U.S. patent application number 11/027336 was filed with the patent office on 2005-07-21 for high concentration medicament and polymer coated device for passive diffusional medicament delivery.
Invention is credited to Burkoth, Terry Lee, Harris, Scott L., Scott, Neal.
Application Number | 20050159704 11/027336 |
Document ID | / |
Family ID | 25544479 |
Filed Date | 2005-07-21 |
United States Patent
Application |
20050159704 |
Kind Code |
A1 |
Scott, Neal ; et
al. |
July 21, 2005 |
High concentration medicament and polymer coated device for passive
diffusional medicament delivery
Abstract
The present invention relates to a catheter with an expandable
distal end for delivering one or more medicaments. The catheter
also has a means for controlling or manipulating the expandable
distal end to expand and contract into various configurations to
apply pressure and achieve good contact against the walls of
structures into which it is advanced. The distal end of the
catheter is processed by a specific method of manufacturing whereby
the expandable distal end is coated with one or more layers of a
polymer wherein the surface layer of which coating carries one or
more medicaments at very high concentration and zero or more
excipients to facilitate the diffusional penetration of the
medicaments into contacted tissues.
Inventors: |
Scott, Neal; (Mountain View,
CA) ; Burkoth, Terry Lee; (Palo Alto, CA) ;
Harris, Scott L.; (San Diego, CA) |
Correspondence
Address: |
MICHAEL E. KLICPERA
PO BOX 573
LA JOLLA
CA
92038-0573
US
|
Family ID: |
25544479 |
Appl. No.: |
11/027336 |
Filed: |
December 30, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11027336 |
Dec 30, 2004 |
|
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|
09997855 |
Nov 29, 2001 |
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Current U.S.
Class: |
604/103.02 |
Current CPC
Class: |
A61P 43/00 20180101;
A61M 29/02 20130101; A61M 2025/0008 20130101; A61P 37/02 20180101;
A61M 2025/0175 20130101; A61M 2025/0183 20130101; A61P 9/00
20180101; A61M 2025/105 20130101; A61N 1/306 20130101; A61P 35/00
20180101; A61M 2025/0004 20130101 |
Class at
Publication: |
604/103.02 |
International
Class: |
A61M 031/00 |
Claims
We claim:
1. An apparatus for delivering a therapeutic agent or medicament
comprising: a catheter with an expandable portion having a surface
adapted to contract a vessel wall when in an expanded condition,
said expandable portion having a perfusion means therein to allow
blood flow through the expandable portion; a first flexible polymer
coating on the expandable portion; a second coating on the
expandable portion, disposed substantially over the first flexible
polymer, said second coating having a therapeutic agent or
medicament to polymer ratio of at least 4 to 1 by weight.
2. An apparatus as recited in claim 1 further comprising one or
more excipients interacting with said polymer incorporating one or
more therapeutic agents or medicaments.
3. An apparatus as recited in claim 1, wherein said catheter with
polymer retaining a high concentration therapeutic agent or
medicament will function to release the medicaments from the
polymer into tissue by diffusional means.
4. An apparatus as recited in claim 1, wherein said catheter with
polymer carrying a therapeutic agent or medicament will function to
deliver the medicaments into target tissues of said vascular
segment or body passageway by diffusional means because of high
concentration at the surface.
5. An apparatus as recited in claim 1, wherein said therapeutic
agent or medicament is a compound that inhibits cellular
proliferation, paclitaxel and paclitaxel derivatives or rapamycin
and rapamycin derivatives, and any combinations thereof.
6. An apparatus as recited in claim 1, wherein said therapeutic
agent or medicament will migrate into target tissues when exposed
to a high concentration of the drug at the surface.
7. An apparatus as recited in claim 1, further comprising a solvent
that rapidly evaporates and exposes a crystalline therapeutic agent
or medicament.
8. An apparatus as recited in claim 1, wherein said therapeutic
agent or medicaments crystallize and become exposed on the surface
of said expansion member.
9. An apparatus as recited in claim 1, wherein said therapeutic
agent or medicament is a combination of one or more
medicaments.
10. An apparatus as recited in claim 1, wherein said catheter
coated with a therapeutic agent or medicament and polymer matrix is
an over-the wire design.
11. An apparatus as recited in claim 1, wherein said catheter
coated with a therapeutic agent or medicament and polymer matrix
employs a rapid exchange design.
12. An apparatus as recited in claim 1 further comprised by a first
contracted configuration and a second expanded configuration
wherein said expandable distal end is adapted to allow blood
perfusion while said expandable distal is in either in said first
contracted configuration or in said second expanded
configuration.
13. An apparatus as recited in claim 1, further comprising said
first polymer having a low drug content such that the flexibility
of the first flexible polymer is not substantially degraded.
14. An apparatus as recited in claim 1 wherein said apparatus is
coated with a first flexible polymer without a medicament or
excipient, said first flexible polymer is substantially coated with
a very high medicament concentration of a solvent that has a rate
of evaporation to promote high drug deposition at the surface.
15. A drug delivery device comprising; a catheter having an
expandable portion having a surface adapted to substantially
contact a vessel wall when in a expanded condition; said expandable
portion have a perfusion means therein to allow blood flow through
the expandable position; and paclitaxel or paclitaxel derivative
disposed on the surface of the expandable portion, said coated
expandable portion having some crystalline paclitaxel or paclitaxel
derivative disposed on the surface said coated expandable
portion.
16. A drug delivery device comprising; a catheter having an
expandable portion having a surface adapted to substantially
contact a vessel wall when in a expanded condition; said expandable
portion have a perfusion means therein to allow blood flow through
the expandable position; and rapamycin or rapamycin derivative
disposed on the surface of the expandable portion, said coated
expandable portion having some crystalline rapamycin or rapamycin
derivative disposed on the surface said coated expandable
portion.
