Colocasia Esculenta and Bombax Ceiba Mucilages: in Vitro and in Vivo Characterization
Colocasia Esculenta and Bombax Ceiba Mucilages: in Vitro and in Vivo Characterization
Colocasia Esculenta and Bombax Ceiba Mucilages: in Vitro and in Vivo Characterization
ae
101
Current Drug Therapy, 2016, 11, 101-114
RESEARCH ARTICLE
ISSN: 1574-8855
eISSN: 2212-3903
microspheres. The developed microspheres show effective in vivo ulcer healing activity in
Wistar male albino rats.
Conclusion: The preliminary results of this study suggest that the developed mucoadhesive
microspheres containing GAA could be a promising tool in the treatment of gastric ulcer and
can be advantageous over the conventional anti ulcer therapy. The study also suggested that the
extracted mucilages can be used in the preparation of the mucoadhesive microspheres.
Keywords: Bombax ceiba mucilage, Colocasia esculenta mucilage, glycyrrhetinic acid, microspheres, mucoadhesive.
overcome by developing mucoadhesive micro- to improve its oral absorption and to decrease the
spheres. Conferring mucoadhesive properties to drug administration frequency.
microspheres will increase intimate contact with
the mucosal membrane, which leads to the MATERIALS AND METHODS
prolonged retention of dosage form in the
gastrointestinal tract, which is the foremost Materials
requirement in the treatment of gastric ulcer [4-9].
The dried stolons of Liquorice (Glycyrrhiza
Gastric ulcer is a small erosion of gastric glabra) were purchased from the local market of
mucosa due to the imbalance between aggressive Meerut, India. The flowers of Bombax ceiba and
and defensive factors. Stomach defends itself from rhizome of Colocasia esculenta were procured,
pepsin and hydrochloric acid either by the respectively, from Meerut and Rudraprayag, India.
production of a mucus coating on stomach tissue The herbs were authenticated at the National
or by producing bicarbonate. According to Lucas, Bureau of Plant Genetic Resources (NBPGR), New
the earliest evidence of the application of licorice Delhi. Pure Glycyrrhetinic acid (Sigma Aldrich)
in medicine comes from the stores of licorice was purchased from RK Enterprises, Meerut,
found in the ancient tombs of Egyptian Pharaohs India. Carbenoxolone sodium was purchased from
[10]. It is obtained from dried, peeled or unpeeled Aar Vee and Company, Meerut, India. All the
roots and stolen of Glycyrrhiza glabra Linn, chemicals used were of analytical grade and used
(Leguminosae) [11, 12]. Its chief constituent is as such without further purification.
triterpenoid saponin, glycyrrhizin, which hydrolyzes
in acidic media and yields one molecule of Methods
glycyrrhetinic acid (aglycon) and two molecules of
glucuronic acid (glycon). Glycyrrhetinic acid (GA) Extraction of Glycyrrhetinic Acid as its
protects the stomach by stimulation of gastric Ammonium Salt
mucus production. It enhances the rate of Glycyrrhetinic acid (GA) was extracted from
incorporation of various sugars into gastric dried stolons of Glycyrrhiza glabra. Briefly,
mucosal glycoproteins, promotes mucosal cell accurately weighed 100 g liquorice powder
proliferation, inhibits mucosal cell exfoliation, (Glycyrrhiza glabra) was soaked in 500 ml pre-
inhibits prostaglandin degradation, increases the acidified distilled water. This leads to the
release of PGEs, reduces the formation of hydrolysis of ether bond of glycyrrhizin resulting
thromboxane B2 and regulates DNA and protein in one molecule of aglycon i.e., glycyrrhetinic acid
synthesis in gastric mucosa. It does not inhibit acid and two molecules of glycon, i.e., glucuronic acid.
secretion. GA increases mucus production, which The strong ammonia solution was added to the
remain adhered to the gastric mucosa [13, 14]. mixture and filtered. Activated charcoal was used
Other action includes prolongation of life span of for de-pigmentation. The product was crystallized
gastric epithelial cell, prevention of bile reflux and and purified by column chromatography using
slowing of prostaglandin degradation in gastric chloroform: methanol (1:1) as mobile phase [15].
mucosa.
