U.S. patent application number 09/930455 was filed with the patent office on 2003-02-20 for devices for intrabody delivery of molecules and systems and methods utilizing same.
Invention is credited to Doron, Eyal, Penner, Avi.
Application Number | 20030036746 09/930455 |
Document ID | / |
Family ID | 25459350 |
Filed Date | 2003-02-20 |
United States Patent
Application |
20030036746 |
Kind Code |
A1 |
Penner, Avi ; et
al. |
February 20, 2003 |
Devices for intrabody delivery of molecules and systems and methods
utilizing same
Abstract
A device for controlled release of molecules is provided. the
device including: (a) a device body having at least one reservoir
therein for containing the molecules, the at least one reservoir
being formed with a barrier impermeable to the molecules thereby
preventing release thereof from the at least one reservoir; and (b)
at least one acoustic transducer being attached to, or forming a
part of, the device body, the at least one acoustic transducer
being for converting an acoustic signal received thereby into an
electrical signal, the electrical signal leading to barrier
permeabilization and therefore release of the molecules from the at
least one reservoir.
Inventors: |
Penner, Avi; (Tel Aviv,
IL) ; Doron, Eyal; (Kiryat Yam, IL) |
Correspondence
Address: |
G.E. EHRLICH (1995) LTD.
C/O ANTHONY CASTORINA
SUITE 207
2001 JEFFERSON DAVIS HIGHWAY
ARLINGTON
VA
22202
US
|
Family ID: |
25459350 |
Appl. No.: |
09/930455 |
Filed: |
August 16, 2001 |
Current U.S.
Class: |
604/891.1 |
Current CPC
Class: |
H01L 41/04 20130101;
A61K 9/0097 20130101; A61K 9/0024 20130101; A61K 9/0009
20130101 |
Class at
Publication: |
604/891.1 |
International
Class: |
A61K 009/22 |
Claims
What is claimed is:
1. A device for controlled release of molecules comprising: (a) a
device body having at least one reservoir therein for containing
the molecules, said at least one reservoir being formed with a
barrier impermeable to the molecules thereby preventing release
thereof from said at least one reservoir; and (b) at least one
acoustic transducer being attached to, or forming a part of, said
device body, said at least one acoustic transducer being for
converting an acoustic signal received thereby into an electrical
signal, said electrical signal leading to barrier permeabilization
and therefore release of the molecules from said at least one
reservoir.
2. The device of claim 1, further comprising a cathode, and an
anode, whereas said electrical signal generates an electric
potential between said cathode and said anode leading to
permeabilization of said barrier and release of the molecules from
said at least one reservoir.
3. The device of claim 2, wherein said anode is attached to or
forms at least a part of said barrier.
4. The device of claim 2, wherein said electrical signal directly
generates said electric potential between said cathode and said
anode.
5. The device of claim 2, further comprising a power source for
generating said electric potential between said cathode and said
anode upon receiving said electrical signal from said at least one
acoustic transducer.
6. The device of claim 1, wherein said at least one acoustic
transducer serves as an acoustic switch.
7. The device of claim 1, wherein permeabilization of said barrier
is effected by at least partial disintegration thereof.
8. The device of claim 1, wherein a type or duration of said
electrical signal controls a degree of permeabilization of said
barrier and thus an amount of the molecules released.
9. The device of claim 1, wherein the device includes a plurality
of reservoirs.
10. The device of claim 9, wherein the device includes a plurality
of acoustic transducers.
11. The device of claim 10, wherein each of said plurality of
acoustic transducers generates an electrical signal which leads to
permeabilization of a barrier of a corresponding reservoir of said
plurality of reservoirs.
12. The device of claim 11, wherein each of said plurality of
acoustic transducers is capable of converting an acoustic signal of
a distinct frequency or frequencies into said electrical
signal.
13. The device of claim 9, wherein said plurality of reservoirs are
for containing different types of molecules, different amounts of
molecules, or combinations thereof.
14. The device of claim 1, wherein the molecules are drug
molecules.
15. The device of claim 1, wherein said at least one acoustic
transducer includes: (i) a cell member having a cavity; (ii) a
substantially flexible piezoelectric layer attached to said cell
member, said piezoelectric layer having an external surface and an
internal surface, said piezoelectric layer featuring such
dimensions so as to enable fluctuations thereof at its resonance
frequency upon impinging of an external acoustic wave; and (iii) a
first electrode attached to said external surface and a second
electrode attached to said internal surface.
16. A device for controlled drug release comprising: (a) a device
body including at least one reservoir being for containing a
prodrug form of a drug, said at least one reservoir being formed
with a barrier impermeable to said prodrug thereby preventing
release thereof from said at least one reservoir; and (b) at least
one acoustic transducer being attached to, or forming a part of
said device body, said at least one acoustic transducer being for
converting an acoustic signal received thereby into an electrical
signal, said electrical signal leading to a conversion of said
prodrug into said drug, said drug being capable of traversing said
barrier thereby releasing from said at least one reservoir.
17. The device of claim 16, further comprising a cathode, and an
anode disposed within said at least one electrode, whereas said
electrical signal generates an electric potential between said
cathode and said anode leading to said conversion of said prodrug
into said drug.
18. The device of claim 16, wherein said anode is attached to or
forms at least a part of said barrier.
19. The device of claim 17, wherein said electrical signal directly
generates said electric potential between said cathode and said
anode.
20. The device of claim 17, further comprising a power source for
generating said electric potential between said cathode and said
anode upon receiving said electrical signal from said at least one
acoustic transducer.
21. The device of claim 16, wherein said at least one acoustic
transducer serves as an acoustic switch.
22. The device of claim 16, wherein a type or duration of said
electrical signal controls a degree of said conversion and thus an
amount of said drug formed and released
23. The device of claim 16, wherein the device includes a plurality
of reservoirs.
