Natural Gums and Mucilage as Gelling agents in Topical
Gel Formulation
Krishna Kumari J, Bandaru Hemanth Kumar, Prasanthi D*
Department of Pharmaceutics, G.
Pulla Reddy College of Pharmacy,
Mehdipatnam, Hyderabad, Telangana
– 500028.
*Corresponding Author E-mail:
prasanthidhanu@gmail.com
ABSTRACT:
The study was conducted to study the gelling
efficiency of natural gums (tamarind seed gum) and mucilage (moringa mucilage)
using ibuprofen as model drug. Topical drug delivery (TDS) eliminates first
pass metabolism and improves bioavailability. Hydrogels are dispersions of
network of polymer chains in water as colloidal gels. Ibuprofen an
anti-inflammatory, was chosen as a model drug in the preparation of hydrogel
for site targeted action and to avoid side effects. Physical properties like
swelling index, solubility, loss on drying, flow properties were evaluated.
Chemical characterization of isolated gum and mucilage revealed presence of
polysaccharides. Ibuprofen topical gels with natural gum (tamarind seed gum
(1-7%), moringa mucilage (2-8%) were compared with official xanthan gum (1-4%),
guar gum (1-3%) as natural gelling agents and HPMC K4M (1-6%), HPMC K100M
(1-6%) and sodium alginate (2-6%) as semi synthetic gelling agents. Drug and
excipients are compatible with each other by FTIR studies. The prepared gel
formulations were evaluated for clarity, homogeneity, spreadability, drug
content, in-vitro diffusion, ex-vivo permeation, skin irritation and stability
studies. All formulations have shown better physicochemical properties. Based
on the maximum percentage of drug release, formulations containing natural
polymers tamarind seed gum (5%), moringa mucilage (8%), xanthan gum (4%), guar
gum (3%) were optimized. And semi synthetic polymers HPMC K4M (4%), HPMC K100M
(3%), sodium alginate (6%) were optimized. NF10 formulation with guar gum (3%)
is optimized based on the percentage of drug release (27.0±0.14%) for 8 hrs, flux
of (427.2±0.09µg/cm2/hr), cumulative amount of drug permeated Q8
(329±1.53µg/cm˛) and permeability coefficient of (17.08±1.04
×10-3cm/hr) when compared with tamarind gum (5%), NF1 (23.8±0.13%), (290±1.04µg/cm˛), (376.6±0.04µg/cm2/hr),
(15.04±0.03×10-3cm/hr) and moringa mucilage (8%), NF3 (14.3±0.19%), (175±0.90µg/cm˛), (227.1±0.03µg/cm2/hr),
(9.08±0.02×10-3cm/hr). The drug release
pattern was found to follow first order kinetics and korsemeyer peppas release
mechanism with fickian diffusion release. Formulations were found to be
non-irritant and stable. Tamarind gum and moringa mucilage were efficient as
gelling agent in preparation of ibuprofen topical gel but showed retarding
effect when compared with official guar gum.
KEYWORDS: Topical drug delivery system, Ibuprofen,
Anti-inflammatory agent, moringa mucilage and natural gums.
INTRODUCTION:
Polymers derived from
plant origin have evoked tremendous interest due to their
diverse applications in drug delivery as a disintegrant, gelling agent,
emulsifying agent, suspending agents and as binders1. These natural
excipients are biocompatible, cheap, less toxic, non-irritant, soothing action and simply available than the synthetic ones2,3.
Gums are formed by
gummosis, a process of disintegration of internal
plant tissues. This results in cavities, which
exudates transformed carbohydrates called gums. Mucilage’s are metabolic
products (physiological products), formed within the cell (intracellular
formation)4. Gums dissolve in water and mucilages form slimy masses.
Both gums and mucilage’s are plant hydrocolloids yielding mixture of sugars and
uronic acids on hydrolysis5. Tamarind gum is a polysaccharide
composed of glucosyl: xylosyl: galactosyl within the ratio
of 3:2:1. It's used as gelling agent, thickening,
suspending, stabilizers, emulsifying agent4. Moringa oleifera gum is
obtained from exudes of stem of Moringa oleifera (family: Moringaceae). The gum
may be a polyuronide constituting Arabinose,
galactose and glucuronic acid5 10: 7: 2. It's used
as a tablet binder, emulsifiers, gelling agents, suspending agents, stabilizers,
and thickeners. Guar gum called as guaran, is galactomannan
polysaccharide extracted from guar beans that has thickening and stabilizing
properties useful in food, feed, and industrial applications6. The
guar seeds are mechanically dehusked, hydrated, milled and screened7.
