Transdermal Delivery of Vaccines and Proteins using a Hand

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Transcript Transdermal Delivery of Vaccines and Proteins using a Hand

3M Drug Delivery Systems
Transdermal Delivery of Vaccines and Proteins using a
Hand-Applied, Polymeric Microstructured Array (sMTS-hand and Press&Patch)
K.J. Hansen, D. Duan, A. Determan, J. Gysbers, D. Brandwein, C. Moeckly, P. Johnson., G. Prochnow, T. Alston, K. Siebenaler
Fast, Local Delivery of Lidocaine
sMTS versus EMLA
Abstract
Polymeric microstructured microneedle arrays that can be hand inserted (sMTS-hand) have been developed and used to demonstrate
efficacious delivery of vaccines and drugs intended for extended release. The application/wear time associated with sMTS-hand is less
than 30 seconds, approximately the same time required for syringe administration. The microstructures are less than 1 mm in length and
do not reach the nerve endings in the skin; less than 3 pounds of force is required for insertion. The array is well-tolerated in humans.
The immune response generated upon delivery of protein antigen coated on the sMTS-hand is equivalent to that achieved when the same
antigen is administered via a conventional IM route and, in some cases, may decrease the time required to achieve seroconversion.
The microneedle array has also been used as a skin pre-treatment prior to application of transdermal patches containing proteins,
peptides or water soluble small molecules (Press & Patch). With Press & Patch, the pre-treatment allows hydrophilic drugs to cross the
stratum corneum and enter the systemic circulation. The transdermal patch maintains the channels during wear and provides a reservoir
to achieve extended release of the API from the patch.
Immunogenicity and pharmacokinetic studies were conducted in-vivo to demonstrate the potential for a hand-applied, polymeric,
microstructured array to deliver molecules not typically compatible with transdermal delivery. The sMTS-hand and the Press & Patch
systems offer a simple, non-threatening way to provide efficient delivery of vaccines and a means of providing an extended release for
molecules typically confined to bolus delivery via syringe.
A tolerability study in humans using sMTS-hand with no API showed excellent tolerability to the pre-treatment. Slight erythema was
observed in a small number of subjects, but the results were transient and the skin quickly recovered.
Extended Release Delivery of Peptides
MTS Press & Patch
Parathyroid hormone, 1-34 (PTH) was coated onto
a patch that was secured to an occlusive, adhesive
patch. The coated patch was dried and stored with
desiccant until use.
Prior to patch application, the hams of swine were
clipped, shaved and washed with soap and water.
MTS arrays with 700µm tall square pyramid
structures were applied by hand, a single time, with
approximately five pounds of force. The PTH
patches were applied immediately after MTS pretreatment. In the untreated group, PTH patches
were applied to uncompromised skin. Patches
were removed after 6 hours.
Blood samples were collected prior to patch
application and at designated time point following
application. PTH levels were quantitatively
assessed using an ELISA assay.
Results show that blood levels of PTH in pigs pretreated with MTS greatly exceed those in pigs who
were not pre-treated with MTS.
3M Drug Delivery Systems, 3M Center, St. Paul, MN 55144
A hand-insertable sMTS array (sMTS-hand) has been developed for the delivery of vaccines and drugs. The application/wear time
associated with sMTS-hand is less than 30 seconds. For vaccine delivery, an integrated design of antigen coated onto the hand-inserted
array was evaluated, and the resulting immune response was equivalent to that of IM injection.
Lidocane hydrochlordie was coated onto the sMTS array (500µm tall,
square pyramid structures). Using 3M’s POC applicator system, the
array was applied to the ribs of an anesthetized swine (approx 30kg).
The array was held in place on the swine for 1 minute and then
removed. The skin was swabbed to remove drug on the surface and
the application site was biopsied. The biopsy was cut to separate the
dermal tissue from the underlying fat. The dermal tissue was
extracted and analyzed quantitatively for lidocane.
