U.S. patent application number 11/239555 was filed with the patent office on 2006-03-30 for pre-dried drug delivery coating for use with a stent.
This patent application is currently assigned to ATRIUM MEDICAL CORPORATION. Invention is credited to Suzanne Conroy, Joseph Ferraro, Georgette Henrich, Steve A. Herweck, Theodore Karwoski, Roger Labrecque, Paul Martakos, Geoffrey Moodie, Lisa Rogers, Brian Sunter.
Application Number | 20060067977 11/239555 |
Document ID | / |
Family ID | 36119235 |
Filed Date | 2006-03-30 |
United States Patent
Application |
20060067977 |
Kind Code |
A1 |
Labrecque; Roger ; et
al. |
March 30, 2006 |
Pre-dried drug delivery coating for use with a stent
Abstract
A method and apparatus for the provision of a coating for
application to a medical device results in a medical device having
a bio-absorbable coating. The coating includes a bio-absorbable
carrier component. In addition to the bio-absorbable carrier
component, a therapeutic agent component and solvent can also be
provided. The solvent is removed from the coating before the
coating is applied to the medical device. The coated medical device
is implantable in a patient to effect controlled delivery of the
coating, including the therapeutic agent, to the patient.
Inventors: |
Labrecque; Roger;
(Londonderry, NH) ; Moodie; Geoffrey; (Hudson,
NH) ; Ferraro; Joseph; (Londonderry, NH) ;
Rogers; Lisa; (Londonderry, NH) ; Martakos; Paul;
(Pelham, NH) ; Karwoski; Theodore; (Hollis,
NH) ; Herweck; Steve A.; (Nashua, NH) ;
Conroy; Suzanne; (Dracut, MA) ; Sunter; Brian;
(Londonderry, NH) ; Henrich; Georgette; (Dracut,
MA) |
Correspondence
Address: |
LAHIVE & COCKFIELD, LLP.
28 STATE STREET
BOSTON
MA
02109
US
|
Assignee: |
ATRIUM MEDICAL CORPORATION
Hudson
NH
|
Family ID: |
36119235 |
Appl. No.: |
11/239555 |
Filed: |
September 28, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60613745 |
Sep 28, 2004 |
|
|
|
Current U.S.
Class: |
424/426 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 47/44 20130101; A61L 31/08 20130101; A61L 2300/45 20130101;
A61L 31/148 20130101; A61F 2/86 20130101; A61F 2250/0067 20130101;
A61L 2420/02 20130101; A61K 47/10 20130101; A61M 25/0009 20130101;
A61L 31/10 20130101; A61L 2300/22 20130101; A61P 29/00 20180101;
A61F 2/82 20130101; A61L 2300/416 20130101; A61L 2300/606 20130101;
A61L 2300/802 20130101; A61P 7/02 20180101; A61L 2300/428 20130101;
A61L 31/16 20130101; A61M 25/0045 20130101; A61P 3/00 20180101;
A61K 47/22 20130101 |
Class at
Publication: |
424/426 |
International
Class: |
A61F 2/00 20060101
A61F002/00 |
Claims
1. A coated medical device, comprising: a coating having a
bio-absorbable carrier component, the coating further including a
therapeutic agent and solvent; wherein at least a portion of the
solvent is removed from the coating before the coating is applied
to the medical device.
2. The device of claim 1, wherein a remaining portion of the
solvent is removed from the coating after the coating is applied to
the medical device.
3. The device of claim 1, wherein the coated medical device is
implantable in a patient to effect controlled delivery of the
therapeutic agent to the patient.
4. The device of claim 1, wherein the solvent comprises
C.sub.2-C.sub.6 alkanols, 2-ethoxyethanol, ethanol, isopropanol,
butanol, benzyl alcohol, ethylene glycol, propylene glycol,
butanediols and isomers thereof, glycerol, pentaerythritol,
sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene
glycol, polypropylene glycol, 2-pyrrolidone, 2-piperidone,
2-caprolactam, N-alkylpyrrolidone, N-methyl-2-pyrrolidone,
N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,
dimethylacetamide; ethyl acetate, methyl acetate, butyl acetate,
ethylene glycol diethyl ether, ethylene glycol dimethyl ether,
propylene glycol dimethyl ether, ethyl proprionate,
tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate,
triethylcitrate, ethyl oleate, ethyl caprylate, ethyl cutyrate,
tracetin, .epsilon.-caprolactone and isomers thereof,
.delta.-valerolactome and isomers thereof, .beta.-butyrolactone and
isomers thereof, water, dimethylsulfoxide, benzyl benzoate, ethyl
lactate, acetone, methylethyl ketone, dimethylsolfone,
tetrahydrofuran, decylmethylsufoxide, N,N-diethyl-m-toulamide or
1-dodecylazacycloheptan-2-one, hexane, chloroform, dichloromethane,
or a combination thereof.
5. The device of claim 1, wherein the coating further comprises at
least one component selected from a group of components comprising
a compatibilizer and a preservative.
6. The device of claim 1, wherein the bio-absorbable carrier
component comprises at least one component selected from a group of
components comprised of a naturally occurring oil, and an oil
composition.
7. The device of claim 1, wherein the medical device comprises a
stent.
8. The device of claim 1, wherein the solvent is removed from the
coating with vacuum or heat.
9. The device of claim 1, wherein the solvent is removed from the
coating with blowing air or an inert gas over the coating.
10. The device of claim 1, wherein the solvent is removed during
rotation of the coating.
11. The device of claim 1, wherein the solvent is removed with
mixing the coating to accelerate a removal rate of the solvent.
12. The device of claim 1, wherein the solvent is removed with
stirring the coating to accelerate a removal rate of the
solvent.
13. The device of claim 1, wherein the solvent is removed with
agitating the coating to accelerate a removal rate of the
solvent.
14. An apparatus for drying a coating material prior to application
to a medical device, the apparatus comprising: a first container
providing a vacuum within the first container; a second container
disposed within the first container for containing a coating
material having a bio-absorbable carrier component, the coating
material further including a therapeutic agent and solvent; and a
rotator for rotating the second container to remove the solvent
from the coating material.
15. The apparatus of claim 14, wherein the first container
comprises a vacuum oven.
16. The apparatus of claim 14, wherein the first container
comprises a bell jar.
17. The apparatus of claim 14, wherein the second container
comprises a syringe.
18. The apparatus of claim 14, wherein the rotator comprises an
electric rotator.
19. The apparatus of claim 14, wherein the rotator comprises a
mechanical rotator.
20. The apparatus of claim 14, further comprising a temperature
controller for controlling a temperature within the first
container.
21. The apparatus of claim 14, further comprising a vacuum
controller for controlling a vacuum within the first container.
22. The apparatus of claim 14, wherein the coating material is
mixed to accelerate a removal rate of the solvent.
23. The apparatus of claim 14, wherein the coating material is
stirred to accelerate a removal rate of the solvent.
24. The apparatus of claim 14, wherein the coating material is
agitated to accelerate a removal rate of the solvent.
25. A method of making a coated medical device, the method
comprising: providing a coating material having a bio-absorbable
carrier component, the coating material further including a
therapeutic agent and solvent; removing the solvent from the
coating material; and applying the dried coating material to the
medical device to form a coating.
26. The method of claim 25, wherein the coated medical device is
implantable in a patient to effect controlled delivery of the
therapeutic agent to the patient.
27. The method of claim 25, wherein the step of removing comprises
the step of: providing a vacuum in a first container within which
the solvent is removed from the coating material.
28. The method of claim 27, wherein the step of removing comprises
the step of: disposing a second container within the first
container for containing the coating material; and rotating the
second container to remove the solvent from the coating material
under vacuum.
29. The method of claim 28, further comprising the step of: mixing
the coating material to accelerate a removal rate of the
solvent.
30. The method of claim 28, wherein the step of removing comprises
the step of: stirring the coating material to accelerate a removal
rate of the solvent.
31. The method of claim 28, wherein the step of removing comprises
the step of: agitating the coating material to accelerate a removal
rate of the solvent.
32. The method of claim 25, wherein the step of removing comprises
the step of: removing the solvent with heat.
33. The method of claim 25, wherein the step of removing comprises
the step of: removing the solvent with blowing air over the coating
material.
34. The method of claim 25, wherein the step of removing comprises
the step of: removing the solvent with blowing an inert gas over
the coating material.
35. The method of claim 25, wherein the step of removing comprises
the step of: mixing the coating material to accelerate a removal
rate of the solvent.
36. The method of claim 25, wherein the step of removing comprises
the step of: stirring the coating material to accelerate a removal
rate of the solvent.
37. The method of claim 25, wherein the step of removing comprises
the step of: agitating the coating material to accelerate a removal
rate of the solvent.
38. A method of making a coated medical device, the method
comprising: providing a coating material having a bio-absorbable
carrier component, the bio-absorbable carrier component being at
least partially formed of a cellular uptake inhibitor and a
cellular uptake enhancer, and the coating material further
including a therapeutic agent and solvent; removing the solvent
from the coating material to modify the coating material to a state
of viscosity; and applying the coating material to the medical
device to form a coating.
39. A method of making a coated medical device, the method
comprising: providing a coating material having a bio-absorbable
carrier component, the coating material further including a
therapeutic agent and solvent; removing a portion of the solvent
from the coating material; applying the coating material to the
medical device; and removing a remaining portion of the solvent
from the coating material applied to the medical device.
Description
RELATED APPLICATION
[0001] This application claims priority to, and the benefit of,
co-pending U.S. Provisional Application No. 60/613745, filed Sep.
28, 2004, for all subject matter common to both applications. The
disclosure of said provisional application is hereby incorporated
herein by reference in its entirety. This application also relates
to co-pending U.S. patent application Ser. No. 10/______ (Attorney
Docket No. ATA-426), filed concurrently with this application on
September 28, 2005.
FIELD OF THE INVENTION
[0002] The present invention relates to coatings suitable for
application to medical devices for delivery of one or more
biologically active agents, and more particularly to a
bio-absorbable coating in which solvent is removed before the
coating material is applied to the medical devices, and an
apparatus and method for removing solvent from the coating
material.
BACKGROUND OF THE INVENTION
[0003] Therapeutic agents may be delivered to a targeted location
in a human utilizing a number of different methods. For example,
agents may be delivered nasally, transdermally, intravenously,
orally, or via other conventional methods. Delivery may vary by
release rate (i.e., quick release or slow release). Delivery may
also vary as to how the drug is administered. Specifically, a drug
may be administered locally to a targeted area, or administered
systemically.
[0004] With systemic administration, the therapeutic agent is
administered in one of a number of different ways including orally
or intravenously to be systemically processed by the patient.
