U.S. patent application number 10/116713 was filed with the patent office on 2002-12-19 for regulation of drug delivery through flow diversion.
Invention is credited to Brown, James E., Nelson, Timothy Scott, Theeuwes, Felix.
Application Number | 20020193751 10/116713 |
Document ID | / |
Family ID | 23649732 |
Filed Date | 2002-12-19 |
United States Patent
Application |
20020193751 |
Kind Code |
A1 |
Theeuwes, Felix ; et
al. |
December 19, 2002 |
Regulation of drug delivery through flow diversion
Abstract
The present invention features methods and devices for
modulating the rate of delivery of a drug formulation from a drug
delivery device by diverting drug away from a drug delivery
pathway. In one embodiment, a flow regulator is positioned relative
to a drug delivery pathway of a drug delivery system so that
adjustment of the flow regulator can provide for diversion of drug
away from the drug delivery pathway. Diverted drug can be either
delivered into the systemic circulation of the subject, or can be
captured in a waste reservoir.
Inventors: |
Theeuwes, Felix; (Los Altos
Hills, CA) ; Brown, James E.; (Los Gatos, CA)
; Nelson, Timothy Scott; (Los Gatos, CA) |
Correspondence
Address: |
BOZICEVIC, FIELD & FRANCIS LLP
200 MIDDLEFIELD RD
SUITE 200
MENLO PARK
CA
94025
US
|
Family ID: |
23649732 |
Appl. No.: |
10/116713 |
Filed: |
April 2, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10116713 |
Apr 2, 2002 |
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PCT/US00/28440 |
Oct 12, 2000 |
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10116713 |
Apr 2, 2002 |
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09416379 |
Oct 12, 1999 |
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Current U.S.
Class: |
604/248 ;
604/284; 604/500 |
Current CPC
Class: |
A61M 39/28 20130101;
A61M 5/14276 20130101; A61M 5/16813 20130101; A61M 2205/3523
20130101; A61M 5/16804 20130101; A61M 39/22 20130101 |
Class at
Publication: |
604/248 ;
604/284; 604/500 |
International
Class: |
A61M 005/00 |
Claims
What is claimed is:
1. A method for delivering a desired amount of a drug to a
treatment site of a subject, the method comprising: causing a
quantity of drug to exit from a drug reservoir of a drug delivery
device in a direction toward a treatment site; and diverting a
portion of the quantity of drug exiting the drug delivery device
away from the treatment site such that said diverted portion does
not reach the treatment site; wherein said diverting results in
delivery of a desired amount of drug to the treatment site.
2. The method of claim 1, wherein the treatment site is a
biologically confined treatment site and the diverted drug is
diverted into a systemic site within the subject.
3. The method of claim 1, wherein the diverted drug is collected
into a waste reservoir.
4. The method of claim 1, wherein the desired amount of drug is
delivered to the treatment site by varying the amount of drug
delivered to the treatment site relative to the amount of drug
diverted from the drug delivery device.
5. The method of claim 1, wherein said diverting is by intermittent
disruption of flow of drug exiting the drug delivery device.
6. A flow regulator (10) for regulating the flow of a drug from a
drug delivery device (110) to a treatment site in the body of a
subject, the flow regulator comprising: a proximal delivery inlet
(21), wherein the proximal delivery inlet is proximal to and
communicably attached to the drug delivery device; a distal
delivery outlet (22), wherein the distal delivery outlet is distal
to the drug delivery device; a delivery conduit (20) extending
between the proximal delivery inlet and the distal delivery outlet,
the delivery lumen defining a delivery pathway (60); and a
diversion element (40) positioned so as to facilitate diversion of
flow of the drug in a direction away from the distal delivery
outlet.
7. The flow regulator of claim 6, wherein the diversion element
(40) is manually adjustable.
8. The flow regulator of claim 6, wherein the diversion element
(40) is remotely adjustable.
9. The flow regulator of claim 8, wherein the diversion element
(40) is adjustable by use of a remote actuation device.
10. The flow regulator of claim 6, wherein the diversion element
(40) is a valve.
11. The flow regulator of claim 10, wherein the valve is a
compression valve for compressing against a deformable wall of the
delivery conduit (20) at a site distal to a proximal drug exit
outlet (25).
12. The flow regulator of claim 10, wherein the valve is a
rotatable valve (42).
13. The flow regulator of claim 10, wherein the valve is a solenoid
(47).
14. The flow regulator of claim 6, wherein the flow regulator
further comprises: a diversion conduit (30) comprising a diversion
inlet (31), a diversion outlet (32), and a diversion lumen
extending between the diversion inlet and diversion outlet, the
diversion conduit lumen defining a diversion pathway (70); wherein
drug diverted by the diversion element (40) flows into the
diversion pathway defined by the diversion conduit.
15. The flow regulator of claim 14, wherein the delivery conduit
(20) and the diversion conduit (30) intersect in a substantially
T-shaped configuration.
16. The flow regulator of claim 14, wherein the delivery conduit
(20) and the diversion conduit (30) intersect in a substantially
Y-shaped configuration.
17. The flow regulator of claim 14, wherein the delivery conduit
(20) and the diversion conduit (30) intersect in a substantially
U-shaped configuration.
18. The flow regulator of claim 14, wherein the diversion conduit
(20) is in fluid communication with a waste reservoir (90) for
receiving drug from the diversion outlet (32).
19. The flow regulator of claim 18, wherein the waste reservoir
comprises (90) a self-sealing septum.
20. The flow regulator of claim 6, wherein the delivery conduit
(20) comprises an attachment element (130) for attaching a drug
delivery (110) device for delivery of drug into the proximal
delivery inlet (21).
21. The flow regulator of claim 6, wherein the delivery conduit
(20) comprises a valve at a delivery conduit distal end.
22. The flow regulator of claim 6, wherein the flow regulator (10)
is contained within a housing element (45).
23. The flow regulator of claim 14, wherein the housing element
(45) comprises a biocompatible, implantable material.
24. The flow regulator of claim 6, wherein the flow regulator (10)
is attached to a drug delivery catheter (120) at a delivery conduit
distal end to provide for flow of drug from the delivery pathway
(60), out the distal delivery outlet (22), and into a lumen of the
drug delivery catheter.
25. The flow regulator of claim 9, wherein the remote actuation
device comprises power source for actuation of the diversion
element.
26. The flow regulator of claim 9, wherein the flow regulator is
programmable by the remote actuation device.
27. A drug delivery system (100) comprising; the flow regulator
(10) of claim 6; and a drug delivery device (110); wherein the drug
delivery device is attached to the flow regulator to facilitate
delivery of a drug from the drug delivery device, through the
delivery conduit (20) lumen, and out the distal delivery outlet
(22).
28. The drug delivery system of claim 27, wherein the flow
regulator is detachably attached to the drug delivery device
(110).
29. The drug delivery system of claim 27, wherein the drug delivery
device (110) is a convective drug delivery device.
30. The drug delivery system of claim 27, wherein the drug delivery
device (110) is a diffusive drug delivery device.
31. The drug delivery system of claim 27, wherein the flow
regulator further (110) comprises: a diversion conduit (30)
comprising a diversion inlet (31), a diversion outlet (32), and a
diversion lumen extending between the diversion inlet and diversion
outlet, the diversion conduit lumen defining a diversion pathway
(70); wherein drug diverted by the diversion element (40) flows
into the diversion pathway defined by the diversion conduit.
32. The drug delivery system of claim 27, wherein the drug delivery
device (110) is implantable.
33. The drug delivery system of claim 27, wherein the system
further comprises a remote actuation device for actuation of the
diversion element (40).
34. A drug delivery catheter (120) comprising a catheter body
defining a proximal opening, a distal opening, and a catheter lumen
extending between the proximal and distal openings, the catheter
further comprising a flow regulator (10) according to claim 6,
wherein the catheter lumen and the flow regulator delivery lumen
are in fluid communication.
35. The drug delivery catheter of claim 34, wherein the flow
regulator delivery conduit (20) is continuous and integral to the
catheter body.
36. The drug delivery catheter of claim 34, wherein the flow
regulator (10) is positioned at a proximal portion of the
catheter.
37. A method of administering drug to a treatment site in a
subject, the method comprising: implanting at least the distal end
of the flow regulator delivery conduit of the flow regulator of
claim 1 at a treatment site within a subject; and delivering drug
from a drug delivery device, through the drug delivery pathway of
the flow regulator, and to the treatment site; wherein the drug is
administered to the treatment site in the subject.
38. The method of claim 37, wherein the delivery conduit lumen is
suitable for delivery of the drug at a low volume rate.
39. The method of claim 37, wherein the flow regulator drug
delivery conduit provides for delivery of drug to at least two
treatment sites.
40. The method of claim 37, wherein the treatment site is
subcutaneous, percutaneous, intravenous, intramuscular,
intra-arterial, intravascular, intraperitoneal, intraspinal,
epidural, intrathecal, intracranial, intracardial, peritumoral, or
intratumoral.
