Construction Of PH And PH-delayed Double Sensitive Colon-specific Drug Delivery System By Utilizing Functional Polymer Microspheres

The incidence of colon cancer and colitis are rising as people living standard rise. Thetraditional oral preparation or injection to colon concentration is low, bioavailability of drugis small, and side effects are big. In order to improve treatment effect of the local colondisease, researchers develop the oral colon specific drug delivery system (OCDDS) in recentyears. The drug delivery system can avoid drug release in the stomach and small intestine, butrelease locating in colon and rectum. The targeted delivery to colon via oral route is intendedto improve the efficacy and safety of the drug therapy by exerting high drug concentrationstopically at the disease site, enhance the bioavailability of drugs, and reduce side-effects.According to the molecule design, building and developing high efficient OCDDS is animportant research subject in the field of medicine based on physical and chemical propertiesof pharmaceutical polymers and drugs.The pH sensitive and pH-delayed double sensitive colon specific drug release systemswere constructed by surface grafted polymerization and the molecular surface imprintingtechnology based on biocompatible crosslinked poly (vinyl alcohol)(CPVA) microspheres asthe matrix. The drug delivery systems can promote the development of OCDDS, and theyhave important scientific significance in sustained and controlled drug release research area.Firstly, the graft-polymerization of sodium4-styrene sulfonate (SSS) was performed onthe surfaces of CPVA microspheres by using cerium salt-hydroxyl group redox initiationsystem, and the grafted microspheres CPVA-g-PSSS was obtained. The chemical structureand physicochemistry characters of CPVA-g-PSSS microspheres were adequatelycharacterized with infrared spectrum (FTIR), scanning electron microscope (SEM) anddetermining zeta potential. The experimental results show that cerium salt-hydroxyl groupredox initiation system can effectively initiate the polymerization of SSS on CPVA microspheres, and under the suitable conditions, PSSS grafting degree can get up to16.1g/100g. Zeta potential shows the grafted CPVA-g-PSSS have low negative value in a wide pHrange, namely there are higher density of negative charge on the surface of theCPVA-g-PSSS.Then, the adsorption property of the grafted microspheres CPVA-g-PSSS for5-fluorouracil (5-FU), namely drug loading ability, was mainly investigated and theadsorption mechanism was explored. The in vitro release behavior of the drug-loadedmicrospheres was also examined. In the acidic medium, the amino groups in5-FU moleculewill be highly protonated, and a strong electrostatic interaction between CPVA-g-PSSS and5-FU molecule will be produced, resulting in high absorption capacity, reaching105mg/g,and displaying the high efficiency of drug loading. When pH value is increased, theprotonation degree of the amino groups in5-FU molecule decrease, and the electrostaticinteraction reduce, leading to low absorption capacity of grafted microspheres CPVA-g-PSSStowards5-FU. The adsorption capacity increases with temperature decreasing, showing thecharacteristic of physical absorption, and capacity reduce with the salinity rising. The in vitrorelease drug shows in the medium of pH=1, the drug does not be released, and in the mediumof pH=6.8, the part of drug is released, while in the medium of pH=7.4, the sudden deliveryphenomenon will be produced. The in vitro release behavior of the drug loading microspheresis highly pH-dependent and is a pH-sensitive drug delivery system.Surface imprinting of5-FU was performed on CPVA microspheres with sodium4-styrene sulfonate (SSS) as functional monomer,5-FU as template and withN,N’-Methylene bisacrylamide (MBA) as crosslinker in aqueous solution by using ceriumsalt-hydroxyl group redox initiation system, and5-FU-imprinted microspheresMIP-PSSS/CPVA, on which there exists a layer of molecular imprinting cavies, wereobtained. The chemical structure and morphology of MIP-PSSS/CPVA microspheres werecharacterized with infrared spectrum (FTIR) and scanning electron microscope (SEM). Thebinding and recognizing property of the imprinted microspheres MIP-PSSS/CPVA