U.S. patent application number 10/384763 was filed with the patent office on 2004-02-26 for transdermal integrated actuator device, methods of making and using same.
Invention is credited to Eppstein, Jonathan, McRae, Stuart.
Application Number | 20040039342 10/384763 |
Document ID | / |
Family ID | 28041719 |
Filed Date | 2004-02-26 |
United States Patent
Application |
20040039342 |
Kind Code |
A1 |
Eppstein, Jonathan ; et
al. |
February 26, 2004 |
Transdermal integrated actuator device, methods of making and using
same
Abstract
The invention provides for an integrated device for forming a
cavity in a surface of a tissue of an animal comprising: a) a
controller board connected to an energy source for actuating at
least one porator; b) a fluid reservoir in fluid communication with
the tissue; and c) a tissue interface layer, the tissue interface
layer containing the at least one porator, the porator in contact
with the tissue for forming the cavity. The invention also provides
for methods of making and methods of using the same.
Inventors: |
Eppstein, Jonathan;
(Atlanta, GA) ; McRae, Stuart; (Atlanta,
GA) |
Correspondence
Address: |
NATH & ASSOCIATES
1030 15th STREET
6TH FLOOR
WASHINGTON
DC
20005
US
|
Family ID: |
28041719 |
Appl. No.: |
10/384763 |
Filed: |
March 11, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10384763 |
Mar 11, 2003 |
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09590787 |
Jun 8, 2000 |
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60363022 |
Mar 11, 2002 |
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Current U.S.
Class: |
604/200 |
Current CPC
Class: |
A61M 2230/20 20130101;
A61M 2205/33 20130101; A61N 1/0424 20130101; A61N 1/044 20130101;
A61M 2037/0007 20130101; A61M 2210/04 20130101; A61M 2037/0023
20130101; A61N 1/327 20130101; A61M 37/0015 20130101; A61N 1/325
20130101; A61N 1/0476 20130101; A61M 2037/0061 20130101; A61M
2205/3303 20130101; A61N 1/326 20130101; A61M 37/00 20130101 |
Class at
Publication: |
604/200 |
International
Class: |
A61M 005/24 |
Claims
1. An integrated device for forming a cavity in a surface of a
tissue of an animal comprising: a) a controller board connected to
an energy source for actuating at least one porator; b) a fluid
reservoir in fluid communication with said tissue; and c) a tissue
interface layer, said tissue interface layer containing said at
least one porator, said porator in contact with said tissue for
forming said cavity.
2. The integrated device according to claim 1 wherein said tissue
interface layer comprises: a) a substrate, said at least one
porator being located on or within said substrate; and b) an
adhesive layer for attaching said integrated poration device to
said tissue membrane.
3. The integrated device according to claim 2 wherein said tissue
interface layer further comprises at least one additional reservoir
for storing a permeant composition or a biological fluid.
4. The integrated device according to claim 2 wherein said
substrate is selected from the group consisting of a woven
material, a film, a supporting layer and a sheet.
5. The integrated device according to claim 1 wherein said at least
one porator is selected from the group consisting of a probe
element, an electromechanical actuator, a microlancet, an array of
micro-needles or lancets, a thermal energy ablator, a sonic energy
ablator, a laser ablation system, and a high pressure fluid jet
puncturer.
6. The integrated device according to claim 1 wherein said
reservoir and said tissue interface layer are removably attached to
said outer body.
7. The integrated device according to claim 1 further comprising a
first control button for initiating poration of said membrane.
8. The integrated device according to claim 7 further comprising a
second control button for initiating delivery of a permeant
composition to said membrane or extraction of an analyte from said
membrane.
9. The integrated device according to claim 1 wherein said tissue
interface layer further comprises one or more additional
reservoirs.
10. The integrated device according to claim 9 wherein two of said
additional reservoirs contain different permeant compositions to be
applied to said tissue membrane.
11. The integrated device according to claim 1 wherein one of said
additional reservoirs contains a permeant composition to be applied
to said tissue membrane, while a second of said additional
reservoirs contains an analyte extracted from said tissue
membrane.
12. An integrated poration device comprising: a) a poration device
comprising: i) an outer body defining a top of said poration
device, said outer body containing a cavity; ii) a controller board
comprising driving electronics and a battery, said controller board
being positioned within said cavity; and iii) a tissue interface
layer for contacting a tissue membrane of an animal, said tissue
interface layer containing at least one porator, and said tissue
interface layer forming the bottom of said poration device; and b)
a reservoir patch, said reservoir patch being applied to said
porated area of said tissue membrane after poration.
13. The integrated poration device according to claim 12 wherein
said reservoir patch further comprises: a) a top layer; b) a middle
layer that has at least one cavity for containing a drug or other
permeant composition to be applied to said membrane; and c) a
bottom layer, said bottom layer containing pores through which said
drug is applied to said tissue membrane, and said bottom layer
containing an adhesive for attachment of said reservoir patch to
said microporated area of said tissue membrane.
14. The integrated poration device according to claim 13 wherein
said reservoir patch further comprises a cover layer attached to
said bottom layer to retain said drug in said middle layer until
said patch is applied to said tissue membrane.
15. The integrated poration device according to claim 12 wherein
said tissue interface layer comprises a material selected from the
group consisting of a woven material, a film, a supporting layer
and a sheet.
16. The integrated poration device according to claim 12 wherein
said at least one porator is selected from the group consisting of
a probe element, an electromechanical actuator, a microlancet, an
array of micro-needles or lancets, a thermal energy ablator, a
sonic energy ablator, a laser ablation system, and a high pressure
fluid jet puncturer.
17. The integrated poration device according to claim 16 wherein
said at least one porator is a probe element, said probe element
being a heated resistive element.
18. The integrated poration device according to claim 12 wherein
said tissue interface layer is removably attached to said outer
body.
19. The integrated poration device according to claim 12 further
comprising a control button for initiating poration of said
membrane.
20. The integrated poration device system according to claim 12
wherein said tissue interface layer further comprises an adhesive
layer for attachment of said poration device to said tissue
membrane.
21. An integrated poration device comprising: a) an actuator
comprising: i) an outer body defining a top of said actuator, said
outer body containing a cavity; ii) a controller board comprising
driving electronics and a battery, said controller board being
positioned within said cavity; and iii) an interface connection
port for receiving a porator array, said interface connection port
containing an anode and a cathode; b) said porator array
comprising: i) a top surface, with a removable adhesive attached to
said top surface, said top surface containing two concentric
electrical contact rings for contacting said interface connection
port at said anode and said cathode upon removal of said adhesive
layer; ii) a bottom surface comprising a tissue interface membrane,
said tissue interface layer further comprising a substrate with at
least one porator contained on or within said substrate, said
bottom surface further comprising an adhesive layer for attaching
said porator array to a tissue membrane; and iii) a release liner
removably attached to said bottom surface; and c) a reservoir
patch, said reservoir patch being applied to said microporated area
of said tissue membrane after poration.
22. The integrated poration device according to claim 21 wherein
said reservoir patch further comprises: a) a top layer; b) a middle
layer that has at least one cavity for containing a drug or other
permeant composition to be applied to said membrane; and c) a
bottom layer, said bottom layer containing pores through which said
drug is applied to said tissue membrane, and said bottom layer
containing an adhesive for attachment of said reservoir patch to
said microporated area of said tissue membrane.
23. The integrated poration device according to claim 22 wherein
said reservoir patch further comprises a cover layer attached to
said bottom layer to retain said drug in said middle layer until
said patch is applied to said tissue membrane.
24. The integrated poration device according to claim 21 wherein
said tissue interface layer comprises a material selected from the
group consisting of a woven material, a film, a supporting layer
and a sheet.
25. The integrated poration device according to claim 21 wherein
said at least one porator is a probe element, said probe element
being a heated resistive element.
26. The integrated poration device according to claim 21 wherein
said porator is removably attached to said actuator.
27. The integrated poration device according to claim 21 wherein
said actuator further comprises a control button for initiating
poration of said membrane.
28. A poration system comprising: a) a porator array comprising at
least one porator; and b) an actuator comprising: i) an outer body
defining a top of said actuator, said outer body containing a
cavity; ii) a controller board comprising driving electronics and a
battery, said controller board being positioned within said cavity;
and iii) an interface connection port for receiving said porator
array.
29. The poration system according to claim 28 further comprising a
reservoir patch, said reservoir patch being applied to said
microporated area of said tissue membrane after poration.
30. The poration system according to claim 28 wherein said
reservoir patch further comprises: a) a top layer; b) a middle
layer that has at least one cavity for containing a drug or other
permeant composition to be applied to said membrane; and c) a
bottom layer, said bottom layer containing pores through which said
drug is applied to said tissue membrane, and said bottom layer
containing an adhesive for attachment of said reservoir patch to
said microporated area of said tissue membrane.
31. The poration system according to claim 30 wherein said
reservoir patch further comprises a cover layer attached to said
bottom layer to retain said drug in said middle layer until said
patch is applied to said tissue membrane.
32. The poration system according to claim 28 wherein said porator
array comprises: a) a top surface, with a removable adhesive
attached to said top surface, said top containing two concentric
electrical contact rings for contacting said interface connection
port at said anode and said cathode upon removal of said adhesive
layer; b) a bottom surface comprising a tissue interface membrane,
said tissue interface membrane further comprising a substrate with
at least one porator contained on or within said substrate, said
bottom surface further comprising an adhesive layer for attaching
said porator array to a tissue membrane; and c) a release liner
removably attached to said bottom surface.
33. The poration system according to claim 32 wherein said tissue
interface layer comprises a material selected from the group
consisting of a woven material, a film, a supporting layer and a
sheet.
34. The poration system according to claim 28 wherein said at least
one porator is a probe element, said probe element being a heated
resistive element.
35. The poration system according to claim 28 wherein said porator
array is removably attached to said actuator.
36. The poration system according to claim 28 wherein said actuator
further comprises a control button for initiating poration of said
membrane.
37. An method of monitoring an analyte extracted from a patient and
delivering a permeant composition to said patient, comprising the
steps of: a) contacting a poration device to a tissue membrane of
said patient, said poration device comprising: i) an outer body
defining a top of said integrated poration device, said outer body
containing a cavity; ii) a controller board comprising driving
electronics and a battery, said controller board being positioned
within said cavity; iii) a first reservoir comprising a top, side
walls and a bottom, said top comprising a thin film top plate
abutting a bottom of said controller board and fitting within said
cavity; and iv) a tissue interface layer for contacting said tissue
membrane, said tissue interface layer containing at least one
porator array and a second reservoir, and said tissue interface
layer forming the bottom of said first reservoir and of said
integrated poration device; b) actuating poration of said tissue
membrane using said at least one poration array in said poration
device; c) extracting an analyte from said microporated tissue
membrane by way of said at least one micropore array; d) analyzing
said analyte to determine concentration of same within said tissue
membrane; and e) delivering a permeant composition to said tissue
membrane by way of said at least one micropore array.
38. The method according to claim 37 wherein said reservoir and
said tissue interface layer are removably attached to said outer
body.
39. The method according to claim 37 further comprising a first
control button for actuating poration of said membrane.
40. The method according to claim 37 further comprising a second
control button for initiating delivery of a permeant composition to
said membrane or extraction of an analyte from said membrane.
41. The method according to claim 37 wherein said tissue interface
layer further comprises one or more additional reservoirs.
42. The method according to claim 41 wherein two of said additional
reservoirs contain different permeant compositions to be applied to
said tissue membrane.
43. The method according to claim 37 wherein said substrate is
selected from the group consisting of a woven material, a film, a
supporting layer and a sheet.
44. A method of delivering two or more biologically active
compounds to a patient in need thereof by way of a tissue membrane,
said method comprising the steps of: a) forming at least one
micropore in said tissue membrane by contacting a poration device
with said tissue membrane and activating said poration device,
thereby forming said at least one micropore, said poration device
comprising: i) an outer body defining a top of said integrated
poration device, said outer body containing a cavity; ii) a
controller board comprising driving electronics and a battery, said
controller board being positioned within said cavity; iii) a first
reservoir comprising a top, side walls and a bottom, said top
comprising a thin film top plate abutting a bottom of said
controller board and fitting within said cavity; and iv) a tissue
interface layer for contacting said tissue membrane, said tissue
interface layer containing at least one porator array and a second
reservoir, and said tissue interface layer forming the bottom of
said first reservoir and of said integrated poration device; b)
applying a first compound contained in said first reservoir of said
poration device to said tissue membrane by way of said at least one
micropore; and c) applying a second compound contained in said
second reservoir of said poration device to said tissue membrane by
way of said at least one micropore.
45. The method according to claim 44 wherein said first and second
compounds are simultaneously applied to said tissue membrane.
46. The method according to claim 44 wherein said first compound is
a first biologically active agent and said second compound is a
different biologically active agent.
47. The method according to claim 44 wherein said first compound is
a biologically active agent and said second compound is a
pharmaceutically acceptable excipient.
48. The method according to claim 44 wherein said first and second
compounds are mixed within said poration device prior to being
applied to said tissue membrane.
49. A method of facilitating passage of biological compounds across
a tissue membrane comprising the steps of: a) forming at least one
micropore in said tissue membrane by contacting a poration device
with said tissue membrane and activating said poration device,
thereby forming said at least one micropore, said poration device
comprising: i) an outer body defining a top of said integrated
poration device, said outer body containing a cavity; ii) a
controller board comprising driving electronics and a battery, said
controller board being positioned within said cavity; iii) a first
reservoir comprising a top, side walls and a bottom, said top
comprising a thin film top plate abutting a bottom of said
controller board and fitting within said cavity; and iv) a tissue
interface layer for contacting said tissue membrane, said tissue
interface layer containing at least one porator array and a second
reservoir, and said tissue interface layer forming the bottom of
said first reservoir and of said integrated poration device; b)
applying a first compound contained in said first reservoir of said
poration device to said tissue membrane by way of said at least one
micropore; and c) extracting a second compound from said tissue
membrane and storing said second compound in said second reservoir
in said poration device.
50. The method according to claim 49 wherein said steps of applying
said first compound to said tissue membrane and extracting said
second compound from said tissue membrane are executed
simultaneously.
51. The method according to claim 49 wherein said step of
extracting said second compound from said tissue membrane is
carried out prior to said step of applying said first compound to
said tissue membrane.
52. The method according to claim 51 further comprising the step of
analyzing said second compound and applying said first compound
based on said analysis.
53. A method of manufacturing an integrated poration device
comprising the steps of: a) forming an outer body defining a top of
said integrated poration device, said outer body containing a
cavity; b) assembling a controller board comprising driving
electronics and a battery, and positioning said controller board
within said cavity; c) assembling a reservoir comprising a top,
side walls and a bottom, said top comprising a thin film top plate
abutting a bottom of said controller board and positioning said
reservoir within said cavity; and d) forming a tissue interface
layer along the bottom of said reservoir, said tissue interface
layer contacting a tissue membrane of an animal and containing at
least one porator, and said tissue interface layer forming the
bottom of said reservoir and of said integrated poration
device.
54. The method according to claim 53 wherein said tissue interface
layer comprises: a) a substrate, said at least one porator being
located on or within said substrate; and b) an adhesive layer for
attaching said integrated poration device to said tissue
membrane.
55. The method according to claim 54 further comprising the step of
storing a permeant composition or a biological fluid within said
reservoir.
56. The method according to claim 54 wherein said substrate is
selected from the group consisting of a woven material, a film, a
supporting layer and a sheet.
57. The method according to claim 53 wherein said at least one
porator is selected from the group consisting of a probe element,
an electromechanical actuator, a microlancet, an array of
micro-needles or lancets, a thermal energy ablator, a sonic energy
ablator, a laser ablation system, and a high pressure fluid jet
puncturer.
58. The method according to claim 53 wherein said reservoir and
said tissue interface layer are removably attached to said outer
body.
59. The method according to claim 53 wherein said tissue interface
layer further comprises one or more additional reservoirs.
60. The method according to claim 59 wherein two of said additional
reservoirs contain different permeant compositions to be applied to
said tissue membrane.
61. The method according to claim 53 wherein one of said additional
reservoirs contains a permeant composition to be applied to said
tissue membrane, while a second of said additional reservoirs
contains an analyte extracted from said tissue membrane.
62. An integrated poration device comprising: a) an outer body
defining a top of said integrated poration device, said outer body
containing a cavity; b) a controller board comprising driving
electronics and a battery, said controller board being positioned
within said cavity; c) a reservoir comprising a top, side walls and
a bottom, said top comprising a thin film top plate abutting a
bottom of said controller board and fitting within said cavity; and
d) a tissue interface layer for contacting a tissue membrane of an
animal, said tissue interface layer containing at least one
porator, and said tissue interface layer forming the bottom of said
reservoir and of said integrated poration device.
63. The integrated poration device according to claim 62 wherein
said tissue interface layer comprises: a) a substrate, said at
least one porator being located on or within said substrate; and b)
an adhesive layer for attaching said integrated poration device to
said tissue membrane.
64. The integrated poration device according to claim 63 wherein
said tissue interface layer further comprises at least one
additional reservoir for storing a permeant composition or a
biological fluid.
65. The integrated poration device according to claim 63 wherein
said substrate is selected from the group consisting of a woven
material, a film, a supporting layer and a sheet.
66. The integrated poration device according to claim 62 wherein
said at least one porator is selected from the group consisting of
a probe element, an electromechanical actuator, a microlancet, an
array of micro-needles or lancets, a thermal energy ablator, a
sonic energy ablator, a laser ablation system, and a high pressure
fluid jet puncturer.
67. The integrated poration device according to claim 62 wherein
said reservoir and said tissue interface layer are removably
attached to said outer body.
68. The integrated poration device according to claim 62 further
comprising a first control button for initiating poration of said
membrane.
69. The integrated poration device according to claim 68 further
comprising a second control button for initiating delivery of a
permeant composition to said membrane or extraction of an analyte
from said membrane.
70. The integrated poration device according to claim 62 wherein
said tissue interface layer further comprises one or more
additional reservoirs.
71. The integrated poration device according to claim 70 wherein
two of said additional reservoirs contain different permeant
compositions to be applied to said tissue membrane.
72. The integrated poration device according to claim 62 wherein
one of said additional reservoirs contains a permeant composition
to be applied to said tissue membrane, while a second of said
additional reservoirs contains an analyte extracted from said
tissue membrane.
Description
TECHNICAL FIELD
[0001] This invention relates to devices and method for the
creation of small holes or perforations or micropores in biological
membranes, such as the outer layers of the skin or the mucosal
linings, the delivery of drugs or other permeants through the
micropores, the extraction of biological fluids through the
micropores, the integration within the device and method of an
assay for selected of analytes in the extracted biological fluids,
and the increase of flux through these micropores by one or more of
pressure modulation, the mechanical manipulation or distortion of
the microporated tissue and adjacent tissue, electro-transport,
electro-osmosis, iontophoresis and sonic energy. All publications,
patents and patent applications referred to herein are incorporated
herein by reference in their entirety.
BACKGROUND ART
[0002] The stratum corneum is chiefly responsible for the barrier
properties of skin. Thus, it is this layer that presents the
greatest barrier to transdermal flux of drugs or other molecules
into the body and of analytes out of the body. The stratum corneum,
the outer horny layer of the skin, is a complex structure of
compact keratinized cell remnants separated by lipid domains.
Compared to the oral or gastric mucosa, the stratum corneum is much
less permeable to molecules either external or internal to the
body. The stratum corneum is formed from keratinocytes, which
comprise the majority of epidermal cells that lose their nuclei and
become corneocytes. These dead cells comprise the stratum corneum,
which has a thickness of only about 10-30 microns and, as noted
above, is a very resistant waterproof membrane that protects the
body from invasion by exterior substances and the outward migration
of fluids and dissolved molecules. The stratum corneum is
continuously renewed by shedding of corneum cells during
desquamination and the formation of new corneum cells by the
keratinization process.
[0003] Historically, drugs have been delivered across the skin by
injection. However, this method of administration is inconvenient
and uncomfortable, and is not suited for self-administration by
members of the general public. Additionally, used needles continue
to pose a hazard after their use. Therefore, transdermal drug
delivery to the body is particularly desired.
[0004] There are many techniques known in the art for transdermal
drug delivery and monitoring applications. One well-known example
of the need in the art for less painful puncturing of a biological
membrane is in the field of diabetes monitoring. The current
standard of care for a patient with diabetes includes a
recommendation of 3 to 5 painful finger-stick blood draws per day
to allow them to monitor their blood glucose levels. Other than the
relative size of the lancets decreasing over the last few years,
the use of lancets, and the resulting finger sensitivity and pain,
has not changed for many years.
