U.S. patent application number 14/562579 was filed with the patent office on 2015-04-02 for medicament delivery systems.
The applicant listed for this patent is CALIFORNIA INSTITUTE OF TECHNOLOGY. Invention is credited to Hesham Azizgolshani, Morteza Gharib, Derek Rinderknecht.
Application Number | 20150094697 14/562579 |
Document ID | / |
Family ID | 47296749 |
Filed Date | 2015-04-02 |
United States Patent
Application |
20150094697 |
Kind Code |
A1 |
Rinderknecht; Derek ; et
al. |
April 2, 2015 |
MEDICAMENT DELIVERY SYSTEMS
Abstract
Described herein are systems, devices, and methods for the
delivery of substances to, or the sampling of substances from, a
patient using a portable and preferably implantable device. The
substances introduced to and/or taken from the patient are
preferably fluidic and are driven by a miniature pump, such as a
microimpedance pump. A number of design variations are explicitly
and implicitly described, such as the use of multiple pumps and
multiple reservoirs for containing medicaments. Methods of
manufacture of these systems and devices are also described, for
instance, using molding, micromachining, or lithographic
processes.
Inventors: |
Rinderknecht; Derek;
(Arcadia, CA) ; Azizgolshani; Hesham; (Winnetka,
CA) ; Gharib; Morteza; (Altadena, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CALIFORNIA INSTITUTE OF TECHNOLOGY |
Pasadena |
CA |
US |
|
|
Family ID: |
47296749 |
Appl. No.: |
14/562579 |
Filed: |
December 5, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13491385 |
Jun 7, 2012 |
8945448 |
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14562579 |
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61562957 |
Nov 22, 2011 |
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61494317 |
Jun 7, 2011 |
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Current U.S.
Class: |
604/891.1 ;
156/145; 156/293 |
Current CPC
Class: |
A61M 2205/8206 20130101;
A61M 2210/0693 20130101; A61M 5/14276 20130101; A61M 5/14224
20130101; G01F 11/08 20130101; A61M 2205/8212 20130101; A61M
2207/00 20130101; A61M 2210/0662 20130101; A61M 2210/0612 20130101;
A61M 2205/8243 20130101; A61M 37/00 20130101 |
Class at
Publication: |
604/891.1 ;
156/293; 156/145 |
International
Class: |
A61M 5/142 20060101
A61M005/142 |
Claims
1. A method of manufacturing an implantable drug delivery system
including an impedance pump, comprising: forming a first layer of a
substrate having a pump chamber wall on which an activation element
can be mounted; forming a second layer of the substrate having an
elongate recess connected to a plurality of elongate channels;
coupling the first layer to the second layer such that the pump
chamber wall is positioned over the elongate recess and such that
the elongate recess and the plurality of elongate channels are
covered by the first layer; and coupling the activation element to
the pump chamber wall.
2. The method of claim 1, wherein the first layer is formed with a
reservoir, and wherein the first and second layers are coupled
together such that the reservoir is in communication with at least
one of the plurality of elongate channels.
3. The method of claim 2, further comprising inserting a medicament
into the reservoir and sealing the reservoir.
4. The method of claim 1, wherein the plurality of elongate
channels terminate in two or more openings in the sidewall of the
substrate, the method further comprising: inserting drug perfusion
tubing into the two or more openings; and overmolding the tubing to
secure and seal the tubing to the substrate.
5. The method of claim 4, further comprising adding adhesive to
further secure and seal the tubing to the substrate.
6. The method of claim 1, wherein the first and second layers are
formed with a mold having features micromachined thereon.
7. A medicament delivery system, comprising: a substrate; an
impedance pump coupled to the substrate; and at least one
medicament reservoir formed in the substrate and in fluid
communication with the impedance pump.
8. The system according to claim 7, further comprising: an
activation element disposed on the impedance pump, wherein
activation of the activation element causes a cross-section of a
portion of the impedance pump to decrease.
9. The system according to claim 8, wherein the activation element
is a magnet.
10. The system according to claim 7, further comprising: a first
tube and a second tube, each coupled to the substrate; a first
channel in the substrate adapted to provide fluid communication
between the impedance pump and the first tube; and a second channel
in the substrate adapted to provide fluid communication between the
impedance pump and the second tube.
11. The system according to claim 10, wherein a first cross-section
of the first channel and a second cross-section of the second
channel are less than a cross-section of the impedance pump.
12. The system according to claim 10, wherein the first and second
tubes extend laterally from the substrate.
13. The system according to claim 12, wherein the first and second
tubes are coupled to an interface component.
14. The system according to claim 12, further comprising a dual
lumen tube, wherein the first tube and the second tube are in fluid
communication with lumens in the dual-lumen tube.
15. The system according to claim 12, wherein portions of the first
and second tubes are covered by a sheath.
16. The system according to claim 10, wherein the at least one
medicament reservoir is in fluid communication with the first
channel or the second channel.
17. The system according to claim 7, further comprising a
medicament stored in the at least one medicament reservoir.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation application of
U.S. patent application Ser. No. 13/491,385, filed Jun. 7, 2012,
which claims the benefit of U.S. provisional patent application
Ser. No. 61/494,317, filed Jun. 7, 2011 and U.S. provisional patent
application Ser. No. 61/562,957, filed Nov. 22, 2011, all of which
are hereby incorporated by reference in their entirety as if fully
set forth herein.
