U.S. patent application number 13/926619 was filed with the patent office on 2013-10-31 for atraumatic occlusion balloons and skirts, and methods of use thereof.
The applicant listed for this patent is Genzyme Corporation. Invention is credited to William E. Cohn, Jean-Marie Vogel.
Application Number | 20130289605 13/926619 |
Document ID | / |
Family ID | 38882980 |
Filed Date | 2013-10-31 |
United States Patent
Application |
20130289605 |
Kind Code |
A1 |
Vogel; Jean-Marie ; et
al. |
October 31, 2013 |
Atraumatic Occlusion Balloons and Skirts, and Methods of Use
Thereof
Abstract
One aspect of the present invention relates to catheters that
can be placed in or around bodily conduits to occlude or widen a
biological lumen without imparting significant trauma to the lumen.
In certain embodiments, the invention particularly relates to the
use of a polymer composition which can be made to gel upon
insertion into said balloon or skirt. In certain embodiments, the
inflating viscous polymer composition is a liquid at room
temperature and a gel at mammalian physiological temperature. In
certain embodiments, the inflating viscous polymer composition
comprises an optionally purified inverse thermosensitive
polymer.
Inventors: |
Vogel; Jean-Marie; (Lincoln,
MA) ; Cohn; William E.; (Bellaire, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Genzyme Corporation |
Cambridge |
MA |
US |
|
|
Family ID: |
38882980 |
Appl. No.: |
13/926619 |
Filed: |
June 25, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11851848 |
Sep 7, 2007 |
8491623 |
|
|
13926619 |
|
|
|
|
60843601 |
Sep 11, 2006 |
|
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Current U.S.
Class: |
606/192 |
Current CPC
Class: |
A61B 17/12131 20130101;
A61B 17/12186 20130101; A61B 17/12195 20130101; A61M 29/02
20130101; A61B 17/1204 20130101; A61M 2025/1052 20130101; A61B
17/12136 20130101; A61B 17/12045 20130101; A61B 17/12109 20130101;
A61B 17/12031 20130101; A61B 17/08 20130101; A61B 2017/1205
20130101 |
Class at
Publication: |
606/192 |
International
Class: |
A61B 17/12 20060101
A61B017/12; A61M 29/02 20060101 A61M029/02 |
Claims
1. A method of occluding, widening or stenting a lumen in a mammal,
comprising the steps of: positioning a catheter into said mammalian
lumen at a location, wherein said catheter comprises an elongated
shaft having an inflation lumen and a balloon connected to a distal
end of the elongated shaft so that an interior chamber of the
balloon is in fluid communication with the inflation lumen; and
wherein an open proximal end of the balloon is in fluid
communication with said mammalian lumen; deploying said balloon,
via said inflation lumen, with a composition comprising at least
one polymer by introducing the composition in a manner sufficient
to expand the balloon, wherein said composition gels partially or
completely in said balloon.
2. The method of claim 1, wherein said method is substantially
atraumatic to said mammalian lumen.
3. The method of claim 1, wherein said mammalian lumen is
temporarily occluded.
4. The method of claim 1, wherein said mammalian lumen is
permanently occluded.
5. The method of claim 1, wherein said at least one polymer is at
least one purified inverse thermo sensitive polymer.
6. The method of claim 5, wherein said purified inverse
thermosensitive polymer has a polydispersity index from about 1.5
to about 1.0.
7. The method of claim 5, wherein said purified inverse
thermosensitive polymer has a polydispersity index from about 1.2
to about 1.0.
8. The method of claim 5, wherein said purified inverse thermo
sensitive polymer has a polydispersity index from about 1.1 to
about 1.0.
9. The method of claim 5, wherein said purified inverse thermo
sensitive polymer is a polyoxyalkylene block copolymer.
10. The method of claim 5, wherein said purified inverse thermo
sensitive polymer is selected from the group consisting of
poloxamers and poloxamines.
11. The method of claim 5, wherein said purified inverse
thermosensitive polymer is selected from the group consisting of
poloxamer 407, poloxamer 338, poloxamer 118, Tetronic.RTM. 1107 and
Tetronic.RTM. 1307.
12. The method of claim 5, wherein said purified inverse thermo
sensitive polymer is poloxamer 407.
13. The method of claim 1, wherein said mammal is a human.
14. The method of claim 1, wherein said mammalian lumen is an
artery, a vein, a kidney, a gall bladder, a ureter, a urinary
bladder, a pancreatic duct, a fallopian tube, a sinus, a tear duct,
a salivary gland, lumens or other cavities of the lymphatic system,
a colon, a small intestine or a large intestine.
15. The method of claim 1, wherein said mammalian lumen is an
artery.
16. The method of claim 1, wherein said mammalian lumen is a gun
shot wound or a laceration.
17. The method of claim 1, wherein said mammalian lumen is
calcified.
18. The method of claim 1, wherein said method is part of a
surgical procedure; and said location is a surgical site.
19. The method of claim 18, wherein said surgical site is at or
proximal to a hemorrhage, cancerous tissue, tumor, or organ.
20. The method of claim 18, wherein said surgical procedure
comprises anastomosis.
21. The method of claim 2, wherein said balloon is a standard
balloon, a conical balloon, a square balloon, a spherical balloon,
a conical/square balloon, a long conical/square balloon, a
conical/spherical balloon, a long spherical balloon, a tapered
balloon, a dog bone balloon, a stepped balloon, an offset balloon,
or a conical/offset balloon.
22. The method of claim 1, wherein said balloon is formed from a
polymer selected from the group consisting of polybutylene
terephthalate-polyethene glycol block copolymers, polyurethenes,
ABS (acrylonitrile-butadiene-styrene), ABS/nylon, ABS/polyvinyl
chloride (PVC), ABS/polycarbonate, acrylonitrile copolymer,
polyacrylamide, polyacrylate, polyacrylsulfone, polyesters,
polyethylene terephthalate (PET), polybutylene terephthalate (PBT),
polyethylene naphthalate (PEN), liquid crystal polymer (LCP),
polyester/polycaprolactone, polyester/polyadipate,
polyetheretherketone (PEEK), polyethersulfone (PES), polyetherimide
(PEI), polyetherketone (PEK), polymenthylpentene, polyphenylene
ether, polyphenylene sulfide, styrene acrylonitrile (SAN),
polyamides, nylon 6, nylon 6/6, nylon 6/66, nylon 6/9, nylon 6110,
nylon 6/12, nylon 11, nylon 12, ethylene, propylene ethylene
vinylacetate, ethylene vinyl alcohol (EVA), ionomers, polyethylene
type I-IV, polyolefins, polyurethane, polyvinyl chloride,
polysiloxanes (silicones), fluorocarbons, polychlorotriethylene
(CTFE), poly[ethyleneco-chlorotrifluoroethylene] (ECTFE) copolymer
ethylene tetrafluoroethylene (ETFE), copolymers of
tetrafluoroethylene and hexafluoropropylene (FEP), perfluoroalkane
(PFA) and poly[vinylidene fluoride] (PVDF).
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/851,848, filed Sep. 7, 2007, which claims the benefit of
U.S. Provisional Application No. 60/843,601, filed Sep. 11,
2006.
[0002] The entire teachings of the above applications are
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0003] Mammalian (e.g., human) bodies include various lumen, such
as arteries, other blood vessels and bodily cavities. The mammalian
lumen, such as a coronary artery, sometimes become constricted or
blocked, for example, by plaque or a tumor. A constricted
passageway may be widened using an angioplasty procedure using a
catheter, which includes a balloon carried by a catheter shaft.
