U.S. patent application number 10/302830 was filed with the patent office on 2003-04-24 for implantable or insertable therapeutic agent delivery device.
Invention is credited to Palasis, Maria.
Application Number | 20030077253 10/302830 |
Document ID | / |
Family ID | 24466709 |
Filed Date | 2003-04-24 |
United States Patent
Application |
20030077253 |
Kind Code |
A1 |
Palasis, Maria |
April 24, 2003 |
Implantable or insertable therapeutic agent delivery device
Abstract
Disclosed herein is an implantable or insertable therapeutic
agent delivery device comprising a coating material provided on at
least a portion of said device, said coating material prohibiting
substantial release therefrom of a therapeutic agent at or below
about a physiological pH and allowing substantial release therefrom
of a therapeutic agent at or above about said physiological pH.
Also disclosed herein are coating materials for the implantable or
insertable therapeutic agent delivery device. The coating materials
are preferably polymers derivatized to contain moieties that are
cationically charged at a pH below their pKa values and which thus
can attract negatively charged therapeutically agents at pH values
below their pKa values and which become predominantly uncharged at
pH values above about their pKa values and thus substantially
release the negatively charged therapeutic agents at such pH
values, which are preferably about physiological pH. Also disclosed
are methods of derivatizing a polymer to contain such moieties and
methods of providing a coating of the derivatized polymer onto at
least a portion of a surface of an implantable or insertable
therapeutic agent delivery device.
Inventors: |
Palasis, Maria; (Wellesley,
MA) |
Correspondence
Address: |
KENYON & KENYON
1500 K STREET, N.W., SUITE 700
WASHINGTON
DC
20005
US
|
Family ID: |
24466709 |
Appl. No.: |
10/302830 |
Filed: |
November 25, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10302830 |
Nov 25, 2002 |
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09615764 |
Jul 13, 2000 |
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6506408 |
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Current U.S.
Class: |
424/93.2 ;
514/16.4; 514/44R; 604/890.1 |
Current CPC
Class: |
A61L 31/145 20130101;
A61K 9/0024 20130101; A61L 29/145 20130101; A61L 2300/602 20130101;
A61P 9/10 20180101; A61P 9/00 20180101; A61L 31/16 20130101; A61L
2300/606 20130101; A61L 29/16 20130101 |
Class at
Publication: |
424/93.2 ; 514/2;
514/44; 604/890.1 |
International
Class: |
A61K 048/00; A61K
038/16; A61K 009/22 |
Claims
We claim:
1. An implantable or insertable therapeutic agent delivery device
comprising a coating material provided on at least a portion of
said device, said coating material prohibiting substantial release
therefrom of a therapeutic agent at or below about a physiological
pH and allowing substantial release therefrom of a therapeutic
agent at or above about said physiological pH.
2. The device of claim 1 wherein said coating material further
comprises said therapeutic agent.
3. The device of claim 2 wherein said therapeutic agent is
negatively charged and said coating material comprises moieties
that carry a positive charge at a pH at or below about said
physiological pH and that are substantially uncharged at or above
about said physiological pH.
4. The device of claim 3 wherein said negatively charged
therapeutic agent is selected from the group consisting of DNA,
RNA, nucleotides, proteins, oligopeptides, viruses, nonviral
vectors, and drugs.
5. The device of claim 3 wherein said physiological pH is in the
range of from about 7.2 to about 7.6.
6. The device of claim 5 wherein said physiological pH is about the
pH of mammalian blood.
7. The device of claim 6 wherein said pH is about 7.4.
8. The device of claim 3 wherein said coating material comprises a
polymeric material.
9. The device of claim 8 wherein said polymeric material comprises
a hydrogel polymer.
10. The device of claim 9 wherein said hydrogel polymer comprises a
poly(acrylic acid) polymer.
11. The device of claim 10 wherein said moieties are provided by at
least one compound selected from the group consisting of aminoethyl
pyridine or aminopropyl imidazole.
12. The device of claim 1 which is a stent or balloon catheter.
13. A method of delivering a therapeutic agent to a mammal
comprising implanting or inserting the device of claim 1 into a
mammal.
14. A method of derivatizing a polymer comprising reacting, in the
presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide
hydrochloride, carboxyl groups in said polymer with a compound
containing a moiety that carries a positive charge at or below
about a physiological pH and that is substantially uncharged above
about said physiological pH.
15. The method of claim 14 wherein said physiological pH is in the
range of from about 7.2 to about 7.6.
16. The method of claim 15 wherein said physiological pH is about
the pH of mammalian blood.
17. The method of claim 16 wherein said pH is about 7.4.
18. The method of claim 13 wherein said compound has a pKa less
than about a physiological pH.
19. The method of claim 14 wherein said compound bears an amino
group.
20. The method of claim 19 wherein said compound is selected from
the group consisting of aminoethyl pyridine or aminopropyl
imidazole.
21. A polymer made by the method of claim 14.
22. A method of coating at least a portion of an implantable or
insertable medical device comprising contacting said medical device
with a coating material that prohibits substantial release
therefrom of a therapeutic agent at or below about a physiological
pH and allows substantial release therefrom of a therapeutic agent
at or above about said physiological pH.
23. The method of claim 22 wherein said medical device is contacted
with said coating material by a method selected from the group
consisting of dipping said device into or spraying onto said device
a solution or suspension of said coating material.
24. A method of coating at least a portion of an implantable or
insertable medical device comprising contacting said medical device
with a polymer and subsequently reacting, in the presence of
1-ethyl-3-(3-dimethylaminop- ropyl)-carbodiimide hydrochloride,
carboxyl groups in said polymer with a compound containing a moiety
that carries a positive charge at or below about a physiological pH
and that is substantially uncharged at or above about said
physiological pH, thereby forming a coating on at least a portion
of the implantable or insertable medical device which prohibits
substantial release therefrom of a therapeutic agent at or below
about a physiological pH and which allows substantial release
therefrom of a therapeutic agent at or above about said
physiological pH.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to an apparatus and a method
for localized delivery of therapeutic agents, and more
particularly, to an implantable or insertable medical device having
a coating, on at least a portion of a surface of the device, of a
pH-sensitive polymer that allows release therefrom of a negatively
charged therapeutic agent when contacted with a fluid at or above
about a physiological pH.