RELEVANT FIELD
[0002] The systems and methods disclosed herein relate generally to
portable drug delivery and sampling devices having impedance
pumps.
BACKGROUND
[0003] For many diseases, treatment with oral or parenteral
medicament administration requires a high dose which would lead to
side effects that would inhibit a therapeutic concentration of the
medicament from reaching diseased tissue. Thus, for such diseases,
local medicament delivery to the diseased tissue is a desirable
objective. It can provide higher concentrations of the medicament
to the diseased tissue and allow control of the amount, rate and
timing of delivery, which makes local delivery an option for
long-term continuous treatment and potentially reduces systemic
side effects. However, for some anatomical structures, such as the
inner ear, local medicament delivery has special challenges due to,
for example, limited natural points of entry, complex structures,
barriers, and delicate environments. Known delivery modalities,
e.g., systemic, intratympanic, etc., have not adequately or
effectively addressed these challenges. Therefore, there is a need
for a medicament delivery system that can provide localized
delivery of a medicament.
SUMMARY
[0004] Described herein are systems, devices, and methods for the
delivery of substances to, or the sampling of substances from, a
patient using a portable and preferably implantable device. The
substances introduced to and/or taken from the patient are
preferably fluidic and are driven by a miniature pump, such as a
microimpedance pump. A number of design variations are explicitly
and implicitly described, such as the use of multiple pumps and
multiple reservoirs for containing medicaments. Methods of
manufacture of these systems and devices are also described, for
instance, using molding, micromachining, or lithographic
processes.
[0005] Other systems, methods, features and advantages of the
subject matter described herein will be or will become apparent to
one with skill in the art upon examination of the following figures
and detailed description. It is intended that all such additional
systems, methods, features and advantages be included within this
description, be within the scope of the subject matter described
herein, and be protected by the accompanying claims. In no way
should the features of the example embodiments in this summary
section, or in the following description sections, be construed as
limiting the appended claims, absent express recitation of those
features in the claims.
BRIEF DESCRIPTION OF FIGURES
[0006] The details of the systems, devices, and methods described
herein, both as to their structure and operation, can be gleaned in
part by study of the accompanying figures, in which like reference
numerals refer to like parts. The components in the figures are not
necessarily to scale, emphasis instead being placed upon
illustrating principles. Moreover, all illustrations are intended
to convey concepts, where relative sizes, shapes and other detailed
attributes may be illustrated schematically rather than literally
or precisely.
[0007] FIG. 1 is a schematic view depicting an example embodiment
of a medicament delivery system.
[0008] FIGS. 2A-F are cross-sectional views depicting an example
method of manufacture of a medicament delivery system.
[0009] FIGS. 2G-H are schematic views depicting an example method
of securing inlet and/or outlet tubes to the delivery system
substrate.
[0010] FIGS. 3A-E are cross-sectional views depicting example flow
distributions for medicament exiting a medicament delivery
system.
[0011] FIGS. 4A-B depict another example embodiment of a medicament
delivery system.
DETAILED DESCRIPTION
[0012] The detailed description set forth below in connection with
the appended drawings is intended to describe various example
embodiments and is not intended to represent the only embodiments
that may be practiced.
[0013] In the following section, numerous examples and example
embodiments are described. These embodiments are not described as
rigid alternatives, but are rather intended to illustrate the broad
scope and interchangeability of the systems, devices, and methods
described herein. Thus, any feature, element, step, or aspect of
one embodiment can be added to or substituted within any other
embodiment described herein.
[0014] An example embodiment of a medicament delivery system 10 is
shown in FIG. 1. Generally, the delivery system 10 is intended to
be used to deliver a medicament into the inner ear for the
treatment of inner ear and/or vestibular system disorders (e.g.,
tinnitus, SNHL, presbycusis, meniere's disease, etc.). While the
embodiments described herein will be done so generally with regard
to inner ear delivery, it should be understood that these
embodiments can be used to deliver substances to any desired tissue
or anatomical structure, including but not limited to intrathecal
delivery (e.g., for pain management) and intraocular delivery.
Likewise, the delivery system can be used to deliver any desired
substance, drug, medicament, or therapeutic, including but not
limited to cancer therapeutics and insulin.
[0015] In the example embodiment of FIG. 1, the delivery system 10
can be implanted in the mastoid portion of the temporal bone. In an
example implantation procedure, a pocket can be formed in the
mastoid bone for insertion of the delivery system 10. Holes can be
drilled to provide access to the scala tympani for the delivery
system 10. In another example embodiment, the delivery system 10
can be implanted using a postauricular mastoidomy or posterior
tympanotomy. The delivery system 10 can also be configured to lie
outside the body and deliver a substance through a catheter or
subcutaneously through a needle. Alternatively, the delivery system
10 can lie outside the body and sample body fluids through a
catheter or subcutaneously through a needle. In yet another
example, the delivery system 10 can lie outside the body and
deliver or sample substances through the dermis.
[0016] The delivery system 10 includes a substrate (or body) 12,
pump 16 and tubing that can be manufactured from biocompatible
polymeric materials (including, but not limited to, silicone, PDMS,
PEEK, PTFE and Polysulfone (PSU), other fluoropolymers, PVDF,
parylene, polyurethane, polysulphone, polyolefin, polyvinyl
chloride, polypropylene, polycarbonate, and PMMA), metallic
materials (including, but not limited to, nickel, titanium, and any
alloys thereof (e.g., Ti6A14V), stainless steel, and chromium),
ceramics (including, but not limited to, zirconia and alumina), or
combinations of the same.