Additionally, it may be medically desirable to occlude temporarily
or permanently a biological lumen to diagnose or treat an ailment.
Such an occlusion may also be realized through the use of a
catheter.
[0004] Unfortunately, the pressure needed to use a balloon to open
or occlude a biological lumen may itself cause injury. For example,
in the case of arteries, inflated balloons are known to cause
dilation of the artery and the resulting injury to the intima can
lead to thickening and narrowing of the artery (Wainwright C L,
Miller A M, Wadsworth R M. "Inflammation as a key event in the
development of neointima following vascular balloon injury," Clin.
Exp. Pharmacol. Physiol. 2001, 28(11), 891-5; and Labropoulos N,
Giannoukas A D, Volteas S K, al Kutoubi A. "Complications of the
balloon assisted percutaneous transluminal angioplasty," J.
Cardiovasc. Surg. (Torino) 1994, 35(6), 475-89). Consequently,
there is a need for improved methods for using catheters to widen
or occlude biological passageways without injuring the lumen. The
present invention addresses this need and others.
SUMMARY OF THE INVENTION
[0005] One aspect of the present invention relates to catheters
that can be placed in or around bodily conduits to occlude or widen
a biological lumen without imparting significant trauma to the
lumen. Typically, catheters have a balloon or skirt fastened to at
least one end around the exterior of a hollow catheter shaft. The
hollow interior of the balloon or skirt is in fluid flow relation
with the hollow interior of the shaft. The shaft then may be used
to provide a fluid supply for inflating the balloon or deploying
the skirt.
[0006] In certain embodiments, the invention particularly relates
to the use of a polymer composition which can be made to gel upon
insertion into said balloon or skirt. In certain embodiments, the
inflating viscous polymer composition is a liquid at room
temperature and a gel at mammalian physiological temperature. In
certain embodiments, the inflating viscous polymer composition
comprises an optionally purified inverse thermosensitive
polymer.
[0007] The present invention has a number of advantages over
traditional fluid-filled balloons. For example, by using a polymer
composition, the reduced need for pressure allows the use of
thinner or flimsier materials that better conform to the shape of
the lumen wherein the balloon or skirt is deployed. In addition,
since the present invention can better conform to the target lumen,
it can be used in a wider range of diagnostic and therapeutic
applications. Because the firmness of the balloon is not due to
internal pressure, a full balloon may not be necessary to achieve
occlusion of the lumen. Also sufficient in many instances will be
an open structure in the shape or the form of an umbrella (e.g., a
skirt) filled with an aforementioned polymer composition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 depicts a graph of viscosity as a function of
temperature for various solutions of purified poloxamer 407.
[0009] FIG. 2 depicts [A] a table showing the results of the
purification of poloxamer 407 (wherein a "*" indicates a viscosity
of a 25% solution measured at 30.degree. C. using a cone and plate
viscometer); and [B] a table of the gelation temperature of
selected reverse phase media in saline.
[0010] FIG. 3 shows selected balloon shapes of the invention.
[0011] FIG. 4 shows additional selected balloon shapes of the
invention.
[0012] FIG. 5 shows a shirt shape of the invention.
[0013] FIG. 6 shows a shirt shape of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0014] For convenience, before further description of the present
invention, certain terms employed in the specification, examples,
and appended claims are collected here. These definitions should be
read in light of the remainder of the disclosure and understood as
by a person of skill in the art.
[0015] The indefinite articles "a" and "an," as used herein in the
specification and in the claims, unless clearly indicated to the
contrary, should be understood to mean "at least one."
[0016] The phrase "and/or," as used herein in the specification and
in the claims, should be understood to mean "either or both" of the
elements so conjoined, i.e., elements that are conjunctively
present in some cases and disjunctively present in other cases.
Multiple elements listed with "and/or" should be construed in the
same fashion, i.e., "one or more" of the elements so conjoined.
Other elements may optionally be present other than the elements
specifically identified by the "and/or" clause, whether related or
unrelated to those elements specifically identified. Thus, as a
non-limiting example, a reference to "A and/or B", when used in
conjunction with open-ended language such as "comprising" can
refer, in one embodiment, to A only (optionally including elements
other than B); in another embodiment, to B only (optionally
including elements other than A); in yet another embodiment, to
both A and B (optionally including other elements); etc.
[0017] As used herein in the specification and in the claims, the
phrase "at least one," in reference to a list of one or more
elements, should be understood to mean at least one element
selected from any one or more of the elements in the list of
elements, but not necessarily including at least one of each and
every element specifically listed within the list of elements and
not excluding any combinations of elements in the list of elements.
This definition also allows that elements may optionally be present
other than the elements specifically identified within the list of
elements to which the phrase "at least one" refers, whether related
or unrelated to those elements specifically identified. Thus, as a
non-limiting example, "at least one of A and B" (or, equivalently,
"at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in one embodiment, to at least one,
optionally including more than one, A, with no B present (and
optionally including elements other than B); in another embodiment,
to at least one, optionally including more than one, B, with no A
present (and optionally including elements other than A); in yet
another embodiment, to at least one, optionally including more than
one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
[0018] It should also be understood that, unless clearly indicated
to the contrary, in any methods claimed herein that include more
than one step or act, the order of the steps or acts of the method
is not necessarily limited to the order in which the steps or acts
of the method are recited.
[0019] In the claims, as well as in the specification above, all
transitional phrases such as "comprising," "including," "carrying,"
"having," "containing," "involving," "holding," "composed of," and
the like are to be understood to be open-ended, i.e., to mean
including but not limited to. Only the transitional phrases
"consisting of" and "consisting essentially of" shall be closed or
semi-closed transitional phrases, respectively, as set forth in the
United States Patent Office Manual of Patent Examining Procedures,
Section 2111.03.
[0020] The term "anastomosis" as used herein refers to a surgical
connection between tubular structures, such as blood vessels.
"Beating heart" bypass surgeries, also known as "off-pump" bypass
surgeries, are examples of surgical procedures in which anastomoses
are performed.
[0021] The term "ischemia" as used herein refers to a lack of blood
supply (and thus oxygen) to an organ or tissue.
[0022] The term "ischemic preconditioning" as used herein refers to
a technique in which tissue is rendered resistant to the
deleterious effects of prolonged ischemia by prior exposure to
brief, repeated periods of vascular occlusion.
[0023] The term "balloon" as used herein refers to non-compliant
balloons, semi-compliant balloons and compliant balloons. "Skirts,"
as used herein, refer to what looks like a half balloon or an
umbrella. Skirts can be convex or concave with respect to the
catheter. See FIGS. 5 (convex) and 6 (concave).
[0024] The term "lumen" denotes the space enclosed by a tube-like
structure or hollow organ, such as inside an artery, a vein, a
kidney, a gall bladder, a ureter, a urinary bladder, a pancreas, a
salivary gland, a colon, a small intestine or a large intestine
(i.e., an opening, space, or cavity in a biological system). Lumen,
as used herein, encompasses both natural lumen (as described above)
and unnatural lumen (such as gun shot wounds or lacerations).
Importantly, as used herein, lumen refers to the passageways that
connect organs and the organs themselves.
[0025] The term "contrast-enhancing" refers to materials capable of
being monitored during injection into a mammalian subject by
methods for monitoring and detecting such materials, for example by
radiography or fluoroscopy. An example of a contrast-enhancing
agent is a radiopaque material. Contrast-enhancing agents including
radiopaque materials may be either water soluble or water
insoluble. Examples of water soluble radiopaque materials include
metrizamide, iopamidol, iothalamate sodium, iodomide sodium, and
meglumine. Examples of water insoluble radiopaque materials include
metals and metal oxides such as gold, titanium, silver, stainless
steel, oxides thereof, aluminum oxide, zirconium oxide, etc.
