U.S. patent application number 10/414928 was filed with the patent office on 2003-09-18 for transdermal delivery.
This patent application is currently assigned to Massachusetts General Hospital. Invention is credited to Doukas, Apostolos, Flotte, Thomas J., Lee, Shun Kwan.
Application Number | 20030176836 10/414928 |
Document ID | / |
Family ID | 24349381 |
Filed Date | 2003-09-18 |
United States Patent
Application |
20030176836 |
Kind Code |
A1 |
Doukas, Apostolos ; et
al. |
September 18, 2003 |
Transdermal delivery
Abstract
A device for transdermal delivery of a composition includes a
housing partitioned into a delivery chamber arranged to contain the
composition and a detonation chamber mechanically coupled to the
delivery chamber. The detonation chamber is intended to contain an
energetic material producing an impulse transient in response to a
detonating stimulus. The housing is coupled to an energy coupling
element, or detonator, for communicating energy provided by an
external energy source into the detonating stimulus in the
detonation chamber. The detonator can detonate the energetic
material by causing an electrical discharge or spark within the
detonation chamber. The detonator can be a piezoelectric film in
electrical communication with the energetic material.
Inventors: |
Doukas, Apostolos; (Belmont,
MA) ; Lee, Shun Kwan; (Boston, MA) ; Flotte,
Thomas J.; (Boston, MA) |
Correspondence
Address: |
FISH & RICHARDSON PC
225 FRANKLIN ST
BOSTON
MA
02110
US
|
Assignee: |
Massachusetts General
Hospital,
|
Family ID: |
24349381 |
Appl. No.: |
10/414928 |
Filed: |
April 16, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10414928 |
Apr 16, 2003 |
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09587333 |
Jun 5, 2000 |
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6562004 |
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Current U.S.
Class: |
604/93.01 ;
604/69 |
Current CPC
Class: |
A61K 9/0009 20130101;
A61M 2037/0007 20130101; A61K 9/7023 20130101; A61K 9/0021
20130101; A61M 37/00 20130101 |
Class at
Publication: |
604/93.01 ;
604/69 |
International
Class: |
A61M 031/00 |
Claims
What is claimed is:
1. A device for transdermal delivery of a composition, the device
comprising: a delivery chamber arranged to contain the composition;
and a detonation chamber arranged to contain an energetic material;
a first dividing membrane between the delivery chamber and the
detonation chamber; and a detonator that causes the energetic
material to explode, thereby initiating an impulse transient that
passes from the detonation chamber, through the delivery chamber,
and out of the transdermal delivery device.
2. The device of claim 1, further comprising an expansion chamber
arranged between the delivery chamber and the detonation chamber,
and a second dividing membrane between the expansion chamber and
the detonation chamber.
4. The device of claim 1, wherein the delivery chamber and the
detonation chamber are substantially parallel layers.
5. The device of claim 2, wherein the delivery chamber, the
detonation chamber, and the expansion chamber are substantially
parallel layers.
6. The device of claim 1, wherein the detonator comprises a
piezoelectric film in electrical communication with the energetic
material in the detonation chamber.
7. The device of claim 1, wherein the detonator comprises an
electrode for connecting to a DC voltage source, the electrode
being in electrical communication with the energetic material in
the detonation chamber.
8. The device of claim 1, wherein the detonator comprises a DC
voltage source and an electrode for connecting the DC voltage
source to the energetic material in the detonation chamber.
9. The device of claim 2, wherein the expansion chamber contains an
expansion material selected to increase in volume in response to
the impulse transient.
10. The device of claim 9, wherein the expansion material is a
hydrogel.
11. The device of claim 2, wherein the expansion chamber contains
precursors to an expansion material, the precursors forming the
expansion material in response to the impulse transient.
12. The device of claim 11, wherein the expansion chamber contains
a first compartment containing a first precursor and a second
compartment containing a second precursor and the first and second
compartment are configured to rupture in response to the impulse
transient, thereby allowing mixing of the first and second
precursors to form the expansion material.
13. The device of claim 1, wherein the delivery chamber contains a
surfactant.
14. The device of claim 13, wherein the surfactant is selected from
the group consisting of sodium lauryl sulfate, benzalkonium
chloride, and cocoamidopropyl betaine.
15. The device of claim 1, wherein the delivery chamber contains a
composition that includes a pharmaceutical agent.
16. The device of claim 15, wherein the pharmaceutical agent is
selected from the group consisting of a protein, a nucleic acid, a
local anesthetic, and a photosensitizer.
17. The device of claim 1, wherein the delivery chamber contains a
composition that includes a cosmetic agent.
18. The device of claim 1, wherein the delivery chamber contains
precursors to the composition, the precursors forming the
composition in response to the impulse transient.
19. The device of claim 1, wherein the delivery chamber contains a
first compartment containing a first precursor and a second
compartment containing a second precursor and the first and second
compartment are configured to rupture in response to the impulse
transient, thereby allowing mixing of the first and second
precursors to form the composition.
20. The device of claim 1, wherein the detonation chamber contains
an energetic material selected to generate an impulse transient
having a peak pressure in excess of 350 bar.
21. The device of claim 20, wherein the energetic material is
selected to generate an impulse transient having a peak
overpressure in the range between approximately 600 bar and
approximately 800 bar.
22. The device of claim 1, wherein the detonation chamber contains
an energetic material selected from the group consisting of
nitrocellulose, glycidyl azide polymer, bis-azidomethyloxetane
polymer, azidomethyl methyloxetane polymer, and silver azide.
