Cold Atmospheric Plasma Surface Nanoengineered Carboxymethyl Cellulose Hydrogels As Oral Ibuprofen Carriers
Cold Atmospheric Plasma Surface Nanoengineered Carboxymethyl Cellulose Hydrogels As Oral Ibuprofen Carriers
Cold Atmospheric Plasma Surface Nanoengineered Carboxymethyl Cellulose Hydrogels As Oral Ibuprofen Carriers
Abstract
Smart hydrogels comprising polyvinyl alcohol and carboxymethyl cellulose have been fabricated using a green crosslinker
tetraethyl orthosilicate. The hydrogels were subjected to cold atmospheric plasma-treatment using pure Ar, pure NH3 and
a mixture of the two. Enhanced surface wettability was witnessed post-plasma treatment; irrespective of the plasma gas
employed. An insignificant surface ageing of the hydrogels was marked upon exposure to air for 10 days. AFM analyses
revealed the surface topographical changes at the nano level while the bulk attributes remained unaffected. The hydro-
gels displayed smart swelling features. The release of ibuprofen from the hydrogels in simulated gastric and intestinal
fluids affirmed their potential towards oral colon-targeted drug delivery. The preliminary kinetics of drug release indicated
the anomalous nature of drug transport mechanism. More so, drug release from plasma-treated hydrogels were pre-
dominantly governed by diffusion process rather than polymer chain relaxational process. The hydrogels demonstrated
good biodegradability and could be efficaciously utilized as potential oral drug delivery candidates.
* Smruti Prava Das, spdas@ravenshawuniversity.ac.in; * Subhraseema Das, subhraseema@gmail.com | 1Plasma Research Laboratory,
Department of Chemistry, Ravenshaw University, Cuttack, Odisha 753003, India.
Received: 9 August 2019 / Accepted: 27 September 2019 / Published online: 4 October 2019
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natural resource on earth, is of great importance and finds Ibuprofen (IBF) and TEOS were procured from Sigma-
unparallel applications in medicine [17–20]. However, the Aldrich, India and used as received. Chloroacetic acid was
applicability of cellulose is largely impeded owing to its procured from Merck India Ltd. and used as such. Deion-
insolubility in a variety of solvents [21, 22]. One of the sim- ized water from a Millipore Milli Q system was employed
plest strategies to obviate this shortcoming has been by the throughout. All other reagents used were of analytical
synthesis of cellulose derivatives such as hydroxypropyl-cel- grade purity.
lulose or carboxymethyl-cellulose. Carboxymethylation, in
general, is mostly chosen due to the technical simplicity of 2.2 Synthesis of carboxymethyl cellulose (CMC)
the process [23]. Carboxymethylation increases the hydro-
philicity and solution clarity thereby improving the aqueous CMC was synthesized as per the reported method [54].
solubility of cellulose [23, 24]. Additionally, pendant carbox- Briefly, cellulose (3 g) was dispersed in 100 mL of isopro-
ylic acid groups that tend to attach to the cellulose back- panol and mechanically stirred at room temperature for
bone post-carboxymethylation render a pH-sensitivity to 2 h. 80 mL of 60% NaOH (w/v) was added gradually over
the otherwise unresponsive pristine cellulose [25]. Carboxy- a period of 20 min and left under continuous stirring
methylated cellulose (CMC) has often been amalgamated for 2 h. Subsequently, 100 mL of chloroacetic acid (60%
with various polymers to cater to a wide array of biomedi- w/v) was added to the reaction mixture; the temperature
cal applications [25–30]. One such polymer of eminence is raised to 60 °C and allowed to react for the next 6 h. It
polyvinyl alcohol (PVA) that has carved a niche for itself in was filtered, suspended in 150 mL of 80% methanol and
pharmaceutical utilities. The versatility of PVA is paramount neutralized with acetic acid. The final solid product (CMC),
in the fabrication of a variety of architectures including films, thus obtained, was thoroughly washed with methanol and
microgels, microspheres, microbubbles and microcapsules dried at 60 °C.