[0026] As used herein, the term "polymer" means a molecule, formed
by the chemical union of two or more oligomer units. The chemical
units are normally linked together by covalent linkages. The two or
more combining units in a polymer can be the same, in which case
the polymer is referred to as a homopolymer. They can be also be
different and, thus, the polymer will be a combination of the
different units; these polymers are referred to as copolymers.
[0027] As used herein, "cross linking" is when individual polymer
chains are linked together by covalent bonds ("chemical
crosslinking") or ionic bonds ("ionic crosslinking") to form a
three dimensional network. In certain polymers this kind of process
has the effect of producing a gel.
[0028] As used herein, the term "inverse thermosensitive polymer"
indicates polymers which become more viscous at body temperature,
but less viscous at cooler temperature. In certain embodiments it
refers to a polymer that is soluble in water at ambient
temperature, but at least partially phase-separates out of water at
physiological temperature. Inverse thermosensitive polymers
include, for example, poloxamer 407, poloxamer 188, Pluronic.RTM.
F127, Pluronic.RTM. F68, poly(N-isopropylacrylamide), poly(methyl
vinyl ether), poly(N-vinylcaprolactam); and certain
poly(organophosphazenes). See, for example, Lee, B H et al.
"Synthesis and Characterization of Thermosensitive
Poly(organophosphazenes) with Methoxy-Poly(ethylene glycol) and
Alkylamines as Side Groups," Bull. Korean Chem. Soc. 2002, 23,
549-554.
[0029] The terms "reversibly gelling" and "inverse thermosensitive"
refer to the property of a inverse thermosensitive polymers wherein
gelation takes place upon an increase in temperature, rather than a
decrease in temperature.
[0030] The term "transition temperature" refers to the temperature
or temperature range at which gelation of an inverse
thermosensitive polymers occurs.
[0031] The phrase "polydispersity index" refers to the ratio of the
"weight average molecular weight" to the "number average molecular
weight" for a particular polymer; it reflects the distribution of
individual molecular weights in a polymer sample.
[0032] The phrase "weight average molecular weight" refers to a
particular measure of the molecular weight of a polymer. The weight
average molecular weight is calculated as follows: determine the
molecular weight of a number of polymer molecules; add the squares
of these weights; and then divide by the total weight of the
molecules.
[0033] The phrase "number average molecular weight" refers to a
particular measure of the molecular weight of a polymer. The number
average molecular weight is the common average of the molecular
weights of the individual polymer molecules. It is determined by
measuring the molecular weight of n polymer molecules, summing the
weights, and dividing by n.
[0034] The term "biocompatible", as used herein, refers to having
the property of being biologically compatible by not producing a
toxic, injurious, or immunological response in living tissue.
[0035] The term "poloxamer" denotes a symmetrical block copolymer,
consisting of a core of PPG polyoxyethylated to both its terminal
hydroxyl groups, i.e., conforming to the interchangeable generic
formula (PEG).sub.X-(PPG).sub.Y-(PEG).sub.X and
(PEO).sub.X-(PPO).sub.Y-(PEO).sub.X. Each poloxamer name ends with
an arbitrary code number, which is related to the average numerical
values of the respective monomer units denoted by X and Y.
[0036] The term "poloxamine" denotes a polyalkoxylated symmetrical
block copolymer of ethylene diamine conforming to the general type
[(PEG).sub.X-(PPG).sub.Y].sub.2-NCH.sub.2CH.sub.2N-[(PPG).sub.Y-(PEG).sub-
.X].sub.2. Each Poloxamine name is followed by an arbitrary code
number, which is related to the average numerical values of the
respective monomer units denoted by X and Y.
[0037] "Alginic acid" as used here in is a naturally occurring
hydrophilic colloidal polysaccharide obtained from the various
species of brown seaweed (Phaeophyceae). It occurs in white to
yellowish brown filamentous, grainy, granular or powdered forms. It
is a linear copolymer consisting mainly of residues of
.beta.-1,4-linked D-mannuronic acid and .alpha.-1,4-linked
L-glucuronic acid. These monomers are often arranged in
homopolymeric blocks separated by regions approximating an
alternating sequence of the two acid monomers, as shown below:
##STR00001##
The formula weight of the structural unit is 176.13 (theoretical;
200 is the actual average). The formula weight of the macromolecule
ranges from about 10,000 to about 600,000 (typical average).
[0038] "Sodium alginate" and "potassium alginate" are salts of
alginic acid. For example, "potassium alginate" is shown below:
##STR00002##
[0039] "Gellan gum" is a high molecular weight polysaccharide gum
produced by a pure culture fermentation of a carbohydrate by
Pseudomonas elodea, purified by recovery with isopropyl alcohol,
dried, and milled. The high molecular weight polysaccharide is
principally composed of a tetrasaccharide repeating unit of one
rhamnose, one glucuronic acid, and two glucose units, and is
substituted with acyl (glyceryl and acetyl) groups as the
O-glycosidically-linked esters. The glucuronic acid is neutralized
to a mixed potassium, sodium, calcium, and magnesium salt. It
usually contains a small amount of nitrogen containing compounds
resulting from the fermentation procedures. It has a formula weight
of about 500,000. "Sodium gellan" and "potassium gellan" are salts
of gellan gum.
[0040] Carboxymethylcellulose (CMC) is a polymer derived from
natural cellulose. Unlike cellulose, CMC is highly water-soluble.
The CMC structure is based on the .beta.-(1,4)-D-glucopyranose
polymer of cellulose. Different preparations may have different
degrees of substitution, but it is generally in the range of about
0.6 to about 0.95 derivatives per monomer unit, as shown below:
##STR00003##
[0041] CMC molecules are somewhat shorter, on average, than native
cellulose with uneven derivatization giving areas of high and low
substitution. This substitution is mostly 2-O- and 6-O-linked,
followed in order of importance by 2,6-di-O- then 3-O-, 3,6-di-O-,
2,3-di-O- lastly 2,3,6-tri-O-linked. It appears that the
substitution process is a slightly cooperative (within residues)
rather than random process giving slightly higher than expected
unsubstituted and trisubstituted areas. CMC molecules are most
extended (rod-like) at low concentrations but at higher
concentrations the molecules overlap and coil up and then, at high
concentrations, entangle to become a thermoreversible gel.
Increasing ionic strength and reducing pH both decrease the
viscosity as they cause the polymer to become more coiled. The
average chain length and degree of substitution are of great
importance; the more-hydrophobic lower substituted CMCs are
thixotropic but more-extended higher substituted CMCs are
pseudoplastic. At low pH, CMC may form cross-links through
lactonization between carboxylic acid and free hydroxyl groups.
[0042] "Poly vinyl alcohol" (PVA) is a water soluble polymer
synthesized by hydrolysis of a poly vinyl ester such as the acetate
and used for preparation of fibers. PVA is a thermoplastic that is
produced from full or partial hydrolysis of vinyl ester such as
vinyl acetate resulting in the replacement of some or all of the
acetyl groups with hydroxyl groups. For example:
##STR00004##
In certain embodiments polyvinyl alcohol (PVA) is a synthetic resin
produced by polymerization of vinyl acetate (VAM) followed by
hydrolysis of the polyvinyl acetate (PVAc) polymer. The degree of
polymerisation determines the molecular weight and viscosity in
solution. The degree of hydrolysis (saponification) signifies the
extent of conversion of the polyvinyl acetate to the polyvinyl
alcohol For example n (degree of hydrolysis) may be in the range of
about 68.2 to about 99.8 mol. % and the MW (weight average
molecular weight) may range from about 10,000 to about 190,000.
