U.S. patent application number 12/471973 was filed with the patent office on 2009-09-17 for multi-reservoir device and method for transdermal sensing.
This patent application is currently assigned to MICROCHIPS, INC.. Invention is credited to Stephen J. Herman, John T. Santini, JR., Mark A. Staples.
Application Number | 20090234214 12/471973 |
Document ID | / |
Family ID | 35539550 |
Filed Date | 2009-09-17 |
United States Patent
Application |
20090234214 |
Kind Code |
A1 |
Santini, JR.; John T. ; et
al. |
September 17, 2009 |
MULTI-RESERVOIR DEVICE AND METHOD FOR TRANSDERMAL SENSING
Abstract
Devices and methods are provided for transdermal diagnostic
sensing, alone or in combination with transdermal drug delivery.
The device includes a substrate having a plurality of discrete
reservoirs, each reservoir having at least one opening; contents
disposed in the reservoirs, the contents of each reservoir
including a diagnostic agent or a sensor for measuring an analyte;
at least one discrete reservoir cap which cover said at least one
opening; control means for disintegrating or permeabilizing the
reservoir cap; means for transporting an analyte from the skin to
said sensors and/or for transporting said diagnostic agent to the
skin following release of said diagnostic agents from said
reservoir; and means for securing the device to the skin of a
patient.
Inventors: |
Santini, JR.; John T.;
(North Chelmsford, MA) ; Staples; Mark A.;
(Cambridge, MA) ; Herman; Stephen J.; (Andover,
MA) |
Correspondence
Address: |
SUTHERLAND ASBILL & BRENNAN LLP
999 PEACHTREE STREET, N.E.
ATLANTA
GA
30309
US
|
Assignee: |
MICROCHIPS, INC.
Bedford
MA
|
Family ID: |
35539550 |
Appl. No.: |
12/471973 |
Filed: |
May 26, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11194157 |
Aug 1, 2005 |
7537590 |
|
|
12471973 |
|
|
|
|
60592537 |
Jul 30, 2004 |
|
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|
Current U.S.
Class: |
600/365 ;
600/309 |
Current CPC
Class: |
A61K 9/0097 20130101;
A61K 9/0009 20130101; A61K 9/0021 20130101; A61K 9/703 20130101;
A61K 9/7084 20130101; A61K 9/7092 20130101; A61F 2013/00642
20130101; A61M 37/0015 20130101; A61N 1/30 20130101; A61M 2037/0023
20130101 |
Class at
Publication: |
600/365 ;
600/309 |
International
Class: |
A61B 5/145 20060101
A61B005/145 |
Claims
1. A device for sensing an analyte in a human or other animal
comprising: a substrate having a plurality of discrete reservoirs,
each reservoir having at least one opening; contents disposed in
the reservoirs, the contents of each reservoir comprising a
diagnostic agent or a sensor for measuring an analyte; at least one
discrete reservoir cap which cover said at least one opening;
control means for disintegrating or permeabilizing the reservoir
cap; means for transporting an analyte from the skin to said
sensors and/or for transporting said diagnostic agent to the skin
following release of said diagnostic agents from said reservoir;
and means for securing the device to the skin of a patient.
2. The device of claim 1, wherein the reservoir cap is formed of an
electrically conductive material and the circuitry comprises an
electrical input lead connected to said reservoir cap, an
electrical output lead connected to said reservoir cap, wherein the
reservoir cap is ruptured by application of an electrical current
through the reservoir cap via the input lead and output lead.
3. The device of claim 1, wherein the reservoir cap comprises a
metal film.
4. The device of claim 1, wherein the means for transporting
comprises a transport medium disposed between the reservoir caps
and the skin.
5. The device of claim 4, wherein the transport medium comprises a
permeable body through which the one or more diagnostic agents
released from the reservoirs can diffuse.
6. The device of claim 4, wherein the transport medium comprises a
reservoir containing a liquid, gel, or semi-solid permeation
material.
7. The device of claim 1, wherein the means for transporting
comprises a flexible or rigid member having media-filled holes with
spacing corresponding to reservoir membrane openings.
8. The device of claim 6, wherein the transport medium reservoir
comprises a single pool of a biocompatible transport fluid into
which the one or more diagnostic agents are diluted prior to
delivery to the skin.
9. The device of claim 6, wherein the transport medium reservoir
comprises individual channels for delivery of the one or more
diagnostic agents with no or minimal dilution prior to delivery to
the skin.
10. The device of claim 1, further comprising a housing which
contains the substrate and control means.
11. The device of claim 1, comprising a removably attachable
electronics portion which comprises a power source and at least a
portion of the control means.
12. The device of claim 1, wherein the means for transporting
comprises a plurality of microneedles.
13. The device of claim 1, wherein the means for transporting
comprises one or more chemical penetration enhancers.
14. The device of claim 1, wherein the means for transporting
comprises an ultrasound generator.
15. The device of claim 1, wherein the means for transporting
comprises means for effecting iontophoresis, electroosmosis, or
electroporation.
16. The device of claim 1, wherein the means for transporting
comprises a heating element.
17. The device of claim 1, wherein the reservoirs are
microreservoirs.
18. The device of claim 1, wherein the means for securing comprises
a pressure sensitive adhesive, an adhesive layer which is permeable
to the one or more diagnostic agents, or a combination thereof.
19. The device of claim 1, wherein the diagnostic agent comprises a
Small Molecule Metabolite Reporter.
20. The device of claim 1, wherein the sensor can measure the
epidermal skin or blood glucose level in a patient.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional of U.S. application Ser. No.
11/194,157, filed Aug. 1, 2005, which claims the benefit of U.S.
Provisional Application No. 60/592,537, filed Jul. 30, 2004. The
applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] This invention is generally in the field of devices and
methods for the transdermal drug delivery and analyte sensing.
[0003] Transdermal drug delivery systems generally rely on
diffusion of drug across the skin. In a typical conventional
technology, the transdermal drug delivery system is in the form of
a multi-layered patch that includes a backing or cover layer, a
drug matrix/reservoir, a diffusion control membrane, and an
adhesive layer for attaching the system to the surface of the skin.
Examples of drugs delivered with such systems include scopolamine
(Trasderm-Scop.TM.), nicotine, nitroglycerin (Nitro-Dur.TM.),
estradiol (Estraderm.TM.), and testosterone. However, transdermal
patches generally are unsuitable for delivery of macromolecules.
Others have sought to improve transdermal delivery of drug
molecules, particularly where the size and hydrophilicity of the
drug molecules significantly hinders diffusion through the stratum
corneum, over that obtained with passive diffusion alone, by
including with the transdermal drug delivery systems an active
mechanism, such as iontophoresis, electroporation, ultrasound, or
heat, or by disrupting the stratum corneum with microneedles or the
like.
[0004] In transdermal and other drug delivery systems, it is
generally desirable to store and protect the drug formulation until
the time it is to be delivered to a patient, because exposure to
environmental components (e.g., oxygen, humidity) may damage or
prematurely degrade the pharmaceutical agent. However, in various
conventional transdermal drug delivery systems which contain
several days worth of doses of the drug, the entire drug
formulation is contained in a single reservoir, such that is it not
possible to protect or isolate individual doses. It would be
desirable to be able to do so, particularly for relatively fragile
pharmaceutical agent molecules.
[0005] In addition, with a conventional patch-type drug delivery
system, it generally is not possible to change or fine-tune the
rate of administration of drug once the patch is applied to the
patient. It would be desirable to provide new and improved methods
and devices for the controlled delivery of one or more drugs to a
patient by transdermal administration. For example, it would be
advantageous to be able to store and transdermally administer
multiple discrete doses of a drug formulation, using a device which
the physician can easily vary or fine tune the time and rate of
drug administration.
