U.S. patent application number 10/388468 was filed with the patent office on 2003-09-25 for methods of sealing an injection site.
Invention is credited to Gordon, Lucas S., Palasis, Maria.
Application Number | 20030181908 10/388468 |
Document ID | / |
Family ID | 26831067 |
Filed Date | 2003-09-25 |
United States Patent
Application |
20030181908 |
Kind Code |
A1 |
Palasis, Maria ; et
al. |
September 25, 2003 |
Methods of sealing an injection site
Abstract
Methods of sealing an injection site of a tissue are provided,
where therapeutic agent has been injected into tissue, resulting in
increased efficiency or agent uptake. Also provided are methods for
delivering therapeutic agent to a tissue, which include injecting a
therapeutic agent into a tissue and subsequently sealing the
injection site, or engaging an injection device with the tissue for
a sufficient period of time that sealing is not necessary to avoid
leakage of the therapeutic agent. In one embodiment radio frequency
cautery is used to seal the injection site upon needle removal from
the tissue. In other embodiments, the injection site is sealed by
resistance heating, laser heating or plugging the site with a solid
plug or coagulating material at the site.
Inventors: |
Palasis, Maria; (Wellesley,
MA) ; Gordon, Lucas S.; (Redmond, WA) |
Correspondence
Address: |
KENYON & KENYON
1500 K STREET, N.W., SUITE 700
WASHINGTON
DC
20005
US
|
Family ID: |
26831067 |
Appl. No.: |
10/388468 |
Filed: |
March 17, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10388468 |
Mar 17, 2003 |
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09521473 |
Mar 8, 2000 |
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6554851 |
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60133122 |
May 7, 1999 |
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Current U.S.
Class: |
606/49 ; 606/2;
606/28 |
Current CPC
Class: |
A61B 2017/00247
20130101; A61B 2018/1425 20130101; A61B 18/1477 20130101; A61M
25/0084 20130101; A61B 2018/00392 20130101; A61B 2218/002 20130101;
A61B 17/3207 20130101; A61B 17/0057 20130101; A61B 2017/22077
20130101; A61K 9/0019 20130101 |
Class at
Publication: |
606/49 ; 606/2;
606/28 |
International
Class: |
A61B 018/18 |
Claims
What is claimed is:
1. A method of sealing an injection site comprising performing
radio frequency cautery at a mouth of a needle track in tissue to
seal the mouth; wherein the needle track is formed by injecting a
therapeutic agent into a tissue with an injection device and
removing the injection device from the tissue.
2. A method of sealing an injection site comprising performing
resistance heating at a mouth of a needle track in tissue to seal
the mouth; wherein the needle track is formed by injecting a
therapeutic agent into a tissue with an injection device and
removing the injection device from the tissue.
3. A method of sealing an injection site comprising performing
laser heating at a mouth of a needle track in tissue to seal the
mouth; wherein the needle track is formed by injecting a
therapeutic agent into a tissue with an injection device and
removing the injection device from the tissue.
4. A method of sealing an injection site comprising plugging a
mouth of a needle track in tissue with a solid plug to seal the
mouth; wherein the needle track is formed by injecting a
therapeutic agent into a tissue with an injection device and
removing the injection device from the tissue.
5. A method of sealing an injection site comprising coagulating at
least one material at a mouth of a needle track in tissue to seal
the mouth; wherein the needle track is formed by injecting a
therapeutic agent into a tissue with an injection device and
removing the injection device from the tissue.
6. The method of claim 5, wherein said material is a polymeric
material or a monomeric material that is polymerized into a
polymeric material.
7. The method of claim 6, wherein said polymeric material is
selected from the group consisting of poly(oxyalkene) polymers and
copolymers and blends with poly(alpha-hydroxy) acids, collagen,
fibrin, elastin, agarose, agar, hyaluronic acid, hyalobiuronic
acid, heparin, cellulose, alginate, curdlan, chitin, chitosan, and
derivatives thereof, cellulose acetate, carboxymethyl cellulose,
hydroxymethyl cellulose, cellulose sulfate sodium salt,
ethylcellulose, poly(acrilic acids), poly(acrylates),
polyacrylamides, polyvinyl alcohols, polyethylene glycols, ethylene
vinyl acetates, and amino containing polymers.
8. The method of claim 5, wherein said material is a non-polymeric
material.
9. The method of claim 8, wherein said non-polymeric material is
selected from the group consisting of sterols, cholesteryl esters,
C.sub.12-C.sub.14 fatty acids, C.sub.18-C.sub.3, mono-, di- and
triacylglyciderides, sucrose fatty acid esters, sorbitan fatty acid
esters, C.sub.16-C.sub.18 fatty alcohols, esters of fatty alcohols,
esters of fatty acids, anhydrides of fatty acids, phospholipids,
sphingosine, spingomyelins, ceramides, glycosphingolipids, lanolin,
lanolin alcohols, and derivatives, combinations, and mixtures
thereof.
10. A method for delivering a therapeutic agent into a tissue in a
mammal, comprising injecting a therapeutic agent into tissue of a
mammal in need of said therapeutic agent, with an injection device;
and delivering a thickening agent to the tissue of said mammal, in
combination with said therapeutic agent.