[0043] Hyaluronic acid (HA) is a polymer composed of repeating
dimeric units of glucuronic acid and N-acetyl glucosamine. It may
be of extremely high molecular weight (up to several million
daltons) and forms the core of complex proteoglycan aggregates
found in extracellular matrix. HA is comprised of linear,
unbranching, polyanionic disaccharide units consisting of
glucuronic acid (GlcUA) an N-acetyl glucosamine (GlcNAc) joined
alternately by .beta.-1-3 and .beta.-1-4 glycosidic bonds (see
below). It is a member of the glycosaminoglycan family which
includes chondroitin sulphate, dermatin sulphate and heparan
sulphate. Unlike other members of this family, it is not found
covalently bound to proteins.
##STR00005##
[0044] When incorporated into a neutral aqueous solution hydrogen
bond formation occurs between water molecules and adjacent carboxyl
and N-acetyl groups. This imparts a conformational stiffness to the
polymer, which limits its flexibility. The hydrogen bond formation
results in the unique water-binding and retention capacity of the
polymer. It also follows that the water-binding capacity is
directly related to the molecular weight of the molecule. Up to six
liters of water may be bound per gram of HA.
[0045] HA solutions are characteristically viscoelastic and
pseudoplastic. This rheology is found even in very dilute solutions
of the polymer where very viscous gels are formed. The viscoelastic
property of HA solutions which is important in its use as a
biomaterial is controlled by the concentration and molecular weight
of the HA chains. The molecular weight of HA from different sources
is polydisperse and highly variable ranging from 10.sup.4 to
10.sup.7 Da. The extrusion of HA through the cell membrane as it is
produced permits unconstrained polymer elongation and hence a very
high molecular weight molecule.
[0046] The term "degradable", as used herein, refers to having the
property of breaking down or degrading under certain conditions,
e.g., by dissolution.
[0047] Contemplated equivalents of the polymers, subunits and other
compositions described above include such materials which otherwise
correspond thereto, and which have the same general properties
thereof (e.g., form inverse thermosensitive polymer compositions),
wherein one or more simple variations of substituents are made
which do not adversely affect the efficacy of such molecule to
achieve its intended purpose. In general, the compositions of the
present invention may be prepared by, for example, described below,
or by modifications thereof, using readily available starting
materials, reagents and conventional synthesis procedures. In these
reactions, it is also possible to make use of variants which are in
themselves known, but are not mentioned here.
[0048] Selected Polymer Compositions of the Invention.
[0049] In certain embodiments, the polymers used in the inventive
methods gel by one or more physical phenomena, such as temperature,
pH changes and/or ionic interactions. In certain embodiments, the
polymers used in a method of the invention are crosslinkable
polymers. Also, the polymer compositions of the invention can
include one or more additives; for example, contrast agents may be
added to the inverse thermosensitive polymers.
[0050] In certain embodiments, the polymer composition of the
invention may be a flexible or flowable material. By "lowable" is
meant the ability to assume, over time and at body temperature, the
shape of the space into which the composition or material is
introduced. Also encompassed by the term "flowable" are highly
viscous, gel-like materials at room temperature that may be
delivered into the balloon by being injected with anyone of the
commercially available power injection devices that provide
injection pressures greater than would be exerted by manual means
alone. When the polymer used is itself flowable, the polymer
composition of the invention, even when viscous, need not include a
biocompatible solvent to be flowable, although trace or residual
amounts of biocompatible solvents may be present.
[0051] In one embodiment, two solutions--a polymer solution and a
crosslinker solution--are injected separately (e.g., through a dual
lumen catheter) into a balloon or skirt wherein they form a gel. In
a related embodiment, two solutions are mixed just prior to
injection. Said polymer solutions may comprise an anionic polymer,
a cationic polymer or a non-ionically crosslinkable polymer. Such
polymers may be selected from one or more of the following: alginic
acid, sodium alginate, potassium alginate, sodium gellan, potassium
gellan, carboxy methyl cellulose, hyaluronic acid, and polyvinyl
alcohol. The cross-linking of the polymer may be achieved with
anionic crosslinking ions, cationic crosslinking ions, or non-ionic
crosslinking agents. Crosslinking agents include, but are not
limited to, one or more of the following: phosphate, citrate,
borate, succinate, maleate, adipate, oxalate, calcium, magnesium,
barium and strontium. Exemplary pairings of polymers and
crosslinkers include anionic polymer monomers with cations, such
as, for example, alginates with calcium, barium or magnesium;
gellans with calcium, magnesium or barium; or hyaluronic acid with
calcium. An example of an exemplary pairing of a non-ionic polymer
with a chemical crosslinking agent is a polyvinyl alcohol with
borate (at a slightly alkaline pH).
[0052] In addition, in certain embodiments, the polymer composition
of the invention may be formed from an aqueous solution of inverse
thermosensitive polymers. These polymer solutions are liquids below
body temperature and gel at about body temperature. The polymer
solution is prepared external of the body, i.e., at a temperature
below body temperature. The polymer solution may be further chilled
to prolong the time the gel stays in the liquid form upon
introduction into the body. A preferred temperature is about
10.degree. C. below the gelation temperature of the polymer
solution.
[0053] In general, the inverse thermosensitive polymers used in the
methods of the invention can be administered in a liquid form. The
material, upon reaching body temperature, undergoes a transition
from a liquid to a gel. In certain embodiments, the inverse thermo
sensitive polymers used in connection with the methods of the
invention may comprise a block copolymer with inverse thermal
gelation properties. The block copolymer can further comprise a
polyoxyethylene-polyoxypropylene block copolymer, such as a
biodegradable, biocompatible copolymer of polyethylene oxide and
polypropylene oxide.
[0054] In certain embodiments, the block copolymers have molecular
weights ranging from about 2,000 to about 1,000,000 Daltons, more
particularly at least about 10,000 Daltons, and even more
specifically at least about 25,000 Daltons or even at least about
50,000 Daltons. In a preferred embodiment, the block copolymers
have a molecular weight between about 5,000 Daltons and about
30,000 Daltons. Number-average molecular weight (M.sub.n) may also
vary, but will generally fall in the range of about 1,000 to about
400,000 Daltons, preferably from about 1,000 to about 100,000
Daltons and, even more preferably, from about 1,000 to about 70,000
Daltons. Most preferably, M.sub.n varies between about 5,000 and
about 300,000 Daltons.
[0055] The molecular weight of the inverse thermosensitive polymers
is preferably between 1,000 and 50,000, more preferably between
5,000 and 35,000. Preferably the polymer is in an aqueous solution.
For example, typical aqueous solutions contain about 5% to about
30% polymer, preferably about 10% to about 25%. The molecular
weight of a suitable inverse thermosensitive polymers (such as a
poloxamer or poloxamine) may be, for example, between 5,000 and
25,000, and more particularly between 7,000 and 20,000.
[0056] The pH of the inverse thermosensitive polymers formulation
administered to a mammal is, generally, about 6.0 to about 7.8,
which are suitable pH levels for injection into the mammalian body.
The pH level may be adjusted by any suitable acid or base, such as
hydrochloric acid or sodium hydroxide.