SUMMARY OF THE INVENTION
[0006] Devices and methods have been developed for transdermal
administration of one or more pharmaceutical agents to a patient in
need thereof. In one aspect, the device includes a substrate, a
plurality of discrete reservoirs in the substrate, one or more
pharmaceutical agents stored in the reservoirs, discrete reservoir
caps that prevent the pharmaceutical agent from passing out from
the reservoirs, control means for actuating release of the
pharmaceutical agent from one or more of the reservoirs by
disintegrating or permeabilizing the reservoir caps, means for
securing the device to the skin of the patient, and means for
transporting to the skin the one or more pharmaceutical agents
following release from the one or more of the reservoir. In one
embodiment, the device includes a housing which contains the
substrate, reservoirs, control means, and a power source. In one
embodiment, the device further includes a removably attachable
electronics portion which comprises the power source and at least a
portion of the control means.
[0007] In one embodiment, the reservoir cap is formed of an
electrically conductive material and the control means comprises an
electrical input lead connected to said reservoir cap, an
electrical output lead connected to said reservoir cap, wherein the
reservoir cap is disintegrated by application of an electrical
current through the reservoir cap via the input lead and output
lead. The device may further include a source of electric power,
such as a battery or capacitor, for applying the electrical
current.
[0008] In one embodiment, the reservoirs are microreservoirs. In
one embodiment, the reservoir cap comprises a metal film.
[0009] In one embodiment, the means for securing the device
comprises a pressure sensitive adhesive. In one embodiment, the
means for securing comprises an adhesive layer that is permeable to
the pharmaceutical agent or analyte.
[0010] In one embodiment, the means for transporting includes a
transport medium disposed between the reservoir caps and the skin.
For example, the transport medium can include a permeable body
through which the pharmaceutical agent released from the reservoirs
can diffuse. In one embodiment, the transport medium comprises a
reservoir containing a liquid, gel, or semi-solid permeation
material. In another embodiment, the means for transporting
comprises a plurality of microneedles. In still another embodiment,
the means for transporting comprises one or more chemical
penetration enhancers. In various embodiments, the means for
transporting comprises means for effecting iontophoresis,
electroosmosis, or electroporation. In one embodiment, the means
for transporting comprises an ultrasound generator. In a further
embodiment, the means for transporting comprises a heating element.
In one embodiment, the means for transporting comprises a flexible
or rigid member having media-filled holes with spacing
corresponding to reservoir membrane openings, which allows release
of reservoir contents without dilution.
[0011] In various specific embodiments, the one or more
pharmaceutical agents include a drug selected from among androgen,
estrogen, non-steroidal anti-inflammatory agents, anti-hypertensive
agents, analgesic agents, anti-depressants, antibiotics,
anti-cancer agents, local anesthetics, antiemetics,
anti-infectants, contraceptives, anti-diabetic agents, steroids,
anti-allergy agents, anti-migraine agents, agents for smoking
cessation, anti-obesity agents, nicotine, testosterone, estradiol,
nitroglycerin, clonidine, dexamethasone, wintergreen oil,
tetracaine, lidocaine, fentanyl, sufentanil, progestrone, insulin,
Vitamin A, Vitamin C, Vitamin E, prilocaine, bupivacaine,
sumatriptan, dihydroergotamine, and combinations thereof.
[0012] In another aspect, a medical device is provided for
transdermal administration of one or more pharmaceutical agents to
a patient in need thereof, which includes a substrate, a plurality
of discrete reservoirs in the substrate, one or more pharmaceutical
agents stored in the reservoirs, discrete reservoir caps which
prevent the one or more pharmaceutical agents from passing out from
the reservoirs, control means for actuating release of the one or
more pharmaceutical agents from one or more of the reservoirs by
disintegrating or permeabilizing the reservoir caps, an adhesive or
strap material for securing the device to the skin of the patient,
and a body defining a transport medium reservoir disposed between
the reservoir caps and the skin of the patient, the body and
reservoir facilitating transport of the pharmaceutical agent to the
skin following its release from one or more of the reservoir. In
one embodiment, the transport medium reservoir contains a liquid,
gel, or semi-solid permeation material. In one embodiment, the
transport medium reservoir comprises a single pool of a
biocompatible transport fluid into which the pharmaceutical agent
is diluted prior to delivery to the skin. In another embodiment,
the transport medium reservoir comprises individual channels for
delivery of the pharmaceutical agent with no or minimal dilution
prior to delivery to the skin.
[0013] In another aspect, a device is provided for sensing an
analyte in a human or other animal. In one embodiment, the device
includes a substrate; a plurality of discrete reservoirs in the
substrate, the reservoirs having at least one opening; one or more
sensors or diagnostic agents stored in the reservoirs; discrete
reservoir caps which cover said at least one opening; control means
for disintegrating or permeabilizing the reservoir caps; means for
securing the device to the skin of the patient; and means for
transporting an analyte from the skin to the one or more sensors or
for transporting the one or more diagnostic agents to the skin
following release of said diagnostic agents from the one or more of
the reservoir.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 is a cross-sectional view of one embodiment of the
medical device for transdermal drug delivery or analyte sensing
described herein.
[0015] FIGS. 2A and 2B are a perspective view (FIG. 2A) and a
cross-sectional view (FIG. 2B) of another embodiment of the medical
device for transdermal drug delivery or analyte sensing described
herein.
[0016] FIG. 3 is a perspective, cross-sectional view of one
embodiment of the reservoir and body portion of the drug delivery
or sensing device described herein.
[0017] FIG. 4 is a schematic of the operation of one embodiment of
the control means for the medical device for transdermal drug
delivery or analyte sensing described herein.
[0018] FIG. 5 is a cross-sectional view of one portion of one
embodiment of the device shown in FIG. 1, showing one reservoir
pre-actuation and one reservoir post-actuation.
[0019] FIG. 6 is a cross-sectional view of one embodiment of the
medical device for transdermal drug delivery or analyte sensing
that includes microneedles.
DETAILED DESCRIPTION OF THE INVENTION
[0020] Medical devices have been developed for the transdermal
administration of one or more pharmaceutical agents to patient in
need thereof, or for analyte sensing/diagnostics. In a preferred
embodiment, the devices isolate each dose or portions of a dose of
the pharmaceutical agent within multiple individual (discrete)
reservoirs, which typically are arrayed in/across a body portion of
the device. Advantageously, the isolated doses or partial doses are
protected from environmental components that may damage or
prematurely degrade the pharmaceutical agent or other reservoir
contents, until the desired time for release or exposure of the
pharmaceutical agent or other reservoir contents.
[0021] As used herein, the terms "comprise," "comprising,"
"include," and "including" are intended to be open, non-limiting
terms, unless the contrary is expressly indicated.
The Medical Device
[0022] In one aspect, the device comprises a substrate; a plurality
of discrete reservoirs in the substrate; one or more pharmaceutical
agents stored in the reservoirs; discrete reservoir caps that
prevent the one or more pharmaceutical agents from passing out from
the reservoirs; control means for actuating release of the
pharmaceutical agents from one or more of the reservoirs by
disintegrating or permeabilizing the reservoir caps; means for
securing the device to the skin of the patient; and means for
transporting the pharmaceutical agent to the skin following release
from one or more of the reservoirs.
[0023] In another aspect, the device is used to deliver a
diagnostic agent into the skin. For instance, the agent could be a
small molecule metabolite reporter, used in glucose detecting.
[0024] In still another aspect, the device is not used to deliver
something but to contain a plurality of sensors for selective
exposure. For example, the device could be adapted to sense an
analyte withdrawn, either by passive or active mechanisms, from or
through the skin.
