U.S. patent application number 10/773756 was filed with the patent office on 2004-11-11 for drug formulations for coating medical devices.
Invention is credited to Schultz, Robert K..
Application Number | 20040224003 10/773756 |
Document ID | / |
Family ID | 33423097 |
Filed Date | 2004-11-11 |
United States Patent
Application |
20040224003 |
Kind Code |
A1 |
Schultz, Robert K. |
November 11, 2004 |
Drug formulations for coating medical devices
Abstract
The present invention relates to oil-based formulations of
hydrophobic drugs for the uniform coating of medical devices such
as vascular stents and balloons. Another aspect of the present
invention is an intravascular medical device having an oil-based
coating suitable for delivering a water-insoluble drug, comprising
one or more of an anti-oxidant, an anti-inflammatory and an
anti-restenotic agent.
Inventors: |
Schultz, Robert K.; (Poway,
CA) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
33423097 |
Appl. No.: |
10/773756 |
Filed: |
February 6, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60446318 |
Feb 7, 2003 |
|
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Current U.S.
Class: |
424/423 ;
514/458; 514/54; 514/579 |
Current CPC
Class: |
A61K 31/739 20130101;
A61L 31/16 20130101; A61L 2420/02 20130101; A61L 31/08 20130101;
A61K 31/739 20130101; A61K 31/355 20130101; A61L 2300/606 20130101;
A61L 29/16 20130101; A61K 31/355 20130101; A61K 45/06 20130101;
A61L 29/08 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
424/423 ;
514/579; 514/054; 514/458 |
International
Class: |
A61K 031/739; A61K
031/355 |
Claims
What is claimed is:
1. A formulation for coating a medical device with a hydrophobic
therapeutic agent, comprising the hydrophobic therapeutic agent, a
non-volatile oil-based solvent, and an amount of a volatile solvent
sufficient to decrease the viscosity of the non-volatile oil-based
solvent, such that the formulation is adapted to uniformly coat the
medical device.
2. The formulation of claim 1, wherein the hydrophobic therapeutic
agent is a restenosis-inhibiting agent.
3. The formulation of claim 2, wherein the hydrophobic
restenosis-inhibiting agent is C6-ceramide.
4. The formulation of claim 1, wherein the hydrophobic therapeutic
agent is an anti-inflammatory agent.
5. The formulation of claim 1, wherein the hydrophobic therapeutic
agent is an anti-oxidant.
6. The formulation of claim 1, wherein the non-volatile oil-based
solvent comprises Vitamin E.
7. The formulation of claim 1, wherein the volatile solvent
comprises an alcohol.
8. The formulation of claim 7, wherein said alcohol comprises
ethanol or isopropanol.
9. A pharmaceutical formulation, comprising C6-ceramide and Vitamin
E.
10. A medical device comprising a surface adapted to contact a
vessel wall, wherein said surface has a coating comprising a
hydrophobic therapeutic agent, and a non-volatile oil-based solvent
in which said agent is dissolved.
11. The medical device of claim 10, wherein said device is an
intravascular balloon.
12. The medical device of claim 10, wherein said device is an
intravascular stent.
13. The medical device of claim 10, wherein said oil-based solvent
comprises Vitamin E.
14. The medical device of claim 10, wherein said hydrophobic
therapeutic agent is a restenosis-inhibiting agent.
15. The medical device of claim 14, wherein said
restenosis-inhibiting agent is C6-ceramide.
16. A method for producing a drug-coated intravascular device,
comprising: producing a coating composition by mixing a drug
composition comprising a drug and an oil-based non-volatile solvent
in a volatile solvent, coating said intravascular device with said
coating composition; and causing said volatile solvent to
evaporate.
17. The method of claim 16, wherein said oil-based non-volatile
solvent comprises Vitamin E
18. The method of claim 16, wherein said volatile solvent comprises
an alcohol.
19. The method of claim 18, wherein said alcohol is ethanol or
isopropanol.
