Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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DRUG DELIVERY SYSTEM INCLUDING A DRUG TRANSPORT
ENHANCEMENT MECHANISM
BACKGROUND OF THE INVENTION
Various techniques are used to introduce medicinal drugs into a patient's
body,
including injection and oral administration of medicine in solid or liquid
form.
Injection is an effective way to rapidly introduce medicine into a patient's
bloodstream.
However, patients often experience anxiety and discomfort from injections.
Further,
infection due to needle contamination is of growing and significant concern.
One type of conventional "needleless" drug injection system includes a
mechanism, such as a plunger, by which a narrow stream of medicine is forced
out of
a nozzle at a very high speed to penetrate the patient's skin. Illustrative
"needleless"
injection systems are described in U.S. Patent Nos. 5,599,302 (Lilley et al.),
5,383,851
(McKinnon et al.) and 5,064,413 (McKinnon et al.). While such apparatus
prevents
infection due to needle contamination, injection of the high speed stream can
still cause
discomfort and anxiety.
While oral administration of medicine is often preferable to injection, this
technique suffers certain drawbacks. For example, in some circumstances,
manufacture
of a drug in a form suitable for oral administration degrades the
effectiveness of the
drug. Other drawbacks are related to the taste of a liquid medicine, the shape
and/or
size of a pill or tablet form, and stomach irritation.
Another technique for administering certain medicines is by absorption through
the patient's skin (i.e., transdermally). Conventional transdermal drug
delivery
techniques include the use of ultrasonic energy or other forms of high-
frequency
energy. For example, in U.S. Patent No. 5,421,816 (Lipkovker), ultrasound
energy
is used to move a drug through a patient's skin into the bloodstream. In U.S.
Patent
No. 5,386,837 (Sterzer), pulse shocks of high-frequency energy, such as RF,
microwave, infra-red or laser energy, are employed to create transient pores
in the
membranes of targeted diseased cells through which drug or chemotherapeutic
agents
can easily enter the targeted cells. U.S. Patent No. 5,614,502 (Flotte et al.)
describes
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the use of high pressure impulse transients, as may be created by laser-
induced
ablation, in combination with the administration of certain compounds. The
high
pressure, laser generated impulse works in combination with the therapeutic
compound
by generally increasing cell permeability in the region of impulse
administration.
As used herein, the term "drug delivery" refers to the action by which a drug,
medicament, compound, chemical agent, biological agent or the like
(collectively,
"agents") passes from the outside of cells) to the interior of cells) to
effect a
therapeutic, chemical or biological activity. Drug delivery includes
transdermal drug
delivery, the passage of drugs, compounds and the like through tissue
including organs
and cell cultures, both in vivo and in vitro. The term "biologic material"
encompasses
skin, organ tissue, cell cultures and the like.
BRIEF SUMMARY OF THE INVENTION
The invention relates to a drug delivery system including a drug delivery
initiator for generating a shock wave and a membrane receiving the shock wave
and
transmitting the shock wave to a target material. The target material may be
the
membrane or may be a biologic material, such as a cell or tissue culture, a
patient's
skin, or a medicament in contact with a biologic material. The drug delivery
initiator
includes a proximal shock generating chamber and a distal shock delivery tube
having
a distal end. The membrane is disposed adjacent to, or in contact with, the
distal end
of the shock tube.
The drug delivery system further includes a shock wave generating mechanism
disposed within the shock generating chamber which may take various forms. In
one
embodiment, the shock wave generating mechanism includes at least one pair of
electrodes for generating a shock wave by electric discharge. Alternative
shock wave
generating mechanisms described herein include a rapidly removable membrane
and a
piston arrangement.
In the embodiment in which the shock wave generating mechanism includes at
least one pair of electrodes, passing an electric current between the
electrodes causes
a shock wave to be generated and directed through the shock tube. The shock
wave
is transmitted to the distal end of the initiator to impinge on the membrane
which, in
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turn, transfers the shock wave to the biologic material. Impact of the shock
wave on
the skin increases the porosity of any of the biomembranes at or below the
skin,
thereby enhancing absorption of the medicament.
The medicament may be applied to the biologic material in various ways,
including direct topical application or through a permeable or rupturable drug
containing ampule that is positioned adjacent to the biologic material. In one
embodiment, the medicament is topically applied with the use of a penetratable
drug
containing ampule or drug housing mountable in substantially fluid tight
communication
to the patient's skin. An optional sealing element provides the fluid tight
communication between the drug housing and the patient's skin. To this end,
the
sealing element includes a cavity having an opening in the bottom surface and
at least
one piercing element. In use, the drug containing ampule is placed in the
cavity of the
sealing element and is punctured by the piercing element, causing the
medicament to
contact the patient's skin through the opening in the sealing element cavity.
One
embodiment of the sealing element includes straps with which the element is
mountable
over the patient's skin in the manner of a wrist watch.
The drug delivery initiator may be "closed-ended," with the membrane mounted
to the distal end of the shock tube. Alternatively, the initiator may be "open-
ended,"
with the membrane being a separate component or being mounted to, or
integrally
formed with the drug housing or mounted to, or integrally formed with the
sealing
element.
In one embodiment, two pairs of electrodes are disposed in the shock
generating
chamber. A first current passing between one electrode of the first electrode
pair and
one electrode of the second electrode pair generates a first shock wave and a
second
current passing between a second electrode of the first and second electrode
pairs
causes a second shock wave to be generated. The composite shock wave travels
through the shock tube to impinge on the membrane.