Results show that tissue levels of lidocane after 1 minute of exposure
to an array coated with 78µg of lidocane are nearly double those
measured in the tissue following a 60 minute application of EMLA
cream. The EMLA site was prepared and analyzed in exactly the
same manner as the site to which the sMTS array was applied. We
estimate that approximately 0.5 grams of EMLA were applied. At
2.5% w/w lidocane, this corresponds to an application of
approximately 12mg of lidocane, nearly 200 times more API than that
applied via sMTS.
Systemic Availability of Drugs
Delivered via 3M solid Microstructured Transdermal System (sMTS)
The 3M solid Microstructured Transdermal System (sMTS) consists of an application device which can place a
drug-coated patch onto the skin for transdermal delivery of vaccines and drugs (photo at left). The patch contains
a plastic microstructured array (diameter approximately 1cm), having up to 1300 microstructures (upper photo at
right). Depending upon the desired depth of drug delivery, microstructure heights can range from 250 – 900
hMTS:
an integrated
application,
microns. A precision coating technology is used
to place
the drug on
the upper half of the microstructures (lower
reservoir and infusion device that provides
photo at right).
sMTS-hand: a hand-applied
rapid delivery of high volume liquid
system for simple, fast, efficacious
formulations of small molecules, and
delivery of vaccines
proteins, including antibodies
delivery of small molecule salts and
proteins, offering local delivery or
sustained release
A comparison of
immune response for
model antigen (8µgovalbumin) delivered
to hairless guinea pigs
by the sMTS
integrated device,
sMTS-hand and IM
injection. Blood
samples were drawn
at 3 weeks post-prime
and 3 weeks postboost, and then tested
for antigen-specific
antibody.
Coated microstructures,
8µg (top) and 25 µg
(bottom) of antigen per
array
These data indicate that an sMTS-lidocane product may provide an
alternative to EMLA pretreatment in patients that require local
anesthesia prior to IV placement, injection or minor dermal surgeries.
Press&Patch: a 2-step system for
Immunogenicity of Antigens
sMTS and sMTS-hand vs IM Injection
Conclusions
Building on 3M’s MTS foundation, several systems have been developed that utilize a polymeric microstructured array to deliver a variety of
therapeutics, including local delivery of lidocane, intradermal delivery of vaccines and systemic delivery of peptides and proteins. MTS can
provide fast and efficacious delivery of compounds that are not usually compatible with transdermal delivery.
MTS delivery may be facilitated by use of an external applicator or require only hand application of a coated – or uncoated - microneedle
array. When used in combination with a patch, the applicator-free MTS Press&Patch technology demonstrates delivery of peptides, proteins
and small molecules not typically compatible with transdermal delivery. An sMTS array coated with a small amount of lidocane can provide
almost immediate delivery of lidocane into the skin to enable medical procedures such as minor dermal surgery and needle placement; peak
tissue levels are achieved much more rapidly than conventional lidocane delivery systems from creams or gels. These results are intriguing
when considered next to existing techniques of topical or iontophoretic application of lidocane. The sMTS-hand technology utilizes a coated
array to provide delivery of vaccines that may result in comparable, or improved immune response when considered versus a conventional
IM syringe injection. The sMTS-hand system embodies the potential for simplicity and efficacious vaccine delivery and removes the risk and
fear associated with conventional needle use.
MTS
sMTS: efficient delivery of potent
proteins, peptides and vaccines with
a fully integrated or reusable
applicator
As with all MTS technologies, these capabilities are built around a manufacturable, polymeric microstructured array, designed and
engineered using various 3M technologies and expertise.
Acknowledgments
The authors wish to thank Ken Brown, Ryan Simmers, Stan Rendon, Kevin Puckett, David Wirtanen, Lester Harrison, Kraig Kroells,
Ron Krienke, Jim Christensen, Pat Young, Joann Oesterich, Chris Webb , Mary Hopp and Tonya Grunwald
sMTS-device: a skin pre-treatment
device to penetrate the stratum corneum