U.S. patent application number 11/295167 was filed with the patent office on 2006-06-22 for coatings with crystallized active agent(s) and methods.
Invention is credited to Ralph A. Chappa, Kimberly K.M. Lindsoe.
Application Number | 20060134168 11/295167 |
Document ID | / |
Family ID | 36337373 |
Filed Date | 2006-06-22 |
United States Patent
Application |
20060134168 |
Kind Code |
A1 |
Chappa; Ralph A. ; et
al. |
June 22, 2006 |
Coatings with crystallized active agent(s) and methods
Abstract
The present invention relates to coatings with crystallized
active agent(s) and related methods. In an embodiment, the
invention includes a method for coating a medical device including
selecting a solvent and a polymer, selecting a concentration of an
active agent of at least a certain amount of saturation, forming a
coating composition having the selected concentration of the active
agent, and applying the coating composition to the medical device.
In an embodiment, the invention includes an elution control coating
disposed on a medical device, the elution control coating including
a polymer, and an active agent, wherein the active agent is at
least about 80% crystallized within one week of being disposed on
the medical device. In an embodiment, the invention includes a
method for enhancing the formation of active agent crystals within
a coating layer including forming a coating solution and adjusting
the concentration of the active agent in the coating solution to
reach some percentage of the active agent saturation point. In an
embodiment, the invention includes a method of enhancing
crystallization of an active agent, the method including forming a
coating solution comprising a polymer, an active agent, and a
solvent; applying the coating solution to a substrate; and
increasing the rate of active agent nucleation within the
coating.
Inventors: |
Chappa; Ralph A.; (Prior
Lake, MN) ; Lindsoe; Kimberly K.M.; (Savage,
MN) |
Correspondence
Address: |
PAULY, DEVRIES SMITH & DEFFNER, L.L.C.
900 IDS CENTER
80 SOUTH EIGHTH STREET
MINNEAPOLIS
MN
55402-8773
US
|
Family ID: |
36337373 |
Appl. No.: |
11/295167 |
Filed: |
December 6, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60634070 |
Dec 7, 2004 |
|
|
|
Current U.S.
Class: |
424/422 ;
427/2.26; 514/171 |
Current CPC
Class: |
A61K 6/20 20200101; A61L
2300/216 20130101; A61L 2300/43 20130101; A61L 31/16 20130101; A61K
31/56 20130101; A61L 2300/63 20130101; A61L 2300/606 20130101; A61L
27/54 20130101; A61L 2300/602 20130101; A61L 31/10 20130101; A61L
31/14 20130101; A61L 27/50 20130101; A61L 2300/222 20130101; A61L
2420/02 20130101; A61L 27/34 20130101; A61L 2420/06 20130101 |
Class at
Publication: |
424/422 ;
427/002.26; 514/171 |
International
Class: |
A61K 6/083 20060101
A61K006/083; A61K 31/56 20060101 A61K031/56; B05D 3/02 20060101
B05D003/02 |
Claims
1. A method for coating a medical device comprising: selecting a
solvent and a polymer; selecting a concentration of an active agent
at least 80% of saturation in a composition comprising the solvent
and about 1.0 to about 99.0 wt. % polymer; combining the active
agent, the polymer, and the solvent to form a coating composition
having the selected concentration of the active agent; and applying
the coating composition to the medical device.
2. The method of claim 1, comprising selecting a concentration of
an active agent at least 90% of saturation in a composition
comprising the solvent and about 1.0 to about 99.0 wt. %
polymer.
3. The method of claim 1, comprising selecting a concentration of
an active agent at least 95% of saturation in a composition
comprising the solvent and about 1.0 to about 99.0 wt. %
polymer.
4. The method of claim 1, comprising selecting a concentration of
an active agent at least 99% of saturation in a composition
comprising the solvent and about 1.0 to about 99.0 wt. %
polymer.
5. The method of claim 1, the active agent comprising a
steroid.
6. The method of claim 1, the active agent comprising
estradiol.
7. The method of claim 1, the active agent comprising
dexamethasone.
8. The method of claim 1, the solvent comprising a first solvent
and a second solvent; wherein the active agent is soluble in the
first solvent and insoluble in the second solvent.
9. The method of claim 8, the first solvent having a higher vapor
pressure than the second solvent.
10. The method of claim 1, the first solvent comprising THF and the
second solvent comprising toluene.
11. The method of claim 1, the polymer comprises a first polymer
component comprising at least one poly(alkyl)(meth)acrylate and a
second polymer component comprising poly(ethylene-co-vinyl
acetate), wherein the second polymer component is selected from the
group consisting of poly(ethylene-co-vinyl acetate) polymers having
vinyl acetate concentrations of between about 10% and about 50% by
weight.
12. The method of claim 1, the polymer comprises a first polymer
component comprising at least one poly(alkyl)(meth)acrylate and a
second polymer component comprising polybutadiene.
13. The method of claim 1, wherein the steps of combining and
adjusting are performed simultaneously.
14. An elution control coating disposed on a medical device, the
elution control coating comprising: a polymer, and an active agent,
wherein the active agent is at least about 80% crystallized within
one week of being disposed on the medical device.
15. The elution control coating of claim 14, wherein the active
agent is at least about 90% crystallized within one week of being
disposed on the medical device.
16. The elution control coating of claim 14, wherein the active
agent is at least about 95% crystallized within one week of being
disposed on the medical device.
17. The elution control coating of claim 14, wherein the active
agent is at least about 95% crystallized within one day of being
disposed on the medical device.
18. The elution control coating of claim 14, the active agent
comprising a steroid.
19. The elution control coating of claim 14, the active agent
comprising estradiol.
20. The elution control coating of claim 14, the active agent
comprising dexamethasone.
21. The elution control coating of claim 14, the polymer comprises
a first polymer component comprising at least one
poly(alkyl)(meth)acrylate and a second polymer component comprising
poly(ethylene-co-vinyl acetate), wherein the second polymer
component is selected from the group consisting of
poly(ethylene-co-vinyl acetate) polymers having vinyl acetate
concentrations of between about 10% and about 50% by weight.
22. The elution control coating of claim 14, the polymer comprises
a first polymer component comprising at least one
poly(alkyl)(meth)acrylate and a second polymer component comprising
polybutadiene.
23. A method for enhancing the formation of active agent crystals
within a coating layer comprising: combining a polymer, an active
agent, and a solvent to form a coating solution comprising between
5 mg/ml and 200 mg/ml total solids concentration; adjusting the
concentration of the active agent in the coating solution to reach
at least 80% of the active agent saturation point; applying the
coating solution to a device; and evaporating the solvent to form
crystals of the active agent.
24. A method for enhancing crystallization of an active agent
within an elution control coating, the method comprising: forming a
coating solution comprising a polymer, an active agent, and a
solvent; applying the coating solution to a substrate; and
increasing the rate of active agent nucleation within the coating.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/634,070, filed Dec. 7, 2004, the contents of
which are herein incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to coating compositions and
related methods. More specifically, the present invention relates
to coatings with crystallized active agent(s) and related
methods.
BACKGROUND OF THE INVENTION
[0003] Therapeutic benefits can be achieved in some instances by
providing an active agent to a specific target tissue, instead of
systemically. This is because the effect of the agent on the target
tissue can be maximized while limiting side effects on other
tissues. Therapeutic benefits can also be achieved by providing an
active agent to a subject in a manner that extends the time over
which the active agent is released. One approach to providing these
benefits is to use a coating system containing an active agent on a
medical device.
[0004] Predictability and consistency of the elution rate of an
active agent from a coating or material on devices is of
importance, particularly in the clinical context. Specifically, in
some applications it can be problematic if two devices manufactured
in the same batch have significantly different elution rates, or if
the elution rates vary significantly between separate batches.
Finally, shelf stability of coated devices is of significance as an
excessively short shelf-life may raise costs associated with
maintaining an inventory sufficient to meet demand.
[0005] Accordingly, there is a need for coatings and methods of
coating providing consistent elution rates. There is also a need
for coatings and methods of coating providing adequate
shelf-stability.
SUMMARY OF THE INVENTION
[0006] The present invention relates to coatings with crystallized
active agent(s) and related methods. In an embodiment, the
invention includes a method for coating a medical device including
selecting a solvent and a polymer, selecting a concentration of an
active agent of at least a certain amount of saturation, forming a
coating composition having the selected concentration of the active
agent, and applying the coating composition to the medical device.
In an embodiment, the invention includes an elution control coating
disposed on a medical device, the elution control coating including
a polymer, and an active agent, wherein the active agent is at
least about 80% crystallized within one week of being disposed on
the medical device. In an embodiment, the invention includes a
method for enhancing the formation of active agent crystals within
a coating layer including forming a coating solution and adjusting
the concentration of the active agent in the coating solution to
reach some percentage of the active agent saturation point. In an
embodiment, the invention includes a method of enhancing
crystallization of an active agent, the method including forming a
coating solution comprising a polymer, an active agent, and a
solvent; applying the coating solution to a substrate; and
increasing the rate of active agent nucleation within the
coating.
BRIEF DESCRIPTION OF THE FIGURES
[0007] FIG. 1 is a microscopic view of a coating on a device taken
under polarizing light.
[0008] FIG. 2 is a microscopic view of a coating on a device of
FIG. 1 taken under polarizing light four days later.
[0009] FIG. 3 is an image of the surface features of a coating on a
device taken using scanning electron microscopy (SEM).
[0010] FIG. 4 is an image of the surface features of a coating on a
device taken using SEM.
[0011] FIG. 5 is an image of a coating on a device taken using
darkfield microscopy.
[0012] FIG. 6 is an image of the surface features of a coating on a
device taken using SEM.
[0013] FIG. 7 is an image of the surface features of a coating on a
device taken using SEM.
[0014] FIG. 8 is an image of the surface features of a coating on a
device taken using SEM.
[0015] FIG. 9 is an image of the surface features of a coating on a
device taken using SEM.
[0016] FIG. 10 is a series of six images of two different coatings
taken over a period of two weeks using polarized light optical
microscopy.
[0017] FIG. 11 is a series of two images of two different coatings
taken using polarized light optical microscopy at high
magnification showing the distinction in crystal sizes between the
two different coatings.
[0018] While the invention is susceptible to various modifications
and alternative forms, specifics thereof have been shown by way of
example and drawings, and will be described in detail. It should be
understood, however, that the invention is not limited to the
particular embodiments described. On the contrary, the intention is
to cover modifications, equivalents, and alternatives falling
within the spirit and scope of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0019] As used herein, the term "solubility" refers to the amount
of a substance (called the solute) that can be dissolved in given
quantity of another substance (called the solvent) at given
environmental conditions, such as at a given temperature.
[0020] As used herein, the term "saturated" shall refer to the
condition wherein a solvent cannot dissolve any more of a solute
(such as an "active agent") at a given temperature and pressure. As
used herein, the term saturated shall also include the condition of
supersaturation.
[0021] As used herein, the term "supersaturated" shall refer to the
condition where more of a solute is dissolved in a solvent than is
stable at a given temperature. Supersaturation may occur in
instances such as when a saturated solution is cooled down.