23. The device of claim 1, wherein the detonation chamber is filled
with a medium that contains an energetic material.
24. The device of claim 1, wherein the energetic material is
deposited on the first dividing membrane.
25. The device of claim 1, wherein the detonation chamber contains
precursors to the energetic material, the precursors being
configured to form the energetic material in response to the
detonating stimulus.
26. The device of claim 1, wherein the detonation chamber contains
a first compartment containing a first precursor and a second
compartment containing a second precursor and the first and second
compartment are configured to rupture in response to the detonating
stimulus, thereby allowing mixing of the first and second
precursors to form the energetic material.
27. The device of claim 1, wherein the first dividing membrane is
made from a material selected from the group consisting of mylar
and polyethylene.
28. The device of claim 2, wherein the second dividing membrane is
made from a material selected from the group consisting of mylar
and polyethylene.
29. The device of claim 2, wherein the second dividing membrane is
selected to be deformable in response to the impulse transient.
30. The device of claim 1, wherein the first dividing membrane is
selected to provide an impedance match between the delivery chamber
and the detonation chamber.
31. A method for delivering a composition through the skin, the
method comprising: contacting the skin with a delivery chamber
containing the composition, the delivery chamber being mechanically
coupled to a detonation chamber; and detonating an energetic
material disposed in a detonation chamber, thereby generating an
impulse transient that propagates through the delivery chamber and
permeabilizes the skin, wherein the composition is delivered
through the skin.
32. The method of claim 31, wherein detonating the energetic
material comprises deforming a piezoelectric film in electrical
communication with the energetic material, thereby generating an
electrical discharge to detonate the energetic material.
33. The method of claim 31, wherein detonating the energetic
material comprises applying a voltage across first and second
electrodes, the first and second electrodes being in electrical
communication with the energetic material.
34. A method of manufacturing a transdermal delivery device, the
method comprising: dividing a housing into separate delivery and
detonation chambers; placing an energetic material in the
detonation chamber; and coupling a detonator to the energetic
material for transforming energy provided by an external energy
source into a detonating stimulus.
35. The method of claim 34, wherein coupling a detonator comprises
providing a piezoelectric material on the housing, the
piezoelectric material being in electrical communication with the
energetic material.
36. The method of claim 34, wherein coupling a detonator comprises
providing electrodes for connection to a voltage source, the
electrodes being in electrical communication with the energetic
material.
37. The method of claim 34, further comprising dividing the housing
into an expansion chamber in mechanical communication with the
delivery chamber and the detonation chamber.
38. The method of claim 35, further comprising placing an expansion
material in the expansion chamber, the expansion material being
selected to expand in volume in response to an impulse transient
generated by the energetic material.
39. The method of claim 34 further comprising placing a composition
into the delivery chamber.
Description
FIELD OF THE INVENTION
[0001] This invention relates to transdermal delivery of
compositions.
BACKGROUND OF THE INVENTION
[0002] Despite its often placid appearance, the environment we live
in is one that is unrelentingly hostile to human life. In addition
to being contaminated by pathogenic microorganisms, the environment
is filled with compositions that, if permitted to interact with the
internal structures of the human body, would seriously interfere
with the many chemical reactions required to sustain life. An
important function of the human skin is to limit the entry of
undesirable compositions into the human body.
[0003] The effectiveness of the skin at excluding harmful
compositions from the interior of the human body allows us to
freely apply lotions, cosmetics, topical ointments, and insect
repellents on the skin with little concern about the toxicity of
those compositions. However, this same effectiveness sharply
curtails our ability to deliver medicines intended for systemic
distribution through the skin and into the bloodstream.
[0004] There exist devices that passively deliver compositions
through the skin. Because of their reliance on diffusion, only very
small molecules can readily be delivered using such passive
devices. In addition, the time required to deliver the composition
is limited by the rate of diffusion and by the concentration
gradient.
[0005] There also exist devices that actively deliver compositions
through the skin. Such active transdermal delivery devices
typically rely on iontophoresis, in which a voltage drives charged
molecules of the composition through the skin, phonophoresis, in
which ultrasonic waves exert a mechanical force that drives the
composition through the skin, and photophoresis, in which a laser
assists in the delivery of a composition through the skin. The
requirement of complex devices in the latter two cases and the need
to ionize the composition in the former case limits the widespread
use of these devices.
SUMMARY OF THE INVENTION
[0006] The invention is based on the discovery that an explosion
can be used to generate a high pressure impulse transient or stress
wave that is effective to temporarily enhance the permeability of
the skin. The invention provides transdermal delivery devices and
methods for safely and efficiently delivering a composition through
the skin. These devices include an explosive material that is
detonated to generate impulse transients that permeabilize the skin
and to thereby allow the composition to diffuse passively through
the permeabilized skin. The invention also provides devices and
methods for harnessing the forces generated by these impulse
transients to actively drive the composition through the
temporarily permeabilized skin.
[0007] Each impulse transient is a broad-band compressive wave
having a rise time of approximately 1 nanosecond and a peak
pressure approximately 600 bar less than that overpressure that
would cause skin damage. The impulse transient typically has a
duration between 100 nanoseconds and 1100 nanoseconds, e.g.,
500-700 nanoseconds. The impulse transient is typically generated
by detonating an energetic material in the device or by causing an
explosive reaction in the device.
