U.S. patent application number 10/160451 was filed with the patent office on 2004-06-10 for methods and implantable devices and systems for long term delivery of a pharmaceutical agent.
This patent application is currently assigned to MicroSolutions, Inc.. Invention is credited to Harper, Derek J., Milo, Charles F..
Application Number | 20040111080 10/160451 |
Document ID | / |
Family ID | 23755651 |
Filed Date | 2004-06-10 |
United States Patent
Application |
20040111080 |
Kind Code |
A1 |
Harper, Derek J. ; et
al. |
June 10, 2004 |
Methods and implantable devices and systems for long term delivery
of a pharmaceutical agent
Abstract
Implantable devices and osmotic pump and catheter systems for
delivering a pharmaceutical agent to a patient at selectable rates
include an impermeable pump housing and a moveable partition
disposed within the housing, the partition dividing the housing
into an osmotic driving compartment having an open end and a
pharmaceutical agent compartment having a delivery orifice. A
plurality of semi permeable membranes may be disposed in the open
end of the osmotic driving compartment and a number of impermeable
barriers may seal selected ones of the plurality of semi permeable
membranes from the patient until breached. Breaching one or more of
the impermeable barriers increases the surface area of semi
permeable membrane exposed to the patient and controllably
increases the delivery rate of the pharmaceutical agent through the
delivery orifice and catheter. Each of the plurality of semi
permeable membranes may have a selected surface area, composition
and/or thickness, to allow a fine-grained control over the infusion
rate while the pump is implanted in the patient.
Inventors: |
Harper, Derek J.; (Santa
Inez, CA) ; Milo, Charles F.; (Atherton, CA) |
Correspondence
Address: |
YOUNG LAW FIRM
A PROFESSIONAL CORPORATION
4370 ALPINE ROAD SUITE 106
PORTOLA VALLEY
CA
94028
|
Assignee: |
MicroSolutions, Inc.
|
Family ID: |
23755651 |
Appl. No.: |
10/160451 |
Filed: |
May 29, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10160451 |
May 29, 2002 |
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09442128 |
Nov 16, 1999 |
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6436091 |
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Current U.S.
Class: |
604/892.1 |
Current CPC
Class: |
A61M 2005/14513
20130101; A61M 31/002 20130101 |
Class at
Publication: |
604/892.1 |
International
Class: |
A61K 009/22 |
Claims
What is claimed is:
1. An implantable osmotic pump for delivering a pharmaceutical
agent to a patient, comprising: a pump housing; a moveable
partition disposed within the housing, the partition dividing the
housing into an osmotic driving compartment having an open end and
a pharmaceutical agent compartment having a delivery orifice; a
first semi permeable membrane disposed in the open end of the
osmotic driving compartment, the first semi permeable membrane
being exposed to the patient; a second semi permeable membrane
disposed in the open end of the osmotic driving compartment, and a
first impermeable barrier disposed over the second semi permeable
membrane, the second semi permeable membrane being sealed from the
patient until the first barrier is breached, wherein breaching the
first barrier increases the surface area of semi permeable membrane
exposed to the patient and increases a delivery rate of the
pharmaceutical agent through the delivery orifice.
2. The pump of claim 1, wherein the first impermeable barrier
includes at least one of titanium and stainless steel.
3. The pump of claim 1, further comprising a saturated solution
including NaCl between the first impermeable barrier and the second
semi permeable membrane.
4. The pump of claim 1, wherein the first and second semi permeable
membranes have a same composition.
5. The pump of claim 1, wherein the first and second semi permeable
membranes have a same thickness.
6. The pump of claim 1, wherein the first and second semi permeable
membranes have mutually different compositions.
7. The pump of claim 1, wherein the first and second semi permeable
membranes have mutually different thickness.
8. The pump of claim 1, further including: a third semi permeable
member, and a second impermeable barrier nested within the first
impermeable barrier, the second impermeable barrier being disposed
over the third semi permeable membrane, the third semi permeable
membrane being sealed from the patient until the second impermeable
barrier is breached, wherein breaching the second barrier increases
the surface area of semi permeable membrane exposed to the patient
and increases a delivery rate of the pharmaceutical agent through
the delivery orifice.
9. The pump of claim 8, further comprising a saturated solution
including NaCl between the second barrier and the third semi
permeable membrane.
10. The pump of claim 1, wherein the pharmaceutical agent
compartment contains sufentanil.
11. The pump of claim 10, wherein the sufentanil is at a
concentration selected between about 200 .mu.g/mL and about 15,000
.mu.g/mL.
12. The pump of claim 1, wherein the daily delivery rate of the
pharmaceutical agent through the delivery orifice is selected from
about: 0.5 micrograms per day to about 25 micrograms per day when
the pump is configured to be implanted intraventricularly; 0.5
micrograms per day to about 50 micrograms per day when the pump is
configured to be implanted intrathecally; 5 micrograms per day to
about 300 micrograms per day when the pump is configured to be
implanted epidurally, and 10 micrograms per day to about 300
micrograms per day when the pump is configured to be implanted
subcutaneously.
13. The pump of claim 1, wherein the first and second semi
permeable membranes include cellulose acetate.
14. The pump of claim 1, wherein the first semi permeable membrane
is shaped as a torus and is disposed adjacent an outer periphery of
the first impermeable barrier and wherein the second semi permeable
membrane is disposed in a center opening of the torus.
15. The pump of claim 1, further comprising a catheter coupled to
the delivery orifice.
16. The pump of claim 15, wherein the catheter has an inner
diameter of between about 0.001 inches and about 0.010 inches.
17. The pump of claim 15, wherein the catheter includes a guidewire
lumen and a pharmaceutical agent infusion lumen.
18. The pump of claim 17, wherein the pharmaceutical agent infusion
lumen has an inner diameter selected between about 0.001 inches to
about 0.010 inches.
19. The pump of claim 15, wherein the catheter and the pump are
dimensioned to infuse a volume of pharmaceutical agent of between
about 1 .mu.L/day and about 10 .mu.L/day over a treatment
period.
20. The pump of claim 15, wherein the catheter and the pump are
dimensioned to infuse a dose of pharmaceutical agent of between
about 0.5 .mu.g/day and about 300 .mu.g/day over a treatment
period.
21. The pump of claim 15, wherein at least a portion of the
catheter is radiopaque.
22. The pump of claim 17, wherein the guidewire lumen includes a
valve to prevent back flow of fluid into the guidewire lumen.
23. A method for achieving an analgesic effect in a patient, the
method comprising the step of administering a therapeutically
effective dose of a sufentanil-containing analgesic to the patient
using a device that is fully implanted in the patient.
24. The method of claim 23, wherein the dose is administered one of
intravascularly, subcutaneously, epidurally, intrathecally and
intraventricularly.
25. The method of claim 23, further comprising the step of
selectively increasing the dose in a stepwise manner over a
treatment period without removing the device from the patient.
26. The method of claim 25, wherein the dose is administered using
an implanted osmotic pump that includes a first semi permeable
membrane exposed to the patient and a second semi permeable
membrane initially not exposed to the patient and wherein the
increasing step includes a step of exposing the second semi
permeable membrane to the patient.
27. The method of claim 26, wherein the second semi permeable
membrane exposing step includes a step of breaching an impermeable
barrier sealing the second semi permeable membrane from the
patient.
28. The method of claim 27, wherein the breaching step includes a
step of puncturing the impermeable barrier using a lancet while the
pump remains implanted in the patient.
29. The method of claim 23, wherein the therapeutically effective
dose is selected within the range of about 0.5 .mu.g/day to about
300 .mu.g/day.
30. A method for achieving an analgesic effect in a patient, the
method comprising intraspinal administration of a
therapeutically-effective dose of an analgesic to the patient by an
osmotic pump and catheter integrated combination, the pump
including a first semi permeable membrane across which an osmotic
pressure gradient develops when the pump is implanted in the
patient.
31. The method of claim 30, further including the step of
selectively increasing a surface area of semi permeable membrane
exposed to the patient in a stepwise manner.
32. The method of claim 30, wherein the analgesic includes
sufentanil.
33. The method of claim 30, further including a second semi
permeable membrane and wherein the surface area of semi permeable
membrane exposed to the patient is increased by breaching an
impermeable barrier initially sealing the second semi permeable
membrane from the patient.
34. The method of claim 33, wherein the impermeable barrier is
breached by puncturing the impermeable barrier.
35. The method of claim 31, wherein the dose is increased in a
stepwise manner by sequentially breaching one of a plurality of
nested impermeable barriers disposed over a corresponding plurality
of the semi permeable membranes, each sequential breach exposing
additional surface area of semi permeable membrane to the
patient.