11. The method of claim 10, wherein said thickening agent is
selected from the group consisting of albumin, iohexol, alginates,
polyacrylic acid, hyaluronic acid, dextran, poloxamers, collagen,
gelatin, polyethylene glycol, polycarboxylic acids, cellulosic
polymers, gelatin, polyvinylpyrrolidone, cross-linked
polyvinylpyrrolidone, hydrogels, polyanhydrides, polyamides,
polyvinyl alcohols, copolymers of vinyl monomers, polyvinyl ethers,
polyvinyl aromatics, polyethylene oxides, glycosaminoglycans,
polysaccharides, ethylene vinylacetate, polyesters,
polyacrylamides, polyethers, polyether sulfone, polycarbonate,
polyalkylenes, halogenated polyalkylenes, polyurethanes,
polyorthoesters, proteins, polypeptides, silicones, siloxane
polymers, polylactic acid, polyglycolic acid, polycaprolactone,
polyhydroxybutyrate valerate and blends and copolymers thereof.
12. The method of claim 10, wherein said combination is sufficient
to inhibit leaking of said agent from said tissue when said device
is withdrawn from said tissue.
13. A method for delivering a therapeutic agent into a tissue in a
mammal, comprising injecting a therapeutic agent into tissue of a
mammal in need of said therapeutic agent, with an injection device;
and delivering a bioadhesive material to the tissue of said mammal,
in combination with said thickening agent.
14. The method of claim 13, wherein said bioadhesive material is
selected from the group consisting of fibrinogen with or without
thrombin, fibrin, fibropectin, elastin, laminin, cyano-acrylates,
polyacrylic acid, polystyrene, polymers derivatized with arginine,
polymers derivatized with glycine, polymers derivatized with
aspartic acid, and copolymers.
15. The method of claim 13, wherein said combination is sufficient
to inhibit leaking of said agent from said tissue when said device
is withdrawn from said tissue.
16. A method for delivering a therapeutic agent into a tissue in a
mammal, comprising injecting a therapeutic agent into tissue of a
mammal in need of said therapeutic agent, with an injection device;
and delivering a tissue sealant to the tissue of said mammal, in
combination with said therapeutic agent.
17. The method of claim 16, wherein the tissue sealant is selected
from the group consisting of cyanoacrylates, collagen, fibrinogen
with or without thrombin, fibrin, fibrin glue, fibropectin,
elastin, laminin, cyano-acrylates, polyacrylic acid, polystyrene,
polymers derivatized with arginine, polymers derivatized with
glycine, polymers derivatized with aspartic acid, and
copolymers.
18. The method of claim 16, wherein said combination is sufficient
to inhibit leaking of said agent from said tissue when said device
is withdrawn from said tissue.
19. A method for delivering a therapeutic agent into a tissue in a
mammal, comprising injecting a therapeutic agent into tissue of a
mammal in need of said therapeutic agent, with an injection device;
withdrawing said injection device from said tissue forming a needle
track having a mouth in the tissue; and sealing the mouth of said
needle track.
20. The method of claim 19, wherein the mouth of the needle track
is sealed by radio frequency cautery.
21. The method of claim 19, wherein the mouth of the needle track
is sealed by resistance heating.
22. The method of claim 19, wherein the mouth of the needle track
is sealed by laser heating.
23. The method of claim 19, wherein the mouth of the needle track
is sealed by plugging the mouth with a solid plug.
24. The method of claim 19, wherein the mouth of the needle track
is sealed by coagulating a material at the site.
25. The method of claim 24, wherein the material is selected from
the group consisting of fibrin glue and cyanoacrylate adhesive.
Description
[0001] The present application claims the benefit of U.S.
Provisional Application No. 60/133,122, filed May 7, 1999.
FIELD OF THE INVENTION
[0002] The present invention relates to methods of sealing an
injection site, where therapeutic agent has been injected into
tissue resulting in increased efficiency or agent uptake. The
present invention also relates to methods for delivering
therapeutic agent to a tissue, which include injecting a
therapeutic agent into a tissue and subsequently sealing the
injection site, or engaging an injection device with the tissue for
a sufficient period of time that sealing is not necessary to avoid
leakage of the therapeutic agent.
BACKGROUND OF THE INVENTION
[0003] The treatment of disease such as vascular disease by local
pharmacotherapy presents a means of delivering therapeutic drug
doses to target tissues while minimizing systemic side effects.
Such localized delivery of therapeutic agents has been proposed or
achieved using medical devices such as catheters, needle devices
and various coated implantable devices such as stents.
[0004] The localized delivery of therapeutic agents using needle
devices has the advantages of precise placement and accurate
control over the volume and rate of delivery. The processing
mechanisms by which therapeutic agent is released from the needle
and absorbed by surrounding tissue, however, is not
well-characterized.
SUMMARY OF THE INVENTION
[0005] In one embodiment, the invention includes a method of
sealing an injection site by performing radio frequency cautery at
the mouth of a needle track in tissue in order to seal the mouth of
the needle track. The needle track is formed in tissue after a
therapeutic agent has been injected into a tissue with an injection
device and subsequently removed from the tissue.