[0005] To enhance transdermal drug delivery, there are known
methods for increasing the permeability of the skin to drugs. For
example, U.S. Pat. No. 5,885,211 is directed to thermal
microporation techniques and devices to form one or more micropores
in a biological membrane and methods for selectively enhancing
outward flux of analytes from the body or the delivery of drugs
into the body. PCT WO 00/03758, published Jan. 27, 2000 is directed
to methods and apparatus for forming artificial openings in a
selected area of a biological membrane using a pyrotechnic element
that is triggered to explode in a controlled fashion so that the
micro-explosion produces the artificial opening in the biological
membrane to a desired depth and diameter. PCT WO98/29134, published
Jul. 9, 1998 discloses a method of enhancing the permeability of a
biological membrane, such as the skin of an animal, using
microporation and an enhancer such as a sonic, electromagnetic,
mechanical, thermal energy or chemical enhancer. Methods and
apparatus for delivery or monitoring using microporation also are
described in PCT WO 99/44637, published Sep. 10, 1999; U.S. Pat.
No. 6,022,316; PCT WO 99/44508, published Sep. 10, 1999; PCT WO
99/44507, published Sep. 10, 1999; PCT WO 99/44638, published Sep.
10, 1999; PCT WO 00/04832, published Feb. 3, 2000; PCT WO 00/04821,
published Feb. 3, 2000; and PCT WO 00/15102, published Mar. 23,
2000.
[0006] There remains a need for improved methods and devices for
transdermal delivery of agents such as drugs and monitoring of
analytes such as blood components.
SUMMARY OF THE INVENTION
[0007] This invention relates to an integrated device for forming a
cavity in a surface of a tissue of an animal comprising: a) a
controller board connected to an energy source for actuating at
least one porator; b) a fluid reservoir in fluid communication with
said tissue; and c) a tissue interface layer, said tissue interface
layer containing said at least one porator, said porator in contact
with said tissue for forming said cavity.
[0008] Another embodiment of the present inventive subject matter
is directed to an integrated poration device comprising: a) a
poration device comprising: i) an outer body defining a top of said
poration device, said outer body containing a cavity; ii) a
controller board comprising driving electronics and a battery, said
controller board being positioned within said cavity; and iii) a
tissue interface layer for contacting a tissue membrane of an
animal, said tissue interface layer containing at least one
porator, and said tissue interface layer forming the bottom of said
poration device; and b) a reservoir patch, said reservoir patch
being applied to said porated area of said tissue membrane after
poration.
[0009] A further embodiment of the present inventive subject matter
is directed to an integrated poration device comprising: a) an
actuator comprising: i) an outer body defining a top of said
actuator, said outer body containing a cavity; ii) a controller
board comprising driving electronics and a battery, said controller
board being positioned within said cavity; and iii) an interface
connection port for receiving a porator array, said interface
connection port containing an anode and a cathode; b) said porator
array comprising: i) a top surface, with a removable adhesive
attached to said top surface, said top surface containing two
concentric electrical contact rings for contacting said interface
connection port at said anode and said cathode upon removal of said
adhesive layer; ii) a bottom surface comprising a tissue interface
membrane, said tissue interface layer further comprising a
substrate with at least one porator contained on or within said
substrate, said bottom surface further comprising an adhesive layer
for attaching said porator array to a tissue membrane; and iii) a
release liner removably attached to said bottom surface; and c) a
reservoir patch, said reservoir patch being applied to said
microporated area of said tissue membrane after poration.
[0010] A still further embodiment of the present inventive subject
matter is directed to a poration system comprising: a) a porator
array comprising at least one porator; and b) an actuator
comprising: i) an outer body defining a top of said actuator, said
outer body containing a cavity; ii) a controller board comprising
driving electronics and a battery, said controller board being
positioned within said cavity; and iii) an interface connection
port for receiving said porator array.
[0011] An even further embodiment of the present inventive subject
matter is directed to An method of monitoring an analyte extracted
from a patient and delivering a permeant composition to said
patient, comprising the steps of: a) contacting a poration device
to a tissue membrane of said patient, said poration device
comprising: i) an outer body defining a top of said integrated
poration device, said outer body containing a cavity; ii) a
controller board comprising driving electronics and a battery, said
controller board being positioned within said cavity; iii) a first
reservoir comprising a top, side walls and a bottom, said top
comprising a thin film top plate abutting a bottom of said
controller board and fitting within said cavity; and iv) a tissue
interface layer for contacting said tissue membrane, said tissue
interface layer containing at least one porator array and a second
reservoir, and said tissue interface layer forming the bottom of
said first reservoir and of said integrated poration device; b)
actuating poration of said tissue membrane using said at least one
poration array in said poration device; c) extracting an analyte
from said microporated tissue membrane by way of said at least one
micropore array; d) analyzing said analyte to determine
concentration of same within said tissue membrane; and e)
delivering a permeant composition to said tissue membrane by way of
said at least one micropore array.
[0012] A still even further embodiment of the present inventive
subject matter is directed to a method of delivering two or more
biologically active compounds to a patient in need thereof by way
of a tissue membrane, said method comprising the steps of: a)
forming at least one micropore in said tissue membrane by
contacting a poration device with said tissue membrane and
activating said poration device, thereby forming said at least one
micropore, said poration device comprising: i) an outer body
defining a top of said integrated poration device, said outer body
containing a cavity; ii) a controller board comprising driving
electronics and a battery, said controller board being positioned
within said cavity; iii) a first reservoir comprising a top, side
walls and a bottom, said top comprising a thin film top plate
abutting a bottom of said controller board and fitting within said
cavity; and iv) a tissue interface layer for contacting said tissue
membrane, said tissue interface layer containing at least one
porator array and a second reservoir, and said tissue interface
layer forming the bottom of said first reservoir and of said
integrated poration device; b) applying a first compound contained
in said first reservoir of said poration device to said tissue
membrane by way of said at least one micropore; and c) applying a
second compound contained in said second reservoir of said poration
device to said tissue membrane by way of said at least one
micropore.
[0013] Furthermore, the present inventive subject matter is
directed to a method of facilitating passage of biological
compounds across a tissue membrane comprising the steps of: a)
forming at least one micropore in said tissue membrane by
contacting a poration device with said tissue membrane and
activating said poration device, thereby forming said at least one
micropore, said poration device comprising: i) an outer body
defining a top of said integrated poration device, said outer body
containing a cavity; ii) a controller board comprising driving
electronics and a battery, said controller board being positioned
within said cavity; iii) a first reservoir comprising a top, side
walls and a bottom, said top comprising a thin film top plate
abutting a bottom of said controller board and fitting within said
cavity; and iv) a tissue interface layer for contacting said tissue
membrane, said tissue interface layer containing at least one
porator array and a second reservoir, and said tissue interface
layer forming the bottom of said first reservoir and of said
integrated poration device; b) applying a first compound contained
in said first reservoir of said poration device to said tissue
membrane by way of said at least one micropore; and c) extracting a
second compound from said tissue membrane and storing said second
compound in said second reservoir in said poration device.
[0014] Still further, the present inventive subject matter is
directed to a method of manufacturing an integrated poration device
comprising the steps of: a) forming an outer body defining a top of
said integrated poration device, said outer body containing a
cavity; b) assembling a controller board comprising driving
electronics and a battery, and positioning said controller board
within said cavity; c) assembling a reservoir comprising a top,
side walls and a bottom, said top comprising a thin film top plate
abutting a bottom of said controller board and positioning said
reservoir within said cavity; and d) forming a tissue interface
layer along the bottom of said reservoir, said tissue interface
layer contacting a tissue membrane of an animal and containing at
least one porator, and said tissue interface layer forming the
bottom of said reservoir and of said integrated poration
device.
[0015] Yet still further, the present inventive subject matter is
directed to an integrated poration device comprising: a) an outer
body defining a top of said integrated poration device, said outer
body containing a cavity; b) a controller board comprising driving
electronics and a battery, said controller board being positioned
within said cavity; c) a reservoir comprising a top, side walls and
a bottom, said top comprising a thin film top plate abutting a
bottom of said controller board and fitting within said cavity; and
d) a tissue interface layer for contacting a tissue membrane of an
animal, said tissue interface layer containing at least one
porator, and said tissue interface layer forming the bottom of said
reservoir and of said integrated poration device.
BRIEF DESCRIPTION OF THE FIGURES
[0016] FIG. 1 is a general embodiment of a Thin Film Tissue
Interface (TFTI) device showing an enlarged view of a single
resistive element.
[0017] FIG. 2 shows an example of parallel conductive network and
resistive elements.
[0018] FIG. 3 illustrates the operation of a simple wire element
actuator.
[0019] FIG. 4 shows a machined element actuator.
[0020] FIG. 5 is an enlargement of a hybrid woven material used as
a basis for the manufacture of an example embodiment.
[0021] FIG. 6 is the same woven material shown in FIG. 5 with
screen-printed conductive traces that form resistive elements along
with the wire conductors.
[0022] FIG. 7 illustrates a unique screen-printing technique used
to manufacture an example embodiment.
[0023] FIG. 8 is an enlarged side view of a single poration element
in an example embodiment shown during manufacture, completed and
after activation.
[0024] FIG. 9 is a tantalum, parallel conductive network and
resistive elements deposited in an example embodiment.
[0025] FIG. 10 is an enlarged side view of a single poration
element in an example embodiment shown during manufacture and in
its final form.
[0026] FIG. 11 is an enlarged side view of a single poration
element in an example embodiment shown, during manufacture and in
its final form.
[0027] FIG. 12 shows a perforated polycarbonate sheet that is the
basis for an example embodiment.
[0028] FIG. 13 shows the perforated sheet in FIG. 12 with
screen-printed conductive traces.
[0029] FIG. 14 shows the perforated sheet and conductive network of
FIG. 13 with screen-printed plug material.
[0030] FIG. 15 shows the device of FIG. 14 with a screen-printed
resistive element.
[0031] FIG. 16 shows the final form of an example embodiment with a
screen-printed skin sealing adhesive layer.
[0032] FIG. 17 is an exploded view of one embodiment of an
integrated device.
[0033] FIG. 18 shows one embodiment of the integrated device, with
one permeant chamber and a tissue interface.
[0034] FIG. 19 shows one embodiment of a totally disposable
integrated device.
[0035] FIG. 20 shows one embodiment of an integrated device where
one component of the device is reusable and the other component is
disposable.
[0036] FIG. 21 shows one embodiment of a single cell flux
enhancement device.
[0037] FIG. 22 shows cross sectional view of an embodiment of a
mechanically actuated pressure modulation device for transcutaneous
drug delivery or analyte monitoring applications.
[0038] FIG. 23 shows cross-sectional views of a pressure modulation
device before activation of poration elements and after activation
of poration elements and actuation of pressure modulation.
[0039] FIG. 24 shows a close-up view of a single pressure
modulation micro-cell before activation.
[0040] FIG. 25 shows an embodiment of an integrated device having a
closed loop delivery and monitoring system with multi-function
capabilities.
[0041] FIG. 26 shows a photomicrograph of an Actuated Planar array
of microporation elements fabricated by direct laser machining of a
tungsten film.
[0042] FIG. 27 shows a photomicrograph of a series/parallel
interconnected planar array of microporation elements fabricated by
direct laser machining of a tungsten film.
[0043] FIG. 28 shows an actuator section of a poration device.
[0044] FIG. 29 shows a porator section of a poration device
[0045] FIG. 30 shows a reservoir patch that is applied to the body
tissue after the poration is accomplished.
[0046] FIG. 31 shows a top view of a release liner for use in an
embodiment of the present inventive subject matter.
[0047] FIG. 32 depicts a top view of another release liner for
protecting the bottom of a suitable porator array.
[0048] FIG. 33 depicts a top view of a porator array.
[0049] FIG. 34 shows a bottom view of one embodiment of a porator
array.
[0050] FIG. 35 shows a porator array after the poration elements
have been removed from the locator ring.
[0051] FIG. 36 depicts a drug reservoir patch applied to the
porated area of the tissue membrane.
[0052] FIG. 37 shows reservoir patch following removal of the
remaining portions of the porator array.
[0053] FIG. 38 shows a single piece disposable patch design.
DETAILED DESCRIPTION
[0054] Definitions
[0055] As used herein, "stratum corneum" refers to the outermost
layer of the skin, consisting of from about 15 to about 20 layers
of cells in various stages of drying out. The stratum corneum
provides a barrier to the loss of water from inside the body to the
external environment and from attack from the external environment
to the interior of the body.
[0056] As used herein, "tissue" refers to an aggregate of cells of
a particular kind, together with their intercellular substance,
that forms a structural material. At least one surface of the
tissue must be accessible to the device. The preferred tissue is
the skin. Other tissues suitable for use with this invention
include mucosal tissue and soft organs.
[0057] As used herein, the term, "interstitial fluid" is the clear
fluid that occupies the space between the cells in the body. As
used herein, the term "biological fluid" is defined as a fluid
originating from a biological organism, including blood serum or
whole blood as well as interstitial fluid.
[0058] As used herein, "poration," "microporation," or any such
similar term means the formation of a small hole or crevice in
(defined herein as a "micropore") or through the biological
membrane, such as skin or mucous membrane, or the outer layer of an
organism to lessen the barrier properties of this biological
membrane the passage of biological fluids, such as analytes from
below the biological membrane for analysis or the passage of active
permeants or drugs from without the biological membrane for
selected purposes. Preferably the hole or "micropore" so formed is
approximately 1-1000 microns in diameter and would extend into the
biological membrane sufficiently to break the barrier properties of
the stratum corneum without adversely affecting the underlying
tissues. It is to be understood that the term "micropore` is used
in the singular form for simplicity, but that the device of the
present invention may form multiple artificial openings. Poration
could reduce the barrier properties of a biological membrane into
the body for selected purposes, or for certain medical or surgical
procedures. For the purposes of this application, "poration" and
"microporation" are used interchangeably and mean the same
thing.
[0059] A "microporator" or "porator" is a component for a
microporation device capable of microporation. Examples of a
microporator or porator include, but are not limited to, a heated
probe element capable of conductively delivering thermal energy via
direct contact to a biological membrane to cause the ablation of
some portion of the membrane deep enough to form a micropore the
heated probe may be comprised of an electrically heated resistive
element capable of ablating a biological membrane or an optically
heated topical dye/absorber layer, electromechanical actuator, a
microlancet, an array of microneedles or lancets, a sonic energy
ablator, a laser ablation system, and a high pressure fluid jet
puncturer. As used herein, "microporator" and "porator" are used
interchangeably.
[0060] As used herein "penetration" means the controlled removal of
cells caused by the thermal and kinetic energy released when the
pyrotechnic element explodes which causes cells of the biological
membrane and possibly some adjacent cells to be "blown away" from
the site. As used herein, "fusible" and "fuse" refer to an element
that could remove itself from and electrical circuit when a
sufficient amount of energy or heat has been applied to it. i.e.,
when a resistive, electrically activated poration element is
designed to be a fusible element this means that upon activation,
during or after the formation of the micropore in the biological
membrane, the element breaks, stopping the current flow through
it.
[0061] As used herein, "penetration enhancement" or "permeation
enhancement" means an increase in the permeability of the
biological membrane to a drug, analyte, or other chemical molecule,
compound, particle or substance (also called "permeant"), i.e., so
as to increase the rate at which a drug, analyte, or other chemical
molecule, compound or particle permeates the biological membrane
and facilitates the increase of flux across the biological membrane
for the purpose of the withdrawal of analytes out through the
biological membrane or the delivery of drugs across the biological
membrane and into the underlying tissues.
[0062] As used herein, "enhancer", "chemical enhancer,"
"penetration enhancer", "permeation enhancer," and the like
includes all enhancers that increase the flux of a permeant,
analyte, or other molecule across the biological membrane, and is
limited only by functionality. In other words, all cell envelope
disordering compounds and solvents and any other chemical
enhancement agents are intended to be included. Additionally, all
active force enhancer technologies such as the application of sonic
energy, mechanical suction, pressure, or local deformation of the
tissues, iontophoresis or electroporation are included. For
example, ammonia may be used as an enhancer for the device of the
present invention. In this example, the ammonia may increase the
permeability of selected tissue structures, such as the capillary
walls, within the tissues proximate to, or extending some distance
from, the formed micropore. One or more enhancer technologies may
be combined sequentially or simultaneously. For example, the
ammonia enhancer may first be applied to permealize the capillary
wall and then an iontophoretic or sonic energy field may be applied
to actively drive a permeant into those tissues surrounding and
comprising the capillary bed. The shock wave generated by the
detonation of the pyrotechnic element of the present invention is
itself a sonic permeation enhancer.
[0063] As used herein, "transdermal" or "percutaneous" means
passage of a permeant into and through the biological membrane to
achieve effective therapeutic blood levels or local tissue levels
of a permeant, or the passage of a molecule or fluid present in the
body ("analyte") out through the biological membrane so that the
analyte molecule maybe collected on the outside of the body.
[0064] As used herein, the term "permeant," "drug," "permeant
composition," or "pharmacologically active agent" or any other
similar term means any chemical or biological material or compound
suitable for transdermal administration by the methods previously
known in the art and/or by the methods taught in the present
invention, that induces a desired biological or pharmacological
effect, which may include but is not limited to (1) having a
prophylactic effect on the organism and preventing an undesired
biological effect such as an infection, (2) alleviating a condition
caused by a disease, for example, alleviating pain or inflammation
caused as a result of disease, and/or (3) either alleviating,
reducing, or completely eliminating the disease from the organism.
The effect may be local, such as providing for a local anesthetic
effect, or it may be systemic. Such substances include broad
classes of compounds normally delivered into the body, including
through body surfaces and membranes, including skin. In general,
this includes but is not limited to: anti-infectives such as
antibiotics and antiviral agents; analgesics and analgesic
combinations; anorexics; antihelminthics; antiarthritics;
antiasthmatic agents; anticonvulsants; antidepressants;
antidiabetic agents; antidiarrheals; antihistamines;
anti-inflammatory agents; antimigraine preparations; antinauseants;
antineoplastics; antiparkinsonism drugs; antipruritics;
antipsychotics; antipyretics; antispasmodics; anticholinergics;
sympathomimetics; xanthine derivatives; cardiovascular preparations
including potassium and calcium channel blockers, beta-blockers,
alpha-blockers and antiarrhythmics; antihypertensives; diuretics
and antidiuretics; vasodilators including general coronary,
peripheral and cerebral; central nervous system stimulants;
vasoconstrictors; cough and cold preparations, including
decongestants; hormones such as estradiol and other steroids,
including corticosteroids; hypnotics; immunosuppressives; muscle
relaxants; parasympatholytics; psychostimulants; sedatives; and
tranquilizers. By the method of the present invention, both ionized
and nonionized drugs maybe delivered, as could drugs of either high
or low molecular weight. Additionally, microparticles, DNA, RNA,
viral antigens or any combination of the permeants listed above may
be delivered by the present invention. Examples include
polypeptides, including proteins and peptides (e.g., insulin);
releasing factors, including Luteinizing Hormone Releasing Hormone
(LHRH); and carbohydrates (e.g., heparin). Ionized and nonionized
permeants may be delivered, as could permeants of any molecular
weight including substances with molecular weights ranging from
less than 50 Daltons to greater than 1,000,000 Daltons.
[0065] As used herein, an "effective" amount of a pharmacologically
active agent means a sufficient amount of a compound to provide the
desired local or systemic effect and performance at a reasonable
benefit/risk ratio attending any medical treatment. An "effective"
amount of a permeation or chemical enhancer as used herein means an
amount selected so as to provide the desired increase in biological
membrane permeability, the desired depth of penetration, rate of
administration, and amount of drug delivered.
[0066] As used herein, a "pyrotechnic element" means any chemical,
matter or combination of chemicals and/or matters that have an
explosive characteristic when suitably detonated. The pyrotechnic
element of the present invention undergoes very rapid decomposition
(as combustion) with the production of heat and the formation of
more stable materials (as gases) which exert pressure as they
expand at the high temperature produced thereby creating a shock
wave with a high peak pressure lasting for a short period of time.
Thus, the energy produced by the pyrotechnic element includes both
high temperature and high pressure. One example of a pyrotechnic
element suitable for the present invention includes a
stoichiometric mixture of zirconium powder and potassium
perchlorate combined with a nitrocellulose binder of 1-5 parts per
100 parts of the stoichiometric mixture as a suspension in an
organic solvent. Another example would be a gelled form of
nitroglycerin, which has the additional advantage of already being
an approved drug for transdermal delivery applications.