BACKGROUND OF THE INVENTION
[0002] The systemic administration of drug agents, such as by
transdermal or intravenous means, treats the body as a whole even
though the disease to be treated may be localized. In such a case,
systemic administration may not be desirable because the drug
agents often have unwanted effects on parts of the body that are
not intended to be treated, or because treatment of the diseased
part of the body requires a high concentration of drug agent that
may not be achievable by systemic administration. For example, when
administered to a patient systemically, some drugs (e.g.,
chemotherapeutic drugs such as those used to treat cancer and other
proliferative disorders) may cause undesirable side effects.
[0003] It is therefore often desirable to administer drug agents at
a localized site within the body. Localized drug delivery is often
desirable for the treatment of heart disease by delivery of a
therapeutic agent to an occluded or stenosed vascular lumen as well
as to deliver therapeutic agents to other target sites in the body
including other occluded or stenosed body lumens.
[0004] Various methods have been proposed for such localized drug
administration. For example, U.S. Pat. No. 5,304,121, which is
incorporated herein by reference, discloses a method of delivering
water-soluble drugs to tissue at a desired location of a body lumen
wall. The method includes the steps of impregnating a hydrogel
polymer provided as a coating on a balloon catheter or other
implantable or insertable medical device with an aqueous drug
solution, inserting the catheter into a blood vessel at a desired
location, and expanding the balloon portion of the catheter against
the surrounding tissue to allow the release of the drug from the
hydrogel polymer coating. The drug is preferably released from the
hydrogel polymer coating upon compression thereof against the body
lumen wall. This method of drug delivery is convenient, but is
limited by the fact that many drugs either release from the
hydrogel before reaching the target site or are not released
effectively when the target site is reached.
[0005] There remains a need for effective localized delivery of
therapeutic agents. In particular, there exists a need for
localized delivery of negatively charged therapeutic agents such as
nucleic acid, for example. Nucleic acids are often difficult to
remove when immobilized in a conventional polymer coating
containing fixed positively charged moieties, i.e., moieties whose
charge does not substantially depend on the ambient pH conditions.
Thus, there is a need for a method for obtaining the release of
therapeutic agents from a medical device at a target site within
the body, particularly for the release of therapeutic agents from a
medical device provided with a coating on at least a portion of a
surface thereof which coating also contains therein or thereon a
therapeutic agent, preferably a negatively charged therapeutic
agent.
SUMMARY OF THE INVENTION
[0006] In one aspect, the present invention is directed to an
implantable or insertable therapeutic agent delivery device
comprising a coating material provided on at least a portion of a
surface of the device, the coating material prohibiting substantial
release therefrom of a therapeutic agent at or below about a
physiological pH and allowing substantial release therefrom of a
therapeutic agent at or above about physiological pH. In a
preferred embodiment of the present invention, the coating material
further comprises the therapeutic agent. Preferably, the
therapeutic agent is negatively charged and the coating material
comprises moieties that carry a positive charge at a pH at or below
about physiological pH and are substantially uncharged at or above
about physiological pH. Thus, the coating materials of the present
invention are provided with moieties whose charge depends on pH,
rather than being substantially fixed, i.e., substantially
unaffected by varying pH conditions, such as occurs by known
methods of derivatization of coating materials. Preferably, the
moieties have a pKa less than about physiological pH. In a
preferred embodiment, the polymeric material comprises a polymer
which is preferably a poly(acrylic acid) polymer. In a particularly
preferred embodiment, the poly(acrylic acid) polymer is a hydrogel
polymer. In another preferred embodiment, moieties whose charge
depends on pH as described herein are provided by compounds
selected from the group consisting of aminoethyl pyridine or
aminopropyl imidazole, each of which contains a moiety having a pKa
less than about 7.4. In a preferred embodiment, the polymer is
derivatized with at least one of these preferred compounds to
result in a derivatized polymer containing moieties whose charge
depends on pH as disclosed herein.
[0007] In another aspect, the present invention is directed to a
method for delivering a therapeutic agent to a mammal by implanting
or inserting into a mammal an implantable or insertable medical
device according to the present invention.
[0008] In another aspect, the present invention is directed to a
method of derivatizing a polymer by reacting, in the presence of
l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride or
dicyclohexylcarbodiimide, carboxyl groups in the polymer with a
compound containing a moiety that has a positive charge at or below
about physiological pH and that is substantially uncharged at or
above about physiological pH. Preferably, the moiety in the
compound reacted with the polymer has a pKa less than physiological
pH of about than 7.4. The preferred compounds containing a moiety
that has a pKa less than a physiological pH of about 7.4 are basic
compounds of which aminoethyl pyridine and aminopropyl imidazole
are most preferred.
[0009] In yet another aspect, the present invention is directed to
a polymer made by the method described above.
[0010] In another aspect, the present invention is directed to a
method of coating at least a portion of the surface of an
implantable or insertable medical device comprising contacting the
medical device with a coating material that prohibits substantial
release therefrom of a therapeutic agent at or below about
physiological pH and allows substantial release therefrom of a
therapeutic agent at or above about physiological pH. In preferred
embodiments, the medical device is contacted with the coating
material by dipping the implantable or insertable medical device
into a solution or suspension of the coating material, or by
spraying a solution or suspension of the coating material onto at
least a portion of the implantable or insertable medical
device.
[0011] In yet another aspect, the present invention is directed to
a method of coating at least a portion of an implantable or
insertable medical device comprising contacting the medical device
with a polymer and subsequently reacting, in the presence of
1-ethyl-3-(3-dimethylaminop- ropyl)-carbodiimide hydrochloride or
dicyclohexylcarbodiimide, carboxyl groups in the polymer with a
compound that contains a moiety that is positively charged at or
below about physiological pH and that is substantially uncharged at
or above about physiological pH, thereby forming a coating on at
least a portion of the implantable or insertable medical device
which prohibits substantial release therefrom of a therapeutic
agent at or below about physiological pH and which allows
substantial release therefrom of a therapeutic agent at or above
about physiological pH.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The various features of the invention will best be
appreciated by simultaneous reference to the description that
follows and the accompanying drawings, in which:
[0013] FIG. 1 shows the release in phosphate-buffered saline (PBS),
pH 7.4, of methyl orange from balloon catheters provided with a
coating of a hydrogel acrylic acid polymer derivatized with
aminopropyl imidazole or aminoethyl pyridine in accordance with
preferred embodiments of the present invention.