[0008] A transdermal delivery device according to the invention
includes a housing having a partition that divides the housing into
a detonation chamber for containing an energetic, or explosive
material and a delivery chamber, for containing a composition to be
delivered across a patient's skin. The detonation chamber is
mechanically coupled to the delivery chamber so that an impulse
transient generated within the detonation chamber propagates into
and through the delivery chamber and into the patient's skin. The
device further includes an energy coupling element for transforming
energy provided by an external source into a detonating stimulus
for detonating the energetic material in the detonation
chamber.
[0009] In one embodiment, the transdermal delivery device includes
a second partition across the housing so that the housing also
includes an expansion chamber that is in mechanical communication
with both the detonation chamber and the delivery chamber. The
expansion chamber contains an expansion material that expands in
volume in response to an impulse transient. Preferably, the
expansion chamber is disposed between the detonation chamber and
the delivery chamber.
[0010] The energy coupling element can be a piezoelectric film in
electrical communication with the energetic material in the
detonation chamber. Another convenient energy coupling element for
the transdermal delivery device is a DC voltage source in
electrical communication with the energetic material in the
detonation chamber.
[0011] The invention also includes a method of manufacturing a
transdermal delivery device by dividing a housing into a delivery
chamber and a detonation chamber separate from the delivery
chamber. An energetic material is then placed in the detonation
chamber and a composition to be delivered transdermally can be
placed in the delivery chamber. An energy coupling element, or
detonator, is then coupled to the energetic material within the
detonation chamber for transforming energy provided by an external
energy source into a detonating stimulus.
[0012] Preferably, the energy coupling element is a piezoelectric
material on the housing, the piezoelectric material being in
electrical communication with the energetic material. However, the
energy coupling element can also include electrodes in
communication with the energetic material. The electrodes can be
attached to a voltage source when the device is to be
detonated.
[0013] The method can also include dividing the housing into an
expansion chamber in mechanical communication with both the
delivery chamber and the detonation chamber. The expansion chamber
is then filled with an expansion material selected to expand in
volume in response to an impulse transient generated by the
energetic material.
[0014] A method for delivering a composition across the skin, in
accord with the principles of the invention, includes placing, on
the skin, a housing having a detonation chamber mechanically
coupled to a delivery chamber containing the composition. With the
housing on the skin, an energetic material disposed in a detonation
chamber is then detonated. This generates an impulse transient that
propagates through the delivery chamber and permeabilizes the
skin.
[0015] In one embodiment, the method also includes providing an
expansion chamber in mechanical communication with the detonation
chamber and the delivery chamber. This expansion chamber contains
an expansion material selected to expand in volume in response to
the impulse transient generated within the detonation chamber.
[0016] To detonate the energetic material, one deforms a
piezoelectric film in electrical communication with the energetic
material. This generates an electrical discharge to detonate the
energetic material. Alternatively, the energetic material can be
detonated by applying a voltage across first and second electrodes
in electrical communication with the energetic material.
[0017] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, suitable methods and materials are described below. All
publications, patent applications, patents, and other references
mentioned herein are incorporated by reference in their entirety.
In case of conflict, the present specification, including
definitions, will control. In addition, the materials, methods, and
examples are illustrative only and not intended to be limiting.
[0018] A transdermal delivery device according to the invention
enables the rapid delivery of a composition through the skin by
harnessing the energy from an explosion to permeabilize the skin.
The explosion is detonated without the intervention of complex
devices such as lasers or ultrasound generators. This greatly
simplifies the administration of compositions.
[0019] In addition, the transdermal delivery device harnesses the
force of the explosion to propel the composition across the skin.
As a result, considerably greater quantities of the composition can
be transported across the skin during the interval in which the
skin is rendered permeable by the impulse transient generated by
the explosion.
[0020] Other features and advantages of the invention will be
apparent from the following detailed description, and from the
claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 is a schematic cross-section of a transdermal
delivery device having a piezoelectric film.
[0022] FIG. 2A is a schematic cross-section of a transdermal
delivery device in which the composition to be delivered is
separated into two compartments.
[0023] FIG. 2B is a schematic cross-section of the transdermal
delivery device of FIG. 2A in which the compartments have been
ruptured.
[0024] FIG. 3A is a schematic cross-section of a transdermal
delivery device in which the expansion material is separated into
two compartments and the energetic material is deposited onto the
proximal dividing membrane.
[0025] FIG. 3B is a schematic cross-section of a transdermal
delivery device in which a precursor of an energetic material is
separated into a compartment.
[0026] FIG. 3C is a schematic cross-section of the transdermal
delivery device of FIG. 3B in which the compartment has been
ruptured.
[0027] FIG. 4 is a schematic cross-section of a transdermal
delivery device connected to a DC voltage source.
[0028] FIG. 5 is an impulse transient generated by an explosion in
the detonation chamber of the device shown in FIG. 1.
[0029] FIG. 6 is a schematic cross-section of the transdermal
delivery device of FIG. 1 following detonation.
[0030] FIG. 7 is a schematic cross-section of a transdermal
delivery device having only two layers.
[0031] FIG. 8 is a schematic cross-section of a multi-element
transdermal delivery device.
DETAILED DESCRIPTION
[0032] The invention provides transdermal delivery devices and
methods for delivering compositions through the skin by harnessing
the energy generated from an explosion to permeabilize the skin,
and, optionally, to propel the composition through the
permeabilized skin. The composition can include one or more
constituents dissolved or suspended in a coupling medium.