24. The device of claim 16, wherein the device includes a plurality
of acoustic transducers.
25. The device of claim 24, wherein each of said plurality of
acoustic transducers generates an electrical signal which leads to
said conversion of said prodrug to said drug contained in a
corresponding reservoir of said plurality of reservoirs.
26. The device of claim 25, wherein each of said plurality of
acoustic transducers is capable of converting an acoustic signal of
a distinct frequency or frequencies into said electrical
signal.
27. The device of claim 23, wherein said plurality of reservoirs
are for containing different types of prodrugs, different amounts
of prodrugs, or combinations thereof.
28. The device of claim 16, wherein said at least one acoustic
transducer includes: (i) a cell member having a cavity; (ii) a
substantially flexible piezoelectric layer attached to said cell
member, said piezoelectric layer having an external surface and an
internal surface, said piezoelectric layer featuring such
dimensions so as to enable fluctuations thereof at its resonance
frequency upon impinging of an external acoustic wave; and (iii) a
first electrode attached to said external surface and a second
electrode attached to said internal surface.
29. A method of delivering molecules to a specific body region, the
method comprising: (a) implanting within the body region a device
including: (i) a device body having at least one reservoir therein
containing the molecules, said at least one reservoir being formed
with a barrier impermeable to the molecules thereby preventing
release thereof from said at least one reservoir; and (ii) at least
one acoustic transducer being attached to, or forming a part of,
said device body, said at least one acoustic transducer being for
converting an acoustic signal received thereby into an electrical
signal, said electrical signal leading to barrier permeabilization
and therefore release of the molecules from said at least one
reservoir; and (b) extracorporeally irradiating the body with an
acoustic signal thereby causing the subsequent release of the
molecules from said at least one reservoir.
30. The method of claim 29, wherein said device includes a
plurality of reservoirs each containing molecules of a specific
type and each capable of releasing said molecules upon provision of
an acoustic signal of a specific frequency or frequencies, such
that a frequency content of said acoustic signal determines a type
of said molecules released.
31. The method of claim 29, wherein a frequency content or duration
of said acoustic signal controls a degree of permeabilization of
said barrier and thus an amount of the molecules released.
32. The method of claim 29, wherein said molecules are drug
molecules.
33. The method of claim 29, wherein said device further includes a
cathode, and an anode, whereas said electrical signal generates an
electric potential between said cathode and said anode leading to
permeabilization of said barrier and release of the molecules from
said at least one reservoir.
34. The method of claim 33, wherein said anode is attached to or
forms at least a part of said barrier.
35. The method of claim 33, wherein said electrical signal directly
generates said electric potential between said cathode and said
anode.
36. The method of claim 33, wherein said device further includes a
power source for generating said electric potential between said
cathode and said anode upon receiving said electrical signal from
said at least one acoustic transducer.
37. The method of claim 29, wherein said acoustic transducer serves
as an acoustic switch.
38. A system for localized delivery of molecules within the body
comprising: (a) an intrabody implantable device including: (i) a
device body having at least one reservoir therein for containing
the molecules, said at least one reservoir being formed with a
barrier impermeable to the molecules thereby preventing release
thereof from said at least one reservoir; and (ii) at least one
acoustic transducer being attached to, or forming a part of, said
device body, said at least one acoustic transducer being for
converting an acoustic signal received thereby into an electrical
signal, said electrical signal leading to barrier permeabilization
and therefore release of the molecules from said at least one
reservoir; and (b) an extracorporeal unit for generating said
acoustic signal.
39. A system for localized delivery of molecules within the body
comprising: (a) an intrabody implantable device including: (i) a
device body including at least one reservoir being for containing a
prodrug form of a drug, said at least one reservoir being formed
with a barrier impermeable to said prodrug thereby preventing
release thereof from said at least one reservoir; and (ii) at least
one acoustic transducer being attached to, or forming a part of
said device body, said at least one acoustic transducer being for
converting an acoustic signal received thereby into an electrical
signal, said electrical signal leading to a conversion of said
prodrug into said drug, said drug being capable of traversing said
barrier thereby releasing from said at least one reservoir; and (b)
an extracorporeal unit for generating said acoustic signal.
40. A method of fabricating a device for controllable release of
molecules, the method comprising: (a) providing a substrate; (b)
configuring said substrate with at least one reservoir; (c) capping
said at least one reservoir with a cap material which acts as an
impermeable barrier to the molecules, said material becoming
permeable to the molecules following generation of an electrical
potential in or around said at least one reservoir; and (d)
providing an inlet port for filling said at least on reservoir with
the molecules, said inlet being sealable following said filling,
thereby generating the device for controllable release of
molecules.
41. The method of claim 40, further comprising the step of: (e)
attaching to, or fabricating within, said substrate, at least one
acoustic transducer, said at least one acoustic transducer being
for generating an electrical signal from an acoustic signal
received thereby, said electrical signal leading to generation of
said electrical potential in or around said at least one
reservoir.
42. The method of claim 41, wherein said at least one acoustic
transducer includes: (i) a cell member having a cavity; (ii) a
substantially flexible piezoelectric layer attached to said cell
member, said piezoelectric layer having an external surface and an
internal surface, said piezoelectric layer featuring such
dimensions so as to enable fluctuations thereof at its resonance
frequency upon impinging of an external acoustic wave; and (iii) a
first electrode attached to said external surface and a second
electrode attached to said internal surface.
43. The method of claim 40, wherein step (b) is effected by etching
said substrate.
Description
FIELD AND BACKGROUND OF THE INVENTION
[0001] The present invention relates to a device for intrabody
delivery of molecules, to a method and system of utilizing same and
to a method of fabricating same. More particularly, embodiments of
the present invention relate to a drug delivery device which
utilizes an acoustic transducer for generating an electrical
activation signal from an acoustic signal received thereby.