[0017] In an example embodiment, the substrate 12 can include a
pump chamber 14 which houses a pump 16 for circulating fluid
through the delivery system 10. Pump 16 preferably utilizes a
mismatch in impedance to drive flow and can be embodied by a
compressible section or movable wall coupled at either end to wave
reflection sites or locations where pressure wave energy is
reflected. Here, pump 16 is an impedance pump enclosed within
substrate 12. Pump 16 can be manufactured from one or more
materials and can assume any desired shape. In this example, pump
16 is made from silicon and is rectangular. In embodiments where
pump 16 is manufactured from two or more materials, the first
material can have a first impedance and the second material can
have a second impedance, different from the first. Of course, any
number of materials having different impedances can be used.
Further examples of pump 16 can be, but are not limited to, those
pump configurations and geometries described in U.S. Pat. Nos.
6,254,355, 6,679,687, 7,387,500, 7,163,385 and U.S. Patent
Application Publication Nos. 2007/0177997 and 2011/0125136. Every
patent and published application in the preceding sentence is
expressly incorporated herein by reference for all purposes.
[0018] Here, pump 16 has a longitudinal axis L and a transverse (or
lateral) axis T. An activation element 18 (e.g., a magnet) can be
disposed on a surface of substrate 12, preferably a surface of a
thin wall or membrane opposite pump chamber 14. Activation element
18 is adapted to activate and/or instigate the mechanism that
causes the pumping action, which in this embodiment is the movement
of the thin wall underlying element 18. Activation element 18 can
be a piezoelectric, electromagnetic, or magnetostrictive device, to
name a few. Activation element 18 preferably interfaces with a
control device, which can also be a portable (e.g., wearable,
implantable, or handheld) device located in proximity with delivery
system 10. The control device (not shown) can generate a permanent
or variable magnetic field that interfaces with, e.g., a magnetic
activation element 18 and causes that activation element to move.
The control device is preferably programmable and adjustable based
on user input. In one example embodiment, the control device has
on-board electronics such as power management, frequency
synthesizer, controller, communication links, and a battery.
[0019] The device 10 itself may be implanted subcutaneously or worn
externally with the drug perfusion tubing extending into the
patient. In another example embodiment, the device functions as an
in hospital delivery platform for drug perfusion through a venous
or arterial catheter placed in the patient. In another embodiment
device 10 functions in combination with a cochlear implant
providing both stimulation and therapeutic treatments.
[0020] In the instance where the geometry of the ends of channels
20, 24 leading into pump chamber 14 are the same, then magnet 18 is
preferably disposed at a position longitudinally offset from the
central transverse axis T of pump chamber 14. This asymmetry leads
to the addition of pressure waves within chamber 14 that in turn
creates the pumping effect (see, e.g., the incorporated U.S. Pat.
No. 7,163,385). The geometry of the ends of channels 20, 24 leading
into pump chamber 14 can also be different, sized in the
appropriate manner to allow activation element 18 to be centrally
placed along axis T.
[0021] A first channel 20 is disposed in substrate 12 and has a
first opening 51 in fluid communication with pump 16 and a second
opening 52 in fluid communication with an inlet tube 22. Here,
openings 51 and 52 are also located at opposite terminal ends of
channel 20. A second channel 24 is disposed in substrate 12 and has
a first opening 53 in fluid communication with pump 16 (at an end
of pump 16 opposite opening 51 of first channel 20) and a second
opening 54 disposed in fluid communication with an outlet tube 26.
Here, openings 53 and 54 are also located at opposite terminal ends
of channel 24. First and second channels 20, 24 define a fluid path
through substrate 12 for fluid being pumped by the pump 16. The
cross-sectional area of the channels 20, 24 can be the same or
different from each other, but in either case are substantially
less than the transverse cross-sectional area of pump 16.
[0022] Delivery system 10 can be used with multiple pumps. These
additional pumps can be used to deliver different drugs (e.g., to
allow the delivery of drug combinations or drug cocktails), or used
in a cascaded or additive configuration (e.g., to increase the flow
rate of the pumping mechanism with system 10). In another
embodiment, one or more pumps are used to draw fluid out of a
liquid reservoir to combine drugs or drug components. In another
embodiment, delivery system 10 contains a mixer utilizing an
unsteady output of a pump to combine drugs or drug components.
[0023] Although the term "delivery system" is used, it should be
noted that in all of the embodiments described herein, the pump can
be used with the primary intent to deliver a foreign substance into
the patient, or with the primary intent to extract a substance from
the patient (such as blood for diagnostic purposes). In embodiments
where a fluid circuit is used to both pass a substance into the
patient and extract a substance from the patient, those of skill in
the art will readily recognize that the pump accomplishes both a
delivery and extraction function. In FIG. 1, a single pump 16
accomplishes both functions, but system 10 can be configured with
dedicated pumps where one or more pumps primarily (or exclusively)
deliver a substance to the body and one or more different pumps
primarily (or exclusively) extract a substance from the body.
