U.S. patent application number 13/112779 was filed with the patent office on 2011-10-06 for stent having active release reservoirs.
This patent application is currently assigned to BOSTON SCIENTIFIC SCIMED, INC.. Invention is credited to Charles E. Hutchinson, John T. Santini, Jr..
Application Number | 20110245914 13/112779 |
Document ID | / |
Family ID | 22603004 |
Filed Date | 2011-10-06 |
United States Patent
Application |
20110245914 |
Kind Code |
A1 |
Santini, Jr.; John T. ; et
al. |
October 6, 2011 |
STENT HAVING ACTIVE RELEASE RESERVOIRS
Abstract
Devices for the controlled release of one or more drugs are
provided. The devices include an implantable stent, at least two
reservoirs in the stent, and a release system contained in each of
the at least two reservoirs, wherein the release system comprises
one or more drugs for release.
Inventors: |
Santini, Jr.; John T.;
(North Chelmsford, MA) ; Hutchinson; Charles E.;
(Canaan, NH) |
Assignee: |
BOSTON SCIENTIFIC SCIMED,
INC.
Maple Grove
MN
|
Family ID: |
22603004 |
Appl. No.: |
13/112779 |
Filed: |
May 20, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11373805 |
Mar 10, 2006 |
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13112779 |
|
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10768315 |
Jan 30, 2004 |
7041130 |
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11373805 |
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|
10637319 |
Aug 8, 2003 |
7052488 |
|
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10768315 |
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10314838 |
Dec 9, 2002 |
6656162 |
|
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10637319 |
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09715493 |
Nov 17, 2000 |
6491666 |
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10314838 |
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60166370 |
Nov 17, 1999 |
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Current U.S.
Class: |
623/1.42 |
Current CPC
Class: |
A61L 2300/416 20130101;
A61M 15/0031 20140204; A61M 5/1407 20130101; A61M 15/008 20140204;
A23L 2/52 20130101; A61M 15/009 20130101; A61F 2250/0068 20130101;
A61K 9/0009 20130101; A61K 9/0097 20130101; A61L 31/16 20130101;
A61M 15/005 20140204; A61M 2205/8225 20130101; A61F 2250/0035
20130101; A61M 15/0083 20140204; A61F 2/91 20130101; A61M 15/0045
20130101; A61L 31/14 20130101 |
Class at
Publication: |
623/1.42 |
International
Class: |
A61F 2/82 20060101
A61F002/82 |
Claims
1. A system for controlled delivery of a drug comprising: a
substrate positioned on an implantable delivery device; at least
two reservoirs in the substrate, each reservoir defining an
opening; at least one therapeutic agent disposed in each of the
reservoirs; a reservoir cap sealing each opening; a mechanical
rupturing mechanism configured to produce sonic waves that rupture
the reservoir cap to permit release of the therapeutic agent from
the reservoir through the opening; and a mixing chamber adjacent
the reservoirs, wherein upon release of the therapeutic agent from
at least one of the reservoirs, the therapeutic agent is combined
with a carrier fluid in the mixing chamber and then transported to
a delivery site in a patient.
2. The system of claim 1, wherein the mechanical rupturing
mechanism comprises a piezoelectric material.
3. The system of claim 2, wherein the piezoelectric material
comprises any material having a crystal structure that is
non-centrosymmetric.
4. The system of claim 2, wherein the piezoelectric material
comprises a ceramic material.
5. The system of claim 2, wherein the piezoelectric material
comprises a polymer.
6. The system of claim 1, wherein the mechanical rupturing
mechanism is positioned on the implantable delivery device.
7. The system of claim 1, wherein the mechanical rupturing
mechanism is positioned outside of the implantable delivery
device.
8. The system of claim 1, wherein the reservoir cap comprises a
thin film formed of a metal, a polymer, or a combination
thereof.
9. The system of claim 1, wherein the therapeutic agent is in a
matrix formed of degradable material or a material which releases
the therapeutic agent by diffusion out of or disintegration of the
matrix.
10. The system of claim 1, wherein the implantable delivery device
is a stent.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation of U.S. application Ser. No.
11/373805, filed Mar. 10, 2006, now pending, which is a
continuation of U.S. application Ser. No. 10/768,315, filed Jan.
30, 2004, now U.S. Pat. No. 7,041,130, which is a continuation of
U.S. application Ser. No. 10/637,319, filed Aug. 8, 2003, now U.S.
Pat. No. 7,052,488, which is a continuation of U.S. application
Ser. No. 10/314,838, filed Dec. 9, 2002, now U.S. Pat. No.
6,656,162, which is a continuation of U.S. application Ser. No.
09/715,493, filed Nov. 17, 2000, now U.S. Pat. No. 6,491,666, which
claims the benefit of U.S. Provisional Application No. 60/166,370,
filed Nov. 17, 1999. All of these applications are incorporated
herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] This invention relates generally to miniaturized devices for
controlled delivery of chemical molecules into a carrier fluid.
BACKGROUND OF THE INVENTION
[0003] Accurate delivery of small, precise quantities of one or
more chemicals into a carrier fluid are of great importance in many
different fields of science and industry. Examples in medicine
include the delivery of drugs to patients using intravenous
methods, by pulmonary or inhalation methods, or by the release of
drugs from vascular stent devices. Examples in diagnostics include
releasing reagents into fluids to conduct DNA or genetic analyses,
combinatorial chemistry, or the detection of a specific molecule in
an environmental sample. Other applications involving the delivery
of chemicals into a carrier fluid include the release of fragrances
and therapeutic aromas from devices into air and the release of
flavoring agents into a liquid to produce beverage products.
[0004] U.S. Pat. No. 5,547,470 to Johnson, et al., discloses
automated devices for intravenous drug delivery in which plural
pumping channels independently infuse drugs and fluid. These
devices and delivery methods require that the drugs be carefully
pre-mixed and stored in a liquid form. A liquid form can, however,
reduce the stability of some drugs and therefore can cause
undesirable variability of the drug concentration. It would be
desirable to more accurately and reliably measure the amount of
drug introduced into the intravenous carrier fluid, as well as to
store the drug in a more stable form, for example as a solid.
[0005] U.S. Pat. No. 5,972,027 to Johnson discloses the use of
porous metallic stents as vascular drug delivery devices. The
devices reportedly deliver a drug from the porous structure of the
stent to the surrounding tissue. Such devices, however, are limited
in the number of drugs that they can deliver and are severely
limited in the control of both the rate and time of drug delivery,
as the delivery rate is governed by the porous structure. It would
be advantageous to provide active and more precise control over the
time and rate of delivery of a one or more of variety of drugs from
the stents into, for example, the bloodstream passing through the
implanted stent.
[0006] Microchip delivery devices, described in U.S. Pat. No.
5,797,898 and U.S. Pat. No. 6,123,861 to Santini et al., provide a
means to control both the rate and time of release of a variety of
molecules, such as drugs, in either a continuous or pulsatile
manner The devices further provide a means for storing the
chemicals in their most stable form. These patents describe, for
example, implanting the microchip devices by themselves into a
patient for delivery of drug. It would be advantageous, however, to
adapt the precise control of molecule release provided by these
microchip devices into a variety of other applications.