[0002] The efficacy of drug treatment is oftentimes dependent upon
the mode of drug delivery.
[0003] Localized drug delivery is oftentimes preferred since it
traverses limitations associated with systemic drug delivery
including rapid drug inactivation and/or ineffectual drug
concentrations at the site of treatment. In addition, in some
cases, systemic drug delivery can lead to undesired cytotoxic
effects at tissue regions other than that to be treated.
[0004] Since localized intrabody delivery of medication is central
to efficient medical treatment attempts have been made to design
and fabricate intrabody delivery devices which are capable of
controlled and localized release of a wide variety of molecules
including, but not limited to, drugs and other therapeutics.
[0005] Controlled release polymeric devices have been designed to
provide drug release over a period of time via diffusion of the
drug out of the polymer and/or degradation of the polymer over the
desired time period following administration to the patient.
Although these devices enable localized drug delivery, their
relatively simple design is limited in that it does not enable
accurate and controlled delivery of the drug.
[0006] U.S. Pat. No. 5,490,962 to Cima, et al. discloses the use of
three dimensional printing methods to make more complex devices
which provide release over a desired time frame, of one or more
drugs. Although the general procedure for making a complex device
is described, specific designs are not detailed.
[0007] U.S. Pat. No. 4,003,379 to Ellinwood describes an
implantable electromechanically driven device that includes a
flexible retractable walled container, which receives medication
from a storage area via an inlet and then dispenses the medication
into the body via an outlet.
[0008] U.S. Pat. Nos. 4,146,029 and 3,692,027 to Ellinwood disclose
self-powered medication systems that have programmable miniaturized
dispensing means.
[0009] U.S. Pat. No. 4,360,019 to Jassawalla discloses an
implantable infusion device that includes an actuating means for
delivery of the drug through a catheter. The actuating means
includes a solenoid driven miniature pump.
[0010] Since such devices include miniature power-driven mechanical
parts which are required to operate in the body, i.e., they must
retract, dispense, or pump, they are complicated and subject to
frequent breakdowns. Moreover, due to complexity and size
restrictions, they are unsuitable for delivery of more than a few
drugs or drug mixtures at a time.
[0011] U.S. Pat. Nos. 6,123,861 and 5,797,898 both to Santini, Jr.,
et al. disclose microchips devices which control both the rate and
time of release of multiple chemical substances either in a
continuous or a pulsatile manner. Such microchip devices employ a
reservoir cap which is fabricated of a material that either
degrades or allows the molecules to diffuse passively out of the
reservoir over time or materials that oxidize and dissolve upon
application of an electric potential. Release from the microchip
device can be controlled by a preprogrammed microprocessor, via a
radiofrequency (RF) activation signal, or by biosensors.
[0012] Although the microchip device described by Santini, Jr., et
al. presents substantial improvements over other prior art devices,
it suffers from several inherent limitations which will be
described in detail hereinbelow.
[0013] There is thus a widely recognized need for, and it would be
highly advantageous to have, a delivery device and methods of
fabricating and utilizing same which device can be used for
accurate and timely delivery of a drug or drugs within a body
tissue region devoid of the above limitation.
SUMMARY OF THE INVENTION
[0014] According to one aspect of the present invention there is
provided a device for controlled release of molecules comprising:
(a) a device body having at least one reservoir therein for
containing the molecules, the at least one reservoir being formed
with a barrier impermeable to the molecules thereby preventing
release thereof from the at least one reservoir; and (b) at least
one acoustic transducer being attached to, or forming a part of,
the device body, the at least one acoustic transducer being for
converting an acoustic signal received thereby into an electrical
signal, the electrical signal leading to barrier permeabilization
and therefore release of the molecules from the at least one
reservoir.
[0015] According to an additional aspect of the present invention
there is provided system for localized delivery of molecules within
the body comprising: (a) an intrabody implantable device including:
(i) a device body having at least one reservoir therein for
containing the molecules, the at least one reservoir being formed
with a barrier impermeable to the molecules thereby preventing
release thereof from the at least one reservoir; and (ii) at least
one acoustic transducer being attached to, or forming a part of,
the device body, the at least one acoustic transducer being for
converting an acoustic signal received thereby into an electrical
signal, the electrical signal leading to barrier permeabilization
and therefore release of the molecules from the at least one
reservoir; and (b) an extracorporeal unit for generating the
acoustic signal.
[0016] According to another aspect of the present invention there
is provided a method of delivering molecules to a specific body
region, the method comprising: (a) implanting within the body
region a device including: (i) a device body having at least one
reservoir therein containing the molecules, the at least one
reservoir being formed with a barrier impermeable to the molecules
thereby preventing release thereof from the at least one reservoir;
and (ii) at least one acoustic transducer being attached to, or
forming a part of, the device body, the at least one acoustic
transducer being for converting an acoustic signal received thereby
into an electrical signal, the electrical signal leading to barrier
permeabilization and therefore release of the molecules from the at
least one reservoir; and (b) extracorporeally irradiating the body
with an acoustic signal thereby causing the subsequent release of
the molecules from the at least one reservoir.
[0017] According to further features in preferred embodiments of
the invention described below, the device further comprising a
cathode, and an anode, whereas the electrical signal generates an
electric potential between the cathode and the anode leading to
permeabilization of the barrier and release of the molecules from
the at least one reservoir.
[0018] According to still further features in the described
preferred embodiments the anode is attached to or forms at least a
part of the barrier.
[0019] According to still further features in the described
preferred embodiments the electrical signal directly generates the
electric potential between the cathode and the anode.
[0020] According to still further features in the described
preferred embodiments the device further comprising a power source
for generating the electric potential between the cathode and the
anode upon receiving the electrical signal from the at least one
acoustic transducer.
[0021] According to still further features in the described
preferred embodiments the at least one acoustic transducer serves
as an acoustic switch.
