3M Drug Delivery Systems Transdermal Delivery of Vaccines ......3M Drug Delivery Systems Transdermal...
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K.J. Hansen, D. Duan, A. Determan, J. Gysbers, D. Brandwein, C. Moeckly, P. Johnson., G. Prochnow, T. Alston, K. Siebenaler 3M Drug Delivery Systems, 3M Center, St. Paul, MN 55144 A hand-insertable sMTS array (sMTS-hand) has been developed for the deli veryof vaccines and drugs. The application/wear time associated with sMTS-hand is l ess than 30 seconds. For vaccine del ivery, an i ntegrated design ofantigen coated onto the hand-inserted array was evaluated, and the resul tingimmune response was equi valent to that of IMinjection. Building on 3M’s MTS foundation, several systemshave been developed that util ize a polymeric microstructured array to del iver a vari ety of therapeutics, including l ocal deli very of lidocane, intradermal delivery ofvaccines and syst emic deli veryof pepti des and prote ins. MTS can provide fast and efficaci ous de livery of compounds t hat are not usually compatibl e with transderma l del ivery. MTS delivery may be facili tated by use of an externa l appl icator or requi re only hand appli cati on of a coated – or uncoated - microneedl e array. When used in combination with a patch, the appli cator-freeMTS Press&Patch technology demonstrat es del ivery of peptides, prote i ns and small molecul es not typi caly compati ble with transdermal delivery. An sMTS array coated with a sma ll amount oflidocane can provide almost immediate delivery of l idocane i nto the ski n to enable medical procedures such asminor dermal surgery and needle p lac ement; peak tissue levels areachi eved muchmore rapi dlythan conventional lidocane deli very systems f rom creams or gels. These resul ts are i ntrigu ing when considered next to existing techni quesof topi cal or iontophoretic appl icat ion oflidocane. The sMTS-hand technol ogy ut ilizes a coated array to provide delivery of vaccines that may result in comparable, or improved i mmune response when considered versus a conventiona l IM syringe injecti on. The sMTS-hand system embodi es the potential for simplicity and effi cacious vaccine delivery and removes t he risk and fear associated with convent ional needl e use. As with all MTS technologies, these capabi lities are built around amanufacturabl e, pol ymeri c mi crost ructuredarray, designed and engineered using vari ous 3M technolog ies and expertise. Polymeric microstructured mi croneedle arrays that can be hand inserted (sMTS-hand) have been developed and used to demonstrate efficacious deli very of vaccines and drugs i ntended for extended release. The appli cati on/wear time associ ated with sMTS-hand is l ess than 30 seconds, approximately the same ti me requ ired for syringe admi nistration. The mi crostructures are less than 1 mm in l ength and do not reach the nerve end ings in the ski n; less than 3 poundsof force is required for insertion. The array is well-tolerated in humans. The immune response generated upon delivery ofproteinantigen coated on t he sMTS-hand is equi valent to that achi ev ed 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 ski n pre-treatment pri or to app lication of transdermalpatches containi ng prot eins, peptides or water solublesmal mol ecul es (Press & Patch). With Press & Patch, the pre-treatment alows hydrophi lic drugs t o cross the stratum corneum and enter the system ic circu lation. The transdermal pat ch ma intai ns the channels duringwear and provides a reservo ir to achieve extended release of the API from the patch. Immunogenicity and pharmacoki netic stud ieswere conducted i n-vivo to demonstrate the potenti al for a hand-applied, pol ymeri c, microstructured array to deliver mol ecul es nottypi call y compati ble withtransdermal de livery. The sMTS-hand and the Press & Patch systems offer a si mple,non-threat ening way to provide efficient de livery of vaccines and ameans of providing an extended release for molecules typically conf ined to bolus del ivery via syri nge. A tolerability study in humansusing sMTS-hand with noAPI showed excelent to lerabi lity to the pre-treatment. Slight erythema was observed in a small number of subjects, but the results were transi ent and the skin quickly recovered. The 3M solidMicrostructuredTransdermalSystem (sMTS) consists of anappl ication devi cewh ichcanplacea drug-coated patchontotheski n for transdermaldel ivery of vaccines and drugs(photoat l eft). The patchcontains a plastic microstructured array(diameter approximatel y 1cm),havingup to1300 m icrostructures(upper photoat right). Depending upon the desired depth of drugdeli very, m icrostructure hei ghtscanrange from250 –900 microns. A preci sioncoatingtechnology i s usedto place thedrug on the upper half of the m icrostructures (l ower photo at right). 