[0067] As used herein, a "pyrotechnic ink" means any pyrotechnic
element that is applied in a liquid form and which subsequently
cures into the solid or gelled shape of the pyrotechnic
element.
[0068] As used herein, the term "biological membrane" or "tissue
membrane" means the structure separating one area of an organism
from another, such as a capillary wall, lining of the gut or the
outer layer of an organism which separates the organism from it's
external environment, such as epithelial tissue, skin, buccal
mucosa or other mucous membrane. The stratum corneum of the skin
may also be included as a biological membrane.
[0069] As used herein, "animal" or "organism" refers to humans and
other living organisms including plants, to which the present
invention maybe applied.
[0070] As used herein, "analyte" means any chemical or biological
material or compound suitable for passage through a biological
membrane by the technology taught in this present invention, or by
technology previously known in the art, of which an individual
might want to know the concentration or activity inside the body.
Glucose is a specific example of an analyte because it is a sugar
suitable for passage through the skin, and individuals, for example
those having diabetes, might want to know their blood glucose
levels. Other examples of analytes include, but are not limited to,
such compounds as sodium, potassium, bilirubin, urea, ammonia,
calcium, lead, iron, lithium, salicylates, and the like.
[0071] As used herein, "transdermal flux rate" is the rate of
passage of any analyte out through the skin of an individual, human
or animal, or the rate of passage of any permeant, drug,
pharmacologically active agent, dye, or pigment in and through the
skin of an organism.
[0072] As used herein, "artificial opening" or "micropore" means
any physical breach of the biological membrane of a suitable size
for delivering or extraction fluid therethrough, including
micropores. "Artificial opening" or "micropore" or any such similar
term thus refers to a small hole, opening or crevice created to a
desired depth in or through a biological membrane. The opening
could be formed via the conduction of thermal energy as described
in U.S. Pat. No. 5,885,211, or through a mechanical process, or
through a pyrotechnic process. The size of the hole or pore is for
example approximately 1-1000 microns in diameter. It is to be
understood that the term micropore is used in the singular form for
simplicity, but that the devices and methods may form multiple
openings or pores.
[0073] As used herein, "use" or "single use" is a single
application of the device that could last for example, for a few
seconds to a few days. An application is denoted by applying the
device tissue interface to the tissue, the poration process, the
delivery or extraction step, and the removal of the device tissue
interface from the tissue. This "use" or "single use" could last
for seconds, minutes, or days depending on the nature of the
permeants delivered, the biological fluids extracted, and the flux
rates desired.
[0074] "Iontophoresis" refers to the application of an external
electric field to the tissue surface through the use of two or more
electrodes and delivery of an ionized form of drug or an un-ionized
drug carried with the water flux associated with ion transport
(electro-osmosis) into the tissue or the similar extraction of a
biological fluid or analyte.
[0075] "Electroporation" refers to the creation through electric
current flow of openings in cell walls that are orders of magnitude
smaller than micropores. The openings formed with electroporation
are typically only a few nanometers in any dimension.
Electroporation is useful to facilitate cellular uptake of selected
permeants by the targeted tissues beneath the outer layers of an
organism after the permeant has passed through the micropores into
these deeper layers of tissue.
[0076] "Sonophoresis" or "sonification" refers to sonic energy,
which may include frequencies normally described as ultrasonic,
generated by vibrating a piezoelectric crystal or other
electromechanical element by passing an alternating current through
the material. The use of sonic energy to increase the permeability
of the skin to drug molecules has been termed sonophoresis or
phonophoresis.
[0077] "Integrated device" means a device suitable for forming
artificial openings in tissue and further suitable for one or more
additional applications, for example, delivering one or more
permeants into the tissue (preferably through the artificial
openings), and optionally collecting a biological fluid from the
tissue (preferably through the artificial openings) and optionally
analyzing the biological fluid to determine a characteristic
thereof.
[0078] As used herein, "non-invasive" means not requiring the entry
of a needle, catheter, or other invasive medical instrument into
apart of the body.
[0079] As used herein, "minimally invasive" refers to the use of
mechanical, hydraulic, or electrical means that invade the stratum
corneum to create a small hole or micropore without causing
substantial damage to the underlying tissues.
[0080] As used herein, "pharmaceutically acceptable carrier" refers
to a carrier in which a substance such as a pharmaceutically
acceptable drug could be provided for deliver. Pharmaceutically
acceptable carriers are described in the art, for example, in
"Remington: The Science and Practice of Pharmacy," Mack Publishing
Company, Pennsylvania, 1995, the disclosure of which is
incorporated herein by reference. Carriers could include, for
example, water and other aqueous solutions, saccharides,
polysaccharides, buffers, excipients, and biodegradable polymers
such as polyesters, polyanhydrides, polyamino acids, liposomes and
mixtures thereof.
[0081] As used herein, "reservoir" refers to a designated area or
chamber within a device which is designed to contain a permeant for
delivery through an artificial opening in a biological membrane
into an organism or may be designed to receive a biological fluid
sample extracted from an organism through an artificial opening in
a biological membrane. A reservoir could also contain excipient
compounds which enhance the effect of a separately contained
bioactive permeant. Additionally, a reservoir could contain or be
treated with reactive enzymes or reagents designed to allow the
measurement or detection of a selected analyte in an extracted
biological fluid. A reservoir may be comprised of a open volume
space, a gel, a flat planar space which has been coated or treated
with a selected compound for subsequent release or reaction, or a
permeable solid structure such as a porous polymer.
[0082] The present invention comprises a device and a method for
painlessly creating microscopic holes, i.e. micropores, from about
1 to 1000 microns across, in the stratum corneum of human skin. The
device uses thermal energy source, or heat probe, which is held in
contact with the stratum corneum, for creating micropores. The
thermal micropores are created using short time-scale (1
microsecond to 50 milliseconds), thermal energy pulses to ablate
the tissue of biological membranes. This process is described in
detail in U.S. Pat. No. 5,885,211 and is hereby included in its
entirety by reference.
[0083] The present invention facilitates a rapid and painless
method of eliminating the barrier function of the stratum corneum
to facilitate the transcutaneous transport of therapeutic
substances into the body when applied topically or to access the
analytes within the body for analysis. The method utilizes a
procedure that begins with the contact application of a small area
heat source to the targeted area of the stratum corneum or other
selected biological membrane.
[0084] The heat source has the following properties. First, the
heat source must be sized such that contact with the biological
membrane is confined to a small area, typically about 1 to 1000
.mu.m in diameter. Second, it must have the capability to modulate
the temperature of the stratum corneum at the contact point from
ambient skin surface temperature levels (33.degree. C.) to greater
than 123.degree. C. (preferably to a temperature greater than
400.degree. C.) and then return to approximately ambient skin
temperature with total cycle times within the 1 microsecond to 50
milliseconds range to minimize collateral damage to adjacent viable
tissues and sensation to the subject individual. This modulation
could be created electronically, mechanically, or chemically.
[0085] With the heat source placed in contact with the skin, it is
cycled through a series of one or more modulations of temperature
from an initial point of ambient skin temperature to a peak
temperature in excess of 123.degree. C. to approximately ambient
skin temperature. To minimize or
[0086] eliminate the subject's sensory perception of the
microporation process, these pulses are limited induration, and the
interpulse spacing is long enough to allow cooling of the viable
tissue layers in the skin, and most particularly the enervated
dermal tissues, to achieve a mean temperature of less than about
45.degree. C. These parameters are based on the thermal time
constants of the viable epidermal and dermal tissues (roughly 30-80
ms) located between the heat probe and the enervated tissue in the
underlying dermis. The result of this application of pulsed thermal
energy is that enough energy is conducted into the stratum corneum
within the tiny target spot that the local temperature of this
volume of tissue is elevated sufficiently higher than the
vaporization point of the tissue-bound volatile components, such as
water and lipids in the stratum corneum. As the temperature
increases above 100.degree. C., these volatile components of the
stratum corneum (typically comprising 5% to 15% within the stratum
corneum) within this localized spot, are induced to vaporize and
expand very rapidly, causing a vapor-driven removal of those
corneocytes in the stratum corneum located in proximity to this
vaporization event. U.S. Pat. No. 4,775,361 teaches that a stratum
corneum temperature of 123.degree. C. represents a threshold at
which this type of flash vaporization occurs. As subsequent pulses
of thermal energy are applied, additional layers of the stratum
corneum are removed until a micropore is formed through the stratum
corneum down to the next layer of the epidermis, the stratum
lucidum. By limiting the duration of the heat pulse to less than
one thermal time constant of the epidermis and allowing any heat
energy conducted into the epidermis to dissipate for a sufficiently
long enough time, the elevation in temperature of the viable layers
of the epidermis is minimal. This allows the entire microporation
process to take place without any sensation to the subject and no
damage to the underlining and surrounding tissues.
[0087] One embodiment of this invention relates to designs and
manufacturing techniques suitable for creating a practical, low
cost, Thin Film Tissue Interface (TFTI) device that creates
micropores using thermal energy produced by the passage of
electrical current through resistive elements and methods of
manufacturing and functional operation of the TFTI devices. TFTI
devices create one or more micropores on a wide range of biological
membranes. TFTIs have applications that include thermal
microporation of human skin for the enhancement of analyte
monitoring and delivery of permeants such as a therapeutic drug or
a tattoo dye.
[0088] TFTIs are characterized by their ability to rapidly and
efficiently create a pattern or array of micropores on the surface
of a biological membrane. The pattern may be any geometric spacing
of micropores with pore densities as high as one pore every 0.2
square mm and covering a total porated area ranging from a few
square millimeters to greater than several hundred square
centimeters. TFTI devices are designed to be thin, flexible,
conformable structures that form the interface between a biological
membrane and the controller portion of the integrated device that
supplies each poration element or electrode or other active
component such as a piezo-transducer in the TFTI with the required
electrical signal to effect the poration or other function of the
TFTI such as, but not limited to, iontophoresis, sonophoresis,
electroporation, or impedance measurement of the contacted tissue.
TFTIs are flexible and able to conform to the shape of the targeted
biological membranes. The TFTIs are fabricated to be very thin,
light in weight, and integrated with a reservoir and are also
connected to the controller, current source through an umbilical
cable to allow a more user-friendly configuration. When one or more
controllable active additional flux enhancement features are
incorporated into the TFTI, such as, but not limited to, pressure
modulation, mechanical manipulation, iontophoresis,
electro-osmosis, sonophoresis or electroporation, the activation of
this additional flux control feature could be controlled by the
remote controller module either in a preprogrammed fashion, a user
controlled fashion via inputs to the controller, or in an
automatic, closed loop fashion wherein the rate of infusion of a
permeant is modulated as a function of the measured level of a
selected analyte within or other measurable property of the
organism. The other measurable property could include heart rate,
blood pressure, temperature, respiration and skin surface
conductivity. For example, if would be very useful to control the
rate of insulin infusion based on the real-time measurement of
glucose concentrations in the interstitial fluid or serum of an
organism. Alternatively, it may be desirable with some therapeutic
compounds, particularly those with narrower therapeutic windows
defining what an effective drug level is versus when the negative
side effects become too intolerable, to modulate the infusion rates
based on the measurable levels of this compound within the
organism, thereby allowing a very accurate, and self adaptive
method for achieving and maintaining the drug concentration within
a desired therapeutic window regardless of patient body mass or
metabolism. In the design and manufacture of the TFTI, many of the
electrically conductive traces comprising the TFTI could be used to
serve multiple functions. For example, the traces used to deliver
the short pulses of current to the resistive poration elements to
induce the thermal cycling, could also be used as electrodes for an
iontophoretic or electro-poration process, carried out after the
micropores have been formed.
[0089] This invention relates to a microporation device, comprising
at least one reservoir and a tissue interface comprising at least
one microporator and a substrate, wherein the microporator is
located on or within the substrate. In one embodiment, the
substrate is selected from the group consisting of a woven
material, a film, a supporting layer and a sheet. The woven
material comprises conductive fibers and non-conductive fibers. In
another embodiment, the substrate comprises perforations.
[0090] The microporator may be selected from the group consisting
of a probe element capable of conductively delivering thermal
energy via direct contact to a biological membrane to cause the
ablation of some portion of the membrane deep enough to form a
micropore, electromechanical actuator, a microlancet, an array of
micro-needles or lancets, a sonic energy ablator, a laser ablation
system, and a high pressure fluid jet puncturer; and the probe
element could be selected from the group consisting of an
electrically heated resistive element capable of ablating a
biological membrane, an optically heated topical dye absorber layer
and optically heated topical dye layer.
[0091] In some embodiments of the microporation device of this
invention, the probe element could be selected from the group
consisting of a preformed wire conductor, a deposited conductive
material, a machined conductive material, a laser cut conductive
material, an adhesive foil, an electroplated material, a
screen-printed material and an etched conductive material. In some
embodiments, the probe element could be destroyed while ablating
the biological membrane.
[0092] In an embodiment of this invention, at least one
microporator comprises multiple microporators. In another
embodiment of the microporation device, the multiple microporators
are probe elements.
[0093] The microporation device of this invention could comprise
diodes for isolating the electrical circuits used for activating
the probe elements. The microporation device could comprise two or
more of the probe elements are connected in a parallel circuit
configuration or a series circuit configuration or a combination
thereof.
[0094] The microporation device could comprise a material near the
microporator, wherein the material could be capable of producing an
exothermic or endothermic reaction. The microporation device could
comprise a micro actuator. The microactuator could be selected from
the group consisting of electro-static microactuators, thermal
bimorph microactuators, piezoelectric microactuators,
electromagnetic microactuators, magneto-restrictive microactuators
and shape memory alloy microactuators.
[0095] The microporation device could comprise an electronic
circuitry and a power source: The probe element could comprise a
conductive wire and the substrate could comprise a nonconductive
fabric. The conductive wire could be woven in the non-conductive
fabric.
[0096] The microporation device could comprise a plug material on
the perforations. The plug material could comprise a volatile
material. In one embodiment of the microporation device, the
substrate could be embossed. The microporation device could
comprise an enhancer material for enhancing transmembrane or
transdermal transport of a fluid across the biological
membrane.
[0097] The microporation device could comprise multiple chambers.
The multiple chambers could comprise different substances. At least
one of the multiple chambers could be disposed after a single use
of the microporation device. The multiple chambers could comprise
at least first and second chambers, the first chamber comprising a
first substance and the second chamber comprising a second
substance. The first and second substances could be first and
second biologically active agents. The first substance could be a
dry formulation pharmaceutically active agent, and the second
substance could be a diluent for reconstituting thee dry
formulation into a pharmaceutically acceptable liquid or gel
formulation.
[0098] The microporation device could be capable of transdermal
delivery of a substance in the first chamber or withdrawal of an
analyte transdermally into the second chamber. The microporation
device could be capable of simultaneous transdermal delivery of a
substance in the first chamber and withdrawal of an analyte
transdermally into the second chamber. The substance could be
insulin and the analyte could be glucose. The substances could be
selected from the group consisting of bioactive peptides or
proteins, therapeutic drugs, vaccines, pain medications, permeation
enhancers and pH stabilizers. The different substances could be
delivered by the microporation device in modulated amounts. At
least one of the different substances could passively diffuse into
the biological membrane. The substances, which could be the same or
different, could be delivered simultaneously, sequentially,
alternately, or any combination thereof. The different substances
could be delivered by the microporation device into the organism in
adjacent locations in the biological membrane such that the
different substances could combine and mix once they are within the
tissue matrix of the organism.
[0099] The microporation device could comprise an analyzer for
detecting or quantitating the analyte. The microporation device
could comprise a control module for controlling the delivery of the
substance based on a quantitative value of the analyte detected by
the analyzer.
[0100] The microporation device could comprise a divider or valve
disposed between the first and second chambers that prevents
mixture of the first and second substances until the divider could
be removed or the valve could be opened. The divider could be a
membrane. The first substance could be a pharmaceutically active
agent, and the second substance could a pharmaceutically acceptable
carrier.
[0101] The microporation device could comprise a flux enhancement
microporation device, wherein the flux enhancement microporation
device enhances a flux rate of a substance into the biological
membrane. The flux enhancement microporation device enhances a flux
rate of a substance into the biological membrane by a technique
selected from the group consisting of iontophoresis,
electroporation, electro-osmosis, sonophoresis, and
pressurization.
[0102] The microporation device could comprise a disposable
component or the microporation device could be for a single use
after which the microporation device could be discarded. The
disposable component could be treated with reagents which react
with a biological fluid withdrawn from the biological membrane to
produce a signal or measurable change in properties which could be
predictably related to the quantity of an analyte within the
biological fluid. The disposable component could be treated with
one or any combination thereof of surfactants, hydrophilic or
hydrophobic compounds. The disposable component could be treated
with antimicrobial or anticoagulent or protease inhibitor
compounds. The disposable component could comprise
stimuli-responsive polar gel sections comprising a material that
could be released by a thermal, chemical or electrical stimulus.
The disposable component could comprise a material that releases a
compound when heated.
[0103] The-microporation device could comprise a mixer located on
or within the substrate, the mixer being capable of mixing a
substance prior to transdermal delivery of a substance into the
biological membrane. The microporation device could comprise a
closed-loop delivery and monitoring system, wherein the closed-loop
delivery and monitoring system is capable of modulating transdermal
delivery of a substance through a biological membrane based on a
value of a property of an animal.
[0104] Another embodiment of this invention is a method of
manufacturing a microporation device, comprising obtaining a
substrate and forming a conductive network on the substrate,
wherein the conductive network provides electrical connections to a
microporator. The method could comprise bonding an adhesive layer
over the conductive network. The method could comprise forming a
non-conductive plug on the perforations. The method could comprise
bonding the conductive network to a reservoir.
[0105] Another embodiment is a method for forming openings in a
biological membrane, comprising placing a microporation device in
close proximity of the biological membrane and triggering the
microporation device to form at least one opening in the biological
membrane, the microporation device comprising at least one
reservoir and a tissue interface comprising at least one
microporator and a substrate, wherein the microporator is located
on or within the substrate. The triggering could transfer heat to
the biological membrane. The opening could have a diameter of
1-1,000 microns. The opening or artificial pore could be formed by
a method selected from the group consisting of local heating,
mechanical puncture, sonic energy, hydraulic puncture, and
electroporation. The method could comprise anyone or more of the
following: (a) applying an enhancer to the opening; (b) applying a
permeant to the opening; (c) collecting a fluid from the opening;
(d) monitoring an analyte in the fluid; (e) delivering a substance
into the biological membrane; (f) mixing a substance prior to
delivery of a substance into the biological membrane; and (g)
delivering a substance into the biological membrane and collecting
a fluid from the biological membrane.
[0106] An object of this invention is a method for administering a
compound through a biological membrane to an underlying tissue
matrix or obtaining a biological fluid sample from a tissue matrix
under a biological membrane, comprising a) contacting a flux
enhancement cell with a biological membrane, b) forming a seal
between the outer wall and the membrane, wherein the reservoir
outlet is in communication with an artificial pore in the membrane;
c) applying positive pressure to the inner cavity of the reservoir;
d) biasing the reservoir towards the membrane, thereby producing
the compressed state of the membrane; e) biasing the reservoir away
from the membrane, thereby producing the relieved state; and f) the
biological membrane having an inner surface in intimate contact
with the tissue matrix and an outer surface, thereby producing the
relieved state, wherein the biological membrane has a resting
state, a pressurized state in which the outer surface of the
membrane is depressed to a substantially concave form relative to
the resting state and the underlying tissue matrix is compressed,
and a relieved state, wherein the outer surface of the membrane is
biased into a substantially convex shape and the underlying tissue
matrix is subjected to reduced pressure, and ii) wherein the flux
enhancement cell comprises an outer wall, the outer wall defining a
cell cavity, and a reservoir movably contained therein, the
reservoir comprising an inner cavity and an outlet; the inner
cavity containing a permeant. One embodiment of the method for
administering a compound through a biological membrane to an
underlying tissue matrix or obtaining a biological fluid sample
from a tissue matrix underlying a biological membrane, comprises g)
biasing the reservoir towards the membrane, thereby producing the
compressed state of the membrane; h) biasing the reservoir away
from the membrane.
[0107] Another object of this invention is a flux enhancement
device comprising an outer wall, the outer wall defining a cell
cavity; and a reservoir comprising an inner cavity and an outlet,
wherein the reservoir is movably contained within the cell cavity.
