Mucoadhesive membranes were proposed in this study as drug delivery system for betamethasone-17-valerate (BMV) in the treatment of recurrent aphthous stomatitis (RAS). The membranes were obtained by using the polymers chitosan (CHI) in both presence and absence of polyvinilpyrrolidone (PVP), following the solvent evaporation method.
Trang 1Contents lists available atScienceDirect
Carbohydrate Polymers journal homepage:www.elsevier.com/locate/carbpol
Chitosan/pvp-based mucoadhesive membranes as a promising delivery
system of betamethasone-17-valerate for aphthous stomatitis
R.H Sizílioa, J.G Galvãoa, G.G.G Trindadea, L.T.S Pinaa, L.N Andradeb, J.K.M.C Gonsalvesa,
A.A.M Liraa, M.V Chaudc, T.F.R Alvesc, M.L.P.M Arguelhod, R.S Nunesa,⁎
a Pharmacy Department, Federal University of Sergipe, São Cristóvão, SE, Brazil
b Instituto de Tecnologia e Pesquisa (ITP), Tiradentes University, Aracaju, SE, Brazil
c Laboratory of Biomaterial and Nanotechnology, University of Sorocaba, Sorocaba, SP, Brazil
d Chemistry Department, Federal University of Sergipe, São Cristóvão, SE, Brazil
A R T I C L E I N F O
Keywords:
Betamethasone-17-valerate
Aphthous stomatitis
Chitosan
Polymeric blends
PVP
A B S T R A C T Mucoadhesive membranes were proposed in this study as drug delivery system for betamethasone-17-valerate (BMV) in the treatment of recurrent aphthous stomatitis (RAS) The membranes were obtained by using the polymers chitosan (CHI) in both presence and absence of polyvinilpyrrolidone (PVP), following the solvent evaporation method The presence of PVP in the membranes causes significant modifications in its thermal properties Changes in the thermal events at 114 and 193 °C (related to BMV melting point), and losses in mass (39.38 and 30.68% for CH:PVP and CH:PVP-B, respectively), suggests the incorporation of BMV in these membranes However, the morphological aspects of the membranes do not change after adding PVP and BMV PVP causes changes in swelling ratios (> 80%) of the membranes, and it is suggested that the reorganization of the polymer mesh was highlighted by the chemical interactions between the polymers leading to different percentages of BMV released ∼40% and ∼80% from CH-B and CH:PVP-B BMV release profile follows Korsmeyer and Peppas model (n > 0.89) which suggests that the diffusion of the drug in the swollen matrix is driven by polymer relaxation In addition, the membranes containing PVP (higher swelling ability) present high rates of tensile strength, and therefore, higher mucoadhesion Moreover, given the results presented, the de-veloped mucoadhesive membranes are a promising system to deliver BMV for the treatment of RAS
1 Introduction
Recurrent aphthous stomatitis (RAS) is an oral disease that affects
one quarter of the world’s population, and it is common in the first
stage of human development (Kürklü-Gürleyen, Öğüt-Erişen, Çakır,
Uysal, & Ak, 2016;Scully, 2006) This disease is characterized by oval
or round shaped lacerations in the oral mucosa and lips, and pain
ranging from mild to moderate in the first 24 h Moreover, RAS are
small ulcers (2–10 mm of diameter) presenting well-defined edges and
white-yellowish color Besides that, RAS affects the non-keratinazed
mucosa, and may occur isolated or associated with other diseases The
mucous tissue is able to restructure spontaneously in 7–14 days after
the lesion first appears (Kürklü-Gürleyen et al., 2016; Scully, 2006;
Tappuni, Kovacevic, Shirlaw, & Challacombe, 2013) The mucosa
la-cerations may lead to impairment of upper digestive tract functions,
since these ulcers cause difficulties in speaking and swallowing food,
liquids and saliva (Kürklü-Gürleyen et al., 2016;Tappuni et al., 2013)
The treatment of RAS is focused on accelerating the healing, as well
as, easing the pain In general, corticoids are thefirst choice in the treatment of oral autoimmune diseases According to Carrozzo and Gandolfo (cited by (Rogulj, Brkic, Alajbeg, Džanić, & Alajbeg, 2014)), steroidal anti-inflammatory drugs such as betamethasone-17-valerate (BMV) are indicated to treat oral mucosa lesions, as they act reducing
inflammation and pain without leading to undesirable effects in short term However, the prolonged use of these drugs may cause adverse
effects that would result in non-adherence to treatment Thus, poly-meric systems have been investigated as an interesting viable option to transport steroidal anti-inflammatory drugs, since they can deliver a limited and continuous amount of drug, and can contribute to the tissue healing process at the same time (Rogulj et al., 2014)
Mucoadhesive polymeric systems play a crucial role in the RAS therapy as they are a suitable vehicle to deliver drugs as well as they can cover the oral lesion for a long-term preventing the worsening of the lesion and proliferation of bacteria (Kürklü-Gürleyen et al., 2016)
https://doi.org/10.1016/j.carbpol.2018.02.079
Received 28 November 2017; Received in revised form 17 January 2018; Accepted 23 February 2018
⁎ Corresponding author at: Pharmacy Department, Federal University of Sergipe, Av Marechal Rondon, s/n, Prof José Aloísio de Campos City University, 49100-000, São Cristóvão, Sergipe, Brazil.