However, there are drawbacks to systemic delivery of a therapeutic
agent, one of which is that high concentrations of the therapeutic
agent travels to all portions of the patient's body and can have
undesired effects at areas not targeted for treatment by the
therapeutic agent. Furthermore, large doses of the therapeutic
agent only amplify the undesired effects at non-target areas. As a
result, the therapeutic dose required for a specific target
location in a patient may have to be reduced when administered
systemically to reduce complications from systemic toxicity.
[0005] An alternative to the systemic administration of a
therapeutic agent is the use of a targeted local therapeutic agent
delivery approach. With local delivery of a therapeutic agent, the
therapeutic agent is administered using a medical device or
apparatus, directly by hand, or sprayed on the tissue, at a
selected targeted tissue location of the patient that requires
treatment. The therapeutic agent emits, or is otherwise delivered,
from the medical device apparatus, and/or carrier, and is applied
to the targeted tissue location. The local delivery of a
therapeutic agent enables a more concentrated and higher quantity
of therapeutic agent to be delivered directly at the targeted
tissue location, without having broader systemic side effects. With
local delivery, the therapeutic agent that escapes the targeted
tissue location dilutes as it travels to the remainder of the
patient's body, substantially reducing or eliminating systemic side
effects.
[0006] Local delivery is often carried out using a medical device
as the delivery vehicle. One example of a medical device that is
used as a delivery vehicle is a stent. Boston Scientific
Corporation sells the Taxus.RTM. stent, which contains a polymeric
coating for delivering Paclitaxel. Johnson & Johnson, Inc.
sells the Cypher.RTM. stent which includes a polymeric coating for
delivery of Sirolimus.
[0007] Targeted local therapeutic agent delivery using a medical
device can be further broken into two categories, namely, short
term and long term. The short term delivery of a therapeutic agent
occurs generally within a matter of seconds or minutes to a few
days or weeks. The long term delivery of a therapeutic agent occurs
generally within several weeks to a number of months. Typically, to
achieve the long term delivery of a therapeutic agent, the
therapeutic agent must be combined with a delivery agent, or
otherwise formed with a physical impediment as a part of the
medical device, to slow the release of the therapeutic agent.
[0008] U.S. patent Publication Ser. No. 2003/0204168 is directed to
the local administration of drug combinations for the prevention
and treatment of vascular disease. The publication discusses using
intraluminal medical devices having drugs, agents, and/or compounds
affixed thereto to treat and prevent disease and minimize
biological reactions to the introduction of the medical device. The
publication states that both bio-absorbable and biostable
compositions have been reported as coatings for stents. They have
been polymeric coatings that either encapsulate a
pharmaceutical/therapeutic agent or drug, e.g. rapamycin, taxol
etc., or bind such an agent to the surface, e.g. heparin-coated
stents. These coatings are applied to the stent in a number of
ways, including, though not limited to, dip, spray, or spin coating
processes.
[0009] The publication goes on to state that although stents
prevent at least a portion of the restenosis process, a combination
of drugs, agents or compounds which prevents smooth muscle cell
proliferation, reduces inflammation and reduces thrombosis or
prevents smooth muscle cell proliferation by multiple mechanisms,
reduces inflammation and reduces thrombosis combined with a stent
may provide the most efficacious treatment for post-angioplasty
restenosis. The systemic use of drugs, agents or compounds in
combination with the local delivery of the same or different
drug/drug combinations may also provide a beneficial treatment
option.
[0010] The invention subsequently described in the '168 publication
relates to the provision of polymeric coatings comprising a
polyfluoro copolymer and implantable medical devices, for example,
stents coated with a film of the polymeric coating in amounts
effective to reduce thrombosis and/or restenosis when such stents
are used in, for example, angioplasty procedures. Blends of
polyfluoro copolymers are also used to control the release rate of
different agents or to provide a desirable balance of coating
properties, i.e. elasticity, toughness, etc., and drug delivery
characteristics, for example, release profile. Polyfluoro
copolymers with different solubilities in solvents may be used to
build up different polymer layers that may be used to deliver
different drugs or to control the release profile of a drug.
[0011] The coatings and drugs, agents or compounds described are
described as being useful in combination with any number of medical
devices, and in particular, with implantable medical devices such
as stents and stent-grafts. Other devices such as vena cava filters
and anastomosis devices may be used with coatings having drugs,
agents, or compounds therein.
[0012] U.S. Pat. No. 6,358,556 is directed to a drug release stent
coating. The patent describes processes for producing a relatively
thin layer of biostable elastomeric material in which an amount of
biologically active material is dispersed as a coating on the
surfaces of a deployable stent. The coating is described as
preferably being applied as a mixture, solution, or suspension of
polymeric material and finely divided biologically active species
dispersed in an organic vehicle or a solution or partial solution
of such species in a solvent or vehicle for the polymer and/or
biologically active species. Essentially the active material is
dispersed in a carrier material that may be a polymer, a solvent,
or both.
[0013] U.S. Pat. No. 6,299,604 is directed to a coated implantable
medical device having a layer of bioactive material and a coated
layer providing controlled release of the bioactive material. The
patent discusses the idea that the degradation of an agent, a drug,
or a bioactive material, applied to an implantable medical device
may be avoided by covering the agent, drug, or bioactive material,
with a porous layer of a biocompatible polymer that is applied
without the use of solvents, catalysts, heat or other chemicals or
techniques, which would otherwise be likely to degrade or damage
the agent, drug or material. Those biocompatible polymers may be
applied preferably by vapor deposition or plasma deposition, and
may polymerize and cure merely upon condensation from the vapor
phase, or may be photolytically polymerizable and are expected to
be useful for this purpose. As such, this patent focuses on the use
of polymers to act as drug delivery agents in providing a
controlled release of a drug from an implanted medical device.
[0014] U.S. Publication Ser. No. 2003/0004564 is directed to a drug
delivery platform. The publication describes compositions and
methods for a stent based drug delivery system. The stent comprises
a matrix, where the matrix has entrapped a pharmaceutical agent of
interest. The matrix, for example microspheres, etc. resides within
a channel formed on one or both of the abluminal or adluminal
surfaces of the stent, and allows for release, usually sustained
release, of the entrapped agent. The stent and matrix is encased
with a gel covalently bound to the stent surface and optionally
also covalently bound to the matrix, which prevents loss of the
matrix during transport and implantation of the stent, and which
affects the release of the biologically active agent, through
degradation and diffusion characteristics. The matrix is described
as a biodegradable, bioerodible, or biocompatible non-biodegradable
matrix comprising a biologically active agent that is placed within
the channels of the stent surface. The matrix may be of any
geometry including fibers, sheets, films, microspheres, circular
discs, plaques and the like. The gel is selected to be a polymeric
compound that will fill the spaces between the matrix and the
channel, that can be covalently bound to the stent surface and
optionally covalently bound to the matrix, and that provides a
porous protective barrier between the matrix and the environment,
for example during storage, implantation, flow conditions, etc. The
gel may contribute to the control of drug release through its
characteristics of degradation and diffusion.
[0015] U.S. Pat. No. 4,952,419 is directed to a method of making
antimicrobial coated implant devices. The reference discusses the
desire to have better retention of coatings on the implant surface
during mechanized implant packaging operations. The solution
presented involves the use of a silicone fluid in contact with the
surface of the implant and an antimicrobial agent in contact with
the silicone fluid. There is no discussion of any therapeutic
benefit inherent in the silicone fluid itself, and there is no
suggestion that other oils can be utilized to control the delivery
of the antimicrobial agent
[0016] The above-described references fail to teach or suggest the
use of bio-absorbable fats or oils in any form as the drug delivery
platform. In each instance, the drug delivery platform includes the
use of a form of polymeric material, or silicone material, with a
solvent additive. The polymeric material serves as either a base
upon which a drug coating is applied, a substance mixed in with the
drug to form the coating, or a top coating applied over a
previously applied drug coating to control the release of the
drug.
[0017] PCT application publication No. WO 00/62830 is directed to a
system and method for coating medical devices using air suspension.
The technique involves suspending a medical device in an air stream
and introducing a coating material into the air stream such that
the coating material is dispersed therein and coats the medical
device. The publication discusses applying the coating to a number
of different medical devices formed of a number of different
materials. The publication further suggests that the coating
materials can be comprised of therapeutic agents alone or in
combination with solvents, and that the coating may provide for
controlled release, which includes long-term or sustained release.
As stated in the publication, a list of coating materials other
than therapeutic agents include polymeric materials, sugars, waxes,
and fats applied alone or in combination with therapeutic agents,
and monomers that are cross-linked or polymerized. The publication
goes on to discuss the use of a drug matrix formed of a polymer
structure, which can be used to control the release rate of drugs
combined with the polymer.
[0018] Although the '830 publication attempts to discuss every
possible combination of delivery coating in combination with every
drug or therapeutic agent that may have some utility in targeted
delivery applications, there is no realization of the difficulty of
using an oil for the controlled release of a therapeutic agent in a
long term application. A list of potential delivery vehicles
identifies waxes and fats, however there is no indication that such
vehicles can be utilized for anything other than a short term drug
delivery. A later discussion of controlled long term release of a
drug mentions only the use of polymers to control the release.
[0019] U.S. Pat. No. 6,117,911 is directed to the use of compounds
and different therapies for the prevention of vascular and
non-vascular pathologies. The '911 patent discusses the possibility
of using many different types of delivery methods for a therapeutic
agent or agents to prevent various vascular and non-vascular
pathologies. One such approach is described as providing a method
of preventing or treating a mammal having, or at risk of
developing, atherosclerosis, including administering an amount of a
combination of aspirin or an aspirinate and at least one omega-3
fatty acid, wherein said amount of omega-3 fatty acid is effective
to maintain or increase the level of TGF-beta so as to provide a
synergistic effect with a therapeutic compound to inhibit or reduce
vessel lumen diameter dimension. As such, the patent discusses some
of the therapeutic benefits of primarily systemic administration of
omega-3 fatty acids to affect TGF-beta levels when a therapeutic
agent is combined with aspirin or aspirinate. That is, the dose or
concentration of omega-3-fatty acid required to increase the level
of TGF-beta is significantly greater, requiring long term systemic
delivery.
[0020] PCT Application Publication No. WO 03/028622 is directed to
a method of delivering drugs to a tissue using drug coated medical
devices. The drug coated medical device is brought into contact
with the target tissue or circulation and the drugs are quickly
released onto the area surrounding the device in a short period of
time after contact is made. The release of the drug may occur over
a period of 30 seconds, 1 minute or 3 minutes. In one embodiment
described in the publication, the carrier of the drug is a
liposome. Other particles described as potential drug carriers
include lipids, sugars, carbohydrates, proteins, and the like. The
publication describes these carriers as having properties
appropriate for a quick short term release of a drug combined with
the carriers.