[0014] FIG. 2 shows the release in PBS, pH 7.4, of plasmid DNA from
balloon catheters provided with a coating of a hydrogel acrylic
acid polymer derivatized with aminopropyl imidazole or aminoethyl
pyridine in accordance with preferred embodiments of the present
invention.
DEFINITIONS
[0015] An "implantable or insertable therapeutic agent delivery
device" is any device which can be implanted and/or inserted into a
mammalian body and which can also be adapted to provide localized
delivery of a therapeutic agent. Such implantable or insertable
therapeutic agent delivery devices that are within the scope of the
present invention include, but are not limited to, stents of
various types such as, for example, self-expandable and
balloon-expandable vascular stents, stent grafts, biliary stents,
colonic stents, bronchial/pulmonary stents, esophageal stents, and
ureteral stents; catheters, including catheters having an
expandable balloon portion, such as, for example, perfusion balloon
catheters and needle injection catheters; filters such as blood
clot filters; grafts such as vascular grafts and stent grafts;
aneurysm filling coils and other coiled devices; transmyocardial
revascularization ("TMR") devices; percutaneous myocardial
revascularization ("PMR") devices, etc., as are known in the art;
and devices such as hypodermic needles, soft tissue clips, holding
devices, muscle implants such as spikes and plugs, as well as other
types of medically useful needles. Such devices are generally
constructed of biostable and biocompatible materials such as coated
and non-coated metals, metal alloys, polymeric materials, ceramic
materials and combinations of such materials. The devices are
generally delivered to the target location within the body by known
techniques. Delivery is optionally performed with a sheath covering
the implantable or insertable medical device to protect premature
release of the therapeutic agent provided on or within the coating
material as described, prior to the device reaching the target
location within the body.
[0016] "Drug" and "therapeutic agent" are used interchangeably and
refer to any substance used in the prevention, diagnosis,
alleviation, mitigation, treatment or cure of any disease.
[0017] "Negatively charged therapeutic agent" refers to any drug or
therapeutic agent that carries a negative charge.
[0018] "Physiological pH" refers to a normal pH of a physiological
fluid in an animal, which is preferably a mammal such as a human.
Physiological pH of a human is generally in the range of from about
pH 7.2 to about 7.6.
[0019] "pKa" is defined as -log Ka; where Ka is the equilibrium
constant for the dissociation of an acid to the hydronium ion
(H.sub.3O.sup.+) and the counteranion of the acid.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The coating material used in the present invention prohibits
substantial release therefrom of a therapeutic agent at or below
about a physiological pH and allows substantial release of the
therapeutic agent at or above about physiological pH. Preferably,
the coating material is a polymeric material, more preferably a
hydrogel polymeric material. Even more preferably, the polymeric
material is a polymer that has been derivatized with a compound
that contains basic moieties that are positively charged at or
below about physiological pH. The moieties are substantially
uncharged at or above about physiological pH. Preferably, these
moieties have a pKa that is less than a physiological pH of about
7.4. The preferred moieties are predominantly positively charged at
a pH below their pKa value. Thus, the derivatized polymer is able
to associate with a negatively charged therapeutic agent when
contacted with the therapeutic agent at a pH below the pKa of the
moieties, which is preferably less than about a physiological pH of
7.4. When the polymer containing such moieties is contacted with a
physiological fluid such as blood having a pH greater than the pKa
of the moieties, i.e., a pH preferably greater than about 7.4, the
moieties begin to lose their positive charge. Thus, when contacted
with a physiological fluid having a pH greater than the pKa of the
moieties, the negatively charged therapeutic agent, such as nucleic
acid, which is preferably associated with the moieties on the
polymer through ionic binding, tends to be substantially released
from the polymer coating. The negatively charged therapeutic agent
tends to remain substantially unreleased from the derivatized
polymer coating until contacted with a fluid or other substance,
preferably a physiological fluid having a pH greater than the pKa
of the moieties as described above. By "substantially released" or
"substantially unreleased" is meant that at least about 50-60%,
preferably about 70-80%, more preferably about 80-90%, and, most
preferably, about 90-100% of the therapeutic agent is released or
unreleased from its association with the coating material. Thus, at
pH below physiological pH, the derivatized polymer coating contains
positively charged moieties that attract and bind to the negatively
charged therapeutic agent by ionic bonding. When the derivatized
polymer of the invention is contacted with a physiological fluid or
substance, such as blood or tissue, for example, which has a pH of
about 7.4, the positively charged moieties lose their positive
charge and no longer attract the negatively charged therapeutic
agents. As a result, the negatively charged therapeutic agent is
substantially released from the polymer at a desired location
within the body. Since the positive charge on the moieties in the
coating materials of the present invention is dependent on pH, the
coating materials are able to effectively release therefrom a
negatively charged therapeutic agent when the pH conditions to
which the coating materials are exposed are such that the
positively charged moieties become substantially uncharged.
[0021] One type of polymer that is useful in the present invention
is an acrylic acid polymer. Such acrylic acid polymers that can be
derivatized in accordance with the present invention are disclosed,
e.g., in U.S. Pat. No. 5,091,205, which is incorporated herein in
its entirety. However, it is to be understood that any acrylic acid
polymer and, indeed, any of the poly(carboxylic acid) homopolymers
and copolymers disclosed in U.S. Pat. No. 5,091,205 can be
derivatized in the manner that is discussed in more detail below.
Such acrylic acid polymers and other derivatizable polymers and
sources thereof are well known to the ordinarily skilled artisan.
Indeed, any polymeric or other material that contains moieties that
are predominantly positively charged (i.e. about 50% or greater of
the moieties are positively charged) at or below about their pKa
values, which is preferably less than a physiological pH, and which
are substantially uncharged at or above about a physiological pH,
can be used to carry the negatively charged therapeutic agents in
accordance with the present invention. Thus, any polymeric material
which is biocompatible with the animal into which the implantable
or insertable medical device is to be inserted and which bears
moieties as described herein, or that can be derivatized to bear
such moieties, can be used in accordance with the present
invention. Examples of such derivatizable polymers include, but are
not limited to, homopolymers of acrylic acid such as poly(acrylic
acid), copolymers of acrylic acid such as copolymers of acrylic
acid and acrylamide, poly(maleic acid), polysaccharides such as
cellulosic ether polymers including carboxymethylcellulose,
hyaluronic acid and other mucopolysaccharides found in mammalian
fluids and connective tissues.