[0022] In some coating systems used for drug delivery, the coating
is applied to a substrate as a coating solution containing
polymer(s), active agent(s), and solvent(s). Typically, the
solvents evaporate from the coating solution during and/or after
application to the substrate to form a coating layer or layers. In
some cases, the active agent crystallizes over a period of days,
weeks, or even months. The final extent of crystallization (e.g.,
the percentage of the total active agent that eventually turns into
a crystalline form) depends on many factors including the
particular active agent being used, the polymers used, the amount
of residual solvent, the presence of other components such as
additives or impurities, etc. In some cases, substantially all of
the active agent crystallizes. In other cases, virtually none of
the active agent crystallizes. In still other cases, some
percentage of the active agent crystallizes while the rest remains
non-crystalline (or amorphous).
[0023] Batch-to-batch consistency of active agent elution rates for
coated devices can be affected by the extent of crystallization.
For some active agents, elution of a crystalline form is slower
than elution of a non-crystalline form. This is because solvation
of the compound generally occurs before the compound can be eluted
and crystalline forms generally form solvates more slowly than
otherwise similar non-crystalline forms. Thus, for the sake of
elution consistency, it is desirable to have some degree of
consistency regarding the total percentage of the active agent that
crystallizes from batch to batch. Embodiments of the invention can
increase elution consistency by enhancing the crystallization
process resulting in more rapid and uniform crystallization within
and across batches.
[0024] In addition, where the crystallization process occurs
relatively slowly, such as over multiple days or weeks, the
percentage of active agent crystallizing is more likely to be
affected by other variables such as post-manufacturing temperature
and humidity, and this can affect both batch-to-batch elution
consistency as well as intra-batch elution consistency. For
example, a device that is subject to relatively colder transport
and/or storage conditions between the time of manufacturing and end
use may exhibit a greater degree of crystallization in contrast to
a device manufactured as a part of the same batch but that was
subject to warmer transport and/or storage conditions. Embodiments
of the invention can increase elution consistency by speeding up
the crystallization process resulting in devices that are less
susceptible to variations in transport and/or storage
conditions.
[0025] In addition, active agents are more stable in a crystalline
form. Thus, enhancing the crystallization process can enhance the
stability of active agents in coatings. Embodiments of the
invention can include coatings with active agents having enhanced
stability because they are in a crystalline form.
[0026] Sometimes, during the crystallization process that occurs
after a coating solution is applied to a substrate, crystals form
in a manner such that they break-through, or erupt from, the
surface of the coating. If enough crystals erupt through the
surface of the coating, the performance of the coating may be
compromised. For example, active agent that is not covered by any
coating material will elute off faster than active agent that is
disposed within the coating material. Thus, crystals erupting
through the surface can cause the initial elution burst to be
increased, potentially to an undesirable level. It is believed that
the process of crystals erupting from the surface of a coating is
related to average crystal size. Specifically, it is believed that
larger crystals erupt from the surface of a coating to a greater
extent than do smaller crystals. In many cases, a more rapid
crystallization process results in a smaller crystal size on
average than does a slower crystallization process. Embodiments of
the invention can increase the speed of the crystallization process
resulting in the formation of smaller crystals that are less likely
to erupt from the surface of a coating than are larger
crystals.
[0027] Crystallization involves the formation of a solid aggregate
in which the plane faces intersect at definite angles and in which
there is a regular internal structure of the constituent chemical
species. Nucleation is the formation in a solution of a number of
minute solid bodies, embryos, nuclei or seeds that then act as
centers of crystallization. Nucleation may occur spontaneously or
it may be induced artificially. Nucleation can be classified as
either primary or secondary. Primary nucleation refers to all cases
of nucleation in systems that do not contain crystalline matter to
start. Primary nucleation can be further divided into homogeneous
primary nucleation, which is spontaneous primary nucleation, and
heterogeneous primary nucleation which is primary nucleation
induced by foreign particles. Secondary nucleation refers to
nucleation induced by crystals. Crystallization depends on both the
condition of supersaturation (as defined above) and the process of
nucleation. Accordingly, crystallization can be enhanced or
accelerated by increasing the degree of supersaturation and/or
enhancing the nucleation process.
[0028] In some embodiments of the invention, crystallization is
enhanced by increasing the degree of supersaturation or increasing
the speed with which the coating solution becomes supersaturated
during or after application to a substrate. By way of example, it
has been discovered that adjusting the concentration of an active
agent in a coating solution to a point, by way of example to the
saturation point, enhances rapid crystal formation. For example,
assuming a solution containing active agent is at the limit of
solubility, as soon as some solvent starts to evaporate, the
remaining solvent becomes supersaturated with the active agent.
This rapid state of supersaturation causes crystallization to occur
more rapidly and frequently more consistently. In an embodiment,
the invention includes a method for coating a medical device
including selecting a solvent and a polymer, selecting a
concentration of an active agent of at least 80% of saturation in a
composition comprising the solvent and about 1.0 to about 99.0 wt.
% polymer, combining the active agent, the polymer, and the solvent
to form a coating composition having the selected concentration of
the active agent, and applying the coating composition to the
medical device. In an embodiment, the invention includes a method
for rapidly crystallizing an active agent in a coating layer
including combining a polymer, an active agent, and a solvent to
form a coating solution having between 5 mg/ml and 200 mg/ml total
solids concentration, adjusting the concentration of the active
agent in the coating solution to reach at least 80% of the active
agent saturation point, applying the coating solution to a device,
and evaporating the solvent to form crystals of the active
agent.
[0029] Embodiments of the invention can include coatings that can
be used to control the elution rate of active agents therefrom. In
an embodiment, the invention includes an elution control coating
disposed on a medical device, the elution control coating including
a polymer, and an active agent, wherein the active agent is at
least about 80% crystallized within one week of being disposed on
the medical device. In an embodiment, the active agent is at least
about 90% crystallized within one week of being disposed on the
medical device. The active agent can be at least about 95%
crystallized within one week of being disposed on the medical
device. The active agent can be at least about 95% crystallized
within one day of being disposed on the medical device.
[0030] In some embodiments, supersaturation is increased by
addition of a component to a coating solution that decreases
solubility of the active agent in the solvent.
[0031] In some embodiments of the invention, crystallization is
enhanced by enhancing the nucleation process. By way of example, in
some embodiments, nucleation is enhanced by seeding the coating
solution as it is applied with crystals of the active agent. In
other embodiments, nucleation is enhanced by the addition of
foreign particles to the coating solution that function to trigger
heterogeneous primary nucleation.
Coating Composition:
[0032] Coating compositions used in embodiments of the invention
can include components such as polymer(s), solvent(s), active
agent(s), additives, etc. In an embodiment, the coating composition
is saturated with active agent or near saturation. In an
embodiment, the concentration of active agent in the coating
composition is at least 60% of saturation limit at an ambient
temperature. In an embodiment, the concentration of active agent in
the coating composition is at least 70% of the saturation limit at
an ambient temperature. In an embodiment, the concentration of
active agent in the coating composition is at least 80% of the
saturation limit at an ambient temperature. In an embodiment, the
concentration of active agent in the coating composition is at
least 90% of the saturation limit at an ambient temperature. In an
embodiment, the concentration of active agent in the coating
composition is at least 95% of the saturation limit at an ambient
temperature. In an embodiment, the concentration of active agent in
the coating composition is at least 99% of the saturation limit at
an ambient temperature. In an embodiment, the concentration of
active agent in the coating composition is at least 100% of the
saturation limit at an ambient temperature.
[0033] In some embodiments, the coating solution can be
characterized with respect to the total amount of solids in the
composition including the active agent and polymer(s). In an
embodiment, the total amount of solids concentration in the
solution is between 5 mg/ml and 200 mg/ml. In an embodiment, the
total solids concentration is between 10 mg/ml and 80 mg/ml. In an
embodiment, the total solids concentration is between 20 mg/ml and
60 mg/ml. In an embodiment, the total solids concentration is
between 30 mg/ml and 50 mg/ml. In an embodiment, the total solids
concentration is about 40 mg/ml.
[0034] In some embodiments, the coating solution includes a first
solvent and a second solvent, wherein the active agent is insoluble
or only sparingly soluble in the first solvent but soluble or
freely soluble in the second solvent. In an embodiment, the
polymer(s) of the coating composition are soluble in both the first
and second solvent. One method of preparing the coating composition
with two solvents, wherein the active agent is only soluble in one
of them, includes mixing the polymer(s) with the particular solvent
that the active agent is insoluble or only sparingly soluble in,
then mixing the active agent with the other solvent, and finally
combining the two solutions in various proportions until it is
determined what percentage of the first solvent causes the active
agent to start precipitating out of the solution. A coating
solution can then be prepared with a percentage of the first
solvent that pushes the amount of active agent to the saturation
limit for the relative proportions of the two solvents being
used.
[0035] The coating composition may also include other components.
By way of example, the coating composition may include agents that
aid in the nucleation process (homogenous or heterogenous) to
enhance crystallization. In an embodiment, the composition may
include a component that serves as a seed. This component may
include crystallized active agent or another compound that enhances
the crystallization process. In an embodiment, a component that
triggers heterogeneous nucleation is deposited onto a substrate and
then the coating solution is deposited onto that component.
[0036] The coating composition may also include other components
that enhance crystallization. By way of example, the coating
composition may include other solvents that enhance crystallization
of a particular active agent.
Solvents:
[0037] Many different solvents can be used with embodiments of the
present invention depending on the particular polymers and active
agents used. Solvents can include water, alcohols (e.g., methanol,
butanol, propanol, and isopropanol (isopropyl alcohol)), alkanes
(e.g., halogenated or unhalogenated alkanes such as hexane and
cyclohexane), amides (e.g., dimethylformamide), ethers (e.g., THF
and dioxolane), ketones (e.g., methylethylketone), aromatic
compounds (e.g., toluene and xylene), nitriles (e.g., acetonitrile)
and esters (e.g., ethyl acetate). In an embodiment, the solvent is
one in which a polymer component(s) forms a true solution.
[0038] In an embodiment, the invention includes a first solvent and
a second solvent, wherein the active agent is soluble or freely
soluble in the first solvent but insoluble or only sparingly
soluble in the second solvent. In an embodiment, the first solvent
can be THF. In an embodiment, the second solvent can be toluene. In
an embodiment, the first solvent has a higher vapor pressure than
the second solvent and is thus more volatile than the second
solvent.
Polymers
[0039] Coating solutions used in embodiments of the invention can
include one or more polymers. In an embodiment, the coating
solution includes a plurality of polymers, including a first
polymer and a second polymer. When the coating solution contains
only one polymer, it can be either a first or second polymer as
described herein. As used herein, term "(meth)acrylate" when used
in describing polymers shall mean the form including the methyl
group (methacrylate) or the form without the methyl group
(acrylate).
[0040] Examples of suitable first polymers include
poly(alkyl(meth)acrylates), and in particular, those with alkyl
chain lengths from 2 to 8 carbons, and with molecular weights from
50 kilodaltons to 900 kilodaltons. An exemplary first polymer is
poly(n-butyl methacrylate) (pBMA). Such polymers are available
commercially, e.g., from Aldrich, with molecular weights ranging
from about 200,000 Daltons to about 320,000 Daltons, and with
varying inherent viscosity, solubility, and form (e.g., as crystals
or powder).