The drug delivery initiator may be gas and/or liquid impermeable and able to
receive a pressurized gas and/or liquid. Use of a pressurized gas or liquid in
the
initiator permits characteristics of the shock wave, such as rise time and
magnitude, to
be varied. Suitable gases are rare gases, such as nitrogen and helium, and
suitable
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liquids are ones having a high dielectric breakdown, such as water.
A drug transport enhancement mechanism is described which takes advantage
of the increased porosity of the target material achieved with the application
of the
shock wave, thereby further enhancing absorption of a drug or medicament. The
drug
transport enhancement mechanism may take various forms, including ultrasound,
iontophoresis, mechanical vibration, high pressure gradients, and surfactants
and may
include apparatus coupled to the drug delivery initiator or provided as a
separate unit.
Further, the transport enhancement mechanism may be actuated simultaneously
with
generation and transmission of the shock wave or may be actuated before or
after
transmission of the shock wave to the target material.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing features of this invention, as well as the invention itself, may
be
more fully understood from the following description of the drawings in which:
Figure 1 is a cross-sectional view of a transdermal drug delivery system
according to the invention;
Figure 2 is a cross-sectional view of an alternate transdermal drug delivery
system according to the invention;
Figure 3 is a cross-sectional view of the transdermal drug delivery system of
Figure 2 in use;
Figure 4 is a cross-sectional view of a further alternate transdermal drug
delivery system according to the invention;
Figure 5 is a cross-sectional view of a still further alternate transdermal
drug
delivery system according to the invention;
Figure 6 an exploded, cross-sectional view of yet another alternate
transdermal
drug delivery system according to the invention;
Figure 7 is a cross-sectional view of the transdermal drug delivery system of
Figure 6 in use;
Figure 8 is an exploded, cross-sectional view of still another transdermal
drug
delivery system according to the invention;
Figure 9 is a cross-sectional view of the transdermal drug delivery system of
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Figure 8 in use;
Figure 10 is a cross-sectional view of a further alternate transdermal drug
delivery system according to the invention;
Figure 11 shows an illustrative circuit for delivering current to the system
of
Figure 10;
Figure 12 is a cross-sectional view of a still further alternate transdermal
drug
delivery system according to the invention; and
Figure 13 is a cross-sectional view of an illustrative transdermal drug
delivery
system including a transport enhancement mechanism.
DETAILED DESCRIPTION OF THE INVENTION
Refernng to Figure 1, a shock wave generating system 10 suitable for drug
delivery applications includes a shock wave initiator 12 and a shock wave
transmission
membrane 30. The initiator 12 includes a container 20 having a rapidly
openable, or
removable divider 24 positioned to separate the container into a first,
proximal chamber
28 and a second, distal chamber 32. The proximal chamber 28 is selectively gas
impermeable and is able to receive a pressurized gas from an external source
(not
shown) via a gas port 34. The container 20 communicates with the membrane 30
via
an opening 40 at the distal end of the distal chamber 32.
In use, the distal opening 40 of the container 20 is brought into shock wave
communication with the membrane 30 which is further brought into shock wave
communication with a target material 14. The target material may be a biologic
material, such as a patient's skin, or a medicament in contact with a biologic
material.
Rapid opening, or removal of the divider 24 causes a shock wave to be
generated upon
the release of pressurized gas from the proximal chamber 28 to the distal
chamber 32.
The shock.wave travels through the distal opening 40 to impinge on the
membrane 30
which transfers the shock wave to the biologic material 14.
The shock wave is a high-pressure wave propagating at supersonic speeds, with
a typical rise time on the order of one to one-hundred nanoseconds and a
useful
duration on the order of several hundred nanoseconds, following which the
shock wave
dissipates significantly. Typical shock wave magnitudes are characterized by a
pressure
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on the order of between one and five-hundred barns.
The delivery apparatus and techniques described herein are suitable for
transmitting shock waves to various biological materials to enhance absorption
of
various compounds, medicaments and other agents by the biologic material. For
simplicity of illustration, the apparatus and techniques are described herein
primarily
with reference to transdermal drug delivery, with the biologic material 14
being a
patient's skin. Other applications for the shock wave generating systems
described
herein include in vitro applications to effect absorption of such agents by
cell cultures,
and other in vivo applications, including gene therapy, invasive surgery
and/or delivery
of agents through forms of organs, tissue and physiological systems other than
skin.
Impact of the shock wave on the biologic material (e.g., patient's skin)
causes
the porosity of the biologic material (i.e., the permeability of the cells) to
increase
temporarily, thereby enhancing absorption of the agent (i.e., diffusion of the
agent
through the cell wall). Typically, the shock wave propagates through the
biologic
material (e.g., patient's skin) to a depth on the order of a few centimeters
before
significant dispersion occurs.
The extent to which the cell porosity is increased can be manipulated by
varying
the rise time and magnitude of the generated shock waves. In general, the rise
time
and magnitude of the shock waves are selected to ensure that the permeability
of the
skin 14 is optimally affected, without destroying the viability of the target
cells. As one
example, the cell permeability is affected for a duration of between several
seconds and
several minutes and the temporary permeability increase is sufficient to
permit a variety
of medicinal compounds and other agents, with a wide range of molecular
weights, to
enter the cells. It is believed that the molecular weights of agents useful
with the
system of the invention ranges from about 100 kilodaltons to several thousand
kilodaltons. It will be appreciated by those of ordinary skill in the art that
various
factors, other than the rise time and magnitude of the shock wave, affect the
absorption
of the medicament by the skin, including electrostatic forces between cell
membranes,
the form, type and amount of the compound and the pH level.