[0021] PCT application publication No. WO 02/100455 is directed to
ozonated medical devices and methods of using ozone to prevent
complications from indwelling medical devices. The application
discusses having the ozone in gel or liquid form to coat the
medical device. The ozone can be dissolved in olive oil, or other
types of oil, to form a gel containing ozone bubbles, and the gel
applied to the medical device as a coating. The application later
asserts a preference for the gel or other coating formulation to be
composed so that the ozone is released over time. However, there is
no indication in the application as to how a slow controlled
release of ozone can be affected. There is no enablement to a long
term controlled release of ozone from the olive oil gel, however,
there is mention of use of biocompatible polymers to form the
coating that holds and releases the ozone. Other drugs are also
suggested for combination with the ozone for delivery to a targeted
location. The application later describes different application
methods for the coating, including casting, spraying, painting,
dipping, sponging, atomizing, smearing, impregnating, and
spreading.
[0022] U.S. Pat. No. 5,509,899 is directed to a medical device
having a lubricious coating. In the background section of this
patent, it states that catheters have been rendered lubricious by
coating them with a layer of silicone, glycerin, or olive oil in
the past. It further states that such coatings are not necessarily
satisfactory in all cases because they tend to run off and lose the
initial lubricity rather rapidly and they can also lack abrasion
resistance. Hydrophilic coatings have also been disclosed such as
polyvinyl pyrrolidone with polyurethane interpolymers or
hydrophilic polymer blends of thermoplastic polyurethane and
polyvinyl pyrrolidone. Accordingly, the invention in the '899
patent is described as providing a biocompatible surface for a
device which can impede blocking or sticking of two polymer
surfaces when the surfaces are placed in tight intimate contact
with each other such as is the case when the balloon is wrapped for
storage or when a surface of one device will contact a surface of
another device. The description goes on to describe numerous
polymeric substances.
[0023] European Patent Application No. EP 1 273 314 is directed to
a stent having a biologically and physiologically active substance
loaded onto the stent in a stable manner. The biologically and
physiologically active substance is gradually released over a
prolonged period of time with no rapid short term release. In order
to achieve the long term controlled release, the application
describes placing a layer of the biologically and physiologically
active substance on the surface of the stent, and placing a polymer
layer on top of the biologically and physiologically active
substance layer. The polymer layer acts to slow the release of the
biologically and physiologically active substance. There is no
discussion of an alternative to the polymer substance forming the
polymer layer for controlling the release of the biologically and
physiologically active substance. There are instances discussed
when the biologically and physiologically active substance has
insufficient adhesion characteristics to adhere to the stent. In
such instances, the application describes using an additional
substance mixed with the biologically and physiologically active
substance to increase its adhesion properties. In the case of a fat
soluble substance, the recommendation is the use of a low molecular
weight fatty acid having a molecular weight of up to 1000, such as
fish oil, vegetable oil, or a fat-soluble vitamin such as vitamin A
or vitamin E. The application always requires use of the additional
polymer coating to create the long term controlled release of the
biologically and physiologically active substance.
[0024] A paper entitled "Evaluation of the Biocompatibility and
Drug Delivery Capabilities of Biological Oil Based Stent Coatings",
by Shengqiao Li of the Katholieke Universiteit Leuven, discusses
the use of biological oils as a coating for delivering drugs after
being applied to stents. Three different coatings were discussed, a
glue coating (cod liver oil mixed with 100% ethanol at a 1:1
ratio), a vitamin E coating (97% vitamin E oil solution mixed with
100% ethanol at a 1:1 ratio), and a glue+vitamin E coating (cod
liver oil and 97% vitamin E oil solution mixed with 100% ethanol at
a 1:1 ratio). Bare stents and polymer coated stents, along with
stents having each of the above coatings, were implanted into test
subjects, and analyzed over a four week period. At the end of the
period, it was observed that the bare stents and polymer coated
stents resulted in some minor inflammation of the tissue. The main
finding of the study was that the glue coatings have a good
biocompatibility with coronary arteries, and that the glue coating
does not affect the degree of inflammation, thrombosis, and
neointimal proliferation after endovascular stenting compared with
the conventional stenting approach. A further hypothesis asserted
was that the oil coating provided lubrication to the stent, thus
decreasing the injury to the vascular wall.
[0025] The study went on to analyze the drug loading capacity of
biological oil based stent coatings. Balloon mounted bare stents
were dip-coated in a biological oil solution with the maximal
solublizable amount of different drugs (a separate drug for each
trial), and compared with polymer coated, drug loaded, stents.
According to the release rate curves, there was a clear indication
that drug release was fast in the first 24 hours with more than 20%
of the drug released, for the oil based coatings. The release rate
after the first 24 hours was much slower, and continued for a
period up to about six weeks.
[0026] Another aspect of the study looked at the efficacy of drug
loaded biological stents to decrease inflammation and neointimal
hyperplasia in a porcine coronary stent model. In this part of the
study, glue or modified glue (biological oil) coated stainless
steel stents were loaded with different drugs. The result was that
the characteristics of the particular drug loaded onto the stent
were the major factor to the reduction of restenosis, and the
biological oil did not have a major impact on either causing or
reducing inflammation.
[0027] A further comment indicated that in the studies comparison
was made between biological oil based drug loaded stents and bare
stents to find differences in inflammation, injury, and
hyperplasia. Inflammation, injury, and neointimal hyperplasia
resulted in in-stent area stenosis. Any anti-inflammation observed
was the result of the particular drug loaded on the stent,
regardless of biological oil, or polymer, coating.
[0028] PCT Application Publication No. WO 03/039612 is directed to
an intraluminal device with a coating containing a therapeutic
agent. The publication describes coating an intraluminal device
with a therapeutic agent comprised of a matrix that sticks to the
intraluminal device. The matrix is formed of a bio-compatible oil
or fat, and can further include alpha-tocopherol. The publication
further indicates that an oil or fat adheres sufficiently strongly
to the intraluminal device so that most of the coating remains on
the intraluminal device when it is inserted in a body lumen. The
publication further states that the oil or fat slows the release of
the therapeutic agent, and also acts as an anti-inflammatory and a
lubricant. The publication goes on to indicate that the oil or fat
can be chemically modified, such as by the process of
hydrogenation, to increase their melting point. Alternatively,
synthetic oils could be manufactured as well. The oil or fat is
further noted to contain fatty acids.
[0029] The '612 publication provides additional detail concerning
the preferred oil or fat. It states that a lower melting point is
preferable, and a melting point of 0.degree. C. related to the oils
utilized in experiments. The lower melting point provides a fat in
the form of an oil rather than a wax or solid. It is further stated
that oils at room temperature can be hydrogenated to provide a more
stable coating and an increased melting point, or the oils can be
mixed with a solvent such as ethanol. Preferences were discussed
for the use of oils rather than waxes or solids, and the operations
performed on the fat or oil as described can be detrimental to the
therapeutic characteristics of some oils, especially
polyunsaturated oils containing omega-3 fatty acids.
[0030] U.S. Publication Ser. No. 2003/0083740 similarly discusses
the use of certain oils as a matrix for delivery of drugs. More
specifically, this publication is directed to a method for forming
liquid coatings for medical devices such as stents and angioplasty
balloons. The liquid coatings can be made from biodegradable
materials in liquid, low melting solid, or wax forms, which
preferably degrade in the body without producing potentially
harmful fragments. These fragments occur with harder coatings that
fracture and break off after implantation. The liquid coatings may
also contain biologically active components, such as drugs, which
are released from the coatings through diffusion from the coatings
and the degradation of the coatings.
[0031] Some of this second group of references do refer to the use
of oils as a drug delivery platform. However, there is no
realization of the difficulty of using an oil for the controlled
release of a therapeutic agent in a long term application. There is
further no indication that the coatings described in the above
references are bio-absorbable, while also providing a controlled
release of biologically active components, such as drugs. For
controlled release of a drug, the above references require use of a
polymer based coating either containing the drug or applied over
the drug on the medical device.
[0032] What is desired is a bio-absorbable delivery agent having
non-inflammatory characteristics that is able to be prepared in
combination with at least one therapeutic agent for the delivery of
that therapeutic agent to body tissue in a long term controlled
release manner.
SUMMARY OF THE INVENTION
[0033] There is a need for a bio-absorbable coating for application
to an implantable medical device for therapeutic purposes. There is
also a need for solvent in the coating material to be removed
before the coating material is applied to the medical device. In
particular, there is a need for accelerating the removal rate of
solvent from the coating material. The present invention is
directed toward further solutions to address this need.
[0034] In accordance with one embodiment of the present invention,
a coated medical device includes a coating having a bio-absorbable
carrier component, the bio-absorbable carrier component being at
least partially formed of a cellular uptake inhibitor and a
cellular uptake enhancer. The coating further includes a
solubilized or dispersed therapeutic agent and solvent. The solvent
is removed from the coating before the coating is applied to the
medical device. The coated medical device may be in some cases
implantable in a patient to effect controlled delivery of the
therapeutic agent to the patient. The controlled delivery is at
least partially characterized by total and relative amounts of the
cellular uptake inhibitor and cellular uptake enhancer in the
bio-absorbable carrier component.
[0035] In accordance with aspects of the present invention, the
bio-absorbable carrier component contains lipids. The
bio-absorbable carrier component can be a naturally occurring oil,
such as fish oil. The bio-absorbable carrier component can be
modified from its naturally occurring state to a state of increased
viscosity in the form of a cross-linked gel. The bio-absorbable
carrier component can contain omega-3 fatty acids.
[0036] It should be noted that as utilized herein, the term fish
oil fatty acid includes but is not limited to omega-3 fatty acid,
fish oil fatty acid, free fatty acid, esters of fatty acids,
triglycerides, or a combination thereof. The fish oil fatty acid
includes one or more of arachidic acid, gadoleic acid, arachidonic
acid, eicosapentaenoic acid, docosahexaenoic acid or derivatives,
analogs and pharmaceutically acceptable salts thereof. Furthermore,
as utilized herein, the term free fatty acid includes but is not
limited to one or more of butyric acid, caproic acid, caprylic
acid, capric acid, lauric acid, myristic acid, palmitic acid,
palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic
acid, alpha-linolenic acid, gamma-linolenic acid, behenic acid,
erucic acid, lignoceric acid, analogs and pharmaceutically
acceptable salts thereof.
[0037] It should be noted that the term cross-linked gel, as
utilized herein with reference to the present invention, refers to
a gel that is non-polymeric and is derived from an oil composition
comprising molecules covalently cross-linked into a
three-dimensional network by one or more of ester, ether, peroxide,
and carbon-carbon bonds in a substantially random configuration. In
various preferred embodiments, the oil composition comprises a
fatty acid molecule, a glyceride, and combinations thereof.