[0022] According to still further features in the described
preferred embodiments permeabilization of the barrier is effected
by at least partial disintegration thereof.
[0023] According to still further features in the described
preferred embodiments a type or duration of the electrical signal
controls a degree of permeabilization of the barrier and thus an
amount of the molecules released.
[0024] According to still further features in the described
preferred embodiments the device includes a plurality of
reservoirs.
[0025] According to still further features in the described
preferred embodiments the device includes a plurality of acoustic
transducers.
[0026] According to still further features in the described
preferred embodiments each of the plurality of acoustic transducers
generates an electrical signal which leads to permeabilization of a
barrier of a corresponding reservoir of the plurality of
reservoirs.
[0027] According to still further features in the described
preferred embodiments each of the plurality of acoustic transducers
is capable of converting an acoustic signal of a distinct frequency
or frequencies into the electrical signal.
[0028] According to still further features in the described
preferred embodiments the plurality of reservoirs are for
containing different types of molecules, different amounts of
molecules, or combinations thereof.
[0029] According to still further features in the described
preferred embodiments the molecules are drug molecules.
[0030] According to still further features in the described
preferred embodiments the at least one acoustic transducer
includes: (i) a cell member having a cavity; (ii) a substantially
flexible piezoelectric layer attached to the cell member, the
piezoelectric layer having an external surface and an internal
surface, the piezoelectric layer featuring such dimensions so as to
enable fluctuations thereof at its resonance frequency upon
impinging of an external acoustic wave; and (iii) a first electrode
attached to the external surface and a second electrode attached to
the internal surface.
[0031] According to still further features in the described
preferred embodiments the device includes a plurality of reservoirs
each containing molecules of a specific type and each capable of
releasing the molecules upon provision of an acoustic signal of a
specific frequency or frequencies, such that a frequency content of
the acoustic signal determines a type of the molecules
released.
[0032] According to an additional aspect of the present invention
there is provided a device for controlled drug release comprising:
(a) a device body including at least one reservoir being for
containing a prodrug form of a drug, the at least one reservoir
being formed with a barrier impermeable to the prodrug thereby
preventing release thereof from the at least one reservoir; and (b)
at least one acoustic transducer being attached to, or forming a
part of the device body, the at least one acoustic transducer being
for converting an acoustic signal received thereby into an
electrical signal, the electrical signal leading to a conversion of
the prodrug into the drug, the drug being capable of traversing the
barrier thereby releasing from the at least one reservoir.
[0033] According to yet an additional aspect of the present
invention there is provided a system for localized delivery of
molecules within the body comprising: (a) an intrabody implantable
device including: (i) a device body including at least one
reservoir being for containing a prodrug form of a drug, the at
least one reservoir being formed with a barrier impermeable to the
prodrug thereby preventing release thereof from the at least one
reservoir; and (ii) at least one acoustic transducer being attached
to, or forming a part of the device body, the at least one acoustic
transducer being for converting an acoustic signal received thereby
into an electrical signal, the electrical signal leading to a
conversion of the prodrug into the drug, the drug being capable of
traversing the barrier thereby releasing from the at least one
reservoir; and (b) an extracorporeal unit for generating the
acoustic signal.
[0034] According to still further features in the described
preferred embodiments a type or duration of the electrical signal
controls a degree of the conversion and thus an amount of the drug
formed and released
[0035] According to still further features in the described
preferred embodiments the device includes a plurality of reservoirs
and a plurality of acoustic transducers, each of the plurality of
acoustic transducers generates an electrical signal which leads to
the conversion of the prodrug to the drug contained in a
corresponding reservoir of the plurality of reservoirs.
[0036] According to still further features in the described
preferred embodiments the plurality of reservoirs are for
containing different types of prodrugs, different amounts of
prodrugs, or combinations thereof.
[0037] According to still an additional aspect of the present
invention there is provided a method of fabricating a device for
controllable release of molecules, the method comprising: (a)
providing a substrate; (b) configuring the substrate with at least
one reservoir; (c) capping the at least one reservoir with a cap
material which acts as an impermeable barrier to the molecules, the
material becoming permeable to the molecules following generation
of an electrical potential in or around the at least one reservoir;
and (d) providing an inlet port for filling the at least on
reservoir with the molecules, the inlet being sealable following
the filling, thereby generating the device for controllable release
of molecules.
[0038] According to still further features in the described
preferred embodiments the method further comprising the step of:
(e) attaching to, or fabricating within, the substrate, at least
one acoustic transducer, the at least one acoustic transducer being
for generating an electrical signal from an acoustic signal
received thereby, the electrical signal leading to generation of
the electrical potential in or around the at least one
reservoir.
[0039] According to still further features in the described
preferred embodiments the at least one acoustic transducer
includes: (i) a cell member having a cavity; (ii) a substantially
flexible piezoelectric layer attached to the cell member, the
piezoelectric layer having an external surface and an internal
surface, the piezoelectric layer featuring such dimensions so as to
enable fluctuations thereof at its resonance frequency upon
impinging of an external acoustic wave; and (iii) a first electrode
attached to the external surface and a second electrode attached to
the internal surface.
[0040] According to still further features in the described
preferred embodiments step (b) is effected by etching the
substrate.
[0041] The present invention successfully addresses the
shortcomings of the presently known configurations by providing a
device, system and method for efficient intrabody delivery of
molecules such as drugs as well as a method of manufacture.
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] The invention is herein described, by way of example only,
with reference to the accompanying drawings. With specific
reference now to the drawings in detail, it is stressed that the
particulars shown are by way of example and for purposes of
illustrative discussion of the preferred embodiments of the present
invention only, and are presented in the cause of providing what is
believed to be the most useful and readily understood description
of the principles and conceptual aspects of the invention. In this
regard, no attempt is made to show structural details of the
invention in more detail than is necessary for a fundamental
understanding of the invention, the description taken with the
drawings making apparent to those skilled in the art how the
several forms of the invention may be embodied in practice.