20. The method of claim 16, wherein said drug is hydrophobic.
21. The method of claim 20, wherein said hydrophobic drug is a
restenosis-inhibiting agent.
22. The drug-coated intravascular device produced by the method of
claim 16.
Description
RELATED APPLICATIONS
[0001] This Applications claims the benefit of U.S. Provisional
Patent Application No. 60/446,318 filed Feb. 7, 2003.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is related to the delivery of drugs
from implantable medical devices. More specifically, the present
invention relates to formulations of hydrophobic anti-oxidant,
anti-inflammatory and anti-restenotic agents and vascular stents
and balloons having an oil-based coating suitable for delivering
anti-oxidant, anti-inflammatory and anti-restenotic agents.
[0004] 2. Description of the Related Art
[0005] Over one million angioplasty procedures are performed
annually with about 80% of these involving the placement of a metal
stent. Although, both balloon angioplasty and stenting of clogged
coronary arteries result in an immediate clearing of the
obstruction and resumption of coronary blood flow, within six
months 20-50% of the arteries require revascularization. The
mechanism of restenosis has been found to be related to both
mechanical stretch injury and remodeling of the artery wall due to
smooth muscle cell proliferation into the lumen called neointimal
hyperplasia (NIH). In both instances, the cause of the reduced
artery flow is actually induced by balloon angioplasty and/or
placement of the stent. Originally, balloon angioplasty by itself
was responsible for stretch injury and recoil that lead to as much
as 50% restenosis in susceptible patients. To counter the effects
of recoil and prop the artery open further, the practice of
deploying a metal stent was introduced and the values of restenosis
have dropped to between 20-30% depending on the patient
population.
[0006] Drugs such as rapamycin and paclitaxel have been
demonstrated to reduce NIH and further reduce the rate of stenosis
when coated on a metal stent. These drugs act to prevent smooth
muscle cell (SMC) proliferation which is a direct consequence of
the damage done to the internal elastica and the medial layers
during the deployment of the balloon and/or stent. A new agent
C6-ceramide (CERACOR.TM.)--a water insoluble lipid, has also been
demonstrated to inhibit SMC proliferation in both in vitro cell
culture and in vivo animal studies (rabbit carotid model and pig
coronary) (Charles et al. 2000 Circ Res 87:282-288). C6-ceramide
has been shown to initiate activity within 15 minutes of
application of a single dose from an angioplasty balloon.
[0007] Initial experiments with C6-ceramide coated on the balloon
from a dimethylsulfoxide/ethanol solution revealed that the
physical form of the drug changes with time. Initially, the
deposited lipid form a translucent film, but within an hour or so
the deposited material slowly transforms to a white crystallite
appearance. The deposition uniformity as measured by microscopy is
spotty across the balloon surface. After several days, the white
powder continues to transform until it flakes off the balloon and
is no longer believed to be in an available state. Decreased
availability may be described as the dissolution/deaggregation time
of the solid relative to deposition and diffusion within the
artery, which prevents it from exerting its effect. Currently, to
study the effect of C6-ceramide in animal models, the DMSO/ethanol
formulation containing C6-ceramide is coated onto the balloon just
prior to insertion into the artery. The role of the solvent is to
keep the lipid material in an available film-like state sufficient
for it to be rapidly deposited and absorbed quickly in the artery,
where it is shown to exert an effect within 15 minutes. However,
organic solvents, in which the drug is very soluble, tend to
evaporate rapidly and the solvents may also penetrate and affect
the balloon performance. Alternative solvents and formulations are
needed that permit the drug to remain in a dissolved state yet
remain physically stable without changing with time.
SUMMARY OF THE INVENTION
[0008] In one embodiment, the present invention relates to a
formulation for coating a medical device with a hydrophobic
restenosis-inhibiting agent. The formulation comprises the
hydrophobic restenosis-inhibiting agent, a non-volatile oil-based
solvent, and an amount of a volatile solvent sufficient to decrease
the viscosity of the non-volatile oil-based solvent, such that the
formulation is adapted to uniformly coat the medical device.