The patient's skin can be prepared for shock wave application by treatment
with
a medicament. The medicament may be adrriinistered either locally or
systemically, by
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various conventional pharmaceutical techniques. For example, the medicament
may be
applied topically or internally (i.e., orally or with an injection, such as an
intravenous,
intramuscular or intradermal injection). Further, the sequence of applying a
drug and
a shock wave to a target material may be varied. That is, the drug may be
applied
S before, during and/or after application of the shock wave to the target
material.
As one example, direct topical application may be performed prior to shock
wave treatment, such as by spreading the compound over a localized region of
the skin
targeted for subsequent shock wave treatment. In some applications, it may be
advantageous to wait a predetermined amount of time after application of the
medicament and before shock wave application, in order to permit dispersion of
the
medicament. Alternatively, the compound may be present within a drug-
containing
ampule which is applied to the skin during and subjected to shock wave
treatment, with
the use of a drug housing, as described in conjunction with Figures 6-9. As a
further
example, a transdermal patch may be used to apply the medicament to the target
material. The patch may be applied before application of the shock wave and
thus, be
subject to the shock wave or, alternatively the patch may be applied after
application
of the shock wave to the target material.
In many applications, it is advantageous to apply the medicament to the body
internally (i.e., orally or with an injection, such as an intravenous,
intramuscular or
intradermal injection). Application of shock waves to the skin following
injection of
an agent into the body renders the body more amenable to the effects of the
agent. In
some applications, it is advantageous to administer the agent such that the
level of the
agent in the surrounding tissue is less than fifty percent of the level of the
agent in the
target tissue. Thus, compounds are applied in a way that produces greater
concentrations in the target material than in the surrounding area and
compounds which
are taken up in greater amounts and/or retained substantially longer in the
target tissue
relative to the surrounding tissue are preferred. Specifically, advantageous
compounds
include antibiotics, cytotoxic compounds, light activated dyes and
salicylates.
The container 20 may take various forms, in terms of its size and shape.
Ideally, the size of the container 20 has a height on the order of six to
eight inches
long, with a diameter on the order of one to two inches, with the height of
the proximal
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chamber 28 being approximately four times greater than the height of the
distal
chamber 32. Generally, the container 20 is comprised of a material having
suitable
strength and gas impermeability characteristics. Exemplary materials for
providing the
container 34 include metals and metal alloys, such as stainless steel, copper
and
S aluminum, and various polymeric materials.
In the illustrative embodiment, the container 20 is tapered so as to have a
slightly smaller diameter at its distal end than at its proximal end and the
opening 40
is substantially circular in shape. It will be appreciated by those of
ordinary skill in the
art that the particular size and shape of the container 20 and its features,
including the
distal opening 40, can be readily modified suit a particular application. As
one
example, the size of the distal opening 40 may be decreased in order to focus
the shock
waves transmitted therethrough.
The rapidly openable divider 24 may take various forms, including a
rupturable,
gas impermeable diaphragm as shown in Figure 1 or a valve as is shown in
Figure 5.
In the case of a rupturable diaphragm providing the divider 24, the diaphragm
is
removably and replaceably mounted within the container 20, such as with the
use of
mounting brackets 46 fastened to, or integrally formed with the inner wall of
the
container 20.
Suitable materials for providing the gas impermeable diaphragm 24 include
metals, such as titanium, titanium alloys, aluminum, tin, stainless steel and
copper and
polymeric materials, such as polyaramid fibers, polyamides, cellulose,
cellulose acetate,
polyvinyl chloride, polyester and mylar. The diaphragm 24 may be self
rupturable in
response to the pressure differential across it exceeding a predetermined
magnitude
(i.e., the "rupture point"). Further, the gas impermeable diaphragm 24 may be
scored
and the rupture point may be varied by varying the scoring pattern and/or
extent.
Alternatively, the diaphragm 24 may be rupturable in response to an external
force,
such as an electric charge, heat or a mechanical action.
The shock wave transmission membrane 30 is deflectable in response to shock
wave impact. However, the extent of deflection may be so small as to be
undetectable
by the naked eye and/or negligible. Suitable materials for fabricating the
membrane
30 include metals, such as titanium, titanium alloys, aluminum, tin, stainless
steel,
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molybdenum and copper and polymers, such as polyaramid fibers, polyamides,
cellulose, cellulose acetate, polyvinyl chloride, polyester and mylar.
The membrane 30 may be gas impermeable or alternatively, may be gas
permeable. A gas permeable membrane may include one or more perforations,
preferably having a relatively small size as compared to the surface area of
the
membrane 30 and, more preferably, having a size on the order of 0.1 to 1.0
millimeters. The gas flowing through a gas permeable membrane works in
conjunction
with the force of the shock wave, albeit over a much longer time constant than
the
shock wave, to force the medicament into the patient's skin. While the shock
wave
lasts on the order of several hundred nanoseconds before dissipating
significantly, the
impact of gas from the distal chamber passing through the membrane 30 and to
the
medicament and patient's skin 14 continues for a duration on the order of
milliseconds.
Thus, once the shock wave has dissipated, the gas movement through the
membrane
30 serves to provide additional force on the medicament and the patient's skin
14,
thereby improving absorption of the medicament.