41. The method of claim 37, wherein the treatment site is a site
within a kidney, liver, pancreas, heart, lung, eye, ear, lymph
node, breast, prostate, ovary, testicle, thyroid, spleen, central
nervous system, skeletal muscle, bone, lymph vessel, artery,
arteriole, capillary bed, blood vessel, vein, peripheral nervous
system, digestive system, gastrointestinal tract, urinary bladder,
gall bladder, adrenal gland, adipose tissue, parathyroid gland,
uterus, fallopian tube, skin, tumorous growth, autologous graft,
synthetic graft, or site of microbial infection.
42. A method of controlling an amount of drug administered to a
treatment site in a subject, the method comprising: introducing a
drug into the flow regulator proximal delivery inlet of the drug
delivery system of claim 1, said introducing resulting in drug
flowing through the drug delivery pathway and to a treatment site
in a subject at which a distal end of the drug delivery conduit is
implanted; and adjusting the diversion element of the flow
regulator to divert drug from the drug delivery pathway; wherein
said adjusting alters the amount of drug that is delivered to the
treatment site in the subject.
43. The method of claim 42, wherein the drug delivery device is a
constant rate drug delivery device.
44. The method of claim 42, where drug diverted from the drug
delivery pathway is delivered to the subject systemically.
45. The method of claim 42, wherein the flow regulator comprises a
waste reservoir for receiving drug diverted from the delivery
pathway.
46. The method of claim 42, wherein the distal end of the drug
delivery conduit is attached to a drug delivery catheter to provide
for extension of the drug delivery pathway to a catheter delivery
outlet at the catheter distal end, wherein at least the catheter
distal end is implanted at the treatment site.
47. The method of claim 46, wherein the catheter is adapted for
delivery of drug to two treatment sites.
48. The method of claim 42, wherein the treatment site is
subcutaneous, percutaneous, intravenous, intrathecal,
intramuscular, intra-arterial, intravascular, intraperitoneal,
intraspinal, epidural, intracranial, intracardial, peritumoral, or
intratumoral.
49. The method of claim 42, wherein the treatment site is a site
within a kidney, liver, pancreas, heart, lung, eye, ear, lymph
node, breast, prostate, ovary, testicle, thyroid, spleen, central
nervous system, skeletal muscle, bone, lymph vessel, artery,
arteriole, capillary bed, blood vessel, vein, peripheral nervous
system, digestive system, gastrointestinal tract, urinary bladder,
gall bladder, adrenal gland, adipose tissue, parathyroid gland,
uterus, fallopian tube, skin, tumorous growth, autologous graft,
synthetic graft, or site of microbial infection.
50. The method of claim 42, wherein the diversion element is
adjusted for a first time period so as to facilitate flow through
the delivery conduit, and for a second time period so as to
decrease flow through the diversion conduit, wherein varying the
length of the first and second time periods results in alteration
in the amount of drug delivery to the treatment site.
51. The method of claim 42, wherein the flow regulator further
comprises: a diversion conduit comprising a diversion inlet, a
diversion outlet, and a diversion lumen extending between the
diversion inlet and diversion outlet, the diversion conduit lumen
defining a diversion pathway; wherein drug diverted by the
diversion element flows into the diversion pathway defined by the
diversion conduit.
52. The method of claim 51, wherein the diversion element is
adjusted so that the delivery conduit and the diversion conduit are
each partially open.
53. The flow regulator of claim 6, wherein at least the distal
delivery outlet (22) is adapted for implantation at the treatment
site.
54. The flow regulator of claim 53, wherein the diversion element
(40) is adapted for implantation.
55. The flow regulator of claim 6, wherein the diversion element
(40) is provided to divert drug away from the distal delivery
outlet (22) and to a systemic site within the subject.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of PCT application serial
no. PCT/US00/28440, filed Oct. 12, 2000, pending, which application
designates the United States; and a continuation-in-part of U.S.
application Ser. No. 09/416,379, filed Oct. 12, 1999, pending; each
of which applications are incorporated herein by reference in their
entirety.
FIELD OF THE INVENTION
[0002] This invention relates generally to catheters for use in
delivery of drug, particularly in the context of site-specific drug
delivery.
BACKGROUND OF THE INVENTION
[0003] Many diseases or indications require long term, chronic
delivery of drugs or agents to a patient, e.g., cancer, arthritis,
heart disease, etc. Long term delivery of drugs or agents can be
accomplished by use of drug delivery systems comprising drug
delivery devices which may be implanted in a patient's body or
retained externally. Drug delivery systems can also deliver drugs
or agents to a targeted site within the body via catheters attached
to drug delivery devices with the distal end of such catheters
placed at the desired site of delivery in the body, with the
catheter acting a conduit for the drug or desired agent from the
drug delivery device to the desired site of delivery in the body.
Drug delivery devices which have adjustable drug delivery rates are
known in the art (see, e.g., U.S. Pat. No. 4,692,147). However,
such devices with variable or programmable drug delivery rates
often include complex mechanical elements which may make such drug
delivery devices bulky and subject to failure. Constant drug
delivery devices provide for delivery of drug at a pre-selected,
substantially nonfluctuating rate, thus providing for
predictability of the dose delivered. However, constant drug
delivery devices have the limitation that the rate of drug or agent
delivered cannot be readily adjusted, particularly where the drug
delivery device is implanted in the body. The ability to readily
alter the rate at which drug is administered is often desirable in
that it provides flexibility in a therapeutic regimen, and in
certain cases, may be a requirement in certain therapies. For
example, the drug requirements of a patient may not be
ascertainable prior to the commencement of a therapy (e.g., dose
titration may be required to determine appropriate dosage), or a
patient may require increasing doses (e.g., due to development of
tolerance) or decreasing doses (e.g., as the patient gets well). In
a constant drug delivery device, adjusting the rate of drug
delivery can require the removal of the device from the body of a
patient and/or detachment from a drug delivery system (e.g.,
detachment from a catheter) and adjustment or even replacement of
the device.
[0004] There is thus a need in the field for a mechanism which
allows for adjustment of the rate of a drug delivery device yet
obviates the need for complex or bulky regulatory elements
associated with the drug delivery device. The present invention
addresses this problem.
SUMMARY OF THE INVENTION
[0005] The present invention features methods and devices for
modulating the rate of delivery of a drug formulation from a drug
delivery device by diverting drug away from a drug delivery
pathway. In one embodiment, a flow regulator is positioned relative
to a drug delivery pathway of a drug delivery system so that
adjustment of the flow regulator can provide for diversion of drug
away from the drug delivery pathway. Diverted drug can be either
delivered into the systemic circulation of the subject, or can be
captured in a waste reservoir.
[0006] In one aspect the invention features a flow regulator
comprising a delivery conduit defining a proximal delivery inlet, a
distal delivery outlet, and a delivery lumen extending between the
proximal delivery inlet and the distal delivery outlet, the
delivery conduit lumen defining a delivery pathway; and a diversion
element positioned at the diversion inlet so as to facilitate
diversion of flow of drug away from the delivery pathway.
[0007] In another embodiment, the flow regulator further comprises
a diversion conduit defining a diversion inlet, a diversion outlet,
and a diversion lumen extending between the diversion inlet and
diversion outlet, the diversion conduit lumen defining a diversion
pathway, wherein the diversion inlet is in fluid communication with
the delivery conduit lumen. In this latter embodiment, drug is
diverted from the delivery pathway and into the diversion pathway
defined by the diversion conduit.
[0008] In another embodiment, the diversion element of the flow
diverter is actuated manually or remotely when desired by either
patient or the clinician so as to regulate the flow of drug in the
delivery conduit and, where provided, through the diversion
conduit. Remote actuation devices can comprise programming devices
(which can be external to the body) to adjust programming circuitry
associated with the implanted diversion element or can comprise
power sources (which can be external to the body) which can provide
signals to actuate the diversion element.
[0009] In another aspect the invention features a drug delivery
system comprising a flow regulator and a drug delivery device, and
optionally a drug delivery catheter.
[0010] In another aspect the invention features methods for
administering drug to a subject and for controlling an amount of
drug administered to a subject using the flow regulator of the
invention.
[0011] A primary object of the invention is to provide a device and
method for adjustment of the rate at which drug is delivered from a
drug delivery device.
[0012] Another advantage of the invention is that the control of
drug delivery from a drug delivery device to a treatment site is
accomplished without the need for adjustment of any element the
drug delivery device per se, e.g., without adjusting the volume
rate of delivery generated by a drug delivery device. This is
particularly advantageous where there may be particular
difficulties or inconveniences in adjusting the amount of drug
delivered from the drug delivery device.