[0033] A transdermal delivery device incorporating principles of
the invention exploits the fact that an impulse transient incident
on the skin temporarily enhances its permeability, thereby creating
a window of opportunity for the transdermal delivery of the
composition. During this window of opportunity, hereafter referred
to as a "delivery interval," the transdermal delivery device either
allows the composition to flow passively into and through the
permeabilized skin or harnesses the forces generated by an
explosion to actively propel the composition through the
temporarily permeabilized skin.
[0034] Structure of the Transdermal Delivery Device
[0035] Referring to FIG. 1, a transdermal delivery device 10
includes a vertical wall 14 having a distal rim 16 and a proximal
rim 18. A distal cap 20 and a proximal cap 22 engage, respectively,
the distal rim 16 and the proximal rim 18 of the vertical wall 14.
Together, the vertical wall 14, the distal cap 20, and the proximal
cap 22 form a housing 24 enclosing an interior volume. A proximal
dividing membrane 26 and a distal dividing membrane 28 span the
interior volume enclosed by the housing 24, thereby partitioning
the interior volume into a delivery chamber 30, a detonation
chamber 32, and an expansion chamber 34 disposed between the
delivery chamber 30 and the detonation chamber 32.
[0036] The vertical wall 14 preferably has sufficient flexibility
to conform to the shape of the body surface and sufficient rigidity
to withstand the forces generated by an explosion in the detonation
chamber 32. Typically, the peak pressure generated in the
detonation chamber 32 is on the order of 600-1000 bar. However,
higher peak pressures, such as 900 bar to 2000 bar are possible
depending on the nature of the composition to be delivered,
provided that the peak pressure is less than that which would cause
permanent skin damage. In addition, lower peak pressures, for
example 400-600 bar, can be generated, with the lower bound being
the peak pressure that fails to sufficiently permeabilize the skin.
A suitable vertical wall 14 can be fabricated from stacked rubber
washers or similar annular structures (e.g., plastic washers). The
dimensions of the interior volume are tailored for the particular
application. For example, a large dosage can require a large
footprint on the skin and will therefore require the vertical wall
14 to enclose a large area. The height of the vertical wall 14
likewise depends on the specific application. For example, if rapid
delivery is required, the expansion chamber 34 may need more
volume, in which case the vertical wall 14 will need to be high
enough to accommodate an expansion chamber 34 having the requisite
volume. Similarly, depending on the nature of the explosive
material, the detonation chamber 32 may need more volume to
accommodate gaseous byproducts of the explosion. For most
applications, the vertical wall 14 is no more than about 5 mm high,
but can vary from 2 mm to 10 mm.
[0037] It is desirable that the impulse transient generated in the
detonation chamber 32 be transmitted into the expansion chamber 34.
For this reason, the proximal dividing membrane 26 separating the
detonation chamber 32 from the expansion chamber 34 is selected to
provide an impedance match between the wave propagation medium in
the detonation chamber 32 and that in the expansion chamber 34,
thereby minimizing any reflections at the boundary between the two
chambers. The impedance required of the proximal dividing membrane
26 depends on both the material properties of the wave propagation
medium in the detonation chamber 32 and that in the expansion
chamber 34. However, if the proximal dividing membrane 26 is
sufficiently thin relative to the spatial extent (typically 1.5 mm)
of the pressure wave, the effect of the proximal dividing membrane
26 will be minimal. In one embodiment, the proximal dividing
membrane 26 is a polyethylene membrane or a mylar membrane
sandwiched between a pair of rubber washers or similar annular
structures.
[0038] The distal dividing membrane 28 separating the expansion
chamber 34 from the delivery chamber 30 is preferably impermeable.
This will ensure that forces generated by expansion of the material
within the expansion chamber 34 are not dissipated by diffusion or
transport through the distal dividing membrane 28. In addition, the
distal dividing membrane 28 is sufficiently flexible so that forces
generated by expansion of material within the expansion chamber 34
can force the distal dividing membrane 28 into the delivery chamber
30, thereby reducing the volume of the delivery chamber 30 and
providing motive force for transdermal delivery of its contents. In
one embodiment, the distal dividing membrane 28 is a polyethylene
membrane or a mylar membrane sandwiched between a pair of rubber
washers or similar annular structures.
[0039] The distal cap 20 is preferably flexible enough to conform
to the portion of the body on which the transdermal delivery device
10 is to be applied. In addition, the distal cap 20 must be
sufficiently permeable so that the rapid decrease in volume of the
delivery chamber 30 propels the contents of the delivery chamber 30
through the distal cap 20 and into the skin, rather than rupturing
the device. The distal cap 20 can be permeable at the molecular
level. However, the distal cap 20 can also include perforations 21
to facilitate the exit of the contents of the delivery chamber 30.
These perforations 21 can be covered with a plastic film adhering
to the distal cap 20 that is peeled off before using the device
10.
[0040] The proximal cap 22 is selected to be sufficiently rigid to
avoid dissipating energy through deformation when an explosion
occurs in the detonation chamber. The proximal cap 22 must,
however, also be sufficiently flexible to conform to the shape of
the body part to which the transdermal delivery device 10 is
applied. Both the dimensions of the proximal cap 22 and the
materials of which it is made can be altered for particular
applications so long as the foregoing constraints are met. For
example, virtually any material can form a rigid proximal cap 22 if
it is made sufficiently thick. Similarly, if the explosive force is
not excessive, materials and dimensions that would otherwise be
unusable will become usable. The extent to which the proximal cap
22 must be flexible depends on the radius of curvature of the body
part to which the transdermal delivery device 10 is to be applied,
the cross-sectional area of the transdermal delivery device 10, and
the height of the vertical wall 14.