3M Drug Delivery Systems Transdermal Delivery of Vaccines and Proteins using a Hand-Applied, Polymeric Microstructured Array (sMTS-hand and Press&Patch) Systemic Availability of Drugs Delivered via 3M solid Microstructured Transdermal System (sMTS) Extended Release Delivery of Peptides MTS Press & Patch Fast, Local Delivery of Lidocaine sMTS versus EMLA Abstract Lidocane hydrochlord ie was coatedonto the sMTS array (500 µ m ta ll, square pyramid structures). Using 3M’ s POC app licator system, the array was applied to the ribs of an anesthetized swine (approx 30kg). The array was held in place on the swinefor 1 mi nute and then removed. The skin was swabbed to remove drug on the surfaceand the application si te was bi opsi ed. Thebiopsy was cut to separate the dermal tissue from the underlyingfat. Thedermal tissue was extracted and analyzed quantitati vel y for li docane. Results show that tissue leve ls of lidocaneafter 1 m inute of exposure to an array coated with 78µg of l idocane are nearly doubl e those measured in the tissue folowing a60 mi nute applicationof EMLA cream. The EMLA site was prepared and analyzedin exactl y the same manner as the si te to whi ch the sMTS array was app lied. We estimate that approximately 0.5 grams of EMLA were appl ied. At 2.5% w/w lidocane, this corresponds to an appli cati on of approximately 12mgof lidocane, nearly 200 t imes moreAPI than that applied via sMTS. These data indicate that an sMTS-lidocaneproduct mayprovide an alternative to EMLA pretreatment inpatients that requireloca l anesthesia prior to IV placement, inj ecti on or mi nor dermal surgeries. Acknowledgments The authors wis h to thank Ken Brown, Ryan S immers, St anRendon,Kevin Puck ett, Dav i d Wi rtanen, Les ter Harri s on, Kraig K roe ll s, Ron Krienke, Jim Chri s tensen, PatYoung, Joann Oesteric h, Chris Webb ,Mary Hoppand TonyaG runwal d A comparison of immune response for model antigen (8µg- ovalbumin) delivered to hairless guinea p i gs by the sMTS integrated device, sMTS-hand and IM injection. Blood samples were drawn at 3 weeks post-prime and 3 weeks post- boost, and then tested for antigen-specific antibody. Immunogenicity of Antigens sMTS and sMTS-hand vs IM Injection Conclusions Coated microstructures, 8µg (top) and 25 µg (bottom) of antigen per array MTS hMTS: an integrated appli c ation, reservo ir and infusi ondevice t hatprovides rap id delivery of hi ghvo lumeliquid formu lati ons of small mol ecules,and pr otei ns, i ncl ud ing antibodies sMTS: efficient de li veryofpotent proteins, pepti des andv ac cines w i th a fully int egrated orreusab le applicator Press&Patch: a 2-step syst em for delivery of smal mol ecule s a lts and proteins, oferi nglocal de livery or sustained rel ease sMTS-device: a skin pre-t reat ment device topenetratethestratum corneum sMTS-hand: a hand-appli ed system for si mp le,fast, effi c ac ious delivery of vaccines Parathyroid hormone, 1-34 (PTH) was coated onto a patch that was securedto an occlusive, adhesive patch. The coated patch was dried and stored w ith desiccant until use. Prior to patch application, the hamsof swinewere clipped, shaved and washedwith soap and water. MTS arrays with 700µm tall square pyram id structures were applied by hand,a single ti me, w ith approximately five pounds of force. The PTH patches were applied immediately after MTS pre- treatment. In the untreated group, PTH patches were applied to uncompromi sedski n. Patches were removed after 6 hours. Blood samples were coll ected prior to patch application and at designated ti me poi nt folowing application. PTH levels were quanti tatively assessed using an ELISA assay. Results show that blood levels of PTH in pi gs pre- treated with MTS greatly exceed those inpigswho were not pre-treated with MTS.
Transcript of 3M Drug Delivery Systems Transdermal Delivery of Vaccines ......3M Drug Delivery Systems Transdermal...
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K.J. Hansen, D. Duan, A. Determan, J. Gysbers, D. Brandwein, C. Moeckly, P. Johnson., G. Prochnow, T. Alston, K. Siebenaler 3M Drug Delivery Systems, 3M Center, St. Paul, MN 55144
A hand-insertable sMTS array (sMTS-hand) has been developed for the delivery of vacc ines and drugs. The application/wear time associated with sMTS-hand is less than 30 seconds. For vacc ine 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.
Building on 3M’s MTS foundation, several systems have been developed that uti lize a polymeric microstructured array to deliver a variety of therapeutics, inc luding local delivery of l idocane, intradermal delivery of vaccines and systemic delivery of peptides and proteins. MTS can prov ide fast and efficac ious delivery of compounds that are not usually compatible with transdermal delivery.