17. A method for introducing encapsulated medicaments into cells of
a patient, comprising the steps of: selecting as an elongated
catheter a substantially cylindrical shaped expansion member
located on a distal end, said expansion member having a first end
and a second end, said first end being a distance from said second
end, an altering means engagable to said first end and said second
end of said expansion member for altering said first distance
therebetween to move said expansion member between a first
configuration wherein said expansion member is characterized by a
first diameter and a second configuration wherein said expansion
member is characterized by a second diameter, said second diameter
being greater than said first diameter; said expansion member
having at least one coating, an outer coating having a therapeutic
agent or medicament to polymer ratio of at least 4 to 1 by weight;
locating said catheter into a selected blood vessel or other
lumenal physiological structure of a patient; expanding said
cylindrical expansion member wherein a portion of said cylindrical
expansion member contacts the vessel wall at a predetermined
location;
18. A method for delivering a medicament to an obstruction in a
body passageway which comprises the steps of: advancing a polymer
coated device for diffusional mediated drug delivery to a
predetermined site with a body passageway, said catheter having an
substantially cylindrical expansion member coated with a high
concentration of a therapeutic agent or medicament, said expansion
member being moveable between a first contracted configuration
wherein said expansion member is defined by a first dimension
extending in a radial direction, and a second expanded
configuration wherein said member is defined by a second dimension
extending in said radial direction; applying a force on said coated
expansion member in an axial direction to move said expansion
member between said first contracted configuration to said second
expanded configuration wherein said expansion member dilates said
obstruction or body passageway and delivers the therapeutic agent
or medicament firmly against said obstruction or body
passageway.
19. A method as recited in claim 18 which further comprises the
step of positioning a guidewire in the body passageway, and wherein
said advancing step is accomplished by threading said expansion
member over said guidewire.
20. A method as recited in claim 18 which further comprises the
step of allowing said expansion member to be in said second
expanded configuration for a predetermined period of time after the
dilatation step to further expose said obstruction to the
medicament.
21. A method for dilating and delivering a medicament to an
obstruction in a body passageway which comprises the steps of:
advancing a polymer coated device for diffusion mediated drug
delivery to a predetermined site within a body passageway, said
device having an expansion member coated with a polymer and a
crystalline medicament, said expansion member being moveable
between a first contracted configuration wherein said member is
defined by a first dimension extending in a radial direction, and a
second expanded configuration wherein said member is defined by a
second dimension extending in said radial direction; applying a
force on said expansion member in an axial direction to move said
expansion member between said first contracted configuration to
said second expanded configuration wherein said obstruction is
dilated; applying a pressure against the tissue to deliver the
crystalline medicament into said obstruction or body
passageway.
22. A method as recited in claim 21 which further comprises the
step of positioning a guidewire in the body passageway, and wherein
said advancing step is accomplished by threading said catheter over
said guidewire.
23. A method as recited in claim 21 which further comprises the
step of allowing said expansion member to be in said second
expanded configuration for a predetermined period of time after the
dilatation step to further expose said obstruction to the
medicament.
24. An apparatus for delivering a medicament to an obstruction
within a vascular segment or a body passageway which comprises: a
catheter with an expandable mechanical distal end; said distal end
incorporating a polymer carrying one or more medicaments at high
surface concentrations, a medicament formulation that does not
release significant drug into the systemic circulation, and a
medicament formulation and polymer that upon wetting and flexing
the apparatus causes a portion of the medicament formulation to
crystallize and to become exposed at the surface of the expandable
mechanical distal end and increase exposure to the tissue.
25. An apparatus as recited in claim 24, wherein said catheter with
polymer carrying a therapeutic agent or medicament will function to
release the medicaments from the polymer by diffusional means.
26. An apparatus as recited in claim 24, wherein said catheter with
polymer encapsulating a therapeutic agent or medicament will
function to deliver the medicaments into target tissues of said
vascular segment or body passageway by diffusional means.
27. An apparatus as recited in claim 24, wherein said therapeutic
agent or medicament is a compound that inhibits cellular
proliferation, paclitaxel and paclitaxel derivatives or rapamycin
and rapamycin derivatives, and any combinations thereof.
28. An apparatus as recited in claim 24, wherein said polymer
carried agent or medicament is a combination of one or more
medicaments.
29. An apparatus as recited in claim 24, wherein said catheter with
polymer carrying a therapeutic agent or medicament is an over-the
wire design.
30. An apparatus as recited in claim 24, wherein said catheter with
polymer carrying a therapeutic agent or medicament employs a rapid
exchange design.
31. An apparatus as recited in claim 24, further comprised by a
first contracted configuration and a second expanded configuration
wherein said expandable distal end is adapted to allow blood
perfusion while said expandable distal end is either in said first
contracted configuration or in said second expanded
configuration.
32. An apparatus as recited in claim 24, wherein said expandable
distal end can perform dilatation and drug delivery while
simultaneously allow blood perfusion.
33. An apparatus as recited in claim 24, wherein said crystalline
medicament formulation is paclitaxel or a paclitaxel
derivative.
34. An apparatus as recited in claim 24, wherein said crystalline
medicament formulation is rapamycin or a rapamycin derivative.
35. A method for coated a stent with multiple coatings: employing a
water based solvent to incorporate one or more medicaments into a
polymer to comprise a first base coating; coating a portion of the
distal expandable end of a drug delivery catheter with said first
base coating; employing an organic based solvent to incorporate one
or more medicament into a polymer to comprise a second top coating,
said second top coating having medicament to polymer ratio of at
least 4 to 1 by weight; coating said second top coating
substantially over said first base coating.
36. A method as recited in claim 35, further comprising that said
water based solvent is H.sub.2O, ethanol or any alcohol derivative,
or any combination of H.sub.2O, ethanol or any alcohol derivative
thereof.
37. A method as recited in claim 35, further comprising that said
organic based solvent is tetrahydrofuran or toluene, or any
combination of tetrahydorfuran and toluene thereof.
Description
PRIOR APPLICATIONS
[0001] This application is a continuation-in-part of application
Ser. No. 09/997,855 filed on Nov. 29, 2001.
BACKGROUND OF THE INVENTION
[0002] Cardiovascular disease is commonly accepted as being one of
the most serious health risks facing our society today. Diseased
and obstructed coronary arteries can restrict the flow of blood and
cause tissue ischemia and necrosis. After over two decades of
investigation, the exact etiology of sclerotic cardiovascular
disease is still in question, the treatment of narrowed coronary
arteries is more defined. Surgical construction of coronary artery
bypass grafts (CABG) is often the method of choice when there are
several diseased segments in one or multiple arteries. Open heart
surgery is, of course, very traumatic for patients. In many cases,
less traumatic, alternative methods are available for treating
cardiovascular disease percutaneously. These alternate treatment
methods generally employ various types of percutaneous transluminal
angioplasty (PTCA) balloons or excising devices (atherectomy) to
remodel or debulk diseased vessel segments. A further alternative
treatment method involves percutaneous, intraluminal installation
of expandable, tubular stents or prostheses in sclerotic
lesions.