[31, 32]. Owing to its good film forming ability, long-term
temperature and pH stability; PVA-based hydrogels find a
greater call in biomedical research [33–36]. Several studies 2.3 Synthesis of PVA/CMC hydrogels
have reported the successful design of PVA/CMC hydrogels
for potential applications in medicine [23, 37–42]. Literature PVA solution (10 wt%) was prepared by dissolving in water.
also points towards the utilities of the aforesaid hydrogels in Aqueous CMC solution (10 wt%) was added to PVA solu-
agriculture, dye removal and other industrial areas [43–52]. tion to form a homogeneous solution. To the above solu-
However, till date, no work has focussed on the surface engi- tion mixture, TEOS (2 mL) was added dropwise and the
neering of PVA/CMC hydrogels by DBD plasma, their subse- reaction mixture was stirred for a brief period. The solution
quent physicochemical properties and application as oral was then cast onto petri plates and dried in vacuo. The
drug carriers. hydrogels were repeatedly washed with deionized water
In this research contribution, surface modification of to remove the unreacted reagents and dried for further
PVA/CMC hydrogels have been performed in atmospheric uses.
pressure Ar, NH3 and a mixture of Ar and NH3 DBD plasmas.
The hydrogels have been fabricated using tetraethyl ortho- 2.4 DBD plasma treatment of hydrogels
silicate (TEOS) as the crosslinker. TEOS has particularly been
chosen because it is a green crosslinker and widely accepted Surface modification of the hydrogels was performed in
in pharmaceutical formulations [53]. The influence of plasma an atmospheric pressure DBD plasma reactor. A sche-
treatment on the hydrogels have been investigated by con- matic of the DBD set-up is presented in Fig. 1. The DBD
tact angle, FTIR and AFM analyses. This study also explores system consists of two parallel stainless-steel electrodes
the possible application of the hydrogels towards the (30 cm × 30 cm) and a 2 mm-thick dielectric glass plate
oral delivery of the non-steroidal anti-inflammatory drug covering both the electrodes. The upper electrode is con-
(NSAID), ibuprofen, to the colon. Further, the biodegradabil- nected to a high voltage AC source (0–30 kV, 50 Hz, Zeon-
ity of the hydrogels has been assessed by the soil burial test. ics Systech, India), while the lower electrode is grounded.
The hydrogel specimen was kept in-between the two
electrodes and the plasma-generating gas was driven into
2 Experimental the plasma chamber. The gas flowrate was monitored by a
digital mass-flow controller (Sevenstar Electronics Co. Ltd.,
2.1 Materials China). For pure Ar and pure ammonia; the gas flowrate
was maintained at 0.5 Lpm (Litre per minute). For the Ar/
PVA (Mw = 89,000–98,000; 99.0% hydrolyzed), Cellulose NH3 mixture; Ar flowrate was maintained at 0.5 Lpm while
(microcrystalline powder having particle size 20 μm), it was kept constant at 0.125 Lpm for NH3.
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Fig. 1 Schematic illustration of
the DBD plasma reactor set-up
2.5.1 Contact angle (CA) and surface free energy (SFE) The hydrogels were allowed to swell in phosphate buffer
(PBS, pH 7) till equilibrium, then frozen at − 20 °C for 5 h
The wettability of the hydrogels has been determined followed by lyophilization at − 55 °C for 24 h (Biobase
from CA measurement using the sessile drop method in Freeze Dryer). The lyophilized samples were sputtered
a Rame-Hart Tensiometer, USA. The static contact angle coated and their morphology was investigated on a Carl
was measured by employing distilled water and ethylene Zeiss-EVO@18 SEM.
glycol as polar and non-polar probe liquids respectively.
A drop of the test liquid was positioned on the surface of
the hydrogels and the images were captured immediately. 2.6 Smart swelling response of hydrogels
Ten different measurements of each sample were taken
and the results have been reported as mean ± SD. The SFE The pH-dependant swelling behaviour was inspected
was also estimated using Owens, Wendt, Rabel and Kaelble by immersing the hydrogels in solutions of desired pH
(OWRK) method. (2.0–12.0) at 37 °C. At regular time intervals; samples
In order to examine their durability; the hydrogel speci- were taken out, gently wiped with filter paper to remove
mens were exposed to air for a certain time period. The the excess surface water and weighed. The process was
durability was estimated from CA analyses as described continued till a constant weight was obtained. The equi-
above. librium swelling ratio was calculated according to the
following formula:
2.5.2 FTIR
Ws − Wd
Swelling (%) = × 100 (1)
Wd
The hydrogels were triturated with dry KBr, compressed
into pellets and the spectra collected in a Thermo where Ws and Wd are the weights of the swollen and dried
Nicolet iS5 FTIR spectrophotometer in the range of hydrogels, respectively.