[0024] Drug perfusion tubing in the form of inlet and outlet tubes
22, 26 can extend laterally from substrate 12 with terminal ends
coupled in proximity to each other or coupled to an interface
component 28 (e.g., a connector). For instance, the terminal ends
of the tubes 22, 26 on the patient-side can be configured or molded
as a single dual lumen tube. Interface component 28 can be
implanted into the inner ear (e.g., via a cochleostomy), allowing
perilymph to circulate through tubes 22 and 26, channels 20 and 24,
and pump 16. Interface component 28 can also be secured to the
scala tympani with an adhesive or a graft. While tubes 22, 26 are
described as "inlet" and "outlet" tubes in the example embodiment,
those of skill in the art will understand that such terminology is
for reference only, and that each tube can act as an inlet or an
outlet depending on the direction of circulation of fluid through
delivery system 10. Tubes 22, 26 can be manufactured from any
desired metal, metallic alloy, or polymeric material (e.g., PEEK).
One or more sheaths (not shown) can be used to cover each of tubes
22, 26, for example, to prevent kinking of tubes 22, 26 or
accommodate potential displacement of delivery system 10 within the
mastoid bone. One sheath can cover both tubes 22, 26 or separate
sheaths can cover each tube 22, 26 alone.
[0025] A sensor (not shown) can also be included along inlet tube
22 or first channel 52 and used to analyze the fluid sampled by the
system 10. Alternatively (or additionally), the sensor (or the
fluid being delivered by system 10).
[0026] In an example embodiment, one or more reservoirs 30 are
formed in substrate 12 for containing a substance, e.g., a
medicament, a diagnostic agent, etc. Reservoir 30 can be in fluid
communication with first channel 20 and/or second channel 24 such
that the fluid circulating through delivery system 10 contacts the
medicament contained in reservoir 30. Reservoir 30 can be in fluid
communication with first channel 20 and/or second channel 24 such
that fluid does not circulate through delivery system 10 yet
contacts the medicament contained in reservoir 30. A plurality of
reservoirs 30 can be in disposed in substrate 12. In such
embodiments, reservoirs 30 can be disposed in series or parallel
along a channel. Examples of such arrangements are described in the
incorporated U.S. Patent Application Publication 2011/0125136.
[0027] FIG. 4A is a top down view of another example embodiment of
delivery system 10 where multiple reservoirs 30 are present. FIG.
4B is a cross-sectional view taken along line 4B-4B of FIG. 4A.
Here, four reservoirs are present and immediately adjacent channel
24. Medicament 40 in the form of a solid pill-like element is
present within each reservoir 30, where one type of medicament 40-1
is in two reservoirs and another type of medicament 40-2 is in the
other two reservoirs. It should be noted that system 10 can be an
integrated (or monolithic) device, or can be modular with, for
instance, pump 16 in one module and reservoir 30 in a separate
connectable module. Such a configuration would allow for easy
replacement of the medicament.
[0028] Reservoirs 30 can also be piggy-backed on each other, such
that pumped fluid will contact a substance in a first reservoir,
and that reservoir will empty (or the substance will be exhausted)
before fluid contacts the same or a different substance in a second
reservoir. In another embodiment, the terminal ends of the tubes
22, 26 are coupled to two separate interface components, for
example, to allow outlet tube 26 to be located in the tissue of
interest and to allow inlet tube 22 to be coupled to a liquid
reservoir containing, e.g., a liquid formulated drug or a carrier
fluid for a drug in solid form located in reservoir 30.
[0029] The medicament contained in any reservoir 30 can be a solid
formulation (e.g., a monolithic pill, particulates, etc.), a gel
formulation (with or without a suspension), a liquid formulation, a
slurry formulation, and the like. Example medicaments which can be
included in the delivery system 10 are nomifensine and
dexmethasone. However, those of skill in the art will understand
that other medicaments can be utilized depending on the therapeutic
purpose of the delivery system 10. A more comprehensive (but
non-exhaustive) list is provided in the "Substances and
Applications" section.
[0030] The medicament is preferably formulated to prevent portions
of the medicament from breaking off and occluding any portion of
system 10, particularly channels 20, 24 and/or tubes 22, 26. For
example, the medicament can be disposed in a polymeric matrix which
maintains structural integrity while in contact with the fluid
circulating through delivery system 10. A physical safeguard can
also be used to prevent partial or complete occlusion. For
instance, the medicament can be disposed in a semi-permeable
membraneous coating, which can allow for diffusion of the fluid and
the dissolved medicament, but prevent large particles of medicament
from passing through. Alternatively (or additionally), a molecular
sieve can be used as a filter that allows diffusion of the fluid
and the dissolved medicament, but prevents large particles of
medicament from passing through.
[0031] The main body of system having substrate 12 is preferably
small enough to be implanted without difficulty. In one example,
which is provided for illustrative purposes only and is not
intended to be limiting, the dimensions of the main body of system
10 (without the perfusion tubing) is 5 mm by 20 mm by 20 mm,
although both smaller and larger sizes are possible. The perfusion
tubes each preferably have a diameter of less than 1 mm, although
larger sizes can be used. When used to treat diseases of the inner
ear, e.g., tinnitus, the preferred depth of implantation into the
scala tympani is less than 0.5 mm.
[0032] FIGS. 2A-F depict an example embodiment of a manufacturing
process for a delivery system 10. This embodiment generally relates
to a two layer system, although one of ordinary skill in the art
will readily recognize that three or more layers can be used,
depending on the complexity of the system, the number of pumps,
reservoirs, sampling wells, channels, etc.
