ABSTRACT
The preparation of ketoprofen (KP) sustained release (SR) suppositories was designed according to the 3(2) x 2(1) factorial design as three different KP:Eudragit RL 100 ratios (1:0.5, 1:1, 1:2), three particle sizes of prepared granules (250-500, 500-710, and 710-1000 microm) and two different PEG 400:PEG 6000 ratios (40:60, 50:50). The conventional KP suppositories were also prepared by using Witepsol H 15, Massa Estarinum B, Cremao and the mixture of PEG 400:PEG 6000. The dissolution studies of suppositories prepared were carried out according to the USP XXIII basket method in the phosphate buffer (pH = 7.2) at 50 rpm, and it was shown that the dissolution time was sustained up to 8 hours. According to the results of the factorial design, the most important independent variable on t50 and t80 was drug:polymer ratios. The log of partition coefficient of KP was determined as 1.46, showing the high affinity to the oily phase. n exponent and kinetic studies were conducted to explain diffusion mechanism, and it is understood that if the inert KP:Eudragit RL 100 ratio is increased in the particles, the Fickian difusion dominates and the best kinetic turns to Higuchi from the Hixson-Crowell. There is neither crystalline form of KP nor degradation product in the suppositories detected with the differential scanning calorimetry (DSC) studies. In addition to these studies, antiinflammatory activity of SR suppositories also determined that it was significantly extended according to the conventional suppositories.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Ketoprofen/administration & dosage , Acrylic Resins , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Calorimetry, Differential Scanning , Carrageenan , Chemical Phenomena , Chemistry, Pharmaceutical , Chemistry, Physical , Delayed-Action Preparations , Diffusion , Drug Compounding , Excipients , Inflammation/chemically induced , Inflammation/drug therapy , Ketoprofen/chemistry , Ketoprofen/pharmacology , Kinetics , Male , Octanols/chemistry , Rats , Solubility , Suppositories , Water/chemistryABSTRACT
The antiproliferative effect of As(2)O(3)-loaded microemulsion (As(2)O(3)-M) on human MDAH 2774 ovarian cancer cells was compared with a regular solution of the As(2)O(3). We used MDAH 2774 as model cell lines for ovarian cancer. The (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide) (XTT) and trypane blue dye exclusion tests were used to evaluate cytotoxicity. Apoptotic effect of solutions was evaluated using cell death detection kit. Standard microemulsion formulation used in this experiment contains 5 x 10(-6) M As(2)O(3). It was clearly demonstrated that As(2)O(3)-M had a significant cytotoxic effect on MDAH 2774 cell line, and the cytotoxic effect of As(2)O(3)-M was significantly higher than that of regular As(2)O(3) solutions. Even approximately 6000 times diluted microemulsion formulation loaded with 5 x 10(-6) M As(2)O(3) showed a cytotoxic effect. As a result, this diluted concentration (approximately 8 x 10(-10) M) was found to be approximately 6000 times more effective than regular As(2)O(3) solutions (5 x 10(-6) M). Moreover, this diluted concentration resulted in 1.5-fold enhancement of apoptosis. According to the in vitro cytotoxicity studies, we concluded that by incorporating As(2)O(3) into the microemulsion (As(2)O(3)-M), which is a new drug carrier system, it is possible to increase antiproliferative effect of regular As(2)O(3) on MDAH 2774 cells. Translating these results to in vivo conditions would open new windows in the treatment of ovarian cancer.