36. The method of claim 35, wherein each of the plurality of nested
barriers is configured to be breached by a lancet, an outer
diameter of the lancet determining which of the plurality of nested
barriers is breached.
37. The method of claim 30, wherein the analgesic is administered
one of intravascularly, subcutaneously, epidurally and
intrathecally.
38. The method of claim 33, wherein the second semi permeable
membrane has one of a same and different composition as the first
semi permeable membrane.
39. The method of claim 33, wherein the second semi permeable
membrane has one of a same and different thickness as the first
semi permeable membrane.
40. An integrated implantable pump and catheter system for
delivering a dose of sufentanil to a patient over a treatment
period, comprising: a pump housing; a moveable partition disposed
within the housing, the partition dividing the housing into an
driving engine compartment and a pharmaceutical agent compartment
having a delivery orifice; a catheter coupled to the delivery
orifice, and a preloaded amount of sufentanil in the pharmaceutical
agent compartment.
41. The system of claim 40, wherein the pump and catheter are
dimensioned to deliver sufentanil at an infusion rate of about 0.5
.mu.g/day to about 300 .mu.g/day over a treatment period.
42. The system of claim 40, wherein the system further includes a
mechanical infusion rate selection structure configured to allow
the infusion rate of the pump to be increased while the system is
implanted in the patient.
43. The system of claim 40, wherein the infusion rate selection
feature includes a plurality of semi permeable membranes across
each of which osmotic pressure develops when selectively and
sequentially exposed to the patient.
44. The system of claim 43, wherein each of the plurality of semi
permeable membranes has a selected thickness, composition and
surface area, the selected thickness, composition and surface area
contributing to a rate at which the sufentanil is infused into the
patient.
45. A kit comprising: an osmotic pump; sufentanil preloaded in the
osmotic pump, and a delivery catheter configured to be coupled to
the osmotic pump.
46. The kit of claim 45, wherein the osmotic pump includes a
mechanical infusion rate selection structure.
47. The kit of claim 45, and further comprising a lancet configured
to act upon the infusion rate selection structure to increase an
infusion rate of the sufentanil through the delivery catheter.
48. The kit of claim 45, wherein the pump is configured to deliver
sufentanil at an infusion rate of a bout 0.5 .mu.g/day to about 300
.mu.g/day over a treatment period.
49. The kit of claim 45, wherein the catheter includes a guidewire
lumen and a sufentanil delivery lumen.
50. The kit of claim 49, further comprising a guidewire.
51. The kit of claim 49, further comprising: a guidewire; a needle,
and a splittable introducer.
52. The kit of claim 51, wherein the needle is one of a hypodermic
needle and a non-coring needle.
53. A kit comprising: an osmotic pump that includes a mechanical
infusion rate selection structure; an amount of pharmaceutical
agent preloaded into the pump, and a delivery catheter.
54. The kit of claim 53, wherein the pharmaceutical agent includes
sufentanil.
55. The kit of claim 53, wherein the infusion rate selection
structure is configured to allow the infusion rate to be increased
while the pump is implanted into a patient.
56. The kit of claim 53, wherein the infusion rate selection
structure includes a plurality of semi permeable membranes, each of
which being selectably exposable to the patient to increase a dose
of pharmaceutical agent delivered to the patient.
57. The kit of claim 56, wherein each of the plurality of semi
permeable membranes has an individually selected thickness,
composition and surface area.
58. A method of delivering a pharmaceutical agent to a patient,
comprising the steps of: implanting an osmotic pump within the
patient, the osmotic pump including the pharmaceutical agent and a
plurality of semi permeable membranes across which osmotic pressure
develops when exposed to the patient, and controlling a surface
area of semi permeable membrane exposed to the patient to control
an infusion rate of the pharmaceutical agent analgesic to the
patient.
59. The method of claim 58, further comprising the step of
controlling at least one of a thickness and a composition of each
of the plurality of semi permeable membranes.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to the field of drug delivery. In
particular, the present invention relates to methods, devices and
systems adapted to sub-chronic implantation (less than or equal to
12 months and typically less or equal to about 6 months) in the
patient's body to deliver a drug or other pharmaceutical agent at a
sustained rate.
[0003] 2. Description of the Related Art
[0004] Since the beginning of modem medicine, drugs have been
administered orally. Patients have taken pills as recommended by
their physician. The pills must pass through the digestive system
and then the liver before they reach their intended delivery site
(e.g., the vascular system). The actions of the digestive tract and
the liver often reduce the efficacy of medication; furthermore,
medications delivered systemically sometimes cause undesirable side
effects. Over the course of the past few decades, drug delivery
technology and administration has evolved from oral delivery to
site-specific delivery. In addition to the oral route of
administration, drugs are also routinely administered via the
vascular system (intravenous or IV). Intravenous drug delivery has
the advantage of bypassing the acidic and enzymatic action of the
digestive system. Unfortunately, IV administration requires the use
of a percutaneous catheter or needle to deliver the drug to the
vein. The percutaneous site requires extra cleanliness and
maintenance to minimize the risk of infection. Infection is such a
significant risk that IV administration is often limited to a
number of weeks, at most. In addition, the patient must wear an
external pump connected to the percutaneous catheter.
[0005] The next step in the evolution of drug delivery was the
implanted pump. The implanted pump is a device that is completely
implanted under the skin of a patient, thereby negating the need
for a percutaneous catheter. These implanted pumps provide the
patient with a drug at a constant or a programmed delivery rate.
Constant rate or programmable rate pumps are based on either
phase-change or peristaltic technology. When a constant, unchanging
delivery rate is required, a constant-rate pump is well suited for
long-term implanted drug delivery. If changes to the infusion rate
are expected, a programmable pump may be used in place of the
constant rate pump. Fully implanted constant rate and programmable
rate infusion pumps have been sold in the United States for human
use since the late 1970s and early 1980s, respectively. Two
problems associated with such 1970s and 1980s vintage constant rate
and programmable rate infusion pumps relate to their size and their
cost. Current implantable constant rate and programmable pumps are
about the size and shape of hockey pucks, and they typically are
sold to the hospital for $5,000-$9,000. The current implantable
pumps must be implanted in the Operating Room under general
anesthesia, which further increases costs, as well as the risk, and
discomfort to the patient. The size and cost of such pumps has
proven to be a substantial barrier to their use, and they are
rarely used to deliver medication. An added drawback of
phase-change and peristaltic pumps is that they must be refilled
with drug every 3-8 weeks. Refills constitute an added burden to
the caregiver, and add further costs to an already overburdened
healthcare system. The burden associated with such refills,
therefore, further limits the use of phase-change and peristaltic
pumps.
[0006] In the 1970s, a new approach toward implanted pump design
was commercialized for animal use only. The driving force of the
pumps based upon this new approach utilized the principle of
osmosis. Osmotic pumps may be much smaller than other constant rate
or programmable pumps, because their infusion rate can be very low.
An example of such a pump is described listed in U.S. Pat. No.
5,728,396. This patent discloses an implantable osmotic pump that
achieves a sustained delivery of leuprolide. The pump includes an
impermeable reservoir that is divided into a water-swellable agent
chamber and a drug chamber. Fluid from the body is imbibed through
a semi permeable plug into the water-swellable agent chamber and
the drug is released through a diffusion outlet at a substantially
constant rate.
[0007] A limitation of the osmotic pump disclosed in the
above-identified patent, however, is that its infusion rate cannot
be adjusted once it is implanted. This is acceptable for
medications that do not need rate adjustment, but often physicians
desire to adjust the infusion rate based on the clinical status of
the patient. One example of when a physician would want to increase
the infusion rate is in the field of pain management. Implanted
pumps can be used to deliver medication to treat pain lasting over
an extended period of time. Pain, however, often increases with
time, and sometimes patients become tolerant to pain medications;
therefore, more medication is needed to effectively treat the pain.
The system disclosed in the above-identified patent does not allow
a rate increase after implantation, so the physician must either
replace the current implant or implant an additional pump to
replace or supplement the system. However, the prospect of yet
another surgical procedure may cause many patients to forego the
potential benefits of the larger dose and may also cause their
physicians to advise against the initial procedure altogether. For
such patients for whom the implantable pump no longer delivers an
adequate dosage of medication, the physician may opt to supplement
the dosage delivered by the implantable device by other means, such
as by intravenous delivery, in which case the same side effects
discussed above may again occur.
[0008] Pain management medications are only one example of
medications that need to be increased in dosage over time. Other
applications may include but are not limited to hypertensive
medications, other cardiovascular medications, and medications to
treat disorders of the brain and endocrine system.
SUMMARY OF THE INVENTION
[0009] An object of the present invention, therefore, is to provide
methods and implantable devices and systems for long-term delivery
of a pharmaceutical agent at selectable rates. It is another object
of the present invention to provide implantable devices and systems
for long term delivery of a drug that are small in size and that
may be readily implanted in a physician's procedure room or a
radiology suite.
