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The aim of the present study is to reduce the ulcerogenic effect of
piroxicam by controlling its dissolution rate. Piroxicam is a class II drug
according to BCS, thus dissolution is the rate limiting step for its
bioavailability. To control the bioavailability of piroxicam and reduce its
side effects dissolution rate was attempted to be controlled by preparing
microspheres having a solid dispersion structure. Two different polymers were
used one is solid dispersing polymer to enhance dissolution rate of piroxicam
and the other is a retarding polymer in order to control its release. Depending
on the ratio of the two polymer combinations, drug release can be controlled.
Percentage yield and entrapment efficiency of prepared formulations ranges from
45.21% ± 0.01 to 87.79% ± 0.01 and 23.87% ± 0.89 to 56.13% ± 7.06, respectively
depending on polymer concentration. Characterization of piroxicam and other
formulations using DSC and FTIR analysis reflects possibility of transformation
of the drug from crystalline to amorphous state. Release of piroxicam was
faster from microspheres having solid dispersion structure (about 74.98% ± 1.5 after
15 min). In order to control the release of the drug, ethyl cellulose as well
as eudragit Rs100 was added. The release pattern of piroxicam from different
prepared formulations followed Higuchi matrix kinetic model. In vivo
ulcerogenic studies revealed that piroxicam containing eudragit S100 was the
formula of the least ulcer incidence (50%) showing gastric mucosa with (mild
mucosal edema as well as minimal sloughed area and also minimal vascular
congestion) than those showed by other animals.
Keywords: Ulcerogenic,
Piroxicam, Polymers, Microspheres
INTRODUCTION
The permeability besides the solubility behavior of a
drug is a key determinant of its oral bioavailability [1]. Formulation of
poorly soluble compounds for oral delivery now presents one of the interesting
challenges to formulation scientists in the pharmaceutical industry where more
than 40% new chemical entities are practically insoluble [2].
Piroxicam is a member of the oxicam group of
non-steroidal anti-inflammatory drugs (NSAIDs) that is indicated for acute or
long-term use in the relief of signs and symptoms of osteoarthritis and
rheumatoid arthritis and also has gastrotoxic as well as duodenotoxic effects
[3,4].
According to the Biopharmaceutical Drug Classification
System (BCS) piroxicam is a class II drug, characterized by low solubility-high
permeability, where drug dissolution is the rate limiting step in drug
absorption and bioavailability [5].
Solid dispersion systems in which the drug is dispersed
in solid water-soluble matrices either molecularly or as fine particles have
shown promising results in increasing bioavailability of poorly water-soluble
drugs [6,7]. Solid dispersion techniques including dissolution method, fusion
method and fusion-dissolution method were commonly used.
Microencapsulation
for oral use has been employed to sustain the drug release and to reduce or
eliminate gastrointestinal tract irritation. In addition, multiparticulate
delivery systems spread out more uniformly in the gastrointestinal tract. Small
particle size, are widely distributed throughout the gastrointestinal tract
which improves drug absorption and reduces side effects due to localized
build-up of irritating drugs against the gastrointestinal mucosa [10,11].
Emulsion solvent
evaporation method was used for the preparation of microspheres due to its ease
of fabrication without compromising the activity of drug and it requires only
mild conditions such as ambient temperature and constant stirring [12,13].
Piroxicam may cause
serious GI side effects, including ulceration as well as intestine and stomach
perforation, which can also be fatal [14,15]. Piroxicam side effects are
similar to other NSAIDs, its GI damage is the most serious one (GI adverse
effects is 3.7-10 fold) [16].
Attempts to overcome
the undesired effects of piroxicam include modifications in the manner of
administration [17-19]; in pharmaceutical forms [20], in the preparation of
pro-drugs [21]; and in the synthesis of complexes [22].
The aim of the
present study is preparation of piroxicam microspheres with different polymers
to obtain different dissolution patterns and comparing it’s in vivo gastro ulcerogenic activity with
free piroxicam and piroxicam microspheres containing eudragit S100 which was
previously prepared by El-Kayad et al. [23].