Substrate/Reservoirs
[0025] The device comprises a substrate, i.e., a body portion, that
includes the plurality of discrete reservoirs, e.g., in the form of
a two-dimensional array of selectively spaced reservoirs--located
in discrete positions--across at least one surface of the body
portion. A reservoir is a well, a recess, a hole or a cavity,
located in a solid structure and suitable for containing a quantity
of another material and/or a secondary device.
[0026] In various embodiments, the body portion comprises silicon,
a metal, a ceramic, a polymer, or a combination thereof. Examples
of suitable substrate materials include metals, ceramics,
semiconductors, glasses, and degradable and non-degradable
polymers. In one embodiment, each reservoir is formed of hermetic
materials (e.g., metals, silicon, glasses, ceramics) and is
hermetically sealed by at least one reservoir cap. In one case, if
the reservoir has a second opening, distal the reservoir cap-sealed
opening, then a hermetic seal can be formed at that distal opening
as well, in order for the reservoir contents to be hermetically
isolated within the reservoir. Alternatively, where the reservoir
has two opposed openings, each can be covered by a reservoir cap
which can be opened for release or exposure of the reservoir
contents. In still another case, a reservoir can have two or more
separate openings on the same side of the reservoir, which can be
covered by one or two or more discrete reservoir caps. The
reservoirs can be in essentially any shape, and typically are
shaped to facilitate reservoir manufacture and loading of contents,
as well as packing of reservoirs into the substrate.
[0027] The substrate can have a variety of shapes, or shaped
surfaces. It can, for example, have a release side (i.e., an area
having reservoir caps) that is planar or curved. The substrate may,
for example, be in a shape selected from circular, square, or ovoid
disks. In one embodiment, the release side can be shaped to conform
to a curved tissue surface.
[0028] The device body can be flexible or rigid. In one embodiment,
the device flexibly conforms to a tissue surface as taught in U.S.
Patent Application Publication No. 2002/0099359 to Santini et al.,
which is incorporated herein by reference.
[0029] The substrate may consist of only one material, or may be a
composite or multi-laminate structure, that is, composed of several
layers of the same or different substrate materials bonded or fused
together. In one embodiment, the substrate comprises layers of
silicon and Pyrex bonded together. In another embodiment, the
substrate comprises multiple silicon wafers bonded together. In yet
another embodiment, the substrate comprises a low-temperature
co-fired ceramic (LTCC). In one embodiment, the body portion is the
substrate of a microchip device. In one example, this substrate is
formed of silicon.
[0030] In one embodiment, the substrate is formed from one or more
polymers, copolymers, or blends thereof. For some transdermal
applications, the reservoirs need not be defined/enclosed by
hermetic materials, particularly where the time the reservoir
contents are isolated is relatively short, for example, when the
transdermal device is used only for a period of a few days (e.g.,
less than 2 days, less than 3 days). In such cases, polymeric
substrates may be preferred, particularly because they can be less
costly to manufacture than some silicon or ceramic substrate
devices. In addition, the polymeric substrate can be easily made to
conform to a particular skin surface area of the human or animal
body.
[0031] In a preferred embodiment, the reservoirs are
microreservoirs. As used herein, the term "microreservoir" refers
to a discrete hole or concave-shaped space in a solid structure
suitable for releasably containing a material. The structure is of
a size and shape suitable for filling with a microquantity of the
material, which comprises a drug. In one embodiment, the
microreservoir has a volume equal to or less than 500 .mu.L (e.g.,
less than 250 .mu.L, less than 100 .mu.L, less than 50 .mu.L, less
than 25 .mu.L, less than 10 .mu.L, etc.) and greater than about 1
nL (e.g., greater than 5 nL, greater than 10 nL, greater than about
25 nL, greater than about 50 nL, greater than about 1 .mu.L, etc.).
The shape and dimensions of the microreservoir can be selected to
maximize or minimize contact area between the drug material and the
surrounding surface of the microreservoir. As used herein, the term
"microquantity" refers to small volumes between 1 nL and 500 .mu.L.
In one embodiment, the microquantity is between 1 nL and 1 .mu.L.
In another embodiment, the microquantity is between 10 nL and 500
nL.
[0032] Microreservoirs can be fabricated in a structural body
portion using fabrication techniques known in the art.
Representative fabrication techniques include MEMS fabrication
processes or other micromachining processes, various drilling
techniques (e.g., laser, mechanical, and ultrasonic drilling,
electrical discharge machining (EDM)), and build-up techniques,
such as LTCC (low temperature co-fired ceramics), punch- or
embossing-type processes, thin film or tape processes. The surface
of the microreservoir optionally can be treated or coated to alter
one or more properties of the surface. Examples of such properties
include hydrophilicity/hydrophobicity, wetting properties (surface
energies, contact angles, etc.), surface roughness, electrical
charge, release characteristics, biocompatibility, and the like.
The coating material also can be selected to affect biostability or
tissue interactions with the device or with the reservoir contents.
Other fabrication processes, particularly ones useful with
polymeric substrates, can be used, including injection molding,
thermal compression molding, extrusion, embossing, solvent casting,
and other polymer forming techniques known in the art. See also
U.S. Patent Application Publication No. 2002/0107470 A1 to
Richards, et al., which is incorporated herein by reference.
[0033] In other embodiments, the reservoirs are larger than
microreservoirs and can contain a quantity of drug formulation
larger than a microquantity. For example, the volume of each
reservoir can be greater than 10 .mu.L (e.g., at least 20 .mu.L, at
least 50 .mu.L, at least 100 .mu.L, at least 250 .mu.L, etc.) and
less than 10 mL (e.g., less than 5 mL, less than 1000 .mu.L, less
than 500 .mu.L, less than 300 .mu.L, etc.). These may be referred
to as macro-reservoirs and macro-quantities, respectively. Unless
explicitly indicated to be limited to either micro- or macro-scale
volumes/quantities, the term "reservoir" is intended to include
both.
[0034] Total substrate thickness and reservoir volume can be
increased by bonding or attaching wafers or layers of substrate
materials together. The device thickness may affect the volume of
each reservoir and/or may affect the maximum number of reservoirs
that can be incorporated onto a substrate. The size and number of
substrates and reservoirs can be selected to accommodate the
quantity and volume of reservoir contents needed for a particular
application, manufacturing limitations, and/or total device size
limitations suitable for reasonably comfortable attachment to a
patient's skin.
[0035] Different device thicknesses may be chosen, depending for
example of the type of application. For example, in
sensing/diagnostic applications, the thickness may impact analyte
transport and thus sensor response. Accordingly, it may be useful
to provide a relatively thin substrate for certain sensing devices.
As another example, in drug delivery applications, thicker
substrates may be desired in order to increase reservoir depth and
volume to contain more drug formulation, enabling increased dosage
loading.
[0036] The substrate has at least two, or preferably many, discrete
reservoirs. In various embodiments, tens, hundreds, or thousands of
reservoirs are arrayed across the substrate. For instance, the
device could include between 50 and 250 reservoirs, where each
reservoir contains a single dose of a drug for release, which for
example could be released hourly or daily over a period of several
days. Unlike a typical conventional transdermal device, the present
multi-reservoir devices can readily store and delivery different
drug formulations from a single device. For example, different
reservoirs could contain different drugs, or different reservoirs
could contain different dosages or concentrations of the same
drug.
[0037] In a preferred embodiment, the device comprises a microchip
chemical delivery device, as taught in U.S. Pat. No. 5,7979,898,
which is incorporated herein by reference. In other embodiments,
the device could include polymeric chips or devices, as well other
devices containing arrays of reservoirs, composed of non-silicon
based materials that might not be referred to as "microchips."
