U.S. patent application number 10/719007 was filed with the patent office on 2004-08-12 for devices and methods for pain management.
Invention is credited to Johnson, Randolph Mellus, Theeuwes, Felix.
Application Number | 20040157884 10/719007 |
Document ID | / |
Family ID | 22420446 |
Filed Date | 2004-08-12 |
United States Patent
Application |
20040157884 |
Kind Code |
A1 |
Johnson, Randolph Mellus ;
et al. |
August 12, 2004 |
Devices and methods for pain management
Abstract
The invention features devices and methods for the systemic
delivery of fentanyl or a fentanyl congener (e.g., sufentanil) to
treat pain. In the present invention, a drug formulation comprising
fentanyl or a fentanyl congener is stored within a drug delivery
device (e.g., contained in a reservoir or impregnated within a
matrix within the controlled drug delivery device). The drug
formulation comprises an amount of drug sufficient for treatment
and is stable at body temperatures (i.e., no unacceptable
degradation) for the entire pre-selected treatment period. The drug
delivery devices store the drug formulation safely (e.g., without
dose dumping), provide sufficient protection from bodily processes
to prevent unacceptable degradation of the formulation, and release
the drug formulation in a controlled fashion at a therapeutically
effective rate to treat pain. In use, the drug delivery device is
implanted in the subject's body at an implantation site, and the
drug formulation is released from the drug delivery device to a
delivery site. The delivery site may be the same as, near, or
distant from the implantation site. Once released at the delivery
site, the drug formulation enters the systemic circulation and is
transported to the site of action in the body to modulate the pain
response (e.g., the brain or other pain sensory location).
Inventors: |
Johnson, Randolph Mellus;
(Half Moon Bay, CA) ; Theeuwes, Felix; (Los Altos
Hills, CA) |
Correspondence
Address: |
BOZICEVIC, FIELD & FRANCIS LLP
200 MIDDLEFIELD RD
SUITE 200
MENLO PARK
CA
94025
US
|
Family ID: |
22420446 |
Appl. No.: |
10/719007 |
Filed: |
November 20, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10719007 |
Nov 20, 2003 |
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10306727 |
Nov 26, 2002 |
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6689373 |
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10306727 |
Nov 26, 2002 |
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09522535 |
Mar 10, 2000 |
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6541021 |
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60125589 |
Mar 18, 1999 |
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Current U.S.
Class: |
514/317 ;
604/890.1 |
Current CPC
Class: |
A61P 25/04 20180101;
A61K 31/4468 20130101; A61M 37/0069 20130101; A61K 31/4535
20130101; A61K 47/26 20130101; A61K 9/0024 20130101; A61K 9/0004
20130101; A61K 47/14 20130101; A61K 47/10 20130101; A61K 9/0019
20130101; A61K 9/0014 20130101; A61P 25/00 20180101 |
Class at
Publication: |
514/317 ;
604/890.1 |
International
Class: |
A61K 031/445; A61K
009/22 |
Claims
What is claimed is:
1. A method of treating pain in a subject, the method comprising
the steps of: implanting a controlled release drug delivery device
in an implantation site in the body of the subject; and delivering
systemically from said drug delivery device a formulation
comprising fentanyl or a fentanyl congener in an amount effective
to alleviate pain in the subject.
2. The method of claim 1, wherein the drug delivery device is
implanted at a subcutaneous site.
3. The method of claim 1, wherein the formulation is delivered at a
volume rate of from about 0.01 .mu.l/day to 2 ml/day.
4. The method of claim 1, wherein the fentanyl or a fentanyl
congener in the formulation is delivered at a rate of from about
0.01 .mu.g per hour to 200 .mu.g per hour.
5. The method of claim 1, wherein said delivering of the
formulation is substantially continuous.
6. The method of claim 1, wherein the drug delivery device is
coupled to a proximal end of a catheter for delivery of the
formulation to a delivery site at a distance from the implantation
site.
7. The method of claim 1, wherein the drug delivery device is a
convective drug delivery device.
8. The method of claim 7, wherein the convective device is selected
from the group consisting of an electromechanical pump, an
electroosmotic pump, a hydrolytic system, a piezoelectric pump, an
elastomeric system, a vapor pressure pump, an electrolytic pump and
an osmotic bursting matrix.
9. The method of claim 7, wherein the convective device is an
osmotic pump.
10. The method of claim 1, wherein the drug delivery device is a
diffusion system.
11. The method of claim 1, wherein the drug delivery device is an
erodible drug-comprising matrix.
12. The method of claim 1, wherein said delivering is for a period
of from about 4 weeks to 12 months.
13. The method of claim 1 wherein the drug delivery device
comprises an amount of fentanyl or fentanyl congener sufficient for
alleviation of pain in the subject for a period of more than 3
days.
14. The method of claim 1, wherein the drug delivery device
comprises an amount of fentanyl or fentanyl congener sufficient to
provide for alleviation of pain in the subject for a period of more
than 30 days.
15. The method of claim 1, wherein the drug delivery device
comprises an amount of fentanyl or fentanyl congener sufficient to
provide for alleviation of pain in the subject for a period of more
than 100 days.
16. The method of claim 1, wherein the formulation comprises
sufentanil.
17. The method of claim 16, wherein sufentanil is delivered at a
rate of from about 0.01 .mu.g/hr to about 200 .mu.g/hr.
18. The method of claim 16, wherein the drug delivery device
comprises an amount of sufentanil sufficient for alleviation of
pain in the subject for a period of more than 2 days.
19. The method of claim 16, wherein the drug delivery device
comprises an amount of sufentanil sufficient for alleviation of
pain in the subject for a period of more than 20 days.
20. A method of treating pain in a subject suffering from pain, the
method comprising: administering a formulation comprising fentanyl
or a fentanyl congener to a subject, said administering being by
systemic delivery at a volume rate of less than about 2 ml/day;
wherein pain is alleviated in the subject.
21. The method of claim 20, wherein said administering is by
implanting a drug delivery device at an implantation site in the
subject.
22. The method of claim 20, wherein the implantation site is a
subcutaneous site.
23. The method of claim 20, wherein the drug delivery device is a
convective device.
24. The method of claim 23, wherein he convective device is
selected from the group consisting of an electromechanical pump, an
electroosmotic pump, a hydrolytic system, a piezoelectric pump, an
elastomeric system, a vapor pressure pump, an electrolytic pump and
an osmotic bursting matrix.
25. The method of claim 20, wherein the convective device is an
osmotic pump.
26. The method of claim 20, wherein the drug delivery device is a
diffusion system.
27. The method of claim 20, wherein the drug delivery device is an
erodible drug-comprising matrix.
28. The method of claim 20, wherein systemic delivery is
substantially continuous.
29. The method of claim 20, wherein the formulation is administered
for a pre-selected administration period.
30. The method of claim 29, wherein the preselected administration
period is from about 4 weeks to 12 months.
31. The method of claim 20, wherein the formulation comprises
sufentanil.
32. The method of claim 31, wherein sufentanil is delivered at a
rate of from about 0.01 .mu.g/hr to about 200 .mu.g/hr.
33. The method of claim 31, wherein the formulation is within a
drug delivery device implanted in the subject.
34. The method of claim 33, wherein the drug delivery device
comprises an amount of sufentanil sufficient for alleviation of
pain in the subject for a period of more than 2 days.
35. The method of claim 33, wherein the drug delivery device
comprises an amount of sufentanil sufficient for alleviation of
pain in the subject for a period of more than 20 days.
36. The method of claim 20, wherein the drug delivery device is
substantially completely implanted.
37. A device for the treatment of pain, comprising: an implantable
controlled drug delivery device for implanting at an implantable
site in a patient in need of pain treatment, the device comprising
a formulation comprising fentanyl or a fentanyl congener; wherein
the implantable device is suitable for delivery of fentanyl or
fentanyl congener into the systemic circulation in an amount
effective for treatment of pain in the subject.
38. The device of claim 37, wherein the device comprises an amount
of formulation sufficient for delivery of an amount of fentanyl or
fentanyl congener effective for treatment of pain in the subject
for a period of at least about 3 days to about 10 days.
39. The device of claim 37, wherein the device comprises an amount
of formulation sufficient for delivery of an amount of fentanyl or
fentanyl congener effective for treatment of pain in the subject
for a period of at least about 4 weeks.
40. The device of claim 37, wherein the device comprises an amount
of formulation sufficient for delivery of an amount of fentanyl or
fentanyl congener effective for treatment of pain in the subject
for a period of at least about 100 days.
41. The device of claim 37, wherein the device administers
formulation at a rate of from about 0.01 .mu.g/hour to 200
.mu.g/hr.
42. The device of claim 37, wherein the formulation comprises
sufentanil.
43. The device of claim 37, wherein the device is suitable for
delivery of fentanyl or fentanyl congener at a rate of from about
0.01 .mu.g/hr to about 200 .mu.g/hr.
44. The device of claim 37, wherein the device is suitable for
delivery of fentanyl or fentanyl congener at a volume rate of from
about 0.01 .mu.l/day to 2 ml/day.
45. The device of claim 37, wherein the drug delivery device
comprises an amount of fentanyl or fentanyl congener sufficient for
delivery for alleviation of pain in the subject for a period of
more than 2 days.
46. The method of claim 37, wherein the drug delivery device
comprises an amount of fentanyl or fentanyl congener sufficient for
delivery for alleviation of pain in the subject for a period of
more than 20 days.
47. The method of claim 37, wherein the drug delivery device
comprises an amount of fentanyl or fentanyl congener sufficient for
alleviation of pain in the subject for a period of more than 100
days.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Serial No. 60/125,589, filed Mar. 18, 1999, which
application is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention relates to devices and methods for the
management of pain.
BACKGROUND OF THE INVENTION
[0003] Many medications are used for the treatment of pain, ranging
from well known, over-the-counter compounds such as aspirin,
acetominophen, ibuprofen and other non-steroidal anti-inflammatory
compounds to, the newly developed chemical entities such as the
cyclooxygenase II inhibitor compounds. Opiates in various forms,
including opium, heroine and morphine which derive from the opium
poppy, have very powerful analgesic properties. Opiates have been
widely used for anesthesia as well for the treatment of pain,
especially where the pain is very severe. In addition to these
natural opiates, many synthetic opioids have since been synthesized
including methadone, fentanyl and congeners of fentanyl such as
sufentanil, alfentanil, lofentanil, carfentanil, remifentanil, etc.
