FORMULATION AND EVALUATION OF MELOXICAM GELS FOR TOPICAL

ADMINISTRATION
.Nagia, A. El-Megrab; Hanan, M. El-Nahas* and Gehan, F.Balata
Department of Pharmaceutics. Faculty of Pharmacy . University of Zagazig. Egypt.
ABSTRACT
For topical administration of meloxicam (ME), microemulsion gels and lipogels containing
either ethyl oleate or oleic acid as an oil phase were prepared. In addition, Hydrogel and
hydroalcoholic gels containing carbopol 940 as a gelling agent were also prepared. In-vitro
drug release through cellophane membrane and permeation through the excised rabbit skin in
Srensen`s phosphate buffer (pH 7.4) containing 1% w/v sodium lauryl sulphate were
performed .The influence of initial drug concentration (0.5, 0.65, 1% w/w) was studied. The
permeation properties of ME from ethyl oleate microemulsion which is the best formula
achieved was studied in comparison to the commercially available piroxicam gel. Moreover,
the anti-inflammatory activity of ME after oral and topical administration in rats was studied
and compared to that of piroxicam gel. The results of an in-vitro drug release and its
percutaneous permeation revealed that the ethyloleate microemulsion gel showed the highest
results. Meloxicam gel (ethyl oleate microemulsion gel 1%) showed good protection against
.inflammation as compared to Feldene gel in rats
INTRODUCTION
Meloxicam, a non-steroidal anti-inflammatory drug (NSAID), is a preferential inhibitor of
cyclooxygenase-2 and has demonstrated potent analgesic and anti-inflammatory activity after
oral administration (1). NSAIDs have been widely used in the treatment of rheumatoid
arthritis and other related conditions. However, they carry the risk of undesirable systemic
side effects and gastrointestinal irritation at the usual dose of oral administration (2).
Considering the fact that most inflammatory diseases occur locally and near the surface of the
* Corresponding author: Hananelnahas@yahoo.Com.
1

body, topical application of NSAIDs on the inflamed site can offer the advantage of delivering
a drug directly to the disease site and producing its local effect. This occurs by avoiding
gastric irritation and also reduces adverse systemic effects (3, 4). However, the barrier
properties of intact skin limit the permeability of wide variety of substances, including
pharmaceutical active agents.
To overcome these problems, the development of an optimal vehicle system for rapid skin
permeation of ME is required. Currently, microemulsions have been recognized as good
vehicles for percutaneous absorption of drugs (5, 6). They are clear or slightly opalescent,
isotropic; thermodynamically stable systems of two immiscible liquids. Microemulsions are
created by the presence of a suitable surfactant, usually in conjunction with a co-surfactant.
They are relatively stable and can solubilize a considerable amount of hydrophobic drugs in
their lipophilic domain (7).
Recently, lipogels-semisolid ointment like preparations- have been investigated as vehicles for
topical drug delivery. Lipogels are obtained by gelling an oleaginous phase with a lipophilic
substance (8-10).
The purpose of this study was to formulate ME in different types of gels, namely, hydrogel,
hydroalcoholic gel, microemulsion gel and lipogel using different oils. The second goal was
to evaluate the properties of ME gels like in-vitro drug release, percutaneous absorption and
comparison anti-inflammatory effect of this gel with the marketed piroxicam gel.

EXPERIMENTAL
Materials
Meloxicam powder was donated as a gift from Delta Pharma, Tenth of Ramadan City,
Egypt), Mexicam tablets were purchased from Delta Pharma, Tenth of Ramadan City,
Egypt), Feldene gel was purchased from (Pfizer Pharm.Co., Cairo, Egypt), Carbopol 940
was purchased from (BF Goodrich Co., OH), Ethyl oleate (EO) was purchased from (Aldrich
2