MATERIALS AND METHODS
Materials
Piroxicam was
obtained as a gift sample from Medical Union Pharmaceuticals, Ismailia, Egypt.
Ethyl cellulose, Eudragit Rs100 and Eudragit L100-55 were obtained as gift
samples from Sigma for Pharmaceutical Industries, Quesna, Egypt. Aerosil
(ISO-CHEM, China). Ethanol, methanol, dichloromethane, sodium lauryl sulphate
(pharmaceutical grade) were obtained from El Nasr pharmaceutical chemicals
company, Cairo, Egypt. All other chemicals used were of analytical grade.
Equipment
Mechanical paddle
stirrer (Heidolph RZR-2000), U.V. visible spectrophotometer (Shimadzu
UV-visible UV-160 A, Japan), USP II dissolution apparatus (paddle type, Copley
Scientific Dis 6000, Nottingham, UK).
Determination of piroxicam by UV-visible
spectrophotometric method
A stock solution of
piroxicam in methanol (1000 µg/ml) was prepared. The standard stock solution
was further diluted to the required concentration for method development and
validation. Calibration curve was constructed at different pH values (1.2, 6.8
and 7.4) using 0.1 N HCl and phosphate buffer, respectively. Ultraviolet
absorbance of the solutions was determined spectrophotometrically (Thermo,
Evo300pc, USA) at the wavelength of maximum absorbance at 334, 354 and 353 nm
for pH values 1.2, 6.8 and 7.4, respectively [24].
Preparation of piroxicam microspheres
Surface morphology (SEM): The surface
morphology and texture of the prepared microspheres were determined using
scanning electron microscope (SEM). A small amount of each sample was spread on
aluminum stub and coated with gold then placed in SEM chamber using SEM
(JEOL-JSM-5200 LV, Japan). SEM photomicrograph was taken at acceleration
voltage of 25 KV.
Percentage-yield: The prepared microspheres
were collected after drying and weighed [27]. Percentage yield of the
microspheres was calculated as follow:
% yield of prepared microspheres = (actual weight of
the product/total weight of excipients and drug) × 100
Fourier transformed infrared spectroscopy (FT-IR): Interaction between drug and polymers was investigated using IR
spectrophotometer. IR spectroscopy was performed using Fourier- transform
infrared spectrophotometer, (Jasco, Japan). Eudragit L100-55, eudragit Rs100,
ethyl cellulose, aerosil, piroxicam, prepared formulations and physical mixture
between drug and different polymers spectrum were recorded using FTIR spectrophotometer.
Samples were mixed with potassium bromide (spectroscopic grade) and compressed
into disks using hydraulic press before scanning between 4000 and 400 cm-1
at a resolution of 4 cm-1 [28].
Entrapment efficiency: The entrapment efficiency
(%) of the prepared microspheres was evaluated using the method of Gangadhar et
al. [29]. with certain modification. 25 mg of each prepared formula were
crushed into powder and were completely dissolved in 100 ml of phosphate buffer
solution (pH 7.4) using magnetic stirrer. 5 ml of the obtained solution was
filtered using syringe filter (0.45 µm) and the concentration of the drug was
determined spectrophotometrically at 353 nm after appropriate dilution [30,31].
The actual drug loading and encapsulation efficiency (EE %) were calculated
using the following equations:
Encapsulation efficiency (%) = (Actual drug
loading/Theoretical drug loading) × 100
Differential scanning calorimetry (DSC): DSC studies were performed using a DSC Perkin Elmer with thermal
analyzer. A known weight of the test sample was loaded in aluminum pans which
were crimped and mounted on the DSC before heating under nitrogen flow (20
ml/min). Thermal results were recorded while heating from 30 to 400°C at a
heating rate of 10°C/min. An empty aluminum pan was used as a reference. DSC
thermograms of pure substances, their physical mixture and drug loaded
microspheres were recorded.