[0003] A recurrent problem with the previous devices and PTCA
procedures is their failure to maintain patency due to the growth
of injured vascular tissue. This is known as "restenosis" and may
be a result of the original injury to the vessel wall occurring
during the angioplasty procedure. Pathologically restenosis
represents a neointimal proliferative response characterized by
smooth muscle cell hyperplasia that results in reblockage of the
vessel lumen necessitating repeat PTCA procedures in up to 35-50%
of all cases. It has been generally accepted that certain
therapeutic agents or medicaments may be capable of selectively
inhibiting the growth of these hyperproliferating smooth muscle
cells and thereby reduce the rate of restenosis after the primary
interventional procedure.
[0004] Heretofore, various devices have been disclosed which may be
used to deliver a therapeutic agent or medicament to a blood vessel
while undergoing angioplasty. Balloon angioplasty catheters have
been used to place and deliver various therapeutic agents or
medicaments within human vessels. For example, in U.S. Pat. Nos.
5,112,305, 5,746,716, 5,681,281, 5,873,852, 5,713,863 and 6,102,904
disclose and claim a balloon catheter system with various injector
plates mounted on the balloon for delivering a drug into an
arterial segment.
[0005] Alternatively a standard angioplasty balloon may be coated
with a substrate or polymeric material which either incorporates,
or is then used to bond, certain medicaments or theraputic agents.
These agents are then delivered to the desired therapeutic site by
inflation of the balloon and diffusion of the medicament or
therapeutic agent into the vessel wall. Only limited quantities of
therapeutic agents can be delivered because of "wash-out" of the
drug into the circulation during balloon placement and due to the
limited time the inflated balloon can be left in place due to
ischemia caused by the balloon.
[0006] In addition, previously disclosed methods of delivering drug
to a site of treatment are described which utilize iontophoretic or
electrophoretic means as disclosed in U.S. Pat. No. 5,499,971.
Using these iontophoretic or electrophoretic means passive
diffusion of the drug or medicament is enhanced by placing the
medicament or therapeutic agent in close proximity to the site of
treatment and then using electrical energy to augment delivery of
the drug into the tissues or cells. These methods generally place
the drug inside a balloon mounted distally on a catheter whereby
the balloon is composed of a semi-porous material through which the
drug can diffuse.
[0007] Additional devices have been disclosed which attempt to
improve the depth of penetration into tissue by pressure driving a
solution of the drug into the vessel wall through small orifices in
the balloon material. There-is, however, some evidence that high
pressure "jetting" of a drug solution out of small pores close to
the vessel lumen can in fact cause vessel wall injury. The
development of double skinned, microporous (or weeping) balloons
obviated this "jetting" effect to some extent, but diffusion of the
drug into the vessel wall is still slow, and much of the drug can
be lost through subsequent "washout effects". This method leads to
limited amounts of drugs or therapeutic agents delivered to the
tissues or cells. Furthermore, in all of these methods the balloon
must be expanded and thereby restricts blood flow to the distal
arterial segments while the balloon is in the expanded
configuration thus limiting the time the drug delivering balloon
can be clinically utilized.
[0008] There are also several disadvantages to using either a stent
or balloon catheter to deliver a therapeutic agent or medicament to
a vascular segment. Regarding the therapeutic agent eluting stents,
once the stent is deployed, there is no means outside of invasive
surgical excision, to remove the eluting stent from the vascular
segment. Therefore, stents or implanted prostheses with therapeutic
agent eluting properties must be precisely calibrated to deliver an
exact quantity of the therapeutic agent or medicament to the
vascular segment upon stent deployment. Balloon catheters employed
to deliver a therapeutic agent or medicament to a vascular segment
have limitations including potential balloon rupture and ischemia
due to balloon inflation limiting distal blood flow to the artery.
This leads to tissue ischemia and potential necrosis. Even
"perfusion" type angioplasty balloons used to delivery a
therapeutic agent or medicament to the affected artery provide far
less than physiological blood flow during balloon inflation and
dwell times are limited by ischemia and tissue necrosis.
[0009] Additional devices have been disclosed which utilize
catheter based multiple injecton ports to inject the drug directly
into the vessel walls. Disadvantages of this system include
potential injury to vessel walls, non-uniform drug delivery and the
requirement that the drug must be carried either in the solubilized
form or in fine suspensions which is a particular problem for drugs
that are not water-soluble).
[0010] Recent studies have demonstrated the effectiveness of a
number of agents (e.g., paclitaxel, rapamycin, Actinomycin D) to
prevent unwanted cellular proliferation. These agents have proven
efficacy in the treatment of cancer transplant rejection and
restenosis following angioplasty. A major advantage of these agents
is their high lipid solubility that causes tissue levels of these
agents to remain high for an extended period of time since they
cannot be rapidly cleared. However, the delivery of these
lipophillic medicaments generally present formulation and transport
challenges in aqueous media. Furthermore, they are less likely to
permeate across hydrophilic boundaries and cell membranes into
tissue.
[0011] In general, it is an object of this present invention to
provide a catheter coated with a polymer containing or carrying one
or more medicaments at sufficient concentration to be capable of
delivering, by passive diffusion means, the medicament(s) to the
vessel segment or obstruction.
[0012] In general, it is an object of this present invention to
provide a catheter system whereby the catheter can be applied in
pressurized contact with the vascular surface and remain in place
for sufficient time without ischemic effect to facilitate the
release of medicaments present from the high concentration in the
polymer present on a portion of the catheter.
[0013] In general, it is an object of this present invention to
provide a method whereby the medicament is presented in the right
physical-chemical form and in sufficient concentration to be
released from the polymer and transported into the surrounding
tissues at therapeutic levels. The delivery of the medicaments can
be without any excipients or with one or more excipients chosen to
alter drug solubility or to aid in tissue penetration. The
excipients can be charged or nonionic surfactants,
polyelectrolytes, lipids, fatty acids or esters, liposomes or other
solubility-altering entities.
[0014] Another object of the invention is to provide a method to
deliver high concentrations of agents that are poorly soluble or
insoluble in aqueous media to selected sites in the body including
arteries, veins or other tubular structures, prosthetic devices
such as grafts, and tissues such as, but not limited to, brain,
myocardium, colon, liver, breast and lung or to other abnormal or
pathological tissues such as tumors or wounds.