[0013] Another important advantage of the invention is that the
devices of the invention can be used in a manner that avoids the
need to perform invasive procedures to adjust the dose delivered
from a drug delivery device. For example, the flow regulator can be
provided such that the diversion element of the flow regulator
remains accessible outside the subject's body. Alternatively, the
diversion element can be remotely controllable, thus allowing for
adjustment of the implanted flow regulator from outside the
body.
[0014] The invention is also advantageous for use where
microquantities of drug are to be delivered to a treatment site,
where the treatment site is a relatively confined space, and/or
where the drug delivery is site-specific. In these contexts,
diversion of even a small volume of drug can elicit a
proportionately greater effect upon the total volume of drug
delivered to the treatment site and/or the biological effect at the
treatment site.
[0015] Another advantage of the invention is that where the
invention is used in connection with delivery of drug to a specific
treatment site. The diverted, waste drug can be dumped into the
systemic circulation, where the drug is rapidly metabolized,
inactivated, and/or eliminated and thus has no substantial systemic
effect upon the subject. Only drug delivered to a specific
treatment site has the desired biological effect. This invention is
particularly advantageous where the desired site for drug delivery
is a site which is relatively isolated from systemic clearance
effects (e.g., within the pericardial sac of the heart or the
intrathecal space of the central nervous system), because small
adjustments made to the amount of drugs being delivered to the
desired site can cause significant changes to local concentrations
of the drug at the site thus the therapeutic effect.
[0016] Where the flow regulator is used with a remote adjustment
source, the invention is also advantageous in that provides for
control over the therapy, providing the clinician or the patient
the ability to adjust dosing without the need to remove the
implant. In addition, a remote adjustment source that is external
to the body is more readily accessible for maintenance (e.g.,
replacement of batteries). Where the external remote adjustment
source signals the diversion element periodically (e.g., only for a
length of time necessary to actuate the diversion element), the
power requirements are significantly minimized, thus extending the
time between maintenance periods (e.g., battery changes).
[0017] These and other objects, advantages and features of the
present invention will become apparent to those skilled in the art
upon reading this disclosure in combination with drawings wherein
like numerals refer to like components throughout.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIGS. 1A, 1B, and 1C are schematics outlining the method of
drug delivery control and use of a flow regulator to accomplish
same.
[0019] FIG. 1D is a cut-away view of a solenoid useful as a
diversion element in the flow regulator of the invention.
[0020] FIG. 2 is a cut-away view of a flow regulator 10 comprising
a rotatable valve 42 with the delivery conduit 20 open.
[0021] FIG. 3 is a cut-away view of a flow regulator 10 comprising
a rotatable valve 42 with the diversion conduit 30 open.
[0022] FIG. 4 is a cut-away view of a flow regulator 10 comprising
a rod element 52 positioned so that the delivery conduit 20 is open
and the diversion conduit 30 is closed.
[0023] FIG. 5 is a cut-away view of a flow regulator 10 comprising
a rod element 52 positioned so that the delivery conduit 20 is
closed and the diversion conduit 30 is open.
[0024] FIG. 6 is a cut-away view of a flow regulator 10 comprising
a rod 52 and toggle switch 54 positioned so that delivery conduit
20 is open and diversion conduit 30 is closed.
[0025] FIG. 7 is a cut-away view of a flow regulator 10 comprising
a rod 52 and toggle switch 54 positioned so that delivery conduit
20 is closed and the diversion conduit 30 is open.
[0026] FIG. 8 is schematic illustrating regulation of flow rate of
a delivery pathway 60 by modulation of relative resistance upon
delivery pathway 60 and diversion pathway 70.
[0027] FIG. 9 is a cut-away view of flow regulator 10 comprising an
substantially uninflated cuff 57 positioned over a deformable
distal portion of delivery conduit 20.
[0028] FIG. 10 is a cut-away view of flow regulator 10 comprising
an inflated cuff 57 positioned over a deformable distal portion of
delivery conduit 20 to impede flow through delivery pathway 60 and
increase flow through diversion pathway 70.
[0029] FIGS. 11 and 12 are cut-away views of flow regulator 10
comprising a hydraulic cuff 57 positioned over a deformable distal
portion of delivery conduit 20 and over a deformable portion of
diversion conduit 30.
[0030] FIG. 13 is a cut-away view of flow regulator 10 comprising a
rod 52 positioned for impinging upon deformable surfaces of
delivery conduit 20 and diversion conduit 30, with rod 52 in
position for substantial closing of diversion conduit 30.
[0031] FIG. 14 is a cut-away view of flow regulator 10 comprising a
rod 52 positioned for impinging upon deformable surfaces of
delivery conduit 20 and diversion conduit 30, with rod 52 in
position for substantial closing of delivery conduit 20.
[0032] FIG. 15 is a cut-away view of a flow regulator 10 in a
Y-shaped configuration, with valve 31 positioned for diversion of
approximately 50% of drug into diversion conduit 30.
[0033] FIG. 16 is a cut-away view of a flow regulator 10 in a
Y-shaped configuration, with valve 31 positioned for substantial
closure of diversion conduit 30.
[0034] FIG. 17 is a cut-away view of a flow regulator 10 in a
Y-shaped configuration, with valve 31 positioned for substantial
closure of delivery conduit 20.
[0035] FIG. 18 is a cut-away view of a flow regulator 10 in a
U-shaped configuration, with rod-like valve 57 positioned for
substantially complete closure of diversion conduit 30 and
substantially complete opening of delivery conduit 20.
[0036] FIG. 19 is a cut-away view of a flow regulator 10 in a
U-shaped configuration, with rod-like valve 57 positioned for
substantially complete closure of delivery conduit 20 and complete
opening of diversion conduit 30.
[0037] FIG. 20 is cut-away view of a flow regulator 10 of the
invention comprising a waste reservoir 90.
[0038] FIG. 21 is a cut-away view of a flow regulator 10 of the
invention operably attached to a drug delivery device 110 and to a
waste reservoir 90.
[0039] FIG. 22 is a cut-away view of a delivery system 100 of the
invention comprising a drug delivery device 110 and a flow
regulator 10.
[0040] FIG. 23 is cut-away view of a flow regulator 10 provided as
a single, attachable unit.
[0041] FIG. 24 is a schematic illustrating use of drug delivery
system 100 implanted for use in site-specific drug delivery to a
treatment site 7, with diverted drug delivered to a systemic site
within the subject's body 5.
[0042] FIG. 25 is a cut-away view of a drug delivery system 100
comprising a drug delivery device 110 attached to a catheter 120,
which catheter 120 comprises a flow regulator 10 as an integral
component.
DETAILED DESCRIPTION OF THE INVENTION
[0043] Before the present methods and devices are described, it is
to be understood that this invention is not limited to the
particular embodiments described, as such may, of course, vary. It
is also to be understood that the terminology used herein is for
the purpose of describing particular embodiments only, and is not
intended to limit the scope of the present invention which will be
limited only by the appended claims.
[0044] It must be noted that as used herein and in the appended
claims, the singular forms "a," "an," and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "a formulation" includes mixtures of
different formulations, and reference to "the method of delivery"
includes reference to equivalent steps and methods known to those
skilled in the art, and so forth.
[0045] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limits of that range is also specifically disclosed. Each
smaller range between any stated value or intervening value in a
stated range and any other stated or intervening value in that
stated range is encompassed within the invention. The upper and
lower limits of these smaller ranges may independently be included
or excluded in the range, and each range where either, neither or
both limits are included in the smaller ranges is also encompassed
within the invention, subject to any specifically excluded limit in
the stated range. Where the stated range includes one or both of
the limits, ranges excluding either or both of those included
limits are also included in the invention.
[0046] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, the preferred methods and materials are now described.
All publications mentioned herein are incorporated herein by
reference to disclose and describe the specific methods and/or
materials in connection with which the publications are cited.
[0047] The publications discussed herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the present invention is not entitled to antedate such publication
by virtue of prior invention. Further, the dates of publication
provided may be different from the actual publication dates which
may need to be independently confirmed.
[0048] Definitions
[0049] "Drug delivery system" is meant to refer to any device or
combination of devices that can provide for transfer of drug from a
drug reservoir to a treatment site. "Drug delivery device" thus
encompasses, for example, a drug delivery device (e.g., implantable
pump) with a flow regulator of the invention; a drug delivery
device, flow regulator, and drug delivery catheter combination; and
the like.