SUMMARY OF THE INVENTION
[0007] Apparatus and methods are provided for the delivery of
molecules to a site via a carrier fluid. The apparatus include
microchip devices which have reservoirs containing the molecules
for release. The apparatus and methods provide for active or
passive controlled release of the molecules. The microchip devices
include (1) a substrate, (2) at least two reservoirs in the
substrate containing the molecules for release, and (3) a reservoir
cap positioned on, or within a portion of, the reservoir and over
the molecules, so that the molecules are controllably released from
the device by diffusion through or upon disintegration or rupture
of the reservoir caps. Each of the reservoirs of a single microchip
can contain different molecules and/or different amounts and
concentrations, which can be released independently. The filled
reservoirs can be capped with materials that passively or actively
disintegrate. Passive release reservoir caps can be fabricated
using materials that allow the molecules to diffuse passively out
of the reservoir over time. Active release reservoir caps can be
fabricated using materials that disintegrate upon application of
electrical, mechanical, or thermal energy. Release from an active
device can be controlled by a preprogrammed microprocessor, remote
control, or by biosensors.
[0008] The carrier fluids into which the molecules are released can
be, for example, environments such as intravenous infusions,
beverage mixtures, vascular fluids, and gaseous phases. In a
preferred embodiment, the microchip device releases molecules that
are contained within the reservoirs into a fluid that is delivered
to a patient intravenously.
[0009] In another embodiment, the microchip device is integrated
into a stent for the delivery of drugs, such as anti-restenosis
drugs or such as pravastatin or other hypertension medications.
[0010] In yet another embodiment, the microchip delivers molecules,
which can be in the form of, but not limited to aerosols, vapors,
gases, or a mixture thereof, into a stream for either therapeutic
or aesthetic purposes.
[0011] In general, the microchip provides a method for storing
molecular species in their most stable form, which can be a solid,
liquid, gel, or gas. Upon either passive or active reservoir
opening, the one or more types of molecules are released into the
carrier fluid in either a pulsatile or continuous manner These
methods will provide fine control over the amount of the molecules
delivered as well as the time and rate at which delivery occurs.
Additionally, the molecular delivery device will extend the
shelf-life (i.e. stability) of the molecules offering new potential
applications.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 is a perspective view of a typical microchip device
for chemical delivery.
[0013] FIGS. 2a-e are cross-sectional schematic views of various
embodiments of devices having substrates formed from two fabricated
substrate portions which have been joined together.
[0014] FIGS. 3a-c are cross-sectional views showing the active
release of molecules from a microchip device into a carrier
liquid.
[0015] FIGS. 4a-c are cross-sectional views showing the active
release of molecules into a carrier gas.
[0016] FIGS. 5a-c are cross-sectional views showing a reservoir cap
of a microchip device being ruptured by direct application of a
mechanical force.
[0017] FIGS. 6a-b are cross-sectional views showing a reservoir cap
of a microchip device being ruptured by application of
ultrasound.
[0018] FIGS. 7a-c are cross-sectional views showing the passive
release of molecules from a microchip device into a carrier
liquid.
[0019] FIGS. 8a-b are cross-sectional views of two embodiments of
intravenous drug delivery systems having integrated drug delivery
microchips that release drug into a fluid delivered intravenously.
FIG. 8c is a perspective view of an intravenous drug delivery
system including a multi-chambered interface console and a
communications and digital control station.
[0020] FIGS. 9a-c illustrate one embodiment of a stent-microchip
drug delivery device, showing a perspective view (FIG. 9a), and two
sectional views (FIGS. 9b and 9c).
[0021] FIGS. 10a-c illustrate one embodiment of an inhalation
device (a metered dose inhaler) having a microchip drug delivery
device incorporated therein.
DETAILED DESCRIPTION OF THE INVENTION
[0022] I. Delivery Apparatus and Systems
[0023] The delivery system includes one or more microchip devices,
as described, for example, herein and in U.S. Pat. Nos. 5,797,898
and 6,123,861 to Santini et al., which are hereby incorporated by
reference in their entirety. See, for example, FIG. 1, which
illustrates a typical microchip device 10 with substrate 12,
reservoirs 16, and reservoir caps 14. The microchip device is
integrated with an apparatus providing active and passive release
of molecules into a carrier fluid. The apparatus may include a
quantity of the carrier fluid or the carrier fluid may be external
to the apparatus.
[0024] A. Microchip Devices
[0025] The microchip devices typically include a substrate having a
plurality of reservoirs containing a release system that includes
the molecules to be released. The microchip devices in some
embodiments further includes one or more reservoir caps covering
the reservoir openings. The reservoir caps can be designed and
formed from a material which is selectively permeable to the
molecules, which disintegrates to release the molecules, which
ruptures to release the molecules, or a combination thereof. Active
release systems may further include control circuitry and a power
source.
[0026] 1. The Substrate
[0027] The substrate contains the etched, molded, or machined
reservoirs and serves as the support for the microchip. Any
material that can serve as a support, is suitable for etching,
molding, or machining, and is impermeable to the molecules to be
delivered and to the surrounding fluids, for example, water,
organic solvents, blood, electrolytes or other solutions, may be
used as a substrate. Examples of substrate materials include
ceramics, semiconductors, and degradable and non-degradable
polymers. For drug delivery applications outside of the body, such
as drug release into a gaseous stream in an inhaler, it is
preferred that the substrate itself is non-toxic, but it is not
required. For in vivo applications such as stent drug delivery into
vascular fluids, a sterile, biocompatible material is preferred.
Nevertheless, toxic or otherwise non-biocompatible materials may be
encapsulated in a biocompatible material, such as poly(ethylene
glycol) or tetrafluoroethylene-like materials, before use.
[0028] For applications outside of drug delivery, such as
diagnostics or fragrance delivery, substrate biocompatibility may
be much less of an issue. 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. An example of a
class of strong, biocompatible materials are the
poly(anhydride-co-imides) described in Uhrich et al., "Synthesis
and characterization of degradable poly(anhydride-co-imides)",
Macromolecules, 28:2184-93 (1995).
[0029] The substrate can be formed of only one material or can be a
composite or multi-laminate material, e.g., several layers of the
same or different substrate materials that are bonded together.
Multi-portion substrates can include any number of layers of
ceramics, semiconductors, metals, polymers, or other substrate
materials. Two or more complete microchip devices also can be
bonded together to form multi-portion substrate devices, as
illustrated for example in FIGS. 2a-e. FIG. 2a, for comparison,
shows a "single" substrate device 200, which has substrate 210, in
which reservoirs 220 are filled with molecules to be released 240.
