Design And Application Of Glucose-regulating Materials For Transdermal Delivery Of Drugs

Diabetes mellitus,is one of the public health problems in wordwide,which seriously threatens the health of people.The clinical characters are metabolic disorders in the body with insufficient or lack of insulin secretion,resulting in elevated blood glucose levels.The traditional administration to treat diabetes is subcutaneously or intravenous inject insulin solution.However,this administration requires repeated injection,which can caused pain to the patient,inflammation and other infectious disease can occur at the site of injection.More importantly,such “direct administration” does not effectively control the blood glucose levels,the injection of insulin solution is unsatisfactory in the treatment of diabetes,making people pay attention to how to make the treatment of diabetes slightly painful and also can effectively control blood glucose levels.In recent years,microneedle transdermal delivery system has emerged as a new type of drug delivery system,which provides a non-invasive or minimally invasive route of administration.The microscopic needle is used to pierce the stratum corneum of skin,and then the drug can be break through the skin barrier into the circulation.Among this,the souble microneedle transdermal delivery system has great research prospects.Because they can completely dissolve in the body while releasing the preloaded drug,resulting in no pain or other infectious diseases.However,simple drug loaded microneedle does not achieve the control of blood glucose levels,so the drug delivery system that combines soluble microneedle integrated with multifunctional drug-loaded nanoparticles has received great attention and research.In this paper,combination of soluble microneedles and multifunctional drugloaded nanoparticles is used to prepare three different sensitive microneedle transdermal delivery system for the fluctuate of the blood glucose levels.The response release of drug and transdermal drug delivery to diabetes rats are studied.The thesis contains three pats as follows:1.Mesoporous silica nanoparticles(MSN)is firstly prepared by template method,then the amino group is introduced on the surface of mesoporous silica by modifying 3-aminopropyltriethoxysilane(APTES),and finally the hydrogen peroxide-sensitive 4-(imidazoyl carbamate)phenylboronic acid pinacol ester(ICBE)is modified on MSN.The hypoglycemic drug(insulin)and glucose oxidase are loaded in hydrogen peroxidesensitive MSN,and the insulin was sealed by the function of host-guest between ?-cyclodextrin and phenylborate.The microneedle is prepared by a micro-template method using a gel obtained by mixing hydrogen peroxide-sensitive MSN with a soluble polymer polyvinylpyrrolidone(PVP).The response properties of drug-loaded hydrogen peroxide-sensitive MSN in vitro release are investigated.The result showes that the drug-loaded MSN has significant hydrogen peroxide-sensitive behiviour of release.At the presence of high glucose concentration and glucose oxidase,the drugloaded MSN also has significant response release.The mechanical performance of asprepared microneedle is tested.The result shows that microneedles have excellent mechanical properties,and the breaking force of each microneedle can be reached 0.28 N at 500 ?m.The ability of microneedle to penetrate the skin and the release of insulin are investigated by applying a thiocyanate fluorescein(FITC)-labelled insulin microneedle patches on skin(diabetic groups and health groups).Laser confocal images show that microneedle can easily penetrated into skin tissue and quickly dissolve.FITC-insulin can be delivered deep into the skin tissue of diabetic rats,but not found they are in the skin tissue of health rats.Diabetic rats are used as diabetic model to evaluate the hypoglycemic effect of insulin-loaded microneedle in vivo.The result shows that as-prepared insulin-loaded microneedle patches have great hypoglycemic effect and the duration of drug was longer than that of the injected insulin solution.The above results indicate microneedles integrated with insulin-loaded hydrogen peroxidesensitive MSN for transdermal delivery of insulin have great potential and prospects in the treatment of diabetes.2.Mesoporous bioactive glass nanoparticles(MBGs)are prepared by sol-gel method.The hypoglycemic drugs(insulin),glucose oxidase and catalase are loaded into MBGs.pH-sensitive zinc oxide quantum dots(ZnO QDs)are adsorbed on the surface of MBGs by electrostatic interaction.Microneedle is prepared by micro-template method using a gel obtained by mixing pH-sensitive drug-loaded MBGs with PVP.The responsive ability of pH-sensitive drug-loaded MBGs in vitro release are evaluated.The result indicates that insulin-loaded MBGs have excellent performance of pHsensitive release.At the presence of high glucose concentration and glucose oxidase,insulin-loaded MBGs also have significant property of response release.The mechanical performance of prepared microneedles is tested.The result shows that microneedles have excellent mechanical property,and the breaking force of each microneedle can be reached 0.3 N at 500 ?m.The ability of skin insertion in vitro and the release of insulin are investigated by applying FITC-labelled insulin loaded microneedles to healthy rats and diabetic rats,respectively.Laser confocal images show that microneedles can be easily penetrated and dissolved quickly.FITC-labelled insulin can be delivered deep into the skin tissue of diabetic rats but can not found in the skin of healthy rats.The hypoglycemic effect of microneedles in diabetic SD rat is evaluated.The result shows that prepared microneedles have excellent hypoglycemic effect,and the duration of the drug effect is twice that of injection groups at the same dose.The risk of hypoglycemia in the prepared microneedle for healthy rats is investigated and the result shows that the as-prepared microneedle have a lower risk of hypoglycemia.The above results indicate that the prepared microneedle integrated with pH-sensitive MBGs have great prospects in the treatment of diabetes.3.In this study,mesoporous bioactive glass nanoparticles(BGNs)are prepared by co-solvent and template method.The hypoglycemic drug insulin is loaded into BGNs,and polyethyleneimine(PEI)is costed on the surface of BGNs by electrostatic interaction.The PEI,glucose oxidase and catalase are modified on the surface of BGNs under the crosslinking of glutaraldehyde to form a glucose-sensitive complex enzyme layer.Microneedles are prepared by micro-template method using a gel obtained by mixing glucose-sensitive drug-loaded BGNs with PVP.The property of responsive release in vitro of glucose-sensitive BGNs are investigated.The result shows that the drug-loaded BGNs have excellent characteristics of glucose-sensitive release.The mechanical properties of the prepared microneedles are tested.The result shows that the microneedles have good mechanical properties,and the breaking force of each microneedle can be reached 0.32 N at 500 ?m.The ability of the microneedles penetrates into skin,and the release of insulin in the skin are investigated by applying FITC-labelled insulin-loaded microneedles to healthy rats and diabetic rats,respectively.Laser confocal images show that microneedles can be easily penetrated into the skin and quickly dissolved.FITC-labelled insulin can be delivered deep into the skin tissue of diabetic rats but that is not can be found in healthy rats.The hypoglycemic effect of microneedle in diabetic rats are investigated.The result shows that the prepared microneedles have excellect hypoglycemic effect,and the duration of the drug effect is 2.2 times than that of injection at the same dose.The risk of hypoglycemia of prepared microneedles in healthy rats are investigated and the result shows that prepared microneedles have a low risk of hypoglycemia.The above results indicate that the as-prepared microneedles integrated with glucose-sensitive and drugloaded BGNs for transdermal delivery have great potential and prospects in the treatment of diabetes.