DIABETES TECHNOLOGY & THERAPEUTICSVolume 3, Number 2, 2001Mary Ann Liebert, Inc.

Analysis

Overcoming Skin’s Barrier: The Search for Effective andUser-Friendly Drug Delivery

MARK R. PRAUSNITZ, Ph.D.

ABSTRACT

Although hypodermic needles rapidly deliver large doses of drugs such as insulin across theskin for systemic administration, the pain, local trauma, and difficulty to achieve sustainedor complex delivery profiles has motivated development of novel alternative technologies.Microneedles, jet injectors, and thermal poration make micron-scale holes in skin throughwhich drugs can be driven in a user-friendly manner. Chemical enhancers, iontophoresis,electroporation, and ultrasound increase skin permeability by making submicron alterationsin skin microstructure for continuous delivery over time.

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INTRODUCTION

MOLECULAR BIOLOGY and biotechnology areproducing increasingly potent and spe-

cific pharmaceutical agents, such as recombi-nant human insulin, growth hormone, and ery-thropoietin. These drugs often cannot bedelivered orally, due to poor absorption andenzymatic degradation in the gastrointestinaltract and the need for sustained or complex de-livery profiles.1 Although there is increasing in-terest in delivery via the lungs, nose, andmouth as alternative sites of drug absorption,drug delivery across the skin remains the pri-marily alternative to oral administration. Thetransdermal route is appealing because skin iseasily accessible, has a large surface area withmany possible sites for delivery, and readily re-covers from minor injury.2

Because skin permeability is extremely low,drug delivery across skin is usually achievedusing a hypodermic needle, which causes bothpain and trauma. Without the aid of a needleor other enhancement technology, most drugsare blocked by skin’s barrier, with a few ex-ceptions, such as nicotine and scopolamine,which have physicochemical and pharmaco-logical properties that permit them to cross skinat therapeutic rates.2 This barrier comes largelyfrom skin’s outer 10–20 mm, called the “stratumcorneum.” This nonviable tissue contains acomposite structure of cross-linked keratinblocks surrounded by an extracellular lipid ma-trix organized in multilamellar bilayers. Nervesand capillaries are found deeper within theskin.

Although hypodermic needles have servedmedicine well, the need for user-friendly meth-

Schools of Chemical and Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia.Mark Prausnitz has a significant financial interest in a company called Redeon, Inc., which is developing products

related to this study. The terms of this arrangement have been reviewed and approved by George Institute of Tech-nology and Emory University in accordance with their conflict of interest policies.

Analysis

ods to deliver drugs over extended periods hasprompted the development of a variety ofnovel technologies to overcome skin’s barrier,which are the subject of this brief review andsummarized in Table 1.

TECHNOLOGIES TO OVERCOME SKIN’S BARRIER

The most common way to overcome skin’sbarrier is by piercing a hypodermic needlethrough the skin and injecting drug under pres-sure. Although extremely effective at rapidlydelivering large amounts of drug subcuta-neously, intramuscularly, intravenously, or lo-cally, injections cause damage and pain at thesite of injection and generally do not permitslow delivery over time. In special circum-stances, sustained delivery can be achievedthrough the use of an indwelling catheter, suchas used in conjunction with insulin pumps, orby rapidly injecting a formulation which re-leases drug slowly over time, as is done withlente and ultra-lente formulations of insulin.3

A novel alternative to the conventional hy-podermic needle is the use of microscopic nee-dles that pierce the skin with holes that aremuch narrower and shallower.4 In this way,microneedles measuring tens to hundreds ofmicrons in size can deliver drugs across thestratum corneum, albeit at slower rates thanhypodermic needles, but do so in a painlessmanner by avoiding nerves found deeper in theskin.5 Published studies have shown sustainedtransdermal delivery of small marker com-pounds in vitro6; unpublished work has dem-onstrated delivery of macromolecules in ani-

mals and humans, suggesting that, for exam-ple insulin delivery using microneedles islikely to be possible. Using microfabricationtechnology from the microelectronics industry,mass-produced microneedles are expected tobe sufficiently inexpensive for use as dispos-able devices.

Abandoning needles altogether, jet injectionhas been developed to fire liquid droplets orsolid particles at high velocity to pierce into oracross the skin.7,8 In this manner, largeamounts of drug can be rapidly delivered and,because there are no needles, patient accep-tance and compliance can be improved,9 al-though reduction in pain by jet injection ap-pears to be modest and bruising is increasedrelative to hypodermic needles.10 Jet injectionhas been used clinically for decades and hasmost recently found success as a means to de-liver insulin to diabetics and growth hormoneto children.10 Limitations of jet injection are thatit cannot readily be employed for sustained de-livery and often requires a one-time investmentin a reusable device.

Another needle-free method involves burn-ing 100-mm holes in the skin.11 Using a laser tobriefly heat a dye on the skin’s surface, smallpieces of stratum corneum can be destroyedwithout damaging underlying tissue or stimu-lating nerves deeper in the skin. This approachhas been demonstrated clinically for continu-ous extraction of interstitial fluid as a mean tomeasure glucose levels in diabetics and is be-ing pursued for transdermal delivery of largemolecules, such as insulin. There is some ex-pense associated with this technology, sinceelectronic controls and a laser or other heatsource are required.

