Preparation Of Phase Transition Hydrogel Microneedle Arrays For Transdermal Delivery Insulin

This study demonstrates a novel drug delivery system“phase transition hydrogel microneedle arrays”, which has the potential to deliver Insulin (including other protein, peptide drugs) across the skin in a minimally invasive way and offers sustained and controlled delivery.Biomacromolecules, including proteins, peptides, make up a large portion of all new drugs and have unique and good effects on some diseases. Although oral delivery of these biotherapeutics would be desirable, there is low bioavailability of these biomolecules administered by this route due to enzymatic degradation and poor absorption in the GI tract, as well as first-pass metabolism of the liver. As a result, most biotherapeutics are administered by frequent injection. To avoid the pain caused by frequent injection, non-invasive delivery of these drugs for long-term treatment of chronic diseases has been a long-standing objective in drug delivery field. Taking diabetes for example, to avoid the life-time long frequent injection of Insulin, the research efforts to replace injection with non-injection dosage forms started since 1921. Since then, many non-injective systems have been tested, including the inhalation delivery system developed by Pfizer which was withdrawn from the market soon as commercialization in 2006. The drop-off of Exubera reconfirmed the difficulty to deliver biomacromolecules by non-injection route.Thanks to the advances in MEMS technology, microneedles, which were designed for transdermal delivery, have provided a promising solution for cross-skin drug delivery with mild and painless skin damage. The needles may penetrate the most impermeable layer of skin (corneum) without hurting the dermis and nerves. Drug can across the skin through the micro-holes created by microneedles. In the past ten years, a series of microneedles were developed one after another, including solid microneedle made of metal and silicon, polymer microneedle. Although the principle of microneedle seems so easy, there are lots of problems and bottle-necks with the microneedle technology. The present microneedles, used for transdermal delivery, are complicated and costly in fabrication, and less biocompatible. They are too expensive as a daily disposable dosage form. The solid microneedle array was used to punch micro-holes on the skin first, and then drug solutions were dropped on the punching site. The punch-drop drug administration is, however, compromised with lack of control in dose and skin up-take of the drug. The holes punched by the micro-needle array may close after removing of the needles. Micro-needle arrays made of polymeric materials are still incapable to offer a controlled drug delivery due to the rapid dissolution of polymer. In addition, the microneedles made of silicon or metal have to be retained in the skin for long time. This may cause skin irritation. In case the needles break and leave metal or other particles in the skin, more serious skin irritation may be induced. The ideal microneedle patch should offer a comprehensive yet cost-effective solution comprising sustained and controlled release, biocompatible skin contact, durative diffusion channels and easy fabrication.In our study, the phase transition hydrogel microneedle arrays, developed by our lab, have the potential to solve all the problems above. The polymer materials used for fabrication of microneedle are the mixtures of PVA and Dextran, which are safe and biocompatible. Here, we detail the microneedle fabrication process: Insulin containing PVA and Dextran solution is casted onto female molds of microneedle array, followed by a gelling and hardening process by repeated“Freeze-Thaw”treatments. Finally, dry and remove the PVA/Dextran microneedle from female molds (the addition of Dextran may regulate the mechanical strength and the size of diffusional channel of hydrogel microneedles). For more sophisticated drug release, such as multi-pulse release, several hydrogel formulations are casted in program onto the microneedle female molds. The hydrogel formula is designed in such a way: at dry state, the needle material is in glassy state and hard enough to penetrate human skin, while after absorption of body fluid, the needles swell and turn to be hydrogel to allow therapeutics to pass through. The rate and profile of drug release may easily be adjusted by composition of the hydrogel formula, density of cross-link junctions within the hydrogel phase. The cross-linking treatment of hydrogel by Freeze-thaw cycles keeps the microneedles from dissolution by body fluid so that the microneedles stay in the skin to create a durative diffusion channels for the therapeutics loaded in the patch.As far as the female microneedle mold used in the fabrication process was concerned, we developed a very simplified method to prepare female microneedle molds using crewel needles and plaster without Micro Machining technology. Although the process was nonstandard, it was very useful for us to test the feasibility of good idea. From another perspective, the preparation of female microneedle molds made of plaster is another Creative point.