[0041] Examples of suitable first polymers also include polymers
selected from the group consisting of poly(aryl(meth)acrylates),
poly(aralkyl (meth)acrylates), and
poly(aryloxyalkyl(meth)acrylates). Such terms are used to describe
polymeric structures wherein at least one carbon chain and at least
one aromatic ring are combined with acrylic groups, typically
esters, to provide a composition. In particular, exemplary
polymeric structures include those with aryl groups having from 6
to 16 carbon atoms and with weight average molecular weights from
about 50 to about 900 kilodaltons. Suitable
poly(aralkyl(meth)acrylates), poly(arylalky(meth)acrylates) or
poly(aryloxyalkyl (meth)acrylates) can be made from aromatic esters
derived from alcohols also containing aromatic moieties. Examples
of poly(aryl(meth)acrylates) include poly(9-anthracenyl
methacrylate), poly(chlorophenylacrylate),
poly(methacryloxy-2-hydroxybenzophenone),
poly(methacryloxybenzotriazole), poly(naphthylacrylate) and
-methacrylate), poly(4-nitrophenyl acrylate),
poly(pentachloro(bromo, fluoro) acrylate) and -methacrylate), and
poly(phenyl acrylate) and -methacrylate). Examples of poly(aralkyl
(meth)acrylates) include poly(benzyl acrylate) and -methacrylate),
poly(2-phenethyl acrylate) and -methacrylate, and
poly(1-pyrenylmethyl methacrylate). Examples of poly(aryloxyalkyl
(meth)acrylates) include poly(phenoxyethyl acrylate) and
-methacrylate), and poly(polyethylene glycol phenyl ether
acrylates) and -methacrylates with varying polyethylene glycol
molecular weights.
[0042] Examples of suitable second polymers are available
commercially and include poly(ethylene-co-vinyl acetate) (pEVA)
having vinyl acetate concentrations of between about 10% and about
50% (12%, 14%, 18%, 25%, 33% versions are commercially available),
in the form of beads, pellets, granules, etc. pEVA co-polymers with
lower percent vinyl acetate become increasingly insoluble in
typical solvents, whereas those with higher percent vinyl acetate
become decreasingly durable.
[0043] An exemplary polymer mixture for use in this invention
includes mixtures of pBMA and pEVA. This mixture of polymers can be
used with absolute polymer concentrations (i.e., the total combined
concentrations of both polymers in the coating material), of
between about 0.25 wt. % and about 99 wt. %. This mixture can also
be used with individual polymer concentrations in the coating
solution of between about 0.05 wt. % and about 99 wt. %. In one
embodiment the polymer mixture includes pBMA with a molecular
weight of from 100 kilodaltons to 900 kilodaltons and a pEVA
copolymer with a vinyl acetate content of from 24 to 36 weight
percent. In an embodiment the polymer mixture includes pBMA with a
molecular weight of from 200 kilodaltons to 400 kilodaltons and a
pEVA copolymer with a vinyl acetate content of from 24 to 36 weight
percent. The concentration of the active agent or agents dissolved
or suspended in the coating mixture can range from 0.01 to 99
percent, by weight, based on the weight of the final coating
material.
[0044] Second polymers of the invention can also comprise one or
more polymers selected from the group consisting of (i)
poly(alkylene-co-alkyl(meth)acrylates, (ii) ethylene copolymers
with other alkylenes, (iii) polybutenes, (iv) diolefin derived
non-aromatic polymers and copolymers, (v) aromatic group-containing
copolymers, and (vi) epichlorohydrin-containing polymers. First
polymers of the invention can also comprise a polymer selected from
the group consisting of poly(alkyl(meth)acrylates) and
poly(aromatic (meth)acrylates), where "(meth)" will be understood
by those skilled in the art to include such molecules in either the
acrylic and/or methacrylic form (corresponding to the acrylates
and/or methacrylates, respectively).
[0045] Poly(alkylene-co-alkyl(meth)acrylates) include those
copolymers in which the alkyl groups are either linear or branched,
and substituted or unsubstituted with non-interfering groups or
atoms. Such alkyl groups can comprise from 1 to 8 carbon atoms,
inclusive. Such alkyl groups can comprise from 1 to 4 carbon atoms,
inclusive. In an embodiment, the alkyl group is methyl. In some
embodiments, copolymers that include such alkyl groups can comprise
from about 15% to about 80% (wt) of alkyl acrylate. When the alkyl
group is methyl, the polymer contains from about 20% to about 40%
methyl acrylate in some embodiments, and from about 25% to about
30% methyl acrylate in a particular embodiment. When the alkyl
group is ethyl, the polymer contains from about 15% to about 40%
ethyl acrylate in an embodiment, and when the alkyl group is butyl,
the polymer contains from about 20% to about 40% butyl acrylate in
an embodiment.
[0046] Alternatively, second polymers for use in this invention can
comprise ethylene copolymers with other alkylenes, which in turn,
can include straight and branched alkylenes, as well as substituted
or unsubstituted alkylenes. Examples include copolymers prepared
from alkylenes that comprise from 3 to 8 branched or linear carbon
atoms, inclusive. In an embodiment, copolymers prepared from
alkylene groups that comprise from 3 to 4 branched or linear carbon
atoms, inclusive. In a particular embodiment, copolymers prepared
from alkylene groups containing 3 carbon atoms (e.g., propene). By
way of example, the other alkylene is a straight chain alkylene
(e.g., 1-alkylene). Exemplary copolymers of this type can comprise
from about 20% to about 90% (based on moles) of ethylene. In an
embodiment, copolymers of this type comprise from about 35% to
about 80% (mole) of ethylene. Such copolymers will have a molecular
weight of between about 30 kilodaltons to about 500 kilodaltons.
Exemplary copolymers are selected from the group consisting of
poly(ethylene-co-propylene), poly(ethylene-co-1-butene),
polyethylene-co-1-butene-co-1-hexene) and/or
poly(ethylene-co-1-octene).
[0047] "Polybutenes" suitable for use in the present invention
includes polymers derived by homopolymerizing or randomly
interpolymerizing isobutylene, 1-butene and/or 2-butene. The
polybutene can be a homopolymer of any of the isomers or it can be
a copolymer or a terpolymer of any of the monomers in any ratio. In
an embodiment, the polybutene contains at least about 90% (wt) of
isobutylene or 1-butene. In a particular embodiment, the polybutene
contains at least about 90% (wt) of isobutylene. The polybutene may
contain non-interfering amounts of other ingredients or additives,
for instance it can contain up to 1000 ppm of an antioxidant (e.g.,
2,6-di-tert-butyl-methylphenol). By way of example, the polybutene
can have a molecular weight between about 150 kilodaltons and about
1,000 kilodaltons. In an embodiment, the polybutene can have
between about 200 kilodaltons and about 600 kilodaltons. In a
particular embodiment, the polybutene can have between about 350
kilodaltons and about 500 kilodaltons. Polybutenes having a
molecular weight greater than about 600 kilodaltons, including
greater than 1,000 kilodaltons are available but are expected to be
more difficult to work with.
[0048] Additional alternative second polymers include
diolefin-derived, non-aromatic polymers and copolymers, including
those in which the diolefin monomer used to prepare the polymer or
copolymer is selected from butadiene
(CH.sub.2.dbd.CH--CH.dbd.CH.sub.2) and/or isoprene
(CH.sub.2.dbd.CH--C(CH.sub.3).dbd.CH.sub.2). In an embodiment, the
polymer is a homopolymer derived from diolefin monomers or is a
copolymer of diolefin monomer with non-aromatic mono-olefin
monomer, and optionally, the homopolymer or copolymer can be
partially hydrogenated. Such polymers can be selected from the
group consisting of polybutadienes prepared by the polymerization
of cis-, trans- and/or 1,2-monomer units, or from a mixture of all
three monomers, and polyisoprenes prepared by the polymerization of
cis-1,4- and/or trans-1,4-monomer units. Alternatively, the polymer
is a copolymer, including graft copolymers, and random copolymers
based on a non-aromatic mono-olefin monomer such as acrylonitrile,
and an alkyl (meth)acrylate and/or isobutylene. In an embodiment,
when the mono-olefin monomer is acrylonitrile, the interpolymerized
acrylonitrile is present at up to about 50% by weight; and when the
mono-olefin monomer is isobutylene, the diolefin is isoprene (e.g.,
to form what is commercially known as a "butyl rubber"). Exemplary
polymers and copolymers have a molecular weight between about 150
kilodaltons and about 1,000 kilodaltons. In an embodiment, polymers
and copolymers have a molecular weight between about 200
kilodaltons and about 600 kilodaltons.
[0049] Additional alternative second polymers include aromatic
group-containing copolymers, including random copolymers, block
copolymers and graft copolymers. In an embodiment, the aromatic
group is incorporated into the copolymer via the polymerization of
styrene. In a particular embodiment, the random copolymer is a
copolymer derived from copolymerization of styrene monomer and one
or more monomers selected from butadiene, isoprene, acrylonitrile,
a C.sub.1-C.sub.4 alkyl (meth)acrylate (e.g., methyl methacrylate)
and/or butene. Useful block copolymers include copolymer containing
(a) blocks of polystyrene, (b) blocks of an polyolefin selected
from polybutadiene, polyisoprene and/or polybutene (e.g.,
isobutylene), and (c) optionally a third monomer (e.g., ethylene)
copolymerized in the polyolefin block. The aromatic
group-containing copolymers contain about 10% to about 50% (wt.) of
polymerized aromatic monomer and the molecular weight of the
copolymer is from about 300 kilodaltons to about 500 kilodaltons.
In an embodiment, the molecular weight of the copolymer is from
about 100 kilodaltons to about 300 kilodaltons.
[0050] Additional alternative second polymers include
epichlorohydrin homopolymers and poly(epichlorohydrin-co-alkylene
oxide) copolymers. In an embodiment, in the case of the copolymer,
the copolymerized alkylene oxide is ethylene oxide. By way of
example, epichlorohydrin content of the epichlorohydrin-containing
polymer is from about 30% to 100% (wt). In an embodiment,
epichlorohydrin content is from about 50% to 100% (wt). In an
embodiment, the epichlorohydrin-containing polymers have a
molecular weight from about 100 kilodaltons to about 300
kilodaltons.
[0051] In an embodiment, polymers of the invention include
hydrophobic polymers. One method of defining the hydrophobicity of
a polymer is by the solubility parameter (or Hildebrand parameter)
of the polymer. The solubility parameter describes the attractive
strength between molecules of the material. The solubility
parameter is represented by Equation 1:
.delta.=(.DELTA.E.sup.v/V).sup.1/2 (Equation 1)
[0052] where .delta.=solubility parameter
((cal/cm.sup.3).sup.1/2)
[0053] .DELTA.E.sup.v=energy of vaporization (cal)
[0054] V=molar volume (cm.sup.3)
[0055] Solubility parameters cannot be calculated for polymers from
heat of vaporization data because of their nonvolatility.
Accordingly, solubility parameters must be calculated indirectly.
One method involves identifying solvents in which a polymer
dissolves without a change in heat or volume and then defining the
solubility parameter of the polymer to be the same as the
solubility parameters of the identified solvents. A more complete
discussion of solubility parameters and methods of calculating the
same can be found in Brandup et al., Polymer Handbook, 4th Ed.,
John Wiley & Sons, N.Y. (1999) beginning at VII p. 675.
[0056] As a general rule, the value of the solubility parameter
.delta. is inversely proportional to the degree of hydrophobicity
of a polymer. Thus, polymers that are very hydrophobic may have a
low solubility parameter value. This general proposition is
particularly applicable for polymers having a glass transition
temperature below physiological temperature. In an embodiment,
polymers used with the invention have a solubility parameter less
than about 11.0 (cal/cm.sup.3).sup.1/2. In an embodiment polymers
used with the invention have a solubility parameter of less than
about 10.0 (cal/cm.sup.3).sup.1/2.