The membrane 30 may be part of various components of the drug delivery
system 10. For example, in the embodiment of Figure 1, the membrane 30 is a
separate component. Alternatively, the membrane may be mounted to the
container 20
as shown in Figure 2, may be part of an optional drug housing as shown in
Figure 3
or may be part of a sealing element as shown in Figure 6.
In use, the distal chamber 32 of the container 20 is initially filled with a
gas,
at a predetermined pressure, and the proximal chamber 28 receives a
pressurized gas
via the gas port 34. In the illustrative embodiment, the distal chamber 32 is
filled with
air at ambient atmospheric pressure. Many pressurized gases are suitable for
introduction into the proximal chamber 28, including carbon dioxide, hydrogen,
argon,
nitrogen, air and rare gases, including helium, argon, neon and xenon.
In the case where the divider 24 is a self-rupturable diaphragm, as gas is
being
pumped into the proximal chamber and when the pressure differential between
the
proximal and distal chambers 28, 32, respectively, reaches a predetermined
magnitude,
the diaphragm 24 ruptures. This rapid opening of the divider 24 causes a shock
wave
to be generated and transmitted into the distal chamber 32. The shock wave
travels
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through the opening 40 at the distal end of the chamber 32 and impinges on the
adjacent membrane 30 which, in turn, transmits the shock waves to the
patient's
medicament-treated skin 14. Impact of the shock waves on the patient's skin 14
causes
the porosity of the skin cells to increase temporarily, as described above.
A release valve 18 in the wall of the proximal chamber 28 permits any gas
remaining in the container 20 after shock wave generation to be purged. In
this way,
the proximal chamber 28 of the initiator container 20 is readied to accept
pressurized
gas for reuse.
With this arrangement, an effective drug delivery system is provided using an
apparatus which is relatively simple and inexpensive. In this way, the
advantages of
transdermal drug delivery, as compared to injections and oral administration,
are
realized, without the drawbacks associated with complex and expensive
equipment, such
as ultrasonic andlor laser equipment.
The shock wave generating system 10 of Figure 1 can be characterized as
"open-ended" in the sense that the container 20 has an opening 40 at its
distal end.
Figure 2 shows a "closed-ended" shock wave generating system 50 suitable for
transdermal drug delivery, with like reference characters referring to like
elements. In
the embodiment of Figure 2, the membrane 30 is mounted to the container 20, at
the
distal end of the distal chamber 32. More particularly, the membrane 30 is
mounted
to the container so as to cover the opening 40 at the distal end and, thus, to
close the
container, as shown, and may be mounted with a gas tight seal.
The system 50 includes container 20 in which the rapidly openable divider 24
is disposed to divide the container into the proximal chamber 28 and the
distal chamber
32, as described above in conjunction with Figure 1. The gas port 34 permits
introduction of a pressurized gas into the distal chamber 28 from an external
gas source
(not shown).
Referring to Figure 3, use of the closed-ended shock wave generating system
50 is illustrated, with the container 20 brought into shock wave communication
with the
patient's skin 14 for generation and transmission of shock waves to the
patient's skin
14 upon the rapid opening of the divider 24. More particularly, in the
illustrated
application, the container 20 is brought into contact with a medicament, or
drug 54
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suitable for absorption by the skin 14.
The medicament 54 may be provided in various forms in accordance with the
various manners by which the skin is treated. As examples, the medicament 54
may
be a liquid, gel, ointment or creme which is applied topically to the
patient's skin 14.
Alternatively, the medicament 54 may be contained in a penetratable drug
housing, as
in the embodiments of Figures 6-9, or a drug housing which is permeable to the
drug.
Referring to Figure 4, a shock wave generating system 60 includes an
alternative
mechanism for introducing pressurized gas into the proximal chamber. The shock
wave
generating system 60, like the above-described embodiments, includes an
initiator 62
comprising a container 64 in which a rapidly openable divider 66 is disposed
to
separate the container 64 into a first, proximal chamber 68 and a second,
distal
chamber 70 having an opening at the distal end. The system 60 of Figure 4 is
closed-
ended in the sense that the shock wave transmission membrane 74 is mounted to
the
container 64 at the distal end so as to cover the distal opening 76 and is
operative in
the same manner as described above to generate and transfer shock waves
through the
membrane 74 to the medicament 54 and patient's skin 14.
A pressurized gas cartridge 80 is removably and replaceably disposed in the
proximal chamber 68. In order to facilitate removal and replacement of the
cartridge
80 for subsequent use of the shock wave generating system 60, the container 64
is
provided with a removable cover 88 which is designed to maintain the gas
impermeability of the container 64, such as with the use of a rubber gasket. A
release
valve 72 is disposed through the cover 88 in order to permit any gas remaining
in the
container 64 after use to be purged.
A mounting bracket, or frame 84 is provided for securing the cartridge 80
within the proximal chamber 68. It will be appreciated by those of ordinary
skill in the
art, however, that various techniques are suitable for mounting the cartridge
80 within
the proximal chamber 68. An actuator 86 accessible from the exterior of the
container
64 permits the pressurized gas cartridge 80 to be punctured upon actuation,
thereby
releasing the pressurized gas into the proximal chamber 68. Release of the
pressurized
gas into the proximal chamber 68 causes the pressure differential across the
diaphragm
66 to exceed its "rupture point." The rupturing of the diaphragm 66 causes
shock
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waves to be generated and transmitted through the distal chamber 70 and
membrane 74
in the manner described above.