Pharmaceutical Agent/Formulation
[0038] Essentially any pharmaceutical agent, i.e., therapeutic or
prophylactic agent (e.g., an active pharmaceutical ingredient or
API), suitable for transdermal administration can be used with the
device described herein. The present devices would be particularly
useful for the storage and delivery of drugs that currently are not
suitable for use with conventional transdermal systems due to
instability issues associated with the drug. For example, a drug or
drug formulation that is easily degradable could be protected until
needed using the multiple reservoirs, each of which can be
hermetically sealed until ruptured when needed to release the drug
contained therein. In this way, only the quantity of the drug
needed at a particular time is exposed; the remaining drug remains
stored and protected. The device can deliver a single
pharmaceutical agent or a combination of pharmaceutical agents,
which can be stored together in the same reservoir or stored in
separate reservoirs. Depending on the application, the device and
formulation may be tailored to deliver the active ingredient
locally or systemically.
[0039] The pharmaceutical agent (also referred to herein as a drug)
can be provided in the reservoirs in a solid, liquid, semi-solid,
solution, or suspension, or emulsion formulation. It can be in a
pure form or combined with one or more excipient materials. As used
herein, "pure form" of the drug includes the API, residual
moisture, and any chemical species combined with the API in a
specific molar ratio that is isolated with the API during
preparation of the API (for instance, a counter-ion) and which has
not been added as an excipient.
[0040] In one embodiment, the drug is formulated in a matrix form,
comprising a matrix material in which the drug is contained or
dispersed. The matrix material further controls release of the drug
by controlling dissolution and/or diffusion of the drug from the
reservoir, and may enhance stability of the drug molecule while
stored in the reservoir.
[0041] In one embodiment, the drug is formulated with an excipient
material that is useful for accelerating release, e.g., a
water-swellable material that can aid in pushing the drug out of
the reservoir and through any tissue capsule over the reservoir.
Examples include hydrogels and osmotic pressure generating agents
known in the art.
[0042] In another embodiment, the drug is formulated with a
penetration enhancer(s). The penetration enhancer(s) further
controls release of the drug by facilitating transport of the drug
across the skin into the local administration site or systemic
delivery.
[0043] Pharmaceutical Agent
[0044] The drug can comprise small molecules, large (i.e., macro-)
molecules, or a combination thereof. In one embodiment, the large
molecule drug is a protein or a peptide. In various other
embodiments, the drug can be selected from amino acids, vaccines,
antiviral agents, gene delivery vectors, interleukin inhibitors,
immunomodulators, neurotropic factors, neuroprotective agents,
antineoplastic agents, chemotherapeutic agents, polysaccharides,
anti-coagulants (e.g., LMWH, pentasaccharides), antibiotics (e.g.,
immunosuppressants), analgesic agents, and vitamins.
[0045] In one embodiment, the drug is a protein. Examples of
suitable types of proteins include glycoproteins, enzymes (e.g.,
proteolytic enzymes), hormones or other analogs (e.g., LHRH,
steroids, corticosteroids, growth factors), antibodies (e.g.,
anti-VEGF antibodies, tumor necrosis factor inhibitors), cytokines
(e.g., .alpha.-, .beta.-, or .gamma.-interferons), interleukins
(e.g., IL-2, IL-10), and diabetes/obesity-related therapeutics
(e.g., insulin, exenatide, PYY, GLP-1 and its analogs). In one
embodiment, the drug is a gonadotropin-releasing (LHRH) hormone
analog, such as leuprolide. In another exemplary embodiment, the
drug comprises parathyroid hormone, such as a human parathyroid
hormone or its analogs, e.g., hPTH(1-84) or hPTH(1-34). In a
further embodiment, the drug is selected from nucleosides,
nucleotides, and analogs and conjugates thereof. In yet another
embodiment, the drug comprises a peptide with natriuretic activity,
such as atrial natriuretic peptide (ANP), B-type (or brain)
natriuretic peptide (BNP), C-type natriuretic peptide (CNP), or
dendroaspis natriuretic peptide (DNP). In still another embodiment,
the drug is selected from diuretics, vasodilators, inotropic
agents, anti-arrhythmic agents, Ca.sup.+ channel blocking agents,
anti-adrenergics/sympatholytics, and renin angiotensin system
antagonists. In one embodiment, the drug is a VEGF inhibitor, VEGF
antibody, VEGF antibody fragment, or another anti-angiogenic agent.
Examples include an aptamer, such as MACUGEN.TM. (Pfizer/Eyetech)
(pegaptanib sodium)) or LUCENTIS.TM. (Genetech/Novartis) (rhuFab
VEGF, or ranibizumab), which could be used in the prevention of
choroidal neovascularization. In yet a further embodiment, the drug
is a prostaglandin, a prostacyclin, or another drug effective in
the treatment of peripheral vascular disease.
[0046] In one embodiment, the device delivers one or more drugs
known in the art for use in pain management. Examples include
lidocaine and fentanyl. In a further embodiment, the drug is an
anti-inflammatory, such as dexamethasone.
[0047] In another embodiment, the drug is an anti-emetic, such as a
5HT-5 antagonist. In yet another embodiment, the drug is a NSAID,
such as ketaprofen. In another embodiment, the drug is an
anti-anxiety drug, such as benzodiazepines. In still another
embodiment, the drug is a dipeptidyl peptidase 4 inhibitor (DPP-4
inhibitor). In a further embodiment, the drug is an anticoagulant,
such as warfarin, heparin, LMWH, oligo-asaccharides such as
idraparinux and fondaparinux, and ximelagatran. In still another
embodiment, the drug is an angiogenic agent, such as VEGF. In one
embodiment, a device includes both angiogenic agents and
anti-inflammatory agents. In various embodiments, the drug is a
bone morphogenic protein, a growth factor, or a growth or
differentiation factor.
[0048] The reservoirs in one device can include a single drug or a
combination of two or more drugs, and can further include one or
more pharmaceutically acceptable carriers. Two or more can be
stored together and released from the same one or more reservoirs
or they can each be stored in and released from different
reservoirs.
[0049] The device is useful to delivery a variety of drugs, either
passively or with the aid of some acceleration means. For example,
oligonucleotide drugs may be delivered with the aid of
iontophoresis or electroporation.
[0050] Drugs that may be delivered using the devices and methods
described herein include those listed in Table 1 below.
TABLE-US-00001 TABLE 1 Transdermal Drug Delivery Compounds Current
Delivery Existing Drug Name Mechanism(s) Notes Clonidine Passive
Marketed Estradiol Passive Marketed Fentanyl Passive, Iontophoresis
Marketed Nicotine Passive Marketed Nitroglycerin Passive Marketed
Scopolamine Passive Marketed Testosterone Passive Marketed
Lidocaine Iontophoresis Marketed Epinephrine Iontophoresis Research
Corticosteroids Iontophoresis Research Pilocarpine Iontophoresis
Marketed; cystic fibrosis diagnosis Nafarelin Iontophoresis
Research; Pharm Res 13, 798 Leuprolide Iontophoresis Research; J.
Control. Release 31, 41 Vasopressin Iontophoresis Research Salmon
calcitonin Iontophoresis Research; Pharm. Res. 14, 63 Insulin
Iontophoresis Research; Electrically Assisted Transdermal &
Topical Drug Delivery 1998 LHRH Iontophoresis Research; J. Phar.
Sci. 87, 462 Parathyroid hormone Iontophoresis Research
Desmopressin Iontophoresis Research; Biol. Pharm. Bull. 21, 268
.delta.-sleep-inducing peptide Iontophoresis Research; Drug. Dev.
