Design And Evaluation Of Environment-Sensitive Of Hydrogel Modified By β-cyclodextrin As Novel Drug Delivery System

β-cyclodextrin（β-CD） has a torus structure characterized by a hydrophilic exterior and a hydrophobic cavity.Furthermore,β-CD is well known for its ability to bond with suitably sized drugs within their hydrophobic cavity,thereby changing the physicochemical properties of the drug. Because of this unique behavior,β-CD and its derivatives includingβ-CD containing polymers have been studied extensively in many research fields such as drug delivery system.When incorporatingβ-CD to polymer,the hydrophilic property ofβ-CD may vary the phase transition temperature of polymer;the rigid structure and inclusion property ofβ-CD may adjust the swelling ratio and the drug release ratio of polymer.It is found that the incorporation ofβ-CD into polymeric drug delivery systems could improve the drug-carrier interaction and as a result,the mechanisms of drug release may be modified.Based on this premise,we examined a series of hydrogel,with a good combination of pH and temperature sensitivity and ability for molecular inclusion.When synthesized and used as a drug carrier,the hydrogels allows manipulation of drug loading and release kinetics,facilitating formulation of more advanced drug delivery system.Firstly,we focused on using water solubleβ-cyclodextrin polymers（β-CDP_S） with different cross-linking degree（CLD） as carriers to form inclusion complexes of drug for examining the effects of structural and compositional factors on controlling drug loading and release behaviors.A series ofβ-CDP_S with different CLD were prepared under alkaline conditions using epichlorohydrin （PEI） as a cross-linking agent by controlling the reacting condition.The structure ofβ-CDP was characterized by FT-IR,DSC,X-ray and ¹³C-NMR.Theβ-CDP_S were systemically characterized for the relation between the CLD and the drug loading,the drug release and the drug release kinetics. The results indicated that theβ-CDP still retained original cavity structure ofβ-CD.The CLD inβ-CDP played a critical role in the drug loading and release,increasing the CLD resulted in reduction of drug loading,but increase of drug release.The experiment has demonstrated thatβ-CDP_S with different CLD have different drug loading and release characteristics.By choosingβ-CDP as drug carrier,the drug loading and release may be controlled through varying the CLD of β-cdp.Secondly,a reactiveβ-cyclodextrin（β-CD） based monomer carrying vinyl carylboxic acid functional groups was synthesized by reaction ofβ-CD with maleic anhydride（MAH）.Through graft copolymerization of the monomer with acrylic acid（AAc）,a novel hydrogel, Poly（β-CD-g-AAc） hydrogel with molecular inclusion function and pH-sensitivity.was prepared by free radical polymerization using a redox system as the initiator in an aqueous solution.The structure and properties were characterized by FT-IR,¹³C-NMR and elemental analysis.The equilibrium swelling ratio（ESR） was tested at different pH.The results indicated that the ESR of the Poly（β-CD-g-AAc） hydrogel presented marked variations following the change of pH,and functioned in a transition region when pH ranged from 4.5 to 5.5.Using drug Ketoprofen as a model molecule,the drug release from the poly（β-CD-g-AAc） hydrogel in pH 7.4 medium was higher than that in a medium with a pH 1.4.The drug release from the poly（β-CD-g-AAc） hydrogel at a low content ofβ-CD was obtained comparing at high content ofβ-CD.When pH was changed across both simulated gastric and intestinal pH conditions,reversible pH-sensitive drug release behavior was observed.A positive thermo-responsive hydrogel composed of poly（acrylic acid）-graft-β-cyclodextrin Poly（β-CD-g-AAc） and poly（acrylamide）（PAAm）,was synthesized using sequential interpenetrating polymer networks（IPN） method for the purpose of improving its loading and release of drugs.The structure and properties of the Poly（β-CD-g-AAc）/PAAm hydrogel（IPN hydrogel） were characterized by FT-IR,DSC and swelling measurements.FT-IR studies showed the IPN hydrogel is primarily composed of an interpenetrating polymer network of Poly（β-CD-g-AAc） and PAAm.The data of DSC and swelling measurement indicated that the phase transition temperature(T_pt) or upper critical solution temperature（UCST） of the IPN hydrogel was approximately 35℃.By measuring the temperature dependence of the swelling,an increase in UCST and nor -sensitivity to change in salt concentration were observed for the IPN hydrogel compared with normal PAAc/PAAm hydrogel（withoutβ-CD）.Furthermore,the swelling/deswelling kinetics of the IPN hydrogel also exhibited improved controllable response rate compared with normal PAAc/PAAm hydrogel.Ibuprofen（IBU） was chosen as the model drug for examining its loading and release from the IPN hydrogel.The experimental data proved that the IPN hydrogel provides a positive drug release pattern and the IBU released faster at 37℃than that of 25℃,and an improved drug loading and controlled release could be achieved by the IPN hydrogel when compared with the normal PAAc/PAAm hydrogel. In vivo study of the ketoprofen/poly（β-CD-g-AAc） complex was carried out using healthy rats. The blood samples were withdrawn periodically and analyzed for its drug content by HPLC method. With the ketoprofen/β-CD complex and ketoprofen PBS solution as the references,the pharmacokinetics of ketoprofen/Poly（β-CD-g-AAc） complex in rats was investigated.The pharmacokinetics parameters were obtained from in vivo administration,by which the t_max and C_max of ketoprofen/Poly（β-CD-g-AAc） complex were determined in comparing with ketoprofen/β-CD complex and ketoprofen PBS solution,and the results showed that the AUC and C_max of ketoprofen/Poly（β-CD-g-AAc） complex has no significantly difference as compared to ketoprofen/β-CD complex in the same dose,but the t_1/2 and t_max of the former was increased than the latter.The AUC and C_max of ketoprofen/ Poly（β-CD-g-AAc） complex significantly increases as compared to ketoprofen PBS solution in the same dose,and t_1/2 and t_max of the former were also increased than the latter.Next,to investigating the thermo-sensitive property of the Poly（β-CD-g-AAc）/PAAm hydrogel and its controlled release effect as implant.The insulin was selected as model drug to evaluate the thermo-sensitive release effect in vivo.The result indicated that the Poly（β-CD-g-AAc）/PAAm hydrogel could result in sustain release of insulin through implant in healthy rats,and also demonstrated that hydrogel could protect the activity of insulin to some extent due to it decrease the opportunity of contact with the protease.When carry out the heating stimulate in the position of where the Poly（β-CD-g-AAc）/PAAm implanted,the result indicated that the serum glucose level is decreased obviously compare with the normal temperature. The results demonstrated that the drug released from the Poly（β-CD-g-AAc）/PAAm hydrogel could be adjusted by environmental temperature stimuli and temperature dependent release behavior was observed.