Reservoirs 220 are covered by reservoir caps 230 and sealed with
backing plate 250 or other type of seal. FIG. 2b shows device 300
having a substrate formed of a top substrate portion 310a bonded to
bottom substrate portion 310b. Reservoirs 320a, in top substrate
portion 310a are in communication with reservoirs 320b in bottom
substrate portion 310b. Reservoirs 320a/320b are filled with
molecules to be released 340 and are covered by reservoir caps 330
and sealed with backing plate 350 or other type of seal. FIG. 2c
shows device 400 having a substrate formed of a top substrate
portion 410a bonded to bottom substrate portion 410b. Top substrate
portion 410a has reservoir 420a which is in communication with
reservoir 420b in bottom substrate portion 410b. Reservoir 420b is
much larger than reservoir 420a and reservoirs 420a/420b contain
molecules to be released 440. Reservoirs 420a/420b are filled with
molecules to be released 440 and are covered by reservoir cap 430
and sealed with backing plate 450 or other type of seal. FIG. 4d
shows device 500 having a substrate formed of a top substrate
portion 510a bonded to bottom substrate portion 510b. Top substrate
portion 510a has reservoir 520a which contains first molecules to
be released 540a. Bottom substrate portion 510b has reservoir 520b
which contains second molecules to be released 540b. First
molecules to be released 540a can be the same or different from
second molecules to be released 540b. Reservoir 520a is covered by
reservoir cap 530a and sealed by reservoir cap 530b (formed of an
anode material) and partially by bottom substrate portion 510b.
Reservoir 520b is covered by internal reservoir cap 530b and sealed
with backing plate 550 or other type of seal. Cathodes 560a and
560b are positioned to form an electric potential with anode
reservoir cap 530b. In one embodiment of the device shown in FIG.
2d, second molecules to be released 540b are first released from
reservoir 520b, through or following the disintegration of
reservoir cap 530b, into reservoir 520a, wherein the second
molecules mix with first molecules to be released 540a before the
mixture of molecules is released from reservoir 520a through or
following the disintegration of reservoir cap 530a. FIG. 2e shows
another reservoir shape configuration in cross-section. Substrate
portions 310a/410a/510a can be formed from the same or different
materials and can have the same or different thicknesses as
substrate portions 310b/410b/510b. These substrate portions can be
bonded or attached together after they have been individually
processed (e.g., etched), or they may be formed before they have
any reservoirs or other features etched or micro-machined into them
(such as in SOI substrates).
[0030] 2. Release System
[0031] The molecules to be delivered may be inserted into the
reservoirs in their pure form, as a liquid solution or gel, or they
may be encapsulated within or by a release system. As used herein,
"release system" includes both the situation where the molecules
are in pure form, as either a solid or liquid, or are in a matrix
formed of degradable material or a material which releases
incorporated molecules by diffusion out of or disintegration of the
matrix. The molecules can be sometimes contained in a release
system because the degradation, dissolution, or diffusion
properties of the release system provide a method for controlling
the release rate of the molecules. The molecules can be
homogeneously or heterogeneously distributed within the release
system. Selection of the release system is dependent on the desired
rate of release of the molecules. Both non-degradable and
degradable release systems can be used for delivery of molecules.
Suitable release systems include polymers and polymeric matrices,
non-polymeric matrices, or inorganic and organic excipients and
diluents such as, but not limited to, calcium carbonate and sugar.
Release systems may be natural or synthetic, although synthetic
release systems typically are preferred due to the better
characterization of release profiles.
[0032] The release system is selected based on the period over
which release is desired. In the case of applications outside of
the body, the release times may range from a fraction of a second
to several months. In contrast, release times for in vivo
applications, such as stent drug delivery, generally are within the
range of several minutes to a year. In some cases, continuous
(constant) release from a reservoir may be most useful. In other
cases, a pulse (bulk) release from a reservoir may provide more
effective results. A single pulse from one reservoir can be
transformed into pulsatile release by using multiple reservoirs. It
is also possible to incorporate several layers of a release system
and other materials into a single reservoir to achieve pulsatile
delivery from a single reservoir. Continuous release can be
achieved by incorporating a release system that degrades,
dissolves, or allows diffusion of molecules through it over an
extended period of time. In addition, continuous release can be
simulated by releasing several pulses of molecules in quick
succession.
[0033] The release system material can be selected so that
molecules of various molecular weights are released from a
reservoir by diffusion out of or through the material or by
degradation of the material. In one embodiment for the technology
outside of the body, the degradation or disintegration of the
release system may occur by increasing its equilibrium vapor
pressure causing the release system to evaporate, thereby releasing
the molecules. This can be achieved by actively increasing the
temperature of the release system with thin film resistors or
passively through chemical interactions with the carrier liquids
and/or gases. In the case of in vivo applications, it may be
preferred that biodegradable polymers, bioerodible hydrogels, and
protein delivery systems are used for the release of molecules by
diffusion, degradation, or dissolution. In general, these materials
degrade or dissolve either by enzymatic hydrolysis or exposure to
water, or by surface or bulk erosion. Representative synthetic,
biodegradable polymers include: poly(amides) such as poly(amino
acids) and poly(peptides); poly(esters) such as poly(lactic acid),
poly(glycolic acid), poly(lactic-co-glycolic acid), and
poly(caprolactone); poly(anhydrides); poly(orthoesters);
poly(carbonates); and chemical derivatives thereof (substitutions,
additions of chemical groups, for example, alkyl, alkylene,
hydroxylations, oxidations, and other modifications routinely made
by those skilled in the art), copolymers and mixtures thereof.
Representative synthetic, non-degradable polymers include:
poly(ethers) such as poly(ethylene oxide), poly(ethylene glycol),
and poly(tetramethylene oxide); vinyl polymers-poly(acrylates) and
poly(methacrylates) such as methyl, ethyl, other alkyl,
hydroxyethyl methacrylate, acrylic and methacrylic acids, and
others such as poly(vinyl alcohol), poly(vinyl pyrolidone), and
poly(vinyl acetate); poly(urethanes); cellulose and its derivatives
such as alkyl, hydroxyalkyl, ethers, esters, nitrocellulose, and
various cellulose acetates; poly(siloxanes); and any chemical
derivatives thereof (substitutions, additions of chemical groups,
for example, alkyl, alkylene, hydroxylations, oxidations, and other
modifications routinely made by those skilled in the art),
copolymers and mixtures thereof
[0034] 3. Reservoir Caps
[0035] (i) Passive Release by Disintegration or Diffusion
[0036] In the passive timed release drug delivery devices, the
reservoir caps are formed from a material that degrades or
dissolves over time, or does not degrade or dissolve, but is
permeable to the molecules to be delivered. These materials are
preferably polymeric materials. Materials can be selected for use
as reservoir caps to give a variety of degradation rates,
dissolution rates, or permeabilities to enable the release of
molecules from different reservoirs at different times and, in some
cases, different rates. To obtain different release times (amounts
of release time delay), caps can be formed of different polymers,
the same polymer with different degrees of crosslinking, or a UV
polymerizable polymer. In the latter case, varying the exposure of
this polymer to UV light results in varying degrees of crosslinking
and gives the cap material different diffusion properties or
degradation or dissolution rates. Another way to obtain different
release times is by using one polymer, but varying the thickness of
that polymer. Thicker films of some polymers result in delayed
release time. Any combination of polymer, degree of crosslinking,
or polymer thickness can be modified to obtain a specific release
time or rate. In one embodiment, the release system containing the
molecules to be delivered is covered by a degradable cap material
that is nearly impermeable to the molecules. The time of release of
the molecules from the reservoir will be limited by the time
necessary for the cap material to degrade or dissolve. In another
embodiment, the cap material is non-degradable and is permeable to
the molecules to be delivered. The physical properties of the
material used, its degree of crosslinking, and its thickness will
determine the time necessary for the molecules to diffuse through
the cap material. If diffusion out of the release system is
limiting, the cap material delays the onset of release. If
diffusion through the cap material is limiting, the cap material
determines the release rate of the molecules in addition to
delaying the onset of release.