[0006] In other embodiments the mouth of a needle track in tissue
is sealed by performing resistance heating at the mouth, performing
laser heating at the mouth, plugging the mouth with a solid plug,
and coagulating material at the mouth of the needle track.
[0007] In another embodiment, the invention includes a method of
delivering therapeutic agent to tissue by injecting the therapeutic
agent into the tissue of a mammal with an injection device, where
the injection device is kept engaged with the tissue for a
sufficient period of time after the injection has been completed to
prevent the therapeutic agent from leaking from the injection
site.
[0008] In other embodiments, the invention includes methods of
delivering therapeutic agent to tissue, wherein a thickening agent,
bioadhesive material or tissue sealant is added to the materials
being delivered to reduce or eliminate dispersion or leakage of the
therapeutic agent from the tissue after injection into the tissue.
The therapeutic agent is delivered by injecting the therapeutic
agent into tissue, preferably by an injection needle.
[0009] In another embodiment, the invention includes a method for
delivering a therapeutic agent into a tissue in a mammal, which
includes injecting a therapeutic agent into tissue with an
injection needle, withdrawing the injection needle from the tissue,
thus forming a needle track having a mouth in the tissue, and
sealing the mouth of said needle track. Preferably, the mouth of
the needle track is sealed by radio frequency cautery. In other
embodiments, the mouth of the needle track is sealed by resistance
heating, laser heating, plugging the mouth with a solid plug, or by
coagulating a material at the mouth of the needle track.
DETAILED DESCRIPTION
[0010] The inventors have surprisingly found that when therapeutic
agent is delivered to target tissue with an injection device such
as a needle, leaking and dispersion often result upon removal of
the device from the tissue. For example, the inventors have
discovered that where an injection is performed via a needle, there
is potential for leakage of the administered therapeutic agent
along the needle track left by needle withdrawal. This problem is
exacerbated in situations where the therapeutic agent is injected
into the tissue of an organ that undergoes expansion and
contraction, such as the heart. In such cases, the organ wall thins
during organ expansion, thus facilitating the leakage of
previously-injected therapeutic agent from the organ tissue through
the needle track and thereby decreasing the actual dose of
therapeutic agent delivered to the target site and increasing
systemic distribution of the drug.
[0011] The problem of leakage of injected therapeutic agent has not
previously been appreciated. Conventionally, injection devices are
immediately withdrawn from target tissue following injection
without safeguards for the possibility of leakage because it has
been assumed, given the relatively small volume of therapeutic
agent that is administered by injection, that the therapeutic agent
is immediately absorbed by the target tissue.
[0012] The present invention solves the problems discovered by the
inventors by providing any suitable means for inhibiting loss of
injected therapeutic agent prior to cell uptake. Embodiments of the
invention thus result in an increased exposure of the target tissue
to the therapeutic agents administered, and thus, increased
efficiency of localized drug delivery. Other embodiments of the
invention include sealing the mouth of the needle track (at the
injection site) upon needle removal. The methods of the invention
have the additional benefit of permitting a relatively large volume
of therapeutic agent to be effectively and efficiently
administered. Examples of injection volumes of the present
invention include a range of about 1 .mu.l to about 1 ml,
preferably 10-100 .mu.l.
[0013] The invention is described herein with specific reference to
an injection needle as the delivery device. Examples of specific
devices incorporating injection needles, and thus within the scope
of the invention, include needle injection catheters, hypodermic
needles, biopsy needles, ablation catheters, cannulas and any other
type of medically useful needle. It will be understood by one of
ordinary skill in the art that other injection devices are
contemplated and are within the scope of the invention.
Specifically, any device competent to penetrate tissue is
contemplated, particularly those that create an opening through
which a delivered agent may escape or "leak out." Non-needle
injection devices are also contemplated by the present invention.
Examples of non-needle injection devices include, but are not
limited to, transmural myocardial revascularization (TMR) devices
and percutaneous myocardial revascularization (PMR) devices or any
other device capable of wounding or creating a channel or crater in
tissue. Further examples of suitable injection devices include
ablation devices and needle-free injectors which propel fluid using
a spring or pressurized gas, such as carbon dioxide injection
devices.
[0014] In one embodiment of the present invention, therapeutic
agent is delivered to tissue by injecting the therapeutic agent
into tissue via an injection device, preferably an injection
needle. Following injection, the injection needle may be kept
engaged with the tissue (i.e., the needle is not withdrawn) for a
period of time after the injection has been completed. The time
period that the needle is kept engaged with the tissue is
sufficient for the therapeutic agent to be substantially completely
absorbed by the target tissue and may include a prolonged time
period. Preferably, this time period is within the range of about 5
seconds to about 2 minutes; more preferably, the time period is
within the range of about 5 seconds to about 30 seconds. When the
needle is subsequently withdrawn, leakage of the therapeutic agent
is minimized or eliminated because it has already been absorbed by
the target tissue.
