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The 4th IEEE International Conference on E-Health and Bioengineering - EHB 2013

Grigo re T Po pa University o{Medicine and Pharmacy, ia:ji, Ro mania, November 21-23,2013

Use of Bacterial Cellulose-Glycerol-Poly(vinyl


alcohol) Composites in Drug Release
Ramona-Daniela Pavaloiu, Tanase Dobre
Faculty of Applied Chemistry and Material Science
University Politehnica of Bucharest
Bucharest, Romania
pavaloiu_daniella@yahoo.com

Cristina Hlevca
National Institute For Chemical-Pharmaceutical Research and
Development - ICCF Bucharest
Bucharest, Romania

Abstract- Bacterial cellulose (BC) is a biomaterial suited for

elastic modulus. Also, it has a high surface area per unit mass,
feature combined with its highly hydrophilic nature, confers a
high liquid loading capacity [1].
The above listed properties make BC an attractive
biomaterial as scaffold material for tissue regeneration or
replacement, wound dressings, artificial skin, film coating
agent and matrix for drug loading and drug release [2-5].
A method to improve further more the remarkable features
of BC is through combination of bacterial cellulose with other
polymers (poly(vinyl alcohol) [6], poly(ethylene glycol) [7],
alginate [8], starch [9, 10], chitosan [11, 12]) or with
inorganic materials (hydroxyapatite [13]).
Several preparation methods of BC based composites were
reported: direct addition of polymer into BC culture medium
[14], mixing BC powder or BC ground with polymer solution
[15] and impregnation method by immersing BC membranes
in polymer solution [7]. Although, in present, there are a
considerable number of articles about the preparation and
characterization of various BC composites for biomedical
applications, only a small number of papers related to drug
delivery have been published [16,17].
The aim of this paper was to investigate the use of BC
composites for drug release. In this purpose multilayer
composites BC-Glycerol- Poly(vinyl alcohol) were prepared
and in vitro drug release studies were performed to evaluate
their overall potential in drug delivery applications.
Poly(vinyl alcohol) (PVA) materials present also desirable
characteristics for drug delivery applications, such as: high
degree of swelling, simple chemical structure, elastic nature,
non-toxic, non-carcinogenic, and bio-adhesive properties.
Amoxicillin, an antibiotic with high solubility in water (3.4
mg/mL) and commonly used against a broad-spectrum of
Gram-positive and Gram-negative microorganisms, was
chosen as model drug.
To our best knowledge, this is the first time that a
multilayer composite system based on BC-Glycerol and PVA
prepared in this manner was investigated for drug release
studies.

various biomedical applications, due to its unique nanostructure,


that confers remarkable physical and chemical properties, such as:
excellent elasticity, biocompatibility, high purity, high tensile
strength and high elastic modulus. The article describes the
mechanism and amoxicillin release profiles from bacterial
cellulose-glycerol-poly(vinyl alcohol) composites, in the aim to use
such systems in controlled drug delivery field. Obtained data from
these composites were slightly smaller than Be-Glycerol, probably
due to the fact that PVA layers provide an additional barrier for
drug release. The presented data are of interest for the
biomaterials community.
Keywords- bacterial cellulose, drug release, biomaterial.

I.

INTRODUCTION

The use of biopolymers in biomedical applications has


gained an increased interest due to their renewable nature,
biocompatibility and biodegradability. As example,
biopolymers like cellulose, starch, chitosan, alginate,
carrageenan, hyaluronic acid were investigated for
biomedical and pharmaceutical field. These biopolymers are
available, biodegradable, biocompatible, have low level of
toxicity and can be chemical modified; all properties listed
above are relevant for drug delivery applications. Although a
considerable palette of products based on conventional
biopolymers has been research and developed, there is still
the need to discover and explore new materials that can be
used to design drug-delivery systems.
A biopolymer with great potential is bacterial cellulose or
biocellulose (Be), also known as microbial cellulose. BC is a
polysaccharide synthesized by various species of bacteria,
such
as
Aerobacter,
Acetobacter,
Achromobacter,
Agrobacterium, Alacaligenes, Azo to bacter, Rhizobium and
Sarcina. It is chemically identical to plant cellulose, but with
a significantly different fibrous nanostructure.
Due to its unique structure, BC possesses superior physical
and chemical properties compared to plant cellulose. BC has
excellent elasticity, biocompatibility, high purity, and good
mechanical properties, including high tensile strength and

978-1-4799-2373-1/13/$31.00 2013 IEEE

[I.

