Non-invasive delivery of protein and peptide therapeutics has been a long-standing objective in pharmaceutical development. Taking diabetes for example, to avoid the life-time long frequent injection, the research efforts for noninvasive routes to replace injection started as earlier as 1921. Since then, many non-injective strategies have been examined, including the inhalation delivery system developed by Pfizer and Nekerta which was withdrawn from the market as soon as commercialization. The recent drop-off of the Pfizer-Nekerta product, Exubera, (together with GlaxoSmithKline's recent failure in developing oral insulin with Nobex) have proven again that to deliver hydrophilic drugs including protein-peptides across our natural biological barriers is a daunting task.
Thanks to the advances in Micro-Electro-Mechanical Systems (MEMS) technology, microneedles, an array of needles several hundreds micron in length, became available. The availability of microneedle array has provided a promising solution for cross-skin drug delivery without pain feeling and skin damage. The needles may penetrate the most impermeable layer of skin (corneum) without hurt the dermis and nerves. Theoretically, a transdermal patch equipped with such an array of the hollow micro-needles to penetrate corneum and with a drug reservoir to store therapeutics may be an idea solution for transdermal delivery of hydrophilic agents. From a practical point of view, however, micro-needle arrays made by MEMS technology are too expensive as a daily disposable dosage form. For extended drug delivery, the metal needles have to be retained in the skin for pro-longed period of time. This may cause skin irritation and delay the recovery of skin punched holes by the needles. In case the needles break and leave metal or other inorganic particles in the skin, more serious skin irritation may be induced. In addition, protein therapeutics stored in the reservoir in solutions state may have stability problem when they are attached on skin at body temperature.
To reduce cost and simplify microneedle fabrication process, arrays with solid needles made of silicon, metals, polymers and sugars were used for transdermal delivery of drugs. A solid microneedle array was used to punch microholes on the skin first, then drug solutions were dropped on the punching site immediately after the microneedle array was removed. The punch-drop type of drug administration is, however, compromised with lack of control in dose and skin up-take of the drug. The holes punched by the microneedle array may close after removing of the needles so that drug diffusion across the skin may be terminated as incident.
Fabricating microneedle arrays using polymeric materials such as polylactic acid (PLA), polyglycolic acid (PGA), polylacitc-co-glycolic acid (PLGA), cellulose, amylopectin, maltose, cross-linked polyvinyl pyrrolidone (PVP) is a reasonable strategy to improve biocompatibility of the patch. These systems, however, are still incapable to offer a sustained or controlled release drug delivery. Microneedle arrays made of PLA, PGA or PLGA may contain no drug and are used in the same way as the solid metal needles: to punch microholes on the skin, followed by spreading drug solutions on the punching site. The problem by incident closing of the microholes remains. These microneedle array systems may also be fabricated with drug load in the matrix of needles. Drugs may be release subcutaneously by gradual degradation of the polymer of which microneedles are formed. However, degradation of PLA, PGA and PLGA is often too slow to deliver drug at required rate. In addition, loading proteins in a hydrophobic matrix may cause the macromolecules to denature. Furthermore, after degradation of the microneedles (made of the degradable polymers), the trans-corneum channels will no long exist so that only the drugs loaded in the needle matrix have the chance to be delivered.
Microneedle arrays made of cellulose, amylopectin, maltose cross-linked PVP are water soluble and contain drugs in the body of the needles. Drugs are delivered when the micro-needles are dissolved by body fluid. This type of microneedle arrays offer a well-defined dose of drug, but are not able for a sustained or controlled delivery over a prolonged period of time since the holes may close after the needles are dissolved. There has yet to be a microneedle array system that provides sustained and controlled transdermal drug delivery to date.