Ind. Pharm. 24, 431
[0051] Excipients and Matrix Materials
[0052] The drug can be dispersed in a matrix material, to further
control the rate of release of drug. This matrix material can be a
"release system," as described in U.S. Pat. No. 5,797,898, the
degradation, dissolution, or diffusion properties of which can
provide a method for controlling the release rate of the chemical
molecules.
[0053] The release system may provide a temporally modulated
release profile (e.g., pulsatile release) when time variation in
plasma levels is desired or a more continuous or consistent release
profile when a constant plasma level as needed to enhance a
therapeutic effect, for example. Pulsatile release can be achieved
from an individual reservoir, from a plurality of reservoirs, or a
combination thereof. For example, where each reservoir provides
only a single pulse, multiple pulses (i.e., pulsatile release) are
achieved by temporally staggering the single pulse release from
each of several reservoirs. Alternatively, multiple pulses can be
achieved from a single reservoir by incorporating several layers of
a release system and other materials into 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. In addition, continuous release
can be approximated by releasing several pulses of molecules in
rapid succession ("digital" release). The active release systems
described herein can be used alone or on combination with passive
release systems, for example, as described in U.S. Pat. No.
5,797,898. For example, the reservoir cap can be removed by active
means to expose a passive release system, or a given substrate can
include both passive and active release reservoirs.
[0054] In one embodiment, the drug formulation within a reservoir
comprises layers of drug and non-drug material. After the active
release mechanism has exposed the reservoir contents, the multiple
layers provide multiple pulses of drug release due to intervening
layers of non-drug. In another variation, the same layering system
could be used in device operating by passive release.
[0055] The pharmaceutical agent can be formulated with one or more
pharmaceutically acceptable excipients. Representative examples
include bulking agents, wetting agents, stabilizers, crystal growth
inhibitors, antioxidants, antimicrobials, preservatives, buffering
agents (e.g., acids, bases), surfactants, desiccants, dispersants,
osmotic agents, binders (e.g., starch, gelatin), disintegrants
(e.g., celluloses), glidants (e.g., talc), diluents (e.g., lactose,
dicalcium phosphate), color agents, lubricants (e.g., magnesium
stearate, hydrogenated vegetable oils) and combinations thereof. In
some embodiments, the excipient is a wax or a polymer. In one
embodiment, the polymer comprises polyethylene glycol (PEG), e.g.,
typically one having a molecular weight between about 100 and
10,000 Daltons (e.g., PEG 200, PEG 1450). In another embodiment,
the polymer comprises poly lactic acid (PLA), poly glycolic acid
(PGA), copolymers thereof (PLGA), or ethyl-vinyl acetate (EVA)
polymers. In yet another embodiment, the excipient material
comprises a pharmaceutically acceptable oil (e.g., sesame oil).
[0056] In one embodiment, the excipient material includes a
saturated drug solution. That is, the excipient material comprises
a liquid solution formed of the drug dissolved in a solvent for the
drug. The solution is saturated so that the solvent does not
dissolve the solid matrix form of the drug. The saturated solution
acts as a non-solvent excipient material, substantially filling
pores and voids in the solid matrix.
[0057] In another embodiment, the excipient material comprises a
pharmaceutically-acceptable perhalohydrocarbon or unsubstituted
saturated hydrocarbon. See, for example, U.S. Pat. No. 6,264,990 to
Knepp et al., which describes anhydrous, aprotic, hydrophobic,
non-polar liquids, such as biocompatible perhalohydrocarbons or
unsubstituted saturated hydrocarbons, such as perfluorodecalin,
perflurobutylamine, perfluorotripropylamine,
perfluoro-N-methyldecahydroquindine, perfluoro-octohydro
quinolidine, perfluoro-N-cyclohexylpyrilidine,
perfluoro-N,N-dimethylcyclohexyl methylamine,
perfluoro-dimethyl-adamantane, perfluorotri-methylbicyclo (3.3.1)
nonane, bis(perfluorohexyl) ethene, bis(perfluorobutyl) ethene,
perfluoro-1-butyl-2-hexyl ethene, tetradecane, methoxyflurane and
mineral oil.).
[0058] In one embodiment, the pharmaceutically acceptable excipient
material comprises dimethyl sulfoxide (DMSO), glycerol, or
ethanol.
[0059] In certain embodiments, the excipient material can be one
that would not ordinarily be considered as ingredient in a dosage
form. Where the implantable drug delivery device comprises one or
more discrete reservoirs of small volume, e.g., microreservoirs,
then it may be desirable to use organic solvents that are not
possible to use in large amounts, for example due to toxicity
concerns. In various embodiments, the solvents listed in Table 2
can be used as the excipient material if the device reservoir
volumes are small enough to ensure that the daily exposure to the
excipient cannot exceed predetermined limits, for example described
in ICH Guideline Q3C: Impurities: Residual Solvents.
TABLE-US-00002 TABLE 2 Excipient Materials and Exposure Limits
Excipient Daily limit (mg) Benzene 0.02 Carbon tetrachloride 0.04
1,2-Dichloroethane 0.05 1,1-Dichloroethene 0.08
1,1,1-Trichloroethane 15 Acetonitrile 4.1 Chlorobenzene 3.6
Chloroform 0.6 Cyclohexane 38.8 1,2-Dichloroethene 18.7
Dichloromethane 6.0 1,2-Dimethoxyethane 1.0 N,N-Dimethylacetamide
10.9 N,N-Dimethylformamide 8.8 1,4-Dioxane 3.8 2-Ethoxyethanol 1.6
Ethyleneglycol 6.2 Formamide 2.2 Hexane 2.9 Methanol 30.0
2-Methoxyethanol 0.5 Methylbutyl ketone 0.5 Methylcyclohexane 11.8
N-Methylpyrrolidone 5.3 Nitromethane 0.5 Pyridine 2.0 Sulfolane 1.6
Tetrahydrofuran 7.2 Tetralin 1.0 Toluene 8.9 1,1,2-Trichloroethene
0.8 Xylene 21.7 Acetic acid 50 Acetone 50 Anisole 50 1-Butanol 50
2-Butanol 50 Butyl acetate 50 tert-Butylmethyl ether 50 Cumene 50
Dimethyl sulfoxide 50 Ethanol 50 Ethyl acetate 50 Ethyl ether 50
Ethyl formate 50 Formic acid 50 Heptane 50 Isobutyl acetate 50
Isopropyl acetate 50 Methyl acetate 50 3-Methyl-1-butanol 50
Methylethyl ketone 50 Methylisobutyl ketone 50 2-Methyl-1-propanol
50 Pentane 50 1-Pentanol 50 1-Propanol 50 2-Propanol 50 Propyl
acetate 50
Reservoir Caps/Control Means
[0060] The device includes structural components for controlling
the time at which release of the pharmaceutical agent from the
reservoir is initiated. These components include reservoir caps and
reservoir control means. In one embodiment, the control means
includes control circuitry, which includes the hardware, electrical
components, and software needed to control and deliver electric
energy from a power source to selected reservoir(s) for actuation,
e.g., reservoir opening.
[0061] Reservoir Caps
[0062] As used herein, the term "reservoir cap" includes a membrane
or other structure suitable for separating the contents of a
reservoir from the environment outside of the reservoir. It
generally is self-supporting across the reservoir opening, although
caps having additional structures to provide mechanical support to
the cap can be fabricated. See, e.g., U.S. Patent Application
Publication Nos. 2002/0183721 A1, which is incorporated herein by
reference. Selectively removing the reservoir cap or making it
permeable will then "expose" the contents of the reservoir to the
environment (or selected components thereof) surrounding the
reservoir. In preferred embodiments, the reservoir cap is
selectively disintegrated. As used herein, the term "disintegrate"
includes degrading, dissolving, rupturing, fracturing or some other
form of mechanical failure, as well as a loss of structural
integrity due to a chemical reaction (e.g., electrochemical
degradation) or phase change (e.g., melting) in response to a
change in temperature, unless a specific one of these mechanisms is
indicated. In one specific embodiment, the "disintegration" is by
an electrochemical activation technique, such as described in U.S.
