Polymer Microneedles For Controlled Transdermal Drug Delivery

Controlled drug delivery systems could be beneficial in numerous disease treatment through maintaining steady therapeutic concentration for the desired treatment duration while eliminating the need for frequent or specialized drug administration.Over the past few decades,researchers in this field incorporated the therapeutic agents within polymers to produce a range of controlled-release formulations to satisfy the treatment of different pathological and clinical conditions.Oral controlled-release formulations have been the emphasis of pharmaceutical research owing to ease of administration and cost-effective manufacturing processes,but the drug release profile is susceptible to the frequently changing gastrointestinal physiology during the practical application.Thus,for the biopharmaceuticals and drugs with a narrow therapeutic index,parenteral injections or surgical implants are typically required to attain either the desired systemic or local effect.However,the complex application process and invasive medical procedures significantly reduce the patients' compliance with medication.Guided by these motivations,this work combined the microneedle technology with drug controlled-release systems to develop a polymer microneedle-based drug delivery system that is minimally-invasive and suitable for self-administration by patients at home.Furthermore,to exploit the full potential of microneedle system for regulating drug release kinetics and improving therapeutic potency of the payloads,we focused on the development of polymer microneedle controlled-release systems through manipulating the physicochemical properties of needle matrix materials,the combination of drug molecules and the matrix materials,as well as structural design of the microneedle systems.All these studies will provide theoretical and technical support for further applications of microneedles in transdermal drug delivery.The results of this work are mainly divided into three chapters:(1)Development of single drug-loaded polymer microneedles for controlled transdermal drug releaseIn this chapter,the subcutaneous release of the preloaded drug is controlled by adjusting the matrix material of the polymer microneedles.First,the dissolvable microneedles are made out of gelatin and other FDA-approved biomaterials by using a vacuum molding process.After drying,the microneedles are strong enough for reliable skin insertion and dissolved to release drugs once contact with the tissue fluid.Guided by these results,we next sought to control the release kinetics of the incorporated drugs from the polymer microneedles by using the PVA with different molecular weights or genipin-crosslinked gelatin with different crosslinking degree.The in-vitro and in-vivo insulin release tests,as well as the hypoglycemic effect in mice show the higher molecular weight or crosslinked polymer microneedles result in characteristic controlled insulin release.(2)Development of integrated drug-loaded polymer microneedles for transdermal drug releaseGuided by the results of the previous chapter,in this chapter we developed a single integrated microneedle patch(IMP)with multiple release kinetics to provide better physiologic insulin coverage for postprandial glycemic excursion in a convenient and pain-free manner.The combination of rapid separating technique and multiple individual microneedle arrays provides the combined ability to efficiently deliver insulin into the skin within seconds and to independently control insulin release kinetics.In addition,the diabetic rats with a traditional breakfast-lunch-dinner lifestyle exhibit obvious intraday glucose fluctuations,while the hypoglycemic experiments indicate that the IMP is capable of simultaneous bolus and sustained insulin delivery to closely match the glucose rise that occurs in response to meals and efficiently minimize excessive fluctuations,suggesting the potential of this new transdermal insulin delivery system as substitutes for multiple daily injections.(3)Development of novel bio-needles with high drug loadings for controlled transdermal drug deliveryIn this chapter,we developed a novel bio-needle with high drug loading rates based on the microneedle technology,and the biodegradable drug-loaded microparticles will be introduced in the dissolving bio-needles to achieve rapid delivery of the drug carriers into subcutaneous tissues for intradermal sustained long-term drug release.The mechanical properties and drug loading experiments comprehensively determined that the fabricated bio-needle has the skin insertion ability and the maximum drug loading efficiency when the mass ratio of the loaded microparticles was 51%(w/w)to the bio-needles.Furthermore,by using the matching portable applicator,the bio-needles can be efficiently delivered into the skin within seconds,do not cause bleeding or skin infections during the application process,and the insertion site recovered barrier property within 3 h of insertion.With the in-vivo test in rats,the bio-needles are able to achieve and maintain effective drug concentrations during the treatment period,exhibiting a reliable controlled-release property.In general,comparing with the microneedle systems and traditional subcutaneous implantation,the proposed bio-needles have advantages of high drug loading and self-administrable without the traumatic surgery.