[0057] In certain embodiments, the inverse thermosensitive polymers
of the invention are poloxamers or poloxamines. Pluronic.RTM.
polymers have unique surfactant abilities and extremely low
toxicity and immunogenic responses. These products have low acute
oral and dermal toxicity and low potential for causing irritation
or sensitization, and the general chronic and sub-chronic toxicity
is low. In fact, Pluronic.RTM. polymers are among a small number of
surfactants that have been approved by the FDA for direct use in
medical applications and as food additives (BASF (1990)
Pluronic.RTM. & Tetronic.RTM. Surfactants, BASF Co., Mount
Olive, N.J.). Recently, several Pluronic.RTM. polymers have been
found to enhance the therapeutic effect of drugs, and the gene
transfer efficiency mediated by adenovirus. (March K L, Madison J
E, Trapnell B C. "Pharmacokinetics of adenoviral vector-mediated
gene delivery to vascular smooth muscle cells: modulation by
poloxamer 407 and implication for cardiovascular gene therapy," Hum
Gene Therapy 1995, 6, 41-53).
[0058] Interestingly, poloxamers (or Pluronics), as nonionic
surfactants, are widely used in diverse industrial applications.
(Nonionic Surfactants: polyoxyalkylene block copolymers, Vol. 60.
Nace V M, Dekker M (editors), New York, 1996. 280 pp.) Their
surfactant properties have been useful in detergency, dispersion,
stabilization, foaming, and emulsification. (Cabana A, Abdellatif A
K, Juhasz J. "Study of the gelation process of polyethylene oxide.
polypropylene oxide-polyethylene oxide copolymer (poloxamer 407)
aqueous solutions," Journal of Colloid and Interface Science 1997,
190, 307-312.) Certain poloxamines, e.g., poloxamine 1307 and 1107,
also display inverse thermosensitivity.
[0059] Importantly, several members of this class of polymer (e.g.,
poloxamer 188, poloxamer 407, poloxamer 338, poloxamines 1107 and
1307) show inverse thermosensitivity within the physiological
temperature range. (Qiu Y, Park K. "Environment-sensitive hydrogels
for drug delivery," Adv. Drug Deliv. Rev. 2001, 53(3), 321-339; and
Ron E S, Bromberg L E Temperature-responsive gels and thermogelling
polymer matrices for protein and peptide delivery," Adv. Drug
Deliv. Rev. 1998, 31(3), 197-221.) In other words, these polymers
are members of a class that are soluble in aqueous solutions at low
temperature, but gel at higher temperatures. Poloxamer 407 is a
biocompatible polyoxypropylene-polyoxyethylene block copolymer
having an average molecular weight of about 12,500 and a
polyoxypropylene fraction of about 30%; poloxamer 188 has an
average molecular weight of about 8400 and a polyoxypropylene
fraction of about 20%; poloxamer 338 has an average molecular
weight of about 14,600 and a polyoxypropylene fraction of about
20%; poloxamine 1107 has an average molecular weight of about
14,000, poloxamine 1307 has an average molecular weight of about
18,000. Polymers of this type are also referred to as reversibly
gelling because their viscosity increases and decreases with an
increase and decrease in temperature, respectively. Such reversibly
gelling systems are useful wherever it is desirable to handle a
material in a fluid state, but performance is preferably in a
gelled or more viscous state. As noted above, certain
poly(ethyleneoxide)/poly(propylene-oxide) block copolymers have
these properties; they are available commercially as Pluronic.RTM.
poloxamers and Tetronic.RTM. poloxamines (BASF, Ludwigshafen,
Germany) and generically known as poloxamers and poloxamines,
respectively. (See U.S. Pat. Nos. 4,188,373, 4,478,822 and
4,474,751; all of which are incorporated by reference).
[0060] The average molecular weights of commercially available
poloxamers and poloxamines range from about 1,000 to greater than
16,000 Daltons. Because the poloxamers are products of a sequential
series of reactions, the molecular weights of the individual
poloxamer molecules form a statistical distribution about the
average molecular weight. In addition, commercially available
poloxamers contain substantial amounts of poly(oxyethylene)
homopolymer and poly(oxyethylene)/poly(oxypropylene diblock
polymers. The relative amounts of these byproducts increase as the
molecular weights of the component blocks of the poloxamer
increase. Depending upon the manufacturer, these byproducts may
constitute from about 15% to about 50% of the total mass of the
commercial polymer.
[0061] Purification of Inverse Thermosensitive Polymers.
[0062] The inverse thermosensitive polymers may be purified using a
process for the fractionation of water-soluble polymers, comprising
the steps of dissolving a known amount of the polymer in water,
adding a soluble extraction salt to the polymer solution,
maintaining the solution at a constant optimal temperature for a
period of time adequate for two distinct phases to appear, and
separating physically the phases. Additionally, the phase
containing the polymer fraction of the preferred molecular weight
may be diluted to the original volume with water, extraction salt
may be added to achieve the original concentration, and the
separation process repeated as needed until a polymer having a
narrower molecular weight distribution than the starting material
and optimal physical characteristics can be recovered.
[0063] In certain embodiments, a purified poloxamer or poloxamine
has a polydispersity index from about 1.5 to about 1.0. In certain
embodiments, a purified poloxamer or poloxamine has a
polydispersity index from about 1.2 to about 1.0.
[0064] The aforementioned process consists of forming an aqueous
two-phase system composed of the polymer and an appropriate salt in
water. In such a system, a soluble salt can be added to a single
phase polymer-water system to induce phase separation to yield a
high salt, low polymer bottom phase, and a low salt, high polymer
upper phase. Lower molecular weight polymers partition
preferentially into the high salt, low polymer phase. Polymers that
can be fractionated using this process include polyethers, glycols
such as poly(ethylene glycol) and poly(ethylene oxide)s,
polyoxyalkylene block copolymers such as poloxamers, poloxamines,
and polyoxypropylene/polyoxybutylene copolymers, and other polyols,
such as polyvinyl alcohol. The average molecular weight of these
polymers may range from about 800 to greater than 100,000 Daltons.
See U.S. Pat. No. 6,761,824; hereby incorporated by reference. The
aforementioned purification process inherently exploits the
differences in size and polarity, and therefore solubility, among
the poloxamer molecules, the poly(oxyethylene) homopolymer and the
poly(oxyethylene)/poly(oxypropylene) diblock byproducts. The polar
fraction of the poloxamer, which generally includes the lower
molecular weight fraction and the byproducts, is removed allowing
the higher molecular weight fraction of poloxamer to be recovered.
The larger molecular weight poloxamer recovered by this method has
physical characteristics substantially different from the starting
material or commercially available poloxamer including a higher
average molecular weight, lower polydispersity and a higher
viscosity in aqueous solution.
[0065] Other purification methods may be used to achieve the
desired outcome. For example, WO 92/16484 discloses the use of gel
permeation chromatography to isolate a fraction of poloxamer 188
that exhibits beneficial biological effects, without causing
potentially deleterious side effects. The copolymer thus obtained
had a polydispersity index of 1.07 or less, and was substantially
saturated. The potentially harmful side effects were shown to be
associated with the low molecular weight, unsaturated portion of
the polymer, while the medically beneficial effects resided in the
uniform higher molecular weight material. Other similarly improved
copolymers were obtained by purifying either the polyoxypropylene
center block during synthesis of the copolymer, or the copolymer
product itself (e.g., U.S. Pat. Nos. 5,523,492 and 5,696,298; both
of which are herein incorporated by reference).
[0066] Further, a supercritical fluid extraction technique has been
used to fractionate a polyoxyalkylene block copolymer as disclosed
in U.S. Pat. No. 5,567,859 (hereby incorporated by reference). A
purified fraction was obtained, which was composed of a fairly
uniform polyoxyalkylene block copolymer having a polydispersity of
less than 1.17. According to this method, the lower molecular
weight fraction was removed in a stream of carbon dioxide
maintained at a pressure of 2200 pounds per square inch (psi) and a
temperature of 40.degree. C.