Of the opioids, morphine is still the drug of choice for management
of pain at least in part due to its low cost, the ability of the
drug to provide relief from pain of a variety of origins, and the
vast experience with this drug. Despite its therapeutic advantages
and vast experience with the drug, many pain management experts
believe that morphine and other opioids are under-prescribed for
parents who require long-term pain therapy.
[0004] One reason for underprescription is the risk of the side
effects associated with long-term administration of opioids in
general, such as development of opiate tolerance, dependence,
constipation, and/or other undesirable side effects (see, e.g.,
Moulin et al. 1992 Can Med. Assoc. J. 146:891-7). Patients who
develop opioid tolerance require increased doses to achieve a
satisfactory analgesic effect, and risk the development of further
undesirable side effects such as respiratory depression, which can
be life threatening. Physical dependence, which is related to
factors such as the dose administered and the length of the
administration period, can generally only be resolved by
discontinuing opioid administration, which in turn results in the
onset of severely painful withdrawal symptoms. Other side effects
that can be associated with administration of opioids include
reduced cough reflex, bronchial spasms, nausea, vomiting,
peripheral vasodilation, orthostatic hypotension, vagal impact on
the heart, contraction of smooth muscles (sphincters), reduced
peristaltic motility in the gastrointestinal tract (e.g.,
constipation), urinary retention, changes in regulation of body
temperature and sleep pattern, and release of histamine, adrenalin,
and anti-diuretic hormone. The negative effects on respiratory
function especially impact postoperative patients, who are
particularly susceptible to depression of respiratory function.
Even where the concerns regarding side effects might be outweighed
by the serious need for pain relief as interminally ill patients,
many doctors still avoid prescribing opioids due to concerns of
abuse of surplus medication by others in contact with the patient,
or even that their frequent prescription of the drug might lead to
criminal investigation.
[0005] In addition to the disadvantages listed above pertaining to
opioids in general, morphine itself has also been associated with
particular side effects, at times so severe as to make such therapy
intolerable, especially for patients who are on long-term pain
therapy or who require high doses of medication to obtain relief.
Some of these side effects associated with morphine usage,
particularly at high doses, include nausea and vomiting (see for
example Paix et al. (1995) Pain 63:263-9) and severe constipation.
In addition, Sjorgen et al. (1994 Pain 59:313-316) have reported
the phenomena of hyperalgesia (increased response to certain
stimulus which is not normally painful), allodynia (sensation of
pain felt even when stimulus is not normally painful) and myoclonus
associated with morphine use. It has been hypothesized that
morphine and its metabolites may induce such abnormal sensitivity
(see, e.g., Sjorgen et al. (1994) Pain 59:313-316).
[0006] Fentanyl and its congeners were originally developed as
anesthesia agents, and are generally used in the United States for
the limited purposes of intravenous administration in balanced
general anesthesia, as a primary anesthetic, or, in the case of
sufentanil, for epidural administration during labor and delivery.
However, these drugs also have powerful analgesic properties and
are several hundred or thousand times more potent than morphine
depending on the particular congener. A few studies have in fact
suggested that fentanyl and its congeners be used instead of
morphine due to their increased potency and decreased side effects
relative to morphine (see e.g., Sjorgen et al. (1994) Pain
59:313-316 and Paix et al. (1995) Pain 63:263-9). Fentanyl and its
congeners are, however, more difficult to administer than morphine
since they are not orally absorbed, are extremely potent (requiring
very precise, accurate dosing of small amounts) and have very short
half lives in the body thus requiring frequent dosing. For these
reasons, conventional methods for delivery of opioid analgesics are
inadequate to meet these delivery requirements. For example,
fentanyl has been administered in single, small intravenous doses,
but this method of administration, besides being impractical for
long-term therapy, results in a short duration of action and rapid
recovery due to a redistribution into fat stores and a rapid
decline in plasma concentration. The development of transdermal
patch delivery technology allowed fentanyl to be delivered
continuously through the skin (e.g., the commercial Duragesic.TM.
transdermal patch). Since the transdermal delivery method provided
for constant drug delivery, it was a marked improvement relative to
bolus injection; however, transdermal delivery also has several
limitations. For example, transdermal delivery is disadvantageous
in that the dose of drug that can be delivered is limited by the
available skin surface area, thus making transdermal delivery
suitable for low-to-medium opioid dose requirements, but often
inadequate for more high dose requirements. In addition,
transdermal delivery of drug is disadvantageous in that there is a
delay in obtaining steady state plasma concentrations upon
initiation of therapy, as well as a prolonged period of continued
effect even after removal of the patch. Other problems associated
with transdermal delivery include skin irritation, loss of adhesion
after exposure to moisture (e.g., perspiration, bathing) the
potential for diversion of drug for illicit purposes and patient
distaste for the unsightliness of highly visible patches.
[0007] While subcutaneous infusion of fentanyl and sufentanil have
been the subject of experimentation on a limited basis, the methods
disclosed in the prior art are impractical as long-term pain
therapies. Paixt et al. (1995 Pain 63:263-9), for example,
discloses the use of subcutaneous fentanyl and sufentanil as an
alternative therapy in a small number of patients who suffered
significant side effects associated with administration of
morphine. In Paix et al., the drug was infused into the
subcutaneous space at relatively large volume rates (e.g., on the
order of 3 mL/day to 40 mL/day) via an external syringe driver. The
treatment method disclosed by Paix et al. has several major
disadvantages that render it impractical for long-term therapy.
First, the provision of drug from an external source adversely
affects mobility of the patient and is therefore inconvenient for
ambulatory patients, increases the risk of infections at the
subcutaneous delivery site and provides an opportunity for drug to
be diverted for illicit uses. Second, the infusion of large volumes
of fluid may result in tissue damage or edema at the site of
infusion. In addition, the absorptive capacity of the subcutaneous
space limits the volume of fluid that can be delivered (see, e.g.,
Anderson et al., supra), and this volumetric limitation can in turn
limit the amount of drug that can be administered (e.g., in Paix et
al., more potent opioids were administered to some patients
requiring high doses since the volume of morphine required was too
large to be effectively absorbed in the subcutaneous tissues).
[0008] As is evident from the above, there is a great need for
devices and methods for effective and practical management of pain,
particularly pain of long duration, with better efficacy and
reduced side effects. The present invention addresses this
problem.
SUMMARY OF THE INVENTION
[0009] The invention features devices and methods for the systemic
delivery of fentanyl or a fentanyl congener (e.g., sufentanil) to
treat pain. In the present invention, a drug formulation comprising
fentanyl or a fentanyl congener is stored within a drug delivery
device (e.g., contained in a reservoir or impregnated within a
matrix within the controlled drug delivery device). The drug
formulation comprises an amount of drug sufficient for treatment
and is stable at body temperatures (i.e., no unacceptable
degradation) for the entire pre-selected treatment period. The drug
delivery devices store the drug formulation safely (e.g., without
dose dumping), provide sufficient protection from bodily processes
to prevent unacceptable degradation of the formulation, and release
the drug formulation in a controlled fashion at a therapeutically
effective rate to treat pain. In use, the drug delivery device is
implanted in the subject's body at an implantation site, and the
drug formulation is released from the drug delivery device to a
delivery site. The delivery site may be the same as, near, or
distant from the implantation site. Once released at the delivery
site, the drug formulation enters the systemic circulation and is
transported to the site of action in the body to modulate the pain
response (e.g., the brain or other pain sensory location).
[0010] In one aspect the invention features devices for and methods
of treating pain in a subject suffering from pain comprising
systemic delivery of a formulation comprising fentanyl or fentanyl
congener to the subject via an implantable drug delivery device,
where such formulation is delivered at a rate sufficient to
ameliorate pain. In specific embodiments, the formulation comprises
sufentanil, which can be administered at a rate of from about 0.01
.mu.g per hour to 200 .mu.g per hour.
[0011] In another aspect, the invention features devices for and
methods of treating pain by systemic delivery of a formulation
comprising fentanyl or fentanyl congener to the subject via an
implantable drug delivery device for a pre-selected period data low
volume rate (e.g., from about 0.01 .mu.l/day to 2 ml/day).
[0012] In another aspect, the invention features devices for and
methods of treating pain in a subject comprising the steps of
implanting a drug delivery device at an implantation site in the
body of a subject, where the drug delivery device is capable of
controlled drug release; and delivering a formulation comprising
fentanyl or a fentanyl congener from the device to a delivery site
for entering into the systematic circulation in an amount effective
to alleviate pain in the subject.
[0013] In various exemplary embodiments of the invention and
various aspects thereof, drug of the drug formulation administered
is delivered at a low dose rate due the potency of the subject
drugs, e.g., from about 0.01 .mu.g/hr or 0.1 .mu.g/hr, 0.25
.mu.g/hr, 1 .mu.g/hr, generally up to about 200 .mu.g/hr. Specific
ranges of amount of drug delivered will vary depending upon, for
example, the potency and other properties of the drug used and the
therapeutic requirements of the subject. In one specific
embodiment, the formulation comprises sufentanil and, in a specific
embodiment, is delivered at a rate of from about 0.01 .mu.g/hr or
0.1 .mu.g/hr, 0.25 .mu.g/hr, 1 .mu.g/hr, generally up to about 200
.mu.g/hr.
[0014] In another exemplary embodiment, the drug formulation is
delivered at a low volume rate e.g., a volume rate of from about
0.01 .mu.l/day to about 2 ml/day.
[0015] In another exemplary embodiment, delivery of the formulation
is substantially continuous, and can be for a pre-selected
administration period ranging from several hours to years,
preferably from about 4 weeks to 12 months.
[0016] The drug delivery device can be any implantable device,
which device can be based on, for example, diffusive, erodible or
convective systems, e.g., osmotic pumps, biodegradable implants,
electrodiffusion systems, electroosmosis systems, vapor pressure
pumps, electrolytic pumps, effervescent pumps, piezoelectric pumps,
erosion-based systems, or electromechanical systems.