In vitro drug release study
In vitro drug release from the prepared microspheres was performed at different
pH values (1.2 and 6.8) at 37 ± 0.5°C. The release of piroxicam from
microspheres was determined using type II dissolution apparatus (Copley, NG
42JY, Nottingham, UK). Microspheres equivalent to 20 mg were weighed and added
to 900 ml of dissolution medium with a stirring rate of 100 rpm. For
microspheres having solid dispersion structure release was measured at pH 1.2
for 1 h. The pH of the dissolution medium was kept at 1.2 for 2 h then adjusted
to 6.8 for 4 h to evaluate release of piroxicam from microspheres containing
eudragit Rs100 and ethyl cellulose. Samples (5 ml) were withdrawn from the
dissolution medium at various time intervals and replaced with 5 ml fresh media
to keep sink conditions. The amount of drug released at each time interval was
calculated and the cumulative amount of drug released was calculated as a
function of time to construct the drug release profile.
Release kinetics studies
To determine the possible release mechanism of
different prepared formulations the release data was fitted to different
kinetic models. Thus, the release data was fitted to zero order, first order
and Higuchi kinetic models [32].
In vivo ulcerogenicity
studies
Animals, treatment and collection of tissue samples:
Male Wistar-strain rats weighing (160-180) g were obtained from National
researches center (Cairo, Egypt). In vivo ulcerogenicity studies were conducted
according to the procedure reported by previous study with some modifications
[33].
Animals were maintained at 22 ± 1°C with 12 h
light/dark cycle using galvanized wire cages and allowed rat chow and water ad libitum for 14 days to get adapted to
laboratory conditions. In vivo
experimental protocols were approved by the Animal Care and Use Committee and
were in accordance with all recommendations in the University Guide for the
Care and Use of Experimental Animals.
The animals were divided into four groups each
containing 6 animals (n=6). Animals were fasted 40 h with free access to water
[34]. The first group of animals is the control group, the second group of animals
was treated with free piroxicam (30 mg/kg), the third group of animals was
treated with piroxicam microspheres containing eudragit S100 in the ratio (1:3)
in a dose equivalent to (30 mg/kg) of piroxicam while the fourth group of
animals was treated with piroxicam microspheres containing aerosil and eudragit
L100-55 in the ratio (1:4:2) in a dose equivalent to (30 mg/kg) of
piroxicam.
Piroxicam and prepared formulae were administrated
orally to each corresponding group as 1 ml suspension by oral gavage using an
intubation needle fitted onto a syringe of appropriate size in a dose
equivalent to 30 mg/kg of piroxicam or its equivalent in different formulations
[35,36].
6 h later, each animal was removed from its cage,
anaesthetized with ether and the abdomen was opened. Each stomach was excised,
dissected along the greater curvature and contents were emptied by gently
rinsing with isotonic saline solution [37].
Macroscopic examination of gastric ulcers: After the
animals were sacrificed, each stomach was pinned out on a flat surface with the
mucosal surface uppermost. Then a 10x binocular magnifier was used to examine
and assess presence of hemorrhagic lesions and/or gastric ulcers expressed as
the ulcer incidence.
The number of erosions per stomach was assessed for
severity according to the scoring system described [38]. The grade of lesions
was scored according to the following scale- 0: no pathology; 1: small (1-2 mm
ulcers); 2: medium (3-4 mm ulcers); 4: large (5-6 mm ulcers); 8: ulcers
(greater than 6 mm). The sum of the total ulcer scores in each group of rats
was divided by the number of animals in the group to give the mean ulcer index
for that group.
Histopathological examination of stomach sections: The collected stomachs samples were fixed overnight in 10% w/v buffered
formalin. Each specimen was sectioned, processed overnight and then embedded in
paraffin. The paraffin blocks were sectioned and the slides were stained with a
standard haematoxylin and eosin stain then photographed under 20x magnifications
using a Nikon Eclipse 80i light microscope (Nikon Corporation, Japan) [39].