[0037] (ii) Active Release by Disintegration
[0038] In one embodiment of the active timed-release devices, the
reservoir caps consist of a thin film of conductive material that
is deposited over the reservoir, patterned to a desired geometry,
and serves as an anode. Cathodes are also fabricated on the device
with their size and placement dependent on the device's application
and method of electric potential control. The anode is defined as
the electrode where oxidation occurs. Any conductive material
capable of dissolving into solution or forming soluble ions or
oxidation compounds upon application of an electric current or
potential (electrochemical dissolution) can be used for the
fabrication of the anodes and cathodes. In addition, materials that
normally form insoluble ions or oxidation products in response to
an electric potential can be used if, for example, local pH changes
near the anode cause these oxidation products to become soluble.
Examples of suitable reservoir cap materials include metals such as
copper, gold, silver, and zinc, and some polymers, as described,
for example, in Kwon et al., "Electrically erodible polymer gel for
controlled release of drugs", Nature, 354:291-93 (1991); and Bae et
al., "Pulsatile drug release by electric stimulus", ACS Symposium
Series, 545: 98-110 (1994).
[0039] (iii) Release by Rupture
[0040] In another embodiment, the reservoir cap is positioned on
the reservoir over the molecules, which are released from the
reservoir upon heating or cooling the device, or a portion thereof,
to rupture the reservoir cap. As used herein, the term "rupture"
includes fracture or some other form of mechanical failure, as well
as a loss of structural integrity due to a phase change, e.g.,
melting, in response to a change in temperature, unless a specific
one of these mechanisms is indicated.
[0041] In a preferred embodiment, heating or cooling causes the
molecules in the reservoir to thermally expand (i.e. increase in
volume). At a given temperature (T1), the release system completely
fills the volume of the reservoir. Upon heating to temperature T2,
the release system begins to expand and applies a force on the
reservoir cap. Once this force exceeds the fracture strength of the
cap, the reservoir cap fractures and the molecules are released. In
a variation of this embodiment, the molecules can vaporize or
undergo a reaction, thereby elevating the pressure within the
reservoir sufficiently to cause the reservoir cap to rupture due to
the mechanical stress. Prior to the application of heat, the
pressure within the reservoir is lower than that needed to rupture
the reservoir cap. The addition of heat increases the equilibrium
pressure within the reservoir and the forces acting on the cap
material increase. Further increases in temperature cause the
pressure to continue to increase until the internal pressure
overcomes the fracture strength of the reservoir cap. Typically the
thermal expansion, vaporization, or reaction is induced by heating
the molecules in the reservoir, e.g. above ambient temperatures. In
certain applications, however, the thermal expansion or reaction
can be induced by cooling the molecules in the reservoir. Water,
for example, expands upon freezing. If a material that thermally
contracts upon cooling is used as the reservoir cap over aqueous
molecules, then the mechanical failure should be further enhanced
by sufficient cooling.
[0042] In one embodiment, the reservoir cap is ruptured by physical
(i.e. structural) or chemical changes in the reservoir cap material
itself, for example, a change caused by a temperature change For
example, the reservoir cap can be made of or include a material
that expands when heated. When the reservoir cap is secured in a
fixed position and heated, the reservoir cap expands until it
cracks or ruptures due to the increase in volume. This embodiment
permits heating of the reservoir cap with minimal or no heating of
the reservoir contents, a feature that is particularly important
when the reservoir contains heat-sensitive molecules, such as
protein drugs, which can denature upon exposure to excessive
heat.
[0043] In another embodiment using an active release mechanism, the
reservoir cap material is melted (i.e. undergoes a phase change)
using resistive heating. For in vivo applications, the reservoir
cap preferably is composed of biocompatible copolymers, such as
organic hydroxy acid derivatives (e.g., lactides and lactones),
which can offer a range of selectable melting temperatures (see PCT
WO 98/26814). Particular melting temperatures, for example between
about 2.degree. C. and about 12.degree. C. above normal body
temperature, can be selected for the reservoir caps by proper
selection of starting monomer ratios and the resulting molecular
weight of the copolymer. This type of reservoir opening mechanism
offers at least two delivery schemes. A first scheme is based on
individual reservoir caps having various melting temperatures. By
heating the device, or portion thereof, to a constant temperature,
only specific reservoir caps melt, opening the reservoir and
exposing the molecules. The application of different temperature
profiles therefore provides for the selective molecular release. A
second scheme, shown in FIG. 13, focuses on all caps having a fixed
composition and a uniform melting temperature. The cap is a solid
phase at temperature T1. Locally heating individual reservoir caps
to temperature T2 causes the reservoir cap to become molten. The
fluidized reservoir cap is then mobile, which facilitates the
opening of the reservoir and release of molecules. In the case of
in vitro applications, similar active schemes are possible with
less stringent compositional and temperature requirements.
[0044] In the passive release embodiments, reservoir cap rupture is
triggered by environmental temperature changes, for example, due to
the placement of the device onto or into the body of a human or
other animal. The passive mechanism differs from the active
mechanism in that rupture of the reservoir cap of the active device
is triggered by a directly applied temperature change rather than
an environmental one.
[0045] In one embodiment of passive devices, the reservoir cap is
thermally stimulated to enhance degradation. For example, the
kinetics of reservoir cap degradation can be very slow at room
temperature and the cap can be considered chemically stable.
However, the kinetics of degradation are significantly increased by
increasing the temperature of the cap material, e.g., by in vivo
implantation. The absolute rate of degradation can be selected by
controlling the composition of the reservoir cap material. For
example, the degradation rate of biocompatible copolymers (e.g.,
lactones and lactides) can be between several hours and several
years, preferably between two days and one year at a temperature of
37.degree. C., depending on the specific molar ratios of the
primary structural units. By using an array of reservoir caps, each
having a different composition, complex molecular release profiles
can be achieved once the device reaches a critical temperature
defined by its environment.
[0046] In another embodiment of passive devices, all reservoir caps
have constant disintegration rates (e.g., temperature independent)
and the release profile is controlled by selection of the physical
dimensions of the reservoir cap material. By fixing the rate of
disintegration, the time for cap disintegration is dependent on the
thickness of the reservoir cap material. For example, in an
embodiment in which all reservoir caps have identical compositions,
molecular release can be controlled by varying the thickness of the
cap.