The actuator 86 may take various forms. In the illustrative embodiment, the
actuator 86 is a lever having a handle 90 and a puncturing element 94. In use,
moving
S the handle 90 toward the proximal end of the container 64 causes the
puncturing
element 94 to move into contact with, and puncture the mouth 82 of the
cartridge 80.
It will be appreciated by those of ordinary skill of the art that various
mechanical
mechanisms, other than the illustrated puncturing element 94, are suitable for
puncturing the pressurized gas cartridge 80. Further, the cartridge 80 may be
punctured by other means.
Refernng to Figure 5, a closed-ended shock wave generating system 100
including an initiator 102 for transmitting shock waves to a patient's skin 14
includes
a rapidly openable divider 108 in the form of a valve. The valve 108 is
disposed in a
container 104 of the initiator 102 so as to divide the container 104 into a
first, proximal
chamber 110 and a second, distal chamber 112 having a membrane 114 mounted
over
an opening at the distal end. A gas port 116 permits pressurized gas to be
introduced
into the proximal chamber 110 from an external source (not shown) and a
release valve
106 permits gas remaining in the container 104 after use to be purged, thereby
readying
the system 100 for subsequent use.
The valve 108 includes a sliding portion 118 which is movable by an actuator
120 between a first, closed position (shown by dotted lines) in which the
sliding portion
118 abuts a stop 124 and a second, open position (shown by solid lines) in
which the
sliding portion 118 is spaced from the stop 124. With the sliding portion 118
of the
valve in the closed position, the valve provides a gas impermeable seal
between the
proximal chamber 110 and the distal chamber 112.
Actuation of the valve 108 via actuator 120 causes very rapid movement of the
sliding portion 118 from the first, closed position to the second, open
position. It is
this rapid opening of the valve which causes a shock wave to be generated and
transmitted through the distal chamber 112 to impact the shock wave
transmission
membrane 114, medicament 54 and skin 14 in the manner described above.
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The actuator 120 may take various forms, such as an electric circuit, a
mechanical actuator, or an electromechanical actuator. Further, it will be
appreciated
by those of ordinary skill in the art that while the illustrated valve 108 is
relatively
simple in design, more elaborate valves, such as gate valves or piston-based
valves may
be used.
Referring to Figure 6, an alternate transdermal drug delivery system 130
includes a closed-ended shock wave initiator 134 of the type described above
in
conjunction with Figure 2, a drug housing 136 and a sealing element 140. The
drug
housing 136 is adapted for containing a medicament and includes a first
surface 138
adapted for being penetrated to permit the medicament to flow towards the
patient's
skin 156 and a second, opposite surface 168.
The shock wave initiator 134 includes a container 128 in which a rapidly
openable divider 142 in the form of a rupturable diaphragm is mounted so as to
divide
the container into a first, proximal chamber 144 and a second, distal chamber
146
having an opening 148 at the distal end thereof. A shock wave transmission
membrane
150 is mounted to the container 128 so as to cover the opening 148 at the
distal end of
the chamber 146. A gas port 152 permits a pressurized gas to be introduced
into the
first chamber 144 from an external source (not shown) and a release valve 154
permits
gas remaining in the container 128 after use to be purged.
The sealing element 140 is mountable to the patient's skin 156 and is adapted
for receiving the drug housing 136 and providing a fluid tight seal between
the drug
housing 136 and the patient's skin 156. To this end, the sealing element 140
includes
a cavity 160 sized and shaped to receive the drug housing 136 and having an
opening
166 in the bottom surface 144 for permitting the medicament to contact the
patient's
skin 156. The sealing element 140 further includes a mechanism for mating with
the
container X28. In the illustrative embodiment, screw threads 162 disposed in
the
sealing element cavity 160 are mateable with complimentary screw threads 164
disposed
around the distal end of the container 128. It will be appreciated by those of
ordinary
skill in the art that various mechanisms may be used for mating the sealing
element 140
and the container 128, such as a Luer lock.
The sealing element 140 includes a mechanism for penetrating the surface 138
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of the drug housing 136, thereby causing the medicament to flow through the
opening
166 toward the patient's skin 156. In the illustrative embodiment, piercing
elements
146 project upward from the cavity 160 of the sealing element so as to
puncture the
surface 138 of the drug housing.
In the illustrative embodiment, the sealing element 140 includes a straps 158
which permit the element to be worn by the patient in the manner of a wrist
watch.
It will be appreciated by those of ordinary skill in the art however that the
sealing
element 140 may take various forms.
The drug housing 136 may be comprised of various materials and the size and
shape of the housing 136 may be readily varied to suit a particular
application and
sealing element 140, as will become apparent. For example, the drug housing
may be
adapted to mate with the drug delivery initiator container 128 as shown in
Figure 8.
As another example, the drug housing 136 may not require puncturing, but
rather may
be permeable to the medicament or may be ruptured by impact of the shock
waves.
Refernng also to Figure 7, the transdermal drug delivery system 130 is shown
in assembly, prior to shock wave generation. The drug housing 136 is disposed
within
the cavity 160 of the sealing element 140 and the bottom surface 138 of the
drug
housing has been penetrated by piercing elements 146. The shock wave initiator
container 128 is brought into shock wave communication with the drug housing
136 and
the patient's skin 156 by mating the distal end of the container chamber 146
with the
mateable portion 162 of the sealing element 140. More particularly, the
container 128
is placed over the sealing element 140 and is screwed down so that the screw
threads
164 of the initiator container 128 engaged the screw threads 162 of the
sealing element
140. With the system 130 disposed as shown in Figure 7, a pressurized gas is
introduced into the first chamber 144 via the gas port 152 for rupturing the
diaphragm
142 as described above in order to generate a shock wave for transmission to
the
patient's skin 156.