[0041] Contents of the Structure: Composition
[0042] When configured for operation, the delivery chamber 30
contains a composition 36 to be delivered transdermally. The
composition 36 can include one or more constituents in a coupling
medium. Typical coupling media for use in the composition 36
include: aqueous media, such as water in solution with a
surfactant; or oil-based media, such as castor oil. The addition of
a surfactant is particularly advantageous because a surfactant
tends to extend the delivery interval. Examples of suitable
surfactants include sodium lauryl sulfate, benzalkonium chloride,
and cocoamidopropyl betaine. The choice of a surfactant and the
concentration of surfactant depend on the irritability of the
person's skin and the desired delivery interval. This in turn will
depend on the composition 36 to be delivered and the rate at which
it can be delivered.
[0043] Constituents that can be included in the composition 36
include: large protein molecules such as insulin, polypeptides,
antibodies, or antigens for allergy testing; vaccines; genetic
material such as oligonucleotides, DNA, RNA, and plasmids; local
anesthetics such as lidocaine and benzocaine; and photosensitizers
such as benzoporpherene derivative monoacid ring A (BPD-MA). Other
examples include hormones such as adrenaline, testosterone,
estrogen, and various pituitary hormones; olfactory agents intended
to introduce a pleasing aroma on the skin; antibiotics, such as
penicillin, and streptomycine; nitroglycerine for use in connection
with cardiac difficulties; psychopharmacological agents;
tranquilizers that can be quickly applied by law enforcement agents
during the course of apprehending a particularly unwilling suspect;
nicotine; analgesics such as acetominophen, ibuprofein and the
like; anti-allergy medications; and vitamins and antioxidants that
would otherwise be degraded in the digestive tract. Any of these,
and other compositions, can be heated before generation of the
impulse transient in order to facilitate their transport through
the skin.
[0044] If the desired composition 36 has a short shelf life,
precursors of that composition 36 may be separated into individual
compartments 37a, 37b within the delivery chamber 30 as shown in
FIG. 2A. These compartments 37a, 37b are configured and selected to
rupture in response to the impulse transient, thereby spilling
their contents into the delivery chamber 30 as shown in FIG. 2B.
Once mixed together in the delivery chamber 30, the precursors form
the desired composition 36. This design can also be used to deliver
compositions that should not be in contact prior to delivery.
[0045] Compositions 36 can also include such cosmetic agents such
as tattoo inks. For example, a device can be designed to apply a
portion of a tattoo image or an entire image in one quick and
painless operation. These tattoos would typically be temporary,
because the inks are deposited into the epidermis rather than the
dermis. In addition, a multiplicity of transdermal delivery devices
10 loaded with inks or coloring agents can cover a substantial
portion of the body, thereby providing the ability to
subcutaneously change the color of a large portion of the skin to
simulate a suntan without the risk of excessive UV exposure.
[0046] A multiplicity of transdermal delivery devices 10 having
distal caps perforated according to particular designs and loaded
with inks of different color can be disposed to cover expanses of
skin. When detonated, each transdermal delivery device 10 will
imprint on the skin a portion of an image, thereby forming a
wearable mosaic on the skin. Because the inks are delivered
subcutaneously, the mosaic thus impregnated into the person's skin
can last long enough and withstand the environmental stresses
associated with a weekend on the beach, during which the wearable
mosaic can be suitably displayed. However, since the stratum
corneum layer in which the ink is impregnated will eventually
slough off, the wearable mosaic can be replaced from time to
time.
[0047] The use of a luminous component that is invisible under
ordinary light but visible in the dark would enable one to "wear"
such novelties as a luminous skeleton for Halloween costumes.
Diferent effects can be achieved by providing transdermal delivery
devices 10 having delivery chambers 30 loaded with materials that
fluoresce when exposed to UV light.
[0048] Localization of the composition using the methods and
devices of the invention is advantageous because the composition
can be delivered with highly localized effects to areas of diseased
cells, thereby sparing other tissues of the body. This advantage is
particularly apparent when the alternative is to deliver a drug
systemically, in which case the drug must be delivered in
substantially higher concentrations in order to compensate for
dilution in the bloodstream and in which case the drug is apt to
reach all internal organs and require metabolization by the
liver.
[0049] Contents of the Structure: Energetic Material
[0050] The detonation chamber 32 contains one or more materials,
collectively referred to as energetic material 40, that are
selected to detonate or to react in a manner resulting in
detonation when exposed to a stimulus of energy.
[0051] The energetic material 40 contained within the detonation
chamber 32 is selected to generate, upon detonation, an impulse
transient having a peak pressure greater than the 350 bar needed to
permeabilize the skin. Typically, the peak pressure is, between
about 600 and 1000 bar. The peak pressure can be high as about 2000
bar. However, such high pressures are not needed to permeabilize
the skin. The range of peak pressure is selected to be sufficient
to permeabilize the outermost layer of the epidermis 52, the
stratum corneum without causing damage to the viable parts of the
skin, such as the dermis and the epidermis.