[0047] In both the active and passive devices, the reservoir cap is
formed of a material having a yield or tensile strength beyond
which the material fails by fracture or a material that undergoes a
phase change (for example, melts) with selected changes in
temperature. The material preferably is selected from metals, such
as copper, gold, silver, platinum, and zinc; glasses; ceramics;
semiconductors; and brittle polymers, such as semicrystalline
polyesters. Preferably the reservoir cap is in the form of a thin
film, e.g., a film having a thickness between about 0.1 .mu.m and 1
.mu.m. However, because the thickness depends on the particular
material and the mechanism of rupture (i.e. electrochemical vs.
mechanical breakdown), thicker reservoir caps, e.g., having a
thickness between 1 .mu.m and 100 .mu.m or more, may work better
for some materials, such as certain brittle materials.
[0048] The reservoir cap optionally can be coated with an overcoat
material to structurally reinforce the rupturable material layer
until the overcoat material has been substantially removed by
dissolving, eroding, biodegrading, oxidizing, or otherwise
degrading, such as upon exposure to water in vivo or in vitro.
Representative suitable degradable materials include synthetic or
natural biodegradable polymers.
[0049] Reservoir caps in either passive or active embodiments can
be formed of a material that functions as a permeable or
semi-permeable membrane depending on the temperature.
[0050] In one preferred embodiment of the active release device, a
resistor is integrated into the reservoir or mounted near the
reservoir, which upon application of an electric current through
the resistor, heats the contents of the reservoir, the cap
material, or both. In typical embodiments, resistors are located at
the bottom or along the inside walls of the reservoirs, or they may
be located on or near the reservoir caps covering the small
reservoir openings. The resistor generally is a thin-film resistor,
which can be integrated with the reservoir during the manufacturing
process. Such resistors can be made of metals such as platinum or
gold, ceramics, semiconductors, and some polymers.
[0051] Methods for fabricating these resistors are described, for
example, in Wogersien et al. "Fabrication of Thin Film Resistors
and Silicon Microstructures Using a Frequency Doubled
Nd:YAG-Laser," Proc. SPIE-Int. Soc. Opt. Eng., 3680:1105-12 (1999);
Bhattacharya & Tummala, "Next Generation Integral Passives:
Materials, Processes, and Integration of Resistors and Capacitors
on PWB Substrates," J. Mater. Sci.-Mater. Electron. 11 (3):253-68
(2000); and Vladimirsky et al., "Thin Metal Film Thermal
Micro-Sensors," Proc. SPIE-Int. Soc. Opt. Eng., 2640:184-92 (1995).
Alternatively, small chip resistors can be surface mounted on the
device in close proximity to the reservoir or reservoir cap.
[0052] 4. Molecules to be Delivered
[0053] Any natural or synthetic, organic or inorganic molecule or
mixture thereof can be delivered. In one embodiment, the microchip
is used to deliver drugs systemically to a patient by releasing the
drugs into a fluid delivered intravenously. As used herein, the
term "drug" includes therapeutic, prophylactic, and diagnostic
agents, unless otherwise indicated. Drug molecules to be released
during intravenous drug delivery applications include, but are not
limited to, antibiotics, chemotherapeutic agents, in vivo
diagnostic agents (e.g., contrast agents), sugars, vitamins, toxin
antidotes, anti-inflammatory agents, painkillers, and medications
useful for renal procedures such as dialysis (e.g., heparin). In
another embodiment, the microchip releases molecules into a fluid
stream for therapeutic or aesthetic purposes. For example, the
molecules to be released into liquid or gaseous fluids may include,
but are not limited to, aromatherapy hydrosols, various fragrances,
colorants, and artificial and natural sweeteners. The field of
analytical chemistry represents yet another embodiment in which a
small (milligram to nanogram) amount of one or more molecules is
required. Effective example molecules are pH buffering agents,
diagnostic agents, and reagents in complex reactions such as the
polymerase chain reaction or other nucleic acid amplification
procedures.
[0054] One embodiment for in vivo molecular release is stent drug
delivery into vascular fluids. Possible molecules to be released
include anti-restinosis compounds, proteins, nucleic acids,
polysaccharides and synthetic organic molecules, having a bioactive
effect, for example, anesthetics, vaccines, chemotherapeutic
agents, hormones, painkillers, metabolites, sugars,
immunomodulators, antioxidants, ion channel regulators, and
antibiotics. The drugs can be in the form of a single drug or drug
mixtures and can include pharmaceutically acceptable carriers.
[0055] B. Other System or Apparatus Components
[0056] The delivery system or apparatus for releasing molecules
into a carrier fluid can further include a variety of other
components depending on the particular application.
[0057] 1. Mixing Chambers, Mixers, and Pumps
[0058] In a preferred embodiment for some applications, such as in
the intravenous (IV) drug administration system described below,
the system further includes a mixing chamber in which the carrier
fluid and released drug are combined. As used herein, unless
otherwise indicated, a "mixing chamber" can be essentially any
structure in which a carrier fluid can be temporarily contained,
e.g., through which the carrier fluid can flow, while the molecules
from the microchip device can contact the carrier fluid. A mixing
chamber can be located adjacent the microchip device or downstream
in a system in which the carrier fluid flows past a surface of the
microchip device from which molecules are released. The carrier
fluid and the drug mix locally by diffusion driven by concentration
gradients or due to the reduction in the chemical potential of the
fluid.
[0059] To speed the mixing process, a mixer (i.e. mixing device)
optionally may be incorporated into the mixing chamber of the
apparatus in order to use turbulence or convective transport to
ensure a homogenous mixture. Dynamic and static mixers suitable for
use in these devices are known in the art.
[0060] Carrier fluid can be provided at one or more surfaces of the
microchip device in a static or flowing manner Flow can be
produced, for example, by gravity, capillary action, or through the
use of one or more pumps. For embodiments utilizing a pump, the
pump can be located separate from the apparatus or can be provided
in the apparatus or system, for example in the mixing chamber.
Pumps suitable for use in these devices are known in the art. See,
e.g., U.S. Pat. No. 5,709,534 to O'Leary and U.S. Pat. No.
5,056,992 to Simons. In some embodiments, a pump can produce
sufficient turbulence to mix the drug and carrier fluid, such that
a separate mixer is not needed.
[0061] In the IV application described herein, the drug solution
can enter the patient by gravity feed methods or alternatively one
or more pumps can be integrated with the apparatus to pump the
solution into the patient.
[0062] 2. Stents
[0063] In one embodiment, the microchip device is incorporated into
a stent. Stents are currently used in a range of medical
applications, normally to prevent reocclusion of a vessel. Examples
include cardiovascular and gastroenterology stents. Generally these
stents are non-degradable. Ureteric and urethral stents are used to
relieve obstruction in a variety of benign, malignant and
post-traumatic conditions such as the presence of stones and/or
stone fragments, or other ureteral obstructions such as those
associated with ureteral stricture, carcinoma of abdominal organs,
retroperitoneal fibrosis or ureteral trauma, or in association with
Extracorporeal Shock Wave Lithotripsy. The stent may be placed
using endoscopic surgical techniques or percutaneously. Examples of
state of the art stents include the double pigtail ureteral stent
(C. R. Bard, Inc., Covington, Ga.), SpiraStent (Urosurge,
Coralville, Iowa), and the Cook Urological Ureteral and Urethral
Stents (Cook Urological, Spencer, Ind.).