4000–400 cm−1.
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2.7 In vitro drug release studies and kinetics embedded in 1 kg of soil (collected from Ravenshaw Uni-
versity at Cuttack and used for gardening purposes). Water
IBF is a potent NSAID widely prescribed for its analgesic, was sprinkled at regular intervals to prevent the drying of
antipyretic and anti-inflammatory properties. It is used to the soil. The biodegradability was calculated by the follow-
relieve pain and inflammation in a wide spectrum of mus- ing equation [52]:
culoskeletal conditions including arthritis, gout, sprains and G1 − G2
rheumatism [55]. In this study, IBF has been loaded onto the W= × 100 (7)
G1
hydrogels and its release studied. The dried hydrogels were
equilibrated with IBF (25 mg/25 mL) solution (methanol: where G1 and G2 are the weights of the hydrogels before
water = 1:2) for 48 h in dark. The release from the hydrogels and after test, respectively.
was studied in phosphate buffer of pH 7.4. The release stud-
ies were also carried out in simulated gastric (SGF, pH 1.2)
and intestinal (SIF, pH 7.4) fluids prepared according to the 3 Results and discussion
standard procedures. 3 mL aliquot samples were withdrawn
from 50 mL of the releasing medium at regular intervals and 3.1 CMC synthesis and characterization
analysed spectrophotometrically (Cary UV-100, Agilent Tech-
nologies) at 276 nm. The withdrawn samples were replen- The schematic representation of carboxymethylation of
ished with 3 mL of fresh buffer to simulate physiological cellulose is presented in Fig. 2a. The formation of CMC
conditions. The data were expressed as the mean value of has been verified from FTIR spectral analysis (Fig. 2b). The
three independent experiments and the standard deviations key cellulose spectral peaks constitute O–Hstr vibration
are presented as error bars. at 3380 cm−1, C–Hstr vibration around 2900 cm−1 and an
The drug release data were fit to four basic kinetic mod- absorption band at 890 cm−1 typical of β-glucan [21]. The
els namely zero order, Higuchi, Ritger–Peppas and Pep- spectrum of CMC was significantly different from that of
pas–Sahlin equations and the best fit was determined pristine cellulose. Two characteristic peaks at 1600 cm−1
2. These
against the highest value of correlation coefficient, R and 1425 cm−1 which are associated with COO− antisym-
equations are given by [56]: metric and symmetric stretching respectively was
observed suggesting the presence of carboxymethyl
Zero Order: Mt ∕M∞ = k0 t (2)
groups [52, 57]. Thus, the FTIR analyses affirmed the suc-
Higuchi: Mt ∕M∞ = kH t 1∕2 (3) cessful carboxymethylation of cellulose.
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Fig. 3 Proposed schematic
illustration of PVA/CMC hydro-
gel formation using TEOS as
crosslinker
respectively for PCMC@UT, PCMC@Ar, PCMC@NH3 and characterizes the degree of wetting of a solid surface by a
PCMC@Ar + NH 3 hydrogels respectively. The higher liquid droplet [59]. The chemical composition and surface
degree of surface roughness of PCMC@Ar + NH3 could be topography are crucial in deciphering the wettability of a
accounted for the coupled effects of the Ar and NH3 plas- polymeric surface. Surface wettability directly influences
mas impinging on hydrogel surface [58]. The AFM analyses cell-biomaterial interaction in terms of adhesion, prolifera-
were clearly suggestive of the surface nanotexturing of the tion, viability and differentiation; thereby ultimately affect-
hydrogels while the bulk attributes remained undeterred. ing the biocompatibility [11]. The CA of the hydrogels was
estimated using water and ethylene glycol as probe liq-
3.4 Surface wettability analyses uids and the corresponding surface energies have been
depicted in Fig. 5a, b respectively.
