Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-09-28
2004-04-06
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S400000, C424S423000, C424S424000, C424S426000
Reexamination Certificate
active
06716444
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to implantable medical devices that release a drug.
2. Description of the Background
Percutaneous transluminal coronary angioplasty (PTCA) is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially compress against the atherosclerotic plaque of the lesion to remodel the arterial lumen. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient's vasculature.
In treating the damaged vasculature tissue, and to deter thrombosis and restenosis, drugs are commonly administered to the treatment site. For example, anticoagulants are commonly used to prevent thrombosis of the coronary lumen. Antiplatelets are administered to reduce the incidence of major adverse cardiac events. Cytostatic agents are presently used in clinical trials to reduce post-angioplasty proliferation of the vascular tissue.
Systemic administration of such drugs in sufficient amounts to supply an efficacious concentration to the local treatment site often produces adverse or toxic side effects for the patient. Accordingly, local delivery is a preferred method of treatment since smaller amounts of medication are administered in comparison to systemic dosages, but the medication is concentrated at a specific treatment site. Local delivery thus produces fewer side effects and achieves more effective results.
A common technique for local delivery of drugs involves coating a stent or graft with a polymeric material which, in turn, is impregnated with a drug or a combination of drugs. Once the stent or graft is implanted within a cardiovascular system lumen, the drug(s) is released from the polymer for the treatment of the local tissues. U.S. Pat. No. 5,605,696 to Eury et al., U.S. Pat. No. 5,464,650 to Berg, et al., and U.S. Pat. No. 5,700,286 to Tartaglia, et al. provide examples illustrating the use of a polymeric coating for the local delivery of a drug or substance.
Stents are scaffoldings, usually cylindrical or tubular in shape, which are inserted into an anatomical passageway and operate to physically hold open and, if desired, to expand the wall of a passageway. Stents are capable of being crimped onto balloon catheters for insertion through small cavities, positioned in a desired location, and then expanded to a larger diameter. Stents can be either balloon expandable or self-expanding.
Grafts are typically placed in a blood vessel to either replace a diseased segment that has been removed, or to form a bypass conduit through a damaged segment of the vessel wall as is the case with an aneurysm, for example. The graft has a tubular portion which spans the site of the damaged tissue and through which the blood flows. The graft has sections at both ends of the tube that are used to secure the graft to the inside of a vessel wall. The graft also has an outer surface, portions of which are in contact with an inner surface of the blood vessel wall, and an inner surface in contact with the blood flowing through the vessel.
FIG. 1
shows an implantable medical device
10
, which may be a stent or graft. Device
10
includes a substrate
12
that may be formed of stainless steel, nickel titanium alloy, or another biocompatible metal. Substrate
12
is covered (usually conformally) by a first layer
14
. First layer
14
includes polymer containing a drug
16
.
An equation describing the drug release rate per unit area of device
10
is as follows:
Φ
(
t
)
=
D
p
∑
n
=
0
∞
b
n
exp
(
-
π
2
D
p
t
(
2
n
+
1
)
2
4
T
2
)
(
-
π
2
T
(
2
n
+
1
)
n
)
(
Equation
1
)
where
&PHgr;(t)=release rate of drug as a function of time,
D
p
=diffusivity of drug
16
in polymer film
14
,
&pgr;=3.14159,
T=thickness of polymer film
14
,
and
b
n
=
2
T
∫
o
T
C
o
cos
{
π
x
(
2
n
+
1
)
2
T
}
ⅆ
x
where C
o
is the concentration of drug in the polymer at time zero.
Equation 1 assumes that: (1) all resistance to drug release is determined by the diffusivity of drug
16
in polymer
14
; (2) the concentration of drug
16
is uniform throughout; (3) drug
16
does not go into the metallic surface
12
; and (4) drug
16
is rapidly removed from the surface of polymer
14
as soon as drug
16
is released from polymer
14
.
The diffusivity of drug
16
in polymer
14
, D
p
, in turn is determined by certain properties of drug
16
(e.g., molecular weight, size) and physical properties of the polymer
14
through which drug
16
is diffusing (e.g., pore size, crystallinity, glass transition temperature, polarity or hydrophobicity).
FIG. 2
illustrates the predicted drug release rate curve for a polymer matrix carrying a drug, such as first layer
14
, illustrated in FIG.
1
. Curve
8
is an exponentially decreasing curve.
A problem associated with the use of a polymeric coating as a matrix for carrying the drug is that the rate at which the drug is released is highly variable, typically exhibiting a very high rate of release after the medical device is implanted in the patient, followed by a significantly lower rate of release. This may be undesirable in many applications, since the initial concentrations may be too high (causing undesirable side effects or even cell death), the later concentrations may be too low to have any therapeutic effect, and the overall residence time of the drug in the target area may be too short to provide the desired therapeutic effect.
For example, for certain antiproliferative drugs, a residence time of thirty minutes may be all that is required to achieve a permanent effect, while others may take up to two weeks. Where nitrous oxide (NO) is used as the antiproliferative drug, a residence time of four to eight weeks is desirable, but even longer durations up to twelve weeks may be beneficial, depending on the patient.
With respect to anti-inflammatory drugs, a long residence time (e.g., several weeks) is desirable, because the anti-inflammatory drug should be delivered until some amount of healing has occurred. Anti-thrombogenic drugs also may require a long residence time, for example, up to five months, since that much time may be required for a stent to become endothelialized.
Thus, there is a need for a mechanism for controlling the release rate of drugs from implantable medical devices to increase the efficacy of local drug delivery in treating patients.
SUMMARY OF THE INVENTION
The present invention allows for a controlled rate of release of a drug or drugs from a polymer carried on an implantable medical device. The controlled rate of release allows localized drug delivery for extended periods, e.g., weeks to months, depending upon the application. This is especially useful in providing therapy to reduce or prevent cell proliferation, inflammation, or thrombosis in a localized area.
One embodiment of an implantable medical device in accordance with the present invention includes a substrate, which may be, for example, a metal or polymeric stent or graft, among other possibilities. At least a portion of the substrate is coated with a first layer that includes one or more drugs in a polymer carrier. A barrier coating overlies the first layer. The barrier (which may be considered a coating) reduces the rate of release of the drug from the polymer once the medical device has been placed into the patient's body, thereby allowing an extended period of localized drug delivery once the medical device is in situ.
The barrier is necessarily biocompatible (i.e., its presence does not
Castro Daniel
Pacetti Stephen D.
Advanced Cardiovascular Systems Inc.
Evans Charesse
Kerrigan Cameron K.
Page Thurman K.
Squire Sanders & Dempsey L.L.P.
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