[0064] Bioabsorbable stents are particularly desirable in
applications such as urological applications, since a second
procedure is not required to remove the stent. Furthermore, one of
the main problems in using metallic stents in cardiovascular
applications is the subsequent restenosis caused by excessive
growth of the endothelial wall, which is believed due, at least in
part, to irritation caused by the metallic stent on the vessel wall
(see Behrend, American J. Cardiol. p. 45, TCT Abstracts (October
1998); Unverdorben, et al., American J. Cardiol. p. 46, TCT
Abstracts (October 1998)). A bioabsorbable stent made from, or
coated with appropriate materials should produce reduced or no
irritation. Bioabsorbable stents can be fabricated using methods
known in the art, for example the methods and procedures described
in U.S. Pat. Nos. 5,792,106; 5,769,883; 5,766,710; 5,670,161;
5,629,077; 5,551,954; 5,500,013; 5,464,450; 5,443,458; 5,306,286;
5,059,211, and 5,085,629. See also Tanquay, Cardiology Clinics,
23:699-713 (1994), and Talja, J. Endourology, 11:391-97 (1997).
[0065] Integration of microchip devices into stents is described in
further detail in the "Applications" section below.
[0066] II. Carrier Fluid
[0067] The molecules contained in the reservoirs of the microchip
device can be released into a variety of carrier fluids, depending
on the particular application. The carrier fluid can be essentially
of any composition in a fluid form. As used herein, the term
"fluid" includes, but is not limited to, liquids, gases,
supercritical fluid, solutions, suspensions, gels, and pastes.
[0068] Representative examples of suitable carrier fluids for
medical applications include natural biological fluids and other
physiologically acceptably fluids such as water, saline solution,
sugar solution, blood plasma, and whole blood, as well as oxygen,
air, nitrogen, and inhalation propellants The choice of carrier
fluid depends on the particular medical application, for example,
stent applications, intravenous delivery systems, implantable
delivery systems, or systems for respiratory (e.g., pulmonary)
administration.
[0069] Representative examples of suitable carrier fluids for use
in fragrance release systems include water, organic solvents (such
as ethanol or isopropyl alcohol), aqueous solutions, and mixtures
of any of these.
[0070] Representative examples of suitable carrier fluids for use
in beverage additive systems include beverages or beverage bases of
any type, such as water (both carbonated and non-carbonated), sugar
solutions, and solutions of artificial sweeteners.
[0071] Essentially any chemical fluid can be used as the carrier
fluid in an analytical or diagnostic system, depending on the
specific fluid being analyzed. Examples include, but are not
limited to, environmental samples of air or water, industrial or
laboratory process sampling analysis, fluid samples to be screened
in quality control assessments for food, beverage, and drug
manufacturing, and combinatorial screening fluids.
[0072] III. Operation and Molecule Release
[0073] One preferred embodiment is the active release of molecules
into a liquid carrier from a microchip that releases molecules in
response to electrochemical stimulation, which is shown in FIG. 3.
The application of an electrical potential (see FIG. 3a) causes the
cap material to dissolve (see FIG. 3b) providing for the release of
the molecules into the liquid flowing adjacent to the reservoir
opening as shown in FIG. 3c. In a preferred embodiment, the
electric current is modulated, rather than maintained at a constant
value.
[0074] Another embodiment includes the release of the molecular
species into a flowing gaseous phase (see FIGS. 4a-4c). The
application of heat to the release system can cause it to expand
and apply pressure to the cap material (temperature
T1<temperature T2). At some critical temperature and applied
pressure, the cap will fracture exposing and releasing the
molecules into the flowing gases that surround the device
(temperature T2<temperature T3).
[0075] An alternative embodiment of an active release device uses
the rupture of the membrane by a mechanical force as the release
mechanism. See e.g., U.S. Pat. No. 5,167,625 to Jacobsen et al.,
which describes rupturing means that may be modified or adapted to
the devices described herein. One non-limiting example is the
rupturing of caps by forceful contact of the cap surface with an
array of cantilevers that are fabricated using similar MEMS
techniques or any other machining techniques (see FIG. 5).
Ultrasonic waves are an alternative method capable of rupturing the
cap material in order to expose the release system and release the
molecules (see FIG. 6). Actuation of piezoelectric elements on or
near the reservoir produces sonic waves that rupture the cap
material. The piezoelectric elements can be composed of any
material having crystal structure that is non-centrosymetric.
Preferred piezoelectric materials are ceramics, such as
BaTiO.sub.3, LiNbO.sub.3 and ZnO (Chiang, Y., "Physical Ceramics",
John Wiley & Sons, Inc., New York, pp. 37-66 (1997)), and
polymers, such as polyvinylidene (Hunter & Lafontaine, "A
Comparison of Muscle with Artificial Actuators," Technical Digest
of the 1992 Solid State Sensor and Actuator Workshop, pp. 178-85
(1992)). These actuators can be fabricated in the form of thin
films using standard techniques such as ion sputtering (Tjhen, et
al., "Properties of Piezoelectric Thin Films for Micromechanical
Devices and Systems", Proceedings--IEEE Micro Electro Mechanical
Systems, pp. 114-19 (1991)) and sol-gel processing as described,
for example, in Klein, "Sol-Gel Optics: Processing and
Applications", Kluwer Academic Publishers, 1994). The ultrasonic
energy can be supplied by components located on the delivery
device, in the carrier fluid, or outside of the delivery device.
Methods for selecting which reservoirs are exposed include, for
example, wave interference using secondary ultrasonic waves. The
secondary waves can act to destructively interfere with the primary
ultrasonic waves thus restricting the application of energy to only
a selected set of reservoirs.
[0076] Additional embodiments involve the passive release of
molecules into the carrier fluid. One general example of this
application is the degradation of the release system when placed
into or exposed to the carrier fluid. The chemical nature of the
fluid, e.g., acid versus basic or polar versus non-polar, may cause
the cap material to degrade or dissolve (see FIG. 6b). Once the cap
material is completely dissolved, the molecules will be released
into the liquid flowing adjacent to the reservoir opening (see FIG.
6c). The fluid can be any liquid or any gas that causes the
disintegration of the release system or the cap material.
[0077] IV. Methods for Manufacture or Assembly
[0078] The microchip devices can be made, for example, using
techniques known in the art, particularly the methods described in
U.S. Pat. No. 6,123,861 to Santini et al., which is incorporated by
reference. Although the fabrication methods described in the patent
use microfabrication and microelectronic processing techniques, it
is understood that fabrication of active and passive microchip
chemical delivery devices is not limited to materials such as
semiconductors or processes typically used in microelectronics
manufacturing. For example, other materials, such as metals,
ceramics, and polymers, can be used in the devices Similarly, other
fabrication processes, such as plating, casting, or molding, can
also be used to make them.
[0079] In one embodiment, reservoirs also can be formed using
silicon-on-insulator (SOI) techniques, such as is described in S.
Renard, "Industrial MEMS on SOI," J. Micromech. Microeng.