[0015] In another embodiment, therapeutic agent is delivered to
tissue by injecting therapeutic agent into tissue with an injection
needle, wherein a thickening agent is added to the therapeutic
agent prior to injection. As used herein, "thickening agent" refers
to any biocompatible additive that results in an increased
viscosity of the materials being injected. By way of example,
suitable thickening agents include albumin, iohexol or other
contrast agent, alginates, polyacrylic acid, hyaluronic acid,
dextran, collagen, gelatin, polyethylene glycol, poloxamers and
various biocompatible polymers.
[0016] Suitable biocompatible polymers for use in the present
invention are hydrophilic or hydrophobic, and include, but are not
limited to, polycarboxylic acids, cellulosic polymers, including
cellulose acetate and cellulose nitrate, gelatin,
polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, hydrogels,
polyanhydrides including maleic anhydride polymers, polyamides,
polyvinyl alcohols, copolymers of vinyl monomers such as EVA,
polyvinyl ethers, polyvinyl aromatics, polyethylene oxides,
glycosaminoglycans, polysaccharides, ethylene vinylacetate,
polyesters including polyethylene terephthalate, polyacrylamides,
polyethers, polyether sulfone, polycarbonate, polyalkylenes
including polypropylene, polyethylene and high molecular weight
polyethylene, halogenated polyalkylenes including
polytetrafluoroethylene, polyurethanes, polyorthoesters, proteins,
polypeptides, silicones, siloxane polymers, polylactic acid,
polyglycolic acid, polycaprolactone, polyhydroxybutyrate valerate
and blends and copolymers thereof as well as other biodegradable,
bioabsorbable and biostable polymers and copolymers.
[0017] By adding a thickening agent, the therapeutic agent has an
increased ability to resist forces tending to push the therapeutic
agent out of the tissue via the needle tracks. Preferably in this
embodiment, the injection needle remains engaged with the tissue
for a period of time sufficient to allow cellular uptake of
substantially all of the therapeutic agent. In an even more
preferred embodiment, the combination of therapeutic agent and
thickening agent is sufficient to inhibit any leaking of the
therapeutic agent from the tissue when the delivery device is
withdrawn from the tissue.
[0018] In another embodiment, therapeutic agent is delivered to
tissue by injecting therapeutic agent into tissue with an injection
needle, wherein a bioadhesive material is added to the materials
being injected. As used herein, "bioadhesive material" refers to
any biocompatible additive that results in an increase of the
affinity of the injected material for tissue. Bioadhesive materials
for use in conjunction with the invention include suitable
bioadhesive materials known to those of ordinary skill in the art.
By way of example, suitable bioadhesive materials include
fibrinogen with or without thrombin, fibrin, fibropectin, elastin,
laminin, cyano-acrylates, polyacrylic acid, polystyrene,
bioabsorbable and biostable polymers derivatized with sticky
molecules such as arginine, glycine, and aspartic acid, and
copolymers.
[0019] Preferably in this embodiment, the injection needle remains
engaged with the tissue for a period of time sufficient to allow
cellular uptake of substantially all of the therapeutic agent. In
an even more preferred embodiment, the combination of therapeutic
agent and bioadhesive material is sufficient to inhibit any leaking
of the therapeutic agent from the tissue when the delivery device
is withdrawn from the tissue.
[0020] In another embodiment, therapeutic agent is delivered to
tissue by injecting the therapeutic agent into the tissue with an
injection needle, wherein a tissue sealant is used to seal the
mouth of the needle track upon needle removal. The sealant is
delivered to the mouth of the needle track by any suitable means,
such as through a lumen of a multi-lumen catheter, in which case
the injection needle is delivered via a separate lumen.
Alternatively, for example, the sealant may be added to the
material being injected, or may be coated onto the exterior of the
needle. Tissue sealants for use in conjunction with the invention
include suitable sealants known to those of ordinary skill in the
art. Such tissue sealants preferably include those having suitable
bonding properties, elasticity and biodegradability for the tissue
to which the sealant is to be applied. By way of example, suitable
sealants include cyanoacrylates, collagen, fibrinogen with or
without thrombin, fibrin, fibrin glue, fibropectin, elastin,
laminin, cyano-acrylates, polyacrylic acid, polystyrene,
bioabsorbable and biostable polymers derivatized with sticky
molecules such as arginine, glycine, and aspartic acid, and
copolymers.
[0021] Preferably in this embodiment, the injection needle remains
engaged with the tissue for a period of time sufficient to allow
cellular uptake of substantially all of the therapeutic agent. In
an even more preferred embodiment, the combination of therapeutic
agent and tissue sealant is sufficient to inhibit any leaking of
the therapeutic agent from the tissue when the delivery device is
withdrawn from the tissue.
[0022] The invention also includes a method of sealing an injection
site at the mouth of a needle track in tissue. A needle track is
formed in tissue after a therapeutic agent has been injected into a
tissue with an injection device and subsequently removed from the
tissue.
[0023] According to a preferred embodiment, one method of sealing
the injection site is by performing radio frequency cautery at the
mouth of the needle track to seal the mouth upon needle removal
from the tissue. Cauterization involves using such intense heat to
seal the open ends of the tissue. Radio frequency cautery may be
performed by any suitable method. Such methods are known to those
skilled in the art.
