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Size and Stability Optimization for Polyurethane Nanostructures
used as Transdermal Drug Vehicle
FLORIN BORCAN1, CODRUTA MARINELA SOICA1*, CRISTINA ADRIANA DEHELEAN1, SRINIVAS GANTA2, MANSOOR M. AMIJI2
“Victor Babes” University of Medicine and Pharmacy Timisoara, Faculty of Pharmacy, 2nd Eftimie Murgu Sq., Timisoara, 300041,
Romania
2
Northeastern University, Department of Pharmaceutical Sciences, 360 Huntington Ave., Boston, Massachusetts, USA
1
Polymer nanostructures (nanocapsules, nanospheres or nanotubes) are used to improve the drug efficiency
and release. Our group has synthesized polyurethane nanostructures (PUNs) by interfacial polyaddition
combined with spontaneous emulsification. The synthesis involves the emulsification of organic phase
consisting of isophorone diisocyanate (IPDI) dissolved in acetone with the aqueous phase formed by diols,
polyether and different surfactants dissolved in water. Physical and chemical properties of nanostructures
were evaluated using scanning electron microscopy, pH, size and Zeta potential measurements. The
conclusion of the study was that these products can be successfully used as drug carriers for transdermal
delivery.
Keywords: polyurethane nanostructure, stirring speed, surfactant, Zeta potential
Nanostructures used as drug delivery systems are hollow
nanoparticles in which the desired substance may be
included. So far, the main studies in encapsulating material
field were about minimizing hygroscopic and chemical
interactions, elimination of oxidation and drug controlled
release [1]. Nanoparticles size generally varies between
10-1000 nm. The drug is dissolved, entrapped,
encapsulated or attached to a nanoparticle matrix and,
depending upon the method of preparation, nanoparticles,
nanospheres or nanocapsules can be obtained [2].
Many biological active substances are sensitive, easily
and quickly degraded in the presence of light, heat or
atmospheric oxygen. Thus the researchers have turned their
attention to the synthesis of nanostructures used as
transdermal drug carrier [3, 4]. A scientists team from
U.S.A. synthesized a biocompatible and biodegradable
polyurethane transport system based on lysinediisocyanate and glycerol for a chemotherapeutic agent
(DB-67) [5]. Also in the United States, the effect of local
liberation of platelet growth factor from a bicomponent
polyurethane in order to heal the rat skin has been studied
[6]. To prevent the infections due to medical instruments,
a group from University of Rome synthesized nanoparticles
which carry an antibiotic agent [7]. Polyurethanes based
on poly(ε-caprolactone) have been the subject of several
studies because this precursor is often used in the synthesis
of biodegradable polyurethanes [8-13].
We developed PUNs based on isophorone diisocyanate
and used them for the transdermal drug delivery in order to
avoid the toxicity of products based on aromatic
diisocyanates [14]. Our aim was to obtain PUNs of size
around 400 nm. We studied the influence of stirring speed
during the synthesis and of surfactant structure over the
PUNs size and stability.
Experimental part
Mono-ethylene glycol (MEG) was purchased from LachNer s.r.o. (Czech Rep.) and 1,4-butanediol (BD) was
purchased from Carl Roth GmbH (Germany). All the other
raw materials, isophorone diisocyanate (IPDI),
polyethylene glycol, M = 200 (PEG) and solvent (acetone)
were obtained from Merck (Germany). Surfactants were
kindly donated by our colleagues from University of Szeged
(Hungary).
The polyaddition reaction between diols/polyols and
IPDI for PUNs synthesis is as follows:
Synthesis involves a six steps procedure: 1. preparation
of the organic solution (1.6 ml IPDI was mixed with 20 ml
acetone and heated at 40 o C); 2. preparation of the
homogeneous aqueous phase (0.6 mL MEG, 0.6 mL BD,
1.2 mL PEG were mixed with 40 mL distilled water and
heated at 40 oC); 3. organic phase was injected into the
aqueous phase at 40 oC under magnetic stirring (PUNs
were formed in this step); 4. stirring was continued for four
hours at 40 oC to ensure the maturation of the PUNs walls;
5. solvent (acetone) as well as a part of water was removed
by slow evaporation keeping the suspension in Petri dishes
(approx. 3 mm thickness) at 60 oC in oven for 12 hours; 6.
obtained products were purified by three times cycle of
centrifugation - redispersion in a mixture of water-acetone
1:1 (v/v).