[0010] In accordance with the above-described objects and those
that will be mentioned and will become apparent below, an
implantable osmotic pump for delivering a pharmaceutical agent to a
patient comprises a pump housing; a moveable partition disposed
within the housing, the partition dividing the housing into an
osmotic driving compartment having an open end and a pharmaceutical
agent compartment having a delivery orifice; a first semi permeable
membrane disposed in the open end of the osmotic driving
compartment, the first semi permeable membrane being exposed to the
patient; a second semi permeable membrane disposed in the open end
of the osmotic driving compartment, and a first impermeable barrier
disposed over the second semi permeable membrane, the second semi
permeable membrane being sealed from the patient until the first
barrier is breached, wherein breaching the first barrier increases
the surface area of semi permeable membrane exposed to the patient
and increases a delivery rate of the pharmaceutical agent through
the delivery orifice.
[0011] According to further embodiments, the first impermeable
barrier may include titanium and/or stainless steel. A saturated
solution including NaCl may be present between the first
impermeable barrier and the second semi permeable membrane. The
first and second semi permeable membranes may the same composition
and/or may have the same thickness. Alternatively, the first and
second semi permeable membranes may have mutually different
compositions and/or mutually different thickness. The pump may
further include a third semi permeable member, and a second
impermeable barrier may be nested within the first impermeable
barrier. The second impermeable barrier may be disposed over the
third semi permeable membrane and may seal the third semi permeable
membrane from the patient until the second impermeable barrier is
breached. Breaching the second barrier increases the surface area
of semi permeable membrane exposed to the patient and increases the
delivery rate of the pharmaceutical agent through the delivery
orifice.
[0012] A saturated solution including NaCl may be present between
the second barrier and the third semi permeable membrane. The
pharmaceutical agent compartment may contain sufentanil, for
example, and may also contain other medications. The sufentanil may
be at a concentration selected between about 200 .mu.g/mL and about
15,000 .mu.g/mL. The daily delivery rate of the pharmaceutical
agent through the delivery orifice may be selected from about 0.5
micrograms per day to about 25 micrograms per day when the pump is
configured to be implanted intraventricularly; about 0.5 micrograms
per day to about 50 micrograms per day when the pump is configured
to be implanted intrathecally; about 5 micrograms per day to about
300 micrograms per day when the pump is configured to be implanted
epidurally; about 10 micrograms per day to about 300 micrograms per
day when the pump is configured to be implanted subcutaneously.
[0013] The first and second semi permeable membranes may include
cellulose acetate. The first semi permeable membrane may be shaped
as a torus and may be disposed adjacent the outer periphery of the
first impermeable barrier. The second semi permeable membrane may
be disposed in the center opening of the torus.
[0014] A catheter may be coupled to the delivery orifice and the
catheter may have an inner diameter of between about 0.001 inches
and about 0.010 inches. The catheter may include a guidewire lumen
and a pharmaceutical agent infusion lumen. The pharmaceutical agent
infusion lumen may have an inner diameter selected between about
0.001 inches to about 0.010 inches. The catheter and the pump may
be dimensioned to infuse a volume of pharmaceutical agent of
between about 1 .mu.L/day and about 10 .mu.L/day over a treatment
period. The catheter and the pump may be dimensioned to infuse a
dose of pharmaceutical agent of between about 0.5 .mu.g/day and
about 300 .mu.g/day over a treatment period.
[0015] At least a portion of the catheter may be radiopaque. The
guidewire lumen may include a valve to prevent back flow of fluid
into the guidewire lumen.
[0016] The present invention is also a method for achieving an
analgesic effect in a patient. The method comprises the step of
administering a therapeutically effective dose of a
sufentanil-containing analgesic to the patient using a device that
is fully implanted in the patient. The dose may be administered
intravascularly, subcutaneously, epidurally, intrathecally or
intraventricularly. A step of selectively increasing the dose in a
stepwise manner over a treatment period without removing the device
from the patient may also be carried out. The dose may be
administered using an implanted osmotic pump that includes a first
semi permeable membrane exposed to the patient and a second semi
permeable membrane initially not exposed to the patient and wherein
the increasing step may include a step of exposing the second semi
permeable membrane to the patient. The second semi permeable
membrane exposing step may include a step of breaching an
impermeable barrier sealing the second semi permeable membrane from
the patient. The breaching step may include a step of puncturing
the impermeable barrier using a lancet while the pump remains
implanted in the patient. The therapeutically effective dose may be
selected within the range of about 0.5 .mu.g/day to about 300
.mu.g/day.
[0017] According to another embodiment, the present invention may
also be viewed as a method for achieving an analgesic effect in a
patient, the method comprising intraspinal administration of a
therapeutically-effecti- ve dose of an analgesic to the patient by
an osmotic pump and catheter integrated combination, the pump
including a first semi permeable membrane across which an osmotic
pressure gradient develops when the pump is implanted in the
patient.
[0018] The method may also include the step of selectively
increasing a surface area of semi permeable membrane exposed to the
patient in a stepwise manner. The analgesic may include sufentanil
and/or other medication(s). A second semi permeable membrane may be
provided, and the surface area of semi permeable membrane exposed
to the patient may be increased by breaching an impermeable barrier
initially sealing the second semi permeable membrane from the
patient. For example, the impermeable barrier may be breached by
puncturing the impermeable barrier. The dose may be increased in a
stepwise manner by sequentially breaching one of a plurality of
nested impermeable barriers disposed over a corresponding plurality
of the semi permeable membranes, each sequential breach exposing
additional surface area of semi permeable membrane to the patient.
Each of the plurality of nested barriers may be configured to be
breached by a lancet, an outer diameter of the lancet determining
which of the plurality of nested barriers is breached. The
analgesic may be administered intravascularly, subcutaneously,
epidurally or intrathecally. The second semi permeable membrane may
have the same or a different composition as the first semi
permeable membrane. Similarly, the second semi permeable membrane
may have the same or a different thickness as the first semi
permeable membrane.
[0019] The present invention is also an integrated implantable pump
and catheter system for delivering a dose of sufentanil to a
patient over a treatment period, comprising a pump housing; a
moveable partition disposed within the housing, the partition
dividing the housing into an driving engine compartment and a
pharmaceutical agent compartment having a delivery orifice; a
catheter coupled to the delivery orifice, and a preloaded amount of
sufentanil in the pharmaceutical agent compartment.
[0020] The pump and the catheter may be dimensioned to deliver
sufentanil at an infusion rate of about 0.5 .mu.g/day to about 300
.mu.g/day over a treatment period. The system further may further
include a mechanical infusion rate selection structure configured
to allow the infusion rate of the pump to be increased while the
system is implanted in the patient. The infusion rate selection
feature may include a plurality of semi permeable membranes across
each of which osmotic pressure develops when selectively and
sequentially exposed to the patient. Each of the plurality of semi
permeable membranes may have the same or a different thickness,
composition and surface area, the selected thickness, composition
and surface area contributing to a rate at which the sufentanil is
infused into the patient.
[0021] The present invention also encompasses a kit comprising an
osmotic pump; sufentanil preloaded in the osmotic pump, and a
delivery catheter configured to be coupled to the osmotic pump. The
osmotic pump may include a mechanical infusion rate selection
structure. The kit may further include a lancet configured to act
upon the infusion rate selection structure to increase an infusion
rate of the sufentanil through the delivery catheter. The pump may
be configured to deliver sufentanil at an infusion rate of a bout
0.5 .mu.g/day to about 300 .mu.g/day over a treatment period. The
catheter may include a guidewire lumen and a sufentanil delivery
lumen. The kit may further include a guidewire. The kit may also
include a guidewire, a needle and a splittable introducer.
According to still further embodiments, the needle may be a
hypodermic needle or a non-coring needle, for example.
[0022] The present invention is also a kit comprising an osmotic
pump that includes a mechanical infusion rate selection structure;
an amount of pharmaceutical agent preloaded into the pump, and a
delivery catheter. The pharmaceutical agent may include sufentanil
and/or other medication(s). The infusion rate selection structure
may be configured to allow the infusion rate to be increased while
the pump is implanted into a patient. The infusion rate selection
structure may include a plurality of semi permeable membranes, each
of which being selectably exposable to the patient to increase a
dose of pharmaceutical agent delivered to the patient. Each of the
plurality of semi permeable membranes may have an individually
selected thickness, composition and/or surface area.
