The Research Of Key Technologies For Advanced Dissolving Microneedles As Transdermal Delivery System

Dissolving microneedles is a new type of transdermal preparation.It is safety,convenient,and has a large drug loading capacity.Currently,there is a worldwide lack of a method for preparing a female mold with hole depth over 500 ?m and have relatively fine needle shape at a relatively low cost;and lacking a evaluation method of microneedles insertion efficiency with high degree of quantification,easy operation,and low cost;lacking a systematic research and comparison of matrix materials microneedles.So the main purpose of this study is to solve the problems about the preparation method,penetration performance evaluation method,and matrix materials of dissolving microneedles.This article consists of four chapters.In the first chapter,the concept and category of microneedles were introduced,then the preparation methods,mechanical performance evaluation methods and matrix materials of dissolving microneedles were reviewed.It also pointed out the defects of the existing technologies and research contents.In the second chapter,the design and preparation technology of dissolving microneedles molds and the method of matrix injection into molds were studied.Using a modified commercial metal stamp microneedles as inverted mold,the grooved PDMS negative mold was prepared for the first time.This method avoids the influence of PDMS fluid's surface tension and air bubbles during the production process,and also solved the problem that the matrix solution gathers on the PDMS surface when the dissolving microneedles are poured.In addition,the difference between the two methods of evacuation and centrifuging when matrix solution was injected into the mold was compared.It was found that the method of centrifuging not only enabled the matrix solution to enter the mold effectively,but also eliminated bubbles effectively,which was a superior method.In the third chapter,the evaluation method of microneedles insertion efficiency was studied.Based on a monolayer parafilm,this chapter puts forward three novel testing methods.After MN insertion,parafilm integrity,characterized by electrical impedance,water leakage velocity,and dye imaging of pinhole,was used to confirm MN insertion efficiency.Meanwhile,we modified the previous method by dye imaging the pinhole.Data showed that all methods were able to reflect MN insertion efficiency to a certain extent.Among those four methods,the electrical-impedance method cannot only reflect the MN insertion efficiency quantitatively,but can also detect tiny pinholes on parafilm and could be used as a comparative testing method for insertion efficiency between different candidates for MN formulations.In the fourth chapter,according to the concept of ductile material and brittle material about dissolving microneedles matrix material proposed by the author's published review,28 kinds of matrix materials were used to prepare the microneedles.Moldability and ductile/brittleness of the microneedles were inspected,the above materials were classified into ductile/brittleness property attribution.The classification and the respective characteristics of ductil materials and brittle materials are described.Drawing on the theory of “reinforced concrete” in the field of architecture,for the first time,in the process of preparing microneedles for brittle materials,a layer of hydrophilic fibrous web was added to the backing layer of the microneedle,and it was found that the resulting microneedle sheet has better formability.However,since the fiber network skeleton does not extend into the needle body,the needle containing rate of the microneedles array produced by the brittle material has not been improved.Microneedles were preparaed by the combination of ductile /brittle,ductile / ductile,and brittle /brittle materials,and their moldability and variability were investigated.It was found that the microneedles produced by the combination of the ductile / ductile material and the brittle/brittle material are not superior to the single material in terms of moldability.Only the ductile /brittle material can achieve the synergistic effect and the obtained microneedle bahaves both advantages of ductile material and brittle material.However,not a combination of any flexible material and brittle material can be prepared composite microneedles successfully,some of the ductile / brittle materials mixed microneedle preparation process may occur flocculation or phase separation phenomenon.The results of the pressure-variability examination and SEM analysis further verified that the microneedles made of composite ductile/brittle composites have both advantages in terms of mechanical and micro level.In view of the synergistic effect produced during the composite process of ductile and brittle materials,we speculate that the Skeleton filling mechanism may exist.Ductile materials tend to have longer molecular chains and are easier to form space skeletons,while brittle materials have smaller molecular structures.If brittle materials can be filled into the framework space formed by ductile materials,making the composite,the obtained microneedles will be toughness,and not easy to break,and will not be soft and weak.In summary,this article has achieved certain results in the preparation of dissolving microneedles,the evaluation methods of microneedles insertion efficiency,the classification and comparative study of matrix materials,etc.It provides some reference for the subsequent research and development of dissolving microneedles.