10:245-249 (2000). SOI methods can be usefully adapted to form
reservoirs having complex reservoir shapes, for example, as shown
in FIGS. 2b, 2c, and 2e. SOI wafers behave essentially as two
substrate portions that have been bonded on an atomic or
molecular-scale before any reservoirs have been etched into either
portion. SOI substrates easily allow the reservoirs (or reservoir
sections) on either side of the insulator layer to be etched
independently, enabling the reservoirs on either side of the
insulator layer to have different shapes. The reservoir (portions)
on either side of the insulator layer then can be connected to form
a single reservoir having a complex geometry by removing the
insulator layer between the two reservoirs using methods such as
reactive ion etching, laser, ultrasound, or wet chemical
etching.
[0080] The other system components are provided from known sources
or can be easily fabricated or adapted from known devices and
methods.
[0081] The microchip devices can be integrated into other system or
device components (i.e. assembly of the system or apparatus) using
techniques known in the art, such as by using adhesives and
mechanical means such as fasteners, depending on the particular
application.
[0082] IV. Applications
[0083] The microchip delivery systems can be used to release
molecules into a variety of carrier fluids in a wide variety of
forms. Representative examples include drug delivery into a fluid
to be introduced or administered to a patient, such as
intravenously or to the respiratory system; drug delivery from
implanted systems including stents or micropumps; analytical or
diagnostic chemistry; fragrance release systems; and beverage
additive systems.
[0084] It is understood that the number, geometry, and placement of
each reservoir, reservoir cap, or other object (e.g., resistors
(heaters), electrodes, or channels) in or near each reservoir can
be modified for a particular application. For simplicity, only one
reservoir is shown in some Figures. However, it is understood that
a microchip component or device would contain at least two, and
preferably many more, reservoirs. Detailed below are some of the
many useful applications.
[0085] A. Intravenous Drug Delivery System
[0086] An intravenous (IV) drug delivery system is provided that
includes one or more microchip chemical delivery devices that
release molecules into a physiologically acceptably carrier fluid
for intravenous administration.
[0087] As illustrated in FIG. 8a, the IV system 100 includes
console 108 which is connected to a catheter 106 extending from a
container 102 (e.g., bag or bottle) of a carrier fluid 104. The
carrier fluid flows from container 102 via catheter 106 (or other
flexible hollow tubing) to console 108. In console 108, the carrier
fluid 104 flows past one or more surfaces of the microchip device
112, mixes with released molecules in mixing chamber 130 using
mixer 114 (optional) and then flows to the patient through a second
catheter 116 (or other flexible hollow tubing) into the
patient.
[0088] Another embodiment of the system is shown in FIG. 8b. This
IV system 120 includes microchip devices 122a and 122b provided
within container 126 of the carrier fluid 104. Carrier fluid 104 in
mixing chamber 130 is mixed with released drug molecules using
mixer 124 (optional). The resulting mixture flows from container
126, through tubing 128 to the patient. If an active microchip
device is used in this way, the control electronics and power
source preferably are integrated with the microchip device
itself.
[0089] In a preferred embodiment, shown in FIG. 8c, the IV system
150 includes a console 156 that contains "plug in" cartridges 152
comprising one or more drug-containing microchip devices, control
electronics 154, and a container of IV carrier fluid 158.
[0090] In one embodiment, the IV system includes an electronic
control system which can be programmed to send a signal to the
microchip devices to release one or more drugs from one or more of
the reservoirs of the microchip devices, thereby releasing the
drugs into the carrier fluid as it passes by microchip devices and
making a drug solution that is delivered into the patient. The
electronic control systems can be connected to the console or to
the microchip devices by cables or can transmit signals to the
console or to the microchip devices by wireless communication means
known in the art. Such an IV system may also include a digital
readout that would display the critical drug delivery parameters
such as the drug name, the release frequency, the release rate, the
amount of drug left in the microchip, and the time at which the
microchip will need to be replaced with a full one. The electronics
also allow the physician to program in the type of release pattern
desired, either pulsatile release or continuous release.
[0091] The inclusion of a microprocessor, memory, and a timer into
the electronic control systems also can help decrease the potential
for drug overdoses or the administration of the wrong drugs to
patients. Safety protocols can be stored in the memory and
continuously checked by the microprocessor to prohibit (i) the
release of too much drug to a patient over a particular time
interval, and/or (ii) the simultaneous release of two or more
incompatible drugs. In addition, the microchip can store in memory
the exact amount of drug delivered, its time of delivery, and the
amount of drug remaining in the microchip. This information can be
transmitted using wireless technology (e.g., for implants) or using
standard computer connections (e.g., for external, in-line, or IV
systems) to the physician or to a central monitoring system on a
real-time basis. This allows the physician to remotely monitor the
patient's condition.
[0092] One advantage provided by these embodiments is the ability
to store drugs in the microchip in its most stable form (e.g.,
liquid, gel, or crystalline or powdered solid) until release into
solution and delivery to the patient is desired. This can
drastically increase the shelf-life (i.e. stability) of many drugs,
particularly protein or biologic drugs, for which the stability is
limited once dissolved in solution.
[0093] Another advantage is the reduction of medical errors. For
example, numerous medical errors can result from traditional IV
bags that are inadvertently filled with the incorrect amount of
drug or bags that are mislabeled. Microchip "cartridges" as
described herein can be labeled with a bar code indicating the type
and amount of drug in the microchip. Once the microchip cartridge
is plugged into the IV system or console, the IV system can detect
the type and amount of drug and display it on the digital readout,
which allows a physician or nurse to easily verify that the correct
medication and dosage is delivered to the patient. It is understood
that the microchip could also be placed at other locations between
the carrier fluid container and the patient.
[0094] The body of the console preferably is made of a molded
plastic. All parts in contact with the carrier fluid and/or the
drug preferably are formed from or coated with a biocompatible
material, preferably one, such as poly(tetrafluoroethylene) or a
similar material, that does not interact with the fluids or
released drugs. The mixing chamber and fluid connections should be
leak-proof
[0095] B. Drug Delivery Stent
[0096] One embodiment of a microchip device for the release of
molecules into a carrier fluid involves integrating one or more
drug delivery microchips into/onto a stent, such as a vascular
stent. The drug-containing microchips preferably are provided on
one or more surfaces of the stent, for example as illustrated in
FIGS. 9a-c. The microchip devices can be present in the stent
during implantation and stent expansion, or the microchip devices
can be attached to the inside of the stent in a separate procedure
immediately following stent implantation and expansion. If the
microchips are small enough, implantation and attachment of a
microchip to a stent can be completed using the same catheter
technology used in the implantation of stents. In a preferred
embodiment, the microchips of the stent-microchip device are
programmed or activated by remote or wireless means to deliver
drugs directly from the stent.
[0097] One preferred application of the stent-microchip device is
the local delivery of anti-restenosis drugs to an artery that has
recently undergone an angioplasty procedure. In another embodiment,
the stent-microchip devices are used to systemically deliver one or
more drugs to a patient via blood flowing through the stent. In
another embodiment, stents can be designed and fabricated to have
drug reservoirs and caps as part of the stent itself, that is, not
as a separate microchip device, but rather as part of a monolithic
stent device. It is understood that both systemic and local
delivery of any drug is possible using the microchip technology in
combination with stents.