Chemical, Milwaukee,WI), Oleic acid was purchased from (Fluka, Buchs, CH), Glyceryl
monostearate (Henkel, Dsseldorf, Germany), Propylene glycol (PG) was purchased from
(Carl Roth, W, Germany), Tween 80 (Polyoxyethylene Sorbitan Monooleate) , Sodium Lauryl
sulphate, Potassium dihydrogenorthophosphate, disodiumhydrogen phosphate, sodium
chloride and ethanol were purchased from (El-Nasser Pharmaceutical Chemicals, Cairo,
Egypt), Triethanolamine was purchased from (Merck, Darmstadt, Germany), Carrageenan and
hydroxyl propylmethylcellulose (HPMC) were purchased from (Sigma, St, Louis, MO),all
chemicals were analytical grade. Semipermeable Cellophane membrane 30/32 (Fischer
Scientific Co., London, England). Distilled water.
Methods
Preparation of hydrogel and hydroalcoholic gel samples
The gel samples were prepared by dispersing 1% Carbopol 940 in a mixture of water and PG
(80: 20 w/w) in case of hydrogel or a mixture of water, ethanol and PG ( 40: 40: 20 w/w) in
case of hydroalcoholic gel. ME (1% w/w) was added to the mixtures and kept under magnetic
stirring for 12 hrs (Formulas 1 and 2, Table 1). The dispersions were then neutralized (pH 7.4)
and their viscosity was improved by adding triethanolamine 0.01% (11).
Preparation of microemulsion gel samples
The appropriate amounts of Tween 80, PG and oil (EO or oleic acid) were weighed into
screw-capped vial as surfactant, co-surfactant, and oil (50:10:40), respectively. ME was added
in a concentration of 1% w/w into the vial. The mixture was shaken by using a magnetic
stirrer (1 cm), then the microemulsion gel was formed by the addition of 25 % water with
continuous stirring, and it was enhanced by using a vortex mixer for 2 min. The gel of ME
samples were stored at 25C for 24 hrs for equilibration (Formula 3, Table 1).

Preparation of lipogel samples

The calculated amount (15% w/w) of monoglyceryl stearate was heated at 70 C with oil (EO
or oleic acid) to complete melting, then 1% ME was dissolved into the melted mass (formula
4 table 1). The mass was then gelled by cooling under stirring (100 rpm) to 50C until
clouding of the melted mass, then allowing to gel at rest. The sample was then maintained at
25 C for 24 hrs before use (10).
Effect of initial drug concentration
Further study was done upon ethyl oleate microemulsion gel as it gave the best results of drug
release and skin permeation. The effect of initial ME concentration was tested on the
permeation properties of that gel by using other two drug concentrations 0.5 and 0.65%
besides 1% ME.
Solubility measurements
The solubility of ME in either EO or oleic acid was determined by adding excess amount of
drug into 10 ml of oil in a screw-capped vial. The vials were equilibrated at 25C for 72 hrs in
a thermostatic shaker water bath. The suspension was centrifuged at 3000 rpm for 15 min, and
the supernatant was diluted with ethanol and used for the determination of ME
spectrophotometrically at max = 362 nm, the blank was EO or oleic acid in ethanol.
Viscosity measurements
The different formulations were tested at room temperature using Viscostar viscometer
(Fungilab S.A., Spain). The measurements were made using spindle number 5 at 2 rpm.
In-Vitro drug release
A one gram sample of each formulation was accurately weighed and placed on a
semipermeable cellophane membrane (previously immersed in srencen`s phosphate buffer,
pH 7.4 for 20 hrs) to occupy a circle of 2.9 cm diameter. The loaded membrane was stretched
over the lower open end of a glass tube of 2.9 cm diameter and made water tight by rubber
band. The tube was immersed in a beaker containing 150 ml of Srencens phosphate buffer
4

pH 7.4. Sodium lauryl sulphate 1% w/w was added to the medium to ensure sink condition.
The system was maintained for 4 hrs at 32C in a thermostatic shaker water bath at 100 rpm
(Figure1). Samples 3 ml were withdrawn at intervals of 15, 30, 45, 60, 90, 120, 180, and 240
min, the volume of each sample was replaced by the same volume of fresh buffer to maintain
constant volume, samples were analyzed without dilution or filtration

for ME content

spectrophotometrically at max = 362 nm. In case of Feldene gel, samples were analyzed
for piroxicam content at max = 358 nm.
In-Vitro permeation studies
In-vitro permeation studies with excised rabbit skin (13) were performed as follows:
Abdominal full-thickness skin of male rabbit was obtained from white New Zealand rabbits
weighing 3-4 kg. The skin was carefully removed from animals and the hair was clipped
without damaging the skin. The fat was removed with the aid of scissor and skin was washed
and soaked over night in 0.9 % sodium chloride solution. The excised skin was used as a
permeation membrane with the epidermal surface upward, the stratum corneum was facing
the donor side of the cell and the dermal side of the skin was allowed to be in contact with a
buffer solution (Figure 1). The procedure for the release test described above was used except
that the receptor medium contained 150 ml 0.9% sodium chloride of pH 7.4 with the addition
of sodium lauryl sulphate (1% w/v). Samples of 3 ml were withdrawn periodically for 9 hrs
and replaced with an equal volume of fresh receptor solution. ME and piroxicam were
assayed spectrophotometrically at 362 nm and 358nm, respectively.
Calculation of cumulative drug release
The amount of ME in the total receptor solution was determined from a calibration curve. The
cumulative drug permeated (Qn) corresponding to the time of the n th sample was calculated
from the following equation (14):
n-1
Qn = VRCn + VsCi
i=0
5