for5-fluorouracil (5-FU), namely drug loading ability, was mainly investigated and the binding mechanism was explored. The in vitro release behavior of the drug-loaded microspheres wasalso examined. The experimental results show that based on the special cerium salt-hydroxylgroup redox initiation system in this investigation, the5-FU surface imprinting can beeffectively realized, and a polymer layer, in which a lot of5-FU-imprinted cavies aredistributed, can be formed on the surfaces of CPVA microspheres. In the acidic medium, theimprinted microspheres MIP-PSSS/CPVA exhibit very strong binding ability for5-FU bydriving of electrostatic interaction, displaying the high efficiency of drug loading, andbinding capacity reaching110mg/g. However, for relative to5-FU, MIP-PSSS/CPVAmicrospheres have low binding capacity towards tegafur (TE) and Uridine (UR). Compare tothe above5-FU-loaded CPVA-g-PSSS, in vitro release of the drug loaded MIP-PSSS/CPVAmicrospheres is not only pH-sensitive, but also time-delayed. The synergistic effect of strongelectrostatic interaction and the spatial resistance of drug molecule diffused from imprintedcavies delay effectively the drug release process and resulting in the slower release rate from5-FU-loaded MIP-PSSS/CPVA microspheres. The drug does not be released in the simulatedstomach fluid (pH=1), in the simulated intestine fluid (pH=6.8), the drug release is small, andin the simulated colon fluid (pH=7.4), the sudden delivery phenomenon will be produced,displaying an excellent colon-specific drug delivery behavior. Therefore, drug-loadedMIP-PSSS/CPVA microspheres are a new-style and high-efficient pH-delayed doublesensitive colon specific drug release systems.The adsorption abilities and mechanism of the grafted microspheres CPVA-g-PSSS forMetronidazole (MTZ) were also studies. The in vitro release behavior of the MTZ-loadedmicrospheres was also examined. The experiment results show that CPVA-g-PSSSmicrospheres possess also very strong adsorption ability for MTZ by right of electrostaticinteraction, and the adsorption capacity reaches112mg/g. The protonation degree of theamino groups in MTZ molecule decreases when pH value increases, and the electrostaticinteraction weaken, resulting in low absorption capacity. The adsorption capacity decreaseswith the rise of temperature and this reveals the character of physical adsorption. And theincrease of salinity causes the decrease of the adsorption capacity. The in vitro release experiments show the release of the MTZ-loaded CPVA-g-PSSS microspheres increases withthe pH rises, and electrostatic interaction weakens, showing pH-sensitivity.Subsequently, MTZ surface imprinting was performed on CPVA with sodium4-styrenesulfonate (SSS) as functional monomer, MTZ as template and N, N’-Methylenebisacrylamide (MBA) as crosslinking agent in aqueous solution by using ceriumsalt-hydroxyl group redox initiation system, and obtaining MTZ surface imprintedmicrospheres MIP-PSSS/CPVA. The binding property of the imprinted microspheresMIP-PSSS/CPVA for MTZ, namely drug loading ability, was mainly investigated profoundlywith static method and the binding mechanism was explored. The in vitro release behavior ofthe drug-loaded microspheres was also examined. The experimental results show that in theacidic medium, the MIP-PSSS/CPVA microspheres exhibit very strong binding ability forMTZ by driving of electrostatic interaction while the binding ability is weak for Tinidazole(TNZ) and Ornidazole (ONZ). The in vitro release of the MTZ-loaded MIP-PSSS/CPVA isnot only pH-sensitive but also time-delayed in contrast to MTZ-loaded CPVA-g-PSSS. Thesynergistic effect of strong electrostatic interaction and the spatial resistance of drug moleculediffused from imprinted cavies delay effectively the drug release process and resulting in theslower release rate from MTZ-loaded MIP-PSSS/CPVA microspheres. The release behaviorshows in simulated gastric fluid (pH=1), the drug do not be released, and in the simulatedsmall intestine fluid (pH=6.8), the drug release is smaller, whereas, in the simulated colonfluid (pH=7.4), an abrupt release will be firstly produced and then sustained and slowedrelease occur, displaying an excellent pH-delayed double sensitive colon specific drug releasesystems.