[0043] In the drawings:
[0044] FIG. 1 is a cross sectional view of a general configuration
of the device of the present invention;
[0045] FIGS. 2-3 illustrate cross sectional views of a prior art
transducer element utilizable by the device of the present
invention;
[0046] FIG. 4 illustrates a "direct activation" configuration of
the device of the present invention;
[0047] FIG. 5 illustrates an "indirect activation" configuration of
the device of the present invention;
[0048] FIG. 6 is a schematic diagram illustrating an acoustic
switch utilizable by the device of the present invention;
[0049] FIG. 7 is a black box diagram of a drug delivery system
according to the teachings of the present invention; and
[0050] FIG. 8 is schematic diagram illustrating a control circuitry
of the acoustic switch illustrated in FIG. 6.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0051] The present invention is of a device, system and method
which can be used for localized intrabody delivery of molecules.
Specifically, the present invention can be used to release
molecules such as drugs within a specific body region using an
acoustic activation signal provided from outside the body.
[0052] The principles and operation of the present invention may be
better understood with reference to the drawings and accompanying
descriptions.
[0053] Before explaining at least one embodiment of the invention
in detail, it is to be understood that the invention is not limited
in its application to the details of construction and the
arrangement of the components set forth in the following
description or illustrated in the drawings. The invention is
capable of other embodiments or of being practiced or carried out
in various ways. Also, it is to be understood that the phraseology
and terminology employed herein is for the purpose of description
and should not be regarded as limiting.
[0054] Referring now to the drawings, FIG. 1 illustrates the device
for controlled release of molecules, which is referred to herein as
device 10.
[0055] Device 10 includes a device body 12 having at least one
reservoir 14 formed therein for containing the molecules to be
delivered.
[0056] Preferably, device body 12 includes a plurality of
reservoirs 14 (four shown in FIG. 1) each being configured for
containing therapeutic molecules such as drugs and/or diagnostic
molecules such as dyes preferably in a solution or as a suspension.
Reservoirs 14 can be of various dimensions depending on the
molecule type and quantity to be delivered therefrom.
[0057] Device body 12 can be of a planar shape, spheroidal shape or
any shape suitable for intrabody implantation and delivery of
molecules stored thereby. Reservoirs 14 can be formed within a
surface of device body 12 or within an interior volume thereof,
provided molecules released therefrom can disperse into a medium
surrounding device 10.
[0058] The dimensions of device 10 are limited by the site of
implantation and delivery, the quantity of drugs or drugs to be
delivered thereby, and the specific components used thereby for
drug release activation.
[0059] Reservoirs 14 can be formed within device body 12 using any
method known in the art including, but not limited to, etching,
machining and the like. Alternatively, device body 12 may be
pre-formed with reservoirs 14 by, for example, casting or milling
techniques.
[0060] Device body 12 is fabricated from a material which is
impermeable to the molecules to be delivered and to the surrounding
fluids, for example, water, blood, electrolytes or other solutions.
Examples of suitable materials include ceramics, semiconductors,
biological membranes, and degradable and non-degradable polymers;
biocompatibility is preferred, but not required.
[0061] For in-vivo applications, non-biocompatible materials may be
encapsulated in a biocompatible material, such as
polyethyleneglycol or polytetrafluoroethylene-like materials,
before use. One example of a strong, non-degradable, easily etched
substrate that is impermeable to the molecules to be delivered and
the surrounding fluids is silicon.
[0062] Alternatively, device body 12 can also be fabricated from a
material which degrades or dissolves over a period of time into
biocompatible components such as Polyvinyl Alcohol (PVA). This
embodiment is preferred for in vivo applications where the device
is implanted and physical removal of the device at a later time is
not feasible or recommended, as is the case with, for example,
brain implants. An example of a class of strong, biocompatible
materials are the poly(anhydride-co-imides) discussed by K. E.
Uhrich et al., "Synthesis and characterization of degradable
poly(anhydride-co-imides)", Macromolecules, 1995, 28, 2184-93.
[0063] Reservoir 14 is formed (capped) with a barrier 16 which is
impermeable to the molecules to be delivered. As such barrier 16
serves for preventing molecules contained within reservoir 14 from
releasing into the surrounding medium when device 10 is implanted
within the body.
[0064] Reservoir 14 can be filled with molecules of interest either
prior to capping with barrier 16 or following such capping. In the
latter case, reservoir 14 also includes an inlet port 18, which
serves for filling reservoir 14 with molecules of choice following
fabrication of device 10. Inlet port 18 is designed to be sealable
following filling, such that accidental drug release therefrom does
not occur.
[0065] Device 10 further includes at least one acoustic transducer
20. Acoustic transducer 20 can be attached to, or it can form a
part of, device body 12. Acoustic transducer 20 serves for
converting an acoustic signal received thereby into an electrical
signal. The electrical signal generated by transducer 20 is
preferably rectified via a full or half-bridge rectifier into a DC
current signal. The converted electrical signal can be used to
directly or indirectly release the molecules stored in reservoir 14
as described hereinbelow.
[0066] According to a preferred embodiment of the present
invention, the electrical signal generates (directly or indirectly)
an electrical potential within reservoir 14.
[0067] To this end, device 10 further includes at least one pair of
electrodes 21, which are preferably positioned within reservoir 14
and which serve for providing the electrical potential therein.
[0068] According to one preferred embodiment of the present
invention, the electrical potential converts the molecules stored
within reservoir 14 into an active and barrier permeable form.
[0069] For example, the molecules contained within reservoir 14 can
be provided as large aggregates which are unable to traverse
barrier 16 which can be, in this case, a size selective membrane.
Upon provision of the electrical potential the molecules
disaggregate into smaller active units which are able to diffuse
out of reservoir 14 through barrier 16.