Where Cn and Ci are the drug concentrations of the receptor solution at the time of the n th
sample and the i ( the first) sample, respectively and VR and VS are the volumes of the receptor
solution and the sample, respectively.
Calculation of permeation parameters
The permeation profiles of ME across rabbit skin from different gel formulations were
constructed by plotting the total cumulative amount of ME penetrated per unit surface area
(g/cm2) versus time (hour) as shown in figure 4. Meloxicam steady state flux (Jss) was
calculated as the slope of linear regression line at the steady state phase for each experimental
run. Permeability coefficient (Kp) was calculated using the relation derived from Ficks first
law of diffusion, which described in the following equation:
Jss = Kp /Co
where, Co is the initial drug concentration in the donor (15).
Anti-inflammatory activity of Meloxicam gel
Acute inflammatory activity model, carrageenan induced rat paw edema method (16) was
.applied in this study
The rats weighing about 200 gm were divided into 6 groups, each group containing 4 rats.
The animals of groups 1, 2 and 3 received 1ml oral suspension of meloxicam (0.2 mg/kg) in
0.9 % sodium chloride (17), 200 mg of EO microemulsion gel topically and 200 mg of
feldene gel topically, respectively. The gels were applied to the surface of the right hind
paw, then the treated area was immediately covered by thin vinyl sheet and gauze. Two hours
later, the covers were removed and 0.1 ml of 1% carrageenan solution was injected
subcutaneously into both treated area and the left hind paw. The animals of control groups 4,5
and 6 were treated with sodium chloride solution orally, microemulsion placebo gel topically
and HPMC placebo gel topically respectively. The carrageenan was injected in the same
manner as above. Three hours later, the thickness of the right and left paws was measured
6

using a dial micrometer and the percentage inhibition of edema was calculated (18). The data
were reported as mean SEM (n=4) and statistical analysis was carried out using ANOVAtest at a level of significance of P< 0.05.
RESULTS AND DISCUSSION
In-Vitro Drug Release and Permeation Studies
Effect of gel type
The data obtained from release and permeation studies were shown in Figures 2-5 and Table
2. The amount of ME released from all gel formulations show a linear relationship with the
square root of time (r >0.9), therefore, the release rate of the test drug followed Higuchi
theoretical model (19).
It was observed that the in-vitro release data as well as the permeation studies were superior
from EO microemulsion gel. The cumulative amounts permeated at 9 hrs were 616.1, 295.15,
141.5 and 235.2 g/cm2 for EO microemulsion gel, EO lipogel, carpobol gel and
hydroalcoholic carpobol gel respectively. These results were in agreement with El-Laithy and
El-Shaboury, Who reported that maximum fluconazole permeation and 1.5 fold improvement
in drug release were achieved from microemulsion prepared with jojoba oil in comparison to
its corresponding lipogel (20). Thacharodi and Panduranga Rao (7) explained the mechanism
by which microemulsions enhance the percutaneous absorption of drugs on the basis of the
combined effect of both the lipophilic and hydrophlilic domains of microemulsion. The
lipophilic domain of the microemulsion can interact with the stratum corneum in many ways.
The drug dissolved in the lipid domain of a microemulsion can directly partition into the lipid
of the stratum corneum or lipid vesicles themselves can intercalate between the lipid chains of
stratum corneum, thereby destabilizing its bilayer structure. These interactions will lead to
increased permeability of the lipid pathway to the drugs. On the other hand, the hydrophilic
domain of the microemulsion can hydrate the stratum corneum to a greater extent. When the
aqueous fluid of the microemulsion enters the polar pathway, it will increase inter lamellar
7