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TABLE 1. COMPARISON OF METHODS TO DELIVER DRUGS ACROSS SKIN

Sustained Pain/ Cost/Delivery method Small drugs Macromolecules delivery irritation complexity

Hypodermic needle XXX XXX XX XXX XMicroneedles XX XX XXX X XXJet injection XXX XXX X XXX XXThermal poration XX XX XXX X XXXChemical enhancers X X XXX XX XIontophoresis XX X XXX X XXXElectroporation XX XX XXX XX XXXUltrasound XX XX XXX X XXX

Increases transport

In contrast to the methods described abovethat cut, burrow, or burn “large” holes of mi-crons to millimeters in size, a number of othertechnologies have been developed to adminis-ter drugs across the skin slowly over timethrough much smaller transdermal pathways.The most widely studied approach involves theuse of chemicals to increase skin permeability,largely by changing the local chemical andstructural environment within the skin at themolecular level.12

Although a number of different chemical en-hancers have been shown to increase skin per-meability to small molecules by as much as anorder of magnitude or more, chemical ap-proaches are limited by their inability to sig-nificantly increase skin permeability to macro-molecules. Moreover, most chemical enhancersthat significantly increase transport cause skinirritation or raise other safety concerns.

A number of physical methods have beenshown to drive drugs across the skin throughexisting, enlarged, or newly created pathwaysof sub-micron dimensions.13 For example, elec-tric fields have been used to increase transder-mal transport, especially for charged drugs.Commonly called iontophoresis, a continuouselectric current is applied to the skin to elec-trophoretically, or electroosmostically, drivecompounds across the skin.14 This method hasbeen used for decades to transport pilocarpineinto skin to promote sweating as part of a cys-tic fibrosis diagnostic test15 and, more recently,for lidocaine delivery to locally numb the skinbefore needle injection.16 On the near horizonare iontophoretic patches that deliver fentanylfor on-demand systemic analgesia17 and, usinga reverse-iontophoresis approach, a device thatelectrically extracts interstitial glucose for non-invasive glucose monitoring of diabetics.18 Al-though limited animal experiments have shownsignificant insulin delivery by iontophoresis,19

delivery of insulin or other macromolecules tohumans has had limited success. Iontophoresisdevices can be worn for continuous or pulsatiledelivery and do not cause pain or irritation ifcurrents are kept sufficiently low. Expenses in-clude the one-time cost of a reusable power sup-ply or purchase of relatively costly fully dis-posable systems.

Another electrical approach involves short,

high-voltage pulses applied to the skin not onlyto drive molecules electrophoretically, but to si-multaneously make short-lived, nanometer-scale disruptions in skin structure by a phe-nomenon called “electroporation.”20 Becausethe skin is electrically permeabilized, transder-mal transport is increased, especially for largemolecules. Animal studies have demonstrateddelivery of fentanyl21 and in vitro studies haveshown transdermal transport of a broad rangeof different compounds,20 including those aslarge as oligonucleotides, heparin and IgG an-tibodies, especially when electroporation wasused in combination with certain chemical en-hancers.22 Although insulin delivery has notbeen reported, these studies suggest that skinelectroporation may be capable of transportinginsulin across skin. An electroporation devicecan probably be made small enough to be wornby a patient. Methods to eliminate nerve stim-ulation by the electric pulses and reduce devicecost are currently under investigation.

Ultrasound has also been used to drive mol-ecules across skin. Early attempts utilized MHz-frequency devices used for physical therapy andshowed modest increases in transdermal trans-port of some small molecules, such as steroidsand nonsteroidal antiinflammatories.23 More re-cently, kHz frequencies have been employedwith much greater success. Ultrasound appliedat these lower frequencies produces cavitation,which involves the creation, oscillation and im-plosion of tiny gas bubbles that can make tran-sient changes in skin microstructure. In vitro,animal and human studies have shown sus-tained delivery and extraction of a broad rangeof molecules, including insulin delivery torats24 and glucose extraction from humans.25

Although more studies are needed, transder-mal ultrasound has not been reported to causepain or irritation. Device size and cost remainunresolved issues, although miniaturization tohand-held or smaller sizes is likely.

CONCLUSION

The challenges to drug delivery posed by ad-vanced pharmaceuticals are being met by noveltechnologies to deliver drugs across the skin.Although injections with hypodermic needles

OVERCOMING SKIN’S BARRIER 235

are effective, other mechanical, chemical, elec-trical, ultrasonic and thermal approaches arebeing developed to drive drugs across skin inpainless, user-friendly ways that are amenableto sustained or complex delivery profiles. Hy-podermic needles will always have a place inmedicine, but they are rapidly becoming justone of an array of methods to administer drugsacross the skin.

ACKNOWLEDGMENTS

This work was supported in part by theAmerican Diabetes Association and the Na-tional Institutes of Health.

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Address reprint requests to:Mark R. Prausnitz, Ph.D.

Schools of Chemical and Biomedical EngineeringGeorgia Institute of Technology

Atlanta, GA 30332-0100

E-mail: mark.prausnitz@che.gatech.edu

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