[0070] According to another preferred embodiment of the present
invention, the electrical potential leads to permeabilization of
barrier 16 and subsequent release of the molecules from reservoir
14.
[0071] For example, the electrical potential generated by
electrodes 21 can cause the partial or full disintegration of
barrier 16 and as such the release of the molecules from reservoir
14.
[0072] In such a case, barrier 16 can be composed of a thin film of
conductive material that is deposited over the reservoir, patterned
to a desired geometry, and function as an anode 22. The size and
placement of cathode 23 depends upon the device's application and
method of electric potential control.
[0073] Conductive materials capable of dissolving into solution or
forming soluble compounds or ions upon the application of an
electric potential, include, but are not limited to, metals such as
copper, gold, silver, and zinc and some polymers.
[0074] Thus, according to this configuration of device 10, when an
electric potential is applied between anode 22 and cathode 23, the
conductive material of the anode above the reservoir oxidizes to
form soluble compounds or ions that dissolve into solution,
exposing the molecules to be delivered to the surrounding
medium.
[0075] Alternatively, the application of an electric potential can
be used to create changes in local pH near barrier 16 thereby
leading to dissolving of barrier 16 and release of the
molecules.
[0076] Still alternatively, the application of an electric
potential can be used to create changes in the net charge of
barrier 16 or the net charge or solubility of the molecules thereby
enabling barrier 16 traversing.
[0077] In any case, the molecules to be delivered are released into
the surrounding medium by diffusion out of or by degradation or
dissolution of the release system. The frequency and quantity of
release can be controlled via the acoustic signal received by
acoustic transducer 20 as is further described hereinbelow.
[0078] According to a preferred embodiment of the present invention
and as specifically shown in FIGS. 2-3, acoustic transducer 20
includes at least one cell member 22 including a cavity 24 etched
or drilled into a substrate and covered by a substantially flexible
piezoelectric layer 26. Attached to piezoelectric layer 26 are an
upper electrode 28 and a lower electrode 30 which are connectable
to an electronic circuit.
[0079] The substrate is preferably made of an electrical conducting
layer 32 disposed on an electrically insulating layer 34, such that
cavity 24 is etched substantially through the thickness of
electrically conducting layer 32.
[0080] Electrically conducting layer 32 is preferably made of
copper and insulating layer 34 is preferably made of a polymer such
as polyimide. Conventional copper-plated polymer laminate such as
Kapton.TM. sheets may be used for the production of transducer 20.
Commercially available laminates such as Novaclad.TM. may be used.
Alternatively, the substrate may include a silicon layer, or any
other suitable material. Alternatively, layer 32 is made of a
non-conductive material such as Pyralin.TM..
[0081] An insulating chamber 36 is etched into the substrate,
preferably through the thickness of conducting layer 32, so as to
insulate the transducer element from other portions of the
substrate which may include other electrical components such as
other transducer elements etched into the substrate.
[0082] According to a specific embodiment, the width of insulating
chamber 36 is about 100 .mu.m. As shown, insulating chamber 36 is
etched into the substrate so as to form a wall 38 of a
predetermined thickness enclosing cavity 24, and a conducting line
40 integrally made with wall 38 for connecting the transducer
element to another electronic component preferably etched into the
same substrate, or to an external electronic circuit.
[0083] Upper electrode 28 and lower electrode 30 are preferably
precisely shaped, so as to cover a predetermined area of
piezoelectric layer 26. Electrodes 28 and 30 may be deposited on
the upper and lower surfaces of piezoelectric layer 26,
respectively, by using various methods such as vacuum deposition,
mask etching, painting, and the like.
[0084] Lower electrode 30 is preferably made as an integral part of
a substantially thin electrically conducting layer 42 disposed on
electrically conducting layer 32. Preferably, electrically
conducting layer 42 is made of a Nickel-Copper alloy and is
attached to electrically conducting layer 32 by means of a sealing
connection 44. Sealing connection 44 may be made of chemical or
physical metal vapour deposition (CVD or PVD) indium. According to
a preferred configuration, sealing connection 44 may feature a
thickness of about 10 .mu.m, such that the overall height of wall
38 of cavity 24 is about 20-25 .mu.m.
[0085] Preferably, cavity 24 is etched or drilled into the
substrate by using conventional printed-circuit photolithography
methods. Alternatively, cavity 24 may be etched into the substrate
by using VLSI/micro-machining technology or any other suitable
technology. Cavity 24 preferably includes a gas such as air. The
pressure of gas within cavity 24 may be specifically selected so as
to predetermine the sensitivity and ruggedness of the transducer as
well as the resonant frequency of layer 26.
[0086] Piezoelectric layer 26 may be made of PVDF or a copolymer
thereof. Alternatively, piezoelectric layer 26 is made of a
substantially flexible piezoceramic. Preferably, piezoelectric
layer 26 is a poled PVDF sheet having a thickness of about 9-28
.mu.m.
[0087] Preferably, the thickness and radius of flexible layer 26,
as well as the pressure within cavity 24, are specifically selected
so as to provide a predetermined resonant frequency.
[0088] The use of a substantially flexible piezoelectric layer 26,
allows to produce a miniature transducer element whose resonant
frequency is such that the acoustic wavelength is much larger than
the extent of the transducer. This enables the transducer to be
omnidirectional even at resonance, and further allows the use of
relatively low frequency acoustic signals which do not suffer from
significant attenuation in the surrounding medium.
[0089] The configuration and acoustic properties of such an
acoustic transducer and variants thereof as well as general
acoustic transduction principles are described in detail in U.S.
patent application Ser. No. 09/000,553 and PCT Publication No. WO
99/34,453 the disclosures of which are expressly incorporated by
reference as if fully set forth herein.
