الفهرس | Only 14 pages are availabe for public view |
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. |