[0033] In FIGS. 2A-B, a first layer 32 and a second layer 36 of
substrate 12 are provided. Layers 32 and 36 can be formed or molded
with the appropriate elements therein. This can be done by first
creating a mold with the positive impressions of the elements
thereon, such as through micromachining (e.g., soft lithography) or
photolithography. Layers 32 and 34 will then be formed with
negative impressions of those elements therein. For layer 32, this
includes a chamber for magnet 18, reservoir 30, and a vertical
channel 34, while for layer 36, this includes the pump chamber 14
(present in this stage as an elongate recess), and first and second
elongate channels 20, 24 (not shown). The formation of layers 32,
36 can also be done by micromachining or photolithography to etch
or carve the elements directly into layers 32, 36.
[0034] Magnet 18 is coupled to (or seated in) layer 32 after
formation the magnet chamber. Afterwards, the magnet chamber can be
filled with silicon. Beneath magnet 18 is a thin wall or membrane
that can be displaced to generate the pumping forces. As shown in
FIG. 2A, a vertical channel 34 is present to create a fluid path
to/from reservoir 30. FIG. 2C depicts a reservoir plug 38.
[0035] FIG. 2D depicts a medicament 40 disposed in reservoir 30. In
this example embodiment, medicament 40 is a solid pellet which sits
in reservoir 30 and abuts an open end of vertical channel 34. FIG.
2E shows reservoir plug 38 coupled to first layer 32 to seal
medicament 40 in reservoir 30. Plug 38 can be bonded to first layer
32 by plasma treatment, curing of first layer 32, or through the
use of an adhesive. In another example embodiment, plug 38 can be
molded into first layer 32. In yet another example embodiment, plug
38 can be a resealable septum which covers reservoir 30 but allows
for re-filling, e.g., by a needle injecting a medicament into
reservoir 30.
[0036] FIG. 2F shows first layer 32 coupled to the second layer 36.
First layer 32 forms a cover or roof to second layer 36, enclosing
the elongate recess to form pump chamber 14 with the thin pump
chamber wall present in layer 32. The elongate channels are also
covered to fully enclose them (with the exception of the open ends
through which fluid flows). In an example embodiment, layers 32, 36
are bonded by 02 plasma treatment and a subsequent bond curing
period in an oven at 80.degree. C. In another example embodiment,
layers 32, 36 can be bonded through thermal treatments at
80.degree. C. by adjusting a ratio of a curing agent in a mixture
used to fabricate layers 32, 36. In yet another example embodiment,
layers 32, 36 are sealed using UV ozone treatment or any other
treatment which hydrophilizes the surface of silicone. In yet
another example embodiment, layers 32, 36 are bonded using an
adhesive, e.g., uncured PDMS. In still another example embodiment,
system 10 is hermetically sealed to prevent the intrusion of bodily
fluids.
[0037] An overmolding process is preferably used to secure the
inlet and outlet tubes 22, 26 with respect to channels 20, 24.
FIGS. 2G-H depict an example method used in the securement of tubes
22, 26 with respect to substrate 12 for a similar but alternate
layout to system 10. In this layout, reservoir 30 is located
laterally offset from channel 24 and is coupled to channel 24 by
way of two feeder channels 55 and 56, each having a cross-sectional
dimension less than channel 24. This layout can allow for less
concentrated doses.
[0038] Preferably, after first layer 32 is coupled to second layer
36, tubes 22, 26 are press-fit into openings 60, 61 for channels
20, 24, respectively. FIG. 2G shows the press-fitting insertion of
tube 22 into opening 60 and along a length of channel 20. An
adhesive can be used to further secure the coupling of tubes 22, 24
to substrate 12 after press-fitting.
[0039] After both tubes are inserted, an overmolding process can
then be used to encapsulate and fully secure tubes 22, 26 to
substrate 12. Uncured silicone is poured into a mold holding tubes
22, 26 in the substrate 12 and also holding layers 32, 36 together.
A priming solution can be used to increase bond strength between
tubes 22, 26 and substrate 12. This assembly can then be baked in
an oven (e.g., at 80.degree. C.) and cured. The overmolding process
adds an overmolded portion 58 to the length of substrate 12 and
surrounds (or encapsulates) and stabilizes tubes 22, 26 and layers
32, 36. The overmolding process can be followed by application of
an adhesive to tubes 22, 26 to further secure them to substrate 12.
In another example embodiment, tubes 22, 26 are molded into first
layer 32 or second layer 36, or one tube is molded into first layer
32 and the other tube is molded into second layer 36.
[0040] FIGS. 3A-E show an example embodiment of medicament delivery
by delivery system 10. In FIG. 3A, fluid (e.g., perilymph)
circulating through delivery system 10 contacts medicament 40. For
example, as the fluid enters delivery system 10, the fluid can push
up through vertical channel 34 and contact medicament 40, which
allows medicament 40 to dissolve or disperse into the fluid. As
shown in FIG. 3B, prolonged contact between the fluid and
medicament 40, such as when pump 16 is inactive, can allow more of
medicament 40 to dissolve into the fluid. Delivery system 10 can
include valves to restrict flow during periods of pump inactivity.
Multiple valves can be used. One or more valves can be placed
before or after the pump along channel 20 and/or 24. One or more
valves can also be placed between reservoir 30 and channels 20 or
24 (e.g., valves in one or more of feeder channel 55, feeder
channel 56, and vertical channel 34). The valves can be
off-the-shelf or custom built. The valves can be micro-machined, or
fabricated in MEMS, multi-leaflet (e.g., bi-leaflet), check, or
pincher-type, to name a few.