[0009] In a preferred embodiment of the coating formulation, the
hydrophobic restenosis-inhibiting agent is C6-ceramide. In another
preferred variation of the coating formulation, the non-volatile
oil-based solvent comprises Vitamin E. Preferably, the volatile
solvent comprises ethanol. In one particularly preferred
embodiment, the pharmaceutical formulation, comprising C6-ceramide
and Vitamin E.
[0010] In another aspect, the present invention relates to an
implantable medical device comprising a surface adapted to contact
a vessel wall, wherein the surface has a coating comprising a
hydrophobic restenosis-inhibiting agent, and a non-volatile
oil-based solvent in which said agent is dissolved. This device may
be an intravascular balloon. In a variation, the device may be an
intravascular stent. Preferably, the oil-based solvent comprises
Vitamin E. More preferably, the device is coated with Vitamin E and
C6-ceramide.
[0011] In another aspect, the present invention relates to a method
for producing a drug-coated intravascular device. The method
comprises the steps of producing a coating composition by mixing a
drug composition comprising a water-insoluble restenosis inhibiting
agent and an oil-based non-volatile solvent in a volatile solvent;
coating the intravascular device with the coating composition; and
causing the volatile solvent to evaporate. Preferably, the
oil-based non-volatile solvent comprises Vitamin E, and the
volatile solvent comprises ethanol. Preferably, the
restenosis-inhibiting agent is C6-ceramide. In a further aspect,
the present invention is the drug-coated intravascular device
produced by the above method.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 shows the results of screening of activity of several
formulations in the rabbit carotid stretch injury model.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0013] In one embodiment, the present invention is an oil-based
formulation of hydrophobic anti-restenosis drugs for uniform
coating of a medical implantable device such as a vascular balloon
or a stent.
[0014] In another embodiment, the present invention is a method of
coating of medical implantable devices such as vascular balloons
and stents with water-insoluble drugs dissolved in an oil-based
solvent.
[0015] In another embodiment, the present invention is a medical
implantable device such as a vascular balloon or a stent coated
with an oil-based formulation containing a water-insoluble
drug.
[0016] For the purpose of this invention by a water-insoluble drug,
or hydrophobic drug we mean a drug with a water solubility of less
than about 1 mg/ml at room temperature and a logP, where P is the
partition coefficient between octanol and water, of at least 1.5,
preferably at least 2.
[0017] Three formulation approaches have shown significant promise
for the delivery of rapidly acting water-insoluble drugs to the
coronary arteries.
[0018] Formulation Approach 1: Propylene glycol+Surfactant.
[0019] Formulation Approach 2: Intravenously acceptable oils
(cottonseed, peanut), Vitamin E.
[0020] Formulation approach 3: Propylene glycol+Surfactant+oil.
[0021] C6-ceramide was found to be sufficiently soluble
and/dispersible in all three formulation approaches when all
components were first dissolved in a volatile solvent, such as
ethanol. In all cases the drug was coated onto a balloon from an
ethanol solution containing C6-ceramide and the other solvents in
each formulation. Once the ethanol evaporated from the surface of
the device, the drug was uniformly dispersed over the surface and
dissolved within the non-volatile solvent(s). The ethanol was
useful in that it decreased the viscosity of the oil/drug mixture
thereby promoting uniform coating. It was found that although the
oils, other than vitamin E, formed an emulsion with ethanol, the
coating performance was adequate.
[0022] In all cases the C6-ceramide coated onto the angioplasty
balloon in a formulation containing a non-volatile solvent appeared
to maintain the drug in the dissolved state rather than forming a
dispersed solid, as was the case for DMSO formulations. Maintaining
the drug in the dissolved state uniformly coated over the surface
of the balloon is desirable for improving uniformity of delivery to
the artery wall.