[0024] According to another preferred embodiment, a method for
sealing the injection site is by resistance heating at the mouth of
the needle track. Intense heat may be used to seal the mouth of the
needle track upon needle removal. Intense heat used to seal open
ends of tissue may be generated by a variety of different methods.
In a preferred embodiment, intense heat is generated by resistance
heating a metallic probe, such that the generated heat is intense
enough to seal the open ends of tissue. Methods of delivering
intense heat, and more preferably resistance heating, are known to
those skilled in the art.
[0025] Another preferred embodiment includes a method for sealing
the injection site by performing laser heating at the mouth of the
needle track to seal the mouth upon needle removal. In this
embodiment, laser emitted optical energy may be used to heat
biological tissue to a degree suitable for denaturing the tissue
proteins such that the collagenous elements of the tissue form a
"biological glue" to seal the tissue. Suitable methods of laser
heating a tissue are known to those skilled in the art.
[0026] According to yet another preferred embodiment, the present
invention includes a method for sealing the injection site by
plugging the mouth of a needle track with a solid plug or by
coagulating one or more materials at the mouth upon needle removal.
Examples of materials that may be used in accordance with this
embodiment in order to seal the mouth of the needle track include
fibrin glue, cyanoacrylate-based adhesives and the like. Other
suitable sealant plugs would be apparent to those in the art based
on the present disclosure. In a preferred embodiment, the sealant
plug may be heated (or cooled, depending on the temperature at
which the material being used is liquid) prior to application to
the mouth of the needle track, and subsequent cooling (or heating)
may aid in solidifying and sealing the tissue. For example, a
temperature sensitive polymer, which is liquid at above or below
physiological temperature (i.e. about 37.degree. C.) and solidifies
at physiological temperature may be used in this embodiment.
Examples of suitable materials for use in this embodiment include
N-isoproylacrylamide and certain celluloses.
[0027] When the injection site is sealed by a coagulating material,
the coagulating material is applied to the mouth of the injection
site while the material is in a first fluent state. Then the
material is maintained in a position so as to plug the mouth of the
injection site under conditions which convert the material in situ
into a second less-fluent or essentially non-fluent state. The
conversion may be achieved either by changing the environment
surrounding the material by the addition or removal of chemicals or
energy, or by passive means such as maintaining the material at the
normal internal body temperature of a patient. The transition of
the state of the material from a fluent state to a less fluent or
essentially non-fluent state may be the result of a phase change or
of a viscosity change or of polymerization.
[0028] Preferably the material is one or more biocompatible
materials. In a preferred embodiment the material is a polymeric
material, which can be applied as polymers, monomers, macromers or
combinations thereof. The polymeric materials are preferably those
materials that can be polymerized or have their viscosity altered
in vivo, preferably by the application of light, ultrasound,
radiation or chelation, alone or in the presence of added catalyst
or by a change to physiological pH, diffusion or calcium ions
(alginate) or borate ions (polyvinyl alcohol) into the polymer or
change in temperature to body temperature.
[0029] Examples of polymers that may be suitable for use in this
embodiment include those polymers listed above as being suitable
thickening agents. Examples of in situ polymerization include, but
are not limited to, alginates crosslinked with multivalent cations,
fibrinogen crosslinked with thrombin and photochemical
crosslinking. Further examples of suitable polymers include the
following. Materials which polymerize or alter viscosity as a
function of temperature include poly(oxyalkene) polymers and
copolymers such as poly(ethylene oxide)-poly(propylene oxide)
(PEO-PPO) copolymers, and copolymers and blends of these polymers
with polymers such as poly(alpha-hydroxy) acids, including but not
limited to lactic, glycolic and hydroxybutyric acids,
polycaprolactones, and polyvalerolactones. Examples of materials
which polymerize in the presence of divalent ions such as calcium,
barium, magnesium, copper, and iron include naturally occurring
polymers collagen, fibrin, elastin, agarose, agar, polysaccharides
such as hyaluronic acid, hyalobiuronic acid, heparin, cellulose,
alginate, curdlan, chitin and chitosan, and derivatives thereof,
cellulose acetate, carboxymethyl cellulose, hydroxymethyl
cellulose, cellulose sulfate sodium salt, and ethylcellulose.
Examples of materials that can be crosslinked photochemically with
ultrasound or with radiation generally include those materials that
contain a double bond or a triple bond; examples include monomers
which are polymerized into poly(acrilic acids), poly(acrylates),
polyacrylamides, polyvinyl alcohols, polyethylene glycols, and
ethylene vinyl acetates. Examples of materials that can be
crosslinked by the addition of covalent crosslinking agents, such
as glutaraldehyde, succindialdehyde or carbodiimide, include amino
containing polymers including polypeptides and proteins such as
albumin and polyethyleneimine.
[0030] In an alternative embodiment, a non-polymeric coagulant may
be used, wherein the non-polymeric material is capable of
transforming into a substantially solid matrix in situ is either
added to the therapeutic agent prior to injection or applied to the
mouth of a needle track after a needle is removed from tissue.