Colocasia esculenta (CE) is a perennial herb Identification of GAA
that belongs to the Araceae family. Colocasia Isolated and purified GAA was characterized
esculenta originates from the tropical region for physical characteristics, organoleptic properties,
between India and Indonesia and has been grown melting point, loss on drying and pH. Elemental
in the South Pacific for hundreds of years. Bombax analysis was performed to ensure the counter ions.
ceiba (BC) is a tree of the genus Bombax and it is The calibration curve of GAA was prepared in 0.1
commonly known as cotton tree or Red Silk- N HCl using a UV spectrophotometer (1700S,
Cotton or Red Cotton Tree. The dry cores of the Shimadzu, Japan). The Fourier Transform Infrared
Bombax ceiba flower contain mucilage. The Spectroscopy (FTIR) (8400S, Shimadzu, Japan)
present work was aimed to formulate and was performed in order to confirm the molecular
characterize mucoadhesive microspheres of entity using KBr disk method. The sample was
glycyrrhetinic acid ammonium (GAA) using gently triturated with KBr powder at a weight ratio
mucilages obtained from natural sources in order of 1:100 and compacted into a disc using a KBr
Glycyrrhetinic Acid Ammonium Loaded Microspheres Current Drug Therapy, 2016, Vol. 11, No. 2 103
press at 10 tons for 2 min. The sample disc was and loss on drying. The chemical tests were
scanned from 4000 to 400 cm-1 at a resolution of 4 performed to find out the presence of unwanted
cm-1. Reverse Phase High Performance Liquid chemicals, if any [20]. The Fourier Transform
Chromatography (HPLC) (8400S, Shimadzu, Infrared (FTIR) spectral data of mucilage were
Japan) was carried out using C-18 column. taken for the identification of mucilage by the KBr
Acetonitrile: phosphoric acid (3:1), pH 2.5, was disc method using FTIR spectrophotometer
used as mobile phase at a flow rate of 0.5 ml/min (8400S, Shimadzu, Japan).
using a UV detector at 252 nm. Dilutions of the
sample were prepared in chloroform. The injection Formulation of Mucoadhesive Microspheres
volume was kept at 20 μl.
Mucoadhesive microspheres containing GAA
were prepared using CE and BC mucilages alone
Extraction of Mucilages and in combination using the single phase
The mucilages were extracted from the herbs of emulsification technique (Table 1). An accurately
Colocasia esculenta (rhizomes) and Bombex Ceiba weighed amount of GAA was dissolved in 25 ml
(red flowers) using cold maceration method. of freshly prepared and cooled distilled water. The
Acetone was used as precipitation solvent [16-19]. mucilage was added with constant stirring for 12 h,
The extracted mucilages were washed three times at 1500 rpm using a mechanical stirrer (RQT-124A,
with ethanol to decrease microbial load. Remi, Mumbai, India), to swell the mucilage. The
mixture was dispersed slowly in 250 ml of
Identification of Mucilages preheated (40°C) light paraffin at 1500 rpm using
a mechanical stirrer for 12 h. Glutaraldehyde
Isolated mucilages were characterized for solution (2%) in methanol (cross-linking agent)
physical characteristics, organoleptic properties was added drop wise to the resultant mixture. The
Amount (mg)
Formulation Code D:P P1:P2 Mucilage RPM
Drug (mg)
P1 P2
Dissolution medium (0.1 N HCl, pH 1.2, 900 ml) daily for two weeks. After two weeks all the
was filled in the dissolution vessel and stirred at 50 animals were anaesthetized using anesthetic ether
rpm. The temperature was maintained at 37 ± and sacrificed to measure/score the lesions of
0.5°C. Microspheres equivalent to 100 mg of ulceration. The percent of ulcer protection was
GAA were placed in the dissolution vessel, and the determined as follows [32]:
basket was rotated at 100 rpm. Aliquots were Protection (%) = (Control mean ulcer index -
withdrawn every 15 min in the first hour and then
Test mean ulcer index)/ (Control mean ulcer
every hour till the 4th hour, followed by the 6th,
index) × 100
8th, 10th, 12th, 14th and 24th h. Same amount of
medium was transferred to the dissolution vessel Statistical analysis of data obtained from in vivo
in order to maintain the sink conditions. The ulcer healing activity (area and percentage
samples were analyzed by a UV spectro- inhibition) was carried out by One-way analysis of
photometer (UV - 1700, Shimadzu) at 252 nm variance (ANOVA) followed by Tukey's multiple
after suitable dilution. The study was conducted in comparison test.