The wettability of any polymer surface can be described by As evident from Fig. 5a, the water CA of PCMC@UT
the intermolecular interaction with the liquid phase that was observed to be 67.40° ± 1.42°. However, the water
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Fig. 4 3D AFM images of a PCMC@UT, b PCMC@Ar, c PCMC@NH3 and d PCMC @Ar + NH3 hydrogels
CA values decreased to 53.65° ± 0.70°, 38.65° ± 0.83° and NH3 and PCMC@Ar + NH3 respectively. The PCMC@Ar + NH3
25.93° ± 0.45° for PCMC@Ar, PCMC@NH3, PCMC@Ar + NH3 was found to be the optimum of the lot with lowest CA
hydrogels. This lowering in CA values could be particularly and highest SFE characteristics.
ascribed to the addition of new polar functional groups
on the hydrogel surfaces post-plasma modification (γp 3.5 Hydrophobic recovery: ageing effect
in Fig. 5b). Generally, N H3-plasma is known to introduce of hydrogels
amine or –CONH2 or N–C=O functionalities which are polar
in nature [58, 60]. Typically, following an Ar-plasma treat- The durability of the pristine and plasma-modified hydro-
ment, free radicals are generated at the hydrogel surface. gels has been determined from the CA measurements by
These free radicals react with the oxygen from the atmos- exposing them to air. When the plasma-treated samples
phere that eventually lead to incorporation of hydro- are exposed to ambient environment; the newly added
philic C–O groups on the surface [10, 58, 60]. Conversely, polar functionalities on the hydrogel films post-plasma
enhanced surface hydrophilicity of PCMC@Ar + NH3 could treatment are gradually lost to the atmosphere. This phe-
be explained by taking into account the coupled effects nomenon is generally referred to as hydrophobic recovery
of both Ar and NH3 plasmas impinging on its surface. or ageing [61]. Figure 6 displays the progression in water
The surface hydrophilicity of the hydrogels was found to CA values of the hydrogels with an ageing up to 10 days.
increase in the order of PCMC@UT < PCMC@Ar < PCMC@ As evident from Fig. 6, the water CA of the plasma-
NH3 < PCMC@Ar + NH3. treated samples showed a slight upward trend after
Surface free energy (SFE) is an important criterion that 10 days of storage. This observation could be rationalized
has often been strongly correlated with the cell-biomate- by considering the rearrangement of the hydrophilic polar
rial interfacial interactions. Higher the SFE; stronger is the groups incorporated onto the hydrogel surface during
adhesion between the two surfaces. It was witnessed that plasma treatment and the subsequent reorientation of a
PCMC@UT presented a lower SFE value of 37.12 ± 1.35 mJ/ part of these hydrophilic groups towards the bulk thereby
m 2 whereas the energies increased to 46.20 ± 0.64, reducing the acquired hydrophilic nature of the treated
62.86 ± 1.21 and 74.93 ± 0.53 mJ/m2 for PCMC@Ar, PCMC@ surface [61]. Subsequent to 10 days of exposure to air;
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features of the hydrogels were more or less similar; how- by considering its improved surface hydrophilicity ensuing
ever, the plasma-modified hydrogels displayed more sig- from DBD plasma treatment.
nificant hydroxyl absorption bands that was suggestive
of their hydrophilic nature acquired post-plasma modifi-
3.8 Morphological analyses
cation. Among all, the PCMC@Ar + NH3 exhibited higher
O–Hstr which implied an increase in the hydrophilic moie-
The equilibrium swollen hydrogels (in pH 7) were lyo-
ties in the hydrogel.
philized and their morphology has been visualized by
SEM (Fig. 9). The micrograph of PCMC@ UT revealed a
3.7 Smart swelling responsivity
fairly firm surface structure with the distribution of some
bulges (Fig. 9a, a′). However, following DBD plasma treat-
pH is a crucial parameter to be assessed for biomaterials
ment; the hydrogels exhibited a relatively regular surface.
designed for drug delivery purposes. In this study, the
A continuous and evenly distributed 3D macroporous
swelling response of the hydrogels was investigated at
network structure was evident for the plasma-modified
different pHs. The influence of pH on the swelling of the
hydrogels (Figs. 9b, b′, c, c′, d, d′). This morphological
hydrogels is shown in Fig. 8.
observation could be justified by considering the surface
The hydrogels exhibited pH-sensitive swelling with
alterations attained upon plasma-treatment that provided
maximum swelling at neutral pH and lower swelling at
a new corridor for the water molecules to enter into the
acidic and basic pH. The pH-responsivity of the hydro-
hydrogel matrix, thereby enhancing the porosity. Taken
gels could be ascribed to the presence of CMC which is
together with the deductions from CA, FTIR and swelling
anionic in nature and endowed with pendant carboxylic
experiments; it could be inferred that plasma treatment
acid groups [25]. In acidic pH, most of the carboxylate
promoted more junctions and pores in the hydrogels.
anions are protonated. Thus, hydrogen-bonding inter-
Hydrogels possessing such porous morphology could be
action among carboxylic acid groups was generated.
utilized as scaffolds in tissue engineering applications or
H-bonding, being a physical crosslinker, tends to shrink
as wound healing agents.
the matrix thereby resulting in a decreased swelling [62].