[0017] Pain amenable to alleviation includes, but is not
necessarily limited to various types of acute or chronic pain,
including cancer pain, inflammatory disease pain, neuropathic pain,
nociceptive pain, postoperative pain, iatrogenic pain, complex
regional pain syndrome, failed-back pain, soft tissue pain, joint
pain, bone pain, central pain, injury pain, arthritic pain,
hereditary disease, infectious disease, headache, causalgia,
hyperesthesia, sympathetic dystrophy, phantom limb syndrome, and
denervation. This invention is particularly useful in the treatment
of pain of long duration or chronic pain.
[0018] A primary object of the invention is provide a method for
convenient, long-term management of pain.
[0019] One advantage of the invention is that the devices and
methods described herein provide effective management of pain by
administration of a relatively small quantity of fentanyl or a
fentanyl congener (e.g., sufentanil), providing adequate pain
relief and an improvement in adverse side effects relative to
morphine. Given the adverse effects of opioid analgesics, this
advantage is of considerable benefit to those requiring pain
relief, particularly in relatively long term (e.g., 1-4 months)
pain situations. Furthermore,the method may be more cost-effective,
and thus may make pain, management available to a broader
population.
[0020] Another advantage of the invention is that the invention can
be used to deliver relatively small quantities of fentanyl and
fentanyl congeners accurately and precisely and thus safely
delivering such drugs despite the extreme potency of these drugs
compared to morphine. Thus, the invention allows for the convenient
use of these drugs for treatment of pain ranging in severity from
mild to severe.
[0021] One particularly surprising advantage of the invention is
that an amount of fentanyl or a fentanyl congener sufficient to
provide a relatively long duration of therapy can be stored safely
and stably within the body and without deleterious effect given the
high potency of the subject compounds.
[0022] Another notable advantage of the invention is that the use
of an implantable drug delivery device avoids the need for
placement of external needles and/or catheters in the subject,
which might provide sites susceptible to infection. In addition,
use of an implanted device increases patient compliance with a
prescribed therapeutic regimen, substantially decreases or
completely avoids the risk of abuse of the drug by the patient or
others in contact with the patient, and affords greater mobility
and easier outpatient management.
[0023] Another advantage of the invention is that fentanyl or a
fentanyl congener can be delivered into the systemic circulation
with such accuracy and precision and at such low quantities as to
permit long-term use of such compounds to treat pain.
[0024] A further advantage is that a therapeutically effective dose
of fentanyl and fentanyl congeners can be delivered at such
relatively low volume rates, e.g., from about 0.01 .mu.l/day to 2
ml/day so as to minimize tissue disturbance or trauma.
[0025] Another advantage is that fentanyl and fentanyl congeners
(e.g., sufentanil) delivery according to the invention provides for
effective drug delivery to provide the desired therapeutic effect
while avoiding local irritation.
[0026] Another advantage of the invention is that substantially
continuous delivery of small quantities of fentanyl or fentanyl
congener (e.g., sufentanil) is effective in long-term (e.g.,
chronic) administration (e.g., from several weeks or from about 1
to 12 months or more).
[0027] Another advantage of the invention is that the marked
potency of the selected opioids (fentanyl, sufentanil, or other
fentanyl congener) relative to other opioids such as morphine
allows for its administration at effective doses in small amounts
and volumes that make it a convenient therapy.
[0028] The method of the invention is also advantageous in that
since the selected drugs (e.g., sufentanil) are highly lipophilic
relative to other opioids, thus facilitating delivery of the drug
across the blood-brain barrier. For example, the octanol/water
partition coefficient of sufentanil is 1,727, compared to a
coefficient of 1.4 for morphine. Systemic administration (e.g., by
subcutaneous delivery) of certain lipophilic fentanyl congeners,
e.g., sufentanil, may be as effective as if the drug were delivered
directly to the central nervous system.
[0029] Yet another advantage is that the invention provides for
precise delivery of the selected fentanyl-comprising or fentanyl
congener-comprising formulation, thus allowing delivery of lower
doses and/or for delivery of precisely metered doses at consistent
delivery volume rates (e.g., on the order of microliters to
milliliters per hour).
[0030] Still another advantage is that the invention may decrease
the severity or incidence of side effects normally associated with
use of morphine in pain management.
[0031] These and other objects, advantages and features of the
present invention will become apparent to those persons skilled in
the art upon reading the details of the methodology and
compositions as more fully set forth below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 illustrates systemic delivery of drug using an
implanted drug delivery device.
[0033] FIG. 2 is a perspective view of an exemplary drug delivery
device useful in the present invention.
[0034] FIG. 3 illustrates intravenous delivery using a drug
delivery device implanted subcutaneously via a catheter positioned
for delivery of drug intravenously.
[0035] FIG. 4 is a cut-away view of an exemplary drug delivery
device comprising a catheter.
[0036] FIG. 5 is a graph showing release of sufentanil from an
exemplary osmotic pump at a rate of 20 .mu.g/hr.
[0037] FIG. 6 is a graph showing cumulative release of sufentanil
from exemplary osmotic pumps at a rate of 20 .mu.g/hr.
[0038] FIG. 7 is a graph showing release of sufentanil from
exemplary osmotic pumps at a rate of 5 .mu.g/hr.
[0039] FIG. 8 is a graph showing the average pumping rates of the
pumps of FIGS. 5 and 7.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0040] Before the present device and methods for treatment of pain
are described, it is to be understood that this invention is not
limited to the specific methodology, devices, therapeutic
formulations, and pain syndromes 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.
[0041] It must be noted that as used herein and in the appended
claims, the singular forms "a", "and", and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "a drug delivery device" includes a plurality
of such devices and reference to "the method of delivery" includes
reference to equivalent steps and methods known to those skilled in
the art, and so forth.
[0042] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood to one of
ordinary skill in the art to which this invention belongs. Although
any methods, devices and materials similar or equivalent to those
described herein can be used in the practice or testing of the
invention, the preferred methods, devices and materials are now
described.
[0043] All publications mentioned herein are incorporated herein by
reference for the purpose of describing and disclosing the
compositions and methodologies which are described in the
publications which might be used in connection with the presently
described invention. 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 invention is not entitled to antedate such a disclosure by
virtue of prior invention.
[0044] Definitions
[0045] The term "drug" as used herein is generally meant to refer
to fentanyl or a fentanyl congener (e.g., sufentanil, alfentanil,
lofentanil, carfentanil, remifentanil, trefentanil, and
mirfentanil), as well as formulations comprising one or more of
these compounds. Use of "drug" or the phrase "fentanyl or fentanyl
congener" is not meant to be limiting to use of, or formulations
comprising, only one of these selected opioid compounds.
Furthermore, reference to fentanyl alone or to a selected fentanyl
congener alone, e.g., reference to "sufentanil," is understood to
be only exemplary of the drugs suitable for delivery according to
the methods of the invention, and is not meant to be limiting in
any way.
[0046] The term "subject" is meant any subject, generally a mammal
(e.g., human, canine, feline, equine, bovine, etc.), in which
management of pain is desired.
[0047] The term "systemic delivery" is meant to encompass all
parenteral routes of delivery which permit drug to enter into the
systemic circulation, e.g., intravenous, intra-arterial,
intramuscular, subcutaneous, intra-adipose tissue, intra-lymphatic,
etc.
[0048] The term "therapeutically effective amount" is meant an
amount of a therapeutic agent, or a rate of delivery of a
therapeutic agent, effective to facilitate a desired therapeutic
effect. The precise desired therapeutic effect (e.g., the degree of
pain relief, and source of the pain relieved, etc.) will vary
according to the condition to be treated, the formulation to be
administered, and a variety of other factors that are appreciated
by those of ordinary skill in the art. In general, the method of
the invention involves the suppression or mitigation of pain in a
subject suffering from pain that may be associated with any of a
variety of identifiable or unidentifiable etiologies.
[0049] The term "pain management or treatment" is used here to
generally describe regression, suppression, or mitigation of pain
so as to make the subject more comfortable as determined by
subjective criteria, objective criteria, or both. In general, pain
is assessed subjectively by patient report, with the health
professional taking into consideration the patient's age, cultural
background, environment, and other psychological background factors
known to alter a person's subjective reaction to pain.
[0050] "Delivery site" as used herein is meant to refer to an area
of the body to which drug is delivered for entry into the systemic
circulation, e.g., a site which allows systemic access of drug
delivered to the site. Exemplary delivery sites compatible with
systemic delivery of drug include, but are not necessarily limited
to, subcutaneous, intravenous, intra-arterial, intra-muscular,
intra-adipose tissue, and intra-lymphatic sites.
[0051] The term "implantation site" is used to refer to a site
within the body of a subject at which a drug delivery device is
introduced and positioned.
[0052] "Drug delivery device" as used herein is meant to any
implantable device suitable for delivering the formulations for
pain management according to the invention. "Drug delivery device"
thus encompasses any implantable device with any mechanism of
action including diffusive, erodible, or convective systems, e.g.,
osmotic pumps, biodegradable implants, electrodiffusion systems,
electroosmosis systems, vapor pressure pumps, electrolytic pumps,
effervescent pumps, piezoelectric pumps, erosion-based systems, or
electromechanical systems.
[0053] "Patterned" or "temporal" as used in the context of drug
delivery is meant delivery of drug in a pattern, generally a
substantially regular pattern, over a pre-selected period of time
(e.g., other than a period associated with, for example a bolus
injection). "Patterned" or "temporal" drug delivery is meant to
encompass delivery of drug at an increasing, decreasing,
substantially constant, or pulsatile rate or range of rates (e.g.,
amount of drug per unit time, or volume of drug formulation for a
unit time), and further encompasses delivery that is continuous or
substantially continuous, or chronic.
[0054] The term "controlled drug delivery device" is meant to
encompass any device wherein the release (e.g., rate, timing of
release) of a drug or other desired substance contained therein is
controlled by or determined by the device itself and not the
environment of use.
[0055] By "substantially continuous" as used in, for example, the
context of "substantially continuous subcutaneous infusion" or
"substantially continuous delivery" is meant to refer to delivery
of drug (e.g., sufentanil) in a manner that is substantially
uninterrupted for a pre-selected period of drug delivery (other
than a period associated with, for example, a bolus injection).
Furthermore, "substantially continuous" drug delivery can also
encompass delivery of drug at a substantially constant,
pre-selected rate or range of rates (e.g., amount of drug per unit
time, or volume of drug formulation for a unit time) that is
substantially uninterrupted for a pre-selected period of drug
delivery.