[0057] Polymers can also include a poly(ether ester) multiblock
copolymer based on poly(ethylene glycol) (PEG) and poly(butylene
terephthalate) and can be described by the following general
structure:
[--(OCH.sub.2CH.sub.2).sub.n--O--C(O)--C.sub.6H.sub.4--C(O)--]x[--O--(CH.-
sub.2).sub.4--O--C(O)--C.sub.6H.sub.4--C(O)--]y, where
--C.sub.6H.sub.4-- designates the divalent aromatic ring residue
from each esterified molecule of terephthalic acid, n represents
the number of ethylene oxide units in each hydrophilic PEG block, x
represents the number of hydrophilic blocks in the copolymer, and y
represents the number of hydrophobic blocks in the copolymer. n can
be selected such that the molecular weight of the PEG block is
between about 300 and about 4000. X and y can be selected so that
the multiblock copolymer contains from about 55% up to about 80%
PEG by weight.
[0058] The block copolymer can be engineered to provide a wide
array of physical characteristics (e.g., hydrophilicity, adherence,
strength, malleability, degradability, durability, flexibility) and
active agent release characteristics (e.g., through controlled
polymer degradation and swelling) by varying the values of n, x and
y in the copolymer structure. Degradation of the copolymer does not
create toxic degradation products or an acid environment, and its
hydrophilic nature conserves the stability of labile active agents,
such as proteins (e.g., lysozymes).
[0059] Polymers of the invention also include biodegradable
polymers. Suitable biodegradable polymeric materials are selected
from: (a) non-peptide polyamino polymers; (b) polyiminocarbonates;
(c) amino acid-derived polycarbonates and polyarylates; and (d)
poly(alkylene oxide) polymers. The biodegradable polymeric
materials can break down to form degradation products that are
non-toxic and do not cause a significant adverse reaction from the
body.
[0060] In an embodiment, the biodegradable polymeric material is
composed of a non-peptide polyamino acid polymer. Suitable
non-peptide polyamino acid polymers are described, for example, in
U.S. Pat. No. 4,638,045 ("Non-Peptide Polyamino Acid Bioerodible
Polymers," Jan. 20, 1987). Generally speaking, these polymeric
materials are derived from monomers, including two or three amino
acid units having one of the following two structures illustrated
below: ##STR1##
[0061] wherein the monomer units are joined via hydrolytically
labile bonds at not less than one of the side groups R.sub.1,
R.sub.2, and R.sub.3, and where R.sub.1, R.sub.2, R.sub.3 are the
side chains of naturally occurring amino acids; Z is any desirable
amine protecting group or hydrogen; and Y is any desirable carboxyl
protecting group or hydroxyl. Each monomer unit comprises naturally
occurring amino acids that are then polymerized as monomer units
via linkages other than by the amide or "peptide" bond. The monomer
units can be composed of two or three amino acids united through a
peptide bond and thus comprise dipeptides or tripeptides.
Regardless of the precise composition of the monomer unit, all are
polymerized by hydrolytically labile bonds via their respective
side chains rather than via the amino and carboxyl groups forming
the amide bond typical of polypeptide chains. Such polymer
compositions are nontoxic, are biodegradable, and can provide
zero-order release kinetics for the delivery of active agents in a
variety of therapeutic applications. According to these aspects,
the amino acids are selected from naturally occurring L-alpha amino
acids, including alanine, valine, leucine, isoleucine, proline,
serine, threonine, aspartic acid, glutamic acid, asparagine,
glutamine, lysine, hydroxylysine, arginine, hydroxyproline,
methionine, cysteine, cystine, phenylalanine, tyrosine, tryptophan,
histidine, citrulline, ornithine, lanthionine, hypoglycin A,
.beta.-alanine, .gamma.-amino butyric acid, alpha aminoadipic acid,
canavanine, venkolic acid, thiolhistidine, ergothionine,
dihydroxyphenylalanine, and other amino acids well recognized and
characterized in protein chemistry.
[0062] In an embodiment, the biodegradable polymeric material can
be composed of polyiminocarbonates. Polyiminocarbonates are
structurally related to polycarbonates, wherein imino groups
(>C.dbd.NH) are present in the places normally occupied by
carbonyl oxygen in the polycarbonates. Thus, the biodegradable
component can be formed of polyiminocarbonates having linkages
##STR2## For example, one useful polyiminocarbonate has the general
polymer structural formula ##STR3## wherein R is an organic
divalent group containing a non-fused aromatic organic ring, and n
is greater than 1. Embodiments of the R group within the general
formula above are exemplified by, but is not limited to the
following:
[0063] R group ##STR4## [0064] wherein R' is lower alkene C.sub.1
to C.sub.6 ##STR5##
[0065] wherein n is an interger equal to or greater than 1, X is a
hetero atom such as --O--, --S--, or a bridging group such as
--NH--, --S(.dbd.O)--, --SO.sub.2--, --C(.dbd.O)--,
--C(CH.sub.3).sub.2--, --CH(CH.sub.3)--,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3)--, ##STR6## Also, compounds
of the general formula ##STR7##
[0066] can be utilized, wherein X is O, NH, or NR''', wherein R'''
is a lower alkyl radical; and R'' is a divalent residue of a
hydrocarbon including polymers such as a polyolefin, an oligoglycol
or polyglycol such as polyalkylene glycol ether, a polyester, a
polyurea, a polyamine, a polyurethane, or a polyamide. Exemplary
starting material for use in accordance with these embodiments
include diphenol compounds having the ##STR8## and dicyanate
compounds having the ##STR9##
[0067] with R.sub.1 and R.sub.2 being the same or different and
being alkylene, arylene, alkylarylene or a functional group
containing heteroatoms. Z.sub.1, and Z.sub.2 can each represent one
or more of the same or different radicals selected from the group
consisting of hydrogen, halogen, lower-alkyl, carboxyl, amino,
nitro, thioether, sulfoxide, and sulfonyl. Each of Z.sub.1 and
Z.sub.2 can be hydrogen.
[0068] In an embodiment, the biodegradable polymeric material can
be composed of various types of amino acid-derived polycarbonates
and polyarylates. These amino acid-derived polycarbonates and
polyarylates can be prepared by reacting certain amino acid-derived
diphenol starting materials with either phosgene or dicarboxylic
acids, respectively. Exemplary amino acid-derived diphenol starting
materials for the preparation of the amino acid-derived
polycarbonates and/or polyarylates of this embodiment are monomers
that are capable of being polymerized to form polyiminocarbonates
with glass transition temperatures ("Tg's") sufficiently low to
permit thermal processing. The monomers according to this
embodiment are diphenol compounds that are amino acid ester
derivatives having the formula shown below: ##STR10##
[0069] in which R.sub.1 is an alkyl group containing up to 18
carbon atoms.
[0070] In yet another embodiment, the biodegradable polymeric
material can be composed of copolymers containing both hydrophilic
poly(alkylene oxides) (PAO) and biodegradable sequences, wherein
the hydrocarbon portion of each PAO unit contains from 1 to 4
carbon atoms, or 2 carbon atoms (i.e., the PAO is poly(ethylene
oxide)). For example, useful biodegradable polymeric materials can
be made of block copolymers containing PAO and amino acids or
peptide sequences and contain one or more recurring structural
units independently represented by the structure
-L-R.sub.1-L-R.sub.2-, wherein R.sub.1 is a poly(alkylene oxide), L
is --O-- or --NH--, and R.sub.2 is an amino acid or peptide
sequence containing two carboxylic acid groups and at least one
pendent amino group.
[0071] Other useful biodegradable polymeric materials are composed
of polyarylate or polycarbonate random block copolymers that
include tyrosine-derived diphenol monomers and poly(alkylene
oxide), such as the polycarbonate shown below: ##STR11##
[0072] wherein R.sub.1 is --CH.dbd.CH-- or (--CH.sub.2--).sub.j, in
which j is 0 to 8; R.sub.2 is selected from straight and branched
alkyl and alkylaryl groups containing up to 18 carbon atoms and
optionally containing at least one ether linkage, and derivatives
of biologically and pharmaceutically active compounds covalently
bonded to the copolymer; each R.sub.3 is independently selected
from alkylene groups containing 1 to 4 carbon atoms; y is between 5
and about 3000; and f is the percent molar fraction of alkylene
oxide in the copolymer and ranges from about 0.01 to about
0.99.
[0073] In some embodiments, pendent carboxylic acid groups can be
incorporated within the polymer bulk for polycarbonates,
polyarylates, and/or poly(alkylene oxide) block copolymers thereof,
to further control the rate of polymer backbone degradation and
resorption.
[0074] Polymers used in embodiments of the invention can include
polymers that are components of elution control coatings. By way of
example, U.S. Pat. No. 6,214,901 (Chudzik et al.) discloses
polymers used in bioactive agent release coatings, the contents of
which is herein incorporated by reference.
Active Agents
[0075] Coating solutions used with methods of the invention can
contain one or more active agents. As used herein, the term "active
agent" means a compound that has a particular desired activity. For
example, an active agent can be a therapeutic compound that exerts
a specific activity on a subject. In some embodiments, active agent
will, in turn, refer to a peptide, protein, carbohydrate, nucleic
acid, lipid, polysaccharide or combinations thereof, or synthetic
inorganic or organic molecule, that causes a desired biological
effect when administered in vivo to an animal, including but not
limited to birds and mammals, including humans. In some
embodiments, the active agent can be a bioactive agent. Active
agents can have many different types of elution profiles.
[0076] Active agents useful according to the invention include
substances that possess desirable therapeutic characteristics for
application to the implantation site. Active agents useful in the
present invention can include many types of therapeutics including
thrombin inhibitors, antithrombogenic agents, thrombolytic agents,
fibrinolytic agents, anticoagulants, anti-platelet agents,
vasospasm inhibitors, calcium channel blockers, steroids,
vasodilators, anti-hypertensive agents, antimicrobial agents,
antibiotics, antibacterial agents, antiparasite and/or
antiprotozoal solutes, antiseptics, antifungals, angiogenic agents,
anti-angiogenic agents, inhibitors of surface glycoprotein
receptors, antimitotics, microtubule inhibitors, antisecretory
agents, actin inhibitors, remodeling inhibitors, antisense
nucleotides, anti-metabolites, miotic agents, anti-proliferatives,
anticancer chemotherapeutic agents, anti-neoplastic agents,
antipolymerases, antivirals, anti-AIDS substances,
anti-inflammatory steroids or non-steroidal anti-inflammatory
agents, analgesics, antipyretics, immunosuppressive agents,
immunomodulators, growth hormone antagonists, growth factors,
radiotherapeutic agents, peptides, proteins, enzymes, extracellular
matrix components, ACE inhibitors, free radical scavengers,
chelators, anti-oxidants, photodynamic therapy agents, gene therapy
agents, anesthetics, immunotoxins, neurotoxins, opioids, dopamine
agonists, hypnotics, antihistamines, tranquilizers,
anticonvulsants, muscle relaxants and anti-Parkinson substances,
antispasmodics and muscle contractants, anticholinergics,
ophthalmic agents, antiglaucoma solutes, prostaglandins,
antidepressants, antipsychotic substances, neurotransmitters,
anti-emetics, imaging agents, specific targeting agents, and cell
response modifiers.