[0022] The coating material that is to be applied to at least a
portion of the surface of an implantable or insertable medical
device in accordance with the present invention can be made in the
following manner. For purposes of example only, the starting
polymer, that is derivatized in the manner described below, is an
acrylic acid polymer. However, the polymer is not to be construed
as being limited to acrylic acid polymers and may include, for
example, other polymers as described above and that can be
derivatized in a similar manner and function similarly. Polymeric
coating materials that already contain the appropriate moieties
that have a pKa less than about a physiological pH and which can
thus associate with the negatively charged therapeutic agents in
the manner described herein, e.g., poly (4-vinyl pyridine),
polyethyleneimine and polypeptides including proteinaceous
materials such as gelatin, collagen and albumin can also be applied
to the surface of an implantable or insertable medical device to
form the implantable or insertable therapeutic agent delivery
devices of the present invention.
[0023] The coating material, which is preferably an acrylic acid
polymer, can be derivatized and then applied to the surface of an
implantable or insertable medical device. Alternatively, and in a
preferred embodiment of the present invention, an underivatized
polymer, such as an acrylic acid polymer or hydrogel polymer as
described above can be initially applied to the surface of an
implantable or insertable medical device and then derivatized in
situ (i.e., while on the medical device) in a similar manner.
[0024] The implantable or insertable medical device of the present
invention can be provided with the therapeutic agent associated
with the coating. Alternatively, the medical device will have the
derivatized coating applied thereto and the user of the medical
device, prior to implantation or insertion thereof, can contact the
coated medical device with the therapeutic agent so as to cause
association of the therapeutic agent with the coating material
prior to the insertion or implantation of the device. Thus, the
implantable or insertable medical device of the present invention
need not contain therein or thereon the negatively charged
therapeutic agent, but may simply be coated with the derivatized
polymer. In such a case, the therapeutic agent is applied to the
coated device prior to use of the device.
[0025] Derivatization of an acrylic acid polymer will now be
described in more detail. The carboxylic acid groups on a poly
(acrylic acid) polymer, for example, are reacted with a compound
containing both a basic moiety that functions to associate with the
therapeutic agent in the pH dependent manner described herein and a
substituent that binds to the carboxyl groups in the polymer. The
substituent that binds to the carboxyl groups in the polymer may,
for example, be an amino group in the compound containing the basic
moiety. In such case, the compound containing the basic moiety will
be bonded to the polymer through an amide linkage. The basic moiety
in the compound will have a pKa value of less than about 7.4. The
resultant derivatized polymer will thus contain basic moieties that
are positively charged at a pH of less than their pKa values, which
is preferably less than about a physiological pH, and thus have an
affinity to associate with the negatively charged therapeutic
agent. Association of the negatively charged therapeutic agent with
the positively charged moieties of the derivatized polymer is
preferably by ionic bonding. These basic moieties are substantially
uncharged at or above a pH greater than their pKa values, and thus
substantially release the negatively charged therapeutic agent
associated therewith when the pH is increased beyond the pKa
values.
[0026] Among preferred compounds containing a basic moiety that
functions in the pH dependent manner described herein are
aminoethyl pyridine and aminopropyl imidazole. The primary amino
groups in aminoethyl pyridine and aminopropyl imidazole are able to
bind through an amide linkage to, for example, carboxyl groups in a
poly(acrylic acid) polymer to form a derivatized polymer, as
described above, containing the pH dependent basic moieties. The
basic moieties in aminoethyl pyridine and aminopropyl imidazole
which function in the pH-dependent manner as described herein are,
respectively, the pyridinyl and imidazolyl groups in these
compounds. Pyridinyl and imadazolyl are merely exemplary preferred
basic moieties that function in the pH dependent manner described
herein. Thus, any compound containing a basic moiety having a pKa
less than or equal to about physiological pH and which also has a
substituent that can react with a derivatizable group in a polymer
are useful in the present invention. Such basic moieties include,
for example, cyclic and non-cyclic groups. The cyclic groups can be
aromatic or non-aromatic and include heterocyclic and
non-heterocyclic groups. Examples of non-aromatic heterocyclic
groups include, but are not limited to, heterocyclic non-aromatic
groups such as piperidinyl and pyrrolidinyl. Examples of aromatic
heterocyclic groups include, but are not limited to, heterocyclic
aromatic groups such as pyridinyl, imidazolyl, guaninyl, indolyl,
pyrazolyl, pyridazinyl, pyrimidinyl, quinolinyl, pyrazinyl,
thiazolyl, purinyl as well as the heterocyclic bases including
guaninyl, adeninyl, cytosinyl, thyminyl and uracilyl. Examples of
aromatic non-heterocyclic groups include, but are not limited to,
pyridinyl, toluidinyl and anilinyl. Examples of non-cyclic groups
include, but are not limited to guanidinyl and diamino(C1-C6)alkyl.
It is to be understood that the substituent that bonds the compound
containing the pH dependent basic moiety to a reactive group in the
polymer is generally distinct from the basic moiety itself, which
also forms part of the compound. Thus, the basic moiety in the
compound attached to the polymer remains free to bind to the
therapeutic agent. To further illustrate the present invention, the
compound which is attached to the polymer may, for example, be a
compound of the general formula
H.sub.2N--(CH.sub.2).sub.n-(basic moiety).
[0027] In this exemplary compound, the primary amino group is able
to attach the compound to the polymer by reacting with, for
example, carboxyl moieties in the polymer, to form an amide linkage
which links the compound containing the basic moiety to the
polymer. The alkylene group, i.e. --(CH.sub.2).sub.n--, in which n
can range from 0 to 6, acts as a tether or spacer group which
provides distance between the polymer and the basic moiety. Thus,
the tether or spacer, which is optional, may be beneficial by
providing a spacial separation between the polymer and the basic
moiety in the compound attached to the polymer. This spacial
separation may reduce steric hindrance between the therapeutic
agent and the polymer to which the compound is attached, thus
increasing the amount of the therapeutic agent which is effectively
able to bind to the basic moiety in the pH dependent manner
described herein. It is to be understood that the tether or spacer
moiety is optional and, when present in the compound containing the
basic moiety, is preferably a divalent organic radical that
connects the basic moiety and the group in the compound, such as
amino, that attaches to the reactive group in the polymer. Such
divalent organic radicals include, but are not limited to,
alkylene, alkyleneoxy, oxyalkylene, alkyleneamino, aminoalkylene,
alkyleneoxyalkylene, alkylenethio, thioalkylene, alkylenecarbonyl,
aminocarbonyl, carbonylamino, akyleneaminocarbonyl,
aminocarbonylalkylene, oxy, oxycarbonyl, carbonyloxy,
alkyleneoxycarbonyl, oxycarbonylalkylene, aminosulfonyl, or
sulfonylamino. Of course, other divalent organic radicals can
equally well serve as the spacer or tether group where-such group
is present in the compound containing the basic moiety.