RESULTS AND DISCUSSION
Surface morphology
The percentage yield of different formulations was
represented in Table 2 ranging from 45.21 ± 0.01 to 87.79 ± 0.01. The
percentage yield of microspheres having solid dispersion structure is less than
those containing controlling release polymers. Formula F3 and formula F4 having
high percentage of aerosil has been found to have the least yield. This can be
attributed to that aerosil have high porosity and specific surface area to act
as dispersing agent may cause loss of the drug. By increasing polymer amount,
percentage yield of the obtained formulations is increased. This was approved
by work of other researchers who study the effect of the polymer concentration
on the percentage yield of the resulting microspheres [40].
Entrapment efficiency varies according to polymer
type, drug to polymer ratio and aerosil percentage as shown in Table 2.
Effect of aerosil on entrapment efficiency is due to the fact that aerosil
particles have high porosity and large specific surface area leading to drug
loss during evaporation of organic solvent within the preparation process. Thus
increasing amount of aerosil decreases entrapment efficiency as shown for
formula F2 which has the highest entrapment efficiency (about 56%) having the
least amount of aerosil and the highest amount of eudragit L100-55. Increasing
polymer percentage increases the entrapment efficiency due to better coating of
drug resulting from precipitation of polymer on the surface of the dispersed
phase which leads to preventing of drug diffusion across the phase boundary
[41]. Similar results were obtained by Mehta et al. [42] and Sharma et al. [43].
Fourier transformed infrared spectroscopy (FTIR)
Accordingly, the results ruled out the possibility
of disappearance of intramolecular hydrogen bonding as 1632 cm-1
stretching peak which is involved in the formation of this intramolecular
hydrogen bond shifted to higher value 1642 cm-1. For IR spectrum of
microspheres containing eudragit Rs100 presence of 1527 cm-1, 1601
cm-1, 1329 cm-1 peak may be due to intermolecular
interaction between drug and polymer. The same results were obtained by other
investigators studying interaction between piroxicam and eudragit polymers
[47]. Physical mixture spectrum indicates only the summation of different
components of microspheres.
Differential scanning calorimetry (DSC)
According to biopharmaceutical classification system
piroxicam is a class II drug having low solubility and high permeability so
drug release is a crucial and a limiting step for oral drug bioavailability
particularly for drugs with low gastrointestinal solubility and high
permeability. By improving the drug release profile of these drugs it is
possible to enhance their bioavailability and reduce side effects [52].
As piroxicam has both acidic and basic groups, its
solubility is pH dependent so the difference in the degree of the dissolution
of the drug is dependent on the ionization of the drug at different pH values
[53]. Release of the drug at different pH values is illustrated in Figure 4.
In vivo ulcerogenicity
studies
Macroscopic analysis: Experimental design, animal groups as well as ulcer incidence and ulcer index of different formulations are illustrated in Table 4. Figure 8 shows macroscopic observations of stomach mucosa of the animals of different groups which differ according to presence or absence of hemorrhagic lesions.
Histopathological analysis: The results of the
histopathological analysis of different stomach specimens of the animals of
different groups after investigation under microscope are illustrated in Figure
9.
Piroxicam treated rat (group II) represented by Figure
9D show stomach mucosa of gastro-esophageal junction of the treated group
with piroxicam (30 mg/kg) after 6 h having focal superficial degeneration,
congestion and sloughing of gastric mucosa with wide inflammatory cellular
infiltration and dense mononuclear cell infiltration, respectively.
Figure 9E (group III) show stomach mucosa of animals
treated with microspheres containing piroxicam and eudragit S100
(equivalent to 30 mg piroxicam/kg) after 6 h. It shows gastric mucosa having
(mild mucosal edema with minimal sloughed area and vascular congestion).
Figure 9F (group IV) show stomach mucosa of animals
treated with microspheres containing piroxicam and eudragit L100-55
(equivalent to 30 mg piroxicam/kg) after 6 h. It shows superficial diffuse,
sloughing of the covering epithelium, severe congestion and inflammatory
cellular infiltration of (group IV). So according to the obtained results it
was found that group III of microspheres containing eudragit S100
and piroxicam was the group of decreased in vivo gastric ulcerogenic activity compared
to other groups.
CONCLUSION
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Table 1 -
Table 2
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Table 3
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Table 4