[0052] The energetic material 40 can generate an impulse transient
by, for example, rapidly vaporizing upon exposure to an energy
stimulus. Alternatively, the energy stimulus may provide the
activation energy for a rapid and exothermic chemical reaction. In
another embodiment, the energy stimulus may place reactants into
proximity so that a spontaneous, rapid and exothermic reaction
occurs. Alternatively, the energy stimulus can place reactants into
contact with a catalyst that will lower the activation energy
sufficiently to allow a spontaneous reaction to occur.
[0053] The selection of an energetic material 40 depends on the
particular application. Examples of suitable energetic materials
include nitrocellulose, glycidyl azide polymer,
bis-azidomethyloxetane polymer, azidomethyl methyloxetane polymer
and silver azide.
[0054] The energetic material 40 can be dispersed throughout the
detonation chamber 32 in an optional coupling medium such as a gel,
as shown in FIG. 1. Alternatively, the energetic material 40 can be
deposited onto the proximal dividing membrane 26 so that the
detonation chamber 32 can be used to contain gaseous byproducts of
the explosion, as shown in FIG. 3A. In another embodiment, shown in
FIG. 3B, a precursor for formation of an explosive material can be
contained within a sealed compartment 41 in the detonation chamber
32. The sealed compartment 41 can be ruptured upon the application
of an external force, as shown in FIG. 3C. The precursor can then
mix with remaining contents in the detonation chamber 32 to form an
energetic material 40 that can be detonated upon application of an
appropriate stimulus. Alternatively, the precursor can chemically
react with remaining contents in the detonation chamber 32 and
cause an explosion as a byproduct of the reaction.
[0055] Contents of the Structure: Expandable Material
[0056] The expansion chamber 34 contains an-expandable material 42
selected to expand in volume in response to an explosion in the
adjacent detonation chamber 32. The expandable material 42 within
the expansion chamber 34 is a material, or a combination of
materials, that expands in response to an impulse transient.
Precursors to the expandable material can be contained within
sealed compartments 43a, 43b in the expansion chamber 34, as shown
in FIG. 3A. These sealed compartments 43a, 43b can be ruptured by
the force of an explosion in the detonation chamber 32. The choice
of an expandable material 42 depends on the details of the
particular application. An expandable material 42 that expands
rapidly is useful when the composition in the delivery chamber 30
must be delivered rapidly. An example of a suitable expandable
material 42 is a hydrogel formed by rupturing a water bag within
the expansion chamber 34 and wetting a hydrogel precursor contained
within the expansion chamber 34. Other examples of expandable
materials include heparinized polymers, polypeptide elastomers,
chitosan poly(ethylene oxide), crosslinked cellulose ethers, and
poly(N-isopropylacrylamide).
[0057] Detonator
[0058] The detonation chamber 32 is coupled to an energy source for
providing the energy stimulus required to detonate the energetic
material 40 contained within the detonation chamber 32. In the
embodiment shown in FIG. 1, this coupling is achieved by a
piezoelectric film 44 in electrical communication with the
detonation chamber 32. A transdermal delivery device 10 in which a
piezoelectric film 44 couples energy into the detonation chamber 32
is particularly advantageous because such a device can be easily
activated by a mechanical deformation, for example by squeezing or
pressing the piezoelectric film 44.
[0059] A distal surface 46 of the piezoelectric film 44 is in
electrical communication with a first electrode 48 that penetrates
the proximal cap 22. This places the first electrode 46 into
contact with the energetic material 40 in the detonation chamber
32. In this configuration, a deformation of the piezoelectric film
44 causes charge to migrate to the distal surface 46. This surface
charge then migrates to the surface of the first electrode 48
located inside the detonation chamber 32.
[0060] A proximal surface 50 of the piezoelectric film 44 is in
electrical communication with a second electrode 52 disposed on the
proximal surface 50. This second electrode is, in turn, in
electrical communication with a third electrode 54 disposed on the
proximal dividing membrane 26 by way of a conducting path 56 that
penetrates the proximal cap 22 and travels along an inner surface
58 of the vertical wall 14. The third electrode is thus in
electrical contact with the energetic material 40 in the detonation
chamber 32. In this configuration, deformation of the piezoelectric
layer 44 causes charge to collect on the proximal surface 50 of the
piezoelectric film 44. This surface charge in turn migrates to the
third electrode 54 by way of the second electrode 52 and the
conducting path 54.
[0061] In the embodiment shown in FIG. 3A, in which the energetic
material 40 is imprinted on the proximal dividing membrane 26, the
surface charge generated on the distal surface 46 of the
piezoelectric film 44 must be brought into contact with the
energetic material 40. This can be achieved, as shown in FIG. 3A,
by providing a second conducting path 60 between the first
electrode 48 and a fourth electrode 62 disposed on the proximal
dividing membrane 26.
[0062] In the embodiment shown in FIG. 1, a deformation of the
piezoelectric film 44 causes surface charge to collect on the first
and third electrodes 48, 54. Depending on the extent of the
deformation, this surface charge generates, within the detonation
chamber 32, an electric field of sufficient magnitude to cause an
electrical discharge within the detonation chamber 32. This
discharge triggers detonation of the energetic material 40 in the
detonation chamber 32.
[0063] As shown in FIG. 4, the detonation chamber 32 can also be
coupled to an energy source by placing first and second electrodes
60, 62 in electrical communication with the detonation chamber 32
and connecting the first and second electrodes 60, 62 to a DC
voltage source 64. A transdermal delivery device 10 in which the
energy source is a DC voltage source 64 is advantageous because the
voltage can more readily be controlled and because higher voltages
can be generated, thereby ensuring the occurrence of an electrical
discharge even when the medium within the detonation chamber 32 has
a very high resistivity.