[0098] The microchip-stent drug delivery devices are not limited to
arterial and vascular applications. Microchips integrated with
stenting technology can serve to deliver drugs within a variety of
other channels in the body of humans and animals. Representative
examples include the gastrointestinal tract, respiratory passages,
reproductive and urinary tracts, renal vessels, cerebrospinal fluid
passages, and sinuses.
[0099] C. Drug Inhalation Device
[0100] In another embodiment, microchip devices are used to release
molecules into a gaseous carrier fluid, e.g., air, for subsequent
inhalation by a patient. In one system, for example, a
drug-containing microchip device is integrated into a metered dose
inhaler (MDI) to provide a simple method for accurately controlling
the molecular dose that is to be delivered. The microchip device
also provides a controlled environment (within the reservoirs) that
can function to extend the stability of the stored drug.
[0101] Many different styles of metered dose applicators
appropriate for use with the drug-filled microchips are described
in the art such as, for example, U.S. Pat. No. 6,116,234 to Genova
et al. FIGS. 10a-c illustrate one embodiment of a schematic flow
diagram of the drug delivery mechanism in a microchip metered dose
inhaler. The drug-filled microchips are located on the inner wall
of a replaceable cartridge on the open end of the applicator. Upon
triggering an electrical signal from the power circuitry to the
microchip(s) through a switch or timer, the doses can be released
into a gas stream using various release techniques, such as the
methods described in FIGS. 4 through 6. Once the reservoir cap has
disintegrated or ruptured, a stream of gas flowing over the opened
reservoir transports the drug molecules from the reservoirs to the
patient. The carrier gas can be provided to the microchip device
upon release of a pressurized gas or upon inhalation by the
patient. The drug molecules can come out of reservoirs in the MDI
by any of several mechanisms, including vaporization, formation of
an aerosol, atomization, or by Bernoulli's principle. In an
alternative embodiment, the molecules are released by diffusion or
vaporization from the opened reservoirs into a static volume of the
gas, which subsequently is inhaled by the patient, in a second
step.
[0102] The dosage of the drug can be accurately measured by
triggering release from a select number of reservoirs having a
precise quantity of the drug. Each dosage can be composed of the
molecules released by one or more reservoirs.
[0103] In preferred embodiments, the microchip-inhalation device
advantageously provides reservoirs that are sealed until the
patient activates the required molecular dose. Therefore,
potentially harsh environments encountered during packaging, use,
or storage will not affect the stability and concentration of each
dose within the reservoir. The microchip devices can be contained,
for example, within a replaceable cartridge located within the flow
path of the carrier gas.
[0104] D. Diagnostic System
[0105] Microchips containing molecules for release into liquid and
gaseous carrier fluids have a wide range of potential applications
in diagnostics and analytical chemistry. In one embodiment of a
diagnostic system, the microchip technology described herein can be
integrated with a microfluidic array used in DNA testing, blood
analysis, or testing of an environmental sample. In a preferred
embodiment, a carrier fluid such as a saline solution is
electrophoretically pumped through a tiny channel in a microfluidic
array. Reservoirs containing reagent molecules and having active
reservoir caps are located along the bottom of the microfluidic
channels. As the saline solution is pumped into a channel
containing the reagent filled reservoirs, a signal (e.g., an
electric current) is sent to the reservoir caps to cause them to
disintegrate, allowing the reagents inside the reservoirs to
diffuse out into the saline solution in the channel The release of
reagents can occur while the fluid is stopped above the reservoirs
or while the carrier fluid is flowing by the reservoirs. The saline
solution containing the reagents is now pumped to a mixing chamber
where the reagents are mixed with the sample of interest (e.g. a
blood sample) and the desired interaction occurs.
[0106] Another example of a diagnostic system comes from
combinatorial chemistry. Colloidal practices (e.g., the paint and
coating industry) often necessitate the stabilization of
suspensions which require a large array of experiments in search of
an optimum chemistry. Chemicals such as surface-active catalysts,
macromolecules and ionic salts, are just a few of the reagents used
to determine the proper colloidal composition. Microchip devices
filled with one or more of these colloidal additives can be placed
in an agitated liquid medium containing the particulates. By
disintegrating specific reservoir caps, for example by using a
thermal activation technique, specific chemical species can be
released in a controlled manner over time. This offers a method for
accurately and automatically carrying out extensive combinatorial
experiments.
[0107] Microchip devices also can be provided with integrated
electrodes and circuitry that provide the means to characterize the
stability of the colloid. Characterizations techniques such as
ultrasound vibration potential (UVP) and electrokinetic sonic
amplitude (ESA) are well known and have been described in detail by
M. Rahaman in "Ceramics Processing and Sintering" (New York 1995).
Therefore, the microchip device can provide information on both the
chemistry required for stabilization and the stabilization
kinetics. It is understood that the microchip device can serve in
many other diagnostic and combinatorial applications such as DNA or
genetic analyses, drug discovery, and environmental testing.
[0108] E. Microchip Device with Implantable Pump
[0109] In another embodiment, a microchip device is incorporated
into an implantable micropumping system, for example for the
delivery of drugs over extended periods of time, such as is needed
the delivery of insulin to diabetics and treating certain kind of
severe chronic pain. Micropump apparatus suitable for use in these
devices are known in the art (see, e.g., U.S. Pat. No. 4,596,575 to
Rosenberg). The micropump pumps the carrier fluid across one or
more surfaces of the microchip device. A variety of carrier fluids
can serve as the pumped fluid, including, but not limited to,
filtered extra-cellular fluid, saline solution, or water.
[0110] In a preferred embodiment, release of doses is actively
controlled, such as by disintegration of reservoir caps via
electrochemical dissolution, as described in U.S. Pat. Nos.
5,797,898 and 6,123,861 to Santini. The release system preferably
is in the form of a solid that is soluble in the carrier fluid. As
the fluid passes over or around the activated and opened reservoir,
the solid drug dissolves in the carrier fluid, forming a solution
that is pumped into the extra-cellular environment.
[0111] F. Renal Applications
[0112] In renal dialysis procedures, the patient's blood flows
through an ex vivo dialysis machine where toxic molecules are
selectively removed from the blood, and the "cleaned" blood is
returned to the patients body. These toxic molecules, which are
normally removed from the blood by the kidneys, accumulate over
time due to the decreased or improper functioning of the kidneys.
While toxic molecules are removed from the patient's blood as it
passes through the dialysis machine, therapeutic molecules and
drugs can easily be added to the blood. This leads to a potential
method for systemic delivery of multiple drugs or other molecules
to a patient using a microchip device located ex vivo. In a
preferred embodiment, microchip devices filled with drug molecules
are placed in tubing through which blood flows during a dialysis
procedure. The microchips can actively or passively delivery one or
more types of molecules to the patients blood as it passes through
the tubing. This method allows multiple drugs to be delivered
accurately and directly into a patient's blood without having to
implant the delivery device into the patient's body.
[0113] Modifications and variations of the methods and devices
described herein will be obvious to those skilled in the art from
the foregoing detailed description. Such modifications and
variations are intended to come within the scope of the appended
claims.
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