[0015] Another object of the invention is to provide an apparatus
and a method to deliver a wide range of medicaments with different
degrees of solubility, molecular sizes and chemical structures
These medicaments can be charged or neutral. The medicaments can
include, but not exclusively, genetic agents
[0016] Another object of the invention is to provide an apparatus
and a method that can control and direct the active release or
diffusion of a medicament or therapeutic agent to minimize
potential systemic effects and promote and maximize the delivery of
the medicament or therapeutic agent into the surrounding tissue
[0017] Another object of the invention is to provide an apparatus
and a method to promote and maximize the penetration of a
medicament or therapeutic agent into the surrounding tissues
uniformly throughout the diseased area and to facilitate the
binding to the tissue and thus promote a therapeutic effect.
[0018] Another object of the invention is to provide a apparatus
and method that can promote the active release or diffusion of a
medicament or therapeutic agent while simultaneously dilating an
obstruction within a blood vessel or organ.
[0019] Another object of the invention is to provide an apparatus
and method that can promote the diffusion of a medicament or
therapeutic agent while simultaneously allowing perfusion of blood
or liquid to occur through the apparatus delivering the medicament
or therapeutic agent.
SUMMARY OF THE INVENTION
[0020] The present invention relates to a catheter with an
expandable distal end. The catheter is manufactured with materials
of construction that has a means for controlling or manipulating
the expandable distal end to expand and contract into various
configurations.
[0021] The distal end of the catheter is processed by a specific
method of manufacturing whereby the expandable distal end is coated
with one or more layers of a polymer at least one layer of which
coating contains or retains one or more medicaments and zero or
more excipients to facilitate delivery of the medicaments into
target tissue.
[0022] The successful diffusion of the desired medicaments out of
or off the polymer coating and into surrounding tissue in this
invention, depends on many factors. Diffusion is dependent on the
solubility of the medicament in the tissue at the interface as well
as the surface characteristics, rough or smooth, of the coating and
the pressure of the catheter at the surface to gain contact and
exclude the hydrophillic barrier of a layer of liquid. Other
factors affecting migration and tissue penetration include the
selection of the polymer and its chemical and physical
characteristics, the selection of any excipients to alter
solubility or aid in tissue penetration, and the residence time for
tissue contact.
[0023] The present invention relates to the delivery of medicaments
within the body of a patient. The invention uses high concentration
diffusion mediated drug delivery with a specially designed
catheter. The catheter has a metal mesh on its distal end that
expands against a solid, tubular or hollow structure. The mesh is
coated with one or more layers of polymer at least one layer of
which contains at least one drug or medicament and zero or more
excipients.
[0024] The polymer used in the present invention is a hydrophilic
polyurethane that exhibits moderate swelling in aqueous media. It
is anticipated by the Applicants that other hydrophilic polymers
having similar properties as the polyurethane polymer can function
with the present invention. The polymer used in the current
invention possesses the following characteristics. It forms strong
adhesion or cohesion with the catheter metal surface. The adhesion
or cohesion must sustain repeated contraction and expansion of the
catheter mesh during application. Furthermore, the polymer must
possess certain tensile and mechanical properties that preserve the
coating integrity during the contraction and expansion operations
of the catheter mesh.
[0025] In the present invention the ratio of drug to polymer at the
surface is much higher than prior, traditional drug polymeric drug
delivery systems in which the polymer exerts some control of
delivery. In one embodiment the medicament paclitaxel is
incorporated only in the final topcoat of a polymer/drug
combination at a range of 60-90/40-10 weight/weight drug to polymer
ratio of solids, with a preferred 80/20 weight/weight drug to
polymer ratio or solids. This composition is applied with a solvent
or mixture of solvents chosen to be sufficiently rapidly
evaporating that during deposition and drying the drug does not
penetrate significantly into the base coats. For example, a solvent
consisting of an ethanol/H.sub.2O can be used for the base coating
and then tetrahydrofuran (THF) and toluene as a solvent for the
heavily laden top coating. Using the same polymer for each coating,
the base coating will resist dissolving and inhibit migration of
the medicament from the heavily laden top coating. The mixed
solvent is chosen to be of intermediate dissolution capability for
both polymer and medicament so as to minimize penetration-migration
into the polymer base coats. The polymer structure is also chosen
to be sufficiently lipophobic that crystalline paclitaxel is
excluded or blooms during drying. Further crystallization occurs
upon flexing of the catheter. Because it is in crystalline form and
a very hydrophobic medicament there is minimal loss of paclitaxel
into the bloodstream during placement in vascular applications.
Like drugs of lipophillic nature would behave similarly, but for
more soluble drugs, excipients including materials that encapsulate
the medicament would be used.
[0026] The chemical characteristics of a polymer, such as the
degree of hydrophilicity, and physical characteristics such as
mechanical strength, may be also be controlled by the chemical
structure, crosslinking and molecular weight range. The flexibility
to adjust the chemical composition of a suitable polymer makes it
possible to carry a wide range of medicaments of different chemical
and physical properties. Other specific polymers and polymer
classes that have necessary physical properties and form
water-filled porous structures will be obvious to those skilled in
the art.
[0027] Conventional coating methods can be used to apply a viscous
polymer solution, melt or suspension to the catheter surface to
form a thin layer of coating. The polymer coats may be dried in air
or dried with heating or coagulated and precipitated in the
presence of a non-solvent. The present invention requires multiple
coating layers with the same or different polymer. Each layer may
or may not contain medicaments but the final coating contains a
very high proportion of medicament on a solids weight basis. In the
event a multiple layer coating is employed with a hydrogel or other
similar type polymer, the introduction of water to completely
coagulate the copolymer is the final step. Other methods of
deposition or coating such as spraying, application of melts or
powders with annealing will be well-known to those skilled in the
art.
[0028] The delivering of medicaments by the present invention and
methods generally comprises the steps of advancing a catheter or
medical device generally including a distal expansion member and
advancing the expansion member to an obstruction within a vessel or
to the desired site of treatment. At this time the clinician
applies forces on the expansion member causing the expansion member
to become fully expanded wherein the expansion member contacts the
surrounding tissue. Prolonged strong contact between the high
concentration of the medicament including crystals of the
medicament on the surface of the expansion member and the tissue
being treated results in some dissolution and diffusion of the
medicament into the lipid components of the tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] FIG. 1 is a side-elevational view partially in section of a
medicament delivery device incorporating a polymer coating carrying
a therapeutic agent.