[0050] The term "treatment site" as used herein is meant to refer
to a desired site for delivery of drug from a drug delivery device
of the invention. "Treatment site" is thus meant to include,
although is not necessarily limited to, a subcutaneous,
percutaneous, intravenous, intrathecal, intramuscular,
intra-arterial, intravascular, intraperitoneal, intraspinal,
epidural, intracranial, peritumoral, or intratumoral (i.e., within
a cancerous growth) site within a subject, as well as sites within
or near a selected organ or tissue (e.g., central nervous system
(e.g., intraspinal (e.g., epidural, intrathecal, etc.) within the
spinal fluid, brain, etc.), peripheral nervous system, kidney,
liver, pancreas, heart (e.g., intrapericardial), lung, eye, ear
(e.g., inner ear), lymph nodes, breast, prostate, ovaries,
testicles, thyroid, spleen, etc.), digestive system (e.g., stomach,
gastrointestinal tract, etc.), skeletal muscle, bone, urinary
bladder, gall bladder, adrenal gland, adipose tissue, parathyroid
gland, uterus, fallopian tube, skin, into a vessel associated with
the circulatory system (e.g., artery, arteriole, blood vessel,
vein, capillary bed, lymph vessel, particularly arteries that feed
a selected organ or tissue)), a tumorous growth (e.g., cancerous
tumor (e.g., solid tumor), cyst, etc.), at a site associated with a
microbial infection (e.g., bacterial, viral, parasitic or fungal
infection), or to an autologous or synthetic graft (e.g., a
vascular graft).
[0051] The term "access site" or "implantation site" is used to
refer to a site on or in a subject at which a catheter of the
invention is introduced for implantation and positioning within the
subject's body, e.g., for delivery of drug to a desired treatment
site. For example, where a catheter is implanted in a subject for
delivery of drug to the spinal cord, the access site or
implantation site can be a subcutaneous site at which a proximal
end of the catheter is substantially retained, and the treatment
site is a position within or adjacent the spinal cord (treatment
site) at which a distal end of the catheter is positioned for
delivery of drug.
[0052] The term "subject" is meant any subject, generally a mammal
(e.g., human, canine, feline, equine, bovine, etc.), to which drug
delivery is desired.
[0053] The terms "drug," "therapeutic agent," or "active agent" as
used herein are meant to encompass any substance suitable for
delivery to a treatment site of a subject, which substances can
include pharmaceutically active drugs, as well as biocompatible
substances that do not exhibit a pharmaceutical activity in and of
themselves, but that provide for a desired effect at a treatment
site, e.g., to flush or irrigate a treatment site (e.g., saline),
provide for expression or production of a desired gene product
(e.g., pro-drug, polynucleotide, and the like), etc. In general,
"drug" and the like are used to encompass any drug administered by
parenteral administration, particularly by injection (e.g.,
intravascularly, intramuscularly, subcutaneously, intrathecally,
etc.). Drugs compatible for delivery using the devices and methods
of the invention are discussed below, and are readily apparent to
the ordinarily skilled artisan upon reading the disclosure provided
herein. Drugs may optionally be provided in combination with
pharmaceutically acceptable carriers and/or other additional
compositions such as antioxidants, stabilizing agents, permeation
enhancers, etc.
[0054] The term "therapeutically effective amount" is meant an
amount of a drug, or a rate of delivery of a drug, effective to
facilitate a desired therapeutic effect. The precise desired
therapeutic effect will vary according to the condition to be
treated, the drug to be administered, and a variety of other
factors that are appreciated by those of ordinary skill in the art.
Determinations of precise dosages are routine and well within the
skill in the art.
[0055] The term "treatment" is used here to cover any treatment of
any disease or condition in a mammal, particularly a human, and
includes: a) preventing a disease, condition, or symptom of a
disease or condition from occurring in a subject which may be
predisposed to the disease but has not yet been diagnosed as having
it; b) inhibiting a disease, condition, or symptom of a disease or
condition, e.g., arresting its development and/or delaying its
onset or manifestation in the patient; and/or c) relieving a
disease, condition, or symptom of a disease or condition, e.g.,
causing regression of the disease and/or its symptoms.
[0056] Overview
[0057] The present invention encompasses methods and devices for
regulating the rate of drug delivery from a drug delivery device.
As illustrated in the schematic of FIGS. 1A-1C, the invention
accomplishes regulation of drug delivery rate from a drug delivery
device 110 by diverting the flow of drug away from a primary drug
delivery pathway 60 (flow direction indicated by arrow 61) and into
diversion pathway 70 (flow direction exemplified by arrow 71).
Diversion of drug away from the drug delivery pathway 60 is
accomplished using a flow regulator 10. In general, flow regulator
10 comprises: 1) a delivery conduit, which defines delivery pathway
60 that flows toward a treatment site during use; and 2) a
diversion element 40 (represented schematically by a valve symbol),
which may be a valve or other element that facilitates diversion of
drug flow from the delivery pathway 60, e.g., out of the delivery
conduit through a proximal drug exit outlet positioned along the
delivery conduit body. In another embodiment, the flow regulator
comprises a diversion conduit, which is in fluid communication with
the delivery conduit and defines diversion pathway 70 that flows
away from delivery pathway 60. For clarity, the majority of
embodiments of the invention exemplified herein comprise both a
delivery conduit and a diversion conduit; however, the invention is
not meant to be so limited.
[0058] The flow regulator can be provided in a variety of
embodiments. For example, the diversion element of the flow
regulator can be positioned at the juncture of the delivery and
diversion pathways (see, e.g., FIG. 1A), at a site of the delivery
pathway distal to the diversion outlet (see, e.g., FIG. 1B), or,
where the flow regulator comprises a diversion conduit that defines
the diversion pathway, the diversion element can be positioned
along the body of the diversion conduit (see, e.g., FIG. 1C).
[0059] In one embodiment, the diverted drug is collected in a waste
reservoir. This embodiment is particularly useful where the drug
delivery system is for systemic drug delivery, i.e., the rate of
systemic drug delivery can be regulated by diverting the drug into
a waste reservoir.
[0060] In another embodiment, drug diverted into the diversion
pathway 70 can be delivered to a site within the subject where the
drug will have few or no undesirable side effects, e.g., to a site
in the body away from the site of action of a drug. This embodiment
of the invention is particularly useful where there is a local
advantage to delivery of drug to a target site, which local
advantage can be due to, for example, delivery of drug to directly
to the desired site of action (e.g., to avoid side effects
associated with systemic delivery), concentration effects (e.g.,
site-specific delivery provides for a drug concentration at the
treatment site that is difficult or undesirable to accomplish
through systemic delivery routes), and/or characteristics of the
drug itself (e.g., short half-life, inactivation in the systemic
circulation, etc.). This embodiment of the invention provides an
elegant means for regulating drug delivery rate by taking advantage
of the difference in the amount of drug that elicits a biological
effect at a specific site relative to an amount of drug that
elicits a biological effect when delivered systemically. The
invention takes advantage of this difference in relative
therapeutic thresholds to use the systemic circulation as a "waste
reservoir" for drug diverted from a drug delivery pathway that
targets a specific treatment site.
[0061] In another embodiment, the diversion element of the flow
regulator is actuated by a remote actuating device. The remote
actuation device can signal the diversion element to open
completely to the drug delivery pathway, open completely to a
diversion pathway, or to provide for adjustment of the diversion
element at any position in between these extremes to allow for
adjustment of drug flow to the treatment site. The remote actuation
device can also be used to actuate the diversion element
intermittently to provide for, for example, variable switching
between the opening and closing of the delivery pathway, e.g., the
diversion element can cause drug to be delivered into the delivery
pathway for a selected period of time at specified intervals
depending on factors such as the half-life of the drug at the
delivery site, e.g., drug can be delivered into the delivery
pathway for 1 hour followed by 3 hours where the drug flow will be
diverted to the diversion pathway.
[0062] Specific exemplary embodiments of the invention are
described below in more detail. The embodiments described below and
in the figures are only exemplary and are not meant to be limiting
in any way.
[0063] Exemplary Flow Regulator Embodiments
[0064] The flow regulator of the invention can comprise any element
suitable for facilitating a degree of opening and closing of the
drug diversion pathway and/or for redirecting a portion of the drug
flow in delivery pathway into the diversion pathway. Diversion
elements suitable for use in a flow regulator of the invention
include, but are not necessarily limited to, any of a variety of
remotely controllable or manually actuated valves, piezoelectric
valves, solenoids, and switches, as well as any of a variety of
devices that can provide for varying relative resistance to flow
through the drug delivery pathway and the drug diversion pathway of
the drug delivery system. In one embodiment, the diversion element
of the flow diverter is actuated remotely by a remote actuation
device external to the body when desired by either patient or the
clinician so as to regulate the flow of drug in the delivery
conduit and, where provided, through the diversion conduit. For
example, in one embodiment, the diversion element 40 is a valve,
which, as exemplified in FIG. 1D, can be in the form of a solenoid
47. Any of a variety of solenoids, which are well known in the art,
are suitable for use as valves in the diversion element. For
example, the diversion element can be a valve in the form of a
solenoid. The solenoid can be positioned for opening and closing of
a proximal drug exit outlet of a delivery conduit, for opening and
closing of the delivery conduit lumen (e.g., thereby increasing
flow through a proximal drug exit outlet of a delivery conduit), or
within a diversion conduit.