[0031] The non-polymeric material in this embodiment may be
combined with at least one organic solvent. Suitable organic
solvents are those that are biocompatible,
pharmaceutically-acceptable, and will at least partially dissolve
the non-polymeric material. The organic solvent has a solubility in
water ranging from miscible to dispersible. The solvent is capable
of diffusing, dispersing, or leaching from the composition in situ
into aqueous tissue fluid of the implant site such as blood serum,
lymph, cerebral spinal fluid (CSF), saliva, and the like. Solvents
that are useful include, for example, substituted heterocyclic
compounds such as N-methyl-2-pyrrolidone (NMP) and 2-pyrrolidone
(2-pyrol); esters of carbonic acid and alkyl alcohols such as
propylene carbonate, ethylene carbonate and dimethyl carbonate;
fatty acids such as acetic acid, lactic acid and heptanoic acid;
alkyl esters of mono-, di-, and tricarboxylic acids such as
2-ethyoxyethyl acetate, ethyl acetate, methyl acetate, ethyl
lactate, ethyl butyrate, diethyl malonate, diethyl glutonate,
tributyl citrate, diethyl succinate, tributyrin, isopropyl
myristate, dimethyl adipate, dimethyl succinate, dimethyl oxalate,
dimethyl citrate, triethyl citrate, acetyl tributyl citrate,
glyceryl triacetate; alkyl ketones such as acetone and methyl ethyl
ketone; ether alcohols such as 2-ethoxyethanol, ethylene glycol
dimethyl ether, glycofurol and glycerol formal; alcohols such as
ethanol and propanol; polyhydroxy alcohols such as propylene
glycol, polyethylene glycol (PEG), glycerin (glycerol),
1,3-butyleneglycol, and isopropylidene glycol; dialkylamides such
as dimethylformamide and dimethylacetamide; dimethylsulfoxide
(DMSO) and dimethylsulfone; tetrahydrofuran; lactones such as
.epsilon.-caprolactone and butyrolactone; cyclic alkyl amides such
as caprolactam; aromatic amides such as N,N-dimethyl-m-toluamide,
and 1-dodecylazacycloheptan-2-on- e; and the like; and mixtures and
combinations thereof. Preferred solvents include
N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl
lactate, propylene carbonate, glycofurol, glycerol, and
isopropylidene glycol. Preferably the organic solvent is
biocompatible and non-toxic.
[0032] A composition of the non-polymeric material is preferably
flowable with a consistency that ranges from watery to slightly
viscous to a putty or paste. The non-polymeric material eventually
coagulates to a microporous, solid matrix upon the dissipation of
the organic solvent into adjacent tissue fluids. The non-polymeric
composition can be manipulated and shaped within the defect site as
it solidifies. Advantageously, the moldability of the composition
as it hardens allows it to conform to irregularities, crevices,
cracks, holes, and the like, in the implant site. The resulting
substantially solid matrix is preferably biodegradable,
bioabsorbable, and/or bioerodible, and will be gradually absorbed
into the surrounding tissue fluids, and become disintegrated
through enzymatic, chemical and/or cellular hydrolytic action. The
term "biodegradable" means that the non-polymeric material and/or
matrix of the implant will degrade over time by the action of
enzymes, by simple or enzymatically catalyzed hydrolytic action
and/or by other similar mechanisms in the human body. The term
"bioerodible" means that the implant matrix will erode or degrade
over time due, at least in part, to contact with substances found
in the surrounding tissue fluids, cellular action, and the like. By
"bioabsorbable," it is meant that the non-polymeric matrix will be
broken down and absorbed within the human body, for example, by a
cell, a tissue, and the like.
[0033] Optionally, the composition of non-polymeric material of
this embodiment can be combined with a minor amount of a
biodegradable, bioabsorbable thermoplastic polymer such as a
polylactide, polycaprolactone, polyglycolide, or copolymer thereof,
to provide a more coherent solid implant or a composition with
greater viscosity so as to hold it in place while it solidifies.
The non-polymeric materials are also capable of coagulating or
solidifying to form a solid implant matrix upon the dissipation,
dispersement or leaching of the solvent component from the
composition and contact of the non-polymeric material with an
aqueous medium. The solid matrix has a firm consistency ranging
from gelatinous to impressionable and moldable, to a hard, dense
solid.