[0067] Additionally, U.S. Pat. No. 5,800,711 (hereby incorporated
by reference) discloses a process for the fractionation of
polyoxyalkylene block copolymers by the batchwise removal of low
molecular weight species using a salt extraction and liquid phase
separation technique. Poloxamer 407 and poloxamer 188 were
fractionated by this method. In each case, a copolymer fraction was
obtained which had a higher average molecular weight and a lower
polydispersity index as compared to the starting material. However,
the changes in polydispersity index were modest and analysis by gel
permeation chromatography indicated that some low-molecular-weight
material remained. The viscosity of aqueous solutions of the
fractionated polymers was significantly greater than the viscosity
of the commercially available polymers at temperatures between
10.degree. C. and 37.degree. C., an important property for some
medical and drug delivery applications. Nevertheless, some of the
low molecular weight contaminants of these polymers are thought to
cause deleterious side effects when used inside the body, making it
especially important that they be removed in the fractionation
process. As a consequence, polyoxyalkylene block copolymers
fractionated by this process are not appropriate for all medical
uses.
[0068] Selected Balloons and Skirts of the Invention.
[0069] Balloon and skirts of the invention can be of various shapes
and sizes (for example, those shown in FIGS. 3-6) and can be formed
from a variety of polymers and polymer combinations. For example,
elastomers, such as thermoplastic elastomers and engineering
thermoplastic elastomers, such as polybutylene
terephthalate-polyethene glycol block copolymers, which are
available, for example, as HYTREL.RTM., can be used. These are
discussed in U.S. Pat. No. 5,797,877, which is incorporated herein
by reference. Other polymers which may be used include
polyurethenes. Other polymers include copolymers such as ABS
(acrylonitrile-butadiene-styrene), ABS/nylon, ABS/polyvinyl
chloride (PVC), ABS/polycarbonate, acrylonitrile copolymer,
polyacrylamide, polyacrylate and polyacrylsulfone, polyesters such
as polyethylene terephthalate (PET), polybutylene terephthalate
(PBT), polyethylene naphthalate (PEN), liquid crystal polymer
(LCP), polyester/polycaprolactone and polyester/polyadipate; and
high melt temperature polyethers including polyetheretherketone
(PEEK), polyethersulfone (PES), polyetherimide (PEI) and
polyetherketone (PEK), polymenthylpentene, polyphenylene ether,
polyphenylene sulfide, and styrene acrylonitrile (SAN), polyamides
such as nylon 6, nylon 6/6, nylon 6/66, nylon 6/9, nylon 6/10,
nylon 6/12, nylon 11, nylon 12, ethylene, propylene ethylene
vinylacetate and ethylene vinyl alcohol (EVA), various ionomers,
polyethylene type I-IV, polyolefins, polyurethane, polyvinyl
chloride, and polysiloxanes (silicones). In addition fluorocarbons
such as polychlorotriethylene (CTFE),
poly[ethylene-co-chlorotrifluoroethylene] (ECTFE) copolymer
ethylene tetrafluoroethylene (ETFE), copolymer tetrafluoroethylene
and hexafluoropropylene (FEP), perfluoroalkane (PFA) and
poly[vinylidene fluoride] (PVDF) can be used. Other polymers
suitable for use in the balloons of the invention are described in
US Patent Applications Publication Nos. 2006/0182913 and
2006/0184112, both of which are hereby incorporated by
reference.
[0070] In certain embodiments, the balloons and skirts of the
invention have a minimum wall thickness of at least about 1 micron
(e.g., at least about 1.5 micron, at least about 2 micron, at least
about 2.5 micron, at least about 3.0 microns, at least about 3.5
microns), and/or a maximum thickness of at most about 100 microns
(e.g., at most about 5 microns, at most about 10 microns, at most
about 20 microns, at most about 25 microns, at most about 30
microns, at most about 40 microns, at most about 45 microns, at
most about 50 microns, at most about 60 microns, at most about 70
microns, at most about 80 microns, at most about 90 microns).
[0071] In certain embodiments, a balloon of the invention has a
burst pressure of at least about 0.5 to 10 atm (e.g., about 10 atm
of greater). In certain embodiments, a balloon of the invention has
a burst pressure of up to about 30 atm or up to about 40 atm. As
referred to herein, the burst pressure of a balloon refers to the
internal pressure at which the balloon bursts. One way the burst
pressure of a balloon is determined is by measuring the internal
pressure of the balloon as the balloon is inflated at a rate of two
psi per second with a 10 second hold at every 50 psi interval until
the balloon bursts.
[0072] Selected Methods of the Invention.
[0073] In certain embodiments, the invention relates to
polymer-filled balloons or skirts, and catheters using such
balloons or skirts, for administering treatments to widen
constricted passages in, for example, angioplasty, valvuloplasty,
or urological procedures. In other embodiments, the invention
relates to the use of polymer-filled balloons or skirts to prevent
the flow of fluids through bodily passageways. In certain
embodiments the polymer-filled balloons or skirts can be punctured
or inverted, respectively, allowing the contained polymer to be
dissolved in the surrounding bodily fluid or irrigation fluid. In
certain embodiments, saline or cold saline can be used to dissolve
the gelled polymer.
[0074] One aspect of the invention relates to a method of
occluding, widening or stenting a lumen in a mammal, comprising the
steps of:
[0075] positioning a catheter into said mammalian lumen at a
location, wherein said catheter comprises an elongated shaft having
an inflation lumen and a balloon or skirt connected to the
elongated shaft so that an interior chamber of the balloon or skirt
is in fluid communication with the inflation lumen;
[0076] filling said balloon or skirt, via said inflation lumen,
with a composition comprising at least one polymer, wherein said
composition gels partially or completely in said balloon or
skirt.
[0077] In certain embodiments, the present invention relates to the
aforementioned method, wherein said catheter comprises a
balloon.
[0078] In certain embodiments, the present invention relates to the
aforementioned method, wherein said catheter comprises a skirt.
[0079] In certain embodiments, the present invention relates to the
aforementioned method, wherein said method is substantially
atraumatic to said mammalian lumen.
[0080] In certain embodiments, the present invention relates to the
aforementioned method, wherein said mammalian lumen is temporarily
occluded.
[0081] In certain embodiments, the present invention relates to the
aforementioned method, wherein said mammalian lumen is permanently
occluded.
[0082] In certain embodiments, the present invention relates to the
aforementioned method, wherein said catheter further comprises a
guidewire lumen.
[0083] In certain embodiments, the present invention relates to the
aforementioned method, wherein said catheter is a stent delivery
catheter with a stent mounted on the balloon or skirt.
[0084] In certain embodiments, the present invention relates to the
aforementioned method, wherein said catheter is a stent delivery
catheter with a stent mounted on the balloon or skirt; and the
stent carries a therapeutic agent.
[0085] In certain embodiments, the present invention relates to the
aforementioned method, wherein said at least one polymer is at
least one optionally purified inverse thermosensitive polymer.
[0086] In certain embodiments, the present invention relates to the
aforementioned method, wherein said at least one polymer is at
least one purified inverse thermosensitive polymer.
[0087] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition has a transition
temperature of between about 10.degree. C. and about 40.degree.
C.
[0088] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition has a transition
temperature of between about 15.degree. C. and about 30.degree.
C.
[0089] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition has a transition
temperature of about 25.degree. C.