Xanthan gum is produced by fermentation of simple
sugars, and derives its name from the species of bacteria used, campestris. This is often an equivalent bacterium
liable for causing plant disease
to make on broccoli, cauliflower, and other
leafy vegetables. Ibuprofen, a non-selective COX
inhibitor, decreases the synthesis of prostaglandins involved in mediating
inflammation and is assumed to cause a number of the side effects including GI ulceration8,9.
There's great interest to develop non-oral dosage form of ibuprofen to attenuate its
gastric side effects, while at an equivalent time
delivering consistent drug levels at the application site
for prolonged periods10. Hence, it's been
envisaged to formulate ibuprofen topical gel to avoid the systemic side
effects, using natural gums, mucilage like tamarind
seed gum, moringa mucilage, xanthan gum, guar gum as
gelling agent. And comparison with synthetic gelling agents.
MATERIALS AND METHODS:
Materials:
Ibuprofen was gifted by Medico Remedies Pvt. Ltd., tamarind seed powder was purchased from Local Market,
moringa gum was purchased from Jagadish enterprises, xanthan gum and guar gum
was purchased from Yarrow chem products, Carbopol was gifted from RA Chem
pharma Ltd., glycerin, propylene glycol, isopropyl alcohol, benzoic acid,
tri-ethanolamine were procured from S.D. Fine Chemicals Ltd.
Drug-excipient compatibility study:
Interactions by FTIR:
The spectrum analysis of
pure drug and physical mixture of drug with different excipients which are used
for preparation of gel was studied by FTIR by KBr pellet method using shimadzu (Koyto, Japan) facility (model-8400S). They were
observed for the presence of characteristic peaks for the respective function11.
The resultant spectrum was compared for any spectra changes.
Isolation of natural polymers:
Isolation of tamarind seed gum:
To 20g of tamarind seed
powder, 200ml of cold water was added and slurry was
prepared. This was added to 800ml boiling water and boiled for 20min. It was
then kept aside overnight and then centrifuged for 20 min at 5000rpm. To the
supernatant absolute ethanol was added and precipitated mass was pressed
between felt. The precipitate was washed with absolute ethanol, diethyl ether
and then dried at 50-60°C under vacuum. The dried material was ground and
sieved through 100 mesh (Figure 1) and stored in a desiccator until used for
further studies12.
Figure 1: In the extraction of tamarind seed gum
a) Precipitated mass and b) tamarind seed gum
powder.
Isolation of Moringa gum:
Dried gum (10 g) was
stirred in water (250 ml) for 6-8hr at temperature 30°C. The supernatant was obtained by
centrifugation. The residue was washed with water and the washings were added
to separated supernatant. The procedure was repeated four more times. Finally,
the supernatant was treated with twice the quantity of
acetone by continuous stirring. The precipitated material was washed with
distilled water and dried at 50-60° under vacuum and sieved to form mucilage
powder 5 (Figure 2).
Figure 2: In the extraction of moringa gum a)
Precipitated mass and b) moringa mucilage powder.
Evaluation of isolated tamarind seed gum and moringa
mucilage:
Organoleptic evaluation of isolated gum and mucilage
powder:
The isolated gum powder
and mucilage powder was characterized for organoleptic properties like colour, odour, taste, fracture, and texture.
Solubility of isolated gum and mucilage:
One part of dry gum and mucilage powder separately was
shaken with different solvents and solubility was determined13.
pH of gum and mucilage powder:
The gum and mucilage
powder were weighed and dissolved in water separately to
prepare 1% w/v solution. The pH of solution
was studied using digital pH meter.
Swelling index:
The swelling index was
determined by accurately weighing 500 mg of sample and 25ml of water was added
and mixture was shaken thoroughly every 10 min for 1hr. It was then allowed to
stand at room temperature for 3 hrs. Then the quantity occupied
by gum, was measured. The same procedure was repeated thrice and the mean value
was calculated14.
z
Loss on drying:
Specific amount of sample was taken and its weight was
measured and it was placed in a hot air oven maintained at temperature 70°C for
30 minutes. After 30 minutes, the sample was weighed and the process was
repeated till constant weight was achieved. Final Loss on drying is calculated
using formula
Mass of waste in sample
LOD (%) = ––––––––––––––––––––––––– × 100
Total weight of wet sample
Micromeritic properties of isolated gum and mucilage
powder15:
Bulk density, tapped density and angle of
repose were determined by taking the weight of sample, bulk volume and tapped
volume. Angle of repose was determined by using the standard funnel method.
Preliminary confirmation test for gum and mucilage
powder15:
Molisch’s test:
100 mg of dried mucilage powder was taken in a test
tube. To this dried mucilage powder Molisch’s reagent was added and conc.H2SO4
was added along the sides of the test tube.