A further alternate transdermal drug delivery system 170 is shown in Figure 8,
with like numerals referring to like elements. In the system 170, the drug
delivery
container 174 is mateable to a drug housing 176 and the shock wave
transmission
membrane is provided as part of the drug housing 176. More particularly, the
initiator
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container 174 is open-ended and includes a rapidly openable divider 180
mounted to
divide the initiator container 174 into a proximal chamber 182 and a distal
chamber
184, as shown. A gas port 186 permits communication of an external source (not
shown) of pressurized gas with the proximal chamber 182 and a release valve
198
permits gas remaining in the container 174 after use to be purged. The distal
chamber
184 terminates at a mating portion 188 which defines an opening 190 at the
distal end.
In the illustrative embodiment, the mating portion 188 includes screw threads.
The drug housing 176 is adapted for containing a medicament and has a first
surface 192 adapted for being punctured or otherwise opened to release the
medicament
and a second, opposite surface 194. The drug housing 176 further includes a
mating
portion 196 suitable for mating to pardon 188 of the initiator container 174.
The
second surface 194 of the drug housing 176 provides the shock wave
transmission
membrane (like membrane 150 in Figure 6, for example). This membrane 194 may
be integrally formed with the drug housing 176 or, alternatively, may be a
separate
component positioned over the surface of the drug housing 176.
A sealing element 200 is provided for receiving the drug housing 176 and for
affecting a fluid tight seal between the drug housing and the patient's skin
204. The
sealing element 200 is substantially similar to sealing element 140 (Figures 6
and 7),
with the exception that the sealing element 200 does not include mating
portion 162.
This is because the initiator container 174 mates with the drug housing 176 as
opposed
to mating with the sealing element 200. The sealing element 200 thus includes
a cavity
206 which is adapted for receiving the drug housing 176 and in which piercing
elements
208 are disposed for piercing the first surface 192 of the drug housing. An
opening
212 in the bottom surface 214 of the sealing element permits the medicament to
flow
toward the patient's skin. The illustrative sealing element 200, like sealing
element
140, includes straps 210 to permit the sealing element to be worn by the
patient in the
manner of a wrist watch.
Referring to Figure 9, the transdermal drug delivery system 170 is shown
placed
over the patient's skin 204 and ready for use. The drug housing 176 is
positioned
within the cavity 206 of the sealing element 200, with the first surface 192
of the drug
housing penetrated by the piercing elements 208. Thus, the medicament contacts
the
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patient's skin 204 via the opening 212 within the sealing element 200. The
drug
delivery initiator container 174 is brought into engagement with the drug
housing 176,
with the threaded portion 188 of the container mated with the threaded portion
196 of
the drug housing. With the system 170 thus positioned, the container 174 is
ready to
receive a pressurized gas via the gas port 186. Rapid rupture of the diaphragm
180 due
to a predetermined pressure differential between the proximal chamber 182 and
the
distal chamber 184 causes a shock wave to be created and transmitted through
the distal
chamber 184, distal opening 190 and drug housing 176 to impinge on the
patient's skin
204.
One of ordinary skill in the art will appreciate that the container 20 may be
altered in size and shape to be useful in applications other than transdermal
drug
delivery. As examples, the distal chamber 31 may be comprised of a flexible
material
and/or system can be dimensioned to be used with or in a catheter to be useful
in
minimally invasive surgical techniques (e.g., endoscopic surgery) or open
surgery.
Referring to Figure 10, an alternate transdermal drug delivery system 300
comprising a drug delivery initiator 3i6 and a shock wave transmission
membrane 310
delivers shock waves to a target material, such as a patient's skin, disposed
adjacent to
a distal end 304 of a shock delivery tube 308 in response to an electric
discharge. The
shock wave transmission membrane 310 is disposed at, or adjacent to, the end
304 of
the tube 308 and may be mounted to the tube end 304 or may be placed in direct
contact with the biologic material or with a drug housing containing a
medicament, as
described above. The system 300 of Figure 10 further includes a drug transport
enhancement mechanism 36 which will be described further in conjunction with
Figure
13.
The membrane 310 is provided as described above in conjunction with
membrane, 30 (Figure 1). That is, the membrane 310 is deflectable in response
to
shock wave impact, but the extent of deflection may be so small as to be
undetectable
by the naked eye andlor negligible. Suitable materials for fabricating the
membrane
310 include metals, such as titanium, titanium alloys, aluminum, tin,
stainless steel,
molybdenum and copper and polymers, such as polyaramid fibers, polyamides,
cellulose, cellulose acetate, polyvinyl chloride, and polyester. Further, the
membrane
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30 may be gas impermeable or gas permeable, but preferably, is gas
impermeable.
The drug delivery initiator 316 includes a shock generating chamber 322 and
the
shock tube 308 coupled to and extending from the chamber 322 to terminate at
the
distal end 304. The shock generating chamber 322 has a mechanical coupling 318
at
a proximal end 320 which is adapted for mating with a cable 324 through which
an
electrical current is provided to the system 300. In the illustrated
embodiment, the
cable 324 is a fifty kilovolt insulated cable having a screw thread connector
326 which
is matable with the coupling 318 of the chamber 322. However, it will be
appreciated
by those of ordinary skill in the art that alternative types of mechanical
couplings are
possible and are within the spirit and scope of the invention.