[0090] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition gels over a
temperature range of about 2.degree. C. to about 5.degree. C.
[0091] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition gels over a
temperature range of about 2.degree. C. to about 3.degree. C.
[0092] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition gels over a
temperature range of about 2.degree. C.
[0093] In certain embodiments, the present invention relates to the
aforementioned method, wherein said optionally purified inverse
thermosensitive polymer has a polydispersity index from about 1.5
to about 1.0.
[0094] In certain embodiments, the present invention relates to the
aforementioned method, wherein said optionally purified inverse
thermosensitive polymer has a polydispersity index from about 1.2
to about 1.0.
[0095] In certain embodiments, the present invention relates to the
aforementioned method, wherein said optionally purified inverse
thermosensitive polymer has a polydispersity index from about 1.1
to about 1.0.
[0096] In certain embodiments, the present invention relates to the
aforementioned method, wherein said optionally purified inverse
thermosensitive polymer is selected from the group consisting of
block copolymers, random copolymers, graft polymers, and branched
copolymers.
[0097] In certain embodiments, the present invention relates to the
aforementioned method, wherein said optionally purified inverse
thermosensitive polymer is a polyoxyalkylene block copolymer.
[0098] In certain embodiments, the present invention relates to the
aforementioned method, wherein said optionally purified inverse
thermosensitive polymer is selected from the group consisting of
poloxamers and poloxamines.
[0099] In certain embodiments, the present invention relates to the
aforementioned method, wherein said optionally purified inverse
thermosensitive polymer is selected from the group consisting of
poloxamer 407, poloxamer 338, poloxamer 118, Tetronic.RTM. 1107 and
Tetronic.RTM. 1307.
[0100] In certain embodiments, the present invention relates to the
aforementioned method, wherein said optionally purified inverse
thermosensitive polymer is poloxamer 407.
[0101] In certain embodiments, the present invention relates to the
aforementioned method, wherein said optionally purified inverse
thermosensitive polymer is a poloxamer or poloxamine; and said
composition has a transition temperature of between about
10.degree. C. and 40.degree. C.
[0102] In certain embodiments, the present invention relates to the
aforementioned method, wherein said optionally purified inverse
thermosensitive polymer is a poloxamer or poloxamine; and said
composition has a transition temperature of between about
15.degree. C. and 30.degree. C.
[0103] In certain embodiments, the present invention relates to the
aforementioned method, wherein said optionally purified inverse
thermosensitive polymer is a poloxamer or poloxamine; and said
composition has a transition temperature of about 25.degree. C.
[0104] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition comprises about 5%
to about 35% of said optionally purified inverse thermosensitive
polymer.
[0105] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition comprises about 10%
to about 30% of said optionally purified inverse thermosensitive
polymer.
[0106] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition comprising at least
one polymer comprises an anionic, cationic, or non-ionically
crosslinkable polymer.
[0107] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition comprising at least
one polymer comprises a polymer selected from the group consisting
of alginic acid, sodium alginate, potassium alginate, sodium
gellan, potassium gellan, carboxy methyl cellulose, hyaluronic acid
and polyvinyl alcohol.
[0108] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition comprising at least
one polymer further comprises phosphate, citrate, borate,
succinate, maleate, adipate, oxalate, calcium, magnesium, barium,
strontium, or a combination thereof.
[0109] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition comprising at least
one polymer comprises a polymer selected from the group consisting
of alginic acid, sodium alginate, potassium alginate, sodium gellan
and potassium gellan; and said composition comprising at least one
polymer further comprises calcium, magnesium or barium.
[0110] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition comprising at least
one polymer comprises a polymer selected from the group consisting
of alginic acid, sodium alginate or potassium alginate; and said
composition comprising at least one polymer further comprises
calcium.
[0111] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition comprising at least
one polymer comprises a polymer selected from the group consisting
of sodium gellan and potassium gellan; and said composition
comprising at least one polymer further comprises magnesium.
[0112] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition comprising at least
one polymer comprises hyaluronic acid; and said composition
comprising at least one polymer further comprises calcium.
[0113] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition comprising at least
one polymer comprises polyvinyl alcohol; and said composition
comprising at least one polymer further comprises borate.
[0114] In certain embodiments, the present invention relates to the
aforementioned method, wherein the volume of said composition at
physiological temperature is about 80% to about 120% of its volume
below its transition temperature.
[0115] In certain embodiments, the present invention relates to the
aforementioned method, wherein said composition further comprises a
contrast-enhancing agent.
[0116] In certain embodiments, the present invention relates to the
aforementioned method, wherein said contrast-enhancing agent is
selected from the group consisting of radiopaque materials,
paramagnetic materials, heavy atoms, transition metals,
lanthanides, actinides, dyes, and radionuclide-containing
materials.
[0117] In certain embodiments, the present invention relates to the
aforementioned method, wherein said mammal is a human.
[0118] In certain embodiments, the present invention relates to the
aforementioned method, wherein said mammalian lumen is an artery, a
vein, a kidney, a gall bladder, a ureter, a urinary bladder, a
pancreatic duct, a fallopian tube, a sinus, a tear duct, a salivary
gland, lumens or other cavities of the lymphatic system, a colon, a
small intestine or a large intestine.
[0119] In certain embodiments, the present invention relates to the
aforementioned method, wherein said mammalian lumen is an
artery.
[0120] In certain embodiments, the present invention relates to the
aforementioned method, wherein said mammalian lumen is a gun shot
wound or a laceration.
[0121] In certain embodiments, the present invention relates to the
aforementioned method, wherein said mammalian lumen is
calcified.
[0122] In certain embodiments, the present invention relates to the
aforementioned method, wherein said mammalian lumen is occluded for
diagnostic purposes.
[0123] In certain embodiments, the present invention relates to the
aforementioned method, wherein said mammalian lumen is occluded for
therapeutic purposes.
[0124] In certain embodiments, the present invention relates to the
aforementioned method, further comprising the step of cooling said
location, thereby liquefying the gel in said balloon or skirt.
[0125] In certain embodiments, the present invention relates to the
aforementioned method, wherein said location is cooled by using a
cold aqueous solution or ice.
[0126] In certain embodiments, the present invention relates to the
aforementioned method, further comprising the step of injecting an
aqueous solution into said balloon or skirt, thereby dissolving
said gel in said balloon or skirt.
[0127] In certain embodiments, the present invention relates to the
aforementioned method, further comprising the step of injecting an
aqueous solution into said balloon or skirt, thereby dissolving
said gel in said balloon or skirt.
[0128] In certain embodiments, the present invention relates to the
aforementioned method, further comprising the step of piercing the
balloon or inverting the skirt to allow release of the polymer
composition contained within, thereby dissolving it in the
surrounding bodily fluid.
[0129] In certain embodiments, the present invention relates to the
aforementioned method, further comprising the steps of piercing the
balloon or inverting the skirt to allow release of the polymer
composition contained within; and injecting saline into said
balloon or skirt, thereby dissolving the polymer composition.
[0130] In certain embodiments, the present invention relates to the
aforementioned method, wherein the temperature of said saline is
below 25.degree. C.
[0131] In certain embodiments, the present invention relates to the
aforementioned method, wherein said skirt is a convex skirt.
[0132] In certain embodiments, the present invention relates to the
aforementioned method, further comprising the step of pulling the
catheter shaft to cause inversion of the skirt and dissolution of
the gel.
[0133] In certain embodiments, the present invention relates to the
aforementioned method, wherein said skirt is a concave skirt.
[0134] In certain embodiments, the present invention relates to the
aforementioned method, further comprising the step of pushing the
catheter shaft to cause inversion of the skirt and dissolution of
the gel.