[0034] Non-polymeric materials according to this embodiment that
are suitable for use in the present invention generally include any
having the foregoing characteristics. Examples of useful
non-polymeric materials include sterols such as cholesterol,
stigmasterol, .beta.-sitosterol, and estradiol; cholesteryl esters
such as cholesteryl stearate; C.sub.12-C.sub.24 fatty acids such as
lauric acid, myristic acid, palmitic acid, stearic acid, arachidic
acid, behenic acid, and lignoceric acid; C.sub.18-C.sub.36 mono-,
di- and triacylglycerides such as glyceryl monooleate, glyceryl
monolinoleate, glyceryl monolaurate, glyceryl monodocosanoate,
glyceryl monomyristate, glyceryl monodicenoate, glyceryl
dipalmitate, glyceryl didocosanoate, glyceryl dimyristate, glyceryl
didecenoate, glyceryl tridocosanoate, glyceryl trimyristate,
glyceryl tridecenoate, glycerol tristearate and mixtures thereof;
sucrose fatty acid esters such as sucrose distearate and sucrose
palmitate; sorbitan fatty acid esters such as sorbitan
monostearate, sorbitan monopalmitate and sorbitan tristearate;
C.sub.16-C.sub.18 fatty alcohols such as cetyl alcohol, myristyl
alcohol, stearyl alcohol, and cetostearyl alcohol; esters of fatty
alcohols and fatty acids such as cetyl palmitate and cetearyl
palmitate; anhydrides of fatty acids such as stearic anhydride;
phospholipids including phosphatidylcholine (lecithin),
phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol,
and lysoderivatives thereof; sphingosine and derivatives thereof;
spingomyelins such as stearyl, palmitoyl, and tricosanyl
spingomyelins; ceramides such as stearyl and palmitoyl ceramides;
glycosphingolipids; lanolin and lanolin alcohols; and combinations
and mixtures thereof. Preferred non-polymeric materials include
cholesterol, glyceryl monostearate, glycerol tristearate, stearic
acid, stearic anhydride, glyceryl monooleate, glyceryl
monolinoleate, and acetylated monoglycerides.
[0035] The present invention also includes a method for delivering
a therapeutic agent into a tissue in a mammal, which includes
injecting a therapeutic agent into tissue of a mammal in need of
said therapeutic agent, with an injection needle, withdrawing the
injection needle from the tissue, thus, forming a needle track in
the tissue, and sealing the mouth of the needle track. Preferably,
the mouth of the needle track is sealed by radio frequency cautery.
In other embodiments, the mouth of the needle track is sealed by
resistance heating, laser heating, plugging the mouth with a solid
plug, by coagulating a material at the mouth of the needle track or
by other methods known to those skilled in the art as described
above.
[0036] In addition to the above embodiments, other methods of
sealing an injection site such as cryogenic techniques and
electrosurgical techniques are contemplated by the present
invention.
[0037] Any of the above-described thickening agents, bioadhesive
materials, tissue sealants, solid plugs, or coagulants (including
polymeric and non-polymeric coagulants), or compositions containing
any of the above, may contain one or more additives that would be
known to those in the art.
[0038] The term "therapeutic agent" as used herein includes one or
more "therapeutic agents" or "drugs". The terms "therapeutic
agents" and "drugs" are used interchangeably herein and include
pharmaceutically active compounds, nucleic acids with and without
carrier vectors such as lipids, compacting agents (such as
histones), virus (such as adenovirus, andenoassociated virus,
retrovirus, lentivirus and .alpha.-virus), polymers, hyaluronic
acid, proteins, cells and the like, with or without targeting
sequences. The injection administered in accordance with the
invention includes the therapeutic agent(s) and solutions
thereof.
[0039] Specific examples of therapeutic agents used in conjunction
with the present invention include, for example, pharmaceutically
active compounds, proteins, cells, oligonucleotides, ribozymes,
anti-sense oligonucleotides, DNA compacting agents, gene/vector
systems (i.e., any vehicle that allows for the uptake and
expression of nucleic acids), nucleic acids (including, for
example, recombinant nucleic acids; naked DNA, cDNA, RNA; genomic
DNA, cDNA or RNA in a non-infectious vector or in a viral vector
and which further may have attached peptide targeting sequences;
antisense nucleic acid (RNA or DNA); and DNA chimeras which include
gene sequences and encoding for ferry proteins such as membrane
translocating sequences ("MTS") and herpes simplex virus-1
("VP22")), and viral, liposomes and cationic and anionic polymers
and neutral polymers that are selected from a number of types
depending on the desired application. Non-limiting examples of
virus vectors or vectors derived from viral sources include
adenoviral vectors, herpes simplex vectors, papilloma vectors,
adeno-associated vectors, retroviral vectors, and the like.
Non-limiting examples of biologically active solutes include
anti-thrombogenic agents such as heparin, heparin derivatives,
urokinase, and PPACK (dextrophenylalanine proline arginine
chloromethylketone); antioxidants such as probucol and retinoic
acid; angiogenic and anti-angiogenic agents and factors; agents
blocking smooth muscle cell proliferation such as rapamycin,
angiopeptin, and monoclonal antibodies capable of blocking smooth
muscle cell proliferation; anti-inflammatory agents such as
dexamethasone, prednisolone, corticosterone, budesonide, estrogen,
sulfasalazine, acetyl salicylic acid, and mesalamine; calcium entry
blockers such as verapamil, diltiazem and nifedipine;
antineoplastic/antiproliferative/anti-mitotic agents such as
paclitaxel, 5-fluorouracil, methotrexate, doxorubicin,
daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine,
epothilones, endostatin, angiostatin and thymidine kinase
inhibitors; antimicrobials such as triclosan, cephalosporins,
aminoglycosides, and nitorfurantoin; anesthetic agents such as
lidocaine, bupivacaine, and ropivacaine; nitric oxide (NO) donors
such as lisidomine, molsidomine, L-arginine, NO-protein adducts,
NO-carbohydrate adducts, polymeric or oligomeric NO adducts;
anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD
peptide-containing compound, heparin, antithrombin compounds,
platelet receptor antagonists, anti-thrombin antibodies,
antiplatelet receptor antibodies, enoxaparin, hirudin, Warafin
sodium, Dicumarol, aspirin, prostaglandin inhibitors, platelet
inhibitors and tick antiplatelet factors; vascular cell growth
promoters such as growth factors, growth factor receptor
antagonists, transcriptional activators, and translational
promoters; 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; agents
which interfere with endogeneus vascoactive mechanisms; survival
genes which protect against cell death, such as anti-apoptotic
Bcl-2 family factors and Akt kinase; and combinations thereof.