Ruthenium test:
A small quantity of dried mucilage powder was taken on
a slide with ruthenium red solution and observed under microscope.
Iodine test:
100 mg of dried mucilage powder was taken in a test
tube and 1 ml of 0.2N Iodine solution was added to it.
Preparation of gels16:
Different concentrations of isolated tamarind seed gum powder (1% to
7%), moringa gum mucilage powder (2% to 8%), xanthan gum (1% to 4%), guar gum
(1% to 3%), HPMCK4M (1% to 6%), HPMCK100M (1% to 6%) and sodium alginate (2% to
6%) were initially tried as gelling agents. Based on optimum gel consistency,
concentration of each gelling agent was selected and then formulated as gels
with drug 15%w/w (according to IP monograph). Glycerin or propylene glycol or
PEG 400 were added as plasticizer and benzoic acid as preservative. The
dispersion was allowed to stand at room temperature for 1 hour to obtain
viscous mixture. The required quantity of tri-ethanolamine was then added to
gel by mixing gently for adjustment of skin pH. The formulation table of gels
with natural polymers is given in table 1 and with semi synthetic polymers is
given in table 2.
Table 1: Formulation of ibuprofen topical gels with
different concentrations of natural polymers
|
Ingredients
|
NF1
|
NF2
|
NF3
|
NF4
|
NF5
|
NF6
|
NF7
|
NF8
|
NF9
|
NF10
|
|
Drug (g)
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
|
Tamarind seed gum (%)
|
5
|
7
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
|
Moringa gum mucilage (%)
|
-
|
-
|
8
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
|
Xanthan gum (%)
|
-
|
-
|
-
|
1
|
2
|
3
|
4
|
-
|
-
|
-
|
|
Guar gum (%)
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
1
|
2
|
3
|
|
Glycerin (%)
|
10
|
10
|
10
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
|
Propylene glycol (%)
|
-
|
-
|
-
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
|
Benzoic acid (%)
|
0.1
|
0.1
|
0.1
|
0.1
|
0.1
|
0.1
|
0.1
|
0.1
|
0.1
|
0.1
|
|
Isopropyl alcohol (ml)
|
3
|
3
|
3
|
3
|
3
|
3
|
3
|
3
|
3
|
3
|
|
Triethanolamine (%)
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
|
Distilled water
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
|
Total weight of gel (g)
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
Table 2: Formulation of ibuprofen topical gels with
different concentrations of semi synthetic polymers
|
Ingredients
|
SF1
|
SF2
|
SF3
|
SF4
|
SF5
|
SF6
|
SF7
|
SF8
|
|
Drug (g)
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
|
HPMC K4M (%)
|
4
|
5
|
6
|
-
|
-
|
-
|
-
|
-
|
|
HPMC K100M (%)
|
-
|
-
|
-
|
3
|
4
|
5
|
6
|
-
|
|
Sodium alginate (%)
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
6
|
|
PEG 400 (%)
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
|
Propanol (%)
|
30
|
30
|
30
|
30
|
30
|
30
|
30
|
30
|
|
Distilled water
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
Q.S
|
|
Total weight of gel (g)
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
The topical gels of ibuprofen were evaluated for the
following parameters.
Clarity17:
Clarity of prepared ibuprofen hydrophilic gel was
determined by visual inspection and it was graded as follows: turbid +, clear
++, very clear +++.
Homogeneity18:
Gels are tested for homogeneity by visual inspection.
They are tested for their appearance and presence of any aggregates.
pH Measurement19:
The pH of formulated gels is determined by using
digital pH meter. 1g of gel is dissolved in 100ml distilled water and stored
for two hours. The measurement of pH of each formulation is done in triplicate
and average values are calculated.
Viscosity Measurement20:
Viscosity of prepared gels was determined by
Brookfield programmable viscometer LVDV-II+PRO. The spindle number 64 was
rotated at 20rpm. Samples of the gels were allowed to settle over 30 minutes at
the temperature (25±1°C) before measuring.
Spreadability15:
For the determination of spreadability, 1g of sample
was applied between the two 20x20cm glass slides and was compressed by placing
10g weight for 1min. The distance moved by gel due to pressure was measured as
length. Using the given formula spreadability (S) was calculated.
S = M.L / T
Where,
S = Spreadability, M = Weight tide to the upper slide,
L = distance moved by gel, T = Time of study.
Extrudability15:
The extrudability test was performed by Pfizer
hardness tester. Gel was filled in aluminum tube and plunger was adjusted to
hold the tube properly, pressure was applied for 30 sec. The quantity of gel
extruded was weighed. Test was carried in triplicate.