[0038] In accordance with further aspects of the present invention
the therapeutic agent component mixes with the bio-absorbable
carrier component. The therapeutic agent component can include an
agent selected from the group consisting of antioxidants,
anti-inflammatory agents, anti-coagulant agents, drugs to alter
lipid metabolism, anti-proliferatives, anti-neoplastics, tissue
growth stimulants, functional protein/factor delivery agents,
anti-infective agents, imaging agents, anesthetic agents,
chemotherapeutic agents, tissue absorption enhancers, anti-adhesion
agents, germicides, antiseptics, proteoglycans, GAG's, gene
delivery (polynucleotides), antifibrotics, analgesics, prodrugs,
polysaccharides (e.g., heparin), anti-migratory agents, pro-healing
agents, and ECM/protein production inhibitors. The therapeutic
agent component can alternatively take the form of an agent
selected from the group consisting of cerivastatin, cilostazol,
fluvastatin, lovastatin, paclitaxel, pravastatin, rapamycin, and
simvastatin. The coating can be bio-absorbable, inhibit restenosis,
and/or be non-polymeric.
[0039] In accordance with further aspects of the present invention,
the solvent can be Ethanol, N-Methyl-2-Pyrrolidone (NMP), or some
other solvent compatible with the coating, therapeutic agent, and
intended use. The coating can further include a compatibilizer,
such as vitamin E or its derivatives, which also acts as a
stabilizer and/or preservative, therapeutic agent, antioxidant,
thickener, or tactifyer.
[0040] It should be noted that as utilized herein to describe the
present invention, the term vitamin E and the term
alpha-tocopherol, are intended to refer to the same or
substantially similar substance, such that they are interchangeable
and the use of one includes an implicit reference to both. Further
included in association with the term vitamin E are such variations
including but not limited to one or more of alpha-tocopherol,
beta-tocopherol, delta-tocopherol, gamma-tocopherol,
alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol,
gamma-tocotrienol, alpha-tocopherol acetate, beta-tocopherol
acetate, gamma-tocopherol acetate, delta-tocopherol acetate,
alpha-tocotrienol acetate, beta-tocotrienol acetate,
delta-tocotrienol acetate, gamma-tocotrienol acetate,
alpha-tocopherol succinate, beta-tocopherol succinate,
gamma-tocopherol succinate, delta-tocopherol succinate,
alpha-tocotrienol succinate, beta-tocotrienol succinate,
delta-tocotrienol succinate, gamma-tocotrienol succinate, mixed
tocopherols, vitamin E TPGS, derivatives, analogs and
pharmaceutically acceptable salts thereof. It should also be noted
that other antioxidants may be used as a substitute to fulfill the
functions of Vitamin E in this coating.
[0041] In accordance with further aspects of the present invention,
the medical device can be a stent. The stent can be formed of a
metal. The stent can further be formed of a substance selected from
the group consisting of stainless steel, Nitinol alloy, nickel
alloy, titanium alloy, cobalt-chromium alloy, ceramics, plastics,
and polymers.
[0042] In accordance with further aspects of the present invention,
the surface of the medical device can be provided with a surface
preparation prior to the application of the coating comprising the
bio-absorbable carrier component. The pre-treatment, or preparation
of the surface, improves coating conformability and consistency and
enhances the adhesion of the coating comprising the bio-absorbable
carrier component. The pre-treatment can be bio-absorbable, and can
contain lipids. The pre-treatment can be a naturally occurring oil,
such as fish oil, and can be modified from its naturally occurring
state to state of increased viscosity in the form of a cross-linked
gel. The pre-treatment can contain omega-3 fatty acids. The
pre-treatment can contain a drug.
[0043] In accordance with another embodiment of the present
invention, a method of making a coated medical device includes
providing the medical device. A coating is also provided having a
bio-absorbable carrier component, the bio-absorbable carrier
component being at least partially formed of a cellular uptake
inhibitor and a cellular uptake enhancer. The coating further
includes a solubilized or dispersed therapeutic agent and solvent.
After the solvent is removed from the coating, the coating is
applied to the medical device. The coated medical device is
implantable in a patient to effect controlled delivery of the
therapeutic agent to the patient. The controlled delivery is at
least partially characterized by total and relative amounts of the
cellular uptake inhibitor and cellular uptake enhancer in the
bio-absorbable carrier component.
[0044] In accordance with aspects of the present invention, the
bio-absorbable carrier component can contain lipids, and can be
naturally occurring oil, such as fish oil.
[0045] In accordance with aspects of the present invention, the
method can further include modifying the bio-absorbable carrier
component from its naturally occurring state to a state of
increased viscosity in the form of a cross-linked gel. The
bio-absorbable carrier component can contain omega-3 fatty
acids.
[0046] In accordance with further aspects of the present invention,
the solvent can be Ethanol, NMP, or another solvent compatible with
the coating and the therapeutic component. The solvent can be a
solvent or mixture of solvents and include solvents that are
generally acceptable for pharmaceutical use. Suitable solvents
include, for example: alcohols and polyols, such as C.sub.2-C.sub.6
alkanols, 2-ethoxyethanol, ethanol, isopropanol, butanol, benzyl
alcohol, ethylene glycol, propylene glycol, butanediols and isomers
thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol,
dimethyl isosorbide, polyethylene glycol, and polypropylene glycol;
amides, such as 2-pyrrolidone, 2-piperidone, 2-caprolactam,
N-alkylpyrrolidone, N-methyl-2-pyrrolidone,
N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,
dimethylacetamide; esters, such as ethyl acetate, methyl acetate,
butyl acetate, ethylene glycol diethyl ether, ethylene glycol
dimethyl ether, propylene glycol dimethyl ether, ethyl proprionate,
tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate,
triethylcitrate, ethyl oleate, ethyl caprylate, ethyl cutyrate,
tracetin, .epsilon.-caprolactone and isomers thereof,
.delta.-valerolactome and isomers thereof, .beta.-butyrolactone and
isomers thereof; and other solvents, such as water,
dimethylsulfoxide, benzyl benzoate, ethyl lactate, acetone,
methylethyl ketone, dimethylsolfone, tetrahydrofuran,
decylmethylsufoxide, N,N-diethyl-m-toulamide or
1-dodecylazacycloheptan-2-one, hexane, chloroform, dichloromethane.
The solvent can be removed with vacuum or heat.
[0047] The method can further provide a compatibilizer, such as
vitamin E or its derivatives, which also acts as a stabilizer and
preservative during formation of the coating.
[0048] The medical device coating using the method can be a stent.
The stent can be formed of a metal, or other substance such as
stainless steel, Nitinol alloy, nickel alloy, titanium alloy,
cobalt-chromium alloy, ceramics, plastics, and polymers.
[0049] In accordance with further aspects of the present invention,
the method can further include providing a surface preparation or
pre-treatment on the surface of the medical device prior to
application of the coating comprising the bio-absorbable carrier
component, wherein the pre-treatment improves the coating
consistency and conformability and enhances the adhesion of the
coating comprising the bio-absorbable carrier component. The
pre-treatment can be bio-absorbable, contain lipids, and/or take
the form of a naturally occurring oil, such as fish oil. The
pre-treatment can be modified from its natural state to a state of
increased viscosity in the form of a cross-linked gel. The
pre-treatment can contain a therapeutic agent. The pre-treatment
can contain reactive oils.
[0050] In accordance with further aspects of the present invention,
the step of applying the coating can include at least one of
spraying the coating substance on the medical device, brushing the
coating substance on the medical device, swabbing the coating
substance on the medical device, painting the coating substance on
the medical device, wiping the coating substance on the medical
device, printing the coating substance on the medical device, and
electrostatically applying the coating substance to the medical
device, with or without an applicator.
[0051] The method can further include curing the coating on the
medical device. Curing can involve applying at least one of heat,
UV light, chemical cross-linker, or reactive gas to cure the
coating. Curing with respect to the present invention generally
refers to thickening, hardening, or drying of a material brought
about by heat, UV, or chemical means.
[0052] In addition, methods can be used to enhance the curing
process. These methods include, for example, the addition of other
reactive oils, such as linseed oil, and the application of reactive
gasses, such as oxygen, fluorine, methane or propylene, plasma
treatment, and pressure in the presence of reactive gasses and the
like.
[0053] The method can further include sterilizing the coating and
the medical device. Sterilization can involve use of at least one
of ethylene oxide, gamma radiation, e-beam, steam, gas plasma, and
vaporized hydrogen peroxide (VHP). It should be noted that those
listed herein are merely examples of sterilization processes and
other sterilization processes can also be applied that result in a
sterilization of the coated medical device, preferably without
having a detrimental effect on the coating.
[0054] In accordance with another embodiment of the present
invention, an apparatus is provided for drying a coating material
applied to a medical device. The term "drying" is used to refer to
removing solvent from the coating material in the description of
the present invention. The apparatus includes a device for
providing an environment in which the coating material can be
dried. For example, the device can provide a vacuum or heat to dry
the coating material. It should be noted that the use of vacuum
and/or heat is illustrative and the coating material can be dried
using other methods in different embodiments. For example, the
coating material can be dried while blowing air or an inert gas
over the surface of the coating material either in an oven or on a
bench.
[0055] The apparatus can also include a mechanism for agitating,
mixing, stirring or otherwise replenishing the surface of coating
substance to increases the rate of solvent evaporation. The
mechanism accelerates the transfer of solvent to the surrounding
environment. For example, the apparatus can include a rotating
fixture containing the coating material. By rotating the fixture,
it can continuously disturb and refresh the surface of the coating
material in the fixture, and hence increase the drying rate of the
coating material in the fixture.
BRIEF DESCRIPTION OF THE DRAWINGS
[0056] The aforementioned features and advantages, and other
features and aspects of the present invention, will become better
understood with regard to the following description and
accompanying drawings, wherein:
[0057] FIG. 1 is a diagrammatic illustration of a medical device,
according to one embodiment of the present invention;
[0058] FIG. 2 is a cross-sectional view of the medical device in
accordance with one aspect of the present invention;
[0059] FIG. 3 is a cross-sectional view of the medical device in
accordance with another aspect of the present invention;
[0060] FIG. 4 is a flow chart illustrating a method of making the
coated medical device of the present invention, in accordance with
one embodiment of the present invention;
[0061] FIG. 5 is a flow chart illustrating a variation of the
method of FIG. 4, in accordance with one embodiment of the present
invention;
[0062] FIG. 6A is a flow chart illustrating another variation of
the method of FIG. 4, in accordance with one embodiment of the
present invention;
[0063] FIG. 6B shows an exemplary apparatus for drying the solvent
from the coating substance in accordance with one embodiment of the
present invention;
[0064] FIG. 6C shows another exemplary apparatus for drying the
solvent from the coating substance in accordance with one
embodiment of the present invention;
[0065] FIG. 7 is a flow chart illustrating another variation of the
method of FIG. 4, in accordance with one embodiment of the present
invention; and
[0066] FIG. 8 is a diagrammatic illustration of a coated medical
device in accordance with one embodiment of the present
invention.