[0077] More specifically, in embodiments the active agent can
include heparin, covalent heparin, synthetic heparin salts, or
another thrombin inhibitor; hirudin, hirulog, argatroban,
D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone, or another
antithrombogenic agent; urokinase, streptokinase, a tissue
plasminogen activator, or another thrombolytic agent; a
fibrinolytic agent; a vasospasm inhibitor; a calcium channel
blocker, a nitrate, nitric oxide, a nitric oxide promoter, nitric
oxide donors, dipyridamole, or another vasodilator; HYTRIN.RTM. or
other antihypertensive agents; a glycoprotein IIb/IIIa inhibitor
(abciximab) or another inhibitor of surface glycoprotein receptors;
aspirin, ticlopidine, clopidogrel or another antiplatelet agent;
colchicine or another antimitotic, or another microtubule
inhibitor; dimethyl sulfoxide (DMSO), a retinoid, or another
antisecretory agent; cytochalasin or another actin inhibitor; cell
cycle inhibitors; remodeling inhibitors; deoxyribonucleic acid, an
antisense nucleotide, or another agent for molecular genetic
intervention; methotrexate, or another antimetabolite or
antiproliferative agent; tamoxifen citrate, TAXOL.RTM., paclitaxel,
or the derivatives thereof, rapamycin (or other rapalogs e.g.
ABT-578 or sirolimus), vinblastine, vincristine, vinorelbine,
etoposide, tenopiside, dactinomycin (actinomycin D), daunorubicin,
doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycin,
plicamycin (mithramycin), mitomycin, mechlorethamine,
cyclophosphamide and its analogs, chlorambucil, ethylenimines,
methylmelamines, alkyl sulfonates (e.g., busulfan), nitrosoureas
(carmustine, etc.), streptozocin, methotrexate (used with many
indications), fluorouracil, floxuridine, cytarabine,
mercaptopurine, thioguanine, pentostatin, 2-chlorodeoxyadenosine,
cisplatin, carboplatin, procarbazine, hydroxyurea, morpholino
phosphorodiamidate oligomer or other anti-cancer chemotherapeutic
agents; cyclosporin, tacrolimus (FK-506), pimecrolimus,
azathioprine, mycophenolate mofetil, mTOR inhibitors, or another
immunosuppressive agent; cortisol, cortisone, dexamethasone,
dexamethasone sodium phosphate, dexamethasone acetate,
dexamethasone derivatives, betamethasone, fludrocortisone,
prednisone, prednisolone, 6U-methylprednisolone, triamcinolone
(e.g., triamcinolone acetonide), or another steroidal agent;
trapidil (a PDGF antagonist), angiopeptin (a growth hormone
antagonist), angiogenin, a growth factor (such as vascular
endothelial growth factor (VEGF)), or an anti-growth factor
antibody (e.g., ranibizumab, which is sold under the tradename
LUCENTIS.RTM.), or another growth factor antagonist or agonist;
dopamine, bromocriptine mesylate, pergolide mesylate, or another
dopamine agonist; .sup.60Co (5.3 year half life), .sup.192Ir (73.8
days), .sup.32P (14.3 days), .sup.111In (68 hours), .sup.90Y (64
hours), .sup.99Tc (6 hours), or another radiotherapeutic agent;
iodine-containing compounds, barium-containing compounds, gold,
tantalum, platinum, tungsten or another heavy metal functioning as
a radiopaque agent; a peptide, a protein, an extracellular matrix
component, a cellular component or another biologic agent;
captopril, enalapril or another angiotensin converting enzyme (ACE)
inhibitor; angiotensin receptor blockers; enzyme inhibitors
(including growth factor signal transduction kinase inhibitors);
ascorbic acid, alpha tocopherol, superoxide dismutase,
deferoxamine, a 21-aminosteroid (lasaroid) or another free radical
scavenger, iron chelator or antioxidant; a .sup.14C-, .sup.3H-,
.sup.131I, .sup.32P- or .sup.36S-radiolabelled form or other
radiolabelled form of any of the foregoing; an estrogen (such as
estradiol, estriol, estrone, and the like) or another sex hormone;
AZT or other antipolymerases; acyclovir, famciclovir, rimantadine
hydrochloride, ganciclovir sodium, Norvir, Crixivan, or other
antiviral agents; 5-aminolevulinic acid,
meta-tetrahydroxyphenylchlorin, hexadecafluorozinc phthalocyanine,
tetramethyl hematoporphyrin, rhodamine 123 or other photodynamic
therapy agents; an IgG2 Kappa antibody against Pseudomonas
aeruginosa exotoxin A and reactive with A431 epidermoid carcinoma
cells, monoclonal antibody against the noradrenergic enzyme
dopamine beta-hydroxylase conjugated to saporin, or other antibody
targeted therapy agents; gene therapy agents; enalapril and other
prodrugs; PROSCAR.RTM., HYTRIN.RTM. or other agents for treating
benign prostatic hyperplasia (BHP); mitotane, aminoglutethimide,
breveldin, acetaminophen, etodalac, tolmetin, ketorolac, ibuprofen
and derivatives, mefenamic acid, meclofenamic acid, piroxicam,
tenoxicam, phenylbutazone, oxyphenbutazone, nabumetone, auranofin,
aurothioglucose, gold sodium thiomalate, a mixture of any of these,
or derivatives of any of these.
[0078] Other biologically useful compounds that can also be
included in the coating include, but are not limited to, hormones,
.beta.-blockers, anti-anginal agents, cardiac inotropic agents,
corticosteroids, analgesics, anti-inflammatory agents,
anti-arrhythmic agents, immunosuppressants, anti-bacterial agents,
anti-hypertensive agents, anti-malarials, anti-neoplastic agents,
anti-protozoal agents, anti-thyroid agents, sedatives, hypnotics
and neuroleptics, diuretics, anti-parkinsonian agents,
gastro-intestinal agents, anti-viral agents, anti-diabetics,
anti-epileptics, anti-fungal agents, histamine H-receptor
antagonists, lipid regulating agents, muscle relaxants, nutritional
agents such as vitamins and minerals, stimulants, nucleic acids,
polypeptides, and vaccines.
[0079] Antibiotics are substances which inhibit the growth of or
kill microorganisms. Antibiotics can be produced synthetically or
by microorganisms. Examples of antibiotics include penicillin,
tetracycline, chloramphenicol, minocycline, doxycycline,
vancomycin, bacitracin, kanamycin, neomycin, gentamycin,
erythromycin, geldanamycin, geldanamycin analogs, cephalosporins,
or the like. Examples of cephalosporins include cephalothin,
cephapirin, cefazolin, cephalexin, cephradine, cefadroxil,
cefamandole, cefoxitin, cefaclor, cefuroxime, cefonicid,
ceforanide, cefotaxime, moxalactam, ceftizoxime, ceftriaxone, and
cefoperazone.
[0080] Antiseptics are recognized as substances that prevent or
arrest the growth or action of microorganisms, generally in a
nonspecific fashion, e.g., either by inhibiting their activity or
destroying them. Examples of antiseptics include silver
sulfadiazine, chlorhexidine, glutaraldehyde, peracetic acid, sodium
hypochlorite, phenols, phenolic compounds, iodophor compounds,
quaternary ammonium compounds, and chlorine compounds.
[0081] Antiviral agents are substances capable of destroying or
suppressing the replication of viruses. Examples of anti-viral
agents include .alpha.-methyl-1-adamantanemethylamine,
hydroxy-ethoxymethylguanine, adamantanamine,
5-iodo-2'-deoxyuridine, trifluorothymidine, interferon, and adenine
arabinoside.
[0082] Enzyme inhibitors are substances that inhibit an enzymatic
reaction. Examples of enzyme inhibitors include edrophonium
chloride, N-methylphysostigmine, neostigmine bromide, physostigmine
sulfate, tacrine HCL, tacrine, 1-hydroxy maleate, iodotubercidin,
p-bromotetramisole,
10-(.alpha.-diethylaminopropionyl)-phenothiazine hydrochloride,
calmidazolium chloride, hemicholinium-3,3,5-dinitrocatechol,
diacylglycerol kinase inhibitor I, diacylglycerol kinase inhibitor
II, 3-phenylpropargylaminie, N-monomethyl-L-arginine acetate,
carbidopa, 3-hydroxybenzylhydrazine HCl, hydralazine HCl,
clorgyline HCl, deprenyl HCl L(-), deprenyl HCl D(+), hydroxylamine
HCl, iproniazid phosphate, 6-MeO-tetrahydro-9H-pyrido-indole,
nialamide, pargyline HCl, quinacrine HCl, semicarbazide HCl,
tranylcypromine HCl, N,N-diethylaminoethyl-2,2-di-phenylvalerate
hydrochloride, 3-isobutyl-1-methylxanthne, papaverine HCl,
indomethacind, 2-cyclooctyl-2-hydroxyethylamine hydrochloride,
2,3-dichloro-.alpha.-methylbenzylamine (DCMB),
8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride,
p-aminoglutethimide, p-aminoglutethimide tartrate R(+),
p-aminoglutethimide tartrate S(-), 3-iodotyrosine,
alpha-methyltyrosine L(-), alpha-methyltyrosine D(-), cetazolamide,
dichlorphenamide, 6-hydroxy-2-benzothiazolesulfonamide, and
allopurinol.
[0083] Anti-pyretics are substances capable of relieving or
reducing fever. Anti-inflammatory agents are substances capable of
counteracting or suppressing inflammation. Examples of such agents
include aspirin (salicylic acid), indomethacin, sodium indomethacin
trihydrate, salicylamide, naproxen, coichicine, fenoprofen,
sulindac, diflunisal, diclofenac, indoprofen and sodium
salicylamide.
[0084] Local anesthetics are substances that have an anesthetic
effect in a localized region. Examples of such anesthetics include
procaine, lidocaine, tetracaine and dibucaine.
[0085] Imaging agents are agents capable of imaging a desired site,
e.g., tumor, in vivo. Examples of imaging agents include substances
having a label that is detectable in vivo, e.g., antibodies
attached to fluorescent labels. The term antibody includes whole
antibodies or fragments thereof.
[0086] Cell response modifiers are chemotactic factors such as
platelet-derived growth factor (PDGF). Other chemotactic factors
include neutrophil-activating protein, monocyte chemoattractant
protein, macrophage-inflammatory protein, SIS (small inducible
secreted), platelet factor, platelet basic protein, melanoma growth
stimulating activity, epidermal growth factor, transforming growth
factor alpha, fibroblast growth factor, platelet-derived
endothelial cell growth factor, insulin-like growth factor, nerve
growth factor, bone growth/cartilage-inducing factor (alpha and
beta), and matrix metalloproteinase inhibitors. Other cell response
modifiers are the interleukins, interleukin receptors, interleukin
inhibitors, interferons, including alpha, beta, and gamma;
hematopoietic factors, including erythropoietin, granulocyte colony
stimulating factor, macrophage colony stimulating factor and
granulocyte-macrophage colony stimulating factor; tumor necrosis
factors, including alpha and beta; transforming growth factors
(beta), including beta-1, beta-2, beta-3, inhibin, activin, and DNA
that encodes for the production of any of these proteins, antisense
molecules, androgenic receptor blockers and statin agents.