[0056] Pain Susceptible to Management with the Devices and Methods
of the Invention
[0057] In general, administration of fentanyl or a fentanyl
congener according to the invention can be used to facilitate
management of pain (e.g., palliative care through, e.g., systemic
or centrally mediated analgesia) that is associated with any of a
wide variety of disorders, conditions, or diseases. "Pain" as used
herein, unless specifically noted otherwise, is meant to encompass
pain of any duration and frequency, including, but not limited to,
acute pain, chronic pain, intermittent pain, and the like. Causes
of pain may be identifiable or unidentifiable. Where identifiable,
the origin of pain may be, for example, of malignant,
non-malignant, infectious, non-infectious, or autoimmuneorigin. Of
particular interest is the management of pain associated with
disorders, 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 2 weeks 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 pain
management using the devices and methods of the invention, e.g.,
prior to traumatic surgery. Pain amenable to therapy according to
the invention may involve prolonged episodes of pain alternating
with pain-free intervals, or substantially unremitting pain that
varies in severity.
[0058] In general, pain can be nociceptive, somatogenic,
neurogenic, or psychogenic. Somatogenic pain can be muscular or
skeletal (i.e., osteoarthritis, lumbosacral back pain,
posttraumatic, myofascial), visceral (i.e., pancreatitis, ulcer,
irritable bowel), ischemic (i.e., arteriosclerosis obliterans), or
related to the progression of cancer (e.g., malignant or
non-malignant). Neurogenic pain can be due to posttraumatic and
postoperative neuralgia, can be related to neuropathies (i.e.,
diabetes, toxicity, etc.), and can be related to nerve entrapment,
facial neuralgia, perineal neuralgia, postamputation, thalamic,
causalgia, and reflex sympathetic dystrophy.
[0059] Specific examples of conditions, diseases, disorders, and
origins of pain amenable to management according to the present
invention include, but are not necessarily limited to, cancer pain
(e.g., metastatic or non-metastatic cancer), inflammatory disease
pain, neuropathic pain, postoperative pain, iatrogenic pain (e.g.,
pain following invasive procedures or high dose radiation therapy,
e.g., involving scar tissue formation resulting in a debilitating
compromise of freedom of motion and substantial pain), complex
regional pain syndromes, failed-back pain (e.g., acute or chronic
back pain), soft tissue pain, joints and bone pain, central pain,
injury (e.g., debilitating injuries, e.g., paraplegia,
quadriplegia, etc., as well as non-debilitating injury (e.g., to
back, neck, spine, joints, legs, arms, hands, feet, etc.)),
arthritic pain (e.g., rheumatoid arthritis, osteoarthritis,
arthritic symptoms of unknown etiology, etc.), hereditary disease
(e.g., sickle cell aremia), infectious disease and resulting
syndromes (e.g., Lyme disease, AIDS, etc.), headaches (e.g.,
migraines), causalgia, hyperesthesia, sympathetic dystrophy,
phantom limb syndrome, denervation, and the like. Pain can be
associated with any portion(s) of the body, e.g., the
musculoskeletal system, visceral organs, skin, nervous system,
etc.
[0060] Cancer pain is an example of one broad category of pain that
can be alleviated according to the methods of the invention. One of
the underlying causes of cancer pain is the severe local stretching
of tissues by the neoplastic lesion. For example, as the cancer
cells proliferate in an unrestricted manner, the tissues in the
local region of cancer cell proliferation are subjected to
mechanical stress required to displace tissue and accommodate the
increased volume occupied by the tumor mass. When the tumor burden
is confined to a small enclosed compartment, such as the marrow of
a bone, the resulting pressure can result in severe pain. Another
cause of cancer pain call result from the aggressive therapies used
to combat the patient's cancer, e.g., radiation therapy,
chemotherapy, etc. Such cancer therapies can involve localized or
widespread tissue damage, resulting in pain.
[0061] Pain associated with any type of malignant or non-malignant
cancer is amenable to alleviation according to the invention.
Specific examples of cancers that can be associated with pain (due
to the nature of the cancer itself or therapy to treat the cancer)
include, but are not necessarily limited to lung cancer, bladder
cancer, melanoma, bone cancer, multiple myeloma, brain cancer,
non-Hodgkins lymphoma, breast cancer, oral cancers, cervical
cancer, ovarian cancer, colon cancer, rectal cancer, pancreatic
cancer, dysplastic nevi, endocrine cancer, prostate cancer, head
and neck cancers, sarcoma, Hodgkins disease, skin cancer, kidney
cancer, stomach cancer, leukemia, testicular cancer, liver cancer,
uterine cancer, and aplastic anemia. Certain types of neuropathic
pain can also be amenable to treatment according to the
invention.
[0062] Back pain, which is also amenable to management using the
methods of the invention, is another broad category of pain that
can be alleviated by application of the methods of the invention.
Back pain is generally due to one or more of the following six
causes: (i) stress on intervertebral facet joints, caused by
slippage, arthritis, wedging, or scoliosis; (ii) radiculopathy, the
mechanical compression of the nerve root due to bulging discs or
tumors; (iii) tendonitis or tendon sprain; (iv) muscle spasm or
muscle sprain; (v) ischemia, a local insufficiency in circulatory
flow; and (vi) neuropathy, damage to nervous tissue of metabolic
etiology or arising from cord tumors or central nervous system
disease.
[0063] The methods of the invention can be used to manage pain in
patients who are opioid naive or who are no longer opioid naive,
although due to the potency of the drugs administered, patients are
preferably not opioid naive. Exemplary opioid naive patients are
those who have not received long-term opioid therapy for pain
management. Exemplary non-opioid naive patients are those who have
received short-term or long-term opioid therapy and have developed
tolerance, dependence, or other undesirable side effect. For
example, patients who have intractablte adverse side effects with
oral, intravenous, or intrathecal morphine, transdermal fentanyl
patches, or conventionally administered subcutaneous infusions of
fentanyl, morphine or other opioid can achieve good analgesia and
maintain favorable side-effects profiles with delivery of fentanyl
or a fentanyl congener when administered in the dose ranges and/or
low volume rates described above.
[0064] Fentanyl and Fentanyl Congeners and Formulations
[0065] Fentanyl, congeners of fentanyl, and specific derivatives or
analogs of fentanyl (e.g., other derivatives, particularly
4-anilidopiperidine derivatives of morphine) are contemplated for
delivery according to the invention, although variations within the
scope of the invention will be readily apparent to the ordinarily
skilled artisan upon reading the disclosure provided herein.
Exemplary fentanyl congeners include, but are not necessarily
limited to sufentanil, alfentanil, lofentanil, carfentanil,
remifentanil, trefentanil, and mirfentanil.
[0066] The specific fentanyl congener used can vary with a variety
of factors, including the type of pain to be alleviated, the
patient's tolerance and/or previous exposure to opioids, etc. The
relative potency of fentanyl or the fentanyl congener may also be
considered in selection of the drug to be delivered. For example,
the rank order of potency of fentanyl and selected fentanyl
congeners relative to morphine is as follows:
morphine<alfentanil<fentanyl<sufentanil<lofentanil&l-
t;carfentanil. Fentanyl is estimated to be 292 times, sufentanil,
4,521 times, lofentanil 5,440 times, and carfentanil 9,441 times
more potent than morphine. For a review of the pharmacokinetics of
sufentanil, fentanyl, and other fentanyl congeners, see, e.g.,
Meert (1996) Pharm. World Sci. 18:1-15; Scholz et al. 1996 Clin.
Pharmacokinet. 31:275-92.
[0067] In a preferred embodiment, the drug is the fentanyl congener
sufentanil. Sufentanil is preferred because it exhibits an
appropriate potency, has been previously administered according to
conventional methods, has a wide therapeutic index (see Meert
(1996) Pharm. World Sci. 18:1-15), exhibits good stability, and
provides for reduced side effects when delivered according to the
methods of the invention. Furthermore, the inventors have found
that the lipophilicity of sufentanil is particularly suitable for
subcutaneous delivery.
[0068] Methods for manufacture of fentanyl, sufentanil and other
fentanyl congenersare well known in the art, see, e.g., sufentanil
(e.g., U.S. Pat. No. 3,998,834; chemical name:
((N-[4-(methyoxymethyl)-1-[2-(2-thieny-
l)ethyl]-4-piperidinyl]-N-phenylpropariamide
2-hydroxy-1,2,3,-propanetrica- rboxylate (1:1);
C.sub.22H.sub.30N.sub.2O.sub.2S), fentanyl (e.g., U.S. Pat. No.
3,141,823; chemical name: N-phenyl-N-[1-(2-phenylethyl)-4-piperi-
dinyl]propanamide), alfentanil (e.g., U.S. Pat. No. 4,167,574;
chemical name:
N-[1-[2-(4-ethyl4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methox-
ymethyl)-4-piperidinyl]-N-phenylpropanamide
(C.sub.21H.sub.32N.sub.6O.sub.- 3)), lofenatnil (e.g., U.S. Pat.
No. 3,998,834; chemical name:
3-methyl-4-[(1-oxopropyl)phenylamino]-1-(2-phenylethyl)-4-piperidinecarbo-
xylic acid methyl ester), carfentanil (chemical name:
methyl4-[(1-oxopropyl)phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxyl-
ate (C.sub.24H.sub.30N.sub.2O.sub.3)), remifentanil (chemical name:
3-[4-methoxycarbonyl-4-[(1-oxopropyl)
phenylamino]1-piperidine]propanoic acid), trefentanil (chemical
name: N-(1-(2-(4-ethyl-4,5-dihydro-5-oxo-1H-- tetrazol-1
-yl)ethyl)-4-phenyl-4-piperidinyl)-N-(2-fluorophenyl)-propanami-
de, and mirfentanil (chemical name:
[N-(2-pyrazinyl)-N-(1-phenethyl-4-pipe- ridinyl)-2-furamide).
[0069] Fentanyl and fentanyl congeners are discussed in detail in,
for example, Goodman and Gilman's The Pharmacological Basis of
Therapeutics, Chapter 23, "Opioid Analgesics and Antagonists", pp.
521-555 (9.sup.th Ed. 1996); Baly et al. 1991 Med Res. Rev.