The shock wave generating chamber 322 houses at least one pair of electrodes
334a, 334b mounted to an electrode support 336. The electrode support 336 is a
conductive member attached to a rigid extension 328 of the cable 324 and
electrically
connected to the center conductor of the cable. In the illustrative
embodiment, the
electrode support 336 has a substantially concave shape, as shown. While other
shapes
for the electrode support 336 are possible, the concave shape advantageously
assists in
focusing the current, and thus improves the reproducibility of the device.
A second pair of electrodes 340a, 340b may also be housed within the shock
wave generating chamber 322 in juxtaposition to the first electrode pair 334a,
334b,
respectively, as shown. The electrodes 340a, 340b are supported by respective,
elongated electrode support members 344a, 344b which are coupled to the wall
348 of
the chamber 322 by any suitable mechanism.
In use, a user actuatable switch (Figure 11) is actuated to cause an
electrical
current to be provided to the electrodes 334a, 334b via the cable 324 and the
conductive electrode support 336. The electrical current thus provided passes
between
electrode 334a and electrode 340a, as well as between electrode 334b and
electrode
340b. The electrodes 340a, 340b, which are mechanically and electrically
coupled to
the chamber wall 348, provide a return path for the current. Each of the two
currents
causes a respective shock wave to be generated having a wavefront which is
substantially orthogonal with respect to the current path. The resulting shock
waves
combine to generate a composite shock wave which has a wavefront oriented
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orthogonally with respect to the elongated axis of the delivery tube 308,
resulting in the
shock wave traveling along the elongated axis of the tube 308. With this
arrangement,
a shock wave is delivered to the membrane 310 for transfer to the target.
The characteristics of the shock wave thus produced, including magnitude and
rise time, can be varied by varying the level of the current passed between
the electrode
pairs and/or by introducing a gas or liquid into the initiator 316. Suitable
gases include
rare gases, such as nitrogen and helium. Suitable liquids include water and
other
liquids having a high dielectric breakdown characteristic. The gas or liquid
thus
introduced establishes different pressures within the initiator 316 and thus
different
shocks produced by the electric current.
Each of the electrodes 334a, 334b and 340a, 340b is comprised of a conductive
material having strength characteristics suitable for withstanding the shock
waves
generated in the system 300. Suitable materials include steel, titanium,
tungsten, and
carbon. Similarly, the drug delivery initiator 316 may be comprised of various
materials having strength characteristics suitable for withstanding the
generated shock
waves. In the illustrative embodiment, the initiator 316 is comprised of
stainless steel.
Alternative suitable materials for the initiator 316 include steel, titanium,
tungsten, and
carbon.
The drug delivery initiator 316 may be a unitary structure or, alternatively,
may
be comprised of more than one element assembled together for use, as shown in
the
embodiment of Figure 10. In particular, the initiator 316 includes a back
plate 350 on
which the mechanical coupling 318 is provided and a forward section 354 having
a
flange 356 suitable for mating with the back plate 350. In the illustrative
embodiment,
the forward section 354 is unitarily formed with the shock wave delivery tube
308.
Various mechanisms are suitable for securing the back plate 350 to the flange
356,
including the use of screws, as shown. The interface between the back plate
350 and
the forward section 354 may include one or more gaskets or other gas and/or
liquid
sealing mechanisms.
An inlet/outlet port 360 provides access to the shock wave generating chamber
322 through a valve 364. The tube 360 may be used to introduce pressurized gas
and/or liquid into the chamber 322 and/or to purge the chamber 322 between
uses.
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It will be appreciated by those of ordinary skill in the art that while the
embodiment of Figure 10 utilizes two electrode pairs, each of which generates
a shock
wave which combine to provide the composite shock wave which travels along the
elongated axis of the tube 308, a more simple, single electrode pair
arrangement may
be used. In this case, the two electrodes of the single electrode pair would
be disposed
along an axis substantially orthogonal to the elongated axis of the shock tube
308 in
order to generate a shock wave for transmission along the length of the tube.
As one
particular example, the electrodes 334x, 334b may be eliminated and a single
current
passed between electrodes 340a and 340b. As a further alternative, more than
two
electrode pairs may be used to generate a shock wave for delivery through the
tube
308.
Referring to Figure 11, an electrical circuit 370 for use with the system 300
of
Figure 10 to generate the current provided through the cable 324 is shown. The
circuit
370 includes a user actuatable switch 374 which, when actuated, couples a
supply
voltage, such as 110 volts AC, to the circuit. Actuation of the switch 374
causes a
relay 378 to close and a current to be provided through a first, pulse
transformer 376
and a second transformer 382.
The current through the pulse transformer 376 activates a high voltage/high
current switch 380, such as a Thyrotron or silicon controlled rectifier (SCR).
Firing
of the switch 380 causes a current to be provided to the electrodes 334x, 334b
via the
cable 324.
Referring to Figure 12, an alternate transdermal drug delivery system 400
includes a drug delivery initiator 402 comprising a shock generating chamber
404 and
a shock tube 406 coupled to and extending from the chamber 404. Like the
previously
described embodiment, a distal end 408 of the shock tube 406 is in shock wave
communication with a membrane 410 which is adapted for being disposed adjacent
to
a target material, e.g., a patient's skin, which is either in contact with the
skin or with
a drug housing containing a medicament. The membrane 410 may or may not be
attached to the distal end 408 of the shock tube 406 (i.e., the initiator 402
may be
either open or closed ended), but preferably is closed ended.