[0090] As mentioned hereinabove, the electrical signal generated by
acoustic transducer 20 can directly or indirectly activate the
release of the molecules from reservoir 20.
[0091] In the direct embodiment of device 10 which is specifically
shown in FIG. 4, the electrical signal generated by acoustic
transducer 20 is communicated directly (via circuitry) to
electrodes 21 to thereby generate the electrical potential.
[0092] It will be appreciated that in such cases, the degree of
barrier permeabilization and as such the degree of drug release can
be controlled by the duration and/or frequency of the acoustic
signal and/or its intensity received by acoustic transducer 20.
[0093] It will further be appreciated that in cases where device 10
includes a plurality of reservoirs, several acoustic transducers
can be utilized such that various activation schemes can be
employed.
[0094] For example, device 10 can include a plurality of acoustic
transducers 20 each dedicated to a specific reservoir of reservoirs
14. In such a case, each acoustic transducer 20 can function within
a specific frequency range and as such activate release from a
specific reservoir 14 only upon reception of an acoustic signal of
the specific frequency of frequency range.
[0095] Such a configuration enables selective activation of
specific reservoirs enabling control over the amount and rate of
molecules released as well as enabling control over the type of
molecules released, in cases where specific molecules are stored
within specific reservoirs.
[0096] In the indirect embodiment of device 10 which is
specifically shown in FIG. 5, the electrical signal generated by
acoustic transducer 20 serves to activate an energy storage device
54 which in turn generates the electrical potential between
electrodes 21.
[0097] In such cases, acoustic transducer 20 preferably forms a
part of an acoustic switch 50 which can be configured as described
below.
[0098] As specifically shown in FIG. 6, acoustic switch 50 includes
an electrical circuit 52 configured for performing one or more
functions or commands when activated.
[0099] Acoustic switch 50 further includes an energy storage device
54 (power source) and an acoustic transducer 20 coupled to
electrical circuit 52 and energy storage device 54.
[0100] In addition, acoustic switch 50 also includes a switch 56,
such as the switch described in the Examples section below,
although alternatively other switches, such as a miniature
electromechanical switch and the like (not shown) may be
provided.
[0101] Energy storage device 54 may be any of a variety of known
devices, such as an energy exchanger, a battery and/or a capacitor
(not shown). Preferably, energy storage device 54 is capable of
storing electrical energy substantially indefinitely. In addition,
energy storage device 54 may be capable of being charged from an
external source, e.g., inductively, as will be appreciated by those
skilled in the art. In a preferred embodiment, energy storage
device 54 includes both a capacitor and a primary, non-rechargeable
battery. Alternatively, energy storage device 54 may include a
secondary, rechargeable battery and/or capacitor that may be
energized before activation or use of acoustic switch 50.
[0102] Acoustic switch 50 operates in one of two modes, a "sleep"
or "passive" mode when not in use, and an "active" mode, when
commanding electrical energy delivery from energy storage device 54
to electrical circuit 52 in order to activate release of molecules
from reservoir 14 as described hereinabove.
[0103] When in the sleep mode, there is substantially no energy
consumption from energy storage device 54, and consequently,
acoustic switch 50 may remain in the sleep mode virtually
indefinitely, i.e., until activated. Thus, acoustic switch 50 may
be more energy efficient and, therefore, may require a smaller
capacity energy storage device 54 than power switching devices that
continuously draw at least a small amount of current in their
"passive" mode.
[0104] To activate the acoustic switch, one or more external
acoustic energy waves or signals 57 are transmitted until a signal
is received by acoustic transducer 20. Upon excitation by acoustic
wave(s) 57, acoustic transducer 20 produces an electrical output
that is used to close, open, or otherwise activate switch 56.
Preferably, in order to achieve reliable switching, acoustic
transducer 20 is configured to generate a voltage of at least
several tenths of a volt upon excitation that may be used as an
activation signal to close switch 56.
[0105] As a safety measure against false positives (either
erroneous activation or deactivation), switch 56 may be configured
to close only upon receipt of an initiation signal followed by a
confirmation signal. For example, an activation signal that
includes a first pulse followed by a second pulse separated by a
predetermined delay may be employed.
[0106] It will be appreciated that in the case of device 10 of the
present invention, the use of a confirmation signal may be
particularly advantageous since it can prevent unintentional
release of drugs.
[0107] In addition to an activation signal, acoustic transducer 20
may be configured for generating a termination signal in response
to a second acoustic excitation (which may be of different
frequency or duration than the activation signal) in order to
return acoustic switch 50 to its sleep mode.
[0108] For example, once activated, switch 56 may remain closed
indefinitely, e.g., until energy storage device 54 is depleted or
until a termination signal is received by acoustic transducer 20.
Alternatively, acoustic switch 50 may include a timer (not shown),
such that switch 56 remains closed only for a predetermined time,
whereupon it may automatically open, returning acoustic switch 50
to its sleep mode.
[0109] Acoustic switch may also include a microprocessor unit which
serves to interpret the electrical signal provided from acoustic
transducer 20 (e.g., frequency thereof) into a signal for switching
switch 56.
[0110] Such interpretation enables to modulate the duration and
strength of an electrical potential provided within reservoir 14 by
simply varying the frequency and/or duration and/or intensity
modulation of the acoustic signal provided from outside the
body.
[0111] Additional acoustic switch configurations which are
utilizable by the present invention are described in U.S. patent
application Ser. No. 09/690,615 filed Oct. 16, 2000, the disclosure
of which is expressly incorporated by reference as if fully set
forth herein.
[0112] Device 10 of the present invention can form a part of a
system for localized release of, for example, drugs, which is
referred to herein as system 100.
[0113] As shown in FIG. 7, system 100 also includes an
extracorporeal unit 102 which serves for generating an acoustic
signal outside the body, which acoustic signal is received by
device 10 implanted within the body. Numerous devices capable of
generating acoustic signal which can serve as extracorporeal unit
102 are known in the art, and as such no further description
thereof is given herein.