A. Materials
Amoxicillin, G[ycero[, HexadecyItrimethy[ ammonium
bromide (CTABr, chemical formula: CI9H4zNBr), PVA
(average Mr
145000 Da, 99 mole % hydrolyzed) were
purchased from Sigma Aldrich. All chemicals and reagents
used were of analytical grades.
BC membranes (99% water content) were produced in the
Microbiology
Laboratory
of
Chemical
Engineering
Department (UPB).
=

A. Preparation oiBC-Glycerol Membranes


Bacterial cellulose (BC) membranes were obtained from
Acetobacter sp. in static culture using a modified HS medium
containing fructose (2%).
Wet BC membranes were weighted, drained at 50%
humidity, soaked in 25 mL of an aqueous buffer solution (pH
7.4) of different compositions (listed in Table I) and slightly
shaken for 2 h. The drug concentration was kept constant for
all samples (1.5 mg/mL). After drug adsorption, the BC
membranes were dried at room temperature. Half of these
prepared membranes were used in drug release study (A [,
A2, A3 and A4), and the other half were used further for
multilayer composite preparation.
B.
Preparation ofBC-Glycerol-PVA Composite
PVA solution was prepared by dissolving PVA in distilled
water at 90C (4%). The solution was kept under stirring until
was cooled down to room temperature to prevent polymer
agglomeration.
A multilayer composite was prepared as follows: a PVA
layer was poured in a plate, a BC-Glycerol membrane was
placed above it, and then another PYA layer was poured. The
prepared composites were allowed to dry at room
temperature. After drying, composites were removed from the
cast plate and used in drug release study (B1, B2, B3 and B4).
C. Drug release study
In vitro drug release profiles were obtained by immersing
composites into 25 mL buffer solution until maximum release
is achieved. Aqueous buffer pH 7.4 was chosen as drug
release medium because simulates the condition of intestinal
fluid. All the substances used (drug, glycerol and emulsifier)
were soluble in this medium. The samples were kept at room
temperature (25C) and slightly shaken.
At predetermined moments, the amount of drug released
was determined at 229 nm wavelength using an UV-V[S
spectrophotometer C[NTRA 6 (GBS-Australia), according to
the standard amoxicillin calibration curve. All release studies
were performed in duplicate.

HO

TABLE I

EXPERIMENTAL PART

-oJY,)=t'x

}o

Fig. 1. The chemical formula of amoxicillin.

OH

SAMPLE COMPOSITION
Composition

---

Sample name

Glycerol

CTABr
mM

Al

0.5

0.5

A2

1.0

0.5

A3

0.5

0.75

A4

1.0

0.75

Bl

0.5

0.5

B2

1.0

0.5

B3

0.5

0.75

B4

1.0

0.75

III.

PYA

RESULTS

In previous studies the release of amoxicillin from BC


Glycerol composites membranes was investigated using a
Box Behnken Design as statistical tool. Obtained data proved
that release was influenced by drug concentration, glycerol
concentration, interaction term between drug concentration
and glycerol concentration and interaction term between
glycerol concentration and an emulsifier concentration [18].
This research continues the investigation of BC based
composite for drug release, designing new multilayer
composites
starting
from
BC-Glycerol
composites
membranes prepared in the same manner used in our previous
experiments.
The incorporation of drug, glycerol and enhancer into BC
membranes was performed after removing approximately a
half of BC water content to assure total absorption. Glycerol
was used as a plasticizer due to the fact it increases low
malleability and as well as the swelling (water holding and
retention) of dry BC membranes.
The multilayer composites were prepared by placing dried
BC-Glycerol membrane between two PVA layers, in order to
obtain modified drug release rates. Because of the hydrophilic
nature of both BC and PVA, it is expected a strong interaction
between them.
Amoxicillin release values of BC-Glycerol-PVA multilayer
composites and BC-Glycerol composites were present in Fig.
2. The results were presented in terms of the ratio MtlMoo as a
function of time, where Mt is the cumulative amount of
amoxicillin released from composites at time t, and Moo is the
cumulative amount of amoxicillin released from composites
at infinite time.
It was observed that values obtained from BC-Glycerol
PVA multilayer composites were slightly smaller than BC
Glycerol, due to the fact that PYA layers confer an additional
barrier for drug release.
Obtained data suggest that these composites could be
exploited in controlled delivery field and the amount of drug
released could be adjusted by varying glycerol and emulsifier
concentrations and also by adding PVA layers.