E-mail address: rogeria.ufs@hotmail.com (R.S Nunes).
Available online 06 March 2018
0144-8617/ © 2018 Elsevier Ltd All rights reserved.
T
Trang 2Among polymers, chitosan (CHI) has been widely investigated for
biomedical application and drug delivery system
CHI is a natural polysaccharide constituted of β-(1–4)-linked D
-glucosamine and N-acetyl-D-glucosamine units and presents functional
groups such as amine and hydroxyl that have influence over its
biolo-gical properties, especially in the cellular adherence and interaction
with mucosa proteins, particularly onα-2,3 and α-2,6 sialic acids In
addition, CHI is considered non-toxic, biocompatible, mucoadhesive,
aids tissue healing, and is able to interact with human cells (Cai et al.,
2009;Liu et al., 2014;Swetha et al., 2010) However, it has been
re-ported that one of the major drawbacks of CHI-based hydrogel
mem-branes is their low mechanical stability because of their high water
content (especially in acidic solutions) and relatively loose three
di-mensional (3D) network formed by linear polyssacaride molecules
(Ostrowska-Czubenko, Pierõg, & Gierszewska-Druzyńska, 2013)
Ac-cording toGierszewska & Ostrowska-Czubenko (2016), the modi
fica-tion of chitosan by crosslinking is an effective strategy to improve its
mechanical resistance Therefore, in this work, a crosslinking agent
(TPP) was used for all membranes
The combination of CHI and other polymers (mainly hydrophilic)
can also be used to improve its functional properties (e.g
mucoadhe-sive) The polyvinylpyrrolidone (PVP) is a synthetic copolymer,
bio-compatible and non-toxic (Elsabee & Abdou, 2013) This polymer has
been applied in formulations for controlled drug delivery, and wound
dressings by pharmaceutical and biomedical industries, respectively
(Archana, Singh, Dutta, & Dutta, 2013;Elsabee & Abdou, 2013)
The interaction between PVP and CHI occurs through the formation
of hydrogen bonds between the pyrrolidine rings of PVP and; amino
and hydroxyl groups of CHI, which can present high material
mis-cibility with improved properties (Li, Zivanovic, Davidson, & Kit,
2010) Khoo, Frantzich, Rosinski, Sjöström, and Hoogstraate (2003)
evaluated the miscibility between CHI and hydrophilic polymers such
as PVP observing improved mechanical/physical and thermal
proper-ties when PVP was present
Thus, the aim of this study is to develop BMV loaded CH-PVP
mu-coadhesive membranes as a potential drug delivery system for RAS
treatment Furthermore, this work evaluates the influence of PVP in the
membranes regarding thermal properties, swelling capacity, drug
re-lease profile and mucoadhesive ability
2 Material and methods
2.1 Material
Lower molecular weight chitosan (degree of deacetylation 95.25%
obtained experimentally) was acquired from Sigma-Aldrich®(St Louis,
USA), betamethasone-17-valerate (BMV) was purchased from
Henrifarma®(São Paulo, Brazil), and polyvinylpyrrolidone (PVP),
so-dium tripolyphosphate (TPP) from SYNTH®(São Paulo, Brazil) Also
were used monobasic potassium phosphate USP-standard (KH2PO4)
(SYNTH®, São Paulo, Brazil), sodium hydroxide (NaOH) analytical
grade from SYNTH® (São Paulo, Brazil), ethanol analytical grade
(NEON®, São Paulo, Brazil), and propylene glycol (PPG) (VETEC®, Rio
de Janeiro, Brazil) Water used in this study was obtained from the
Milli-Q®purification water system (Millipore, Darmstadt, Germany)
2.2 Methods
2.2.1 Preparation of CH membranes
The membranes were obtained by using the casting/solvent
eva-poration technique (Liang, Liu, Huang, & Yam, 2009; Srinivasa,