[0041] FIG. 3C shows a displacement of the dissolved medicament 40
when pump 16 is activated, e.g., by passing an external actuator
(magnet) over magnet 18. When this occurs, magnet 18 on pump 16
moves the wall on which it is mounted and compresses the pump
chamber to push fluid through delivery system 10. Vibrational waves
travel along pump 16 and bounce off an interface between pump 16
and channels 20, 24, due to the rapid change in surface area
between the cross-sectional area of pump chamber 14 and the
cross-sectional area of channels 20, 24. Changing location of
magnet 18 on axis L of pump 16 and/or changing the frequency of
oscillations of pump 16 can increase/decrease, or even reverse
direction of, fluid flow. FIG. 3D shows that while pump 16 is
activated, the fluid can be pushed past vertical channel 34 and
less fluid can contact medicament 40. Thus, when pump 16 is
inactive, a "dose" of medicament 40 can be allowed to dissolve into
the fluid, as shown in FIG. 3E.
[0042] In one example method of delivery, the fluid channels are
allowed to fill with the drug and, while the pump remains inactive,
the drug spreads diffusely as depicted in FIGS. 3A-B. This can be
referred to as mode one. Once the effective dose has been reached,
determined either by time or the presence of a sensor, pump 16 is
activated and the drug is washed out with the fluid transitioning
through the channels, as depicted in FIGS. 3C-D. This can be
referred to as mode two. After this the pump is turned off again
(or made inactive) as shown in FIG. 3E. The combination of modes
one and two result in the delivery of the effective dose.
[0043] Substances and Applications
[0044] The substances that can be used with delivery system 10, as
well as the applications in which system 10 can be used, are very
broad. As described in US Patent Application Publication
2009/0209945, there are numerous circumstances in which it can be
desirable to deliver drugs or other agents in a tissue-specific
manner, on an intermittent or continuous basis and using
implantable drug delivery systems such as those described herein,
to treat a particular condition. Disorders of the middle and inner
ear can be treatable using the systems and methods described
herein. Examples of middle and inner ear disorders include (but are
not limited to) autoimmune inner ear disorder (AIED), Meniere's
disease (idiopathic endolymphic hydrops), inner ear disorder
associated with metabolic imbalances, inner ear disorder associated
with infections, inner ear disorder associated with allergic or
neurogenic factors, blast injury, noise-induced hearing loss,
drug-induced hearing loss, tinnitus, presbycusis, barotrauma,
otitis media (acute, chronic or serious), infectious mastoiditis,
infectious myringitis, sensorineural hearing loss, conductive
hearing loss, vestibular neuronitis, labyrinthitis, post-traumatic
vertigo, perilymph fistula, cervical vertigo, ototoxicity, Mal de
Debarquement Syndrome (MDDS), acoustic neuroma, migraine associated
vertigo (MAV), benign paroxysmal positional vertigo (BPPV),
eustachian tube dysfunction, cancers of the middle or inner ear,
and infections (bacterial, viral or fungal) of the middle or inner
ear. Degenerative ocular disorders can also be treatable using the
systems and methods described herein. Examples of such degenerative
ocular disorders include (but are not limited to) dry macular
degeneration, glaucoma, macular edema secondary to vascular
disorders, retinitis pigmentosa and wet macular degeneration.
Similarly, inflammatory ocular diseases (including but not limited
to birdshot retinopathy, diabetic retinopathy, Harada's and
Vogt-Koyanagi-Harada syndrome, iritis, multifocal choroiditis and
panuveitis, pars planitis, posterior scleritis, sarcoidosis,
retinitis due to systemic lupus erythematosus, sympathetic
ophthalmia, subretinal fibrosis, uveitis syndrome and white dot
syndrome), ocular disorders associated with neovascularization
(including but not limited to age-related macular degeneration,
angioid streaks, choroiditis, diabetes-related iris
neovascularization, diabetic retinopathy, idiopathic choroidal
neovascularization, pathologic myopia, retinal detachment, retinal
tumors, and sickle cell retinopathy), and ocular infections
associated with the choroids, retina or cornea (including but not
limited to cytomegalovirus retinitis, histoplasma
retinochoroiditis, toxoplasma retinochoroiditis and tuberculous
choroiditis) and ocular neoplastic diseases (including but not
limited to abnormal tissue growth (in the retina, choroid, uvea,
vitreous or cornea), choroidal melanoma, intraocular lymphoma (of
the choroids, vitreous or retina), retinoblastoma, and vitreous
seeding from retinoblastoma) can be treatable using the devices and
methods described herein.