[0023] According to a still further embodiment thereof, the present
invention is a method of delivering a pharmaceutical agent to a
patient, comprising the steps of implanting an osmotic pump within
the patient, the osmotic pump including the pharmaceutical agent
and a plurality of semi permeable membranes across which osmotic
pressure develops when exposed to the patient, and controlling a
surface area of semi permeable membrane exposed to the patient to
control an infusion rate of the pharmaceutical agent analgesic to
the patient. A step of controlling the thickness and/or a
composition of each of the plurality of semi permeable membranes
may also be carried out.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] For a further understanding of the objects and advantages of
the present invention, reference should be made to the following
detailed description, taken in conjunction with the accompanying
figures, in which:
[0025] FIG. 1 is a schematic diagram illustrating a conventional
drug delivery osmotic pump.
[0026] FIG. 2 is a block diagram illustrating an implantable pump
for long-term delivery of a pharmaceutical agent at selectable
rates according to an embodiment of the present invention, wherein
an impermeable barrier is disposed across an underlying central
semi permeable membrane.
[0027] FIG. 3 is a block diagram illustrating the implantable
device of FIG. 2, illustrating the breaching of the impermeable
barrier.
[0028] FIG. 4 is a block diagram illustrating the implantable
device of FIG. 3, wherein the impermeable barrier is breached,
thereby increasing the aggregate surface area of semi permeable
membrane exposed to the patient.
[0029] FIG. 5 is a block diagram of an implantable pump for
long-term delivery of a pharmaceutical agent at selectable rates
according to another embodiment of the present invention, wherein
the pump includes a plurality of nested impermeable barriers
disposed over and sealing respective underlying semi permeable
membranes.
[0030] FIG. 6 is a block diagram of the implantable pump of FIG. 5,
wherein an outermost impermeable barrier is breached, thereby
increasing the aggregate surface area of semi permeable membrane
exposed to the patient.
[0031] FIG. 7 is a block diagram of the implantable pump of FIG. 6,
wherein the middle impermeable barrier is breached; thereby further
increasing the aggregate surface area of semi permeable membrane
exposed to the patient.
[0032] FIG. 8 is a block diagram of the implantable pump of FIG. 7,
wherein the innermost impermeable barrier is breached; thereby
still further increasing the aggregate surface area of semi
permeable membrane exposed to the patient.
[0033] FIG. 9A is a diagram of a complete implantable pump and
catheter system for long-term delivery of a pharmaceutical agent at
selectable rates, according to an embodiment of the present
invention.
[0034] FIG. 9B is a cross-sectional view of the catheter portion of
the implantable pump of FIG. 9A, taken along lines AA'.
[0035] FIG. 9C is a perspective view of the distal end of the
catheter portion of the implantable pump of FIG. 9A, according to
an embodiment of the present invention.
[0036] FIG. 10 is a cross-sectional side view of an implantable
pump according to an embodiment of the present invention.
[0037] FIG. 11 shows a proximal portion of the implantable pump of
FIG. 10, showing the manner in which the pharmaceutical agent
(e.g., drug) delivery rate of the pump may be increased, according
to an embodiment of the present invention.
[0038] FIG. 12A shows a cross section of the proximal portion of
the implantable pump of FIG. 11 after the impermeable barrier has
been breached.
[0039] FIG. 12B shows an end view of the implantable pump of FIG.
12A.
[0040] FIG. 13 shows a cross-sectional side view of an embodiment
of a lancet that may be utilized to breach the impermeable barrier
of the implantable pump, according to an embodiment of the present
invention.
[0041] FIG. 14A depicts the proximal portion of an implantable pump
for long-term delivery of a drug at selectable rates, wherein the
end-cap portion thereof is removed, according to another embodiment
of the present invention.
[0042] FIG. 14b is a perspective view of the end-cap portion of the
implantable pump of FIG. 14A.
[0043] FIG. 15 is a cross-sectional diagram of tissue surrounding
the spinal fluid wherein the implantable pump according to the
present invention may infuse one or more pharmaceutical agents.
[0044] FIG. 16 is a cross-sectional diagram illustrating the first
steps in introducing the implantable pump into the tissue of FIG.
15, according to the present invention.
[0045] FIG. 17 is a cross-sectional diagram of further steps to be
carried out in introducing the implantable pump system of the
present invention into the tissue of FIG. 15.
[0046] FIG. 18 illustrates a pump for long-term delivery of a
pharmaceutical agent at selectable rates according to the present
invention, fully implanted into the tissue of FIG. 15.
[0047] FIG. 19A is a cross-sectional diagram of a split introducer
and needle used to insert the catheter into the patient, according
to an embodiment of the present invention.
[0048] FIG. 19B shows a longitudinal cross section of a non-coring
needle that may be utilized in combination with the split
introducer of FIG. 19A to insert the catheter into the patient,
according to another embodiment of the present invention.
DESCRIPTION OF THE INVENTION
[0049] FIG. 1 shows a schematic diagram of a conventional osmotic
pump. The pump includes a housing 100. The housing 100 may be
shaped as a cylinder and may be divided into a drug reservoir 102
and an osmotic engine compartment 106. A piston 104 separates the
drug reservoir 102 and the osmotic engine compartment 106. The
movement of the piston 104 toward the delivery orifice 112 provides
the driving force to effuse the drug contained within the drug
reservoir 102. A semi permeable membrane 108 is disposed at one end
of the pump, covering the opening thereof opposite the delivery
orifice 112. The semi permeable membrane 108 is permeable to water.
Therefore, when the pump is placed within the patient's body or
other aqueous medium, water tends to cross the semi permeable
membrane 108 into the osmotic engine compartment 106. The osmotic
engine within the compartment 106 is the driving force that
maintains the solution inside the pump (but outside the reservoir
102) at a fully saturated state. A fully saturated state ensures
that the osmotic pressure differential between the body tissue and
the inside of the pump remains constant. The pressure differential
is maintained constant by a block of osmotic agent (e.g., a salt
block) inside of the osmotic agent compartment 106. In operation,
the piston 104 slides within the housing toward the delivery
orifice 112 as water from the patient's body crosses the semi
permeable membrane 108. In turn, the sliding piston 104 causes the
drug within the reservoir 102 to effuse from the delivery orifice
112.
[0050] FIG. 2 is a block diagram illustrating an implantable pump
for long-term delivery of a pharmaceutical agent (such as a drug or
drugs, for example) at selectable rates, according to an embodiment
of the present invention. The present invention achieves such
selectable effusion rates by exploiting the property of osmotic
pumps that the effusion rate of the drug from the pump of is
substantially proportional to the surface area (among other
factors, such as composition and thickness) of the semi permeable
membrane (such as cellulose acetate, for example) exposed to the
patient or other aqueous solution. The implantable pump according
to an embodiment of the present invention, as shown in FIG. 2,
includes an impermeable rigid (and cylindrical, for example,
although other shapes are also possible) pump housing 200 that is
internally divided into a pharmaceutical agent compartment 202 and
an osmotic driving compartment 206. A piston or other moveable
partition 204 separates the pharmaceutical agent compartment 202
from the osmotic driving compartment 206. The pharmaceutical agent
compartment 202 includes a delivery orifice 212 through which the
pharmaceutical agent is delivered. The delivery orifice 212 may be
coupled to a catheter (not shown in FIG. 2) to deliver the
pharmaceutical agent from the delivery orifice 212 to a selected
location (subcutaneously, epidurally, subdurally, in the
subarachnoid space or thecal sac, intravenously or
intraventricularly, for example) within the patient. The osmotic
driving compartment 206 includes an open end within which a
plurality of semi permeable membranes (two such semi permeable
membranes 214a, 214b being shown in FIG. 2) is disposed. At least a
portion of a peripheral semi permeable membrane 214a is initially
exposed to the patient, thereby allowing a net influx of water from
the patient's body through the exposed peripheral semi permeable
membrane 214a to the osmotic driving engine within the osmotic
driving engine compartment 206. As water from the patient's body
crosses the exposed peripheral semi permeable membrane 214, the
moveable partition 204 is driven toward the delivery orifice 212,
constrained in its motion by the pump housing 200. As the pump
housing 200 is rigid, a volume of pharmaceutical agent
substantially equal to the increase in volume of the osmotic engine
is displaced and pushed out of the pump through the delivery
orifice 212.