The reservoir could be movably linked to the outer wall with a
compliant membrane. The flux enhancement device could comprise a
microporator. The microporation device or flux enhancement device
could comprise a closed-loop delivery and monitoring system,
wherein the closed-loop delivery and monitoring system is capable
of transdermal delivery of a substance through a biological
membrane and withdrawal of an analyte transdermally through the
biological membrane. The flux enhancement device could comprise
could comprise a closed-loop delivery and monitoring system,
wherein the closed-loop delivery and monitoring system is capable
of modulating transdermal delivery of a substance through a
biological membrane based on a value of a property of an
animal.
[0108] FIG. 1 shows the general configuration of a TFTI (1) with
plurality of poration elements (2). The microporators of a TFTI
device are heated probe elements capable of conductively delivering
thermal energy via direct contact to a biological membrane to cause
the ablation of some portion of the membrane deep enough to form
micropores. In FIG. 1, the poration elements (2) are resistive
elements.
[0109] The resistive elements could take almost any shape, but are
typically high aspect ratio, straight cylinders or bars with
diameters or square cross-sections that range from 1 micron to 150
microns and lengths from 100 microns to 3000 microns respectively.
When an electrical current pulse is applied to each element, the
pulsed element could be controllably and rapidly brought to a
specified high temperature, ranging from 120.degree. C. to greater
than 3000.degree. C. (the upper limit is really set by the melting
point of the material comprising the resistive element, for most
tungsten alloys this is in excess of 3000.degree. C.), whereupon
this thermal energy could then be delivered to the contacting
tissue to effect the thermal poration of the tissue.
[0110] The patterned array of resistive elements is connected to a
conductive network that passes electrical energy to each of the
resistive elements. The array of resistive elements are connected
to the current pulse source either individually, as a series
electrical system, parallel electrical system or some combination
thereof. The instantaneous current required for the operation of
the TFTIs depends mainly on the number of resistive elements in a
device, parallel or series network configuration and size of the
resistive elements. Instantaneous current flowing through the
resistive element network could range from 1 milliamps to 40 amps,
however, as the pulse duration is typically only a few milliseconds
long, and the impedance of each element is quite low (in practice
the typical resistance of a single tungsten alloy poration element
has been measured to be less than 0.1 ohms) the average power
requirements are quite modest. For example, in the extreme case of
a 40 amp current pulse of 1 millisecond duration applied to the 0.1
ohm element, the total power delivered is:
[0111] P=Watt.times.seconds
[0112] P=1.sup.2R/1000=(40.times.40).times.(0.1).times.(0.001), or
P=160 milliwatts per poration element.
[0113] More common values of power consumption based on the
practical parameters (1 amp peak current, 1 millisecond pulse
duration, 0.05 ohm poration element impedance) used in the
preferred embodiments of the invention are:
[0114] P=1.sup.2(0.05)(0.001)=50 microwatts per poration
element.
[0115] With a power requirement of only 50 microwatts per poration
element, for a typical delivery patch which utilizes 100 individual
poration elements the total power requirement to perform the
thermal poration process is still only 5 milliwatts, power levels
easily delivered from very small, low cost batteries.
[0116] The resistive elements are arranged in a two-dimensional
pattern that is transferred directly to the surface of a biological
membrane. The type of pattern produced is dependent on the
application. For example a set of micropores designed to deliver a
local anesthetic to an IV insertion site may have a narrow pore
pattern beginning at the needle insertion site and extending along
the expected path of the needle. The desired pore depth is also
dependent on the application. Using the example above, the pore
depths formed maybe designed to be relatively shallow at the needle
insertion site and deeper along the needles path within the
body.
[0117] FIG. 2 shows one embodiment of a parallel conductive network
(3) with anode side (4), cathode side (5), poration elements (2)
and supporting substrate (6). Each TFTI could be connected to an
external electronic control module to supply electrical energy with
the required current and pulse duration parameters.
[0118] The mechanism that forms a micropore is a result of the
intimate contact of the biological membrane with the resistively
heated element. In its most simple form, the TFTI would have
resistive elements that stayed in contact with the skin before,
during and after the poration process without moving. This would be
known as a non-actuated poration process where resistive elements
remain passively in the same location within the apparatus. The
devices using micro-actuation combined with the resistive elements
would be known as actuated microporation or actuation of poration
elements.
[0119] The mechanism that forms a micropore is a result of the
intimate contact of the biological membrane with the resistively
heated element. In its most simple form, the TFTI of FIG. 2 would
have resistive elements that stayed in contact with the skin before
during and after the poration process without moving. This is known
as a non-actuated poration process where resistive elements remain
passively in the same location within the apparatus.
[0120] Another embodiment of this invention uses micro-actuation
combined with the resistive elements and is known as actuated
thermal microporation or actuation of poration elements.
Micro-actuators produce a mechanical actuation of the poration
elements and achieve greater control over pore depth, act to remove
the resistive element from the micropore once it has been formed or
perform a function such as opening a barrier that isolates a
reservoir. An illustrative embodiment of an actuated microporator
is shown in FIG. 3, which shows a wire resistive element in the
unheated position (7) and the heated position (8).
[0121] The actuated microporator of FIG. 3 is a straight tungsten
wire element. FIG. 3 shows that the straight tungsten wire element
undergoes a significant increase in length from position (7) to
position (8) during the heating pulse as a result of the wires
coefficient of thermal expansion as it undergoes the dramatic
change in temperature of a typical thermal poration cycle. The
anode side (4) and the cathode side (5) of the wire element are
immobile and the wire reacts to the heating pulse by bending
outward to accommodate its thermally induced increased length, away
from the original centerline of the element. The direction of the
wire motion could be designed to be directed away from the
substrate (6) by forming a small initial bend in the poration
element when in the unheated position. With this embodiment of an
actuated TFTI device, micropores could be created without requiring
an initial intimate contact between the biological membrane and the
poration element. That is, when the poration element is heated and
subsequently is actuated to move towards the biological tissue
surface, the necessary contact between the poration element and the
biological surface could be ensured by designing the geometries of
the system and the amount of actuation travel to guarantee the
required physical contact. The choice of wire element length,
initial bend and wire temperature could be used to control the
resulting pore depth in the biological membrane as well. Also, by
knowing the actuation response as it relates to temperature, and by
also knowing the change in impedance of the resistive poration
element as it relates to temperature, one could monitor
dynamically, both the temperature of the poration element and the
resulting amount of actuation. Similarly, once contact is
established with the targeted biological membrane, a detectable
shift in the relationship between the amount of energy delivered to
the poration element and the change in heat would occur, adding yet
another level of dynamically measurable parameters to the poration
process which could be used to help ensure the formation of
controllably, repeatable pores at each poration element. By using
these measurable parameters as feedback inputs to the controller,
current source, the variance in individual poration elements which
may result from the tolerances of the manufacturing process, could
also be accommodated, allowing for additional cost savings in the
manufacturing processes of the TFTI by being able to accept looser
tolerances;
[0122] Another embodiment of an actuated microporator of this
invention is shown in FIG. 4, wherein the actuated element is
formed from a thin sheet of element material (9) such as tungsten
or copper. Some of the element material is removed using a process
such as laser micromachining to produce the resistive element shown
in FIG. 4. During the laser micromachining process, it is possible
to dynamically monitor the impedance of each poration element as it
is formed. By using this sort of dynamically monitored fabrication
process, a parallel or series array of poration elements could be
formed where it could be ensured that the current pulse delivered
is distributed in a balanced, uniform manner to each individual
element. The shape of this resistive element was chosen to produce
motion in the direction perpendicular to the plane of the sheet
material during heating. The physical expansion of the curved
sections (10) of the structure force the tip (11) of the element to
lift away from the plane of the sheet material. Since the entire
element reaches a high temperature, the tip (11) ablates tissue as
it is forced into the biological membrane. The resulting pore depth
in this case is controlled by the arc length of the curved sections
(10), length of the tip region (11) and element temperature.
[0123] To additionally ensure the equal distribution of a current
pulse to each poration element in an array, the specific thermal
coefficient of resistance for the resistive poration element could
be selected or designed such that as the individual element heats
up, its resistance increases, thereby causing less current to flow
in that specific poration element within a parallel network and at
the same time forcing more current to go to the other poration
elements in this same network. By using this natural phenomenon a
self-balancing parallel network of resistive elements could more
easily be designed and manufactured. This is similar to how a
standard parallel wiring of a home lighting system operates when
several incandescent lamps are connected on the same circuit.
[0124] In another embodiment of this invention, shape memory alloy
(SMA) materials are used for the body of the resistive element. The
use of SMA materials has the potential to maximize the efficiency
and effectiveness of actuated poration.
[0125] A wide variety of micro-actuators could be used for the
purpose of actuated poration. Manufacturing methods that employ
more advanced processes such as photolithography are capable of
producing more complex micro-actuators. Some
micro-electromechanical systems that could be incorporated into
TFTI devices include but are not limited to electrostatic
microactuators, thermal bimorph microactuators, piezoelectric
microactuators, electromagnetic microactuators and SMA
microactuators.
[0126] A preferred embodiment of the present inventive subject
matter is a transdermal drug delivery device for forming a
micropore in a tissue membrane of an animal. The transdermal
delivery devices comprising a tissue interface layer having a
substrate and at least one porator located on or within said
substrate, at least one reservoir in communication with the tissue
interface layer, and a controller for controlling the formation of
the micropore by the porator. The porator is constructed of a heat
resistive element which deforms when heated, thereby allowing the
heat resistive element to contact the tissue membrane and form the
micropore by ablating the tissue membrane. A permeant or analyte is
stored within the reservoir. The substrate is selected from the
group consisting of a woven material, a film, a supporting layer
and a sheet. In a preferred embodiment, the controller applies a
stimulus to the porator for forming the pore by deforming the heat
resistive element. Further, the porator is selected from the group
consisting of a wire conductor, a machined conductive material, a
laser cut conductive material, an adhesive foil, an electroplated
material, a shape memory alloy material and an etched conductive
material. The device may further comprise an adhesive layer to bind
the device to the tissue membrane.
[0127] The present inventive subject matter is also drawn to a
method of using such a transdermal drug delivery device. In
particular, the present inventive subject matter contemplates a
method of forming at least one micropore in a tissue membrane of an
animal. The method comprises the steps of: a) providing a poration
device; b) contacting said poration device with the tissue
membrane; c) providing a stimulus to at least one porator by way of
a controller, thereby heating the at least one porator and
increasing the length of and deforming same, causing the at least
one porator to come into contact with the tissue membrane; d)
forming at least one micropore; and e) cooling the porator, thereby
decreasing the length of same and returning same to its original
shape, resulting in the porator no longer contacting the tissue
membrane. The poration device includes a tissue interface layer, at
least one reservoir in communication with the tissue interface
layer; and a controller for controlling the formation of said
micropore by said at least one porator. The tissue interface layer
comprises a substrate and at least one porator. The porator is
located on or within the substrate and is constructed of a heat
resistive element which deforms when heated. The substrate may be
selected from the group consisting of a woven material, a film, a
supporting layer and a sheet. The porator may be selected from the
group consisting of a wire conductor, a machined conductive
material, a laser cut conductive material, an adhesive foil, an
electroplated material, a shape memory alloy material and an etched
conductive material. The method may also include the step of
applying a permeant composition stored in the reservoir to the
micropore, or extracting an analyte by way of the micropore and
storing the analyte in the reservoir.
[0128] Fusible TFTI designs are an alternative to actuated and
non-actuated poration schemes. In the case of a fusible design,
enough electrical energy is passed through the resistive element to
destroy the element, taking it out of the electrical circuit. This
also provides a mechanism of removing the element from the pore
site. This embodiment of the invention also has the potential to
greatly simplify the supporting electronics requirements. In the
case of resistive elements that do not fuse or break their
connection, the driving electronics are required to generate a
signal of controlled duration and amplitude for sensation
management. In the case of fusible elements, the thermal pulse
duration could be controlled mainly by the physical failure
properties of the element and the electronics are only required to
deliver an impulsive signal with uncontrolled duration, as in the
case of a capacitor discharging. Whereas simply delivering enough
energy to the poration element to cause the conductive trace to
melt or vaporize is one method of `blowing the fuse`, a more
preferable method may be to fabricate the substrate holding the
element out of a material which has been specified to undergo a
thermal shrinking or tearing process when exposed to the elevation
of temperature due to the activation of the poration element. With
suitable attachment of the poration element trace to this tear-able
substrate, when the substrate tears, it would also rip the element
apart and thereby break the current path while simultaneously
opening a path into a reservoir adjacent to the poration element.
If this now connected reservoir contained a permeant for delivery,
this permeant would now be disposed directly onto the just formed
micropore in the biological membrane. By appropriately selecting
the material for this tear-able substrate, this process could be
made to occur at much lower, and more biocompatible temperatures,
than what might be required if one were to simply `blow the fuse`.
Some materials that have this type of desired thermal properties
are the heat-shrinkable polymers and vinyls commonly used in
electrical insulation. To help ensure that the tear or rip occurs
when and where desired, and at the designated temperature, this
substrate could be formed with a small etch line, embossed stress
point, or other such feature to provide the `flaw` from which the
thermally induce tear would originate. Another significant
advantage of this type of thermally induced tearing is that the
opening of the pore into a drug or assay containing reservoir could
be produced with only a minimal amount of temperature for a very
short period of time, minimizing the amount of thermal energy and
peak temperature being presented to the reservoir. This feature is
of particular importance when the reservoir contains thermally
fragile peptides, proteins, assay enzymes or other drugs sensitive
to thermal stress.
[0129] An embodiment of the present inventive subject matter is
directed to a transdermal drug delivery device for forming a
micropore in a tissue membrane of an animal, comprising a tissue
interface, at least one reservoir in communication with the tissue
interface layer, and a controller for controlling formation of the
micropore by the porator. The tissue interface layer further
comprises a substrate and at least one porator, wherein the porator
is located on or within the substrate and the porator is
constructed of a material in which the porator is destroyed upon
forming the micropore. A permeant or an analyte may be stored
within the reservoir. In a preferred embodiment, the controller
applies a stimulus to the porator, and the stimulus initiates
formation of the pore by the porator and then destroying the
porator following formation of the micropore. The stimulus may be a
thermal pulse or an electrical pulse.
[0130] A further embodiment of the present inventive subject matter
is drawn to a method of forming at least one micropore in a tissue
membrane of an animal. The method comprises the steps of: a)
providing a poration device; b) contacting the poration device with
the tissue membrane; c) providing a thermal or electrical pulse to
the porator in the poration device by way of a controller, thereby
forming the micropore in the tissue membrane; and, d) destroying
the porator after forming the one micropore by sustaining the
thermal or electrical pulse for a duration sufficient to destroy
the porator. The poration device includes a tissue interface layer
comprising, at least one reservoir in communication with the tissue
interface layer; and a controller for controlling the formation of
the micropore by the porator. The tissue interface layer further
comprises a substrate and at least one porator, wherein the porator
is located on or within the substrate and the porator is
constructed of a material in which the porator is destroyed upon
forming said micropore.
[0131] In another preferred embodiment of the device and methods,
the substrate is constructed of a material which undergoes thermal
shrinking when exposed to an elevated temperature due to activation
of the porator, whereby the thermal shrinking results in a tear in
the substrate and destruction of the porator. Suitable
heat-shrinking materials have been previously discussed. In
addition, the substrate may be formed with a flaw from which a tear
would form.
[0132] The TFTI devices of this invention could also be enhanced by
the addition of a range of substances at or near the poration
element. This approach also has particular utility with elements
that are fusible as previously described. The object of these
substances is to produce a chemical reaction at the pore sites and
during the poration process.
[0133] This chemical reaction could be tailored to perform a
variety of functions. One example is coating an element with a
pyrotechnic material or other material that results in an
exothermic reaction. The energy used to ablate tissue would then
come mainly from the exothermic reaction. This allows a simple way
to reduce the electrical energy required to trigger poration and
thus reduce the overall size of the integrated device. A second
example is a combined exothermic and endothermic reaction. An
initial exothermic reaction would produce a micropore and be
followed closely by an endothermic reaction to cool the pore site
and improve sensation experienced by patients.
[0134] A chemical reaction at the pore site could also be useful
for the byproducts of the reaction. With appropriate choice of
reactants, byproducts could perform all or some of the functions of
flux enhancers, anti-clogging agents, permeants, therapeutic
agents, reactants to drive subsequent reactions or other beneficial
purposes.
[0135] The TFTIs comprising a resistive element could be
manufactured by different methods. The first method uses a
previously formed wire conductor to create the resistive element.
By the second method, the resistive elements are created by a
deposition of conductive material. By the third method, the
resistive elements are formed by etching or machining of the
element material. In addition, some manufacturing methods employ
both deposition and etching. Several examples of TFTI manufacturing
processes to demonstrate the manufacture of TFTI devices and
illustrate the variety of manufacturing methods available as shown
below. The invention is illustrated in the following non-limiting
examples.
EXAMPLE 1
A Woven Material TFTI Device
[0136] Some embodiments of the TFTI devices involve the use of
previously manufactured wire conductors such as tungsten, tantalum,
or tungsten alloy wire as the resistive element. There are a
variety of methods for incorporating the wire conductors into a
TFTI design. These methods include, but are not limited to weaving,
sewing, bonding, brazing, spot welding, connecting with conductive
adhesives or resins and laminating to a thin film or laminated
structure.
[0137] The basis of a woven material TFTI device is a hybrid woven
fabric such as what is shown in FIG. 5. FIG. 5 is an enlargement of
a section of the hybrid woven fabric and should be considered as
extending outward in two dimensions as a repeating structure. The
hybrid woven fabric contains a combination of structural fibers
(10) and (11) which are not electrically conductive (such as
polyester, fiberglass, nylon, mylar, polycarbonate, or the like)
and electrically conductive fibers or strands (12) (such as
tungsten or tantalum or copper wires, conductive polymers, glass or
carbon fibers, or the like). In this example, polyester fibers of
50-micron (10) and 80 micron (11) diameters are woven with
50-micron diameter tungsten wire (12).
[0138] The electrically conductive fibers or strands are woven into
the fabric and run in only one of the weave directions, spaced
apart by a specific number of structural fibers depending on the
desired poration element array density. Here the number of
polyester fibers between two tungsten wires is 28 that would result
in an element spacing of about 1.4 millimeters.
[0139] The woven material is then processed to apply conductive
traces on one side as shown in FIG. 6, creating the desired
conductive network (13) with the interwoven conductive fibers
forming the resistive elements (14). These traces may be created in
a variety of ways including: pressure transfer of conductive/self
adhesive foils onto this surface; electroplating into the desired
pattern using either a shadow mask or resist mask to define the
traces; or simply screen-printing with electrically conductive ink
or resins and curing. Most conductive inks are designed to allow a
certain amount of flexibility after curing which results in a more
compliant TFTI device. For this example, the conductive network in
FIG. 6 is arranged as a parallel electrical circuit although series
or combined series and parallel configurations could be
accommodated by this design. A silver impregnated epoxy is used to
form the conductive network that is applied using standard
screen-printing techniques.
[0140] An added advantage of the woven material TFTI devices is
that proper choice of conductor thread count would result in
resistive elements on both sides of the TFTI. This results in the
optional use of the TFTI to breach or open a drug reservoir
simultaneously with the creation of micropores. Areas of the fabric
that are not covered by the conductive network would then be able
to pass a deliverable substance from a drug reservoir, through the
TFTI and into the micropores.
[0141] Once the application of the conductive network to the woven
fabric has been completed, further integration of the TFTI could
take place that may include bonding to a drug reservoir or addition
of an adhesive layer to maintain contact between the TFTI and the
biological membrane to be porated. This design is also conducive to
the integration of other functional features that include
iontophoretic electrodes, flux enhancer releasing elements, buffer
releasing elements, analyte assay electrodes. The analyte assay
process could also be accomplished via optical means by looking for
a calorimetric shift in response to the selected analyte's
concentration.
[0142] The present inventive subject matter is directed to a
transdermal drug delivery device for forming a micropore in a
tissue membrane of an animal. The transdermal drug delivery device
comprises a tissue interface layer. The tissue interface layer
further comprises a substrate comprising a woven fabric, with the
woven fabric comprising structural fibers and electrically
conductive fibers interwoven together as is discussed above. The
tissue interface layer also comprises at least one porator, wherein
the porator is located on or within the substrate and is formed by
the electrically conductive fibers acting as a heat resistive
element. The transdermal drug delivery device also includes at
least one reservoir in communication with the tissue interface
layer and a controller for controlling the formation of the
micropore by the porator. The transdermal drug delivery device of
the present embodiment may also have the electrically conductive
fibers connected in parallel or series by conductive traces,
thereby forming a conductive network. The conductive traces are
selected from the group consisting of foils, inks, resins,
electroplating products and mixtures thereof.