MTS delivery may be fac il itated 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 l idocane can provide almost immediate delivery of lidocane into the sk in to enable medical procedures such as minor dermal surgery and needle placement; peak tissue levels are achieved much more rapidly than conventional l idocane delivery systems from creams or gels . These results are intriguing when considered next to ex isting techniques of topical or iontophoretic application of l idocane. The sMTS-hand technology uti l izes a coated array to prov ide 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 s implicity and efficacious vacc ine delivery and removes the risk and fear associated with conventional needle use.
As with all MTS technologies, these capabil i ties are built around a manufacturable, polymeric microstructured array, des igned and engineered us ing various 3M technologies and expertise.
Polymeric microstructured microneedle arrays that can be hand inserted (sMTS-hand) have been developed and used to demonstrate efficac ious delivery of vacc ines and drugs intended for extended release. The application/wear time associated with sMTS-hand is less than 30 seconds, approx imately 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 sk in; 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 seroconvers ion.
The microneedle array has also been used as a sk in 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 hydrophil ic drugs to cross the s tratum 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.
Immunogenic ity and pharmacokinetic s tudies were conducted in-v ivo 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 s imple, non-threatening way to provide efficient delivery of vaccines and a means of providing an extended release for molecules typically confined to bolus delivery v ia syringe.
A tolerabil i ty s tudy in humans us ing sMTS-hand with no API showed excellent tolerabil i ty to the pre-treatment. Slight ery thema was observed in a small number of subjects , but the results were trans ient and the skin quickly recovered.
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 microns. A precision coating technology is used to place the drug on the upper half of the microstructures (lower photo at right).
3M Drug Delivery Systems
Transdermal Delivery of Vaccines and Proteins using a Hand-Applied, Polymeric Microstructured Array (sMTS-hand and Press&Patch)
Systemic Availability of Drugs Delivered via 3M solid Microstructured Transdermal System (sMTS)
Extended Release Delivery of Peptides MTS Press & Patch
Fast, Local Delivery of Lidocaine sMTS versus EMLAAbstract
Lidocane hydrochlordie was coated onto the sMTS array (500µm tall, square pyramid s tructures). Us ing 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 sk in was swabbed to remove drug on the surface and the application s ite was biops ied. The biopsy was cut to separate the dermal tissue from the underlying fat. The dermal tissue was extracted and analyzed quantitatively for l idocane.
Results show that tissue levels of l idocane 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 s ite was prepared and analyzed in exactly the same manner as the s ite to which the sMTS array was applied. We estimate that approx imately 0.5 grams of EMLA were applied. At 2.5% w/w l idocane, this corresponds to an application of approx imately 12mg of l idocane, nearly 200 times more API than that applied v ia sMTS.
These data indicate that an sMTS-lidocane product may prov ide an alternative to EMLA pretreatment in patients that require local anesthes ia prior to IV placement, injection or minor dermal surgeries.
AcknowledgmentsThe authors wish to thank Ken Brown, Ryan Simmers, Stan Rendon, Kevin Puckett, David Wirtanen, Lester Harrison, Kraig Kroells, Ron Krienke, Jim Chris tensen, Pat Young, Joann Oesterich, Chris Webb , Mary Hopp and Tonya Grunwald
A comparison of immune response for model antigen (8µg-ovalbumin) delivered to hairless guinea pigs by the sMTS integrated dev ice, sMTS-hand and IM injection. Blood samples were drawn at 3 weeks post-prime and 3 weeks post-boost, and then tested for antigen-specific antibody.
Immunogenicity of Antigens sMTS and sMTS-hand vs IM Injection
Conclusions
Coated microstructures, 8µg (top) and 25 µg
(bottom) of antigen per array
MTS
hMTS: an integrated application, reservoir and infus ion device that prov ides rapid
delivery of high volume l iquid formulations of small molecules, and proteins, inc luding
antibodies
sMTS: effic ient deliveryof potent proteins, peptides and vaccines with
a ful ly integrated or reusable applicator
Press&Patch: a 2-step system for delivery of small molecule salts and
proteins, offering local delivery or sustained release
sMTS-device: a sk in pre-treatment dev ice to penetrate the s tratum corneum
sMTS-hand: a hand-applied system for s imple, fast, efficac ious
delivery of vaccines
Parathyroid hormone, 1-34 (PTH) was coated onto a patch that was secured to an occ lus ive, adhesive patch. The coated patch was dried and stored with des iccant unti l use.
Prior to patch application, the hams of swine were c lipped, shaved and washed with soap and water. MTS arrays with 700µm tall square pyramid s tructures were applied by hand, a s ingle time, with approx imately five pounds of force. The PTH patches were applied immediately after MTS pre-treatment. In the untreated group, PTH patches were applied to uncompromised sk in. Patches were removed after 6 hours.
Blood samples were collected prior to patch application and at des ignated time point following application. PTH levels were quantitatively assessed us ing an ELISA assay.
Results show that blood levels of PTH in pigs pre-treated with MTS greatly exceed those in pigs who were not pre-treated with MTS.
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