[0051] A plurality of semi permeable membranes may be disposed
across the open end of the osmotic driving compartment 206. At
least one of these semi permeable membranes may be covered by an
impermeable barrier, such as shown at 220 in FIG. 2. The barrier
220 may be formed of a biologically inert material that is
impermeable to water and/or other bodily fluids that may be found
in the patient's body at the location wherein the pump is
implanted. For example, the impermeable barrier 220 may include
titanium and/or stainless steel. As shown in FIG. 2, the
impermeable barrier 220 may be disposed away from the surface of
the semi permeable membranes by a spacer 218. The spacer 218 may be
shaped as a cylinder supporting the impermeable barrier 220 above
the central semi permeable membrane 214b underlying the barrier
220. The impermeable barrier 220 may be sealed to the spacer 218
such as to seal the central semi permeable membrane 214b from the
patient. Indeed, as long as the impermeable barrier 220 is intact,
there is no (or substantially no) net influx of water from the
patient into the osmotic engine through the central semi permeable
membrane 214b. When the impermeable barrier 220 is intact, however,
water reaches the osmotic engine only through a plurality of
openings 216 aligned with the peripheral semi permeable membrane
214a, the openings 216 being defined in the structure supporting
the spacer 218 across the open end of the osmotic driving
compartment 206. The interstitial space 224 between the impermeable
barrier 220 and the surface of the central semi permeable membrane
214b may include a saturated saline solution, to prevent the
underlying semi permeable membrane 214b from drying out and to
maintain solutions of equal osmolarity on either side of the
central semi permeable membrane 214b. The peripheral semi permeable
membrane 214a may be a torus-shaped (doughnut-shaped) membrane
disposed adjacent an outer periphery of spacer 218 sealing the
underlying central semi permeable membrane 214b from the patient.
The spacer 218 (and thus the central semi permeable membrane 214b)
may be disposed in the center opening of the torus-shaped
peripheral permeable membrane 214a. The underlying central semi
permeable membrane 214b, therefore, may be concentric with the
peripheral permeable membrane 214a.
[0052] There are occasions when the physician may wish to increase
the dose of the pharmaceutical agent initially delivered to the
patient, such as when the level of pain experienced by the patient
increases, as a result of the progression of the patient's disease
or habituation, for example. Previously, increasing the infusion
dose of an osmotic pump entailed subjecting the patient to a
further procedure to remove the previously implanted pump to
substitute therefor a new pump that delivers a larger dose.
According to an embodiment of the present invention, however, the
physician may increase the dose of pharmaceutical agent delivered
while the pump disclosed herein remains implanted within the
patient through a simple and short procedure that may be carried
out within the physician's office or in a radiology suite, for
example. Indeed, when the physician wishes to increase the delivery
rate of the pharmaceutical agent through the delivery orifice 212
(or a catheter coupled thereto), the impermeable barrier 220 may be
breached percutaneously by a thin, elongated and rigid member 222
(hereafter lancet), as shown in FIG. 3. Preferably, the outer
diameter of the lancet 222 is somewhat greater than the inner
diameter of the spacer 218. These relative dimensions prevent the
lancet 222 from being inserted too far. That is, the relative
dimensions of the lancet 222 and the spacer 218 are such that when
the lancet 222 is percutaneously inserted in the patient to breach
the impermeable barrier 220, the spacer 218 prevents the lancet 222
from damaging the underlying central semi permeable membrane 214b,
breaching the osmotic driving compartment 206 or otherwise damaging
the pump. Preferably, the lancet 222 is inserted only as far as to
breach the impermeable barrier 220 and to allow a free influx of
water from the patient's body into the previously sealed
interstitial space 224 between the underlying central semi
permeable membrane 214b and the impermeable barrier 220.
[0053] When the impermeable barrier 220 is breached and the lancet
222 is retracted from the spacer 218, water from the patient's body
reaches the central semi permeable membrane 214b, as indicated by
the arrows pointing within the spacer 218 shown in FIG. 4. The
effect of breaching the impermeable barrier 220 and allowing water
to reach the central semi permeable membrane 214b is to increase
the net surface area of semi permeable membrane exposed to the
patient. Indeed, once the impermeable barrier 220 is breached, the
aggregate surface area of semi permeable membrane exposed to the
patient is substantially equal to the sum of the surface areas of
the peripheral and central semi permeable membranes 214a and 214b.
When the barrier 220 is breached, water from the patient also
reaches the osmotic engine through openings 217 aligned with the
semi permeable membrane 214b. Increasing the surface area of semi
permeable membrane exposed to the patient, therefore, increases the
influx of water therethrough, which in turn increases the delivery
rate of the pharmaceutical agent through the delivery orifice 212.
Thus, the effusion rate of the pump according to the present
invention has been increased without removing the pump from the
patient, thereby affording the patient an increased dose of
pharmaceutical agent (such as an analgesic, for example). The
surface area, thickness and/or composition of the semi permeable
membranes 214a and 214b may be manipulated to achieve a
fine-grained control over the effusion rate of the pharmaceutical
agent from the orifice 212 and any catheter coupled thereto.
[0054] The embodiment of the present invention shown in FIGS. 2
through 4 allows a one step increase in the dose of pharmaceutical
agent delivered to the patient, from a first initial dose to a
subsequent second, larger dose. However, the present invention is
not limited to a one step increase in the dose of pharmaceutical
agent delivered to the patient. Indeed, FIGS. 5 though 8 illustrate
another embodiment of the present invention wherein the dose
delivered to the patient may be increased in situ three times, from
a first initial dose to a fourth dose, each subsequent dose being
larger than the previous dose. The present invention may also
readily be configured for a lesser or greater number of
physician-selectable effusion rates. Turning first to FIG. 5,
reference numerals 200, 202, 204, 206 and 212 denote structures
finding exact counterparts in FIGS. 2 through 4. The description
above of the structures referenced by these numerals is, therefore,
incorporated herein by reference.
[0055] Rather than the single spacer 218 supporting a single
impermeable barrier 220 as illustrated in FIGS. 2-4, the embodiment
of FIGS. 5 through 8 includes three such spacers, each of which
supports a separate and distinct impermeable barrier. Indeed, the
pump of FIGS. 5 through 8 includes a first spacer 518a that
supports a first impermeable barrier 520a. Nested within the first
spacer 518a, according to the embodiment shown in FIGS. 5 through
8, is a second spacer 518b that supports a second impermeable
barrier 520b. In turn, nested within the second spacer 518b is a
third spacer 518c that supports a third impermeable barrier 520c.
Each of the barriers 520a, 520b and 520c is sealed to its
respective spacer 518a, 518b and 518c. Disposed within the open end
of the osmotic driving compartment 206 is a plurality of separate
semi permeable membranes. As shown in FIG. 5, a peripheral semi
permeable membrane 514p is disposed adjacent an outer periphery of
the base of the first spacer 518a. At least a portion of the
peripheral semi permeable membrane 514p is exposed to the patient
environment when the pump is initially implanted into the patient.
Therefore, water or other aqueous fluid from the patient that has
traveled through the peripheral semi permeable membrane 514p may
reach the osmotic driving engine within the compartment 206 through
the openings 516 facing the peripheral semi permeable membrane
514p. The openings 516 are defined by the pump housing 200 and the
structure supporting the spacer 518a across the open end of the
osmotic driving compartment 206. In the state of the pump
illustrate in FIG. 5, the patient receives an initial first dose of
pharmaceutical agent, the dose being proportional to the surface
area (and/or composition and/or thickness) of the peripheral semi
permeable membrane 514p exposed to the patient.
[0056] Turning now to FIG. 6, a first lancet 522a may be used to
breach the first impermeable barrier 520a. The outer diameter of
the lancet 522a is preferably somewhat larger than the inner
diameter of the first spacer 518a, so as to cause the lancet 522a
to breach only the first impermeable barrier 520a. Once the lancet
522a is retracted from the pump, fluids from the patient may reach
the first inner semi permeable membrane 514a. Therefore, water or
other aqueous fluid from the patient that has traveled through the
first inner semi permeable membrane 514a may reach the osmotic
driving engine within the compartment 206 through the openings 517
facing the first inner semi permeable membrane 514a. The aggregate
surface area of semi permeable membrane exposed to the patient is,
in the state of the pump shown in FIG. 6, the sum of the surface
areas of the peripheral semi permeable membrane 514p and the first
inner semi permeable membrane 514a. Therefore, the effusion rate of
the pharmaceutical agent from the compartment 202 to the patient is
now proportional to the increased area (and/or composition and/or
thickness) of the semi permeable membrane exposed to the patient,
resulting in the delivery of a second dose of pharmaceutical agent,
the second dose being greater than the first dose administered when
the pump is in the state illustrated in FIG. 5.