Pat. No. 5,797,898. In another specific embodiment, the
"disintegration" is by an electro-thermal ablation technique, as
described in U.S. Patent Application Publication No. 2004/0121486
A1 to Uhland et al., which is incorporated herein by reference in
its entirety.
[0063] In one embodiment, the reservoir cap is a thin metal film
and is impermeable to the surrounding environment (e.g., body
fluids or another chloride containing solution). In one variation,
a particular electric potential is applied to the metal reservoir
cap, which is then oxidized and disintegrated by an electrochemical
reaction, to release the drug from the reservoir. Examples of
suitable reservoir cap materials include gold, silver, copper, and
zinc.
[0064] In another variation, the reservoir cap is heated (e.g.,
using resistive heating) to cause the reservoir cap to melt and be
displaced from the reservoir to open it. See U.S. Pat. No.
6,527,762, which is incorporated herein by reference. This latter
variation could be used, for example, with reservoir caps formed of
a metal or a non-metal material, e.g., a polymer. In yet another
variation, the reservoir cap is formed of a polymer or other
material that undergoes a temperature-dependent change in
permeability such that upon heating to a pre-selected temperature,
the reservoir is rendered permeable to the drug and bodily fluids
to permit the drug to be released from the reservoir through the
reservoir cap.
[0065] In still another embodiment, the reservoir cap is formed of
a conductive material, such as a metal film, through which an
electrical current can be passed to electrothermally ablate it, as
described in U.S. Patent Application Publication No. 2004/0121486
A1 to Uhland et al. Representative examples of suitable reservoir
cap materials include gold, copper, aluminum, silver, platinum,
titanium, palladium, various alloys (e.g., Au--Si, Au--Ge, Pt--Ir,
Ni--Ti, Pt--Si, SS 304, SS 316), and silicon doped with an impurity
to modulate the conductivity/resistivity because one can use the
impurity to increase or decrease the conductivity or resistivity of
the silicon, as known in the art. In one embodiment, the reservoir
cap is in the form of a thin metal film. In one embodiment, the
reservoir cap is part of a multiple layer structure, for example,
the reservoir cap can be made of multiple metal layers, such as a
multi-layer/laminate structure of platinum/titanium/platinum. The
reservoir cap is operably (i.e., electrically) connected to an
electrical input lead and to an electrical output lead, to
facilitate flow of an electrical current through the reservoir cap.
When an effective amount of an electrical current is applied
through the leads and reservoir cap, the temperature of the
reservoir cap is locally increased due to resistive heating, and
the heat generated within the reservoir cap increases the
temperature sufficiently to cause the reservoir cap to be
electrothermally ablated and ruptured. In this embodiment, the
reservoir cap is formed of an electrically conductive material and
the control circuitry comprises an electrical input lead connected
to said reservoir cap, an electrical output lead connected to said
reservoir cap, wherein the reservoir cap is ruptured by application
of an electrical current through the reservoir cap via the input
lead and output lead. Preferably, the control circuitry further
comprises a source of electric power for applying the electrical
current.
[0066] In yet another embodiment, the reservoir opening is closed
by a reservoir cap comprising a dielectric or ceramic film layer
and the actuation means comprises (i) a electrically conductive
(e.g., metal) layer on top of the dielectric or ceramic film layer,
and (ii) power source and control circuitry for delivering an
electric current through the electrically conductive layer in an
amount effective to rupture the dielectric or ceramic film layer,
wherein the rupture is due to thermal expansion-induces stress on
the dielectric or ceramic film layer. The electrically conductive
layer and the actuation means can be designed thermally ablate the
electrically conductive layer or the electrically conductive layer
could remain, in whole or in part, after rupturing the dielectric
or ceramic film layer, depending on the particular design for
opening/actuation the release of drug from the reservoir.
[0067] In passive release devices, the reservoir cap is formed from
a material or mixture of materials that degrade, dissolve, or
disintegrate over time, or that do not degrade, dissolve, or
disintegrate, but are permeable or become permeable to molecules or
energy. Representative examples of reservoir cap materials include
polymeric materials, and non-polymeric materials such as porous
forms of metals, semiconductors, and ceramics. Passive
semiconductor reservoir cap materials include nanoporous or
microporous silicon membranes. Characteristics can be different for
each reservoir cap to provide different times of release of drug
formulation. For example, any combination of polymer, degree of
crosslinking, or polymer thickness can be modified to obtain a
specific release time or rate.
[0068] A combination of passive and/or active release reservoir cap
can be present in a single delivery device. For example, the
reservoir cap can be removed by electrothermal ablation to expose a
passive release system that only begins its passive release after
the reservoir cap has been actively removed. Alternatively, a given
device can include both passive and active release reservoirs.
[0069] In still another embodiment, release can be controlled from
the substrate reservoirs using passive control means, such as a
biodegradable matrix material or layering of drug material with
non-drug material, without the use of reservoir caps. In one
variation of this "no cap" approach, reservoir caps are provided
prior to device use, i.e., prior to application of (adhering) the
device to the skin, and then immediately before application to the
skin all of these reservoir caps are (manually) removed. For
instance, these caps could be part of a protective layer that is
removed just prior to adhering the patch to the skin.
[0070] In one embodiment, each reservoir includes a single,
discrete reservoir cap, covering a single opening that can be
opened. In another embodiment, each reservoir includes two or more
openings that can be covered by two or more discrete reservoir
caps, where each reservoir cap can, but need not, be independently
disintegrated to open the reservoir. There can be a one-to-one
correspondence between the number of reservoir openings and the
number of reservoir caps; however, in various embodiments, it is
possible that a single discrete reservoir can cover more than one
reservoir opening.
[0071] Control Means
[0072] The reservoir control means can provide intermittent or
effectively continuous release of the drug formulation. The
particular features of the control means depend on the mechanism of
reservoir cap activation described herein. For example, the control
means can include an input source, a microprocessor, a timer, a
demultiplexer (or multiplexer), and a power source. The power
source provides energy to activate the selected reservoir, e.g., to
trigger release of the drug formulation from the particular
reservoir desired for a given dose. See FIG. 4. For example, the
operation of the reservoir opening system can be controlled by an
on-board microprocessor. The microprocessor can be programmed to
initiate the disintegration or permeabilization of the reservoir
cap at a pre-selected time or in response to one or more of signals
or measured parameters, including receipt of a signal from another
device (for example by remote control or wireless methods) or
detection of a particular condition using a sensor such as a
biosensor. In another embodiment, a simple state machine is used,
as it typically is simpler, smaller, and/or uses less power than a
microprocessor. The device can also be activated or powered using
wireless means, for example, as described in U.S. 2002/0072784 A1
to Sheppard et al., which is incorporated herein by reference.
[0073] In one embodiment, the device includes a substrate having a
two-dimensional array of reservoirs arranged therein, a drug
formulation contained in the reservoirs, anode reservoir caps
covering a semi-permeable membrane for each of the reservoirs,
cathodes positioned on the substrate near the anodes, and means for
actively controlling disintegration of the reservoir caps. The
means includes a power source and circuitry to control and deliver
an electrical potential; the energy drives a reaction between
selected anodes and cathodes. Upon application of a potential
between the electrodes, electrons pass from the anode to the
cathode through the external circuit causing the anode material
(reservoir cap) to oxidize and dissolve into the surrounding
fluids, exposing and releasing the drug formulation. The
microprocessor directs power to specific electrode pairs through a
demultiplexer as directed by an EPROM, remote control, or
biosensor.