DETAILED DESCRIPTION
[0067] An illustrative embodiment of the present invention relates
to the provision of a coating on an implantable medical device. The
coating includes a bio-absorbable carrier component. In addition to
the bio-absorbable carrier component, a therapeutic agent component
can also be provided. The coated medical device is implantable in a
patient to effect controlled delivery of the coating to the
patient. In particular, the illustrative embodiment provides an
apparatus and method for removing solvent from the coating before
the coating is applied to the medical device.
[0068] As utilized herein, the term "bio-absorbable" generally
refers to having the property or characteristic of being able to
penetrate the tissue of a patient's body. In certain embodiments of
the present invention bio-absorption occurs through a lipophilic
mechanism. The bio-absorbable substance is soluble in the
phospholipid bi-layer of cells of body tissue, and therefore
impacts how the bio-absorbable substance penetrates into the
cells.
[0069] It should be noted that a bio-absorbable substance is
different from a biodegradable substance. Biodegradable is
generally defined as capable of being decomposed by biological
agents, or capable of being broken down by microorganisms or
biological processes, in a manner that does not result in cellular
uptake of the biodegradable substance. Biodegradation thus relates
to the breaking down and distributing of a substance through the
patient's body, verses the penetration of the cells of the
patient's body tissue. Biodegradable substances can cause
inflammatory response due to either the parent substance or those
formed during breakdown, and they may or may not be absorbed by
tissues.
[0070] The phrase "controlled release" generally refers to the
release of a biologically active agent in a predictable manner over
the time period of weeks or months, as desired and predetermined
upon formation of the biologically active agent on the medical
device from which it is being released. Controlled release includes
the provision of an initial burst of release upon implantation,
followed by the predictable release over the aforementioned time
period.
[0071] With regard to the aforementioned oils, it is generally
known that the greater the degree of unsaturation in the fatty
acids the lower the melting point of a fat, and the longer the
hydrocarbon chain the higher the melting point of the fat. A
polyunsaturated fat, thus, has a lower melting point, and a
saturated fat has a higher melting point. Those fats having a lower
melting point are more often oils at room temperature. Those fats
having a higher melting point are more often waxes or solids at
room temperature. Therefore, a fat having the physical state of a
liquid at room temperature is an oil. In general, polyunsaturated
fats are liquid oils at room temperature, and saturated fats are
waxes or solids at room temperature.
[0072] Polyunsaturated fats are one of four basic types of fat
derived by the body from food. The other fats include saturated
fat, as well as monounsaturated fat and cholesterol.
Polyunsaturated fats can be further composed of omega-3 fatty acids
and omega-6 fatty acids. Under the convention of naming the
unsaturated fatty acid according to the position of its first
double bond of carbons, those fatty acids having their first double
bond at the third carbon atom from the methyl end of the molecule
are referred to as omega-3 fatty acids. Likewise, a first double
bond at the sixth carbon atom is called an omega-6 fatty acid.
There can be both monounsaturated and polyunsaturated omega fatty
acids.
[0073] Omega-3 and omega-6 fatty acids are also known as essential
fatty acids because they are important for maintaining good health,
despite the fact that the human body cannot make them on its own.
As such, omega-3 and omega-6 fatty acids must be obtained from
external sources, such as food. Omega-3 fatty acids can be further
characterized as containing eicosapentaenoic acid (EPA),
docosahexanoic acid (DHA), and alpha-linolenic acid (ALA). Both EPA
and DHA are known to have anti-inflammatory effects and wound
healing effects within the human body.
[0074] Oil that is hydrogenated becomes a waxy solid. Attempts have
been made to convert the polyunsaturated oils into a wax or solid
to allow the oil to adhere to a device for a longer period of time.
One such approach is known as hydrogenation, which is a chemical
reaction that adds hydrogen atoms to an unsaturated fat (oil) thus
saturating it and making it solid at room temperature. This
reaction requires a catalyst, such as a heavy metal, and high
pressure. The resultant material forms a non-crosslinked
semi-solid. Hydrogenation can reduce or eliminate omega-3 fatty
acids, and any therapeutic effects (both anti-inflammatory and
wound healing) they offer.
[0075] In addition, some curing methods have been indicated to have
detrimental effects on the therapeutic agent combined with the
omega-3 fatty acid, making them partially or completely
ineffective. As such, oils, and more specifically oils containing
omega-3 fatty acids, have been utilized as a delivery agent for the
short term uncontrolled release of a therapeutic agent, so that
minimal or no curing is required. However, there are no known uses
of oils containing omega-3 fatty acids for combination with a
therapeutic agent in a controlled release application that makes
use of the therapeutic benefits of the omega-3 fatty acids.
Further, some heating of the omega-3 fatty acids to cure the oil
can lessen the total therapeutic effectiveness of the omega-3 fatty
acids, but not eliminate the therapeutic effectiveness. One
characteristic that can remain after certain curing by heating
methods is the non-inflammatory response of the tissue when exposed
to the cured material. As such, an oil containing omega-3 fatty
acids can be heated for curing purposes, and still maintain some or
even a substantial portion of the therapeutic effectiveness of the
omega-3 fatty acids. In addition, although the therapeutic agent
combined with the omega-3 fatty acid and cured with the omega-3
fatty acid can be rendered partially ineffective, the portion
remaining of the therapeutic agent can, in accordance with the
present invention, maintain pharmacological activity and in some
cases be more effective than an equivalent quantity of agent
delivered with other coating delivery agents. Thus, if for example,
80% of a therapeutic agent is rendered ineffective during curing,
the remaining 20% of therapeutic agent, combined with and delivered
by the coating can be efficacious in treating a medical disorder,
and in some cases have a relatively greater therapeutic effect than
the same quantity of agent delivered with a polymeric or other type
of coating.
[0076] For long term controlled release applications, polymers, as
previously mentioned, have been utilized in combination with a
therapeutic agent. Such a combination provides a platform for the
controlled long term release of the therapeutic agent from a
medical device. However, polymers have been determined to
themselves cause inflammation in body tissue. Therefore, the
polymers often must include at least one therapeutic agent that has
an anti-inflammatory effect to counter the inflammation caused by
the polymer delivery agent. In addition, patients that received a
polymer-based implant must also follow a course of long term
systemic anti-platelet therapy, on a permanent basis, to offset the
thrombogenic properties of the non-absorbable polymer. A
significant percentage of patients that receive such implants are
required to undergo additional medical procedures, such as
surgeries (whether related follow-up surgery or non-related
surgery) and are required to stop their anti-platelet therapy. This
can lead to a thrombotic event, such as stroke, which can lead to
death. Use of the inventive coating described herein can negate the
necessity of anti-platelet therapy, and the corresponding related
risks described, because there is no thrombogenic polymer reaction
to the coating.
[0077] FIGS. 1 through 8, wherein like parts are designated by like
reference numerals throughout, illustrate an example embodiment of
a pre-drying apparatus and method of using the apparatus along with
resulting coatings and coated medical devices according to the
present invention. Although the present invention will be described
with reference to the example embodiments illustrated in the
figures, it should be understood that many alternative forms can
embody the present invention. One of ordinary skill in the art will
additionally appreciate different ways to alter the parameters of
the embodiments disclosed, such as the size, shape, or type of
elements or materials, in a manner still in keeping with the spirit
and scope of the present invention.
[0078] FIG. 1 illustrates a stent 10 in accordance with one
embodiment of the present invention. The stent 10 is representative
of a medical device that is suitable for having a coating applied
thereon to effect a therapeutic result. The stent 10 is formed of a
series of interconnected struts 12 having gaps 14 formed
therebetween. The stent 10 is generally cylindrically shaped.
Accordingly, the stent 10 maintains an interior surface 16 and an
exterior surface 18.
[0079] One of ordinary skill in the art will appreciate that the
illustrative stent 10 is merely exemplary of a number of different
types of stents available in the industry. For example, the strut
12 structure can vary substantially. The material of the stent can
also vary from a metal, such as stainless steel, Nitinol, nickel,
and titanium alloys, to cobalt chromium alloy, ceramic, plastic,
and polymer type materials. One of ordinary skill in the art will
further appreciate that the present invention is not limited to use
on stents. Instead, the present invention has application on a wide
variety of medical devices. For purposes of clarity, the following
description will refer to a stent as the exemplar medical device.
The terms medical device and stent are interchangeable with regard
to the applicability of the present invention. Accordingly,
reference to one or another of the stent, or the medical device, is
not intended to unduly limit the invention to the specific
embodiment described.
[0080] FIG. 2 illustrates one example embodiment of the stent 10
having a coating 20 applied thereon in accordance with the present
invention. FIG. 3 is likewise an alternative embodiment of the
stent 10 having the coating 20 also applied thereon. The coating 20
is applied to the medical device, such as the stent 10, to provide
the stent 10 with different surface properties, and also to provide
a vehicle for therapeutic applications.
[0081] In FIG. 2, the coating 20 is applied on both the interior
surface 16 and the exterior surface 18 of the strut 12 forming the
stent 10. In other words, the coating 20 in FIG. 2 substantially
encapsulates the struts 12 of the stent 10. In FIG. 3, the coating
20 is applied only on the exterior surface 18 of the stent 10, and
not on the interior surface 16 of the stent 10. The coating 20 in
both configurations is the same coating; the difference is merely
the portion of the stent 10 that is covered by the coating 20. One
of ordinary skill in the art will appreciate that the coating 20 as
described throughout the Description can be applied in both manners
shown in FIG. 2 and FIG. 3, in addition to other configurations
such as, partially covering select portions of the stent 10
structure. All such configurations are described by the coating 20
reference.
[0082] In accordance with embodiments of the present invention, the
stent 10 includes the coating 20, which is bio-absorbable. The
coating 20 has a bio-absorbable carrier component, and can also
include a therapeutic agent component that can also be
bio-absorbable. When applied to a medical device such as a stent
10, it is often desirable for the coating to inhibit or prevent
restenosis. Restenosis is a condition whereby the blood vessel
experiences undesirable cellular remodeling after injury. When a
stent is implanted in a blood vessel, and expanded, the stent
itself may cause some injury to the blood vessel. The treated
vessel typically has a lesion present which can contribute to the
inflammation and extent of cellular remodeling. The end result is
that the tissue has an inflammatory response to the conditions.
