointerfaces 91 (2012) 162–167
relation when n is 0.43 or 0.85. These results suggest that the release
mechanism is neither diffusion nor matrix erosion solely driven
process only but controlled by both of them. Drug release model
of these PLA/p-NMCS multiple capsules has not yet been reported
until now.
This fitting equation is quite suitable for our present micro-
capsules. The above release mechanism revealed the correct of
felodipine distribution in PLA/p-NMCS microcapsules shown in
Scheme 1(b). Felodipine released from p-NMCS microcapsules
through diffusion process in the first stage and the release rate is
fast due to the high drug concentration entrapped in the capsules.
And then the release becomes slower and more stable. For PLA/p-
NMCS multiple microcapsules with a 1/3 ratio of PLA to NMCS, the
release rate becomes slower than that of p-NMCS microcapsules
(Fig. 4(a)). This result is caused by the stronger interaction between
the drug and PLA/NMCS multiple microcapsules than that between
the drug and p-NMCS microcapsules. When the ratio of PLA to
NMCS increases to 1/1 and 3/1, the release behavior becomes quite
different. There is a platform appeared. This platform means that
there is no drug released from PLA/p-NMCS microcapsules during
platform duration. As discussed above, it is easy to speculate that
at the platform stages, the drugs entrapped in p-NMCS shell and on
the interface of p-NMCS shell and PLA core have been diffused out
completely. After that, the drugs come from PLA degradation will
release from the PLA/p-NMCS core–shell microcapsules in a slow
release manner.
4. Conclusions
In present study, we prepared felodipine-loaded PLA/p-NMCS
core–shell multiple microcapsules with high encapsulation effi-
ciency and monodispersed property, using oil in water interface
radical polymerization. The core–shell multiple PLA/p-NMCS
microcapsules show regular spherical morphology with a big PLA
core and a thin p-NMCS shell. The hydrodynamic diameter of
PLA/p-NMCS microcapsules is ∼550 nm. The ratio of PLA to p-
NMCS of PLA/p-NMCS microcapsules affects the encapsulation
efficiency, drug-loading content, release kinetics and mechanism.
The release mechanism of p-NMCS microcapsules is diffusion-
driven process, while the release mechanism of PLA/p-NMCS
microcapsules depends on the ratio of PLA to p-NMCS. For the
PLA/p-NMCS microcapsules with high ratio of PLA to NMCS (such
as 1/1 and 3/1), the experimental fitting data demonstrate com-
bined diffusion and erosion process controlled release mechanism.
Therefore the newly developed PLA/p-NMCS core–shell multiple
167
microcapsules may have great potential in controlled drug release
applications.
Acknowledgements
This research was supported by a National Natural Science Foun-
dation of China (No. 51073133), a China Jiangsu Provincial Natural
& Scientific Grant (Project SBK200930208), China Jiangsu Provin-
cial Innovative Grant (Project SBC200910282), and was supported
by Jiangsu Province, Project No. 08KJA430003 (China).
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