triplicate [23, 27-29]. The drug release data of
formulation C was analyzed for release kinetics Stability Study
using BIT 1.12 software [30].
In the present work, stability study of the
selected formulation (formulation C) was
In Vivo Ulcer Healing Activity of Microspheres
performed after storing the microspheres at
Animals Used 25±2°C/60±5% RH, 30±2°C/65±5% RH,
40±2°C/75±5% RH for 6 months in screw capped
In vivo antiulcer study to ascertain the efficacy amber colored glass bottles. After 1, 3 and 6
of formulated microspheres (formulation C) was months, the microspheres were evaluated for
carried out in male Wistar albino rats weighing colour change and percent drug content. The initial
around 200 g. The animal experimental protocol drug content was considered as 100%.
was approved by the Institutional Animal Ethical
Committee (No. 711/02/a/CPCSEA). The animals
were handled as per the guidance of the RESULTS AND DISCUSSION
Committee for the Purpose of Control and
Characterization of GAA
Supervision on Experimental animals (CPCSEA),
New Delhi, India. The animals were housed in The percentage yield of GAA was found to be
polypropylene cages and maintained at 24°C ± 5.23% w/w. Isolated GAA was crystalline, white,
2°C under a 12 h light/dark cycle and were fed odorless powder, and had characteristic taste. The
with ad libitum with standard pellet diet and had melting point, loss on drying, and pH of isolated
free access to water [31]. GAA were 293±0.5°C, 0.1%, and 4.2±0.01,
respectively. The results of elemental analysis
Acetic Acid Induced Ulcer Model indicated the presence of ammonium ion as
counter ion. The λmax for GAA was observed at
The ulcer was induced by injecting 0.05 ml of 252 nm in 0.1 N HCl (pH 1.2). The equation of
30% acetic acid into the gastric wall of the rat. The the line for calibration curve was Y = 0. 0012X,
animals were divided into four groups (n = 6) as, r² = 0.9987. The Fourier Transform Infra Red
Group 1: control (treated with saline solution); (FTIR) Spectroscopy showed that principle peaks
Group 2: standard, treated with cabenoxolone obtained in the FTIR spectrum of extracted GAA
sodium; Group 3: treated with pure GAA in 1% were in compliance with the standard spectra of GA.
CMC; and Group 4: treated with GAA
mucoadhesive microspheres (formulation C). A Standard GA, extracted GA and GAA showed
small incision was made in the abdomen and the presence of several bonds like C-C and C-O
stomach and exposed, followed by injection of between 1300-800 cm-1, C=C and C=O between
0.05 ml of 30% acetic acid into the gastric 1900-1500 cm-1, C-H and O-H between 3800-2700
submucosal layer of a glandular portion of the cm-1. FTIR spectrum of GA (standard), GA
stomach. The cabenoxolone sodium, pure GAA (extracted) and GAA are shown in Fig. 1. The
and mucoadhesive microspheres were administered results of HPLC analysis for the extracted GAA
orally at a dose of 100 mg/kg body weight once showed retention time (rt) of 7.3 min (Fig. 2).