[0045] Further examples of conditions that can be treatable using
the devices and methods described herein include, but are not
limited to, the following: ocular, inner ear or other neural
trauma; disorders of the auditory cortex; disorders of the inferior
colliculus (by surface treatment or injection); neurological
disorders of the brain on top of or below the dura; chronic pain;
hyperactivity of the nervous system; migraines; Parkinson's
disease; Alzheimer's disease; seizures; hearing related disorders
in addition to those specified elsewhere herein; nervous disorders
in addition to those specified elsewhere herein; ophthalmic
disorders in addition to those specified elsewhere herein; ear,
eye, brain disorders in addition to those specified elsewhere
herein; cancers in addition to those specified elsewhere herein;
bacterial, viral or fungal infections in addition to those
specified elsewhere herein; endocrine, metabolic, or immune
disorders in addition to those specified elsewhere herein;
degenerative or inflammatory diseases in addition to those
specified elsewhere herein; neoplastic diseases in addition to
those specified elsewhere herein; conditions of the auditory,
optic, or other sensory nerves; sensory disorders in additions to
those specified elsewhere herein; conditions treatable by delivery
of drug to the vicinity of the pituitary, adrenal, thymus, ovary,
testis, or other gland; conditions treatable by delivery of drug to
the vicinity of the heart, pancreas, liver, spleen or other organs;
and conditions treatable by delivery of drug to specific regions of
the brain or spinal cord.
[0046] The preceding identification of conditions is not intend to
be exhaustive. Drug delivery systems and devices according to the
embodiments described herein can be used to deliver one or more
drugs to a particular target site so as to treat one or more of the
conditions described above, as well as to treat other conditions.
Drugs that can be delivered using the embodiments described herein
include, but are not limited to, the following: antibiotics
(including but are not limited to an aminoglycoside, an ansamycin,
a carbacephem, a carbapenum, a cephalosporin, a macrolide, a
monobactam, and a penicillin); anti-viral drugs (including but not
limited to an antisense inhibitor, fomiversen, lamivudine,
pleconaril, amantadine, and rimantadine); anti-inflammatory factors
and agents (including but not limited to glucocorticoids,
mineralocorticoids from adrenal cortical cells, dexamethasone,
triamcinolone acetonide, hydrocortisone, sodium phosphate,
methylprednisolone acetate, indomethacin, and naprosyn);
neurologically active drugs (including but not limited to ketamine,
caroverine, gacyclidine, memantine, lidocaine, traxoprodil, an NMDA
receptor antagonist, a calcium channel blocker, a GABA.sub.A
agonist, an 2.delta. agonist, a cholinergic, and an
anticholinergic); anti-cancer drugs (including but not limited to
abarelix, aldesleukin, alemtuzamab, alitretinoin, allopurinol,
altretamine, amifostine, anastrolzole, anti-hormones such as
Arimidex, azacitidine, bevacuzimab, bleomycin, bortezomib,
busulfan, capecitabine, carboplatin, carmustine, chlorambucil,
cisplatin, cyclophosphamide, cyclosporine, darbepoetin,
daunorubicin, docetaxel, doxorubicine, epirubicin, epoetin,
etoposide, fluorouracil, gemicitabine, hydroxyurea, idarubicin,
imatinib, interferon, letrozole, methotrexate, mitomycin C,
oxaliplatin, paclitaxel, tamoxifen, taxol and taxol analogs,
topothecan, vinblastine and related analogs, vincristine, and
zoledronate); fungicides (including but not limited to azaconazole,
a benzimidazole, captafol, diclobutrazol, etaconazole, kasugamycin,
and metiram); anti-migraine medication (including but not limited
to IMITREX); autonomic drugs (including but not limited to
adrenergic agents, adrenergic blocking agents, anticholinergic
agents, and skeletal muscle relaxants); anti-secretory molecules
(including but not limited to proton pump inhibitors (e.g.,
pantoprazole, lansoprazole and rabprazole) and muscarinic
antagonists (e.g., atropine and scopalomine)); central nervous
system agents (including but not limited to analgesics,
anti-convulsants, and antipyretics); hormones and synthetic
hormones in addition to those described elsewhere herein;
immunomodulating agents (including but not limited to etanercept,
cyclosporine, FK506 and other immunosuppressant); neurotrophic
factors and agents (factors and agents retarding cell degeneration,
promoting cell sparing, or promoting new cell growth); angiogenesis
inhibitors and factors (including but not limited to COX-2
selective inhibitors (e.g., CELEBREX), fumagillin (including
analogs such as AGM-1470), and small molecules anti-angiogenic
agents (e.g., thalidomide)); neuroprotective agents (agents capable
of retarding, reducing or minimizing the death of neuronal cells)
(including but not limited to N-methyl-D-aspartate (NMDA)
antagonists, gacyclidine (GK11), and D-JNK-kinase inhibitors); and
carbonic anhydrase inhibitors (including but not limited to
acetazolamide (e.g., DIAMOX), methazolamide (e.g., NEPTAZANE),
dorzolamide (e.g., TRUSOPT), and brinzolamide (e.g., AZOPT)).
[0047] In at least some embodiments, an implanted drug delivery
system such as is described herein is used to deliver a drug
(including but not limited to one or more of the drugs listed
above) as a pure drug nanoparticle and/or microparticle suspension,
as a suspension of nanoparticles and/or microparticles formed from
drug formulated with binders and other ingredients to control
release, or as some other type of nanoparticle- and/or
microparticle-bound formulation. Nanoparticle- and/or
microparticle-based delivery is advantageous in closed loop
embodiments by allowing drug-containing particles to circulate
within the closed loop as a solid suspended in the vehicle while
delivering the desired therapeutic dose to the target tissue
through the semi-permeable membrane or hollow fiber. Nanoparticle-
and/or microparticle-bound delivery also offers the advantage of
maintaining drug stability and avoiding loss of drug to polymeric
components that can be encountered in a fluid pathway.