Ramesh, Kumar, & Tharanathan, 2004) Firstly, CHI (1.5% w/v) was
solubilized in a 2% (v/v) acetic acid solution, and kept under stirring
for 24 h For the membranes containing PVP, PVP solution (15%, w/v)
was added to the chitosan hydrogel, as described inTable 1 The
ob-tained hydrogel had the pH adjusted to 5.0 using NaOH 1 mol L−1
solution, poured into Petri dishes and maintained overnight in the oven
at 50 ± 2 °C, to allow the solvent evaporation Subsequently, the membranes were immersed in a 5% TPP solution (w/v, pH adjusted to 5.0), and kept at 4 °C for 1 h Afterwards, the membranes were thor-oughly washed several times with distilled water When completely dried, the membranes were kept in a desiccator to avoid humidity Following a similar procedure, membranes without PVP were prepared,
in order to evaluate its influence in membrane properties, as detailed in Table 1 For the loaded BMV membranes, the addition of BMV (1 mg mL−1), which was solubilized in PPG (10% of the membrane composition as shown inTable 1), occurred soon after hydrogel pre-paration, by stirring continuously for 24 h The other steps followed the same procedures, as the inert membrane, previously described
2.2.2 Thermal analysis DSC curves were obtained using a DSC-TA Instruments (New Castle, USA) under nitrogen dynamic atmosphere (20 mL min−1), heating rate
of 10 °C min−1, in the temperature range 25–300 °C About 5 mg of sample was sealed tightly in aluminum crucibles DSC cell was cali-brated with indium (m.p 156.6 °C; ΔHmelt = 28.54 J g−1
) and zinc (m.p 419.6 °C) TG curves were carried out using a thermobalance, model TGA-50 Shimadzu (Kyoto, Japan), in the temperature range of 25–800 °C, using alumina crucibles with approximately 5 mg of samples under dynamic nitrogen atmosphere (50 mL min−1) and heating rate of
10 °C min−1 TG/DTG was calibrated using a CaC2O4·H2O standard in conformity to ASTM
2.2.3 X-ray diffaction X-ray diffraction of CHI, TPP, PVP, BMV and membranes (CH and CH-PVP) with or without the presence of BMV were performed in a Rigaku Diffractometer, with CuKα (1.5406 Å) in the range of 3° < 2θ < 40° using 40 kV of voltage and 30 mA of current The measurements were carried out using steps at 0.02 and speed of 2°/min
2.2.4 Scanning electron microscopy (SEM) The morphology of the membranes was analyzed by scanning electron microscope (model JCM-5700, Tokyo, Japan) with LV accel-eration voltage of 20 kV, and a magnitude of 500× and 1000× The samples were placed on copper strips, attached to a blade, and then covered with goldfilm SEM analysis was performed in the Northeast Center for Strategic Tecnologies (CETENE, Pernambuco, Brazil)
2.2.5 Thickness and swelling studies The thickness of the membranes were measured infive different points of each sample using a manual micrometer Starrett®n° 436.2, 0–25 mm
Swelling degree was evaluated through (%) hydration determina-tion The membranes of 2 cm2were weighed and immersed in phos-phate buffer pH 7.4 at 37 ± 2 °C After immersion, the membranes were taken out from the medium, excessfluid was removed with filter paper and then the membranes were weighed at predetermined times (10, 30, 60, 90, 120 min) All samples were performed in triplicate Swelling ratio was calculated based on the mass gain in relation to dry membrane, according to Eq (1) The results were expressed by the average percentage and its standard deviation In the equation, the swollen membrane weight is represented by Pfand the dry membrane
Table 1 CH-PVP blends and CH films composition.
SAMPLES CHI (mL) PVP (mL) PPG (mL) BMV (mg)
Trang 3by Pi.
