Devices to enable transdermal delivery of vaccines and biopharmaceuticals
Abrasion and microporation + patch technologies.
Several transdermal or intradermal delivery devices have been developed in an effort to access the unique delivery characteristics
associated with the skin. Most of these devices are built primarily around a mechanism for mechanically disrupting the barrier
properties of the stratum corneum. Transdermal delivery of vaccines has been demonstrated via a simple device that uses mild
abrasion to disrupt the stratum corneum. Following pretreatment with an abrasive strip, a patch containing a vaccine or a
vaccine adjuvant is applied over the treatment site (36, 37). The utility of this technology has been demonstrated clinically
for the delivery of a traveler's diarrhea vaccine (37) and a heat-labile enterotoxin that act as antigen and adjuvant, respectively
Other technologies take a slightly more ordered approach to disrupting the stratum corneum. There are several microporation
technologies that place discreet holes into the skin applying a drug-delivery patch. These technologies may use thermal energy
(38), radiofrequency (39), or mechanical disruption with microprojections (40, 41) to create channels in the stratum corneum.
Figure 7 shows a histological cross section of guinea pig skin following application of microprojections designed to breach
the stratum corneum.
Figure 7: Cross-sectional view of hairless guinea pig skin (stratum corneum, pale pink), epidermis (purple), and dermis (dark
pink) following application of polymeric microprojections. (FIGURE 7 IS BY J. GYSBERS/D. BRANDWEIN/COURTESY AUTHOR)
When followed by application of a transdermal patch, the microporation technologies facilitate enhanced delivery of hydrophilic
drugs and peptides such as vaccines, interferons, insulin, growth hormone, and parathyroid hormone (38–44).
Coated microneedle technologies. There are several technologies in development built around the concept of coating a vaccine or a drug onto solid microneedles.
Upon insertion, the drug is released from the microneedle into the epidermis or dermis. A Phase II clinical study has been
completed with a solid microneedle device coated with PTH. A dose of 20–60µg of drug was coated onto the arrow-shaped blades,
each of which was 190 µm long (45). The device was worn by the patient for 30 min. Over the course of the 6 months study,
patch application was well-tolerated, and the resulting pharmacodynamic profile compared favorably with that achieved following
SC injection of the same drug (46).
Other coated microneedle technologies have been used to deliver vaccines, vaccine adjuvants, small molecules, peptides, and
proteins (47–50). Generally, coating capacity is limited to a few hundred micrograms, so coated microneedle technologies are
targeted for the delivery of potent drugs or vaccines. Release of drugs from the microneedles into the epidermis/dermis can
be highly efficient and very fast. Figure 8 shows a release profile for the delivery of 18 µg of ovalbumin applied via a solid
microneedle array in swine where complete delivery (95% of the coated protein) is achieved in thirty seconds (12).
Figure 8: Release profile for ovalbumin (ova) coated on solid microneedles from Hansen et al. (Ref. 58).
Hollow micro- or minineedle technologies.
Technologies that facilitate drug delivery using hollow micro (< 1mm) or mini (> 1mm, < 2mm) needles are becoming more common.
A microinjection system designed around a 1.5mm short-bevel minineedle (51) was used to deliver 100µL of inactivated influenza
vaccine to healthy adults in two separate studies. The vaccine administration was both well-tolerated (52) and demonstrated
dose-sparing performance. Nine micrograms of antigen administered intradermally had comparable immunogenicity to 15 µg administered
by a traditional IM injection (53).
A hollow microneedle delivery device has been used to deliver 100–200 µL of influenza vaccine into the intradermal space.
Immunogenicity was evaluated relative to subjects receiving a 500 µL IM injection of the same vaccine. The microneedle-based
delivery system compared favorably with the IM injection despite the reduction in delivered antigen dose (54).
Systemic delivery of APIs has also been accomplished using hollow microneedle systems, though human data collected with these
systems is not nearly as prevalent as for vaccine delivery. Using a minineedle-based experimental system powered by a syringe
pump, intradermal delivery of up to 250 µL of various API formulations has been tracked via PK profiles in swine (27). In addition to demonstrating the viability of ID delivery for therapeutic proteins, this work
has done much to demonstrate the role of lymphatic uptake in ID delivery.
Another study using a minineedle-based experimental system found that patients exhibited excellent glycemic control for diabetes
and reported a favorable patient experience when needles were inserted 1mm into the skin (using rotary drilling device) for
insulin delivery (28). Diabetic subjects received up to 300 µL of a 50 U insulin solution (50 U/mL). Although a small study,
the work clearly demonstrates the utility of microneedles and the compatibility of the dermis for delivery of biopharmaceuticals.
Further emphasizing this potential, an integrated hollow microneedle patch and delivery system for insulin has been developed
and characterized in vivo (55).
A hollow microneedle device designed for higher volume delivery (1-2 mL) has been developed and tested in preclinical studies.
A microneedle array consisting of 18 hollow microneedles is inserted into the skin, and liquid formulations are delivered
into the intradermal space via a mechanical spring. Figure 9 shows a picture of the hollow microneedle array.
Figure 9: Polymeric hollow microneedle. (FIGURE 9 IS BY R. KRIENKE/COURTESY OF AUTHOR)
The system is designed for self-application and can be worn by the patient during delivery (56, 57). Despite the high delivery
volume, delivery of placebo formulations into humans does not cause discomfort (58).
Delivery to the skin, a specialized organ long targeted for delivery of vaccines, is blossoming into a new frontier for expanded
application for vaccine delivery and for delivery of biotherapeutics. An increased understanding of the potential advantages
associated with ID delivery and a growing number of components and devices with demonstrated utility around meeting the delivery
challenges for these large classes of drugs have fueled interest in broader commercial application of ID delivery techniques.
The ID devices discussed here have the potential to provide the comfort and convenience that meet the emotional needs of patients
along with the delivery performance that address more fundamental therapeutic needs for many biotherapeutics.
Kris J. Hansen, PhD, is the MTS Technology and Product Development Manager at 3M Drug Delivery Systems, 3M Center, Bldg 260-3A-05, St. Paul, MN
55144, tel. 651.733.-2062, fax 651.733.3512,