volume of stratum corneum lipid bilayer, resulting in the disruption of its interfacial structure.
Since, some lipid chains are covalently attached to corneocytes, hydration of these proteins
will also lead to the disorder of lipid bilayers. Similarly, swelling of the intercellular proteins
may also disturb the lipid bilayers; a lipophilic penetrant like ME can then permeate more
easily through the lipid pathway of stratum corneum.
It was observed that the type of oil affect the release and permeation properties of ME
from microemulsion gels and lipogels. The cumulative amounts of ME permeated From EO
microemulsion gel and lipogel were 616.1 and 295.1 g/cm2 respectively, compared with
260.5 and 248.8 g/cm2 from oleic acid microemulsion gel and lipogel, respectively. This may
be due to increased solubility of ME in oleic acid where it was 0.35 mg/ml and 2.42 mg/ml in
EO and oleic acid respectively (Table 3), which lead to decreased partitioning of ME into the
skin and hence decreased permeation (21).
Our investigation revealed that meloxicam gels have greater viscosity in oleic acid
formulation than EO formulation (Table 4). Consequently there was a decreased release and
permeation of ME from oleic acid gels than EO gels. The result is in agreement with that
previously mentioned by Httenrauch et al (22) and Ugri-Hunyavari and Ers (23). They
stated that, gel having a compact and close structure may have a slower release rate than one
of lower consistency.
The enhanced drug release and permeation properties from the hydroalcoholic carbopol gel
compared to the hydrogel, could be ascribed to two factors; first, ethanol is a vehicle known
to increase the permeation of drugs through the skin either by attacking the dense barrier
structure of the skin (24) or by augment the solubility and partitioning of the drug in stratum
cornium (25 ). Second, ethanol decreases the viscosity of carpobol gel (Table 4) which lead to
improved drug release and permeation from the gel (Figures 3 and 5). The results are in
agreement with the previous investigation performed by Chi and Jun (26), who demonstrated

that the enhancement effect of ethanol in ketoprofen gel formulations is due to decrease of
viscosity and increased solubility of drug in the gel.
Comparison of the results (Figures 2 and 3) indicated that although there is a better in-vitro
release of piroxicam than meloxicam from their formulations, figure 4 and 5 reflect inferior
skin permeation of the former. These results can be attributed to the physicochemical
properties of drugs such as partition coefficient, vehicle solubility and molecular weight
which determine there permeation through the complicated structure of the skin (27,28).
Effect of initial drug concentration
Figure 6 and Table 2 show the effect of initial drug concentration (0.5, 0.65, 1% w/w) on the
release and permeation of ME from EO microemulsion gel. The results revealed that
increasing the drug concentration, results in increasing the cumulative amount permeated. The
cumulative amounts permeated at 9 hrs were 133.6, 208.5 and 616.1 g/cm2 for gel prepared
with 0.5, 0.65, and 1% ME, respectively. A close parallel results were reported by Fergany
(29).
Anti-inflammatory activity of meloxicam gel
Table 5 shows the inhibitory effects of ME gel on the carrageenan- induced paw edema
compared with oral Mexicam and Feldene gel (0.5% piroxicam). The data were reported
as mean SEM (n=4) and statistical analysis was carried out using ANOVA-test at a level of
significance of P< 0.05. ME gel (EO microemulsion) produced significant inhibitory effects,
with a 42.37% inhibition after 4 hrs and the activity was approximately equivalent to that of
Mexicam oral tablet, while more effective than that of Feldene gel. In this experiment, the
normal saline and the placebo gel had no effect on carrageenan edema. ME gel significantly
inhibited inflammation in the treated paw and had also some influence on edema of nonapplied paw. While, Feldene had no influence on edema of non-applied paw indicating
absence of any systemic effects. These results were in agreement with that previously
mentioned by Gupta et al (1). They reported that, meloxicam gel (1%w/w) showed increased
9

protection against inflammation as compared to piroxicam (0.5 % w/w) and diclofenac (1%
w/w) gels.
CONCLUSION
The results indicated that topical preparation of miloxicam (EO microemulsion gel) could be
an effective topical dosage form beside its oral dosage form (Mexicam tablet) in
.inflammatory condition with the possibility of less systemic side effects

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Hammad, M; Mokhtar, M.

