Preparation And Evaluation Of Biodegradable Molecularly Imprinted Polymers

Novel drug delivery system has become a hot research direction in pharmaceutical field,while the researches on drug carriers and materials were more important.Ideal drug carrier should have good biocompatibility,biodegradability,chemical and biological stability,low toxicity and high drug loading,and can control the drug release for achieving ideal therapeutic effects.Molecularly imprinted polymer(MIP)is a kind of new polymer which has significant adsorption performance to template molecule.During MIP preparation,template molecule and functional monomer is first self-assembled,and then fixed by cross-linker.MIP is obtained after removal of the template molecule.MIP draws more attentions recently in drug delivery system(DDS)due to its good stability,resistance to enzyme's degradation,tolerance in different pH environment,high drug loading and sustain release.The outstanding performance of MIP in DDS is owing to its inherent structure characteristics.MIP prepared with the drug as template shows high affinity and special adsorption performance to drug because of the"footprint" left by drug during the preparation.This adsorption is unlike previous simple physical mixing or obscure covalent bonding and is maintained through non-covalent supramolecular interaction such as intermolecular hydrogen bonds,?-?,electrostatic role.After entered into the body,non covalent bond gradually breaks because of the influence of polar environment of body and the drug slowly and continuously released.Carriers for transporting drugs in the body must be bio-friendly materials,namely,secure and non-toxic.They can decompose to small molecules by biological or enzymatic degradation which can be absorbed by the body and excreted.Polyester polymer is a kind of biodegradable material currently approved by FDA for using in biomedical field,including PGA,PLA,PLGA,PCL.Whether MIP is bio-friendly or not,it is closely connected with the performance of the cross-linking which is the main part supporting the skeleton of MIP.At present,EDGMA and TRIM are the widely used cross-linking in the preparation of MIP,whose biocompatibility and biodegradability is still not clear.In this paper,biodegradable MIP was prepared with modified PCL as the cross-linking,and acrylic acid as functional monomer under UV-photo polymerization.Moreo-ver,its structure and performance were evaluated.Finally,in simulated conditions of human physiological system,drug release and biodegradation in vitro were also investigated preliminarily.1.Objectives and ContentsA new biodegradable MIP was prepared by UV-Photo polymerization with theophylline as the template,acrylic acid as functional monomer,and biodegradable acryloyl PCL as the cross-linking.Its structure was characterized by SEM,IR,DSC and adsorption capacity was studied by isothermal adsorption,Scatchard analysis and kinetic curve.The preliminary studies of drug release and degradation in vitro were conducted in simulated conditions of human physiological system.(1)Preparation of PCL cross-linking(2)Preparation of MIP(3)Structure characterization and adsorption evaluation of MIP(4)Drug release and degradation performances in vitro2.Methods2.1 Preparation and optimization of cross-linker acryloyl PCLPCL diol was end-capped with acrylate groups to form a polymerizable macromere.The reaction mixture was stirred for 3 h at 80C.After the reaction,the mixture was filtered to remove triethylamine hydrochloride.The diacrylated macromere was obtained by pouring the filtrate into a large excess of hexane.The solid precipitate was dried under vacuum for 24 h.Compare the infrared spectroscopy of reaction material PCL diol and the reaction product acryloyl PCL.2.2 Preparation of theophylline-MIPWith theophylline as template molecule,acrylic acid as function monomer and acryloyl PCL as cross-linker,novel biodegradable molecularly imprinted polymers were synthesized by UV-photo polymerization.And the preparation process was optimized.2.3 Structure characterization and adsorption evaluation of MIP(1)Theophylline-MIP was characterized by SEM,FT-IR and DSC.(2)The adsorption of MIP toward theophylline was evaluated by adsorption isotherm,Scatchard analysis and kinetic curve.(3)The binding property and completive adsorption of MIP and NIP towards different substrates was evaluated by static adsorption isotherm.