[0028] Derivatization of a polymer by formation of an amide linkage
between an compound containing the basic moiety and a carboxyl
group containing polymer, such as poly(acrylic acid), may be
conducted in the presence of a compound that facilitates reaction
of an amino group in the compound containing the basic moiety with
a carboxylic acid moiety in the polymer. Such facilitating
compounds include, for example,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, also
known as EDC and dicyclohexylcarbodiimide, also known as DCC. EDC
and DCC, for example, react with the carboxylic acid group in the
polyacrylic acid, activating the carboxyl. The amino group in, for
example, aminoethyl pyridine or aminopropyl imidazole, then couples
to the activated carboxyl group forming an amide linkage. The
resultant derivatized polymer then contains the desired basic
moiety that functions in the pH dependent manner described herein.
The reaction can be conducted in an aqueous or organic environment.
Typically, EDC is used in an aqueous environment or in a mixed
aqueous/organic environment. DCC is typically used in an organic
environment. Where the reaction medium is organic or part organic,
the organic component may be any conventionally used organic
solvent including, but not limited to, DMF (dimethylformamide),
methylene chloride, hexanes, methanol and mixtures thereof. In the
derivatization with EDC, a soluble O-acyl isourea derivative is
produced as a by-product, which is easily removed from the
resultant derivatized polymer by washing, for example. It is to
understood that EDC is merely exemplary of reagents that may
facilitate connection of the compound containing the basic moiety
to the polymer. Indeed, the ordinarily skilled artisan will readily
appreciate numerous conventional reactions by which the compound
containing the basic moiety can be attached, either directly or
through the use of a facilitating compound such as EDC, to the
derivatizable group in the polymer. Moreover, it is to be
understood that the group in the compound containing the basic
moiety that is attached to the derivatizable group in the polymer
need not be an amino group, which is merely described herein for
purposes of exemplification. Thus, it is entirely possible and
within the scope of the present invention for the compound
containing the basic moiety that functions in the pH dependent
manner described herein to be linked to the polymer by other than
an amide linkage, such as, for example, by an ester linkage, an
ether linkage, etc.
[0029] As discussed above, amide linkages are preferred for
connecting the compound containing the pH dependent basic moiety to
the polymer. Such amide linkages will typically be formed by
reaction of an amino group in the compound containing the basic
moiety with a carboxyl group in the polymer. The preferred
amino-group containing compounds which can be linked to the
carboxyl groups using, EDC as described above are those compounds
containing, in addition to the basic moiety that functions in the
pH dependent manner described herein, those compounds containing a
primary amino group. As discussed above, particularly preferred
amino-group containing compounds whose primary amino group can
react with the carboxylic group in the above-described reaction to
produce a derivatized hydrogel polymer that functions in accordance
with the present invention include aminopropyl imidazole (pKa=6.92)
and aminoethyl pyridine (pKa=5.19). These compounds are merely
preferred amino-group containing compounds and the present
invention is not to be construed as being limited thereto. Any
amino-group containing compound that also has a basic moiety having
a pKa less than about a physiological pH and which is substantially
positively charged at below about a physiological pH and
substantially uncharged at or above about a physiological pH may be
employed to produce the derivatized polymers in accordance with the
present invention. Indeed, the present invention is not limited to
derivatization of a polymeric coating material by forming an amide
linkage via an amino-group in the compound containing the pH
dependent basic moiety as described herein. Any compound which
contains a moiety that is substantially positively charged at or
below about a physiological pH and which is substantially uncharged
at or above about a physiological pH may be employed in the present
invention, subject to its reactivity with a suitable functional
group on a biocompatible material, preferably a biocompatible
polymeric material as described herein.
[0030] The negatively charged therapeutic agent can be any
therapeutic agent that will associate with the positively charged
moieties on the derivatized polymer at below about a physiological
pH, which is preferably about 7.4, and that will be substantially
released therefrom at or above about a physiological pH. Such
negatively charged therapeutic agents include, but are not limited
to nucleic acids such as DNA, cDNA, RNA, antisense DNA or RNA,
nucleotides, proteins such as aFGF and other acidic proteins,
oligopeptides, cells, virus particles such as adenoviruses,
adeno-associated viruses, alpha viruses and lentiviruses, liposomes
or lipoplexes, polyplexes such as polylysine conjugates,
"starburst" dendrimer conjugates, etc.; small and large molecular
weight drugs including, but not limited to, heparin, hyaluronic
acid, etc.
[0031] Polynucleotide sequences useful as therapeutic agents in the
present invention include, for example, DNA or RNA sequences having
a therapeutic effect after being taken up by a cell. Examples of
therapeutic polynucleotides include anti-sense DNA and RNA; DNA
coding for an anti-sense RNA; or DNA coding for tRNA or rRNA to
replace defective or deficient endogenous molecules. The
polynucleotides useful in the invention can also code for
therapeutic polypeptides. A polypeptide is understood to be any
translation product of a polynucleotide regardless of size, and
whether glycosylated or not. Therapeutic polypeptides include as a
primary example, those polypeptides that can compensate for a
defective or deficient species in an animal, or those that act
through toxic effects to limit or remove harmful cells from the
body. In addition, the polypeptides or proteins that can be
incorporated into the coating material of the present invention, or
whose DNA can be incorporated, include without limitation,
angiogenic factors including acidic and basic fibroblast growth
factors, vascular endothelial growth factor, epidermal growth
factor, transforming growth factor .alpha. and .beta.,
platelet-derived endothelial growth factor, platelet-derived growth
factor, tumor necrosis factor .alpha., hepatocyte growth factor and
insulin like growth factor; growth factors; cell cycle inhibitors
including CD inhibitors; thymidine kinase ("TK") and other agents
useful for interfering with cell proliferation, including agents
for treating malignancies. Still other useful factors, which can be
provided as polypeptides or as DNA encoding these polypeptides,
include the family of bone morphogenic proteins ("BMP's"). The
known proteins include BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1),
BMP-7 (OP-1), BMP-S, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14,
BMP-15, and BMP-16. Currently preferred BMP's are any of BMP-2,
BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These dimeric proteins can be
provided as homodimers, heterodimers, or combinations thereof,
alone or together with other molecules. Alternatively or, in
addition, molecules capable of inducing an upstream or downstream
effect of a BMP can be provided. Such molecules include any of the
"hedgehog" proteins, or the DNA's encoding them.