[0030] FIG. 2 is a cross-sectional view taken along the line 2-2 of
FIG. 1.
[0031] FIG. 3 is a cross-sectional view taken along the line 3-3 of
FIG. 1.
[0032] FIG. 4 is a cross-sectional view taken along the line 4-4 of
FIG. 1.
[0033] FIG. 5 is a cross-sectional view taken along the line 6-6 of
FIG. 1.
[0034] FIG. 6 is a greatly enlarged view of a portion of the
dilatation and medicament delivery device in a partially expanded
state.
[0035] FIG. 7 is a side-elevational view of the distal extremity of
the device shown in FIGS. 1-6 showing the distal extremity with the
expansion member in an expanded condition showing the polymer with
therapeutic agents or medicaments coated on the distal expansion
member.
[0036] FIG. 8 is a representation of the multi-layered polymer
coating that carries a very high concentration of therapeutic
agents or medicaments and includes exposed crystalline therapeutic
agents or medicaments on the surface of the distal expansion
member.
[0037] FIG. 9 is a greatly enlarged view of a portion of the
polymer with therapeutic agents of medicaments coated on the distal
expansion member.
[0038] FIG. 10 is a greatly enlarged view of a portion of the
multilayer coating the carries a very high concentration including
exposed crystalline therapeutic agents of medicaments on the
surface.
DETAILED DESCRIPTION OF THE DRAWINGS
[0039] In general, the present invention relates generally to
devices that are used to dilate and dispense a medicament or
therapeutic agent to an obstruction within a stenotic segment of a
vessel or other tubular structure. The device is comprised of a
cylindrical expansion member to be disposed in an obstruction in a
vessel carrying flowing blood. The cylindrical expansion member has
first and second ends and an intermediate portion between the first
and second ends. The cylindrical expansion member also has a flow
passage extending therethrough with a diameter and a longitudinal
central axis. The diameter of the flow passage is a variable with
movement of the first and second ends relative to each other along
the longitudinal central axis from a diametrically contracted
position to a diametrically expanded condition. The cylindrical
expansion member is comprised of a plurality of flexible elongate
elements each of which extends helically about the longitudinal
extending central axis. The flexible elongate elements are coated
with a polymer carrying a therapeutic agent, medicaments, drugs,
pharmaceuticals, plasmids, genes, double and single stranded DNA
double and single stranded RNA or other agents. For the purposes of
this application, the terms polymer carrying a medicament or
therapeutic agent, drugs, pharmaceuticals, plasmids, genes or other
agents, will be used to encompass all the particular agents
described herein. It is also contemplated that the polymer carrying
medicament or therapeutic agent may be incorporated with a
non-medicament substrate that has been previously or simultaneously
coated on the flexible elongate elements.
[0040] Means are provided for engaging the first and second ends of
said cylindrical expansion member for retaining said first and
second ends in contracted positions. Means are provided for causing
relative axial movement of the first and second ends towards each
other to cause the intermediate cylindrical portion of the
expansion member to contract longitudinally and to expand
diametrically by causing the flexible elongate elements in the
intermediate portion of the cylindrical member to move closer to
each other expanding the diametric dimensions of the cylindrical
expansion member thereby allowing it to contact the vessel wall and
enable it to dilate an obstruction within the vessel. Flexible
elongate elements at the first and second ends of the cylindrical
expansion member remain contracted around and within first and
second means and are thereby prevented from moving closer which
maintains spacing between the flexible elongate members so that
blood in the vessel can continue to flow through the first and
second ends and through the flow passage in the cylindrical
expansion member while the cylindrical expansion member is in
engagement with vessel wall and dilating an obstruction within the
vessel.
[0041] More in particular as shown in FIGS. 1-6 of the drawings,
the mechanical dilation and medicament delivery device 11 shown
therein consists of a first or outer flexible elongate tubular
member 12 having proximal and distal extremities 13 and 14 with the
outer flow passage 16 extending from the proximal extremity 13 to
the distal extremity 14. A second or inner flexible tubular member
21 is coaxially and slidably disposed within the outer flow passage
16 of the first or outer flexible elongate tubular member 12 and is
provided with proximal and distal extremities 22 and 23 with a
lumen 24 extending from the proximal extremity 22 to the distal
extremity 23. The flexible elongate elements of the dilating member
are made of a metallic material such as stainless steel,
Elgiloy.RTM. or other biocompatible metal.
[0042] A guide wire 26 of a conventional type is adapted to be
introduced through the lumen 24 in the inner flexible elongate
tubular member for use in guiding the mechanical dilatation and
medicament delivery device 11 as a over-the-wire design as
hereinafter described. The guide wire 26 can be of a suitable size
as for example 0.010"-0.035" and can have a suitable length ranging
from 150 to 300 centimeters. For example, the first or outer
flexible elongate tubular member 12 can have an outside diameter of
0.6-3 millimeters with a wall thickness of 0.12 millimeters to
provide a flow passage 16 of 0.75 millimeters in diameter.
Similarly, the second or inner flexible elongate tubular member 21
can have a suitable outside diameter as for example 0.6 millimeters
with a wall thickness of 0.12 millimeters and an inner lumen 24 of
0.45 millimeters in diameter. The flexible elongate tubular members
12 and 21 can be formed of a suitable plastic as for example a
polyimide, polyethylene, Nylon or polybutylteraphthalate (PBT).
[0043] In accordance with the present invention an essentially
cylindrically shaped expansion member 31 is provided which has a
first or proximal end 32 and a second or distal end 33 with a
central or inner flow passage 34 extending from the proximal end 32
to the distal end 33 along a longitudinally extending central axis
and has a diameter which is a variable as hereinafter described.
The cylindrically shaped expansion member 31 is comprised of a
plurality of flexible elongate elements or filaments 36 each of
which extends helically about the longitudinally extending central
axis. The flexible elongate elements 36 are formed of suitable
materials which can be utilized in the human blood as for example
stainless steel, Nitinol, AerMet.RTM., Elgiloy.RTM. or certain
other metal fibers. The flexible elongate elements 36 can have a
suitable diameter as for example 0.001 to 0.010 inches or can be
configured as a round, elliptical, flat or triangular wire ribbon.