[0087] In an embodiment, the active agent used with the invention
includes compounds having a steroid ring system. Compounds having a
steroid ring system can be referred to as steroids. In an
embodiment, the active agent is a steroid. Steroids include both
naturally occurring compounds and synthetic analogues based on the
cyclopenta[a]phenanthrene carbon skeleton, partially or completely
hydrogenated. Steroids can include glucocorticoids, estrogens and
androgens. By way of example, steroids can include dexamethasone,
dexamethasone acetate, dexamethasone sodium phosphate, cortisone,
cortisone acetate, hydrocortisone, hydrocortisone acetate,
hydrocortisone cypionate, hydrocortisone sodium phosphate,
hydrocortisone sodium succinate, prednisone, prednisolone,
prednisolone acetate, prednisolone sodium phosphate, prednisolone
tebutate, prednisolone pivalate, triamcinolone, triamcinolone
acetonide, triamcinolone hexacetonide, triamcinolone diacetate,
methylprednisolone, methylprednisolone acetate, methylprednisolone
sodium succinate, flunsolide, beclomethasone dipropionate,
betamethasone sodium phosphate, betamethasone, vetamethasone
disodium phosphate, vetamethasone sodium phosphate, betamethasone
acetate, betamethasone disodium phosphate, chloroprednisone
acetate, corticosterone, desoxycorticosterone, desoxycorticosterone
acetate, desoxycorticosterone pivalate, desoximethasone, estradiol,
fludrocortisone, fludrocortisone acetate, dichlorisone acetate,
fluorohydrocortisone, fluorometholone, fluprednisolone,
paramethasone, paramethasone acetate, androsterone,
fluoxymesterone, aldosterone, methandrostenolone,
methylandrostenediol, methyl testosterone, norethandrolone,
testosterone, testosterone enanthate, testosterone propionate,
equilenin, equilin, estradiol benzoate, estradiol dipropionate,
estriol, estrone, estrone benzoate, acetoxypregnenolone, anagestone
acetate, chlormadinone acetate, flurogestone acetate,
hydroxymethylprogesterone, hydroxymethylprogesterone acetate,
hydroxyprogesterone, hydroxyprogesterone acetate,
hydroxyprogesterone caproate, melengestrol acetate,
normethisterone, pregnenolone, progesterone, ethynyl estradiol,
mestranol, dimethisterone, ethisterone, ethynodiol diacetate,
norethindrone, norethindrone acetate, norethisterone, fluocinolone
acetonide, flurandrenolone, hydrocortisone sodium succinate,
methylprednisolone sodium succinate, prednisolone phosphate sodium,
triamcinolone acetonide, hydroxydione sodium, spironolactone,
oxandrolone, oxymetholone, prometholone, testosterone cypionate,
testosterone phenylacetate, estradiol cypionate, and norethynodrel,
analogs thereof, or combinations thereof.
[0088] Active agents used with the invention can include
macromolecules, small molecules, hydrophilic molecules, hydrophobic
molecules, and the like. Macromolecular active agents used with
embodiments of the invention can include proteins, nucleic acids,
and polysaccharides. By way of example, proteins can include
glycosylated proteins, antibodies (both monoclonal and polyclonal),
antibody derivatives (including diabodies, f(ab) fragments,
humanized antibodies, etc.), cytokines, growth factors, receptor
ligands, enzymes, and the like. Nucleic acids can include RNA, DNA,
cDNA, and the like.
[0089] In an embodiment, macromolecular active agents used with the
invention have a molecular weight (or average molecular weight) of
greater than about 10 kD (1 kilodalton is equal to 1,000 atomic
mass units). In an embodiment, the macromolecular active agent
includes a protein of greater than about 10 kD. In an embodiment,
the macromolecular active agent includes a protein of greater than
about 100 kD.
[0090] In some embodiments, the active agent of the coating can
include agents that are small molecules. In some embodiments, the
active agent can include therapeutic agents that are hydrophilic
small molecules. In some embodiments, the active agent can include
therapeutic agents that are hydrophobic small molecules. As used
herein, small molecules can include those with a molecular weight
of equal to or less than 10 kilodaltons. In an embodiment, small
molecules have a molecular weight of less than about 5
kilodaltons.
[0091] By way of example, small molecule active agents can include
Trigonelline HCL, diclofenac, and chlorhexidine diacetate. Small
molecules can include many types of therapeutics including those as
described above with respect to macromolecules (e.g., thrombin
inhibitors, antithrombogenic agents, etc.).
[0092] The weight of the coating attributable to the active agent
can be in any range desired for a given active agent in a given
application. In some embodiments, weight of the coating
attributable to the active agent is in the range of about 1
microgram to about 10 milligrams of active agent per cm.sup.2of the
effective surface area of the device. By "effective" surface area
it is meant the surface amenable to being coated with the
composition itself. For a flat, nonporous, surface, for instance,
this will generally be the macroscopic surface area itself, while
for considerably more porous or convoluted (e.g., corrugated,
pleated, or fibrous) surfaces the effective surface area can be
significantly greater than the corresponding macroscopic surface
area. In an embodiment, the weight of the coating attributable to
the active agent is between about 0.01 mg and about 0.5 mg of
active agent per cm.sup.2 of the gross surface area of the device.
In an embodiment, the weight of the coating attributable to the
active agent is greater than about 0.01 mg.
[0093] In some embodiments, more than one active agent can be used
as a part of the coating material. Specifically, co-agents or
co-drugs can be used. A co-agent or co-drug can act differently
than the first agent or drug. The co-agent or co-drug can have an
elution profile that is different than the first agent or drug. In
some embodiments, accessory agents are included such as
chaperoning.
Devices
[0094] Embodiments of the invention can be used to coat many
different types of devices including medical devices. Medical
devices can include both implantable devices and non-implantable
medical devices.
[0095] Embodiments of the invention can be used with implantable,
or transitorily implantable, devices including, but not limited to,
vascular devices such as grafts (e.g., abdominal aortic aneurysm
grafts, etc.), stents (e.g., self-expanding stents typically made
from nitinol, balloon-expanded stents typically prepared from
stainless steel, degradable coronary stents, etc.), catheters
(including arterial, intravenous, blood pressure, stent graft,
etc.), valves (e.g., polymeric or carbon mechanical valves, tissue
valves, valve designs including percutaneous, sewing cuff, and the
like), embolic protection filters (including distal protection
devices), vena cava filters, aneurysm exclusion devices, artificial
hearts, cardiac jackets, and heart assist devices (including left
ventricle assist devices), implantable defibrillators,
electro-stimulation devices and leads (including pacemakers, lead
adapters and lead connectors), implanted medical device power
supplies (e.g., batteries, etc.), peripheral cardiovascular
devices, atrial septal defect closures, left atrial appendage
filters, valve annuloplasty devices (e.g., annuloplasty rings),
mitral valve repair devices, vascular intervention devices,
ventricular assist pumps, and vascular access devices (including
parenteral feeding catheters, vascular access ports, central venous
access catheters); surgical devices such as sutures of all types,
staples, anastomosis devices (including anastomotic closures),
suture anchors, hemostatic barriers, screws, plates, clips,
vascular implants, tissue scaffolds, cerebro-spinal fluid shunts,
shunts for hydrocephalus, drainage tubes, catheters including
thoracic cavity suction drainage catheters, abscess drainage
catheters, biliary drainage products, and implantable pumps;
orthopedic devices such as joint implants, acetabular cups,
patellar buttons, bone repair/augmentation devices, spinal devices
(e.g., vertebral disks and the like), bone pins, cartilage repair
devices, and artificial tendons; dental devices such as dental
implants and dental fracture repair devices; drug delivery devices
such as drug delivery pumps, implanted drug infusion tubes, drug
infusion catheters, and intravitreal drug delivery devices;
ophthalmic devices including orbital implants, glaucoma drain
shunts and intraocular lenses; urological devices such as penile
devices (e.g., impotence implants), sphincter, urethral, prostate,
and bladder devices (e.g., incontinence devices, benign prostate
hyperplasia management devices, prostate cancer implants, etc.),
urinary catheters including indwelling ("Foley") and non-indwelling
urinary catheters, and renal devices; synthetic prostheses such as
breast prostheses and artificial organs (e.g., pancreas, liver,
lungs, heart, etc.); respiratory devices including lung catheters;
neurological devices such as neurostimulators, neurological
catheters, neurovascular balloon catheters, neuro-aneurysm
treatment coils, and neuropatches; ear nose and throat devices such
as nasal buttons, nasal and airway splints, nasal tampons, ear
wicks, ear drainage tubes, tympanostomy vent tubes, otological
strips, laryngectomy tubes, esophageal tubes, esophageal stents,
laryngeal stents, salivary bypass tubes, and tracheostomy tubes;
biosensor devices including glucose sensors, cardiac sensors,
intra-arterial blood gas sensors; oncological implants; and pain
management implants.
[0096] Classes of suitable non-implantable devices can include
dialysis devices and associated tubing, catheters, membranes, and
grafts; autotransfusion devices; vascular and surgical devices
including atherectomy catheters, angiographic catheters,
intraaortic balloon pumps, intracardiac suction devices, blood
pumps, blood oxygenator devices (including tubing and membranes),
blood filters, blood temperature monitors, hemoperfusion units,
plasmapheresis units, transition sheaths, dialators, intrauterine
pressure devices, clot extraction catheters, percutaneous
transluminal angioplasty catheters, electrophysiology catheters,
breathing circuit connectors, stylets (vascular and non-vascular),
coronary guide wires, peripheral guide wires; dialators (e.g.,
urinary, etc.); surgical instruments (e.g. scalpels and the like);
endoscopic devices (such as endoscopic surgical tissue extractors,
esophageal stethoscopes); and general medical and medically related
devices including blood storage bags, umbilical tape, membranes,
gloves, surgical drapes, wound dressings, wound management devices,
needles, percutaneous closure devices, transducer protectors,
pessary, uterine bleeding patches, PAP brushes, clamps (including
bulldog clamps), cannulae, cell culture devices, materials for in
vitro diagnostics, chromatographic support materials, infection
control devices, colostomy bag attachment devices, birth control
devices; disposable temperature probes; and pledgets.
[0097] In some aspects, embodiments of the invention can be
utilized in connection with ophthalmic devices. Suitable ophthalmic
devices in accordance with these aspects can provide bioactive
agent to any desired area of the eye. In some aspects, the devices
can be utilized to deliver bioactive agent to an anterior segment
of the eye (in front of the lens), and/or a posterior segment of
the eye (behind the lens). Suitable ophthalmic devices can also be
utilized to provide bioactive agent to tissues in proximity to the
eye, when desired.
[0098] In some aspects, embodiments of the invention can be
utilized in connection with ophthalmic devices configured for
placement at an external or internal site of the eye. Suitable
external devices can be configured for topical administration of
bioactive agent. Such external devices can reside on an external
surface of the eye, such as the cornea (for example, contact
lenses) or bulbar conjunctiva. In some embodiments, suitable
external devices can reside in proximity to an external surface of
the eye.
[0099] Devices configured for placement at an internal site of the
eye can reside within any desired area of the eye. In some aspects,
the ophthalmic devices can be configured for placement at an
intraocular site, such as the vitreous. Illustrative intraocular
devices include, but are not limited to, those described in U.S.
Pat. Nos. 6,719,750 B2 ("Devices for Intraocular Drug Delivery,"
Varner et al.) and 5,466,233 ("Tack for Intraocular Drug Delivery
and Method for Inserting and Removing Same," Weiner et al.); U.S.