[0135] In certain embodiments, the present invention relates to the
aforementioned method, wherein said method is part of a surgical
procedure; and said location is a surgical site.
[0136] In certain embodiments, the present invention relates to the
aforementioned method, wherein said surgical site is at or proximal
to a hemorrhage, cancerous tissue, tumor, or organ.
[0137] In certain embodiments, the present invention relates to the
aforementioned method, wherein said surgical procedure comprises
anastomosis.
[0138] In certain embodiments, the present invention relates to the
aforementioned method, wherein said anastomosis comprises
connecting a first vessel and a second vessel.
[0139] In certain embodiments, the present invention relates to the
aforementioned method, wherein said connecting a first vessel and a
second vessel comprises suturing, laser welding or laser
soldering.
[0140] In certain embodiments, the present invention relates to the
aforementioned method, wherein said anastomosis is selected from
the group consisting of end-to-end anastomosis, side-to-end
anastomosis and side-to-side anastomosis.
[0141] In certain embodiments, the present invention relates to the
aforementioned method, wherein said occlusion reduces bleeding
during said surgical procedure.
[0142] In certain embodiments, the present invention relates to the
aforementioned method, wherein said occlusion enables controlled
ischemic preconditioning of said surgical site.
[0143] In certain embodiments, the present invention relates to the
aforementioned method, wherein said occlusion is at or proximal to
an incision site for minimally invasive surgery and decreases
bleeding through the incision.
[0144] In certain embodiments, the present invention relates to the
aforementioned method, wherein said balloon is a standard balloon,
a conical balloon, a square balloon, a spherical balloon, a
conical/square balloon, a long conical/square balloon, a
conical/spherical balloon, a long spherical balloon, a tapered
balloon, a dog bone balloon, a stepped balloon, an offset balloon,
or a conical/offset balloon.
[0145] In certain embodiments, the present invention relates to the
aforementioned method, wherein said balloon or skirt is formed from
a polymer selected from the group consisting of polybutylene
terephthalate-polyethene glycol block copolymers, polyurethenes,
ABS (acrylonitrile-butadiene-styrene), ABS/nylon, ABS/polyvinyl
chloride (PVC), ABS/polycarbonate, acrylonitrile copolymer,
polyacrylamide, polyacrylate, polyacrylsulfone, polyesters,
polyethylene terephthalate (PET), polybutylene terephthalate (PBT),
polyethylene naphthalate (PEN), liquid crystal polymer (LCP),
polyester/polycaprolactone, polyester/polyadipate,
polyetheretherketone (PEEK), polyethersulfone (PES), polyetherimide
(PEI), polyetherketone (PEK), polymenthylpentene, polyphenylene
ether, polyphenylene sulfide, styrene acrylonitrile (SAN),
polyamides, nylon 6, nylon 6/6, nylon 6/66, nylon 6/9, nylon 6/10,
nylon 6/12, nylon 11, nylon 12, ethylene, propylene ethylene
vinylacetate, ethylene vinyl alcohol (EVA), ionomers, polyethylene
type I-IV, polyolefins, polyurethane, polyvinyl chloride,
polysiloxanes (silicones), fluorocarbons, polychlorotriethylene
(CTFE), poly[ethylene-co-chlorotrifluoroethylene] (ECTFE) copolymer
ethylene tetrafluoroethylene (ETFE), copolymers of
tetrafluoroethylene and hexafluoropropylene (FEP), perfluoroalkane
(PFA) and poly[vinylidene fluoride] (PVDF).
[0146] In certain embodiments, the present invention relates to the
aforementioned method, wherein said balloon or skirt has a wall
thickness of between about 1 micron and about 20 microns.
[0147] In certain embodiments, the present invention relates to the
aforementioned method, wherein said balloon has a burst pressure of
between about 0.5 atm and about 30 atm.
[0148] In certain embodiments, the present invention relates to the
aforementioned method, wherein said balloon substantially conforms
to the shape of the mammalian lumen.
[0149] In certain embodiments, the present invention relates to the
aforementioned method, wherein said balloon is filled to a
pressure.
[0150] In certain embodiments, the present invention relates to the
aforementioned method, wherein said pressure is between about 1 atm
and about 20 atm.
[0151] In certain embodiments, the present invention relates to the
aforementioned method, wherein said pressure is between about 1 atm
and about 15 atm.
[0152] In certain embodiments, the present invention relates to the
aforementioned method, wherein said pressure is between about 1 atm
and about 10 atm.
[0153] In certain embodiments, the present invention relates to the
aforementioned method, wherein said pressure is between about 1 atm
and about 5 atm.
EXEMPLIFICATION
[0154] The invention now being generally described, it will be more
readily understood by reference to the following examples, which
are included merely for purposes of illustration of certain aspects
and embodiments of the present invention, and are not intended to
limit the invention.
Example 1
Purification of Poloxamer 407
[0155] Poloxamer 407 (486.0 g, lot number WPHT-543B), purchased
from BASF Corporation, Mount Olive, N.J., was dissolved in
deionized water (15,733 g). The solution was maintained at
0.1.degree. C. and 2335.1 g of (NH.sub.4).sub.2SO.sub.4 were added.
The solution was equilibrated at 2.degree. C. and after two
distinct phases formed, the lower phase was discarded, and the
upper phase (2060 g) was collected and weighed. Deionized water
(14159 g) was added and the solution was equilibrated to 2.degree.
C. Next, 2171.6 g of (NH.sub.4).sub.2SO.sub.4 were added with
stirring. After the salt was dissolved, the solution was maintained
at approximately 2.degree. C. until two phases formed. The upper
phase (3340 g) was isolated and diluted with 12879 g of deionized
water. The solution was chilled to about 2.2.degree. C. and 2062 g
of (NH.sub.4).sub.2SO.sub.4 were added. The phases were allowed to
separate as above. The upper phase was isolated and extracted with
4 liters of dichloromethane. Two phases were allowed to form
overnight. The organic (lower) phase was isolated and approximately
2 kg of sodium sulfate (Na.sub.2SO.sub.4) were added to it to
remove the remaining water. The dichloromethane phase was filtered
through a PTFE filter (0.45 .mu.m pore size) to remove the
undissolved salts. The dichloromethane was removed under vacuum at
approximately 30.degree. C. Final traces of dichloromethane were
removed by drying in an oven overnight at about 30.degree. C. A
total of 297.6 g of fractionated poloxamer 407 (lot number
00115001) were recovered. The chemical and physical characteristics
of the fractionated poloxamer 407 are compared to those of the
starting material in FIG. 2[A].
Example 2
Gelation Temperature of Selected Reverse Phase Media
[0156] The optionally-purified polymer was weighed into a plastic
tube. To achieve the required concentration the weight was
multiplied by 4, for 25 weight percent (w %), and by 5, for 20
weight percent (w %), and the required final weight was achieved by
adding saline. The solutions were placed in the fridge at 4.degree.
C. and usually were ready within 24 hours. Gelation points were
measured in a Brookfield viscometer and the point at which
viscosity exceeded the range of the plate/cone (greater than about
102,000 cP) was called the gelation temperature. Results are shown
in FIG. 2[B].
INCORPORATION BY REFERENCE
[0157] US Patent Application 2005/0147585 is hereby incorporated by
reference in its entirety. U.S. Pat. No. 4,708,140 is hereby
incorporated by reference in its entirety. In addition, all of the
US patents and US Published patent applications cited herein are
hereby incorporated by reference.
EQUIVALENTS
[0158] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
following claims.
* * * * *