Preparation Of Oxime Esters Of Polyoxyethylene And Its Ph Sensitivity Of Drug Release Properties Of,

Hydroxamic acid (RCONHOH) can be considered as the derivative of carboxylic acids, which poses a wide spectrum of biological activities,such as antiinflammatory, antiasthmatic, antimetastatic, antibiotic, psychotropic, insecticidal, acaricidal and nematocidal activity. Hydroxamic ester (—COONHCO—) is a product from the reaction of hydroxamic acid with acylation. Hydroxamic ester received great interest previously, but its pH sensitivity was rarely refered. It is stable in an acid solution but abruptly increase hydrolysis rate at pH around 7.4. Because of this pH sensitivity of hydroxamic ester, in this study, we chose polyacrylamide as a polymeric backone, so polyacryl hydroxamic benzyl ester (PAHB) and poly(acryl-co-vinylpyrrolidone) hydroxamic benzyl ester (PAVHB) were synthesized by hydroxamation and esterification of amide groups of polyacrylamide and poly(acrylamide-co-vinylpyrrolidone). Taking advantage of their pH-sensitive degradation properties, enteric drug delivery systems were prepared. In vitro and vivo drug release from this system also exhibited pH sensitivity, which was consistent with the degradation feature of the polymers. PAHB with pH sensitivity is a potential enteric drug carrier for oral administration.Polyacrylamide(PAM) and poly(acrylamide-co-vinylpyrrolidone) (PAV) were synthesized by a radical polymerization in the mixture of ethanol and acetone with suitable proportions, using AIBN as an initiator. The ethanol and acetone can also work as a chain transfer agent, and the molecular weight of PAM and PAV can be controlled by the ratios of ethanol to acetone.There are several methods have been developed to prepare hydroxamic acids and have been well documented in the literature, among which the reaction of carboxylic acids and hydroxylamine hydrochloride in an aqueous solution is most widely used.The condition of reaction is very mild and the method is simple and efficient. First, PAM and PAV were converted to the corresponding hydroxamic acid in an aqueous solution at about 85 ℃ and a pH about 10 to 11. Then by treating the hydroxamic acids with acylhalideC6H5COC1 in an aqueous solution, pH sensitive PAHB and PAVHB were obtained. FT-IRn 'H-NMR> element analysis > DSC were employed to characterize the polymers;the pH sensitivity was charactered by UV and weight loss.In vitro degration tests of PAHB and PAVHB were carried out in PBS at various pHs from 5.0 to 8.0 at 37"C respectively. PAHB and PAVHB exhibited strong pH sensitive degradation property. Their degradation rate enhanced abruptly as pH increased from 6.0 to 7.4. In vitro drug release from the delivery system based on this novel polymer was carried out in PBS in the pH range of 5.0-8.0 at 37°C respectively, using bovine serum albumin (BSA) and trypan blue (TB) as model drugs. In vitro release of soluble drugs from this system also revealed pH sensitivity, which was consistent with the degradation feature. But the rates of drug release were more quickly then that of degration in all of the pHs since the drug release was not only controlled by the degration of polymer but also influenced by the diffuse behavior and the character of the drugs themselves. In the studies, we also used acrylic acid resin III as a contrast carrier. The results indicate that PAHB and PAVHB owe stronger pH-sensitivity than acrylic acid resin III.In vivo studies were carried out using healthy rabbits weighting 2.3±0.2kg.The sample was administrated at high and low dosages by oral. The blood sample were withdrawn periodically and analyzed for drug content by HPLC method. The time-blood concentration data were disposed by DAS pharmacokinetics computer program and the pharmacokinetics parameters were statisticsly analyzed. 20 //I of the drug solution was eluted from a Diamonsil?Cl 8 column (5n 250X 4. 6 mm) at 25 °C with a mobile phase consisting of MeOH-pH 3.6 NaAc/HAc(77: 23, v/v) at lml/min flow rate of using UV detector at 278 nm. The peak area was increased linearly with the increased concentration of DS(80. 0 ng/ml —16000. 0 ng/ml), C= —151. 45354+ 4250. 71249 'A^o^O. 99935). The mean recoveries of the low> middle and high DS concentration were 96. 9%, 98. 5%, 96. 7%, intra-day precision were 3. 0%, 2. 3%, 3.1% and inter-day precision were 3. 6%, 4. 7%, 3. 8%. The data of mean recovery and precision indicated that the HPLC analysis method was accurate and feasible. From DAS program, various pharmacokinetics parameters were calculated. The AUCand Cmax of entric table were significantly different from that of DS/PAHB solution at the same dose. The Tmax and t\n of the former were higher than the latter. The more dose of the entric tables had, the higher Cmax is.