11:403-36 (evolution of the 4-anilidopiperidine opioids); and
Feldman et al. 1991 J. Med. Chem. 34:2202-8 (design, synthesis, and
pharmacological evaluation of opioid analgesics). For additional
information on fentanyl and fentanyl congeners, see, e.g., Scholz
et al. 1996 Clin. Pharmacokihet. 31:275-92 (clinical
pharmacokinetics of alfentanil, fentanyl, and sufentanil); Meert
1996 Pharmacy World Sci. 18:1-15 (describing-pharmacotherapy of
morphine, fentanyl, and fentanyl congeners); Lemmens et al. 1995
Anesth. Analg. 80:1206-11 (pharmacokinetics of mirfentanil); Minto
et al., 1997 Int. Anesihesiol. Clin. 35:49-65 (review of recently
developed opioid analgesics); James 1994 Expert Opin. Invest. Drugs
3:331-40 (discussion of remifentanil); Rosow 1993 Anesthesiology
79:875-6 (discussion of remifentanil); Glass 1995 Eur.
J.Anaesthesiol. Suppl. 10:73-4. (pharmacology of remifentanil); and
Lemmens et al. 1994 Clin. Pharnacol. Ther.56:261-71
(pharmacokinetics of trefentanil)
[0070] Fentanyl or a fentanyl congener can be provided in the
formulation as the opioid base and/or the opioid pharmaceutically
acceptable salt. The pharmaceutically acceptable salt embraces the
inorganic and the organic salt. Representative salts include a
member selected from the group consisting of hydrobromide,
hydrochloride, mucate, citrate, succinate, n-oxide,
sulfate,malonate, acetate, phosphate dibasic, phosphate monobasic,
acetate trihydtate, bi(heplafluorobutyrate), maleate,
bi(methylcarbamate), bi(pentafluoropropionate), mesylate,
bi(pyridine-3-carboxylate), bi(trifluoroacetate), bitartrate,
chlorhydrate, fumarate and sulfate pentahydrate.
[0071] Fentanyl or a fentanyl congener can be provided in any of a
variety of formulations compatible with parenteral delivery,
provided that such formulation is stable (i.e., not subject to
degradation to an unacceptable amount at body temperature). The
concentration of fentanyl or fentanyl congener in the formulation
may vary from about 0.1 wt. % to about 50 or 75 wt. %. The drug can
be provided in any form suitable to be carried by the controlled
drug delivery device and released parenterally for systemic
distribution, e.g., solid, semi-solid, gel, liquid, suspension,
emulsion, osmotic dosage formulation, diffusion dosage formulation,
erodible formulation, etc. Of particular interest is the
administration of sufentanil in an form suitable for administration
using an implanted pump, e.g., an osmotic pump.
[0072] In one embodiment, the fentanyl or fentanyl congener is
present in the formulation in a concentration substantially higher
than conventional formulations, e.g., current commercially
available formulations. By "substantially higher," it is intended
that the fentanyl or fentanyl congener is present in the
formulation in a concentration of at least about 2, at least about
5, at least about 10, at least about 20, at least about 50, at
least about 100, at least about 250, at least about 500, at least
about 1000, at least about 1500, at least about 2000, at least
about 2500, at least about 3000, at least about 3500, at least
about 4000, at least about 5000, at least about 6000, at least
about 7000, at least about 8000, at least about 9000, at least
about 10,000 times, or greater, than the solubility of fentanyl or
fentanyl congener in aqueous solution.
[0073] Formulations of the invention comprise fentanyl or a
fentanyl congener in a concentration of at least about 0.5 mg/mL, 1
mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, 75 mg/mL, 100 mg/mL, 150
mg/mL, 200 mg/mL, 225 mg/mL, 250 mg/mL, 300 mg/mL, 350 mg/mL, 400
mg/mL, 450 mg/mL, 500 mg/mL, or greater. Formulations of the
invention comprising fentanyl or fentanyl congener are in solution,
e.g., are dissolved in a liquid.
[0074] Pharmaceutical grade organic or inorganic carriers and/or
diluents suitable for systemic delivery can be included in the
formulations suitable for delivery according to the invention. Such
physiologically acceptable carriers are well known in the art.
Exemplary liquid carriers for use in accordance with the present
invention can be sterile non-aqueous or aqueous solutions which
contain no materials other than the active ingredient. In general,
hydrophobic solvents are generally preferred due to the
lipophilicity of fentanyl and fentanyl congeners. The formulations
can optionally further comprise a buffer such as sodium phosphate
at physiological pH value, physiological saline or both (i.e.,
phosphate-buffered saline). Suitable aqueous carriers may
optionally further comprise more than one buffer salt, as well as
other salts (such as sodium and potassium chlorides) and/or other
solutes.
[0075] In some exemplary embodiments, the formulation comprises
fentanyl or a fentanyl congener (generally as a base) and a low
molecular weight (e.g., MW less than about 300 g/mol) alcohol. In
these embodiments, the fentanyl or fentanyl congener is present in
the formulation in a concentration of from about 0.5 mg/mL to about
500 mg/mL, from about 1 mg/mL to about 450 mg/mL, from about 50
mg/mL to about 400 mg/mL, from about 75 mg/mL to about 300 mg/mL,
or from about 100 mg/mL to about 250 mg/mL. Suitable low molecular
weight alcohols include those which are pharmaceutically
acceptable, and which preferably comprise an aromatic moiety, and
which are relatively immiscible in water (e.g., less than about 5,
less than about 4, less than about 3, less than about 2, less than
about 1 gram can dissolve in 25 ml H.sub.2O), including, but not
limited to, benzyl alcohol, and derivatives thereof. Small amounts
of other pharmaceutically acceptable substances such as other
pharmaceutically acceptable alcohols, e.g., ethanol, or water, may
also be present, and, if present, are present in an amount of less
than about 10%, less than about 5%, or less than about 1%. In a
particular embodiment, the formulation comprises fentanyl or
fentanyl congener, with sufentanil being of particular interest, in
100% benzyl alcohol.
[0076] In additional exemplary embodiments, the formulation
comprises fentanyl or a fentanyl congener (generally as a base),
and a nonionic surfactant, in an alcohol ester, e.g., an ester of a
low molecular weight alcohol as described above. In these
embodiments, the fentanyl or fentanyl congener is present in the
formulation in a concentration of from about 0.5 mg/ml or 1 mg/mL
to about 500 mg/mL, from about 50 mg/mL to about 300 mg/mL, from
about 75 mg/mL to about 275 mg/mL, or from about 100 mg/mL to about
250 mg/mL. Suitable alcohol esters include those which are
pharmaceutically acceptable, which preferably comprise an aromatic
moiety, and which are insoluble in water, including, but not
limited to, benzyl benzoate, and derivatives thereof. Small amounts
of pharmaceutically acceptable substances such as pharmaceutically
acceptable alcohols or other pharmaceutically acceptable alcohol
esters, or water, may also be present, and, if present, are present
in an amount of less than about 10%, less than about 5%, or less
than about 1%. In a particular embodiment, the alcohol ester is
100% benzyl benzoate, with sufentanil as the fentanyl congener
being of particular interest.
[0077] Suitable nonionic surfactants include those which are
pharmaceutically acceptable, including but not limited to,
polysorbate, e.g., polysorbate 20, polysorbate 40, polysorbate 60;
sorbitan trioleate; polyoxyethylene polyoxypropylene glycol, e.g.,
polyoxyethylene(160)glycol- , and polyoxypropylene(30)glycol. Other
nonionic surfactants which are suitable for use in the formulations
include nonionic surfactants of the fatty acid polyhydroxy alcohol
ester type such as sorbitan monolaurate, monooleate, monostearate
or monopalmitate, sorbitan tristearate or trioleate, adducts of
polyoxyethylene and fatty acid polyhydroxy alcohol esters such as
polyoxyethylene sorbitan monolaurate, monooleate, monostearate,
monopalmitate, tristearate or trioleate, polyethylene glycol fatty
acid esters such as polyoxyethyl stearate, polyethylene glycol 400
stearate, polyethylene glycol 2000 stearate, in particular ethylene
oxide-propylene oxide block copolymers of the Pluronics (Wyandotte)
or Synperonic (ICI). In particular embodiments, the nonionic
surfactant is polysorbate 20, polysorbate 40, polysorbate 60, or
sorbitan trioleate, or mixtures of one or more of the
foregoing.
[0078] In general, a nonionic surfactant is present in the
formulation in a concentration of from about 50 mg/mL to about 200
mg/mL, from about 75 mg/mL to about 175 mg/mL, or from about 100
mg/mL to about 150 mg/mL. In a particular embodiment, the nonionic
surfactant is present in the formulation at 100 mg/mL.
[0079] Formulations of particular interest for delivery are
characterized in that the fentanyl or fentanyl congener is present
in a high concentration, as described above. The fentanyl or
fentanyl congener is soluble in the formulation, i.e., little or no
fentanyl or fentanyl congener precipitates are present, and
further, little or no fentanyl or fentanyl congener precipitates
form when the formulation comes in contact with an aqueous
environment such as a body fluid. Precipitates of fentanyl or
fentanyl congeners, when present at all, are present in the
formulation at less than about 10%, less than about 7.5%, less than
about 5%; less than about 2.5%, less than about 1%, or less than
about 0.1% by weight of the total fentanyl or fentanyl congener
present in the formulation. Whether precipitates have formed can be
determined using any method known in the art, including, but not
limited to, visual inspection with the unaided eye, or under low
(e.g., 10.times. or 25.times.) magnification.
[0080] The formulations comprising fentanyl or a fentanyl congener
and suitable for administration according to the invention may
comprise additional active or inert components that are
pharmaceutically acceptable and compatible with the active
ingredient. Suitable excipients can comprise dextrose, glycerol,
alcohol (e.g., ethanol), and the like, and combinations of one or
more thereof with vegetable oils, propylene glycol polyethylene
glycol, benzyl alcohol, benzyl benzoate, dimethyl sulfoxide (DMSO),
organics, and the like to provide a suitable composition. In
addition, if desired, the composition can comprise hydrophobic or
aqueous surfactants, dispersing agents, wetting or emulsifying
agents, isotonic agents, pH buffering agents, dissolution promoting
agents, stabilizers, antiseptic agents and other typical auxiliary
additives employed in the formulation of pharmaceutical
preparations.
[0081] Exemplary additional active ingredients that can be present
in the formulations useful with the invention can include an opioid
antagonist (e.g., to further decrease the possibility of addiction
or dependence, see, e.g., an exemplary osmotic dosage formulation
comprising an opioid agonist and an opioid antagonist is described
in U.S. Pat. No. 5,866,164.
