الفهرس 
Pharmacokinetic propertiesOnly 14 pages are availabe for public view
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Abstract
The aim of this study is to decrease the gastro-ulcerogenic side effects of piroxicam by preparing piroxicam microspheres with different polymers using solvent evaporation technique and comparing its in vivo ulcerogenic action on stomach of rats with piroxicam. Piroxicam belongs to the oxicam group of non-steroidal anti-inflammatory drugs. It is indicated for acute or long term use in the release of signs and symptoms of osteoarthritis and rheumatoid arthritis. Piroxicam is a class II drug. Piroxicam is described as practically insoluble in water as its aqueous solubility is 0.023 mg/ml. Piroxicam is ionized under GI conditions, in the stomach (where the pH is acidic) in the cationic form, and in small intestine (pH near neutral) in the anionic form. piroxicam solubility is pH dependent as its solubility increases at low and high pH values and decreases in the middle pH range where the drug is unionized. The maximum daily dose of piroxicam is 20 mg as a single dose or it may be divided if desired. The partition coefficient for piroxicam log P was 0.29 while distribution coefficient log D was 0.72 at pH 6.629 and -1.13 at pH 6.5. piroxicam has two pKa values pKa1=1.86 can be due to the weakly basic pyridyl nitrogen and pKa2=5.46 can be due to the weakly acidic 4-hydroxy proton. Piroxicam is a highly permeable compound as it is completely and rapidly absorbed following oral administration. Peak plasma levels occur within 2-5 h (Tmax). Terminal elimination half-life ranges between 30 and 60 h.
XIV
Abstract
The most common piroxicam adverse effects are
gastrointestinal damage and cardiovascular side effects as it exerts
its action by non-selective inhibition of COX enzyme leading to
inhibition of PGE2 synthesis.
GI damage of piroxicam is one of the most serious as the
relative risk of GI damage compared with non-use is 6.2 fold.
Microencapsulation is used for different reasons as
protection of the sensitive substances from the external
environment, masking the organoleptic properties like colour,
odour and taste of the substance, controlling release of the drug
and avoiding adverse effects like gastric irritation.
One of the most used methods of microencapsulation is
solvent evaporation technique because it requires only mild
conditions such as ambient temperature and constant stirring. In
contrast several variables could affect the formulation of
microspheres as drug to polymer ratio, rate of solvent removal, etc.
Different polymers were used for preparation of the
microspheres including time dependent eudragit polymers
(eudragit Rs100 and eudragit Rl100) which are insoluble but
permeable in digestive fluids, pH dependent eudragit polymers
(eudragit L100 and eudragit S100) which are soluble in digestive fluids
by salt formation according to pH value, eudragit L100-55 as solid
dispersing carrier and ethyl cellulose as controlled release polymer.
For different piroxicam microsphere formulations which were
prepared by solvent evaporation technique it was found that;
Spectrophotometric determination of piroxicam using UV
spectrophotometer is a reproducible method which was
proved by the linearity of the calibration curve at different
pH values (1.2, 6.8, 7.4).
XV
Abstract
Formula F15 containing piroxicam, aerosil and eudragit L100-
55 in the ratio (1:4:1) respectively was the formula of the
least percentage yield (45.21%±0.01) while other
formulations have percentage yield ranging from
57.73%±0.18 to 92.03%±0.18.
Different factors affect entrapment efficiency of different
formulations like interaction between drug and polymer,
concentration of polymer, dispersed phase to continuous
phase ratio, etc. Formula F16 of solid dispersion properties
containing piroxicam, aerosil and eudragit L100-55 in the ratio
(1:4:2) respectively was the formula of the least entrapment
efficiency (23.87%±0.01) while for other formulations
containing aerosil it ranges from 26.88%±0.01 to
56.13%±0.03 depending on amount of aerosil and other
polymers ratio. Formulations containing only eudragit
polymers without aerosil have entrapment efficiency
ranging from 50.96%±0.03 to 80%±0.01.
For SEM microphotograph of piroxicam microspheres it was
found that the prepared microspheres were spherical and
porous in nature due to solvent evaporation. Depending on
type of polymer and rate of solvent removal, surface
properties of microspheres differs.
FTIR spectrophotometer was used to investigate interaction
between drug and different polymers. It was found that IR
peaks of piroxicam at 1632 cm-1 and 1529 cm-1 due to
stretching vibration of carbonyl group and second amide
group respectively. For different piroxicam microspheres
formulations IR peak at 1632 cm-1 was shifted to around
1640 cm-1 due to disappearance of intramolecular hydrogen
bond present in the piroxicam structure. Shifting of 1529
cm-1 band to lower value around 1526 cm-1 with eudragit
polymers may indicate intermolecular interaction between
piroxicam and eudragit polymers.
XVI
Abstract
Piroxicam shows a sharp endothermic melting peak at
200.09 ͦc that indicates its crystalline nature which then
disappeared from DSC thermogram of different piroxicam
microsphere formulations. This may indicate transformation
of drug to amorphous state.
Piroxicam is a class II drug having low solubility and high
permeability so dissolution is very crucial for its
bioavailability. Piroxicam solubility is pH dependent
(solubility increases at low and high pH values and
decreases in the middle pH range.
For piroxicam microspheres containing eudragit Rs100 and
eudragit Rl100 polymers, dissolution of drug depends on its
diffusion from polymer. As eudragit Rl100 is more permeable
than eudragit Rs100 , the formula of the least dissolution
(67.16%±2.5) after 8 h was F3 containing drug and eudragit
Rs100 in the ratio (1:5) respectively.
For piroxicam microspheres containing eudragit L100 and
eudragit S100 polymers, dissolution of drug depends on pH at
which polymer dissolves. Formula F11 containing drug and
eudragit S100 in the ratio (1:3) respectively was the formula
of the best coating, least burst release and least dissolution
at pH 1.2 releasing only (6.4%±0.7) after 2 h.
Formula F16 containing piroxicam, aerosil (solid dispersing
agent) and eudragit L100-55 (solid dispersing carrier)in the
ratio (1:4:2) respectively was selected as the formula of solid
dispersion properties releasing (74.98%±1.5) after 15 min. at
pH 1.2 which then formulated with eudragit Rs100 and ethyl
cellulose as controlled release polymers. Depending on the
ratio between these polymers dissolution can be increased
or decreased to control bioavailability.
Comparing dissolution of different formulations, formula of
the least dissolution F11 and that of the highest dissolution
F16 was compared with free drug (piroxicam) for in vivo
gastro ulcerogenic effect in rats. It was found that formula
F11 was selected as the best formula to decrease gastro
ulcerogenic effect of piroxicam.