106 Current Drug Therapy, 2016, Vol. 11, No. 2 Visht and Kulkarni
80
%T
70
%T 70
60
60
50
50
40
40
30
30
20
GA Std 20 GA Extracted
4000 3500 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400 4000 3750 3500 3250 3000 2750 2500 2250 2000 17501500 1250 1000 750 500
1/cm 1/cm
80
%T
40
70 %T
35
60
30
50 25
20
40
15
30
10
20 GA A 5 B. ceiba mucilage
67.5
120 %T
%T 60
105
52.5
90
45
75
37.5
60 30
4500 4000 3500 3000 2500 2000 1750 1500 1250 1000 750 500 1/cm 4500 4000 3500 3000 2500 2000 1750 1500 1200 1000 750 500 1/cm
Fig. (1). FTIR of GA (standard), GA (extracted), GAA, BC mucilage, CE mucilage, GAA + BC mucilage microspheres, GAA
+ CE mucilage microspheres, GAA + CE mucilage + BC mucilage microspheres.
203.7 43
Signal [mV]
152.8 20
Area [mAS]
101.8 -3
50.9 -26
-49
0
0 2.0000 4.0000 6.0000 8.0000 10.0000 00:00 02:00 04:00 06:00 08:00 10:00
Quality Time [mm:ss]
treated with thionine solution followed by washing increase in the particle size was observed with an
with alcohol, indicating presence of mucilage. The increase in polymer concentrations, which might
results of chemical tests performed on both the be due to the more viscous nature of polymer
mucilages confirmed absence of starch, alkaloids, solutions at higher concentrations (Table 3). The
saponins and tannins (Table 2). CE mucilage was developed microspheres had a spherical shape
more viscous than BC mucilage. FTIR spectrum of with a smooth surface. The SEM micrographs
BC mucilage and CE mucilage are presented in presenting morphological characteristics are
Fig. (1). The mucilages showed the presence of shown in Fig. (3).
lactone at 1734 cm-1, -OH between 3400-3200 cm-
1
, -COOH between 1574-1557 cm-1, -CH3 at 2923 Drug-Excipients Compatibility
cm-1, -OH between 3609-3288 cm-1, ether linkage
between 1455-1400 cm-1, -CH stretching between GAA-BC mucilage microspheres, GAA-CE
2923-2854 cm-1, -C-O stretching at 1018 cm-1, and mucilage microspheres and GAA microspheres
-CH3 at 2923 cm-1. containing combination of BC and CE mucilages
are presented in Fig. (1). No sign of any loss or
generation of any characteristic peak in the FTIR
Table 2. Results of chemical tests of extracted CE and
BC mucilage.
spectrum of formulations was observed on a
comparison with the FTIR spectrum of pure GAA
and mucilages. This suggested that all the process
Test Remark* conditions were relevant to the formation of
Alkaloids - microspheres and which in turns showing the
absence of any kind of interaction in between the
Carbohydrates -
GAA and mucilages.
