Construction Of Hyaluronic Acid Microneedles For Transdermal Drug Delivery

Transdermal drug delivery is a usual administration.However,stratum corneum is the major obstacle for most drugs to pass through the skin,especially hydrophilic drugs or macromolecular drugs.Polymer microneedles can not only puncture the stratum corneum to improve the penetration of drugs,but these microneedles also have good biocompatibility,relatively larger drug loading capacity and easy fabrication.Construction of polymer microneedles for transdermal drug delivery is one of the research focuses in the field of transdermal drug delivery system.Dissolvable polymer microneedles made of hydrophilic polymer can be rapidly dissolved by extracting skin's interstitial fluid to release the encapsulated drug,improving patient compliance.However,some drugs such as vaccine and human growth hormone,can achieve better effect with longer exposure time in the skin,which means a kind of polymer microneedles with drug sustained release is needed.Hyaluronic acid(HA)that is approved by FDA as dermal filler is not only a main ingredient of skin,but also has good biocompatibility and biodegradability.In this dissertation,HA was chosen as the matrix of polymer microneedles to fabricate HA microneedles with various drug release behaviour.The effect of HA microneedles on drug release and therapy was studied in detail.The main work of the dissertation consisted of the following two parts:1.5-Aminolevulinic acid(ALA),the precursor of protoporphyrin IX(PPIX),is generally used for photodynamic therapy(PDT).After a series of reactions in mitochondria,ALA is converted to endogenous PPIX to treat tumor in situ.However,the physicochemical properties of ALA such as hydrophilicity and potential make it difficult to penetrate into the skin to cure the subcutaneous tumor.Faced with this question,HA was utilized to fabricate tip-loaded dissolving polymer microneedle patches to deliver ALA transdermally for subcutaneous tumor therapy.ALA was mainly dispersed in the tips of microneedle arrays by two casting method.It meant this design,tip-loaded dissolving microneedles,could improve the utilization of drug and avoid waste of drug residues in the base of microneedle arrays after treatment.The fabricated HA microneedles had sufficient mechanical strength to pierce the stratum corneum to promote transdermal drug delivery.The insertion depth was about 200 ?m.After insertion,tip-loaded dissolving HA microneedles were rapidly dissolved to release the encapsulated ALA.Microneedles were dissolved approximately 75%of their initial height after insertion for 4min.The released ALA bypassed the stratum corneum through the microchannels created by microneedles and was then converted to endogenous PPIX to treat the subcutaneous tumor in situ.This tip-loaded dissolving HA microneedles improved the transdermal permeation and utilization of ALA,which dramatically enhanced the therapeutic efficacy of photodynamic therapy(PDT)for the subcutaneous tumor compared with injecting ALA through caudal vein.The inhibition efficacy of tip-loaded dissolving HA microneedles was up to 97%.In addition,the skin had good recovering ability after microneedle treatment.2.To make full play of the effect of some drugs like vaccine and human growth hormone,a kind of HA microneedles with separable and crosslinked tips was created.Methyacrylated HA(Me-HA)was firstly synthesized to introduce double bond to serve as cross-linking points.Then Me-HA and HA(Mw?10 kDa)were utilized to fabricated the HA microneedles with separable and crosslinked tips.Rh 6G was used as a model drug and mainly dispersed in the tips by casting mathod,which could improve the utilization of drug and avoid waste of drug residues in the base of microneedle arrays after treatment.The HA microneedles with separable and crosslinked tips had enough mechanical strength to puncture the stratum corneum to improve transdermal drug delivery.Results from mechanical compression test showed the force reached at least 0.44 N/Needle when the displacement was 200 ?m.After tips soaking for 2 min,water rapidly dissolved the junction between crosslinked tips and no crosslinked base to make the crosslinked tips separate.The separated and crosslinked tips continued to swell by extracting water to extend drug release.These results served as a proof-of-concept of polymer microneedles with separable and crosslinked tips.HA microneedles with various drug release behaviour provided a new idea for transdermal drug delivery.