Thus, when a stent is implanted, there is often a need for the
stent to include a coating that inhibits inflammation, or is
non-inflammatory, and prevents restenosis. These coatings have been
provided using a number of different approaches as previously
described in the Background. However, none of the prior coatings
have utilized a bio-absorbable carrier component to create a
bio-absorbable coating with suitable non-inflammatory properties
for controlled release of a therapeutic agent.
[0083] In accordance with one embodiment of the present invention,
the bio-absorbable carrier component is in the form of a naturally
occurring oil. An example of a naturally occurring oil is fish oil
or cod liver oil. A characteristic of the naturally occurring oil
is that the oil includes lipids, which contributes to the
lipophilic action described later herein, that is helpful in the
delivery of therapeutic agents to the cells of the body tissue. In
addition, the naturally occurring oil includes omega-3 fatty acids
in accordance with several embodiments of the present invention. As
previously described, omega-3 fatty acids and omega-6 fatty acids
are known as essential fatty acids. Omega-3 fatty acids can be
further characterized as eicosapentaenoic acid (EPA),
docosahexanoic acid (DHA), and alpha-linolenic acid (ALA). Both EPA
and DHA are known to have anti-inflammatory effects and wound
healing effects within the human body.
[0084] In further detail, the term "bio-absorbable" generally
refers to having the property or characteristic of being able to
penetrate the tissues of a patient's body. In example embodiments
of the present invention, the bio-absorbable coating contains
lipids, many of which originate as triglycerides. It has previously
been demonstrated that triglyceride products such as partially
hydrolyzed triglycerides and fatty acid molecules can integrate
into cellular membranes and enhance the solubility of drugs into
the cell. Whole triglycerides are known not to enhance cellular
uptake as well as partially hydrolyzed triglyceride, because it is
difficult for whole triglycerides to cross cell membranes due to
their relatively larger molecular size. Vitamin E compound can also
integrate into cellular membranes resulting in decreased membrane
fluidity and cellular uptake. There are no break down products of
the coating that induce an inflammatory response.
[0085] It is also known that damaged vessels undergo oxidative
stress. A coating containing an antioxidant such as
alpha-tocopherol may aid in preventing further damage by this
mechanism.
[0086] Compounds that move too rapidly through a tissue may not be
effective in providing a sufficiently concentrated dose in a region
of interest. Conversely, compounds that do not migrate in a tissue
may never reach the region of interest. Cellular uptake enhancers
such as fatty acids and cellular uptake inhibitors such as
alpha-tocopherol can be used alone or in combination to provide an
effective transport of a given compound to a given region or
location. Both fatty acids and alpha-tocopherol are accommodated by
the coating of the present invention described herein. Accordingly,
fatty acids and alpha-tocopherol can be combined in differing
amounts and ratios to contribute to a coating in a manner that
provides control over the cellular uptake characteristics of the
coating and any therapeutic agents mixed therein.
[0087] It should further be emphasized that the bio-absorbable
nature of the carrier component and the resulting coating (in the
instances where a bio-absorbable therapeutic agent component is
utilized) results in the coating 20 being completely absorbed over
time by the cells of the body tissue. There are no break down
products of the coating that induce an inflammatory response. In
short, the coating 20 is generally composed of fatty acids,
including in some instances omega-3 fatty acids, bound to
triglycerides, potentially also including a mixture of free fatty
acids and vitamin E. The triglycerides are broken down by lipases
(enzymes) which result in free fatty acids that can than be
transported across cell membranes. Subsequently, fatty acid
metabolism by the cell occurs to metabolize any substances
originating with the coating. The bio-absorbable nature of the
coating of the present invention thus results in the coating being
absorbed, leaving only an underlying delivery or other medical
device structure. There is no foreign body response to the
bio-absorbable carrier component, including no inflammatory
response. The modification of the oils from a more liquid physical
state to a more solid, but still flexible, physical state is
implemented through the curing process. As the oils are cured,
especially in the case of fatty acid-based oils such as fish oil,
cross-links form creating a gel. As the curing process is performed
over increasing time durations and/or increasing temperature
conditions, more cross-links form transitioning the gel from a
relatively liquid gel to a relatively solid-like, but still
flexible, gel structure.
[0088] As previously mentioned, the coating can also include a
therapeutic agent component. The therapeutic agent component mixes
with the bio-absorbable carrier component as described later
herein. The therapeutic agent component can take a number of
different forms including but not limited to anti-oxidants,
anti-inflammatory agents, anti-coagulant agents, drugs to alter
lipid metabolism, anti-proliferatives, anti-neoplastics, tissue
growth stimulants, functional protein/factor delivery agents,
anti-infective agents, anti-imaging agents, anesthetic agents,
therapeutic agents, tissue absorption enhancers, anti-adhesion
agents, germicides, antiseptics, proteoglycans, GAG's, gene
delivery (polynucleotides), polysaccharides (e.g., heparin),
anti-migratory agents, pro-healing agents, and ECM/protein
production inhibitors, analgesics, prodrugs, and any additional
desired therapeutic agents such as those listed in Table 1 below.
TABLE-US-00001 TABLE 1 CLASS EXAMPLES Antioxidants
Alpha-tocopherol, lazaroid, probucol, phenolic antioxidant,
resveretrol, AGI-1067, vitamin E Antihypertensive Agents Diltiazem,
nifedipine, verapamil Antiinflammatory Agents Glucocorticoids (e.g.
dexamethazone, methylprednisolone), leflunomide, NSAIDS, ibuprofen,
acetaminophen, hydrocortizone acetate, hydrocortizone sodium
phosphate, macrophage-targeted bisphosphonates Growth Factor
Angiopeptin, trapidil, suramin Antagonists Antiplatelet Agents
Aspirin, dipyridamole, ticlopidine, clopidogrel, GP IIb/IIIa
inhibitors, abcximab Anticoagulant Agents Bivalirudin, heparin (low
molecular weight and unfractionated), wafarin, hirudin, enoxaparin,
citrate Thrombolytic Agents Alteplase, reteplase, streptase,
urokinase, TPA, citrate Drugs to Alter Lipid Fluvastatin,
colestipol, lovastatin, atorvastatin, amlopidine Metabolism (e.g.
statins) ACE Inhibitors Elanapril, fosinopril, cilazapril
Antihypertensive Agents Prazosin, doxazosin Antiproliferatives and
Cyclosporine, cochicine, mitomycin C, sirolimus Antineoplastics
micophenonolic acid, rapamycin, everolimus, tacrolimus, paclitaxel,
QP-2, actinomycin, estradiols, dexamethasone, methatrexate,
cilostazol, prednisone, cyclosporine, doxorubicin, ranpirnas,
troglitzon, valsarten, pemirolast, C- MYC antisense, angiopeptin,
vincristine, PCNA ribozyme, 2-chloro-deoxyadenosine Tissue growth
stimulants Bone morphogeneic protein, fibroblast growth factor
Promotion of hollow Alcohol, surgical sealant polymers, polyvinyl
particles, 2- organ occlusion or octyl cyanoacrylate, hydrogels,
collagen, liposomes thrombosis Functional Protein/Factor Insulin,
human growth hormone, estradiols, nitric oxide, delivery
endothelial progenitor cell antibodies Second messenger Protein
kinase inhibitors targeting Angiogenic Angiopoetin, VEGF
Anti-Angiogenic Endostatin Inhibitation of Protein Halofuginone,
prolyl hydroxylase inhibitors, C-proteinase Synthesis/ECM formation
inhibitors Antiinfective Agents Penicillin, gentamycin, adriamycin,
cefazolin, amikacin, ceftazidime, tobramycin, levofloxacin, silver,
copper, hydroxyapatite, vancomycin, ciprofloxacin, rifampin,
mupirocin, RIP, kanamycin, brominated furonone, algae byproducts,
bacitracin, oxacillin, nafcillin, floxacillin, clindamycin,
cephradin, neomycin, methicillin, oxytetracycline hydrochloride,
Selenium. Gene Delivery Genes for nitric oxide synthase, human
growth hormone, antisense oligonucleotides Local Tissue perfusion
Alcohol, H2O, saline, fish oils, vegetable oils, liposomes Nitric
oxide Donor NCX 4016 - nitric oxide donor derivative of aspirin,
Derivatives SNAP Gases Nitric oxide, compound solutions Imaging
Agents Halogenated xanthenes, diatrizoate meglumine, diatrizoate
sodium Anesthetic Agents Lidocaine, benzocaine Descaling Agents
Nitric acid, acetic acid, hypochlorite Anti-Fibrotic Agents
Interferon gamma -1b, Interluekin - 10 Immunosuppressive/Immu-
Cyclosporine, rapamycin, mycophenolate motefil, nomodulatory Agents
leflunomide, tacrolimus, tranilast, interferon gamma-1b, mizoribine
Chemotherapeutic Agents Doxorubicin, paclitaxel, tacrolimus,
sirolimus, fludarabine, ranpirnase Tissue Absorption Fish oil,
squid oil, omega 3 fatty acids, vegetable oils, Enhancers
lipophilic and hydrophilic solutions suitable for enhancing
medication tissue absorption, distribution and permeation
Anti-Adhesion Agents Hyaluronic acid, human plasma derived surgical
sealants, and agents comprised of hyaluronate and
carboxymethylcellulose that are combined with dimethylaminopropyl,
ehtylcarbodimide, hydrochloride, PLA, PLGA Ribonucleases Ranpirnase
Germicides Betadine, iodine, sliver nitrate, furan derivatives,
nitrofurazone, benzalkonium chloride, benzoic acid, salicylic acid,
hypochlorites, peroxides, thiosulfates, salicylanilide Antiseptics
Selenium Analgesics Bupivicaine, naproxen, ibuprofen,
acetylsalicylic acid
[0089] Some specific examples of therapeutic agents useful in the
anti-restenosis realm include cerivastatin, cilostazol,
fluvastatin, lovastatin, paclitaxel, pravastatin, rapamycin, a
rapamycin carbohydrate derivative (for example as described in U.S.
patent application Publication Ser. No. 2004/0235762), a rapamycin
derivative (for example as described in U.S. Pat. No. 6,200,985),
everolimus, seco-rapamycin, seco-everolimus and simvastatin.
Depending on the type of therapeutic agent component added to the
coating, the resulting coating can be bio-absorbable if the
therapeutic agent component is also bio-absorbable. As described in
the Summary of the Invention, the present invention relates to
coating a medical device such as the stent 10 with a coating such
as coating 20. The coating 20 is formed of at least two primary
components, namely a bio-absorbable carrier component and a
therapeutic agent component. The therapeutic agent component has
some form of therapeutic or biological effect. The bio-absorbable
carrier component can also have a therapeutic or biological effect.