[0082] Implantation and Delivery Sites
[0083] The drug delivery device can be implanted at any suitable
implantation site using methods and devices well known in the art.
As noted infra, an implantation site is a site within the body of a
subject at which a drug delivery device is introduced and
positioned. Implantation sites include but are not necessarily
limited to a subdermal, subcutaneous, intramuscular, or other
suitable site within a subject's body. Subcutaneous implantation
sites are preferred because of convenience in implantation and
removal of the drug delivery device. In some embodiments, the
implantation site is at or near the delivery site (e.g., the
delivery site is not distant from the implantation site), and thus
should be a site compatible with systemic delivery of drug (e.g., a
subcutaneous site). Where the implantation site and the delivery
site are distant, then it is not necessary that the implantation
site be a site compatible with systemic delivery of drug. For
example, the drug delivery device can be implanted at a
subcutaneous site, and the delivery site can be an intravenous or
other site suitable for systemic delivery of drug. Delivery of drug
from a drug delivery device at an implantation site that is distant
from a delivery site can be accomplished by providing the drug
delivery device with a catheter, as described in more detail
below.
[0084] The delivery site is an area of the body to which drug is
delivered for entry into the systemic circulation, i.e., a site
which allows systemic access of the drug. Delivery sites include,
but are not necessarily limited to, subcutaneous, intravenous,
intra-arterial, intra-muscular, intra-adipose tissue,
intra-lymphatic and sublingual sites. Subcutaneous delivery sites
are of particular interest in the present application. Exemplary
subcutarieous delivery sites include external subcutaneous sites
(e.g., under the skin of the arm, shoulder, neck, back, or leg) and
internal subcutaneous sites within a body cavity (e.g., within the
mouth). Delivery to a subcutaneous site further enhances these
advantages of the invention, since delivery to a subcutaneous site
involves the greatest contact with tissue that can readily absorb
the drug. Furthermore, the present invention treats pain by
delivery of fentanyl or its congeners (e.g., sufentanil), which
drugs are lipophilic. The lipophilicity of these drugs further
enhances their absorption at a delivery site, particularly at a
subcutaneous delivery site.
[0085] Delivery of Fentanyl or Fentanyl Congeners.
[0086] In general, the formulation of fentanyl or fentanyl congener
is delivered at a volume rate that is compatible with the delivery
site, and at a dose that is therapeutically effective in reduction
of pain (e.g., sufficient to accomplish substantial management of
pain) while reducing the presence or risk of side effects that can
be associated with administration of opioid drugs.
[0087] Subjects suffering from or susceptible to pain can receive
alleviation of pain according to the method of the invention for
any desired period of time. In general, administration of fentanyl
or fentanyl congener according to the invention can be sustained
for several hours (e.g., 2 hours, 12 hours, or 24 hours to 48 hours
or more), to several days (e.g., 2 to 5 days or more), to several
months or years. Typically, delivery can be continued for a period
ranging from about 1 month to about 12 months or more. The fentanyl
or fentanyl congener may be administered to an individual for a
period of, for example, from about 2 hours to about 72 hours, from
about 4 hours to about 36 hours, from about 12 hours to about 24
hours, from about 2 days to about 30 days, from about 5 days to
about 20 days, from about 7 days or more, from about 10 days or
more, from about 100 days or more, from about 1 week to about 4
weeks, from about 1 month to about 24 months, from about 2 months
to about 12 months, from about 3 months to about 9 months, from
about 1 month or more, from about 2 months or more, or from about 6
months or more; or other ranges of time, including incremental
ranges, within these ranges, as needed. This extended period of
opioid delivery is made possible by the ability of the invention to
provide both adequate pain relief, while minimizing the severity of
opioid side effects (e.g., nausea, vomiting, sedation, confusion,
respiratory depression, etc.). In particular embodiments, the
fentanyl or fentanyl congener is delivered to the subject without
the need for re-accessing the device and/or without the need for
re-filling the device. In these embodiments, high-concentration
formulations of fentanyl or fentanyl congener are of particular
interest.
[0088] Preferably, delivery of fentanyl or fentanyl congener is in
a patterned fashion, more preferably in a substantially continuous
fashion, e.g., substantially uninterrupted for a pre-selected
period of drug delivery, and more preferably at a substantially
constant, pre-selected rate or range of rates (e.g., amount of drug
per unit time, or volume of drug formulation for a unit time). The
drug is preferably delivered at a low volume rate of from about
0.01 .mu.l/day to about 2 ml/day, preferably about 0.04 .mu.l/day
to about 1 ml/day, generally about 0.2 .mu.l/day to about 0.5
ml/day, typically from about 2.0 .mu.l/day to about 0.25
ml/day.
[0089] Systemic administration of drug by delivery using an
implanted pump according to the invention is particularly preferred
where delivery by other routes has become undesirable, e.g., the
subject has experienced intractable adverse side effects with oral,
intravenous, or intrathecal morphine, transdermal fentanyl patches,
or conventionally administered subcutaneous infusions (e.g., using
a syringe driver system or other delivery system that requires
relatively high volume delivery). Delivery using an implanted pump
is convenient for the subject, as the implantation and removal
procedures are simple and can be conducted on an out-patient basis
where the patient's health allows such. Subcutaneously implanted
drug delivery devices also increase patient compliance, prevent
drug diversion and abuse, reduce the risk of infection associated
with external pumps or other methods that require repeated breaking
of the skin and/or maintenance of a port for administration.
[0090] Delivery of drug to a subcutaneous site at a low volume rate
is a particularly preferred embodiment of the invention. In
general, low volume rate drug delivery avoids accumulation of drug
at the delivery site (e.g., depot or pooling effect) by providing
for a rate of administration that is less than, the same as, or
only very slightly greater than the rate of removal of drug from
the delivery site (e.g., by absorption of drug in tissues at the
site, movement of drug away from the site by flow of blood or other
bodily fluids, etc.). Thus, in addition to providing an implantable
system for delivery of highly potent drugs such as fentanyl and
fentanyl congeners (e.g., sufentanil), the present invention also
provides a method for treating pain by elegantly balancing the
rates of drug absorption and drug delivery to accomplish
administration of a therapeutically effective amount of drug, while
avoiding accumulation of drug at the delivery site.
[0091] In one embodiment, a drug delivery device provides for
substantially continuous, subcutaneous delivery of drug at a
preselected rate. For example, for subcutaneous delivery of
sufentanil, the drug can be delivered at a rate of from about 0.01
.mu.g/hr to about 200 .mu.g/hr, usually from about 0.01 .mu.g/hr;
0.25 .mu.g/hr, or 3 .mu.g/hr to about 85 .mu.g/hr, and typically
between about 5 .mu.g/hr to about 100 .mu.g/hr. In a specific
exemplary embodiment, sufentanil is delivered at a rate of from
about 0.01 .mu.g/hr, 0.1 .mu.g/hr, 0.25 .mu.g/hr, 1 .mu.g/hr,
generally up to about 200 .mu.g/hr. Appropriate amounts of fentanyl
or fentanyl congener can be readily determined by the ordinarily
skilled artisan based upon, for example, the relative potency of
these drugs. The actual dose of drug delivered will vary with a
variety of factors such as the potency and other properties of the
selected drug used (e.g., lipophilicity, etc.).
[0092] Drug Delivery Devices for use in the Invention
[0093] Any of a variety of controlled drug delivery devices can be
used in the present invention to accomplish delivery of a drug
formulation comprising fentanyl or fentanyl congener. In general,
the drug delivery device minimally comprises a controlled drug
delivery device and, in one embodiment, further comprises and a
drug delivery catheter, e.g., where the implantation site is
distant from the delivery site.
[0094] Drug delivery devices suitable for use with the present
invention can take advantage of any of a variety of controlled drug
release devices. In general, the drug release devices suitable for
use in the invention comprise a drug reservoir for retaining a drug
formulation or alternatively some substrate or matrix which can
hold drug (e.g., polymer, binding solid, etc.). The drug release
device can be selected from any of a variety of implantable
controlled drug delivery system known in the art. Controlled drug
release devices suitable for use in the present invention generally
can provide for delivery of the drug from the device at a selected
or otherwise patterned amount and/or rate to a selected site in the
subject.
[0095] In some embodiments, the delivery device is one that is
adapted for delivery of fentanyl or fentanyl congener over extended
periods of time. Such delivery devices may be adapted for
administration of fentanyl or fentanyl congener for several hours
(e.g., 2 hours, 12 hours, or 24 hours to 48 hours or more), to
several days (e.g., 2 to 5 days or more, from about 100 days or
more), to several months or years. In some of these embodiments,
the device is adapted for delivery for a period ranging from about
1 month to about 12 months or more. The drug delivery device may be
one that is adapted to administer fentanyl or fentanyl congener to
an individual for a period of, for example, from about 2 hours to
about 72 hours, from about 4 hours to about 36 hours, from about 12
hours to about 24 hours, from about 2 days to about 30 days, from
about 5 days to about 20 days, from about 7 days or more, from
about 10 days or more, from about 100 days or more; from about 1
week to about 4 weeks, from about 1 month to about 24 months, from
about 2 months to about 12 months, from about 3 months to about 9
months, from about 1 month or more, from about 2 months or more, or
from about 6 months or more; or other ranges of time, including
incremental ranges, within these ranges, as needed. In these
embodiments, high-concentration formulations of fentanyl or
fentanyl congener described herein are of particular interest for
use in the invention.
[0096] Release of drug from the device, particularly controlled
release of drug, can be accomplished in any of a variety of ways
according to methods well known in the art, e.g., by incorporation
of drug into a polymer that provides for substantially controlled
diffusion of drug from within the polymer, incorporation of drug in
a biodegradable polymer, providing for delivery of drug from an
osmotically-driven device, etc. Where the drug delivery device
comprises a drug delivery catheter, drug can be delivered through
the drug delivery catheter to the delivery site as a result of
capillary action, as a result of pressure generated from the drug
release device, by diffusion, by electrodiffusion or by
electroosmosis through the device and/or the catheter.