One-way ANOVA followed by the Tukey’s post-test was carried out
using the statistical program Graph Pad Prism v 5.0 DEMO
2.2.6 In vitro release studies
In vitro release studies of BMV were conducted using suitable
ap-paratus connected to thermostatically-controlled water bath at
37 ± 0.5 °C Release medium was composed by phosphate buffer pH
7.4 and ethanol (7:3) which was kept under constant stirring (600 rpm)
The membranes were attached in proper holders and immersed in the
release medium that was appropriately sealed At time intervals of
0–8 h, 5 mL of release medium was taken out and immediately replaced
by new medium solution, at each sample, in order to maintain sink
conditions Drug released amount was measured by spectrophotometry
(UV/VIS FEMTO®, 800 XI, São Paulo, Brazil) at the wavelength of
240 nm (Rodrigues et al., 2009) In addition, BMV release data was
evaluated using kinetic models such as zero order,first order, Higuchi,
Korsmeyer & Peppas and Weibull by KinetDS Copyright (C) 2010
Aleksander Mendyk software
2.2.7 Mucoadhesive property evaluation
The mucoadhesive property evaluation was determined by the
re-lation of load (N) as a function of time (s) using texture analyzer (Stable
Micro Systems - TA-XT Plus Analyzer Surrey, United Kingdom) The
texturometer was, previously, calibrated with 5 kg load cell and
equipped with 10 mm diameter analytical probe To determine the
mucoadhesive property, a compact disc of the mucin from porcine
stomach was used (150 mg and 0.2 mm of thickness)
The discs werefixed with double-sided cohesive tape on the lower
base of the test piece (n.15347) The samples were transferred to
mu-coadhesion test apparatus (n.15467) Mucin discs were previously
hy-drated with ultrapure water During the whole experiment, the
tem-perature was kept constant at 37 °C The method executed in this test
was adapted from (Fransén, Björk, & Edsman, 2008), and performed in
speed compression mode at 0.5 mm s−1, under a force of 5 g After 60 s
of contact, the test piece was moved in opposite direction at 1.0 mm s−1
of speed The maximum force required to separate the mucin disc on the
sample surface was detected and analyzed by Texture Expoente Lite
software The measurements were performed in triplicate One-way
ANOVA followed by the Tukey’s post-test was carried out using the
statistical program Graph Pad Prism v 5.0 DEMO
3 Results and discussion
Thermal analysis is an important technique for the evaluation of
polymeric membranes regarding mass variations and thermal events
related to the blend formation (Abdelrazek, Elashmawi, & Labeeb,
2010;Rafique, Zia, Zuber, Tabasum, & Rheman, 2016) TG/DTG curves
of the membranes are shown inFig 1 All samples presents different
losses in mass possibly related to chemical changes that occurred after
the membrane formation PVP as blend forming provides changes in the
thermal profile of the membranes The first thermal event regarding
water loss (Nieto-Suárez, López-Quintela, & Lazzari, 2016) was
Δm = 17% and 12% (DTGpeak = 53 °C), with and without PVP
re-spectively Thermal decomposition and release of carbonaceous
mate-rial are higher in the membrane containing PVP (Δm = 23%,
DTGpeak = 436 °C, and Δm = 4%, DTGpeak = 534 °C, against
Δm = 11%, above 343 °C of the membrane without PVP) After the
incorporation of PVP, the thermal stability of the membranes changed
exhibiting new losses in mass Similar results were found byBigucci
et al (2015)in which blends composed of chitosan and hyaluronic acid
presented different losses in mass compared with pure chitosan
The thermal profile of the membranes containing BMV did not
change significantly in relation to the inert membranes (Fig 1) For the CH-B, the first loss in mass was lower (1°Δm = 17% and 14%− DTGpeak = 53 °C; CH and CH-B, respectively) which indicates that some water molecules were displaced in order to accommodate the drug The second event also occurred in the same range and identical DTGpeak with higher loss in mass for CH, indicating that BMV de-monstrated a better thermal stability for these temperature ranges (2°Δm = 39% and 30% − DTGpeak = 231 °C; CH and CH-B, respec-tively) On the other hand, the presence of the drug was enough to increase in 100% the last loss in mass step (11–32%) The higher the amount of organic material, higher the loss in mass of carbonaceous compounds that occurs exactly in this range of temperature For the membranes containing PVP was observed a strong possibility of fa-vorable interaction between BMV and polymeric matrix due to the disappearance of the last loss in mass in the membrane containing BMV The membranes (CH:PVP-B, CH-B, CH:PVP and CH) also were evaluated by DSC (Fig 2(a)) The inert membranes (CH:PVP and CH) exhibited endothermic events associated to water loss and hydroxyl groups of the chitosan and PPG at 108 and 125 °C for CH and CH:PVP, respectively (Abdelrazek et al., 2010;Li et al., 2010) CH membranes presented lower temperature of this first event than CH:PVP mem-branes, probably due to the interaction between hydroxyl groups of chitosan and carbonyl group of PVP suggesting the blend formation Moreover, CH:PVP showed other endothermic events at 188 and
