Doğal polimerler kullanılarak hazırlanan boncuk şeklindeki kontrollü salım sistemlerinin tasarımı ve gerçekleştirilmesi

Abstract

131 I. SUMMARY Alginates, which are obtained from marine brown algea, are natural polymers that are biocompatible and biodegradable The use of alginates have received much attention in pharmaceutical preparations, particularly as a vehicle for controlled drug delivery. Nicardipine HCI, which is a calcium channel blocker, is used in angina pectoris and hypertension. Its bioavailability decreases because of the first pass effect. It has a short biological half life(about one hour) and its absorption is rapid and complete. Nicardipine has to be taken at multiple dosing interval to get the constant therapeutic blood level. So, it has a need to evaluate controlled release dosage forms. It is aimed to prepare alginate-gel beads, which were formed based on the ion exchange between sodium alginate and divalent cations and to investigate the factors, which affect the formulation, in this study. First, the release profiles of the formulations which were prepared by using alginates with different M/G content and viscosity were compared. The release was extended with the alginates which have high guluronic acid content. Two formulations which gave the most close release profile to target profile were chosen and the effect of the factors which affect the formulations were investigated by 23 factorial design. The effect of drug:polymer ratio, CaCI2 concentration, curing time and Na-alginate concentration on the time for 50% of the drug to be released(t%50) and drug entrapment efficiency were evaluated with analysis of variance The in vitro release studies were carried out by flow-through cell apparatus at different media (pH 1.2, 2.5, 4.5, 7, 7.5 buffer solutions). It was found that, nicardipine:alginate ratio was a significant parameter which affect both the t^ and drug entrapment efficiency. The release of nicardipine from the alginate beads, which were prepared in a ratio of 1:1, was more extended than those of the 1:2 beads. The drug release from alginate beads in a ratio of 1:1 increased by increasing CaCI2 concentration. But the opposite relationship was observed in the case of 1:2 beads. It was found that curing time was not a significant parameter in tA50 but Na-alginate concentration slightly effects the t%50. It was also132 seen that Na-alginate concentration did not affect the drug entrapment efficiency; whereas the effect of CaCI2 concentration was significant for the 1 :2 beads. Different polymers were added to the 1:1 beads and the release profiles and kinetics of them were investigated. The release rate of formulation which was prepared by adding chitosan was in most agreement with the target profile. It was seen that the erosion of alginate-gel matrix at pH 7-7.5, was reduced by using chitosan. Swelling studies showed that the alginate-gel beads swelled slightly at pH 1.2 and 2.5. They reached the maximum swelling ratio at pH 4.5 and then eroded at pH 7-7.5. The calcium content of the alginate gel beads was assayed by using atomic absorption. It was found that, the Ca++ content of the beads which were prepared with alginates containing high guluronic acid was greater than those of the alginates with low guluronic acid. The particle size of all formulations was measured with a micrometer and the mean radius and standart deviation were calculated. The particle size distribution of each formulation was within a narrow range. The mean particle size was differed among the formulations. The interaction between nicardipine, alginate, chitosan and CaCI2 in the final formulation has also been investigated by using differential scanning calorimeter(DSC). No interection was observed between nicardipine and these substances. Morphological examination of the surfaces of alginate-beads were carried out using scanning electron microscope(SEM). The surface photographs of formulations 1:1 and 1:2 and the swelling of the final formulation in different medium was determined. In conclusion, the controlled zero order release bead dosage form of nicardipine based on ion exchange between alginate chitosan and Ca++ can be developed.

131 I. SUMMARY Alginates, which are obtained from marine brown algea, are natural polymers that are biocompatible and biodegradable The use of alginates have received much attention in pharmaceutical preparations, particularly as a vehicle for controlled drug delivery. Nicardipine HCI, which is a calcium channel blocker, is used in angina pectoris and hypertension. Its bioavailability decreases because of the first pass effect. It has a short biological half life(about one hour) and its absorption is rapid and complete. Nicardipine has to be taken at multiple dosing interval to get the constant therapeutic blood level. So, it has a need to evaluate controlled release dosage forms. It is aimed to prepare alginate-gel beads, which were formed based on the ion exchange between sodium alginate and divalent cations and to investigate the factors, which affect the formulation, in this study. First, the release profiles of the formulations which were prepared by using alginates with different M/G content and viscosity were compared. The release was extended with the alginates which have high guluronic acid content. Two formulations which gave the most close release profile to target profile were chosen and the effect of the factors which affect the formulations were investigated by 23 factorial design. The effect of drug:polymer ratio, CaCI2 concentration, curing time and Na-alginate concentration on the time for 50% of the drug to be released(t%50) and drug entrapment efficiency were evaluated with analysis of variance The in vitro release studies were carried out by flow-through cell apparatus at different media (pH 1.2, 2.5, 4.5, 7, 7.5 buffer solutions). It was found that, nicardipine:alginate ratio was a significant parameter which affect both the t^ and drug entrapment efficiency. The release of nicardipine from the alginate beads, which were prepared in a ratio of 1:1, was more extended than those of the 1:2 beads. The drug release from alginate beads in a ratio of 1:1 increased by increasing CaCI2 concentration. But the opposite relationship was observed in the case of 1:2 beads. It was found that curing time was not a significant parameter in tA50 but Na-alginate concentration slightly effects the t%50. It was also132 seen that Na-alginate concentration did not affect the drug entrapment efficiency; whereas the effect of CaCI2 concentration was significant for the 1 :2 beads. Different polymers were added to the 1:1 beads and the release profiles and kinetics of them were investigated. The release rate of formulation which was prepared by adding chitosan was in most agreement with the target profile. It was seen that the erosion of alginate-gel matrix at pH 7-7.5, was reduced by using chitosan. Swelling studies showed that the alginate-gel beads swelled slightly at pH 1.2 and 2.5. They reached the maximum swelling ratio at pH 4.5 and then eroded at pH 7-7.5. The calcium content of the alginate gel beads was assayed by using atomic absorption. It was found that, the Ca++ content of the beads which were prepared with alginates containing high guluronic acid was greater than those of the alginates with low guluronic acid. The particle size of all formulations was measured with a micrometer and the mean radius and standart deviation were calculated. The particle size distribution of each formulation was within a narrow range. The mean particle size was differed among the formulations. The interaction between nicardipine, alginate, chitosan and CaCI2 in the final formulation has also been investigated by using differential scanning calorimeter(DSC). No interection was observed between nicardipine and these substances. Morphological examination of the surfaces of alginate-beads were carried out using scanning electron microscope(SEM). The surface photographs of formulations 1:1 and 1:2 and the swelling of the final formulation in different medium was determined. In conclusion, the controlled zero order release bead dosage form of nicardipine based on ion exchange between alginate chitosan and Ca++ can be developed.