[0057] As shown in FIG. 7, a second lancet 522b may be used to
breach the second impermeable barrier 520b. The outer diameter of
the second lancet 522b is preferably somewhat larger than the inner
diameter of the second spacer 518b (and smaller than the inner
diameter of the lancet 522a), so as to cause the lancet 522b to
breach only the second impermeable barrier 520b. Once the lancet
522b is retracted from the pump, fluids from the patient
environment in which the pump is implanted may also reach the
second inner semi permeable membrane 514b. Therefore, water or
other aqueous fluid from the patient that has traveled through the
second inner semi permeable membrane 514b may reach the osmotic
driving engine within the compartment 206 through the openings 518
facing the second semi permeable membrane 514b. The surface area of
semi permeable membrane exposed to the patient is, in the state of
the pump shown in FIG. 7, the sum of the surface areas of the
peripheral semi permeable membrane 514p, the first inner semi
permeable membrane 514a and the second inner semi permeable
membrane 514b. Therefore, the effusion rate of the pharmaceutical
agent from the compartment 202 to the patient is now proportional
to this increased area (and/or composition and/or thickness) of
semi permeable membrane exposed to the patient, thereby resulting
in the delivery of a third dose of pharmaceutical agent, the third
dose being greater than either of the first and second doses
administered when the pump is in the states illustrated in FIGS. 5
and 6.
[0058] Similarly, as shown in FIG. 8, a third lancet 522c may be
used to breach the third impermeable barrier 520c. The outer
diameter of the lancet 522b is preferably somewhat larger than the
inner diameter of the third spacer 518c (and smaller than the inner
diameter of the first or second effusion pens 522a, 522b), so as to
cause the lancet to breach only the third impermeable barrier 520c
without, however, damaging the third semi permeable membrane 514c.
Once the lancet 522c is retracted from the pump, fluids from the
patient environment in which the pump is implanted may also reach
the third inner semi permeable membrane 514c. Therefore, water or
other aqueous fluid from the patient that has traveled through the
third inner semi permeable membrane 514c may reach the osmotic
driving engine within the compartment 206 through the openings 519
facing the third inner semi permeable membrane 514c. The surface
area of semi permeable membrane exposed to the patient is, in the
state of the pump shown in FIG. 8, the sum of the surface areas of
the peripheral semi permeable membrane 514p, the first semi
permeable membrane 514a, the second semi permeable membrane 514b
and the third semi permeable membrane 514c. Therefore, the effusion
rate of the pharmaceutical agent from the compartment 202 to the
patient is now proportional to this increased area (and/or
composition and/or thickness) of semi permeable membrane exposed to
the patient, thereby resulting in the delivery of a fourth dose of
pharmaceutical agent, the fourth dose being greater than the first,
second or third doses administered when the pump is in the states
illustrated in FIGS. 5, 6 and 7. A saturated saline solution is
present in each of the interstitial spaces shown at reference
numerals 524a, 524b and 524c.
[0059] The peripheral semi permeable membrane 514p may be a
torus-shaped membrane disposed adjacent the outer periphery of the
first spacer 518a. Likewise, the first semi permeable membrane 514a
may be a torus-shaped membrane disposed adjacent an outer periphery
of the second spacer 518b. Similarly, the second semi permeable
membrane 514b may be a torus-shaped membrane disposed adjacent an
outer periphery of the third spacer 518c. The third semi permeable
membrane 514c may be shaped as a right cylinder or a disk disposed
within the open end of the osmotic driving compartment 206, aligned
with the third spacer 518c. The semi permeable membranes 514p,
514a, 514b and 514c may, therefore, be concentrically disposed
relative to one another. Moreover, each of the semi permeable
membranes 514p, 514a, 514b and 514c may have a different surface
area and/or thickness and/or composition, thereby allowing a high
degree of control over the effusion rate of the pharmaceutical
agent to the patient.
[0060] Various modifications to the above-described pump may occur
to those of skill in this art. For example, the pump housing 200
may be extended at least as far as to cause the proximal edge
thereof (the proximal end of the pump being defined as that end of
the pump that is closest to the semi permeable membranes and the
distal end thereof being defined as that end that is closest to the
delivery orifice 212) to be coplanar with the first impermeable
barrier 520a, to protect the nested spacers 518a, 518b and 518c and
to provide additional rigidity to the pump. Also, the lancets 522a,
522b and 522c may be combined in a single adjustable device,
wherein structural characteristics of the lancet such as the
diameter of the device and/or the length to which it penetrates
within the nested spacer structures 518a, 518b and 518c may be
selectively adjusted by the physician depending upon the dose of
pharmaceutical agent to be delivered. For example, such structural
characteristics may be selected on such a lancet by "dialing" the
selected dose increase on the lancet on an adjusting wheel or dial
integrated in the pen.
[0061] FIG. 9A is a diagram of a complete fully implantable pump
and catheter assembly 600 for long-term delivery of a
pharmaceutical agent at selectable rates, according to an
embodiment of the present invention. As shown, the implantable pump
includes two major portions: the pump 610 and the catheter 650. The
pump 610 and the catheter 650, according to an embodiment of the
present invention, are preferably coupled together, so that the
physician needs not perform any assembly before implanting the
device into the patient. Moreover, the pharmaceutical agent may be
preloaded into the compartment 202 (see FIGS. 2 through 8) of pump
610 to allow immediate use of the pump and catheter assembly 600
upon unpacking thereof in the physician's procedure room or
radiology suite. The pump 610 may include the structures and
functionality of the pumps discussed above relative to FIGS. 2-4
and/or FIGS. 5-8. According to an embodiment of the present
invention, the catheter 650 may be a dual-lumen catheter. FIG. 9B
is a cross-sectional view of such a dual-lumen catheter 650, taken
along lines AA' of FIG. 9A. As shown therein, the catheter 650
includes an infusion lumen 652 that is proximately attached to the
osmotic pump 610, such as to its delivery orifice 212, as shown in
FIGS. 2-8. The pharmaceutical agent, therefore, flows from the pump
610 to the distal end of the catheter 650 (the end thereof farthest
away from the pump 610) to be released within the patient (such as
within the patient's epidural and/or intrathecal space, for
example). The catheter 650 may also include a guidewire lumen 654
through which may be inserted a guidewire 656. The guidewire 656
may be equipped with a guidewire torque 658, to facilitate
manipulation of the guidewire 656 within the patient. The guidewire
lumen 654 may span at least a portion of the length of the catheter
650. The guidewire 656 may be inserted into the guidewire lumen 654
of the catheter 650 through a guidewire port 660. The guidewire
port 660 may be formed, for example, as a slit in the catheter
650.
[0062] FIG. 9C is a perspective view of the distal end of the
catheter 650 of the implantable pump and catheter assembly of FIG.
9A, according to an embodiment of the present invention. As shown
therein, the infusion lumen may terminate as an open lumen, to
allow the pharmaceutical agent to exit the catheter 650. The
guidewire lumen 654, according to an embodiment of the present
invention, may include a distal valve 662, such as a plug of
elastomeric material (such as silicone or polyurethane, for
example) with a slit therein. The distal valve 662 prevents back
flow of the pharmaceutical agent released into the patient through
the guidewire lumen 654. Such back flow may occur due to the
pressure differential between the patient environment (such as the
spinal fluid) and the guidewire port 660. That is, the spinal fluid
may be at a higher pressure than the pressure in the guidewire
lumen 654 and the outside. In the absence of a distal valve 662 or
other means for preventing back flow, the pharmaceutical agent
effluent and spinal fluid may tend to flow back proximally toward
the pump 610 through guidewire lumen 654 (once implanted). Such a
distal valve 662 allows the guidewire 656 to be pushed therethrough
but prevents back flow of the pharmaceutical agent or bodily fluids
(such as spinal fluid) through the guidewire lumen 654 when the
guidewire 656 is removed.
[0063] The distal end of the catheter 650, as shown in FIG. 9C, may
include a radio opaque marker 664 to allow the distal tip of the
catheter 650 to be clearly visible through fluoroscopy. Such distal
marker 664 facilitates the insertion of the catheter portion 650 of
the implantable pump 600 and catheter assembly under fluoroscopic
guidance in a radiology suite, for example. To further aid
implantation of the pump 600 under fluoroscopic guidance, radio
opaque length markers 666 may be disposed on or incorporated within
the length of the catheter 650. This allows the physician to gauge
the length of catheter 650 inserted into the patient.
Alternatively, the entire length of the catheter 650 may include a
radio opaque material.
[0064] Alternatively still, the distal valve 662 may be omitted, as
may be the distal radio opaque marker 664. Instead, the catheter
650 according to the present invention may be radio opaque over at
least a portion of its entire length and include a proximal
guidewire valve 668 disposed within the guidewire lumen 654 at or
adjacent to the guidewire port 660. The combination of a radio
opaque catheter 650 and a proximal guidewire valve 668 allows the
physician to adjust the length of the catheter 650 by trimming the
distal end thereof according to the needs of the procedure at hand
and/or the patient's anatomy. Any suitable radio opaque material
may be used to render all or a portion or selected portions of the
catheter 650 radio opaque. For example, the catheter 650 may be
formed of silicone or polyurethane and may be doped with barium
sulfate, for example. The length of the catheter 650 may be most
any therapeutically effective length. A longer length, however,
increases the dead space therein and delays the effusion of the
pharmaceutical agent into the patient, as it will take longer for
the agent to travel from the delivery orifice 212 to the free
distal end of the infusion lumen 652. For example, the catheter 650
may be about 5 cm to about 100 cm in length. More preferably, the
catheter 650 may be about 10 cm to about 30 cm in length. More
preferably still, the catheter 650 may be about 15 cm to about 25
cm in length. For example, the catheter 650 may be about 20 cm in
length. The guidewire 656 may be about 0.014 inches to about 0.038
inches in diameter. The internal diameter (ID) of the infusion
lumen 652 may be selected within the range of about 0.001 inches to
about 0.010 inches. The walls of the catheter 650 may be about
0.001 inches to about 0.006 inches in thickness. According to an
embodiment of the present invention, the outer diameter (OD) of the
catheter 650 may be selected between about 0.024 inches and about
0.066 inches in thickness.