Drug content:
Gel sample equivalent to
5mg of drug was taken into 100ml volumetric flask of phosphate buffer saline
(pH 7.4). The sample was dissolved and filtered. With appropriate dilutions the
sample was analysed at 224nm by UV Spectrophotometric method.
In-Vitro Drug Release Studies by Diffusion studies16:
The formulated gels were studied using open end tube
method. Dialysis membrane was fixed to one end of the cylinder and 500mg of the
prepared gel was placed. This was immersed in a beaker containing 250ml of
buffer, which was agitated by magnetic stirrer and temperature maintained at 37˚±1˚C.
Samples were withdrawn at periodic intervals and analysed
spectrophotometrically at 224nm.
Ex-vivo permeation studies16:
Ex-vivo permeation studies were performed using rat
abdominal skin. The study was performed with approval from Institutional animal
ethical committee GPRCP/IAEC/09/19/11/PCL/AE/5/RATS-M/F-30.
Locally fabricated Franz diffusion cells with 25ml receptor volume were used.
The excised rat skin was mounted onto diffusion cell. 500mg of gel was applied
to the donor compartment and the hydrodynamics in the receptor compartment were
maintained by stirring on magnetic stirrer at 600rpm. 1ml sample was withdrawn
at predetermined time intervals for 24 hours and drug content was analyzed by
UV-VIS double beam spectrophotometer at 224nm.
Ex-vivo permeation rate parameters such as % drug
release, cumulative amount permeated in 24hrs (Q24), steady state
transdermal flux (SSTF), permeability coefficient and lag time for percutaneous
absorption of ibuprofen were
calculated. Various models were tested for explaining the kinetics of drug
release. Data was fitted into zero-order, first order, Higuchi and
Korsemeyer-peppas release model.
Skin irritation studies16:
Skin irritation studies were performed on rabbits
after the approval by the Institutional animal ethical committee. A primary
skin irritation test was performed on three healthy rabbits weighing between
1.5-2kg. Gels was applied (0.5g/animal) twice a day for 7 days. The site was
observed for any sensitivity and reaction, if any was observed it was graded as
0,1,2,3 for no reaction, slight patchy erythema, slight but confluent or
moderate but patchy erythema and serve erythema with or without edema,
respectively.
Stability test :
Optimised formulations of natural and semi-synthetic
polymers were subjected to stability at room temperature for one month. The
physicochemical properties and drug content were evaluated every week.
RESULTS AND DISCUSSION:
Compatibility studies by Fourier Transform Infrared
spectroscopy were carried out to study the possible interaction between
Ibuprofen and other excipients.
The various FTIR graphs both of pure drug and various excipients in
combination are given in Figure no 3. The wave numbers of the principal peaks
(2953.45 cm-1; 2360.44 cm-1;
1720 cm-1; and 1227.47 cm-1)
of Ibuprofen indicating the
presence of aliphatic methylene group, hydroxyl group, ketone group and alkyl
group respectively, appeared as characteristic peaks in the IR graphs of the
pure drug and physical mixture of drug with excipient.
Figure 3: FTIR graph of A) pure drug
(Ibuprofen) B) Ibuprofen +Tamarind seed gum
powder
C)
Ibuprofen + Moringa gum mucilage D) Ibuprofen + Guar gum
Table 3: Physicochemical properties and flow properties
of isolated gum and mucilage
|
Parameters
|
Organoleptic
|
Solubility
|
pH
|
Swelling index
|
Loss on drying (%)
|
Bulk density g/cc
|
Tapped density g/cc
|
Angle of repose (θ)
|
|
Tamarind seed gum
|
Light brownish in color with rough texture and rough
fracture, odorless.
|
Soluble in hot water, insoluble in organic solvent
such as benzene, ether, chloroform
|
6.7
|
11.2±
0.02
|
0.0052±
0.05
|
0.442±
0.04
|
0.589±
0.05
|
26.5±
0.02
|
|
Moringa mucilage
|
White colour but changes to reddish brown or brownish
exposure.
|
Sparingly soluble in water forming viscous solution,
insoluble in ethanol, methanol, acetone, ether.
|
5.77
|
19.7±
0.94
|
0.0068±
0.06
|
0.716±
0.12
|
0.895±
0.05
|
30.8±
0.01
|
Note:
Values are expressed as Mean ±SD, n=3
This indicates no interaction between drug and excipient and that the
pure drug was not altered functionally. Thus, the excipients were found to be
compatible. So, polymers can
be employed for the topical drug delivery of ibuprofen.