(4)The swelling behavior of molecularly imprinted hydrogels was evaluated by water swelling experiments.2.4 Drug release behavior and of degradation behavior in vitro(1)Prepared the theophylline loading MIP by immersion adsorption and caculated the encapsulation efficiency and drug loading.(2)Investigated the release behavior in PBS.(3)Observed the degradation behavior of PCL diol and MIP in vitro.3.Results3.1 Preparation of acryloyl PCLAfter investigating the factors in preparing acryloyl PCL,including dosage and adding method of acryloyl chloride,reaction system,reaction temperature,the optimal process of preparing acryloyl PCL was determined:6mmol acryloyl chloride dissolved in 3ml benzene were added dropwise to 20 ml of benzene containing 2mmol PCL(M=2000)at room temperature.After adding finish,6mmol of triethylamine were added and then stirred 3h at 80?.Filtered the mixture and poured the filtrate into 80ml of n-hexane,white sediment solid emerged.The solid was dried under vacuum at 35?.The characteristic peak of terminal hydroxy of PCL in 3451cm-1 almost disappeared after acryloyl modified and a characteristic peak of C=C double bond in 1600cm'1 emerged in IR,it suggesting that acryloyl reaction almost succeeded.3.2 Preparation of MIPThe optimal MIP synthesis was as follow:0.2mmol of theophylline and 0.8mmol of acrylic acid were dissolved in 15ml of chloroform.And then added 1.5 mmol of acryloyl PCL,0.5 mmol of initiator and the mixture were polymerized under 366nm for 1h.The gel polymer was obtained and extracted with chloroform-glacial acetic acid(v/v,9:1)until no theophylline could be detected.3.3 Structure characterization of MIPSEM showed that the surface of MIP was smooth and had no obvious difference with NIP.There was no C?C absorption peak in IR,confirmed the free radical polymerization was complete.No heat change of MIP and NIP was observed at the point of theophylline heat change,demonstrated that theophylline formed complexe in MIP with other components.3.4 Adsorption evaluation of MIPThe adsorption of MIP to theophylline was associated with the substrate concentration and the adsorption time,With theophylline concentration in the solution increasing,the adsorption quantity of MIP to theophylline increased gradually and reached the peak at 0.06mmol/L.Theophylline adsorbed quickly in initial 1h and reached adsorption equilibrium at about 3h.The adsorption of MIP to theophylline was 1.27?mol/g,which was 5 times to caffeine,the structural analog of theophylline.The results exhibited that MIP had specific selectivity to the template.Water swelling experiments showed that the swelling performance of MIP was higher than that of NIP,and the swelling in the high pH environment displayed more obvious.3.5 Behavior of theophylline-MIP release in vitro(1)The drug loading of theophylline-MIP and utilization ratio of drug were 1.54%,12.48%respectively.(2)It was founded that the drug almost released at a constant speed within 3?6h,then reached plateau within 6?12h,finally released at another constant speed from 12h later.After 24 h the accurmulative drug release was 11.6%in simulating body fluid.3.6 Behavior of theophylline-MIP degradation in vitroDegradation rate of MIP is higher than that of PCL diol during observing period,and the degradation ratio of MIP was 6.60%,5 times of PCL diol.Acryloyl PCL could reduce the degree of crystallinity of original material and speed up the degradation.4.Conclusion4.1 The biodegradable cross-linking acryloyl PCL was synthesized.The MIP was prepared with thetheophylline as the template,acrylic acid as the functional monomer,modified PCL as cross-linking by UV initiating.The surface of obtained MIP was smooth and possessed water swelling ability.4.2 The adsorption of MIP was associated with the concentration of theophylline and adsorption time.The adsorption capacity of MIP was 1.40?mol/g,NIP?mol/g at 0.06mmol/L of theophylline after adsorbing 3h.The adsorption of MIP to theophylline was 5 times higher than that of caffeine demonstrated MIP had specific selectivity to theopyhlline.It was explained by the imprints in the MIP which matched with the template not only in the spatial configuration but also interacted with the functional groups of the template.4.3 The drug loading was 1.54%,and the drug availability was 12.48%.the accumulative release was 11.6%after 24h.MIP could be degraded in the physiological system and the degradability was 6.60%.It suggested that MIP may be a potent drug carrier for long-term drug release.