[0064] In the embodiment shown in FIG. 4, the DC voltage source 64
generates an electric field within the detonation chamber 32 by
causing surface charge to collect on the first and second
electrodes 60, 62. The first electrode 60 penetrates the distal cap
so that it is in intimate contact with the explosive material 40 in
the detonation chamber 32. The second electrode 62 is disposed on
the proximal dividing membrane and brought into contact with the DC
voltage source 64 by way of a conducting strip 66 on the inside
surface 58 of the vertical wall 14. The DC voltage source can be a
line-powered DC power supply, e.g. a transformer with a rectifier
having suitable ripple cancellation filters, or a battery, such as
a NiCad battery, an alkaline battery, a conventional carbon core
zinc battery, a lithium battery, or a lead acid battery. By
suitable choice of voltage, the electric field can be made of
sufficient magnitude to cause an electrical discharge within the
detonation chamber 32. This discharge triggers detonation of the
energetic material 40 in the detonation chamber 32.
[0065] Other energy sources can also be used to detonate an
explosion in the detonation chamber 32. For example, a catalyst
moved into contact with the energetic material 40 can be used to
detonate the explosion. Alternatively, the detonation chamber 32
can include reactants that are brought together so as to initiate a
reaction that ultimately results in an explosion. The reactants
may, for example, occupy two regions within the detonation chamber
32 that are separated by an easily ruptured membrane, as shown in
FIGS. 3B and 3C. Another mechanism for detonating the energetic
material 40 is to locally apply heat to the material. This can be
achieved by applying a heat source to the energetic material.
Examples of such heat sources include hot water bottles, electric
heat pads, heat pads powered by an exothermic reaction caused by
bringing reactants into contact, e.g. by breaking membranes
separating the reactants, the body heat from a hand, solar heat,
augmented perhaps by a suitable lens or magnifying glass, heat from
a match held in proximity to the device, or a fuse lit by a
flame.
[0066] Method of Manufacture
[0067] Referring again to FIG. 1, the transdermal delivery device
10 as described herein can be manufactured by gluing a first rubber
washer 67a to a distal cap 20 so that the inner surface of the
first rubber washer 67a forms a wall for the delivery chamber 30
and the distal cap 20 forms a floor of the delivery chamber 30. The
delivery chamber 30 is then filled with a suitable composition 36
and covered with the distal dividing membrane 28. A second rubber
washer 67b is then glued onto the first rubber washer 67a so that
the first and second rubber washers hold between them the distal
dividing membrane 28. A suitable adhesive for use in assembly of
the device 10 is an epoxy. However, other adhesives, e.g. rubber
cement, silicone, urethane, UV cured adhesives, cyanoacrylates, or
other acrylic based adhesives can be used.
[0068] The inner surface of the second rubber washer 67b forms the
wall of the expansion chamber 34 and the distal dividing membrane
28 forms the floor of the expansion chamber 34. The expansion
chamber 34 is then filled with the expandable material 42 or with
structures that contain precursors of the expandable material 42.
Once this is done, the proximal dividing membrane 26 is placed over
the expansion chamber 34 and a third rubber washer 67c is glued
onto the second rubber washer 67b so that the second and third
washers hold between them the proximal dividing membrane 26. The
inner surface of the third washer 67a and the proximal dividing
membrane 26 now form the wall and floor of the detonation chamber
32. The stacked first, second, and third washers together form the
vertical wall 14 of the transdermal delivery device 10.
[0069] The next step in the manufacture of the transdermal delivery
device 10 is to imprint electrical connections on the wall of the
detonation chamber 32, so as to form the conducting path 56, and on
the proximal surface of the proximal dividing membrane 26, so as to
form the third electrode 54. This is most easily accomplished by
stenciling conductive paint on those surfaces.
[0070] Once the electrical connections are in place, the energetic
material is placed in the detonation chamber 32 and the proximal
cap 22 is glued onto the third washer 67c. The first electrode 48
is then inserted through the proximal cap 22 and a piezoelectric
material is glued onto the proximal cap 22. The second electrode 52
and the remainder of the conducting path 56 is then stenciled onto
the proximal cap 22.
[0071] The Impulse Transient
[0072] An impulse transient generated by an explosion in the
detonation chamber 32 has a peak pressure that is sufficient to
permeabilize the skin but not sufficient to cause skin damage. The
numerical quantities will depend on what portion of the skin is to
be permeabilized. To permeabilize most areas of skin covered by the
stratum corneum, this peak pressure is more than about 400 bar,
which is the approximate threshold for permeabilizing the stratum
corneum, and less than about 1800 to 2000 bar. Preferably, the
pressure is approximately 1000 bar. For skin covered by a mucosal
layer, the peak pressure required is considerably lower. For
permeabilizing epithelial mucosal layers, the preferred peak
pressure is between about 300 and 600 bar.
[0073] The impulse transient generated by the explosion is not a
shock wave but a pulse having a finite rise time on the order of
200 nanoseconds or less. The preferred duration of the impulse
transient is generally between 100 nanoseconds and 1100
nanoseconds. FIG. 5 shows waveform for a typical impulse
transient.