A plurality of the flexible elongate elements 36 have a first
common direction of rotation about the central axis as shown in
FIGS. 1 and 6 are axially displaced relative to each other and
cross a further plurality of the flexible elongate elements 36 also
axially displaced relative to each other but having a second common
direction of rotation opposite to that of the first direction of
rotation to form a double helix or braided or mesh-like cylindrical
expansion member with the crossing of flexible elongate elements 36
occurring in the area of contact between the flexible elongate
elements to form openings or interstices 37 therebetween. Thus the
flexible elongate elements 36 form an expansion member 31 which
provides a central or inner flow passage 34 which is variable in
diameter upon movement of the first and second ends of the
expansion member 31 relative to each other along the longitudinally
extending central axis.
[0044] Means is provided for constraining the first and second or
proximal and distal ends 32 and 33 of the expansion member 31 and
consists of a first or proximal collar 41 and a second or distal
collar 42. The first and second collars 41 and 42 are formed of a
suitable material such as a polyimide.
[0045] Typically the distance between the first and second collars
41 and 42 can range from between 5 to 150 millimeters. Typically
the distal end 23 of the second or inner flexible elongate tubular
member 21 extends approximately 5-170 millimeters beyond the distal
extremity 14 of the first or outer flexible elongate tubular member
12.
[0046] It can be seen that by moving the first or outer flexible
elongate tubular member 12 and the second inner flexible elongate
tubular member 21 axially with respect to each other, the first and
second ends of the expansion member 31 are moved towards each other
causing the elongate elements or filaments 36 of an intermediate
portion of the cylindrical expansion member between the first and
second ends to move closer to each other to cause these flexible
elongate elements to move into apposition with each other and to
expand in a first radial direction the intermediate portion of the
cylindrical expansion member 31 (FIG. 6) and to cause the diameter
of the central flow passage 34 to increase. The portions of the
expansion member 31 immediately adjacent the first and second
collars 41 and 42 remain restrained by the collars 41 and 42
causing the flexible elongate elements 36 immediately adjacent to
the collars 41 and 42 to curve conically toward and remain crossed
and unable to come into close apposition and thereby provide
openings or interstices 37 therebetween, which remain relatively
constant in shape and size so that blood can flow from the first
and second ends 32 and 33 through the central or inner flow passage
34 as hereinafter described.
[0047] The essentially cylindrical shape of the expansion member
when expanded in a radial direction provides an enlarged surface of
contact between the expansion member and the vessel wall or
obstruction. This enlarged surface of contact enables the
cylindrical expansion member to deliver an increased amount of
medicament or therapeutic agent which is incorporated within and
upon the polymer coated on the surface of the flexible elongate
elements that comprise the expansion member. This delivery of
medicament or therapeutic agent may be by the various well known
means previously described: active diffusion and pressure against
and superficially into the tissue.
[0048] One example of the means provided in the mechanical dilation
and medicament delivery device 11 for causing relative movement
between the first or outer flexible elongate tubular member 12 and
the second or inner flexible elongate tubular member 21 and
consists of a linear movement mechanism 46. The linear movement
mechanism 46 includes a Y-adapter 49 that is provided with a
central arm 51 having a lumen 52 through which the second or inner
flexible elongate tubular member 21 extends.
[0049] It should be appreciated that even though one particular
linear movement mechanism 46 has been provided for advancing and
retracting the flexible elongate members 12 and 21 with respect to
each other, other mechanisms also can be utilized if desired to
provide such relative movement. Other possible designs that could
be employed are scissors-jack, rachet-type or straight slide
mechanisms.
[0050] As shown in FIG. 7 and enlarged in FIG. 9, the distal
extremity of the device shown in FIGS. 1-6 is an expansion member
or mesh 31 in an expanded condition with a the therapeutic agents
or medicaments 40 incorporated within a polymer substrate 43 and
coated on the flexible elongate elements 36 of the distal expansion
member 31. The polymeric coating on the expansion member terminates
at an intermediate position 42a, 1-5 mm distance from the ends of
the expansion member or collar 41. Thus when the distal cylindrical
expansion member is fully expanded, blood or fluid may still freely
flow into the proximal end of the cylindrical expansion member 43a,
through the cylindrical expansion member and out the distal end of
the expansion member 44a. Thus perfusion of blood or liquid is
permitted into the distal vessel or organ even when the expansion
member is fully expanded against the wall of the vessel or tubular
structure for prolonged periods of time. Alternatively, the
polymeric coating may cover only the individual wires and not cover
the interstices of the distal cylindrical expansion member. This
would allow both distal and sidebranch perfusion to occur despite
full expansion of the distal cylindrical expansion member against
the vessel wall for prolonged periods of time. When the polymer
coated distal cylindrical expansion member 35 is fully expanded it
is almost a solid tubular mass which reduces area of the
interstices or openings 37 and maximizes the medicament coated
flexible elongate elements for intimate pressurized contact with
the vessel walls. FIG. 9 demonstrates a greatly enlarged view of a
portion of the polymer with therapeutic agents of medicaments
coated on the distal expansion member.
[0051] Now referring to FIG. 8, the polymer and medicament distal
expansion member 35 is fully expanded it is almost a solid tubular
mass which reduces area of the interstices or openings 37 and
maximizes the medicament coated flexible elongate elements for
intimate pressurized contact with the vessel walls. The embodiment
of FIGS. 8 and 10 comprises a coated distal expansion member 35
including a multi-layered polymer or substrate coating 43 that
carries a base coat 82 of pure substrate 43 or medicament
incorporated polymer 47 together with a top layer 80 of polymer
incorporating the therapeutic agent of medicament 40 in a very high
concentration 48. The top layer 80 also can be disposed with a
solvent that rapidly evaporates but is also a poor solvent for the
polymer/medicament combination and does not significantly penetrate
the base coat. For example, A solvent consisting of a
ethanol/H.sub.2O can be used for the base coating and then
tetrahydrofuran (THF) and toluene as a solvent for the heavily
laden top coating. Using the same polymer for each coating, the
base coating will resist dissolving and inhibit migration of the
medicament from the heavily laden top coating. In addition, the
evaporation of the solvent can leave exposed crystallized
therapeutic agents or medicaments 38 on the surface of the coated
expansion member 35. FIG. 10 demonstrates a greatly enlarged view
of a portion of the multilayer coating the carries a very high
concentration including exposed crystalline therapeutic agents of
medicaments on the surface. There is minimal loss of a lipophilic
therapeutic agent or medicament 40 from the top layer due to low
aqueous solubility. For more soluble medicaments a secondary
coating (not shown) may be applied to retard the loss of previously
coated drugs or medicaments 40 and excipients 39 into the
bloodstream or tissues which may occur prior to the delivery of the
drug or medicaments 40 at the desired tissue site.