[0065] Tables 1 and 2 show the time required to infuse the dead
space volume of the catheter of the implantable pump system
according to the present invention, for an infusion rate of 1.75
and 5 microliters/day (.mu.L/day), respectively.
1TABLE 1 1.75 Microliter/Day infusion Rate Time To Infuse Dead
Space Volume of Catheter (in hours) Catheter Diameter Catheter
Length (cm) (in.) 10 15 20 40 0.001 0.7 1.0 1.4 2.8 0.002 2.8 4.2
5.6 11.1 0.005 17.4 26.1 34.7 69.5 0.010 69.5 104.2 139.0 278.0
[0066]
2TABLE 2 5 Microliter/Day infusion Rate Time To Infuse Dead Space
Volume of Catheter (in hours) Catheter Diameter Catheter Length
(cm) (in.) 10 15 20 40 0.001 0.2 0.4 0.5 1.0 0.002 1.0 1.5 2.0 3.9
0.005 6.1 9.1 12.1 24.3 0.010 24.3 36.5 48.7 97.3
[0067] FIG. 10 is a cross-sectional view of an implantable pump
700, according to a further embodiment of the present invention.
The pump 700 of FIG. 10 includes a rigid pump housing 702. The pump
housing 702 encloses a moveable partition 704 that separates a
pharmaceutical agent compartment 706 for enclosing a pharmaceutical
agent 708 from an osmotic driving compartment 710 for enclosing an
osmotic engine 712 (salt block). At the proximal end of the osmotic
driving compartment 710 is disposed a pair of semi permeable
polymer membranes 728, 730, such as cellulose acetate membranes.
The pump 700 may include a peripheral torus-shaped semi permeable
membrane (or a plurality of such peripheral semi permeable
membranes) 728 and a central semi permeable membrane 730, the
latter being surrounded and sealed from the patient by the spacer
718. The peripheral torus-shaped semi permeable membrane 728 is in
fluid communication with the osmotic engine through openings 736
and the central semi permeable membrane 730 is in fluid
communication with the osmotic engine 712 through openings 738. The
spacer 718 supports an impermeable barrier 716 away from the
underlying central semi permeable membrane 730. The impermeable
barrier 716 may be formed of titanium and/or stainless steel, for
example. The interstitial space between the impermeable barrier 716
and the underlying central semi permeable membrane 730 includes a
saturated saline solution 720. According to the embodiment of FIG.
10, the distal end of the pump 700 defines a threaded opening 732.
A nipple 722 may be screwed onto the threaded opening 732. The
nipple 722 may include a centrally-disposed nipple infusion lumen
734. The nipple infusion lumen 734 may be seen as functionally
equivalent to the delivery orifice 212 of FIGS. 2 through 8. The
nipple 722 may have a shape that tapers distally and may include a
proximal recessed feature 736 that allows an elastomeric strain
relief element 724 to be snapped and secured thereon. The proximal
region of the strain relief element may be flush with the pump
housing 702, while the distal end thereof may taper to allow the
catheter 726 to be sealed or press-fitted thereto. The distal
portion of the catheter 726 is not shown in FIG. 10. The catheter
may have a structure similar to that disclosed relative to catheter
650 in FIG. 9. Alternatively, as shown in FIG. 10, the catheter 726
may include a single effusion lumen 738.
[0068] FIG. 11 shows a cross section (taken along line AA" of FIG.
12B) of the proximal portion of the implantable pump 700 of FIG.
10, showing the manner in which the pharmaceutical agent delivery
(infusion) rate of the pump 700 may be increased, according to an
embodiment of the present invention, whereas FIG. 12A shows a cross
section (also taken along line AA" of FIG. 12B) of the proximal
portion of the implantable pump of FIG. 11 after the impermeable
barrier 716 has been breached. When the implantable pump 700 is
initially implanted into the patient, only the peripheral semi
permeable membrane 728 is exposed to the patient's bodily. The
surface area of the torus-shaped (for example) peripheral semi
permeable membrane 728 establishes the initial effusion rate of the
pharmaceutical agent(s) from the compartment 706. When the lancet
740 breaches the impermeable barrier 716, the surface area of semi
permeable membrane exposed to the patient is increased to include
the surface area of the central semi permeable membrane 730 as
well. According to the present invention, the relative ratio
between the surface areas of the semi permeable membranes exposed
and not exposed to the patient controls the effusion rate of the
pharmaceutical agent from the pump 700. Additionally, by varying
the composition and/or thickness (in place of or in addition to the
surface areas thereof) of the semi permeable membranes of the
present invention, different step effusion rate functions may
readily be achieved upon breaching the impermeable barrier(s) of
the pump.
[0069] FIG. 13 shows an embodiment of a lancet 740 that may be
utilized to breach the impermeable barrier 716 of the implantable
pump according to the present invention. The lancet 740 may include
a hollow cylindrical portion 742 sharpened at its distal end and a
reservoir 744. The reservoir 744 may be formed of an elastomeric
material (such as silicone, for example), to allow the physician to
squeeze the reservoir between his or her fingers. The reservoir 744
may contain water or a saturated saline solution, collectively
referenced by the numeral 746 in FIG. 13. When the physician wishes
to increase the dose of pharmaceutical agent delivered to the
patient, he or she may breach (puncture) the impermeable barrier
716 of the pump 700 using an appropriately dimensioned lancet 740.
Thereafter, the reservoir 744 may be squeezed to flush the saline
solution contained therein into the interstitial space 720 between
the central semipermeable membrane 730 and the impermeable barrier
716. The lancets 222, 522a, 522b and/or 522c or FIGS. 2 through 8
may be configured as shown in FIG. 13a. Alternatively, the
aforementioned lancets may include appropriately dimensioned hollow
or solid needles, such as hypodermic needles, for example.
[0070] FIG. 14A is a perspective view of the proximal portion of an
implantable pump for long-term delivery of a pharmaceutical agent
at selectable rates, wherein an end-cap portion thereof is removed,
to illustrate a further embodiment of the present invention. FIG.
14B is a detail view of an end-cap portion configured to fit on the
proximal portion of the pump shown in FIG. 14A. The implantable
pump shown in FIG. 14A includes a pump housing 800 that encloses a
pharmaceutical agent compartment (not shown in FIG. 14b), a
moveable partition or piston (also not shown in FIG. 14a), as well
as an osmotic driving compartment enclosing an osmotic engine 804.
Semi permeable membranes are disposed adjacent the free end of the
osmotic driving engine compartment 802; namely a peripheral semi
permeable membrane 806 and a central semi permeable membrane 808.
Separating the two semi permeable membranes 806 and 808 is a spacer
810. The spacer 810, as shown in FIG. 14A, may be shaped as a right
cylinder, although other spacer shapes are possible. The peripheral
semi permeable membrane 806 may be disposed about the base of the
spacer 810 that is, in the distal portion thereof. Indeed, the
peripheral semi permeable membrane 806 may be disposed adjacent the
spacer 810 and around its outer periphery, thereby forming a
generally toroidal shape. The central semi permeable membrane 808
may be disposed within the spacer 810, also toward the distal end
thereof. The peripheral semi permeable membrane 806 and the central
semi permeable membrane 808 may be approximately and mutually
co-planar, albeit separated by at least the thickness of the wall
of the spacer 810. The generally disc-shaped structure forming the
distal base of the spacer 810 defines a plurality of openings 816
aligned with the peripheral semi permeable membrane 806 and a
plurality of openings 817 aligned with the central semi permeable
membrane 808. The openings 816 allow the influx of water that has
traveled from the patient's body through the peripheral semi
permeable membrane 806 to reach the osmotic driving compartment 802
and thus to reach the osmotic engine 804. According to an
embodiment of the present invention, the impermeable barrier 822
may be fitted onto the free proximal end 818 of the spacer 810.
