The Preparation Of PH-sensitive/mucoadhesive Amphiphilic Copolymer Micelles And Studies For Drug Loading

Insulin is the most effective medicine at lowering the glucose level in blood for treatment of type I diabetes.However,Frequent subcutaneous is the sole way to type 1diabetes and brings enormous pain to diabetes patients,which usually results in unstable glucose level in blood,low patient compliance and partial lipodystrophy of injecting position.Oral administration of insulin is convenient and possesses good applicability to patients,which is an ideal way of insulin administration,but taking insulin directly encounters some typical barriers like the degradation in the gastrointestinal tract(GIT)and poor permeability of intestinal membrane,resulting in low bioavailability.To overcome these barriers,various polymer with different functions as delivery carriers were developed to improve the oral bioavailability of insulin,such as hydrophobic polymers,pH-sensitive polymers,mucoadhesive polymers and so on,which could protect insulin from being degraded by enzymes in the GIT and promote the absorbtion of cells,beneficial to the increase of insulin oral bioavailability,but the oral absorption of insulin is influenced by their particle size,surface properties,and the release environment,thus there still are not the oral insulin preparations for clinical treatment on the market presently.According to the difference of gastrointestinal pH value and insulin absorption characteristics,we designed and synthesized a novel pH-sensitive/mucoadhesive amphiphilic block copolymer poly(methyl methacrylate-co-methacrylicacid)-b-poly(2-amino ethyl methacrylate)[P(MMA-co-MAA)-b-P(AEMA)],which used block polymer P(MMA-co-MAA)as the pH responsive block from the polymerization between methyl methacrylate(MMA)and methacrylic acid(MAA),a material with good pH responsivity,and poly(2-amino ethyl methacrylate)P(AEMA)as the mucoadhesive block.P(MMA-co-MAA)-b-P(AEMA)could form polymer micelles with core-shell structure in aqueous solution self-assembly,which owned lower the critical micelle concentrations(CMC).The micelles appeared the better function of pH sensitivity and the micelles particle size changed with the change of pH value,about 500 nm at pH2.0and 200 nm at pH7.4.Meanwhile,the micelles presented higher zeta potential,about40 mv at pH2.0 and 20 mv at pH7.4,which suggested micelles owned better mucoadhesion.The insulin-loaded micelles were prepared by the Self-assemblytechnique.The micelles particle size was increased by about 100 nm when insulin was loaded into the polymer micelles and changed with the change of pH value,which suggested the insulin-loaded micelles had good pH responsivity.Due to the embedment of insulin,the zeta potential of micelles was decreased,but it was still positive and keep certain mucoadhesion.The insulin release result from insulin-loaded copolymer in simulated gastric and intestinal in vitro indicated that P(MMA-co-MAA)-b-P(AEMA)could reduce the insulin release amount at pH1.2 and above 70% of insulin was released for 10 h at pH7.4.In this paper,under the instruction of chemical product engineering,we developed a novel copolymer with the pH-sensitivity and mucoadhesion functions,which was applied to the system of oral insulin delivery to overcome the degradation by gastrointestinal enzymes and bad membrane permeability,and the insulin-loaded copolymer micelles were prepared by the diafiltration method,which reduced the loss of insulin in the stomach environment effectively.Therefore,the copolymer P(MMA-co-MAA)-b-P(AEMA)has some potential in oral insulin delivery system and also provides some new ways for the oral proteins drug development.