It should again be noted that the bio-absorbable carrier component
is different from the conventional bio-degradable substances
utilized for similar purposes. The bio-absorbable characteristic of
the carrier component enables the cells of body tissue of a patient
to absorb the bio-absorbable carrier component itself, rather than
breaking down the carrier component into inflammatory by-products
and disbursing said by-products of the component for ultimate
elimination by the patient's body. Accordingly, anti-inflammatory
drug dosages to the patient do not need to be increased to
additionally compensate for inflammation caused by the carrier
component, as is otherwise required when using polymer-based
carriers that themselves cause inflammation.
[0090] It should also be noted that the present description makes
use of the stent 10 as an example of a medical device that can be
coated with the coating 20 of the present invention. However, the
present invention is not limited to use with the stent 10. Instead,
any number of other implantable medical devices can be coated in
accordance with the teachings of the present invention with the
described coating 20. Such medical devices include catheters,
grafts, balloons, prostheses, stents, other medical device
implants, and the like. Implantation refers to both temporarily
implantable medical devices, as well as permanently implantable
medical devices. In the instance of the example stent 10, a common
requirement of stents is that they include some substance or agent
that inhibits restenosis. Accordingly, the example coating 20 as
described is directed toward the reduction or the elimination of
restenosis. However, one of ordinary skill in the art will
appreciate that the coating 20 can have other therapeutic or
biological benefits. The composition of the coating 20 is simply
modified or mixed in a different manner to result in a different
biological effect.
[0091] FIG. 4 illustrates one method of making a coated medical
device, such as stent 10, in accordance with one embodiment of the
present invention. The process involves providing a medical device,
such as the stent 10 (step 100). A coating, such as coating 20, is
then applied to the medical device (step 102). One of ordinary
skill in the art will appreciate that this basic method of
application of a coating to a medical device such as the stent 10
can have a number of different variations falling within the
process described. Depending on the particular application, the
stent 10 with the coating 20 applied thereon can be implanted after
the coating 20 is applied, or additional steps such as curing and
sterilization can be applied to further prepare the stent 10 and
coating 20. Furthermore, if the coating 20 includes a therapeutic
agent that requires some form of activation (such as UV light),
such actions can be implemented accordingly.
[0092] Furthermore, the step of applying a coating substance to
form a coating on the medical device (such as the stent 10) can
include a number of different application methods. For example, the
coating substance can be sprayed onto the stent 10, which results
in application of the coating substance on the exterior surface 18
of the stent 10 as shown in FIG. 3. Another alternative application
method is painting the coating substance on to the stent 10, which
also results in the coating substance forming the coating 20 on the
exterior surface 18 as shown in FIG. 3. One of ordinary skill in
the art will appreciate that other methods, such as electrostatic
adhesion and other application methods, can be utilized to apply
the coating substance to the medical device such as the stent 10.
Some application methods may be particular to the coating substance
and/or to the structure of the medical device receiving the
coating. Accordingly, the present invention is not limited to the
specific embodiment described herein, but is intended to apply
generally to the application of the coating substance to the
medical device, taking whatever precautions are necessary to make
the resulting coating maintain desired characteristics.
[0093] FIG. 5 is a flowchart illustrating one example
implementation of the method of FIG. 4. In accordance with the
steps illustrated in FIG. 5, a bio-absorbable carrier component is
provided along with a therapeutic agent component (step 110). The
provision of the bio-absorbable carrier component and the provision
of the therapeutic agent component can occur individually, or in
combination, and can occur in any order or simultaneously. The
formation of the bio-absorbable carrier component and the
therapeutic agent component can be done in accordance with
different methods. FIG. 6A is a flow chart illustrating one example
method for forming each of the components. Vitamin E is mixed with
a bio-absorbable carrier to form a bio-absorbable carrier component
(step 120). A solvent is mixed with a therapeutic agent to form a
therapeutic agent component (step 122). The solvent can be chosen
from a number of different alternatives, including but not limited
to ethanol or N-Methyl-2-Pyrrolidone (NMP). The solvent can be a
solvent or mixture of solvents and include solvents that are
generally acceptable for pharmaceutical use. Suitable solvents
include, for example: alcohols and polyols, such as C.sub.2-C.sub.6
alkanols, 2-ethoxyethanol, ethanol, isopropanol, butanol, benzyl
alcohol, ethylene glycol, propylene glycol, butanediols and isomers
thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol,
dimethyl isosorbide, polyethylene glycol, and polypropylene glycol;
amides, such as 2-pyrrolidone, 2-piperidone, 2-caprolactam,
N-alkylpyrrolidone, N-methyl-2-pyrrolidone,
N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,
dimethylacetamide; esters, such as ethyl acetate, methyl acetate,
butyl acetate, ethylene glycol diethyl ether, ethylene glycol
dimethyl ether, propylene glycol dimethyl ether, ethyl proprionate,
tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate,
triethylcitrate, ethyl oleate, ethyl caprylate, ethyl cutyrate,
tracetin, .epsilon.-caprolactone and isomers thereof,
.delta.-valerolactorne and isomers thereof, .beta.-butyrolactone
and isomers thereof; and other solvents, such as water,
dimethylsulfoxide, benzyl benzoate, ethyl lactate, acetone,
methylethyl ketone, dimethylsolfone, tetrahydrofuran,
decylmethylsufoxide, N,N-diethyl-m-toulamide or
1-dodecylazacycloheptan-2-one, hexane, chloroform, dichloromethane.
The solvent can be removed with vacuum or heat. The bio-absorbable
carrier component is mixed with the therapeutic agent component or
vice versa to form a coating substance (step 112 in FIG. 5). In
FIG. 6A, the bio-absorbable carrier component is mixed with the
therapeutic agent component to form the coating substance (step
124).
[0094] Referring back to FIG. 5, the solvent is removed or
pre-dried from the coating substance before the coating substance
is applied to the medical device (step 113). The term "drying" is
used to refer to removing solvent from the coating material in the
description of the embodiment. The solvent can be removed with
vacuum or heat. The removal of the solvent will be described below
in more detail with reference to FIG. 6B. The coating substance is
applied to the medical device, such as the stent 10, to form the
coating (step 114). The coated medical device is then sterilized
using any number of different sterilization processes (step 116).
For example, sterilization can be implemented utilizing ethylene
oxide, gamma radiation, E beam, steam, gas plasma, or vaporized
hydrogen peroxide. One of ordinary skill in the art will appreciate
that other sterilization processes can also be applied, and that
those listed herein are merely examples of sterilization processes
that result in a sterilization of the coated stent, preferably
without having a detrimental effect on the coating 20.
[0095] FIG. 6B shows an exemplary apparatus for removing the
solvent from the coating substance in accordance with one
embodiment of the present invention. The apparatus includes a
rotating fixture set up in a bell jar or in a vacuum oven 125. The
vacuum controller 144 controls the vacuum condition within the bell
jar or vacuum oven 125. One of ordinary skill in the art will
appreciate that the bell jar and the vacuum oven are illustrative,
and other types of devices can be used to provide a vacuum. The
rotating fixture can include a syringe 126 disposed within the bell
jar or in the vacuum oven 125 for containing the coating substance
127. The syringe 126 can be coupled to and rotated by an electrical
mechanism, such as a motor 128 powered by a power supply 129. Those
of skill in the art will appreciate that the syringe 126 can be
rotated by a different mechanism in other embodiments, such as a
mechanical mechanism. One of ordinary skill in the art will also
appreciate that the rotating device is illustrative and the
apparatus may include a different mechanism for agitating, mixing,
stirring or otherwise replenishing the surface of coating substance
to increases the rate of solvent evaporation. The mechanism
accelerates the transfer of solvent to the surrounding
environment.
[0096] By rotating the syringe 126 containing the coating substance
under vacuum, the illustrative embodiment continuously disturbs and
refreshes the surface of the coating substance in the syringe 126,
and hence increases the drying rate of the coating substance in the
syringe 126. The apparatus can also include a temperature
controller 140 for making the apparatus versatile. The temperature
controller 140 can change the temperature within the bell jar or
the vacuum oven 125 so that the solvent can be dried or removed at
various temperatures, such as room temperature or elevated
temperatures.
[0097] FIG. 6C shows another exemplary apparatus for removing the
solvent from the coating substance in accordance with one
embodiment of the present invention. The apparatus includes a
rotating fixture. The rotating fixture can include the syringe 126
for containing the coating substance 127. The syringe 126 can be
coupled to and rotated by an electrical mechanism, such as the
motor 128 powered by the power supply 129. The apparatus can also
include a heater 142 powered by the power supply for applying heat
to the coating substance 127 in the syringe 126. The heat from the
heater 142 dries the coating substance 127 in the syringe 126. By
rotating the syringe 126 containing the coating substance, the
illustrative embodiment increases the drying rate of the coating
substance in the syringe 126. One of ordinary skill in the art will
appreciate that the apparatus may or may not be set up in the
vacuum oven 125 including the vacuum controller 144, as described
in FIG. 6B.
[0098] Those of ordinary skill in the art will appreciate that the
use of vacuum or heat is illustrative and the coating material can
be dried using other method in different embodiments. For example,
the coating material can be dried while blowing air or an inert gas
over the surface of the coating material either in an oven or on
the bench.
[0099] The pre-drying of the coating substance in the present
invention is a unique technique because this technique is not
applicable to the conventional polymer based stent coating. The
conventional polymer coating requires the solvent to dissolve the
polymer so that it can be coated onto the stent. Therefore, the
solvent cannot be removed before the coating substance is applied
to the medical device. In the illustrative embodiment of the
present invention, however, the solvent is required to load the
drug and the coating substance can be applied to the stent without
the use of solvent. This characteristic of the present invention
enables the solvent to be removed before the coating substance is
applied to the medical device.
[0100] Additionally, the pre-drying of the present invention
reduces the solvent drying time and hence drastically increases the
number of medical devices that can be coated within a limited time
period. The pre-drying of the present invention allows the
application of a precise amount of coating substance or drug to the
stent by using a dispenser. The pre-drying of the present invention
reduces the amount of capital equipment needed for the production
of the coated medical devices. The pre-drying of the present
invention increases the drug loading compared to dip coating. The
pre-drying of the present invention reduces the handling and
associated risk of damage and/or contamination of the coating and
the medical device.
[0101] In accordance with another aspect of the present invention,
the coating substance can be pre-dried to the state of viscosity
where all of the solvent is not removed from the coating substance.
The rest of the solvent in the coating material can be removed
after the coating material is applied to the medical device, such
as the stent 10.
[0102] In accordance with another embodiment of the present
invention a surface preparation or pre-treatment 22, as shown in
FIG. 8, is provided on a stent 10. More specifically and in
reference to the flowchart of FIG. 7, a pre-treatment substance is
first provided (step 130). The pre-treatment substance is applied
to a medical device, such as the stent 10, to prepare the medical
device surface for application of the coating (step 132). If
desired, the pre-treatment 22 is cured (step 134). Curing methods
can include processes such as application of UV light or
application of heat to cure the pre-treatment 22. A coating
substance is then applied on top of the pre-treatment 22 (step
136). The coated medical device is then sterilized using any number
of sterilization processes as previously mentioned (step 138).