[0143] The present inventive subject matter is also directed to a
method of manufacturing a transdermal drug delivery device in
accordance with the details set forth above. The method comprises
the steps of: weaving electrically conductive fibers into a fabric
of non-electrically conductive fibers to form an electrically
conductive fabric; applying conductive traces to one end of the
electrically conductive fabric to form a conductive network; and
connecting the conductive network with a controller which controls
the application of electricity to the conductive network.
[0144] In another embodiment, the present inventive subject matter
includes a method of forming at least one micropore in a tissue
membrane of an animal. The method includes the steps of: providing
a poration device, contacting the poration device with the tissue
membrane and actuating the poration device to form the micropore in
the tissue membrane. The poration device includes a tissue
interface layer, at least one reservoir in communication with said
tissue interface layer and a controller for controlling the
formation of said micropore by said at least one porator. The
tissue interface layer further includes a substrate comprising a
woven fabric, said woven fabric comprising structural fibers and
electrically conductive fibers interwoven together and at least one
porator located on or within the substrate. The porator is formed
by the electrically conductive fibers acting as a heat resistive
element.
EXAMPLE 2
A Wire Overlay TFTI Device
[0145] This TFTI design utilizes a unique screen-printing process
that involves overlaying wires on a substrate and then printing
conductive traces over the wires to both form electrical
connections with the conductive network and bond the wires to the
substrate. This example design also uses SMA wire as the resistive
element material to produce an optimized actuation of the poration
element. The poration elements are designed to alter their shape
during the poration process and breach a drug reservoir directly
over the pore site.
[0146] As shown in FIG. 7, multiple lengths of SMA wire (15) such
as nitinol are mounted in a frame (16) with a spacing given by the
desired element density in the final array. A spacing of 1.00 mm
between lengths of SMA wire is used. The frame and mounted wires
are then placed over a thin film substrate (17) and standard
screen-printing techniques are used to deposit conductive ink (18)
onto the substrate and SMA wire combination to produce an
electronic network. The SMA material chosen for this application
should have a high melting point such as nitinol. The substrate
material must be non-conductive and have a low melting point such
as polyester. A good candidate conductive ink should have a high
conductivity and be flexible after it is fully cured such as a
silver/polymer conductive ink.
[0147] The next step in the manufacturing process is to emboss the
array at each of the poration element locations. FIG. 8a shows an
enlarged side view of a single poration element after the
screen-printing process and before embossing occurs. A dielectric
or adhesive layer (19) prevents the conductive ink network from
making contact with the skin or other biological membrane.
[0148] FIG. 8b shows an element after it has been embossed. It is
important that the embossing process does not cause the SMA
material to anneal or undergo a change in crystal structure. This
would allow the SMA material to return to its original shape
(straight) when heated resistively by the conductive network as
shown in FIG. 8c. As an element becomes heated, it initially
creates a skin pore due to intimate contact with the surface of the
skin. As further heating of the element occurs, the SMA material
begins to return to its original shape and retract from the newly
created pore while simultaneously forming an opening in the
embossed feature (20) of the supporting substrate. This could then
open a pathway between a reservoir on the opposite side of the
substrate and the microscopic pore as described above. Some
embodiments of the TFTI devices involve resistive elements that are
deposited by processes such as electro-discharge machining (EDM),
sputtering, screen-printing, electroplating and chemical vapor
deposition (CVD) that are common to the flexible circuit and
electronic industries. The following section illustrates a TFTI
device that could be manufactured using any of the above deposition
processes.
EXAMPLE 3
A Sputter Deposited TFTI Device
[0149] The first step involved in manufacturing is the deposition
of a material such as tantalum by sputtering to form the resistive
elements and conductive network on an appropriate substrate such as
50-micron polyamide. FIG. 9 shows the pattern of deposited tantalum
traces (21) on the polyamide substrate (22). A parallel electrical
configuration is used for purposes of illustration, however the
conductive network could be designed to address each poration
element single or in a parallel circuit, series circuit or any
combination of parallel and series circuits.
[0150] Depending on the properties of the material used for the
conductive network and resistive elements, it may be desirable to
deposit additional material onto the pattern everywhere except for
the resistive elements themselves. The additional material could be
any other type of compatible conductive material and serves the
purpose of reducing the resistance of the conductive network and
thus reducing the overall power required to operate the array of
resistive elements, as well as confining more precisely in a
spatial sense those areas of the TFTI which would undergo the
cycling to the ablation temperature threshold. FIG. 10 shows an
enlarged side view of a single resistive element (23) at different
points in the manufacturing process with adjacent conductive
network connections (24). FIG. 10a shows the element after the
initial deposition and an optionally additional layer over the
conductive network (25).
[0151] The next step in the manufacturing process is the placement,
screening or bonding of an adhesive layer (26) over the conductive
network without covering the resistive elements as shown in FIG.
10b. The purpose of the adhesive layer is to bond the biological
membrane such as skin to the TFTI and ensure that there is intimate
contact with the resistive elements. The final step in the
manufacture of the TFTI is optionally embossing in the area of the
resistive elements as shown in FIG. 10c. The purpose of embossing
is to move the resistive element near or even proud of the
adhesive, biological membrane contacting side of the TFTI and
ensure intimate contact between the resistive element and the
biological membrane to be microporated. The embossing process could
also serve to thin the substrate material in the area of the
resistive element. This may help the resistive element to breach
the substrate material during poration, thus providing a mechanism
by which a substance is introduced to the pore site for drug
delivery applications. Another possible advantage of embossing for
any TFTI design is that the resistive element material would
undergo strain hardening and thus provide a method for altering the
electrical and mechanical properties of the element. Additional
flexibility in tailoring of properties is achieved by varying the
temp of the material during the embossing process.
[0152] It should also be noted that many deposition techniques are
conducive to the manufacture of complex resistive element
geometry's for the purposes of actuated poration. Some techniques,
commonly used in the mass-production of electronic components are
capable of depositing structures with feature sizes of 0.5 microns
or less.
[0153] Some embodiments of the TFTI devices involve resistive
elements that are etched or machined from a layer or sheet of
material by processes such as laser micromachining and a range of
photolithography techniques common to experimental MEMS devices and
the electronics industry. The following section illustrates a TFTI
device that could be manufactured using a micromachining
process.
EXAMPLE 4
A Micromachined TFTI Device
[0154] FIG. 11 shows an enlarged side view of a single resistive
element at different points in the manufacturing process. The first
step in the manufacturing process is to laminate thin films of the
resistive element material (27) such as tungsten in a 30 micron
sheet to a supportive or resistance tailoring layer such as copper
(28) in a 50 micron sheet. These layers are then micromachined
using a laser from the tungsten side as shown in FIG. 11a. Laser
power, repetition rate and cutting speed are adjusted so that the
resistive elements (29) and conductive network (30) are produced
without cutting through the supportive or resistive tailoring
layer. Also, during this process of laser micromachining, the laser
energy could be used to effectively form the electrical bonds
between the tungsten poration elements and the resistance-tailoring
layer.
[0155] The next step shown in FIG. 11b is to bond the tungsten side
of the structure in FIG. 11a to a nonconductive layer such as
polyester (31). This laminated structure is then laser
micromachined from the copper side (28). At this point the copper
is no longer needed as a structural support. The result of this
process is to leave copper material on the conductive network only
and remove it from other locations including over the resistive
elements. Care is taken in the laser parameter settings to avoid
cutting through the nonconductive layer (31). The next step in the
process is to bond an adhesive layer (32) over the conductive
network with the resulting structure shown in FIG. 11c. The final
step in the manufacturing process is to emboss the nonconductive
layer at the locations of the resistive elements as shown in FIG.
11d.
EXAMPLE 5
A Simple Screened TFTI Device
[0156] The following example utilizes screen-printing almost
entirely to form the TFTI device. A 20-micron thick polycarbonate
sheet (33) is obtained and about 10-20 micron diameter perforations
(34) are made in the sheet as shown in FIG. 12. The perforations
(34) could be made by laser processing, mechanical punching or
other method for perforating a sheet. The perforations could be of
any shape ranging from 1 micron to several millimeters. The
perforations are generated in tight groups, with multiple tight
groups forming a larger array. The next step is to screen-print a
conductive network (35) without elements onto the polycarbonate
sheet as shown in FIG. 13. The conductive network may be formed
using silver conductive ink in a flexible when cured carrier and
allowed to cure. Next a low melting point, nonconductive plug
material such as wax (36) is screened over the perforations to seal
them as shown in FIG. 14. Then additional conductive ink (37) is
screened to form a fine bridge of material connecting the two sides
of the conductive network over each wax plug as shown in FIG. 15.
This is the resistive element that becomes heated during the
poration process. The conductive ink used to form the resistive
poration element may be the same as that used to form the
conductive network or it maybe selected to be or a different
material, such as a carbon conductive ink, to be more suitable for
this design purpose. This design functions by creating a micropore
initially and then further heating removes the plug material by
either a melting process or the thermal ripping or tearing process
described previously and opens a pathway between the micropore and
a reservoir. The final step in manufacturing the TFTI is to screen
an adhesive (38) as shown in FIG. 16 to ensure intimate contact
between each resistive element and the biological membrane to be
porated and also to act as the principal attachment mechanism of
the device to the subject's body.
[0157] Any of the TFTI designs discussed here could be designed to
allow for individually addressable resistive elements. The addition
of diodes to the conductive network would allow current directional
isolation of individual array elements which supports some schemes
by which individual elements could be activated with a `row-column`
addressing approach, similar to how an individual pixel might be
toggled in a two dimensional visual array. An integrated device
design that used separate reservoirs for each poration element
could benefit from an individually addressable poration element
control scheme. Another advantage of this approach is an overall
reduction in the peak power required to activate the TFTIs. The
maximum peak current required to effect poration would be smaller
than that if single elements were activated one at a time. Also, by
having each cell comprising a poration element, and its associated
micro-reservoir being essentially individual, independently
controlled systems, one could program the controller system to only
activate a certain number of these cells at a time, allowing more
control over a drug delivery profile or when the cells are used to
effect the assay of an analyte, individual assays may be made at
various selected points in time.
[0158] A feature of the TFTI designs of this invention is that
manufacturing processes are used that allow the technology to be
scaled down drastically. Techniques such as photolithography are
able to produce TFTI designs with high densities of extremely small
poration elements. Scaling down the size of poration elements has
potential advantages such as reduced energy required for poration,
improved skin surface healing and improved patient sensation.
[0159] The devices of this invention could be manufactured using
micro-electromechanical systems (MEMS) manufacturing technology.
The micromanufacturing technology is suitable for cost effective
mass production. In other embodiments of the devices of this
invention, there could be micromachines integral to and working
with TFTI devices. For example, microactuators could be designed to
deliver permeants by individual pore microinjectors. The
microinjectors could be made integrally with the resistive element
so that the microinjector body thermally ablated tissue, extended
into the skin layer and delivered a short-duration, high pressure
fluid injection on a microscopic level.
[0160] Another example of microsystem technology could be applied
to TFTI designs is in the area of tattoo removal. An array of
micromachines could be designed to progressively lift up
microscopic flaps of skin and remove dye-bearing tissues. In fact a
closed loop control scheme could be used where integrated
microsensors detect the location of dye bearing tissues, a
microprocessor then determines the best course of action.
[0161] The use of sensors and actuators in the same TFTI device
allows the creation of extremely sophisticated and intelligent
microsystems. A single TFTI device could be built that drew
interstitial fluid from pore sites and assayed for a particular
analyte (such as glucose) and also delivered a substance through
other pores (such as insulin) based on the results of the analyte
measurement.
EXAMPLE 6
Integrated Tissue Poration and Drug Delivery Device
[0162] The microporation device of this invention could be used as
an integrated device for the creation of small holes or
perforations or micropores in tissue, the delivery of drugs or
other permeants through the micropores, the extraction of
biological fluids through the micropores, and the assaying of
analytes in an extracted biological fluid or permeants to be
delivered.
[0163] The integrated device is a multi-component device comprising
a tissue-interface layer comprising at least one microporator and
at least one reservoir, one or more distinct reservoirs, a power
supply, batteries, electronics, display and case. FIG. 17 shows one
embodiment of a single or a multi-component device of this
invention showing a thin cap (39) that forms the outer body of the
device, a controller board (40) that contains driving electronics
and a battery, a thin film top plate (41) and reservoir wall (42)
that forms the top and sides of the chambers that contain the
permeant for delivery. Finally a TFTI device (43) forms the bottom
of the permeant chamber. In this design the top plate (41),
reservoir wall (42) and TFTI device (43) are bonded together to
form the disposable portion of the device containing the permeants
for delivery. The disposable (41-43) and the controller board (40)
are designed to fit completely into the thin cap (39) with the TFTI
exposed on the bottom surface of the device.
[0164] One embodiment of the device is a single, disposable unit.
An alternate embodiment has a subset of the components incorporated
into a disposable portion while the remainder of the components is
reusable. The device may be manufactured in more than one version,
for example a personal version or a clinical version, with slightly
different formats but similar functions. Some versions would be
effective with fewer components and a reduced functionality. All
versions would be discrete and small (on the order of one half
(0.5) to ten (10) cubic inches).
[0165] A further embodiment includes an integrated device for
forming a cavity in a surface of a tissue of an animal. The
integrated device comprises a controller board connected to an
energy source for actuating at least one porator, a fluid reservoir
in fluid communication with the tissue; and a tissue interface
layer, the tissue interface layer containing the at least one
porator, the porator in contact with the tissue for forming the
cavity. The reservoir and the tissue interface layer may be
removably attached to the outer body. In a still further
embodiment, the reservoir patch is separate from the integrated
device and applied to the porated area of the tissue membrane
following poration thereof.
[0166] If the case of a separate reservoir patch, the patch may
comprise a top layer, a middle layer that has at least one cavity
for containing a drug or other permeant composition to be applied
to the membrane, and a bottom layer containing pores through which
the drug is applied to the tissue membrane. The bottom layer may
contain an adhesive for attachment of the reservoir patch to the
microporated area of the tissue membrane.
[0167] The tissue interface layer comprises some or all of the
following: elements for effecting the poration of the tissue,
adhesive for attaching the device to the tissue, reservoirs
containing permeants for delivery, reservoirs for holding extracted
biological fluids, and reagents fur assaying an analyte. The tissue
interface layer could also include hydrophilic and hydrophobic
surface treatments to act as fluid flow modifiers for controlling
the motion of liquid permeants or biological fluids collected. The
tissue interface layer may also incorporate antimicrobial agents to
prevent sepsis or anticlotting or anticoagulents to control the
aggregation of permeants or biological fluids extracted. The tissue
interface layer may also be treated with permeation enhancers or
buffers used for pH stabilization. The tissue interface layer may
contain stimuli-responsive polymer gel sections, saturated with
beneficial permeants, which could be triggered to release the
beneficial permeants through a thermal, chemical or electrical
stimulus. The tissue interface layer may release beneficial
permeants on demand when heated, for example by the poration
elements or other similar elements on the tissue interface layer.
The tissue interface layer may contain piezoelectric elements for
delivery of acoustic energy into the tissue or permeants being
delivered or biological fluids being extracted. The tissue
interface layer is intended to become part of a disposable as shown
in FIGS. 18 and 20 or may be permanently mounted in the integrated
device as in FIG. 19. FIG. 18 shows one embodiment of the
integrated device showing the poration elements 44, conductive
traces to the elements 45, the adhesive layer 46 with holes beneath
the poration elements 44 and a single permeant reservoir 47.
[0168] FIG. 19 shows one embodiment of the integrated device where
the entire device is disposable. In this embodiment, intended for
single use, the poration elements, adhesive layer and permeant
reservoir (all represented as 48) are permanently installed in the
device. This embodiment has two control buttons 49 on the upper
surface of the case. Pressing one button would initiate the
poration process and basal delivery of the permeant. Pressing the
other button would deliver an additional preset amount of
permeant.
[0169] FIG. 20 shows an embodiment of the integrated device having
a reusable component 50 and a disposable component 51. The reusable
component 50 contains a permeant reservoir 53 and a skin interface
52. Batteries and circuits are housed in the reusable component 50.
After a single use, the disposable component 51 would be replaced,
thereby replenishing the permeant, the poration elements, and the
adhesive which are all parts of the skin interface 52.
[0170] In addition to the poration elements, other conductive
traces, or wires may be, incorporated into the tissue interface
layer to act as all or some of the electrodes for electroporation
iontophoretically enhanced delivery of a permeant into the tissue
or for the enhancement of the extraction of biological fluids from
the tissue for the purpose of monitoring one or more analytes.
These electrodes may also be used to provide all or part of the
current path via which one may deliver pulses of electrical energy
into the tissue for the purpose of electroporating selected tissues
within the current path. These electrodes may also be used for
sensing through a drop in impedance that poration has occurred.
Electrically conductive poration elements themselves could be used
as one of the electrodes for either iontophoresis, or
electroporation, or impedance sensing.
[0171] The tissue interface layer may comprise one or more
reservoirs. In the case of multiple reservoirs, these reservoirs
could be used to keep different and perhaps incompatible permeants
separate. Delivery of permeants from the reservoirs could be
simultaneously or sequentially. A reservoir wall is typically
"porated" to breach the reservoir membrane and allow the delivery
of the permeant into the tissue. This poration of the reservoir is
accomplished with the same type of poration elements as are used to
porate the tissue. Prior to the breach of this reservoir, the
reservoir could maintain a stable, sealed, and sterile environment
for the permeant, allowing the entire disposable portion of the
integrated device to be manufactured and packaged efficiently and
economically. The breaching of the reservoir may occur before,
coincidentally with or after the poration of the tissue as
required. Additionally, the flux rate of a permeant from a
particular reservoir into the tissue is proportional to the area of
the micropore coupling the reservoir to the biological membrane, if
all other factors such as micropore density or iontophoretic
current are the same. A reservoir could initially be empty or
contain an absorbent material, in order to serve as a storage
location for extracted biological fluids. Reagents for the assay of
an analyte in the biological fluid would typically be located at
the entrance to the extracted biological fluid storage
reservoir.
[0172] The electronics for controlling the device are responsible
for initiating the poration process, controlling the timing and
amounts of permeants delivered, enforcing limits on the delivery
mechanisms, processing the data for analyte assay and environment
sensing, control of piezoelectric elements, and control of the user
interface display if any.
[0173] Environment sensing could include temperature, humidity, and
pressure. These values, particularly the temperature, could affect
the results of assays performed by the device. Battery requirements
for electroporation, and iontophoresis are minimal due to the large
drop in resistance that typically occurs when the tissue is
porated. Batteries of the flat, coin cell variety are sufficient.
Nevertheless, in a clinical environment where the reusable
component of the integrated device is used frequently, an external
power source could be used. Some embodiments require or are
facilitated by providing information to the user. In these
embodiments, a display is provided on the top of the case.
EXAMPLE 6A
Passive Vaccine Delivery Device
[0174] This embodiment of the device would be used in a clinical
setting, where a patient receives a disposable patch that delivers
the vaccine by diffusion through the micropores over a number of
hours or days. The disposable for this embodiment would be simple,
small, thin and inexpensive. The disposable would consist of a thin
sealed reservoir with thermal poration elements and adhesive on the
bottom and electrical contact pads on the top. The contact pads are
attached to traces that lead to the thermal poration elements. The
reservoir contains the vaccine to be delivered. The disposable is
inserted into the reusable component of the device in a clinical
setting. The entire device is placed against the surface of the
skin so that the adhesive fixes the disposable to the surface of
the skin. The thermal poration elements are activated, porating the
surface of the skin and simultaneously breaching the lower surface
of the reservoir allowing the vaccine to flow down and into the
micropores, The reusable component of the device is then removed
from the disposable portion, leaving the disposable portion
attached to the surface of the skin and precisely registered to the
micropores, allowing the vaccine to passively diffuse into the skin
until the disposable is removed and discarded. This method for
delivering a vaccine antigen has particular advantages in that the
portion of the autoimmune system optimally targeted by an antigen
to induce the best antibody response is the langerhans cells or
dendritic cells. These langerhans cells or dendritic cells exist
within the epidermis, exactly those tissues to which this method of
delivery places the permeant being delivered.
