Professional Documents
Culture Documents
I. INTRODUCTION
A. The Concept of Minimally Invasive Drug Delivery
A discussion of minimally invasive drug delivery must begin with a consideration
of what invasive delivery means. Administration of drugs via needles and sy-
ringes has been with us for more than a hundred years. For example, the first
all-glass syringe patent was licensed to Becton Dickinson & Co. from Luer in
1898 (1). Metal cannula needles on piston syringes have become the most pre-
valent ethical* device-based drug delivery modality in existence, with multiple
billions being used each year in many health care applications. Conventional
needles, whether on syringes or catheters, represent the preeminent invasive de-
livery mode in existence. They are, however, also the most efficient and cost-
effective device-based system for administering agents into the systemic circula-
tion and are presently the general method for delivering polypeptide agents,
which are otherwise proteolyzed by the oral route. Without syringes and needles,
unknown millions of diabetics would have been unable to survive in this century
despite Banting and Best’s discovery of insulin because syringe-based delivery
was an unconditionally necessary component of diabetic therapy.
* We are disregarding cigarettes in this discussion, which are a much more widely used form of drug
delivery “device” than syringes.
B. Mechanical Systems
1. Tape-Stripping
The simplest method for reducing the barrier imposed by the stratum corneum
is to remove it. In this and the next section we discuss methods presently used
to increase skin permeability by mechanical removal of the stratum corneum and
thereby to facilitate enhanced transdermal drug flux via passive delivery systems.
In vivo removal of the stratum corneum by tape stripping is done by repeated
application of adhesive tape to the surface of skin. The technique sees wide usage
in studies of wounding and cosmetics. The method is relatively uncontrolled, and
it is a cumbersome method for increasing skin permeability, but it is included
here for completeness.
Pulling the tape from the skin removes the upper mostlayer of cells. Multi-
ple strips remove substantial skin barrier as evidenced by increases in transepider-
mal water loss of 20 to 25 times (17). In situ occlusion of human skin to increase
hydration has shown to improve the effectiveness of the removal of the skin
layers; for example it reduces the number of strips required to peel off the stratum
corneum from 29 to 10 (18). It was found that hydration weakened the intracellu-
lar attachments within the stratum corneum (19), thereby facilitating skin layer
removal (18). The type of adhesive surface used is also critical to the process,
since adhesives vary in adhesive ability and hygroscopicity (17). One study re-
ported that tape stripping of human subjects was more effective in older subjects
(59–71 years) than in younger (24–35 years), suggesting that adherence of cor-
neocytes is less in aged patients (20). These techniques of stratum corneum re-
moval can be somewhat painful to the subject (21). In fact tape-stripping has
been claimed for removing noxious agents from skin (22).
Singer et al. (21) assessed the effect of stratum corneum removal to acceler-
ate the anesthetic effects of EMLA cream in a clinical study of adult patients
undergoing catheter insertion. EMLA is a eutectic mixture of lidocaine and prilo-
caine (21). It is applied topically for 60 to 90 minutes prior to catheterization in
order to provide topical anesthesia at the insertion site. Successful delivery of
anesthetic was measured as a reduction of pain during catheterization as scored
by the patients on a visual analogue scale (VAS). It was found that VAS scores
were significantly reduced when the anesthetic mixture was applied after tape
2. Suction Ablation
Suction blister formation is an alternative method for removing the stratum cor-
neum. It is done by application of vacuum suction to a limited area of skin to
produce a blister, the upper surface of which is excised to reveal a portal for
entry of drugs into the dermal circulation (23) and sampling of tissue fluids (24).
According to Svedman et al. (25), this technique splits the skin at the stratum
lucidum (see Chapter 1), forming a bleb above the dermis and leaving the skin
vasculature and nociceptors intact. Consequently, this is apparently a painless
and safe process in which the subject may experience a transient tingling sensa-
tion (25) while the “erosion” is performed, prior to application of a passive trans-
dermal patch. Such erosions have been developed by the application of negative
pressure of 180 mm Hg and warming to 38°C on the surface of skin for 15 to
70 minutes (24). The resulting epidermal vesicle was excised to expose the ero-
sion. In contrast to skin blisters produced by compression or burns, and which
incur microvascular damage, ischemia, and necrosis, the method described by
Svedman and colleagues (25,26) has not been found to produce tissue trauma.
Consequently, the production of such erosions is painless and does not form scars.
Tests in normal human volunteers demonstrated that plasma concentration/
time curves for 1-deamino-8-d-arginine vasopressin (DDAVP) administered by
this method approached zero order (26), indicating that infusionlike delivery pro-
files might be obtained. Moreover the patency of the skin erosions was undimin-
ished during the four days that the experiments were carried out, as indicated by
sustained blood levels of DDAVP in the volunteers.
