Design On Microneedle Systems For Transdermal Delivery Based On Thermal-induced Phase Change Materials

At present,diabetes mellitus,as one of the common metabolic diseases,has become an epidemic trend in the world.The prevalence of diabetes mellitus is rising rapidly,which seriously threatens human health.The effective treatment of diabetes has gradually been the focus of attention in medical circles.A great progress has been made in oral administration or subcutaneous injection,which as one of the main treatment methods.However,the drug transport barriers in oral administration and the physical or mental suffering in repeated injection,have greatly limited the development of these drug delivery methods.In recent years,microneedle transdermal drug delivery system as a new drug delivery system has attracted a great attention.The microneedle can penetrate the outermost layer of skin tissue（cuticle）painlessly and minimally,thereby promoting the release of loaded drug for achievement of effective drug administration.However,blood glucose levels should to be stable for a long time in the normal range（80-120 mg/dL on an empty stomach）for maintaining the normal functioning of our body.In this thesis,microneedle transdermal drug delivery systems with active administration were developed by using different phase change materials as release switches with electrothermal or near-infrared light（NIR）as responsive-trigger,to achieve accurate control of blood glucose levels.The thesis is consisted of three parts listed as following:1.The electrothermal triggered ablation separable microneedles were prepared by a two-step method with polycaprolactone（PCL）as a phase-change tip material while polyvinyl alcohol/polyvinylpyrrolidone（PVA/PVP）as a substrate material.When the microneedle is applied to the skin,the water-soluble substrate will be dissolved after an absorbtion of interstitial fluid,thereby embedding the PCL tip in the skin tissue as a warehouse of metformin.And the drug-loaded tips will be a flow dynamic from solid phase by an electrothermal triggering to achieve the release of loaded drug.The morphology of microneedles was characterized by digital microscope and scanning electron microscope（SEM）,and the microneedls displayed a distinct two segment structure on needle body.Their mechanical properties were analyzed by a universal testing machine,and microneedles showed an excellent mechanical strength which enough to penetrate the skin.The thermal ablation properties of PCL tip were studied by an infrared thermography.The data showed that PCL tip was sensitive to heat and the behaviors of circulatory thermal ablation was observed as well.Using rhodamine6G as a model drug,the drug diffusion behaviors from drug-loaded microneedle tips into skin tissues were investigated by laser scanning confocal microscopy（LSCM）.The data showed that rhodamine 6G gradually diffused to deeper tissues after electrothermal triggering.The release behavior of loaded metformin from microneedles in vivo was studied through the establishment of type II diabetic animal model.The results indicated that PCL microneedle transdermal drug delivery system exhibited more durable and effective than subcutaneous injection in hypoglycemic effect.2.A near-infrared phototriggered thermal ablation separable microneedles were prepared by a two-step method with Cu₇S₄ as the photothermal conversion factor and lauric acid/polycaprolactone（LA/PCL）as the microneedle tip material while PVA/PVP as the substrate material.Due to a photothermal conversion of Cu₇S₄,the drug-loaded phase change materials（PCM）microneedle tips were rapidly melted by a near-infrared（NIR）irradiation,resulting in a phase transition from solid state to flow dynamics of PCM to release the loaded drug of metformin.The results of transmission electron microscope（TEM）,SEM and X-ray diffraction（XRD）indicated that the Cu₇S₄nanoparticles were prepared successfully.The methyl thiazolyl tetrazolium（MTT）results showed that Cu₇S₄ nanoparticles had a good biocompatibility.The phase transition temperature range of PCM was determined by a differential scanning calorimetry（DSC）analysis.The correlative experimental results showed that PCM microneedles had an obvious two-stage structure with a good mechanical strength and an excellent photothermal conversion property.Drug release analysis results in vitro and in vivo showed that PCM microneedle transdermal drug delivery system could control the release of metformin via near-infared light triggering.3.Photosensitive drug loading PDA/LA-Met/HMSN composite nanoparticles were synthesized using metformin（Met）as target drug,hollow mesoporous silica（HMSN）as drug warehouse,phase change material of LA as drug release switch and polydopamine（PDA）as photothermal factor.The results of TEM,SEM,fourier transform infrared spectroscopy（FTIR）,DSC and Brunner-Emmet-Teller（BET）showed that the drug-loaded nanocomposite particles（NCs）were successfully prepared and exhibited a good biocompatibility by MTT analysis.PVP soluble microneedles containing NCs were prepared with PVP as substrate material.When PVP microneedles were applied to the skin,the drug-loaded NCs were firstly released into the skin due to an interstitial fluid action,and then the loaded metformin would be released form HMSN under a near-infrared irradiation.The datas showed that PDA/LA-Met/HMSN nanoparticles had an excellent photothermal conversion effect and drug encapsulation ability.Drug release analysis in vitro and in vivo indicated that the PDA/LA-Met/HMSN NCs polymer microneedle transdermal drug delivery system could control the drug delivery of metformin and had hypoglycemic effect on diabetes.