[0023] Additional water-insoluble drugs may be used depending on
their solubility and coating performance, including rapamycin,
rapamycin analogs, ABT-578, everolimus, paclitaxel, dexamethasone
and other lipid materials (e.g., other ceramides, dimethyl
sphingosine, ether-linked diglycerides, ether-linked phosphatidic
acids, and sphinganines, and other phospholipids). Indeed other
compounds could be dispersed in the oil-based formulation of the
present invention. Particularly in cases where, even if they had
low solubility in the oil itself, sufficient drug could be
dispersed either by using appropriate cosolvents and surfactants or
by making a dispersed paste of the hydrophobic drug in the oil.
[0024] The following exemplary hydrophobic materials that may also
be compatible with this oil dispersion approach include but are not
limited to: steroids such as Dexamethasone, 17-beta-Estradiol;
Rapamycin and analogues; Taxol (paclitaxel) and analogues;
Actinomycin D; Prostaglandins (PGE1); Vitamin A; Probucol;
Batimastat; Statins (HMG-CoA Reductase Inhibitors), particularly
the water insoluble base forms that can be formulated as
dispersions in the oil; Trapidil (and other anti-proliferative
Growth Factor Inhibitors); and Cytochalasin B.
[0025] The devices which may be enhanced by coating with the
formulations of the present invention include any intraluminal
devices adapted for delivery to selected sites within the
cardiovascular system. These include, for example, simple
catheter/simple (one) balloon designs, dual balloon catheters,
stents, microporous catheters infusion catheters, rotary
atherectomy devices, ablation catheters, polymeric (e.g.,
polyacrylic acid) coated balloon designs, bioabsorbable coating
designs, stent covers and perivascular matrices.
[0026] The device to be coated is preferably dipped in a vehicle
including a volatile solvent (e.g., ethanol), a non-volatile
oil-based solvent, and a hydrophobic drug. The actual coating
process may be performed in a clean environment. If the device has
a balloon, it is preferably expanded prior to coating. Once the
volatile solvent evaporates from the surface of the device, the
drug is uniformly dispersed over the surface of the device and
dissolved or dispersed within the non-volatile solvent or carrier.
Post-processing sterilization can be accomplished by any methods
known in the art which do not negatively impact the drug activity,
the quality of the coating and/or device itself. For example, the
coated device can be subjected to radiation sterilization.
[0027] When coated onto a standard commercially available
angioplasty balloon/delivery system, the oil-based formulations
containing a water insoluble drug:
[0028] uniformly coat the surface of the expanded balloon;
[0029] the coated balloon can be deflated and re-wrapped to permit
transport to the coronary artery lesion site with the smallest
crossing profile;
[0030] when redeployed the oil-based C6-ceramide coating remains
dispersed over the entire surface of the balloon;
[0031] little dissolution or removal of the drug from the surface
occurs prior to inflation of the balloon in the artery;
[0032] the basis of drug transport remains transfer of drug from
the surface of the balloon to the artery wall during inflation of
the balloon. The amount of drug transferred is typically less than
25% of the total amount of drug available on the surface;
[0033] after inflation the balloon can be rewrapped and removed
from the artery or redeployed elsewhere to another lesion site,
little drug is lost during removal process; and
[0034] the oil-based formulations provide for a lubricious coating
to the balloon without using polymers or hydrogels.
[0035] When used to coat metal coronary stents the oil-based
formulations permit:
[0036] uniform coating of the entire metal surface;
[0037] coating can be applied to both the stent and the delivery
balloon at the same time;
[0038] unlike the balloon-coated option that is removed from the
artery immediately after deployment, the coated stent remains in
place and will slowly deliver the entire amount of drug to the
artery wall. The dissolution rate of the oil-based hydrophobic drug
system is compatible with sustained release delivery of the drug to
the artery wall without a controlling polymer or hydrogel; and
[0039] wound healing potential as vitamin E's antioxidant activity
may augment the anti-restenotic activity of the drug and enhance
wound healing at the site where the stent struts are embedded in
the artery wall.