[0114] System 100 can be used as follows. A device 10 filled with
molecules is implanted within a specific body tissue. Following
implantation, extracorporeal unit 102 generates an acoustic signal
of a predetermined frequency and/or duration thereby activating
release of the molecules from device 10 as described
hereinabove.
[0115] Thus, the present invention provides a device, system and
method useful for localized delivery of molecules such as
drugs.
[0116] The device of the present invention provides several
advantages over prior art devices such as those described in U.S.
Pat. Nos. 6,123,861 and 5,797,898. Such advantages are afforded by
the acoustic transducer component of the device which functions in
converting an acoustic signal into an electrical activation
signal.
[0117] In sharp contrast, the device described in U.S. Pat. Nos.
6,123,861 and 5,797,898, employs radiofrequency (RF) receivers
which activate drug release upon reception of an RF signal
generated outside the body. The use of RF activation is
disadvantageous since RF signals are, at least in part, absorbed by
body tissues and are directionally limited by bulky unidirectional
antennas used for reception.
[0118] On the other hand, acoustic transducers, such as the one
utilized by the device of the present invention, are
omni-directional receivers which do not require antennas and as
such do not suffer from structural and functional limitations which
are inherent to RF receivers.
[0119] In addition, acoustic activation requires far less energy
than RF activation since acoustic waves, unlike RF waves, propagate
well within the aqueous medium which forms a substantial part of
body tissues.
[0120] Additional objects, advantages, and novel features of the
present invention will become apparent to one ordinarily skilled in
the art upon examination of the following examples, which are not
intended to be limiting. Additionally, each of the various
embodiments and aspects of the present invention as delineated
hereinabove and as claimed in the claims section below finds
experimental support in the following examples.
EXAMPLES
Acoustic Switch Circuitry and Function
[0121] Referring again to the drawings, FIG. 8, illustrates an
example of circuitry and components employed by an acoustic switch
200 which is utilizable by the device of the present invention.
[0122] Switch 200 includes a piezoelectric transducer, or other
acoustic transducer such the acoustic transducer described
hereinabove (not shown, but connectable at locations piezo + and
piezo -), a plurality of MOSFET transistors (Q1-Q4) and resistors
(R1-R4), and switch S1.
[0123] In the switch's "sleep" mode, all of the MOSFET transistors
(Q1-Q4) are in an off state. To maintain the off state, the gates
of the transistors are biased by pull-up and pull-down resistors.
The gates of N-channel transistors (Q1, Q3 & Q4) are biased to
ground and the gate of P-channel transistor Q2 is biased to +3V.
During this quiescent stage, switch S1 is closed and no current
flows through the circuit.
[0124] Therefore, although an energy storage device (not shown, but
coupled between the hot post, labeled with an exemplary voltage of
+3V, and ground) is connected to the switch 200, no current is
being drawn therefrom since all of the transistors are
quiescent.
[0125] When the piezoelectric transducer detects an external
acoustic signal, e.g., having a particular frequency such as the
transducer's resonant frequency, the voltage on the transistor Q1
will exceed the transistor threshold voltage of about one half of a
volt. Transistor Q1 is thereby switched on and current flows
through transistor Q1 and pull-up resistor R2. As a result of the
current flow through transistor Q1, the voltage on the drain of
transistor Q1 and the gate of transistor Q2 drops from +3V
substantially to zero (ground). This drop in voltage switches on
the P-channel transistor Q2, which begins to conduct through
transistor Q2 and pull-down resistor R3.
[0126] As a result of the current flowing through transistor Q2,
the voltage on the drain of transistor Q2 and the gates of
transistors Q3 and Q4 increases from substantially zero to +3V. The
increase in voltage switches on transistors Q3 and Q4. As a result,
transistor Q3 begins to conduct through resistor R4 and main
switching transistor Q4 begins to conduct through the "load,"
thereby switching on the electrical circuit.
[0127] As a result of the current flowing through transistor Q3,
the gate of transistor Q2 is connected to ground through transistor
Q3, irrespective of whether or not transistor Q1 is conducting. At
this stage, the transistors (Q2, Q3 & Q4) are latched to the
conducting state, even if the piezoelectric voltage on transistor
Q1 is subsequently reduced to zero and transistor Q1 ceases to
conduct. Thus, main switching transistor Q4 will remain on until
switch S1 is opened.
[0128] In order to deactivate or open switch 200, switch S1 must be
opened, for example, while there is no acoustic excitation of the
piezoelectric transducer. If this occurs, the gate of transistor Q2
increases to +3V due to pull-up resistor R2. Transistor Q2 then
switches off, thereby, in turn, switching off transistors Q3 and
Q4. At this stage, switch 200 returns to its sleep mode, even if
switch S1 is again closed. Switch 200 will only return to its
active mode upon receiving a new acoustic activation signal from
the piezoelectric transducer.
[0129] It should be apparent to one of ordinary skill in the art
that the above-mentioned electrical circuit is not the only
possible implementation of a switch for use with the present
invention. For example, the switching operation my be performed
using a CMOS circuit, which may draw less current when switched on,
an electromechanical switch, and the like.
[0130] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable
subcombination.
[0131] Although the invention has been described in conjunction
with specific embodiments thereof, it is evident that many
alternatives, modifications and variations will be apparent to
those skilled in the art. Accordingly, it is intended to embrace
all such alternatives, modifications and variations that fall
within the spirit and broad scope of the appended claims. All
publications, patents and patent applications mentioned in this
specification are herein incorporated in their entirety by
reference into the specification, to the same extent as if each
individual publication, patent, or patent application was
specifically and individually indicated to be incorporated herein
by reference. In addition, citation or identification of any
reference in this application shall not be construed as an
admission that such reference is available as prior art to the
present invention.
* * * * *