[0065] Various solenoids suitable for use in the invention are well
known in the art. As exemplified in FIG. 1D solenoid 47 can
comprise a rod or piston 52 which is slidably received within shaft
53. Seals 47 provide a fluid-tight seal to inhibit backflow into
the solenoid mechanism. FIG. 1D depicts the solenoid positioned for
opening and closing of a conduit lumen, e.g., positioned within the
body 24, 34 of a delivery conduit 20 or of a diversion conduit 30
to facilitate varying degrees of opening and closing of the
delivery conduit lumen 24 or diversion conduit lumen 34. When the
solenoid 47 is in the open position, rod 52 is completely or
partially withdrawn into shaft 53 to allow flow through lumen 24,
34. When the solenoid 47 is in the fully closed position, rod 52 is
received within abutment 48, providing a fluid seal between rod 52
distal end 51 and the abutment 48. Supplying power to electrical
coils 49 surrounding rod 52 causes movement of rod 52 within shaft
53 to facilitate varying degrees of opening and closing of the
lumen or other opening.
[0066] In another embodiment, illustrated in FIGS. 2 and 3, flow
regulator 10 comprises a diversion element in the form of rotatable
valve 42 comprising a substantially T-shaped conduit 43 seated
within a ring-like structure 44. The rotatable valve is positioned
in a drug delivery conduit 20 and a drug diversion conduit 30. Drug
delivery conduit 20 comprises a substantially elongate member
defining a lumen through which drug delivery pathway 60 travels
from a proximal drug inlet opening 21 to a distal drug delivery
outlet opening 22 when the valve 42 is in a position as illustrated
in FIG. 2. Drug diversion conduit 30 comprises a substantially
elongate member defining a diversion inlet 31 and a diversion
outlet 32, and further defining a lumen through which a drug
diversion pathway 70 travels when the valve 42 is in a position as
illustrated in FIG. 3. Delivery conduit 20 and diversion conduit 30
can be provided as separate, attached components, or molded as a
single piece (e.g., the diversion conduit can be an extended
orifice from a side wall of the delivery conduit). The valve 42 and
at least portions of drug delivery conduit 20 and diversion conduit
30 are mounted within a housing element 45 to maintain the lumen of
conduits 20, 30, and 43 within substantially the same plane and to
optionally provide a liquid tight or liquid resistant compartment
for the flow regulator 40, e.g., to prevent flow of environmental
fluid into the openings of the valve conduit 43. Housing element 45
may comprise elements to facilitate positioning of flow regulator
valve 40 and/or to ensure that rotation of valve 40 is stopped at a
position that provides for fluid communication between drug inlet
opening 21, through valve 40 and out either distal outlet 22 (FIG.
2) or diversion outlet 32 (FIG. 3). Seals 47 positioned around the
outer circumference of rotating valve 40 and/or at the openings of
the drug delivery conduit 20, drug diversion conduit 30, and at a
position within housing element 45 to ensure closure of an end of
T-shaped conduit 43 that is not in communication with either
delivery conduit 20 or diversion conduit 30 during use (see, e.g.,
FIGS. 2 and 3) provide for a liquid-tight seal to facilitate flow
through the valve conduits. The rotatable valve 42 of the flow
regulator can be manually or remotely actuated, and can be rotated
using mechanical, electromechanical (e.g., a microdrive engine), or
electromagnetic (e.g., a solenoid) means.
[0067] In another embodiment, the flow regulator 10 comprises
diversion element in the form of a slidable rod element 52 in a
gearshift-type valve mechanism (see, e.g., FIGS. 4 and 5). The ends
of the rod 52 are slidably received within side openings of the
diversion conduit 30 and of the drug delivery conduit 20. Seals 47
at each of these openings provide a liquid-tight seal with rod 52.
FIG. 4 shows rod 52 positioned such that drug delivery conduit 20
is completely open and diversion conduit 30 is completely closed,
e.g., all drug formulation introduced at inlet 21 flows through
drug delivery pathway 60 to drug outlet 22. Sliding of rod 52 into
the lumen of drug delivery conduit 20 can providing for varying and
inversely proportional degrees of closing of drug delivery conduit
20 and opening of diversion conduit 30, up to and including
complete closure of drug delivery conduit 20 and complete opening
of diversion conduit 30 such that substantially all drug introduced
into inlet 20 flows through diversion pathway 70. The flow
regulator can be housed within a housing element 45 to protect the
mechanics of the flow regulator from environmental fluids. Movement
of rod 52 can be accomplished manually or remotely actuated, and
can be rotated using mechanical, electromechanical (e.g., a
microdrive engine), or electromagnetic (e.g., a solenoid)
means.
[0068] In another embodiment, flow regulator 10 comprises a
diversion element comprising a rod element 52 and a toggle switch
54 contained within housing element 45 (FIGS. 6 and 7). As in the
exemplary embodiments illustrated in FIGS. 4 and 5, rod 52 is
slidably received within a side opening of the diversion conduit 30
and a side opening of the drug delivery conduit 20, with seals 47
at each of these openings providing a liquid-tight seal with rod
52. Toggle switch 54 is attached to rod 52, and hinged within
housing element 45 at pivot point 55 and rod 52 at pivot point 56.
Movement of toggle switch 54 in a direction toward delivery conduit
20 results in simultaneous opening of delivery conduit 20 and
closing of diversion conduit 30; movement of toggle switch 54 in a
direction toward the diversion conduit 30 results in simultaneous
closing of delivery conduit 20 and opening of diversion conduit 30.
The toggle switch 54 and rod 52 can be adjusted to provide for any
relative degree of opening and closing of the conduits 20 and 30.
Movement of toggle switch 55 and rod 52 can be accomplished
manually or remotely actuated, and can be rotated using mechanical,
electromechanical (e.g., a gear drive engine), or electromagnetic
(e.g., a solenoid) means.
[0069] In another embodiment, flow diversion is accomplished by
deformation of the diversion conduit 30 and/or delivery conduit 20
to vary their relative inner diameters. As illustrated
schematically in FIG. 8, increasing the resistance on delivery path
60 (e.g., at point A) relative to the resistance on diversion
pathway 70 (e.g., at point B) will result in diversion of drug into
diversion pathway 70, e.g., out a proximal drug exit outlet 25
which may be in fluid communication with a diversion conduit 30
(represented by dashed lines in FIG. 8). Likewise, increasing the
resistance on diversion path 70 relative to the resistance on
delivery pathway 60 will result in less drug flowing through
diversion pathway 70 and more flowing through delivery pathway 60.
Resistance at diversion pathway 70 and/or delivery pathway 60 can
be provided by application of external pressure which can be
provided by mechanical force, hydraulic pressure and the like to
impinge against a deformable conduit wall portion and/or to pinch
the conduit closed.
[0070] A starting delivery conduit flow rate greater than a
diversion conduit flow rate can be established in order to prevent
drug from simply flowing through the diversion pathway with little
or no drug reaching delivery outlet at the delivery conduit distal
end. For example, the delivery conduit inner diameter can be
greater than the diversion conduit inner diameter, thus providing
for a slower flow rate through the diversion conduit. Alternatively
or in addition, the proximal drug exit outlet of the delivery
conduit can be of a small diameter which allows only a "slow drip"
through the proximal drug exit outlet unless flow resistance is
increased in the delivery conduit at a site distal to the drug exit
outlet. Alternatively or in addition, the diversion conduit inner
diameter can be of a smaller diameter relative to the delivery
conduit inner diameter, allowing only a slow drip into the
diversion conduit in the absence of external pressure on the
delivery conduit. Alternatively or in addition, the proximal drug
exit outlet and/or diversion conduit can be completely or partially
filled with a porous or semi-porous material to increase flow
resistance in the diversion conduit relative to the delivery
conduit.
[0071] Modulating the relative flow resistance of the delivery
pathway 60 relative to the diversion pathway 70 can be accomplished
in a variety of ways. For example, the diversion element of the
flow regulator can comprise a compression element that provides a
means for alternately decreasing and increasing the inner diameter
of the delivery conduit, of the diversion conduit, or both. In one
embodiment exemplified in FIGS. 9 and 10, flow regulator 10
comprises a diversion element in the form of a compression element,
where the compression element is an inflatable cuff 57 positioned
over a deformable distal portion of delivery conduit 20. Cuff 57
can be inflated using a balloon-like inflating element 58, which
comprises a balloon, a connector that communicates the balloon with
the cuff, and a one-way valve positioned between the balloon and
the cuff. When substantially uninflated, cuff 57 does not cause any
substantial deformation of delivery conduit 20. Depression of the
balloon 58 results in inflation of cuff 57, which in turn results
in deformation of delivery conduit 20 beneath cuff 57 and
restriction of flow of drug through delivery pathway 60, thus
increasing flow through diversion pathway 70.