The isolated gum and mucilage were evaluated for organoleptic,
solubility, pH, swelling index, loss on drying and flow properties. The physicochemical properties of isolated
gum and mucilage were within limits (Table 3). Isolated gum and mucilage showed
good flow properties. Gum and mucilage showed swelling properties indicating
they can be used as gelling agent. The isolated gum and mucilage powders were
evaluated for chemical characterization such as Molisch test, Ruthenium test,
Iodine test. In Molisch test violet green colour was observed at the junction
of two layers, in ruthenium test pink colour was developed and in iodine test
no colour was developed in the solution indicating the presence of
carbohydrates, mucilage and polysaccharides respectively.
All the prepared ibuprofen topical gels with natural
polymers and synthetic polymers were evaluated for their physicochemical
properties such as clarity, pH, viscosity, spreadability, extrudability, homogeneity, and drug
content. The gels were found to be clear, homogenous, with optimum pH for skin
application, optimum viscosity required for gel formulation, good
spreadability, better extrudability from packaging and drug content.
Invitro diffusion study was determined by dialysis
membrane. From the results, it
was seen that NF1 formulation containing tamarind seed gum 5% showed 23.8±0.13%
release for 8 hrs, NF3 formulation containing moringa mucilage 8% showed 14.3±0.19% release for 8 hrs, NF7 formulation
containing xanthan gum 4% showed 14.4±0.11% release for 8 hrs, NF10 formulation
containing guar gum 3% showed 27.0±0.13% release for 8 hrs. So, these are
optimized, and further compared with the optimized ibuprofen topical gels of
semi synthetic polymers. In in-vitro release studies it was seen that SF1
formulation containing HPMC K4M 4% showed 17.47±0.21% release for 8 hrs, SF4
formulation containing HPMC K100M 3% showed 19.17±0.09% release for 8 hrs, SF8
formulation containing sodium alginate 6% showed 10.2±0.13% release for 8 hrs.
These optimised formulations were further evaluated
for ex-vivo permeation studies using rat abdominal skin. The percent drug
release graph is given in figure 4 and permeability parameters are given in
table 4. From table 4, the
formulation NF10 has shown the maximum cumulative amount permeated of drug Q8 329±1.53 µg/cm˛, flux 427±0.09µg/cm2/hr and permeability coefficient 17.08±1.04×10-3cm/hr.
Figure 4: Ex-vivo permeation of ibuprofen topical gel
of natural polymers and semi synthetic polymer
Table 4: Permeability parameters of drug /through the
dialysis membrane of optimized formulations
|
Formulation
|
Q8 (µg/cm2)
|
Flux
(µg/cm2/hr)
|
Permeability coefficient (cm/hr×103)
|
|
NF1
|
290±1.04
|
376.6±0.04
|
15.04±0.03
|
|
NF3
|
175±0.90
|
227.1±0.03
|
9.08±0.02
|
|
NF7
|
175±2.00
|
227.2±0.02
|
9.08±0.04
|
|
NF10
|
329±1.53
|
427.2±0.09
|
17.08±1.04
|
|
SF1
|
195.1±0.90
|
253.2±0.06
|
10.1±0.02
|
|
SF4
|
226±1.04
|
293.5±0.04
|
11.7±0.04
|
|
SF8
|
140±2.38
|
181.8±0.03
|
7.24±0.03
|
Note: Values are expressed as Mean ±SD, n=3
From the drug release kinetics, the formulations were
found to follow first order kinetics and Korsemayer peppas release mechanism
with Fickian diffusion release.
The formulations were evaluated for skin irritation
studies using rabbit model. Formulations did not produce any signs of erythema
or edema. Formulations were also found to be stable at room temperature for a period
of one month.
CONCLUSION:
Ibuprofen topical gels were prepared for
site targeted action using natural polymers such as (tamarind seed gum, moringa
mucilage, xanthan gum, guar gum) and semi synthetic polymers such as (HPMC
K100, HPMCK4, sodium alginate). Isolated natural gums such as (tamarind seed
gum, moringa mucilage) was extracted by using absolute ethanol, acetone as
non-solvent. Physicochemical characteristics such as solubility, swelling
index, loss on drying, pH, flow properties showed excellent results. Molisch’s
test, Ruthenium test, Iodine test were studied and revealed presence of
polysaccharides. Gels possessed good physico chemical properties, drug
excipient compatibility, were non-irritant and stable. Gels prepared from
natural polymers showed better permeation then semi-synthetic polymers. Hence
it is concluded that isolated natural gum and mucilage (tamarind seed gum and
moringa mucilage) can be used as gelling agent in formulation of topical gels.
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