319 °C, absent in CH, which also indicates an interaction between CHI and PVP (Fig 2(b)) Marsano, Vicini, Skopińska, Wisniewski, and Sionkowska (2004)reported that the pyrrolidone rings in PVP contain a proton accepting carbonyl moiety, while chitosan presents hydroxyl and amino groups as side groups and, therefore, a hydrogen-bonding interaction may take place between these two chemical moieties They also stated that the hydrogen bonds between two macromolecules compete with the formation of hydrogen bonds between molecules of the same polymer
Another type of interaction that may occurs is associated with the crosslinking of chitosan with TPP The electrostatic interaction between CHI and TPP occurs at molecular level with release of water molecules and displacement of the main thermal events of the polymer (Hashad, Ishak, Fahmy, Mansour, & Geneidi, 2016)
BMV interfered in thermal profile of the blend The membranes containing BMV exhibited an intensity reduction of the DSC peaks The first DSC event of the membranes shift to lower temperatures may be associated with the presence of BMV in polymer matrix, since BMV contributed with hydroxyl groups, indicating the incorporation of BMV
in the membranes In absence of PVP (CH-B membrane), the DSC profile
Fig 1 TG/DTG obtained at 10 °C min−1 under dynamic nitrogen atmosphere (50 mL min−1) for the blends (CH:PVP, CH:PVP-B) and membranes (CH, CH-B).
Trang 4is similar to the raw materials with slightly shifts No BMV melting
point is observed in the membranes containing PVP suggesting a good
miscibility of BMV in the blend
Fig 2(b) shows the DSC curves of chitosan, TPP, PVP and BMV
Chitosan exhibited: i an endothermic event at 97 °C, which corresponds
to water loss; ii an endothermic event at 277 °C, related to
decom-position of amino groups of chitosan (Abdelrazek et al., 2010;Santos,
Soares, Dockal, Campana Filho, & Cavalheiro, 2003); iii a third event,
exothermic, close to 300 °C TPP presents one main endothermic peak
at 114 °C related to melting PVP exhibited an endothermic event at
113 °C regarding glass transition Kadota, Otsu, Fujimori, Sato, and
Tozuka (2016)andKnopp et al (2015)reported PVP glass transition at
168 and 160 °C respectively This difference in glass transition
tem-perature may be associated to changes in molecular weight, purity and
crystallinity degree of PVP obtained from different origins (Homayouni,
Sadeghi, Varshosaz, Garekani, & Nokhodchi, 2014;Knopp et al., 2015)
BMV is considered a crystalline drug, presenting melting point at
195 °C There are three polymorphs of BMV commercially available,
and they differ in crystal lattice due to preparation process and
crys-tallization It was observed that the BMV polymorph studied in this
work is the polymorph II (Näther, Jess, Seyfarth, Bärwinkel, & Senker,
2015)
The XRD profile of the polymers, PVP and CHI are shown inFig 3 It
is possible to observe two main wide assymetric peaks at 11° and 21°;
12° and 20°, respectively, which are indicative of semi-crystalline
ma-terials, as previously described in the literature (Azevedo et al., 2011;
Croisier & Jérôme, 2013;Gonsalves, Ferro, Barreto, Nunes, & Valerio,
2016;Lewandowska, 2011) TPP presented several well-defined peaks, which are related to its crystalline nature The XRD pattern of BMV showed main peaks in 14°, 17°, 28° and a wide peak with maximum intensity between 11° and 12°
Observing the membrane’s diffraction patterns, their similarity was evident and both showed 4 diffraction peaks (two low intensity ones at
18 and 25°, and two high intensity ones at 14 and 16) The pattern shift when comparing to the isolated components suggests a conformational change when the membrane is formed Conformational changes were also observed byAbugoch, Tapia, Villamán, Yazdani-Pedram, and Díaz-Dosque (2011) and by Lewandowska (2011), when they evaluated chitosan/quinoa protein membranes, and chitosan acetate/PVP, re-spectively
The XRD peaks related to the BMV were not observed in the membranes containing the drug (CH-B and CH-PVP-B) According to Subha, Mallikarjuna, Pallavi, Rao, and Rao (2015), this indicates that the drug is dispersed at the molecular level in the membrane and therefore, no drug peaks could be observed
SEM analysis of the membranes is shown inFig 4 It is possible to observe that the membranes present a smooth, compact and homo-geneous surface The absence of defects in the CH and CH-B indicates that PPG contributed to CHI dispersion capacity during solvent casting process showing a good compatibility between them Usually, plasti-cizers acts on the polymer compatibility with CHI during membrane formation (Van Den Broek, Knoop, Kappen, & Boeriu, 2015)
Fig 2 (a) DSC curves for CH:PVP, CH, CH:PVP-B and CH-B; (b) DSC curves for CHI, TPP, PVP and BMV; obtained with a heating rate of 10 °C min−1and dynamic atmosphere of nitrogen (20 mL min−1).