10.8

?i

0.6
0.5

::E 0.4
0.3

Model parameters

+-

PARAMETERS OF POWER LAW MODEL

L-

0.7

TABLE II

0.9

_A4
_84

0.2
0.1
o.
2000

6000

4000

time(s)

8000

0.9

0.8

?i

1=-

0.7
0.6
O.S

::E 0.4
0.3
0.2
0.1

_A1

2000

-0,2

'8
:;;

Cl

.Q

-0,3

7,6

4000

6000

time(s)

8,2

7,8

8000

8,4

A3
Linear(A3)

-0,7

-0,9

A2

-Linear(A2)

-0,6

-0,8

A1

-Linear(A1)

-0,4
-0,5

A4

-Linear(A4)

.6-

-1

log (t)

714
-0,2

'8
:;;
.,

Cl

.Q

7,6

-----, -----,

7,8

-0,4
-0,6

k'102

R2

Al
A2
A3
A4

0.33
0.45
0.63
0.56

4.89
1.65
0.37
0.65

0.99
0.93
0.95
0.96

Bl

Model
constant

Correlation
coefficient

0.28

6.03

0.94

B2

0.22

12.08

0.98

B3

0.47

1.48

0.94

B4

0.71

0.15

0.95

In order to determine the mechanism of the release process,


the power law model was applied to the experimental data,
according to the literature [19]; this model can be expressed
as:

Fig. 2. Fractional release of amoxicillin from BC-Glycerol-PVA


multilayer composites (Bl, B4) and BC-Glycerol composites (AI, A4).

Diflusion
exponent

.01

rl---

_0,1

Sample
name

.6-

.6-

B1

-Linear(B1)
+

B2

-Linear(B2)
B3

-0,8

Linear(B3)
A

-1

B4

-Linear(B4)

-1,2
-1,4
log (t)

Fig. 3. Variation of log (Mf/Moo) with log(t) for BC-Glycerol-PVA


multilayer composites (BI-B4) and BC-Glycerol composites (AI-A4).

MtlMoo =kt,

(1)

Where k is a constant depending on the macromolecular


network characteristics of the composite and n is the diffusion
exponent indicating release kinetic mechanism.
According to the obtained value of diffusion exponent n the
release mechanism can be elucidated. For n < 0.5, drug
release follows Fickian diffusion, for 0.5 < n < 1, release
conforms to an anomalous diffusion (non-Fickian diffusion)
and for n < 1 the drug is released in later stages.
By plotting log (MtIMoo) against log (t), the values of
diffusion exponent n and model constant k were calculated, as
the slopes and as the intercept of the straight lines fitted to the
data. (Fig. 3)
The n, k values and regression coefficients are represented
in Table II. It can be observed a good agreement between the
experimental data and the power law model (correlation
coefficient R2>0.93). Most of the samples have diffusion
exponent value n smaller than 0.5 this indicates that Fickian
diffusion is the dominating process. Samples A3, A4 and B4
have n values higher than 0.5 with release dominated by non
Fickian process, A possible explanation is the fact that
interaction term between glycerol concentration and
emulsifier concentration has high value, parameter with
strong influence upon drug release from Be-Glycerol
membranes.

IV.

CONCLUSION

Multilayer composites based on BC-Glycerol and PVA


were obtained and in vitro drug release was analyzed.
Experiments revealed an important influence at the addition
of PYA layers upon drug release. Values of fractional release
of amoxicillin obtained from BC-Glycerol-PVA were smaller
than those obtained from BC-Glycerol.
The release mechanism was investigated using the power
law model and the characteristic parameters (n, k) were
determined. The mechanism was found to be mostly
dominated by Fickian diffusion due to the fact that majority
of n values obtained were smaller than 0.5.
These preliminary findings suggest that multilayer
composites based on BC-Glycerol and PYA could be
exploited as components in a controlled delivery system.
Further studies are needed to investigate and improve drug
release.
ACKNOWLEDGMENT

We gratefully thank European Social Fund for their


financial support (POSDRU/I 07/1.5/S/76903).
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