[0097] The drug delivery device must be capable of carrying the
drug formulation in such quantities and concentration as
therapeutically required, and must provide sufficient protection to
the formulation from attack by body processes for the duration of
implantation and delivery. The exterior is thus preferably made of
a material that has properties to diminish the risk of leakage,
cracking, breakage, or distortion so as to prevent expelling of its
contents in an uncontrolled manner understresses it would be
subjected to during use, e.g., due to physical forces exerted upon
the drug release device as a result of movement by the subject or
physical forces associated with pressure generated within the
reservoir associated with drug delivery. The drug reservoir or
other means for holding or containing the drug must also be of such
material as to avoid unintended reactions with the active agent
formulation and is preferably biocompatible (e.g., where the device
is implanted, it is substantially non-reactive with respect to a
subject's body or body fluids).
[0098] Suitable materials for the reservoir or drug holding means
for use in the delivery devices of the invention are well known in
the art. For example, the reservoir material may comprise a
non-reactive polymer or a biocompatible metal or alloy. Suitable
polymers include, but are not necessarily limited to, acrylonitrile
polymers such as acrylonitrile-butadiene-styrene polymer, and the
like; halogenated polymers such as polytetrafluoroethylene,
polyurethane, polychlorotrifluoroethylene, copolymer
tetrafiuoroethylene and hexafluoropropylene; polyethylene
vinylacetate (EVA), polyimide; polysulfone; polycarbonate;
polyethylene; polypropylene; polyvinylchloride-acrylic copolymer;
polycarbonate-acrylonitrile-butadien- e-styrene; polystyrene;
cellulosic polymers; and the like. Further exemplary polymers are
described in The Handbook of Common Polymers, Scott and Roff, CRC
Press, Cleveland Rubber Co., Cleveland, Ohio.
[0099] Metallic materials suitable for use in the reservoir of the
drug release device include stainless steel, titanium, platinum,
tantalum, gold and their alloys; gold-plated ferrous alloys;
platinum-plated titanium, stainless steel, tantalum, gold and their
alloys as well as other ferrous alloys; cobalt-chromium alloys; and
titanium nitride-coated stainless steel, titanium, platinum,
tantalum, gold, and their alloys.
[0100] Exemplary materials for use in polymeric matrices include,
but are not necessarily limited to, biocompatible polymers,
including biostable polymers and biodegradable polymers. Exemplary
biostable polymers include, but are not necessarily limited to
silicone, polyurethane, polyether urethane, polyether urethane
urea, polyamide, polyacetal, polyester, poly
ethylene-chlorotrifluoroethylene, polytetrafluoroethylene (PTFE or
"Teflon.TM."), styrene butadiene rubber, polyethylene,
polypropylene, polyphenylene oxide-polystyrene,
poly-a-chloro-p-xylene, polymethylpentene, polysulfone and other
related biostable polymers. Exemplary biodegradable polymers
include, but are.not necessarily limited to, polyanhydrides,
cyclodestrans, polylactic-glycolic acid, polyorthoesters; n-vinyl
alcohol, polyethylene oxide/polyethylene terephthalate,
polyglycolic acid, polylactic acid and other related bioabsorbable
polymers.
[0101] Where the drug formulation is stored in a reservoir
comprising metal or a metal alloy, particularly titanium or a
titanium alloy having greater than 60%, often greater than 85%
titanium is preferred for the most sizeritical applications, for
high payload capability and for long duration applications and for
those applications where the formulation is sensitive to body
chemistry at the implantation site or where the body is sensitive
to the formulation. Most preferably, the drug delivery devices are
designed for storage with drug at room temperature or higher.
[0102] Drug release devices suitable for use in the invention may
be based on any of a variety of modes of operation. For example,
the drug release device can be based upon a diffusive system, a
convective system, or an erodible system (e.g., an erosion-based
system). For example, the drug release device can be an osmotic
pump, an electroosmotic pump, a vapor pressure pump, or osmotic
bursting matrix, e.g., where the drug is incorporated into a
polymer and the polymer provides for release of drug formulation
concomitant with degradation of a drug-impregnated polymeric
material (e.g., a biodegradable, drug-impregnated polymeric
material). In other embodiments, the drug release device is based
upon an electrodiffusion system, an electrolytic pump, an
effervescent pump, a piezoelectric pump, a hydrolytic system,
etc.
[0103] Drug release devices based upon a mechanical or
electromechanical infusion pump, can 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 methods of drug delivery can be accomplished using any of a
variety of refillable, non-exchangeable pump systems. Pumps and
other convective systems are generally preferred due to their
generally more consistent, controlled release overtime. Osmotic
pumps are particularly preferred due to their combined advantages
of more consistent controlled release and relatively small size. Of
the osmotic pumps, the DUROS.TM. osmotic pump is particularly
preferred (see, e.g., WO 97/27840 and U.S. Pat. Nos. 5,985,305 and
5,728,396)).
[0104] In one embodiment, the drug release device is a controlled
drug release device in the form of an osmotically-driven device.
Preferred osmotically-driven drug release systems are those that
can provide for release of drug in a range of rates of from about
0.01 .mu.g/hr to about 200 .mu.g/hr, and which can be delivered at
a volume rate of from about 0.01 .mu.l/day to about 100 .mu.l/day
(i.e., from about 0.0004 .mu.l/hr to about 4 .mu.l/hr), preferably
from about 0.04 .mu.l/day to about 10 .mu.l/day, generally from
about 0.2 .mu.l/day to about 5 .mu.l/day, typically from about 0.5
.mu.l/day to about 1 .mu.l/day. In one embodiment, the volume/time
delivery rate is substantially constant (e.g., delivery is
generally at a rate .+-. about 5% to 10% of the cited volume over
the cited time period, e.g., a volume rate of about
[0105] In general, the drug delivery devices suitable for use in
the invention are those that can deliver drug at a low dose, e.g.,
for sufentanil from about 0.01 .mu.g/hr to about 200 .mu.g/hr, and
preferably at a low volume rate e.g., on the order of nanoliters to
microliters per day. In one embodiment, a volume rate of from about
0.01 .mu.l/day to about 2 ml/day is accomplished by delivery of
about 80 .mu.l/hour over a period of 24 hours, with the delivery
rate over that 24 hours period fluctuating over that period by
about .+-.5% to 10%. 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.
[0106] Delivery of Fentanyl or Fentanyl Congener Using a Drug
Delivery Device Comprising a Drug Delivery Catheter
[0107] In some embodiments it may be desirable to provide a drug
delivery catheter with the drug delivery device, e.g., where the
implantation site and the desired delivery site are not the same or
adjacent. The drug delivery catheter is generally a substantially
hollow elongate member having a first end (or "proximal" end)
associated with the drug release device of the drug delivery
device, and a second end (or "distal" end) for delivery of the
drug-comprising formulation to a desired delivery site. Where a
drug delivery catheter is used, a first end of the drug delivery
catheter is associated with or attached to the drug delivery device
so that the lumen of the drug delivery catheter is in communication
with the drug reservoir in the drug delivery device, so that a
formulation contained in a drug reservoir can move into the drug
delivery catheter, and out a delivery outlet of the catheter which
is positioned at the desired delivery site.
[0108] The body of the catheter defines a lumen, which lumen is to
have a diameter compatible with providing leak-proof delivery of
drug formulation from the drug delivery device. Where the drug
delivery device dispenses drug by convection (as in, e.g., osmotic
drug delivery systems), the size of the catheter lumen leading from
the reservoir of the drug release system can be designed as
described by Theeuwes (1975) J. Pharm. Sci. 64:1987-91.
[0109] The body of the catheter can be of any of a variety of
dimensions and geometries (e.g., curved, substantially straight,
tapered, etc.), that can be selected according to their suitability
for the intended site for drug delivery. The distal end of the drug
delivery catheter can provide a distinct opening for delivery of
drug, or as a series of openings.
[0110] The drug delivery catheter may be produced from any of a
variety of suitable materials, and may be manufactured from the
same or different material as the reservoir of the drug release
device. Impermeable materials suitable for use in production of the
controlled drug release device as described above are generally
suitable for use in the production of the drug delivery catheter.
Exemplary materials from which the drug delivery catheter can be
manufactured include, but are not necessarily limited to, polymers;
metals; glasses; polyolefins (high density polyethylene (HDPE), low
density polyethylene (LDPE), linear low density polyethylene
(LLDPE), polypropylene,(PP), and the like); nylons; polyethylene
terephtholate; silicones; urethanes liquid crystal polymers;
PEBAX.RTM.; HYTRE.RTM.; TEFLON.RTM.; peflouoehylne(PFE)
perflouralkoxy resins (PFA); poly(methyl methacrylate) (PMMA);
multilaminates of polymer, metals, and/or glass; nitinol; and the
like.
[0111] The drug delivery catheter can comprise additional materials
or agents (e.g., coatings on the external or internal catheter body
surface(s)) to facilitate placement of the drug delivery catheter
and/or to provide other desirable characteristics to the catheter.
For example, the drug delivery catheter inner and/or outer walls
can be coated with silver or otherwise coated or treated with
antimicrobial agents, thus further reducing the risk of infection
at the site of implantation and drug delivery.
[0112] In one embodiment, the drug delivery catheter is primed with
a drug-comprising formulation, e.g., is substantially pre-filled
with drug prior to implantation. Priming of the drug delivery
catheter reduces delivery start-up time, i.e., time related to
movement of the drug from the drug delivery device to the distal
end of the drug delivery catheter. This feature is particularly
advantageous in the present invention where the drug release device
of the drug delivery device releases sufentanil at relatively low
flow rates.
[0113] FIG. 1 illustrates one embodiment of the invention, wherein
fentanyl or a fentanyl congener is delivered from, an implanted
drug delivery device that provides for sustained, controlled
release of fentanyl or fentanyl congener from a drug reservoir to a
subcutaneous site. In this example, the drug delivery device 10 is
implanted at a subcutaneous site in the patient's arm 5. Flow of
drug from the device's drug reservoir and to the subcutaneous site
is illustrated by arrows 200. FIG. 2 provides a perspective view of
the exemplary drug delivery device 10 implanted in FIG. 1. The drug
delivery device 10 comprises proximal and distal ends 11 and 12,
with the distal end defining an orifice 15 through which drug exits
the drug reservoir 30 for delivery to the subcutaneous site. In the
exemplary device 10, controlled release of drug from the reservoir
30 is provided by an osmotic engine comprising a piston 41 and an
chamber comprising an osmotic engine 42.