[0072] In another embodiment, the relative flow resistance in
delivery conduit 20 and diversion conduit 30 is controlled using a
hydraulic cuff 80, which comprises balloon elements 81 and 82
positioned over a deformable distal portion of delivery conduit 20
and over a deformable portion of diversion conduit 30,
respectively. The hydraulic cuff 80 comprises a rod 52 that is
slidably positioned within shaft 53. Movement of rod 52 within
shaft 53 in a direction toward diversion conduit 30 increases
pressure on gas or fluid in balloon element 82, and a concomitant
decrease in pressure on gas or fluid in balloon element 81,
resulting in relatively increased flow through delivery conduit 20
and relatively decreased flow through diversion conduit 30 (FIG.
11). Movement of rod 52 within shaft 53 in a direction toward
delivery conduit 20 increases pressure on gas or fluid in balloon
element 81, and a concomitant decrease in pressure on gas or fluid
in balloon element 82, resulting in relatively increased flow
through diversion conduit 30 and relatively decreased flow through
delivery conduit 20 (FIG. 12).
[0073] In another embodiment exemplified in FIGS. 13 and 14, the
diversion element of flow regulator 10 is a compression element
comprising a rod element 52 slidably positioned within shaft 53 so
as to be in alternate or simultaneous contact with a deformable
portion of diversion conduit 30 and a deformable portion of
delivery conduit 20 distal to the diversion conduit 30. Flow
regulator 10 is contained with housing 45, which housing can
provide for a fluid-resistant seal to inhibit entry of
environmental fluids into the flow regulator mechanism. Abutment
walls 85 are positioned adjacent delivery conduit 20 and diversion
conduit 20 at a wall opposite the deformable wall to be contacted
by rod 52. Abutment walls 85 provide resistance to the pressure
generated by rod 52 when impinging upon the opposite conduit wall
to deform the conduit and modulate the conduit inner diameter,
e.g., to facilitate deformation of the conduit wall in contact with
rod 52 rather than movement of the entire conduit. Movement of rod
52 within shaft 53 in a direction toward diversion conduit 30
results in deformation of a deformable portion of diversion conduit
30, resulting in complete or partial pinching of the deformable
portion of diversion conduit 30 (see, e.g., FIG. 13) with
simultaneous opening of delivery conduit 20. Movement of rod 52 in
a direction toward delivery conduit 20 results in deformation of a
deformable portion of delivery conduit 20, resulting in complete or
partial pinching of the deformable portion of delivery conduit 20
with simultaneous opening of diversion conduit 30 (see, e.g., FIG.
14). Rod 52 can be positioned to provide any of a variety of
gradations of relative opening and closing of delivery conduit 20
and diversion conduit 30. Movement of rod 52 can be accomplished
manually or remotely actuated, and can be rotated using mechanical,
electromechanical (e.g., a microdrive engine), or electromagnetic
(e.g., a solenoid) means. In a similar embodiment, rod 52 is
provided in association with a toggle switch that facilitates
movement of rod 52, similar to the embodiment described above and
in FIGS. 6 and 7.
[0074] Conduit configuration
[0075] While the above exemplary embodiments have illustrated the
flow regulators comprising both a delivery conduit and diversion
conduit as comprising a T-shaped intersection between a delivery
conduit and a diversion conduit, other embodiments are contemplated
by the invention. As exemplified in FIGS. 15-17, a proximal portion
of delivery conduit 20a extends from a drug inlet 21 to a Y-shaped
branch point at which the conduit diverges to provide a diversion
conduit 30 and a distal portion of the delivery conduit 20b. Flow
regulator 10 comprises a flap valve 87 positioned at the conduit
branch point, which flap valve 87 pivots at a point within the
conduit branch point to provide for relative opening and closing of
delivery conduit 20b and diversion conduit 30. FIG. 15 illustrates
positioning of flap valve 87 so as to divert approximately half of
the flow of drug from drug inlet 21 into delivery conduit 20b and
half into diversion conduit 30. FIGS. 16 and 17 illustrate flap
valve 87 positioned for substantially complete closure of diversion
conduit 30 (FIG. 16) and substantially complete closure of delivery
conduit 20b (FIG. 17).
[0076] In another embodiment, flow regulator 10 comprises a
tuning-fork or U-shaped configuration (see, e.g., FIGS. 18 and 19).
In this embodiment a proximal portion of delivery conduit 20a and
intersects at a connector conduit 88 which in turn is in
communication with a distal delivery conduit portion 20b and with
diversion conduit 30. A rod 52 is slidably received within shaft 53
and within openings in distal delivery conduit 20 and diversion
conduit 30. Seals 47 positioned around the conduit openings provide
for a liquid tight or liquid resistant seal to prevent leaking of
drug from the conduits. Sliding of rod 52 toward diversion conduit
30 results in closing of diversion conduit 30 and simultaneous
opening of distal delivery conduit 20 to allow flow through
delivery pathway 60. Sliding of rod 52 toward distal delivery
conduit 20b results in closing of distal delivery conduit 20b and
simultaneous opening of diversion conduit 30 to allow flow of drug
through diversion pathway 70. Rod 52 can be moved through
mechanical, electromechanical, or electromagnetic means, and can be
activated manually or remotely. For example, rod 52 can be a
solenoid or a piston-like element.
[0077] Waste reservoir embodiments
[0078] In all embodiments described herein and contemplated by the
invention, drug that flows through the proximal drug exit outlet of
the delivery conduit can be optionally collected in a waste
reservoir. Embodiments with waste reservoirs are particularly
useful when the flow regulator is used as part of a drug delivery
system wherein drug is administered systemically instead of
locally. In general, the waste reservoir is a bag, pouch,
container, receptacle, bellows (e.g., metal bellows) or other
receiving element in fluid communication with the diversion conduit
outlet and/or delivery conduit proximal drug exit outlet. The waste
reservoir can be provided as an extension of the catheter body, or
can be provided as a separate component that is either removably or
permanently attached. Where the waste reservoir is to be positioned
within the subject's body during use, it is preferably permanently
attached and comprises an implantable, biocompatible material.
[0079] The waste reservoir can be of any size or shape suitable for
use with the delivery exit catheter with which it is to be used.
For example, the waste reservoir can be provided as a separate,
closed lumen within the wall of the diversion conduit, the delivery
conduit, or within a wall of a catheter used in connection with the
flow regulator. Alternatively, the waste reservoir can be provided
within a housing element of the flow regulator or within a chamber
of a drug delivery device used in connection with the flow
regulator of the invention. The waste reservoir can comprise any
suitable, substantially drug-impermeable material (e.g.,
multilaminate impermeable polymers/metalized polymer or
metal/plastic laminate), and preferably does not react in an
unintended manner with the active agent formulation. The waste
reservoir can be designed to facilitate removal of drug it
contains, e.g., by means of a self-sealing septum that allows
needle access.
[0080] In one embodiment of particular interest, the waste
reservoir is provided as part of the delivery pump such that on
removal of the pump from the drug delivery system (e.g., detachment
of the pump from a drug delivery catheter) the reservoir is
automatically removed. The waste reservoir can also be co-located
with the pump or molded within the pump body.
[0081] In one embodiment, exemplified in FIG. 20, the waste
reservoir 90 is provided as a component of flow regulator 10. The
proximal end of the delivery conduit can be adapted for receiving a
drug delivery device, exemplified in FIG. 20 as device receiving
chamber 98. The waste reservoir 90 of FIG. 20 comprises a waster
receiving chamber 91. As wasted is delivered into waste receiving
chamber 91, piston 92 is advanced in a direction toward vent hole
93, which allows for displacement of fluid or gas contained within
the proximal portion of waste reservoir 90. Where the waste
reservoir is provided as a detachable component, the waste
reservoir can be removed when descried, e.g., when the waste
reservoir is f all such that piston 92 has reached the waste
reservoir proximal end. In another embodiment, exemplified in FIG.
21, waste is received within an expandable bellows 94.
[0082] Flow regulator as element of drug delivery system
[0083] The flow regulator of the invention can be provided as an
integral or detachable element of a drug delivery system component.
For example, the flow regulator and optional waste reservoir can be
an integral or detachable portion of a drug delivery device. For
example, FIG. 22 illustrates a drug delivery system 100 comprising
a drug delivery device 110 and a flow regulator 40, which drug
delivery system 100 can further comprise a drug delivery catheter
120. In this embodiment, flow regulator 10 is permanently attached
to (e.g., via welding, adhesive bonding, etc.) or an integral
component of drug delivery device 110.