[0048] Many diseases and disorders are associated with one or more
of angiogenesis, inflammation and degeneration. To treat these and
other disorders, the embodiments disclosed herein can permit
delivery of anti-angiogenic factors; anti-inflammatory factors;
factors that retard cell degeneration, promote cell sparing, or
promote cell growth; and combinations of the foregoing.
[0049] Diabetic retinopathy is characterized by angiogenesis. At
least some embodiments contemplate treating diabetic retinopathy by
implanting devices delivering one or more anti-angiogenic factors
either intraocularly, preferably in the vitreous, or periocularly,
preferably in the sub-Tenon's region. It can also be desirable to
co-deliver one or more neurotrophic factors either intraocularly,
periocularly, and/or intravitreally.
[0050] Uveitis involves inflammation. At least some embodiments
contemplate treating uveitis by intraocular, vitreal or anterior
chamber implantation of devices releasing one or more
anti-inflammatory factors. Anti-inflammatory factors contemplated
for use in at least some embodiments include, but are not limited
to, glucocorticoids and mineralocorticoids (from adrenal cortical
cells).
[0051] Retinitis pigmentosa is characterized by retinal
degeneration. At least some embodiments contemplate treating
retinitis pigmentosa by intraocular or vitreal placement of devices
secreting one or more neurotrophic factors.
[0052] Age-related macular degeneration (wet and dry) involves both
angiogenesis and retinal degeneration. Embodiments described herein
can be used to deliver one or more neurotrophic factors
intraocularly, preferably to the vitreous, and/or one or more
anti-angiogenic factors intraocularly or periocularly, preferably
periocularly, most preferably to the sub-Tenon's region.
[0053] Glaucoma is characterized by increased ocular pressure and
loss of retinal ganglion cells. Treatments for glaucoma
contemplated in at least some embodiments include delivery of one
or more neuroprotective agents that protect cells from excitotoxic
damage. Such agents include, but are not limited to,
N-methyl-D-aspartate (NMDA) antagonists and neurotrophic factors.
These agents can be delivered intraocularly, preferably
intravitreally. Gacyclidine (GK11) is an NMDA antagonist and is
believed to be useful in treating glaucoma and other diseases where
neuroprotection would be helpful or where there are hyperactive
neurons. Additional compounds with useful activity are D-JNK-kinase
inhibitors.
[0054] Neuroprotective agents can be useful in the treatment of
various disorders associated with neuronal cell death (e.g.,
following sound trauma, cochlear implant surgery, diabetic
retinopathy, glaucoma, etc.). Examples of neuroprotective agents
that can be used in at least some embodiments include, but are not
limited to, apoptosis inhibitors, caspase inhibitors, neurotrophic
factors and NMDA antagonists (such as gacyclidine and related
analogs).
[0055] At least some embodiments can be useful for the treatment of
ocular neovascularization, a condition associated with many ocular
diseases and disorders and accounting for a majority of severe
visual loss. For example, contemplated is treatment of retinal
ischemia-associated ocular neovascularization, a major cause of
blindness in diabetes and many other diseases; corneal
neovascularization; and neovascularization associated with diabetic
retinopathy, and possibly age-related macular degeneration.
[0056] One or more of the embodiments described herein can be used
to deliver an anti-infective agent, such as an antibiotic,
anti-viral agent or anti-fungal agent, for the treatment of an
ocular infection. They can also be used to deliver a steroid, for
example, hydrocortisone, dexamethasone sodium phosphate or
methylprednisolone acetate, for the treatment of an inflammatory
disease of the eye. One or more of the embodiments described herein
can be used to deliver a chemotherapeutic or cytotoxic agent, for
example, methotrexate, chlorambucil, or cyclosporine, for the
treatment of a neoplasm. They can also be used to deliver an
anti-inflammatory drug and/or a carbonic anhydrase inhibitor for
the treatment of certain degenerative ocular disorders.
[0057] Chronic infections located in a specific tissue and
suppressible by long-term local treatment without developing
resistance (e.g., viral infections) can be treated using one or
more of the embodiments described herein.
[0058] The above list of treating drug and treated condition
examples are merely illustrative and do not exclude uses of one or
more other drugs in the previous list of example drugs to treat a
condition in the previous list of example conditions.
[0059] The devices and systems described herein can be configured
for use in veterinary, diagnostic, laboratory, clinical research
and development ("clinical R&D") or other types of
environments, as well as use of such devices and/or systems in such
environments.
[0060] While the specification describes particular embodiments of
the systems, devices, and methods described herein, those of
ordinary skill can devise variations to this subject matter without
departing from the spirit and scope of the present disclosure.
Thus, the claims are not intended to be limited to the embodiments
shown, but are to be accorded the full scope consistent with the
language of the claims, where reference to an element in the
singular is not intended to mean "one and only one" unless
specifically so stated, but rather "one or more." All structural
and functional equivalents to the elements of the various
embodiments described throughout this disclosure that are known or
later come to be known to those or ordinary skill in the art are
expressly incorporated herein by reference and are intended to be
encompassed by the claims. Moreover, nothing disclosed herein is
intended to be dedication to the public regardless of whether such
disclosure is explicitly recited in the claims. No claim elements
are to be construed under the provisions of 35 U.S.C. .sctn.112,
sixth paragraph, unless the element is expressly recited using the
phrase "means for" or, in the case of a method claim, the element
is recited using the phrase "step for."
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