Saponins -
Phenolic compounds -
Entrapment Efficiency and Percent Drug
Loading
Glycoside test -
It was observed that the entrapment efficiency
Proteins and amino acids -
was increased with an increase in polymer
Phytosterols - concentration. This might be due to the increased
Fixed oils and fats -
viscosity of polymer solutions, which brought
about the increase in the emulsification leading to
Mucilage + the increase drug entrapment (Table 3). The drug
*- Indicates absence, + indicates presence. entrapment was more in microspheres containing
CE mucilage, which might be due to the increased
Characterization of Microspheres viscosity of the dispersion, which limits stripping
of the drug from microspheres. Drug loss in
Particle Size and Morphology continuous phase occurs while the dispersed phase
The mean size range of microspheres was in the stayed in a transitional, semisolid state i.e. mostly
range of 4-12 μm for all the formulations. An during the first 10 min of particle formation. If the
108 Current Drug Therapy, 2016, Vol. 11, No. 2 Visht and Kulkarni
2 mm EHT = 20.00 kV Data:10 Feb 2011 2 mm EHT = 20.00 kV Data:10 Feb 2011
1 mm EHT = 20.00 kV Data:10 Feb 2011 ZEESS AIRF.JNU ZEESS 2 mm EHT = 20.00 kV Data:10 Feb 2011
AIRF.JNU ZEESS AIRF.JNU AIRF.JNU ZEESS
WD = 11.0 mm Mag = 30.10 kX WD = 10.5 mm Mag = 6.10 kX WD = 10.5 mm Mag = 30.90 kX WD = 10.5 mm Mag = 9.91 kX
1 mm EHT = 20.00 kV Data:10 Feb 2011 200 mm EHT = 20.00 kV Data:10 Feb 2011 10 mm EHT = 20.00 kV Data:10 Feb 2011 2 mm EHT = 20.00 kV Data:10 Feb 2011
AIRF.JNU ZEESS AIRF.JNU ZEESS AIRF.JNU ZEESS AIRF.JNU ZEESS
WD = 11.0 mm Mag = 17.34 kX WD = 11.0 mm Mag = 55.63 kX WD = 10.5 mm Mag = 4.34 kX WD = 10.5 mm Mag = 4.96 kX
20 mm EHT = 20.00 kV Data:10 Feb 2011 2 mm EHT = 20.00 kV Data:10 Feb 2011 2 mm EHT = 20.00 kV Data:10 Feb 2011 ZEESS 20 mm EHT = 20.00 kV Data:10 Feb 2011
AIRF.JNU ZEESS AIRF.JNU ZEESS AIRF.JNU AIRF.JNU ZEESS
WD = 10.5 mm Mag = 1.96 kX WD = 10.5 mm Mag = 7.41 kX WD = 10.5 mm Mag = 5.77 kX WD = 10.5 mm Mag = 2.22 kX
2 mm EHT = 20.00 kV Data:10 Feb 2011 2 mm EHT = 20.00 kV Data:10 Feb 2011 2 mm EHT = 20.00 kV Data:10 Feb 2011
AIRF.JNU ZEESS AIRF.JNU ZEESS AIRF.JNU ZEESS
WD = 10.5 mm Mag = 6.19kX WD = 11.0 mm Mag = 6.63 kX WD = 11.0 mm Mag = 6.54 kX
Fig. (3). Scanning electron micrographs of microspheres showing the general appearance of microspheres (Formulation A-O).
Scales are given on individual micrograph.
basic solutions, and less soluble in acidic dissolution data were plotted according to
solutions. If a compound is neutral (neither acidic Higuchi’s equation, which gives steady state drug
nor basic), then its solubility will be unaffected by release:
pH. The pH of isolated GAA was 4.2±0.01. Q = (D ε/τ) (2Ctot - Cs) Cst1/2
Enhanced solubility of GAA from formulated
microspheres in dissolution medium may be due to where Q is the amount of drug released per unit
the increased surface area of microspheres, area exposed to the solvent, D is the diffusion
swelling and hydration of the polymers. coefficient of the drug in the permeating fluid, ε is
the porosity of the matrix, τ is the tortuosity of the
On the basis of results obtained from the drug matrix, Ctot is the concentration of the solid drug in
entrapment, mucoadhesion, and in vitro drug the dissolution medium, Cs is the saturation drug
release study, formulation C was selected as best and t is the time. Assuming that diffusion
formulation. The drug release data of formulation coefficient and other parameters remain constant
C was analyzed using the zero-order and first- during the release, the above equation reduces to
order equations to determine the drug release [24]:
kinetics from the developed mucoadhesive
microspheres. In the present study, formulation C Q = Kt1/2
was found to exhibit first order release in which Thus, for diffusion controlled release mechanism,
the rate of drug release is dependent of time. For a plot of the cumulative percentage of drug
the further confirmation of the order of release, the released versus square root of time should be
110 Current Drug Therapy, 2016, Vol. 11, No. 2 Visht and Kulkarni
100 100
(A) 90
(B)
Cumulative drug released (%) 90
Fig. (4). In vitro drug release profile (A, B and C) from various formulations (formulation A-O) in 0.1 N HCl (pH 1.2) at 37°C
(mean ± SD, n=3).