EXAMPLE 6B
On-Demand Pain Medication Delivery
[0175] This embodiment of the device is entirely disposable. The
device comprises a reservoir for hydromorphone or other suitable
opiate, circuitry required to support the thermal poration process,
circuitry required to support the iontophoretic delivery of the
hydromorphone, adhesive for attaching the device to the surface of
the skin, thermal poration elements, a button to initiate delivery
and a button for breakthrough pain dosing. The device has at least
one counter electrode pad that contacts the skin while the device
is used. The poration elements are used as the delivery electrodes
after the poration step. The device is placed against the surface
of the skin so that the adhesive fixes the device to the surface of
the skin. The initiation button is pressed, activating the thermal
poration elements, porating the surface of the skin and
simultaneously breaching the lower surface of the reservoir
allowing the hydromorphone to flow down and into the micropores
lontophoretic delivery of the hydromorphone at a basal delivery
rate commences. For breakthrough pain, the patient presses the
other button on the surface of the device that temporarily
increases the iontophoretic current to deliver a burst of
hydromorphone. After many hours or days, the entire device is
removed and discarded.
EXAMPLE 6C
Use of Multiple Reservoirs
[0176] This embodiment of the integrated device comprises a
reservoir for a drug, another reservoir for a capillary
permeability enhancer such as NH.sub.3, and another reservoir for a
pH-neutralizing compound. The device includes thermal poration
elements, circuitry required to support the thermal poration of the
tissue, circuitry required to support the thermal poration or
breaching of the reservoir walls, circuitry required to support the
iontophoretic delivery of the permeants, and adhesive for attaching
the device to the surface of the skin. The device has at least one
counter-electrode pad which contacts the skin while the device is
being used. The poration elements are used as the delivery
electrodes after the poration step. The device is placed against
the surface of the skin so that the adhesive fixes the device to
the surface of the skin. The thermal poration elements are
activated, porating the surface of the skin and simultaneously
breaching the lower surface of the reservoir containing the
NH.sub.3. Additional poration elements are used to heat the
NH.sub.3 reservoir, creating gaseous NH.sub.3 and water. After a
short wait, the drug reservoir is breached and the drug is
iontophoretically delivered. An iontophoretic current slowly alters
the pH of the tissue, possibly interfering with further
iontophoretic delivery as well as irritating the tissue, so after a
period of minutes the pH neutralizing reservoir is breached and
some pH neutralizer is delivered into the tissue to bring the pore
interface zone back to near physiological pH of 7.2. Alternate
delivery of drug and pH neutralizer continues as necessary to
delivery the desired amount of drug.
EXAMPLE 7
Pressure Modulation and Flux Enhancer
[0177] The microporation device of this invention could be used as
an integrated device in conjunction with a pressure modulation and
flux enhancer. However, the pressure modulation and flux enhancer
could be used as a stand-alone device or in conjunction with any
other device, preferably medical devices.
[0178] The pressure modulation and flux enhancer of this invention
utilizes pressure modulation to increase transmembrane flux through
one or more micropores in the membrane. Forced compressions
followed by forced expansions of the tissue matrix underlying the
membrane are applied in a coordinated fashion with pressure or
suction from within the reservoir attached to the outer
surface.
[0179] Various embodiments of the pressure modulation and flux
enhancement device of this invention may be used to perform flux
enhancement. Preferably, the devices would have at least one flux
enhancement cell, and certain preferred embodiments would comprise
multiple cells joined into a single array. In a multi-cell array,
the flux cells may be arranged to work synchronously (e.g., by
"parallel" cell function, delivering the permeant(s) from a
plurality of cells at the same time), for example by synchronous
control of individual actuators or by use of actuators which act on
multiple cells. Such devices may be used to administer a single
permeant, particularly when a large dose of the permeant is
required, or to administer different permeants, where combination
therapy is desired. Alternately, multi-cell devices may be arranged
such that the various cells act asynchronously or even perform
different functions. For example, a multi-cell device may comprise
cells with different drugs which are administered on different
schedules, or may comprise cells with different functions, such as
a device comprising cells for delivery of a permeant as well as
cells for sampling of fluid from the tissue matrix.
[0180] The structure of an embodiment of a single cell of a flux
enhancement device of this invention is represented in FIG. 21.
Generally, a single flux enhancement cell would have an outer wall
or an outer annulus (61) defining a cell cavity (62), with the
cavity open at least one end. This open end interfaces with the
biological membrane (74) having a micropore (73) during use of the
device. The outer wall is typically in the shape of a hollow
cylinder having at least one open end, although polygonal
cross-sections are also contemplated. The outer wall is
substantially upstanding, and has an edge bounding the cavity (63,
the "membrane interface 10 edge"). A reservoir (64) defining an
inner cavity or a central portion (65) is movably contained in the
cavity. In devices intended for administration of a permeant, the
reservoir contains the permeant (66). The reservoir has an outlet
(67), which is oriented towards the open (membrane interface) end
of the cavity. In certain embodiments, a compliant membrane (68)
spans the gap between the reservoir and the outer wall at the
membrane interface end of the cavity. An additional compliant
membrane (69) may also be included to form a pressure chamber
defined by the reservoir wall, the outer wall, and the compliant
membranes. The compliant membrane may additionally be coated with
an adhesive (70), to promote a seal with the biological membrane.
In other embodiments, the membrane interface edge of the outer
wall, and the end of the reservoir with the outlet are coated with
an adhesive. The reservoir and the outer wall may additionally
comprise controllable pressure ports (71,72), through which the
pressure in the cell cavity and inner cavity, respectively, maybe
modulated. Underneath the biological membrane (74) is cell matrix
(75) and biological fluid (76) in the space between the cell matrix
(75).
[0181] The principle of the method of operating a flux enhancement
device of this invention could be explained by an analogy wherein
the skin tissue is replaced by a porous sponge upon which one side
has had a non-porous, flexible membrane bonded to it. This membrane
will represent the barrier layer of the skin tissue, which in the
human subject is comprised of the stratum corneum. If a small hole
is formed in the membrane, and then a liquid reservoir is placed
over this, surely some of this liquid will infuse into the sponge
beneath. However, once the sponge becomes fully saturated with
fluid, a condition analogous to the .about.90% water content dermis
in human skin, this initial flux will stop and any further
molecular flux from the outside into the sponge will be driven by
diffusion alone due to concentration differences of selected
compounds between the fluid in the reservoir and that in the
sponge. As previously mentioned the case of animal (or human) skin,
it is fully saturated with fluid to start with, so creating the
micropore and placing the fluid reservoir over it limits the flux
through the opening to that due to a concentration gradient driven
passive diffusion process.
[0182] In one embodiment of this invention, the flux enhancement
device is operated as shown sequentially in FIG. 22. FIG. 22a shows
the initial `neutral` stage of the systems pressure modulation
cycle. FIG. 22a shows a single cell of a flux enhancement device,
which could be a single-cell or a multiple-cell flux enhancement
device. The single cell is adhered to the skin surface of the
biological membrane by an adhesive.
[0183] FIG. 22b shows the blanching, or second, stage of the
pressure modulation cycle. While gradually increasing the pressure
in the reservoir, the entire area of the biological membrane
surrounding the micropore(s) is depressed into the underlying skin
tissue by pushing the central portion. As the force pushing the
central portion increases, it forces the device to assume a conical
shape, pressing into the targeted tissue, as shown in FIG. 22b.
This produces two effects. First, by pushing the device on the
biological membrane, the seal between the fluid reservoir and the
skin surface becomes stronger, allowing a higher pressure to be
maintained within this reservoir minimizing the possibility of a
fluid leak. Second, the cell matrix under the skin tissue is
compressed, forcing much of the fluid trapped within it between the
cells out into the neighboring areas. In the case of human skin,
this second effect is easily observed as the `blanching` of the
tissue when pressure is applied and then quickly removed. This
could be easily demonstrated by pressing a fingertip firmly into
the fleshy underside of ones forearm and then quickly removing it.
The site most recently under compression is clearly whiter than the
surrounding skin on a human subject.
[0184] FIG. 22c shows the tissue expansion, or third stage of the
pressure modulation cycle. The central portion of the device is now
pulled away from the skin tissue surface while the compliant
annular portion is kept attached to the surface of the skin by a
suitable adhesive, a mild pneumatic suction or vacuum, or some
combination of these methods. Simultaneously, the pressure in the
reservoir is dropped to ambient levels to ensure no leaks are
formed from the central reservoir holding the drug payload. At this
time the decompressed state of the recently blanched skin cell
tissue matrix directly beneath the micropore would induce fluid
from the drug reservoir to flow through the pore into these skin
tissues beneath the porated surface.
[0185] FIG. 22d shows return to neutral, or fourth stage of the
pressure modulation cycle. The central portion of the device
surrounding the micropore(s) is now returned back to the neutral
position, while simultaneously increasing the pressure in the
reservoir slightly, as allowed while ensuring that no leaks occur.
At this point, the permeant which had flowed into the cell matrix
immediately beneath the micropore(s) in the previous steps, would
now be induced to flow further away from the entry point into the
larger volume of surrounding tissue and ultimately into contact
with the capillaries whereupon it could then be absorbed into the
blood stream if desired. Repeating this cycle would allow more and
more fluid to be pumped into the tissue.
[0186] Suitable adhesives for attachment to the skin surface could
include any one of the large number of existing, medical grade
adhesives used in bandages, dressings, and transdermal patches
current being produced. Many manufacturers, such as 3M, Avery,
Specialty Adhesives, and the like, build adhesives specifically
designed for this sort of application. Preferably, the adhesive
chosen will have enough tackiness to attach the device to the
tissue surface for the extent of its useful application, which
could range from a few minutes to several days, and yet allow a
painless removal when the system is spent. By combining a
controlled application of suction to assist in this attachment
process, a much less aggressive, and more people friendly adhesive
can be used. When suction is used for assisting the attachment
process, the adhesives stickiness properties become less important,
however its ability to form a pneumatic seal, to contain the
suction becomes more important. Clinical studies have demonstrated
that when suction is used in conjunction with an adhesive, even
very low performance adhesives, such as those used in the 3M
product `Post-Its`, could be used effectively, supporting a
completely painless, non-traumatic removal of the system whenever
desired.
[0187] The compliant portions of the device, designed to interface
and attach to the tissue surface maybe formed from compounds such
as, but not limited to, silicone rubber, latex, vinyl,
polyurethane, plastic, polyethylene or the like. The less flexible,
or rigid portions of the device make be from any suitable,
formable, material, such as metal, plastic, ceramic or the like.
Preferably, materials that could be molded have some manufacturing
advantages and, therefore, end product cost advantages as well. In
some case, with a material such as silicone rubber, latex, vinyl,
polyurethane, plastic, polyethylene or the like, both the flexible
and more rigid portions of the system could be fabricated from the
same material, simply by designing the dimensions of the various
portions of the structure to allow the necessary flexing where
needed and the required stiffness where needed as well. In this
same general manner, a layered process could be utilized wherein
similar, but slightly different compounds are introduced into the
mold sequentially to give more flexibility in some areas and more
stiffness in others, yet provide a good, seamless connection at the
interface of the different `mixes`. This type of selective
variation in tensile properties could also be affected during the
manufacturing process by selectively applying curing energy to
different portions of the whole structure at different rates and
amounts. For example, by irradiating with gamma rays, or
ultraviolet light, one could form a greater number of cross-links
in a polymer compound, dramatically changing its material
properties across the same piece of material which was initial
formed as a single piece. One commercially available example of a
simple structure which exhibits both very compliant, and sticky
qualities on one side, and much stiffer, non-sticky properties on
the other side of a single piece of silicone are the `Corn Pads`
manufactured and sold by `Dr. Scholls` as a foot care product.
[0188] To coordinate the actions of the systems, a pre-programmed
controller would generate the proper sequence of control signals to
cycle the system through these different steps as many times as
desired. The controller may contain a microprocessor which would
generate the appropriate sequence of control signals to enable the
different functions of the system in the desired sequence. A small
pump(s), such as a small diaphragm or peristaltic pump could be
engaged when needed to develop a suction or pressure.
Alternatively, a small pressure reservoir such as a metal or
plastic cylinder or bladder of compressed gas, or a pressure
produced via the electrolysis of a liquid in a closed chamber,
producing gas, could be used to supply pressure. Optionally,
control over all aspects of the movement of the system could easily
be achieved with a simple valving mechanism(s) to provide the
microprocessor coordinated control of reservoir pressure/suction
and the action of a controllable actuator to provide the requisite
movement of the central reservoir relative to the outer portions of
the structure during the compression/decompression cycles. With
suitable additional valves and seals, one could utilize the suction
and pressure sources to provide the depression/withdrawal, action
of the central portion from the skin surface. In this manner, a
single peristaltic pump mechanism, with one or more circuits, could
be engaged in either the forward or reverse direction, generating
either pressure or suction as required, with the proper design of
the swept area of the different pump circuits, and optionally,
appropriately sized pressure bleed ports and one way valves, the
required, coordinated, sequence of suction, pressure and mechanical
translation could all be performed by a system with a single
peristaltic pump based moving part. As peristaltic pumps are by
nature, a positive displacement mechanism, they are very efficient.
Alternatively, these motive forces could easily be provided by a
small motor(s) or actuator(s) under microprocessor control with
appropriate linkage to coordinate movements to the device
cycle.
[0189] If a suitably strong adhesive is used to attach the system
to the tissue surface, the entire sequence of tissue
compression-expansion could be achieved using only the mechanical
deformation of the device and the attached tissue, with atmospheric
pressure providing the only pressure in the
delivery-reservoir/extraction-chamber. In this case, the
compression cycle would be used to generate a sufficiently high
internal pressure in the tissue matrix to exceed the ambient
atmospheric pressure and thereby induce the outflow of an analyte,
such as interstitial fluid, through the pore(s) into the extraction
chamber.
[0190] To utilize this idea to extract analytes from an organism,
one only need to apply the same basic series of steps but while
maintaining the reservoir at a reduced pressure level to induce the
out flux of interstitial fluid through the pore(s) into a sample
chamber. Therefore, when the skin is distended into the
decompression state, the cell matrix will fill with interstitial
fluid and then when the inward compression portion of the cycle
occurs, this matrix trapped fluid will be forced out of the tissue
at the paths of least resistance, one of which will be the
micropore(s) leading into the sample chamber. An improvement on the
extraction application could be made if the downward pressure could
be applied by starting at the outer reaches of the zone involved
and then bring the pressure inward towards the pores. This directed
increase in pressure would tend to force more fluid towards the
micropore(s), rather than letting it escape into the surrounding
tissue matrix. Similarly, a reversal of this radially applied
pressure pattern could be used to enhance the delivery mode
described previously.
[0191] To optimize the process for harvesting or delivery, it is
beneficial to change the relative timing and duration of the
different phases of the process. For example, for a given subject,
it will take a specific amount of time for a given peak distention
of the skin tissue matrix in the decompression cycle to be fully
filled up with interstitial fluid. This time is dependent upon the
subject's level of hydration, their individual skin tissue make-up,
the viscosity of their interstitial fluid and other less obvious
factors such as the local hydraulic permeability of the tissue
matrix, the subject's blood pressure and the like.
[0192] Similarly, optimizing for delivery will involve reversing
the radially directed variation of pressure from the harvesting
sequence described previously, such that after the delivery
reservoir has been allowed to give up some portion of its fluid
payload into the micropore(s) and the tissue beneath, if the
downward pressure could be applied sequentially from the center of
the device, it will tend to flush the fluid out into the
surrounding tissue matrix and away from the micropore(s) in a
peristaltic fashion. The device could also use a plunger mechanism
designed to come down and cover and thereby seal off the
micropore(s), making this directional forcing even more pronounced.
All of these features could readily be included in a low cost
disposable system.
[0193] The manufacture of the entire assembled system of the flux
enhancement device of this invention is through a single molded
component of plastic or silicone or the like. Similarly, the size
of scale of the system could be varied widely, ranging from systems
which may contain all of the active elements shown in FIG. 21
within a small assembly only a few hundred microns across, to
scaled up versions wherein these same functional components may
take up an area up to 10 cm across. For the smaller versions, it
may well be useful to incorporate a plurality of flux enhancement
cells within a single integrated system, with each micro-pressure
modulation system being deployed over a selected number of pores
through the skin. FIGS. 23a and 23b show a cross-sectional
schematic of a multi-chamber, microcell array that also
incorporates a thermal poration element(s) at the skin contact
point for each micro-cell. The multi-chamber, micro-cell array
could operate by the method and principle illustrated in FIGS.
22(a-d).
[0194] FIG. 24 shows a close-up of a single micro-cell from that of
the multi-chamber, micro-cell array of FIG. 23. The pressure
modulation activation links (a) are shown connecting the central
portion near the artificial opening and a separate pair of links
connecting the outer annulus of the cell. By pressing the center
links down in relation to the outer links, the blanching or
compression phase of the cycle is achieved. Conversely, by pulling
back on these central links while pressing the outer links down
into the subject's skin, the decompression phase is formed. The
permeant reservoir (b) is formed within the compliant, molded body
of the patch and the pressure within this chamber is set by the
relative deformation of the surrounding material as the skin
deformation cycle is going through. Alternatively, a portal into
each of these chambers could be molded into the patch body to
facilitate and active and independent control of the pressure in
the reservoir. This portal could also be used in the manufacturing
process for filling the reservoir with the selected permeant(s). An
adhesive disposed on the skin side of the thin film backing (c) and
the conductive traces (d) could provide the necessary attachment to
the skins surface. By using mold based manufacturing techniques, a
patch-like system could be built which could be made to be only a
few mm thick but covering an area of skin ranging from 1 to 20
square cm. This would allow the total system flux capacities to be
scaled for each selected therapeutic compound. Also, a system which
contains a plurality of micro reservoirs, each of which could be
isolated from one another, is a needle-less delivery system able to
delivery a plurality of different drugs, at different, yet
controllable/programmable flux rates. The flux rates could be
controlled or selected by several means including: setting the
number of micro-pressure modulation cells for each drug, varying
the both the rate and depth of actuation of various cells
containing different drugs, varying the number of pores accessible
by each cell, and so on.
[0195] An embodiment of the present inventive subject matter is a
transdermal drug delivery device for forming a micropore in a
tissue membrane of an animal, comprising a tissue interface layer,
a plurality of reservoirs in communication with the tissue
interface layer, and a controller for controlling the formation of
the micropore by the at least one porator. The tissue interface
layer includes a substrate and at least one porator, wherein said
porator is located on or within said substrate. The plurality of
reservoirs may include at least a first reservoir and a second
reservoir. The first reservoir may contain a permeant composition
to be introduced into the tissue membrane, while the second
reservoir may contain an analyte extracted from the tissue membrane
following poration of same. Further, the first reservoir may
contain a first drug or therapeutically active agent and the second
reservoir contains a second drug or therapeutically active agent,
or the first reservoir may contain a drug or therapeutically active
agent and the second reservoir may contain an excipient or other
biologically safe diluent for reconstituting the drug or
therapeutically active agent into a pharmaceutically acceptable
delivery system. The porator in this embodiment may be of any type,
material or form as has been discussed herein.
[0196] In a preferred embodiment, the porator comprises a plurality
of porators, whereby a single porator is associated with a single
reservoir, with the reservoirs containing a permeant composition or
an analyte.
[0197] Another embodiment of the present inventive subject matter
is drawn to a method of delivering two or more biologically active
compounds to a patient in need thereof by way of a tissue membrane.
The method comprises the steps of: a) forming at least one
micropore in the tissue membrane by contacting a poration device
with the tissue membrane and activating the poration device,
thereby forming the at least one micropore; b) applying a first
compound contained in a first reservoir of the poration device to
the tissue membrane by way of the at least one micropore; and c)
applying a second compound contained in a second reservoir of the
poration device to the tissue membrane by way of the at least one
micropore. The first and second compounds may be administered
sequentially or simultaneously to the membrane. The first and
second compounds may be first and second biologically active
agents, or the first compound may be a first biologically active
agent and the second compound may be a pharmaceutically acceptable
excipient. Further, the first and second compounds may be mixed
prior to being applied to the membrane.
[0198] A still further embodiment of the present inventive subject
matter is drawn to a method of facilitating passage of biological
compounds across a tissue membrane comprising the steps of: a)
forming at least one micropore in the tissue membrane by contacting
a poration device with the tissue membrane and activating the
poration device, thereby forming the at least one micropore; b)
applying a first compound contained in a first reservoir of the
poration device to the tissue membrane by way of the at least one
micropore; and c) extracting a second compound from the tissue
membrane and storing the second compound in a second reservoir in
the poration device. The steps of applying the first compound and
extracting the second compound may be executed simultaneously, or
the step of extracting the second compound from the tissue membrane
may be carried out prior to the step of applying the first compound
to the tissue membrane. Further, the method may comprise the step
of analyzing the second compound and applying the first compound
based on the analysis.