Upon increasing the pH to 7; few carboxylic groups in the
CMC network get deprotonated and hence, electrostatic 3.9 IBF release and kinetics
repulsion between carboxylate anions increases and
higher swelling was observed. At basic pH, the deioniza- 3.9.1 In vitro IBF release studies
tion of carboxylate groups in CMC causes a shrinkage in
the hydrogel matrix and swellability is reduced [25, 62]. To evaluate the potential of PCMC hydrogels as drug
The swellability was found to be of the order PCMC@ delivery systems, the release of IBF-loaded hydrogels was
UT < PCMC@Ar < PCMC@NH3 < PCMC@Ar + NH3. The higher assessed. The drug release profiles of the hydrogels have
swelling capacity of PCMC@Ar + NH3 could be explained been presented in Fig. 10.
As evident from Fig. 10a, the rates of IBF release dif-
fered for the pristine PCMC and plasma-modified PCMC
hydrogels. For both the composites; more than 90% of the
drug has been released after 12 h. However, IBF release
was achieved faster from PCMC@Ar + NH3 in comparison
to PCMC@UT. This difference in the release profiles could
be accredited to their swelling behaviour. Since PCMC@
Ar + NH3 matrix has higher swellability features among
others, drug release is achieved sooner.
In order to further imitate the conditions of the gastro-
intestinal tract; IBF release from the PCMC@Ar + NH3 was
studied in SGF and SIF. The hydrogels were immersed in
SGF for 2 h and then transferred to SIF and the release
was monitored. Figure 10b depicts the release profile of
IBF from PCMC@Ar + NH3 in SGF and SIF environments.
Less than 20% of IBF was released during the initial 2 h in
SGF. However, when it was transferred to SIF; the rate of
IBF release increased significantly. This release profile of
Fig. 8 Smart swelling response of PCMC hydrogels at 37 °C IBF fulfils the requirements of US Pharmacopeia for oral
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Fig. 9 SEM images of PCMC hydrogels; a PCMC@ UT (a ×1000; a′ ×10,000), PCMC@Ar (b ×1000; b′ ×5000), PCMC@NH3 (c ×1000; c′ ×10,000)
and PCMC@Ar + NH3 (d × 1000; d′ ×10,000)
Fig. 10 IBF release profiles of PCMC hydrogels in a pH 7.4, and b SGF, SIF at 37 °C
drug delivery to the lower part of the gut targeting the n lie between 0.75 and 0.91, indicating the anomalous
colon [53]. nature of drug release, where both diffusion and relaxa-
tion processes contribute. However, to exactly determine
3.9.2 IBF release kinetics the contribution of these two processes, the ratio of the
polymer relaxation over Fickian contributions (R/F) was
Table 1 summarizes the kinetic parameters for IBF release calculated using the values of k1 and k2 and plotted against
data which provides an approximate idea about the drug the fraction of IBF released (Fig. 11).
transport mechanism from the hydrogels. The predominant influence of macromolecular chain
For a thin film, when n = 0.5, the drug release mecha- relaxation on the drug release was observed for PCMC@UT.
nism is Fickian diffusion. When n = 1, Case II transport However, ensuing plasma-modification, the drug release
occurs leading to zero-order kinetics. When n lies between mechanism was mostly diffusion-controlled. The low-
0.5 and 1, anomalous transport is observed. The values of est R/F values of PCMC@Ar + NH3 were suggestive of the
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@UT 0.215 0.839 0.91 0.132 0.999 0.030 0.102 0.998 0.118 0.994
@Ar 0.232 0.866 0.83 0.171 0.993 0.072 0.100 0.995 0.142 0.970
@NH3 0.261 0.878 0.81 0.196 0.997 0.089 0.107 0.995 0.160 0.965
@Ar + NH3 0.311 0.905 0.75 0.264 0.998 0.145 0.118 0.996 0.217 0.928
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