Fig 3 X-ray diffraction pattern for (a) PVP, CHI, TPP and BMV; (b) CH, CH-B, CH:PVP and CH:PVP-B membranes.
Trang 5The blend formation between CHI and PVP also was observed by
SEM, in which minor imperfections with circular shape were detected
These imperfections may be related to casting process or an
in-compatibility between the polymers Generally, polymeric blends
sur-faces are smooth and homogeneous with a certain degree of
im-miscibility Yin, Luo, Chen, and Khutoryanskiy (2006)reported that
CHI/cellulose derivatives blends presented smooth surface, but in
cross-section view they showed irregularities probably related to polymer
immiscibility Nevertheless, DSC analysis did not demonstrate any
polymer immiscibility suggesting that the imperfections occurred due
to solvent casting process
No changes were detected after drug incorporation (CH:PVP-B and
CH-B) No clusters were observed, suggesting BMV incorporation in the
polymeric matrix These results are in agreement with previous
char-acterizations
The thickness of the inert chitosan membrane containing PVP
(48.66 ± 7.57μm) was slightly thicker than the membrane without
PVP (39.33 ± 1.15μm) On the other hand, almost no changes in
thickness were observed after BMV incorporation
Swelling studies can be very useful to understand the drug delivery
mechanism, since the higher release can be attributed to the higher
extent of water uptake, resulting in increased wetting and penetration
of water into thefilm matrices, and hence, increased diffusion of the
drug (Koland, Charyulu, Vijayanarayana, & Prabhu, 2011) Several
parameters can affect the swelling ratio, hydrophilicity, stiffness and
pore structure of a matrix The higher degree of swelling is, higher the
surface area/volume ratio The hydrophilic nature of chitosan material
may be a major factor that influences the extent of swelling of these
matrices (Archana et al., 2013)
Fig 5presents the swelling profile of the CH membranes with PVP
(CH:PVP-B and CH: PVP) or without (CH-B and CH) It is possible to
observe that the presence of PVP in the membrane allowed higher
percentages of swelling (> 80%) Koland et al (2011) found similar
results where the presence of PVP, a hydrophilic polymer, increased the extent of swelling, and the maximum swelling was obtained in the formulation that contained higher amounts of PVP On the other hand, the presence of the drug in the membranes slightly decreased their swelling, which probably occurred due to the poor solubility of BMV in water (Lucangioli et al., 2003), influencing the extent of swelling of chitosan In addition, as previously shown in the DSC analysis, the presence of BMV in the membranes resulted in displacement of water molecules, which may also reduce the chitosan swelling ability Fig 6shows the in vitro release of betamethasone-17-valerate for chitosanfilms with (CH:PVP-B) or without PVP (CH-B), and in both formulations the drug release occurred very quickly, and plateaus were reached within 30 min and 1 h, respectively (Khoo et al., 2003) Thus, since the BMV needs to reach the oral mucosa quickly, the developed membranes were appropriate As expected, the drug release followed the trends for swelling ability; the chitosanfilms with PVP presented thefinal total drug release of ∼80%, greater than that chitosan films without PVP∼40%
Fig 4 Photomicrographs of inert and drug loaded membranes through scanning electron microscopy.
Fig 5 Swelling profile of the CH:PVP, CH:PVP-B, CH and CH-B performed at 37 °C using phosphate buffer (pH = 7.4) as media.