[0103] FIG. 8 illustrates the stent 10 having two coatings,
specifically, the pre-treatment 22 and the coating 20. The
pre-treatment 22 serves as a base or primer for the coating 20. The
coating 20 conforms and adheres better to the pre-treatment 22
verses directly to the stent 10, especially if the coating 20 is
not heat or UV cured. The pre-treatment can be formed of a number
of different materials or substances. In accordance with one
example embodiment of the present invention, the pre-treatment is
formed of a bio-absorbable substance, such as a naturally occurring
oil (e.g., fish oil). The bio-absorbable nature of the
pre-treatment 22 results in the pre-treatment 22 ultimately being
absorbed by the cells of the body tissue after the coating 20 has
been absorbed.
[0104] It has been previously mentioned that curing of substances
such as fish oil can reduce or eliminate some of the therapeutic
benefits of the omega-3 fatty acids, including anti-inflammatory
properties and healing properties. However, if the coating 20
contains the bio-absorbable carrier component formed of the oil
having the therapeutic benefits, the pre-treatment 22 can be cured
to better adhere the pre-treatment 22 to the stent 10, without
losing all of the therapeutic benefits resident in the
pre-treatment 22, or in the subsequently applied coating 20.
Furthermore, the cured pre-treatment 22 provides better adhesion
for the coating 20 relative to when the coating 20 is applied
directly to the stent 10 surface. In addition, the pre-treatment
22, despite being cured, remains bio-absorbable, like the coating
20.
[0105] The pre-treatment 22 can be applied to both the interior
surface 16 and the exterior surface 18 of the stent 10, if desired,
or to one or the other of the interior surface 16 and the exterior
surface 18. Furthermore, the pre-treatment 22 can be applied to
only portions of the surfaces 16 and 18, or to the entire surface,
if desired.
[0106] The application of the coating 20 to the stent 10, or other
medical device, can take place in a manufacturing-type facility and
subsequently shipped and/or stored for later use. Alternatively,
the coating 20 can be applied to the stent 10 just prior to
implantation in the patient. The process utilized to prepare the
stent 10 will vary according to the particular embodiment desired.
In the case of the coating 20 being applied in a manufacturing-type
facility, the stent 10 is provided with the coating 20 and
subsequently sterilized in accordance with any of the methods
provided herein, and/or any equivalents. The stent 10 is then
packaged in a sterile environment and shipped or stored for later
use. When use of the stent 10 is desired, the stent is removed from
the packaging and implanted in accordance with its specific
design.
[0107] In the instance of the coating being applied just prior to
implantation, the stent can be prepared in advance. The stent 10,
for example, can be sterilized and packaged in a sterile
environment for later use. When use of the stent 10 is desired, the
stent 10 is removed from the packaging, and the coating substance
is applied to result in the coating 20 resident on the stent 10.
The coating 20 can result from application of the coating substance
by, for example, the spraying, brushing, swabbing, wiping,
printing, or painting methods.
[0108] The present invention provides the coating 20 for medical
devices such as the stent 10. The coating is bio-absorbable. The
coating 20 includes the bio-absorbable carrier component and can
include the therapeutic agent component. The coating 20 of the
present invention provides a unique vehicle for the delivery of
beneficial substances to the body tissue of a patient.
[0109] The bio-absorbable carrier component itself, in the form of
fish oil for example, can provide therapeutic benefits in the form
of reduced inflammation, and improved healing, if the fish oil
composition is not substantially modified during the process that
takes the naturally occurring fish oil and forms it into the
coating 20. Some prior attempts to use natural oils as coatings
have involved mixing the oil with a solvent, or curing the oil in a
manner that destroys the beneficial aspects of the oil. The solvent
utilized in the coating 20 of the present invention (NMP) does not
have such detrimental effects on the therapeutic properties of the
fish oil. Thus the omega-3 fatty acids, and the EPA and DHA
substances are substantially preserved in the coating of the
present invention.
[0110] Therefore, the coating 20 of the present invention includes
the bio-absorbable carrier component in the form of the naturally
occurring oil (i.e., fish oil, or any equivalents). The
bio-absorbable carrier component is thus able to be absorbed by the
cells of the body tissue. More specifically, there is a
phospholipid layer in each cell of the body tissue. The fish oil,
and equivalent oils, contain lipids as well. There is a lipophilic
action that results where the lipids are attracted by each other in
an effort to escape the aqueous environment surrounding the lipids.
Accordingly the lipids attract, the fish oil fatty acids bind to
the cells of the tissue, and subsequently alter cell membrane
fluidity and cellular uptake. If there is a therapeutic agent
component mixed with the bio-absorbable carrier component, the
therapeutic component associated with the fish oil lipids
penetrates the cells in an altered manner.
[0111] As previously mentioned, prior attempts to create drug
delivery platforms such as coatings on stents primarily make use of
polymer based coatings to provide the ability to better control the
release of the therapeutic agent. Essentially, the polymer in the
coating releases the drug or agent at a predetermined rate once
implanted at a location within the patient. Regardless of how much
of the therapeutic agent would be most beneficial to the damaged
tissue, the polymer releases the therapeutic agent based on
properties of the polymer coating. Accordingly, the effect of the
coating is substantially local at the surface of the tissue making
contact with the coating and the stent. In some instances the
effect of the coating is further localized to the specific
locations of stent struts pressed against the tissue location being
treated. These prior approaches can create the potential for a
localized toxic effect.
[0112] Contrarily with the present invention, because of the
lipophilic mechanism enabled by the bio-absorbable lipid based
coating 20 formed using a cross-linked gel derived from at least
one fatty acid compound in accordance with the present invention,
the uptake of the therapeutic agent is facilitated by the delivery
of the therapeutic agent to the cell membrane by the bio-absorbable
carrier component. Further, the therapeutic agent is not freely
released into the body fluids, but rather, is delivered directly to
the cells and tissue. In prior configurations using polymer based
coatings, the drugs were released at a rate regardless of the
reaction or need for the drug on the part of the cells receiving
the drug.
[0113] In addition, the bio-absorbable nature of the carrier
component and the resulting coating (in the instances where a
bio-absorbable therapeutic agent component is utilized) results in
the coating 20 being completely absorbed over time by the cells of
the body tissue. There is no break down of the coating into sub
parts and substances which induce an inflammatory response that are
eventually distributed throughout the body and in some instances
disposed of by the body, as is the case with biodegradable
coatings. The bio-absorbable nature of the coating 20 of the
present invention results in the coating being absorbed, leaving
only the stent structure, or other medical device structure. The
bio-absorbable carrier component does not induce a foreign body
inflammatory response.
[0114] Despite action by the cells, the coating 20 of the present
invention is further configured to release the therapeutic agent
component at a rate no faster than a selected controlled release
rate over a period of weeks to months. The controlled release rate
action is achieved by providing an increased level of vitamin E in
the mixture with the fish oil, to create a more viscous, sticky,
coating substance that better adheres and lasts for a longer
duration on the implanted medical device. The controlled release
rate can include an initial burst of release, followed by the
sustained multi-week to multi-month period of release.
Correspondingly, with a greater amount of fatty acids relative to
the level of vitamin E, the controlled release rate can be
increased. The fatty acids can be found in the oil, and/or fatty
acids such as myristic acid can be added to the oil. Thus, the
ratio of fatty acids to alpha-tocopherol can be varied in the
preparation of the coating 20 to vary the subsequent release rate
of the therapeutic agent in a controlled and predictable
manner.
[0115] In addition, the oil provides a lubricious surface against
the vessel walls. As the stent 10 having the coating 20 applied
thereon is implanted within a blood vessel, for example, there can
be some friction between the stent walls and the vessel walls. This
can be injurious to the vessel walls, and increase injury at the
diseased vessel location. The use of the naturally occurring oil,
such as fish oil, provides extra lubrication to the surface of the
stent 10, which reduces the initial injury. With less injury caused
by the stent, there is less of an inflammatory response, and less
healing required.
[0116] Several example implementations have been carried out to
demonstrate the effectiveness of the coating 20 of the present
invention. Details concerning the example implementations
follow.
EXAMPLE 1
[0117] A fish oil:vitamin E coating was mixed at a ratio of
50:50.1.5 grams of this mixture was blended with 1.5 grams of
ethanol. When placed in a bell jar vacuum (50 to 60 mTorr) in a
weigh pan (19.63 cm.sup.2 area), it took 24 hours to completely
remove the ethanol. When placed in a Petri dish (62.07 cm.sup.2
area), it took 4 hours to completely remove the ethanol under
similar vacuum conditions. When the same formulation was placed in
the rotating fixture (FIG. 6B) and the surface area was continually
refreshed, it took 1 hour to remove the ethanol under similar
vacuum conditions. The removal of ethanol was confirmed by
FTIR.
EXAMPLE 2
[0118] A fish oil:vitamin E coating was mixed at a ratio of 50:50.
1.5 grams of this mixture was blended with 1.5 grams of nMP. When
placed in a bell jar vacuum (50 to 60 mTorr) in a weigh pan (19.63
cm.sup.2 area), the nMP could not be removed even after 120 hours
of vacuum. When placed in a Petri dish (62.07 cm.sup.2 area), it
took 96 hours to completely remove the nMP under similar vacuum
conditions. When the same formulation was placed in the rotating
fixture (FIG. 6B) and the surface area was continually refreshed,
it took 30 hours to remove the nMP under similar vacuum conditions.
The removal of NMP was confirmed by FTIR.
EXAMPLE 3
[0119] A 30:70 fish oil:vitamin E formulation was prepared. A
rapamycin pro-drug was dissolved in ethanol and 1.9169 grams of the
drug solution was added to 1.0751 grams of the coating formulation.
This mixture was placed in the rotating fixture (FIG. 6B) and the
surface area was continually refreshed. The final drug
concentration was 24.26% and was confirmed by HPLC analysis. The
ethanol solvent was completely removed after 24 hours of operation.
The removal of the ethanol was confirmed by FTIR analysis.
[0120] Numerous modifications and alternative embodiments of the
present invention will be apparent to those skilled in the art in
view of the foregoing description. Accordingly, this description is
to be construed as illustrative only and is for the purpose of
teaching those skilled in the art the best mode for carrying out
the present invention. Details of the structure may vary
substantially without departing from the spirit of the invention,
and exclusive use of all modifications that come within the scope
of the appended claims is reserved. It is intended that the present
invention be limited only to the extent required by the appended
claims and the applicable rules of law.
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