linear. The linearity of the plots was confirmed by value of n is less than or equal to 0.5, the
the calculation of correlation coefficient. mechanism of drug release is diffusion without
swelling. If the value is greater than 0.5 and less
To find out the mechanism of drug release, and
than 1, the release is through diffusion with
also to verify the fact that whether diffusion is
swelling and if it is above 1, the release
Fickian or non-Fickian, the in vitro dissolution
mechanism is anomalous diffusion, not confirming
data of formulation C was plotted according to
to Fick’s laws (non-Fickian).
Peppas’ equation, in which log cumulative
percentage of drug release was plotted against log The n and k values for the Korsemeyer Peppas
time. According to the logarithmic form of equation were 0.95 and 0.63, respectively. From
Peppas’ equation, the rate of drug release can be the kinetic data (Table 4), it is evident that the
expressed as [33, 34]: drug release kinetics was found to follow
Higuchi’s as well as Peppas’ kinetics for all the
log Q = log K + n log t
formulations and the drug release was Anomalous
where Q is the amount of drug released, t is the Transport. The calculated slope values of
time and n is the slope of the linear plot. If the Higuchi’s and Peppas’ equations gave a value
r2 k r2 k r2 k r2 k r2 k n k
0.7779 0.1336 0.9766 -0.0041 0.9398 10.2534 0.8161 0.6301 0.9247 0.0009 0.9525 0.6301
Glycyrrhetinic Acid Ammonium Loaded Microspheres Current Drug Therapy, 2016, Vol. 11, No. 2 111
Table 5. Comparison of in vivo ulcer healing activity of formulation C. The data represent mean ± SD (n=6).
Table 6. Results of One Way ANOVA on the in vivo ulcer healing activity of formulation C.
Total 136500 11
Total 186.7 8
close to 1 but less than 1, which confirmed that the ulcer healing activity was as carbenoxolone
release mechanism of GAA from the microspheres sodium > GAA microspheres > GAA. In in vivo
was Fickian diffusion with erosion (anomalous ulcer activity study, the animals treated with GAA
transport). The results confirmed that the best fit and microspheres (formulation C) showed a
model was first order, and the drug release significant (P<0.001) difference in ulceration area
mechanism was anomalous transport. when compared to the control and standard groups
(Tables 5 and 6). The results of in vivo ulcer
healing study are shown in Fig. (5). Compare to
In Vivo Ulcer Healing Study GAA, 1.10 fold (p<0.01) higher inhibition of ulcer
In vivo ulcer healing activity was investigated was observed when animals were treated with
using Wistar male albino rats. The order of in vivo formulation C.
112 Current Drug Therapy, 2016, Vol. 11, No. 2 Visht and Kulkarni
Fig. (5). Results of in vivo ulcer healing activity demonstrating effectiveness of Carbenoxolone sodium (A), GAA (B) and
formulation C (C).
Table 7. Results of stability study of microspheres at different storage conditions with variable effect on drug content
(%) and effect on formulation colour (mean ± SD, n=3).
1 No change 99.93±0.13
25±2°C/60±5%RH 3 No change 99.16±0.32
6 No change 98.84±0.11
1 No change 99.87±0.22
6 No change 97.58±0.31
1 No change 99.97±0.26
6 No change 96.25±0.31
HCl = Hydrochloric acid [11] Dehpour AR, Zolfaghari ME, Samadian T, Kobarfard F,
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HPLC = High Performance Liquid Chromato- derivatives in experimental gastric lesion induced by
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RH = Relative hymidity the pharmacology and toxicology of glycyrrhizin. Regul
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SEM = Scanning Electron Microscopy prepared for the gastrointestinal tract using polyglycerol
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extraction of glycyrrhetinic acid from Liquorice root. J
Food Technol 2005; 3: 576-80.
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