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animal model for efficacy evaluation in cutaneous HSV-Infection. Int. J. Pharm. 1990; 65
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Inc., New York, 1992, 825.
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Microemulsion Gel for Topical Administration of Fluconazole. AAPS Pharm. Sci. Tech.
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permeation of ketoprofen and its solubility in mixtures of a pH 6.5 phosphate buffer and
various solvent. Drug Deliv. 2002:9(1); 39-45.
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25- Megrab A.N., William A.C. and Barry B.W. Oestradiol permeation across human skin,
silastic and snak skin membranes: the effect of ethanol: water co-solvent systems. Int. J.
Pharm. 1995; 116:101-112.
26- Chi, S.C and Jun, H.W. Release rate of ketoprofen from poloxamer gel in a membraneless
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Table 1
Components of different gel formulations
Formula
Formula 1
Carbopol hydro-gel
Formula 2
Carbopol hydroalcoholic gel
Formula 3
Microemulsion gel
Formula 4
Lipogel

Quantities by grams required to prepare 10 grams of gel

0.1 g corbopal, 9.9g (80 : 20%w/w) water : PG
0.1 g carbopol , 9.9g (40:40:20%w/w) water : PG : EOH
5g Tween80, 1g PG, 4g ethyl oleate or oleic acid, 2.5g water
1.5g monoglyceryl stearate, 8.5g ethyl oleate or oleic acid

Table2
Percutaneous permeation parameters of ME through abdominal rabbit skin from various
formulations (Mean SE, n = 3)
Cumulative
Flux
Permeability
amount at 9hrs (Jss,
Coefficient
Formulation
(Q9h, g/cm2)
g/cm2/hr)
(Kp, Cm/hr
10 -5)
Microemulsion gel:
EO
616.1 59.73
25.880.051
258.80.51
Oleic acid
260.549.98
14.653.91
146.539.1
Lipogel:
EO
Oleic acid
Feldene (0.5% piroxicam gel)

295.15 102.2
248.8 35.85
198.1 1.2

15.2 10.7
17.23 5.44
11.89 0.559

152 107
172.3 54.4
237.8 11.18

Meloxicam (%)
0.5
0.65
1
Carbopol gel
Hydro alcoholic carbopol gel

133.6 1.34
208.5 15.77
616.1 59.73
141.5 9.99
235.2 19.93

4.38 0.05
6.1 0.997
25.88 0.051
6.34 1.38
15.81 0.655

87.6 1.00
93.8 19.94
258.8 0.51
63.4 13.8
158.1 6.55

Table 3
Solubility of ME in different oils.
Oil
Ethyl oleate

Solubility (mg/ml)
0.355

Oleic acid

2.42

14

Table 4
Viscosity measurements of different gel bases (Mean SE, n=3)
Gel base
Microemulsion gel:
EO
Oleic acid

Viscosity (cp)
32313 2899
74843 5838

Lipogel:
EO
Oleic Acid

39403 10946
144596 1998

Carbopol gel
Hydroalcoholic carbopol gel
Feldene gel

220612 1156
131030 7554
148080 5071
Table 5

Evaluation of the anti-inflammatory activity of meloxicam microemulsion gel (Mean SE, n=4)
Sample
Control 1
Meloxicam tablet

Swelling (mean SEM) %

57.45 3.95
10.25 *33.54

Control 2
EO microemulsion
Control 3
Feldene gel

Treated foot
9.97 46.28
*5.54 26.67
55.78 5.53
41.95 9.51*

Non treated foot

63.66 18.53
50.73 13.3
51.78 8.52
59.34 8.94

.Control 1 = animals administered normal saline

.Control 2 = animals treated with placebo microemulsion gel
.Control 3 = animals treated with placebo HPMC gel
.P*< 0.05 compared with the control

15

inhibition %
41.62
Treated foot Non treated foot
42.37
24.79

20.31
.Zero

Rabbit skin loaded with

sample (donor)
Cover with a small open
250 ml beaker
Shaking water
bath
Figure (1): Cross-sectional diagram of the drug permeation apparatus (Thermostatic shaker
water bath).

Figure 2: Release profiles of meloxicam from different microemulsion gels and lipogels
across standard cellophane membrane in comparison with feldene gel. (n=3, mean + SE)

16

Figure 3: Release profiles of meloxicam from two carbopol gels across standard cellophane
membrane in comparison with Feldene gel.

Figure 4: Permeation profiles of meloxicam across abdominal rabbit skin from different
microemulsion gels and lipogels in comparison with feldene gel. (n=3, mean + SE).

17

Figure 5: Permeation profiles of meloxicam from two carbopol gels across abdominal
skin in comparison with Feldene gel.

rabbit

Figure 6: Effect of initial drug concentration on the amount of meloxicam permeated from EO
microemulsion gel through abdominal rabbit skin.
18

19