[0114] FIG. 3 illustrates an alternative embodiment in which the
drug delivery system 100 comprises a drug delivery device 10 and a
drug delivery catheter 20. In the example in FIG. 3, the drug
release device portion is maintained at a subcutaneous implantation
site and the distal end of the drug delivery catheter 20 is
implanted at an intravenous delivery site. As shown in the cut-away
of the drug delivery. device in FIG. 4, the drug delivery system
100 comprises a drug delivery device 10 and a drug delivery
catheter 20. The walls of the drug delivery catheter define a
lumen, and the drug delivery catheter is associated with the drug
delivery device 10 so that a drug delivery pathway is provided from
the drug reservoir 30, through orifice 15, and out the distal end
12 of the drug delivery device. The catheter 20 can be positioned
for systemic delivery of drug to, for example, vein 7.
[0115] Methods for implanting or otherwise positioning drug
delivery devices for subcutaneous delivery of a drug are well known
in the art. In general, placement of the drug delivery device will
be accomplished using methods and tools that are well known in the
art, and performed under aseptic conditions with at least some
local or general anesthesia administered to the subject. In one
embodiment, the drug delivery device is implanted using an
implanter such as the device provided in, for example, U.S. Design
Pat. No. D402,757; or New Zealand Certificate of Registration of
Design No. 29353. Removal and/or replacement of drug delivery
devices can also be accomplished using tools and methods that are
readily available.
EXAMPLES
[0116] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how to make and use the present invention, and are
not intended to limit the scope of what the inventors regard as
their invention nor are they intended to represent that the
experiments below are all or the only experiments performed.
Efforts have been made to ensure accuracy with respect to numbers
used (e.g., amounts, temperature, etc.) but some experimental
errors and deviations should be accounted for.
EXAMPLE 1
[0117] Treatment Regimen for Subcutaneous Delivery of Fentanyl or
Fentanyl Congener Via DUROS.TM. Pump:
[0118] 1. Evaluation of Patient.
[0119] The physician first examines the potential patient and
evaluates the patient's history to determine if the patient has
pain that amenable to treatment by opioids and can safely tolerate
such treatment.
[0120] 2. Selection of Appropriate Dose.
[0121] If the physician decides to proceed with treatment in
accordance with this invention, the physician determines the
appropriate dose of drug (e.g., sufentanil) to be administered to
the patient. This determination can be performed in a variety of
ways. If the patient is already using certain medication to control
pain (e.g., oral morphine or the fentanyl transdermal patch), the
physician can attempt to correlate the dose of medication
previously used by the patient to an appropriate dose of the
selected drug (e.g., fentanyl or fentanyl congener such as
sufentanil) when infused subcutaneously. This correlation can be
made by reference to dose conversion information (e.g., a dose
conversion chart) between the previous medication and the selected
drug, if such dose conversion information exists. If dose
conversion information does not exist for the previous medications
and the selected drug, the physician can first switch the patient
from the previous medications to another medication for which there
exists dose conversion information with the selected drug (e.g.,
fentanyl or fentanyl congener, e.g., sufentanil).
[0122] In the alternative to resorting to dose conversion
information, or if such information does not exist, the physician
can determine the appropriate dose of drug to treat such patient by
infusing the selected drug (e.g., fentanyl or fentanyl congener,
e.g., sufentanil) subcutaneously by means of an external pump and
adjusting such infusion rates until the proper dose to control the
pain with minimal side effects is located.
[0123] 3. Implantation of DUROS.TM. Pump.
[0124] Once the physician has determined the appropriate dose of
fentanyl or fentanyl congener (e.g., sufentanil), then the
physician selects a DUROS.TM. Pump containing a formulation
comprising the selected drug (e.g., sufentanil) that is capable of
delivering the required dosage for up to 3 months. The physician
will then implant the DUROS.TM. Pump into the subcutaneous tissue
at the inside of the upper arm of the patient.
[0125] 4. Treatment of Pain.
[0126] Once the DUROS.TM. Pump has become activated by
implantation, the formulation of fentanyl or fentanyl congener
(e.g., sufentanil) will be delivered systemically to control pain
for up to 3 months. Treatment can be stopped prior to the end of
such 3 months by explanting the DUROS.TM. Pump. If treatment is
desired beyond 3 months, the expended DUROS.TM. Pump can be
explanted and a replacement DUROS.TM. Pump may be implanted in the
same subcutaneous location.
Example 2
[0127] DUROS.TM. Pump Useful for Delivery of Sufentanil
[0128] The following is a description of exemplary drug loading
parameters of a DUROS.TM. osmotic pump used for the delivery of
sufentanil. The parameters are based on a nominal fill volume of
the pump of 155 .mu.l, with a nominal volumetric delivery rate of
1.4 .mu.l/day for a nominal duration of 110 days (to ensure that a
target delivery period of 90 days is achieved). An exemplary
DUROS.TM. pump useful in this protocol is illustrated in FIG. 2,
and is approximately 3.76 mm in diameter and 44.21 mm in
length.
1TABLE 1 Loading Parameters .mu.g mg Dose Dose delivered delivered
Nominal Nominal DUROS .TM. wt/vol % rate rate over over 110 Rate
Rate Residence formulation .mu.g/hr .mu.g/day 110 days days
.mu.l/day .mu.l/hr Volume load 2.5 60 6600 6.6 1.4 0.058 155 4.28 5
120 10800 10.8 1.4 0.058 155 8.57 7.5 180 16200 16.2 1.4 0.058 155
12.6 10 240 21600 21.6 1.4 0.058 155 17.1 20 460 43200 43.2 1.4
0.058 155 34.3
[0129] These parameters thus dictate the amount of drug to be
included in the formulation of the pump in order to provide for
delivery at the selected dose rate for an approximately 110 day
period (e.g., about 3 months).
Example 3
[0130] Formulations Comprising Sufentanil in Benzyl Alcohol
[0131] 397 mg/mL Formulation
[0132] 3.97 g of sufentanil base were weighed out and added to a
portion of benzyl alcohol. The drug was dissolved in the benzyl
alcohol by stirring with a magnetic stirrer. When the resultant
preparation was clear, additional benzyl alcohol was added to
obtain 10 mL of formulation. The resultant formulation
concentration was 397 mg/mL.
[0133] 310 mg/mL Formulation
[0134] 3.1 g of sufentanil base were weighed out and added to a
portion of benzyl alcohol. The drug was dissolved in the benzyl
alcohol by stirring with a magnetic stirrer. When the resultant
preparation was clear, additional benzyl alcohol was added to
obtain 10 mL of formulation. The resultant formulation
concentration was 310 mg/mL.
Example 4
[0135] Formulations Comprising Sufentanil in Benzyl Benzoate
[0136] 248 mg/mL Formulation
[0137] The vehicle solution was prepared by adding 3 mL of
polysorbate 20 to sufficient benzyl benzoate to make 30 mL of
solution. The mixture was stirred using a magnetic stirrer until
the polysorbate 20 was dispersed in the benzyl benzoate. 7.44 g
sufentanil base was weighed out and added to a portion of the
vehicle solution. The drug was dissolved by sonicating the flask in
a sonication bath. When the resultant preparation was clear, an
additional quantity of the vehicle was added to obtain 30 mL of
formulation. The resultant formulation concentration was 248
mg/mL.
[0138] 77 mg/mL Formulation
[0139] The vehicle solution was prepared by adding 3 mL of
polysorbate 20 to sufficient benzyl benzoate to make 30 mL of
solution. The mixture was stirred using a magnetic stirrer until
the polysorbate 20 was dispersed in the benzyl benzoate. 2.322 g
sufentanil base was weighed out and added to a portion of the
vehicle solution. The drug was dissolved by sonicating the flask in
a sonication bath. When the resultant preparation was clear, an
additional quantity of the vehicle was added to obtain 30 mL of
formulation. The resultant formulation concentration was 77.4
mg/mL.
Example 5
[0140] Release of Sufentanil from DUROS.TM. Osmotic Pump
[0141] The release of drug from a DUROS.TM. osmotic pump at
37.degree. C. was tested in vitro at either 20 .mu.g/hr or 5
.mu.g/hr drug dose rates. Five different systems (five different
pumps) were tested for each of the drug delivery rates (20 .mu.g/hr
and 5 .mu.g/hr) over a 48 day period.
[0142] The release media (RM) is prepared from a phosphate buffered
saline (PBS) solution, available commercially as a powder
preparation and prepared according to manufacturer's directions. 5%
polysorbate 20 was added to the media prior to bringing it to final
volume. This solution is the release media (RM). 6 mL of RM was
dispensed into a 15 mL conical polypropylene tube, with one tube
prepared for each system to be tested. The tubes were placed in a
37.degree. C. water bath and allowed to reach temperature.
[0143] A system containing sufentanil is placed into each tube with
orifice end down, and completely immersed in the RM. At desired
time intervals, the system is removed from the tube using a
transfer rod. The system is placed (orifice end down) into a new
tube of RM which has been equilibrated in the water bath. An
example of time intervals is 0.5 hours, 1, 2, 3, 4, 5, 6, 7, 14,
28, 35 days, continuing weekly until delivery is complete.
[0144] In order to determine the amount of sufentanil released, 4
mL of acetonitrile was added to each sample test tube and mixed
thoroughly. The sample is then assayed to determine the amount of
sufentanil released during the time interval. Sufentanil in the
samples was quantitated, by HPLC or other methodology capable of
quantitating sufentanil in the presence of formulation and RM. The
amount released per unit time was calculated for each interval, and
a release rate profile prepared by plotting the amount released per
unit time on the y-axis against the mean time interval on the
x-axis.
[0145] The results for the 20 .mu.g/hr system are provided in FIG.
5, with the cumulative release provided in FIG. 6. The results for
the 5 .mu.g/hr system are provided in FIG. 7. The average pumping
rate for each group (the 20 .mu.g/hr group of pumps and the 5
.mu.g/hr group of pumps) is provided in FIG. 8. The results
demonstrate that controlled, continuous, and precise low volume
release of the potent opioid sufentanil is achieved with a
DUROS.TM. osmiotic implanted pump. In vitro release by the pump is
correlated to in vivo release because the volume dispensed form the
pump is a pure function of the pump and is independent of the
environment surrounding the pump. Thus, these same pumps are
expected to perform the same in vivo as in vitro.
* * * * *