Trang 6The betamethasone 17-valerate release profiles were fitted to the
Korsmeyer and Peppas model (Ritger & Peppas, 1987) to investigate
whether the release of the drug was related to both the polymer
re-laxation, in contact with the solvent, and/or the diffusion of the active,
through the hydrated matrix This phenomenon has been reported to
occur in swellable polymers, such as chitosan (Talón, Trifkovic, Vargas,
Chiralt, & González-Martínez, 2017) The generalized expression of the
Korsmeyer and Peppas is described in Eq (2)
∞ =
where Mt/M∞corresponds to the fraction of the drug released at
time t, k is the rate constant of the membrane, related to the diffusion
process, and n is the diffusional exponent that is related to the
me-chanisms involved in the release process Thus, for thinfilms a n value
of 0.5 means that the release obeys the Fickian diffusion model,
whereas if the n value is higher than 0.5, known as anomalous
trans-port, the diffusion and the polymer relaxation are coupled (Serra,
Doménech, & Peppas, 2009;Siepmann & Peppas, 2012)
In this work the n value found was higher than 0.5, which
corre-sponds to anomalous transport According to de Souza, Goebel, and
Andreazza (2013), the anomalous transport suggests that the solvent
diffusion rate and polymer relaxation process occur in the same order of
magnitude, in other words, the transport consists in both drug diffusion
in the hydrated matrix and polymer relaxation
Among several factors, the swelling ability is closely related to the
bioadhesive properties of polymers The ability of certain polymers in
absorbingfluids, especially from human body, it becomes possible their
application in mucoadhesive formulations The swelling ability is
es-sential to enable the adherence of the formulation in the mucosa
(Carvalho, Chorilli, & Gremião, 2014) In order to adhere to the
mu-cosa, the polymers should absorb a certain amount of fluid until the
polymeric structure reach the top of remodeling which is succeed by
permeation of mucin and other proteins Only polymers with
dis-sociated functional groups can interact electrostatically with mucin
Table 2 shows that the blends (CH:PVP and CH:PVP-B), which
presented higher rates of water absorption (Fig 5), also demonstrates
higher tensile strength rate, in other words, higher
muco(bio)ad-hesivity As related previously, the chemical interaction between the
functional groups of CHI and PVP provided a better structural
organization, which promoted higher adhesivity These results suggest that there is two mechanism of mucoadhesion acting mutually One by electrostatic force between CHI- sialic acids and other by chain inter-penetration of the PVP into the mucin layer In this case, thefirst one is more important than second
In addition, the presence of BMV in the membranes causes decrease
in mucoadhesion, and probably occurred due to the rearrangement of polymeric chain to accommodate the drug As previously observed in DSC, the incorporation of BMV resulted in displacement of water mo-lecules in order to its incorporation This displacement of water mole-cules led to a reduction in swelling ability (as previously shown in swelling studies) and consequently in the decrease of mucoadhesion
4 Conclusion This study proposed the preparation of mucoadhesive membranes constituted of CHI and PVP as a potential drug delivery system for BMV
in the RAS treatment The presence of PVP in the membranes possibly provides chemical interactions with CHI which improves the thermal stability as observed in thermal analysis Moreover, PVP increased the swelling ratio of the membranes, and therefore improved the BMV re-lease rate (∼80% in less than 1 h) and promoted higher mucoadhesion
On the other hand, BMV modifies the swelling ratio and the mu-coadhesion, probably due to the displacement of water molecules ori-ginally found in the membranes by drug molecules Thus, the results of this study suggest that the developed system is appropriate to deliver BMV aiming the RAS treatment In addition, these systems may be further evaluated using animal model
Acknowledgments The authors are grateful to CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and FAPITEC/SE (Fundação de Apoio à Pesquisa e à Inovação Tecnológica do Estado de Sergipe) forfinancial support CETENE-PE (Centro de Tecnologia do Nordeste, Pernambuco, Brazil), Departments of Physics and Chemistry
of the Federal University of Sergipe (UFS) for carrying out the tests Rosangela H Sizílio is also grateful to CAPES for the Masters grant
Appendix A Supplementary data Supplementary data associated with this article can be found, in the online version, athttps://doi.org/10.1016/j.carbpol.2018.02.079 References
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Fig 6 In vitro release profiles of betamethasone-17-valerate from CH and CH:PVP
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Table 2
Mucoadhesive properties of CH, CH-B, CH:PVP, CH:PVP-B membranes.
Sample Area to Positive Peak (N s) Peak Positive Force
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CH-B −2.590 ± 0.039 0.186 ± 0.021
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