[0199] The design of the system, and the various structures and
embodiments present as described also lend themselves to allow
additional flux enhancement techniques to be utilized and combined
with the basic pressure modulation/mechanical manipulation system
such as electrotransport, electroporation, sonophoresis, chemical
enhancers or the like. For example, if the body of the molded patch
is formed with selected portions of it containing an electrically
conductive polymer, this material, which will be in direct contact
with the drug/permeant in the reservoir, could be used as the
delivery electrode, while a separate, adjacent, conductive but
electrically isolated portion of the patch could serve as the
counter-electrode in an electro-transport enhanced delivery mode,
By incorporating appropriate doping into this molded material to
provide the functionality of an ion-exchange resin with
biocompatible ions, it would also allow the electro-transport
process to proceed without the concern of delivering unwanted
molecules into the skin. These same conductive components could be
used to electroporate the tissue accessible via the current conduit
formed by the artificial opening in the skin's surface. The basic
idea of combining electroporation with the thermal micropores is
described in detail in U.S. Pat. No. 6,022,316, which is
incorporated herein in its entirety. Similarly, with the conductive
traces present on the skin-interface layer of the patch, they also
could be used as electrodes for electro-transport,
electro-poration, or impedance sensing between pores, a technique
which has been shown to be useful to facilitate a closed loop,
dynamic method for ascertaining whether each pore has been formed
to the desired depth into the tissue matrix of the skin. Finally,
by including an acoustic source, such as a sheet or layer of
piezo-active or magneto-restrictive material, coupled to the top of
the patch, the acoustic waves could be directed towards and through
the reservoir, inducing higher drug/permeant flux rates through the
pore into the skin. With acoustic energy, which could be used at
all frequencies from sub-sonic to ultra-sonic, the patch material
selection, and internal shape of the reservoir and other features
of the patch could be used to very effectively focus and/or direct
the acoustic energy as desired. For example, the curved conical
shape of the reservoir (b) shown in FIG. 24, would have the effect
of focusing a transverse acoustic wave propagating from the top of
the figure towards the skins surface. With the correct curvature,
the acoustic energy entering the reservoir could be focused into a
small spot directly coincident with the pore formed at the bottom.
Similarly, the mechanical linkage structures (a) shown in FIG. 24
could be used to form acoustic impedance mismatches and thereby
direct by reflection at this boundary the acoustic waves towards
the pores. This type of acoustic energy focusing could induce
dramatic `acoustic streaming` effects with local fluid velocities,
as high as 50 cm/sec, and all directed through the pore and into
the skin, with very low average sonic power levels.
[0200] The use of mode of sonic energy to induce acoustic
streaming, as a method of transdermal flux enhancement is
significantly different from the traditional mechanism attributed
to sonic energy for this purpose. Whereas sonic and ultrasonic
energy has been experimented with and used clinically for decades
to increase the transdermal delivery of selected small to moderate
molecular weight compounds, the general consensus amongst the
scientific community regarding the actual mechanism of flux
enhancement is that it is either inducing cavitation which causes
microscopic vesicle openings in the various membrane and lipid
bi-layers in the intact stratum corneum or that the sonic energy is
inducing a local hypothermia condition, which is well known to
increase the permeability of the stratum corneum and other skin
tissues, particularly if the temperature exceeds the phase change
point of the solid phase lipid layers in the stratum corneum of
roughly 37.degree. C. With the micropores present, an open channel
with little or no hydraulic resistance is now presented to allow
the influx of a drug formulation. The acoustic streaming effect
allows high, local velocities and fluid pressures to be directed
down these channels into the epidermis. It is noteworthy that this
type of directed fluid velocity and pressure into the micropores is
much more advantageous than merely increasing the hydrostatic
pressure within the delivery reservoir for the following reason. If
one merely increases the pressure within the delivery reservoir,
then, to hold this pressure and not induce a leak at the adhesive
based junction between the patch and the skin surface, the adhesive
used must be very aggressive. In clinical tests wherein patches
have been attached to the subjects with cyanocrylic `super-glue`
adhesive, the continuous application of even a very low positive
pressure of less than 1 psi, induces a leak to form within a few
minutes. Anyone who has ever inadvertently glued their fingers
together with this sort of `super-glue` may find this surprising;
as the inventors did when these experiments were done. However,
upon examining closer where the leaks actually formed, the true
situation is revealed. The following examples explain.
EXAMPLE 7A
Constant Pressure Delivery
[0201] A moderately sized patch of 1 square inch total reservoir to
skin area is applied, attached via adhesive to clean, dry, healthy
human skin, on a non-calloused area such as the volar forearm or
abdomen. The test patch has been formed from a clear plastic that
allows continuous visual observation of the reservoir and the
sealing surface occupying the 1/4" wide outer perimeter of the
patch. The reservoir is filled with an aqueous permeant, which for
this experiment has been dyed a deep blue to assist in detection of
any leaks from the chamber. The adhesive used is a cyanocrylic
anaerobic `super-glue` formulation, which has been applied and held
under moderate but firm pressure for 5 minutes. The clear view
afforded of the adhesive interface to the skin allows a good visual
check for the quality and uniformity of the attachment. After
ascertaining that the glue connection between the patch and the
skin looks good, the dyed permeant solution is loaded into the
delivery reservoir via an injection port, with a bleed port held
open to allow the filling of the reservoir without generating any
pressure. After ascertaining that there are no leaks present, with
the bleed port closed, the injection port is now used to gradually
apply a constant positive pressure to the delivery reservoir of 1
psi. This level of pressure is very low, less than what is
typically present in a child's party balloon when inflated. Upon
initial application of the pressure head, the skin beneath the
reservoir stretches slightly and is bowed downward into the
subject's body. One might expect an equilibrium condition to
quickly establish itself whereon the distension of the skin reaches
its maximum limit under this amount of force, and will stretch no
further, but what was observed in multiple replications of this
study is that the human skin is amazingly elastic under these
conditions, and over the next few minutes, with pressure kept
constant at 1 psi, the distension of the skin under the reservoir
continues. The result of this is that the skin interface, at the
inner surface of the glue attachment, is now being pulled almost
perpendicularly away from the patch body. At this point, with the
mild, but constant force pulling on the skin in this fashion, what
begins to happen is that the stratum corneum itself begins to peel
apart. The outermost layers of the stratum corneum are held
together by a reinforcing network of the `super-glue` which does
penetrate slightly into this tissue, however, where this
penetration stops, the binding forces holding the stratum corneum
together are solely due to the natural, lipid based adhesion of the
body acting as a `mortar` between the `bricks` of the
keratinocytes, and it is this attachment which starts to breakdown
and let go. By allowing the skin to stretch downward, away from the
plane of the glue interface, the resistance to breaking the
attachment is focused on a very few cells within the stratum
corneum layer, rather than being spread out over a larger area.
Once the stratum corneum begins to split in this fashion, as the
pressure is being held constant, this split just continues until a
leakage path is established to the outside of the patch. What this
means is that regardless of how good an adhesive is used to attach
this sort of patch to a human subject, if constant pressure is
applied within the patch, it is almost impossible to stop the
tissue splitting phenomena just described.
EXAMPLE 7B
Constant Pressure Delivery
[0202] The same basic procedure of Example 7A is repeated, however,
certain dimensions are now changed as follows. For the micropore to
enable delivery, a practical density of micropores is to form a
pore on 1-millimeter centers. For a 1-inch square total patch area,
this would equate to 625 pores in a matrix of 25.times.25. Whereas,
our experiments have indicated that essentially no medium to large
molecular weight drug flux will occur through the unbroken skin
between the pores, it seems wasteful to build a reservoir that
covers the entire area. Instead, it makes better sense to construct
the patch in a manner wherein each individual pore has a tiny
micro-reservoir located directly over it. Preferably, if the bottom
surface of the patch is formed such that the adhesive attachment to
the skin runs right up to the edge of the pore which has been
formed in through the stratum corneum layer, this provides the
maximal total area of adhesive attachment to the skin and at the
same time minimizes the total area of the skin which will be
exposed to the constant pressure about to be applied. If each pore
formed is 100 microns (0.0039 inch) in diameter, then the total
skin area exposed to the pressure head is
625.times.3.142.times.(0.002)A2=0.0076 square inches. Comparing
this number to the area presented by the previous example, of 1.0
square inches, the area is reduced by a factor, of 130:1. For each
micropore/microreservoir, if the pressure head is brought back up
to the same 1 psi, the peak force on the skin at each pore site
would be only 0.000012 pounds, whereas in the first example the
skin was being subjected to a total force of 1 pound, more than
80,000 time greater peak force. Under these conditions, it was
found that it is possible to use a mild positive, steady pressure
head to induce fluid flux through the micropores, for a limited
amount of time up to about 20 minutes. However, even as in Example
7A, once any tearing away of the adhesive interface begins to
occur, an avalanche effect comes into play wherein the peak
pressure being presented to the skin starts to increase
geometrically as the area exposed increases, and a leak failure is
certain to occur. So, by merely redesigning the geometry of the
patch interface to the skin, with specific attention to maximizing
the attachment area and reducing the amount of un-porated skin
exposed to the reservoir and the pressure head within the
reservoir, a system could be constructed which does allow the use
of a steady pressure gradient to induce a controlled delivery
profile via the micro-pores for a period of time sufficient for
many applications.
EXAMPLE 7C
Modulated Pressure Delivery
[0203] Based on the results of the experiments described in
Examples 7A and 7B above, a method for increasing the total
duration possible of the pressure application was suggested.
Basically, after examining the visco-elastic properties of the skin
tissues, it was determined that if the patch design presented in
Example 7B were used, but rather than holding a steady, constant
pressure head overtime, that a cyclical pressure modulation should
be applied. By allowing the pressure to drop to null periodically,
two apparent advantages are realized. First, the continual
stretching of the skin tissues is much more stressful on them than
a pulsatile stretching process. By only giving relatively short
pulses of pressure, the skin tissues themselves and more
particularly the glue interface, are not stressed to the tearing
point. Second, as the pressure induces a fluid flow via the
micropore into the viable tissue matrix below, by dropping the
pressure periodically, it allows the fluid perfused into these
tissues to spread out into a larger area meaning that at the next
pressure delivery cycle a more `porous` tissue matrix will be
presented. For the human skin, there are some natural resonant
frequencies for which the time course of this sort of pressure
modulation could be optimized. While there are clearly
inter-subject variances in these resonance modes, our experimental
work has indicated that varying the pressure cycle over a period of
from 0.1 to 10 seconds works well on most subjects tested. It has
also been noted that as the pressure cycle goes to shorter on
periods, with an asymmetric duty cycle, that the peak pressures
sustainable under these conditions start to rise dramatically,
allowing peak pressures of more than 10 psi to be sustained,
without tearing of the skin/adhesive interface if the on time is
kept below 1 second and run at less than a 30% duty cycle.
EXAMPLE 7D
Modulated Pressure Delivery
[0204] In addition to all of the embodiments described in Examples
7A, 7B and 7C, by incorporating an acoustic flux enhancement, and
more particularly an acoustic streaming and focused sonic energy,
an improved micropore based patch delivery system is realized. This
improved delivery system uses a plurality of small, micro-reservoir
chambers over each pore formed, wherein fluid flow and pressure is
directed towards the pores, but no constant, steady pressure is
created in the reservoirs themselves. By pulsing the acoustic
energy focused on the pores with high peak power (0.1 to 100
watts/cm.sup.2), short duration (0.0001 to 0.1 seconds) bursts at
relatively low repetition rates (0; 1 to 50 Hz), short lived,
transient pressure waves of several atmospheres, inducing both a
radiation pressure fluid movement and acoustic streaming effect
directing the permeant fluid through the pores and into the
subjects body. Also, by applying the pressure to the fluid in this
fashion, there is no net, constant pressure maintained in the
reservoir, working to break down the adhesive attachment between
the patch and the skin. In addition, whereas the peak power of the
acoustic energy may be as high as 100 watts/cm.sup.2 at the focal
point, the low duty cycles used, typically 1% or less, reduce this
level to an average power at this point of only 1 watt/cm.sup.2,
and keeping in mind that the actual area of the focal point is only
around 100 microns across, or less than 0.0001 cm.sup.2 for a total
average sonic power level of only 100 microwatts actually being
delivered, allowing for a very low cost, energy efficient system to
be built.
[0205] All of these synergistic combinations of different active
flux enhancement technologies have been described in detail in the
cited granted and co-pending patents of these same inventors.
EXAMPLE 8
Device which Combines Delivery and Monitoring
[0206] FIG. 25 shows a schematic illustration of a device for
applying the micropore method simultaneously to both deliver a
permeant into the subject and extract a biological fluid sample
from the subject which is then analyzed for the lever of a selected
permeant. The particular example shown in the figure is for a
closed-loop insulin delivery/glucose monitoring application. The
disposable patch contains two discrete sections, one devoted to the
delivery of the insulin which contains all of the desired features
of the various micropore based delivery methods and apparatus
described herein, and the second section using the micropores to
allow extraction of an interstitial fluid sample from which a
glucose level could be measured. The controller module could be
programmed with an algorithm designed to modulate the insulin
delivery in a manner responsive to the measured glucose levels with
the desired clinical goal of stabilizing the subject's glucose
levels within the normal range of 80 to 100 mg/dl. The delivery
algorithm could easily incorporate basal infusion rates and even
pre-meal bolus delivery cycles just as today's latest insulin pump
systems do in addition to relying solely on the measurement of the
glucose levels. The disposable patch could be designed to last for
several hours to several days, with the practical limit being
driven by the useable life of the glucose sensor and the amount of
insulin carried in the delivery reservoir. By allowing a direct
measurement of the pharmacodynamic effect of the insulin delivery
on the subject's glucose levels, a true, external, artificial
pancreas has been realized. By using the micropores to establish
both the delivery and extraction conduits, the system is also
non-invasive as compared to the insulin pump which requires the
installation of a physically invasive cannula into the subcutaneous
layers of the skin and the lancet based blood draws to assess
glucose levels. Whereas this example is focused on insulin infusion
and glucose monitoring, the same basic concept can be applied to
wide variety of therapeutic compounds that could benefit from a
dynamically controlled delivery rate designed to achieve and
maintain a specific pharmacokinetic/pharmacodynamic profile. Some
good candidates for this sort of closed loop modulated-delivery
system are; many of the chemotherapies being used which have a
narrow window between when the optimal therapeutic effects are
achieved and when the negative side effects become to oppressive to
the subject; some of the psycho active drugs to control seizures;
as a monitor on a on-demand patient controlled analgesia using
opiate based compounds for treatment of chronic pain where a safety
level threshold could be set which would not allow the subject to
inadvertently over-medicate.
[0207] One embodiment of the present inventive subject matter is an
integrated monitoring and delivery system comprising a delivery and
extraction patch, a controller for actuating the porator array,
thereby forming micropores in the tissue membrane, and an apparatus
for analyzing the analyte. The apparatus contains an algorithm to
determine a concentration of the analyte and control delivery of
the permeant composition based on the analyte concentration. The
delivery and extraction patch further comprises a first section
comprising a first tissue interface layer and a first reservoir for
storing a permeant composition to be applied to a tissue membrane.
The first tissue interface membrane further comprising a substrate
with a first porator array contained on or within the substrate.
The delivery and extraction patch also includes a second section
comprising a second tissue interface layer and a second reservoir
for collecting an analyte from the tissue membrane for analysis.
The second tissue interface membrane contains a substrate with a
second porator array contained on or within the substrate.
Optionally, the delivery and extraction patch includes an adhesive
for adhering said patch to the tissue membrane.
[0208] A preferred embodiment of the present inventive subject
matter is directed to a method of monitoring an analyte extracted
from a patient and delivering a permeant composition to the
patient. The method comprises the steps of: a) contacting a
delivery and extraction patch to a tissue membrane of the patient;
b) actuating poration of the tissue membrane using at least one
poration array in the delivery and extraction patch; c) extracting
an analyte from the microporated tissue membrane by way of at least
one micropore array; d) analyzing the analyte to determine
concentration of same within the tissue membrane; and e) delivering
a permeant composition to the tissue membrane by way of at least
one micropore array. In a preferred embodiment, the delivery and
extraction patch comprises a first section comprising a first
tissue interface layer and a first reservoir for storing a permeant
composition to be applied to a tissue membrane, the first tissue
interface membrane further comprising a substrate with a first
porator array contained on or within the substrate, a second
section comprising a second tissue interface layer and a second
reservoir for collecting an analyte from the tissue membrane for
analysis, the second tissue interface membrane further comprising a
substrate with a second porator array contained on or within the
substrate, and an adhesive for adhering the patch to the tissue
membrane.
[0209] The inventive subject matter contemplates the first and
second porator arrays of the above apparatus and method being the
same porator array, or different porator arrays. Each of the
porator arrays are each selected from the group consisting of a
probe element, an electro-mechanical actuator, a microlancet, an
array of micro-needles or lancets, a thermal energy ablator, a
sonic energy ablator, a laser ablation system, and a high pressure
fluid jet puncturer. Further, each of the reservoirs further
comprise: a) a top layer; b) a middle layer that has at least one
cavity for storing a drug or other permeant composition to be
applied to the membrane in the first reservoir, and for accepting
the analyte in the second reservoir; and c) a bottom layer, the
bottom layer containing pores through which the drug is applied to
the tissue membrane in the first reservoir, and through which the
analyte is extracted in the second reservoir. In addition, the
porator material may be constructed or produced as taught
herein.
EXAMPLE 9
Direct Laser Machining of Planar Arrays of Poration Elements
[0210] FIGS. 26 and 27 show two different design examples of how a
functional planar array of poration elements could be fabricated
using the direct laser machining methods described herein. In FIG.
26, the poration elements (82a-82d) could be fabricated with a
kinked-loop shape. In general, the poration elements will be of the
shape of any one of elements 82a to 82d; however, for ease of
illustration, the different shapes are shown on the same planar
array. In addition, other shapes not illustrated herein are also
contemplated, as the shapes indicated are only for illustrative
purposes and are not meant to be limiting. The shape will force the
element, when heated by passing a current pulse through it, to bend
upward, away from the supporting substrate, towards the biological
membrane to be porated. The conducting traces (80 and 81) allow the
current source to be delivered to the poration elements (82) in a
parallel fashion, connecting simultaneously to the three elements
shown in this figure.
[0211] FIG. 27 shows a similar array of planar poration elements
(93) however not of the actuated design. The conductive traces (90,
91 and 92) connect the poration elements in this array in a series
parallel circuit. In this fashion all eight poration elements (93)
could be activated by passing the current pulse from conductive
trace (90) to conductive trace (92), alternatively, either group of
four elements connecting to the central conductive trace (91) could
be activated as a group of four by selectively applying current
between either traces (90) to (91) or between (91) and (92). Both
examples shown in these photomicrographs of these device designs
were fabricated by starting with a 50-micron thick tungsten alloy
film, which was then cut to the final dimensions shown through a
direct laser machining process. The individual poration elements
each have a nominal width of 50 microns. For the tungsten alloy
used in these devices, a poration element having the roughly square
cross-section of 50 microns by 50 microns could be thermally cycled
to greater than 1000.degree. C. by passing a square wave current
pulse through it having an amplitude of 1 amp, and a duration of
0.001 to 0.003 seconds. Other dimensions are contemplated with
different materials, for example resistive elements made of copper
may have different dimensions based on its conductive
properties.
EXAMPLE 10
Disposable Patch System
[0212] FIG. 28 shows the actuator section of the device. The
actuator section 100 consists a case 102 that houses a electrical
circuit board 104, an actuator button 106, and a battery, not
shown. The battery is a flat coin shaped cell. The electrical
circuit provides a pulsed electrical current when the button is
pressed. The bottom surface of actuator section has two exposed
electrodes that are not shown.
[0213] FIG. 29 shows the microporator section of the device. The
top surface of the microporator section 108 has two electrical
contact areas 110 and 112. The contact areas are electrically
insulated from each other. The top surface also has an adhesive
area so as to permit attachment to the actuator section and contact
between the actuator section electrodes and the contact areas 110
and 112.
[0214] On the bottom surface of the microporator section 108, there
is exposed an array of 80 resistive elements, 114, spaced over an
area of one square inch. The array of resistive elements is
connected to the contact areas 110 and 112 so that electrical
energy is passed from the actuator section to each of the resistive
elements. The elements are expose such that they can be brought
into intimate contact with body tissue without excessive
pressure.