[0052] Once the site of obstruction or treatment is reached and the
distal cylindrical expansion member 31 is expanded, the expansion
member is in physical contact with the surrounding tissue or vessel
wall. The distal expansion member 31 of the catheter is coated with
one or more layers of a polymer material or similar substrate 43,
into and onto which are encapsulated one or more medicaments or
therapeutic agents 40 and zero or more excipients to alter the
solubility of the medicaments or their tissue penetration. These
excipients 39 may include by example, neutral or charged lipids,
surfactants, materials capable of forming crystalline inclusion
complexes or other suitable molecules known to those skilled in the
art to have properties to change solubility characteristics or to
augment the tissue penetration previously described. Plasticizers
well-known to those skilled in the art may be incorporated to alter
the physical properties of the polymer carrier.
[0053] The therapeutic agents or medicaments 40 employed can be
compounds that inhibit cellular proliferation such as paclitaxel,
paclitaxel derivatives, rapamycin (also known as sirolimus) and
rapamycin derivative.
[0054] To perform as a polymer coated device for high dose passive
diffusional therapeutic agent or medicament delivery, the distal
expansion member will be coated as described in more detail
below.
[0055] A precise volume of a viscous polymer solution, either by
itself or mixed with medicaments 43, 47 with or without
solubility-altering excipients 39 or tissue permeation enhancers,
is pumped through a slot into a coating groove as the device is
rotated to evenly coat the mesh. A single layer or multiple layers
of viscous polymer containing medicaments 47 with or without
excipients 39 are then deposited onto the catheter mesh
surface.
[0056] Other coating methods may also be employed to deposit a
uniform and defined layer of polymer solution onto the surface of
the catheter mesh. Conventional coating technology is well known to
those skilled in the art or can be determined in standard
references.
[0057] The coated catheter is then dried in air with or without
heat either between coats or after the final coat. For the present
invention it is preferred that several coats without medicament be
applied and dried to be followed by one or more final coats with a
very high medicament to polymer 48 solids ratio.
[0058] Additional layers serving different purposes may be added.
The additional layers of polymer may be of the same kind, or of a
different kind, of polymers depending on the desired application
For example, a very thin layer of hydrogel may be initially applied
to the catheter mesh surface to promote adhesion. Alternatively, a
secondary layer formed of the same or a different polymer may be
applied to cover the primary coating that contains the drugs or
medicaments 40 in a manner similar to that described above. This
coating may contain zero or more additional drugs or medicaments 40
and zero or more excipients 39. Depending on application
requirements, multiple layers of polymer coating may be used.
[0059] Preferably, the coated expansion member 35 should have a
diameter that is only slightly greater than the tubular member 12,
as for example by 1.0-2.3 millimeters. The first and second collars
41 and 42 also have been sized so they only have a diameter that is
slightly greater than the outer diameter of the outer flexible
elongate tubular member 12. To bring the cylindrical expansion
member 31 to its lowest configuration, the linear movement
mechanism 46 has been adjusted so that there is a maximum spacing
between the distal extremity 23 of the inner flexible elongate
tubular member 21 and the distal extremity 14 of the outer flexible
elongate tubular member 12. In this position of the expansion
member 31, the flexible elongate elements 36 cross each other at
nearly right angles so that the interstices or openings 37
therebetween are elongated with respect to the longitudinal
axis.
[0060] The polymer coated device for passive diffusional drug
delivery 11 is then inserted into a guiding catheter (not shown)
typically used in such a procedure and introduced into the femoral
artery and having its distal extremity in engagement with the
ostium of the selected coronary artery.
[0061] The guide wire 26 is then advanced in a conventional manner
by the physician undertaking the procedure and is advanced into the
vessel containing a stenosis. The progress of the distal extremity
of the guide wire 26 is observed fluoroscopically and is advanced
until its distal extremity extends distally of the stenosis. With
the expansion member 31 in its diametrically contracted position
and the medicament containing polymer or polymer with therapeutic
agent coated thereonis advanced over the guide wire 26 until the
distal end is centered within the region of interest.
[0062] After the polymer-coated cylindrical expansion member 35 is
in a desired position in the stenosis, the cylindrical expansion
member 35 is expanded from its diametrically contracted position to
an expanded position by moving the distal extremities 14 and 23
closer to each other by operation of the screw mechanism 46. This
can be accomplished by holding one distal extremity stationary and
moving the other distal extremity towards it or by moving both
distal extremities closer to each other simultaneously.
[0063] When the polymer coated distal cylindrical expansion member
35 is fully expanded it is almost a solid tubular mass which has
significant radial strength to fully expand a stenosis or secure
intimate pressurized contact with the vessel walls. Since the
expansion member is coated with a polymer with medicament within
and thereon the therapeutic agent or medicament can be delivered to
the vessel during the time of device expansion while blood is
permitted to flow unobstructed to the distal vessel.
[0064] After delivery of the medicaments or therapeutic agent to
the lesion has been carried out for an appropriate length of time,
the expansion member 31 can be returned from its expanded position
to a contracted position. After the expansion member 31 has been
reduced to its contracted or minimum diameter, the polymer coated
device for drug delivery 11 can be moved to another desired
treatment site or removed along with the guide wire 26 after which
the guiding catheter (not shown) can be removed and the puncture
site leading to the femoral artery closed in a conventional
manner.
[0065] Although, the procedure hereinbefore described was for
treatment of a single stenosis or region of interest, it should be
appreciated that if desired during the same time another stenosis
or region of interest need be treated, the catheter may be advanced
to this second area of interest and the procedure repeated.
Alternatively, another polymer coated device for drug delivery 11
may be re-inserted in the same or other vessels or regions of
interest of the patient and can be treated in a similar manner.
[0066] Described below are some examples of experiments conducted
using the present invention.