[0084] The drug delivery device minimally comprises a drug release
device (e.g., a constant rate drug delivery device, such as an
osmotic pump) having a proximal end and a distal end, which distal
end defines a drug delivery orifice. The distal end of the drug
delivery device is attached to a proximal end of the catheter so
that the drug flow pathway from the drug delivery device reservoir
continues through the drug delivery device orifice and into the
delivery conduit of the flow regulator. The present invention finds
particular use with those drug release devices that provide for
delivery of drug at a pre-selected rate that cannot be readily
adjusted, but can be used with any of a wide variety of drug
delivery devices including, but not limited to, diffusion-based
delivery system (e.g., erosion-based delivery systems (e.g.,
polymer-impregnated with drug placed within a drug-impermeable
reservoir in communication with the drug delivery conduit of the
catheter of the invention), electrodiffusion systems, and the like)
and convective drug delivery systems (e.g., systems based upon
electroosmosis, vapor pressure pumps, electrolytic pumps,
effervescent pumps, piezoelectric pumps, osmotic pumps, etc.). Drug
release devices based upon a mechanical or electromechanical
infusion pump, may also be suitable for use with the present
invention. Examples of such devices include those described in, for
example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019;
4,725,852, and the like. In general, the present invention can be
used in conjunction with refillable, non-exchangeable pump systems
that are normally used to deliver a substance through a relatively
impermeable catheter.
[0085] In a preferred embodiment, the drug release device is an
osmotically-driven device. Exemplary osmotically-driven devices
suitable for use in the invention include, but are not necessarily
limited to, those described in U.S. Pat. Nos. 3,760,984; 3,845,770;
3,916,899; 3,923,426; 3,987,790; 3,995,631; 3,916,899; 4,016,880;
4,036,228; 4,111,202; 4,111,203; 4,203,440; 4,203,442; 4,210,139;
4,327,725; 4,627,850; 4,865,845; 5,057,318; 5,059,423; 5,112,614;
5,137,727; 5,234,692; 5,234,693; 5,728,396; and the like. In one
embodiment, the drug release device is an osmotic pump, more
particularly an osmotic pump similar to that described in U.S. Pat.
No. 5,728,396, e.g., a DUROSosmotic pump.
[0086] The drug delivery system 100 can further comprise a drug
delivery catheter 120, which can be attached to drug delivery
device 110 and flow regulator 40 via an attachment element 130
provided at a distal end of delivery conduit 20 of flow regulator
40. The attachment element facilitates permanent or reversible
attachment of the catheter to the drug delivery device and/or
stabilizes such attachment, e.g., substantially diminish movement
of the catheter away from the drug delivery device (e.g., to
provide strain relief), so as to reduce risk of breakage of the
catheter at the attachment site. The attachment element can be
provided as a portion of or component associated with the catheter
proximal end, flow regulator delivery conduit, a combination of
both, or as a separate element. Any of a variety of attachment
elements are suitable for use including, but not limited to, a
press fit lock, threaded connector elements, luer lock elements,
bayonet connectors, etc.
[0087] Flow regulator as element of a drug delivery catheter
[0088] In one embodiment, the flow regulator is provided as an
element of a drug delivery catheter, which catheter is attachable
to a drug delivery device. In general, the catheter comprises: 1) a
catheter body comprising a proximal end defining a drug inlet, a
distal end defining a drug delivery outlet, and a lumen extending
between the proximal and distal ends and defining a drug delivery
pathway; and 2) a flow regulator for control of drug flow from the
drug delivery pathway and into a diversion pathway.
[0089] For example, flow regulator can be provided as a component
of a drug delivery catheter. In this embodiment, delivery conduit
of the flow regulator is positioned within and attached to the body
of the catheter in a liquid-tight manner or the delivery conduit
and catheter lumen can be formed from a single, continuous element
(e.g., are molded or extruded as a single element). The catheter
proximal end can be adapted for attachment to drug delivery device
as described above.
[0090] The catheter body can be any suitable shape including, but
not limited to, tubular, elliptical, cylindrical, etc., and may be
either smooth on the catheter outer surface, or may comprise ridges
(e.g., longitudinal, axial, or circumferential) or other surface
variations as will be desirable for the specific applications for
which the catheter is used. The catheter body comprises a
biocompatible material, more preferably an implantable grade
biocompatible material. Exemplary materials include, but are not
necessarily limited to, biocompatible polymers, elastomers, metals,
metal alloys, glasses, laminates of hydrophilic polymers and
hydrophobic polymers, multilaminates or polymer, metals, and/or
glasses; and the like.
[0091] In general, the catheter and flow regulator can be of any
suitable dimension, which can be varied according to the delivery
site and other factors. For example, the outer diameter of the
catheter body is generally from about 0.01" (about 0.25 mm) to
about 0.200" (about 5 mm). The inner diameter of the catheter and
of the flow regulator delivery conduit can also be varied as
needed, and can range from, for example, about 0.0002" (about 0.005
mm) to about 0.025" (about 5 mm).
[0092] The dimensions of the catheter (e.g., inner diameter, outer
diameter, wall thickness, etc.) can be substantially the same
throughout the length of the catheter, or can be varied. For
example, the catheter body can be tapered at the distal end
relative to the proximal end, e.g., to facilitate implantation into
small and/or delicate structures in the subject and/or to provide a
wider proximal end for receiving a drug delivery device. The
catheter can comprise a single delivery outlet or a plurality of
such delivery outlets. Furthermore, the amount of drug that moves
through the multiple delivery outlets can be controlled by one or
more flow regulators. Catheters comprising multiple drug delivery
outlets can be used to facilitate delivery of drug to multiple
treatment sites, and may further be branched to provide for
delivery to multiple, specific treatment sites. The catheter can
comprise additional elements, such as radiopaque markers to
facilitate implantation, a valve at the catheter distal end (e.g.,
a duckbill valve), a filter positioned within the catheter lumen,
etc.
[0093] Flow regulator as separate unit
[0094] In another embodiment, flow regulator 10 is provided as a
separate element that is adapted for attachment to a drug delivery
device and, optionally, a drug delivery catheter. In one example
illustrated in FIG. 23, flow regulator 10 is provided within
housing 45. Drug inlet 21 of delivery conduit 20 is adapted to
receive a distal portion of a drug delivery device 110 to provide
for flow of drug from the drug delivery device into delivery
conduit 20. One or more seals 47 can be positioned within delivery
conduit 20 or on an external surface of drug delivery device 110 to
facilitate holding drug delivery device 110 in place and/or to
provide a liquid-tight seal. Housing 45 can comprise an attachment
element (exemplified by a press fit lock in FIG. 23) to facilitate
retention of drug delivery device 110 in housing 45. Delivery
conduit distal end 22 can be adapted to receive a drug delivery
catheter to provide for flow of drug from delivery conduit 22 and
into a lumen of the drug delivery catheter. Diversion element 40 of
flow regulator 10 is contained with housing 45, with diversion
conduit 30 optionally attached to waste reservoir 90.
Alternatively, the flow regulator may be adapted to allow for flow
of diverted drug directly into a waste reservoir, e.g., without a
diversion conduit. All components of flow regulator 10 can be
contained within housing 45, as exemplified in FIG. 23, to provide
all elements of flow regulator 10 in a single unit. In this
embodiment, flow regulator 10 can be provided as a disposable,
exchangeable unit that can be adapted for use with a variety of
drug delivery devices and drug delivery catheters.
[0095] During use, drug flows through delivery pathway 60 from drug
reservoir 113 into drug inlet 21, through delivery conduit 20 and,
where used, into drug delivery catheter 120 and out catheter distal
outlet 122 to a treatment site. Activation of the diversion element
40 of flow regulator 10 results in diversion of drug from delivery
pathway 60 and into diversion pathway 70. Where the flow regulator
comprises a diversion conduit, diverted drug flows through a
diversion pathway defined by the diversion conduit. Optionally,
diverted drug can be collected in waste reservoir 90. The
dimensions of the flow regulator (e.g., inner diameter of delivery
and diversion conduits, dimensions of housing element, etc.) can be
varied according to the various drug delivery device and catheters
used with the flow regulator, as well as with the application for
which the flow regulator is to be used.
[0096] Flow regulator with remote actuation device
[0097] In one embodiment, the diversion element of the flow
regulator is actuated by a remote actuation device which can be
used by a patient or clinician to adjust the amount of drug
delivered to the treatment site. As used herein "remote actuation
device" indicates that actuation device separate from the flow
regulator, and may be external to the patient's body, implanted, or
partially implanted, preferably external to the patient's body.
Actuating the diversion element from a remote actuation device
provides for advantage in patient therapy including, but not
necessarily limited to, direct patient or clinical control over the
therapy received without the need for adjustment of the implanted
flow regulator or pump, and flexibility in adjustment of the dose
being delivered. In addition, the remote actuation device can
provide for clinical pre-set upper limits of possible dosage, lower
limits of possible dosage, or both by inputting such limits in the
ability of the remote actuation device to actuate the diversion
element, thus diminishing the likelihood of improper dosing. In
addition, patient therapy can be altered by replacing and adjusting
the remote actuation device and its components rather than
adjusting the implanted flow regulator or other drug delivery
device component.
