Biopharmaceuticals, such as peptides, proteins and future uses of DNA and RNA, represent a rapidly growing segment of pharmaceutical therapies [1
]. These biotechnology drugs are currently delivered almost exclusively by the parenteral route. The oral route is generally not available, due to poor absorption, drug degradation and low bioavailability. This is problematic, because parenteral administration with hypodermic needles requires expertise for delivery, can lead to transmission of blood borne pathogens due to accidental needle sticks or intentional needle reuse, and causes pain, which results in reduced patient compliance due to needle phobia [2
Given these problems, a breadth of research activity has focused on replacing hypodermic needles with alternate drug delivery methods [4
]. Transdermal drug delivery is an especially attractive alternative, because it is usually easy to use, safe, and painless [5
]. However, the tough barrier posed by the skin’s outer layer of stratum corneum has limited the applicability of this method to drugs that are hydrophobic, low molecular weight, and potent.
Micron-scale needles assembled on a transdermal patch have been proposed as a hybrid between hypodermic needles and transdermal patches to overcome the individual limitations of both injections and patches [7
]. Microneedles have been shown to be painless in human subjects relative to hypodermic needles [9
]. Unlike transdermal patches, microneedles have been successfully used to deliver a variety of large and hydrophilic compounds into the skin, including proteins and DNA. In vitro skin permeability enhancement of two to four orders of magnitude was observed for small molecules like calcein and large compounds like proteins and nanoparticles [11
]. In vivo delivery has been shown for peptides, such as insulin and desmopressin [13
]; genetic material, including plasmid DNA and oligonucleotides [15
]; and vaccines directed against hepatitis B, anthrax and Japanese encephalitis [10
]. Microneedles can be fabricated for these applications by adapting the tools of the microelectronics industry for inexpensive, mass production [19
Currently, four different modes of microneedle-based drug delivery have been investigated [7
]. These modes are:(1) piercing an array of solid microneedles into the skin followed by application of a drug patch at the treated site [11
]; coating drug onto microneedles and inserting them into the skin for subsequent dissolution of the coated drug within the skin [14
]; encapsulating drug within biodegradable, polymeric microneedles followed by insertion into skin for controlled drug release [20
]; and injecting drug through hollow microneedles [21
Among these approaches, coated microneedles are attractive for rapid bolus delivery of high molecular weight molecules into the skin, and can be implemented as a simple ‘Band-Aid’-like system for self-administration. Further, storing drugs in a solid phase as a coating on microneedles may enhance their long-term stability, even at room temperature. Consistent with this expectation, desmopressin coated onto microneedles maintained 98% integrity after 6 months storage under nitrogen at room temperature [14
]. Coated microneedles are also especially attractive for vaccine delivery to the skin, because antigens can be released in the skin to target epidermal Langerhans cells and dermal dendritic cells for a more potent immune response [22
]. As a demonstration of this, a strong immune response in guinea pigs was shown against ovalbumin, a model antigen delivered from coated microneedles [23
Despite the attractiveness of coated microneedles, a detailed investigation of the coating process has not been published. In this study, we therefore wanted to develop a microneedle coating process that elucidated issues involved in coating microneedles and to identify the breadth of applicability of coated microneedles by determining the different kinds of molecules and particles that can be coated and delivered into the skin.
This study was guided by identifying essential characteristics needed for the microneedle coating process to achieve precise dose control, safety, and the ability to coat sensitive biological molecules. The coating process should: (1) make a uniform coating as opposed to a patchy coating to provide reproducibility and dosage control, (2) limit deposition only onto microneedles and not on the base substrate for tight dosage control and minimizing drug loss during coating, (3) avoid high temperatures to maintain drug integrity, (4) use aqueous coating solution to prevent denaturing of proteins and other biological molecules, (5) achieve high drug loading per microneedle to maximize drug dosage, (6) provide good adhesion of the coating to the microneedle to prevent wiping off on the skin during insertion and (7) have rapid, or otherwise controlled, dissolution kinetics in the skin for bolus, or sustained, release.
Among the various coating processes, such as dip coating, roll coating and spray coating [24
], dip coating is particularly appealing for coating microneedles because of its simplicity and its ability to coat complex shapes. A dip-coating process typically involves dipping and withdrawing an object from a coating solution, after which a continuous liquid film adheres and dries on the object’s surface, leaving behind a uniform coating. However, dip coating has been developed to coat macroscopic objects mostly by submerging them completely within the coating solution. Because surface tension becomes dominant on the micron scale [25
], conventional dip-coating methods have difficulty controlling coating of specified sections of micron-dimensioned structures, especially when those structures are closely spaced. This study sought to addresses these limitations by developing a micron-scale, dip-coating process to coat microneedles with uniform and spatially controlled coatings using methods applicable to a breadth of drugs and biopharmaceuticals.