[0040] The current formulation approach applied to an angioplasty
balloon demonstrates rapid pressure transfer delivery of a
sufficient amount of water-insoluble materials to the artery wall
using a non-polymer/hydrogel base consisting of oil capable of
dispersing the drug. The formulation approach works to keep a lipid
material in a very deliverable form without further solid-state
changes that could lead to ineffective delivery. The delivery of
the drug is largely based on contact of the balloon surface to the
artery wall and the coating uniformity of the oil-based
formulations is superior to other organic solvents. By increasing
the coating uniformity the resultant deposition of the drug on the
artery wall will be uniform as well as possibly improving the
overall activity of the drug.
[0041] The formulation approach outlined here is applicable to both
stents and balloons. For a stent, the viscosity and dissolution
rate of the resulting oil/drug mixture is tunable based on the
concentration of both oil and drug. Enhanced wound healing and
anti-oxidant behavior likely will increase when the choice of the
oil is vitamin E possibly leading to a synergistic effect of the
drug/oil mixture. Other possible oils that can be used in the
present invention include but are not limited to: fish oils (for
example, EPA, eicosapentanenoic acid, and DHA, docosahexaenoic
acid); vegetable oils (for example, cottonseed, corn, sassafras,
sunflower oils), and Vitamin A. Various surfactants known in the
art may be used in the present invention, for example, Polyoxyl 40
Stearate (Myrj 52), lecithin, Poloxamer, and the like.
[0042] The compatibility of the oil-based formulation approach to
the delivery of many different classes of compounds permits the
combination of anti-oxidant, anti-inflammatory and anti-restenotic
agents into one delivery vehicle that could be an important weapon
in the prevention of restenosis.
[0043] This invention is further illustrated by the following
examples which should not be construed as limiting. It should be
appreciated by those of skill in the art that the techniques
disclosed in the examples which follow represent techniques
discovered by the inventor to function well in the practice of the
invention, and thus can be considered to constitute preferred modes
for its practice. However, those of skill in the art should, in
light of the present disclosure, appreciate that many changes can
be made in the specific embodiments which are disclosed and still
obtain a like or similar result without departing from the spirit
and scope of the invention.
EXAMPLE 1
[0044] Study #1 pERK/ERK
[0045] C6-ceramide has been shown in vitro and in vivo to prevent
the up-regulation of extracellular signal-regulated kinase (ERK) to
its phosphorylated state (PERK) following balloon stretch injury.
The lack of up-regulation in this kinase has been correlated to the
prevention of restenosis in the rabbit carotid stretch injury
model. Using the standard rabbit carotid stretch injury model the
activity of oil-based/non-volatile formulations were screened. FIG.
1 shows the results of this screening. As can be seen with the 1 %
vitamin E (code name Kahlua) formulation, the effect on pERK
following stretch injury was not significantly different from the
sham control artery that did not receive any injury.
[0046] Study #2 Stenosis
[0047] In a parallel study a formulation containing 1% vitamin E,
0.5% propylene glycol, 0.05% Myrj 52 and 0.5% (w/w) C6-ceramide
dissolved in ethanol was evaluated in the rabbit carotid balloon
injury model. The same procedure was used as above except the
endpoint of this study was 14 day histology to measure neointimal
hyperplasia (NIH) as represented by the percentage decrease in the
neointimal area of the injured artery (percent stenosis). Here, the
oil-based formulation resulted in more than a 50% reduction of
neointimal hyperplasia (index of stenosis).
[0048] In both experiments it was possible to achieve equal or
better performance from the oil-based formulation approaches
compared to the existing DMSO/C6-ceramide solvent-treated.
[0049] While the present invention has been described in some
detail for purposes of clarity and understanding, one skilled in
the art will appreciate that various changes in form and detail can
be made without departing from the true scope of the invention. All
figures, tables, and appendices, as well as patents, applications,
and publications, referred to above, are hereby incorporated by
reference.
* * * * *