Publication Nos. 2005/0019371 A1 ("Controlled Release Bioactive
Agent Delivery Device," Anderson et al.), 2004/0133155 A1 ("Devices
for Intraocular Drug Delivery," Varner et al.), 2005/0059956 A1
("Devices for Intraocular Drug Delivery," Varner et al.), and
2003/0014036 A1 ("Reservoir Device for Intraocular Drug Delivery,"
Varner et al.); and U.S. application Ser. Nos. 11/204,195 (filed
Aug. 15, 2005, Anderson et al.), 11/204,271 (filed Aug. 15, 2005,
Anderson et al.), 11/203,981 (filed Aug. 15, 2005, Anderson et
al.), 11/203,879 (filed Aug. 15, 2005, Anderson et al.), 11/203,931
(filed Aug. 15, 2005, Anderson et al.); and related
applications.
[0100] In some aspects, the ophthalmic devices can be configured
for placement at a subretinal area within the eye. Illustrative
ophthalmic devices for subretinal application include, but are not
limited to, those described in U.S. Patent Publication No.
2005/0143363 ("Method for Subretinal Administration of Therapeutics
Including Steroids; Method for Localizing Pharmacodynamic Action at
the Choroid and the Retina; and Related Methods for Treatment
and/or Prevention of Retinal Diseases," de Juan et al.); U.S.
spplication Ser. No. 11/175,850 ("Methods and Devices for the
Treatment of Ocular Conditions," de Juan et al.); and related
applications.
[0101] Suitable ophthalmic devices can be configured for placement
within any desired tissues of the eye. For example, ophthalmic
devices can be configured for placement at a subconjunctival area
of the eye, such as devices positioned extrasclerally but under the
conjunctiva, such as glaucoma drainage devices and the like.
[0102] The present invention may be better understood with
reference to the following examples. These examples are intended to
be representative of specific embodiments of the invention, and are
not intended as limiting the scope of the invention.
EXAMPLES
Example 1
Preparation of Coating Solutions Saturated/Unsaturated
[0103] Coating solutions were prepared with various concentrations
of drug, polymers, and solvents. Specifically, five different
coating solutions were prepared as follows (the coating solutions
are summarized in Table 1 below):
[0104] Solution 1: Estradiol was combined with THF
(tetrahydrofuran) to form an active agent solution. PEVA
(polyethylene-co-vinyl acetate, 33% vinyl acetate) and PBMA
(poly-n-butyl methacrylate) were combined with toluene to form a
polymer solution. The active agent solution and the toluene
solution were combined to form a coating solution having 40 mg/ml
total solids including 30 wt. % estradiol, 20 wt. % PEVA, and 50
wt. % PBMA in a solvent of 80% toluene and 20% THF (four parts
toluene to one part THF). The coating solution was allowed to stand
for a period of minutes at ambient temperature and was observed to
be clear, indicating that the estradiol was at a soluble
concentration for this solvent composition.
[0105] Solution 2: Estradiol was combined with THF
(tetrahydrofuran) to form an active agent solution. PEVA
(polyethylene-co-vinyl acetate, 33% vinyl acetate) and PBMA
(poly-n-butyl methacrylate) were combined with toluene to form a
polymer solution. The active agent solution and the toluene
solution were combined to form a coating solution having 40 mg/ml
total solids including 30 wt. % estradiol, 20 wt. % PEVA, and 50
wt. % PBMA in a solvent of 85% toluene and 15% THF. The coating
solution was allowed to stand for a period of minutes at ambient
temperature and crystal formation was observed, indicating that the
estradiol was at a concentration exceeding solubility limits for
this solvent composition.
[0106] Solution 3: Estradiol was combined with THF
(tetrahydrofuran) to form an active agent solution. PEVA
(polyethylene-co-vinyl acetate, 33% vinyl acetate) and PBMA
(poly-n-butyl methacrylate) were combined with toluene to form a
polymer solution. The active agent solution and the toluene
solution were combined to form a coating solution having 40 mg/ml
total solids including 40 wt. % estradiol, 20 wt. % PEVA, and 40
wt. % PBMA in a solvent of 80% toluene and 20% THF. The coating
solution was allowed to stand for a period of minutes at ambient
temperature and crystal formation was observed, indicating that the
estradiol was at a concentration exceeding solubility limits for
this solvent composition.
[0107] Solution 4: Estradiol was combined with THF
(tetrahydrofuran) to form an active agent solution. PEVA
(polyethylene-co-vinyl acetate, 33% vinyl acetate) and PBMA
(poly-n-butyl methacrylate) were combined with toluene to form a
polymer solution. The active agent solution and the polymer
solution were combined to form a coating solution having 40 mg/ml
total solids including 35 wt. % estradiol, 20 wt. % PEVA, and 45
wt. % PBMA in a solvent of 80% toluene and 20% THF. The coating
solution was allowed to stand for a period of minutes at ambient
temperature and crystal formation was observed, indicating that the
estradiol was at a concentration exceeding solubility limits for
this solvent composition.
[0108] Solution 5: Estradiol was combined with THF
(tetrahydrofuran) to form an active agent solution. PEVA
(polyethylene-co-vinyl acetate, 33% vinyl acetate) and PBMA
(poly-n-butyl methacrylate) were combined with toluene to form a
polymer solution. The active agent solution and the toluene
solution were combined to form a coating solution having 40 mg/ml
total solids including 32.5 wt. % estradiol, 20 wt. % PEVA, and
47.5 wt. % PBMA in a solvent of 80% toluene and 20% THF. The
coating solution was allowed to stand for a period of minutes at
ambient temperature and the start of a small amount of crystal
formation was observed, indicating that the estradiol was at a
concentration slightly exceeding solubility limits for this solvent
composition. TABLE-US-00001 TABLE 1 Solids (40 mg/ml) Estradiol
PEVA PBMA Solvent Solution (wt. %) (wt. %) (wt. %) toluene THF
Result 1 30.0 20.0 50.0 80 20 no crystals 2 30.0 20.0 50.0 85 15
many crystals 3 40.0 20.0 40.0 80 20 many crystals 4 35.0 20.0 45.0
80 20 many crystals 5 32.5 20.0 47.5 80 20 some crystals
[0109] This example demonstrates that at a total solids
concentration of 40 mg/ml the solubility limit of estradiol is
somewhere between 30.0 wt. % and 32.5 wt. % at ambient temperature
(approximately 21-22.degree. C.) for a solvent including 80%
toluene and 20% THF. This is equivalent to a solubility limit of
between about 12 mg/ml and about 13 mg/ml of estradiol in a solvent
including 80% toluene and 20% THF in the presence of PEVA and
PBMA.
Example 2
Non-Saturated Coating Composition with THF/IPA Solvent
[0110] Estradiol, polyethylene-co-vinyl acetate (PEVA) (33% vinyl
acetate), and poly-n-butyl methacrylate (PBMA) were combined in
equal weight proportions in a solution that was 90% tetrahydrofuran
(THF) and 10% isopropyl alcohol (IPA). The resulting solution had a
total solids concentration of 40 mg/ml (33% PEVA/33% PBMA/33%
estradiol). The resulting solution was below the saturation point
for estradiol in a solvent of 90% THF/10% IPA at ambient
temperature (approximately 21-22.degree. C.).
[0111] A stainless steel stent 18 mm in length was obtained and
prepared by first applying a layer of parylene C using a
vapor-deposition technique. After the parylene was disposed onto
the stent, the coating solution was applied to the stent using an
ultrasonic spray technique at a relative humidity of 10%.
Ultrasonic spray techniques are disclosed in U.S. Published
Application 2004/0062875 (Chappa et al.) the contents of which are
herein incorporated by reference. A total coating weight of 657
.mu.g was applied to the stent (measured after the solvent had
substantially evaporated off) resulting in a drug loading of
approximately 217 .mu.g of estradiol.
[0112] On day 0 (the day the coating was applied), optical
microscopy was used with polarized light to evaluate the surface of
the stent. The polarized light image shows the formation of
crystals of active agent not just at the surface of the coating but
throughout the coating thickness. FIG. 1 shows the coating at Day
0. It was estimated that approximately 50% of the coating contained
active agent crystals. On day 4, optical microscopy was again used
with polarized light to evaluate the coating. FIG. 2 shows the
stent surface at Day 4. It was estimated that approximately 95% of
coating contained active agent crystals.
[0113] After 7 days, the surface of the stent was examined using
scanning electron microscopy (SEM) at various magnifications. A
7500.times. view is shown in FIG. 3. SEM analysis revealed that
there were significant quantities of active agent crystals coming
out of the surface of the coating.
[0114] This example shows that when a coating solution is applied
wherein the concentration of the active agent is below the
saturation point, the crystallization process may take place over
an extended period of time.
Example 3
Non-Saturated Coating Composition with Chloroform/Methanol
Solvent
[0115] Estradiol, polyethylene-co-vinyl acetate (PEVA) (33% vinyl
acetate), and poly-n-butyl methacrylate (PBMA) were combined in
equal weight proportions in a solution that was 80% chloroform and
20% methanol. The resulting solution had a total solids
concentration of 40 mg/ml (33% PEVA/33% PBMA/33% estradiol). The
resulting solution was below the saturation point for estradiol in
a solvent of 80% chloroform/20% methanol at ambient temperature
(approximately 21-22.degree. C.).
[0116] A stainless steel stent 18 mm in length was obtained and
prepared by first applying a layer of parylene C using a
vapor-deposition technique. After the parylene was disposed onto
the stent, the coating solution was applied to the stent using an
ultrasonic spray technique. A total coating weight of 683 .mu.g was
applied to the stent (measured after the solvent had substantially
evaporated off) resulting in a drug loading of approximately 225
.mu.g of estradiol.
[0117] After 8 days, the surface of the stent was examined using
scanning electron microscopy (SEM) at various magnifications. A
7500.times. view is shown in FIG. 4. SEM analysis revealed that
there were significant quantities of crystals coming out of the
surface of the coating.
Example 4
Saturated Coating Composition with Toluene/THF/Isopropyl Alcohol
Solvent
[0118] Estradiol was combined with THF. Polyethylenevinylacetate
(PEVA), and poly-n-butyl methacrylate (PBMA) was combined with a
solution containing eight parts toluene and one part isopropyl
alcohol. The estradiol solution was combined with the PEVA/PBMA
solution to form a coating solution containing equal weight
proportions of estradiol, PEVA, and PBMA and a solvent containing
80% toluene, 10% THF, and 10% isopropyl alcohol, with a total
solids concentration of 40 mg/ml (33% PEVA/33% PBMA/33% estradiol).
The resulting solution was approximately at the saturation point
for estradiol in a solvent of 80% toluene, 10% THF, and 10%
isopropyl alcohol at ambient temperature (approximately
21-22.degree. C.).
[0119] Two stainless steel stents (A and B) 18 mm in length were
obtained and prepared by first applying a layer of parylene C using
a vapor-deposition technique. After the parylene was disposed onto
the stents, the coating solution was applied to the stent using an
ultrasonic spray technique at a relative humidity of 10%. A total
coating weight of 688 .mu.g was applied to stent A (measured after
the solvent had substantially evaporated off) resulting in a drug
loading of approximately 227 .mu.g of estradiol. A total coating
weight of 659 .mu.g was applied to stent B (measured after the
solvent had substantially evaporated off) resulting in a drug
loading of approximately 217 .mu.g of estradiol.
[0120] After the coating process was completed, stent B was
evaluated for crystal formation using darkfield microscopy.
Darkfield microscopy shows the formation of crystals not just at
the surface of the coating but throughout the coating thickness.
FIG. 5 shows a darkfield image of the coating on stent B. This
darkfield image shows active agent crystals over substantially 100%
of the coating (within the coating). In contrast to FIG. 1 in
example 2 above, this example demonstrates that rapid
crystallization occurs when using a saturated coating solution.