[0032] One or more negatively charged therapeutic agents may be
associated with the coating material of the present invention.
Moreover, it is also possible for the coating material to contain
one or more other therapeutic agents that are not negatively
charged. Thus, the coating material of the present invention, in
addition to negatively charged therapeutic agents, can contain, for
example, cationically charged, amphoteric or neutral therapeutic
agents as well. Hence, each therapeutic agent in the coating
material in accordance with the present invention need not be
released from the coating material by the mechanism described
herein in which the negatively charged therapeutic agents are
released, i.e., preferably upon contact with fluid or tissue having
a physiological pH. A preferred derivatized polymer in accordance
with the present invention may thus contain one or more negatively
charged therapeutic agents and one or more other therapeutic agents
that are not necessarily ionically bound to the derivatized polymer
coating as are the preferred negatively charged therapeutic
agents.
[0033] Examples of other therapeutic agents (some of which may be
negatively charged) that can be provided in or on a coating
material in accordance with the present invention include, but are
not limited to, anti-thrombogenic agents such as heparin, heparin
derivatives, urokinase, and PPack (dextrophenylalanine proline
arginine chloromethylketone); anti-proliferative agents such as
enoxaprin, angiopeptin, or monoclonal antibodies capable of
blocking smooth muscle cell proliferation, hirudin, and
acetylsalicylic acid; anti-inflammatory agents such as
dexamethasone, prednisolone, corticosterone, budesonide, estrogen,
sulfasalazine, and mesalamine;
antineoplastic/antiproliferative/anti-miotic agents such as
paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,
epothilones, endostatin, angiostatin and thymidine kinase
inhibitors; anesthetic agents such as lidocaine, bupivacaine, and
ropivacaine; anti-coagulants such as D-Phe-Pro-Arg chloromethyl
keton, an RGD peptide-containing compound, a polylysine-containing
compound, heparin, antithrombin compounds, platelet receptor
antagonists, anti-thrombin anticodies, anti-platelet receptor
antibodies, aspirin, prostaglandin inhibitors, platelet inhibitors
and tick antiplatelet peptides; vascular cell growth promotors such
as growth factor inhibitors, growth factor receptor antagonists,
transcriptional activators, and translational promotors; vascular
cell growth inhibitors such as growth factor inhibitors, growth
factor receptor antagonists, transcriptional repressors,
translational repressors, replication inhibitors, inhibitory
antibodies, antibodies directed against growth factors,
bifunctional molecules consisting of a growth factor and a
cytotoxin, bifunctional molecules consisting of an antibody and a
cytotoxin; cholesterol-lowering agents; vasodilating agents; and
agents which interfere with endogenous vascoactive mechanisms.
[0034] The therapeutic agents are in any form capable of
associating with the polymer and subsequently being released from
the polymer. Preferably, the therapeutic agent is applied to the
polymer coating in solution in a suitable solvent, such as water,
for example.
[0035] A polymer that has been derivatized in accordance with the
method as described above can be applied in any conventional manner
to the surface of the implantable or insertable medical device of
the present invention. Such methods include, for example, dipping
the implantable or insertable medical device into a solution or
suspension of the derivatized polymer, followed by drying, or
spraying the derivatized polymer onto the surface of the device.
Any method for coating a surface with a polymeric material can be
employed in this step.
[0036] An implantable or insertable medical device of the present
invention is provided with a coating in accordance with the present
invention that is sufficient to deliver a therapeutically effective
amount of the therapeutic agent. The derivatized polymer is
typically applied to at least a portion of the surface of an
implantable or insertable medical device to a coating thickness of
from about 1 .mu.M to about 1000 .mu.M, more preferably in the
range of from about 10 .mu.M to about 100 .mu.M. However, it is to
be understood that the appropriate thickness of the coating can
vary outside of these preferred ranges and that the coating
thickness that is most suitable may depend on the particular
therapeutic agent contained therein or thereon. The amount of the
therapeutic agent provided in or on the coating will be a
therapeutically effective amount when released from the coating at
the target location in the body. The amount of the therapeutic
agent will typically range from 1 ng to 1 mg or more, and will, of
course, depend on the specific therapeutic agent. Where the
therapeutic agent is a protein, DNA, RNA, or other polynucleotide
or nucleic acid, the therapeutically effective amount will
typically range from about 1 .mu.g to about 10 mg or more and,
again, will depend on the specific DNA, RNA, or other
polynucleotide protein or nucleic acid. Where the therapeutic agent
is a virus, the therapeutically effective amount will again vary
depending on the specific virus, but will typically range from
about 1.times.10.sup.7 to about 1.times.10.sup.13 infectious units,
more preferably from about 1.times.10.sup.9 to about
1.times.10.sup.11 infectious units.
[0037] Alternatively, and in a preferred embodiment of the present
invention, an underivatized polymer, which may be in crosslinked or
un-crosslinked form is applied to at least a portion of the surface
of the implantable or insertable medical device directly by any of
the coating methods known in the art. Once the underivatized
polymer is applied, the derivatization reaction as described above
is utilized to bind the compound containing the basic moiety to the
carboxylic acid groups in the poly(acrylic acid).
[0038] The device of the present invention can also be formed by
applying a commercially available polymer that contains moieties
having a pKa less than about a physiological pH and which are thus
substantially positively charged at a pH below about a
physiological pH and are substantially uncharged at a pH at or
above about a physiological pH. Such a coating functions in the
manner described above with respect to release of the negatively
charged therapeutic agent at or above about a physiological pH.