Two different studies were made using this procedure.
The influence of the stirring speed over PUNs size and
stability was studied using the same reactants ratio, but
changing the stirring speed (3000-8000 rpm). Surfactants
used in the second study for the influence of their structure
over PUNs size and stability are as follows: Polysorbate80
(1.5 mL), Isolan GI34 (1.5 mL), Abril EM90 (1.5 mL),
Labrasol (1.5 mL), Cremophor EL (1.5 mL), Cremophor
A25 (0.2 g), Cremophor A6 (0.2 g), Cremophor RH40 (0.2
g), Sucrose Laurate D1216 (0.2 g), Sucrose Ester (0.2 g).
After the samples were well dried, the pH of PUNs
solutions was measured at the same concentration with a
Schott TitroLine by simply plunging the electrode into the
aqueous solutions (1:5000 v/v). Shape and morphology
* email: [email protected]; Tel.: 0745.379212
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REV. CHIM. (Bucharest) ♦ 63♦ No. 11 ♦ 2012
Fig. 1. Influence of stirring
speed over the diameter mean
of PUNs
were examined using a scanning electron microscope
Hitachi 2400S (Hitachi Scientific Ltd., Japan) using a
voltage of 10 kV. Size and charge were measured using a
Zetasizer Nano series equipment Nano-Zs (Malvern
Instruments). For this, the same aqueous solutions (1:5000
v/v) were used. The measurements were carried out three
times for each sample.
Results and discussions
The data from the first study is shown in figure 1.
The pH values of all PUNs aqueous solutions were in
range of 6.2-7.4 which denote the absence of secondary
products (amines) and it is proper for products intended
for cutaneous administration.
In figure 2, the SEM images reveal that the surfactant
structure has an important influence over the shape and
morphology of PUNs. Polysorbate80, known as Tween®80,
Polysorbate80
Isolan GI34
Abril EM90
Labrasol
Cremophor EL
Cremophor A25
Cremophor A6
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Cremophor RH40
http://www.revistadechimie.ro
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Sucrose Laurate
Sucrose Ester
Fig. 2. SEM images of PUNs based on different surfactants
Table 1
ZETASIZER CHARACTERIZATION FOR
PUNs BASED ON DIFFERENT
SURFACTANTS
Abril EM90 and Sucrose compounds lead to the formation
of nanotubes agglomeration, while the usage of Labrasol,
Cremophor A6, and Cremophor RH40 lead to the formation
of nanocapsules agglomeration. The formation of
agglomerations is also indicated by the data from Zetasizer
(table I).
The large values for the size of PUNs based on Sucrose
compounds are reason enough to consider this type of
surfactants not to be proper for this synthesis. The zeta
potential values are important because if all the particles
have a zeta potential more negative than -30 mV or more
positive than +30 mV the dispersion should remain stable.
This is the reason why we consider that only Abril EM90,
Labrasol, Cremophor EL, Cremophor A6, and Cremophor
RH40 are suitable for this research.
Conclusions
The interfacial polyaddition technique combined with
spontaneous emulsification is a proper procedure for the
PUNs synthesis. PUNs suspensions revealed pH values
which are suitable for products intended to be used for
cutaneous administration. Abril EM90, Labrasol, Cremophor
EL, Cremophor A6, and Cremophor RH40 are surfactants
which give good values for PUNs stability. Best stirring
speed for synthesis of PUNs with 400 nm size is around
7000 rpm.
Acknowledgements: This work was supported by the CNCS-UEFISCDI,
project PNII-PD-586/2010 (contract no. 110 / 12.08.2010).
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Manuscript received: 23.04.2012
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