Preparation And Sustained-release Of Polymeric Drug-saccharide Conjugates With 2-Arylpropionic Acid Pendants

Studies on macromolecules containing saccharide as selective drug delivery system have been developed for biomedicinal application. It has been reported that these systems provide many advantages including prolonged drug release, changed biodistribution, reduced toxicity and increased patient acceptance.Ibuprofen, naproxen and ketoprofen are used as model drug. They are a commonly 2-Arylpropionic acid used as non-steroidal anti-inflammatory drugs (NSAIDs) and widely applied to alleviate pain and inflammation associated with tissue injury. However, the drugs are poorly soluble in aqueous media and cause irritant side effects especially on the gastro-enteric mucosal membranes. Therefore, polymeric prodrugs with saccharide through chemical bond can be designed to overcome such problems and merging the relative advantages of saccharide and macromolecules into a single system. This system can be useful to both increase drug stability and avoid the rapid release.In this paper, a facile and efficient enzymatic and polymerization process was used to prepare polymeric drug-saccharide conjugates with 2-Arylpropionic acid pendants. A series of polymeric prodrugs with different saccharide branches were synthesized and the structures and molecular weight were confirmed by FT-IR, NMR and GPC.Firstly, the paper investigated the influence of various factors to preparation of polymeric prodrugs, such as the molar ratio of drug vinyl ester and sugar vinyl ester (1:1,1:2,2:1,4:1, mol/mol), and the mass of initiator (AIBN,1%,2%,4%, w/w). The obersevations suggested that the molecular weight was influenced by the saccharides variation. Polymeric prodrug with lactose pendant had the highest molecular weight, with Mn of 7.527×104. By increasing saccharide derivatives in raction feed, it caused a decrease in molecular weight of the polymeric prodrugs. For example, the loading capacity of ketoprofen in the polymeric prodrug was only 22.74% (w/w) when glucose vinyl ester was 67% (mol/mol) in the feed, while it reached 42.28% (w/w) when it was 20% in the feed. A reduction of molecular weight was noted by increasing the ratio of initiator. The results suggested that the molecular weight and conversion of the polymeric prodrugs were greatly influenced by the concentration of initiator and the molar ratio of monomers.And then, factors to the in vitro drug release were systematically studied, such as the effects of different saccharides with varying carbon chain length, drug carrier, pH, temperature, ionic strength and solution variation.The drug release profiles could be influenced by the characteristics of these polymers. Among the polymeric conjugates, drug from prodrug with disaccharide pendant was released rapidly. It implied that the type of saccharide branch influenced release capabilities of polymeric prodrugs. The structures of monosaccharides appeared having a little influence on the drug release. The release of drugs was seen to decrease along with increasing the length of spacer bond between saccharide and polymer main chain. The release rate of drug from polymeric prodrugs increased with the raising of saccharide pendants in the macromoleculars.Drug release also could be affected by environmental conditions. It was concluded that different release profiles occurred and these fitted to various kinetic models that were dependent on variations on temperature and pH. It was released rapidly in higher pH, temperature solution. The cumulative drug released in pH 10.0,0.5M NaOH and 50℃solution after 12h reached 42.3%,87%,15.8%, respectively. While it reached 2.5%,2.5%,2.2% after 12h, respectively in pH 1.2,0.5N HC1 and 25℃solution. Ionic strength of the medium appears to have only a minor effect on drug release and higher ionic strength induced a faster drug release. Cumulative drug released was only 1.5% after 12h in distilled water; while it reached 5.6%in 0.5M NaCl.lt was apparent that the polymeric drug-saccharide conjugate had the potential to be developed as a system that enhanced drug delivery.Then, the homopolymer and copolymer of ketoprofen were prepared to nanofibers through electrospinning. The drug release behavior revealed that both polymer drugs and electrospun fibers could prolong the drug release. While, the electrospun fibers had a different drug release mechanism, and the drug release rate was higher than that of polymer particles. The release profiles also suggested that it was possible to control the drug release rate by changing the concentration of polymer drug conjugates in the solution for electrospinning. Over all, the electrospun fibers prepared by electrospinning could increase drug release rate effectively, and also maintain the drug sustained release characteristics.