[0074] Operation of the Transdermal Delivery Device
[0075] In operation, the housing 24 of the transdermal delivery
device 10 rests with its distal cap 20 in contact with the skin 68.
Because the delivery interval for most compositions 36 is brief,
the housing 24 can simply be held on the skin by the patient during
the delivery interval. Alternatively, the housing 24 can be
strapped onto the skin 68, e.g., using adhesive tape or a hook and
loop fastening tape. In an optional feature of the invention, the
adhesive can be applied to the portion of the housing 24 that is to
contact the skin 68. This adhesive can be protected during storage
by a plastic sheet that is peeled off and discarded prior to use of
the transdermal delivery device 10.
[0076] With the distal cap 20 resting securely on or against the
skin 68, the energetic material 40 is detonated using one of the
methods described herein. For example, in the embodiment of FIG. 1,
the patient presses the piezoelectric layer 44 to generate an
electrical discharge. In the embodiment of FIG. 4, the DC voltage
source 64 is activated.
[0077] The explosion within the detonation chamber 32 generates an
impulse transient that propagates through the expansion and
delivery chambers 34, 30 until it reaches the skin 68. At the skin
68, the impulse transient interacts with the outermost layer, the
stratum corneum, so as to significantly increase its permeability.
One or more surfactants, if included in the composition 36, can
delay the stratum corneum's recovery of its impermeability, thereby
extending the delivery interval during which transdermal delivery
of the composition 36 is possible.
[0078] As it propagates through the expansion chamber 34, the
impulse transient generated by the explosion also interacts with
the expandable material 42 contained therein. In response to this
interaction, the expandable material 42 expands in volume. This
expansion in the volume of the expandable material 42 causes the
distal dividing membrane 28 to deform and move distally toward the
epidermis 52 as seen in FIG. 6. The distal dividing membrane 28
thus acts as a plunger exerting a distally directed pressure on the
composition 36 contained within the detonation chamber 32. This
distally directed pressure forces the composition 36 to move
through perforations in the distal cap 20 and through the stratum
corneum, which, as noted earlier, has been made temporarily
permeable by the impulse transient.
[0079] It is apparent from the foregoing description that the
transdermal delivery device 10 provides two modes for transdermal
delivery of a composition. Once the stress wave generated by the
explosion permeabilizes the stratum corneum, the composition 36
diffuses through the epidermis as a result of the concentration
gradient. For certain applications, as described below in
connection with FIG. 7, this mode is adequate.
[0080] Concurrently, the expansion of the expandable material 42 in
the expansion chamber 34 drives the distal membrane 28 in the
distal direction. This provides a motive force that increases the
rate at which the composition 36 passes through the stratum
corneum. As a result of the force generated by the expansion, the
transdermal delivery device 10 propels the composition 36 into the
skin with a high sustained transdermal flow rate thereby allowing
more of the composition 36 to flow across the skin during the
delivery interval.
[0081] In addition to its enhanced performance, the transdermal
delivery device 10 eliminates the need for complex and costly power
sources associated with the operation of conventional active
transdermal delivery systems. For example, the new transdermal
delivery device requires no ultrasound generator or a laser. At
most, the transdermal delivery device 10 requires a simple and
inexpensive DC voltage source 50, as shown in FIG. 4. In the
embodiment shown in FIG. 1, the transdermal deliver device 10 needs
no external energy source other than a force exerted on the
piezoelectric film 44.
[0082] In an alternative embodiment, shown in FIG. 7, a single
dividing membrane 70 divides the interior volume enclosed by the
housing 24 into a delivery chamber 30 and a detonation chamber 32.
This embodiment is thus identical to the embodiment described in
FIG. 1 except that there is no expansion chamber and hence, in
operation, there is no force exerted on the composition 36 to drive
it through the skin 68. The embodiment of FIG. 7 is thus a passive
delivery device.
[0083] In operation, the energetic material 40 is detonated in the
same manner as described in connection with the embodiment of FIG.
1. The resulting impulse transient begins a delivery interval
during which the skin 68 is permeable to the composition 36. The
composition 36 then diffuses into the skin 68 at a rate
proportional to the concentration gradient across the skin 68.
[0084] The advantage of the embodiment shown in FIG. 7 is that the
energetic material 40 is separated from the composition 36. As a
result, it is less likely, in this embodiment, that the
constituents of the composition will be adversely affected by the
brief, but intense, heat flash generated during the explosion of
the energetic material 40.
[0085] In another embodiment, shown in FIG. 8, a multi-element
transdermal delivery device 72 is made up of several transdermal
delivery devices 72a, 72b, 72c as described above, or one device
with several chambers, each of which is independently detonated. A
multi-element transdermal delivery device 72 is useful when several
doses of the composition 36 are required at different times or when
several different compositions are to be adminstered at
substantially the same time. Alternatively, the dosage may be so
high that the cross-sectional area required for a single housing 24
would be very large. Under these circumstances, the excessive
overpressure of the explosion required to deliver the entire
composition 36 may compromise the patient's safety. The
multi-element transdermal delivery device 72 may also be indicated
when the composition 36 includes molecules that penetrate the skin
very slowly, in which case not enough composition can penetrate the
skin during the limited delivery time associated with a single
explosion.
Other Embodiments
[0086] It is to be understood that while the foregoing detailed
description has described selected embodiments of the invention, it
is intended to illustrate and not to limit the scope of the
invention. The invention, together with other aspects, advantages,
and modifications thereof, are limited only by the scope of the
appended claims.
* * * * *