Cells can be of human origin (autologous or allogenic) or from an
animal source (xenogeneic), genetically engineered if desired to
deliver proteins of interest at the injection site. The delivery
mediated is formulated as needed to maintain cell function and
viability. Any modifications are routinely made by one skilled in
the art.
[0040] Polynucleotide sequences useful in practice of the invention
include 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 of the invention can also
code for therapeutic proteins or polypeptides. A polypeptide is
understood to be any translation product of a polynucleotide
regardless of size, and whether glycosylated or not. Therapeutic
proteins and polypeptides include as a primary example, those
proteins or polypeptides that can compensate for 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 injected, or
whose DNA can be incorporated, include without limitation,
angiogenic factors and other molecules competent to induce
angiogenesis, including acidic and basic fibroblast growth factors,
vascular endothelial growth factor, hif-1, 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 CDK
inhibitors; anti-restenosis agents, including p15, p16, p18, p19,
p21, p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase
("TK") and combinations thereof and other agents useful for
interfering with cell proliferation, including agents for treating
malignancies; and combinations thereof. Still other useful factors,
which can be provided as polypeptides or as DNA encoding these
polypeptides, include monocyte chemoattractant protein ("MCP-1"),
and 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-8, 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.
[0041] Organs and tissues that may be treated by the methods of the
present invention include any mammalian tissue or organ, whether
injected in vivo or ex vivo. Non-limiting examples include heart,
lung, brain, liver, skeletal muscle, smooth muscle, kidney,
bladder, intestines, stomach, pancreas, ovary, prostate, eye,
tumors, cartilage and bone.
[0042] The therapeutic agents can be used, for example, in any
application for treating, preventing, or otherwise affecting the
course of a disease or tissue or organ dysfunction. For example,
the methods of the invention can be used to induce or inhibit
angiogenesis, as desired, to prevent or treat restenosis, to treat
a cardiomyopathy or other dysfunction of the heart, for treating
Parkinson's disease or a stroke or other dysfunction of the brain,
for treating cystic fibrosis or other dysfunction of the lung, for
treating or inhibiting malignant cell proliferation, for treating
any malignancy, and for inducing nerve, blood vessel or tissue
regeneration in a particular tissue or organ.
[0043] Therapeutic agents may be directly injected into tissue, or
may be delivered in a solution or other form and may be delivered
via a carrier. Therapeutic agents may be delivered via microspheres
that are injected into the tissue, rather than injecting
therapeutic agents directly into the tissue. In a preferred
embodiment, therapeutic agents may be injected via microspheres
into muscle tissue. Injecting therapeutic agents via microspheres
may result in sustained release or delivery of the drug. Direct
injection of therapeutic agents may represent an effective means to
treat the entire myocardium. The authors have found that injected
agents tend to disperse throughout the myocardium into uninjected
areas. Thus, the number of injections that is necessary in order to
deliver therapeutic agents to a specific area of tissue may be
decreased.
[0044] In a preferred embodiment, therapeutic agents are delivered
to muscle tissue by injecting a solution of microspheres directly
into the muscle tissue. In a more preferred embodiment, the muscle
tissue is the heart.
EXAMPLE
[0045] The myocardium of a mammal was treated by injecting
therapeutic agents into muscle tissue. Upon injection of a gene,
with and without a viral vector, protein expression is limited to
the immediate area where the injections were made. Applicants
surprisingly found that upon injection of a solution of
microspheres directly into muscle tissue, the microspheres became
dispersed throughout the myocardium and away from the injection
site. Single 10-100 .mu.l (in volume) injections of a solution of
microspheres were made into the anterior, lateral and posterior
wall of the left ventrical, resulting in 1-6% of the injectate
being recovered in the uninjected septal wall and 0.1-1% of the
injectate being recovered in the uninjected right ventrical.
[0046] This data shows that an injected solution of microspheres
spreads significantly beyond the site of injection and thus,
delivers therapeutic agent beyond the site of the injection. In
this manner, it may be possible to treat a significant portion of
the heart with a therapeutic protein or drug via a limited number
of injections into the muscle tissue.
[0047] Furthermore, it may be possible to modulate the dispersion
of therapeutic agents in the heart by adding ligand to the
therapeutic agents, which may bind to cell surface receptors,
extracellular matrix components or other components of the
myocardial tissue.
* * * * *