Alternatively, the proximal portion of the spacer 810 may define a
threading 812 adapted to receive a mating threaded end-cap 820, as
shown in FIG. 14B. As shown in FIG. 14B, the end-cap 820 may fit
over and screw on the free proximal end 818 of the spacer 810. The
impermeable barrier 822 may be disposed across the end-cap 820.
When the end-cap 820 is screwed onto the free proximal end 818 of
the spacer 810, the underlying central semi permeable membrane 808
is sealed from the patient's bodily fluids until and if the
impermeable barrier 822 is breached. Struts 824 attached to the
end-cap 820 may span the distance between the end-cap 820 and the
proximal edge of the pump housing 800 to lend additional support
and stability to the assembly including the end-cap 820 and the
pump housing 800. According to an embodiment of the present
invention, the end cap 820 may be welded to the spacer 810 and pump
housing 800. As shown, the proximal edge of the pump housing 800
may be approximately coplanar with the proximal free end 818 of the
spacer 810. The interstitial space between the end-cap 820 and the
underlying central portion 808 of the semi permeable membrane is
preferably filled with a saturated solution of relatively high
osmolarity, such as sodium chloride NaCl). When the impermeable
barrier 822 is breached, the openings 817 (FIG. 14A) allow the
influx of water that has traveled from the patient's body through
the central semi permeable membrane 808 to reach the osmotic
driving compartment 802 and thus to reach the osmotic engine
804.
[0071] FIGS. 15 through 18 illustrate a method of and kits for
implanting an implantable pump for long-term delivery of a
pharmaceutical agent at selectable rates, according to the present
invention. One method of introducing the pump and catheter
combination according to the present invention (shown in FIG. 9a,
for example) is known as the "Seldinger Technique" often used to
insert catheters through patients' vasculatures. FIGS. 15 through
18 illustrate a method of implanting the pump subcutaneously so the
distal free distal end of the integrated catheter lies in the
intraspinal space which contains cerebrospinal fluid (hereafter
CSF). The integrated catheter may also be inserted epidurally; that
is, adjacent the dura matter surrounding the brain and spinal cord.
Returning now to FIG. 15, the CSF is contained within the dura
matter 910, over which lies a superficial tissue layer 900. FIG. 15
does not show the spinal cord or any of the bony structures
thereof.
[0072] As shown in FIG. 16, to insert the integrated pump and
catheter assembly according to the present invention, a split
introducer 930 and hypodermic needle 932 is inserted through the
superficial tissue layer 900 and the dura 910. The preferred split
introducer 930 according to the present invention is shown in cross
section in FIG. 19. As shown therein, the split introducer 930 has
a conical tapered shape to facilitate blunt dissection of the
superficial tissue 900 and the dura matter 910, thereby easing the
introduction of the catheter (such as shown at 650 in FIG. 9A)
therethrough and into the CSF 920. The split introducer 930 may be
shaped so as to be in intimate contact with a needle 932 (such as
the hypodermic needle shown in FIGS. 16 and 19 or the non-coring
needle 932 shown in cross section in FIG. 19, for example), and may
become larger towards its proximal end. As the dura matter 910 is
very elastic, it tends to recoil as the split introducer 930 is
inserted therethrough. The split introducer 930 may blunt dissects
the dura matter 910 and may tear it somewhat as it enlarges the
passageway through which it tunnels. Alternatively, a non-coring
needle (an example of which is shown in cross-section in FIG. 19B)
may be used in place of the hypodermic needle shown in FIGS. 16 and
19A. Returning to FIG. 16, a needle 932 is then inserted through
the split introducer 930. The needle 932 may be formed of metal,
such as stainless steel. Alternatively, the needle 932 may be
inserted into the split introducer 930, and the assembly introduced
through the superficial tissue 900, the dura matter 910 and into
the CSF 920. A guidewire 656 is then introduced through the needle
932 and the guidewire 656 is then left in place. The needle 932 is
then removed, leaving the split introducer 930 and guidewire 656 in
place. The catheter 610 (see FIG. 9A) is then introduced over the
guidewire 656 as shown in FIG. 17, the guidewire 656 traveling
within the guidewire lumen (reference numeral 654 in FIG. 9A). Once
the catheter 650 is in place, the split introducer 930 may be
peeled off and removed. As shown in FIG. 18, a subcutaneous pocket
934 may then be formed between the superficial tissue 900 and the
dura matter 910, and the pump 610 may then be tunneled therein and
the pocket 934 sutured close at 935a. Alternatively, the dura
matter 910 may sutured close around catheter 650 at 935b before the
superficial tissue 900 is sutured. As shown in FIG. 18, the distal
end of the catheter 650 is disposed at the desired location within
the CSF 920 where the pharmaceutical agent 936 may be released.
[0073] Electromechanical implantable pumps are rather large devices
and are designed to deliver relatively large volumes of drugs to
the patient, whether intravenously, epidurally or intrathecally.
The implantable pump system for long-term delivery of a
pharmaceutical agent at selectable rates according to the present
invention, however, is a smaller device able to deliver a minute,
continuous and step-wise selectable flow of a pharmaceutical agent
for a long period of time, such as about 6 or 12 months.
Consequently, the procedure required to implant the pump system
according to the present invention is a less traumatic and simpler
procedure than is traditionally required to implant relatively
larger electromechanical devices.
[0074] For illustrative purposes only and with particular reference
to FIGS. 9A and 10, the length of the pump 610, 700 may be about
1.25 inches and the diameter thereof may be about 0.14 inches. The
pharmaceutical agent compartment (see reference 202 in FIGS. 2
through 8 and reference 708 in FIG. 10) of such a pump 610, 700 may
contain about 0.32 milliliters (ml) of drug or other pharmaceutical
agent. Continuing with the same example, the length of the catheter
650 may be about 12 inches with an ID of 0.0025 inches, for a dead
space volume (primer volume) therein of about 0.001 ml. A small
dead space volume means that the time required for the
pharmaceutical agent to reach its destination from the
pharmaceutical agent compartment is short. Such an osmotic
pump-catheter assembly according to the present invention may
infuse about 1.75 microliters (.mu.L) of a drug per day for about
180 days, or about 6 months. For a larger infusion rate of about,
for example, 5 .mu.L per day for a period of about 180 days, the
length of the pump 610, 700 may be about 1.25 inches and the
diameter thereof may be about 0.24 inches. The pharmaceutical agent
compartment (see reference 202 in FIGS. 2 through 8 and reference
708 in FIG. 10) of such a pump 610, 700 may contain about 0.9 ml of
drug or other pharmaceutical agent. The length of the catheter 650
may be about 12 inches with an ID of 0.005 inches, for a dead space
volume therein of about 0.0038 ml. To offer significant pain relief
while delivering only about 1 to about 5 .mu.L per day (defined as
a 24 hour period), the pharmaceutical agent contained in the
compartment 202, 708 must be a potent analgesic agent. The opioids
(morphine, for example) conventionally used in implantable pumps
would not be therapeutically effective in controlling pain at the
above-cited infusion rates. According to the present invention, the
pharmaceutical agent compartment 202, 708 may contain sufentanil
(such as sufentanil citrate), an opioid that is about 700 to 1,000
times more potent than morphine. This greater potency allows a
small volume of drug to alleviate significant pain.
[0075] Table 3 is provided to allow a comparison of the dosage
needed to achieve a same analgesic effect, across different modes
of delivery using the implantable pump system according to the
present invention.
3 TABLE 3 Equianalgesic Conversion factor Oral 300 Intravascular
100 Subcutaneou 100 Epidural 10 Intrathecal 1
[0076] As can be seen, delivering an analgesic within the
intrathecal space requires a dosage that is 300 hundred times
smaller than the dosage needed to achieve the same analgesic effect
when the drug is given orally. There is, however, not a direct
correlation in the equianalgesic conversion chart for the
intravascular and subcutaneous routes. Indeed, as the patient's
need for more medication increases, they will be converted to other
modes of delivery.
[0077] Table 4 illustrates the starting and expected maximum dosage
range of sufentanil using the implantable pump system of the
present invention, as the system is implanted intravascularly,
subcutaneously, epidurally, intrathecally and intraventricularly,
according to further embodiments of the present invention.
4 TABLE 4 Starting Expected Dosage Maximum Range Dosage (.mu.g/day)
(.mu.g/day) Intravascular 10-100 300 Subcutaneous 10-100 300
Epidural 5.0-50 300 Intrathecal 0.5-5.0 50 Intraventricular 0.5-2.5
25
[0078] While the foregoing detailed description has described
preferred embodiments of the present invention, it is to be
understood that the above description is illustrative only and not
limiting of the disclosed invention. Moreover, Those of skill in
this art will recognize other alternative embodiments and all such
embodiments are deemed to fall within the scope of the present
invention. Thus, the present invention should be limited only by
the claims as set forth below.
* * * * *