[0121] After 7 days, the surface of stent A was examined using
scanning electron microscopy (SEM) at various magnifications. A
7500.times. view is shown in FIG. 6. SEM analysis revealed that
there was crystal formation but that these crystals did not come
out of, or erupt, through the surface of the coating.
[0122] This example shows that applying a coating solution that was
saturated with the active agent reduced the amount of crystals that
erupted through the surface of the coating.
Example 5
Saturated Coating Composition with Toluene/THF Solvent
[0123] Estradiol was combined with THF. Two parts by weight of
polyethylenevinylacetate (PEVA) was combined with five parts by
weight of poly-n-butyl methacrylate (PBMA) in toluene. The
estradiol solution was combined with the PEVA/PBMA solution to form
a coating solution containing 40 mg/ml total solids (30 wt. %
estradiol, 20 wt. % PEVA, and 50 wt. % PBMA) and a solvent
containing 80% toluene and 20% THF. The resulting solution was near
the saturation point for estradiol in a solvent of 80% toluene and
20% THF at ambient temperature (approximately 21-22.degree.
C.).
[0124] A stainless steel stent 28 mm in length was obtained and
prepared by first applying a layer of parylene C using a
vapor-deposition technique. After the parylene was disposed onto
the stent, the coating solution was applied to the stent using an
ultrasonic spray technique at a relative humidity of 30%. A total
coating weight of 2015 .mu.g was applied to the stent (measured
after the solvent had substantially evaporated off) resulting in a
drug loading of approximately 605 .mu.g of estradiol.
[0125] After 7 days, the surface of the stent was examined using
scanning electron microscopy (SEM) at various magnifications. FIG.
7 shows the surface of the coating at 500.times. magnification. SEM
analysis revealed that the surface was somewhat bumpy but that
there were substantially no crystals coming out of, or erupting
through, the surface of the coating.
[0126] This example shows that applying a coating solution that is
saturated with the active agent (or near saturation) can reduce the
amount of crystals that erupt through the surface of the
coating.
Example 6
Unsaturated Coating Composition with Toluene/THF Solvent
[0127] Estradiol was combined with THF. Two parts by weight of
polyethylenevinylacetate (PEVA) was combined with five parts by
weight of poly-n-butyl methacrylate (PBMA) in toluene. The
estradiol solution was combined with the PEVA/PBMA solution to form
a coating solution containing 30 mg/ml total solids (30 wt. %
estradiol, 20 wt. % PEVA, and 50 wt. % PBMA) and a solvent
containing 80% toluene and 20% THF. The resulting solution had an
estradiol concentration that was less than the saturation point for
a solvent of 80% toluene and 20% THF at ambient temperature
(approximately 21-22.degree. C.). The distinction between this
example and example 4 is that here the total solids concentration
was only 30 mg/ml instead of 40 mg/ml. Thus the concentration of
estradiol was at less than the saturation point.
[0128] A stainless steel stent 28 mm in length was obtained and
prepared by first applying a layer of parylene C using a
vapor-deposition technique. After the parylene was disposed onto
the stent, the coating solution was applied to the stent using an
ultrasonic spray technique at a relative humidity of 30%. A total
coating weight of 1000 .mu.g was applied to the stent (measured
after the solvent had substantially evaporated off) resulting in a
drug loading of approximately 300 .mu.g of estradiol. The coating
was evaluated under a microscope at 50.times. magnification (not
shown). The coating had a patchy appearance and the formation of
large crystals was observed. This coating had an appearance similar
to that which could be observed with other non-saturated solutions
such as in Examples 2 and 3 above.
[0129] This example shows that when a coating solution is applied
wherein the concentration of the active agent is below the
saturation point, the crystallization process may result in the
formation of large crystals.
Example 7
Non-Saturated Coating Composition with THF Solvent and Topcoat
[0130] Estradiol, polyethylenevinylacetate (PEVA), and poly-n-butyl
methacrylate (PBMA) were combined in THF to result in weight
proportions of 30% estradiol, 20% PEVA, and 50% PBMA for a total
solids concentration of 40 mg/ml. The resulting solution had a
estradiol concentration that was less than the saturation point for
a solvent of 100% THF at ambient temperature (approximately
21-22.degree. C.).
[0131] A stainless steel stent 9 mm in length was obtained and
prepared by first applying a layer of parylene C using a
vapor-deposition technique. After the parylene was disposed onto
the stent, the coating solution was applied to the stent using an
ultrasonic spray technique at a relative humidity of 30%. A total
coating weight of 615 .mu.g was applied to the stent (measured
after the solvent had substantially evaporated off) resulting in a
drug loading of approximately 185 .mu.g of estradiol.
[0132] Next, a topcoat solution was formed by mixing PBMA with THF
to form a solution with a total solids concentration of 10 mg/ml.
The topcoat solution was applied to the stent using an ultrasonic
spray technique at a relative humidity of 30%, resulting in a
topcoat weight of 107 .mu.g (measured after the solvent had
substantially evaporated off).
[0133] After 7 days, the surface of the stent was examined using
scanning electron microscopy (SEM) at various magnifications. FIG.
8 shows a view of the topcoat surface at 1000.times. X
magnification. SEM analysis revealed that there were significant
amounts of crystals coming out of, or erupting through, the surface
of the topcoat.
[0134] This example shows that when a coating solution is applied
wherein the concentration of the active agent is below the
saturation point, even where a topcoat is added, the
crystallization process can result in crystals of the active agent
erupting through the coating surface.
Example 8
Saturated Coating Composition with Toluene/THF Solvent and
Topcoat
[0135] Estradiol was combined with THF. Two parts by weight of
polyethylenevinylacetate (PEVA) was combined with five parts by
weight of poly-n-butyl methacrylate (PBMA) in toluene. The
estradiol solution was combined with the PEVA/PBMA solution to form
a coating solution containing 40 mg/ml total solids (30 wt. %
estradiol, 20 wt. % PEVA, and 50 wt. % PBMA) and a solvent
containing 80% toluene and 20% THF. The resulting solution was
approximately at the saturation point for estradiol in a solvent of
80% toluene and 20% THF at ambient temperature (approximately
21-22.degree. C.).
[0136] A stainless steel stent 28 mm in length was obtained and
prepared by first applying a layer of parylene C using a
vapor-deposition technique. After the parylene was disposed onto
the stent, the coating solution was applied to the stent using an
ultrasonic spray technique at a relative humidity of 30%. A total
coating weight of 2094 .mu.g was applied to the stent (measured
after the solvent had substantially evaporated off) resulting in a
drug loading of approximately 629 .mu.g of estradiol.
[0137] Next, a topcoat solution was formed by mixing PBMA with
toluene to form a solution with a total solids concentration of 30
mg/ml. The topcoat solution was applied to the stent using an
ultrasonic spray technique at a relative humidity of 10%, resulting
in a topcoat weight of 297 .mu.g (measured after the solvent had
substantially evaporated off).
[0138] After 7 days, the surface of the stent was examined using
scanning electron microscopy (SEM) at various magnifications. FIG.
9 shows the surface of the topcoat at 1000.times. magnification.
SEM analysis revealed that there were substantially no crystals
coming out of, or erupting through, the surface of the coating.
[0139] This example shows that applying a coating solution that is
saturated with the active agent can reduce the amount of crystals
that erupt through the surface of the coating.
Example 9
Saturated versus Unsaturated Coating Compositions including
Dexamethasone
[0140] To form a saturated coating solution (solution one),
dexamethasone (DEX) was combined with polybutadiene (PBD) (MW 160
kD) and poly(n-butyl methacrylate) (pBMA) (MW 250 kD) in a solvent
mixture of 58% THF and 42% chloroform. The saturated coating
solution was made by adding 75 mg of pBMA and 75 mg of PBD to 5 ml
of chloroform on a stir-plate. To this solution, 150 mg of DEX was
added. THF was slowly added to the stirring mixture until the
resulting solution turned clear. A total of 7 ml of THF was added.
The resulting coating solution had a total solids content of 25
mg/ml including (50% DEX), (25% PBD), and (25% PBMA).
[0141] To form an unsaturated control coating solution (solution
two), DEX was combined with polybutadiene (PBD) (MW 160 kD) and
poly(n-butyl methacrylate) (PBMA) (MW 250 kD) in a solvent of 100%
tetrahydrofuran (THF). The resulting coating solution had a total
solids content of 25 mg/ml including (50% DEX), (25% PBD), and (25%
pBMA).
[0142] Four stainless steel stents (OrbusNeich, Netherlands) 18 mm
in length were obtained. Coating solution one was applied to two
stents (1 and 2) using an ultrasonic spray technique at a relative
humidity of 30%. Similarly, coating solution two was applied to two
stents (3 and 4) using an ultrasonic spray technique at a relative
humidity of 30%.
[0143] The surface of the stents was examined using polarized light
optical microscopy at days 0, 7, and 14. Polarized light microscopy
shows the amount of crystallization throughout the entire coating
thickness. FIG. 10, panels A, B, and C, show a representative
portion of stent 1 (saturated) at 100.times. magnification. FIG.
10, panel A, shows that on day 0, stent 1 was approximately 100%
crystallized. FIG. 10, panels B and C show that stent 1 remained
approximately 100% crystallized on days 7 and 14 respectively. FIG.
10, panels D, E, and F, show a representative portion of stent 3
(unsaturated) at 100.times. magnification. FIG. 10, panel D, shows
that on day 0, stent 3 was roughly 10% crystallized. FIG. 10,
panels E and F, show that the degree of crystallization on stent 3
increased over a period of two weeks but remained less than 50%
crystallized. A similar pattern was demonstrated when comparing the
crystallization trends of stents 2 (saturated) and 4
(unsaturated).
[0144] Portions stents 2 and 4 that had crystals were then
evaluated using polarized light optical microscopy at a higher
magnification (500.times.) to further characterize the differences
between the two. The results are shown in FIG. 11, panels A and B.
The crystals in panel A (formed from a saturated coating solution)
are clearly smaller than those shown in panel B (formed from an
unsaturated coating solution).
[0145] This example shows that saturated coating solutions can be
used to enhance the formation of active agent crystals in the
resulting coating. Specifically, this example shows that saturated
coating solutions can be used to accelerate the crystallization
process in elution control coatings. This example also shows that
the use of saturated coating solutions results in smaller more
uniform crystals than does the use of unsaturated coating
solutions.
[0146] It should be noted that, as used in this specification and
the appended claims, the singular forms "a," "an," and "the"
include plural referents unless the content clearly dictates
otherwise. Thus, for example, reference to a composition containing
"a compound" includes a mixture of two or more compounds. It should
also be noted that the term "or" is generally employed in its sense
including "and/or" unless the content clearly dictates
otherwise.
[0147] It should also be noted that, as used in this specification
and the appended claims, the phrase "configured" describes a
system, apparatus, or other structure that is constructed or
configured to perform a particular task or adopt a particular
configuration to. The phrase "configured" can be used
interchangeably with other similar phrases such as arranged and
configured, constructed and arranged, constructed, manufactured and
arranged, and the like.
[0148] All publications and patent applications in this
specification are indicative of the level of ordinary skill in the
art to which this invention pertains. All publications and patent
applications are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated by reference.
[0149] The invention has been described with reference to various
specific and preferred embodiments and techniques. However, it
should be understood that many variations and modifications may be
made while remaining within the spirit and scope of the
invention.
* * * * *