Svedman (23) holds a patent on this technology, and a commercial product,
Cellpatch, (Epiport Pain Relief, Sweden) incorporates all components of the
process: suction device, epidermotome (to remove the blister), and a drug reser-
voir. Clinical studies have tested the feasibility of transepidermal morphine deliv-
ery by this methodology in normal healthy volunteers (27) and in postoperative
patients (25). In the latter clinical trial, drug reservoirs containing 5 mL of aque-
ous morphine solution (20 mg/mL) were applied to the skin for 48 hours after
the suction ablation treatment. In two studies, steady state levels of about 15–
18 nmol/L morphine were substantially obtained within the first few hours of
administration. This declined to about 10–12 nmol/L after 30 hours. Cmax values
of 17.3 ⫾ 3.7 nmol/L and 20.9 ⫾ 7.7 nmol/L with respective CVs of 21 and
33% were seen for the two studies. The variability seen in the latter study was
Figure 2 Device for enhancing transdermal agent flux. (From Ref. 32.)
plural skin needles” to form “the drug pathway on the skin by micropiercing by
penetrating a plurality of skin needles into the skin epidermis at the treatment
site and transferring the ionized drug into the skin at the treatment site by ionto-
phoretic force” (Fig. 5). They claimed transdermal delivery of peptide and protein
drugs by this system.
Eppstein (38) described a device that was likewise useful for reducing the
barrier properties of skin or mucosa. Its claimed use was for delivery of drugs
or for sampling analytes (i.e., via interstitial fluid) from the body. The device
consisted of a base with a reservoir from which extended “puncturing members”
of sufficient length to reduce the barrier properties of “skin or mucosa,” which
he claimed were 30 to 50 microns. The density of the “puncturing members”
was described as being up to 50% of the surface contacting the skin (Fig. 6).
Figure 7 Skin perforating device for transdermal medication. (From Ref. 39.)
confirm the depth of the cuts, since it was claimed that epidermis was stained
specifically by the dye whereas stratum corneum was not.
Finally Kamen (43) developed a system composed of a platen or sheet (e.g.,
a metal sheet) into which were punched holes from which protruded jagged edges.
The edges formed “micropenetrators” or cutting edges that were intended to pro-
duce an array of cuts when contacted to the skin (Fig. 9). Treatment of skin, by
the device containing a “plurality of micropenetrators,” was intended to improve
C. Microfabricated Systems
1. Overview of Fabrication Technology
Many of the previously mentioned devices appear to us to be cumbersome to
use and probably also to manufacture. However, new technology for manufactur-
ing of microscopic three-dimensional (“high aspect ratio”) structures from silicon
and other materials promises to revolutionize how medical devices will be manu-
factured. The advent of chip lithography in the microelectronics industry has
resulted in the rapid expansion of instruments available for etching microstruc-
tures in silicon, platinum, germanium, and other metals. These instruments may
be viewed as precision “milling” equipment, capable of etching structures with
micron-scale dimensions into an otherwise monotonically flat surface. They may
operate on the principles of laser ablation, ion bombardment, deep ion milling,
or on the simplest acid/base reactions to produce semiconductor pathways, and
in the last decade they have also been used to produce mechanical structures
such as gears, valves, and rotors of microscopic size, commonly called microelec-
tromechanical systems (MEMS) devices.
These largely mechanical microdevices are conveniently integrated with
semiconductor electronic functions to produce hybrid devices that may be oper-
ated remotely by electrical impulse, or may trigger an electronic response to a
mechanical stimulus. Commercial applications of these devices have developed
first in the aerospace and automotive industries, where sensitive pressure trans-
ducers and actuators are needed for precise measurement of structural flex, part
fatigue, and impact energy. Those people unfortunate enough to have experienced
intimate contact with an activated automotive airbag have experienced the utility
of these transduction devices first-hand. Newly emerging applications in the com-
munications industry take advantage of the microscale manipulation of light and
electrical energy possible with MEMS “photonics” chips in which thousands of
micron-scale mirrors may be electronically manipulated for signal transduction
and amplification. These microdevices are enabling a new era of cellular commu-
nications, which in turn may indirectly introduce more consumers to the automo-
tive airbag.
Medical applications of MEMS were first developed around pressure trans-
ducers for catheters and heart monitors. These devices share similar architecture
Figure 13 continued
Figure 14 Microneedle array fabricated from silicon via wet etch with potassium hy-
droxide.
REFERENCES
1. Becton Dickinson and Co. Celebrating the First Hundred Years, 1897–
1997, 1997.
2. DA Bucks. Skin structure and metabolism: relevance to the design of cuta-
neous therapeutics. Pharmaceutical Research 1:148–153, 1984.
3. JH McElhaney. Dynamic response of bone and muscle tissue. J Appl Phys-
iol 21:1231, 1966.
4. P Tong, YC Fung. The stress–strain relationship for the skin. J Biomech
9:649, 1976.
5. DJ McAuliffe, S Lee, TJ Flotte, AG Doukas. Stress wave assisted transport