EXAMPLE 1
Local Delivery of Paclitaxel
[0067] 1a Multi-Step Coating of Mesh Catheters
[0068] Metal mesh catheters were coated in several steps with
different polymer compositions to generate suitable physical
properties and a sufficiently high surface concentration of
paclitaxel for in-vivo passive diffusional delivery in pigs.
[0069] The catheter mesh was first coated in three coating steps by
rotation in a measured volume of a 4% w/w solution of a hydrophilic
polyurethane such as Hydromed D3 (CardioTech International, Inc.,
Woburn, Mass.) in 85/15, w/w Ethanol/H2O. After each coating step
each device was dried for an hour at room temperature in a high
ventilation situation such as a chemical fume hood. The thrice
coated meshes are dried overnight in an oven at 40.degree. C.
[0070] The meshes are then final-coated in two steps using the same
method but a different composition. For this procedure the same
polymer is dissolved in tetrahydrofuran (THF) on a stirring
hotplate at 60.degree. C. to reach a final concentration of 4% w/w.
When the polymer is dissolved, paclitaxel is added so that the
paclitaxel to polymer ratio is 82/18 w/w and the solution vortexed
until the paclitaxel is dissolved. One gram of toluene is added to
the mixture for each 3 grams of THF and two coats of the resulting
mix are applied directly to the catheter and dried in the oven at
40.degree. C.
[0071] At the time of testing in vitro or vivo the catheter is
first wetted for one minute in phosphate buffered saline and
flexed. At this time the essentially transparent coating becomes
opaque white, the paclitaxel apparently crystallizing at the
surface.
[0072] 1b Chemical Assay for Paclitaxel in Catheters
[0073] Catheters or collected distal expansion meshes are air or
oven dried (.about.37.degree. C.) before beginning drug extraction
to determine total drug content. Each mesh was placed in an
identified 12 mm by 75 mm disposable test tube. Slowly apply 75
microliters of chloroform was slowly applied to the mesh by means
of a syringe or pipette. The test tube is covered with aluminum
foil to minimize evaporation of the solvent and thus maximize
swelling of the polymer. The swelling should be allowed for at
least 15 minutes.
[0074] After the polymer-swelling interval a 5 ml aliquot of
ethanol is added at once by means of pipette. The mesh is used to
stir the solution and after a few minutes the mesh is withdrawn and
by flicking it carefully against the side to the volume within the
mesh is drained and the central lumen space is refilled by
re-immersion with flicking, noting the bubbles that indicate
refilling. This may be done several times over a period of 30
minutes or more of extraction.
[0075] After the extraction interval is complete the mesh is
carefully drained into a 50 ml screw top scintillation vial and the
remaining contents of the test tube poured into the vial for
submission for filtration to remove particulates if any prior to
reverse phase HPLC analysis using aqueous acetonitrile as the
mobile phase.
[0076] Measurement of the concentration in the solution is by means
of peak integration using a standard contemporary HPLC calibration
curve and the total mass of paclitaxel is calculated based upon the
5 ml extraction volume.
[0077] Analytical method development indicated that a single
extraction was sufficiently efficient in that less than 1% of the
drug could be extracted in a second, identical extraction.
Example Results
[0078] Note: the following results were obtained by methylene
chloride polymer swelling to demonstrate content analysis method
and consistency of the roll-coating method described.
1 Paclitaxel Paclitaxel Sample (.mu.g/ml) (.mu.g) DS2 478 1,432 DS3
495 1,482 DS4 539 1,615 DS5 497 1,489 DS6 529 1,583 Mean 508 1,520
St. Dev. 25.41 76.07
[0079] 1c Ex Vivo Paclitaxel Delivery
[0080] In an experiment to measure the amount of paclitaxel
released, the catheter was placed in an isolated pig blood vessel
and expanded against the vessel walls for 10 minutes. Then the
catheter was removed and the vessel perfused at 80-100 ml per
minute for one hour. The tissue was then analyzed for paclitaxel
concentration.
[0081] 1d In Vivo Paclitaxel Delivery in the Pig
[0082] In an experiment to measure the amount of paclitaxel
released, the catheter was inserted into a coronary blood vessel of
an anesthetized pig and expanded against the vessel walls. Domestic
pigs weighing 30-40 kg were anesthetized in the usual manner. An
introducer sheath was placed into the femoral artery. A guide
catheter was then advanced to the target artery. The artery was
then instrumented with a 0.014 inch guidewire. The passive
diffusion drug delivery catheter was advanced over the guidewire to
the delivery site. The catheter was then expanded for ten minutes.
Distal blood flow to the artery was documented angiographically.
After the delivery period, all equipment was removed and the animal
was recovered. The animal was killed at a later predetermined time
by injection of an overdose of barbiturate. The pig was sacrificed
after 1, 24 48 or 72 hours and the treated blood vessel harvested
and either analyzed immediately or frozen on dry ice for
quantitative chemical assay of paclitaxel.
[0083] 1e Paclitaxel Tissue Assay
[0084] After weighing in polystyrene tubes, tissues are homogenized
in 4% Bovine Serum Albumin (BSA) (w/v in water) using an Omni
International TH 115 tissue homogenizer. About 1 ml of BSA solution
was used per 0.1-0.2 g of tissue.
[0085] The solution was acidified to litmus indicator with 1N
hydrochloric acid. An extraction was performed by adding diethyl
ether (2 ml) to each tube. The tubes were vortexed for 1 minute,
followed by centrifugation at 2000 rpm for 5 min. Next, the aqueous
layer was frozen in ethanol-solid carbon dioxide and the organic
layer was decanted into a clean glass tube. The aqueous layer was
thawed, checked to confirm acidity, followed by the addition of HCl
if necessary, and the extraction procedure was repeated once again.
The diethyl ether fractions were combined and evaporated
overnight.
[0086] The residue was reconstituted in 500/.mu.ul of
water/acetonitrile (50/50) and 0.1% trifluoroacetic acid. The
solution was filtered and injected into an HPLC an for analysis
(column: C18 Hypersil ODS [Agilent], mobile phase: acetonitrile
47%/water 53%, trifluoroacetic acid, 0.1%), flow rate of 1 ml/min,
with an ultraviolet detector set at 204 256 nm. As an example,
arterial tissue concentrations of paclitaxel measured 24 hours
following delivery ranged from less than 1 to greater than 90 ug
per gram tissue.
* * * * *