Such polymers include, for example, poly (4-vinyl pyridine),
polyethyleneimine, polypeptides including proteinaceous materials
such as gelatin, collagen and albumin.
[0039] The therapeutic agent can be associated with the positively
charged moieties in the coating material by contacting, e.g., the
coated medical device of the present invention with a solution or
suspension of the negatively charged therapeutic agent for a period
of time sufficient to allow a therapeutically effective amount of
the negatively charged therapeutic agent to become associated with
the positively charged moieties.
[0040] In another embodiment of the invention, multiple coating
layers are provided on the implantable or insertable medical device
in accordance with the methods of the present invention. While each
layer need not function similarly to the coating material of the
present invention, at least one layer on the implantable or
insertable medical device will function in accordance with the
present invention. Thus, it may be desired to provide a coating of
a derivatized polymer in accordance with the present invention onto
an implantable or insertable medical device to which has previously
been applied one or more layers of other coating materials.
Multiple coating layers may be desirable to produce a coating
thickness required for a specific dose or loading of therapeutic or
bioactive agents or to provide coating layers suitable for
particular therapeutic agents or combinations of therapeutic agents
or to provide differential release rates of therapeutic agents.
[0041] It is to be understood that the mechanism of release of the
therapeutic agent need not be the same for each of any multiple
layers. Hence, any layer may have therapeutic agents incorporated
therein or thereon in a manner different from the association of
the negatively charged therapeutic agents in accordance with the
present invention. Different drugs or different concentrations of
drugs can be incorporated in or on any of the multiple layers, and
the mechanism of release of such drugs from those layers may differ
from the release of the drugs from any layer containing a
derivatized polymer in accordance with the present invention.
[0042] Coating formulations used to coat at least a portion of the
surface of an implantable or insertable medical device generally
contain the formulation components dissolved or suspended in a
solvent medium. A coating formulation typically includes, for
example, the following components: one or more polymers or
copolymers, which form the matrix of the dried coating; one or more
drugs or therapeutic agents, biostatic agents, anti-microbial
agents or other bioactive agents; and a selection of one or more
solvents which are typically removed during drying, e.g., by
evaporation.
[0043] A solvent medium for a subsequently applied coating layer
can partially dissolve or otherwise disrupt the coating material of
any previously applied layers, or can even cause leaching or
removal of a therapeutic agent from a previously applied coating
layer. Thus, when it is desired to apply multiple coating layers to
an implantable or insertable medical device, it is preferred to use
a combination of solvents, which includes at least one poor solvent
for the coating formulation components such that the solubility of
the lower (i.e. previously applied) layers is limited. The
appropriate selection of solvents minimizes, during application of
additional layers, any deleterious affect on previously applied
layers.
[0044] The polymers used in forming multiple coating layers can be
any polymers which are conventionally used as coating materials for
implantable or insertable medical devices. The solvents are
selected such that multiple layers can be applied without removing
or affecting the properties of the previous layers. In order to
achieve this, a solvent/non-solvent combination is preferably used
such that at least one of the selected solvents is considered a
good solvent for the polymer and active components, and at least
one solvent is selected that is a poor solvent for the polymer and
active components. Additionally, a multi-layer coating may be
applied where the solvent or combination of solvents used for each
layer is the same or different. The type of solvent or solvent
ratio may be progressively changed to include a greater amount of
one of the solvents as the layers are built up. The solvents are
preferably selected to minimize or prevent solubilization of the
lower layers during the application of subsequent layers. An
additional reason this may be done is to increase interfacial
mixing and possibly enhance other properties of the multi-layered
coating, such as interfacial adhesion between layers.
[0045] Furthermore, the coatings may be applied using a variety of
techniques, such as dip coating, spraying, and spin coating, or any
other method commonly known to the ordinarily skilled artisan.
[0046] The invention will now be described in greater detail in the
following examples which are provided to illustrate preferred
embodiments of the present invention and are therefore not meant to
be construed as limiting the scope of the present invention.
EXAMPLES 1-6
[0047] Derivatization of a Hydrogel Polymer Coating on a Balloon
Catheter with Aminopropylimidazole
EXAMPLE 1
[0048] An angioplasty balloon catheter was provided with a coating
of HYDROPLUS poly (acrylic acid) polymer as disclosed in U.S. Pat.
No. 5,091,205, which is incorporated herein in its entirety.
[0049] The balloon catheter coated with the HYDROPLUS coating was
placed into 200 .mu.L of a solution of (2-[N-morpholino]ethane
sulfonic acid), "MES," to swell the HYDROPLUS coating. 2 .mu.L of
aminopropylimidazole and 500 .mu.L of MES buffer were added. 10 mg
of 1-ethyl-3-(3-dimethylami- nopropyl)carbodiimide hydrochloride,
"EDC," (from Pierce, Rockford Ill.) were dissolved in 1 mL of
deionized ultrafiltered water and 100 .mu.L of this solution were
then added to the solution containing the HYDROPLUS coated balloon
catheter and the aminopropylimidazole. The derivatized HYDROPLUS
coating on the balloon catheter was then washed with PBS
(phosphate-buffered saline).
[0050] The balloon catheter provided with the derivatized HYDROPLUS
coating was then contacted with 0.1 M hydrochloric acid to maximize
the concentration of positively charged moieties in the derivatized
HYDROPLUS coating. The balloon catheter was then dipped into a
solution of methyl orange, a negatively charged dye. It was
observed that the HYDROPLUS coating was red upon removal of the
catheter containing the derivatized HYDROPLUS coating from the
methyl orange solution. A control catheter provided with an
underivatized HYDROPLUS coating was also dipped into the methyl
orange solution and was red upon removal therefrom. When the
control catheter and the catheter containing the derivatized
coating were contacted with water, the control catheter was clear,
indicating that the methyl orange was completely released from the
underivatized HYDROPLUS coating, whereas the catheter containing
the derivatized coating was orange, indicating only a partial
release of the methyl orange from the derivatized coating. A
catheter containing a derivatized HYDROPLUS coating which was red
from contact with methyl orange solution was also dipped into PBS
at a pH of 7.4. Upon removal from the PBS, the catheter was clear,
indicating that the methyl orange was completely removed therefrom
upon contact with PBS at a pH of 7.4.
EXAMPLE 2
[0051] The procedure of Example I was repeated except that 4 .mu.L
of aminopropylimidazole were used. The balloon catheter showed
staining upon contact with methyl orange.