The system 400 of Figure 12 generates a shock wave in response to actuation
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of a "piston-type" valve arrangement housed within the chamber 404. The piston
412
includes an end cap 432 of the shock tube 406 and a member 434, which elements
are
secured together to move relative to the shock tube 406 and the chamber 404.
More
particularly, a back plate 414 separates the chamber 404 into a rear chamber
416 and
a forward chamber 418 in which the shock tube end cap 432 is disposed.
In use, the piston 412 is positioned as shown, with the end cap 432 covering a
proximal end 422 of the shock tube 406 as the rear chamber 416 is filed with a
pressurized gas. When the rear chamber 416 is vented to a lower pressure, such
as
atmospheric pressure, the piston elements 432, 434 move rapidly toward a rear
flange
428 of the chamber. This rapid movement of the piston 412 causes a shock wave
to
be generated having a wavefront orthogonal to the elongated axis of the shock
tube 406,
such that the shock wave travels along the elongated axis of the shock tube
toward the
membrane 410.
The drug delivery initiator 402 includes several inlet and outlet ports far
introducing gases and/or liquids into the chamber 404 and shock tube 406 and
for
evacuating the chamber and shock tube between uses. The gas handling system of
the
initiator 402 is described in a paper entitled A piston-actuated shock-tube,
with laser-
Schlieren diagnostics, S. M. Hurst and S. H. Bauer, Rev. Sci. Instrum., Vol.
64, No.
5, May 1993, which paper is incorporated herein by reference.
The initiator 402 may be comprised of various materials exhibiting suitable
strength characteristics to withstand the shock waves generated therein, such
as steel.
Likewise, the shock tube 406 may be comprised of various materials, including
steel.
Alternatively, certain components, such as the back plate 414, may be
comprised of
plastic. As with the previously described embodiments, the drug delivery
initiator 402
may be a unitary structure or, alternatively, may be comprised of more than
one
element assembled together for use.
Referring to Figure 13, an illustrative shock wave generating system 50'
includes a drug transport enhancement mechanism 36 for enhancing the
absorption of
a medicament into a patient's skin, beyond the increased absorption caused by
a shock
wave. That is, the transport enhancement mechanism 36 takes advantage of the
increased porosity of the patient's skin achieved with the application of a
shock wave
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transmitted through any of the shock wave generating systems described herein.
The
transport enhancement mechanism 36 may take various forms and may be provided
in
conjunction with any of the shock wave generating systems described herein.
The transport enhancement mechanism 36 may include an apparatus provided
as a separate unit from the shock wave initiator which is moved into alignment
with the
target material and actuated after delivery of the shock wave. Alternatively,
the
transport enhancement mechanism 36 may include an apparatus which is coupled
to the
shock wave initiator and actuated during delivery of the shock wave.
In one embodiment, the transport enhancement mechanism 36 is a pressure
generating unit which is operative to exert additional pressure on the target
(e.g., the
patient's skin) in the manner of the gas permeable membrane described above in
conjunction with Figure 1, to work in conjunction with the force of the shock
wave,
but over a longer time constant, to force the medicament into the skin. Such a
pressure
generating unit may be used to apply a high pressure liquid or gas to the
patient's skin,
for example, through a hose or nozzle directed to the target material.
Alternative suitable types of drug transport enhancement mechanisms include:
ultrasound, iontophoresis, mechanical vibration, surfactants and laser energy.
For
example, in the case of surfactants as a drug transport mechanism, a
surfactant, such
as soap, may be mixed with a medicament or may be applied after application of
the
medicament to the patient's skin in order to maintain the porosity of the skin
which has
been increased by application of a shock wave. One suitable type of
iontophoretic
device includes a patch which contains two reservoirs on its bottom surface
which, in
use, are in contact with the skin. One such reservoir contains a drug and both
reservoirs contain an electrode. In use, an electric current passes between
the
electrodes, with the drug being a carrier of the charge and passing through
the skin
where it is absorbed.
The use of laser energy as a drug transport enhancement mechanism is
particularly well suited for drug, or chemical application to hair follicles,
such as may
be useful in hair removal applications. In this example, the medicament
delivered to
a patient's skin may be a chemical that absorbs laser energy at a
predetermined
wavelength. Once the drug delivery apparatus is actuated, the chemical is
delivered
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through the skin to subdermal structures such as hair follicles. Laser energy
is
subsequently applied to the skin and efficiently delivered to the hair
follicles due to the
presence of the chemical absorber to remove hair.
As noted above, the drug or medicament may be applied to the patient's skin by
a variety of techniques, such as direct topical application or through a
permeable or
rupturable drug containing ampule, or a patch that is positioned adjacent to
the biologic
material.
Having described the preferred embodiments of the invention, it will now
become apparent to one of ordinary skill in the art that other embodiments
incorporating their concepts may be used. For example, it will be appreciated
by those
of ordinary skill in the art that various phenomena, in addition to shock
waves, may be
utilized to increase the porosity of a biologic material so as to enhance
medicament
absorption, such as electrical discharge, laser ablation, piezoelectric
devicestherefore
that these embodiments should not be limited to disclosed embodiments but
rather
i5 should be limited only by the spirit and scope of the appended claims. All
publications
and references cited herein are expressly incorporated herein by reference in
their
entirety.
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