[0098] The remote actuation device can be used so that it signals
the diversion element periodically, and only for a length of time
necessary to actuate the diversion element. When used in this
manner, the power requirements of the remote actuation device are
minimized, and can serve to minimize maintenance (e.g., minimize
battery replacements). In general, the period between signaling
events is determined by several factors, including, but not
necessarily limited to, the half-life of the drug to be delivered,
the amount of drug desired to be delivered along the delivery
pathway of the flow regulator (e.g., relative to the amount to be
diverted through the diversion pathway), and other factors that
will be readily apparent to the ordinarily skilled artisan upon
reading the present disclosure.
[0099] Remote actuation devices can operate in a variety of ways.
For example, the flow regulator may comprise programming circuitry
which controls the diversion element, and the remote actuation
device can transmit signals, by radio frequency telemetry for
example, to the programming circuitry to actuate the diversion
element. Exemplary remote programmers based upon RF signals used to
actuate implanted drug delivery pumps are described in, for
example, U.S. Pat. No. 5,443,486 and 5,820,589, and such mechanisms
can be adapted for use in the present invention by those of skill
in the art.
[0100] In other embodiments, the remote actuation device comprises
a power source that will transmit energy to actuate the diversion
element. In such embodiments, because the power source used to
actuate the diversion element is separate from the flow regulator,
the flow regulator can be much smaller in size, which is
particularly advantageous when the flow regulator is to be
implanted. In one embodiment, the power source on the remote
actuation device is operated only for a period of time during which
drug delivery is desired, where removal of the external power
source results in substantially no delivery of drug to the
treatment site (e.g., the delivery pathway is closed upon removal
of the external power source from operation). In another
embodiment, the external power source is operated to provide for
adjustment of the diversion element, leaving the diversion element
in a desired position to allow for a desired flow rate of drug
through the delivery pathway. Remote power sources capable of
delivery of power to actuate implanted devices are known in the
art, for example in connection with implantable tissue stimulators
such as the Medtronic Itrel II, Model 7424, transcutaneous tissue
stimulators such as the Medtronic Xtrel, Model 3470, and such
mechanisms can be adapted to be used in this invention by those of
skill in the art.
[0101] Drugs for delivery using the drug delivery system of the
invention
[0102] Any of a wide variety of drugs can be delivered using the
drug delivery system of the invention. Drugs suitable for delivery
are preferably provided as flowable formulations, and are generally
provided as liquids, gels, pastes, or semisolids. The drugs may be
anhydrous or aqueous solutions, suspensions or complexes, and may
be formulated with pharmaceutically acceptable vehicles or
carriers, as well as additional inert or active ingredients. The
drugs of formulations suitable for delivery using the invention may
be in various forms, such as uncharged molecules, components of
molecular complexes or pharmacologically acceptable salts. Also,
simple derivatives of the agents (such as prodrugs, ethers, esters,
amides, etc.) that are easily hydrolyzed by body pH, enzymes, etc.,
can be employed. Preferably the agents are formulated so as to
remain stable for long periods of storage on the shelf or under
refrigeration, as well as for long periods stored in an implanted
drug delivery system of the invention.
[0103] Of particular interest is the treatment of diseases or
conditions that require long-term therapy, e.g., chronic and/or
persistent diseases or conditions for which therapy involves
treatment over a period of several days (e.g., about 3 days to 10
days), to several weeks (e.g., about 3 or 4 weeks to 6 weeks), to
several months or years, up to including the remaining lifetime of
the subject. Subjects who are not presently suffering from a
disease or condition, but who are susceptible to such may also
benefit from prophylactic therapies using the devices and methods
of the invention.
[0104] Use of the Flow Regulator in Drug Delivery
[0105] The drug delivery system of the invention can be implanted
at any convenient site within the subject's body using methods and
tools well known in the art, and can be oriented for delivery to
any desired treatment site. The devices of the present invention
are preferably rendered sterile prior to implantation, which can be
accomplished by separately sterilizing each component, e.g., by
gamma radiation, steam sterilization or sterile filtration, etc.,
then aseptically assembling the final system, or by first
assembling the system then sterilizing the system using any
appropriate method. The final sterilized device may be provided in
a package to retain its sterility.
[0106] In one embodiment, the drug delivery system of the invention
is partially or completely implanted, with at least portion of the
drug delivery device retained at an accessible, external or
subcutaneous site within the subject's body (e.g., under the skin
of the arm, shoulder, neck, back, or leg) or within a body cavity
(e.g., within the mouth).
[0107] The relative position of the flow regulator can be varied
with respect to the subject's body. For example, the portion of the
catheter comprising the flow regulator can be maintained at a site
external to the subject's body to allow for ready adjustment of the
flow regulator, e.g., where the flow regulator comprises a manually
adjustable diversion element. Where all or a portion of the flow
regulator is maintained at an external site, it may be desirable
that the drug delivery system further comprise a waste reservoir
for collection of drug that flows through the diversion pathway. In
general, a drug delivery outlet (i.e., the delivery outlet or the
flow regulator, a drug delivery catheter associated with a flow
regulator, or both) is implanted within a subject for delivery of
drug to a treatment site.
[0108] In one embodiment exemplified in FIG. 24, a drug delivery
outlet 22 is implanted for site-specific drug delivery to a
selected treatment site (e.g., within the central nervous system
(e.g., an intraspinal site (e.g., an epidural or intrathecal site,
site within the brain, etc.)), and the diversion outlet 32
positioned within the body at a site outside the specific treatment
site(e.g., at a subcutaneous site or other site external to the
specific treatment site that provides for systemic delivery of the
diverted waste drug). In this embodiment, drug that flows out the
drug delivery outlet 22 is delivered to the selected specific
treatment site 7 (e.g., to the spine), while drug that flows out
the diversion outlet 32 is delivered systemically in the subject's
body 5, where the drug can be safely diluted in the systemic
circulation. In an alternative embodiment, diverted drug flows out
the delivery conduit proximal drug exit outlet and directly into
the systemic circulation, e.g., without flowing through a diversion
conduit.
[0109] Embodiments that involve delivery of diverted drug to the
systemic circulation are particularly attractive where
microquantities of drug (e.g., on the order of micrograms per day)
are delivered to the specific treatment site, and thus the amount
of drug diverted into the diversion conduit and to a systemic site
would be even smaller. These embodiments are also attractive where
the drug's biological activity is substantially specific for the
specific treatment site, and systemic delivery of the drug to the
patient would have no substantial, undesirable effect.
[0110] Where the drug's biological activity might have undesirable
systemic effects, the catheter preferably further comprises a waste
reservoir for collection of drug that flows out of the delivery
conduit through the diversion pathway. It may be desirable to
maintain the waste reservoir at readily accessible site so that
waste drug in the waste reservoir can be readily withdrawn,
particularly where the subject is to receive therapy for an
extended period of time.
[0111] The amount of drug delivered to the treatment site is
adjusted by manipulation of one or more flow regulators of the drug
delivery system. The method of altering an amount of drug
administered to a treatment site according to the invention takes
advantage of the fact that altering the amount of drug that flows
into the diversion pathway alters the amount of drug that flows
through the drug delivery outlet. Specifically, where the flow
regulator is adjusted to increase the amount of drug that flows out
the diversion pathway, the amount of drug delivered through the
delivery outlet to the treatment site is proportionately decreased.
Likewise, where the flow regulator is adjusted to decrease the
amount of drug that flows out the diversion pathway, the amount of
drug delivered through the delivery outlet to the treatment site is
proportionately increased. For example, the flow regulator can
provide for redirection (e.g., into or away from the diversion
pathway) of about 0.5% up to 100%, usually about 5% to 90%,
normally about 10% to 75% or about 25% to 50% of the drug flow in
the drug delivery pathway. The relative amount of drug diverted
into the diversion pathway can be selected according to patient
need, e.g., developments of side-effects, responsiveness to
therapy, etc.
[0112] The overall rate of drug delivery through the drug delivery
pathway can be adjusted using the flow regulator in a variety of
ways. The flow regulator can be set at relative degrees of opening
and closing of the drug diversion pathway and drug delivery
pathway. For example, the relative portions of drug flowing through
the drug delivery pathway and the diversion pathway can be 90:10,
80:20, 50:50, 25:75, etc. Alternatively, the rate of drug flow can
be adjusted by varying the amount of time the drug delivery pathway
is open relative to the amount of time the diversion pathway is
open. For example, over a given time interval (e.g., seconds,
minutes, hours), the ratio of time the drug delivery pathway is
open versus the time the diversion pathway is open
(delivery:diversion) can be 10:1, 5:1, 3:1, 2:1, 0.5:1, etc.
[0113] The invention as shown and described is considered to be the
one of the most practical and preferred embodiments. It is
recognized, however, that the departures may be made therefrom
which are within the scope of the invention and that obvious
modifications will occur to one skilled in the art upon reading
this disclosure.
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