Preparation Of PEGDA-based Polymer Microneedles And Their Application In Transdermal Drug Delivery

The route of administration of drugs plays a decisive role in therapeutics.Oral administration can stimulate the gastrointestinal mucosa.The majority of drugs would be inactivated by the "first pass" effect of liver.Moreover,oral administration reduces the treatment effect,and drug activity could be inhibited in the presenceof food or stomach acid.Subcutaneous injection is recognized to be efficient and accurate,but it always requires professional operation,which may cause psychological fear,infection,discomfort and other security risks.The skin covers the entire body surface,and is the largest and most accessible organ in the human body.The functionalities of skin include protection,secretion,excretion,sensation,and regulation of body temperature.It also serves as a local and systemically important drug application site.However,drugs that could penetrate the skin are usually lipophilic or with small molecules.Most locally administered drugs do not have the ability to penetrate the stratum corneum.Microneedle(length: 100 ?m-1000 ?m)with three-dimensional microstructure can pierce the stratum corneum and produce transient microchannels,which can increase the permeability and adsorption of drugs.Microneedles can reach the specified depth without stimulating nerves and blood vessels in the dermis.Various types of therapeutic molecules can be delivered into the skin in a minimally invasive manner by using microneedles.This technique can effectively avoid the "first pass" inactivation effect of liver,which is observed in oral administration,as well as the pain and fear caused by injection administration.In summary,polymeric microneedles may provide new insights to the functionalization and application of wearble therapeutic devices.This paper aims at some problems in the preparation of polyethylene glycol diacrylate(PEGDA)microneedles.Developed microneedle processing technology with universal applicability.A series of PEGDA-based microneedles were constructed using ultraviolet(UV)polymerization.Surface morphology,mechanical properties and drug release mechanism of microneedles were characterized.The main research contents and results of the paper were as follows:(1)PEGDA with good biocompatibility,adjustable mechanical properties can form refined structure by photopolymerization.,which has been widely used in drug delivery.It can release drugs through swelling in aqueous solutions.However,the current research mainly focuses on simply loading the drug in the PEGDA matrix.The drug release process was passive,and achieving controlled drug delivery was still challenging.PVP has good water solubility,safe,nontoxic and excellent biocompatibility.In this study,One-step photo-induced polymerization using a micro-patterned photomask to fabricate PEGDA/PVP microneedle arrays.PVP particles can be embedded in the PEGDA microneedle matrix through a simple photomask ultraviolet polymerization method.The dissolution of PVP may disintegrate the matrix of PEGDA,and accelerate the swelling of needle matrix to promote the drug release.Rhodamine B(RhB),as a model drug,was encapsulated in various types of microneedles to investigate the effect of PVP on the drug release performance of microneedles.A mechanical compression test was performed to evaluate the strength of microneedles using a universal test machine.The skin recovery capacity was demonstrated by applying microneedle arrays on a live mouse model.PEGDA/PVP microneedles show higher drug controlled release performance than PEGDA microneedles,which may provide a convenient and efficient route for transdermal administration.(2)Herein,we proposed a new PDMS-based micromold comprising a porous fibroin scaffold as a smart “sponge” for instantly absorbing drug-loaded liquid prepolymer during microneedle fabrication,fibroin scaffolds can direct liquid into internal cavities through capillary force spontaneously,which may significantly speed up the fabrication procedure and also improve the quality of microneedle arrays.PEGDA has good biocompatibility and FDA-approved material for biomedical uses,and its monomer can be polymerized into a solid bulky structure initiated by UV irradiation.A sustained drug release capability of PEGDA-based microneedles triggered by polymer swelling after the microneedle penetrates skin,but the drug release process was passive.In order to achieve controlled release of the drug,highly soluble sucrose was added into PEGDA solution,and the PEGDA/sucrose polymeric solution can be distributed in the mold cavity guided by the silk fibroin scaffold,silk fibroin-PEGDA/sucrose polymer microneedles(PEGDA/sucrose)can be obtained after curing by ultraviolet light.The dissolution of sucrose may lead to the PEGDA matrix to be more porous,which could accelerate the swelling of PEGDA and promote drug release.The surface morphology of the PEGDA/sucrose microneedles was characterized by FESEM.Rhodamine B(RhB),as a model drug,was encapsulated in various types of microneedles to investigate the effect of sucrosse on the drug release performance of microneedles.The mechanical properties of the microneedles were evaluated using a universal testing machine.(3)PEGDA microneedles were commonly used to encapsulate small molecule hydrophobic drugs.In order to improve the ability of PEGDA microneedles to encapsulate macromolecular hydrophilic drugs,we prepared a gelatin-sucrose film coated PEGDA polymeric microneedles.Taking advantage of the excellent film forming property of gelatin,we prepared a gelatin/sucrose blend film on the surface of PEGDA needle shaft for transdermal drug delivery.This project proposes a new method for preparing film coated microneedles.First,the hydrophilic polymer solution(gelatin and sucrose mixture)was introduced into the PDMS mold by rapid casting,and dried in ambient environment to obtain a hybrid film.Afterwards,biocompatible PEGDA solution was introduced into the previous film-coated PDMS mold,and film-coated PEGDA microneedles(Film@PEGDA)can be generated after rapid ultraviolet light-induced polymerization.In this study,bovine serum albumin(BSA)was used as a macromolecular hydrophilic drug model.The gelatin-sucrose film on the surface of the microneedles can be easily dissolved to promote drug release.(4)Microneedles destroy the stratum corneum of the skin to form microchannels for transdermal administration.If bacteria enter these microchannels,skin infections may occur.Therefore,it was necessary to keep the microneedle puncture site sterile to minimize the possibility of introducing microbial pathogens at the administration site.Photo-induced polymerization to fabricate an nanosilver-film coated PEGDA microneedles(nAg-Film@PEGDA).The research showed that nAg particles cannot be uniformly dispersed in PEGDA solution,so the method by directly adding nAg into PEGDA solution cannot obtain microneedles with good morphology.In order to solve this problem,a gelatin-sucrose coating containing nAg was prepared,and the coating was wrapped on the surface of PEGDA microneedles to obtain an antibacterial film-coated PEGDA microneedles(nAg-Film@PEGDA).The results showed that nAg can be uniformly distributed in the surface coating of PEGDA microneedles.The drugs in solid phase can retain a long-term stability.NAg was characterized by UV-Vis spectrophotometer,X-ray energy spectroscopy(EDS),transmission electron microscopy(TEM).Antibacterial activity was evaluated by using negative E.coli and P.aeruginosa.In summary,we have prepared four types of PEGDA-based polymeric microneedles andtheir physicochemical properties were investigated.The results showed that the PEGDA-based polymeric microneedles have strong mechanical strength.And the drug release rate can be regulated by customizing the composition of microneedle matrix.Moreover,PEGDA is beneficial to improve the stability of microneedles.To sum up,these PEGDA-based polymeric microneedles can provide new insights to resolve the current problems of low trandermal permeation and low stability of drugs during delivery,and woud advance the clinical commercialization of wearable drug delivery devices.