[0215] The elements are capable of conductively delivering thermal
energy via direct contact to the tissue and act as heated probes to
cause the ablation of a portion of the tissue membrane. The
ablation of tissue forms micropores in the skin. The micropores
formed have a diameter of about 50 microns and a depth of about 50
microns.
[0216] The resistive elements are straight bars with a
cross-sectional area of about 625 square microns and have a length
of 450 microns. When an electrical current pulse is applied to each
element, the pulsed element is rapidly brought to a temperature of
about 450.degree. C. The array of resistive elements is connected
in parallel to the current pulse source. The pulse duration is from
1 to 5 milliseconds; The bottom surface of the microporator section
also has an adhesive area to facilitate maintaining the resistive
elements in intimate contact with the body tissue. The microporator
section has cover release liners on the adhesives areas on the top
and bottom surfaces for protection. These covers are removed prior
to use.
[0217] FIG. 30 shows a reservoir patch 116 that is applied to the
body tissue after the poration is accomplished. The patch consists
of top layer 118, a middle layer 120 that has a cavity or cavities
122 for containing the drug and a bottom adhesive porous layer (not
shown) for attachment to the body tissue over the porated area. The
patch has additionally a cover layer attached to the bottom porous
layer for protection and to retain the drug within the cavity
behind the porous layer. This cover is removed prior to use.
[0218] After porating an area of the skin using this device, the
microporator section 108 along with actuator section 100 are
removed from over the porated area. The cover on the reservoir
patch 116 is removed and patch 116 containing the drug is applied
to the porated area of the skin tissue. The drug moves through
porous layer of the patch and contacts the outer skin. The drug
then diffuses through the micropores in the porated area of the
tissue into the body over a period of time. This period of time may
be minutes or days as appropriate for the specific drug and use
indication for the drug.
[0219] A preferred embodiment is drawn to a poration system
comprising a porator array having at least one porator and an
actuator. The actuator comprises an outer body defining a top of
the actuator and containing a cavity, a controller board comprising
driving electronics and a battery, the controller board being
positioned within the cavity, and an interface connection port for
receiving the porator array.
[0220] A further embodiment of the present inventive subject matter
is an integrated poration device as described above. The integrated
poration device comprises an actuator, a porator array, and a
reservoir patch. The reservoir patch is applied to the microporated
area of the tissue membrane after poration. The actuator further
comprises an outer body containing a cavity and defining a top of
the actuator, a controller board comprising driving electronics and
a battery, and being positioned within the cavity, and an interface
connection port for receiving the porator array and containing an
anode and a cathode. The porator array comprises a top surface,
with a removable adhesive attached to the top surface. The top
surface contains two concentric electrical contact rings for
contacting the interface connection port at the anode and the
cathode upon removal of the adhesive layer. The porator array also
comprises a bottom surface comprising a tissue interface membrane
and a release liner removably attached thereto.
[0221] A further embodiment is drawn to a poration system
comprising a porator array comprising at least one porator and an
actuator. The actuator comprises an outer body defining a top of
the actuator and containing a cavity, a controller board comprising
driving electronics and a battery, the controller board being
positioned within the cavity, and an interface connection port for
receiving the porator array.
[0222] The tissue interface layer further comprises a substrate
with at least one porator contained on or within the substrate, and
the bottom surface further comprises an adhesive layer for
attaching the porator array to a tissue membrane.
[0223] Additionally, the reservoir patch further comprises a top
layer, a middle layer that has at least one cavity for containing a
drug or other permeant composition to be applied to the membrane,
and a bottom layer, the bottom layer containing pores through which
the drug is applied to the tissue membrane, and the bottom layer
containing an adhesive for attachment of the reservoir patch to the
microporated area of the tissue membrane. The reservoir patch may
also include a cover layer attached to the bottom layer to retain
the drug in the middle layer until the patch is applied to the
tissue membrane. The device may include a control button for
initiating poration of the tissue membrane.
[0224] The present inventive subject matter is also drawn to a
method of using the above devices for monitoring of analytes and
delivery of permeant compositions based on the analysis. The method
comprises the steps of: a) contacting the above device to a tissue
membrane of the patient; b) actuating poration of the tissue
membrane using at least one poration array in the delivery and
extraction patch; c) extracting an analyte from the microporated
tissue membrane by way of at least one micropore array; d)
analyzing the analyte to determine concentration of same within the
tissue membrane; and e) delivering a permeant composition to the
tissue membrane by way of at least one micropore array. In an
alternative embodiment, the device may be used to deliver two or
more biological substances to a patient in need thereof.
[0225] In a still further embodiment, the present inventive subject
matter is directed to a method of manufacturing the above poration
device. The method comprises the steps of: a) forming an outer body
defining a top of the integrated poration device, the outer body
containing a cavity; b) assembling a controller board comprising
driving electronics and a battery, and positioning the controller
board within the cavity; c) assembling a reservoir comprising a
top, side walls and a bottom, the top comprising a thin film top
plate abutting a bottom of the controller board and positioning the
reservoir within the cavity; and d) forming a tissue interface
layer along the bottom of the reservoir, the tissue interface layer
contacting a tissue membrane of an animal and containing at least
one porator, and the tissue interface layer forming the bottom of
the reservoir and of the integrated poration device.
EXAMPLE 11
Two Step Locator Alignment System for Positioning a Drug Delivery
Reservoir Over an Area of a Permeated Skin
[0226] It advantageous to be able to form a planar array of
micro-heaters using technologies which suitable for implementation
in a high-volume production environment. A technique which yields a
lower unit cost would be advantageous. Many currently used
deposition techniques, lithographic techniques, and etching
techniques are potential candidates for this application. It may be
advantageous to form the micro-heaters in a manner which are
supported on either end, but are not in contact the carrier
substrate, which supports the planar array, elsewhere. This reduces
conductive heat losses into the substrate and improves the geometry
defining the interface between the heater elements and the outer
skin tissues of an organism that the array is placed in contact
with such that when the heaters are pulsed with energy, micropores
are formed in these skin tissues, as described in U.S. Pat. No.
6,022,316.
[0227] Using a flexible substrate may also be advantageous both for
the end user comfort and manufacturing efficiency. A flexible array
of micro-heaters, elevated or otherwise, can be formed by starting
with a thin flexible substrate such as polyethelene, polycarbonate,
silicone, teflon, kapton, upsilon or other suitable material of
this sort. Apply a layer of conductive material suitable for use as
electric traces such as aluminum, copper, silver, gold, carbon, or
the like. We have used layers of copper from less than 0.6 microns
thick to more than 18 microns thick. These materials (ex: copper on
kapton) are readily available from commercial sources such as
Sheldahl, Dupont, Rogers, Gould as off-the-shelf items, typically
used as a starting point for flexible circuit boards. On top of the
conductive layer, apply a layer of resistive material such as
titanium, titanium nitride, tantalum, tantalum nitride, chromium, a
carbon compound, or the like. In the final array, the lower
impedance conductive traces will be used to deliver a current pulse
to the higher impedance micro-heaters will be formed primarily or
the resistive material. 1) The use of selectively applied etch
resist (photo resist, exposed through a mask could be used for this
step) and an etchant, or an optical machining station, or other
suitable micromachining techniques such as diamond milling,
electron beam etching, or the like, to selectively remove portions
of the conductive layers and resistive layer to create a pattern of
feeder traces and resistors in the array. The use of a laser may be
advantageous in some applications as it only requires one step and
can be designed to form the programmed patterns rapidly in the
resistive layer, as this layer is typically thinner than the
conductive layer, and/or more photo-absorbant. The conductive
traces will typically be several times larger in cross-section than
the micro-heaters. 2) A final step which allows the formation of
the elevated micro-heaters can be achieved by etching the entire
array with a chemical to remove the conductive material but not the
resistive material. This allows the resistive material to act as a
protective layer (like a photo resist layer) over the traces. The
etch time should be sufficient to remove all of the conductive
material from between the traces, and produce some undercutting of
the relatively wide conductive traces. This undercutting allows the
etchant to completely remove the conductive material from beneath
the relatively narrow micro-heaters. In this way, micro-heaters
which are suspended from the substrate by the thickness of the
conductive layer are formed.
[0228] Alternatively, or additionally, the substrate could be
removed from beneath the micro-heater regions by applying a photo
resist pattern and plasma, etching the back side of the array, or
by laser ablation with a suitable laser source which is
sufficiently absorbed by the targeted materials, i.e., remove the
substrate but not the conductive layer, and then the conductive
layer could be removed with an etchant which did not affect the
resistive layer.
[0229] Alternative to traditional photo resist mask, an adhesive
film can be applied to any layer, and a laser machining station
used to remove material to form a mask for etching.
[0230] Alternative to the traditional, photo resist, shadow mask,
an adhesive film can be applied to any layer, and a laser machining
station used to remove material to form a mask for etching the
desired pattern in the layers below the exposed portions of the
mask.
[0231] Supported, elevated filaments could be formed by creating
the conductive traces, applying an adhesive film such as kapton or
a photo resist layer, then patterning the film with a laser
machining station or patterning the photo resist with conventional
photo exposure-developing methods and then etching so that small
pads are formed bridging the gaps in the conductive traces.
Filaments are then deposited through a mask so that they overlap
these pads and touch the traces on either side. This technique
would produce filaments that were the tallest items on the array,
or rather filaments that protrude slightly from the surface of the
array.
[0232] Unsupported, elevated filaments could be formed by creating
the conductive traces, applying an adhesive film such as kapton or
a photo resist layer, then patterning the film with a laser
machining station or patterning the photo resist with conventional
developing/etching methods so that small pads are formed bridging
the gaps in the conductive traces. Filaments are then deposited
through a mask so that they overlap these pads and touch the traces
on either side. The photo resist pads or film pads could then be
removed by chemical or plasma etching, or by CO.sub.2 laser
ablation from the reverse side of the array. This technique would
produce filaments that were the tallest items on the array, or
rather filaments that protrude slightly from the surface of the
array.
[0233] Micro-heaters could be formed over the conductive layer or
over preformed traces by sputtering or evaporating the desired
thickness of resistive material through a shadow mask, for example
of a copper or molybdenum foil, in a vacuum chamber.
[0234] Micro-heaters could be formed over the conductive layer or
over preformed traces by depositing the desired thickness of
resistive material through a shadow mask, for example of a copper
or molybdenum foil, through the use of a combustion deposition
technique such as, but not limited to, that described in U.S. Pat.
No. 6,013,318.
[0235] Micro-heaters could be formed over the conductive layer or
over preformed traces by conductive inks or powders and applied and
formed using direct laser writing techniques, laser fusing of
powders, electro-deposition, ink jet deposition or screen printing
techniques which could be cured into a resistive layer to form the
high impedance heater elements.
[0236] Micro-heaters could be formed over the conductive layer or
over preformed traces by using a pick and place process which
positioned individual preformed heater elements onto the array, and
then mechanically and electrically bonded them as needed. This
process would support the use of a variety of materials for the
heater elements which may not be as easily adapted to the three
previous process, and it would also allow the formation of heater
elements which were mounted proud of the conductive traces.
[0237] The following ideas are related to the material composition
and fabrication/production of the thermal component in the
microporator device. These ideas are relevant to all microporation
and poration devices discussed within this application. 1) The
material composition of the device can be a bimetal foil such that
the trace material is different from the microporation elements. 2)
The materials can be a host of metals (and their alloys) including
but not limited to: copper, aluminum, stainless steel, chromium,
manganese, tantalum, nickel, platinum, evanohm, tungsten, titanium,
gold, silver, titanium nitride. 3) The material can be thin films
deposited by MEMs processes and their derivatives (sputter,
electroplate, evaporation, CVD, CCVD, etc). 4) The component can be
made from conductive inks or powders and manufactured using direct
laser writing techniques, laser fusing of powders,
electro-deposition, ink jet type deposition or screen printing
techniques. 5) The substrate for the component can be thermo set
(phenolics, polyesters, epoxies, urethanes, silicones, etc) or
thermoplastic (polyethylene, polypropylene, polystyrene, PVC,
Polytetrafluorethylene, ABS, Polyamides, polyamides, etc.), ceramic
or stainless steel. 6) The material can also be in wire form. 7)
The component can be manufactured using a variety of MEMs
processes, including, but not limited to lasers, chemical vapor
deposition, physical vapor deposition, combustion deposition,
etc.
EXAMPLE 12
Patch System of FIGS. 31-37
[0238] These shapes and figures are merely to be viewed as one
representative version of these concepts for providing an alignment
or registration mechanism which facilitates the application of an
integrated poration device or a microporation system and then the
subsequent step of applying a drug reservoir patch over the area in
which the micropores are formed. The poration system could be
thermal, mechanical, optical, chemical, electrical or
acoustical.
[0239] Additionally, the two components comprising the porator
array and the drug reservoir may be linked on the same substrate
wherein a folding process can be utilized to bring the drug
reservoir into contact with the porated skin area after removal of
the activator, as is discussed below with respect to FIG. 38. After
the reservoir is pressed into place, the locator components and the
folding mechanism are removed, leaving only the drug reservoir
behind for minimally affected area on the subject's skin.
[0240] FIG. 31 depicts a top view of a release liner 130 for
protecting the top of a suitable porator array. Removal of release
liner 130 exposes the top surface of the porator array which
communicates with a reusable actuator/activator unit (not shown).
Release liner 130 may be constructed of any suitable material which
provides protection of the top of the porator array until it is
time to connect the porator array to the actuator unit.
[0241] FIG. 32 depicts a top view of a release liner 132 for
protecting the bottom of a suitable porator array. Removal of
release liner 132 exposes the bottom surface of the porator array
which is then attached to the tissue membrane to be porated. As
with release liner 130, release liner 132 may be constructed of any
suitable material which provides protection of the bottom of the
porator array until it is time to attach the porator array to the
tissue membrane.
[0242] FIG. 33 depicts a top view of porator array 140 after the
release liner as shown in FIG. 31 is removed. The top of porator
array 140 physically and electrically connects with the actuator
unit (not shown). As can be seen in the figure, the top of porator
array 140 contains a pair of concentric electric contact rings 142
and 144. Electric contact rings 142 and 144 provide electrical
communication between the actuator unit and porator array 140. The
actuator unit contains anode and cathode contact pads on its bottom
which align with electric contact rings 142 and 144. The electric
current from the actuator unit is delivered to porator array 140 by
way of electric contact rings 142 and 144. In addition, electric
contact rings 142 and 144 aid in physically aligning porator array
140 with the actuator unit.
[0243] FIG. 34 shows a bottom view of one embodiment of porator
array 140, which is contacted with the tissue membrane to be
porated. The bottom surface of porator array contains thermal
poration elements 148 for effecting microporation of the tissue
membrane. In this example, poration elements 148 are small
filaments interconnecting wider current deliver traces 150. After
application to the tissue membrane, an electric current pulse from
the actuator unit (not shown) is delivered to porator array 140,
actuating poration elements 148, and forming micropores in the
tissue membrane. Porator array 140 also contains locator ring 152,
which is a ring perforated in the material surrounding poration
elements 148. The geometry for porator array 140 in this example is
for illustrative purposes only and it is contemplated within the
scope of the present inventive subject matter that other geometries
and materials may be used.
[0244] Upon poration of the tissue membrane, poration elements 148
are removed from the tissue membrane by tearing along the locator
ring 152. FIG. 35 shows porator array 140 after the poration
elements have been removed from locator ring 152. Adhesive applied
to this remaining portion of porator array 140 is of sufficient
strength to cause the outer portion of porator array 140 to remain
in place when the poration elements are pulled back from the tissue
membrane. Similarly, the adhesive holding the poration elements to
the tissue membrane is sufficient to pull away the poration
elements away from the skin while breaking the perforations along
locator ring 152.
[0245] FIG. 36 depicts the application of a drug reservoir patch
160 to the porated area of the tissue membrane. As can be seen,
drug reservoir patch, or reservoir patch, 160 is constructed of a
size to fit within the area left behind in porator array 140
following removal of the poration elements. The reservoir patch is
constructed of a top layer, a middle layer that has at least one
cavity for containing a drug or other permeant composition to be
applied to the membrane, and a bottom layer. The bottom layer
contains small holes or pores through which the drug is applied to
the tissue membrane and an adhesive for attachment of the reservoir
patch to the porated area of the tissue membrane. FIG. 37 shows
reservoir patch 160 following removal of the remaining portions of
the porator array.
[0246] In a preferred embodiment, the actuator unit comprises an
outer body containing a cavity and defining a top of the actuator,
a controller board comprising driving electronics and a battery
positioned within the cavity, and an interface connection port for
receiving the porator array with the interface connection port
containing an anode and a cathode.
EXAMPLE 13
Patch System of FIG. 38
[0247] FIG. 38 shows a single piece disposable patch design that
incorporates in an integrated manner a poration array 170, which is
held in registration to a drug reservoir patch or reservoir patch
172. The use of said system would be to first apply the porator
array with an applicator device or actuation unit (not shown), upon
removal of the applicator, the porator array 170 portion of the
one-piece system would tear away from the rest of the system,
leaving the reservoir patch and a folding extension tab 174 tab on
the subject's skin. Reservoir patch 172 would then be applied over
the site where the porator array had been applied by simply folding
along a pre-formed crease line 180 in extension tab 170 and
pressing reservoir patch 172 onto the porated site. The final step
is the removal of the extension tab 174, which tears away from
reservoir patch 172 along preformed perforated tear lines 176,
leaving only reservoir patch 172 remaining on the subject's
skin.
[0248] In a preferred embodiment, reservoir patch 172 is
constructed of a top layer, a middle layer that has at least one
cavity for containing a drug or other permeant composition to be
applied to the membrane, and a bottom layer. The bottom layer
contains small holes or pores through which the drug is applied to
the tissue membrane and an adhesive for attachment of the reservoir
patch to the porated area of the tissue membrane.
[0249] Further, the formation of the porations in the tissue
membrane by the use of an actuation unit or other activation means
may be accomplished by any device described herein and is not
limited to any particular actuation unit.
[0250] A preferred embodiment is drawn to a drug delivery patch
system comprising an actuator, a porator array, and a reservoir
patch attached to an extension tab. The reservoir patch is applied
to said microporated area of said tissue membrane after poration.
The actuator comprises an outer body defining a top and containing
a cavity, a controller board comprising driving electronics and a
battery and being positioned within the cavity, and an interface
connection port for receiving the porator array and containing an
anode and a cathode.
[0251] The porator array further comprises a top surface, a bottom
surface, an extension tab and a release liner removably attached to
the bottom surface. The top surface includes a removable adhesive
and containing two concentric electrical contact rings for
contacting the interface connection port at the anode and the
cathode upon removal of the adhesive layer. The bottom surface
contains a tissue interface membrane comprising a substrate with at
least one porator contained on or within the substrate. The bottom
surface also has an adhesive layer for attaching the porator array
to a tissue membrane. The porator array also includes an extension
tab laterally and removably attached to the bottom surface. The
extension tab further includes an adhesive applied on the bottom
thereof, thereby allowing the extension tab to remain on the tissue
membrane upon removal of the porator array.
[0252] The present inventive subject matter also includes a method
for using such a device for administering a drug or other permeant
to a patient in need thereof.
[0253] The advantages for using such a transdermal drug delivery
patch system include:
[0254] 1. The design eliminates any issues relating to having the
porator array in any close contact with the reservoir patch.
[0255] 2. It also ensures proper registration of the reservoir
patch over the porated skin area after application of the porator
array.
[0256] 3. From the user perspective, what is actually two steps,
(first porate, then apply the reservoir patch) becomes a single
step of applying the porator array, then folding and tearing along
the perforated lines to leave the reservoir patch in place, much
like placing a letter in an envelope, then folding the flap to seal
it, a pair of operations which are so intimately linked that they
quickly become a single process in the minds eye.
[0257] 4. From a marketing perspective, each application of the
reservoir patch is inextricably linked to the use of one of the
porator array disposables.
[0258] 5. From a packaging consideration, a single foil pack can be
used to contain the entire disposable porator array/reservoir patch
assembly.
[0259] 6. For manufacturing, the entire assembly can be formed and
ETH/O sterilized if needed, then filled with the drug (aseptically
if needed) prior to being sealed into the hermetic foil pack.
[0260] The inventive subject matter being thus described, it will
be obvious that the same may be varied in many ways. Such
variations are not to be regarded as a departure from the spirit
and scope of the inventive subject matter, and all such
modifications are intended to be included within the scope of the
following claims.
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