EXAMPLE 3
[0052] The procedure of Example I was repeated except that 8 .mu.L
of aminopropylimidazole were used. The balloon catheter showed no
staining upon contact with methyl orange.
EXAMPLE 4
[0053] The procedure of Example 1 was repeated except that 150
.mu.L of EDC were used. The balloon catheter showed staining upon
contact with methyl orange.
EXAMPLE 5
[0054] The procedure of Example 4 was repeated except that 4 .mu.L
of aminopropylimidazole were used. The balloon catheter showed
staining upon contact with methyl orange.
EXAMPLE 6
[0055] The procedure of example 4 was repeated except that 8 .mu.L
of aminopropylimidazole were used. The balloon catheter showed no
staining upon contact with methyl orange.
EXAMPLES 7-12
[0056] Derivatization of a Hydrogel Polymer Coating on a Balloon
Catheter with Aminoethylpyridine
[0057] Each of Examples 7-12 were performed according to the
procedure of Example 1, except that aminoethylpyridine was used in
place of aminopropylimidazole.
EXAMPLE 7
[0058] The procedure of Example 1 was repeated except that
arninoethylpyridine was used in place of aminopropylimidazole. The
balloon catheter showed staining upon contact with methyl
orange.
EXAMPLE 8
[0059] The procedure of Example 7 was repeated except that 4 .mu.L
of aminoethylpyridine were used. The balloon catheter showed
staining upon contact with methyl orange.
EXAMPLE 9
[0060] The procedure of Example 7 was repeated except that 8 .mu.L
of aminoethylpyridine were used. The balloon catheter showed no
staining upon contact with methyl orange.
EXAMPLE 10
[0061] The procedure of Example 7 was repeated except that 150
.mu.L of EDC were used. The balloon catheter showed staining upon
contact with methyl orange.
EXAMPLE 11
[0062] The procedure of Example I was repeated except that 4 .mu.L
of aminoethylpyridine were used. The balloon catheter showed
staining upon contact with methyl orange.
EXAMPLE 12
[0063] The procedure of example I was repeated except that 8 .mu.L
of aminoethylpyridine were used. The balloon catheter showed no
staining upon contact with methyl orange.
[0064] The release of methyl orange from the cationically
derivatized HYDROPLUS coating on the balloon catheters prepared
according to Examples 1, 2, 4, 5, 7, 8, 10, and 11 in PBS buffer at
pH 7.4 are shown in FIG. 1. Since the balloon catheters prepared
according to Examples 3, 6, 9 and 12 did not show staining with
methyl orange, there is no release data in FIG. 1 for these balloon
catheters.
[0065] The results of Examples 1-12 are present for clarity in the
following Table:
1 Staining with Example Amine EDC methyl orange 1 2 .mu.L 100 .mu.L
stained aminopropylimidazole 2 4 .mu.L 100 .mu.L stained
aminopropylimidazole 3 8 .mu.L 100 .mu.L not stained
ammopropylimidazole 4 2 .mu.L 150 .mu.L stained
aminopropylimidazole 5 4 .mu.L 150 .mu.L stained
amninopropylimidazole 6 8 .mu.L 150 .mu.L not stained
aminopropylimidazole 7 2 .mu.L 100 .mu.L stained aminoethylpyridine
8 4 .mu.L 100 .mu.L stained aminoethylpyridine 9 8 .mu.L 100 .mu.L
not stained aminoethylpyridine 10 2 .mu.L 150 .mu.L stained
aminoethylpyridine 11 4 .mu.L 150 .mu.L stained aminoethylpyridine
12 8 .mu.L 150 .mu.L not stained aminoethylpyridine
EXAMPLES 13-14
[0066] Release of Plasmid DNA from Balloon Catheter Having
Derivatized Hydrogel Polymer Coating
EXAMPLE 13
[0067] A balloon catheter containing a HYDROPLUS coating
derivatized with aminopropylimidazole was prepared in the manner of
Example 4. A solution of plasmid DNA (approximately 5,000 bases)
having a concentration of 167 .mu.g/mL was used. 50 .mu.L of this
DNA solution was diluted with 450 .mu.L of PBS at a pH of 5.7. 200
.mu.L of this solution were then added to an Eppendorf tube into
which solution the balloon catheter containing the derivatized
HYDROPLUS coating was dipped for approximately 20 minutes.
EXAMPLE 14
[0068] The method of Example 13 was repeated, except that a balloon
catheter containing a HYDROPLUS coating derivatized with
aminoethylpyridine prepared in the manner of Example 11 was
used.
[0069] The release, in PBS buffer at pH 7.4, of DNA from the
catheters used in Examples 13 and 14 are compared in FIG. 2 with
the release of DNA from a catheter containing an underivatized
HYDROPLUS coating obtained from Union Carbide Corporation, which
contained quaternary ammonium groups (having fixed positive
charge).
EXAMPLE 15
[0070] A balloon-expandable angioplasty catheter is coated with
HYDROPLUS poly(acrylic acid) hydrogel polymer by dipping the
balloon portion of the catheter for approximately 1 minute into a
1% solution of the polymer in dimethylformamide (DMF) solvent. The
catheter is removed from the solution and dried at 60.degree. C.
for about 30 minutes. In this manner, a hydrogel polymer coating of
approximately 2-20 .mu.m is formed on the expandable balloon
portion of the catheter. The coating is then derivatized with
aminopropyl imidazole in the manner described in Example 4. The
catheter, having the derivatized coating thereon, is then dipped
for approximately 20 minutes into an aqueous 1.times.10.sup.12
viral particles/ml dispersion of a negatively charged adenovirus
vector, the dispersion having a pH of approximately 6.8. The
catheter is removed from the dispersion of the negatively charged
adenoviris. The catheter, via a conventional percutaneous
transdermal angioplasty procedure, is then surgically inserted into
a human subject and positioned adjacent the walls of a partially
occluded coronary artery in the subject. The balloon portion is
then expanded against the walls of the occluded coronary artery and
allowed to remain in the expanded state for approximately 2
minutes. Upon contact of the derivatized hydrogel coating provided
on the balloon with the wall tissue of the partially occluded
artery (pH approximately 7.4), the negatively charged adenovirus is
substantially released from the hydrogel coating and is taken up by
the wall tissue of the occluded artery.
* * * * *