[0074] In another embodiment, the activation energy initiates a
thermally driven rupturing or permeabilization process, for
example, as described in U.S. Pat. No. 6,527,762. For example, the
means for controlling release can actively disintegrate or
permeabilize a reservoir cap using a resistive heater. The
resistive heater can cause the reservoir cap to undergo a phase
change or fracture, for example, as a result of thermal expansion
of the reservoir cap or release system, thereby rupturing the
reservoir cap and releasing the drug from the selected reservoir.
The application of electric current to the resistor can be
delivered and controlled using components as described above for
use in the electrochemical disintegration embodiment. For example,
a microprocessor can direct current to select reservoirs at desired
intervals.
[0075] In a preferred embodiment, control means controls
electro-thermal ablation of the reservoir cap. For example, the
drug delivery device could include a reservoir cap formed of an
electrically conductive material; an electrical input lead
connected to the reservoir cap; an electrical output lead connected
to the reservoir cap; and a control means to deliver an effective
amount of electrical current through the reservoir cap, via the
input lead and output lead, to locally heat and rupture the
reservoir cap, for example to release the drug formulation or
expose the sensor located therein. In one embodiment, the reservoir
cap and conductive leads are formed of the same material, where the
temperature of the reservoir cap increases locally under applied
current because the reservoir cap is suspended in a medium that is
less thermally conductive than the substrate. Alternatively, the
reservoir cap and conductive leads are formed of the same material,
and the reservoir cap has a smaller cross-sectional area in the
direction of electric current flow, where the increase in current
density through the reservoir cap causes an increase in localized
heating. The reservoir cap alternatively can be formed of a
material that is different from the material forming the leads,
wherein the material forming the reservoir cap has a different
electrical resistivity, thermal diffusivity, thermal conductivity,
and/or a lower melting temperature than the material forming the
leads. Various combinations of these embodiments can be employed as
described in U.S. Patent Application Publication No. 2004/0121486
A1 to Uhland et al.
[0076] In one embodiment, the control means includes a
microprocessor, a timer, a demultiplexer (or multiplexer), and an
input source (for example, a memory source, a signal receiver, or a
biosensor), and a power source. The timer and demultiplexer
circuitry can be designed and incorporated directly onto the
surface of the microchip during electrode fabrication, or may be
incorporated in a separate microchip. The microprocessor translates
the output from memory sources, signal receivers, or biosensors
into an address for the direction of power through the
demultiplexer to a specific reservoir on the device. Selection of a
source of input to the microprocessor such as memory sources,
signal receivers, or biosensors depends on the microchip device's
particular application and whether device operation is
preprogrammed, controlled by remote means, or controlled by
feedback from its environment (i.e., biofeedback). For example, a
microprocessor can be used in conjunction with a source of memory
such as erasable programmable read only memory (EPROM), a timer, a
demultiplexer, and a power source such as a battery or a biofuel
cell. A programmed sequence of events including the time a
reservoir is to be opened and the location or address of the
reservoir is stored into the EPROM by the user. When the time for
exposure or release has been reached as indicated by the timer, the
microprocessor sends a signal corresponding to the address
(location) of a particular reservoir to the demultiplexer. The
demultiplexer routes an input, such as an electric potential or
current, to the reservoir addressed by the microprocessor. In
another embodiment, the electronics are included on the
substrate/chip itself, for example, where the electronics are based
on diode or transistor technology known in the art.
[0077] In one preferred embodiment, the electronics are separable
from the transdermal drug delivery device, such that they are
reusable with multiple transdermal drug delivery devices. One
example of such a system is shown in FIG. 2. The cost to use a
transdermal system like this would be significantly less than a
system where the electronics were not separable and only could be
used once.
[0078] Other methods and multi-reservoir devices for controlled
release of drug are described in U.S. Patent Application
Publications Nos. 2002/0072784 A1, 2002/0099359 A1, 2002/0187260
A1, 2003/0010808 A1, 2004/0082937 A1, 2004/016914 A1; and U.S. Pat.
Nos. 6,808,522, 6,730,072, 6,773,429, 6,123,861, all of which are
incorporated by reference herein.
Securing Means
[0079] Essentially any device known in the art for securing objects
to the skin of a human or other mammalian animal can be used. For
example, the securing means can include one or more biocompatible
adhesives, straps, or elastic bands. In one embodiment, the
securing means is provided along the periphery of a housing of the
device. Adhesive securing means can be, or can be readily adapted
from, those known in the art for securing transdermal patches, such
as those currently used in commercially available transdermal
patches. See, e.g., U.S. Pat. No. 6,632,906.
[0080] In one embodiment, the adhesive is provided on a thin
permeable material, such as a porous polymer layer, or a woven or
non-woven fabric layer, which is adjacent the reservoir caps or the
transport means. In one embodiment, the adhesive layer is permeable
to the one or more pharmaceutical agents. In one embodiment, the
polymer layer comprises a hydrogel.
[0081] In a preferred embodiment, the securing means comprises a
pressure sensitive bioadhesive, as known in the art.
Transport Means
[0082] As used herein, "transport means" or "means for
transporting" refers to any devices or materials for transferring
the pharmaceutical agent that has been released from the reservoirs
from the opening of the reservoir to the surface of or into the
skin of the patient.
[0083] The choice of transport mechanism(s) is at least partially
dependent on the drug molecule selected for delivery. Generally,
these delivery mechanisms are characterized as follows: (1)
passive, (2) chemical penetration enhancers, (3) ultrasonography,
(4) iontophoresis, (5) electroosmosis, (6) electroporation, (7)
heat, and (8) microneedles. For passive mechanisms, a therapeutic
dose is achievable without enhancement because of high potency and
desirable physiochemical characteristics, which is typically
associated with small lipophilic molecules. Chemical penetration
enhancers can be added to the drug formulation to increase flux
through the skin or mucosal surface. Examples include phosphate
buffered saline, PEG 200 dilaurate, isopropyl myristate, glycerol
trioleate, 50% ethanol/50% phosphate buffered saline, linoleic acid
in 1/1 ethanol/phosphate buffered saline. With ultrasonography,
low-frequency ultrasound is applied prior to or simultaneously with
drug delivery, particularly for low- and high-molecular weight
drugs. With iontophoresis, a continuous low current is applied to
enhance delivery of a charged molecular species. With
electroosmosis, enhancement is by entrainment of bulk liquid by
charged ions moving in an electric field, which can be used to
deliver neutral and charged species. Electroporation utilizes a
high voltage pulse to help deliver large (proteins,
oligonucleotides) and small molecules. Heat is another mechanism,
where controlled exothermic reaction is used to generate heat to
drive transport across skin. Microneedles, which are used to create
pathways through the stratum corneum, can take a variety of forms,
including an array of titanium microprojections, such as the
MACROFLUX.TM. (Alza Corp.).
[0084] The device can include, or be used with, devices and means
for application of acoustic energy (see, e.g., U.S. Patent
Application Publication No. 2002/0082527 A1; U.S. Patent
Application Publication No. 2002/0045850 A1),
sonophoresis/ultrasound (see, e.g., U.S. Pat. No. 6,620,123, U.S.
Pat. No. 6,491,657), electroporation, iontophoresis (see, e.g.,
U.S. Pat. No. 6,629,968, U.S. Pat. No. 6,377,847, U.S. Patent
Application Publication No. 2001/0056255 A1), heat (see, e.g., U.S.
Pat. No. 6,756,053, U.S. Pat. No. 6,488,959) or other means known
in the art for enhancing transdermal administration of drugs or
transdermal diagnostics (e.g., glucose sensing).
[0085] In one embodiment, the transport means comprises a transport
medium reservoir disposed between the reservoir caps and the skin.
For example, the transport medium can include a permeable body
through which the one or more pharmaceutical agents can diffuse
following their release from the reservoir, or through which an
analyte from the patient's skin can diffuse toward sensors disposed
in the reservoirs. The transport medium can comprise a reservoir
containing a liquid, gel, or semi-solid permeation material (also
referred to in the art as a rate-limiting membrane). Representative
examples of suitable permeation materials include various polymers
and hydrogels known in the art, which preferably are non-reactive
with the drug formulation or skin.
[0086] In one embodiment, the transport means includes one or more
permeation enhancers, as for example, described in U.S. Pat. No.
6,673,363, which is incorporated herein by reference.
[0087] In one embodiment, the means for transporting comprises one
or more microneedles. Examples of microneedles suitable for
transdermal drug delivery and analyte sensing are described in U.S.
Pat. No. 6,743,211, U.S. Pat. No. 6,661,707, U.S. Pat. No.
6,503,231, and U.S. Pat. No. 6,334,856, all to Prausnitz et al.,
and in U.S. Pat. No. 6,230,051 and U.S. Pat. No. 6,219,574, both to
Cormier et al.
[0088] In one embodiment, the device includes positive displacement
mechanisms for driving the one or more pharmaceutical agents out of
the reservoirs. In one embodiment, an osmotic pressure generating
material or other swellable material drives a piston to force a
drug formulation out of the reservoir. In another embodiment, the
device includes features for the positive displacement and/or
accelerated release techniques described in U.S. Patent Application
Publication No. 2004/0106914 to Coppeta et al.
Illustrative Embodiments
[0089] In one embodiment, the transdermal device includes a patch
comprising a secondary reservoir for receiving the drug released
from each reservoir in the substrate. The secondary reservoir may
be a single pool into which the dose is diluted, or the pool space
may be divided into individual channels for delivery of each dose
with minimal dilution. Upon release from the substrate reservoir,
the drug diffuses into and through the secondary reservoir and then
out of the patch and into the patient's skin. See FIG. 5. In an
alternative embodiment (not shown) the secondary reservoir is
replaced with a layer of substrate that has media-filled holes with
spacing corresponding to reservoir membrane openings, which allows
release of reservoir contents without dilution. In one embodiment,
the device includes a rigid or flexible housing that contains the
substrate, as well as the control means and power source. When the
drug enters the secondary reservoir, it may distribute itself
homogeneously throughout the secondary reservoir, such that
diffusion is substantially uniform across the entire surface area
interfacing the skin. The secondary reservoir optionally can
include a permeable or semi-permeable adhesive layer at this
interface.
[0090] FIG. 1 shows device 10 which includes substrate 12 having
reservoirs 14 which contain one or more pharmaceutical agents. The
device 10 further includes fluid reservoir 16 and a permeable
adhesive layer 18 for securing the device to the patient's skin.
The device 10 further includes microprocessor-based or remote
control means 20 and battery or other power supply 22. Preferably,
the portion of the device comprising the control mans and power
supply is flexible. The device includes an optional housing or
outer covering 24. In an alternative embodiment (not shown) fluid
reservoir 16 is replaced with a layer of substrate that has
media-filled holes with spacing corresponding to reservoir membrane
openings, which allows release of reservoir contents without
dilution.
[0091] FIG. 6 shows an alternate version of device 10, wherein the
means for transporting further comprises a plurality of
microneedles 27, which may be solid, hollow, or porous. For
example, U.S. Pat. No. 6,230,051 to Cormier et al. (Alza
Corporation) discloses needle-like protrusions, barbs, or blades
that puncture the stratum corneum, and diffusion of drug proceeds
along the pathway between the outer surface of the needle and the
skin/tissue circumscribing the needle. In an alternative
embodiment, the fluid reservoir is replaced with a layer of
substrate that has media-filled holes with spacing corresponding to
reservoir membrane openings, which allows release of reservoir
contents without dilution. That is, the microneedles can be spaced
to match the reservoir openings. In use, one can apply the solid
microneedles first, then remove them, and then apply the drug
delivery patch, or one can use hollow microneedles matched to the
spacing of the reservoir openings attached to the patch.
[0092] The device electronics optionally can be located in a
separate package. In one embodiment, the device includes a
removably attachable electronics portion that comprises the power
source and at least a portion of the control circuitry. This
electronics portion can be re-used many times and can be
re-programmed wirelessly, which advantageously could improve cost
effectiveness. One embodiment of such a device is illustrated in
FIGS. 2A-B. These Figures show device 50 which includes substrate
52 having reservoirs 54 which contain the drug. The device 50
further includes fluid reservoir 56 and an adhesive layer 66 for
securing the device to the patient's skin. The control means for
selective releasing the drug includes an electronics interface
portion 58, and removable power and electronics portion 60. The
removable power and electronics portion 60 and the electronics
interface portion 58 are can be selectively attached together by
matingly engaging male connector posts 62 with female receptacles
64. The device is sealed or packaged in a protective material 68.
For example, the protective material can be a polymeric coating or
laminate composite structure. In an alternative embodiment (not
shown) fluid reservoir 56 is replaced with a layer of substrate
that has media-filled holes with spacing corresponding to reservoir
membrane openings, which allows release of reservoir contents
without dilution.
[0093] FIG. 3 shows device 70 (shown only in part) which comprises
body portion 72, which includes a first substrate portion 78 and a
second substrate portion 76. Reservoirs 74 are defined in the body
portion. (Two are located in the body portion in this illustration,
but only one can be seen from the cut-away of part of the first
substrate portion.) The release opening of the reservoirs are
covered by reservoir caps 80a and 80b. Metal conductors 82a and 82b
are electrically connected to the reservoir caps, for delivering
electric current to the reservoir caps. Dielectric layer 85 is
provided on the outer surface of the first substrate portion and is
underneath the conductors.
Use of the Medical Device
[0094] In preferred embodiments, the device can be used to delivery
a wide variety of drugs or drug combinations to a patient in need
thereof. The device can be tailored to delivery the drug or drugs
over an extended period of time, with a range of controlled release
profiles, for example, to provide a relatively constant or a varied
plasma drug levels. The device may be removed periodically,
provided it does not undesirably interrupt delivery of the drug.
The drug formulation and device may also be tailored for systemic
(bioavailability goal 100%) or topical (bioavailability goal 0%)
delivery.
[0095] In one embodiment, the medical device is used for
transdermal delivery of parathyroid hormone (PTH). PTH is released
from the reservoirs in a manner to intermittently deliver a
pharmaceutically effective amount of the PTH through the skin for
systemic administration. The delivery optionally can be facilitated
by one or more transport acceleration means as described above.
[0096] Other applications include the delivery of pain medications.
Examples include lidocaine, for needle sticks, IV insertion, or
other dermatological procedures, or the delivery of more potent
pain medications, such as fentanyl, for greater pain relief, such
as for treating breakthrough pain in cancer patients. In still
other applications, the devices can be used to deliver drugs for
joint pain, anti-emetic applications, migraine treatments,
fertility treatments, and Parkinson's medications.
[0097] In still other applications, the device is used in sensing
applications. For example, the micro-reservoirs could contain
sensors for measuring an analyte that can be drawn from the skin.
Alternatively, the device could operate not remove fluid but,
rather, to place small quantities of solution containing low
concentrations of Small Molecule Metabolite Reporters (SMMRs) into
the skin for direct reading of the SMMR fluorescence spectral
characteristics as an indication of both epidermal skin and blood
glucose levels, as known in the art.
[0098] Publications cited herein and the materials for which they
are cited are specifically incorporated by reference. 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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